[The impact of the androgen receptor splice variant AR-V7 on the prognosis and treatment of advanced prostate cancer].

PubMed

Thelen, P; Taubert, H; Duensing, S; Kristiansen, G; Merseburger, A S; Cronauer, M V

2018-01-25

A recently discovered mechanism enabling prostate cancer cells to escape the effects of endocrine therapies consists in the synthesis of C-terminally truncated, constitutively active androgen receptor (AR) splice variants (AR-V). Devoid of a functional C-terminal hormone/ligand binding domain, various AR-Vs are insensitive to therapies targeting the androgen/AR signalling axis. Preliminary studies suggest that AR-V7, the most common AR-V, is a promising predictive tumour marker and a relevant selection marker for the treatment of advanced prostate cancer. This review critically outlines recent advances in AR-V7 diagnostics and presents an overview of current AR-V7 targeted therapies. © Georg Thieme Verlag KG Stuttgart · New York.

Clinical Utility of CLIA-Grade AR-V7 Testing in Patients With Metastatic Castration-Resistant Prostate Cancer.

PubMed

Markowski, Mark C; Silberstein, John L; Eshleman, James R; Eisenberger, Mario A; Luo, Jun; Antonarakis, Emmanuel S

2017-01-01

A splice variant of the androgen receptor, AR-V7, confers resistance to AR-targeted therapies (ATTs) but not taxane chemotherapies in patients with metastatic castration-resistant prostate cancer. Since August 2015, a clinical-grade assay to detect AR-V7 messenger RNA expression in circulating tumors cells (CTCs) has been available to providers through a Clinical Laboratory Improvement Amendments-certified laboratory at Johns Hopkins University. We contacted ordering providers of the first 150 consecutive tests by using a questionnaire-based survey to determine how the results of AR-V7 testing were used to influence clinical practice. In all, 142 (95%) of 150 questionnaires were completed by 38 providers from 29 sites across the United States and Canada. AR-V7 test results were reported either as CTC- (28%), CTC+/AR-V7- (30%), or CTC+/AR-V7+ (42%). Prevalence of AR-V7 detection increased with prior exposure to ATTs (abiraterone and enzalutamide naïve, 22%; after abiraterone or enzalutamide, 35%; after abiraterone and enzalutamide, 43%). Overall, management was affected by AR-V7 testing in 53% of the patients and even more often with CTC+/AR-V7+ results. AR-V7+ patients were commonly switched from ATT to taxane chemotherapy (43%) or were offered a clinical trial (43%); management remained unchanged in only 14% of these patients. Overall, patients who had a change in management on the basis of AR-V7 testing were significantly more likely to achieve a physician-reported 50% decline in prostate-specific antigen response on next-line therapy than those who did not change treatment (54% v 31%; P = .015). Providers used AR-V7 testing to influence clinical decision making more often than not. Physicians reported thatmenwithAR-V7+results had the most treatment changes, and such men were preferentially managed with taxane therapy or offered a clinical trial, which may have improved outcomes.

Histone demethylase JMJD1A promotes alternative splicing of AR variant 7 (AR-V7) in prostate cancer cells.

PubMed

Fan, Lingling; Zhang, Fengbo; Xu, Songhui; Cui, Xiaolu; Hussain, Arif; Fazli, Ladan; Gleave, Martin; Dong, Xuesen; Qi, Jianfei

2018-05-15

Formation of the androgen receptor splicing variant 7 (AR-V7) is one of the major mechanisms by which resistance of prostate cancer to androgen deprivation therapy occurs. The histone demethylase JMJD1A (Jumonji domain containing 1A) functions as a key coactivator for AR by epigenetic regulation of H3K9 methylation marks. Here, we describe a role for JMJD1A in AR-V7 expression. While JMJD1A knockdown had no effect on full-length AR (AR-FL), it reduced AR-V7 levels in prostate cancer cells. Reexpression of AR-V7 in the JMJD1A-knockdown cells elevated expression of select AR targets and partially rescued prostate cancer cell growth in vitro and in vivo. The AR-V7 protein level correlated positively with JMJD1A in a subset of human prostate cancer specimens. Mechanistically, we found that JMJD1A promoted alternative splicing of AR-V7 through heterogeneous nuclear ribonucleoprotein F (HNRNPF), a splicing factor known to regulate exon inclusion. Knockdown of JMJD1A or HNRNPF inhibited splicing of AR-V7, but not AR-FL, in a minigene reporter assay. JMJD1A was found to interact with and promote the recruitment of HNRNPF to a cryptic exon 3b on AR pre-mRNA for the generation of AR-V7. Taken together, the role of JMJD1A in AR-FL coactivation and AR-V7 alternative splicing highlights JMJD1A as a potentially promising target for prostate cancer therapy.

Nuclear-specific AR-V7 Protein Localization is Necessary to Guide Treatment Selection in Metastatic Castration-resistant Prostate Cancer.

PubMed

Scher, Howard I; Graf, Ryon P; Schreiber, Nicole A; McLaughlin, Brigit; Lu, David; Louw, Jessica; Danila, Daniel C; Dugan, Lyndsey; Johnson, Ann; Heller, Glenn; Fleisher, Martin; Dittamore, Ryan

2017-06-01

Circulating tumor cells (CTCs) expressing AR-V7 protein localized to the nucleus (nuclear-specific) identify metastatic castration-resistant prostate cancer (mCRPC) patients with improved overall survival (OS) on taxane therapy relative to the androgen receptor signaling inhibitors (ARSi) abiraterone acetate, enzalutamide, and apalutamide. To evaluate if expanding the positivity criteria to include both nuclear and cytoplasmic AR-V7 localization ("nuclear-agnostic") identifies more patients who would benefit from a taxane over an ARSi. The study used a cross-sectional cohort. Between December 2012 and March 2015, 193 pretherapy blood samples, 191 of which were evaluable, were collected and processed from 161 unique mCRPC patients before starting a new line of systemic therapy for disease progression at the Memorial Sloan Kettering Cancer Center. The association between two AR-V7 scoring criteria, post-therapy prostate-specific antigen (PSA) change (PTPC) and OS following ARSi or taxane treatment, was explored. One criterion required nuclear-specific AR-V7 localization, and the other required an AR-V7 signal but was agnostic to protein localization in CTCs. Correlation of AR-V7 status to PTPC and OS was investigated. Relationships with survival were analyzed using multivariable Cox regression and log-rank analyses. A total of 34 (18%) samples were AR-V7-positive using nuclear-specific criteria, and 56 (29%) were AR-V7-positive using nuclear-agnostic criteria. Following ARSi treatment, none of the 16 nuclear-specific AR-V7-positive samples and six of the 32 (19%) nuclear-agnostic AR-V7-positive samples had ≥50% PTPC at 12 weeks. The strongest baseline factor influencing OS was the interaction between the presence of nuclear-specific AR-V7-positive CTCs and treatment with a taxane (hazard ratio 0.24, 95% confidence interval 0.078-0.79; p=0.019). This interaction was not significant when nuclear-agnostic criteria were used. To reliably inform treatment selection

The impact of taking or not taking ARVs on HIV stigma as reported by persons living with HIV infection in five African countries.

PubMed

Makoae, Lucy N; Portillo, Carmen J; Uys, Leana R; Dlamini, Priscilla S; Greeff, Minrie; Chirwa, Maureen; Kohi, Thecla W; Naidoo, Joanne; Mullan, Joseph; Wantland, Dean; Durrheim, Kevin; Holzemer, William L

2009-11-01

This study examined the impact of taking or not taking antiretroviral (ARV) medications on stigma, as reported by people living with HIV infection in five African countries. A two group (taking or not taking ARVs) by three (time) repeated measures analysis of variance examined change in reported stigma in a cohort sample of 1454 persons living with HIV infection in Lesotho, Malawi, South Africa, Swaziland, and Tanzania. Participants self-reported taking ARV medications and completed a standardized stigma scale validated in the African context. Data were collected at three points in time, from January 2006 to March 2007. Participants taking ARV medications self-reported a mean CD4 count of 273 and those not taking ARVs self-reported a mean CD4 count of 418. Both groups reported significant decreases in total HIV stigma over time; however, people taking ARVs reported significantly higher stigma at Time 3 compared to those not taking ARVs. This study documents that this sample of 1454 HIV infected persons in five countries in Africa reported significantly less HIV stigma over time. In addition, those participants taking ARV medications experienced significantly higher HIV stigma over time compared to those not taking ARVs. This finding contradicts some authors' opinions that when clients enroll in ARV medication treatment it signifies that they are experiencing less stigma. This work provides caution to health care providers to alert clients new to ARV treatment that they may experience more stigma from their families and communities when they learn they are taking ARV medications.

ARV-based HIV prevention for women - where we are in 2014.

PubMed

Mastro, Timothy D; Sista, Nirupama; Abdool-Karim, Quarraisha

2014-01-01

Women continue to be at special risk for HIV acquisition due to a complex mix of biological, behavioural, structural, cultural and social factors, with unacceptable rates of new infection. Scientific advances over the past decade have highlighted the use of antiretroviral (ARV) drugs as pre-exposure prophylaxis (PrEP) to prevent HIV acquisition (sexually, parenterally and vertically) and ARV treatment (ART) for HIV-positive patients to prevent onward transmission (treatment as prevention - TasP). This paper reviews the evidence base for PrEP and TasP, describes new products in development and the need to translate research findings into programmes with impact at the population level.

Androgen Receptor and its Splice Variant, AR-V7, Differentially Regulate FOXA1 Sensitive Genes in LNCaP Prostate Cancer Cells

PubMed Central

Krause, William C.; Shafi, Ayesha A.; Nakka, Manjula; Weigel, Nancy L.

2014-01-01

Prostate cancer (PCa) is an androgen-dependent disease, and tumors that are resistant to androgen ablation therapy often remain androgen receptor (AR) dependent. Among the contributors to castration-resistant PCa are AR splice variants that lack the ligand-binding domain (LBD). Instead, they have small amounts of unique sequence derived from cryptic exons or from out of frame translation. The AR-V7 (or AR3) variant is constitutively active and is expressed under conditions consistent with CRPC. AR-V7 is reported to regulate a transcriptional program that is similar but not identical to that of AR. However, it is unknown whether these differences are due to the unique sequence in AR-V7, or simply to loss of the LBD. To examine transcriptional regulation by AR-V7, we have used lentiviruses encoding AR-V7 (amino acids 1-627 of AR with the 16 amino acids unique to the variant) to prepare a derivative of the androgen-dependent LNCaP cells with inducible expression of AR-V7. An additional cell line was generated with regulated expression of AR-NTD (amino acids 1-660 of AR); this mutant lacks the LBD but does not have the AR-V7 specific sequence. We find that AR and AR-V7 have distinct activities on target genes that are co-regulated by FOXA1. Transcripts regulated by AR-V7 were similarly regulated by AR-NTD, indicating that loss of the LBD is sufficient for the observed differences. Differential regulation of target genes correlates with preferential recruitment of AR or AR-V7 to specific cis-regulatory DNA sequences providing an explanation for some of the observed differences in target gene regulation. PMID:25008967

The Impact of HIV/AIDS and ARV Treatment on Worker Absenteeism: Implications for African Firms

ERIC Educational Resources Information Center

Habyarimana, James; Mbakile, Bekezela; Pop-Eleches, Cristian

2010-01-01

We characterize medium and long-run labor market impacts of HIV/AIDS and ARV treatment using unique panel data of worker absenteeism and information from an AIDS treatment program at a large mining firm in Botswana. We present robust evidence of an inverse-V shaped pattern in worker absenteeism around the time of ARV treatment inception.…

Dual Therapy Treatment Strategies for the Management of Patients Infected with HIV: A Systematic Review of Current Evidence in ARV-Naive or ARV-Experienced, Virologically Suppressed Patients.

PubMed

Baril, Jean-Guy; Angel, Jonathan B; Gill, M John; Gathe, Joseph; Cahn, Pedro; van Wyk, Jean; Walmsley, Sharon

2016-01-01

We reviewed the current literature regarding antiretroviral (ARV)-sparing therapy strategies to determine whether these novel regimens can be considered appropriate alternatives to standard regimens for the initial treatment of ARV-naive patients or as switch therapy for those patients with virologically suppressed HIV infection. A search for studies related to HIV dual therapy published from January 2000 through April 2014 was performed using Biosis, Derwent Drug File, Embase, International Pharmaceutical Abstracts, Medline, Pascal, SciSearch, and TOXNET databases; seven major trial registries, and the abstracts of major conferences. Using predetermined criteria for inclusion, an expert review committee critically reviewed and qualitatively evaluated all identified trials for efficacy and safety results and potential limitations. Sixteen studies of dual therapy regimens were critiqued for the ARV-naive population. Studies of a protease inhibitor/ritonavir in combination with the integrase inhibitor raltegravir or the nucleoside reverse transcriptase inhibitor lamivudine provided the most definitive evidence supporting a role for dual therapy. In particular, lopinavir/ritonavir or darunavir/ritonavir combined with raltegravir and lopinavir/ritonavir combined with lamivudine demonstrated noninferiority to standard of care triple therapy after 48 weeks of treatment. Thirteen trials were critiqued in ARV-experienced, virologically suppressed patients. The virologic efficacy outcomes were mixed. Although overall data regarding toxicity are limited, when compared with standard triple therapy, certain dual therapy regimens may offer advantages in renal function, bone mineral density, and limb fat changes; however, some dual combinations may elevate lipid or bilirubin levels. The potential benefits of dual therapy regimens include reduced toxicity, improved tolerability and adherence, and reduced cost. Although the data reviewed here provide valuable insights into the

High-Content Screening Identifies Src Family Kinases as Potential Regulators of AR-V7 Expression and Androgen-Independent Cell Growth.

PubMed

Szafran, Adam T; Stephan, Cliff; Bolt, Michael; Mancini, Maureen G; Marcelli, Marco; Mancini, Michael A

2017-01-01

AR-V7 is an androgen receptor (AR) splice variant that lacks the ligand-binding domain and is isolated from prostate cancer cell lines. Increased expression of AR-V7 is associated with the transition from hormone-sensitive prostate cancer to more advanced castration-resistant prostate cancer (CRPC). Due to the loss of the ligand-binding domain, AR-V7 is not responsive to traditional AR-targeted therapies, and the mechanisms that regulate AR-V7 are still incompletely understood. Therefore, we aimed to explore existing classes of small molecules that may regulate AR-V7 expression and intracellular localization and their potential therapeutic role in CRPC. We used AR high-content analysis (AR-HCA) to characterize the effects of a focused library of well-characterized clinical compounds on AR-V7 expression at the single-cell level in PC3 prostate cancer cells stably expressing green fluorescent protein (GFP)-AR-V7 (GFP-AR-V7:PC3). In parallel, an orthogonal AR-HCA screen of a small interfering (si)RNA library targeting 635 protein kinases was performed in GFP-AR-V7:PC3. The effect of the Src-Abl inhibitor PD 180970 was further characterized using cell-proliferation assays, quantitative PCR, and western blot analysis in multiple hormone-sensitive and CRPC cell lines. Compounds that tended to target Akt, Abl, and Src family kinases (SFKs) decreased overall AR-V7 expression, nuclear translocation, absolute nuclear level, and/or altered nuclear distribution. We identified 20 protein kinases that, when knocked down, either decreased nuclear GFP-AR-V7 levels or altered AR-V7 nuclear distribution, a set that included the SFKs Src and Fyn. The Src-Abl dual kinase inhibitor PD180970 decreased expression of AR-V7 by greater than 46% and decreased ligand-independent transcription of AR target genes in the 22RV1 human prostate carcinoma cell line. Further, PD180970 inhibited androgen-independent cell proliferation in endogenous-AR-V7-expressing prostate cancer cell lines and also

High-content screening identifies Src family kinases as potential regulators of AR-V7 expression and androgen-independent cell growth

PubMed Central

Szafran, Adam T.; Stephan, Cliff; Bolt, Michael; Mancini, Maureen G.; Marcelli, Marco; Mancini, Michael A.

2018-01-01

Background AR-V7 is an androgen receptor (AR) splice variant that lacks the ligand-binding domain and is isolated from prostate cancer cell lines. Increased expression of AR-V7 is associated with the transition from hormone-sensitive prostate cancer to more advanced castration-resistant prostate cancer (CRPC). Due to the loss of the ligand-binding domain, AR-V7 is not responsive to traditional AR-targeted therapies, and the mechanisms that regulate AR-V7 are still incompletely understood. Therefore, we aimed to explore existing classes of small molecules that may regulate AR-V7 expression and intracellular localization and their potential therapeutic role in CRPC. Methods We used AR high-content analysis (AR-HCA) to characterize the effects of a focused library of well-characterized clinical compounds on AR-V7 expression at the single-cell level in PC3 prostate cancer cells stably expressing green fluorescent protein (GFP)-AR-V7 (GFP-AR-V7:PC3). In parallel, an orthogonal AR-HCA screen of a small interfering (si)RNA library targeting 635 protein kinases was performed in GFP-AR-V7:PC3. The effect of the Src-Abl inhibitor PD 180970 was further characterized using cell-proliferation assays, quantitative PCR, and western blot analysis in multiple hormone-sensitive and CRPC cell lines. Results Compounds that tended to target Akt, Abl, and Src family kinases (SFKs) decreased overall AR-V7 expression, nuclear translocation, absolute nuclear level, and/or altered nuclear distribution. We identified 20 protein kinases that, when knocked down, either decreased nuclear GFP-AR-V7 levels or altered AR-V7 nuclear distribution, a set that included the SFKs Src and Fyn. The Src-Abl dual kinase inhibitor PD180970 decreased expression of AR-V7 by greater than 46% and decreased ligand-independent transcription of AR target genes in the 22RV1 human prostate carcinoma cell line. Further, PD180970 inhibited androgen-independent cell proliferation in endogenous–AR-V7�

An In-Depth Evaluation of the Validity and Logistics Surrounding the Testing of AR-V7 mRNA Expression in Circulating Tumor Cells.

PubMed

Sieuwerts, Anieta M; Mostert, Bianca; van der Vlugt-Daane, Michelle; Kraan, Jaco; Beaufort, Corine M; Van, Mai; Prager, Wendy J C; De Laere, Bram; Beije, Nick; Hamberg, Paul; Westgeest, Hans M; Tascilar, Metin; Dirix, Luc Y; Onstenk, Wendy; de Wit, Ronald; Lolkema, Martijn P; Mathijssen, Ron H J; Martens, John W M; Sleijfer, Stefan

2018-05-01

Recent reports have emphasized the clinical relevance of detecting AR-V7 in circulating tumor cells (CTCs). Our aim was to set up a validated multicenter pipeline to measure AR-V7 by quantitative RT-PCR (RT-qPCR) in RNA isolated from CellSearch-enriched CTCs to provide an AR-V7-positive or AR-V7-negative score in a clinically acceptable time range. CellSearch-enirched CTCs from patients with metastatic castration-resistant prostate cancer were characterized by RT-qPCR. After optimization, it was prospectively tested whether it was possible to report the AR-V7 status within 11 days (PRELUDE study). In the range of the RNA equivalent of 0.2 to 12 VCaP cells, the CV for AR-V7 was 9% (n = 37). The limit of detection was 0.3, and the limit of quantitation was 3 cells in the final RT-qPCR. No differences were observed between AR-V7 data generated by five technicians or in two different laboratories. For the 45 patients in PRELUDE, 13 patients were ineligible, 22 patients were AR-V7 negative, and 10 were AR-V7 positive. The median time to inform the physician of the test result was 7 days (range, 2 to 11 days). This assay can establish the AR-V7 status in CTCs from patients with metastatic castration-resistant prostate cancer. Furthermore, it was possible to provide an AR-V7 outcome within 11 days, indicating that it may be used to choose between an anti-androgen receptor or taxane-based cabazitaxel treatment. Copyright © 2018 American Society for Investigative Pathology and the Association for Molecular Pathology. Published by Elsevier Inc. All rights reserved.

Targeted suppression of AR-V7 using PIP5K1α inhibitor overcomes enzalutamide resistance in prostate cancer cells.

PubMed

Sarwar, Martuza; Semenas, Julius; Miftakhova, Regina; Simoulis, Athanasios; Robinson, Brian; Gjörloff Wingren, Anette; Mongan, Nigel P; Heery, David M; Johnsson, Heather; Abrahamsson, Per-Anders; Dizeyi, Nishtman; Luo, Jun; Persson, Jenny L

2016-09-27

One mechanism of resistance of prostate cancer (PCa) to enzalutamide (MDV3100) treatment is the increased expression of AR variants lacking the ligand binding-domain, the best characterized of which is AR-V7. We have previously reported that Phosphatidylinositol-4-phosphate 5-kinase alpha (PIP5Kα), is a lipid kinase that links to CDK1 and AR pathways. The discovery of PIP5Kα inhibitor highlight the potential of PIP5K1α as a drug target in PCa. In this study, we show that AR-V7 expression positively correlates with PIP5K1α in tumor specimens from PCa patients. Overexpression of AR-V7 increases PIP5K1α, promotes rapid growth of PCa in xenograft mice, whereas inhibition of PIP5K1α by its inhibitor ISA-2011B suppresses the growth and invasiveness of xenograft tumors overexpressing AR-V7. PIP5K1α is a key co-factor for both AR-V7 and AR, which are present as protein-protein complexes predominantly in the nucleus of PCa cells. In addition, PIP5K1α and CDK1 influence AR-V7 expression also through AKT-associated mechanism dependent on PTEN-status. ISA-2011B disrupts protein stabilization of AR-V7 which is dependent on PIP5K1α, leading to suppression of invasive growth of AR-V7-high tumors in xenograft mice. Our study suggests that combination of enzalutamide and PIP5K1α may have a significant impact on refining therapeutic strategies to circumvent resistance to antiandrogen therapies.

Targeted suppression of AR-V7 using PIP5K1α inhibitor overcomes enzalutamide resistance in prostate cancer cells

PubMed Central

Sarwar, Martuza; Semenas, Julius; Miftakhova, Regina; Simoulis, Athanasios; Robinson, Brian; Wingren, Anette Gjörloff; Mongan, Nigel P.; Heery, David M.; Johnsson, Heather; Abrahamsson, Per-Anders; Dizeyi, Nishtman; Luo, Jun; Persson, Jenny L.

2016-01-01

One mechanism of resistance of prostate cancer (PCa) to enzalutamide (MDV3100) treatment is the increased expression of AR variants lacking the ligand binding-domain, the best characterized of which is AR-V7. We have previously reported that Phosphatidylinositol-4-phosphate 5-kinase alpha (PIP5Kα), is a lipid kinase that links to CDK1 and AR pathways. The discovery of PIP5Kα inhibitor highlight the potential of PIP5K1α as a drug target in PCa. In this study, we show that AR-V7 expression positively correlates with PIP5K1α in tumor specimens from PCa patients. Overexpression of AR-V7 increases PIP5K1α, promotes rapid growth of PCa in xenograft mice, whereas inhibition of PIP5K1α by its inhibitor ISA-2011B suppresses the growth and invasiveness of xenograft tumors overexpressing AR-V7. PIP5K1α is a key co-factor for both AR-V7 and AR, which are present as protein-protein complexes predominantly in the nucleus of PCa cells. In addition, PIP5K1α and CDK1 influence AR-V7 expression also through AKT-associated mechanism dependent on PTEN-status. ISA-2011B disrupts protein stabilization of AR-V7 which is dependent on PIP5K1α, leading to suppression of invasive growth of AR-V7-high tumors in xenograft mice. Our study suggests that combination of enzalutamide and PIP5K1α may have a significant impact on refining therapeutic strategies to circumvent resistance to antiandrogen therapies. PMID:27588408

Cost-Savings Analysis of AR-V7 Testing in Patients With Metastatic Castration-Resistant Prostate Cancer Eligible for Treatment With Abiraterone or Enzalutamide.

PubMed

Markowski, Mark C; Frick, Kevin D; Eshleman, James R; Luo, Jun; Antonarakis, Emmanuel S

2016-12-01

Identification of cancer biomarkers that inform clinical decisions and reduce the use of ineffective therapies is a major goal of precision oncology. An abnormal splice variant of the androgen receptor, AR-V7, was recently found to confer resistance to novel hormonal therapies (abiraterone and enzalutamide) in men with metastatic castration-resistant prostate cancer (mCRPC), but did not negatively affect responses to taxane chemotherapies, suggesting that early use of chemotherapy may be a more effective option for AR-V7(+) patients. We calculated the cost savings of performing AR-V7 testing in mCRPC patients prior to starting abiraterone/enzalutamide (and avoiding these drugs in AR-V7(+) men) versus treating all mCRPC patients empirically with abiraterone/enzalutamide (without use of the biomarker). We determined that AR-V7 testing would result in substantial cost savings as long as the true prevalence of AR-V7 was >5%. In our prior studies, we estimated that approximately 30% of mCRPC patients may have detectable AR-V7 in circulating tumor cells (CTCs). In this population, upfront testing of AR-V7 status (at a price of $1,000 per test) would result in a net cost savings of $150 Million in the United States per year. AR-V7 testing in mCRPC patients would be cost-beneficial when considering the current price of treatment, and may reduce the ineffective use of abiraterone/enzalutamide, leading to a significant net cost savings to the healthcare system. Clinical-grade AR-V7 testing is currently available at our institution. Prostate 76:1484-1490, 2016. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

In Situ Detection and Quantification of AR-V7, AR-FL, PSA, and KRAS Point Mutations in Circulating Tumor Cells.

PubMed

El-Heliebi, Amin; Hille, Claudia; Laxman, Navya; Svedlund, Jessica; Haudum, Christoph; Ercan, Erkan; Kroneis, Thomas; Chen, Shukun; Smolle, Maria; Rossmann, Christopher; Krzywkowski, Tomasz; Ahlford, Annika; Darai, Evangelia; von Amsberg, Gunhild; Alsdorf, Winfried; König, Frank; Löhr, Matthias; de Kruijff, Inge; Riethdorf, Sabine; Gorges, Tobias M; Pantel, Klaus; Bauernhofer, Thomas; Nilsson, Mats; Sedlmayr, Peter

2018-03-01

Liquid biopsies can be used in castration-resistant prostate cancer (CRPC) to detect androgen receptor splice variant 7 (AR-V7), a splicing product of the androgen receptor. Patients with AR-V7-positive circulating tumor cells (CTCs) have greater benefit of taxane chemotherapy compared with novel hormonal therapies, indicating a treatment-selection biomarker. Likewise, in those with pancreatic cancer (PaCa), KRAS mutations act as prognostic biomarkers. Thus, there is an urgent need for technology investigating the expression and mutation status of CTCs. Here, we report an approach that adds AR-V7 or KRAS status to CTC enumeration, compatible with multiple CTC-isolation platforms. We studied 3 independent CTC-isolation devices (CellCollector, Parsortix, CellSearch) for the evaluation of AR-V7 or KRAS status of CTCs with in situ padlock probe technology. Padlock probes allow highly specific detection and visualization of transcripts on a cellular level. We applied padlock probes for detecting AR-V7, androgen receptor full length (AR-FL), and prostate-specific antigen (PSA) in CRPC and KRAS wild-type (wt) and mutant (mut) transcripts in PaCa in CTCs from 46 patients. In situ analysis showed that 71% (22 of 31) of CRPC patients had detectable AR-V7 expression ranging from low to high expression [1-76 rolling circle products (RCPs)/CTC]. In PaCa patients, 40% (6 of 15) had KRAS mut expressing CTCs with 1 to 8 RCPs/CTC. In situ padlock probe analysis revealed CTCs with no detectable cytokeratin expression but positivity for AR-V7 or KRAS mut transcripts. Padlock probe technology enables quantification of AR-V7, AR-FL, PSA, and KRAS mut/wt transcripts in CTCs. The technology is easily applicable in routine laboratories and compatible with multiple CTC-isolation devices. © 2017 American Association for Clinical Chemistry.

Detection of AR-V7 mRNA in whole blood may not predict the effectiveness of novel endocrine drugs for castration-resistant prostate cancer.

PubMed

Takeuchi, Takumi; Okuno, Yumiko; Hattori-Kato, Mami; Zaitsu, Masayoshi; Mikami, Koji

2016-01-01

A splice variant of androgen receptor (AR), AR-V7, lacks in androgen-binding portion and leads to aggressive cancer characteristics. Reverse transcription-polymerase chain reactions (PCRs) and subsequent nested PCRs for the amplification of AR-V7 and prostate-specific antigen (PSA) transcripts were done for whole blood of patients with prostate cancer and male controls. With primary reverse transcription PCRs, AR-V7 and PSA were detected in 4.5% and 4.7% of prostate cancer, respectively. With nested PCRs, AR-V7 messenger RNA (mRNA) was positive in 43.8% of castration-sensitive prostate cancer and 48.1% of castration-resistant prostate cancer (CRPC), while PSA mRNA was positive in 6.3% of castration-sensitive prostate cancer and 18.5% of CRPC. Whole-blood samples of controls showed AR-V7 mRNA expression by nested PCR. Based on multivariate analysis, expression of AR-V7 mRNA in whole blood was not significantly correlated with clinical parameters and PSA mRNA in blood, while univariate analysis showed a correlation between AR-V7 mRNA and metastasis at initial diagnosis. Detection of AR-V7 mRNA did not predict the reduction of serum PSA in patients with CRPC following abiraterone and enzalutamide administration. In conclusion, AR-V7 mRNA expression in normal hematopoietic cells may have annihilated the manifestation of aggressiveness of prostate cancer and the prediction of the effectiveness of abiraterone and enzalutamide by the assessment of AR-V7 mRNA in blood.

Efficacy of Cabazitaxel in Castration-resistant Prostate Cancer Is Independent of the Presence of AR-V7 in Circulating Tumor Cells.

PubMed

Onstenk, Wendy; Sieuwerts, Anieta M; Kraan, Jaco; Van, Mai; Nieuweboer, Annemieke J M; Mathijssen, Ron H J; Hamberg, Paul; Meulenbeld, Hielke J; De Laere, Bram; Dirix, Luc Y; van Soest, Robert J; Lolkema, Martijn P; Martens, John W M; van Weerden, Wytske M; Jenster, Guido W; Foekens, John A; de Wit, Ronald; Sleijfer, Stefan

2015-12-01

Androgen receptor splice variant 7 (AR-V7) in circulating tumor cells (CTCs) from patients with metastatic castration-resistant prostate cancer (mCRPC) was recently demonstrated to be associated with resistance to abiraterone and enzalutamide. Cabazitaxel might, however, remain effective in AR-V7-positive patients. To investigate the association between AR-V7 expression in CTCs and resistance to cabazitaxel. We selected patients with mCRPC from the multicenter, randomized, phase 2, randomized, open-label, multicenter study in mCRPC on the pharmacodynamic effects of budesonide on cabazitaxel (Jevtana) (CABARESC). Before the start of the first and third cabazitaxel cycle, CTCs were enumerated using the CellSearch System. In patients with ≥10 CTCs in 7.5 ml blood at baseline, the expression of AR-V7 was assessed by quantitative polymerase chain reaction. The primary end point was the association between the AR-V7 status and the CTC response rate (decrease to fewer than five CTCs in 7.5 ml blood during treatment). Secondary end points were the prostate-specific antigen (PSA) response rate (RR) and overall survival (OS). Analyses were performed using chi-square and log-rank tests. AR-V7 was detected in 16 of 29 patients (55%) with ≥10 CTCs and was more frequently found in abiraterone pretreated patients (5 of 5 [100%] treated vs 7 of 20 [35%] untreated; p=0.009). We found no differences in CTC and PSA RRs. The presence of AR-V7 in CTCs was not associated with progression-free survival (hazard ratio [HR]: 0.8; 95% confidence interval [CI], 0.4-1.8) or overall survival (HR 1.6; 95% CI, 0.6-4.4). The response to cabazitaxel seems to be independent of the AR-V7 status of CTCs from mCRPC patients. Consequently, cabazitaxel might be a valid treatment option for patients with AR-V7-positive CTCs. Tools are needed to select specific treatments for specific patients at specific times. The presence of the gene AR-V7 in CTCs has been associated with resistance to anti

Novel Junction-specific and Quantifiable In Situ Detection of AR-V7 and its Clinical Correlates in Metastatic Castration-resistant Prostate Cancer.

PubMed

Zhu, Yezi; Sharp, Adam; Anderson, Courtney M; Silberstein, John L; Taylor, Maritza; Lu, Changxue; Zhao, Pei; De Marzo, Angelo M; Antonarakis, Emmanuel S; Wang, Mindy; Wu, Xingyong; Luo, Yuling; Su, Nan; Nava Rodrigues, Daniel; Figueiredo, Ines; Welti, Jonathan; Park, Emily; Ma, Xiao-Jun; Coleman, Ilsa; Morrissey, Colm; Plymate, Stephen R; Nelson, Peter S; de Bono, Johann S; Luo, Jun

2018-05-01

Androgen receptor splice variant 7 (AR-V7) has been implicated in resistance to abiraterone and enzalutamide treatment in men with metastatic castration-resistant prostate cancer (mCRPC). Tissue- or cell-based in situ detection of AR-V7, however, has been limited by lack of specificity. To address current limitations in precision measurement of AR-V7 by developing a novel junction-specific AR-V7 RNA in situ hybridization (RISH) assay compatible with automated quantification. We designed a RISH method to visualize single splice junctions in cells and tissue. Using the validated assay for junction-specific detection of the full-length AR (AR-FL) and AR-V7, we generated quantitative data, blinded to clinical data, for 63 prostate tumor biopsies. We evaluated clinical correlates of AR-FL/AR-V7 measurements, including association with prostate-specific antigen progression-free survival (PSA-PFS) and clinical and radiographic progression-free survival (PFS), in a subset of patients starting treatment with abiraterone or enzalutamide following biopsy. Quantitative AR-FL/AR-V7 data were generated from 56 of the 63 (88.9%) biopsy specimens examined, of which 44 were mCRPC biopsies. Positive AR-V7 signals were detected in 34.1% (15/44) mCRPC specimens, all of which also co-expressed AR-FL. The median AR-V7/AR-FL ratio was 11.9% (range 2.7-30.3%). Positive detection of AR-V7 was correlated with indicators of high disease burden at baseline. Among the 25 CRPC biopsies collected before treatment with abiraterone or enzalutamide, positive AR-V7 detection, but not higher AR-FL, was significantly associated with shorter PSA-PFS (hazard ratio 2.789, 95% confidence interval 1.12-6.95; p=0.0081). We report for the first time a RISH method for highly specific and quantifiable detection of splice junctions, allowing further characterization of AR-V7 and its clinical significance. Higher AR-V7 levels detected and quantified using a novel method were associated with poorer response to

Branched Chain RNA In Situ Hybridization for Androgen Receptor Splice Variant AR-V7 as a Prognostic Biomarker for Metastatic Castration-Sensitive Prostate Cancer.

PubMed

Saylor, Philip J; Lee, Richard J; Arora, Kshitij S; Deshpande, Vikram; Hu, Rong; Olivier, Kara; Meneely, Erika; Rivera, Miguel N; Ting, David T; Wu, Chin-Lee; Miyamoto, David T

2017-01-15

The androgen receptor (AR) mRNA splice variant AR-V7 has emerged as a predictive biomarker for response to AR-targeted therapies. There are currently no commercially available assays to detect AR splice variants. The branched chain RNA in situ hybridization (ISH) platform enables the highly sensitive detection of RNA transcripts in formalin-fixed, paraffin-embedded (FFPE) tissues. We designed a branched chain RNA ISH probe to target the unique cryptic exon CE3 of AR-V7 using multiple tiling probes. This automated ISH assay was applied to tumor tissue from two distinct clinical cohorts that we hypothesized would differ in AR-V7 status. We detected AR-V7 in all tumor samples from men with metastatic castration-resistant prostate cancer with tissue obtained after disease progression despite at least one subsequent line of hormonal therapy (abiraterone, enzalutamide, or bicalutamide; n = 12). We detected AR-V7 in just one tumor from men who had undergone prostatectomy for localized adenocarcinoma (n = 30; Gleason 4 + 5 = 9 in the AR-V7-positive sample). Given the apparent distinction between the above groups by AR-V7 signal, we analyzed pretreatment AR-V7 status as a predictive and prognostic biomarker in men with treatment-naïve metastatic disease. Patients with metastases but without detectable AR-V7 RNA at baseline had significantly longer overall survival (log-rank P = 0.044) and a trend toward superior progression-free survival (log-rank P = 0.055). Within an institutional cohort, the RNA ISH assay identified AR-V7 within FFPE tissue and may have prognostic value in metastatic castration-sensitive prostate cancer. These preliminary findings warrant further study in larger cohorts. Clin Cancer Res; 23(2); 363-9. ©2016 AACR. ©2016 American Association for Cancer Research.

[AR-V7 Androgen Receptor Variant as a Predictor of Response to Androgen-receptor Targeting Agents Used to Treat Castration-refractory Metastatic Prostate Cancer].

PubMed

Büchler, Tomáš; Bobek, Vladimír; Kološtová, Katarína

2017-01-01

Several systemic treatment options are currently available for patients with metastatic castration-refractory prostate cancer (mCRPC), including the androgen-receptor targeting agents (ARTA) enzalutamide and abiraterone, the taxanes docetaxel and cabazitaxel, and the radioisotope drug 223-radium dichloride. In some patients with mCRCP, alternative splicing of androgen receptor (AR) mRNA occurs, resulting in the formation of a truncated AR lacking the androgen-binding domain. These receptors activate downstream signalling pathways even without the ligand. Recent studies show that the presence of the AR-V7 (ARV - AR variants) splicing variant is associated with resistance to ARTA. Bec>ause the presence of AR-V7 does not affect the efficacy of other systemic therapies used in mCRCPs, particularly taxanes, AR-V7 is a candidate predictive biomarker for the individualisation of mCRCP treatment. Two types of assays based on mRNA or abnormal protein detection are used to detect AR-V7 in circulating tumour cells. To describe the current status of AR-V7 testing in mCRPC and possible applications of this method for predicting outcomes of ARTA therapy. The percentage of CTC AR-V7+ in ARTA-naive men is relatively low at baseline, but in patients pretreated with ARTA, the prevalence of AR-V7 increases to 19-34%. Given the relatively high expected prevalence, AR-V7 testing may be economically feasible in this population. The proportion of AR-V7+ patients responding to ARTA retreatment appears to be very low, at only 4.8%. AR-V7 testing could thus be useful if an ARTA switch is considered in a patient progressing onto an ARTA drug. Both protein-based tests and mRNA-based tests are currently undergoing clinical validation in prospective studies, with results expected within a year.Key words: prostate cancer - abiraterone - enzalutamide - alternative splicing - drug resistanceSubmitted: 30. 8. 2017Accepted: 5. 11. 2017 doc. MUDr. Tomáš Büchler, Ph.D. received honorary lectures

AR-v7 liquid biopsy for treatment stratification in prostate cancer: how close are we?

PubMed

Fletcher, Claire

2017-09-01

Recent clinical introduction of the novel antiandrogen, Enzalutamide (Enza), CYP17 inhibitor, Abiraterone (Abi), and the second-generation chemotherapeutic, Cabazitaxel, has increased survival of patients with advanced, metastatic castration-resistant prostate cancer (mCRPC). However, de novo and acquired resistance rates are high. A liquid biopsy that can rapidly, sensitively and robustly identify which patients will respond to treatment in a minimally invasive manner is urgently required to permit switch to a potentially more efficacious drug regimen, thus increasing survival whilst avoiding debilitating side effects associated with unnecessary treatment. This review will highlight recent developments in detection of AR-v7 in circulating mRNA/whole blood and circulating tumour cells (CTCs) as a liquid biopsy for patient-stratification in mCRPC. Continued androgen receptor (AR) activity in mCRPC has been linked to the expression of a number of truncated but constitutively active AR isoforms. One such variant, AR-v7, can drive drug resistance in preclinical models and is correlated with disease progression whilst showing dynamic response to AR-targeting treatments when assessed in blood. It has thus been proposed as an Abi/Enza treatment-response biomarker. AR-v7 liquid biopsy has the potential to transform clinical management of mCRPC and increase patient survival. This review will explore recent efforts to validate AR-v7 as a robust, clinically informative biomarker. I will also address potential limitations of detection and quantification that could frustrate its adoption into routine clinical practise.

Overexpression of nuclear AR-V7 protein in primary prostate cancer is an independent negative prognostic marker in men with high-risk disease receiving adjuvant therapy.

PubMed

Chen, Xin; Bernemann, Christof; Tolkach, Yuri; Heller, Martina; Nientiedt, Cathleen; Falkenstein, Michael; Herpel, Esther; Jenzer, Maximilian; Grüllich, Carsten; Jäger, Dirk; Sültmann, Holger; Duensing, Anette; Perner, Sven; Cronauer, Marcus V; Stephan, Carsten; Debus, Jürgen; Schrader, Andres Jan; Kristiansen, Glen; Hohenfellner, Markus; Duensing, Stefan

2018-04-01

Overexpression of the androgen receptor (AR) splice variant 7 (AR-V7) has recently been reported to be associated with resistance to antihormonal therapy. Herein, we address the question whether tumor cells with AR-V7 expression can be detected at the time of radical prostatectomy, that is, before long-term hormonal manipulation and castration resistance, and what the potential prognostic impact on the biochemical recurrence (BCR)-free survival may be. An anti-AR-V7 antibody was first validated in a training set of prostate cancer specimens by a comparison of AR-V7 protein to AR-V7 mRNA expression. We then analyzed nuclear AR-V7 protein expression in the primary tumors and lymph node metastases from 163 predominantly high-risk patients (cohort I) as well as the primary tumors from patients of a second, consecutive patient cohort (n = 238, cohort II) not selected for any clinicopathological features. Staining results were correlated to patient characteristics and BCR-free patient survival. High nuclear AR-V7 protein expression was detected in approximately 30%-40% of patients in cohort I and II at the time of radical prostatectomy. High baseline expression of nuclear AR-V7 protein was associated with an unfavorable BCR-free survival in the high-risk patient cohort I but not in the unselected consecutive cohort II. Remarkably, AR-V7 was an independent negative prognostic factor in high-risk prostate cancer patients of cohort I who were selected to receive adjuvant treatment. Prostate cancer cells with high nuclear AR-V7 protein expression can be detected in a substantial proportion of tumors at the time of radical prostatectomy. The presence of AR-V7-positive tumor cells is associated with an unfavorable prognosis for BCR-free survival in a high-risk patient cohort including a subgroup of patients selected to receive adjuvant therapy, in which AR-V7 was an independent negative prognosticator. Overexpression of nuclear AR-V7 protein hence identifies a subset of tumors

Melatonin Inhibits Androgen Receptor Splice Variant-7 (AR-V7)-Induced Nuclear Factor-Kappa B (NF-κB) Activation and NF-κB Activator-Induced AR-V7 Expression in Prostate Cancer Cells: Potential Implications for the Use of Melatonin in Castration-Resistant Prostate Cancer (CRPC) Therapy

PubMed Central

Liu, Vincent Wing Sun; Yau, Wing Lung; Tam, Chun Wai; Yao, Kwok-Ming; Shiu, Stephen Yuen Wing

2017-01-01

A major current challenge in the treatment of advanced prostate cancer, which can be initially controlled by medical or surgical castration, is the development of effective, safe, and affordable therapies against progression of the disease to the stage of castration resistance. Here, we showed that in LNCaP and 22Rv1 prostate cancer cells transiently overexpressing androgen receptor splice variant-7 (AR-V7), nuclear factor-kappa B (NF-κB) was activated and could result in up-regulated interleukin (IL)-6 gene expression, indicating a positive interaction between AR-V7 expression and activated NF-κB/IL-6 signaling in castration-resistant prostate cancer (CRPC) pathogenesis. Importantly, both AR-V7-induced NF-κB activation and IL-6 gene transcription in LNCaP and 22Rv1 cells could be inhibited by melatonin. Furthermore, stimulation of AR-V7 mRNA expression in LNCaP cells by betulinic acid, a pharmacological NF-κB activator, was reduced by melatonin treatment. Our data support the presence of bi-directional positive interactions between AR-V7 expression and NF-κB activation in CRPC pathogenesis. Of note, melatonin, by inhibiting NF-κB activation via the previously-reported MT1 receptor-mediated antiproliferative pathway, can disrupt these bi-directional positive interactions between AR-V7 and NF-κB and thereby delay the development of castration resistance in advanced prostate cancer. Apparently, this therapeutic potential of melatonin in advanced prostate cancer/CRPC management is worth translation in the clinic via combined androgen depletion and melatonin repletion. PMID:28561752

Melatonin Inhibits Androgen Receptor Splice Variant-7 (AR-V7)-Induced Nuclear Factor-Kappa B (NF-κB) Activation and NF-κB Activator-Induced AR-V7 Expression in Prostate Cancer Cells: Potential Implications for the Use of Melatonin in Castration-Resistant Prostate Cancer (CRPC) Therapy.

PubMed

Liu, Vincent Wing Sun; Yau, Wing Lung; Tam, Chun Wai; Yao, Kwok-Ming; Shiu, Stephen Yuen Wing

2017-05-31

A major current challenge in the treatment of advanced prostate cancer, which can be initially controlled by medical or surgical castration, is the development of effective, safe, and affordable therapies against progression of the disease to the stage of castration resistance. Here, we showed that in LNCaP and 22Rv1 prostate cancer cells transiently overexpressing androgen receptor splice variant-7 (AR-V7), nuclear factor-kappa B (NF-κB) was activated and could result in up-regulated interleukin ( IL ) -6 gene expression, indicating a positive interaction between AR-V7 expression and activated NF-κB/IL-6 signaling in castration-resistant prostate cancer (CRPC) pathogenesis. Importantly, both AR-V7-induced NF-κB activation and IL-6 gene transcription in LNCaP and 22Rv1 cells could be inhibited by melatonin. Furthermore, stimulation of AR-V7 mRNA expression in LNCaP cells by betulinic acid, a pharmacological NF-κB activator, was reduced by melatonin treatment. Our data support the presence of bi-directional positive interactions between AR-V7 expression and NF-κB activation in CRPC pathogenesis. Of note, melatonin, by inhibiting NF-κB activation via the previously-reported MT₁ receptor-mediated antiproliferative pathway, can disrupt these bi-directional positive interactions between AR-V7 and NF-κB and thereby delay the development of castration resistance in advanced prostate cancer. Apparently, this therapeutic potential of melatonin in advanced prostate cancer/CRPC management is worth translation in the clinic via combined androgen depletion and melatonin repletion.

AR-V7 in Peripheral Whole Blood of Patients with Castration-resistant Prostate Cancer: Association with Treatment-specific Outcome Under Abiraterone and Enzalutamide.

PubMed

Seitz, Anna Katharina; Thoene, Silvia; Bietenbeck, Andreas; Nawroth, Roman; Tauber, Robert; Thalgott, Mark; Schmid, Sebastian; Secci, Ramona; Retz, Margitta; Gschwend, Jürgen E; Ruland, Jürgen; Winter, Christof; Heck, Matthias M

2017-11-01

It has been demonstrated that androgen receptor splice variant 7 (AR-V7) expression in circulating tumor cells (CTCs) predicts poor treatment response in metastatic castration-resistant prostate cancer (mCRPC) patients treated with abiraterone or enzalutamide. To develop a practical and robust liquid profiling approach for direct quantification of AR-V7 in peripheral whole blood without the need for CTC capture and to determine its potential for predicting treatment response in mCRPC patients. Whole blood samples from a prospective biorepository of 85 mCRPC patients before treatment initiation with abiraterone (n=56) or enzalutamide (n=29) were analyzed via droplet digital polymerase chain reaction. The association of AR-V7 status with prostate-specific antigen (PSA) response defined by PSA decline ≥50% and with PSA-progression-free survival (PSA-PFS), clinical PFS, and overall survival (OS) was assessed. High AR-V7 expression levels in whole blood were detectable in 18% (15/85) of patients. No patient with high AR-V7 expression achieved a PSA response, and AR-V7 status was an independent predictor of PSA response in multivariable logistic regression analysis (p=0.03). High AR-V7 expression was associated with shorter PSA-PFS (median 2.4 vs 3.7 mo; p<0.001), shorter clinical PFS (median 2.7 vs 5.5 mo; p<0.001), and shorter OS (median 4.0 vs. 13.9 mo; p<0.001). On multivariable Cox regression analysis, high AR-V7 expression remained an independent predictor of shorter PSA-PFS (hazard ratio [HR] 7.0, 95% confidence interval [CI] 2.3-20.7; p<0.001), shorter clinical PFS (HR 2.3, 95% CI 1.1-4.9; p=0.02), and shorter OS (HR 3.0, 95% CI 1.4-6.3; p=0.005). Testing of AR-V7 mRNA levels in whole blood is a simple and promising approach to predict poor treatment outcome in mCRPC patients receiving abiraterone or enzalutamide. We established a method for determining AR-V7 status in whole blood. This test predicted treatment resistance in patients with metastatic castration

The RNA helicase DDX39B and its paralog DDX39A regulate androgen receptor splice variant AR-V7 generation.

PubMed

Nakata, Daisuke; Nakao, Shoichi; Nakayama, Kazuhide; Araki, Shinsuke; Nakayama, Yusuke; Aparicio, Samuel; Hara, Takahito; Nakanishi, Atsushi

2017-01-29

Mounting evidence suggests that constitutively active androgen receptor (AR) splice variants, typified by AR-V7, are associated with poor prognosis and resistance to androgen deprivation therapy in prostate cancer patients. However, mechanisms governing the generation of AR splice variants are not fully understood. In this study, we aimed to investigate the dynamics of AR splice variant generation using the JDCaP prostate cancer model that expresses AR splice variants under androgen depletion. Microarray analysis of JDCaP xenografts before and after expression of AR splice variants suggested that dysregulation of RNA processing pathways is likely involved in AR splice variant generation. To explore factors contributing to generation of AR-V7 mRNA, we conducted a focused RNA interference screen in AR-V7-positive JDCaP-hr cells using an shRNA library targeting spliceosome-related genes. This screen identified DDX39B as a regulator of AR-V7 mRNA expression. Simultaneous knockdown of DDX39B and its paralog DDX39A drastically and selectively downregulated AR-V7 mRNA expression in multiple AR-V7-positive prostate cancer cell lines. DDX39B was upregulated in relapsed JDCaP xenografts expressing AR splice variants, suggesting its role in expression of AR splice variants. Taken together, our findings offer insight into the mechanisms of AR splice variant generation and identify DDX39 as a potential drug target for the treatment of AR splice variant-positive prostate cancer. Copyright © 2016 Elsevier Inc. All rights reserved.

Differential regulation of metabolic pathways by androgen receptor (AR) and its constitutively active splice variant, AR-V7, in prostate cancer cells

PubMed Central

Shafi, Ayesha A.; Putluri, Vasanta; Arnold, James M.; Tsouko, Efrosini; Maity, Suman; Roberts, Justin M.; Coarfa, Cristian; Frigo, Daniel E.; Putluri, Nagireddy; Sreekumar, Arun; Weigel, Nancy L.

2015-01-01

Metastatic prostate cancer (PCa) is primarily an androgen-dependent disease, which is treated with androgen deprivation therapy (ADT). Tumors usually develop resistance (castration-resistant PCa [CRPC]), but remain androgen receptor (AR) dependent. Numerous mechanisms for AR-dependent resistance have been identified including expression of constitutively active AR splice variants lacking the hormone-binding domain. Recent clinical studies show that expression of the best-characterized AR variant, AR-V7, correlates with resistance to ADT and poor outcome. Whether AR-V7 is simply a constitutively active substitute for AR or has novel gene targets that cause unique downstream changes is unresolved. Several studies have shown that AR activation alters cell metabolism. Using LNCaP cells with inducible expression of AR-V7 as a model system, we found that AR-V7 stimulated growth, migration, and glycolysis measured by ECAR (extracellular acidification rate) similar to AR. However, further analyses using metabolomics and metabolic flux assays revealed several differences. Whereas AR increased citrate levels, AR-V7 reduced citrate mirroring metabolic shifts observed in CRPC patients. Flux analyses indicate that the low citrate is a result of enhanced utilization rather than a failure to synthesize citrate. Moreover, flux assays suggested that compared to AR, AR-V7 exhibits increased dependence on glutaminolysis and reductive carboxylation to produce some of the TCA (tricarboxylic acid cycle) metabolites. These findings suggest that these unique actions represent potential therapeutic targets. PMID:26378018

Projected Uptake of New Antiretroviral (ARV) Medicines in Adults in Low- and Middle-Income Countries: A Forecast Analysis 2015-2025

PubMed Central

Gupta, Aastha; Juneja, Sandeep; Vitoria, Marco; Habiyambere, Vincent; Nguimfack, Boniface Dongmo; Doherty, Meg; Low-Beer, Daniel

2016-01-01

With anti-retroviral treatment (ART) scale-up set to continue over the next few years it is of key importance that manufacturers and planners in low- and middle-income countries (LMICs) hardest hit by the HIV/AIDS pandemic are able to anticipate and respond to future changes to treatment regimens, generics pipeline and demand, in order to secure continued access to all ARV medicines required. We did a forecast analysis, using secondary WHO and UNAIDS data sources, to estimate the number of people living with HIV (PLHIV) and the market share and demand for a range of new and existing ARV drugs in LMICs up to 2025. UNAIDS estimates 24.7 million person-years of ART in 2020 and 28.5 million person-years of ART in 2025 (24.3 million on first-line treatment, 3.5 million on second-line treatment, and 0.6 million on third-line treatment). Our analysis showed that TAF and DTG will be major players in the ART regimen by 2025, with 8 million and 15 million patients using these ARVs respectively. However, as safety and efficacy of dolutegravir (DTG) and tenofovir alafenamide (TAF) during pregnancy and among TB/HIV co-infected patients using rifampicin is still under debate, and ART scale-up is predicted to increase considerably, there also remains a clear need for continuous supplies of existing ARVs including TDF and EFV, which 16 million and 10 million patients—respectively—are predicted to be using in 2025. It will be important to ensure that the existing capacities of generics manufacturers, which are geared towards ARVs of higher doses (such as TDF 300mg and EFV 600mg), will not be adversely impacted due to the introduction of lower dose ARVs such as TAF 25mg and DTG 50mg. With increased access to viral load testing, more patients would be using protease inhibitors containing regimens in second-line, with 1 million patients on LPV/r and 2.3 million on ATV/r by 2025. However, it will remain important to continue monitoring the evolution of ARV market in LMICs to

Expression of AR-V7 in Circulating Tumour Cells Does Not Preclude Response to Next Generation Androgen Deprivation Therapy in Patients with Castration Resistant Prostate Cancer.

PubMed

Bernemann, Christof; Schnoeller, Thomas J; Luedeke, Manuel; Steinestel, Konrad; Boegemann, Martin; Schrader, Andres J; Steinestel, Julie

2017-01-01

The androgen receptor splice variant AR-V7 has recently been discussed as a predictive biomarker for nonresponse to next-generation androgen deprivation therapy (ADT) in patients with castration-resistant prostate cancer. However, we recently identified one patient showing a response from abiraterone despite expression of AR-V7 in his circulating tumour cells (CTC). Therefore, we precisely assessed the response in a cohort of 21 AR-V7 positive castration-resistant prostate cancer patients who had received therapy with abiraterone or enzalutamide. We detected a subgroup of six AR-V7 positive patients showing benefit from either abiraterone or enzalutamide. Their progression free survival was 26 d (censored) to 188 d. Four patients displayed a prostate-specific antigen decrease of >50%. When analysing prior therapies, we noticed that only one of the six patients had received next-generation ADT prior to CTC collection. As a result, we conclude that AR-V7 status in CTC cannot entirely predict nonresponse to next generation ADT and AR-V7-positive patients should not be systematically denied abiraterone or enzalutamide treatment, especially as effective alternative treatment options are still limited. A subgroup of patients can benefit from abiraterone and/or enzalutamide despite detection of AR-V7 splice variants in their circulating tumour cells. Copyright © 2016 European Association of Urology. Published by Elsevier B.V. All rights reserved.

The Advanced Re-Entry Vehicle (ARV) A Development Step From ATV Toward Manned Transportation Systems

NASA Astrophysics Data System (ADS)

Bottacini, Massimiliano; Berthe, Philippe; Vo, Xavier; Pietsch, Klaus

2011-05-01

The Advanced Re-entry Vehicle (ARV) programme has been undertaken by Europe with the objective to contribute to the preparation of a future European crew transportation system, while providing a valuable logistic support to the ISS through an operational cargo return system. This development would allow: - the early acquisition of critical technologies; - the design, development and testing of elements suitable for the follow up human rated transportation system. These vehicles should also serve future LEO infrastructures and exploration missions. With the aim to satisfy the above objectives a team composed by major European industries and led by EADS Astrium Space Transportation is currently conducting the phase A of the programme under contract with the European Space Agency (ESA). Two vehicle versions are being investigated: a Cargo version, transporting cargo only to/from the ISS, and a Crew version, which will allow the transfer of both crew and cargo to/from the ISS. The ARV Cargo version, in its present configuration, is composed of three modules. The Versatile Service Module (VSM) provides to the system the propulsion/GNC for orbital manoeuvres and attitude control and the orbital power generation. Its propulsion system and GNC shall be robust enough to allow its use for different launch stacks and different LEO missions in the future. The Un-pressurised Cargo Module (UCM) provides the accommodation for about 3000 kg of unpressurised cargo and is to be sufficiently flexible to ensure the transportation of: - orbital infrastructure components (ORU’s); - scientific / technological experiments; - propellant for re-fuelling, re-boost (and de-orbiting) of the ISS. The Re-entry Module (RM) provides a pressurized volume to accommodate active/passive cargo (2000 kg upload/1500 kg download). It is conceived as an expendable conical capsule with spherical heat-shield, interfacing with the new docking standard of the ISS, i.e. it carries the IBDM docking system, on

The Advanced Re-Entry Vehicle (ARV) a Development Step from ATV Toward Manned Transportation Systems

NASA Astrophysics Data System (ADS)

Bottacini, M.; Berthe, P.; Vo, X.; Pietsch, K.

2011-08-01

The Advanced Re-entry Vehicle (ARV) programme has been undertaken by Europe with the objective to contribute to the preparation of a future European crew transportation system, while providing a valuable logistic support to the ISS through an operational cargo return system. This development would allow: - the early acquisition of critical technologies; - the design, development and testing of elements suitable for the follow up human rated transportation system. These vehicles should also serve future LEO infrastructures and exploration missions. With the aim to satisfy the above objectives a team composed by major European industries and led by EADS Astrium Space Transportation is currently conducting the phase A of the programme under contract with the European Space Agency (ESA). Two vehicle versions are being investigated: a Cargo version, transporting cargo only to/from the ISS, and a Crew version, which will allow the transfer of both crew and cargo to/from the ISS. The ARV Cargo version, in its present configuration, is composed of three modules. The Versatile Service Module (VSM) provides to the system the propulsion/GNC for orbital manoeuvres and attitude control and the orbital power generation. Its propulsion system and GNC shall be robust enough to allow its use for different launch stacks and different LEO missions in the future. The Un-pressurised Cargo Module (UCM) provides the accommodation for about 3000 kg of un-pressurised cargo and is to be sufficiently flexible to ensure the transportation of: - orbital infrastructure components (ORU's); - scientific / technological experiments; - propellant for re-fuelling, re-boost (and deorbiting) of the ISS. The Re-entry Module (RM) provides a pressurized volume to accommodate active/passive cargo (2000 kg upload/1500 kg download). It is conceived as an expendable conical capsule with spherical heat- hield, interfacing with the new docking standard of the ISS, i.e. it carries the IBDM docking system, on a

Macrophage Targeted Nanoparticles for Antiretroviral (ARV) Delivery

PubMed Central

Kutscher, Hilliard L.; Makita-Chingombe, Faithful; DiTursi, Sara; Singh, Ajay; Dube, Admire; Maponga, Charles C.; Morse, Gene D.; Reynolds, Jessica L.

2017-01-01

Objective To reduce the amount of the antiretroviral (ARV) nevirapine necessary to achieve therapeutic concentrations using macrophage targeted nanoparticles. Methods Core-shell nanoparticles were prepared from FDA approved, biodegradable and biocompatible polymers, with poly(lactic-co-glycolic) acid (PLGA) as the core and chitosan (CS) as the shell using a water/oil/water method. Nevirapine was encapsulated in the core of the nanoparticles. β-glucan (GLU) was adsorbed to the surface of the nanoparticle. Macrophage uptake and intracellular nevirapine concentrations were determined by fluorescence imaging and ultra-performance liquid chromatography/mass spectroscopy (UPLC-MS). Optical imaging was employed to characterize the biodistribution of nanoparticles following intravenous injection in CD-1 mice. Results We synthesized spherical shaped 190 nm GLU-CS-PLGA nanoparticles that provide controlled release of nevirapine. In THP-1 macrophage the uptake of PLGA and CS- PLGA nanoparticles was less compared to targeted GLU-CS-PLGA nanoparticles. THP-1 macrophage were dosed with free nevirapine (10 μg/well) and GLU-CS- PLGA nanoparticles containing 1/10 the concentration of free nevirapine (1 μg nevirapine/well). The intracellular concentration of nevirapine was the same for both nanoparticles and free nevirapine at 2 and 24 hrs. No significant change in THP-1 macrophage viability was observed in the presence of nanoparticles relative to the control. Ex vivo imaging demonstrates that nanoparticles are predominantly found in the liver and kidney and at 24 hr there is still a large amount of nanoparticles in the body. Conclusion These data demonstrate that the total dose of nevirapine delivered by GLU-CS-PLGA nanoparticles can be greatly reduced, to limit side effects, while still providing maximal ARV activity in a known cellular reservoir. PMID:29492319

Analytic Validation of RNA In Situ Hybridization (RISH) for AR and AR-V7 Expression in Human Prostate Cancer

PubMed Central

Guedes, Liana B.; Morais, Carlos L.; Almutairi, Fawaz; Haffner, Michael C.; Zheng, Qizhi; Isaacs, John T.; Antonarakis, Emmanuel S.; Lu, Changxue; Tsai, Harrison; Luo, Jun; De Marzo, Angelo M.; Lotan, Tamara L.

2016-01-01

Purpose RNA expression of androgen receptor splice variants may be a biomarker of resistance to novel androgen deprivation therapies in castrate resistant prostate cancer (CRPC). We analytically validated an RNA in situ hybridization (RISH) assay for total AR and AR-V7 for use in formalin fixed paraffin embedded (FFPE) prostate tumors. Experimental Design We used prostate cell lines and xenografts to validate chromogenic RISH to detect RNA containing AR exon 1 (AR-E1, surrogate for total AR RNA species) and cryptic exon 3 (AR-CE3, surrogate for AR-V7 expression). RISH signals were quantified in FFPE primary tumors and CRPC specimens, comparing to known AR and AR-V7 status by immunohistochemistry and RT-PCR. Results The quantified RISH results correlated significantly with total AR and AR-V7 levels by RT-PCR in cell lines, xenografts and autopsy metastases. Both AR-E1 and AR-CE3 RISH signals were localized in nuclear punctae in addition to the expected cytoplasmic speckles. Compared to admixed benign glands, AR-E1 expression was significantly higher in primary tumor cells with a median fold increase of 3.0 and 1.4 in two independent cohorts (p<0.0001 and p=0.04, respectively). While AR-CE3 expression was detectable in primary prostatic tumors, levels were substantially higher in a subset of CRPC metastases and cell lines, and were correlated with AR-E1 expression. Conclusions RISH for AR-E1 and AR-CE3 is an analytically valid method to examine total AR and AR-V7 RNA levels in FFPE tissues. Future clinical validation studies are required to determine whether AR RISH is a prognostic or predictive biomarker in specific clinical contexts. PMID:27166397

IL-1RN and IL-1β Polymorphism and ARV-Associated Hepatotoxicity

PubMed Central

Samani, Dharmesh; Nema, Vijay; Gangakhedkar, R. R.

2018-01-01

The severity of hepatic injury depends upon cytokines. Previous studies associated IL-1RN allele 2 with IL-1β production. Hence, we examined the association of IL-1 RN and IL-1β polymorphisms with ARV-associated hepatotoxicity. Genotyping of IL-1RN (VNTR), IL-1β (-511C/T) polymorphisms was done in 162 HIV-infected patients, 34 with ARV hepatotoxicity, 128 without hepatotoxicity, and 152 healthy controls using PCR and PCR-RFLP method. The haplotypes 1T and 2C enhanced the risk for severe hepatotoxicity (OR = 1.41, P = 0.25; OR = 1.67, P = 0.31). IL-1β-511TT genotype significantly represented among tobacco using HIV-infected individuals compared to nonusers (OR = 3.74, P = 0.05). IL-1β-511TT genotype among alcohol users increased the risk for hepatotoxicity (OR = 1.80, P = 0.90). IL-1β-511CT and -511TT genotypes overrepresented in alcohol using HIV-infected individuals (OR = 2.29, P = 0.27; OR = 2.64, P = 0.19). IL-RN 2/2 and 1/3 genotypes represented higher in nevirapine using hepatotoxicity patients (OR = 1.42, P = 0.64, OR = 8.79, P = 0.09). IL-1β-511CT and -511 TT genotypes among nevirapine users enhanced the risk for severe hepatotoxicity (OR = 4.29, P = 0.20; OR = 1.95, P = 0.56). IL-1β-511CT and -511TT genotypes were overrepresented in combined nevirapine and alcohol using HIV-infected individuals as compared to nevirapine users and alcohol nonusers (OR = 2.56, P = 0.26; OR = 2.84, P = 0.24). IL-1β-511TT genotype with tobacco, alcohol, and nevirapine usage revealed a trend of risk for the development of ARV-associated hepatotoxicity and its severity.

CX4945 suppresses the growth of castration-resistant prostate cancer cells by reducing AR-V7 expression.

PubMed

Deng, Chuangzhong; Chen, Jieping; Guo, Shengjie; Wang, Yanjun; Zhou, Qianghua; Li, Zaishang; Yang, Xingping; Yu, Xingsu; Zhang, Zhenfeng; Zhou, Fangjian; Han, Hui; Yao, Kai

2017-08-01

The aberrant expression of casein kinase 2 (CK2) has been reported to be involved in the tumorigenesis and progression of prostate cancer. The inhibition of CK2 activity represses androgen-dependent prostate cancer cells by attenuating the androgen receptor (AR) signaling pathway. In this study, we examined the effect of CK2 inhibition in castration-resistant prostate cancer (CRPC) cells, in which AR variants (ARVs) play a predominant role. A newly synthetic CK2 selective inhibitor CX4945 was utilized to study the effect of CK2 inhibition in CRPC cells by CCK8 assay and colony formation assay. Protein and mRNA levels of full-length AR (AR-FL) and AR-V7 were determined by qPCR and western blot, respectively. The nuclear translocation of p50 and p65 was assessed to reflect the activity of the NF-κB pathway. CX4945 reduced the proliferation of CRPC cells in a dose-dependent and time-dependent manner. AR-V7 rather than AR-FL was downregulated by CX4945 in both the mRNA and protein level. Furthermore, CX4945 could restore the sensitivity of CRPC cells to bicalutamide. The analysis of possible mechanisms demonstrated that the inhibition of CK2 diminished the phosphorylation of p65 at ser529 and thus attenuated the activity of the NF-κB pathway. The inhibition of CK2 by CX4945 can repress the viability of CRPC cells and restore their sensitivity to anti-androgen therapy by suppressing AR-V7. This finding presents a potential option for the treatment of prostate cancer, especially CRPC.

"It's important to take your medication everyday okay?" An evaluation of counselling by lay counsellors for ARV adherence support in the Western Cape, South Africa.

PubMed

Dewing, S; Mathews, C; Schaay, N; Cloete, A; Louw, J; Simbayi, L

2013-01-01

There is growing interest in standard care programmes for antiretroviral (ARV) adherence support. In South Africa, individual counselling following ARV initiation is a main strategy for supporting adherence in the public sector. Egan's client-centred "Skilled Helper" counselling model is the predominant model used in HIV counselling in this context. This study evaluated counselling delivered by lay ARV adherence counsellors in Cape Town in terms of adherence to Egan's model. Thirty-eight transcripts of counselling sessions with non-adherent patients were analysed based on the methods of content analysis. These sessions were conducted by 30 counsellors. Generally counsellors' practice adhered neither to Egan's model nor a client-centred approach. Inconsistent with evidence-based approaches to counselling for ARV adherence support, counsellors mainly used information-giving and advice as strategies for addressing clients' non-adherence. Recommendations for improving practice are made. The question as to how appropriate strategies from developed countries are for this setting is also raised.

Disclosing in utero HIV/ARV exposure to the HIV-exposed uninfected adolescent: is it necessary?

PubMed Central

Jao, Jennifer; Hazra, Rohan; Mellins, Claude A; Remien, Robert H; Abrams, Elaine J

2016-01-01

Introduction The tremendous success of antiretroviral therapy has resulted in a diminishing population of perinatally HIV-infected children on the one hand and a mounting number of HIV-exposed uninfected (HEU) children on the other. As the oldest of these HEU children are reaching adolescence, questions have emerged surrounding the implications of HEU status disclosure to these adolescents. This article outlines the arguments for and against disclosure of a child's HEU status. Discussion Disclosure of a child's HEU status, by definition, requires disclosure of maternal HIV status. It is necessary to weigh the benefits and harms which could occur with disclosure in each of the following domains: psychosocial impact, long-term physical health of the HEU individual and the public health impact. Does disclosure improve or worsen the psychological health of the HEU individual and extended family unit? Do present data on the long-term safety of in utero HIV/ARV exposure reveal potential health risks which merit disclosure to the HEU adolescent? What research and public health programmes or systems need to be in place to afford monitoring of HEU individuals and which, if any, of these require disclosure? Conclusions At present, it is not clear that there is sufficient evidence on whether long-term adverse effects are associated with in utero HIV/ARV exposures, making it difficult to mandate universal disclosure. However, as more countries adopt electronic medical record systems, the HEU status of an individual should be an important piece of the health record which follows the infant not only through childhood and adolescence but also adulthood. Clinicians and researchers should continue to approach the dialogue around mother–child disclosure with sensitivity and a cogent consideration of the evolving risks and benefits as new information becomes available while also working to maintain documentation of an individual's perinatal HIV/ARV exposures as a vital part of his

ONC201 Targets AR and AR-V7 Signaling, Reduces PSA, and Synergizes with Everolimus in Prostate Cancer.

PubMed

Lev, Avital; Lulla, Amriti R; Ross, Brian C; Ralff, Marie D; Makhov, Petr B; Dicker, David T; El-Deiry, Wafik S

2018-05-01

Androgen receptor (AR) signaling plays a key role in prostate cancer progression, and androgen deprivation therapy (ADT) is a mainstay clinical treatment regimen for patients with advanced disease. Unfortunately, most prostate cancers eventually become androgen-independent and resistant to ADT with patients progressing to metastatic castration-resistant prostate cancer (mCRPC). Constitutively activated AR variants (AR-V) have emerged as mediators of resistance to AR-targeted therapy and the progression of mCRPC, and they represent an important therapeutic target. Out of at least 15 AR-Vs described thus far, AR-V7 is the most abundant, and its expression correlates with ADT resistance. ONC201/TIC10 is the founding member of the imipridone class of small molecules and has shown anticancer activity in a broad range of tumor types. ONC201 is currently being tested in phase I/II clinical trials for advanced solid tumors, including mCRPC, and hematologic malignancies. There has been promising activity observed in patients in early clinical testing. This study demonstrates preclinical single-agent efficacy of ONC201 using in vitro and in vivo models of prostate cancer. ONC201 has potent antiproliferative and proapoptotic effects in both castration-resistant and -sensitive prostate cancer cells. Furthermore, the data demonstrate that ONC201 downregulates the expression of key drivers of prostate cancer such as AR-V7 and downstream target genes including the clinically used biomarker PSA (KLK3). Finally, the data also provide a preclinical rationale for combination of ONC201 with approved therapeutics for prostate cancer such as enzalutamide, everolimus (mTOR inhibitor), or docetaxel. Implications: The preclinical efficacy of ONC201 as a single agent or in combination, in hormone-sensitive or castration-resistant prostate cancer, suggests the potential for immediate clinical translation. Mol Cancer Res; 16(5); 754-66. ©2018 AACR . ©2018 American Association for Cancer

CTC-mRNA (AR-V7) Analysis from Blood Samples—Impact of Blood Collection Tube and Storage Time

PubMed Central

Luk, Alison W. S.; Ma, Yafeng; Ding, Pei N.; Young, Francis P.; Chua, Wei; Balakrishnar, Bavanthi; Dransfield, Daniel T.; de Souza, Paul; Becker, Therese M.

2017-01-01

Circulating tumour cells (CTCs) are an emerging resource for monitoring cancer biomarkers. New technologies for CTC isolation and biomarker detection are increasingly sensitive, however, the ideal blood storage conditions to preserve CTC-specific mRNA biomarkers remains undetermined. Here we tested the preservation of tumour cells and CTC-mRNA over time in common anticoagulant ethylene-diamine-tetra-acetic acid (EDTA) and acid citrate dextrose solution B (Citrate) blood tubes compared to preservative-containing blood tubes. Blood samples spiked with prostate cancer cells were processed after 0, 24, 30, and 48 h storage at room temperature. The tumour cell isolation efficiency and the mRNA levels of the prostate cancer biomarkers androgen receptor variant 7 (AR-V7) and total AR, as well as epithelial cell adhesion molecule (EpCAM) were measured. Spiked cells were recovered across all storage tube types and times. Surprisingly, tumour mRNA biomarkers were readily detectable after 48 h storage in EDTA and Citrate tubes, but not in preservative-containing tubes. Notably, AR-V7 expression was detected in prostate cancer patient blood samples after 48 h storage in EDTA tubes at room temperature. This important finding presents opportunities for measuring AR-V7 expression from clinical trial patient samples processed within 48 h—a much more feasible timeframe compared to previous recommendations. PMID:28498319

A Functional, Genome-wide Evaluation of Liposensitive Yeast Identifies the “ARE2 Required for Viability” (ARV1) Gene Product as a Major Component of Eukaryotic Fatty Acid Resistance*

PubMed Central

Ruggles, Kelly V.; Garbarino, Jeanne; Liu, Ying; Moon, James; Schneider, Kerry; Henneberry, Annette; Billheimer, Jeff; Millar, John S.; Marchadier, Dawn; Valasek, Mark A.; Joblin-Mills, Aidan; Gulati, Sonia; Munkacsi, Andrew B.; Repa, Joyce J.; Rader, Dan; Sturley, Stephen L.

2014-01-01

The toxic subcellular accumulation of lipids predisposes several human metabolic syndromes, including obesity, type 2 diabetes, and some forms of neurodegeneration. To identify pathways that prevent lipid-induced cell death, we performed a genome-wide fatty acid sensitivity screen in Saccharomyces cerevisiae. We identified 167 yeast mutants as sensitive to 0.5 mm palmitoleate, 45% of which define pathways that were conserved in humans. 63 lesions also impacted the status of the lipid droplet; however, this was not correlated to the degree of fatty acid sensitivity. The most liposensitive yeast strain arose due to deletion of the “ARE2 required for viability” (ARV1) gene, encoding an evolutionarily conserved, potential lipid transporter that localizes to the endoplasmic reticulum membrane. Down-regulation of mammalian ARV1 in MIN6 pancreatic β-cells or HEK293 cells resulted in decreased neutral lipid synthesis, increased fatty acid sensitivity, and lipoapoptosis. Conversely, elevated expression of human ARV1 in HEK293 cells or mouse liver significantly increased triglyceride mass and lipid droplet number. The ARV1-induced hepatic triglyceride accumulation was accompanied by up-regulation of DGAT1, a triglyceride synthesis gene, and the fatty acid transporter, CD36. Furthermore, ARV1 was identified as a transcriptional of the protein peroxisome proliferator-activated receptor α (PPARα), a key regulator of lipid homeostasis whose transcriptional targets include DGAT1 and CD36. These results implicate ARV1 as a protective factor in lipotoxic diseases due to modulation of fatty acid metabolism. In conclusion, a lipotoxicity-based genetic screen in a model microorganism has identified 75 human genes that may play key roles in neutral lipid metabolism and disease. PMID:24273168

Early Initiation of ARV During Pregnancy to Move towards Virtual Elimination of Mother-to-Child-Transmission of HIV-1 in Yunnan, China.

PubMed

Meyers, Kathrine; Qian, Haoyu; Wu, Yingfeng; Lao, Yunfei; Chen, Qingling; Dong, Xingqi; Li, Huiqin; Yang, Yiqing; Jiang, Chengqin; Zhou, Zengquan

2015-01-01

To identify factors associated with mother-to-child-transmission and late access to prevention of maternal to child transmission (PMTCT) services among HIV-infected women; and risk factors for infant mortality among HIV-exposed infants in order to assess the feasibility of virtual elimination of vertical transmission and pediatric HIV in this setting. Observational study evaluating the impact of a provincial PMTCT program. The intervention was implemented in 26 counties of Yunnan Province, China at municipal and tertiary health care settings. Log linear regression models with generalized estimating equations were used to identify unadjusted and adjusted correlates for late ARV intervention and MTCT. Cox proportional hazard models with robust sandwich estimation were applied to examine correlates of infant mortality. Mother-to-child- transmission rate of HIV was controlled to 2%, with late initiation of maternal ARV showing a strong association with vertical transmission and infant mortality. Risk factors for late initiation of maternal ARV were age, ethnicity, education, and having a husband not tested for HIV. Mortality rate among HIV-exposed infants was 2.9/100 person-years. In addition to late initiation of maternal ARV, ethnicity, low birth weight and preterm birth were associated with infant mortality. This PMTCT program in Yunnan achieved low rates of MTCT. However the infant mortality rate in this cohort of HIV-exposed children was almost three times the provincial rate. Virtual elimination of MTCT of HIV is an achievable goal in China, but more attention needs to be paid to HIV-free survival.

Biomarkers and biometric measures of adherence to use of ARV-based vaginal rings.

PubMed

Stalter, Randy M; Moench, Thomas R; MacQueen, Kathleen M; Tolley, Elizabeth E; Owen, Derek H

2016-01-01

Poor adherence to product use has been observed in recent trials of antiretroviral (ARV)-based oral and vaginal gel HIV prevention products, resulting in an inability to determine product efficacy. The delivery of microbicides through vaginal rings is widely perceived as a way to achieve better adherence but vaginal rings do not eliminate the adherence challenges exhibited in clinical trials. Improved objective measures of adherence are needed as new ARV-based vaginal ring products enter the clinical trial stage. To identify technologies that have potential future application for vaginal ring adherence measurement, a comprehensive literature search was conducted that covered a number of biomedical and public health databases, including PubMed, Embase, POPLINE and the Web of Science. Published patents and patent applications were also searched. Technical experts were also consulted to gather more information and help evaluate identified technologies. Approaches were evaluated as to feasibility of development and clinical trial implementation, cost and technical strength. Numerous approaches were identified through our landscape analysis and classified as either point measures or cumulative measures of vaginal ring adherence. Point measurements are those that give a measure of adherence at a particular point in time. Cumulative measures attempt to measure ring adherence over a period of time. Approaches that require modifications to an existing ring product are at a significant disadvantage, as this will likely introduce additional regulatory barriers to the development process and increase manufacturing costs. From the point of view of clinical trial implementation, desirable attributes would be high acceptance by trial participants, and little or no additional time or training requirements on the part of participants or clinic staff. We have identified four promising approaches as being high priority for further development based on the following measurements

ARV Re-Entry Module Aerodynmics And Aerothermodynamics

NASA Astrophysics Data System (ADS)

Scheer, Heloise; Tran, Philippe; Berthe, Philippe

2011-05-01

Astrium-ST is the prime contractor of ARV phase A and is especially in charge of designing the Reentry Module (RM). The RM aeroshape has been defined following a trade-off. High level system requirements were derived with particular attention paid on minimum lift-over-drag ratio, trim incidence, centre-of-gravity lateral off-set and box size, volumetric efficiency, attitude at parachute deployment, flight heritage and aeroheating. Since moderate cross-range and thus L/D ratio were required, the aeroshape trade-off has been performed among blunt capsule candidates. Two front- shield families were considered: spherical (Apollo/ARD/Soyuz type) and sphero-conical (CTV type) segment front-shield. The rear-cone angle was set to 20° for internal pressurized volume and accommodation purposes. Figures of merit were assessed and a spherical front- shield of ARD type with a 20° rear-cone section was selected and proposed for further investigations. Maximum benefits will be taken from ARD flight heritage. CFD and WTT campaigns plans will be presented including preliminary results.

AR-V7 in circulating tumor cells cluster as a predictive biomarker of abiraterone acetate and enzalutamide treatment in castration-resistant prostate cancer patients.

PubMed

Okegawa, Takatsugu; Ninomiya, Naoki; Masuda, Kazuki; Nakamura, Yu; Tambo, Mitsuhiro; Nutahara, Kikuo

2018-06-01

We examined whether androgen receptor splice variant 7 (AR-V7) in circulating tumor cell(CTC)clusters can be used to predict survival in patients with bone metastatic castration resistant-prostate cancer (mCRPC) treated with abiraterone or enzalutamide. We retrospectively enrolled 98 patients with CRPC on abiraterone or enzalutamide, and investigated the prognostic value of CTC cluster detection (+ v -) and AR-V7 detection (+ v -) using a CTC cluster detection - based AR-V7 mRNA assay. We examined ≤50% prostate-specific antigen (PSA) responses, PSA progression-free survival (PSA-PFS), clinical and radiological progression-free survival (radiologic PSF), and overall survival (OS). We then assessed whether AR-V7 expression in CTC clusters identified after On-chip multi-imaging flow cytometry was related to disease progression and survival after first-line systemic therapy. All abiraterone-treated or enzalutamide-treated patients received prior docetaxel. The median follow-up was 20.7 (range: 3.0-37.0) months in the abiraterone and enzalutamide cohorts, respectively. Forty-nine of the 98 men (50.0%) were CTC cluster (-), 23 of the 98 men (23.5%) were CTC cluster(+)/AR-V7(-), and 26 of the 98 men (26.5%) were CTC cluster(+)/AR-V7(+). CTC cluster(+)/AR-V7(+) patients were more likely to have EOD ≥3 at diagnosis (P = 0.003), pain (P = 0.023), higher alkaline phosphatase levels (P < 0.001), and visceral metastases (P < 0.001). On multivariable analysis, pretherapy CTC cluster(+), CTC cluster(+)/AR-V7(-), and ALP >UNL were independently associated with a poor PSA-PFS, radiographic PFS, and OS in abiraterone-treated patients and enzalutamide-treated patients. The CTC clusters and AR-V7-positive CTC clusters detected were important for assessing the response to abiraterone or enzalutamide therapy and for predicting disease outcome. © 2018 Wiley Periodicals, Inc.

Adverse drug reactions to antiretroviral therapy (ARVs): incidence, type and risk factors in Nigeria

PubMed Central

2012-01-01

Background Data on adverse drug reactions (ADRs) related to antiretroviral (ARV) use in public health practice are few indicating the need for ART safety surveillance in clinical care. Objectives To evaluate the incidence, type and risk factors associated with adverse drug reactions (ADRs) among patients on antiretroviral drugs (ARV). Methods Patients initiated on ARVs between May 2006 and May 2009 were evaluated in a retrospective cohort analysis in three health facilities in Nigeria. Regimens prescribed include nucleoside backbone of zidovudine (AZT)/lamivudine (3TC), stavudine (d4T)/3TC, or tenofovir (TDF)/3TC in combination with either nevirapine (NVP) or efavirenz (EFV). Generalized Estimating Equation (GEE) model was used to identify risk factors associated with occurrence of ADR. Results 2650 patients were followed-up for 2456 person-years and reported 114 ADRs (incidence rate = 4.6/100 person-years).There were more females 1706(64%) and 73(64%) of the ADRs were reported by women. Overall, 61(54%) of ADRs were reported by patients on AZT with 54(47%) of these occurring in patients on AZT/NVP. The commonest ADRs reported were pain 25(30%) and skinrash 10(18%). Most ADRs were grade 1(39%) with only 1% being life threatening (grade 4). Adjusted GEE analysis showed that ADR was less likely to occur in patients on longer duration of ART compared to the first six months on treatment; 6-12 months AOR 0.38(95% CI:0.16-0.91) and 12-24 months AOR 0.34(95% CI:0.16-0.73) respectively. Compared to patients on TDF, ADR was less likely to occur in patients on d4T and AZT AOR 0.18(95% CI 0.05-0.64) and AOR 0.24(95% CI:0.7-0.9) respectively. Age, gender and CD4 count were not significantly associated with ADRs. Conclusion ADRs are more likely to occur within the first six months on treatment. Close monitoring within this period is required to prevent occurrence of severe ADR and improve ART adherence. Further research on the tolerability of tenofovir in this environment is

Análisis de Minimización de Costo e Impacto Presupuestario del Tratamiento ARV con Abacavir/Lamivudina para el VIH/SIDA en México.

PubMed

Rely, Kely; Martínez Valverde, Silvia; Salinas Escudero, Guillermo

2013-12-01

In Mexico, health authorities have raised reach the total of people living with HIV/ AIDS who need treatment have access to it, with the proper use of the best ARV therapies. Evaluate health spending would mean the management of patients with HIV/AIDS with the first-line therapy of abacavir/lamivudine with respect to tenofovir/emtricitabine and lamivudine-zidovudine. A literature review was conducted to seek evidence from clinical studies that demonstrated similar efficacy of ARV treatment between abacavir-lamivudine medications compared with other options. To calculate the incremental cost between these treatments, there was a Budget Impact Analysis and a pharmacoeconomic model was constructed to estimate the economic benefits by increasing its market share. Increased market penetration of abacavir/lamivudine represent a save of $ 44.8 million for the National Health System in Mexico during the years 2012-2017, without compromising the quality and effectiveness of treatment. Furthermore, this increase in market share with abacavir-lamivudine, the National Health System could get an additional benefit to deal on average 5.197 with HIV patients by 5 years with ARV therapies in Mexico. The use of abacavir/lamivudine in ARV treatment of patients with HIV/AIDS is a cost saving for the Mexican health System, which leads to a potential reduction in resources of US$44.8 million in treatment costs in the five projected years. Copyright © 2013 International Society for Pharmacoeconomics and Outcomes Research (ISPOR). Published by Elsevier Inc. All rights reserved.

A method to manage and share anti-retroviral (ARV) therapy information of human immunodeficiency virus (HIV) patients in Vietnam.

PubMed

Nguyen, Phung Anh; Syed-Abdul, Shabbir; Minamareddy, Priti; Lee, Peisan; Ngo, Thuy Dieu; Iqbal, Usman; Nguyen, Phuong Hoang; Jian, Wen-Shan; Li, Yu-Chuan Jack

2013-08-01

Management of antiretroviral (ARV) drug and HIV patients data is an important component of Vietnam Administration of HIV/AIDS Control (VAAC) Department and hospitals/health care units when people often travel in other places of Vietnam; therefore, it would lead to a number of medical errors in treatment as well as patients do not adhere to ARV therapy. In this paper, we describe a system that manages and shares antiretroviral therapy information of 4438 HIV patients in three healthcare centers in Hanoi capital of Vietnam. The overall design considerations, architecture and the integration of centralized database and decentralized management for the system are also presented. The findings from this study can serve as a guide to consider in the implementation model of health care to manage and share information of patients not only in HIV infection, but also in the other chronic and non-communicable diseases. Copyright © 2013. Published by Elsevier Ireland Ltd.

The association between ARV and TB drug resistance on TB treatment outcome among Kazakh TB/HIV patients.

PubMed

Mishkin, Kathryn; Alaei, Kamiar; Alikeyeva, Elmira; Paynter, Christopher; Aringazina, Altyn; Alaei, Arash

2018-02-26

TB drug resistance poses a serious threat to the public health of Kazakhstan. This paper presents findings related to TB treatment outcome and drug resistant status among people coinfected with HIV and TB in Kazakhstan. Cohort study using data were provided by the Kazakhstan Ministry of Health's National Tuberculosis Program for 2014 and 2015. Chi-square and logistical regression were performed to understand factors associated with drug resistant TB status and TB treatment outcome. In bivariate analysis, drug resistant status was significantly associated with year of TB diagnosis (p=0.001) viral load (p=0.03). TB treatment outcome was significantly associated with age at diagnosis (p=01), ARV treatment (p <0.0001), and TB drug resistant status (p=0.02). In adjusted analysis, drug resistance was associated with increased odds of successful completion of treatment with successful result compared to treatment failure (OR 6.94, 95% CI: 1.39-34.44) CONCLUSIONS: Our results suggest that being drug resistant is associated with higher odds of completing treatment with successful outcome, even when controlling for receipt of ARV therapy. Copyright © 2018. Published by Elsevier Ltd.

Multimodal actions of the phytochemical sulforaphane suppress both AR and AR-V7 in 22Rv1 cells: Advocating a potent pharmaceutical combination against castration-resistant prostate cancer.

PubMed

Khurana, Namrata; Kim, Hogyoung; Chandra, Partha K; Talwar, Sudha; Sharma, Pankaj; Abdel-Mageed, Asim B; Sikka, Suresh C; Mondal, Debasis

2017-11-01

Prostate cancer (PCa) cells expressing full-length androgen receptor (AR-FL) are susceptible to androgen deprivation therapy (ADT). However, outgrowth of castration-resistant prostate cancer (CRPC) can occur due to the expression of constitutively active (ligand-independent) AR splice variants, particularly AR-V7. We previously demonstrated that sulforaphane (SFN), an isothiocyanate phytochemical, can decrease AR-FL levels in the PCa cell lines, LNCaP and C4-2B. Here, we examined the efficacy of SFN in targeting both AR-FL and AR-V7 in the CRPC cell line, CWR22Rv1 (22Rv1). MTT cell viability, wound-heal assay, and colony forming unit (CFU) measurements revealed that 22Rv1 cells are resistant to the anti-androgen, enzalutamide (ENZ). However, co-exposure to SFN sensitized these cells to the potent anticancer effects of ENZ (P<0.05). Immunoblot analyses showed that SFN (5-20 µM) rapidly decreases both AR-FL and AR-V7 levels, and immunofluorescence microscopy (IFM) depicted decreased AR in both cytoplasm and nucleus with SFN treatment. SFN increased both ubiquitination and proteasomal activity in 22Rv1 cells. Studies using a protein synthesis inhibitor (cycloheximide) or a proteasomal inhibitor (MG132) indicated that SFN increases both ubiquitin-mediated aggregation and subsequent proteasomal-degradation of AR proteins. Previous studies reported that SFN inhibits the chaperone activity of heat-shock protein 90 (Hsp90) and induces the nuclear factor erythroid-2-like 2 (Nrf2) transcription factor. Therefore, we investigated whether the Hsp90 inhibitor, ganetespib (G) or the Nrf2 activator, bardoxolone methyl (BM) can similarly suppress AR levels in 22Rv1 cells. Low doses of G and BM, alone or in combination, decreased both AR-FL and AR-V7 levels, and combined exposure to G+BM sensitized 22Rv1 cells to ENZ. Therefore, adjunct treatment with the phytochemical SFN or a safe pharmaceutical combination of G+BM may be effective against CRPC cells, especially those

Multimodal actions of the phytochemical sulforaphane suppress both AR and AR-V7 in 22Rv1 cells: Advocating a potent pharmaceutical combination against castration-resistant prostate cancer

PubMed Central

Khurana, Namrata; Kim, Hogyoung; Chandra, Partha K.; Talwar, Sudha; Sharma, Pankaj; Abdel-Mageed, Asim B.; Sikka, Suresh C.; Mondal, Debasis

2017-01-01

Prostate cancer (PCa) cells expressing full-length androgen receptor (AR-FL) are susceptible to androgen deprivation therapy (ADT). However, outgrowth of castration-resistant prostate cancer (CRPC) can occur due to the expression of constitutively active (ligand-independent) AR splice variants, particularly AR-V7. We previously demonstrated that sulforaphane (SFN), an isothiocyanate phytochemical, can decrease AR-FL levels in the PCa cell lines, LNCaP and C4-2B. Here, we examined the efficacy of SFN in targeting both AR-FL and AR-V7 in the CRPC cell line, CWR22Rv1 (22Rv1). MTT cell viability, wound-heal assay, and colony forming unit (CFU) measurements revealed that 22Rv1 cells are resistant to the anti-androgen, enzalutamide (ENZ). However, co-exposure to SFN sensitized these cells to the potent anticancer effects of ENZ (P<0.05). Immunoblot analyses showed that SFN (5–20 µM) rapidly decreases both AR-FL and AR-V7 levels, and immunofluorescence microscopy (IFM) depicted decreased AR in both cytoplasm and nucleus with SFN treatment. SFN increased both ubiquitination and proteasomal activity in 22Rv1 cells. Studies using a protein synthesis inhibitor (cycloheximide) or a proteasomal inhibitor (MG132) indicated that SFN increases both ubiquitin-mediated aggregation and subsequent proteasomal-degradation of AR proteins. Previous studies reported that SFN inhibits the chaperone activity of heat-shock protein 90 (Hsp90) and induces the nuclear factor erythroid-2-like 2 (Nrf2) transcription factor. Therefore, we investigated whether the Hsp90 inhibitor, ganetespib (G) or the Nrf2 activator, bardoxolone methyl (BM) can similarly suppress AR levels in 22Rv1 cells. Low doses of G and BM, alone or in combination, decreased both AR-FL and AR-V7 levels, and combined exposure to G+BM sensitized 22Rv1 cells to ENZ. Therefore, adjunct treatment with the phytochemical SFN or a safe pharmaceutical combination of G+BM may be effective against CRPC cells, especially those

Assessing the impact of a food supplement on the nutritional status and body composition of HIV-infected Zambian women on ARVs.

PubMed

Zulu, Rodah M; Byrne, Nuala M; Munthali, Grace K; Chipeta, James; Handema, Ray; Musonda, Mofu; Hills, Andrew P

2011-09-21

Zambia is a sub-Saharan country with one of the highest prevalence rates of HIV, currently estimated at 14%. Poor nutritional status due to both protein-energy and micronutrient malnutrition has worsened this situation. In an attempt to address this combined problem, the government has instigated a number of strategies, including the provision of antiretroviral (ARV) treatment coupled with the promotion of good nutrition. High-energy protein supplement (HEPS) is particularly promoted; however, the impact of this food supplement on the nutritional status of people living with HIV/AIDS (PLHA) beyond weight gain has not been assessed. Techniques for the assessment of nutritional status utilising objective measures of body composition are not commonly available in Zambia. The aim of this study is therefore to assess the impact of a food supplement on nutritional status using a comprehensive anthropometric protocol including measures of skinfold thickness and circumferences, plus the criterion deuterium dilution technique to assess total body water (TBW) and derive fat-free mass (FFM) and fat mass (FM). This community-based controlled and longitudinal study aims to recruit 200 HIV-infected females commencing ARV treatment at two clinics in Lusaka, Zambia. Data will be collected at four time points: baseline, 4-month, 8-month and 12-month follow-up visits. Outcome measures to be assessed include body height and weight, body mass index (BMI), body composition, CD4, viral load and micronutrient status. This protocol describes a study that will provide a longitudinal assessment of the impact of a food supplement on the nutritional status of HIV-infected females initiating ARVs using a range of anthropometric and body composition assessment techniques. Pan African Clinical Trial Registry PACTR201108000303396.

Assessing the impact of a food supplement on the nutritional status and body composition of HIV-infected Zambian women on ARVs

PubMed Central

2011-01-01

Background Zambia is a sub-Saharan country with one of the highest prevalence rates of HIV, currently estimated at 14%. Poor nutritional status due to both protein-energy and micronutrient malnutrition has worsened this situation. In an attempt to address this combined problem, the government has instigated a number of strategies, including the provision of antiretroviral (ARV) treatment coupled with the promotion of good nutrition. High-energy protein supplement (HEPS) is particularly promoted; however, the impact of this food supplement on the nutritional status of people living with HIV/AIDS (PLHA) beyond weight gain has not been assessed. Techniques for the assessment of nutritional status utilising objective measures of body composition are not commonly available in Zambia. The aim of this study is therefore to assess the impact of a food supplement on nutritional status using a comprehensive anthropometric protocol including measures of skinfold thickness and circumferences, plus the criterion deuterium dilution technique to assess total body water (TBW) and derive fat-free mass (FFM) and fat mass (FM). Methods/Design This community-based controlled and longitudinal study aims to recruit 200 HIV-infected females commencing ARV treatment at two clinics in Lusaka, Zambia. Data will be collected at four time points: baseline, 4-month, 8-month and 12-month follow-up visits. Outcome measures to be assessed include body height and weight, body mass index (BMI), body composition, CD4, viral load and micronutrient status. Discussion This protocol describes a study that will provide a longitudinal assessment of the impact of a food supplement on the nutritional status of HIV-infected females initiating ARVs using a range of anthropometric and body composition assessment techniques. Trial Registration Pan African Clinical Trial Registry PACTR201108000303396. PMID:21936938

Clinical Pharmacology Quality Assurance (CPQA) Program: Models for Longitudinal Analysis of Antiretroviral (ARV) Proficiency Testing for International Laboratories

PubMed Central

DiFrancesco, Robin; Rosenkranz, Susan L.; Taylor, Charlene R.; Pande, Poonam G.; Siminski, Suzanne M.; Jenny, Richard W.; Morse, Gene D.

2013-01-01

Among National Institutes of Health (NIH) HIV Research Networks conducting multicenter trials, samples from protocols that span several years are analyzed at multiple clinical pharmacology laboratories (CPLs) for multiple antiretrovirals (ARV). Drug assay data are, in turn, entered into study-specific datasets that are used for pharmacokinetic analyses, merged to conduct cross-protocol pharmacokinetic analysis and integrated with pharmacogenomics research to investigate pharmacokinetic-pharmacogenetic associations. The CPLs participate in a semi-annual proficiency testing (PT) program implemented by the Clinical Pharmacology Quality Assurance (CPQA) program. Using results from multiple PT rounds, longitudinal analyses of recovery are reflective of accuracy and precision within/across laboratories. The objectives of this longitudinal analysis of PT across multiple CPLs were to develop and test statistical models that longitudinally: (1)assess the precision and accuracy of concentrations reported by individual CPLs; (2)determine factors associated with round-specific and long-term assay accuracy, precision and bias using a new regression model. A measure of absolute recovery is explored as a simultaneous measure of accuracy and precision. Overall, the analysis outcomes assured 97% accuracy (±20% of the final target concentration of all (21)drug concentration results reported for clinical trial samples by multiple CPLs).Using the CLIA acceptance of meeting criteria for ≥2/3 consecutive rounds, all ten laboratories that participated in three or more rounds per analyte maintained CLIA proficiency. Significant associations were present between magnitude of error and CPL (Kruskal Wallis [KW]p<0.001), and ARV (KW p<0.001). PMID:24052065

Multiple ART Programs Create a Dilemma for Providers to Monitor ARV Adherence in Uganda.

PubMed

Obua, Celestino; Gusdal, Annelie; Waako, Paul; Chalker, John C; Tomson, Goran; Wahlström, Rolf; Team, The Inrud-Iaa

2011-01-01

Increased availability and accessibility of antiretroviral therapy (ART) has improved the length and quality of life amongst people living with HIV/AIDS. This has changed the landscape for care from episodic to long-term care that requires more monitoring of adherence. This has led to increased demand on human resources, a major problem for most ART programs. This paper presents experiences and perspectives of providers in ART facilities, exploring the organizational factors affecting their capacity to monitor adherence to ARVs. From an earlier survey to test adherence indicators and rank facilities as good, medium or poor adherence performances, six facilities were randomly selected, two from each rank. Observations on facility set-up, provider-patient interactions and key informant interviews were carried out. The strengths, weaknesses, opportunities and threats identified by health workers as facilitators or barriers to their capacity to monitor adherence to ARVs were explored during group discussions. Findings show that the performance levels of the facilities were characterized by four different organizational ART programs operating in Uganda, with apparent lack of integration and coordination at the facilities. Of the six facilities studied, the two high adherence performing facilities were Non-Governmental Organization (NGO) programs, while facilities with dual organizational programs (Governmental/NGO) performed poorly. Working conditions, record keeping and the duality of programs underscored the providers' capacity to monitor adherence. Overall 70% of the observed provider-patient interactions were conducted in environments that ensured privacy of the patient. The mean performance for record keeping was 79% and 50% in the high and low performing facilities respectively. Providers often found it difficult to monitor adherence due to the conflicting demands from the different organizational ART programs. Organizational duality at facilities is a major

Genetic characterization of HIV-1 strains in Togo reveals a high genetic complexity and genotypic drug-resistance mutations in ARV naive patients.

PubMed

Yaotsè, Dagnra Anoumou; Nicole, Vidal; Roch, Niama Fabien; Mireille, Prince-David; Eric, Delaporte; Martine, Peeters

2009-07-01

In this study, the genetic diversity of HIV-1 and the presence of genotypic drug-resistance mutations in ARV naive patients in Lomé, the capital city of Togo, was documented for the first time. Between June 2006 and January 2007, 83 plasma samples were collected in Lomé from HIV-1 positive and antiretroviral (ARV) naive individuals. Pol (protease+RT) and env (V3-V5) regions were amplified and sequenced. Phylogenetic and recombination analyses were done to identify the HIV-1 variants. Pol sequences were then inspected to identify presence of drug-resistance mutations based on the WHO list recommended for epidemiological studies. A total of 75 plasma samples were amplified and sequenced in both genomic regions. The phylogenetic analysis showed that CRF02 (48.7% and 51.2%) and G (12.8% and 16.2%) were predominant, followed by A3 (6.4% and 6.2%) and CRF06 (3.8% and 12.5%) in pol and env, respectively. One strain was identified as CRF05 in pol and env. Two divergent subtype A strains in env were undetermined (U) in pol but clustered with a previously described complex recombinant strain, 99GR303. Overall, at least 23/83 (27.7%) strains were recombinant, 19 had a unique recombinant structure in pol, and 4 had discordant subtype/CRF designations between pol and env. The subtypes/CRFs involved in the recombination events corresponded to those already circulating as non-recombinant strains in the country. A total of 8 patients harbored strains with mutations associated to drug resistance: L90M (n=1), K103N (n=1), T69N (n=1), T215S (n=1), M41L (n=4). In this study we showed the complexity of the HIV-1 strains circulating in Togo and documented a relative high proportion of ARV naive patients with drug-resistance mutations. The high number of resistant strains observed in Togo needs further attention and additional studies are needed to confirm this trend especially because the national ART program experienced major problems to provide drugs on a regular base.

Contribution of rainfall, snow and ice melt to the hydrological regime of the Arve upper catchment and to severe flood events

NASA Astrophysics Data System (ADS)

Lecourt, Grégoire; Revuelto, Jesús; Morin, Samuel; Zin, Isabella; Lafaysse, Matthieu; Condom, Thomas; Six, Delphine; Vionnet, Vincent; Charrois, Luc; Dumont, Marie; Gottardi, Frédéric; Laarman, Olivier; Coulaud, Catherine; Esteves, Michel; Lebel, Thierry; Vincent, Christian

2016-04-01

In Alpine catchments, the hydrological response to meteorological events is highly influenced by the precipitation phase (liquid or solid) and by snow and ice melt. It is thus necessary to simulate accurately the snowpack evolution and its spatial distribution to perform relevant hydrological simulations. This work is focused on the upper Arve Valley (Western Alps). This 205 km2 catchment has large glaciated areas (roughly 32% of the study area) and covers a large range of elevations (1000-4500 m a.s.l.). Snow presence is significant year-round. The area is also characterized by steep terrain and strong vegetation heterogeneity. Modelling hydrological processes in such a complex catchment is therefore challenging. The detailed ISBA land surface model (including the Crocus snowpack scheme) has been applied to the study area using a topography based discretization (classifying terrain by aspect, elevation, slope and presence of glacier). The meteorological forcing used to run the simulations is the reanalysis issued from the SAFRAN model which assimilates meteorological observations from the Meteo-France networks. Conceptual reservoirs with calibrated values of emptying parameters are used to represent the underground water storage. This approach has been tested to simulate the discharge on the Arve catchment and three sub-catchments over 1990-2015. The simulations were evaluated with respect to observed water discharges for several headwaters with varying glaciated areas. They allow to quantify the relative contribution of rainfall, snow and ice melt to the hydrological regime of the basin. Additionally, we present a detailed analysis of several particular flood events. For these events, the ability of the model to correctly represent the catchment behaviour is investigated, looking particularly to the relevance of the simulated snowpack. Particularly, its spatial distribution is evaluated using MODIS snow cover maps, punctual snowpack observations and summer

Dolutegravir-lamivudine as initial therapy in HIV-1 infected, ARV-naive patients, 48-week results of the PADDLE (Pilot Antiretroviral Design with Dolutegravir LamivudinE) study.

PubMed

Cahn, Pedro; Rolón, María José; Figueroa, María Inés; Gun, Ana; Patterson, Patricia; Sued, Omar

2017-05-09

A proof-of-concept study was designed to evaluate the antiviral efficacy, safety and tolerability of a two-drug regimen with dolutegravir 50 mg once daily (QD) plus lamivudine 300 mg once daily as initial highly active antiretroviral therapy (HAART) among antiretroviral (ARV)-naive patients. PADDLE is a pilot study including 20 treatment-naive adults. To be selected, participants had no IAS-USA-defined resistance, HIV-1 RNA ≤100,000 copies/mL at screening and negative HBsAg. Plasma viral load (pVL) was measured at baseline; days 2, 4, 7, 10, 14, 21 and 28; weeks 6, 8 and 12; and thereafter every 12 weeks up to 96 weeks. Primary endpoint was the proportion of patients with HIV-1 RNA <50 copies/mL in an intention to treat (ITT)-exposed analysis at 48 weeks (the FDA snapshot algorithm). Median HIV-1 RNA at entry was 24,128 copies/mL (interquartile range (IQR): 11,686-36,794). Albeit as per protocol, all patients had pVL ≤100,000 copies/mL at screening as required by inclusion criteria, four patients had ≥100,000 copies/mL at baseline. Median baseline CD4+ T-cell count was 507 per cubic millimetre (IQR: 296-517). A rapid decline in pVL was observed (median VL decay from baseline to week 12 was 2.74 logs). All patients were suppressed at week 8 onwards up to week 24. At week 48, 90% (18/20) reached the primary endpoint of a pVL <50 copies/mL. Median change in CD4 cell count between baseline and week 48 was 267 cells/mm 3 (IQR: 180-462). No major tolerability/toxicity issues were observed. Nineteen patients completed 48 weeks of the study, and one patient (with undetectable VL at last visit) committed suicide. One patient presented a low-level protocol-defined confirmed virological failure at week 36, being the only observed failure. This patient had pVL <50 copies/mL at the end-of-study visit without having changed the two-drug regimen. Observed failure rate was 5%. This is the first report of integrase strand transfer inhibitor/lamivudine dual regimen in

Detection of Human Papillomavirus Infection in Patients with Vaginal Intraepithelial Neoplasia.

PubMed

Lamos, Cristina; Mihaljevic, Charlotte; Aulmann, Sebastian; Bruckner, Thomas; Domschke, Christoph; Wallwiener, Markus; Paringer, Carmen; Fluhr, Herbert; Schott, Sarah; Dinkic, Christine; Brucker, Janina; Golatta, Michael; Gensthaler, Lisa; Eichbaum, Michael; Sohn, Christof; Rom, Joachim

2016-01-01

Vaginal intraepithelial neoplasia (VAIN) is a pre-malignant lesion, potentially leading to vaginal cancer. It is a rare disease, representing less than 1% of all intraepithelial neoplasia of the female genital tract. Similar to cervical intraepithelial neoplasia (CIN), there are three different grades of VAIN. VAIN 1 is also known as a low-grade squamous intraepithelial lesion (LSIL), whereas VAIN 2 and VAIN 3 both represent high-grade squamous intraepithelial lesions (HSIL). Risk factors for the development of VAIN are similar to those for cervical neoplasia, i.e. promiscuity, starting sexual activity at an early age, tobacco consumption and infection with human papillomavirus (HPV). However, compared to other intraepithelial neoplasia such as CIN or VIN (vulvar intraepithelial neoplasia), there still is little understanding about the natural course of VAIN and its capacity for pro- or regression. Furthermore, there is controversial data about the HPV detection rate in VAIN lesions. 67 patients with histologically confirmed VAIN, who were diagnosed between 2003 and 2011 at the University Women´s Hospital of Heidelberg Germany, were included in this study. The biopsies of all participating patients were subjected to HPV genotyping. GP-E6/E7 Nested Multiplex PCR (NMPCR) was used to identify and genotype HPV. Eighteen pairs of type-specific nested PCR primers were assessed to detect the following "high-risk" HPV genotypes: 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66 and 68, as well as the "low-risk" genotypes 6/11, 42, 43 and 44. The data was analyzed with the software SAS (Statistical Analysis System). All 67 cases were eligible for DNA analysis. The median age was 53 years. The largest group with 53% (n = 36) was formed by women, who were first diagnosed with VAIN between the age of 41 to 60 years. 50% (n = 37) of the patients presented a VAIN in the upper 1/3 of the vagina. 58 (87%) were diagnosed with HSIL (VAIN). The median age in patients with LSIL

[Treatment results for different categories of vaginal intraepithelial neoplasia with electrocoagulation, 5-fluorouracil and combined treatment].

PubMed

Veloz-Martínez, María Guadalupe; Quintana-Romero, Verónica; Contreras-Morales, María del Rosario Sandra; Jiménez-Vieyra, Carlos Ramón

2015-10-01

Vaginal intraepithelial neoplasia (VAIN) represents a variety of changes that initiate as an intraepithelial squamous lesion with the possibility of resulting in cancer. To compare the results of the treatment for the different categories of VAIN with electrocoagulation, 5-fluorouracil and combined treatment. Observational an analytical study. We stablished groups according to the category of VAIN evaluating and comparing remission, persistence, recurrence, or progression of the disease ac- cording to the received treatment, with a 1-year follow up. The results were compared by chi2 and Kruskal Wallis. The statistics analysis was done with the SPSS program version 20. One hundred thirty seven patients between 20 and 81 years of age (mean age: 52.49 years) were included. Seventy-four percent of the patients had a history of premalignant or malignant cervical lesions. Seventy-four patients had VAIN I, 34 patients had VAIN II, 22 patients had VAIN III and there were seven cases of vaginal carcinoma in situ. Fifty-eight patients were treated with electrocoagulation, 55 patients were treated with 5-FU, 16 patients had combined treatment, and eight patients received expectant management. Sixty three percent of patients had total remission of the lesion, 34% had persistence and 3% showed progression, and there were no cases of recurrence. Results were better in patients with VAIN I treated with 5-FU (bigger percentage of remission P .026), for the remaining categories of VAIN, no treatment showed superior results. The superior response occurs in patients with VAIN I treated with 5-FU. None of the treatments achieves a 100% remission. The VAIN frequency is high, patients with a history of malignant or premalignant cervical pathology should undergo a closer surveillance through cytocolposcopic control with respect to the remaining population.

ARV robotic technologies (ART): a risk reduction effort for future unmanned systems

NASA Astrophysics Data System (ADS)

Jaster, Jeffrey F.

2006-05-01

The Army's ARV (Armed Robotic Vehicle) Robotic Technologies (ART) program is working on the development of various technological thrusts for use in the robotic forces of the future. The ART program will develop, integrate and demonstrate the technology required to advance the maneuver technologies (i.e., perception, mobility, tactical behaviors) and increase the survivability of unmanned platforms for the future force while focusing on reducing the soldiers' burden by providing an increase in vehicle autonomy coinciding with a decrease in the total number user interventions required to control the unmanned assets. This program will advance the state of the art in perception technologies to provide the unmanned platform an increasingly accurate view of the terrain that surrounds it; while developing tactical/mission behavior technologies to provide the Unmanned Ground Vehicle (UGV) the capability to maneuver tactically, in conjunction with the manned systems in an autonomous mode. The ART testbed will be integrated with the advanced technology software and associated hardware developed under this effort, and incorporate appropriate mission modules (e.g. RSTA sensors, MILES, etc.) to support Warfighter experiments and evaluations (virtual and field) in a military significant environment (open/rolling and complex/urban terrain). The outcome of these experiments as well as other lessons learned through out the program life cycle will be used to reduce the current risks that are identified for the future UGV systems that will be developed under the Future Combat Systems (FCS) program, including the early integration of an FCS-like autonomous navigation system onto a tracked skid steer platform.

Imiquimod in cervical, vaginal and vulvar intraepithelial neoplasia: a review.

PubMed

de Witte, C J; van de Sande, A J M; van Beekhuizen, H J; Koeneman, M M; Kruse, A J; Gerestein, C G

2015-11-01

Human papillomavirus (HPV) infection is in the vast majority of patients accountable for the development of vulvar, cervical and vaginal intraepithelial neoplasia (VIN, CIN, VAIN); precursors of vulvar, cervical and vaginal cancers. The currently preferred treatment modality for high grade VIN, CIN and VAIN is surgical excision. Nevertheless surgical treatment is associated with adverse pregnancy outcomes and recurrence is not uncommon. The aim of this review is to present evidence on the efficacy, safety and tolerability of imiquimod (an immune response modifier) in HPV-related VIN, CIN and VAIN. A search for papers on the use of imiquimod in VIN, CIN and VAIN was performed in the MEDLINE, EMBASE and Cochrane library databases. Data was extracted and reviewed. Twenty-one articles met the inclusion criteria and were analyzed; 16 on VIN, 3 on CIN and 2 on VAIN. Complete response rates in VIN ranged from 5 to 88%. Although minor adverse effects were frequently reported, treatment with imiquimod was well tolerated in most patients. Studies on imiquimod treatment of CIN and VAIN are limited and lack uniformly defined endpoints. The available evidence however, shows encouraging effect. Complete response rates for CIN 2-3 and VAIN 1-3 ranged from 67 to 75% and 57 to 86% respectively. More randomized controlled trials on the use of imiquimod in CIN, VAIN and VIN with extended follow-up are necessary to determine the attributive therapeutic value in these patients. Copyright © 2015 Elsevier Inc. All rights reserved.

Dolutegravir–lamivudine as initial therapy in HIV-1 infected, ARV-naive patients, 48-week results of the PADDLE (Pilot Antiretroviral Design with Dolutegravir LamivudinE) study

PubMed Central

Cahn, Pedro; Rolón, María José; Figueroa, María Inés; Gun, Ana; Patterson, Patricia; Sued, Omar

2017-01-01

Abstract Introduction: A proof-of-concept study was designed to evaluate the antiviral efficacy, safety and tolerability of a two-drug regimen with dolutegravir 50 mg once daily (QD) plus lamivudine 300 mg once daily as initial highly active antiretroviral therapy (HAART) among antiretroviral (ARV)-naive patients. Methods: PADDLE is a pilot study including 20 treatment-naive adults. To be selected, participants had no IAS-USA-defined resistance, HIV-1 RNA ≤100,000 copies/mL at screening and negative HBsAg. Plasma viral load (pVL) was measured at baseline; days 2, 4, 7, 10, 14, 21 and 28; weeks 6, 8 and 12; and thereafter every 12 weeks up to 96 weeks. Primary endpoint was the proportion of patients with HIV-1 RNA <50 copies/mL in an intention to treat (ITT)-exposed analysis at 48 weeks (the FDA snapshot algorithm). Results: Median HIV-1 RNA at entry was 24,128 copies/mL (interquartile range (IQR): 11,686–36,794). Albeit as per protocol, all patients had pVL ≤100,000 copies/mL at screening as required by inclusion criteria, four patients had ≥100,000 copies/mL at baseline. Median baseline CD4+ T-cell count was 507 per cubic millimetre (IQR: 296–517). A rapid decline in pVL was observed (median VL decay from baseline to week 12 was 2.74 logs). All patients were suppressed at week 8 onwards up to week 24. At week 48, 90% (18/20) reached the primary endpoint of a pVL <50 copies/mL. Median change in CD4 cell count between baseline and week 48 was 267 cells/mm3 (IQR: 180–462). No major tolerability/toxicity issues were observed. Nineteen patients completed 48 weeks of the study, and one patient (with undetectable VL at last visit) committed suicide. One patient presented a low-level protocol-defined confirmed virological failure at week 36, being the only observed failure. This patient had pVL <50 copies/mL at the end-of-study visit without having changed the two-drug regimen. Observed failure rate was 5%. This is the first report of integrase strand

Novel galeterone analogs act independently of AR and AR-V7 for the activation of the unfolded protein response and induction of apoptosis in the CWR22Rv1 prostate cancer cell model.

PubMed

McCarty, David J; Huang, Weiliang; Kane, Maureen A; Purushottamachar, Puranik; Gediya, Lalji K; Njar, Vincent C O

2017-10-24

The androgen receptor (AR) has long been the primary target for the treatment of prostate cancer (PC). Despite continuous efforts to block AR activity through ligand depletion, AR antagonism, AR depletion and combinations thereof, advanced PC tumors remain resilient. Herein, we evaluate two galeterone analogs, VNPT-178 and VNLG-74A, in PC cell models of diverse androgen and AR dependence attempting to delineate their mechanisms of action and potential clinical utility. Employing basic biochemical techniques, we determined that both analogs have improved antiproliferative and anti-AR activities compared to FDA-approved abiraterone and enzalutamide. However, induction of apoptosis in these models is independent of the AR and its truncated variant, AR-V7, and instead likely results from sustained endoplasmic reticulum stress and deregulated calcium homeostasis. Using in silico molecular docking, we predict VNPT-178 and VNLG-74A bind the ATPase domain of BiP/Grp78 and Hsp70-1A with greater affinity than the AR. Disruption of 70 kDa heat shock protein function may be the underlying mechanism of action for these galeterone analogs. Therefore, despite simultaneously antagonizing AR activity, AR and/or AR-V7 expression alone may inadequately predict a patient's response to treatment with VNPT-178 or VNLG-74A. Future studies evaluating the context-specific limitations of these compounds may provide clarity for their clinical application.

Urban planning and interactions with atmospheric pollution in Arve valley

NASA Astrophysics Data System (ADS)

Langlois de Septenville, William; Cossart, Étienne

2017-04-01

Atmospheric pollution is a major concern of urbanised areas and territory managers have to conduct efficient policies to decrease population exposure and vulnerability. Even if pollution peaks are subject to an important mediatisation and to a large part of preventive actions, background pollution remains responsible of the largest sanitary effects. They depend on (1) the concentration and the duration of the exposure and (2) to the kind of pollutants considered. Many sources of pollutants can be identified in urban areas as heating, industry or traffic; and each of them generates specific particles. Currently, the major part of pollution risk studies focuses on modelling particle emissions and their dissemination in the environment. These kinds of studies highlight the hazard intensity and its spatiality, commonly named the hazard exposure. Another part of risk studies, less frequent, considers the vulnerability. Vulnerability is a complex concept that involves a wide range of scales and objects ranging from biophysical parameters to social characteristics. They notably concern accessibility to information, knowledge and perceptions about the risk. The Arve valley (south-east of France) is subject to heavy pollution concentrations. High levels recording in this area have imposed the implementation of an Atmosphere Protection Plan. This type of plan is triggered if a peak occurs and enforces provisional binding measures for polluters, such as highway speed limitation for traffic emissions. These measures are only focused on emissions and have no effect for reducing vulnerability and exposition, for a long- and short-term time scales. An opportunity to ensure this objective is to consider how local urban morphologies can combine exposition and vulnerability situations. Indeed, cities have been planned without taking into account atmospheric pollution and morphologies. This context may conduct to the increase in both of these two risk components and producing

Interplay Between Cytoplasmic and Nuclear Androgen Receptor Splice Variants Mediate Castration Resistance

PubMed Central

Zhan, Yang; Zhang, Guanyi; Wang, Xiaojie; Qi, Yanfeng; Bai, Shanshan; Li, Dongying; Ma, Tianfang; Sartor, Oliver; Flemington, Erik K.; Zhang, Haitao; Lee, Peng; Dong, Yan

2016-01-01

Androgen receptor splice variants (AR-Vs) are implicated in resistance of prostate cancer to androgen-directed therapies. When expressed alone in cells, some AR-Vs (e.g., AR-V7) localize primarily to the nucleus, whereas others (e.g., AR-V1, AR-V4, and AR-V6) localize mainly to the cytoplasm. Significantly, the latter are often co-expressed with the nucleus-predominant AR-Vs and the full-length AR (AR-FL). An important question to be addressed is whether the cytoplasmic-localized AR-Vs play a role in castration-resistant prostate cancer (CRPC) through interaction with the nucleus-predominant AR-Vs and AR-FL. Here, it is demonstrated that AR-V1, -V4, and -V6 can dimerize with both AR-V7 and AR-FL. Consequently, AR-V7 and androgen-bound AR-FL induced nuclear localization of AR-V1, -V4, and -V6, and these variants, in turn, mitigated the ability of the anti-androgen enzalutamide to inhibit androgen-induced AR-FL nuclear localization. Interestingly, the impact of nuclear localization of AR-V4 and -V6 on AR transactivation differs from that of AR-V1. Nuclear localization leads to an increased ability of AR-V4 and -V6 to transactivate both canonical AR targets and AR-V-specific targets and to confer castration-resistant cell growth. However, while AR-V1, which lacks inherent transcriptional activity, appears to activate AR-FL in an androgen-independent manner, it significantly antagonizes AR-V7 transactivation. Together, these data demonstrate that the complex interactions among different AR-Vs and AR-FL play a significant role in castration resistant disease. Implications This study suggests important consequences for clinical castration resistance due to simultaneous expression of AR-FL and AR-Vs in patient tumors and suggests that dissecting these interactions should help develop effective strategies to disrupt AR-V signaling. PMID:27671337

Preferences for ARV-based HIV prevention methods among men and women, adolescent girls and female sex workers in Gauteng Province, South Africa: a protocol for a discrete choice experiment.

PubMed

Quaife, Matthew; Eakle, Robyn; Cabrera, Maria; Vickerman, Peter; Tsepe, Motlalepule; Cianci, Fiona; Delany-Moretlwe, Sinead; Terris-Prestholt, Fern

2016-06-27

For the past few decades, condoms have been the main method of HIV prevention. Recent advances in antiretroviral (ARV)-based prevention products have substantially changed the prevention landscape, yet little is known about how popular these products will be among potential users, or whether new methods might be used in conjunction with, or instead of, condoms. This study will use a discrete choice experiment (DCE) to (1) explore potential users' preferences regarding HIV prevention products, (2) quantify the importance of product attributes and (3) predict the uptake of products to inform estimates of their potential impact on the HIV epidemic in South Africa. We consider preferences for oral pre-exposure prophylaxis; a vaginal microbicide gel; a long-acting vaginal ring; a SILCS diaphragm used in concert with gel; and a long-acting ARV-based injectable. This study will gather data from 4 populations: 200 women, 200 men, 200 adolescent girls (aged 16-17 years) and 200 female sex workers. The DCE attributes and design will be developed through a literature review, supplemented by a thematic analysis of qualitative focus group discussions. Extensive piloting will be carried out in each population through semistructured interviews. The final survey will be conducted using computer tablets via a household sample (for women, men and adolescents) and respondent-driven sampling (for female sex workers), and DCE data analysed using a range of multinomial logit models. This study has been approved by the University of the Witwatersrand Human Research Ethics Committee and the Research Ethics Committee at the London School of Hygiene and Tropical Medicine. Findings will be presented to international conferences and peer-reviewed journals. Meetings will be held with opinion leaders in South Africa, while results will be disseminated to participants in Ekurhuleni through a public meeting or newsletter. Published by the BMJ Publishing Group Limited. For permission to use (where

The Demand for Antiretroviral Drugs in the Illicit Marketplace: Implications for HIV disease management among vulnerable populations

PubMed Central

Tsuyuki, Kiyomi; Surratt, Hilary L.; Levi-Minzi, Maria A.; O’Grady, Catherine L.; Kurtz, Steven P.

2014-01-01

The diversion of antiretroviral medications (ARVs) has implications for the integrity and success of HIV care, however little is known about the ARV illicit market. This paper aimed to identify the motivations for buying illicit ARVs and to describe market dynamics. Semi-structured interviews (n=44) were conducted with substance-involved individuals living with HIV with a history of purchasing ARVs on the street. Grounded theory was used to code and analyze interviews. Motivations for buying ARVs on the illicit market were: to repurchase ARVs after having diverted them for money or drugs; having limited access or low quality health care; to replace lost or ruined ARVs; and to buy a back-up stock of ARVs. This study identified various structural barriers to HIV treatment and ARV adherence that incentivized ARV diversion. Findings highlight the need to improve patient-provider relationships, ensure continuity of care, and integrate services to engage and retain high-needs populations. PMID:25092512

The Demand for Antiretroviral Drugs in the Illicit Marketplace: Implications for HIV Disease Management Among Vulnerable Populations.

PubMed

Tsuyuki, Kiyomi; Surratt, Hilary L; Levi-Minzi, Maria A; O'Grady, Catherine L; Kurtz, Steven P

2015-05-01

The diversion of antiretroviral medications (ARVs) has implications for the integrity and success of HIV care, however little is known about the ARV illicit market. This paper aimed to identify the motivations for buying illicit ARVs and to describe market dynamics. Semi-structured interviews (n = 44) were conducted with substance-involved individuals living with HIV who have a history of purchasing ARVs on the street. Grounded theory was used to code and analyze interviews. Motivations for buying ARVs on the illicit market were: to repurchase ARVs after having diverted them for money or drugs; having limited access or low quality health care; to replace lost or ruined ARVs; and to buy a back-up stock of ARVs. This study identified various structural barriers to HIV treatment and ARV adherence that incentivized ARV diversion. Findings highlight the need to improve patient-provider relationships, ensure continuity of care, and integrate services to engage and retain high-needs populations.

Antiretroviral drug diversion links social vulnerability to poor medication adherence in substance abusing populations.

PubMed

Tsuyuki, Kiyomi; Surratt, Hilary L

2015-05-01

Antiretroviral (ARV) medication diversion to the illicit market has been documented in South Florida, and linked to sub-optimal adherence in people living with HIV. ARV diversion reflects an unmet need for care in vulnerable populations that have difficulty engaging in consistent HIV care due to competing needs and co-morbidities. This study applies the Gelberg-Andersen behavioral model of health care utilization for vulnerable populations to understand how social vulnerability is linked to ARV diversion and adherence. Cross-sectional data were collected from a targeted sample of vulnerable people living with HIV in South Florida between 2010 and 2012 (n = 503). Structured interviews collected quantitative data on ARV diversion, access and utilization of care, and ARV adherence. Logistic regression was used to estimate the goodness-of-fit of additive models that test domain fit. Linear regression was used to estimate the effects of social vulnerability and ARV diversion on ARV adherence. The best fitting model to predict ARV diversion identifies having a low monthly income and unstable HIV care as salient enabling factors that promote ARV diversion. Importantly, health care need factors did not protect against ARV diversion, evidence that immediate competing needs are prioritized even in the face of poor health for this sample. We also find that ARV diversion provides a link between social vulnerability and sub-optimal ARV adherence, with ARV diversion and domains from the Behavioral Model explaining 25 % of the variation in ARV adherence. Our analyses reveal great need to improve engagement in HIV care for vulnerable populations by strengthening enabling factors (e.g. patient-provider relationship) to improve retention in HIV care and ARV adherence for vulnerable populations.

Isolation and molecular characterization of newly emerging avian reovirus variants and novel strains in Pennsylvania, USA, 2011–2014

PubMed Central

Lu, Huaguang; Tang, Yi; Dunn, Patricia A.; Wallner-Pendleton, Eva A.; Lin, Lin; Knoll, Eric A.

2015-01-01

Avian reovirus (ARV) infections of broiler and turkey flocks have caused significant clinical disease and economic losses in Pennsylvania (PA) since 2011. Most of the ARV-infected birds suffered from severe arthritis, tenosynovitis, pericarditis and depressed growth or runting-stunting syndrome (RSS). A high morbidity (up to 20% to 40%) was observed in ARV-affected flocks, and the flock mortality was occasionally as high as 10%. ARV infections in turkeys were diagnosed for the first time in PA in 2011. From 2011 to 2014, a total of 301 ARV isolations were made from affected PA poultry. The molecular characterization of the Sigma C gene of 114 field isolates, representing most ARV outbreaks, revealed that only 21.93% of the 114 sequenced ARV isolates were in the same genotyping cluster (cluster 1) as the ARV vaccine strains (S1133, 1733, and 2048), whereas 78.07% of the sequenced isolates were in genotyping clusters 2, 3, 4, 5, and 6 (which were distinct from the vaccine strains) and represented newly emerging ARV variants. In particular, genotyping cluster 6 was a new ARV genotype that was identified for the first time in 10 novel PA ARV variants of field isolates. PMID:26469681

Isolation and molecular characterization of newly emerging avian reovirus variants and novel strains in Pennsylvania, USA, 2011-2014.

PubMed

Lu, Huaguang; Tang, Yi; Dunn, Patricia A; Wallner-Pendleton, Eva A; Lin, Lin; Knoll, Eric A

2015-10-15

Avian reovirus (ARV) infections of broiler and turkey flocks have caused significant clinical disease and economic losses in Pennsylvania (PA) since 2011. Most of the ARV-infected birds suffered from severe arthritis, tenosynovitis, pericarditis and depressed growth or runting-stunting syndrome (RSS). A high morbidity (up to 20% to 40%) was observed in ARV-affected flocks, and the flock mortality was occasionally as high as 10%. ARV infections in turkeys were diagnosed for the first time in PA in 2011. From 2011 to 2014, a total of 301 ARV isolations were made from affected PA poultry. The molecular characterization of the Sigma C gene of 114 field isolates, representing most ARV outbreaks, revealed that only 21.93% of the 114 sequenced ARV isolates were in the same genotyping cluster (cluster 1) as the ARV vaccine strains (S1133, 1733, and 2048), whereas 78.07% of the sequenced isolates were in genotyping clusters 2, 3, 4, 5, and 6 (which were distinct from the vaccine strains) and represented newly emerging ARV variants. In particular, genotyping cluster 6 was a new ARV genotype that was identified for the first time in 10 novel PA ARV variants of field isolates.

New estimate of valvuloarterial impedance in aortic valve stenosis: A cardiac magnetic resonance study.

PubMed

Soulat, Gilles; Kachenoura, Nadjia; Bollache, Emilie; Perdrix, Ludivine; Diebold, Benoit; Zhygalina, Valentina; Latremouille, Christian; Laurent, Stephane; Fabiani, Jean-Noel; Mousseaux, Elie

2017-03-01

Valvuloarterial impedance (Z VA ), estimating left ventricle (LV) afterload, has been proposed in transthoracic echocardiography (TTE) as a predictor of mortality in aortic valve stenosis (AVS). However, its calculation differs from arterial characteristic impedance (Z C ). Our aim was to apply the concept of Z C calculation to estimate Z VA from MR with carotid tonometry and to evaluate these indices through their associations with symptoms, LV diastolic function and aortic stiffness. In 40 patients with AVS (76 ± 13 years), Z VA-TI derived from velocity time integral and E/Ea were estimated by TTE. Z VA-INS , based on Z C formula, calculated as the instantaneous pressure gradient to peak flow ratio and aortic compliance were estimated by using MRI at 1.5 Tesla. Both Z VA estimates were higher in symptomatic than asymptomatic patients (707 ± 22 versus 579 ± 53 dyne.s/cm 5 , P = 0.031 for Z VA-INS and 4.35 ± 0.16 versus 3.33 ± 0.38 mmHg.m 2 /mL, P = 0.018 for Z VA-TI ). Although they were both associated with aortic compliance (r = -0.45; P = 0.006 for Z VA-INS and r = -0.43; P = 0.008 for Z VA-TI ) only Z VA-INS was associated with E/Ea (r = 0.50; P < 0.001). In multivariate analysis to identify determinants of E/Ea, a model including age, mean blood pressure, LV ejection fraction, LV mass, and aortic valve area was performed (R 2  = 0.41; P < 0.01). When Z VA-INS was added to the model, its overall significance was higher R 2  = 0.56 (P < 0.01) and Z VA-INS and LV mass were the only significant determinants. Z VA-INS was more strongly associated with diastolic dysfunction than usual parameters quantifying AVS severity. This new Z VA estimate could improve LV afterload evaluation. 1 J. Magn. Reson. Imaging 2017;45:795-803. © 2016 International Society for Magnetic Resonance in Medicine.

High levels of the AR-V7 Splice Variant and Co-Amplification of the Golgi Protein Coding YIPF6 in AR Amplified Prostate Cancer Bone Metastases.

PubMed

Djusberg, Erik; Jernberg, Emma; Thysell, Elin; Golovleva, Irina; Lundberg, Pia; Crnalic, Sead; Widmark, Anders; Bergh, Anders; Brattsand, Maria; Wikström, Pernilla

2017-05-01

The relation between androgen receptor (AR) gene amplification and other mechanisms behind castration-resistant prostate cancer (CRPC), such as expression of constitutively active AR variants and steroid-converting enzymes has been poorly examined. Specific aim was to examine AR amplification in PC bone metastases and to explore molecular and functional consequences of this, with the long-term goal of identifying novel molecular targets for treatment. Gene amplification was assessed by fluorescence in situ hybridization in cryo-sections of clinical PC bone metastases (n = 40) and by PCR-based copy number variation analysis. Whole genome mRNA expression was analyzed using H12 Illumina Beadchip arrays and specific transcript levels were quantified by qRT-PCR. Protein localization was analyzed using immunohistochemistry and confocal microscopy. The YIPF6 mRNA expression was transiently knocked down and stably overexpressed in the 22Rv1 cell line as representative for CRPC, and effects on cell proliferation, colony formation, migration, and invasion were determined in vitro. Extracellular vesicles (EVs) were isolated from cell cultures using size-exclusion chromatography and enumerated by nanoparticle tracking analysis. Protein content was identified by LC-MS/MS analysis. Blood coagulation was measured as activated partial thromboplastin time (APTT). Functional enrichment analysis was performed using the MetaCore software. AR amplification was detected in 16 (53%) of the bone metastases examined from CRPC patients (n = 30), and in none from the untreated patients (n = 10). Metastases with AR amplification showed high AR and AR-V7 mRNA levels, increased nuclear AR immunostaining, and co-amplification of genes such as YIPF6 in the AR proximity at Xq12. The YIPF6 protein was localized to the Golgi apparatus. YIPF6 overexpression in 22Rv1 cells resulted in reduced cell proliferation and colony formation, and in enhanced EV secretion. EVs from YIPF6

Teaching Critical Thinking by Asking "Could Lincoln Be Elected Today?"

ERIC Educational Resources Information Center

Jamieson, Kathleen Hall

2012-01-01

Because in his Gettysburg Address, President Abraham Lincoln said, "we here highly resolve that these dead shall not have died in vain," and "...that government of the people, by the people, for the people, shall not perish from the earth," it is accurate to report that he spoke the words "perish from the earth" and "died in vain." But if his 1864…

Antiretroviral Drug Use in a Cohort of HIV-Uninfected Women in the United States: HIV Prevention Trials Network 064.

PubMed

Chen, Iris; Clarke, William; Ou, San-San; Marzinke, Mark A; Breaud, Autumn; Emel, Lynda M; Wang, Jing; Hughes, James P; Richardson, Paul; Haley, Danielle F; Lucas, Jonathan; Rompalo, Anne; Justman, Jessica E; Hodder, Sally L; Eshleman, Susan H

2015-01-01

Antiretroviral (ARV) drug use was analyzed in HIV-uninfected women in an observational cohort study conducted in 10 urban and periurban communities in the United States with high rates of poverty and HIV infection. Plasma samples collected in 2009-2010 were tested for the presence of 16 ARV drugs. ARV drugs were detected in samples from 39 (2%) of 1,806 participants: 27/181 (15%) in Baltimore, MD and 12/179 (7%) in Bronx, NY. The ARV drugs detected included different combinations of non-nucleoside reverse transcriptase inhibitors and protease inhibitors (1-4 drugs/sample). These data were analyzed in the context of self-reported data on ARV drug use. None of the 39 women who had ARV drugs detected reported ARV drug use at any study visit. Further research is needed to evaluate ARV drug use by HIV-uninfected individuals.

Antiretroviral Drug Use in a Cross-Sectional Population Survey in Africa: NIMH Project Accept (HPTN 043).

PubMed

Fogel, Jessica M; Clarke, William; Kulich, Michal; Piwowar-Manning, Estelle; Breaud, Autumn; Olson, Matthew T; Marzinke, Mark A; Laeyendecker, Oliver; Fiamma, Agnès; Donnell, Deborah; Mbwambo, Jessie K K; Richter, Linda; Gray, Glenda; Sweat, Michael; Coates, Thomas J; Eshleman, Susan H

2017-02-01

Antiretroviral (ARV) drug treatment benefits the treated individual and can prevent HIV transmission. We assessed ARV drug use in a community-randomized trial that evaluated the impact of behavioral interventions on HIV incidence. Samples were collected in a cross-sectional survey after a 3-year intervention period. ARV drug testing was performed using samples from HIV-infected adults at 4 study sites (Zimbabwe; Tanzania; KwaZulu-Natal and Soweto, South Africa; survey period 2009-2011) using an assay that detects 20 ARV drugs (6 nucleoside/nucleotide reverse transcriptase inhibitors, 3 nonnucleoside reverse transcriptase inhibitors, and 9 protease inhibitors; maraviroc; raltegravir). ARV drugs were detected in 2011 (27.4%) of 7347 samples; 88.1% had 1 nonnucleoside reverse transcriptase inhibitors ± 1-2 nucleoside/nucleotide reverse transcriptase inhibitors. ARV drug detection was associated with sex (women>men), pregnancy, older age (>24 years), and study site (P < 0.0001 for all 4 variables). ARV drugs were also more frequently detected in adults who were widowed (P = 0.006) or unemployed (P = 0.02). ARV drug use was more frequent in intervention versus control communities early in the survey (P = 0.01), with a significant increase in control (P = 0.004) but not in intervention communities during the survey period. In KwaZulu-Natal, a 1% increase in ARV drug use was associated with a 0.14% absolute decrease in HIV incidence (P = 0.018). This study used an objective, biomedical approach to assess ARV drug use on a population level. This analysis identified factors associated with ARV drug use and provided information on ARV drug use over time. ARV drug use was associated with lower HIV incidence at 1 study site.

Antiretroviral Drug Use in a Cohort of HIV-Uninfected Women in the United States: HIV Prevention Trials Network 064

PubMed Central

Chen, Iris; Clarke, William; Ou, San-San; Marzinke, Mark A.; Breaud, Autumn; Emel, Lynda M.; Wang, Jing; Hughes, James P.; Richardson, Paul; Haley, Danielle F.; Lucas, Jonathan; Rompalo, Anne; Justman, Jessica E.; Hodder, Sally L.; Eshleman, Susan H.

2015-01-01

Antiretroviral (ARV) drug use was analyzed in HIV-uninfected women in an observational cohort study conducted in 10 urban and periurban communities in the United States with high rates of poverty and HIV infection. Plasma samples collected in 2009–2010 were tested for the presence of 16 ARV drugs. ARV drugs were detected in samples from 39 (2%) of 1,806 participants: 27/181 (15%) in Baltimore, MD and 12/179 (7%) in Bronx, NY. The ARV drugs detected included different combinations of non-nucleoside reverse transcriptase inhibitors and protease inhibitors (1–4 drugs/sample). These data were analyzed in the context of self-reported data on ARV drug use. None of the 39 women who had ARV drugs detected reported ARV drug use at any study visit. Further research is needed to evaluate ARV drug use by HIV-uninfected individuals. PMID:26445283

Targeting chromatin binding regulation of constitutively active AR variants to overcome prostate cancer resistance to endocrine-based therapies

PubMed Central

Chan, Siu Chiu; Selth, Luke A.; Li, Yingming; Nyquist, Michael D.; Miao, Lu; Bradner, James E.; Raj, Ganesh V.; Tilley, Wayne D.; Dehm, Scott M.

2015-01-01

Androgen receptor (AR) variants (AR-Vs) expressed in prostate cancer (PCa) lack the AR ligand binding domain (LBD) and function as constitutively active transcription factors. AR-V expression in patient tissues or circulating tumor cells is associated with resistance to AR-targeting endocrine therapies and poor outcomes. Here, we investigated the mechanisms governing chromatin binding of AR-Vs with the goal of identifying therapeutic vulnerabilities. By chromatin immunoprecipitation and sequencing (ChIP-seq) and complementary biochemical experiments, we show that AR-Vs display a binding preference for the same canonical high-affinity androgen response elements (AREs) that are preferentially engaged by AR, albeit with lower affinity. Dimerization was an absolute requirement for constitutive AR-V DNA binding and transcriptional activation. Treatment with the bromodomain and extraterminal (BET) inhibitor JQ1 resulted in inhibition of AR-V chromatin binding and impaired AR-V driven PCa cell growth in vitro and in vivo. Importantly, this was associated with a novel JQ1 action of down-regulating AR-V transcript and protein expression. Overall, this study demonstrates that AR-Vs broadly restore AR chromatin binding events that are otherwise suppressed during endocrine therapy, and provides pre-clinical rationale for BET inhibition as a strategy for inhibiting expression and chromatin binding of AR-Vs in PCa. PMID:25908785

Ethical use of antiretroviral resources for HIV prevention in resource poor settings.

PubMed

Rennie, Stuart

2013-08-01

The effectiveness of antiretroviral regimes (ARVs) to reduce risk of HIV transmission from mother to child and as post-exposure prophylaxis has been known for almost two decades. Recent research indicates ARVs can also reduce the risk of HIV transmission via sexual intercourse in two other ways. With pre-exposure prophylaxis (PrEP), ARVs are used to reduce risk of HIV acquisition among persons who are HIV negative and significantly exposed to the virus. With treatment as prevention (TasP), ARVs are used to reduce risk of HIV transmission from persons who are already HIV positive. The development of these new prevention strategies raises a rationing problem: given the chronic shortage of ARVs for HIV-infected persons in need of treatment, is it ethically justified to allocate ARVs for PrEP and/or TasP? This article examines the intuitively appealing view that allocation of ARVs for treatment should be the highest priority, the use of ARVs for TasP should be a secondary priority, and that utilizing ARVs for PrEP would be unethical. I will argue that selective, evidence-based allocation of ARVs for prevention in certain cases could be ethically justified even when there is insufficient anti-retroviral access for all those needing it for treatment. © 2013 John Wiley & Sons Ltd.

Antiretroviral drug use in a cross-sectional population survey in Africa: NIMH Project Accept (HPTN 043)

PubMed Central

Fogel, Jessica M.; Clarke, William; Kulich, Michal; Piwowar-Manning, Estelle; Breaud, Autumn; Olson, Matthew T.; Marzinke, Mark A.; Laeyendecker, Oliver; Fiamma, Agnès; Donnell, Deborah; Mbwambo, Jessie K. K.; Richter, Linda; Gray, Glenda; Sweat, Michael; Coates, Thomas J.; Eshleman, Susan H.

2016-01-01

Background Antiretroviral (ARV) drug treatment benefits the treated individual and can prevent HIV transmission. We assessed ARV drug use in a community-randomized trial that evaluated the impact of behavioral interventions on HIV incidence. Methods Samples were collected in a cross-sectional survey after a 3-year intervention period. ARV drug testing was performed using samples from HIV-infected adults at four study sites (Zimbabwe; Tanzania; KwaZulu-Natal and Soweto, South Africa; survey period 2009–2011), using an assay that detects 20 ARV drugs (6 nucleoside/nucleotide reverse transcriptase inhibitors [NRTIs]; 3 non-nucleoside reverse transcriptase inhibitors [NNRTIs]; 9 protease inhibitors; maraviroc; raltegravir). Results ARV drugs were detected in 2,011 (27.4%) of 7,347 samples; 88.1% had 1 NNRTI +/− 1–2 NRTIs. ARV drug detection was associated with sex (women>men), pregnancy, older age (>24 years), and study site (p<0.0001 for all four variables). ARV drugs were also more frequently detected in adults who were widowed (p=0.006) or unemployed (p=0.02). ARV drug use was more frequent in intervention versus control communities early in the survey (p=0.01), with a significant increase in control (p=0.004) but not in intervention communities during the survey period. In KwaZulu-Natal, a 1% increase in ARV drug use was associated with a 0.14% absolute decrease in HIV incidence (p=0.018). Conclusions This study used an objective, biomedical approach to assess ARV drug use on a population level. This analysis identified factors associated with ARV drug use and provided information on ARV drug use over time. ARV drug use was associated with lower HIV incidence at one study site. PMID:27828875

Use of IgY antibody to recombinant avian reovirus σC protein in the virus diagnostics.

PubMed

Jung, K M; Bae, E H; Jung, Y T; Kim, J W

2014-01-01

Avian reovirus (ARV) is an important agent of several diseases causing considerable losses in poultry farming. An outer capsid protein (σC) of ARV, is known as a virus-cell attachment protein essential for virus infectivity. In this study, the σC gene of ARV was cloned and expressed in Escherichia coli. The expressed recombinant protein was used as immunogen for raising a specific IgY antibody in laying hens. At 14 weeks post immunization, the antibody titers in serum and egg yolk reached 302,000 and 355,000, respectively. The IgY antibody was capable to neutralize ARV in BHK-21 cells and it strongly reacted in ELISA with ARV but not with heterologous viruses. The IgY antibody detected ARV in field samples of infected animal tissues in dot blot assay. These results suggest that an efficient, economic and rapid diagnostics of ARV can be performed routinely using the IgY antibody against a recombinant ARV σC protein.

Global strategies to reduce the price of antiretroviral medicines: evidence from transactional databases.

PubMed

Waning, Brenda; Kaplan, Warren; King, Alexis C; Lawrence, Danielle A; Leufkens, Hubert G; Fox, Matthew P

2009-07-01

To estimate the impact of global strategies, such as pooled procurement arrangements, third-party price negotiation and differential pricing, on reducing the price of antiretrovirals (ARVs), which currently hinders universal access to HIV/AIDS treatment. We estimated the impact of global strategies to reduce ARV prices using data on 7253 procurement transactions (July 2002-October 2007) from databases hosted by WHO and the Global Fund to Fight AIDS, Tuberculosis and Malaria. For 19 of 24 ARV dosage forms, we detected no association between price and volume purchased. For the other five ARVs, high-volume purchases were 4-21% less expensive than medium- or low-volume purchases. Nine of 13 generic ARVs were priced 6-36% lower when purchased under the Clinton Foundation HIV/AIDS Initiative (CHAI). Fifteen of 18 branded ARVs were priced 23-498% higher for differentially priced purchases compared with non-CHAI generic purchases. However, two branded, differentially priced ARVs were priced 63% and 73% lower, respectively, than generic non-CHAI equivalents. Large purchase volumes did not necessarily result in lower ARV prices. Although current plans for pooled procurement will further increase purchase volumes, savings are uncertain and should be balanced against programmatic costs. Third-party negotiation by CHAI resulted in lower generic ARV prices. Generics were less expensive than differentially priced branded ARVs, except where little generic competition exists. Alternative strategies for reducing ARV prices, such as streamlining financial management systems, improving demand forecasting and removing barriers to generics, should be explored.

Safety of Perinatal Exposure to Antiretroviral Medications: Developmental Outcomes in Infants

PubMed Central

Sirois, Patricia A.; Huo, Yanling; Williams, Paige L.; Malee, Kathleen; Garvie, Patricia A.; Kammerer, Betsy; Rich, Kenneth; Van Dyke, Russell B.; Nozyce, Molly L.

2013-01-01

Background This study evaluated effects of perinatal exposure to antiretroviral (ARV) medications on neurodevelopment of HIV-exposed, uninfected infants. Methods HIV-exposed, uninfected infants (age 9-15 months) enrolled in SMARTT, a multisite prospective surveillance study, completed the Bayley Scales of Infant and Toddler Development—Third Edition (Bayley-III), assessing cognition, language, motor skills, social-emotional development, and adaptive behavior. Linear regression models were used to evaluate associations between Bayley-III outcomes in infants with and without perinatal and neonatal ARV exposure, by regimen (combination ARV [cARV] versus non-cARV), type of regimen (defined by drug class), and individual ARVs (for infants with cARV exposure), adjusting for maternal and infant health and demographic covariates. Results As of May 2010, 374 infants had valid Bayley-III evaluations. Median age at testing was 12.7 months; 49% male, 79% black, 16% Hispanic. Seventy-nine percent were exposed to regimens containing protease inhibitors (PIs; 9% of PI-containing regimens also included non-nucleoside reverse transcriptase inhibitors [NNRTIs]), 5% to regimens containing NNRTIs (without PI), and 14% to regimens containing only nucleoside reverse transcriptase inhibitors (NRTIs). Overall, 83% were exposed to cARV. No Bayley-III outcome was significantly associated with overall exposure to cARV, ARV regimen, or neonatal prophylaxis. For individual ARVs, following sensitivity analyses, the adjusted group mean on the Language domain was within age expectations but significantly lower for infants with perinatal exposure to atazanavir (p=0.01). Conclusions These results support the safety of perinatal ARV use. Continued monitoring for adverse neurodevelopmental outcomes in older children is warranted, and the safety of atazanavir merits further study. PMID:23340561

Global strategies to reduce the price of antiretroviral medicines: evidence from transactional databases

PubMed Central

Kaplan, Warren; King, Alexis C; Lawrence, Danielle A; Leufkens, Hubert G; Fox, Matthew P

2009-01-01

Abstract Objective To estimate the impact of global strategies, such as pooled procurement arrangements, third-party price negotiation and differential pricing, on reducing the price of antiretrovirals (ARVs), which currently hinders universal access to HIV/AIDS treatment. Methods We estimated the impact of global strategies to reduce ARV prices using data on 7253 procurement transactions (July 2002–October 2007) from databases hosted by WHO and the Global Fund to Fight AIDS, Tuberculosis and Malaria. Findings For 19 of 24 ARV dosage forms, we detected no association between price and volume purchased. For the other five ARVs, high-volume purchases were 4–21% less expensive than medium- or low-volume purchases. Nine of 13 generic ARVs were priced 6–36% lower when purchased under the Clinton Foundation HIV/AIDS Initiative (CHAI). Fifteen of 18 branded ARVs were priced 23–498% higher for differentially priced purchases compared with non-CHAI generic purchases. However, two branded, differentially priced ARVs were priced 63% and 73% lower, respectively, than generic non-CHAI equivalents. Conclusion Large purchase volumes did not necessarily result in lower ARV prices. Although current plans for pooled procurement will further increase purchase volumes, savings are uncertain and should be balanced against programmatic costs. Third-party negotiation by CHAI resulted in lower generic ARV prices. Generics were less expensive than differentially priced branded ARVs, except where little generic competition exists. Alternative strategies for reducing ARV prices, such as streamlining financial management systems, improving demand forecasting and removing barriers to generics, should be explored. PMID:19649366

Antiretroviral treatment is associated with iron deficiency in HIV-infected Malawian women that is mitigated with supplementation, but is not associated with infant iron deficiency during 24 weeks of exclusive breastfeeding

PubMed Central

Widen, Elizabeth M; Bentley, Margaret E; Chasela, Charles S; Kayira, Dumbani; Flax, Valerie L; Kourtis, Athena P; Ellington, Sascha R; Kacheche, Zebrone; Tegha, Gerald; Jamieson, Denise J; van der Horst, Charles M; Allen, Lindsay H; Shahab-Ferdows, Setareh; Adair, Linda S

2015-01-01

Objective In resource-limited settings without safe alternatives to breastfeeding, the WHO recommends exclusive breastfeeding and antiretroviral (ARV) prophylaxis. Given the high prevalence of anemia among HIV-infected women, mothers and their infants (via fetal iron accretion) may be at risk of iron deficiency. We assessed the effects of maternal micronutrient-fortified lipid-based nutrient supplements (LNS) and maternal ARV treatment or infant ARV prophylaxis on maternal and infant iron status during exclusive breastfeeding from birth to 24 weeks. Methods The Breastfeeding, Antiretrovirals, and Nutrition Study was a randomized controlled trial conducted in Lilongwe, Malawi from 2004-2010. HIV-infected mothers (CD4>200 cells/ul) and their infants were randomly assigned to 28-week interventions: maternal-LNS/maternal-ARV (n=424), maternal-LNS/infant-ARV (n=426), maternal-LNS (n=334), maternal-ARV (n=425), infant-ARV (n=426), or control (n=334). Longitudinal models tested intervention effects on hemoglobin (Hb). In a subsample (n=537) with multiple iron indicators, intervention effects on Hb, transferrin receptors (TfR) and ferritin were tested with linear and Poisson regression. Results In longitudinal models, LNS effects on maternal and infant Hb were minimal. In subsample mothers, maternal ARVs were associated with tissue iron depletion (TfR>8.3 mg/L) (Risk ratio (RR): 3.1, p<0.01), but not in ARV-treated mothers receiving LNS (p=0.17). LNS without ARVs, was not associated with iron deficiency or anemia (p>0.1). In subsample infants, interventions were not associated with impaired iron status (all p-values>0.1). Conclusions Maternal ARV treatment with protease inhibitors is associated with maternal tissue iron depletion; but LNS mitigates adverse effects. ARVs do not appear to influence infant iron status; however, extended use needs to be evaluated. PMID:25723140

Antiretrovirals for low income countries: an analysis of the commercial viability of a highly competitive market

PubMed Central

2013-01-01

Background The price of antiretroviral drugs (ARVs) in low income countries declined steadily in recent years. This raises concerns about the commercial viability of the market of ARVs in low income countries. Methods Using 2 costing scenarios, we modeled the production cost of the most commonly used ARVs in low income countries in 2010 and 2012, and assessed whether, at the median price paid by low income countries, their manufacturers would still make profits. By interviews we consulted 11 generic manufacturers on the current state of the ARV market, and on what would be required to ensure their continued commitment to supply ARVs to low income countries. Results Using the lowest prices for active pharmaceutical ingredients (API) quoted to WHO, and applying published assumptions about the production cost of ARVs, our baseline estimate was that Indian generic manufacturers would have made profits on only 1 out of 13 formulations of ARVs in both 2010 and 2012, and publicly owned manufacturers would have made profits on 5 and 3 out of 13 formulations in 2010 and 2012, respectively. We needed to assume a 20% and a 40% lower API cost for our model to predict that publicly owned and Indian manufacturers, respectively, would make profits on the sale of the majority of their ARVs. Between 2010 and 2012, we estimate that - across the ARV portfolio - the gross profit on sales of ARVs to low income countries decreased with between 6% and 7% of their sales price. Generic manufacturers consider that current prices are unsustainable. They suggested amendments to the tender procedures, simplified regulatory procedures, improved forecasting, and simplification of the ARV guidelines as critical improvements to maintain a viable ARV market. Conclusions While recent price decreases indicate that there is still space for price reduction, our estimate that gross profit margin on sales decreased by 6 to 7% between 2010 and 2012 lends credibility to assertions by generic manufacturers

Antiretrovirals for low income countries: an analysis of the commercial viability of a highly competitive market.

PubMed

Nakakeeto, Olive N; Elliott, Brian V

2013-02-15

The price of antiretroviral drugs (ARVs) in low income countries declined steadily in recent years. This raises concerns about the commercial viability of the market of ARVs in low income countries. Using 2 costing scenarios, we modeled the production cost of the most commonly used ARVs in low income countries in 2010 and 2012, and assessed whether, at the median price paid by low income countries, their manufacturers would still make profits. By interviews we consulted 11 generic manufacturers on the current state of the ARV market, and on what would be required to ensure their continued commitment to supply ARVs to low income countries. Using the lowest prices for active pharmaceutical ingredients (API) quoted to WHO, and applying published assumptions about the production cost of ARVs, our baseline estimate was that Indian generic manufacturers would have made profits on only 1 out of 13 formulations of ARVs in both 2010 and 2012, and publicly owned manufacturers would have made profits on 5 and 3 out of 13 formulations in 2010 and 2012, respectively. We needed to assume a 20% and a 40% lower API cost for our model to predict that publicly owned and Indian manufacturers, respectively, would make profits on the sale of the majority of their ARVs. Between 2010 and 2012, we estimate that--across the ARV portfolio--the gross profit on sales of ARVs to low income countries decreased with between 6% and 7% of their sales price. Generic manufacturers consider that current prices are unsustainable. They suggested amendments to the tender procedures, simplified regulatory procedures, improved forecasting, and simplification of the ARV guidelines as critical improvements to maintain a viable ARV market. While recent price decreases indicate that there is still space for price reduction, our estimate that gross profit margin on sales decreased by 6 to 7% between 2010 and 2012 lends credibility to assertions by generic manufacturers that the ARV market in low income

Autophagy inhibitors reduce avian-reovirus-mediated apoptosis in cultured cells and in chicken embryos.

PubMed

Duan, Shipeng; Cheng, Jinghua; Li, Chenxi; Yu, Liping; Zhang, Xiaorong; Jiang, Ke; Wang, Yupeng; Xu, Jiansheng; Wu, Yantao

2015-07-01

Avian reovirus (ARV)-induced apoptosis contributes to the pathogenesis of reovirus in infected chickens. However, methods for effectively reducing ARV-triggered apoptosis remain to be explored. Here, we show that pretreatment with chloroquine (CQ) or E64d plus pepstatin A decreases ARV-mediated apoptosis in chicken DF-1 cells. By acting as autophagy inhibitors, CQ and E64d plus pepstatin A increase microtubule-associated protein 1 light chain 3-II (LC3II) accumulation in ARV-infected cells, which results in decreased ARV protein synthesis and virus yield and thereby contributes to the reduction of apoptosis. Furthermore, ARV-mediated apoptosis in the bursa, heart and intestines of chicken embryos is attenuated by CQ and E64d plus pepstatin A treatment. Importantly, treatment with these autophagy inhibitors increases the survival of infected chicken embryos. Together, our data suggest that pharmacological inhibition of autophagy might represent a novel strategy for reducing ARV-mediated apoptosis.

Mobile phone use for a social strategy to improve antiretroviral refill experience at a low-resource HIV clinic: patient responses from Nigeria.

PubMed

Adetunji, Adedotun A; Muyibi, Sufiyan A; Imhansoloeva, Martins; Ibraheem, Olusola M; Sunmola, Adegbenga; Kolawole, Olubunmi O; Akinrinsola, Oluwasina O; Ojo-Osagie, James O; Mosuro, Olusola A; Abiolu, Josephine O; Irabor, Achiaka E; Okonkwo, Prosper; Adewole, Isaac F; Taiwo, Babafemi O

2017-05-01

In sub-Saharan African areas where antiretroviral (ARV) drugs are not available through community pharmacies, clinic-based pharmacies are often the primary source of ARV drug refills. Social pressure is mounting on treatment providers to adjust ARV refill services towards user-friendly approaches which prioritize patients' convenience and engage their resourcefulness. By this demand, patients may be signalling dissatisfaction with the current provider-led model of monthly visits to facility-based pharmacies for ARV refill. Mobile phones are increasingly popular in sub-Saharan Africa, and have been used to support ARV treatment goals in this setting. A patient-centred response to on-going social pressure requires treatment providers to view ARV refill activities through the eyes of patients who are negotiating the challenges of day-to-day life while contemplating their next refill appointment. Using focus groups of five categories of adult patients receiving combination ARV therapy, we conducted this cross-sectional qualitative study to provide insight into modifiable gaps between patients' expectations and experiences of the use of mobile phones in facility-based ARV refill service at a public HIV clinic in Nigeria. A notable finding was patients' preference for harnessing informal social support (through intermediaries with mobile phones) to maintain adherence to ARV refill appointments when they could not present in person. This evolving social support strategy also has the potential to enhance defaulter tracking. Our study findings may inform the development of ARV refill strategies and the design of future qualitative studies on client-provider communication by mobile phones in under-resourced HIV treatment programmes.

Antiretroviral Drugs in Meconium: Detection for Different Gestational Periods of Exposure.

PubMed

Himes, Sarah K; Tassiopoulos, Katherine; Yogev, Ram; Huestis, Marilyn A

2015-08-01

To determine whether antiretroviral (ARV) medications can be detected in meconium from second or third trimester, labor and delivery (L&D), or postnatal exposures. Twenty ARV medications were quantified by liquid chromatography-tandem mass spectrometry in 598 meconium samples from uninfected infants born to pregnant women with HIV enrolled in the Pediatric HIV/AIDS Cohort Study. ARV detection in meconium following third trimester exposure was 85.7%-94.4% for all ARVs except stavudine (0%, n = 2), likely because of low doses and a high limit for quantification. Of 107 samples with some second trimester only ARV exposures, meconium was positive for only lopinavir, tenofovir, or efavirenz in 11.8%-14.3% of exposed neonates; administration of these ARVs occurred between gestational weeks 25-28 in the positive samples. Days without lopinavir or tenofovir before delivery significantly correlated with decreasing concentrations of lopinavir and tenofovir in meconium. Tenofovir and lamivudine concentrations significantly correlated with increasing gestational age among infants with continuous second and third trimester exposure. Zidovudine given during L&D or for neonatal prophylaxis was detected in 95.1% and 94.6% of meconium samples, respectively. Changes in ARV treatments during pregnancy offered a unique opportunity to investigate ARV detection in meconium. ARVs in meconium primarily reflect third trimester ARV exposures, although 6 of 107 second trimester only exposures were detected. Zidovudine administration during L&D was detected in meconium indicating potential urine contamination or rapid incorporation into meconium. These data will improve interpretation of meconium drug test results. Published by Elsevier Inc.

Targeting AR Variant-Coactivator Interactions to Exploit Prostate Cancer Vulnerabilities.

PubMed

Magani, Fiorella; Peacock, Stephanie O; Rice, Meghan A; Martinez, Maria J; Greene, Ann M; Magani, Pablo S; Lyles, Rolando; Weitz, Jonathan R; Burnstein, Kerry L

2017-11-01

Castration-resistant prostate cancer (CRPC) progresses rapidly and is incurable. Constitutively active androgen receptor splice variants (AR-Vs) represent a well-established mechanism of therapeutic resistance and disease progression. These variants lack the AR ligand-binding domain and, as such, are not inhibited by androgen deprivation therapy (ADT), which is the standard systemic approach for advanced prostate cancer. Signaling by AR-Vs, including the clinically relevant AR-V7, is augmented by Vav3, an established AR coactivator in CRPC. Using mutational and biochemical studies, we demonstrated that the Vav3 Diffuse B-cell lymphoma homology (DH) domain interacted with the N-terminal region of AR-V7 (and full length AR). Expression of the Vav3 DH domain disrupted Vav3 interaction with and enhancement of AR-V7 activity. The Vav3 DH domain also disrupted AR-V7 interaction with other AR coactivators: Src1 and Vav2, which are overexpressed in PC. This Vav3 domain was used in proof-of-concept studies to evaluate the effects of disrupting the interaction between AR-V7 and its coactivators on CRPC cells. This disruption decreased CRPC cell proliferation and anchorage-independent growth, caused increased apoptosis, decreased migration, and resulted in the acquisition of morphological changes associated with a less aggressive phenotype. While disrupting the interaction between FL-AR and its coactivators decreased N-C terminal interaction, disrupting the interaction of AR-V7 with its coactivators decreased AR-V7 nuclear levels. Implications: This study demonstrates the potential therapeutic utility of inhibiting constitutively active AR-V signaling by disrupting coactivator binding. Such an approach is significant, as AR-Vs are emerging as important drivers of CRPC that are particularly recalcitrant to current therapies. Mol Cancer Res; 15(11); 1469-80. ©2017 AACR . ©2017 American Association for Cancer Research.

Factors influencing global antiretroviral procurement prices.

PubMed

Wirtz, Veronika J; Forsythe, Steven; Valencia-Mendoza, Atanacio; Bautista-Arredondo, Sergio

2009-11-18

Antiretroviral medicines (ARVs) are one of the most costly parts of HIV/AIDS treatment. Many countries are struggling to provide universal access to ARVs for all people living with HIV and AIDS. Although substantial price reductions of ARVs have occurred, especially between 2002 and 2008, achieving sustainable access for the next several decades remains a major challenge for most low- and middle-income countries. The objectives of the present study were twofold: first, to analyze global ARV prices between 2005 and 2008 and associated factors, particularly procurement methods and key donor policies on ARV procurement efficiency; second, to discuss the options of procurement processes and policies that should be considered when implementing or reforming access to ARV programs. An ARV-medicines price-analysis was carried out using the Global Price Reporting Mechanism from the World Health Organization. For a selection of 12 ARVs, global median prices and price variation were calculated. Linear regression models for each ARV were used to identify factors that were associated with lower procurement prices. Logistic regression models were used to identify the characteristics of those countries which procure below the highest and lowest direct manufactured costs. Three key factors appear to have an influence on a country's ARV prices: (a) whether the product is generic or not; (b) the socioeconomic status of the country; (c) whether the country is a member of the Clinton HIV/AIDS Initiative. Factors which did not influence procurement below the highest direct manufactured costs were HIV prevalence, procurement volume, whether the country belongs to the least developed countries or a focus country of the United States President's Emergency Plan For AIDS Relief. One of the principal mechanisms that can help to lower prices for ARV over the next several decades is increasing procurement efficiency. Benchmarking prices could be one useful tool to achieve this.

Factors influencing global antiretroviral procurement prices

PubMed Central

2009-01-01

Background Antiretroviral medicines (ARVs) are one of the most costly parts of HIV/AIDS treatment. Many countries are struggling to provide universal access to ARVs for all people living with HIV and AIDS. Although substantial price reductions of ARVs have occurred, especially between 2002 and 2008, achieving sustainable access for the next several decades remains a major challenge for most low- and middle-income countries. The objectives of the present study were twofold: first, to analyze global ARV prices between 2005 and 2008 and associated factors, particularly procurement methods and key donor policies on ARV procurement efficiency; second, to discuss the options of procurement processes and policies that should be considered when implementing or reforming access to ARV programs. Methods An ARV-medicines price-analysis was carried out using the Global Price Reporting Mechanism from the World Health Organization. For a selection of 12 ARVs, global median prices and price variation were calculated. Linear regression models for each ARV were used to identify factors that were associated with lower procurement prices. Logistic regression models were used to identify the characteristics of those countries which procure below the highest and lowest direct manufactured costs. Results Three key factors appear to have an influence on a country's ARV prices: (a) whether the product is generic or not; (b) the socioeconomic status of the country; (c) whether the country is a member of the Clinton HIV/AIDS Initiative. Factors which did not influence procurement below the highest direct manufactured costs were HIV prevalence, procurement volume, whether the country belongs to the least developed countries or a focus country of the United States President's Emergency Plan For AIDS Relief. Conclusion One of the principal mechanisms that can help to lower prices for ARV over the next several decades is increasing procurement efficiency. Benchmarking prices could be one useful

Presence of Apis Rhabdovirus-1 in Populations of Pollinators and Their Parasites from Two Continents.

PubMed

Levin, Sofia; Galbraith, David; Sela, Noa; Erez, Tal; Grozinger, Christina M; Chejanovsky, Nor

2017-01-01

The viral ecology of bee communities is complex, where viruses are readily shared among co-foraging bee species. Additionally, in honey bees ( Apis mellifera ), many viruses are transmitted - and their impacts exacerbated - by the parasitic Varroa destructor mite. Thus far, the viruses found to be shared across bee species and transmitted by V. destructor mites are positive-sense single-stranded RNA viruses. Recently, a negative-sense RNA enveloped virus, Apis rhabdovirus-1 (ARV-1), was found in A. mellifera honey bees in Africa, Europe, and islands in the Pacific. Here, we describe the identification - using a metagenomics approach - of ARV-1 in two bee species ( A. mellifera and Bombus impatiens ) and in V. destructor mites from populations collected in the United States and Israel. We confirmed the presence of ARV-1 in pools of A. mellifera , B. impatiens , and V. destructor from Israeli and U.S. populations by RT-PCR and found that it can reach high titers in individual honey bees and mites (10 7 -10 8 viral genomic copies per individual). To estimate the prevalence of ARV-1 in honey bee populations, we screened 104 honey bee colonies across Israel, with 21 testing ARV-1-positive. Tagged-primer-mediated RT-PCR analysis detected the presence of the positive-sense ARV-1 RNA in A. mellifera and V. destructor , indicating that ARV-1 replicates in both hosts. This is the first report of the presence of ARV-1 in B. impatiens and of the replication of a rhabdovirus in A. mellifera and V. destructor . Our data suggest that Varroa mites could act as an ARV-1 vector; however, the presence of ARV-1 in B. impatiens (which are not parasitized by Varroa ) suggests that it may not require the mite for transmission and ARV-1 may be shared among co-foraging bee species. Given that ARV-1 is found in non-Apis bee species, and because "ARV" is used for the Adelaide River virus, we propose that this virus should be called bee rhabdovirus 1 and abbreviated BRV-1. These results

Analytical Validation and Clinical Qualification of a New Immunohistochemical Assay for Androgen Receptor Splice Variant-7 Protein Expression in Metastatic Castration-resistant Prostate Cancer.

PubMed

Welti, Jonathan; Rodrigues, Daniel Nava; Sharp, Adam; Sun, Shihua; Lorente, David; Riisnaes, Ruth; Figueiredo, Ines; Zafeiriou, Zafeiris; Rescigno, Pasquale; de Bono, Johann S; Plymate, Stephen R

2016-10-01

The androgen receptor splice variant-7 (AR-V7) has been implicated in the development of castration-resistant prostate cancer (CRPC) and resistance to abiraterone and enzalutamide. To develop a validated assay for detection of AR-V7 protein in tumour tissue and determine its expression and clinical significance as patients progress from hormone-sensitive prostate cancer (HSPC) to CRPC. Following monoclonal antibody generation and validation, we retrospectively identified patients who had HSPC and CRPC tissue available for AR-V7 immunohistochemical (IHC) analysis. Nuclear AR-V7 expression was determined using IHC H score (HS) data. The change in nuclear AR-V7 expression from HSPC to CRPC and the association between nuclear AR-V7 expression and overall survival (OS) was determined. Nuclear AR-V7 expression was significantly lower in HSPC (median HS 50, interquartile range [IQR] 17.5-90) compared to CRPC (HS 135, IQR 80-157.5; p<0.0001), and in biopsy tissue taken before (HS 80, IQR 30-136.3) compared to after (HS 140, IQR 105-167.5; p=0.007) abiraterone or enzalutamide treatment. Lower nuclear AR-V7 expression at CRPC biopsy was associated with longer OS (hazard ratio 1.012, 95% confidence interval 1.004-1.020; p=0.003). While this monoclonal antibody primarily binds to AR-V7 in PC biopsy tissue, it may also bind to other proteins. We provide the first evidence that nuclear AR-V7 expression increases with emerging CRPC and is prognostic for OS, unlike antibody staining for the AR N-terminal domain. These data indicate that AR-V7 is important in CRPC disease biology; agents targeting AR splice variants are needed to test this hypothesis and further improve patient outcome from CRPC. In this study we found that levels of the protein AR-V7 were higher in patients with advanced prostate cancer. A higher level of AR-V7 identifies a group of patients who respond less well to certain prostate cancer treatments and live for a shorter period of time. Copyright © 2016

Androgen receptor splice variants circumvent AR blockade by microtubule-targeting agents

PubMed Central

Zhang, Guanyi; Liu, Xichun; Li, Jianzhuo; Ledet, Elisa; Alvarez, Xavier; Qi, Yanfeng; Fu, Xueqi; Sartor, Oliver; Dong, Yan; Zhang, Haitao

2015-01-01

Docetaxel-based chemotherapy is established as a first-line treatment and standard of care for patients with metastatic castration-resistant prostate cancer. However, half of the patients do not respond to treatment and those do respond eventually become refractory. A better understanding of the resistance mechanisms to taxane chemotherapy is both urgent and clinical significant, as taxanes (docetaxel and cabazitaxel) are being used in various clinical settings. Sustained signaling through the androgen receptor (AR) has been established as a hallmark of CRPC. Recently, splicing variants of AR (AR-Vs) that lack the ligand-binding domain (LBD) have been identified. These variants are constitutively active and drive prostate cancer growth in a castration-resistant manner. In taxane-resistant cell lines, we found the expression of a major variant, AR-V7, was upregulated. Furthermore, ectopic expression of two clinically relevant AR-Vs (AR-V7 and ARV567es), but not the full-length AR (AR-FL), reduced the sensitivities to taxanes in LNCaP cells. Treatment with taxanes inhibited the transcriptional activity of AR-FL, but not those of AR-Vs. This could be explained, at least in part, due to the inability of taxanes to block the nuclear translocation of AR-Vs. Through a series of deletion constructs, the microtubule-binding activity was mapped to the LBD of AR. Finally, taxane-induced cytoplasm sequestration of AR-FL was alleviated when AR-Vs were present. These findings provide evidence that constitutively active AR-Vs maintain the AR signaling axis by evading the inhibitory effects of microtubule-targeting agents, suggesting that these AR-Vs play a role in resistance to taxane chemotherapy. PMID:26160840

Metabolic complications and selected cytokines in HIV-infected individuals.

PubMed

Bociąga-Jasik, Monika; Polus, Anna; Góralska, Joanna; Śliwa, Agnieszka; Raźny, Urszula; Zdzienicka, Anna; Garlicki, Aleksander; Mach, Tomasz; Dembińska-Kieć, Aldona

2014-01-01

Human immunodeficiency virus (HIV)-infected individuals are at a higher risk of developing metabolic disturbances. The pathogenesis of these complications is complex and not fully explored. The aim of the study was to investigate the effect of HIV infection and antiretroviral (ARV) therapy on the development of metabolic changes and adipocytokine concentrations. The analysis of the differences in the investigated parameters among lipodystrophic and nonlipodystrophic patients was also performed. A total of 42 HIV‑infected patients on ARV therapy (HIV[+]ARV[+]), 13 HIV‑infected ARV naive patients (HIV[+]ARV[-]), and 20 healthy controls were included in the study. A lipid profile, fasting free fatty acids (FFAs), glucose, insulin, and insulin resistance (homeostasis model assessment of insulin resistance--HOMA‑IR) were tested. Serum concentrations of tumor necrosis factor α (TNF‑α), interleukin 6 (IL‑6), adiponectin, leptin, and fatty acid-binding protein 4 (FABP4) were determined. Increased FFA levels were observed in HIV(+)ARV(-) patients. HIV(+)ARV(+) patients had significantly higher triglycerides and insulin level compared with controls. HOMA‑IR showed a tendency to be higher in HIV(+)ARV(+) patients compared with the other study groups. The ARV therapy longer than 2 years resulted in more pronounced metabolic abnormalities. HIV infection itself had a significant effect on inflammation expressed by elevated TNF‑α and IL‑6 levels. We did not observe differences in adiponectin and FABP4 concentrations among the study groups, while the leptin concentration was significantly lower in HIV‑infected lipodystrophic than in nonlipodystrophic patients. HIV infection induces lipid disorders, especially associated with fatty acid turnover augmented by ARV therapy. Compared with FABP4, leptin is a better biological marker of metabolic complications in HIV‑infected patients.

Safety of in utero and neonatal antiretroviral exposure: cognitive and academic outcomes in HIV-exposed, uninfected children 5-13 years of age.

PubMed

Nozyce, Molly L; Huo, Yanling; Williams, Paige L; Kapetanovic, Suad; Hazra, Rohan; Nichols, Sharon; Hunter, Scott; Smith, Renee; Seage, George R; Sirois, Patricia A

2014-11-01

Long-term effects of in utero and neonatal antiretroviral (ARV) exposure on cognitive and academic development in HIV-exposed, uninfected school-age children are unknown. HIV-exposed, uninfected children, ages 5-13 years, in Pediatric HIV/AIDS Cohort Study Surveillance Monitoring for Antiretroviral Treatment Toxicities, a US-based multisite cohort study, completed age-appropriate Wechsler intelligence and academic scales (WPPSI-III, WASI, WIAT-II-A). Associations between cognitive and academic outcomes and in utero ARV exposure by regimen, class and individual ARVs were evaluated, adjusting for potential confounders. Children completing WPPSI-IIIs (n = 350) were 49% male, 74% Black, 25% Hispanic; WASI (n = 337) and WIAT-II-A (n = 415) cohorts were similar. The percentage exposed to combination ARV (cARV) was 84% (WPPSI-III), 64% (WASI) and 67% (WIAT-II-A). Among ARV-exposed children, there were no significant associations between any ARV regimen or class and any cognitive or academic outcome. In addition, in both unadjusted models and after adjustment for caregiver IQ, sociodemographic factors and maternal health and substance use during pregnancy, no individual ARV drug was associated with significantly lower cognitive or academic scores. Factors typically associated with lower cognitive and academic scores in the general population, such as prematurity, small for gestational age, maternal alcohol use and lower maternal cognitive status, were also associated with lower scores in this study. Overall, the safety of prenatal and neonatal ARV use was supported.

MED1 mediates androgen receptor splice variant induced gene expression in the absence of ligand

PubMed Central

Liu, Gang; Sprenger, Cynthia; Wu, Pin-Jou; Sun, Shihua; Uo, Takuma; Haugk, Kathleen; Epilepsia, Kathryn Soriano; Plymate, Stephen

2015-01-01

The appearance of constitutively active androgen receptor splice variants (AR-Vs) has been proposed as one of the causes of castration-resistant prostate cancer (CRPC). However, the underlying mechanism of AR-Vs in CRPC transcriptional regulation has not been defined. A distinct transcriptome enriched with cell cycle genes, e.g. UBE2C, has been associated with AR-Vs, which indicates the possibility of an altered transcriptional mechanism when compared to full-length wild-type AR (ARfl). Importantly, a recent study reported the critical role of p-MED1 in enhancing UBE2C expression through a locus looping pattern, which only occurs in CRPC but not in androgen-dependent prostate cancer (ADPC). To investigate the potential correlation between AR-V and MED1, in the present study we performed protein co-immunoprecipitation, chromatin immunoprecipitation, and cell proliferation assays and found that MED1 is necessary for ARv567es induced UBE2C up-regulation and subsequent prostate cancer cell growth. Furthermore, p-MED1 is bound to ARv567es independent of full-length AR; p-MED1 has higher recruitment to UBE2C promoter and enhancer regions in the presence of ARv567es. Our data indicate that p-MED1 serves as a key mediator in ARv567es induced gene expression and suggests a mechanism by which AR-Vs promote the development and progression of CRPC. PMID:25481872

Provider-patient adherence dialogue in HIV care: results of a multisite study.

PubMed

Laws, M Barton; Beach, Mary Catherine; Lee, Yoojin; Rogers, William H; Saha, Somnath; Korthuis, P Todd; Sharp, Victoria; Wilson, Ira B

2013-01-01

Few studies have analyzed physician-patient adherence dialogue about ARV treatment in detail. We comprehensively describe physician-patient visits in HIV care, focusing on ARV-related dialogue, using a system that assigns each utterance both a topic code and a speech act code. Observational study using audio recordings of routine outpatient visits by people with HIV at specialty clinics. Providers were 34 physicians and 11 non-M.D. practitioners. Of 415 patients, 66% were male, 59% African-American. 78% reported currently taking ARVs. About 10% of utterances concerned ARV treatment. Among those using ARVs, 15% had any adherence problem solving dialogue. ARV problem solving talk included significantly more directives and control parameter utterances by providers than other topics. Providers were verbally dominant, asked five times as many questions as patients, and made 21 times as many directive utterances. Providers asked few open questions, and rarely checked patients' understanding. Physicians respond to the challenges of caring for patients with HIV by adopting a somewhat physician-centered approach which is particularly evident in discussions about ARV adherence.

Comprehensive Profiling of the Androgen Receptor in Liquid Biopsies from Castration-resistant Prostate Cancer Reveals Novel Intra-AR Structural Variation and Splice Variant Expression Patterns.

PubMed

De Laere, Bram; van Dam, Pieter-Jan; Whitington, Tom; Mayrhofer, Markus; Diaz, Emanuela Henao; Van den Eynden, Gert; Vandebroek, Jean; Del-Favero, Jurgen; Van Laere, Steven; Dirix, Luc; Grönberg, Henrik; Lindberg, Johan

2017-08-01

Expression of the androgen receptor splice variant 7 (AR-V7) is associated with poor response to second-line endocrine therapy in castration-resistant prostate cancer (CRPC). However, a large fraction of nonresponding patients are AR-V7-negative. To investigate if a comprehensive liquid biopsy-based AR profile may improve patient stratification in the context of second-line endocrine therapy. Peripheral blood was collected from patients with CRPC (n=30) before initiation of a new line of systemic therapy. We performed profiling of circulating tumour DNA via low-pass whole-genome sequencing and targeted sequencing of the entire AR gene, including introns. Targeted RNA sequencing was performed on enriched circulating tumour cell fractions to assess the expression levels of seven AR splice variants (ARVs). Somatic AR variations, including copy-number alterations, structural variations, and point mutations, were combined with ARV expression patterns and correlated to clinicopathologic parameters. Collectively, any AR perturbation, including ARV, was detected in 25/30 patients. Surprisingly, intra-AR structural variation was present in 15/30 patients, of whom 14 expressed ARVs. The majority of ARV-positive patients expressed multiple ARVs, with AR-V3 the most abundantly expressed. The presence of any ARV was associated with progression-free survival after second-line endocrine treatment (hazard ratio 4.53, 95% confidence interval 1.424-14.41; p=0.0105). Six out of 17 poor responders were AR-V7-negative, but four carried other AR perturbations. Comprehensive AR profiling, which is feasible using liquid biopsies, is necessary to increase our understanding of the mechanisms underpinning resistance to endocrine treatment. Alterations in the androgen receptor are associated with endocrine treatment outcomes. This study demonstrates that it is possible to identify different types of alterations via simple blood draws. Follow-up studies are needed to determine the effect of

Individual and contextual factors of influence on adherence to antiretrovirals among people attending public clinics in Rio de Janeiro, Brazil

PubMed Central

2013-01-01

Background There are inconsistencies in the determinants of adherence to antiretrovirals (ARVs) across settings as well as a lack of studies that take into consideration factors beyond the individual level. This makes it necessary to examine factors holistically in multiple settings and populations while taking into consideration the particularities of each context, in order to understand the patterns of ARV adherence. This research explored ARV adherence and individual, relational and environmental-structural factors. Methods A cross-sectional survey was conducted from August 2008 through July 2009 among participants currently on ARVs recruited from 6 public health clinics, selected to maximize diversity in terms of caseload and location, representing the range of clinics within Rio de Janeiro city, Brazil. Multivariate logistic regression analysis was used to assess the association between our multilevel factors with ARV adherence among participants with complete cases (n = 632). Results Eighty-four percent of respondents reported adherence to all of their ARV doses in the last 4 days. Of the socio-demographic variables, those who had one child were positively associated with adherence (AOR 2.29 CI [1.33-3.94]). On the relational level, those with high social support (AOR 2.85 CI [1.50-5.41]) were positively associated with adherence to ARVs. On the environmental-structural level, we found gender was significant with women negatively associated with adherence to ARVs (AOR 0.58 CI [0.38-0.88]) while those with a high asset index (AOR 2.47 CI [1.79-3.40]) were positively associated with adherence to ARVs. Conclusions This research highlights the importance of examining the multiple levels of influence on ARV adherence. Intervention research in lower and middle-income settings should address and evaluate the impact of attending to both gender and economic inequalities to improve ARV adherence, as well as relational areas such as the provision of social support. PMID

Alternative antiretroviral therapy formulations for patients unable to swallow solid oral dosage forms.

PubMed

Duggan, Joan M; Akpanudo, Barbara; Shukla, Vipul; Gutterson, Glen; Eitniear, Lindsey; Sahloff, Eric G

2015-09-15

Evidence-based guidance is presented to assist clinicians in selecting alternative formulations of antiretroviral (ARV) agents for patients with human immunodeficiency virus (HIV) infection who are unable to swallow tablets or capsules. The inability to take medications in standard oral dosage forms can be associated with nonadherence or the use of alternative administration strategies such as capsule or tablet breaking, crushing, or chewing. Patients with HIV infection require long-term ARV therapy to maintain viral suppression; ARV agents are predominately available as tablets and capsules that may pose swallowing difficulties for some patients. Using a variety of sources (the primary literature, pharmaceutical package inserts, and requests for unpublished data from drug manufacturers), available evidence on the bioavailability of ARV medications after disruption of the capsule or tablet matrix was reviewed; information on alternative formulations of ARV agents was also assessed. With several ARV agents, disruption of the solid oral dosage form by crushing, chewing, or breaking tablets or opening capsules prior to ingestion has been shown to result in altered bioavailability or pharmacokinetics and thus the potential for incomplete virological suppression, increased adverse effects, and suboptimal health outcomes. Of the 33 single-agent ARV medications and combination ARV products in five classes available at the time of review, approximately half exist as powders, liquids, injectables, or chewable or dissolvable tablets. If alternative ARV formulations or administration methods are used, close monitoring for achievement of virological and immunologic success and potential toxicities is recommended. Copyright © 2015 by the American Society of Health-System Pharmacists, Inc. All rights reserved.

Undisclosed antiretroviral drug use in a multinational clinical trial (HIV Prevention Trials Network 052).

PubMed

Fogel, Jessica M; Wang, Lei; Parsons, Teresa L; Ou, San-San; Piwowar-Manning, Estelle; Chen, Ying; Mudhune, Victor O; Hosseinipour, Mina C; Kumwenda, Johnstone; Hakim, James G; Chariyalertsak, Suwat; Panchia, Ravindre; Sanne, Ian; Kumarasamy, Nagalingeswaran; Grinsztejn, Beatriz; Makhema, Joseph; Pilotto, Jose; Santos, Breno R; Mayer, Kenneth H; McCauley, Marybeth; Gamble, Theresa; Bumpus, Namandjé N; Hendrix, Craig W; Cohen, Myron S; Eshleman, Susan H

2013-11-15

The HIV Prevention Trials Network 052 study enrolled serodiscordant couples. Index participants infected with human immunodeficiency virus reported no prior antiretroviral (ARV) treatment at enrollment. ARV drug testing was performed retrospectively using enrollment samples from a subset of index participants. ARV drugs were detected in 45 of 96 participants (46.9%) with an undetectable viral load, 2 of 48 (4.2%) with a low viral load, and 1 of 65 (1.5%) with a high viral load (P < .0001); they were also detected in follow-up samples from participants who were not receiving study-administered treatment. ARV drug testing may be useful in addition to self-report of ARV drug use in some clinical trial settings.

Estimating age-based antiretroviral therapy costs for HIV-infected children in resource-limited settings based on World Health Organization weight-based dosing recommendations.

PubMed

Doherty, Kathleen; Essajee, Shaffiq; Penazzato, Martina; Holmes, Charles; Resch, Stephen; Ciaranello, Andrea

2014-05-02

Pediatric antiretroviral therapy (ART) has been shown to substantially reduce morbidity and mortality in HIV-infected infants and children. To accurately project program costs, analysts need accurate estimations of antiretroviral drug (ARV) costs for children. However, the costing of pediatric antiretroviral therapy is complicated by weight-based dosing recommendations which change as children grow. We developed a step-by-step methodology for estimating the cost of pediatric ARV regimens for children ages 0-13 years old. The costing approach incorporates weight-based dosing recommendations to provide estimated ARV doses throughout childhood development. Published unit drug costs are then used to calculate average monthly drug costs. We compared our derived monthly ARV costs to published estimates to assess the accuracy of our methodology. The estimates of monthly ARV costs are provided for six commonly used first-line pediatric ARV regimens, considering three possible care scenarios. The costs derived in our analysis for children were fairly comparable to or slightly higher than available published ARV drug or regimen estimates. The methodology described here can be used to provide an accurate estimation of pediatric ARV regimen costs for cost-effectiveness analysts to project the optimum packages of care for HIV-infected children, as well as for program administrators and budget analysts who wish to assess the feasibility of increasing pediatric ART availability in constrained budget environments.

Estimating age-based antiretroviral therapy costs for HIV-infected children in resource-limited settings based on World Health Organization weight-based dosing recommendations

PubMed Central

2014-01-01

Background Pediatric antiretroviral therapy (ART) has been shown to substantially reduce morbidity and mortality in HIV-infected infants and children. To accurately project program costs, analysts need accurate estimations of antiretroviral drug (ARV) costs for children. However, the costing of pediatric antiretroviral therapy is complicated by weight-based dosing recommendations which change as children grow. Methods We developed a step-by-step methodology for estimating the cost of pediatric ARV regimens for children ages 0–13 years old. The costing approach incorporates weight-based dosing recommendations to provide estimated ARV doses throughout childhood development. Published unit drug costs are then used to calculate average monthly drug costs. We compared our derived monthly ARV costs to published estimates to assess the accuracy of our methodology. Results The estimates of monthly ARV costs are provided for six commonly used first-line pediatric ARV regimens, considering three possible care scenarios. The costs derived in our analysis for children were fairly comparable to or slightly higher than available published ARV drug or regimen estimates. Conclusions The methodology described here can be used to provide an accurate estimation of pediatric ARV regimen costs for cost-effectiveness analysts to project the optimum packages of care for HIV-infected children, as well as for program administrators and budget analysts who wish to assess the feasibility of increasing pediatric ART availability in constrained budget environments. PMID:24885453

Impact of antiretroviral drugs on the microbiome: unknown answers to important questions

PubMed Central

Pinto-Cardoso, Sandra; Klatt, Nichole R.; Reyes-Terán, Gustavo

2018-01-01

Purpose of review Little is known on how different antiretroviral (ARV) drugs affect the gut microbiome in HIV infection; and conflicting data exists on the effect of ARV drugs on residual inflammation/immune activation and microbial translocation. Recent findings Gut microbiome involvement in the transmission and pathogenesis of HIV infection is increasingly being recognized. Various studies have shown that antiretroviral therapy (ART) is unable to restore gut health despite effective suppression of plasma HIV viremia. Indeed, the resolution of residual inflammation and gut microbial translocation is partial under ART. Very recent studies have provided new evidence that ARV combinations can differentially affect the gut microbiome, immune activation and microbial translocation. Furthermore, a recent article uncovered a link between drug metabolism and specific microbial species indicating that microbes can directly metabolically degrade ARV drugs when administered topically. Summary There are still many unanswered questions regarding ARVs and the gut microbiome. It is, therefore, critical for researchers to address the effect of distinct ARV drugs on the microbiome and vice versa: the effects of the microbiome on ARV drug metabolism, and speculate about possible therapeutic avenues. PMID:29028667

Knowledge and perceptions of HIV-infected patients regarding HIV transmission and treatment in Ho Chi Minh City, Vietnam.

PubMed

Hoang, Don; Dinh, An T; Groce, Nora; Sullivan, Lynn E

2015-03-01

Patient education concerning HIV and antiretroviral (ARV) medications is important for optimal outcomes. The authors assessed the knowledge and perceptions of HIV-infected patients in an ARV education program in Ho Chi Minh City, Vietnam. Of 185 patients, 64 (35%) receiving ARV medications, nearly 80% correctly answered questions regarding HIV. Correct responses were associated with higher education (P < .05) and longer duration of HIV diagnosis (P < .05). A lack of knowledge was observed in 40% of respondents who believed HIV and AIDS were the same and 70% of respondents who believed ARV medications cured HIV. Greater embarrassment of living with HIV was associated with female gender (P < .05) and lower education (P < .05). Patients were concerned over ARV medication use (27%) and its side effects (38%). The study population's knowledge of HIV/AIDS and ARV medications, perceived stigmatization, and areas of knowledge deficits underscore the need for effective patient education programs addressing poorly understood issues around HIV/AIDS. © 2011 APJPH.

Clinical and laboratorial impact of antiretroviral therapy in a cohort of Portuguese patients chronically infected with HIV-2.

PubMed

Miranda, Ana; Peres, Susana; Moneti, Virginia; Azevedo, Telma; Aldir, Isabel; Mansinho, Kamal

2014-01-01

HIV-2 infection is endemic in West Africa and some European countries, namely Portugal. HIV-2 antiretroviral (ARV) treatment presents some restrains related to intrinsic resistance to non-nucleoside reverse transcriptase inhibitors (NNRTI) and fusion inhibitors, and poorer response to protease inhibitors (PI). Retrospective observational study of a cohort of 135 infected HIV-2 patients, diagnosed between 1989 and 2008. Evaluation of epidemiologic, clinical, immunologic and virologic progression, comparing to groups of patients (naïve vs ARV experienced); characterization of therapeutic, immunologic and virologic response. SPSS version 20.0 was used for statistical analysis. The study included 135 patients: 41% (n=55) naïve and 59% (n=80) with ARV experience. The comparison between groups (naïve vs ARV) revealed: male prevalence 76% vs 50%; mean age 54.5 years vs 54.8 (p=0.90); main geographic origin Guiné Bissau (47% vs 44%) and Portugal (22% vs 33%); and transmission mainly acquired by heterosexual contact (87% vs 80%). Mean time since diagnosis was 14 vs 13 years (p=0.31); 2% vs 50% presented AIDS criteria at diagnosis (p<0.001) and 93% vs 38% registered TCD4>350 cell/mm(3) at diagnosis (p<0.001). Immunological evolution showed no significant decline in naïve population (Δ=-67 cell/mm(3) - p=0.18) and a significant recovery in ARV experienced (Δ=+207 cell/mm(3) - p<0.001). Global mortality rate found was 18% (6% vs 13% - p=0.122). Eighty patients initiated ARV: 84% presented a time interval of ARV exposure between 0-5 years (42%) and 5-10 years (42%). Fifty percent experienced ≤2 ARV regimens and the remaining >2 regimes. Considering the first ARV therapy: 56% initiated PI, 30% NTRI and 5% integrase inhibitor (II)-based regimens. Currently, 54 patients maintain regular follow-up and ARV therapy: 60% NTRI+PI; 37% NRTI+PI+II and 3% NRTI+II. TDF/FTC is the backbone in 56%. Most frequent PIs are LPV/r (54%), DRV/r (19%) and ATV/r (12%). Mean time of exposure

Economic evaluation of weekends-off antiretroviral therapy for young people in 11 countries.

PubMed

Tierrablanca, Luis Enrique; Ochalek, Jessica; Ford, Deborah; Babiker, Ab; Gibb, Diana; Butler, Karina; Turkova, Anna; Griffin, Susan; Revill, Paul

2018-02-01

To analyze the cost effectiveness of short-cycle therapy (SCT), where patients take antiretroviral (ARV) drugs 5 consecutive days a week and have 2 days off, as an alternative to continuous ARV therapy for young people infected with human immunodeficiency virus (HIV) and taking efavirenz-based first-line ARV drugs. We conduct a hierarchical cost-effectiveness analysis based on data on clinical outcomes and resource use from the BREATHER trial. BREATHER is a randomized trial investigating the effectiveness of SCT and continuous therapy in 199 participants aged 8 to 24 years and taking efavirenz-based first-line ARV drugs in 11 countries worldwide. Alongside nationally representative unit costs/prices, these data were used to estimate costs and quality adjusted life years (QALYs). An incremental cost-effectiveness comparison was performed using a multilevel bivariate regression approach for total costs and QALYs. Further analyses explored cost-effectiveness in low- and middle-income countries with access to low-cost generic ARV drugs and high-income countries purchasing branded ARV drugs, respectively. At 48 weeks, SCT offered significant total cost savings over continuous therapy of US dollar (USD) 41 per patient in countries using generic drugs and USD 4346 per patient in countries using branded ARV drugs, while accruing nonsignificant total health benefits of 0.008 and 0.009 QALYs, respectively. Cost-effectiveness estimates were similar across settings with access to generic ARV drugs but showed significant variation among high-income countries where branded ARV drugs are purchased. SCT is a cost-effective treatment alternative to continuous therapy for young people infected with HIV in countries where viral load monitoring is available.

Economic evaluation of weekends-off antiretroviral therapy for young people in 11 countries

PubMed Central

Tierrablanca, Luis Enrique; Ochalek, Jessica; Ford, Deborah; Babiker, Ab; Gibb, Diana; Butler, Karina; Turkova, Anna; Griffin, Susan; Revill, Paul

2018-01-01

Abstract Objectives: To analyze the cost effectiveness of short-cycle therapy (SCT), where patients take antiretroviral (ARV) drugs 5 consecutive days a week and have 2 days off, as an alternative to continuous ARV therapy for young people infected with human immunodeficiency virus (HIV) and taking efavirenz-based first-line ARV drugs. Methods: We conduct a hierarchical cost-effectiveness analysis based on data on clinical outcomes and resource use from the BREATHER trial. BREATHER is a randomized trial investigating the effectiveness of SCT and continuous therapy in 199 participants aged 8 to 24 years and taking efavirenz-based first-line ARV drugs in 11 countries worldwide. Alongside nationally representative unit costs/prices, these data were used to estimate costs and quality adjusted life years (QALYs). An incremental cost-effectiveness comparison was performed using a multilevel bivariate regression approach for total costs and QALYs. Further analyses explored cost-effectiveness in low- and middle-income countries with access to low-cost generic ARV drugs and high-income countries purchasing branded ARV drugs, respectively. Results: At 48 weeks, SCT offered significant total cost savings over continuous therapy of US dollar (USD) 41 per patient in countries using generic drugs and USD 4346 per patient in countries using branded ARV drugs, while accruing nonsignificant total health benefits of 0.008 and 0.009 QALYs, respectively. Cost-effectiveness estimates were similar across settings with access to generic ARV drugs but showed significant variation among high-income countries where branded ARV drugs are purchased. Conclusion: SCT is a cost-effective treatment alternative to continuous therapy for young people infected with HIV in countries where viral load monitoring is available. PMID:29384848

Replication and Oncolytic Activity of an Avian Orthoreovirus in Human Hepatocellular Carcinoma Cells

PubMed Central

Kozak, Robert A.; Hattin, Larissa; Biondi, Mia J.; Corredor, Juan C.; Walsh, Scott; Xue-Zhong, Max; Manuel, Justin; McGilvray, Ian D.; Morgenstern, Jason; Lusty, Evan; Cherepanov, Vera; McBey, Betty-Anne; Leishman, David; Feld, Jordan J.; Bridle, Byram; Nagy, Éva

2017-01-01

Oncolytic viruses are cancer therapeutics with promising outcomes in pre-clinical and clinical settings. Animal viruses have the possibility to avoid pre-existing immunity in humans, while being safe and immunostimulatory. We isolated an avian orthoreovirus (ARV-PB1), and tested it against a panel of hepatocellular carcinoma cells. We found that ARV-PB1 replicated well and induced strong cytopathic effects. It was determined that one mechanism of cell death was through syncytia formation, resulting in apoptosis and induction of interferon stimulated genes (ISGs). As hepatitis C virus (HCV) is a major cause of hepatocellular carcinoma worldwide, we investigated the effect of ARV-PB1 against cells already infected with this virus. Both HCV replicon-containing and infected cells supported ARV-PB1 replication and underwent cytolysis. Finally, we generated in silico models to compare the structures of human reovirus- and ARV-PB1-derived S1 proteins, which are the primary targets of neutralizing antibodies. Tertiary alignments confirmed that ARV-PB1 differs from its human homolog, suggesting that immunity to human reoviruses would not be a barrier to its use. Therefore, ARV-PB1 can potentially expand the repertoire of oncolytic viruses for treatment of human hepatocellular carcinoma and other malignancies. PMID:28441762

Antiretroviral procurement and supply chain management.

PubMed

Ripin, David J; Jamieson, David; Meyers, Amy; Warty, Umesh; Dain, Mary; Khamsi, Cyril

2014-01-01

Procurement, the country-level process of ordering antiretrovirals (ARVs), and supply chain management, the mechanism by which they are delivered to health-care facilities, are critical processes required to move ARVs from manufacturers to patients. To provide a glimpse into the ARV procurement and supply chain, the following pages provide an overview of the primary stakeholders, principal operating models, and policies and regulations involved in ARV procurement. Also presented are key challenges that need to be addressed to ensure that the supply chain is not a barrier to the goal of universal coverage. This article will cover the steps necessary to order and distribute ARVs, including different models of delivery, key stakeholders involved, strategic considerations that vary depending on context and policies affecting them. The single drug examples given illustrate the complications inherent in fragmented supply and demand-driven models of procurement and supply chain management, and suggest tools for navigating these hurdles that will ultimately result in more secure and reliable ARV provision. Understanding the dynamics of ARV supply chain is important for the global health community, both to ensure full and efficient treatment of persons living with HIV as well as to inform the supply chain decisions for other public health products.

Patent life of antiretroviral drugs approved in the US from 1987 to 2007.

PubMed

Rodriguez-Monguio, Rosa; Seoane-Vazquez, Enrique

2009-06-01

This study analyzes the effective patent life of antiretroviral (ARV) new molecular entities (NMEs) approved for marketing in the United States (US) between 1987 and 2007. The study includes all NMEs approved during the study period with at least one patent listed in the Orange Book (OB). Drugs discontinued from the market were excluded from the analysis. Data sources are the US Food and Drug Administration (FDA) and the US Patent and Trademark Office. A comparison between the effective patent life of ARV NMEs and NMEs from other therapeutic classes was performed. The first and last patents were used to estimate the minimum and maximum effective patent life of NMEs. Group differences were assessed using group comparison t-tests, Chi-Square and Fishers' exact tests. The FDA approved 547 NMEs during the study period; 153 NMEs did not have a patent listed in the OB or were discontinued from the US market. The patent analysis included 22 ARV NMEs and 372 other NMEs. ARV MNEs had a range from 1 to 15 patents listed in the OB. The FDA new drug application (NDA) review time was shorter for ARVs (5.8+/-2.3 months) than for other NMEs (23.6+/-18.7 months). ARV NMEs had an average of 13.2+/-3.8 years of effective patent life for the first patent versus 11.0+/-4.2 years for other NMEs. ARV NMEs had an average of 17.5+/-3.6 years of effective patent life for the last patent versus the 14.8+/-4.8 years for other NMEs. The effective patent life listed for the last patent of seven ARV NMEs (31.8%) exceeded 20 years. Shortening the drug approval process increased the effective patent life of ARVs and facilitated faster entry of new drugs into the market. ARVs had an average of 2-3 more years of effective patent life than other therapeutic classes and, therefore, a longer period without generic competition.

Allocating scarce financial resources for HIV treatment: benchmarking prices of antiretroviral medicines in Latin America.

PubMed

Wirtz, Veronika J; Santa-Ana-Tellez, Yared; Trout, Clinton H; Kaplan, Warren A

2012-12-01

Public sector price analyses of antiretroviral (ARV) medicines can provide relevant information to detect ARV procurement procedures that do not obtain competitive market prices. Price benchmarks provide a useful tool for programme managers and policy makers to support such planning and policy measures. The aim of the study was to develop regional and global price benchmarks which can be used to analyse public-sector price variability of ARVs in low- and middle-income countries using the procurement prices of Latin America and the Caribbean (LAC) countries in 2008 as an example. We used the Global Price Reporting Mechanism (GPRM) data base, provided by the World Health Organization (WHO), for 13 LAC countries' ARV procurements to analyse the procurement prices of four first-line and three second-line ARV combinations in 2008. First, a cross-sectional analysis was conducted to compare ARV combination prices. Second, four different price 'benchmarks' were created and we estimated the additional number of patients who could have been treated in each country if the ARV combinations studied were purchased at the various reference ('benchmark') prices. Large price variations exist for first- and second-line ARV combinations between countries in the LAC region. Most countries in the LAC region could be treating between 1.17 and 3.8 times more patients if procurement prices were closer to the lowest regional generic price. For all second-line combinations, a price closer to the lowest regional innovator prices or to the global median transaction price for lower-middle-income countries would also result in treating up to nearly five times more patients. Some rational allocation of financial resources due, in part, to price benchmarking and careful planning by policy makers and programme managers can assist a country in negotiating lower ARV procurement prices and should form part of a sustainable procurement policy.

Antiretroviral drug supply challenges in the era of scaling up ART in Malawi.

PubMed

Schouten, Erik J; Jahn, Andreas; Ben-Smith, Anne; Makombe, Simon D; Harries, Anthony D; Aboagye-Nyame, Francis; Chimbwandira, Frank

2011-07-06

The number of people receiving antiretroviral treatment (ART) has increased considerably in recent years and is expected to continue to grow in the coming years. A major challenge is to maintain uninterrupted supplies of antiretroviral (ARV) drugs and prevent stock outs. This article discusses issues around the management of ARVs and prevention of stock outs in Malawi, a low-income country with a high HIV/AIDS burden, and a weak procurement and supply chain management system. This system for ARVs, paid for by the Global Fund to Fight AIDS, Tuberculosis and Malaria, and bypassing the government Central Medical Stores, is in place, using the United Nations Children's Fund's (UNICEF's) procurement services. The system, managed by a handful of people who spend limited time on supply management, is characterized by a centrally coordinated quantification based on verified data from all national ART clinics, parallel procurement through UNICEF, and direct distribution to ART clinics. The model worked well in the first years of the ART programme with a single first-line ARV regimen, but with more regimens becoming available (e.g., alternative first-line, second-line and paediatric regimens), it has become more difficult to administer. Managing supplies through a parallel system has the advantage that weaknesses in the national system have limited influence on the ARV procurement and supply chain management system. However, as the current system operates without a central warehouse and national buffer stock capacity, it diminishes the ability to prevent ARV stock outs. The process of ordering ARVs, from the time that estimates are made to the arrival of supplies in health facilities, takes approximately one year. Addressing the challenges involved in maintaining ARVs through an efficient procurement and supply chain management system that prevents ARV stock outs through the establishment of a dedicated procurement team, a central warehouse and/or national buffer stock is a

Reforming antiretroviral price negotiations and public procurement: the Mexican experience.

PubMed

Adesina, Adebiyi; Wirtz, Veronika J; Dratler, Sandra

2013-01-01

Since antiretroviral (ARV) medicines represent one of the most costly components of therapy for HIV in middle-income countries, ensuring their efficient procurement is highly relevant. In 2008, Mexico created a national commission for the negotiation of ARV prices to achieve price reductions for their public HIV treatment programmes. The objective of this study is to assess the immediate impact of the creation of the Mexican Commission for Price Negotiation on ARV prices and expenditures. A longitudinal retrospective analysis of procurement prices, volumes and type of the most commonly prescribed ARVs procured by the two largest providers of HIV/AIDS care in Mexico between 2004 and 2009 was carried out. These analyses were combined with 26 semi-structured key informant interviews to identify changes in the procurement process. Prices for ARVs dropped by an average of 38% after the first round of negotiations, indicating that the Commission was successful in price negotiations. However, when compared with other upper-middle-income countries, Mexico continues to pay an average of six times more for ARVs. The Commission's negotiations were successful in achieving lower ARV prices. However, price reduction in upper-middle-income countries suggests that the price decrease in Mexico cannot be entirely attributed to the Commission's first round of negotiations. In addition, key informants identified inefficiencies in the forecasting and procurement processes possibly affecting the efficiency of the negotiation process. A comprehensive approach to improving efficiency in the purchasing and delivery of ARVs is necessary, including a better clarification in the roles and responsibilities of the Commission, improving supply data collection and integration in forecasting and procurement, and the creation of a support system to monitor and provide feedback on patient ARV use.

Confocal fluorescence microscopy: An ultra-sensitive tool used to evaluate intracellular antiretroviral nano-drug delivery in HeLa cells

NASA Astrophysics Data System (ADS)

Mandal, Subhra; Zhou, You; Shibata, Annemarie; Destache, Christopher J.

2015-08-01

In the last decade, confocal fluorescence microscopy has emerged as an ultra-sensitive tool for real-time study of nanoparticles (NPs) fate at the cellular-level. According to WHO 2007 report, Human Immunodeficiency Virus/Acquired Immunodeficiency Syndrome (HIV/AIDS) is still one of the world's major health threats by claiming approximately 7,000 new infections daily worldwide. Although combination antiretroviral drugs (cARV) therapy has improved the life-expectancy of HIV-infected patients, routine use of high doses of cARV has serious health consequences and requires complete adherence to the regimen for success. Thus, our research goal is to fabricate long-acting novel cARV loaded poly(lactide-co-glycolic acid) (PLGA) nanoparticles (cARV-NPs) as drug delivery system. However, important aspects of cARV-NPs that require special emphasis are their cellular-uptake, potency, and sustained drug release efficiency over-time. In this article, ultra-sensitive confocal microscopy is been used to evaluate the uptake and sustained drug release kinetics of cARV-NPs in HeLa cells. To evaluate with the above goal, instead of cARV-drug, Rhodamine6G dye (fluorescent dye) loaded NPs (Rho6G NPs) have been formulated. To correlate the Rhodamin6G release kinetics with the ARV release from NPs, a parallel HPLC study was also performed. The results obtained indicate that Rho6G NPs were efficiently taken up at low concentration (<500 ng/ml) and that release was sustained for a minimum of 4 days of treatment. Therefore, high drug assimilation and sustained release properties of PLGA-NPs make them an attractive vehicle for cARV nano-drug delivery with the potential to reduce drug dosage as well as the number of drug administrations per month.

Which Clinician Questions Elicit Accurate Disclosure of Antiretroviral Non-adherence When Talking to Patients?

PubMed

Callon, Wynne; Saha, Somnath; Korthuis, P Todd; Wilson, Ira B; Moore, Richard D; Cohn, Jonathan; Beach, Mary Catherine

2016-05-01

This study evaluated how clinicians assess antiretroviral (ARV) adherence in clinical encounters, and which questions elicit accurate responses. We conducted conversation analysis of audio-recorded encounters between 34 providers and 58 patients reporting ARV non-adherence in post-encounter interviews. Among 42 visits where adherence status was unknown by providers, 4 providers did not discuss ARVs (10 %), 6 discussed ARVs but did not elicit non-adherence disclosure (14 %), and 32 discussed ARVs which prompted disclosure (76 %). Questions were classified as: (1) clarification of medication ("Are you still taking the Combivir?"); (2) broad ("How's it going with your meds?"); (3) positively-framed ("Are you taking your medications regularly?"); (4) negatively-framed ("Have you missed any doses?"). Clinicians asked 75 ARV-related questions: 23 clarification, 12 broad, 17 positively-framed, and 23 negatively-framed. Negatively-framed questions were 3.8 times more likely to elicit accurate disclosure than all other question types (p < 0.0001). Providers can improve disclosure probability by asking directly about missed doses.

Evidence-based guideline: Antiepileptic drug selection for people with HIV/AIDS

PubMed Central

Birbeck, G.L.; French, J.A.; Perucca, E.; Simpson, D.M.; Fraimow, H.; George, J.M.; Okulicz, J.F.; Clifford, D.B.; Hachad, H.; Levy, R.H.

2012-01-01

Objective: To develop guidelines for selection of antiepileptic drugs (AEDs) among people with HIV/AIDS. Methods: The literature was systematically reviewed to assess the global burden of relevant comorbid entities, to determine the number of patients who potentially utilize AEDs and antiretroviral agents (ARVs), and to address AED-ARV interactions. Results and Recommendations: AED-ARV administration may be indicated in up to 55% of people taking ARVs. Patients receiving phenytoin may require a lopinavir/ritonavir dosage increase of ∼50% to maintain unchanged serum concentrations (Level C). Patients receiving valproic acid may require a zidovudine dosage reduction to maintain unchanged serum zidovudine concentrations (Level C). Coadministration of valproic acid and efavirenz may not require efavirenz dosage adjustment (Level C). Patients receiving ritonavir/atazanavir may require a lamotrigine dosage increase of ∼50% to maintain unchanged lamotrigine serum concentrations (Level C). Coadministration of raltegravir/atazanavir and lamotrigine may not require lamotrigine dosage adjustment (Level C). Coadministration of raltegravir and midazolam may not require midazolam dosage adjustment (Level C). Patients may be counseled that it is unclear whether dosage adjustment is necessary when other AEDs and ARVs are combined (Level U). It may be important to avoid enzyme-inducing AEDs in people on ARV regimens that include protease inhibitors or nonnucleoside reverse transcriptase inhibitors, as pharmacokinetic interactions may result in virologic failure, which has clinical implications for disease progression and development of ARV resistance. If such regimens are required for seizure control, patients may be monitored through pharmacokinetic assessments to ensure efficacy of the ARV regimen (Level C). PMID:22218281

Large contribution of human papillomavirus in vaginal neoplastic lesions: a worldwide study in 597 samples.

PubMed

Alemany, L; Saunier, M; Tinoco, L; Quirós, B; Alvarado-Cabrero, I; Alejo, M; Joura, E A; Maldonado, P; Klaustermeier, J; Salmerón, J; Bergeron, C; Petry, K U; Guimerà, N; Clavero, O; Murillo, R; Clavel, C; Wain, V; Geraets, D T; Jach, R; Cross, P; Carrilho, C; Molina, C; Shin, H R; Mandys, V; Nowakowski, A M; Vidal, A; Lombardi, L; Kitchener, H; Sica, A R; Magaña-León, C; Pawlita, M; Quint, W; Bravo, I G; Muñoz, N; de Sanjosé, S; Bosch, F X

2014-11-01

This work describes the human papillomavirus (HPV) prevalence and the HPV type distribution in a large series of vaginal intraepithelial neoplasia (VAIN) grades 2/3 and vaginal cancer worldwide. We analysed 189 VAIN 2/3 and 408 invasive vaginal cancer cases collected from 31 countries from 1986 to 2011. After histopathological evaluation of sectioned formalin-fixed paraffin-embedded samples, HPV DNA detection and typing was performed using the SPF-10/DNA enzyme immunoassay (DEIA)/LiPA25 system (version 1). A subset of 146 vaginal cancers was tested for p16(INK4a) expression, a cellular surrogate marker for HPV transformation. Prevalence ratios were estimated using multivariate Poisson regression with robust variance. HPV DNA was detected in 74% (95% confidence interval (CI): 70-78%) of invasive cancers and in 96% (95% CI: 92-98%) of VAIN 2/3. Among cancers, the highest detection rates were observed in warty-basaloid subtype of squamous cell carcinomas, and in younger ages. Concerning the type-specific distribution, HPV16 was the most frequently type detected in both precancerous and cancerous lesions (59%). p16(INK4a) overexpression was found in 87% of HPV DNA positive vaginal cancer cases. HPV was identified in a large proportion of invasive vaginal cancers and in almost all VAIN 2/3. HPV16 was the most common type detected. A large impact in the reduction of the burden of vaginal neoplastic lesions is expected among vaccinated cohorts. Copyright © 2014 Elsevier Ltd. All rights reserved.

Congenital anomalies and in utero antiretroviral exposure in human immunodeficiency virus-exposed uninfected infants.

PubMed

Williams, Paige L; Crain, Marilyn J; Yildirim, Cenk; Hazra, Rohan; Van Dyke, Russell B; Rich, Kenneth; Read, Jennifer S; Stuard, Emma; Rathore, Mobeen; Mendez, Hermann A; Watts, D Heather

2015-01-01

Most studies examining the association of prenatal antiretroviral (ARV) exposures with congenital anomalies (CAs) in children born to human immunodeficiency virus (HIV)-infected women have been reassuring, but some evidence suggests an increased risk with specific ARV agents. To evaluate the association of in utero ARV exposures with CAs in HIV-exposed uninfected children. Prospective cohort study design. The Pediatric HIV/AIDS Cohort Study's Surveillance Monitoring of ART Toxicities (SMARTT) Study was performed at 22 US medical centers among 2580 HIV-exposed uninfected children enrolled in the SMARTT Study between March 23, 2007, and June 18, 2012. First-trimester exposure to any ARV and to specific ARV medications. The primary end point was a CA based on physician review of infant physical examinations according to the Antiretroviral Pregnancy Registry modification of the Metropolitan Atlanta Congenital Defects Program. Rates of CAs were estimated overall and by birth year. Logistic regression models were used to evaluate the association of CAs with first-trimester ARV exposures, adjusting for demographic and maternal characteristics. Congenital anomalies occurred in 175 of 2580 children, yielding a prevalence of 6.78% (95% CI, 5.85%-7.82%); 242 major CAs were confirmed, including 72 musculoskeletal and 55 cardiovascular CAs. The prevalence of CAs increased significantly among successive birth cohorts (3.8% for children born before 2002 and up to 8.3% for those born 2008-2010). In adjusted models, no association of first-trimester exposures with CAs was found for any ARV, for combination ARV regimens, or for any drug class. No individual ARV in the reverse transcriptase inhibitor drug classes was associated with an increased risk of CAs. Among protease inhibitors, higher odds of CAs were observed for atazanavir sulfate (adjusted odds ratio [aOR], 1.95; 95% CI, 1.24-3.05) and for ritonavir used as a booster (aOR, 1.56; 95% CI, 1.11-2.20). With first

How Many Measurements Are Needed to Estimate Blood Pressure Variability Without Loss of Prognostic Information?

PubMed Central

2014-01-01

BACKGROUND Average real variability (ARV) is a recently proposed index for short-term blood pressure (BP) variability. We aimed to determine the minimum number of BP readings required to compute ARV without loss of prognostic information. METHODS ARV was calculated from a discovery dataset that included 24-hour ambulatory BP measurements for 1,254 residents (mean age = 56.6 years; 43.5% women) of Copenhagen, Denmark. Concordance between ARV from full (≥80 BP readings) and randomly reduced 24-hour BP recordings was examined, as was prognostic accuracy. A test dataset that included 5,353 subjects (mean age = 54.0 years; 45.6% women) with at least 48 BP measurements from 11 randomly recruited population cohorts was used to validate the results. RESULTS In the discovery dataset, a minimum of 48 BP readings allowed an accurate assessment of the association between cardiovascular risk and ARV. In the test dataset, over 10.2 years (median), 806 participants died (335 cardiovascular deaths, 206 cardiac deaths) and 696 experienced a major fatal or nonfatal cardiovascular event. Standardized multivariable-adjusted hazard ratios (HRs) were computed for associations between outcome and BP variability. Higher diastolic ARV in 24-hour ambulatory BP recordings predicted (P < 0.01) total (HR = 1.12), cardiovascular (HR = 1.19), and cardiac (HR = 1.19) mortality and fatal combined with nonfatal cerebrovascular events (HR = 1.16). Higher systolic ARV in 24-hour ambulatory BP recordings predicted (P < 0.01) total (HR = 1.12), cardiovascular (HR = 1.17), and cardiac (HR = 1.24) mortality. CONCLUSIONS Forty-eight BP readings over 24 hours were observed to be adequate to compute ARV without meaningful loss of prognostic information. PMID:23955605

Preliminary evidence of HIV seroconversion among HIV-negative men who have sex with men taking non-prescribed antiretroviral medication for HIV prevention in Miami, Florida, USA.

PubMed

Buttram, Mance E; Kurtz, Steven P

2017-04-01

Background Limited information suggests that men who have sex with men (MSM) are informally obtaining antiretroviral medication (ARVs) and using them for HIV pre-exposure prophylaxis (PrEP). Data are drawn from an on-going study examining the use of non-prescribed ARVs for PrEP. To date, 24 qualitative interviews have been conducted with HIV-negative, substance-using MSM living in Miami, Florida, USA. Data are presented from two participants who reported HIV seroconversion while using non-prescribed ARVs for PrEP. Preliminary data indicate that some young MSM: (i) lack awareness of and accurate information about the efficacious use of PrEP; (ii) obtain non-prescribed ARVs from HIV-positive sex partners and use these medications for PrEP in a way that does not provide adequate protection against HIV infection or cohere with established guidelines; and (iii) engage in multiple HIV transmission risk behaviours, including condomless anal sex and injection drug use. The informal, non-prescribed and non-medically supervised use of ARVs for HIV prevention has the potential to undermine the protective benefits of PrEP and leave men unprotected against HIV transmission and at risk for ARV resistance.

p52 Activation and Enzalutamide Therapy in Prostate Cancer

DTIC Science & Technology

2015-10-01

analyzed extracts from xenograft tumors derived from C4-2B and C4-2B-Enza-R cells using antibodies against AR-V7 and hnRNPA1. Higher levels of AR-V7...were observed in xenografts derived from C4-2B- Enza-R cells, which was correlated well with higher levels of hnRNPA1 and c-Myc (Fig. 3A right panel... Xenografts from C4-2B-Enza-R cells exhibit higher levels of AR-V7, hnRNPA1 and c-Myc. B) Left panel, Western analysis of AR-V7 in 22Rv1-Enza-R cells

Antiretroviral therapy supply chain quality control and assurance in improving people living with HIV therapeutic outcomes in Cameroon.

PubMed

Djobet, M P Ngogang; Singhe, David; Lohoue, Julienne; Kuaban, Christopher; Ngogang, Jeanne; Tambo, Ernest

2017-04-04

Evaluation of medication efficacy and safety is an essential guarantee to successful therapeutic outcome in public health practices. However, larger distribution chain supply in developing countries such as Cameroon is often challenged by counterfeit drugs, poor manufacturing, storage and degradation leading to health and patient adverse consequences. Yet, access to supply chain management in strengthening ARVs quality assurance and outcomes remains poorly documented. More than 53,000 patients have been enrolled on free ARVs medications, but little is documented on quality assurance and validity of safety for affected populations along the supply chain management since 2008. The cross sectional study was conducted in ARVs distribution units and centers in central, littoral and south west regions of Cameroon. ARVs drugs samples included Nevirapine, Efavirenz, and fixed dose combinations of Zidovudine + Lamivudine, Lamivudine + Stavudine and Zidovudine + Lamivudine + Nevirapine. Drugs packaging and labeling was assessed and galenic assays were performed at National Laboratory of quality Control of Medications and Expertise (LANACOME), Yaoundé, Cameroon. The study covered 16 structures located in eight different towns including the central ARVs store, two regional pharmaceutical procurement centers and thirteen HIV approved treatment centers and management units. A total of 35 ARVs products were collected. Only eight ARVs drugs containing Lamivudine and Stavudine presented with white stains on tablets, however these drugs were standard for all other tests performed. The others 28 ARVs products were standards to all assays performed. We concluded that ARVs drugs freely accessible and distributed to PLWHA are of good quality in Cameroon. However, with the increase number of patients under HAART since 2013, adoption of "Test and Treat" approach to reach the 90-90-90 goals and with the implementation of new national antiretroviral regimen guidelines and molecules

Affordability of adult HIV/AIDS treatment in developing countries: modelling price determinants for a better insight of the market functioning

PubMed Central

Sagaon-Teyssier, Luis; Singh, Sauman; Dongmo-Nguimfack, Boniface; Moatti, Jean-Paul

2016-01-01

Introduction This study aims to provide a landscape of the global antiretroviral (ARV) market by analyzing the transactional data on donor-funded ARV procurement between 2003 and 2015, and the ARV price determinants. Design The data were obtained from the Global Price Reporting Mechanism (GPRM) managed by the AIDS Medicines and Diagnostics Service of the WHO, and it consists of information that covers approximately 80% of the total donor-funded adult ARV transactions procurement. Methods ExWorks prices and procured quantities were standardized according to the guidelines in terms of yearly doses. Descriptive statistics on quantities and prices show the main trends of the ARV market. Ordinary least squares estimation was carried out for the whole sample, then stratified according to the type of supplier (originator and generic) and controlled for time and geographical fixed-effects. Given that analyses were carried out on a public dataset on ARV transactional prices from the GPRM, ethics are respected and consent was not necessary. Results Originator medicines are on average the least expensive in the sub-Saharan Africa region, where at the same time, generic medicines are on average the most expensive. By contrast, originator medicines are the most expensive in Europe and Central Asia, and generic medicines are the least expensive. In fact, the data suggest mixed strategies by ARV suppliers to exploit opportunities for profit maximization and to adapt to the specific conditions of market competition in each region. Our results also suggest that the expiration of patents is not sufficient to boost additional developments in generic competition (at least in the ARV market) and that formal or informal agreements between generic firms may de facto slow down or even reverse long-term trends towards price decreases. Conclusions Our findings provide an improved understanding of the ARV market that can help countries strengthen policy measures to increase their bargaining

Role of Androgen Receptor Variants in Prostate Cancer: Report from the 2017 Mission Androgen Receptor Variants Meeting.

PubMed

Luo, Jun; Attard, Gerhardt; Balk, Steven P; Bevan, Charlotte; Burnstein, Kerry; Cato, Laura; Cherkasov, Artem; De Bono, Johann S; Dong, Yan; Gao, Allen C; Gleave, Martin; Heemers, Hannelore; Kanayama, Mayuko; Kittler, Ralf; Lang, Joshua M; Lee, Richard J; Logothetis, Christopher J; Matusik, Robert; Plymate, Stephen; Sawyers, Charles L; Selth, Luke A; Soule, Howard; Tilley, Wayne; Weigel, Nancy L; Zoubeidi, Amina; Dehm, Scott M; Raj, Ganesh V

2018-05-01

Although a number of studies have demonstrated the importance of constitutively active androgen receptor variants (AR-Vs) in prostate cancer, questions still remain about the precise role of AR-Vs in the progression of castration-resistant prostate cancer (CRPC). Key stakeholders and opinion leaders in prostate cancer convened on May 11, 2017 in Boston to establish the current state of the field of AR-Vs. The meeting "Mission Androgen Receptor Variants" was the second of its kind sponsored by the Prostate Cancer Foundation (PCF). This invitation-only event was attended by international leaders in the field and representatives from sponsoring organizations (PCF and industry sponsors). Eighteen faculty members gave short presentations, which were followed by in-depth discussions. Discussions focused on three thematic topics: (1) potential of AR-Vs as biomarkers of therapeutic resistance; (2) role of AR-Vs as functionally active CRPC progression drivers; and (3) utility of AR-Vs as therapeutic targets in CRPC. The three meeting organizers synthesized this meeting report, which is intended to summarize major data discussed at the meeting and identify key questions as well as strategies for addressing these questions. There was a critical consensus that further study of the AR-Vs is an important research focus in CRPC. Contrasting views and emphasis, each supported by data, were presented at the meeting, discussed among the participants, and synthesized in this report. This article highlights the state of knowledge and outlines the most pressing questions that need to be addressed to advance the AR-V field. Although further investigation is needed to delineate the role of androgen receptor (AR) variants in metastatic castration-resistant prostate cancer, advances in measurement science have enabled development of blood-based tests for treatment selection. Detection of AR variants (eg, AR-V7) identified a patient population with poor outcomes to existing AR

Affordability of adult HIV/AIDS treatment in developing countries: modelling price determinants for a better insight of the market functioning.

PubMed

Sagaon-Teyssier, Luis; Singh, Sauman; Dongmo-Nguimfack, Boniface; Moatti, Jean-Paul

2016-01-01

This study aims to provide a landscape of the global antiretroviral (ARV) market by analyzing the transactional data on donor-funded ARV procurement between 2003 and 2015, and the ARV price determinants. The data were obtained from the Global Price Reporting Mechanism (GPRM) managed by the AIDS Medicines and Diagnostics Service of the WHO, and it consists of information that covers approximately 80% of the total donor-funded adult ARV transactions procurement. ExWorks prices and procured quantities were standardized according to the guidelines in terms of yearly doses. Descriptive statistics on quantities and prices show the main trends of the ARV market. Ordinary least squares estimation was carried out for the whole sample, then stratified according to the type of supplier (originator and generic) and controlled for time and geographical fixed-effects. Given that analyses were carried out on a public dataset on ARV transactional prices from the GPRM, ethics are respected and consent was not necessary. Originator medicines are on average the least expensive in the sub-Saharan Africa region, where at the same time, generic medicines are on average the most expensive. By contrast, originator medicines are the most expensive in Europe and Central Asia, and generic medicines are the least expensive. In fact, the data suggest mixed strategies by ARV suppliers to exploit opportunities for profit maximization and to adapt to the specific conditions of market competition in each region. Our results also suggest that the expiration of patents is not sufficient to boost additional developments in generic competition (at least in the ARV market) and that formal or informal agreements between generic firms may de facto slow down or even reverse long-term trends towards price decreases. Our findings provide an improved understanding of the ARV market that can help countries strengthen policy measures to increase their bargaining power in price negotiations and the use of TRIPS

Birth defects among a cohort of infants born to HIV-infected women on antiretroviral medication

PubMed Central

Watts, D. Heather; Huang, Sharon; Culnane, Mary; Kaiser, Kathleen A.; Scheuerle, Angela; Mofenson, Lynne; Stanley, Kenneth; Newell, Marie-Louise; Mandelbrot, Laurent; Delfraissy, Jean-Francois; Cunningham, Coleen K.

2011-01-01

Objective To determine rate of and risk factors for birth defects in infants born to HIV-infected women receiving nucleoside and protease inhibitor antiretroviral (ARV) therapy. Methods Birth defects were evaluated among infants on the Pediatric AIDS Clinical Trials Group 316 trial that studied addition of peripartum nevirapine to established ARV regimen for prevention of mother-to-child transmission. Maternal therapy was categorized by trimester of earliest exposure. Birth defects were coded using conventions of the Antiretroviral Pregnancy Registry. Results Birth defects were detected in 60/1414 (4.2%; 95% CI 3.3–5.4%) infants including 30/636 (4.7%; 95% CI 3.2–6.7%) with first trimester ARV exposure and 30/778 (3.9%; 95% CI 2.6–5.5%) with exposure only after the first trimester (P=0.51). Rates of classes of defects were similar between first trimester compared to later exposure groups except heart defects which occurred in 16 (2.5%; 95% CI 1.4–4.1%) with first trimester ARV exposure and in six (0.8%; 95% CI 0.3–1.7%) infants with later exposure (P=0.02). Exposure to ARV was not associated with specific types of heart defects. Two cases of cardiomyopathy were noted. Conclusion ARV use in early pregnancy was not associated with an increased risk of birth defects overall. The possible association of ARV exposure with heart defects requires further surveillance. PMID:21142844

Impact of the trade-related aspects of intellectual property rights (TRIPS) agreement on India as a supplier of generic antiretrovirals.

PubMed

Babovic, Sonja; Wasan, Kishor M

2011-03-01

This is a commentary on how the trade-related aspects of intellectual property rights (TRIPS) agreement has impacted India as a supplier of generic antiretrovirals (ARVs). We provide a systematic review of the issues related to the TRIPS agreement that affects India. This includes discussion around (a) the legal landscape underpinning India as a supplier of generic ARVs; (b) supply of second-line ARVs; and (c) the future of generic drug production in India. The proclamation into force of TRIPS-compliant intellectual property law in India is likely to affect its position as a supplier of affordable ARVs, especially drugs brought to market after 2005. Currently, mechanisms exist for the generic production of almost all ARVs in India, including second-line drugs; however, the manufacture of these drugs by generic pharmaceutical companies may require additional market incentives. Compulsory licensing may emerge as an additional mechanism by which India can provide affordable versions of patented drugs to Least Developed Countries (LDCs). Copyright © 2010 Wiley-Liss, Inc.

Flock-level prevalence, geographical distribution, and seasonal variation of avian reovirus among broiler flocks in Ontario.

PubMed

Nham, Eric G; Pearl, David L; Slavic, Durda; Ouckama, Rachel; Ojkic, Davor; Guerin, Michele T

2017-08-01

Avian reovirus (ARV) is an economically significant pathogen of broiler chickens. Our objective was to determine the prevalence, geographical distribution, and seasonal variation of ARV infection among commercial broiler flocks in Ontario, Canada during grow-out. A cross-sectional study of 231 randomly selected flocks was conducted from July 2010 to January 2012. Fifteen blood samples, 15 whole intestines, and 15 cloacal swabs per flock were collected at slaughter; ELISA and PCR were used to determine a flock's ARV exposure status. Avian reovirus prevalence was 91% (95% CI: 87 to 94). District alone did not significantly explain the overall variation in the prevalence of ARV (univariable logistic regression; P = 0.073), although geographical differences were identified. The odds of ARV presence were significantly lower in the summer/autumn compared to the winter/spring (univariable exact logistic regression; P < 0.001). There was no association between flock mortality and flock ELISA mean titer or PCR status.

Flock-level prevalence, geographical distribution, and seasonal variation of avian reovirus among broiler flocks in Ontario

PubMed Central

Nham, Eric G.; Pearl, David L.; Slavic, Durda; Ouckama, Rachel; Ojkic, Davor; Guerin, Michele T.

2017-01-01

Avian reovirus (ARV) is an economically significant pathogen of broiler chickens. Our objective was to determine the prevalence, geographical distribution, and seasonal variation of ARV infection among commercial broiler flocks in Ontario, Canada during grow-out. A cross-sectional study of 231 randomly selected flocks was conducted from July 2010 to January 2012. Fifteen blood samples, 15 whole intestines, and 15 cloacal swabs per flock were collected at slaughter; ELISA and PCR were used to determine a flock’s ARV exposure status. Avian reovirus prevalence was 91% (95% CI: 87 to 94). District alone did not significantly explain the overall variation in the prevalence of ARV (univariable logistic regression; P = 0.073), although geographical differences were identified. The odds of ARV presence were significantly lower in the summer/autumn compared to the winter/spring (univariable exact logistic regression; P < 0.001). There was no association between flock mortality and flock ELISA mean titer or PCR status. PMID:28761188

Antiretroviral Drugs-Loaded Nanoparticles Fabricated by Dispersion Polymerization with Potential for HIV/AIDS Treatment

PubMed Central

Ogunwuyi, Oluwaseun; Kumari, Namita; Smith, Kahli A.; Bolshakov, Oleg; Adesina, Simeon; Gugssa, Ayele; Anderson, Winston A.; Nekhai, Sergei; Akala, Emmanuel O.

2016-01-01

Highly active antiretroviral (ARV) therapy (HAART) for chronic suppression of HIV replication has revolutionized the treatment of HIV/AIDS. HAART is no panacea; treatments must be maintained for life. Although great progress has been made in ARV therapy, HIV continues to replicate in anatomical and intracellular sites where ARV drugs have restricted access. Nanotechnology has been considered a platform to circumvent some of the challenges in HIV/AIDS treatment. Dispersion polymerization was used to fabricate two types (PMM and ECA) of polymeric nanoparticles, and each was successfully loaded with four ARV drugs (zidovudine, lamivudine, nevirapine, and raltegravir), followed by physicochemical characterization: scanning electron microscope, particle size, zeta potential, drug loading, and in vitro availability. These nanoparticles efficiently inhibited HIV-1 infection in CEM T cells and peripheral blood mononuclear cells; they hold promise for the treatment of HIV/AIDS. The ARV-loaded nanoparticles with polyethylene glycol on the corona may facilitate tethering ligands for targeting specific receptors expressed on the cells of HIV reservoirs. PMID:27013886

How is adaptation, resilience, and vulnerability research engaging with gender?

NASA Astrophysics Data System (ADS)

Bunce, A.; Ford, J.

2015-12-01

The gendered dimensions of climate change have received increasing interest in climate change adaptation, resilience, and vulnerability (ARV) research. Yet concerns have been expressed that engagement with ‘gender’ in this work has been tokenistic. In this context, we ask: how is climate change ARV research engaging with gender? To answer this question, we develop an assessment framework capturing key attributes of engagement and use it to evaluate peer reviewed ARV articles with a focus on gender published since 2006 (n = 123). Results indicate an increase in ARV studies with a gender focus over this period, with the level of gender engagement also increasing. There are a relatively equal numbers of studies categorized as engaging gender at a high, medium, and low level, with studies from Sub-Saharan Africa consistently exhibiting high levels of gender engagement. Gender focused ARV has a strong focus on examining female experiences, with few studies explicitly focusing on men, and no work accounting for those identifying outside the gender binary.

2005 NDIA Combat Vehicles Conference. Volume 2- Thursday Presentations and Videos

DTIC Science & Technology

2005-09-22

Mounted Combat System MULE: (Countermine) MULE: (Transport) Class II Class III Class IV Armed Robotic Vehicle ARV RSTA ARV Assault FCS Recovery and...Vehicles – Infantry Carrier Vehicle (ICV) – Armed Robotic Vehicle - Assault (ARV (A)) – Recon & Surveillance Vehicle (RSV)  Training Ammo for AP & AB...Holtz and Mr. Dick Williams, Boeing Mr. Dean Vanderstelt, General Dynamics Land Systems ( GDLS ) Mr. Mike Zoltoski, TARDEC Mr. Peter DeMasi, Program

Religion and HIV in Tanzania: influence of religious beliefs on HIV stigma, disclosure, and treatment attitudes.

PubMed

Zou, James; Yamanaka, Yvonne; John, Muze; Watt, Melissa; Ostermann, Jan; Thielman, Nathan

2009-03-04

Religion shapes everyday beliefs and activities, but few studies have examined its associations with attitudes about HIV. This exploratory study in Tanzania probed associations between religious beliefs and HIV stigma, disclosure, and attitudes toward antiretroviral (ARV) treatment. A self-administered survey was distributed to a convenience sample of parishioners (n = 438) attending Catholic, Lutheran, and Pentecostal churches in both urban and rural areas. The survey included questions about religious beliefs, opinions about HIV, and knowledge and attitudes about ARVs. Multivariate logistic regression analysis was performed to assess how religion was associated with perceptions about HIV, HIV treatment, and people living with HIV/AIDS. Results indicate that shame-related HIV stigma is strongly associated with religious beliefs such as the belief that HIV is a punishment from God (p < 0.01) or that people living with HIV/AIDS (PLWHA) have not followed the Word of God (p < 0.001). Most participants (84.2%) said that they would disclose their HIV status to their pastor or congregation if they became infected. Although the majority of respondents (80.8%) believed that prayer could cure HIV, almost all (93.7%) said that they would begin ARV treatment if they became HIV-infected. The multivariate analysis found that respondents' hypothetical willingness to begin ARV treatme was not significantly associated with the belief that prayer could cure HIV or with other religious factors. Refusal of ARV treatment was instead correlated with lack of secondary schooling and lack of knowledge about ARVs. The decision to start ARVs hinged primarily on education-level and knowledge about ARVs rather than on religious factors. Research results highlight the influence of religious beliefs on HIV-related stigma and willingness to disclose, and should help to inform HIV-education outreach for religious groups.

Antiepileptic drug selection for people with HIV/AIDS: evidence-based guidelines from the ILAE and AAN.

PubMed

Birbeck, Gretchen L; French, Jacqueline A; Perucca, Emilio; Simpson, David M; Fraimow, Henry; George, Jomy M; Okulicz, Jason F; Clifford, David B; Hachad, Houda; Levy, René H

2012-01-01

A joint panel of the American Academy of Neurology (AAN) and the International League Against Epilepsy (ILAE) convened to develop guidelines for selection of antiepileptic drugs (AEDs) among people with HIV/AIDS. The literature was systematically reviewed to assess the global burden of relevant comorbid entities, to determine the number of patients who potentially utilize AEDs and antiretroviral agents (ARVs), and to address AED-ARV interactions. Key findings from this literature search included the following: AED-ARV administration may be indicated in up to 55% of people taking ARVs. Patients receiving phenytoin may require a lopinavir/ritonavir dosage increase of approximately 50% to maintain unchanged serum concentrations (Level C). Patients receiving valproic acid may require a zidovudine dosage reduction to maintain unchanged serum zidovudine concentrations (Level C). Coadministration of valproic acid and efavirenz may not require efavirenz dosage adjustment (Level C). Patients receiving ritonavir/atazanavir may require a lamotrigine dosage increase of approximately 50% to maintain unchanged lamotrigine serum concentrations (Level C). Coadministration of raltegravir/atazanavir and lamotrigine may not require lamotrigine dosage adjustment (Level C). Coadministration of raltegravir and midazolam may not require midazolam dosage adjustment (Level C). Patients may be counseled that it is unclear whether dosage adjustment is necessary when other AEDs and ARVs are combined (Level U). It may be important to avoid enzyme-inducing AEDs in people on ARV regimens that include protease inhibitors or nonnucleoside reverse transcriptase inhibitors because pharmacokinetic interactions may result in virologic failure, which has clinical implications for disease progression and development of ARV resistance. If such regimens are required for seizure control, patients may be monitored through pharmacokinetic assessments to ensure efficacy of the ARV regimen (Level C). Wiley

Evaluation of risk for late language emergence after in utero antiretroviral drug exposure in HIV-exposed uninfected infants.

PubMed

Rice, Mabel L; Zeldow, Bret; Siberry, George K; Purswani, Murli; Malee, Kathleen; Hoffman, Howard J; Frederick, Toni; Buchanan, Ashley; Sirois, Patricia A; Allison, Susannah M; Williams, Paige L

2013-10-01

Combination antiretroviral (cARV) regimens are recommended for pregnant women with HIV to prevent perinatal HIV transmission. Safety is a concern for infants who were HIV-exposed but uninfected, particularly for neurodevelopmental problems, such as language delays. We studied late language emergence (LLE) in HIV-exposed but uninfected children enrolled in a US-based prospective cohort study. LLE was defined as a caregiver-reported score ≤10th percentile in any of 4 domains of the MacArthur-Bates Communicative Development Inventory for 1-year olds and as ≥1 standard deviation below age-specific norms for the Ages and Stages Questionnaire for 2-year olds. Logistic regression models were used to evaluate associations of in utero cARV exposure with LLE, adjusting for infant, maternal and environmental characteristics. 1129 language assessments were conducted among 792 1- and 2-year-old children (50% male, 62% black and 37% Hispanic). Overall, 86% had in utero exposure to cARV and 83% to protease inhibitors. LLE was identified in 26% of 1-year olds and 23% of 2-year olds, with higher rates among boys. In adjusted models, LLE was not associated with maternal cARV or ARV drug classes in either age group. Among cARV-exposed 1-year olds, increased odds of LLE was observed for those exposed to atazanavir (adjusted odds ratio = 1.83, 95% confidence interval: 1.10-3.04), particularly after the first trimester (adjusted odds ratio = 3.56, P = 0.001), compared with atazanavir-unexposed infants. No associations of individual ARV drugs with LLE were observed among 2-year olds. In utero cARV exposure showed little association with LLE, except for a higher risk of language delay observed in 1-year-old infants with atazanavir exposure.

The Relationship of the Severity and Category of Acute Rejection With Intimal Arteritis Defined in Banff Classification to Clinical Outcomes.

PubMed

Wu, Kaiyin; Budde, Klemens; Schmidt, Danilo; Neumayer, Hans-Helmut; Rudolph, Birgit

2015-08-01

It is unclear if the category of acute rejection with intimal arteritis (ARV) is relevant to short- and long-term clinical outcomes and if the graft outcomes are affected by the severity of intimal arteritis. One hundred forty-eight ARV episodes were reviewed and categorized according to the 2013 Banff criteria of AMR: T cell-mediated rejection with intimal arteritis (v) lesion (TCMRV; n = 78), total antibody-mediated rejection with v lesion (AMRV), which were further divided into suspicious AMRV (n = 37) and AMRV (n = 33). The Banff scores of intimal arteritis (v1, v2 and v3) represented low, moderate, and high ARV severity. The grafts with TCMRV, suspicious AMRV (sAMRV), and AMRV showed similar responses to antirejection therapy, whereas the grafts with v2- or v3-ARV responded significantly poorer compared to those with v1-ARV. The 8-year death-censored graft survival (DCGS) rate was 56.8% of TCMRV versus 34.1% of total AMRV (Log rank, P = 0.03), but the 1- and 5-year DCGS rates were comparable between the 2 groups; moreover, the 1-, 5-, and 8-year DCGS rates of v1-ARV were evidently higher than v2- and v3-ARV (each pairwise comparison to v1-AVR yields P < 0.01); in contrast, the DCGS rates were similar between sAMRV and AMRV. The existing donor-specific antibodies or moderate microvascular inflammation or C4d-positive staining or intensive tubulointerstitial inflammation played a less significant role on the long-term graft survival. Compared to the category, the ARV severity is more closely associated with the initial response to antirejection therapy and long-term graft failure. The sAMRV and AMRV might represent a spectrum of the same disorder.

Role of vault cytology in follow-up of hysterectomized women: results and inferences from a low resource setting.

PubMed

Gupta, Sanjay; Sodhani, Pushpa; Singh, Veena; Sehgal, Ashok

2013-09-01

The study was undertaken to assess the utility of cervico-vaginal/vault cytology in the follow-up of women treated for cervical cancer and benign gynecological conditions. Records of 3,523 cervico-vaginal smears from 2,658 women who underwent hysterectomy and/or radiotherapy or chemotherapy, over a 10-year period were retrieved. Data was collected on type of treatment received, indication for hysterectomy, age of patient, presenting symptoms, stage of tumor, interval since treatment, cytology and biopsy results. The results of cytology versus other parameters were analyzed separately for women treated for cervical cancer and those hysterectomized for benign indications. Malignant cells were detected in 141/1949 (7.2%) follow-up smears from treated cervical cancer cases (140 recurrences and 1 VAIN). Around 92% of recurrences of cervical cancer were detected with in 2 years of follow-up and 75% of these women were symptomatic. Cytology first alerted the clinicians to a recurrence in a quarter of cases. On the other hand, VAIN was detected in 5/1079 (0.46%) vault smears from 997 women hysterectomized for benign gynecologic disease. All these women were asymptomatic and majority (80%) were detected in follow-up smears performed between 3 and 10 years. Vault cytology is an accurate tool to detect local recurrences/VAIN in women treated for cervical cancer or benign gynecological conditions. It may even first alert the clinicians to a possibility of recurrence. However, due to extremely low prevalence of VAIN/vaginal cancer, it seems unwarranted in women hysterectomized for benign indications, especially in resource constrained settings. Copyright © 2012 Wiley Periodicals, Inc., a Wiley company.

Integrated Attitude Control Strategy for the Asteroid Redirect Mission

NASA Technical Reports Server (NTRS)

Lopez, Pedro, Jr.; Price, Hoppy; San Martin, Miguel

2014-01-01

A deep-space mission has been proposed to redirect an asteroid to a distant retrograde orbit around the moon using a robotic vehicle, the Asteroid Redirect Vehicle (ARV). In this orbit, astronauts will rendezvous with the ARV using the Orion spacecraft. The integrated attitude control concept that Orion will use for approach and docking and for mated operations will be described. Details of the ARV's attitude control system and its associated constraints for redirecting the asteroid to the distant retrograde orbit around the moon will be provided. Once Orion is docked to the ARV, an overall description of the mated stack attitude during all phases of the mission will be presented using a coordinate system that was developed for this mission. Next, the thermal and power constraints of both the ARV and Orion will be discussed as well as how they are used to define the optimal integrated stack attitude. Lastly, the lighting and communications constraints necessary for the crew's extravehicular activity planned to retrieve samples from the asteroid will be examined. Similarly, the joint attitude control strategy that employs both the Orion and the ARV attitude control assets prior, during, and after each extravehicular activity will also be thoroughly discussed.

Recreational Drugs and HIV

MedlinePlus

... understood. Interactions with ARVs are possible but unknown. Marijuana (see fact sheet 731) There are no known interactions between marijuana and ARVs. Interactions may be greater if marijuana ...

Utilization and costs of HIV antiretroviral drugs in Europe during the last ten years: Impact of generic antiretroviral drugs on cost reduction.

PubMed

Rwagitinywa, Joseph; Sommet, Agnès; Palmaro, Aurore; Montastruc, Jean-Louis; Lapeyre-Mestre, Maryse

2018-03-01

Simulation studies showed that generic antiretroviral (ARV) drug utilization could lead to significant cost reduction of HIV treatment in developed world. This study aimed to quantify ARV utilization and costs in European countries between 2006 and 2015. We also assessed the impact of generic ARV drug utilization on cost reduction in real-life. ARV drug utilization in 14 European countries (France, Italy, Germany, Denmark, Netherlands, Norway, Sweden, Finland, Iceland, Croatia, Czech Republic, Estonia, Latvia, and Lithuania) were analysed using defined daily dose (DDD)/1000 inhabitants/year. ARV drug cost was estimated in million euro/year and euro/1000 inhabitants/year. The impact of generics on cost reduction was assessed in three countries: France, Denmark, and Czech Republic, using four parameters: expected savings, observed savings, brand price-reduction savings and overall savings. Between 2006 and 2015, median ARV drug utilization increased from 234 DDDs per 1000 inhabitants per year (IQR 124-388) to 385 (229-670). The median cost increased from €3751/1000 inhabitants/year (1109-4681) to €9158 (3269-10,646). Between 2013 and 2015, overall savings of €0.9, €1.6, and €33.7 million were respectively observed in Denmark, Czech Republic, and France. Overall savings observed in real-life from generic ARV drugs in Denmark were related to high rate of low-price generic utilization, contrarily to France and Czech Republic where these were more related to brand price-reduction than generic utilization itself. Copyright © 2018 Elsevier B.V. All rights reserved.

Effectiveness of a prevention of mother-to-child HIV transmission program in Guangdong province from 2007 to 2010

PubMed Central

2013-01-01

Background To achieve the goal of United Nations of elimination of new HIV infections, a program of prevention of mother-to-child transmission (PMTCT) was launched in Guangdong province. The objective of this study is to evaluate the effectiveness of the PMTCT program. Methods The retrospective cross-section analysis was conducted using the data of case reported cards of HIV positive mothers and their infants from 2007 to 2010 in Guangdong province, and 108 pairs of eligible subjects were obtained. We described the data and compared the rates of MTCT by various PMTCT interventions respectively. Results The overall rate of HIV MTCT was 13.89% (15) among 108 pairs of HIV positive mothers and their infants; 60.19% (65) of the mothers ever received ARVs, 80.56% (87) of infants born to HIV positive mothers ever received ARVs, but 16.67% (18) of the mothers and infants neither received ARVs. Among all the mothers and infants, who both received ARVs, received triple ARVs, mother received ARVs during pregnancy, and both received ARVs and formula feeding showed the lower rates of HIV MTCT, and the rates were 8.06%, 2.50%, 5.77%, and 6.67% respectively. In infants born to HIV positive mother, who received mixed feeding had a higher HIV MTCT up to 60.00%. Delivery mode might not relative to HIV MTCT. Conclusions The interventions of PMTCT program in Guangdong could effectively reduce the rate of HIV MTCT, but the effectiveness of the PMTCT program were heavily cut down by the lower availability of the PMTCT interventions. PMID:23773623

Dietary intake and body composition in HIV-positive and -negative South African women.

PubMed

Wrottesley, Stephanie V; Micklesfield, Lisa K; Hamill, Matthew M; Goldberg, Gail R; Prentice, Ann; Pettifor, John M; Norris, Shane A; Feeley, Alison B

2014-07-01

The present paper examines dietary intake and body composition in antiretroviral (ARV)-naïve HIV-positive compared with HIV-negative South African women, as well as the impact of disease severity on these variables. Baseline data from a longitudinal study assessing bone health in HIV-negative and HIV-positive premenopausal South African women over 18 years of age were used. Anthropometry and body composition, measured by dual energy X-ray absorptiometry, were analysed together with dietary intake data assessed using an interviewer-based quantitative FFQ. Soweto, Johannesburg, South Africa. Black, urban South African women were divided into three groups: (i) HIV-negative (HIV-; n 98); (ii) HIV-positive with preserved CD4 counts (HIV+ non-ARV; n 74); and (iii) HIV-positive with low CD4 counts and due to start ARV treatment (HIV+ pre-ARV; n 75). The prevalence of overweight and obesity was high in this population (59 %). The HIV+ pre-ARV group was lighter and had a lower BMI than the other two groups (all P < 0·001). HIV+ pre-ARV women also had lower fat and lean masses and percentage body fat than their HIV- and HIV+ non-ARV counterparts. After adjustment, there were no differences in macronutrient intakes across study groups; however, fat and sugar intakes were high and consumption of predominantly refined food items was common overall. HIV-associated immunosuppression may be a key determinant of body composition in HIV-positive women. However, in populations with high obesity prevalence, these differences become evident only at advanced stages of infection.

Novel BET protein proteolysis-targeting chimera exerts superior lethal activity than bromodomain inhibitor (BETi) against post-myeloproliferative neoplasm secondary (s) AML cells.

PubMed

Saenz, D T; Fiskus, W; Qian, Y; Manshouri, T; Rajapakshe, K; Raina, K; Coleman, K G; Crew, A P; Shen, A; Mill, C P; Sun, B; Qiu, P; Kadia, T M; Pemmaraju, N; DiNardo, C; Kim, M-S; Nowak, A J; Coarfa, C; Crews, C M; Verstovsek, S; Bhalla, K N

2017-09-01

The PROTAC (proteolysis-targeting chimera) ARV-825 recruits bromodomain and extraterminal (BET) proteins to the E3 ubiquitin ligase cereblon, leading to degradation of BET proteins, including BRD4. Although the BET-protein inhibitor (BETi) OTX015 caused accumulation of BRD4, treatment with equimolar concentrations of ARV-825 caused sustained and profound depletion (>90%) of BRD4 and induced significantly more apoptosis in cultured and patient-derived (PD) CD34+ post-MPN sAML cells, while relatively sparing the CD34+ normal hematopoietic progenitor cells. RNA-Seq, Reverse Phase Protein Array and mass cytometry 'CyTOF' analyses demonstrated that ARV-825 caused greater perturbations in messenger RNA (mRNA) and protein expressions than OTX015 in sAML cells. Specifically, compared with OTX015, ARV-825 treatment caused more robust and sustained depletion of c-Myc, CDK4/6, JAK2, p-STAT3/5, PIM1 and Bcl-xL, while increasing the levels of p21 and p27. Compared with OTX015, PROTAC ARV-771 treatment caused greater reduction in leukemia burden and further improved survival of NSG mice engrafted with luciferase-expressing HEL92.1.7 cells. Co-treatment with ARV-825 and JAK inhibitor ruxolitinib was synergistically lethal against established and PD CD34+ sAML cells. Notably, ARV-825 induced high levels of apoptosis in the in vitro generated ruxolitinib-persister or ruxolitinib-resistant sAML cells. These findings strongly support the in vivo testing of the BRD4-PROTAC based combinations against post-MPN sAML.

Validation of the CNS Penetration-Effectiveness Rank for Quantifying Antiretroviral Penetration Into the Central Nervous System

PubMed Central

Letendre, Scott; Marquie-Beck, Jennifer; Capparelli, Edmund; Best, Brookie; Clifford, David; Collier, Ann C.; Gelman, Benjamin B.; McArthur, Justin C.; McCutchan, J. Allen; Morgello, Susan; Simpson, David; Grant, Igor; Ellis, Ronald J.

2009-01-01

Objective To evaluate whether penetration of a combination regimen into the central nervous system (CNS), as estimated by the CNS Penetration-Effectiveness (CPE) rank, is associated with lower cerebrospinal fluid (CSF) viral load. Design Data were analyzed from 467 participants who were human immunodeficiency virus (HIV) seropositive and who reported antiretroviral (ARV) drug use. Individual ARV drugs were assigned a penetration rank of 0 (low), 0.5 (intermediate), or 1 (high) based on their chemical properties, concentrations in CSF, and/or effectiveness in the CNS in clinical studies. The CPE rank was calculated by summing the individual penetration ranks for each ARV in the regimen. Results The median CPE rank was 1.5 (interquartile range, 1–2). Lower CPE ranks correlated with higher CSF viral loads. Ranks less than 2 were associated with an 88% increase in the odds of detectable CSF viral load. In multivariate regression, lower CPE ranks were associated with detectable CSF viral loads even after adjusting for total number of ARV drugs, ARV drug adherence, plasma viral load, duration and type of the current regimen, and CD4 count. Conclusions Poorer penetration of ARV drugs into the CNS appears to allow continued HIV replication in the CNS as indicated by higher CSF HIV viral loads. Because inhibition of HIV replication in the CNS is probably critical in treating patients who have HIV-associated neurocognitive disorders, ARV treatment strategies that account for CNS penetration should be considered in consensus treatment guidelines and validated in clinical studies. PMID:18195140

HIV Genetic Diversity and Drug Resistance.

PubMed

Santos, André F; Soares, Marcelo A

2010-02-01

Most of the current knowledge on antiretroviral (ARV) drug development and resistance is based on the study of subtype B of HIV-1, which only accounts for 10% of the worldwide HIV infections. Cumulative evidence has emerged that different HIV types, groups and subtypes harbor distinct biological properties, including the response and susceptibility to ARV. Recent laboratory and clinical data highlighting such disparities are summarized in this review. Variations in drug susceptibility, in the emergence and selection of specific drug resistance mutations, in viral replicative capacity and in the dynamics of resistance acquisition under ARV selective pressure are discussed. Clinical responses to ARV therapy and associated confounding factors are also analyzed in the context of infections by distinct HIV genetic variants.

HIV Genetic Diversity and Drug Resistance

PubMed Central

Santos, André F.; Soares, Marcelo A.

2010-01-01

Most of the current knowledge on antiretroviral (ARV) drug development and resistance is based on the study of subtype B of HIV-1, which only accounts for 10% of the worldwide HIV infections. Cumulative evidence has emerged that different HIV types, groups and subtypes harbor distinct biological properties, including the response and susceptibility to ARV. Recent laboratory and clinical data highlighting such disparities are summarized in this review. Variations in drug susceptibility, in the emergence and selection of specific drug resistance mutations, in viral replicative capacity and in the dynamics of resistance acquisition under ARV selective pressure are discussed. Clinical responses to ARV therapy and associated confounding factors are also analyzed in the context of infections by distinct HIV genetic variants. PMID:21994646

The global pediatric antiretroviral market: analyses of product availability and utilization reveal challenges for development of pediatric formulations and HIV/AIDS treatment in children.

PubMed

Waning, Brenda; Diedrichsen, Ellen; Jambert, Elodie; Bärnighausen, Till; Li, Yun; Pouw, Mieke; Moon, Suerie

2010-10-17

Important advances in the development and production of quality-certified pediatric antiretroviral (ARV) formulations have recently been made despite significant market disincentives for manufacturers. This progress resulted from lobbying and innovative interventions from HIV/AIDS activists, civil society organizations, and international organizations. Research on uptake and dispersion of these improved products across countries and international organizations has not been conducted but is needed to inform next steps towards improving child health. We used information from the World Health Organization Prequalification Programme and the United States Food and Drug Administration to describe trends in quality-certification of pediatric formulations and used 7,989 donor-funded, pediatric ARV purchase transactions from 2002-2009 to measure uptake and dispersion of new pediatric ARV formulations across countries and programs. Prices for new pediatric ARV formulations were compared to alternative dosage forms. Fewer ARV options exist for HIV/AIDS treatment in children than adults. Before 2005, most pediatric ARVs were produced by innovator companies in single-component solid and liquid forms. Five 2-in1 and four 3-in-1 generic pediatric fixed-dose combinations (FDCs) in solid and dispersible forms have been quality-certified since 2005. Most (67%) of these were produced by one quality-certified manufacturer. Uptake of new pediatric FDCs outside of UNITAID is low. UNITAID accounted for 97-100% of 2008-2009 market volume. In total, 33 and 34 countries reported solid or dispersible FDC purchases in 2008 and 2009, respectively, but most purchases were made through UNITAID. Only three Global Fund country recipients reported purchase of these FDCs in 2008. Prices for pediatric FDCs were considerably lower than liquids but typically higher than half of an adult FDC. Pediatric ARV markets are more fragile than adult markets. Ensuring a long-term supply of quality, well

Pre-exposure prophylaxis and antiretroviral resistance: HIV prevention at a cost?

PubMed

Hurt, Christopher B; Eron, Joseph J; Cohen, Myron S

2011-12-01

Pre-exposure prophylaxis (PrEP), the use of antiretrovirals (ARVs) by human immunodeficiency virus (HIV)-uninfected individuals to prevent acquisition of the virus during high-risk sexual encounters, enjoyed its first 2 major successes with the Centre for the AIDS Programme of Research in South Africa (CAPRISA) 004 and the Pre-Exposure Prophylaxis Initiative (iPrEx). These successes were buoyed by additional positive results from the TDF2 and Partners PrEP trials. Although no seroconverters in either arm of CAPRISA developed resistance to tenofovir, 2 participants in iPrEx with undetected, seronegative acute HIV infection were randomized to receive daily oral tenofovir-emtricitabine and resistance to emtricitabine was later discovered in both men. A similar case in the TDF2 study resulted in resistance to both ARVs. These cases prompted us to examine existing literature on the nature of resistance mutations elicited by ARVs used for PrEP. Here, we discuss the impact of signature mutations selected by PrEP, how rapidly these emerge with daily ARV exposure, and the individual-level and public health consequences of ARV resistance.

Avian reovirus S1133-induced apoptosis is associated with Bip/GRP79-mediated Bim translocation to the endoplasmic reticulum.

PubMed

Lin, Ping-Yuan; Liu, Hung-Jen; Chang, Ching-Dong; Chen, Yo-Chia; Chang, Chi-I; Shih, Wen-Ling

2015-04-01

In this study the mechanism of avian reovirus (ARV) S1133-induced pathogenesis was investigated, with a focus on the contribution of ER stress to apoptosis. Our results showed that upregulation of the ER stress response protein, as well as caspase-3 activation, occurred in ARV S1133-infected cultured cells and in SPF White Leghorn chicks organs. Upon infection, Bim was translocated specifically to the ER, but not mitochondria, in the middle to late infectious stages. In addition, ARV S1133 induced JNK phosphorylation and promoted JNK-Bim complex formation, which correlated with the Bim translocation and apoptosis induction that was observed at the same time point. Knockdown of BiP/GRP78 by siRNA and inhibition of BiP/GRP78 using EGCG both abolished the formation of the JNK-Bim complex, caspase-3 activation, and subsequent apoptosis induction by ARV S1133 efficiently. These results suggest that BiP/GRP78 played critical roles and works upstream of JNK-Bim in response to the ARV S1133-mediated apoptosis process.

Comparative costs of inpatient care for HIV-infected and uninfected children and adults in Soweto, South Africa.

PubMed

Thomas, Leena S; Manning, Arthur; Holmes, Charles B; Naidoo, Shan; van der Linde, Frans; Gray, Glenda E; Martinson, Neil A

2007-12-01

HIV/AIDS creates a massive burden of care for health systems. A better understanding of the impact of HIV infection on health care utilization and costs may enable better use of limited resources. We compared public sector inpatient costs of HIV-infected versus uninfected adults and children at a large hospital in Soweto, South Africa. Daily hotel costs estimated from hospital financial data and total patient visits were combined with utilization, abstracted from patients' charts, and costed using government price lists to estimate total inpatient costs. A total of 1185 eligible records were included over a 6-week period in 2005. Eight hundred twelve were from HIV-infected patients, and of these, 77 were on antiretroviral (ARV) therapy. The mean length of stay (LOS) and mean drug and intravenous fluid utilization of HIV-infected adults not on ARVs was greater than those of uninfected adults, resulting in a $200 higher total average admission cost. Patients on ARVs had longer LOS and incurred a total average admission cost of $750 more than HIV-infected adults not on ARVs. Inpatient costs were greater for this selected group of HIV-infected adults, and even higher for the small proportion of individuals receiving ARVs. Budget allocations should incorporate case mix by HIV and ARV status as a key determinant of hospital expenditure.

Increased platelet reactivity in HIV-1-infected patients receiving abacavir-containing antiretroviral therapy.

PubMed

Satchell, Claudette S; O'Halloran, Jane A; Cotter, Aoife G; Peace, Aaron J; O'Connor, Eileen F; Tedesco, Anthony F; Feeney, Eoin R; Lambert, John S; Sheehan, Gerard J; Kenny, Dermot; Mallon, Patrick W G

2011-10-15

Current or recent use of abacavir for treating human immunodeficiency virus type 1 (HIV-1) infection has been associated with increased rates of myocardial infarction (MI). Given the role of platelet aggregation in thrombus formation in MI and the reversible nature of the abacavir association, we hypothesized that patients treated with abacavir would have increased platelet reactivity. In a prospective study in adult HIV-infected patients, we determined associations between antiretrovirals (ARVs), and in particular the nucleoside reverse transcriptase inhibitor abacavir, and platelet reactivity by measuring time-dependent platelet aggregation in response to agonists: adenosine diphosphate (ADP), thrombin receptor-activating peptide (TRAP), collagen, and epinephrine. Of 120 subjects, 40 were ARV-naive and 80 ARV-treated, 40 of whom were receiving abacavir. No consistent differences in platelet reactivity were observed between the ARV-naive and ARV-treated groups. In contrast, within the ARV-treated group, abacavir-treated subjects had consistently higher percentages of platelet aggregation upon exposure to ADP, collagen, and epinephrine (P = .037, P = .022, and P = .032, respectively) and had platelets that were more sensitive to aggregation upon exposure to TRAP (P = .025). The consistent increases in platelet reactivity observed in response to a range of agonists provides a plausible underlying mechanism to explain the reversible increased rates of MI observed in abacavir-treated patients.

Antiretroviral purchasing and prescription practices in Mexico: constraints, challenges and opportunities.

PubMed

Chaumont, Claire; Bautista-Arredondo, Sergio; Calva, Juan José; Bahena-González, Roberto Isaac; Sánchez-Juárez, Gerda Hitz; González de Araujo-Muriel, Arturo; Magis-Rodríguez, Carlos; Hernández-Ávila, Mauricio

2015-01-01

This study examines the antiretroviral (ARV) market characteristics for drugs procured and prescribed to Mexico's Social Protection System in Health beneficiaries between 2008 and 2013, and compares them with international data. Procurement information from the National Center for the Prevention and the Control of HIV/AIDS was analyzed to estimate volumes and prices of key ARV. Annual costs were compared with data from the World Health Organization's Global Price Reporting Mechanism for similar countries. Finally, regimens reported in the ARV Drug Management, Logistics and Surveillance System database were reviewed to identify prescription trends and model ARV expenditures until 2018. Results show that the first-line ARV market is concentrated among a small number of patented treatments, in which prescription is clinically adequate, but which prices are higher than those paid by similar countries. The current set of legal and structural options available to policy makers to bring prices down is extremely limited. Different negotiation policies were not successful to decrease ARV high prices in the public health market. The closed list approach had a good impact on prescription quality but was ineffective in reducing prices. The Coordinating Commission for Negotiating the Price of Medicines and other Health Supplies also failed to obtain adequate prices. To maximize purchase efficiency, policy makers should focus on finding long-term legal and political safeguards to counter the high prices imposed by pharmaceutical companies.

Mitochondrial function and apoptosis of peripheral mononuclear cells (PBMCs) in the HIV infected patients.

PubMed

Bociąga-Jasik, Monika; Góralska, Joanna; Polus, Anna; Śliwa, Agnieszka; Gruca, Anna; Raźny, Urszula; Zdzienicka, Anna; Garlicki, Aleksander; Mach, Tomasz; Dembińska-Kieć, Aldona

2013-06-01

HIV infection results in the development of immunodeficiency mainly due to the apoptosis of infected and by stander CD4 cells. The aim of the study was to follow the mitochondrial dependent pathway of apoptosis, one of the suggested mechanisms of above process. The inner mitochondrial membrane potential (MMP), Adenosine-5'-triphosphate (ATP) generation, apoptosis and necrosis markers of peripheral mononuclear cells (PBMCs) were compared in HIV infected patients and HIV negative control group. The correlation of blood viral load, TNFα concentration, CD4 cells count and duration of ARV therapy was considered. Additionally, group of HIV infected ARV-naive patients was involved for the follow-up study and the effects of one year of ARV therapy on measured parameters were studied. PBMCs of HIV infected individuals (especially without ARV therapy) demonstrated lower MMP and ATP generation and higher percentage of apoptotic/necrotic PBMCs. Correlation between blood TNFα level and mitochondrial dysfunction was observed. The first months of ARV therapy resulted in most significant restoration of mitochondrial function and living PBMCs count. HIV infection and ARV therapy have significant impact on mitochondrial function and apoptosis of PBMCs. They are driven by abnormal mitochondrial function apoptosis of immune cells which seems to be the key element leading to immunosuppression, thus an early intervention in this process by therapy can be beneficial for symptomatology of HIV infected patients.

Maternal Antiretroviral Use during Pregnancy and Infant Congenital Anomalies: The NISDI Perinatal Study

PubMed Central

Joao, Esau C.; Calvet, Guilherme A.; Krauss, Margot R.; Hance, Laura Freimanis; Ortiz, Javier; Ivalo, Silvina A.; Pierre, Russell; Reyes, Mary; Watts, D. Heather; Read, Jennifer S.

2009-01-01

Background We evaluated the association between maternal antiretrovirals (ARVs) during pregnancy and infant congenital anomalies (CAs), utilizing data from the NISDI Perinatal Study. Methods The study population consisted of first singleton pregnancies on study, ≥ 20 weeks gestation, among women enrolled in NISDI from Argentina and Brazil who delivered between September 2002 and October 2007. CAs were defined as any major structural or chromosomal abnormality, or a cluster of two or more minor abnormalities, according to the conventions of the Antiretroviral Pregnancy Registry. CAs were identified from fetal ultrasound, study visit, and death reports. The conventions of the Antiretroviral Pregnancy Registry were used. Prevalence rates [number of CAs per 100 live births (LBs)] were calculated for specific ARVs, classes of ARVs, and overall exposure to ARVs. Results Of 1229 women enrolled, 995 pregnancy outcomes (974 LBs) met the inclusion criteria. Of these, 60 infants (59 LBs and 1 stillbirth) had at least one CA. The overall prevalence of CAs (per 100 LBs) was 6.2 (95%CI = 4.6, 7.7). The prevalence of CAs after first trimester ARVs (6.2; 95%CI = 3.1, 9.3) was similar to that after second (6.8; 95%CI = 4.5, 9.0) or third trimester (4.3; 95%CI = 1.5, 7.2) exposure. The rate of CAs identified within seven days of delivery was 2.36 (95%CI: 1.4–3.3). Conclusions The prevalence of CAs following first trimester exposure to ARVs was similar to that following second or third trimester exposure. Continued surveillance for CAs among children exposed to ARVs during gestation is needed. PMID:20104119

Safety and effectiveness of antiretroviral drugs during pregnancy, delivery and breastfeeding for prevention of mother-to-child transmission of HIV-1: the Kesho Bora Multicentre Collaborative Study rationale, design, and implementation challenges.

PubMed

2011-01-01

To evaluate strategies to reduce HIV-1 transmission through breastfeeding, a multicentre study including a nested randomized controlled trial was implemented in five research sites in West, East and South Africa (The Kesho Bora Study). The aim was to optimize the use of antiretroviral (ARV) drugs during pregnancy, delivery and breastfeeding to prevent mother-to-child transmission of HIV-1 (PMTCT) and to preserve the health of the HIV-1-infected mother. The study included long-term ARV treatment for women with advanced disease, and short-course ARV prophylaxis stopped at delivery for women with early disease. Women with intermediate disease participated in a randomized controlled trial to compare safety and efficacy of triple-ARV prophylaxis prolonged during breastfeeding with short-course ARV prophylaxis stopped at delivery. Between January 2005 and August 2008 a total of 1140 women were enrolled. This paper describes the study design, interventions and protocol amendments introduced to adapt to evolving scientific knowledge, international guidelines and availability of ARV treatment. The paper highlights the successes and challenges during the conduct of the trial. The Kesho Bora Study included one of the few randomized controlled trials to assess safety and efficacy of ARV prophylaxis continued during breastfeeding and the only randomized trial to assess maternal prophylaxis started during pregnancy. The findings have been important for informing international and national guidelines on MTCT prevention in developing countries where, due to poverty, lack of reliable and affordable supply of replacement feed and stigma associated with HIV/AIDS, HIV-infected women have little or no option other than to breastfeed their infants. (ISRCTN71468401). Copyright © 2010 Elsevier Inc. All rights reserved.

Five Antiretroviral Drug Class-Resistant HIV-1 in a Treatment-Naïve Patient Successfully Suppressed with Optimized Antiretroviral Drug Selection.

PubMed

Volpe, Joseph M; Ward, Douglas J; Napolitano, Laura; Phung, Pham; Toma, Jonathan; Solberg, Owen; Petropoulos, Christos J; Walworth, Charles M

2015-01-01

Transmitted HIV-1 exhibiting reduced susceptibility to protease and reverse transcriptase inhibitors is well documented but limited for integrase inhibitors and enfuvirtide. We describe here a case of transmitted 5 drug class-resistance in an antiretroviral (ARV)-naïve patient who was successfully treated based on the optimized selection of an active ARV drug regimen. The value of baseline resistance testing to determine an optimal ARV treatment regimen is highlighted in this case report. © The Author(s) 2015.

The psychosocial conditions and intensified education that may affect school performance of HIV/AIDS orphaned children on antiretroviral drugs.

PubMed

Shahum, Gregory; Shahum, Andrea; Sladeckova, Veronika; Hardy, Maria; Rabarova, Lenka; Benca, George J

2013-09-01

This study begins with interpreting basic academic results from the House of Family (HOF) comprehensive project for HIV/AIDS orphaned children. We reviewed school performance during the academic period from 2007 to 2012. All the children in the HOF project have vertically acquired HIV infection, with approximately 90% being with AIDS/Clinical Stage C at the time of admission. Initiation of antiretroviral drugs (ARV) was at the average age of 7 (mean 6.94, median 6.5, and a mode of 6). In the year 2007, 44 children had been receiving ARV. The majority of these children 32 (72.7%) were on ARV for at least 1 year, 6 (13.6%) of the children on ARV for 4 years, 7 (15.9%) were on ARV for 3 years, 5 (11.3%) for 2 years, 14 (31.8%) for 1 year, and 12 (27.2%) started ARV on that year. Later on, an additional 2 children started ARV in 2008, 1 child in 2009, and 4 children in 2010. We found that the total number of children achieving a certain academic level changed very little between each scholastic year. During the four years of school reviewed, it was noted that the Poor performers made improvement and an increase in Good performance grades was also achieved. The trend of Fair levels remained mostly unchanged at 65%, 70.2%, 68.5%, and 64.6% respectively. The overall passing performance, including both Fair and Good scores, improved from 67.5% in 2008 to 80.8% the following year of school. This passing rate of 80.8% in 2009 remains stable over the next two years at 80.3% and 80.3% respectively. Despite the late introduction of ARV medicine, limited family and social support, and deficient academic achievement, the children of HOF were able to improve their school performance due to intensified psychosocial and educational support provided at the HOF comprehensive project.

NF-κB and androgen receptor variant expression correlate with human BPH progression.

PubMed

Austin, David C; Strand, Douglas W; Love, Harold L; Franco, Omar E; Jang, Alex; Grabowska, Magdalena M; Miller, Nicole L; Hameed, Omar; Clark, Peter E; Fowke, Jay H; Matusik, Robert J; Jin, Ren J; Hayward, Simon W

2016-04-01

Benign prostatic hyperplasia (BPH) is a common, chronic progressive disease. Inflammation is associated with prostatic enlargement and resistance to 5α-reductase inhibitor (5ARI) therapy. Activation of the nuclear factor-kappa B (NF-κB) pathway is linked to both inflammation and ligand-independent prostate cancer progression. NF-κB activation and androgen receptor variant (AR-V) expression were quantified in transition zone tissue samples from patients with a wide range of AUASS from incidental BPH in patients treated for low grade, localized peripheral zone prostate cancer to advanced disease requiring surgical intervention. To further investigate these pathways, human prostatic stromal and epithelial cell lines were transduced with constitutively active or kinase dead forms of IKK2 to regulate canonical NF-κB activity. The effects on AR full length (AR-FL) and androgen-independent AR-V expression as well as cellular growth and differentiation were assessed. Canonical NF-κB signaling was found to be upregulated in late versus early stage BPH, and to be strongly associated with non-insulin dependent diabetes mellitus. Elevated expression of AR-variant 7 (AR-V7), but not other AR variants, was found in advanced BPH samples. Expression of AR-V7 significantly correlated with the patient AUASS and TRUS volume. Forced activation of canonical NF-κB in human prostatic epithelial and stromal cells resulted in elevated expression of both AR-FL and AR-V7, with concomitant ligand-independent activation of AR reporters. Activation of NF-κB and over expression of AR-V7 in human prostatic epithelial cells maintained cell viability in the face of 5ARI treatment. Activation of NF-κB and AR-V7 in the prostate is associated with increased disease severity. AR-V7 expression is inducible in human prostate cells by forced activation of NF-κB resulting in resistance to 5ARI treatment, suggesting a potential mechanism by which patients may become resistant to 5ARI therapy. �

An analysis of volumes, prices and pricing trends of the pediatric antiretroviral market in developing countries from 2004 to 2012.

PubMed

Lee, Janice Soo Fern; Sagaon Teyssier, Luis; Dongmo Nguimfack, Boniface; Collins, Intira Jeannie; Lallemant, Marc; Perriens, Joseph; Moatti, Jean-Paul

2016-03-15

The pediatric antiretroviral (ARV) market is poorly described in the literature, resulting in gaps in understanding treatment access. We analyzed the pediatric ARV market from 2004 to 2012 and assessed pricing trends and associated factors. Data on donor funded procurements of pediatric ARV formulations reported to the Global Price Reporting Mechanism database from 2004 to 2012 were analyzed. Outcomes of interest were the volume and mean price per patient-year ARV formulation based on WHO ARV dosing recommendations for a 10 kg child. Factors associated with the price of formulations were assessed using linear regression; potential predictors included: country income classification, geographical region, market segment (originator versus generic ARVs), and number of manufacturers per formulation. All analyses were adjusted for type of formulations (single, dual or triple fixed-dose combinations (FDCs)) Data from 111 countries from 2004 to 2012 were included, with procurement of 33 formulations at a total value of USD 204 million. Use of dual and triple FDC formulations increased substantially over time, but with limited changes in price. Upon multivariate analysis, prices of originator formulations were found to be on average 72 % higher than generics (p < 0.001). A 10 % increase in procurement volume was associated with a 1 % decrease (p < 0.001) in both originator and generic prices. The entry of one additional manufacturer producing a formulation was associated with a decrease in prices of 2 % (p < 0.001) and 8 % (p < 0.001) for originator and generic formulations, respectively. The mean generic ARV price did not differ by country income level. Prices of originator ARVs were 48 % (p < 0.001) and 14 % (p < 0.001) higher in upper-middle income and lower-middle income countries compared to low income countries respectively, with the exception of South Africa, which had lower prices despite being an upper-middle income country. The

Transcript Levels of Androgen Receptor Variant 7 and Ubiquitin-Conjugating Enzyme 2C in Hormone Sensitive Prostate Cancer and Castration-Resistant Prostate Cancer.

PubMed

Lee, Chan Ho; Ku, Ja Yoon; Ha, Jung Min; Bae, Sun Sik; Lee, Jeong Zoo; Kim, Choung-Soo; Ha, Hong Koo

2017-01-01

This study is designed to identify the androgen receptor variant 7 (AR-V7) status, clinical significance of AR-V7 in hormone sensitive prostate cancer (HSPC). Then, we evaluated AR-V7 and changes of its target gene, ubiquitin-conjugating enzyme E2C (UBE2C) which is an anaphase-promoting complex/cyclosome (APC/C)-specific ubiquitin-conjugating enzyme, in castration-resistant prostate cancer (CRPC) in serial tumor biopsies from patients receiving androgen deprivation therapy. We used RT-PCR and Q-PCR assay to evaluate AR-V7, androgen receptor full length (AR-FL), and UBE2C in tumor biopsies from patients with HSPC and CRPC. We examined associations between mRNA expression of AR-V7 and clinicopathologic factors. Furthermore, to identify other potential genes involved in the development of CRPC, RNA sequencing was conducted, using paired prostate cancer (PCa) tissues obtained immediately prior to treatment and at the time of therapeutic resistance. A total of 13 HSPC patients and three CRPC patients were enrolled. Neither a high Gleason score (score of 8 and 9) nor a high risk of PCa (a high risk of locally advanced PCa according to NCCN guidelines) was correlated with mRNA expression of AR-V7 in HSPC (P = 0.153 and P = 0.215). The mRNA expression of AR-FL, but not AR-V7, was significantly associated with the mRNA expression of UBE2C level in HSPC (P = 0.007). However, increased expression of AR-V7, not AR-FL, paralleled increased expression of UBE2C in the CRPC specimens (P = 0.03). AR-V7 expression status before ADT was likely related to shorter CRPC development in patients treating ADT. The result of the RNA-sequencing analysis using serial samples from the same patient before and after castration demonstrated an increased level of the PI3K regulatory subunit 1 (P = 0.018). Our study revealed the role of UBE2C as a marker of the androgen signaling pathway in PCa. Differential gene expression analysis using serial samples from the same patient

The global pediatric antiretroviral market: analyses of product availability and utilization reveal challenges for development of pediatric formulations and HIV/AIDS treatment in children

PubMed Central

2010-01-01

Background Important advances in the development and production of quality-certified pediatric antiretroviral (ARV) formulations have recently been made despite significant market disincentives for manufacturers. This progress resulted from lobbying and innovative interventions from HIV/AIDS activists, civil society organizations, and international organizations. Research on uptake and dispersion of these improved products across countries and international organizations has not been conducted but is needed to inform next steps towards improving child health. Methods We used information from the World Health Organization Prequalification Programme and the United States Food and Drug Administration to describe trends in quality-certification of pediatric formulations and used 7,989 donor-funded, pediatric ARV purchase transactions from 2002-2009 to measure uptake and dispersion of new pediatric ARV formulations across countries and programs. Prices for new pediatric ARV formulations were compared to alternative dosage forms. Results Fewer ARV options exist for HIV/AIDS treatment in children than adults. Before 2005, most pediatric ARVs were produced by innovator companies in single-component solid and liquid forms. Five 2-in1 and four 3-in-1 generic pediatric fixed-dose combinations (FDCs) in solid and dispersible forms have been quality-certified since 2005. Most (67%) of these were produced by one quality-certified manufacturer. Uptake of new pediatric FDCs outside of UNITAID is low. UNITAID accounted for 97-100% of 2008-2009 market volume. In total, 33 and 34 countries reported solid or dispersible FDC purchases in 2008 and 2009, respectively, but most purchases were made through UNITAID. Only three Global Fund country recipients reported purchase of these FDCs in 2008. Prices for pediatric FDCs were considerably lower than liquids but typically higher than half of an adult FDC. Conclusion Pediatric ARV markets are more fragile than adult markets. Ensuring a long

Cancer Among Children With Perinatal Exposure to HIV and Antiretroviral Medications--New Jersey, 1995-2010.

PubMed

Ivy, Wade; Nesheim, Steve R; Paul, Sindy M; Ibrahim, Abdel R; Chan, Miranda; Niu, Xiaoling; Lampe, Margaret A

2015-09-01

Concerns remain regarding the cancer risk associated with perinatal antiretroviral (ARV) exposure among infants. No excessive cancer risk has been found in short-term studies. Children born to HIV-infected women (HIV-exposed) in New Jersey from 1995 to 2008 were identified through the Enhanced HIV/AIDS Reporting System and cross-referenced with data from the New Jersey State Cancer Registry to identify new cases of cancer among children who were perinatally exposed to ARV. Matching of individuals in the Enhanced HIV/AIDS Reporting System to the New Jersey State Cancer Registry was conducted based on name, birth date, Social Security number, residential address, and sex using AutoMatch. Age- and sex-standardized incidence ratio (SIR) and exact 95% confidence intervals (CIs) were calculated using New Jersey (1979-2005) and US (1999-2009) cancer rates. Among 3087 children (29,099 person-years; median follow-up: 9.8 years), 4 were diagnosed with cancer. Cancer incidence among HIV-exposed children who were not exposed to ARV prophylaxis (22.5 per 100,000 person-years) did not differ significantly from the incidence among children who were exposed to any perinatal ARV prophylaxis (14.3 per 100,000 person-years). Furthermore, the number of cases observed among individuals exposed to ARV did not differ significantly from cases expected based on state (SIR = 1.21; 95% CI: 0.25 to 3.54) and national (SIR = 1.27; 95% CI: 0.26 to 3.70) reference rates. Our findings are reassuring that current use of ARV for perinatal HIV prophylaxis does not increase cancer risk. We found no evidence to alter the current federal guidelines of 2014 that recommend ARV prophylaxis of HIV-exposed infants.

Antiretroviral monocyte efficacy score linked to cognitive impairment in HIV.

PubMed

Shikuma, Cecilia M; Nakamoto, Beau; Shiramizu, Bruce; Liang, Chin-Yuan; DeGruttola, Victor; Bennett, Kara; Paul, Robert; Kallianpur, Kalpana; Chow, Dominic; Gavegnano, Christina; Hurwitz, Selwyn J; Schinazi, Raymond F; Valcour, Victor G

2012-01-01

Monocytes transmigrating to the brain play a central role in HIV neuropathology. We hypothesized that the continued existence of neurocognitive impairment (NCI) despite potent antiretroviral (ARV) therapy is mediated by the inability of such therapy to control this monocyte/macrophage reservoir. Cross-sectional and longitudinal analyses were conducted within a prospectively enrolled cohort. We devised a monocyte efficacy (ME) score based on the anticipated effectiveness of ARV medications against monocytes/macrophages using published macrophage in vitro drug efficacy data. We examined, within an HIV neurocognitive database, its association with composite neuropsychological test scores (NPZ8) and clinical cognitive diagnoses among subjects on stable ARV medications unchanged for >6 months prior to assessment. Among 139 subjects on ARV therapy, higher ME score correlated with better NPZ8 performance (r=0.23, P<0.01), whereas a score devised to quantify expected penetration effectiveness of ARVs into the brain (CPE score) did not (r=0.12, P=0.15). In an adjusted model (adjusted r(2)=0.12), ME score (β=0.003, P=0.02), CD4(+) T-cell nadir (β=0.001, P<0.01) and gender (β=-0.456, P=0.02) were associated with NPZ8, whereas CPE score was not (β=0.003, P=0.94). A higher ME score was associated with better clinical cognitive status (P<0.01). With a range of 12.5-433.0 units, a 100-unit increase in ME score resulted in a 10.6-fold decrease in the odds of a dementia diagnosis compared with normal cognition (P=0.01). ARV efficacy against monocytes/macrophages correlates with cognitive function in HIV-infected individuals on ARV therapy within this cohort. If validated, efficacy against monocytes/macrophages may provide a new target to improve HIV NCI.

Case profile, volume analysis, and dropout rate of antirabies vaccination regimens among animal bite victims in Gujarat.

PubMed

Dhaduk, Kishor M; Unadkat, Sumit V; Katharotiya, Pooja R; Mer, Ankit R; Chaudhary, Monika C; Prajapati, Mrudul M

2016-01-01

Rabies is a preventable neglected public health problem and associated with multiple cultural, religious, and social practices, myths in our country. There is a lack of organized surveillance system to measure the incidence of animal bite and human rabies as well as to evaluate cost-saving of different routes, regimen, and types of antirabies vaccines (ARV)/immunoglobulin available in India. The objective of this study is to know dropout rate in intradermal (i.d.) ARV regimen among animal bite and to analyze the utilized volume of ARV by a different route of vaccine administration. A total of 250 animal bite victims were followed up at ARV Clinic (ARVC). Volume utilization of i.d. route over intramuscular (i.m.) route was analyzed among the patients who attended ARVC during the past 2 years. Total dropout and delayed compliance rates of ARV regimen among different group were compared by Chi-square test. The i.d. route was about five times more volume and cost-saving than i.m. route. The majority of victims belonged to 15-30 years (27.60%) and children <15 years (26.40%) and had wound at their lower limbs (85%) mainly bitten by dogs (98%). Thirty-four percent total dropout and 31.5% delayed compliance observed particularly during the last dose of i.d. regimen. There was no significant difference in dropout rates among different demographic groups. Half of the victims practiced wound toilet on the same day of bite. Only 68% received the first dose of ARV within 24 h of the exposure. Children and young adults are at higher risk of having dog bite. I.d. ARV regimen is more volume and cost-saving than i.m. one and proper counseling and follow-up should be arranged to complete the vaccination schedule.

Financial Barriers and Lapses in Treatment and Care of HIV-Infected Adults in a Southern State in the United States.

PubMed

Wohl, David A; Kuwahara, Rita K; Javadi, Kamran; Kirby, Christine; Rosen, David L; Napravnik, Sonia; Farel, Claire

2017-11-01

Antiretroviral (ARV) adherence has largely been considered from the perspective of an individual's behavior with less attention given to potential structural causes for lapses in treatment, such as the cost of medications and care. HIV medication expense is typically covered by third party payers. However, private insurance premiums and deductibles may rise, or policies terminated such as with a change in employment. Likewise, a patient's eligibility for publicly funded coverage like state AIDS Drug Assistance Programs (ADAP) or Medicaid can also be lost. We conducted a one-time survey of a sample of 300 patients receiving HIV care at a single large academic center in the south of United States to examine lapses in HIV therapy due to financial reasons. We found that during the prior year, financial issues including medication cost or coverage led to a lapse in ARVs in 10% (n = 31) of participants. However, of the 42% (n = 125) participants who had been enrolled in ADAP at any time during the prior year, 21% (n = 26) reported an ARV lapse due to problems with ADAP or medication cost. Respondents cited ADAP's required semi-annual renewal process and other administrative issues as the cause of ARV lapses. The median duration of missed ARVs was 2 weeks (range of <1-23 weeks). Non-HIV medication and transportation to and from clinic costs were also identified as financial burdens to care by respondents. In conclusion, although conducted at a single medical center and one state, this study suggests that a significant minority of HIV-infected patients encounter financial barriers to ARV access, and this is paradoxically more common among those enrolled in the state ADAP. Streamlining, supporting, and simplifying ADAP renewal procedures will likely reduce lapses in ARV adherence and persistence.

24-Hour Blood Pressure Variability Assessed by Average Real Variability: A Systematic Review and Meta-Analysis.

PubMed

Mena, Luis J; Felix, Vanessa G; Melgarejo, Jesus D; Maestre, Gladys E

2017-10-19

Although 24-hour blood pressure (BP) variability (BPV) is predictive of cardiovascular outcomes independent of absolute BP levels, it is not regularly assessed in clinical practice. One possible limitation to routine BPV assessment is the lack of standardized methods for accurately estimating 24-hour BPV. We conducted a systematic review to assess the predictive power of reported BPV indexes to address appropriate quantification of 24-hour BPV, including the average real variability (ARV) index. Studies chosen for review were those that presented data for 24-hour BPV in adults from meta-analysis, longitudinal or cross-sectional design, and examined BPV in terms of the following issues: (1) methods used to calculate and evaluate ARV; (2) assessment of 24-hour BPV determined using noninvasive ambulatory BP monitoring; (3) multivariate analysis adjusted for covariates, including some measure of BP; (4) association of 24-hour BPV with subclinical organ damage; and (5) the predictive value of 24-hour BPV on target organ damage and rate of cardiovascular events. Of the 19 assessed studies, 17 reported significant associations between high ARV and the presence and progression of subclinical organ damage, as well as the incidence of hard end points, such as cardiovascular events. In all these cases, ARV remained a significant independent predictor ( P <0.05) after adjustment for BP and other clinical factors. In addition, increased ARV in systolic BP was associated with risk of all cardiovascular events (hazard ratio, 1.18; 95% confidence interval, 1.09-1.27). Only 2 cross-sectional studies did not find that high ARV was a significant risk factor. Current evidence suggests that ARV index adds significant prognostic information to 24-hour ambulatory BP monitoring and is a useful approach for studying the clinical value of BPV. © 2017 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley.

Galeterone and VNPT55 induce proteasomal degradation of AR/AR-V7, induce significant apoptosis via cytochrome c release and suppress growth of castration resistant prostate cancer xenografts in vivo

PubMed Central

Kwegyir-Afful, Andrew K.; Ramalingam, Senthilmurugan; Purushottamachar, Puranik; Ramamurthy, Vidya P.; Njar, Vincent C.O.

2015-01-01

Galeterone (Gal) is a first-in-class multi-target oral small molecule that will soon enter pivotal phase III clinical trials in castration resistant prostate cancer (CRPC) patients. Gal disrupts androgen receptor (AR) signaling via inhibition of CYP17, AR antagonism and AR degradation. Resistance to current therapy is attributed to up-regulation of full-length AR (fAR), splice variants AR (AR-Vs) and AR mutations. The effects of gal and VNPT55 were analyzed on f-AR and AR-Vs (AR-V7/ARv567es) in LNCaP, CWR22Rv1 and DU145 (transfected with AR-Vs) human PC cells in vitro and CRPC tumor xenografts. Galeterone/VNPT55 decreased fAR/AR-V7 mRNA levels and implicates Mdm2/CHIP enhanced ubiquitination of posttranslational modified receptors, targeting them for proteasomal degradation. Gal and VNPT55 also induced significant apoptosis in PC cells via increased Bax/Bcl2 ratio, cytochrome-c release with concomitant cleavage of caspase 3 and PARP. More importantly, gal and VNPT55 exhibited strong in vivo anti-CRPC activities, with no apparent host toxicities. This study demonstrate that gal and VNPT55 utilize cell-based mechanisms to deplete both fAR and AR-Vs. Importantly, the preclinical activity profiles, including profound apoptotic induction and inhibition of CRPC xenografts suggest that these agents offer considerable promise as new therapeutics for patients with CRPC and those resistant to current therapy. PMID:26196320

Modeling HIV/AIDS Drug Price Determinants in Brazil: Is Generic Competition a Myth?

PubMed Central

Meiners, Constance; Sagaon-Teyssier, Luis; Hasenclever, Lia; Moatti, Jean-Paul

2011-01-01

Background Brazil became the first developing country to guarantee free and universal access to HIV/AIDS treatment, with antiretroviral drugs (ARVs) being delivered to nearly 190,000 patients. The analysis of ARV price evolution and market dynamics in Brazil can help anticipate issues soon to afflict other developing countries, as the 2010 revision of the World Health Organization guidelines shifts demand towards more expensive treatments, and, at the same time, current evolution of international legislation and trade agreements on intellectual property rights may reduce availability of generic drugs for HIV care. Methods and Findings Our analyses are based on effective prices paid for ARV procurement in Brazil between 1996 and 2009. Data panel structure was exploited to gather ex-ante and ex-post information and address various sources of statistical bias. In-difference estimation offered in-depth information on ARV market characteristics which significantly influence prices. Although overall ARV prices follow a declining trend, changing characteristics in the generic segment help explain recent increase in generic ARV prices. Our results show that generic suppliers are more likely to respond to factors influencing demand size and market competition, while originator suppliers tend to set prices strategically to offset compulsory licensing threats and generic competition. Significance In order to guarantee the long term sustainability of access to antiretroviral treatment, our findings highlight the importance of preserving and stimulating generic market dynamics to sustain developing countries' bargaining power in price negotiations undertaken with originator companies. PMID:21858138

Inadequate pre-antiretroviral care, stock-out of antiretroviral drugs and stigma: policy challenges/bottlenecks to the new WHO recommendations for earlier initiation of antiretroviral therapy (CD<350 cells/microL) in eastern Uganda.

PubMed

Muhamadi, Lubega; Nsabagasani, Xavier; Tumwesigye, Mbona Nazarius; Wabwire-Mangen, Fred; Ekström, Anna-Mia; Peterson, Stefan; Pariyo, George

2010-10-01

This study explores reasons for late ART initiation among known HIV positive persons in care from a client/caretaker perspective in eastern Ugandan where ART awareness is presumably high yet AIDS related mortality is a common function of late initiation of ARVs. In Iganga, Uganda we conducted in-depth interviews with clients who started ART at 50-200 CD4 cells/microL and those initiated very late at CD4<50 cells/microL. Focus-group discussions were also conducted with caretakers of clients on ART. Content analysis was performed to identify recurrent themes. ARV stock-outs, inadequate pre-antiretroviral care and lack of staff confidentiality were system barriers to timely ART initiation. Weak social support and prevailing stigma and misconceptions about ARVs as drugs designed to kill, cause cancer, infertility or impotence were other important factors. If the new WHO recommendations (start ART at CD4 350 cells/microL) should be feasible, PLHIV/communities need sensitization about the importance of regular pre-ARV care through the local media and authorities. The ARV supply chain and staff attitudes towards client confidentiality must also be improved in order to encourage timely ART initiation. PLHIV/communities should be sensitization about drug package labeling and the use and importance of ARVs. Stronger social support structures must be created through public messages that fight stigma, enhance acceptance of PLHIV and encourage timely ART initiation. Copyright (c) 2010 Elsevier Ireland Ltd. All rights reserved.

Simultaneous quantification of four antiretroviral drugs in breast milk samples from HIV-positive women by an ultra-high performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) method

PubMed Central

Rodríguez-Delgado, Rosa Georgina; Figueroa-Damián, Ricardo; Domínguez-Castro, Mauricio; López-Martínez, Margarita; Flores-García, Zayra

2018-01-01

The primary strategy to avoid mother-to-child transmission of human immunodeficiency virus (HIV) through breastfeeding is administration of highly active antiretroviral therapy (HAART) to HIV-positive pregnant women. Because significant changes in the pharmacokinetics of antiretroviral (ARV) drugs occur during pregnancy, quantifying HAART and the viral load in breast milk in this population is essential. Here, we developed an analytical assay for the simultaneous quantification of four ARV drugs in breast milk using ultra-performance liquid chromatography coupled to tandem mass spectrometry. We validated this method following Mexican and international guidelines. ARV drugs. We extracted the ARV drugs from 200 μL samples of breast milk and detected these drugs in a triple quadrupole mass spectrometer with positive electrospray ionization. The validated concentration ranges (ng/mL) for zidovudine, lamivudine, lopinavir, and ritonavir were 12.5–750, 50–2500, 100–5000 and 5 to 250, respectively. Additionally, the absolute recovery percentages (and matrix effects) were 91.4 (8.39), 88.78 (28.75), 91.38 (11.77) and 89.78 (12.37), respectively. We determined that ARV drugs are stable for 24 h at 8°C and 24°C for 15 days at –80°C. This methodology had the capacity for simultaneous detection; separation; and accurate, precise quantification of ARV drugs in human breast milk samples according to Mexican standard laws and United States Food and Drug Administration guidelines. PMID:29351333

Modeling HIV/AIDS drug price determinants in Brazil: is generic competition a myth?

PubMed

Meiners, Constance; Sagaon-Teyssier, Luis; Hasenclever, Lia; Moatti, Jean-Paul

2011-01-01

Brazil became the first developing country to guarantee free and universal access to HIV/AIDS treatment, with antiretroviral drugs (ARVs) being delivered to nearly 190,000 patients. The analysis of ARV price evolution and market dynamics in Brazil can help anticipate issues soon to afflict other developing countries, as the 2010 revision of the World Health Organization guidelines shifts demand towards more expensive treatments, and, at the same time, current evolution of international legislation and trade agreements on intellectual property rights may reduce availability of generic drugs for HIV care. Our analyses are based on effective prices paid for ARV procurement in Brazil between 1996 and 2009. Data panel structure was exploited to gather ex-ante and ex-post information and address various sources of statistical bias. In-difference estimation offered in-depth information on ARV market characteristics which significantly influence prices. Although overall ARV prices follow a declining trend, changing characteristics in the generic segment help explain recent increase in generic ARV prices. Our results show that generic suppliers are more likely to respond to factors influencing demand size and market competition, while originator suppliers tend to set prices strategically to offset compulsory licensing threats and generic competition. In order to guarantee the long term sustainability of access to antiretroviral treatment, our findings highlight the importance of preserving and stimulating generic market dynamics to sustain developing countries' bargaining power in price negotiations undertaken with originator companies.

The Trans Pacific Partnership Agreement and access to HIV treatment in Vietnam.

PubMed

Moir, Hazel V J; Tenni, Brigitte; Gleeson, Deborah; Lopert, Ruth

2018-04-01

In the Trans Pacific Partnership (TPP) Agreement negotiations, the USA successfully pursued intellectual property (IP) provisions that will affect the affordability of medicines, including anti-retrovirals (ARV) for HIV. Vietnam has the lowest GDP per capita of the 12 TPP countries and in 2013 provided ARVs for only 68% of eligible people living with HIV. Using the current Vietnamese IP regime as our base case, we analysed the potential impact of a regime making full use of legal IP flexibilities, and one based on the IP provisions of the final, agreed TPP text. Results indicate that at current funding levels 82% of Vietnam's eligible people living with HIV would receive ARVs if legal flexibilities were fully utilised, while as few as 30% may have access to ARVs under the TPP Agreement - more than halving the proportion currently treated.

Time to viral load suppression in antiretroviral-naive and -experienced HIV-infected pregnant women on highly active antiretroviral therapy: implications for pregnant women presenting late in gestation.

PubMed

Aziz, N; Sokoloff, A; Kornak, J; Leva, N V; Mendiola, M L; Levison, J; Feakins, C; Shannon, M; Cohan, D

2013-11-01

To compare time to achieve viral load <400 copies/ml and <1000 copies/ml in HIV-infected antiretroviral (ARV) -naive versus ARV-experienced pregnant women on highly active antiretroviral therapy (HAART). Retrospective cohort study. Three university medical centers, USA. HIV-infected pregnant women initiated or restarted on HAART during pregnancy. We calculated time to viral load <400 copies/ml and <1000 copies/ml in HIV-infected pregnant women on HAART who reported at least 50% adherence, stratifying based on previous ARV exposure history. Time to HIV viral load <400 copies/ml and <1000 copies/ml. We evaluated 138 HIV-infected pregnant women, comprising 76 ARV-naive and 62 ARV-experienced. Ninety-three percent of ARV-naive women achieved a viral load < 400 copies/ml during pregnancy compared with 92% of ARV-experienced women (P = 0.82). The median number of days to achieve a viral load < 400 copies/ml in the ARV-naive cohort was 25.0 (range 3.5-133; interquartile range 16-34) days compared with 27.0 (range 8-162.5; interquartile range 18.5-54.3) days in the ARV-experienced cohort (P = 0.02). In a multiple predictor analysis, women with higher adherence (adjusted relative hazard [aRH] per 10% increase in adherence 1.29, 95% confidence interval [CI] 1.08-1.54, P = 0.01) and receiving a non-nucleotide reverse transcriptase inhibitor (NNRTI) -based regimen (aRH 2.48, 95% CI 1.33-4.63, P = 0.01) were more likely to achieve viral load <400 copies/ml earlier. Increased baseline HIV log10 viral load was associated with a later time of achieving viral load <400 copies/ml (aRH 0.60, 95% CI 0.39-0.92, P = 0.02). In a corresponding model of time to achieve viral load <1000 copies/ml, adherence (aRH per 10% increase in adherence 1.79, 95% CI 1.34-2.39, P < 0.001), receipt of NNRTI (aRH 2.95, 95% CI 1.23-7.06, P = 0.02), and CD4 cell count (aRH per 50 count increase in CD4 1.12, 95% CI 1.03-1.22, P = 0.01) were associated with an earlier time to achieve viral load below this

What strategies to boost production of affordable fixed-dose anti-retroviral drug combinations for children in the developing world?

PubMed

Dionisio, Daniele; Gass, Robert; McDermott, Peter; Racalbuto, Vincenzo; Madeo, Marina; Braghieri, Giuseppe; Crowley, Siobhan; Pinheiro, Eloan Dos Santos; Graaff, Peter; Vasan, Ashwin; Eksaengsri, Achara; Moller, Helene; Khanna, Arun Kumar; Kraisintu, Krisana; Juneja, Sandeep; Nicolaou, Stavros; Sengupta, Aloka; Esperti, Francesco; Messeri, Daniela

2007-03-01

No more than 8% of HIV positive children needing treatment in low- and middle-income countries have access to antiretroviral drugs (ARVs). Children presently account for about 4% of all treated patients, while for equitable access they should make up at least 13%. This study explores key issues, implications and interaction dynamics to boost production of easy-to-use and affordable fixed-dose combination (FDC) ARVs for children in the developing world. Potentials for equitable solutions are examined including priority steps and actions, appropriate treatment options and reliable forecasting methods for paediatric ARVs, as well as combination incentives to generic companies against market unattractiveness and enforced intellectual property (IP) rights. Moreover, implementation strategies to enhance the development and production of affordable ARV paediatric formulations and appropriate supply systems to ensure availability are investigated. The current market for FDC paediatric ARVs is already substantial and will only grow with improved and scaled up diagnosis and monitoring of children. This provides an argument for immediate increase of production and development of FDC ARVs for children. These formulations must be low cost and included in the list of Essential Medicines to avoid children continuing to lag behind in access to treatment. Access-oriented, long-term drug policy strategies with the ability to pass muster of governments, the UN system, as well as generic and research-based enterprises are needed to let children gain expanded and sustained access to FDC ARVs. Under the requirements listed above, IP-bound Voluntary License (VL) flexibilities do appear, if coupled with substantial combination incentives to generic firms, as a fitting tool into the needs. Policies must consider enhancing human resource capacity in the area of caregivers and social and health workers aiming to spread correct information and awareness on effectiveness and rationale of FDC

Physiologically-Based Pharmacokinetic Modelling to Inform Development of Intramuscular Long Acting Nanoformulations for HIV

PubMed Central

Rajoli, Rajith KR; Back, David J; Rannard, Steve; Meyers, Caren Freel; Flexner, Charles; Owen, Andrew; Siccardi, Marco

2014-01-01

Background and Objectives Antiretrovirals (ARVs) are currently used for the treatment and prevention of HIV infection. Poor adherence and low tolerability of some existing oral formulations can hinder their efficacy. Long-acting (LA) injectable nanoformulations could help address these complications by simplifying ARV administration. The aim of this study is to inform the optimisation of intramuscular LA formulations for eight ARVs through physiologically-based pharmacokinetic (PBPK) modelling. Methods A whole-body PBPK model was constructed using mathematical descriptions of molecular, physiological and anatomical processes defining pharmacokinetics. These models were validated against available clinical data and subsequently used to predict the pharmacokinetics of injectable LA formulations Results The predictions suggest that monthly intramuscular injections are possible for dolutegravir, efavirenz, emtricitabine, raltegravir, rilpivirine and tenofovir provided that technological challenges to control release rate can be addressed. Conclusions These data may help inform the target product profiles for LA ARV reformulation strategies. PMID:25523214

The Potential for Elimination of Racial-Ethnic Disparities in HIV Treatment Initiation in the Medicaid Population among 14 Southern States

PubMed Central

Zhang, Shun; McGoy, Shanell L.; Dawes, Daniel; Fransua, Mesfin; Rust, George; Satcher, David

2014-01-01

Objectives The purpose of this study was to explore the racial and ethnic disparities in initiation of antiretroviral treatment (ARV treatment or ART) among HIV-infected Medicaid enrollees 18–64 years of age in 14 southern states which have high prevalence of HIV/AIDS and high racial disparities in HIV treatment access and mortality. Methods We used Medicaid claims data from 2005 to 2007 for a retrospective cohort study. We compared frequency variances of HIV treatment uptake among persons of different racial- ethnic groups using univariate and multivariate methods. The unadjusted odds ratio was estimated through multinomial logistic regression. The multinomial logistic regression model was repeated with adjustment for multiple covariates. Results Of the 23,801 Medicaid enrollees who met criteria for initiation of ARV treatment, only one third (34.6%) received ART consistent with national guideline treatment protocols, and 21.5% received some ARV medication, but with sub-optimal treatment profiles. There was no significant difference in the proportion of people who received ARV treatment between black (35.8%) and non-Hispanic whites (35.7%), but Hispanic/Latino persons (26%) were significantly less likely to receive ARV treatment. Conclusions Overall ARV treatment levels for all segments of the population are less than optimal. Among the Medicaid population there are no racial HIV treatment disparities between Black and White persons living with HIV, which suggests the potential relevance of Medicaid to currently uninsured populations, and the potential to achieve similar levels of equality within Medicaid for Hispanic/Latino enrollees and other segments of the Medicaid population. PMID:24769625

Isolation and identification of a lethal rhabdovirus from farmed rice field eels Monopterus albus.

PubMed

Ou, Tong; Zhu, Ruo-Lin; Chen, Zhong-Yuan; Zhang, Qi-Ya

2013-11-06

We provide the first description of a virus responsible for a systemic hemorrhagic disease causing high mortality in farmed rice field eels Monopterus albus in China. Typical signs exhibited by the diseased fish were extensive hemorrhages in the skin and viscera and some neurological signs, such as loss of equilibrium and disorganized swimming. Histopathological examination revealed various degrees of necrosis within the spleen and liver. Virus isolation was attempted from visceral tissues of diseased fish by inoculation on 6 fish cell lines. Typical cytopathic effects (CPE) were produced in bluegill fry (BF2) cells, so this cell line was chosen for further isolation and propagation of the virus. Electron microscopy observation showed that the negative stained viral particles had the characteristic bullet shape of rhabdoviruses and an estimated size of 60 × 120 nm. We therefore tentatively refer to this virus as Monopterus albus rhabdovirus (MoARV). Molecular characterization of MoARV, including sequence analysis of the nucleoprotein (N), phosphoprotein (P), and glycoprotein (G) genes, revealed 94.5 to 97.3% amino acid similarity to that of Siniperca chuatsi rhabdovirus. Phylogenetic analysis based on the amino acid sequences of N and G proteins indicated that MoARV should be a member of the genus Vesiculovirus. Koch's postulates were fulfilled by infecting healthy rice field eels with MoARV, which produced an acute infection. RT-PCR analysis demonstrated that MoARV RNA could be detected in both naturally and experimentally infected fish. The data suggest that MoARV was the causative pathogen of the disease.

Combination Antiretroviral Use and Preterm Birth

PubMed Central

Watts, D. Heather; Williams, Paige L.; Kacanek, Deborah; Griner, Raymond; Rich, Kenneth; Hazra, Rohan; Mofenson, Lynne M.; Mendez, Hermann A.

2013-01-01

Background. Use of antiretroviral drugs (ARVs) during pregnancy has been associated with higher risk of preterm birth. Methods. The Pediatric HIV/AIDS Cohort Study network's Surveillance Monitoring for ART Toxicities study is a US-based cohort of human immunodeficiency virus (HIV)–exposed uninfected children. We evaluated maternal ARV use during pregnancy and the risk of any type of preterm birth (ie, birth before 37 completed weeks of gestation), the risk of spontaneous preterm birth (ie, preterm birth that occurred after preterm labor or membrane rupture, without other complications), and the risk of small for gestational age (SGA; ie, a birth weight of <10th percentile for gestational age). Multivariable logistic regression models were used to evaluate the association of ARVs and timing of exposure, while adjusting for maternal characteristics. Results. Among 1869 singleton births, 18.6% were preterm, 10.2% were spontaneous preterm, and 7.3% were SGA. A total of 89% used 3-drug combination ARV regimens during pregnancy. In adjusted models, the odds of preterm birth and spontaneous preterm birth were significantly greater among mothers who used protease inhibitors during the first trimester (adjusted odds ratios, 1.55 and 1.59, respectively) but not among mothers who used nonnucleoside reverse-transcriptase inhibitor or triple-nucleoside regimens during the first trimester. Combination ARV exposure starting later in pregnancy was not associated with increased risk. No associations were observed between SGA and exposure to combination ARV regimens. Conclusions. Protease inhibitor use early in pregnancy may be associated with increased risk for prematurity. PMID:23204173

The pricing and procurement of antiretroviral drugs: an observational study of data from the Global Fund.

PubMed Central

Vasan, Ashwin; Hoos, David; Mukherjee, Joia S.; Farmer, Paul E.; Rosenfield, Allan G.; Perriëns, Joseph H.

2006-01-01

The Purchase price report released in August 2004 by the Global Fund to Fight AIDS, Tuberculosis, and Malaria (Global Fund) was the first publication of a significant amount of real transaction purchase data for antiretrovirals (ARVs). We did an observational study of the ARV transaction data in the Purchase price report to examine the procurement behaviour of principal recipients of Global Fund grants in developing countries. We found that, with a few exceptions for specific products (e.g. lamivudine) and regions (e.g. eastern Europe), prices in low-income countries were broadly consistent or lower than the lowest differential prices quoted by the research and development sector of the pharmaceutical industry. In lower middle-income countries, prices were more varied and in several instances (lopinavir/ritonavir, didanosine, and zidovudine/lamivudine) were very high compared with the per capita income of the country. In all low- and lower middle-income countries, ARV prices were still significantly high given limited local purchasing power and economic strength, thus reaffirming the need for donor support to achieve rapid scale-up of antiretroviral therapy. However, the price of ARVs will have to decrease to render scale-up financially sustainable for donors and eventually for governments themselves. An important first step in reducing prices will be to make available in the public domain as much ARV transaction data as possible to provide a factual basis for discussions on pricing. The price of ARVs has considerable implications for the sustainability of human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS) treatment in the developing world. PMID:16710550

Combination antiretroviral use and preterm birth.

PubMed

Watts, D Heather; Williams, Paige L; Kacanek, Deborah; Griner, Raymond; Rich, Kenneth; Hazra, Rohan; Mofenson, Lynne M; Mendez, Hermann A

2013-02-15

Use of antiretroviral drugs (ARVs) during pregnancy has been associated with higher risk of preterm birth. The Pediatric HIV/AIDS Cohort Study network's Surveillance Monitoring for ART Toxicities study is a US-based cohort of human immunodeficiency virus (HIV)-exposed uninfected children. We evaluated maternal ARV use during pregnancy and the risk of any type of preterm birth (ie, birth before 37 completed weeks of gestation), the risk of spontaneous preterm birth (ie, preterm birth that occurred after preterm labor or membrane rupture, without other complications), and the risk of small for gestational age (SGA; ie, a birth weight of <10th percentile for gestational age). Multivariable logistic regression models were used to evaluate the association of ARVs and timing of exposure, while adjusting for maternal characteristics. Among 1869 singleton births, 18.6% were preterm, 10.2% were spontaneous preterm, and 7.3% were SGA. A total of 89% used 3-drug combination ARV regimens during pregnancy. In adjusted models, the odds of preterm birth and spontaneous preterm birth were significantly greater among mothers who used protease inhibitors during the first trimester (adjusted odds ratios, 1.55 and 1.59, respectively) but not among mothers who used nonnucleoside reverse-transcriptase inhibitor or triple-nucleoside regimens during the first trimester. Combination ARV exposure starting later in pregnancy was not associated with increased risk. No associations were observed between SGA and exposure to combination ARV regimens. Protease inhibitor use early in pregnancy may be associated with increased risk for prematurity.

The pricing and procurement of antiretroviral drugs: an observational study of data from the Global Fund.

PubMed

Vasan, Ashwin; Hoos, David; Mukherjee, Joia S; Farmer, Paul E; Rosenfield, Allan G; Perriëns, Joseph H

2006-05-01

The Purchase price report released in August 2004 by the Global Fund to Fight AIDS, Tuberculosis, and Malaria (Global Fund) was the first publication of a significant amount of real transaction purchase data for antiretrovirals (ARVs). We did an observational study of the ARV transaction data in the Purchase price report to examine the procurement behaviour of principal recipients of Global Fund grants in developing countries. We found that, with a few exceptions for specific products (e.g. lamivudine) and regions (e.g. eastern Europe), prices in low-income countries were broadly consistent or lower than the lowest differential prices quoted by the research and development sector of the pharmaceutical industry. In lower middle-income countries, prices were more varied and in several instances (lopinavir/ritonavir, didanosine, and zidovudine/lamivudine) were very high compared with the per capita income of the country. In all low- and lower middle-income countries, ARV prices were still significantly high given limited local purchasing power and economic strength, thus reaffirming the need for donor support to achieve rapid scale-up of antiretroviral therapy. However, the price of ARVs will have to decrease to render scale-up financially sustainable for donors and eventually for governments themselves. An important first step in reducing prices will be to make available in the public domain as much ARV transaction data as possible to provide a factual basis for discussions on pricing. The price of ARVs has considerable implications for the sustainability of human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS) treatment in the developing world.

Antiretroviral therapy provided to HIV-infected Malawian women in a randomized trial diminishes the posiitive effect of lipid-based nutrient supplements on breast milk B-vitamins

USDA-ARS?s Scientific Manuscript database

Background: There is little information on B-vitamin concentrations in human milk or how they are affected by maternal B-vitamin deficiencies, antiretroviral (ARV) therapy or maternal supplementation. Objective: To evaluate effects of ARV therapy and/or lipid-based nutrient supplements (LNS) on B-v...

Regulatory challenges in developing long-acting antiretrovirals for treatment and prevention of HIV infection.

PubMed

Arya, Vikram; Au, Stanley; Belew, Yodit; Miele, Peter; Struble, Kimberly

2015-07-01

To outline some of the regulatory challenges inherent to the development of long-acting antiretrovirals (ARVs) for the treatment or prevention of HIV infection. Despite advances in drug development that have reduced ARV dosing to once daily, suboptimal drug adherence remains an obstacle to successful HIV treatment. Further, large randomized trials of once daily oral ARVs for preexposure prophylaxis (PrEP) have shown that drug adherence correlates strongly with prophylactic effect and study outcomes. Thus, the prospect of developing long-acting ARVs, which may mitigate drug adherence issues, has attracted considerable attention lately. Because of their pharmacokinetic properties, the development of long-acting ARVs can present novel regulatory challenges. Chief among them is determining the appropriate dosing regimen, the need for an oral lead-in, and whether existing data with an approved oral agent, if available, can be leveraged for a treatment or prevention indication. For PrEP, because validated biomarkers are lacking, additional nonclinical studies and evaluation of tissue concentrations in multiple compartments may be necessary to identify optimal dosages. Study design and choice of controls for registrational trials of new long-acting PrEP agents might also prove challenging following the availability of an oral PrEP drug.

Generic substitution of antiretrovirals: patients' and health care providers' opinions.

PubMed

Kieran, Jennifer A; O'Reilly, Eimear; O'Dea, Siobhan; Bergin, Colm; O'Leary, Aisling

2017-10-01

There is interest in introducing generic antiretroviral drugs (ARVs) into high-income countries in order to maximise efficiency in health care budgets. Studies examining patients' and providers' knowledge and attitudes to generic substitution in HIV are few. This was a cross-sectional, observational study with a convenience sample of adult HIV-infected patients and health care providers (HCPs). Data on demographics, knowledge of generic medicine and facilitators of generic substitution were collected. Descriptive and univariate analysis was performed using SPSS V.23™. Questionnaires were completed by 66 patients. Seventy-one per cent would have no concerns with the introduction of generic ARVs. An increase in frequency of administration (61%) or pill burden (53%) would make patients less likely to accept generic ARVs. There were 30 respondents to the HCP survey. Concerns included the supply chain of generics, loss of fixed dose combinations, adherence and use of older medications. An increase in dosing frequency (76%) or an increase in pill burden (50%) would make HCPs less likely to prescribe a generic ARV. The main perceived advantage was financial. Generic substitution of ARVs would be acceptable to the majority of patients and HCPs. Reinvesting savings back into HIV services would facilitate the success of such a programme.

Isolation and characterization of vB_ArS-ArV2 - first Arthrobacter sp. infecting bacteriophage with completely sequenced genome.

PubMed

Šimoliūnas, Eugenijus; Kaliniene, Laura; Stasilo, Miroslav; Truncaitė, Lidija; Zajančkauskaitė, Aurelija; Staniulis, Juozas; Nainys, Juozas; Kaupinis, Algirdas; Valius, Mindaugas; Meškys, Rolandas

2014-01-01

This is the first report on a complete genome sequence and biological characterization of the phage that infects Arthrobacter. A novel virus vB_ArS-ArV2 (ArV2) was isolated from soil using Arthrobacter sp. 68b strain for phage propagation. Based on transmission electron microscopy, ArV2 belongs to the family Siphoviridae and has an isometric head (∼63 nm in diameter) with a non-contractile flexible tail (∼194×10 nm) and six short tail fibers. ArV2 possesses a linear, double-stranded DNA genome (37,372 bp) with a G+C content of 62.73%. The genome contains 68 ORFs yet encodes no tRNA genes. A total of 28 ArV2 ORFs have no known functions and lack any reliable database matches. Proteomic analysis led to the experimental identification of 14 virion proteins, including 9 that were predicted by bioinformatics approaches. Comparative phylogenetic analysis, based on the amino acid sequence alignment of conserved proteins, set ArV2 apart from other siphoviruses. The data presented here will help to advance our understanding of Arthrobacter phage population and will extend our knowledge about the interaction between this particular host and its phages.

Computer-based intervention in HIV clinical care setting improves antiretroviral adherence: the LifeWindows Project.

PubMed

Fisher, Jeffrey D; Amico, K Rivet; Fisher, William A; Cornman, Deborah H; Shuper, Paul A; Trayling, Cynthia; Redding, Caroline; Barta, William; Lemieux, Anthony F; Altice, Frederick L; Dieckhaus, Kevin; Friedland, Gerald

2011-11-01

We evaluated the efficacy of LifeWindows, a theory-based, computer-administered antiretroviral (ARV) therapy adherence support intervention, delivered to HIV + patients at routine clinical care visits. 594 HIV + adults receiving HIV care at five clinics were randomized to intervention or control arms. Intervention vs. control impact in the intent-to-treat sample (including participants whose ARVs had been entirely discontinued, who infrequently attended care, or infrequently used LifeWindows) did not reach significance. Intervention impact in the On Protocol sample (328 intervention and control arm participants whose ARVs were not discontinued, who attended care and were exposed to LifeWindows regularly) was significant. On Protocol intervention vs. control participants achieved significantly higher levels of perfect 3-day ACTG-assessed adherence over time, with sensitivity analyses maintaining this effect down to 70% adherence. This study supports the utility of LifeWindows and illustrates that patients on ARVs who persist in care at clinical care sites can benefit from adherence promotion software.

Topical Prophylaxis for HIV Prevention in Women: Becoming a Reality

PubMed Central

Verma, Natasha A.; Lee, Anna C.; Herold, Betsy C.

2011-01-01

Strategies to protect against sexual transmission of HIV include the development of products formulated for topical application, which limit the toxicities associated with systemic oral pre-exposure prophylaxis. Following several clinical trial failures, attention is now focused on antiretroviral (ARV) agents. Highly potent ARV topical formulations provide a female-controlled, targeted, and feasible option for HIV prevention. A recently completed tenofovir gel trial was the first to demonstrate significant protection against HIV acquisition. Topical ARVs have the advantage of delivering high concentration of drug at the site of transmission of HIV, with low systemic absorption. Sustained-release formulations, such as intravaginal rings, will likely improve adherence and can be designed to provide controlled and continuous delivery of ARV combinations. Further studies to test alternative dosing strategies and pharmacokinetic/pharmacodynamic relationships in the genital tract will provide valuable information as the field strives to improve upon the promising tenofovir gel trial results. PMID:21424725

The impact of HIV antiretroviral treatment perception on risky sexual behaviour in Botswana: a short report.

PubMed

Letamo, Gobopamang; Keetile, Mpho; Navaneetham, Kannan

2017-12-01

The aim of this article is to investigate the impact of ART perception on risky sexual behaviours in Botswana. Using binary logistic regression analysis controlling for individual characteristics, the results tend to support the hypothesis that ART misconceptions do not necessarily increase risky sexual behaviours. In particular, the study findings suggest the belief that ARVs cure HIV and AIDS and that people on ARVs should not always use condoms do not necessarily lead to increased risky sexual behaviours, particularly among women. Gender differentials exist in the perceived sexual risk resulting from the use of ART. Risky sexual behaviours increase for women who, wrongly, believed that ARVs cure HIV and AIDS and people on ARVs should not always use condoms. Although there is evidence to suggest ART perceptions do not necessarily lead to increased risky sexual behaviours, HIV and AIDS prevention programmes are needed to strengthen their information, education and communication intervention component that can address misconceptions about ART treatment and provide correct information that is gender-appropriate.

Neurologic Outcomes in HIV-Exposed/Uninfected Infants Exposed to Antiretroviral Drugs During Pregnancy in Latin America and the Caribbean

PubMed Central

Spaulding, Alicen B.; Yu, Qilu; Civitello, Lucy; Mussi-Pinhata, Marisa M.; Pinto, Jorge; Gomes, Ivete M.; Alarcón, Jorge O.; Siberry, George K.; Harris, D. Robert

2016-01-01

Abstract To evaluate antiretroviral (ARV) drug exposure and other factors during pregnancy that may increase the risk of neurologic conditions (NCs) in HIV-exposed/uninfected (HEU) infants. A prospective cohort study was conducted at 24 clinical sites in Latin America and the Caribbean. Data on maternal demographics, health, HIV disease status, and ARV use during pregnancy were collected. Infant data included measurement of head circumference after birth and reported medical diagnoses at birth, 6–12 weeks, and 6 months. Only infants with maternal exposure to combination ARV therapy (cART) (≥3 drugs from ≥2 drug classes) during pregnancy were included. Microcephaly, defined as head circumference for age z-score less than −2, and NC were evaluated for their association with covariates, including individual ARVs, using bivariable and logistic regression analyses. From 2002 to 2009, 1,400 HEU infants met study inclusion criteria. At least one NC was reported in 134 (9.6%; 95% confidence interval [CI]: 8.1–11.2), microcephaly in 105 (7.5%; 95% CI: 6.2–9.0), and specific neurologic diagnoses in 33 (2.4%; 95% CI: 1.6–3.3) HEU infants. Microcephaly and NC were not significantly associated with any specific ARV analyzed (p > 0.05). Covariates associated with increased odds of NC included male sex (odds ratio [OR] = 1.9; 95% CI: 1.3–2.8), birth weight <2.5 kg (OR = 3.1; 95% CI: 2.1–4.8), 1-min Apgar score <7 (OR = 2.5; 95% CI: 1.4–4.4), and infant infections (OR = 2.5; 95% CI: 1.5–4.1). No ARV investigated was associated with adverse neurologic outcomes. Continued investigation of such associations may be warranted as new ARVs are used during pregnancy and cART exposure during the first trimester becomes increasingly common. PMID:26879281

[Alternative medicine, beliefs, and management of people with HIV in Gabon].

PubMed

Yaba, W; Chippaux, J P; Obiang-Ndong, G P; Msellati, P

2013-01-01

According to WHO, 80% of the population in Africa has used alternative medicine for primary health care at least once. Gabon continues to have a high prevalence of HIV, estimated in 2011 at 5.2%. Overall, 22 253 PLWHA (people living with HIV/AIDS) - adults and children - are being treated, including 9976 on ARVs (antiretroviral drugs). The procedures for ARV initiation are very long, ARVs are frequently out of stock, and treatment in care centers for PLWHA is stigmatized: all these factors favor the development of alternative medicine for HIV care in Gabon. To analyze the impact of alternative medicine in the treatment of PLWHA in Gabon. This cross-sectional survey was conducted during a total of four months between May 2009 and September 2010 among PLWHA older than 18 years who had been receiving ARVs for at least 6 months and consented to participate (7 centers) and among physicians and other caregivers of these centers (8 centers). We used a simple random sample method. Epidata software was used for data collection, and the analyses were performed with SAS™ software. Of the 5752 patients on ARVs followed at the 7 study sites, 422 PLWHA were interviewed (58.3% of them women): 284 (67.29%) in Libreville and 138 (38.7) in the provinces. Christians accounted for 90.5% (including 21.5% from Protestant evangelical churches), and Muslins for 5.68%, while 4% stated that they had no religion. 12.5% of doctors referred their patients to religious or spiritual groups. Our study showed that half of PLWHA did not know the procedures for access to ARV treatment and that beliefs about HIV/AIDS differed strongly according to place of residence. Finally, the cultural context related to alternative medicine is very present in the PLWHA treatment settings in Gabon. Although PLWHAs have easy access to ARVs, their association with organized and controlled alternative medicine can be beneficial.

Knowledge of HIV and its treatment among health care providers in South Africa.

PubMed

Ruud, Karine Wabø; Srinivas, Sunitha C; Toverud, Else-Lydia

2014-04-01

In South Africa, availability of antiretroviral (ARV) drugs has increased largely in the public sector since it became available in 2004. Follow-up of stabilized patients on ARV drugs are done in primary health care (PHC) facilities run by nurses, often without specialized training. This has deep impact on the patients' drug adherence. To investigate health care providers' (HCPs) knowledge about human immunodeficiency virus (HIV) and antiretroviral therapy (ART) in the Eastern Cape Province, South Africa. The aim was also to investigate nurses' knowledge and experience regarding adverse drug reaction (ADR) reporting. Public PHC clinics in one district of the Eastern Cape Province. Personal interviews, using a structured questionnaire, were conducted with 102 HCPs (nurses and auxiliary staff) working at six PHC facilities, one community health centre and one health post. Knowledge about HIV and ART among nurses and auxiliary staff. Both nurses and auxiliary staff had some basic knowledge about symptoms of HIV and modes of transmission, but great uncertainty was seen regarding specific topics including ARV drugs, ADRs and HIV complications. The PHC staff were uncertain about how to administer ARV drugs--with or without food--and some of them would advice their patients not to take ARV drugs at times when food was lacking. Both nurses and auxiliary staff knew that HIV was treated with ARV drugs. Only 60 % of the HCPs claimed that ART was the only effective treatment for HIV, whereas 39 % claimed that nutritious food also could treat HIV. Nurses showed lacking ability to manage ADRs. They also had very little knowledge about ADR reporting, and very few had ever submitted a report at all. The study shows that both nurses and auxiliary staff are unable to provide the patients with adequate advice about administration of the ARV drugs and management of ADRs. Serious lack of knowledge among HCPs regarding the treatment of HIV presents structural barriers to the patients

Medication Adherence Challenges among HIV Positive Substance Abusers: The Role of Food and Housing Insecurity

PubMed Central

Surratt, Hilary L.; O’Grady, Catherine L.; Levi-Minzi, Maria A.; Kurtz, Steven P.

2014-01-01

This study examines the prevalence of food/housing insecurity and its association with psychological, behavioral and environmental factors impacting ARV medication adherence and diversion among substance using HIV+ patients in South Florida. 503 HIV+ substance abusers were recruited through targeted sampling. Participants completed a standardized instrument assessing demographics, mental health status, sex risk behaviors, HIV diagnosis, treatment history and access, ARV adherence and diversion, and attitudes toward health care providers. Chi-square and t-tests were used to examine differences by food/housing status and a multivariate linear regression model examined food/housing insecurity and its associations to ARV adherence. Food/housing insecurity was reported by 43.3% of the sample and was associated with higher likelihood of severe psychological distress and substance dependence. Nearly 60% reported recent ARV diversion; only 47.2% achieved 95% medication adherence over one week. Food/housing insecure participants had deficits in their HIV care, including less time in consistent care, lower access to medical care, and less favorable attitudes toward care providers. Multivariate linear regression showed food/housing insecurity demonstrated significant main effects on adherence, including lower past week adherence. Medication diversion was also associated with reduced adherence. Our findings suggest that food/housing insecurity operates as a significant driver of ARV non-adherence and diversion in this population. In the pursuit of better long term health outcomes for vulnerable HIV+ individuals, it is essential for providers to understand the role of food and housing insecurity as a stressor that negatively impacts ARV adherence and treatment access, while also significantly contributing to higher levels distress and substance dependence. PMID:25314042

Prevalence of Congenital Anomalies in Infants with in Utero Exposure to Antiretrovirals

PubMed Central

KNAPP, KATHERINE M.; BROGLY, SUSAN B.; MUENZ, DANIEL G.; SPIEGEL, HANS M.; CONWAY, DANIEL H.; SCOTT, GWENDOLYN B.; TALBOT, JEFFREY T.; SHAPIRO, DAVID E.; READ, JENNIFER S.

2011-01-01

Background While use of efficacious interventions, including antiretrovirals (ARVs), has reduced dramatically the rate of mother-to-child transmission (MTCT) of HIV, the safety of in utero ARV exposure remains of concern. Methods Data regarding 1112 infants enrolled in the International Maternal Pediatric Adolescent AIDS Clinical Trials Group (IMPAACT) protocol P1025 born between 2002 and 2007 were analyzed for this study. Congenital anomalies were classified based on the Metropolitan Atlanta Congenital Defects Program (MACDP) guidelines. Associations between congenital anomalies and timing of first in utero exposure to ARVs were evaluated by logistic regression analysis. Results 61 of the 1112 infants had congenital anomalies identified and confirmed, resulting in a prevalence of 5.49/100 live births (95%CI: 4.22–6.99). Among the 80 anomalies identified, the organ systems involved included: cardiovascular (n=33), musculoskeletal (n=15), renal (n=9), genitourinary (n=6), craniofacial (n=4), and central nervous system (n=2). First trimester exposure to efavirenz was associated with a significantly increased risk of congenital anomalies (OR 2.84, 95%CI: 1.13–7.16). No significant associations were observed between exposure to other individual ARVs or classes of ARVs started at any time during pregnancy and infant congenital anomalies. Conclusions The observed rate of congenital anomalies in this cohort is higher than previously reported for the general population, but is consistent with rates observed in other recent studies of children born to HIV-infected women. Cardiovascular anomalies occurred most frequently. With the exception of a known teratogen (efavirenz), no statistically significant associations between in utero exposure to ARVs and congenital anomalies were identified. PMID:21983213

Birth defects among children born to HIV-infected women: Pediatric AIDS Clinical Trials Protocols 219 and 219C

PubMed Central

Brogly, Susan B.; Abzug, Mark J.; Watts, D. Heather; Cunningham, Coleen K.; Williams, Paige L.; Oleske, James; Conway, Daniel; Sperling, Rhoda S.; Spiegel, Hans; Van Dyke, Russell B.

2010-01-01

Background Some studies have detected associations between in utero antiretroviral therapy (ARV) exposure and birth defects but evidence is inconclusive. Methods 2,202 HIV-exposed children enrolled in the Pediatric AIDS Clinical Trials Group 219 and 219C protocols before one year of age were included. Birth defects were classified using the Metropolitan Atlanta Congenital Defects Program (MACDP) coding. Logistic regression models were used to evaluate associations between first trimester in utero ARV exposure and birth defects. Results 117 live-born children had birth defects for a prevalence of 5.3% (95% CI: 4.4, 6.3). Prevalence did not differ by HIV infection status or overall ARV exposure; rates were 4.8% (95% CI: 3.7, 6.1) and 5.8% (95% CI: 4.2, 7.8) in children without and with first trimester ARV exposure, respectively. The defect rate was higher among children with first trimester efavirenz exposure (5/32, 15.6%) versus children without first trimester efavirenz exposure [adjusted odds ratio (aOR)=4.31 (95% CI: 1.56, 11.86)]. Protective effects of first trimester zidovudine exposure on musculoskeletal defects were detected [aOR=0.24 (95% CI: 0.08, 0.69)], while a higher risk of heart defects was found [aOR=2.04 (95% CI: 1.03, 4.05)]. Conclusion The prevalence of birth defects was higher in this cohort of HIV-exposed children than in other pediatric cohorts. There was no association with overall ARV exposure, but there were some associations with specific agents including efavirenz. Additional studies are needed to rule out confounding and to evaluate newer ARV agents. PMID:20539252

Primary care provider cultural competence and racial disparities in HIV care and outcomes.

PubMed

Saha, Somnath; Korthuis, P Todd; Cohn, Jonathan A; Sharp, Victoria L; Moore, Richard D; Beach, Mary Catherine

2013-05-01

Health professional organizations have advocated for increasing the "cultural competence" (CC) of healthcare providers, to reduce racial and ethnic disparities in patient care. It is unclear whether provider CC is associated with more equitable care. To evaluate whether provider CC is associated with quality of care and outcomes for patients with HIV/AIDS. Survey of 45 providers and 437 patients at four urban HIV clinics in the U.S. Providers' self-rated CC was measured using a novel, 20-item instrument. Outcome measures included patients' receipt of antiretroviral (ARV) therapy, self-efficacy in managing medication regimens, complete 3-day ARV adherence, and viral suppression. Providers' mean age was 44 years; 56 % were women, and 64 % were white. Patients' mean age was 45; 67 % were men, and 77 % were nonwhite. Minority patients whose providers scored in the middle or highest third on self-rated CC were more likely than those with providers in the lowest third to be on ARVs, have high self-efficacy, and report complete ARV adherence. Racial disparities were observed in receipt of ARVs (adjusted OR, 95 % CI for white vs. nonwhite: 6.21, 1.50-25.7), self-efficacy (3.77, 1.24-11.4), and viral suppression (13.0, 3.43-49.0) among patients of low CC providers, but not among patients of moderate and high CC providers (receipt of ARVs: 0.71, 0.32-1.61; self-efficacy: 1.14, 0.59-2.22; viral suppression: 1.20, 0.60-2.42). Provider CC was associated with the quality and equity of HIV care. These findings suggest that enhancing provider CC may reduce racial disparities in healthcare quality and outcomes.

Medication adherence challenges among HIV positive substance abusers: the role of food and housing insecurity.

PubMed

Surratt, Hilary L; O'Grady, Catherine L; Levi-Minzi, Maria A; Kurtz, Steven P

2015-01-01

This study examines the prevalence of food/housing insecurity and its association with psychological, behavioral, and environmental factors impacting antiretroviral (ARV) medication adherence and diversion among substance using HIV+ patients in South Florida. Five hundred and three HIV+ substance abusers were recruited through targeted sampling. Participants completed a standardized instrument assessing demographics, mental health status, sex risk behaviors, HIV diagnosis, treatment history and access, ARV adherence and diversion, and attitudes toward health-care providers. Chi-square and t-tests were used to examine differences by food/housing status and a multivariate linear regression model examined food/housing insecurity and its associations to ARV adherence. Food/housing insecurity was reported by 43.3% of the sample and was associated with higher likelihood of severe psychological distress and substance dependence. Nearly 60% reported recent ARV diversion; only 47.2% achieved 95% medication adherence over one week. Food/housing insecure participants had deficits in their HIV care, including less time in consistent care, lower access to medical care, and less favorable attitudes toward care providers. Multivariate linear regression showed food/housing insecurity demonstrated significant main effects on adherence, including lower past week adherence. Medication diversion was also associated with reduced adherence. Our findings suggest that food/housing insecurity operates as a significant driver of ARV non-adherence and diversion in this population. In the pursuit of better long-term health outcomes for vulnerable HIV+ individuals, it is essential for providers to understand the role of food and housing insecurity as a stressor that negatively impacts ARV adherence and treatment access, while also significantly contributing to higher levels of distress and substance dependence.

An artificial right ventricle for failing fontan: in vitro and computational study.

PubMed

Lacour-Gayet, François G; Lanning, Craig J; Stoica, Serban; Wang, Rui; Rech, Bryan A; Goldberg, Steven; Shandas, Robin

2009-07-01

The aim of this study is to develop a destination low-pressure artificial right ventricle (ARV) to correct the impaired hemodynamics in the failing Fontan circulation. An in vitro model circuit of the Fontan circulation was created to reproduce the hemodynamics of the failing Fontan and test ARV performance under various central venous pressures (CVP) and flows. A novel geometry of the extracardiac conduit was designed to adapt to the need of the pump. The ARV was a low-pressure axial flow pump designed to produce a low suction inflow pressure and moderate outflow increase. With the power off, the passive forward gradient across the propeller is 2 mm Hg at 4.5 L/min. The ARV would require 4 watts at a rotation of 5000 rpm. To examine the shear loading on the red blood cells, virtual particles were injected upstream of the ARV inducer and tracked by computerized modeling. The effect of the ARV on the failing Fontan was studied at various CVP pressures and flows, and under constant values of lung resistances and left atrial pressure set respectively to 2.5 Woods Units and 7 mm Hg. The CVP pressures decreased respectively from 25, 22.5, 20, 17.5, 15, and 10 mm Hg to a minimal value of 2 to 5 mm Hg with a pump speed varying from 1700 to 4500 rpm. The pulmonary artery pressures increased moderately between 12.5 and 25 mm Hg at 4500 rpm. Cardiac output at 4500 rpm was increased by an average gain of 2 L/min. The average blood damage index was 0.92%, far below the 5% value considered to cause hemolysis. The flow structure produced by the pump was suitable. The performance of this novel low-pressure ARV was satisfactory, showing good decrease of CVP pressures, a moderate increase of pulmonary artery pressures, adequate increase of cardiac output, and minimal hemolysis. The use of a mock Fontan model circuit facilitates device prototyping and design to a far greater extent than can be achieved using animal studies, and is an essential first step for rapid design iteration

Prevalence of possible drug-drug interactions between antiretroviral agents in different age groups in a section of the private health care sector setting in South Africa.

PubMed

Katende-Kyenda, N L; Lubbe, M S; Serfontein, J H P; Truter, I

2008-08-01

The chronic nature of human immunodeficiency virus (HIV) infection requires lifelong highly active antiretroviral (ARV) therapy (HAART) to continuously suppress HIV-1 viral replication, thus reducing morbidity and mortality. HAART is restricted by complex dosing, drug-drug interactions (DDIs) and toxicities. To determine the prevalence of possible DDIs between ARV drugs in different age groups in a section of the private primary health care sector in South Africa. A quantitative, retrospective drug utilization review was performed on 47 085 ARV prescriptions claimed through a national medicine claims database during 2006. Possible DDIs identified were classified according to a clinical significance rating as described by Tatro [Drug Interaction Facts 2005. St Louis, MO: Facts and Comparisons (2005)]. The total number of patients who received prescriptions that were claimed through the medicine claims database was 275 424, of whom 25.11% were males, 28.28% were females and the gender of 46.61% patients was unknown. Of the total number of patients, 3.27% were HIV patients of which an average of 5.23 +/- 3.86 ARV prescriptions (n = 47 085) per patient were claimed for representing 4.73% of the total number of prescriptions claimed during the study period (N = 993 804). HIV patients received an average of 2.36 +/- 0.61 ARVs per prescription. Only 4.95% of the prescriptions had one ARV medicine item, 56.04% two, 37.10% three, 1.75% four and <1% had more than four. Of 960 DDIs identified, 1.88% were for patients < or =6 years, 4.27% for patients >6 years and < or =12 years, 0.63% for patients >12 and < or =19 years, 32.40% for patients <19 years and < or =40 years, 60.21% for patients <40 years and < or =60 years and 0.63% for patients >60 years with patients <40 years and < or =60 years having the highest number of DDIs and patients older than 60 years the lowest. The majority of DDIs between the ARVs presented in significance levels 2 and 4. The most important

Strategies for Living with the Challenges of HIV and Antiretroviral Use in Zambia

ERIC Educational Resources Information Center

Jones, Deborah; Zulu, Isaac; Mumbi, Miriam; Chitalu, Ndashi; Vamos, Szonja; Gomez, Jacqueline; Weiss, Stephen M.

2009-01-01

This study sought to identify strategies for living with the challenges of HIV and antiretroviral (ARV) use among new medication users in urban Zambia. Participants (n = 160) were recruited from urban Lusaka, Zambia. Qualitative Data was drawn from monthly ARV treatment education intervention groups addressing HIV and antiretroviral use. Themes…

One-, two-, and three-class resistance among HIV-infected patients on antiretroviral therapy in private care clinics: Mumbai, India.

PubMed

Gupta, Amita; Saple, Dattaray G; Nadkarni, Girish; Shah, Bijal; Vaidya, Satish; Hingankar, Nitin; Chaturbhuj, Devidas; Deshmukh, Praveen; Walshe, Louise; Hudelson, Sarah E; James, Maria; Paranjape, Ramesh S; Eshleman, Susan H; Tripathy, Srikanth

2010-01-01

HIV-infected patients receiving antiretroviral (ARV) therapy (ART) in India are not all adequately virally suppressed. We analyzed ARV drug resistance in adults receiving ART in three private clinics in Mumbai, India. HIV viral load was measured in 200 patients with the Roche AMPLICOR HIV-1 Monitor Test, v1.5. HIV genotyping was performed with the ViroSeq HIV-1 Genotyping System for 61 participants who had HIV-1 RNA >1000 copies/ml. Genotyping results were obtained for 51 samples. The participants with resistance results were on ART for a median of 24 months and were on their current regimen for a median of 12 months (median CD4 cell count: 217 cells/mm(3); median HIV viral load: 28,200 copies/ml). ARV regimens included nonnucleoside reverse transcriptase inhibitor (NNRTI)-based regimens (n = 27), dual nucleoside reverse transcriptase inhibitors (NRTIs, n = 19), protease inhibitor (PI)-based regimens (n = 3), and other regimens (n = 2). Twenty-six participants (51.0%) were on their first ARV regimen and 24 (47%) reported >95% adherence. Forty-nine participants (96.1%) had resistance to at least one ARV drug; 47 (92.2%) had NRTI resistance, 32 (62.7%) had NNRTI resistance, and four (7.8%) had PI resistance. Thirty (58.8%) had two-class resistance and three (5.9%) had three-class resistance. Four (8%) had three or more resistance mutations associated with etravirine resistance and two (4%) had two mutations associated with reduced darunavir susceptibility. Almost all patients with HIV-1 RNA >1000 copies/ml had NRTI resistance and nearly two-thirds had NNRTI resistance; PI resistance was uncommon. Nearly 60% and 6% had two- and three-class resistance, respectively. This emphasizes the need for greater viral load and resistance monitoring, use of optimal ART combinations, and increased availability of second- and third-line agents for patients with ARV resistance.

The Successful Application of a National Peer Advisory Committee for Physicians Who Provide Salvage Regimens to Heavily Antiretroviral-Experienced Patients in Mexican Human Immunodeficiency Virus Clinics

PubMed Central

Calva, Juan J.; Sierra-Madero, Juan; Soto-Ramírez, Luis E.; Aguilar-Salinas, Pedro

2014-01-01

Background  Designing optimal antiretroviral (ARV) salvage regimens for multiclass drug-resistant, human immunodeficiency virus (HIV)-infected patients demands specific clinical skills. Our aim was to assess the virologic and immunologic effects of the treatment recommendations drafted by a peer advisory board to physicians caring for heavily ARV-experienced patients. Methods  We conducted a nationwide, HIV clinic-based, cohort study in Mexico. Adults infected with HIV were assessed for a median of 33 months (interquartile range [IQR] = 22–43 months). These patients had experienced the virologic failure of at least 2 prior ARV regimens and had detectable viremia while currently being treated; their physicians had received therapeutic advice, by a panel of experts, regarding the ARV salvage regimen. The primary endpoint was the incidence of loss of virologic response (plasma HIV-RNA levels of <200 copies per mL, followed by levels above this threshold) during the follow-up assessment using an observed-failure competing risks regression analysis. Results  A total of 611 patients were observed (median ARV therapy exposure = 10.5 years; median prior regimens = 4). The probabilities of virologic failure were 11.9%, 14.4%, 16.9%, and 19.4% at the 12-, 24-, 36-, and 48-month follow-up assessments, respectively. Of the 531 patients who achieved a confirmed plasma HIV-RNA level below 200 copies per mL, the median increase in blood CD4+ T-cell count was 162 cells per mL (IQR = 45–304 cells per mL). Conclusions  In routine practice, a high rate of patients with extensive ARV experience, who received an optimized salvage regimen recommended by a peer advisory committee, achieved a long-term sustained virologic response and immune reconstitution. PMID:25734149

Croton megalobotrys Müll Arg. and Vitex doniana (Sweet): Traditional medicinal plants in a three-step treatment regimen that inhibit in vitro replication of HIV-1.

PubMed

Tietjen, Ian; Gatonye, Teresia; Ngwenya, Barbara N; Namushe, Amos; Simonambanga, Sundana; Muzila, Mbaki; Mwimanzi, Philip; Xiao, Jianbo; Fedida, David; Brumme, Zabrina L; Brockman, Mark A; Andrae-Marobela, Kerstin

2016-09-15

Human Immunodeficiency Virus (HIV) strains resistant to licensed anti-retroviral drugs (ARVs) continue to emerge. On the African continent, uneven access to ARVs combined with occurrence of side-effects after prolonged ARV therapy have led to searches for traditional medicines as alternative or complementary remedies to conventional HIV/AIDS management. Here we characterize a specific three-step traditional HIV/AIDS treatment regimen consisting of Cassia sieberiana root, Vitex doniana root, and Croton megalobotrys bark by combining qualitative interviews of traditional medical knowledge users in Botswana with in vitro HIV replication studies. Crude extracts from a total of seven medicinal plants were tested for in vitro cytotoxicity and inhibition of wild-type (NL4.3) and ARV-resistant HIV-1 replication in an immortalized GFP-reporter CD4+ T-cell line. C. sieberiana root, V. doniana root, and C. megalobotrys bark extracts inhibited HIV-1NL4.3 replication with dose-dependence and without concomitant cytotoxicity. C. sieberiana and V. doniana extracts inhibited HIV-1 replication by 50% at 84.8µg/mL and at 25µg/mL, respectively, while C. megalobotrys extracts inhibited HIV-1 replication by a maximum of 45% at concentrations as low as 0.05µg/mL. Extracts did not interfere with antiviral activities of licensed ARVs when applied in combination and exhibited comparable efficacies against viruses harboring major resistance mutations to licensed protease, reverse-transcriptase, or integrase inhibitors. We report for the first time a three-step traditional HIV/AIDS regimen, used alone or in combination with standard ARV regimens, where each step exhibited more potent ability to inhibit HIV replication in vitro. Our observations support the "reverse pharmacology" model where documented clinical experiences are used to identify natural products of therapeutic value. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Impact of the Data Collection on Adverse Events of Anti-HIV Drugs cohort study on abacavir prescription among treatment-naive, HIV-infected patients in Canada.

PubMed

Antoniou, Tony; Gillis, Jennifer; Loutfy, Mona R; Cooper, Curtis; Hogg, Robert S; Klein, Marina B; Machouf, Nima; Montaner, Julio S G; Rourke, Sean B; Tsoukas, Chris; Raboud, Janet M

2014-01-01

To evaluate the trends in abacavir (ABC) prescription among antiretroviral (ARV) medication-naive individuals following the presentation of the Data Collection on Adverse Events of Anti-HIV Drugs (DAD) cohort study. We conducted a retrospective cohort study of ARV medication-naive individuals in the Canadian Observational Cohort (CANOC). Between January 1, 2000, and February 28, 2010, a total of 7280 ARV medication-naive patients were included in CANOC. We observed a significant change in the proportion of new ABC prescriptions immediately following the release of DAD (-11%; 95% confidence interval [CI]: -20% to -2.4%) and in the months following the presentation of these data (-0.66% per month; 95% CI: -1.2% to -0.073%). A post-DAD presentation decrease in the odds of being prescribed ABC versus tenofovir (TDF) was observed (adjusted odds ratio, 0.72 per year, 95% CI: 0.54-0.97). Presentation of the DAD was associated with a significant decrease in ABC use among ARV medication-naive, HIV-positive patients initiating therapy.

Hormonal Contraceptives Differentially Suppress TFV and TAF Inhibition of HIV Infection and TFV-DP in Blood and Genital Tract CD4+ T cells.

PubMed

Shen, Zheng; Rodriguez-Garcia, Marta; Patel, Mickey V; Bodwell, Jack; Kashuba, Angela D M; Wira, Charles R

2017-12-18

HIV prevention research is focused on combining antiretrovirals (ARV) and progestin contraceptives to prevent HIV infection and pregnancy. The possibility that progestins compromise ARV anti-HIV activity prompted us to evaluate the effects of progestins on tenofovir (TFV) and TFV-alafenamide (TAF) on HIV infection and intracellular TFV-diphosphate (TFV-DP) concentrations in blood and genital CD4+ T cells. Following incubation of blood CD4+ T cells with TFV or TAF, Medroxyprogesterone acetate (MPA), but not Levonorgestrel, Norethisterone or progesterone, suppressed the anti-HIV effect of TFV by reducing intracellular TFV-DP, but had no effect on TAF inhibition of infection or TFV-DP. In contrast, with genital CD4+ T cells, MPA suppressed TAF inhibition of HIV infection and lowered of TFV-DP concentrations without affecting TFV protection. These findings demonstrate that MPA selectively compromises TFV and TAF protection in blood and genital CD4+ T cells and suggests that MPA may decrease ARV protection in individuals who use ARV intermittently for prevention.

Low CD4+ T-cell levels and B-cell apoptosis in vertically HIV-exposed noninfected children and adolescents.

PubMed

Miyamoto, Maristela; Pessoa, Silvana D; Ono, Erika; Machado, Daisy M; Salomão, Reinaldo; Succi, Regina C de M; Pahwa, Savita; de Moraes-Pinto, Maria Isabel

2010-12-01

Lymphocyte subsets, activation markers and apoptosis were assessed in 20 HIV-exposed noninfected (ENI) children born to HIV-infected women who were or not exposed to antiretroviral (ARV) drugs during pregnancy and early infancy. ENI children and adolescents were aged 6-18 years and they were compared to 25 age-matched healthy non-HIV-exposed children and adolescents (Control). ENI individuals presented lower CD4(+) T cells/mm(3) than Control group (control: 1120.3 vs. ENI: 876.3; t-test, p = 0.030). ENI individuals had higher B-cell apoptosis than Control group (Control: 36.6%, ARV exposed: 82.3%, ARV nonexposed: 68.5%; Kruskal-Wallis, p < 0.05), but no statistical difference was noticed between those exposed and not exposed to ARV. Immune activation in CD4(+) T, CD8(+) T and in B cells was comparable in ENI and in Control children and adolescents. Subtle long-term immune alterations might persist among ENI individuals, but the clinical consequences if any are unknown, and these children require continued monitoring.

Which Patients First? Setting Priorities for Antiretroviral Therapy Where Resources Are Limited

PubMed Central

McGough, Laura J.; Reynolds, Steven J.; Quinn, Thomas C.; Zenilman, Jonathan M.

2005-01-01

The availability of limited funds from international agencies for the purchase of antiretroviral (ARV) treatment in developing countries presents challenges, especially in prioritizing who should receive therapy. Public input and the protection of human rights are crucial in making treatment programs equitable and accountable. By examining historical precedents of resource allocation, we aim to provoke and inform debate about current ARV programs. Through a critical review of the published literature, we evaluate 4 precedents for key lessons: the discovery of insulin for diabetes in 1922, the release of penicillin for civilian use in 1943, the development of chronic hemodialysis programs in 1961, and current allocation of liver transplants. We then describe current rationing mechanisms for ARVs. PMID:15983271

A Single-Blind randomized controlled trial to evaluate the effect of extended counseling on uptake of pre-antiretroviral care in eastern uganda

PubMed Central

2011-01-01

Background Many newly screened people living with HIV (PLHIV) in Sub-Saharan Africa do not understand the importance of regular pre-antiretroviral (ARV) care because most of them have been counseled by staff who lack basic counseling skills. This results in low uptake of pre-ARV care and late treatment initiation in resource-poor settings. The effect of providing post-test counseling by staff equipped with basic counseling skills, combined with home visits by community support agents on uptake of pre-ARV care for newly diagnosed PLHIV was evaluated through a randomized intervention trial in Uganda. Methods An intervention trial was performed consisting of post-test counseling by trained counselors, combined with monthly home visits by community support agents for continued counseling to newly screened PLHIV in Iganga district, Uganda between July 2009 and June 2010, Participants (N = 400) from three public recruitment centres were randomized to receive either the intervention, or the standard care (the existing post-test counseling by ARV clinic staff who lack basic training in counseling skills), the control arm. The outcome measure was the proportion of newly screened and counseled PLHIV in either arm who had been to their nearest health center for clinical check-up in the subsequent three months +2 months. Treatment was randomly assigned using computer-generated random numbers. The statistical significance of differences between the two study arms was assessed using chi-square and t-tests for categorical and quantitative data respectively. Risk ratios and 95% confidence intervals were used to assess the effect of the intervention. Results Participants in the intervention arm were 80% more likely to accept (take up) pre-ARV care compared to those in the control arm (RR 1.8, 95% CI 1.4-2.1). No adverse events were reported. Conclusions Provision of post-test counseling by staff trained in basic counseling skills, combined with home visits by community support

An assessment of mother-to-child HIV transmission prevention in 16 pilot antenatal clinics in Jamaica.

PubMed

Harvey, K M; Figueroa, J P; Tomlinson, J; Gebre, Y; Forbes, S; Toyloy, T; Thompson, T; Thompson, K

2004-10-01

This study aims to determine the number and age distribution of pregnant women testing positive for HIV at 16 selected clinics in Jamaica between 2001 and 2002; the utilization of therapeutic interventions to minimize the risk of mother-to-child transmission (MTCT) and the current status of the HIV-exposed infants and, finally, the number of children who received testing for detection of HIV and to calculate the incidence of MTCT in these children. A retrospective study was carried out at sixteen pilot clinic sites by examining the patient records for all confirmed HIV-positive pregnant mothers and the resultant infants at these facilities for the period January 2001 to December 2002. One hundred and twenty-three of 8116 pregnant women newly tested positive during the period January 2001 to December 2002; however, 176 HIV+ women delivered. Fifty-three (30%) knew their HIV status prior to participating in the programme. Sixty-two (1.4%) and 61 (1.6%) tested positive in 2001 and 2002, respectively. One hundred and ten (77%) and 113 (83%) mothers and infants, respectively, received ARV therapy, (92% - nevirapine, 8% - zidovudine). Twenty-three per cent of pregnant women received no ARV Forty-four (25.0%) of the 176 infants had a documented ELISA HIV test before eighteen months of age, none had a PCR test. The health status of 40 (23%) of these children was known: 30 (75%) were alive and well, five of whom did not receive any ARV, one (2.5%) was alive and ill and nine (22.5%) were reported dead, five of whom received ARV; 28.6% of infants who did not receive ARV were reported as either dead or ill compared to 13.8% of those receiving ARV CONCLUSION: Though the majority of pregnant women discovered their HIV status during pregnancy, a significant number got pregnant knowing that they were HIV+. The majority of mothers and infants received ARV but the follow-up and testing of infants was limited. Nevirapine is clearly protective in the prevention of MTCT of HIV and

Awareness, discussion and non-prescribed use of HIV pre-exposure prophylaxis among persons living with HIV/AIDS in Italy: a Nationwide, cross-sectional study among patients on antiretrovirals and their treating HIV physicians.

PubMed

Palummieri, Antonio; De Carli, Gabriella; Rosenthal, Éric; Cacoub, Patrice; Mussini, Cristina; Puro, Vincenzo

2017-11-28

Before Pre-Exposure Prophylaxis (PrEP) was officially recommended and made available, a few surveys among gay and bisexual men, and persons living with HIV/AIDS (PLWHA), identified an informal use of antiretrovirals (ARVs) for PrEP among HIV-negative individuals. Before PrEP availability in Italy, we aimed to assess whether PLWHA in Italy shared their ARVs with HIV-negative individuals, whether they knew people who were on PrEP, and describe the level of awareness and discussion on this preventive measure among them and people in their close circle. Two anonymous questionnaires investigating personal characteristics and PrEP awareness, knowledge, and experience were proposed to HIV specialists and their patients on ARVs in a one-week, cross-sectional survey (December 2013-January 2014). Among PLWHA, a Multivariable Logistic Regression analysis was conducted to identify factors associated with PrEP discussion with peers (close circle and/or HIV associations), and experience (use in close circle and/or personal ARV sharing). Eighty-seven specialists in 31 representative Infectious Diseases departments administered the questionnaire to 1405 PLWHA. Among specialists, 98% reported awareness, 65% knew the dosage schedule, and 14% had previously suggested or prescribed PrEP. Among PLWHA, 45.6% were somehow aware, discussed or had direct or indirect experience of PrEP: 38% "had heard" of PrEP, 24% were aware of studies in HIV-negative individuals demonstrating a risk reduction through the use of ARVs, 22% had discussed PrEP, 12% with peers; 9% reported PrEP use in close circle and 1% personal ARV sharing. Factors predictive of either PrEP discussion with peers or experience differed between men and women, but across all genders were mainly related to having access to information, with HIV association membership being the strongest predictor. At a time and place where there were neither official information nor proposals or interventions to guide public policies on PrEP in

Loss of retrovirus production in JB/RH melanoma cells transfected with H-2Kb and TAP-1 genes.

PubMed

Li, M; Xu, F; Muller, J; Huang, X; Hearing, V J; Gorelik, E

1999-01-20

JB/RH1 melanoma cells, as well as other melanomas of C57BL/6 mice (B16 and JB/MS), express a common melanoma-associated antigen (MAA) encoded by an ecotropic melanoma-associated retrovirus (MelARV). JB/RH1 cells do not express the H-2Kb molecules due to down-regulation of the H-2Kb and TAP-1 genes. When JB/RH1 cells were transfected with the H-2Kb and cotransfected with the TAP-1 gene, it resulted in the appearance of H-2Kb molecules and an increase in their immunogenicity, albeit they lost expression of retrovirus-encoded MAA recognized by MM2-9B6 mAb. Loss of MAA was found to result from a complete and stable elimination of ecotropic MelARV production in the H-2Kb/TAP-1-transfected JB/RH1 cells. Northern blot analysis showed no differences in ecotropic retroviral messages in MelARV-producing and -nonproducing melanoma cells, suggesting that loss of MelARV production was not due to down-regulation of MelARV transcription. Southern blot analysis revealed several rearrangements in the proviral DNA of H-2Kb-positive JB/RH1 melanoma cells. Sequence analysis of the ecotropic proviral DNA from these cells showed numerous nucleotide substitutions, some of which resulted in the appearance of a novel intraviral PstI restriction site and the loss of a HindIII restriction site in the pol region. PCR amplification of the proviral DNAs indicates that an ecotropic provirus found in the H-2Kb-positive cells is novel and does not preexist in the parental H-2Kb-negative melanoma cells. Conversely, the ecotropic provirus of the parental JB/RH1 cells was not amplifable from the H-2Kb-positive cells. Our data indicate that stable loss of retroviral production in the H-2Kb/TAP-1-transfected melanoma cells is probably due to the induction of recombination between a productive ecotropic MelARV and a defective nonecotropic provirus leading to the generation of a defective ecotropic provirus and the loss of MelARV production and expression of the retrovirus-encoded MAA. Copyright 1999

HIV-1 infection and pregnancy in young women in Brazil: socioeconomic and drug resistance profiles in a cross-sectional study.

PubMed

Lima, Yanna Andressa Ramos; Reis, Mônica Nogueira Guarda; Cardoso, Ludimila Paula Vaz; Stefani, Mariane Martins Araújo

2016-07-05

To describe socioeconomic and antiretroviral (ARV) drug resistance profiles among young pregnant women infected with HIV-1. A public health antenatal programme responsible for screening ∼90 000 pregnant women per year for nine different infectious diseases in Central Western Brazil. 96 young pregnant women (15-24 years) infected with HIV-1. Standard interviews and blood samples were taken at the time of recruitment, at the first medical appointment after confirmation of diagnosis of HIV-1 infection, and before ARV prophylaxis initiation. Clinical and laboratory data were retrieved from medical files. HIV-1 pol gene sequences (entire protease/PR, partial reverse transcriptase/RT) were obtained from plasma RNA. ARV resistance mutations (CPR/Stanford HIV-1; International AIDS Society-USA databases) were identified. The median age was 21 years; most reported <8 years education; 73% were recently diagnosed. Approximately 20% (19/96) presented late for antenatal care (after 26 gestational weeks), while 49% reported ≥2 previous pregnancies. Possible heterosexual transmission by an HIV-1 infected partner (17%) and commercial sex work (2%) were reported. The median of CD4 cell count was 526 cells/mm(3); the median viral load was: 10 056 copies/mL in ARV-naïve (48/96) patients and 5881 copies/mL in ARV-exposed (48/96) patients. Two probable seroconversion cases during pregnancy were identified in adolescents. One mother-to-child transmission case (1.0%) was observed. Transmitted drug resistance among ARV-naïve patients was 9.3% (CI 95% 3.3% to 19.6%); secondary drug resistance among ARV-exposed patients was 12.5% (CI 95% 4.7% to 25.6%). Despite high access to antenatal care, the low socioeconomic-educational profiles seen in these young HIV-1-infected women highlight the necessity of improved public health educational and preventive strategies regarding HIV infection and early unplanned pregnancy. Published by the BMJ Publishing Group Limited. For permission

A novel prostate cancer therapeutic strategy using icaritin-activated arylhydrocarbon-receptor to co-target androgen receptor and its splice variants

PubMed Central

Sun, Feng; Indran, Inthrani R.; Zhang, Zhi Wei; Tan, M.H.Eileen; Li, Yu; Lim, Z.L.Ryan; Hua, Rui; Yang, Chong; Soon, Fen-Fen; Li, Jun; Xu, H.Eric; Cheung, Edwin; Yong, Eu-Leong

2015-01-01

Persistent androgen receptor (AR) signaling is the key driving force behind progression and development of castration-resistant prostate cancer (CRPC). In many patients, AR COOH-terminal truncated splice variants (ARvs) play a critical role in contributing to the resistance against androgen depletion therapy. Unfortunately, clinically used antiandrogens like bicalutamide (BIC) and enzalutamide (MDV), which target the ligand binding domain, have failed to suppress these AR variants. Here, we report for the first time that a natural prenylflavonoid, icaritin (ICT), can co-target both persistent AR and ARvs. ICT was found to inhibit transcription of key AR-regulated genes, such as KLK3 [prostate-specific antigen (PSA)] and ARvs-regulated genes, such as UBE2C and induce apoptosis in AR-positive prostate cancer (PC) cells. Mechanistically, ICT promoted the degradation of both AR and ARvs by binding to arylhydrocarbon-receptor (AhR) to mediate ubiquitin-proteasomal degradation. Therefore, ICT impaired AR transactivation in PC cells. Knockdown of AhR gene restored AR stability and partially prevented ICT-induced growth suppression. In clinically relevant murine models orthotopically implanted with androgen-sensitive and CRPC cells, ICT was able to target AR and ARvs, to inhibit AR signaling and tumor growth with no apparent toxicity. Our results provide a mechanistic framework for the development of ICT, as a novel lead compound for AR-positive PC therapeutics, especially for those bearing AR splice variants. PMID:25908644

First population-level effectiveness evaluation of a national programme to prevent HIV transmission from mother to child, South Africa.

PubMed

Goga, Ameena E; Dinh, Thu-Ha; Jackson, Debra J; Lombard, Carl; Delaney, Kevin P; Puren, Adrian; Sherman, Gayle; Woldesenbet, Selamawit; Ramokolo, Vundli; Crowley, Siobhan; Doherty, Tanya; Chopra, Mickey; Shaffer, Nathan; Pillay, Yogan

2015-03-01

There is a paucity of data on the national population-level effectiveness of preventing mother-to-child transmission (PMTCT) programmes in high-HIV-prevalence, resource-limited settings. We assessed national PMTCT impact in South Africa (SA), 2010. A facility-based survey was conducted using a stratified multistage, cluster sampling design. A nationally representative sample of 10 178 infants aged 4-8 weeks was recruited from 565 clinics. Data collection included caregiver interviews, record reviews and infant dried blood spots to identify HIV-exposed infants (HEI) and HIV-infected infants. During analysis, self-reported antiretroviral (ARV) use was categorised: 1a: triple ARV treatment; 1b: azidothymidine >10 weeks; 2a: azidothymidine ≤10 weeks; 2b: incomplete ARV prophylaxis; 3a: no antenatal ARV and 3b: missing ARV information. Findings were adjusted for non-response, survey design and weighted for live-birth distributions. Nationally, 32% of live infants were HEI; early mother-to-child transmission (MTCT) was 3.5% (95% CI 2.9% to 4.1%). In total 29.4% HEI were born to mothers on triple ARV treatment (category 1a) 55.6% on prophylaxis (1b, 2a, 2b), 9.5% received no antenatal ARV (3a) and 5.5% had missing ARV information (3b). Controlling for other factors groups, 1b and 2a had similar MTCT to 1a (Ref; adjusted OR (AOR) for 1b, 0.98, 0.52 to 1.83; and 2a, 1.31, 0.69 to 2.48). MTCT was higher in group 2b (AOR 3.68, 1.69 to 7.97). Within group 3a, early MTCT was highest among breastfeeding mothers 11.50% (4.67% to 18.33%) for exclusive breast feeding, 11.90% (7.45% to 16.35%) for mixed breast feeding, and 3.45% (0.53% to 6.35%) for no breast feeding). Antiretroviral therapy or >10 weeks prophylaxis negated this difference (MTCT 3.94%, 1.98% to 5.90%; 2.07%, 0.55% to 3.60% and 2.11%, 1.28% to 2.95%, respectively). SA, a high-HIV-prevalence middle income country achieved <5% MTCT by 4-8 weeks post partum. The long-term impact on PMTCT on HIV

Efficacy and durability of nevirapine in antiretroviral drug näive patients.

PubMed

Lange, Joep M A

2003-09-01

Nevirapine is a non-nucleoside reverse transcriptase inhibitor (NNRTI) that was first reported in the scientific literature in 1990. Varying doses of nevirapine (NVP) and a number of regimens containing this NNRTI have been studied in antiretroviral (ARV) näive patients. Four key studies have compared the efficacy and safety of triple drug regimens containing NVP in ARV näive, HIV-1 infected patients. The INCAS study was the first demonstration of how to use NVP in an effective and durable manner: as a component of a triple drug regimen. The COMBINE Study was a comparison of protease inhibitor (PI)-based and NVP-based triple regimens. The Atlantic Study is comparing the safety and efficacy of three triple drug regimens in ARV näive patients. In this study, treatment consists of a divergent drug regimen (PI and nucleoside reverse transcriptase inhibitors, NRTIs) targeting both HIV-1 protease and reverse transcriptase or a convergent regimen targeting reverse transcriptase alone (three NRTIs or two NRTIs plus a NNRTI). A clinical endpoint study (BI 1090) compared the efficacy and durability of multi-drug regimens in ARV näive patients with high baseline plasma HIV-1 RNA levels (pVLs) and low peripheral blood CD4+ lymphocyte counts. Data from these studies confirm that triple regimens containing NVP suppressed viral replication for up to one year, even when the ARV näive patients had low CD4+ cell counts at baseline. Nevirapine-containing regimens suppressed pVLs to < 50 copies/ mL in approximately 50% of patients in the studies discussed (Intent to Treat analyses). Data from 96 weeks of follow up in the Atlantic Study demonstrates that the regimens containing didanosine and stavudine plus indinavir or NVP were significantly more successful in suppressing pVLs to < 50 copies/mL during this period than a regimen composed of these NRTIs and lamivudine (p < or = 0.001). As with other ARV drugs, NVP should always be used as part of a fully suppressive ARV regimen

Self-Report and Dry Blood Spot Measurement of Antiretroviral Medications as Markers of Adherence in Pregnant Women in Rural South Africa.

PubMed

Alcaide, Maria L; Ramlagan, Shandir; Rodriguez, Violeta J; Cook, Ryan; Peltzer, Karl; Weiss, Stephen M; Sifunda, Sibusiso; Jones, Deborah L

2017-07-01

Antiretroviral (ARV) adherence is essential to prevent mother-to-child transmission of HIV. This study compared self-reported adherence versus ARV detection in dried blood spots (DBS) among N = 392 HIV-infected pregnant women in South Africa (SA). Women completed two self-reported adherence measures [visual analog scale (VAS), AIDS Clinical Trials Group Adherence (ACTG)]. Adherence was 89% (VAS), 80% (ACTG), and 74% (DBS). Self-report measures marginally agreed with DBS (VAS: Kappa = 0.101, Area under the ROC curve (AUROC) = 0.543; ACTG: Kappa  = 0.081, AUROC = 0.538). Self-reported adherence was overestimated and agreement with DBS was poor. Validation of self-reported ARV adherence among pregnant HIV+ women in SA is needed.

Evolution of antiretroviral drug costs in Brazil in the context of free and universal access to AIDS treatment.

PubMed

Nunn, Amy S; Fonseca, Elize M; Bastos, Francisco I; Gruskin, Sofia; Salomon, Joshua A

2007-11-13

Little is known about the long-term drug costs associated with treating AIDS in developing countries. Brazil's AIDS treatment program has been cited widely as the developing world's largest and most successful AIDS treatment program. The program guarantees free access to highly active antiretroviral therapy (HAART) for all people living with HIV/AIDS in need of treatment. Brazil produces non-patented generic antiretroviral drugs (ARVs), procures many patented ARVs with negotiated price reductions, and recently issued a compulsory license to import one patented ARV. In this study, we investigate the drivers of recent ARV cost trends in Brazil through analysis of drug-specific prices and expenditures between 2001 and 2005. We compared Brazil's ARV prices to those in other low- and middle-income countries. We analyzed trends in drug expenditures for HAART in Brazil from 2001 to 2005 on the basis of cost data disaggregated by each ARV purchased by the Brazilian program. We decomposed the overall changes in expenditures to compare the relative impacts of changes in drug prices and drug purchase quantities. We also estimated the excess costs attributable to the difference between prices for generics in Brazil and the lowest global prices for these drugs. Finally, we estimated the savings attributable to Brazil's reduced prices for patented drugs. Negotiated drug prices in Brazil are lowest for patented ARVs for which generic competition is emerging. In recent years, the prices for efavirenz and lopinavir-ritonavir (lopinavir/r) have been lower in Brazil than in other middle-income countries. In contrast, the price of tenofovir is US$200 higher per patient per year than that reported in other middle-income countries. Despite precipitous price declines for four patented ARVs, total Brazilian drug expenditures doubled, to reach US$414 million in 2005. We find that the major driver of cost increases was increased purchase quantities of six specific drugs: patented lopinavir

Costing of Paediatric Treatment alongside Clinical Trials under Low Resource Constraint Environments: Cotrimoxazole and Antiretroviral Medications in Children Living with HIV/AIDS

PubMed Central

2016-01-01

Introduction. Costing evidence is essential for policy makers for priority setting and resource allocation. It is in this context that the clinical trials of ARVs and cotrimoxazole provided a costing component to provide evidence for budgeting and resource needs alongside the clinical efficacy studies. Methods. A micro based costing approach was adopted, using case record forms for maintaining patient records. Costs for fixed assets were allocated based on the paediatric space. Medication and other resource costs were costed using the WHO/MSH Drug Price Indicators as well as procurement data where these were available. Results. The costs for cotrimoxazole and ARVs are significantly different. The average costs for human resources were US$22 and US$71 for physician costs and $1.3 and $16 for nursing costs while in-patient costs were $257 and $15 for the cotrimoxazole and ARV cohorts, respectively. Mean or average costs were $870 for the cotrimoxazole cohort and $218 for the ARV. The causal factors for the significant cost differences are attributable to the higher human resource time, higher infections of opportunistic conditions, and longer and higher frequency of hospitalisations, among others. PMID:28042479

Synergistic activity profile of carbosilane dendrimer G2-STE16 in combination with other dendrimers and antiretrovirals as topical anti-HIV-1 microbicide.

PubMed

Sepúlveda-Crespo, Daniel; Lorente, Raquel; Leal, Manuel; Gómez, Rafael; De la Mata, Francisco J; Jiménez, José Luis; Muñoz-Fernández, M Ángeles

2014-04-01

Polyanionic carbosilane dendrimers represent opportunities to develop new anti-HIV microbicides. Dendrimers and antiretrovirals (ARVs) acting at different stages of HIV replication have been proposed as compounds to decrease new HIV infections. Thus, we determined the potential use of our G2-STE16 carbosilane dendrimer in combination with other carbosilane dendrimers and ARVs for the use as topical microbicide against HIV-1. We showed that these combinations obtained 100% inhibition and displayed a synergistic profile against different HIV-1 isolates in our model of TZM.bl cells. Our results also showed their potent activity in the presence of an acidic vaginal or seminal fluid environment and did not activate an inflammatory response. This study is the first step toward exploring the use of different anionic carbosilane dendrimers in combination and toward making a safe microbicide. Therefore, our results support further studies on dendrimer/dendrimer or dendrimer/ARV combinations as topical anti-HIV-1 microbicide. This paper describes the first steps toward the use of anionic carbosilane dendrimers in combination with antivirals to address HIV-1, paving the way to further studies on dendrimer/dendrimer or dendrimer/ARV combinations as topical anti-HIV-1 microbicides. © 2014.

Pharmacokinetics of Antiretrovirals in Mucosal Tissue

PubMed Central

Cottrell, M.L.; Srinivas, N.; Kashuba, A.D.M.

2015-01-01

Introduction In the absence of an HIV vaccine or cure, antiretroviral (ARV) based prevention strategies are being investigated to reduce HIV incidence. These prevention strategies depend on achieving effective drug concentrations at the site HIV exposure which is most commonly the mucosal tissues of the lower gastrointestinal tract and the female genital tract. Areas covered This article collates all known data regarding drug exposure in these vulnerable mucosal tissues, and reviews important mechanisms of ARV drug distribution. Research papers and abstracts describing antiretroviral pharmacokinetics in the female genital tract and lower gastrointestinal mucosal tissues available in MEDLINE® or presented at scientific conferences prior to December 2014 are reviewed in detail. Important influences on ARV mucosal tissue distribution, including protein binding, active drug transport, and endogenous hormones, are also reviewed. Expert opinion ARVs exhibit highly variable pharmacokinetics in mucosal tissues. In general, antiretroviral exposure is higher in the lower gastrointestinal tract compared to the female genital tract, but concentrations required for protective efficacy are largely unknown. The expected site of HIV exposure represents an important consideration when designing and optimizing antiretroviral based prevention strategies. PMID:25797064

[Use of Nadis(®) software to improve adverse drug reaction reporting of antiretroviral drugs: experience in south west of France (midi-pyrénées)].

PubMed

Pochard, Liselotte; Hauviller, Laurent; Cuzin, Lise; Eyvrard, Fréderic; Sommet, Agnès; Montastruc, Jean-Louis; Bagheri, Haleh

2014-01-01

To study the value of the module of pharmacovigilance in Nadis® to improve the antiretroviral (ARV) drugs-induced adverse drug reactions (ADRs) reporting. We collected the ADRs reported for 17 months from November 2010 until April 2012. Following data were recorded: characteristics of patients, ADRs, ARV drugs. The number of ADRs was compared to those collected in the same period (17 months) before use of Nadis®. The 119 ADRs reported (an increase of 183%) for 109 patients ADRs were mainly gastrointestinal (21.8%) followed by renal (20.2%), neuro-psychiatric (16.8%), hepatic (13.5%), cutaneous (8.4%), metabolic (6.7%) and others (12.6%). The repartition of ARV drugs was: nucleoside (31.8%), nucleotide (13.6%) reverse transcriptase inhibitors respectively, non-nucleoside reverse transcriptase inhibitors (13.1%), protease inhibitors (36.4%), and integrase inhibitors (5.1%). Our results show the improvement of ARV-induced ADRs reporting by Nadis® which could be used to reduce the rate of under-reporting in patients exposed to these drugs. © 2014 Société Française de Pharmacologie et de Thérapeutique.

Transition to Adulthood and Antiretroviral Adherence Among HIV-Positive Young Black Men Who Have Sex With Men

PubMed Central

Andes, Karen; Gilliard, Danielle; Chakraborty, Rana; del Rio, Carlos; Malebranche, David J.

2015-01-01

Objectives. We conducted a qualitative study of HIV-positive young Black men who have sex with men (YBMSM) to explore their experiences of living with HIV and adhering to antiretroviral medications (ARVs) within the developmental context of their transition to adulthood. Methods. We conducted life history interviews with 20 HIV-positive YBMSM in Atlanta, Georgia, engaged in outpatient HIV care. We addressed these questions: (1) How do YBMSM living with HIV experience the transition to adulthood? and (2) What are the important sociocontextual influences on ARV adherence for YBMSM? Results. Successful transition to adulthood and optimal ARV adherence were inextricably linked. HIV’s detrimental impact on development was moderated by the degree of physical illness at diagnosis. Many participants described resilient trajectories while coping with HIV. Adherence problems occurred primarily among participants who were not meeting their developmental goals. Conclusions. Our findings support the need for early diagnosis and linkage to care, as well as the need to develop holistic, resilience-based interventions focusing on transition to adulthood. These findings have implications for individual clinical outcomes as well as ARV-based prevention efforts among YBMSM. PMID:24922167

Higher Blood Pressure Variability in White Coat Hypertension; from the Korean Ambulatory Blood Pressure Monitoring Registry

PubMed Central

Kang, In Sook; Shin, Jinho; Ihm, Sang-Hyun; Kim, Ju Han; Park, Sungha; Kim, Kwang-Il; Kim, Woo-Shik; Kim, Soon Gil; Shin, Gil Ja

2016-01-01

Background and Objectives Blood pressure variability (BPV) was recently shown to be a risk factor of stroke. White coat hypertension (WCH) used to be regarded as innocuous, but one long-term follow-up study reported that WCH increased stroke rate compared to normotension (NT). In this study, we aimed to evaluate the relationship between WCH and BPV. Subjects and Methods We analyzed 1398 subjects from the Korean Ambulatory Blood Pressure Registry, who were divided into NT (n=364), masked hypertension (n=122), white coat hypertension (n=254), and sustained hypertension (n=658) groups. Results Baseline characteristics were similar among groups. The average real variability (ARV), a highly sensitive BPV parameter, was highest in the WCH group, followed by the sustained hypertension, masked hypertension, and NT groups. The results persisted after being adjusted for covariates. The WCH vs. sustained hypertension results (adjusted mean±standard error) were as follows: 24-h systolic ARV, 22.9±0.8 vs. 19.4±0.6; 24-h diastolic ARV, 16.8±0.6 vs. 14.3±0.5; daytime systolic ARV, 21.8±0.8 vs. 16.8±0.6; and daytime diastolic ARV, 16.2±0.6 vs. 13.4±0.5 (p<0.001 for all comparisons). Conclusion From the registry data, we found that subjects with WCH or masked hypertension had higher BPV than NT. However, long-term follow-up data assessing the clinical influences of WCH on stroke are needed. PMID:27275173

Impact of antiretroviral therapy on selected metabolic disorders - pilot study.

PubMed

Bociąga-Jasik, Monika; Polus, Anna; Góralska, Joanna; Raźny, Urszula; Siedlecka, Dominika; Zapała, Barbara; Chrzan, Robert; Garlicki, Aleksander; Mach, Tomasz; Dembińska-Kieć, Aldona

2014-01-01

Taking into consideration the aging of HIV infected individuals, changes in the metabolism aggravated by the antiretroviral therapy significantly impact their health. Mechanisms responsible for lipodystrophy, dyslipidemia and insulin resistance (IR) occurrence have not been completely understood. Only recently, the free fatty acids (FFAs) metabolic turnover has become considered to be the independent risk factor for cardiovascular complications. We designed the follow-up study in which patients were recruited before the introduction of ARV therapy and then observed up to 1 year. The impact of ARV therapy on the development of metabolic complications, inflammation markers and changes in adipokines secretion was investigated. The fasting and postprandial responses of FFAs, triglycerides (TG), glucose, insulin and glucose-dependent insulinotropic peptide (GIP) were measured. Changes in body composition were followed by impedance and a CT scan of adipose tissue volume of the abdomen and thighs. Significant impact of ARV therapy on metabolic disturbances was reported. Not only fasting, but also postprandial levels of FFAs and TG were found to increase during the follow up. The increased concentration of FFAs is suggested to be the triggering event in the development of hypertriglyceridemia and insulin resistance during ARV therapy. Changes in postprandial FFAs and TG during the follow up indicate the increasing risk of cardiovascular diseases. We conclude that modern ARV therapy during the period of 12 months does not induce changes in the fat distribution, although increased limb fat correlated with higher plasma leptin level, which may be the marker of increased risk of metabolic driven cardiovascular complications.

Progress of the National Pediatric Free Antiretroviral Therapy program in China.

PubMed

Zhao, Yan; Sun, Xin; He, Yun; Tang, Zhirong; Peng, Guoping; Liu, Aiwen; Qiao, Xiaochun; Li, Huiqin; Chen, Zhiqiang; Dou, Zhihui; Ma, Ye; Liu, Zhongfu; Zhang, Fujie

2010-10-01

In 2003, the Chinese Government initiated a free antiretroviral therapy (ART) program focusing on adult AIDS patients. Pediatric antiretroviral (ARV) formulations were yet unavailable. It was not until July 2005, with the initiation of a two-stage program implemented by the Chinese Ministry of Health, that pediatric formulations became accessible in China. Initially, the pediatric ART program was piloted in six provinces with the highest incidences of pediatric HIV/AIDS. The pilot stage allowed the Chinese Center for Disease Control and Prevention (CCDC) to finalize entry criteria, treatment regimen, and patient monitoring and follow-up procedures. The second stage commenced at the end of 2006 when the program was scaled-up nationally. In order to guarantee treatment of pediatric patients, extensive training in the selection of appropriate ARV drug regimen and dosage was provided to doctors, often through on-site collaboration with domestic and international experts. The CCDC simultaneously established a pediatric ARV management system and a pediatric ART information system. CD4 count and other laboratory tests are being routinely performed on these pediatric patients. By the end of June 2009, 1529 pediatric patients had received ARV under the national program. However, challenges remain. Firstly, many children infected with HIV/AIDS live in rural areas where the treatment quality is hindered by the limited number of medical facilities and skilled medical workers. Secondly, much of the pediatric ARV drug supply depends on donation. An effort needs to be made by the Chinese Government to establish China's own drug procurement and supply system.

HIV type-1 genotypic resistance profiles in vertically infected patients from Argentina reveal an association between K103N+L100I and L74V mutations.

PubMed

Aulicino, Paula C; Rocco, Carlos A; Mecikovsky, Debora; Bologna, Rosa; Mangano, Andrea; Sen, Luisa

2010-01-01

Patterns and pathways of HIV type-1 (HIV-1) antiretroviral (ARV) drug resistance-associated mutations in clinical isolates are conditioned by ARV history and factors such as viral subtype and fitness. Our aim was to analyse the frequency and association of ARV drug resistance mutations in a group of long-term vertically infected patients from Argentina. Plasma samples from 71 patients (38 children and 33 adolescents) were collected for genotypic HIV-1 ARV resistance testing during the period between February 2006 and October 2008. Statistically significant pairwise associations between ARV resistance mutations in pol, as well as associations between mutations and drug exposure, were identified using Fisher's exact tests with Bonferroni and false discovery rate corrections. Phylogenetic analyses were performed for subtype assignment. In protease (PR), resistance-associated mutations M46I/L, I54M/L/V/A/S and V82A/F/T/S/M/I were associated with each other and with minor mutations at codons 10, 24 and 71. Mutations V82A/F/T/S/M/I were primarily selected by the administration of ritonavir (RTV) in an historical ARV regimen. In reverse transcriptase, thymidine analogue mutation (TAM)1 profile was more common than TAM2. The non-nucleoside K103N+L100I mutations were observed at high frequency (15.5%) and were significantly associated with the nucleoside mutation L74V in BF recombinants. Associations of mutations at PR sites reflect the frequent use of RTV at an early time in this group of patients and convergent resistance mechanisms driven by the high exposure to protease inhibitors, as well as local HIV-1 diversity. The results provide clinical evidence of a molecular interaction between K103N+L100I and L74V mutations at the reverse transcriptase gene in vivo, limiting the future use of second-generation non-nucleoside reverse transcriptase inhibitors such as etravirine.

A pharmacovigilance study of adults on highly active antiretroviral therapy, South Africa: 2007 - 2011.

PubMed

Dube, Nomathemba Michell; Summers, Robert; Tint, Khin-San; Mayayise, Guistee

2012-01-01

Of the 1.6 million South African people infected with human immunodeficiency virus (HIV), approximately 970,000 (55%) have been initiated on HAART. Despite these numbers, very little has been published about the safety profile of antiretroviral (ARV) medicines in the country. This study was performed at the Medunsa National Pharmacovigilance Centre and aimed to describe the demographic characteristics of patients enrolled in the pharmacovigilance surveillance study; highly active antiretroviral therapy (HAART) initiation regimen patterns; reasons for regimen changes; and adverse effects of ARV medicines. A cohort study of HIV-infected individuals aged 15 years or older who were on ARV medicines was conducted at four sentinel sites. After HAART initiation, with an average lapse of 17.8 months (range: 0 - 83.8 months), 2,815 patients were enrolled into the study. Results show that patients were observed for 1,606.2 person-years for pharmacy visits (collection of ARV medicines) and 817.1 person-years for clinical visits (consultation with the doctor). Females constituted 69.6% (1,958/2,815) of the study population. Almost all patients initiated HAART on first-line regimens (2,801/2,815). Some patients (6.7%, 190/2,815) dropped out of the study after HAART initiation. Reasons for regimen changes were not recorded for 2.5% (22/891) of the patients who changed regimens. The primary reason for regimen changes was drug-related toxicity (76.1%, 678/891), mostly evident in patients taking first-line regimens. Adverse effects experienced by patients were polyneuropathy (24.0%, 163/678); lipodystrophy (23.9%, 162/678); neuropathy (10.6%, 72/678); and suspected lactic acidosis (3.8%, 26/678). The majority of prescribers complied with the HAART guidelines and initiated most patients on first-line regimens. However, adverse effects are evident in patients taking first-line regimens. We recommend that the Department of Health should introduce less toxic first-line ARV regimens

Intervening in global markets to improve access to HIV/AIDS treatment: an analysis of international policies and the dynamics of global antiretroviral medicines markets

PubMed Central

2010-01-01

Background Universal access to antiretroviral therapy (ART) in low- and middle-income countries faces numerous challenges: increasing numbers of people needing ART, new guidelines recommending more expensive antiretroviral (ARV) medicines, limited financing, and few fixed-dose combination (FDC) products. Global initiatives aim to promote efficient global ARV markets, yet little is known about market dynamics and the impact of global policy interventions. Methods We utilize several data sources, including 12,958 donor-funded, adult first-line ARV purchase transactions, to describe the market from 2002-2008. We examine relationships between market trends and: World Health Organization (WHO) HIV/AIDS treatment guidelines; WHO Prequalification Programme (WHO Prequal) and United States (US) Food and Drug Administration (FDA) approvals; and procurement policies of the Global Fund to Fight AIDS, Tuberculosis, and Malaria (GFATM), US President's Emergency Plan for AIDS Relief (PEPFAR) and UNITAID. Results WHO recommended 7, 4, 24, and 6 first-line regimens in 2002, 2003, 2006 and 2009 guidelines, respectively. 2009 guidelines replaced a stavudine-based regimen ($88/person/year) with more expensive zidovudine- ($154-260/person/year) or tenofovir-based ($244-465/person/year) regimens. Purchase volumes for ARVs newly-recommended in 2006 (emtricitabine, tenofovir) increased >15-fold from 2006 to 2008. Twenty-four generic FDCs were quality-approved for older regimens but only four for newer regimens. Generic FDCs were available to GFATM recipients in 2004 but to PEPFAR recipients only after FDA approval in 2006. Price trends for single-component generic medicines mirrored generic FDC prices. Two large-scale purchasers, PEPFAR and UNITAID, together accounted for 53%, 84%, and 77% of market volume for abacavir, emtricitabine, and tenofovir, respectively, in 2008. PEPFAR and UNITAID purchases were often split across two manufacturers. Conclusions Global initiatives facilitated the

Impending flop for brand antiretrovirals in the emerging markets?

PubMed

Daniele, Dionisio; Daniela, Messeri

2008-01-01

Forecasts from Country choices, South-South partnerships and Clinton Foundation-UNITAID coalition show that present policies for brand ARVs are at the risk of flop in emerging South markets such as India, China, Thailand and Brazil.The dynamics explored in this article highlight the risks the originator companies are running in the emerging markets, along with their interest in direct agreements with the generic industry for the manufacturing and marketing of ARVs.Resulting information here would suggest the brand enterprises:To look for fast registration of their ARVs by regulatory authorities in all countries enlisted for differential pricing.To secure all formulations differentiated prices.To align with the Clinton-UNITAID prices for the corresponding generics.To pursue flexible negotiations with the generic companies to secure both counterparts long-term advantages.

Transformational Change of the Texan Army during the Texas War for Independence

DTIC Science & Technology

2010-12-10

violations. These efforts were in vain, as the consul did not understand U.S. standards of evidence or rights to free speech . After repeated attempts to......Martin and Baker until their insubordination led to challenging his authority. Houston endured numerous cases of sedition , only acting when they

Antiretroviral drug expenditure, pricing and judicial demand: an analysis of federal procurement data in Brazil from 2004–2011

PubMed Central

2014-01-01

Background Previous studies have described expenditures for antiretroviral (ARV) medicines in Brazil through 2005. While prior studies examined overall expenditures, they have not have analyzed drug procurement data in order to describe the role of court litigation on access and pricing. Methods ARV drug procurement from private sector sources for the years 2004–2011 was obtained through the general procurement database of the Brazilian Federal Government (SIASG). Procurement was measured in Defined Daily Doses (DDD) per 1000 persons-under-treatment per day. Expenditures and price per DDD were calculated and expressed in U.S. Dollars. Justifications for ARV purchases were examined in order to determine the relationship between health litigation and incorporation into Brazil’s national treatment guidelines. Results Drug procurement of ARVs from private sources underwent marked expansion in 2005, peaked in 2009, and stabilized to 2008 levels by 2011. Expenditures followed procurement curves. Medications which were procured for the first time after 2007 cost more than medicines which were introduced before 2007. Judicial actions initially resulted in purchases of newer medications for a select number of patients in Brazil but ultimately expanded availability to a larger population through incorporation into the national treatment guidelines. Conclusions Drug procurement and expenditures for ARVs in Brazil varied between 2004–2011. The procurement of some drugs from the private sector ceased after public manufacturers started producing them locally. Judicial demand has resulted in the incorporation of newer drugs into the national treatment guidelines. In order for the AIDS treatment program to remain sustainable, efforts should be pursued to reduce prices through generic drugs, price negotiation and other public health flexibilities such as compulsory licensing. PMID:24735589

Association of left ventricular structural and functional abnormalities with aortic and brachial blood pressure variability in hypertensive patients: the SAFAR study.

PubMed

Chi, C; Yu, S-K; Auckle, R; Argyris, A A; Nasothimiou, E; Tountas, C; Aissopou, E; Blacher, J; Safar, M E; Sfikakis, P P; Zhang, Y; Protogerou, A D

2017-10-01

Both brachial blood pressure (BP) level and its variability (BPV) significantly associate with left ventricular (LV) structure and function. Recent studies indicate that aortic BP is superior to brachial BP in the association with LV abnormalities. However, it remains unknown whether aortic BPV better associate with LV structural and functional abnormalities. We therefore aimed to investigate and compare aortic versus brachial BPV, in terms of the identification of LV abnormalities. Two hundred and three participants who underwent echocardiography were included in this study. Twenty-four-hour aortic and brachial ambulatory BP was measured simultaneously by a validated BP monitor (Mobil-O-Graph, Stolberg, Germany) and BPV was calculated with validated formulae. LV mass and LV diastolic dysfunction (LVDD) were evaluated by echocardiography. The prevalence of LV hypertrophy (LVH) and LVDD increased significantly with BPV indices (P⩽0.04) in trend tests. After adjustment to potential confounders, only aortic average real variability (ARV), but not brachial ARV or weighted s.d. (wSD, neither aortic nor brachial) significantly associated with LV mass index (P=0.02). Similar results were observed in logistic regression. After adjustment, only aortic ARV significantly associated with LVH (odds ratio (OR) and 95% confidence interval (CI): 2.28 (1.08, 4.82)). As for LVDD, neither the brachial nor the aortic 24-hour wSD, but the aortic and brachial ARV, associated with LVDD significantly, with OR=2.28 (95% CI: (1.03, 5.02)) and OR=2.36 (95% CI: (1.10, 5.05)), respectively. In summary, aortic BPV, especially aortic ARV, seems to be superior to brachial BPV in the association of LV structural and functional abnormalities.

Antiretroviral drug expenditure, pricing and judicial demand: an analysis of federal procurement data in Brazil from 2004-2011.

PubMed

Luo, Jing; Oliveira, Maria A; Ramos, Mariana B C; Maia, Aurélio; Osorio-de-Castro, Claudia G S

2014-04-16

Previous studies have described expenditures for antiretroviral (ARV) medicines in Brazil through 2005. While prior studies examined overall expenditures, they have not have analyzed drug procurement data in order to describe the role of court litigation on access and pricing. ARV drug procurement from private sector sources for the years 2004-2011 was obtained through the general procurement database of the Brazilian Federal Government (SIASG). Procurement was measured in Defined Daily Doses (DDD) per 1000 persons-under-treatment per day. Expenditures and price per DDD were calculated and expressed in U.S. Dollars. Justifications for ARV purchases were examined in order to determine the relationship between health litigation and incorporation into Brazil's national treatment guidelines. Drug procurement of ARVs from private sources underwent marked expansion in 2005, peaked in 2009, and stabilized to 2008 levels by 2011. Expenditures followed procurement curves. Medications which were procured for the first time after 2007 cost more than medicines which were introduced before 2007. Judicial actions initially resulted in purchases of newer medications for a select number of patients in Brazil but ultimately expanded availability to a larger population through incorporation into the national treatment guidelines. Drug procurement and expenditures for ARVs in Brazil varied between 2004-2011. The procurement of some drugs from the private sector ceased after public manufacturers started producing them locally. Judicial demand has resulted in the incorporation of newer drugs into the national treatment guidelines. In order for the AIDS treatment program to remain sustainable, efforts should be pursued to reduce prices through generic drugs, price negotiation and other public health flexibilities such as compulsory licensing.

Linking HIV and antiretroviral drug resistance surveillance in Peru: a model for a third-generation HIV sentinel surveillance.

PubMed

Lama, Javier R; Sanchez, Jorge; Suarez, Luis; Caballero, Patricia; Laguna, Alberto; Sanchez, Jose L; Whittington, William L H; Celum, Connie; Grant, Robert M

2006-08-01

HIV drug resistance surveillance is limited by recruitment and selection bias and by limited information regarding HIV incidence rates, secondary resistance, and treatment prevalence. A second-generation HIV sentinel surveillance among men who have sex with men (MSM), regardless of prior history of HIV screening, serostatus, or treatment, was conducted in Peru in 2002. Recent HIV infection was estimated using sensitive/less sensitive enzyme immunoassay testing. Genotypic resistance testing was performed. HIV prevalence was 13.9% (456 HIV positive of 3280 participants). HIV incidence was estimated to be 5.1 per 100 person-years (95% confidence interval: 3.1-8.3). Among 143 MSM who were aware of their HIV infection before testing, only 20 (14.0%) were receiving antiretrovirals (ARV). Mutations conferring ARV resistance were found in 12 (3.3%) of 359 treatment-naive and 5 (31.3%) of 16 treatment-experienced participants with successful genotyping. One recently infected man from Lima demonstrated 3-class multidrug resistance. The most frequently observed mutations in treatment-naive, chronically infected persons from Lima were M184V (1.7%), D30N (1.3%), L90M (1.3%), and L10I (1.3%). The prevalence of ARV resistance among treatment-naive MSM in Peru is low, reflecting limited access to treatment before 2004, and contrasts with the history of ARV treatment in developed countries, where high levels of nucleoside reverse transcriptase inhibitor resistance occurred before introduction of highly active antiretroviral therapy. Linking ARV resistance and HIV sentinel surveillance in developing settings is feasible and should be considered in third-generation HIV sentinel surveillance programs.

Projected savings through public health voluntary licences of HIV drugs negotiated by the Medicines Patent Pool (MPP).

PubMed

Juneja, Sandeep; Gupta, Aastha; Moon, Suerie; Resch, Stephen

2017-01-01

The Medicines Patent Pool (MPP) was established in 2010 to ensure timely access to low-cost generic versions of patented antiretroviral (ARV) medicines in low- and middle-income countries (LMICs) through the negotiation of voluntary licences with patent holders. While robust data on the savings generated by MPP and other major global public health initiatives is important, it is also difficult to quantify. In this study, we estimate the savings generated by licences negotiated by the MPP for ARV medicines to treat HIV/AIDS in LMICs for the period 2010-2028 and generate a cost-benefit ratio-based on people living with HIV (PLHIVs) in any new countries which gain access to an ARV due to MPP licences and the price differential between originator's tiered price and generics price, within the period where that ARV is patented. We found that the direct savings generated by the MPP are estimated to be USD 2.3 billion (net present value) by 2028, representing an estimated cost-benefit ratio of 1:43, which means for every USD 1 spent on MPP, the global public health community saves USD 43. The saving of USD 2.3 billion is equivalent to more than 24 million PLHIV receiving first-line ART in LMICs for 1 year at average prices today.

Proper Sterol Distribution Is Required for Candida albicans Hyphal Formation and Virulence

PubMed Central

McCourt, Paula; Liu, Hsing-Yin; Parker, Josie E.; Gallo-Ebert, Christina; Donigan, Melissa; Bata, Adam; Giordano, Caroline; Kelly, Steven L.; Nickels, Joseph T.

2016-01-01

Candida albicans is an opportunistic fungus responsible for the majority of systemic fungal infections. Multiple factors contribute to C. albicans pathogenicity. C. albicans strains lacking CaArv1 are avirulent. Arv1 has a conserved Arv1 homology domain (AHD) that has a zinc-binding domain containing two cysteine clusters. Here, we explored the role of the CaAHD and zinc-binding motif in CaArv1-dependent virulence. Overall, we found that the CaAHD was necessary but not sufficient for cells to be virulent, whereas the zinc-binding domain was essential, as Caarv1/Caarv1 cells expressing the full-length zinc-binding domain mutants, Caarv1C3S and Caarv1C28S, were avirulent. Phenotypically, we found a direct correlation between the avirulence of Caarv1/Caarv1, Caarrv1AHD, Caarv1C3S, and Caarv1C28S cells and defects in bud site selection, septa formation and localization, and hyphal formation and elongation. Importantly, all avirulent mutant strains lacked the ability to maintain proper sterol distribution. Overall, our results have established the importance of the AHD and zinc-binding domain in fungal invasion, and have correlated an avirulent phenotype with the inability to maintain proper sterol distribution. PMID:27587298

Neurotoxicity in the Post-HAART Era: Caution for the Antiretroviral Therapeutics

PubMed Central

Shah, Ankit; Gangwani, Mohitkumar R.; Chaudhari, Nitish S.; Glazyrin, Alexy; Bhat, Hari K.; Kumar, Anil

2016-01-01

Despite the advent of highly active antiretroviral therapy (HAART), HIV-associated neurological disorders (HAND) remain a major challenge in human immunodeficiency virus (HIV) treatment. The early implementation of HAART in the infected individuals helps suppress the viral replication in the plasma and other compartments. Several studies also report the beneficial effect of drugs that successfully penetrate central nervous system (CNS). However, recent data in both clinical setup and in in vitro studies indicate CNS toxicity of the antiretrovirals (ARVs). Although the evidence is limited, correlation between prolonged use of ARVs and neurotoxicity strongly suggests that it is essential to study the underlying mechanisms responsible for such toxicity. Furthermore, closer attention toward clinical outcomes is required to screen various ARV regimens for their association with HAND and other comorbidities. A growing body of literature also indicates a possible role of accelerated aging in the antiretroviral therapy-associated neurotoxicity. Lastly, owing to high pill burden, multiple drugs in the HIV treatment also invite a possible role of drug–drug interaction via various cytochrome P450 enzymes. The particular emphasis of this review is to highlight the need to identify alternative approaches in reducing the CNS toxicity of the ARV drugs in HIV-infected individuals. PMID:27364698

Current status of topical antiretroviral chemoprophylaxis.

PubMed

Van Damme, Lut; Szpir, Michael

2012-11-01

Recent studies suggest that the vaginal delivery of antiretroviral (ARV) agents - such as tenofovir, dapivirine and UC781 - may be a promising way to reduce the high rates of HIV infection among women in developing countries. This review examines these developments. The Microbicide Trials Network 003 study, a large phase IIb trial, was unable to show that daily dosing with 1% tenofovir vaginal gel was effective for HIV prevention. Nevertheless, preclinical and early-phase clinical trials suggest that ARV drugs - formulated in vaginal gels, rings, films, tablets and diaphragms - could be effective for HIV chemoprophylaxis. Investigations of topical chemoprophylaxis methods have seen mixed results in the past 12-18 months. Product adherence may prove to be one of the field's greatest challenges. Phase II and III trials continue to explore different dosing strategies for topical products that contain one or more ARV agents.

Autonomous Research Vessels for Adaptive Upper-Ocean Process Studies

DTIC Science & Technology

2014-09-30

system with the goal  of extending  its mission robustness,  adaptabilit and science capabilities beyond that  of the   Arduino -­‐ based ones... measure the interplay between these finescale dynamics and turbulence, which ultimately drives  the  irreversible  heat/freshwater  transports...profiling in Greenland  Fjords. acquiring CTD cast (and ADCP profiles) within m of a Greenland iceberg.APPROACH: Our first ARV (ARV Rob) was based on

The Do-Gooder, the Vain, the Generous, and Moral Education

ERIC Educational Resources Information Center

Kristjansson, Kristjan

2006-01-01

The virtue of generosity--at least generosity in the context of world poverty--is conspicuously absent from most curricula in the field of moral education. This article explores generosity and its educational ramifications. I start by characterizing two types of persons who may seem to be generous but who do not really possess generosity as a…

HIV/AIDS related commodities supply chain management in public health facilities of Addis Ababa, Ethiopia: a cross-sectional survey.

PubMed

Berhanemeskel, Eyerusalem; Beedemariam, Gebremedhin; Fenta, Teferi Gedif

2016-01-01

A wide range of pharmaceutical products are needed for diagnosis, treatment, and prevention of HIV/AIDS. However, interrupted supplies and stock-outs are the major challenges in the supply chain of ARV medicines and related commodities. The aim of this study was to assess the supply chain management of HIV/AIDS related commodities in public health facilities of Addis Ababa, Ethiopia. A descriptive cross-sectional survey complemented by qualitative method was conducted in 24 public health facilities (4 hospitals and 20 health centers). A semi-structured questionnaire and observation check list were used to collect data on HIV/AIDS related service, reporting and ordering; receiving, transportation and storage condition of ARV medicines and test kits; and supportive supervision and logistics management information system. In addition, in-depth interview with flexible probing techniques was used to complement the quantitative data with emphasis to the storage condition of ARV medicines and test kits. Quantitative data was analyzed using SPSS version-20. Analysis of qualitative data involved rigorous reading of transcripts in order to identify key themes and data was analyzed using thematic approach. The study revealed that 16 health centers and one hospital had recorded and reported patient medication record. Six months prior to the study, 14 health centers and 2 hospitals had stopped VCT services for one time or more. Three hospitals and 18 health centers claimed to have been able to submit the requisition and report concerning ARV medicines to Pharmaceutical Fund and Supply Agency according to the specific reporting period. More than three-fourth of the health centers had one or more emergency order of ARV medicines on the day of visit, while all of hospitals had emergency order more than 3 times within 6 months prior to the study. All of the hospitals and nearly half of the health centers had an emergency order of test kits more than 3 times in the past 6�

Molecular Analysis of Arthrobacter Myovirus vB_ArtM-ArV1: We Blame It on the Tail

PubMed Central

Šimoliūnas, Eugenijus; Truncaitė, Lidija; Zajančkauskaitė, Aurelija; Nainys, Juozas; Kaupinis, Algirdas; Valius, Mindaugas; Meškys, Rolandas

2017-01-01

ABSTRACT This is the first report on a myophage that infects Arthrobacter. A novel virus, vB_ArtM-ArV1 (ArV1), was isolated from soil using Arthrobacter sp. strain 68b for phage propagation. Transmission electron microscopy showed its resemblance to members of the family Myoviridae: ArV1 has an isometric head (∼74 nm in diameter) and a contractile, nonflexible tail (∼192 nm). Phylogenetic and comparative sequence analyses, however, revealed that ArV1 has more genes in common with phages from the family Siphoviridae than it does with any myovirus characterized to date. The genome of ArV1 is a linear, circularly permuted, double-stranded DNA molecule (71,200 bp) with a GC content of 61.6%. The genome includes 101 open reading frames (ORFs) yet contains no tRNA genes. More than 50% of ArV1 genes encode unique proteins that either have no reliable identity to database entries or have homologues only in Arthrobacter phages, both sipho- and myoviruses. Using bioinformatics approaches, 13 ArV1 structural genes were identified, including those coding for head, tail, tail fiber, and baseplate proteins. A further 6 ArV1 ORFs were annotated as encoding putative structural proteins based on the results of proteomic analysis. Phylogenetic analysis based on the alignment of four conserved virion proteins revealed that Arthrobacter myophages form a discrete clade that seems to occupy a position somewhat intermediate between myo- and siphoviruses. Thus, the data presented here will help to advance our understanding of genetic diversity and evolution of phages that constitute the order Caudovirales. IMPORTANCE Bacteriophages, which likely originated in the early Precambrian Era, represent the most numerous population on the planet. Approximately 95% of known phages are tailed viruses that comprise three families: Podoviridae (with short tails), Siphoviridae (with long noncontractile tails), and Myoviridae (with contractile tails). Based on the current hypothesis, myophages

Greater risk for viremia, immunosuppression, serious clinical events, and mortality with increasing age: the US perinatal HIV epidemic in its adolescence

PubMed Central

Neilan, Anne M.; Karalius, Brad; Patel, Kunjal; Van Dyke, Russell B.; Abzug, Mark J.; Agwu, Allison L.; Williams, Paige L.; Purswani, Murli; Kacanek, Deborah; Oleske, James M.; Burchett, Sandra K.; Wiznia, Andrew; Chernoff, Miriam; Seage, George R.; Ciaranello, Andrea L.

2017-01-01

Importance As perinatally HIV-infected youth (PHIVY) in the US grow older and more treatment-experienced, clinicians need updated information about the impact of age, CD4 count, viral load (VL), and antiretroviral drug (ARV) use on risks of opportunistic infections (OIs), key clinical events, and mortality in order to understand patient risks and improve care. Objective To determine the incidence or first occurrence during follow-up of key clinical events (including CDC-B and CDC-C events) and mortality among PHIVY stratified by age, CD4, and VL/ARV status. Design In the PHACS Adolescent Master Protocol (AMP) and IMPAACT P1074 multicenter cohort studies (2007–2015), we estimated event rates during person-time spent in key strata of age (7–12, 13–17, and 18–30 years), CD4 count (<200, 200–499, and ≥500 cells/μL), and VL/ARV status (< or ≥ 400 copies/mL; ARVs or no ARVs). Setting 41 ambulatory sites in the US, including Puerto Rico. Participants 1,562 participants in AMP and P1074 were eligible, 1446 PHIVY were included. Exposure(s) for observational studies Age, CD4 count, VL, ARV use. Main outcomes Clinical event rates stratified by person-time in age, CD4 count, and VL/ARV categories. Results During a mean follow-up of 4.9 years, higher incidences of CDC-B events, CDC-C events and mortality were observed as participants aged. Older PHIVY (13–17 and 18–30 year-olds) spent more time with VL ≥400 copies/mL and with CD4 <200/μL compared to 7–12 year-olds (30% and 44% vs. 22% of person-time with VL ≥400 copies/mL; 5% and 18% vs. 2% of person-time with CD4 <200/μL; p<0.01 for each comparison). We observed higher rates of CDC-B events, CDC-C events, bacterial infections, and mortality at lower CD4 counts, as expected. The mortality rate in older PHIVY was 6–12 times that of the general US population. Higher rates of sexually transmitted infections were also observed at lower CD4 counts, after adjusting for age. Conclusions and relevance Older

Terricolous Lichens in the Glacier Forefield of the Morteratsch Glacier (Eastern Alps, Graubünden, Switzerland)

PubMed Central

Bilovitz, Peter O.; Nascimbene, Juri; Mayrhofer, Helmut

2016-01-01

Summary Three sampling sites were established at increasing distance from the Morteratsch glacier to investigate lichen communities on soil in the glacier forefield. The survey yielded 13 lichen species and one lichenicolous fungus. Peltigera extenuata (Nyl. ex Vain.) Lojka (Peltigerales) is new to the canton of Graubünden. PMID:26877564

Manstein’s Campaigns - More Than Tactics

DTIC Science & Technology

1988-03-22

O . ,S UNCLASSIFIED USAWC MILITARY STUDIES PROGRAM PAPER MANSTEIN’S CAMPAIGNS - MORE THAN TACTICS Acceso ..or NTIS CRA&I DTIC TAB AN INDIVIDUAL...transportation and arteries of communication. And in a similar vain, Liddell Hart writes of the German campaign in Russia: The issue in Russia depended less on

Cotargeting of Androgen Synthesis and Androgen Receptor Expression as a Novel Treatment for Castration Resistant Prostate Cancer

DTIC Science & Technology

2017-08-01

expression of both AR and AR-V7 in CRPC cells, and that knockdown or inhibition of PRMT5 suppresses growth of CRPC cells. These results support our...correlates with the expression of AR [9]. Preliminary data strongly suggest that PRMT5 regulates prostate cancer cell growth through epigenetic...findings as follow. 3B-1. Inhibition of PRMT5 suppresses cell growth and the expression of AR and AR-V7 in CRPC cells. We established inducible

The Biological and Clinical Significance of Androgen Receptor Variants

DTIC Science & Technology

2014-04-01

immunohistochemistry. We tested two antibodies purportedly specific for AR-V7: 1) a mouse monoclonal antibody available from A&G Precision Antibody...a gift from Dr. Luo and tested on AR-V7- high and -low cases from the mixed-grade cohort in our lab. We used a monoclonal antibody against AR as a...fold, as compared with conventional avidin- biotinylated enzyme complex (ABC) procedures. We tested this protocol on four cases of the mixed-grade

Whoonga: potential recreational use of HIV antiretroviral medication in South Africa.

PubMed

Grelotti, David J; Closson, Elizabeth F; Smit, Jennifer A; Mabude, Zonke; Matthews, Lynn T; Safren, Steven A; Bangsberg, David R; Mimiaga, Matthew J

2014-03-01

Whoonga is a drug cocktail in South Africa rumored to contain illicit drugs and HIV antiretroviral (ARV) medication. Although its use may adversely impact adherence to HIV treatment and may have the potential to generate ARV resistance, there is a paucity of research characterizing whoonga. We learned of whoonga during semi-structured interviews about substance abuse and HIV risk at "club-events" known as inkwaris in an urban township of Durban, South Africa. Whoonga was an emerging theme spontaneously identified as a problem for the community by 17 out of 22 informants. Perceptions of whoonga suggest that it is highly addictive, contains ARVs (notably efavirenz), is used by individuals as young as 14, and poses a threat to the health and safety of those who use it, including increasing the risk of HIV infection. Our informants provide preliminary evidence of the dangers of whoonga and reinforce the need for further study.

Community-Based Evaluation of PMTCT Uptake in Nyanza Province, Kenya

PubMed Central

Kohler, Pamela K.; Okanda, John; Kinuthia, John; Mills, Lisa A.; Olilo, George; Odhiambo, Frank; Laserson, Kayla F.; Zierler, Brenda; Voss, Joachim; John-Stewart, Grace

2014-01-01

Introduction Facility-based assessments of prevention of mother-to-child HIV transmission (PMTCT) programs may overestimate population coverage. There are few community-based studies that evaluate PMTCT coverage and uptake. Methods During 2011, a cross-sectional community survey among women who gave birth in the prior year was performed using the KEMRI-CDC Health and Demographic Surveillance System in Western Kenya. A random sample (n = 405) and a sample of women known to be HIV-positive through previous home-based testing (n = 247) were enrolled. Rates and correlates of uptake of antenatal care (ANC), HIV-testing, and antiretrovirals (ARVs) were determined. Results Among 405 women in the random sample, 379 (94%) reported accessing ANC, most of whom (87%) were HIV tested. Uptake of HIV testing was associated with employment, higher socioeconomic status, and partner HIV testing. Among 247 known HIV-positive women, 173 (70%) self-disclosed their HIV status. Among 216 self-reported HIV-positive women (including 43 from the random sample), 82% took PMTCT ARVs, with 54% completing the full antenatal, peripartum, and postpartum course. Maternal ARV use was associated with more ANC visits and having an HIV tested partner. ARV use during delivery was lowest (62%) and associated with facility delivery. Eighty percent of HIV infected women reported having their infant HIV tested, 11% of whom reported their child was HIV infected, 76% uninfected, 6% declined to say, 7% did not recall; 79% of infected children were reportedly receiving HIV care and treatment. Conclusions Community-based assessments provide data that complements clinic-based PMTCT evaluations. In this survey, antenatal HIV test uptake was high; most HIV infected women received ARVs, though many women did not self-disclose HIV status to field team. Community-driven strategies that encourage early ANC, partner involvement, and skilled delivery, and provide PMTCT education, may facilitate further

The effects of a lipid‐based nutrient supplement and antiretroviral therapy in a randomized controlled trial on iron, copper, and zinc in milk from HIV‐infected Malawian mothers and associations with maternal and infant biomarkers

PubMed Central

Shahab‐Ferdows, Setareh; Gertz, Erik; Flax, Valerie L.; Adair, Linda S.; Bentley, Margaret E.; Jamieson, Denise J.; Tegha, Gerald; Chasela, Charles S.; Kamwendo, Debbie; van der Horst, Charles M.; Allen, Lindsay H.

2017-01-01

Abstract We evaluated effects of antiretroviral (ARV) therapy and lipid‐based nutrient supplements (LNSs) on iron, copper, and zinc in milk of exclusively breastfeeding HIV‐infected Malawian mothers and their correlations with maternal and infant biomarkers. Human milk and blood at 2, 6, and 24 weeks post‐partum and blood during pregnancy (≤30 weeks gestation) were collected from 535 mothers/infant‐pairs in the Breastfeeding, Antiretrovirals, and Nutrition study. The participants received ARV, LNS, ARV and LNS, or no intervention from 0 to 28 weeks post‐partum. ARVs negatively affected copper and zinc milk concentrations, but only at 2 weeks, whereas LNS had no effect. Among all treatment groups, approximately 80–90% of copper and zinc and <50% of iron concentrations met the current adequate intake for infants at 2 weeks and only 1–19% at 24 weeks. Pregnancy haemoglobin was negatively correlated with milk iron at 2 and 6 weeks (r = −.18, p < .02 for both). The associations of the milk minerals with each other were the strongest correlations observed (r = .11–.47, p < .05 for all); none were found with infant biomarkers. At 2 weeks, moderately anaemic women produced milk higher in iron when ferritin was higher or TfR lower. At 6 weeks, higher maternal α‐1‐acid glycoprotein and C‐reactive protein were associated with higher milk minerals in mildly anaemic women. Infant TfR was lower when milk mineral concentrations were higher at 6 weeks and when mothers were moderately anaemic during pregnancy. ARV affects copper and zinc milk concentrations in early lactation, and maternal haemoglobin during pregnancy and lactation could influence the association between milk minerals and maternal and infant iron status and biomarkers of inflammation. PMID:28851037

Patient perspectives on de-simplifying their single-tablet co-formulated antiretroviral therapy for societal cost savings.

PubMed

Krentz, H B; Campbell, S; Gill, V C; Gill, M J

2018-04-01

The incremental costs of expanding antiretroviral (ARV) drug treatment to all HIV-infected patients are substantial, so cost-saving initiatives are important. Our objectives were to determine the acceptability and financial impact of de-simplifying (i.e. switching) more expensive single-tablet formulations (STFs) to less expensive generic-based multi-tablet components. We determined physician and patient perceptions and acceptance of STF de-simplification within the context of a publicly funded ARV budget. Programme costs were calculated for patients on ARVs followed at the Southern Alberta Clinic, Canada during 2016 (Cdn$). We focused on patients receiving Triumeq® and determined the savings if patients de-simplified to eligible generic co-formulations. We surveyed all prescribing physicians and a convenience sample of patients taking Triumeq® to see if, for budgetary purposes, they felt that de-simplification would be acceptable. Of 1780 patients receiving ARVs, 62% (n = 1038) were on STF; 58% (n = 607) of patients on STF were on Triumeq®. The total annual cost of ARVs was $26 222 760. The cost for Triumeq® was $8 292 600. If every patient on Triumeq® switched to generic abacavir/lamivudine and Tivicay® (dolutegravir), total costs would decrease by $4 325 040. All physicians (n = 13) felt that de-simplifying could be safely achieved. Forty-eight per cent of 221 patients surveyed were agreeable to de-simplifying for altruistic reasons, 27% said no, and 25% said maybe. De-simplifying Triumeq® generates large cost savings. Additional savings could be achieved by de-simplifying other STFs. Both physicians and patients agreed that selective de-simplification was acceptable; however, it may not be acceptable to every patient. Monitoring the medical and cost impacts of de-simplification strategies seems warranted. © 2018 British HIV Association.

Unanticipated Effects of New Drug Availability on Antiretroviral Durability: Implications for Comparative Effectiveness Research

PubMed Central

Eaton, Ellen F.; Tamhane, Ashutosh R.; Burkholder, Greer A.; Willig, James H.; Saag, Michael S.; Mugavero, Michael J.

2016-01-01

Background. Durability of antiretroviral (ARV) therapy is associated with improved human immunodeficiency virus (HIV) outcomes. Data on ARV regimen durability in recent years and clinical settings are lacking. Methods. This retrospective follow-up study included treatment-naive HIV-infected patients initiating ARV therapy between January 2007 and December 2012 in a university-affiliated HIV clinic in the Southeastern United States. Outcome of interest was durability (time to discontinuation) of the initial regimen. Durability was evaluated using Kaplan-Meier survival analyses. Cox proportional hazard analyses was used to evaluate the association among durability and sociodemographic, clinical, and regimen-level factors. Results. Overall, 546 patients were analyzed. Median durability of all regimens was 39.5 months (95% confidence interval, 34.1–44.4). Commonly prescribed regimens were emtricitabine and tenofovir with efavirenz (51%; median duration = 40.1 months) and with raltegravir (14%; 47.8 months). Overall, 67% of patients had an undetectable viral load at the time of regimen cessation. Discontinuation was less likely with an integrase strand transfer inhibitor (adjusted hazards ratio [aHR] = 0.35, P = .001) or protease inhibitor-based regimen (aHR = 0.45, P = .006) and more likely with a higher pill burden (aHR = 2.25, P = .003) and a later treatment era (aHR = 1.64, P < .001). Conclusions. Initial ARV regimen longevity declined in recent years contemporaneous with the availability of several new ARV drugs and combinations. Reduced durability mostly results from a preference for newly approved regimens rather than indicating failing therapy, as indicated by viral suppression observed in a majority of patients (67%) prior to regimen cessation. Durability is influenced by extrinsic factors including new drug availability and provider preference. Medication durability must be interpreted carefully in the context of a dynamic treatment landscape. PMID

Circumferential urinary sphincter surface electromyography: A novel diagnostic method for intrinsic sphincter deficiency.

PubMed

Heesakkers, John; Gerretsen, Reza; Izeta, Ander; Sievert, Karl-Dietrich; Farag, Fawzy

2016-02-01

The diagnosis of intrinsic sphincter deficiency (ISD) in patients with stress urinary incontinence (SUI) is not well established. We explored the possibility of applying a new tool: minimally invasive circumferential sphincter surface electromyography (CSS-EMG) to assess the muscular integrity of the urethral sphincter in patients with SUI/ISD. CSS-EMG of the urethral sphincter and urodynamic studies were performed in 44 women with SUI. A urethral pressure profile (UPP) was measured in four directions. Maximal urethral closure pressure (MUCP) <40 cm/H2 O or the presence of SUI without urethral hypermobility was used to define ISD. Twenty-one patients had urodynamic SUI, 23 had no SUI and 12 patients had ISD. The mean average rectified value (ARV) of the motor unit action potential (MUAP), an indicator of the strength of urethral rhabdosphincter, was estimated. ARV measured in the 12 o'clock quadrant during maximal contraction was the only CSS-EMG parameter that had significant predictive value for ISD. With an increase in the 12 o'clock ARV value, the likelihood of ISD decreases (Odds Ratio 0.36 95% confidence interval 0.67-0.92). In the ROC curve with ARV measured in the 12 o'clock quadrant during maximal contraction, the explained area was 0.794 (P = 0.02); implying that ARV measured at the 12 o'clock quadrant during maximal contraction was able to predict ISD significantly. Myogenic changes of the urethral sphincter that contribute to ISD can be assessed with CSS-EMG. This new concept for assessing the functionality of the female urethral sphincter may assist with better understanding of the pathophysiology, the diagnosis and the treatment of SUI. © 2014 Wiley Periodicals, Inc.

No Evidence of an Association Between Efavirenz Exposure and Suicidality Among HIV Patients Initiating Antiretroviral Therapy in a Retrospective Cohort Study of Real World Data.

PubMed

Nkhoma, Ella T; Coumbis, John; Farr, Amanda M; Johnston, Stephen S; Chu, Bong Chul; Rosenblatt, Lisa C; Seekins, Daniel; Villasis-Keever, Angelina

2016-01-01

Recently, published studies have reported conflicting results regarding the association between efavirenz exposure and the risk of suicidality among patients with human immunodeficiency virus. The objective of this analysis was to compare the rate of suicidality among patients initiating efavirenz-containing versus efavirenz-free antiretroviral (ARV) regimens.This retrospective cohort study used US administrative claims data for commercially and Medicaid-insured individuals for the years 2006 to 2013. ARV-naive patients aged ≥12 years initiating an efavirenz-containing or efavirenz-free ARV regimen with ≥6 months of continuous insurance enrollment prior to ARV initiation were selected. The primary outcome was suicidality, defined as the occurrence of any medical claim with a diagnosis code for suicidal ideation or an inpatient or emergency department medical claim for suicide attempt. Unadjusted incidence rates were calculated and propensity score-adjusted hazard ratios were estimated to account for differences in patient characteristics.There were 19,983 patients (efavirenz-containing, n = 11,187; efavirenz-free, n = 8796) in the commercial database and 5154 patients (efavirenz-containing, n = 2224; efavirenz-free, n = 2930) in the Medicaid database. Unadjusted incidence rates (95% confidence interval [CI]) of suicidality per 1000 person-years were: commercial, efavirenz-containing (3.3 [2.4-4.4]), efavirenz-free (4.0 [2.7-5.8]); Medicaid, efavirenz-containing (25.7 [18.8-34.4]), efavirenz-free (40.6 [31.9-50.9]). In propensity score-adjusted analyses, efavirenz use was not associated with suicidality: adjusted hazard ratio (95% CI) of suicidality compared with efavirenz-free regimen, commercial, 1.029 (0.636-1.665); Medicaid, 0.902 (0.617-1.319).This analysis found no conclusive evidence of an increased risk of suicidality among patients initiating an efavirenz-containing ARV regimen. However, channeling bias may exist even after adjusting for

Visual function in anterior ischemic optic neuropathy: effect of Vision Restoration Therapy--a pilot study.

PubMed

Jung, Cecilia S; Bruce, Beau; Newman, Nancy J; Biousse, Valérie

2008-05-15

To evaluate the effects of Vision Restoration Therapy (VRT) on the visual function of patients with anterior ischemic optic neuropathy. Randomized controlled double-blind pilot trial. 10 patients with stable anterior ischemic optic neuropathy (AION). All patients were evaluated before VRT and after 3 and 6 months of treatment by Early Treatment Diabetic Retinopathy Study (ETDRS) visual acuity, contrast sensitivity, reading speed, 24-2 SITA-standard Humphrey visual field (HVF), High Resolution Perimetry (HRP) (perimetry obtained during VRT), and vision-based quality of life questionnaire. Patients were randomized between two VRT strategies (5 in each group): I) VRT in which stimulation was performed in the seeing VF of the affected eye ("seeing field-VRT"); II) VRT in which stimulation was performed along the area of central fixation and in the ARV (areas of residual vision) of the affected eye ("ARV-VRT"). The results of the HRP, HVF, and clinical assessment of visual function were compared for each patient and between the two groups at each evaluation. Visual acuity qualitatively improved in the ARV-VRT group, however the change was not statistically significant (p=0.28). Binocular reading speed significantly improved in the ARV-VRT group (p=0.03). HVF foveal sensitivity increased mildly in both groups (p=0.059). HRP analysis showed a similar increase in stimulus accuracy in both groups (mean improvement of about 15%). All patients reported functional improvement after VRT. Despite a small sample, the study showed a trend toward improvement of visual function in the ARV-VRT group. Improvement of HRP in both groups may reflect diffusely increased visual attention (neuronal activation), or improvement of an underlying sub-clinical abnormality in the "seeing" visual field of patients with optic neuropathies.

HIV antiretroviral medication stock-outs in Ghana: contributors and consequences.

PubMed

Poku, Rebecca A; Owusu, Adobea Yaa; Mullen, Patricia Dolan; Markham, Christine; McCurdy, Sheryl A

2017-09-01

Drug stock-outs are an unfortunate yet common reality for patients living in low and middle income countries, particularly in sub-Saharan Africa where trouble with consistent stock of antiretroviral medications (ARVs) continues. Our study takes a snapshot of this problem in Ghana. Although the country launched its antiretroviral therapy (ART) programme in 2003, progress toward realising the full benefit of ART for treated individuals has been limited, in part, because of stock-outs. In Ghana's Greater Accra region, we conducted semi-structured interviews with 40 women living with HIV (WLHIV) and 15 individuals with a history of HIV-related work in government or non-governmental organisations, or healthcare facilities. We used repeated review with coding and mapping techniques to analyse the transcripts and identify common themes. Stock-outs of ARVs result in inconsistent administration of therapy, increased indirect medical costs for WLHIV, and negative labelling of patients. Inefficiencies in drug supply, poor coordination with port authorities, inadequate government funding and dependence on international aid contribute to the stock-outs experienced in Ghana. Although using ARVs produced in-country could reduce supply problems, the domestically-manufactured product currently does not meet World Health Organization (WHO) standards. We recommend focused efforts to produce WHO standard ARVs in Ghana, and a review of current supply chain management to identify and mend pitfalls in the system.

Health Literacy in HIV Treatment: Accurate Understanding of Key Biological Treatment Principles is Not Required for Good ART Adherence

PubMed Central

Laws, M. Barton; Danielewicz, Michael; Rana, Aadia; Kogelman, Laura; Wilson, Ira B.

2016-01-01

Findings on the relationship between health literacy and outcomes in HIV have been inconsistent. Health literacy has previously been operationalized as general functional literacy, but has not included content knowledge about HIV disease and treatment. Semi-structured interviews with people living with HIV in 2 U.S. cities, including questions about the etiology, pathophysiology and treatment of HIV. We compared responses to biomedical conceptions. The 32 respondents were demographically diverse. Although most understood that HIV degrades the immune system, none could explain the nature of a virus, or the mechanism of antiretroviral (ARV) drug action. Fewer than half accurately reported that it is desirable to have a high CD4+ cell count and low viral load. A minority understood the concept of drug resistance. While most believed that strict adherence to ARV regimens was important to maintain health, three believed that periodic treatment interruption was beneficial, and three believed they should not take ARVs when they used alcohol or illicit drugs. Respondents generally had very limited, and often inaccurate biomedical understanding of HIV disease. Most reported good regimen adherence but did not have any mechanistic rationale for it. The failure to find a consistent relationship between health literacy and ARV adherence may be largely because most people simply follow their doctors’ instructions, without the need for deep understanding. PMID:25354736

24-hour aortic blood pressure variability showed a stronger association with carotid damage than 24-hour brachial blood pressure variability: The SAFAR study.

PubMed

Yu, Shikai; Chi, Chen; Protogerou, Athanase D; Safar, Michel E; Blacher, Jacques; Argyris, Antonis A; Nasothimiou, Efthimia G; Sfikakis, Petros P; Papaioannou, Theodore G; Xu, Henry; Zhang, Yi; Xu, Yawei

2018-03-01

We aim to compare 24-hour aortic blood pressure variability (BPV) with brachial BPV in relation to carotid damage as estimated by carotid intima-media thickness (CIMT) and cross-sectional area (CCSA). Four hundred and forty five individuals received brachial and aortic 24-hour ambulatory BP monitoring with a validated device (Mobil-O-Graph). Systolic BPV was estimated by average real variability (ARV) and time-weighted standard deviation (wSD). In multiple logistic regression analysis, CIMT > 900 μm was significantly and independently associated with aortic ARV (OR = 1.38; 95% CI: 1.04-1.84), aortic wSD (OR = 1.65; 95% CI: 1.19-2.29) and brachial ARV (OR = 1.53; 95% CI: 1.07-2.18), but not with brachial wSD. CCSA > 90th percentile was significantly and independently associated with aortic ARV (OR = 1.50; 95% CI: 1.07-2.10) and wSD (OR = 1.70; 95% CI: 1.12-2.56), but not with brachial BPVs. In receiver operator characteristics curve analysis, aortic wSD identified CCSA > 90th percentile better than brachial wSD (AUC: 0.73 vs 0.68, P < .01). In conclusion, aortic 24-hour systolic BPV showed a slightly stronger association with carotid damage than brachial BPV. ©2018 Wiley Periodicals, Inc.

Projected savings through public health voluntary licences of HIV drugs negotiated by the Medicines Patent Pool (MPP)

PubMed Central

Juneja, Sandeep; Gupta, Aastha; Moon, Suerie; Resch, Stephen

2017-01-01

The Medicines Patent Pool (MPP) was established in 2010 to ensure timely access to low-cost generic versions of patented antiretroviral (ARV) medicines in low- and middle-income countries (LMICs) through the negotiation of voluntary licences with patent holders. While robust data on the savings generated by MPP and other major global public health initiatives is important, it is also difficult to quantify. In this study, we estimate the savings generated by licences negotiated by the MPP for ARV medicines to treat HIV/AIDS in LMICs for the period 2010–2028 and generate a cost-benefit ratio–based on people living with HIV (PLHIVs) in any new countries which gain access to an ARV due to MPP licences and the price differential between originator’s tiered price and generics price, within the period where that ARV is patented. We found that the direct savings generated by the MPP are estimated to be USD 2.3 billion (net present value) by 2028, representing an estimated cost-benefit ratio of 1:43, which means for every USD 1 spent on MPP, the global public health community saves USD 43. The saving of USD 2.3 billion is equivalent to more than 24 million PLHIV receiving first-line ART in LMICs for 1 year at average prices today. PMID:28542239

Factors associated with short-course antiretroviral prophylaxis (dual therapy) adherence for PMTCT in Nkangala district, South Africa.

PubMed

Peltzer, Karl; Sikwane, Elisa; Majaja, Mmapaseka

2011-09-01

To identify factors that influence adherence to short-course antiretroviral (ARV) prophylaxis by pregnant women and mothers participating in the HIV prevention of mother to child (PMTCT) programme. The sample interviewed included 139 HIV-positive antenatal women (mean gestational age 32 weeks; sexually transmitted diseases [STD] = 2.8, range 4-9 months) and 607 postnatal HIV-positive women, with either having an infant aged 1-10 weeks (30.8%), 11 weeks to 6 months (36.7%) or 7-12 months (32.5%) from Nkangala district, Mpumalanga province, South Africa. A large percentage of antenatal and postnatal women in this study initiated ARV prophylaxis for PMTCT or were on ARV (85.6% and 98%, respectively). Sixty-one per cent of antenatal and 85.9% of postnatal women reported complete adherence to the appropriate medication schedule in the 4 days preceding the interview or prior to delivery. In multivariate analysis, it was found that women with higher HIV status disclosure and less discrimination were better in maternal AZT adherence, women with higher male involvement were better in maternal and infant nevirapine adherence. Adherence to maternal and infant dual therapy prophylaxis was found to be less than optimal. Community factors (discrimination, HIV disclosure, male involvement) contribute to adherence to short-course ARV prophylaxis in this largely rural setting in South Africa. © 2011 The Author(s)/Acta Paediatrica © 2011 Foundation Acta Paediatrica.

Health literacy in HIV treatment: accurate understanding of key biological treatment principles is not required for good ART adherence.

PubMed

Laws, M Barton; Danielewicz, Michael; Rana, Aadia; Kogelman, Laura; Wilson, Ira B

2015-04-01

Findings on the relationship between health literacy and outcomes in HIV have been inconsistent. Health literacy has previously been operationalized as general functional literacy, but has not included content knowledge about HIV disease and treatment. Semi-structured interviews with people living with HIV in 2 U.S. cities, including questions about the etiology, pathophysiology and treatment of HIV. We compared responses to biomedical conceptions. The 32 respondents were demographically diverse. Although most understood that HIV degrades the immune system, none could explain the nature of a virus, or the mechanism of antiretroviral (ARV) drug action. Fewer than half accurately reported that it is desirable to have a high CD4+ cell count and low viral load. A minority understood the concept of drug resistance. While most believed that strict adherence to ARV regimens was important to maintain health, three believed that periodic treatment interruption was beneficial, and three believed they should not take ARVs when they used alcohol or illicit drugs. Respondents generally had very limited, and often inaccurate biomedical understanding of HIV disease. Most reported good regimen adherence but did not have any mechanistic rationale for it. The failure to find a consistent relationship between health literacy and ARV adherence may be largely because most people simply follow their doctors' instructions, without the need for deep understanding.

Antiretroviral Resistance and Pregnancy Characteristics of Women with Perinatal and Nonperinatal HIV Infection.

PubMed

Lazenby, Gweneth B; Mmeje, Okeoma; Fisher, Barbra M; Weinberg, Adriana; Aaron, Erika K; Keating, Maria; Luque, Amneris E; Willers, Denise; Cohan, Deborah; Money, Deborah

2016-01-01

Objective. To compare HIV drug resistance in pregnant women with perinatal HIV (PHIV) and those with nonperinatal HIV (NPHIV) infection. Methods. We conducted a multisite cohort study of PHIV and NPHIV women from 2000 to 2014. Sample size was calculated to identify a fourfold increase in antiretroviral (ARV) drug resistance in PHIV women. Continuous variables were compared using Student's t-test and Wilcoxon rank-sum tests. Categorical variables were compared using χ (2) and Fisher's exact tests. Univariate analysis was used to determine factors associated with antiretroviral drug resistance. Results. Forty-one PHIV and 41 NPHIV participants were included. Women with PHIV were more likely to have drug resistance than those with NPHIV ((55% versus 17%, p = 0.03), OR 6.0 (95% CI 1.0-34.8), p = 0.05), including multiclass resistance (15% versus 0, p = 0.03), and they were more likely to receive nonstandard ARVs during pregnancy (27% versus 5%, p = 0.01). PHIV and NPHIV women had similar rates of preterm birth (11% versus 28%, p = 0.08) and cesarean delivery (47% versus 46%, p = 0.9). Two infants born to a single NPHIV woman acquired HIV infection. Conclusions. PHIV women have a high frequency of HIV drug resistance mutations, leading to nonstandard ARVs use during pregnancy. Despite nonstandard ARV use during pregnancy, PHIV women did not experience increased rates of adverse pregnancy outcomes.

Photodynamic therapy for premalignant lesions of the vulva and vagina: A long-term follow-up study.

PubMed

Choi, Min Chul; Kim, Mi Sun; Lee, Gee Hoon; Jung, Sang Geun; Park, Hyun; Joo, Won Duk; Lee, Chan; Lee, Je Ho; Hwang, Yoon Young; Kim, Seung Jo

2015-07-14

We aimed to evaluate responses to photodynamic therapy (PDT) and its long-term efficacy in preserving normal anatomy and function in women with premalignant lesions of the lower genital tract. Fifteen patients received PDT for vulvar intraepithelial neoplasia (VIN), vaginal intraepithelial neoplasia (VAIN), or vulvar Paget's disease between January 2003 and December 2013. Patients underwent colposcopy and/or vulvoscopy for assessment of lesions. Surface photoillumination with a 630-nm red laser light was applied to the lesions 48 hours after intravenous injection of 2 mg/kg photosensitizer (PSZ; Photogem®). The light dose to the lesions was 150 J/cm 2 . The median age of the 15 patients (VIN II: 3, VIN III: 4, VAIN II: 2, VAIN III: 3, Paget's disease: 3) was 42.3 years. The complete response (CR) rate was 80% (12/15) at the 3-month follow-up and 71.4% (10/14) at the 1-year follow-up. There were two cases of persistent disease at the 3-month follow-up. One patient with persistent disease underwent partial vulvectomy three times for repetitive recurrence, and the other received secondary PDT with topical 5-aminolevulinic acid (5-ALA) and subsequently showed no evidence of disease (NED). Another patient achieved 90% remission through a combination of additional alternative treatments after showing partial response (PR). In two cases of CR, recurrence was observed at the 1-year follow-up. Regarding adverse events, photosensitivity reactions such as facial edema and urticaria occurred in 13.3% (2/15) and perineal pain occurred in one patient. PDT may be an effective alternative treatment for premalignant lesions of the female lower genital tract to preserve normal anatomy and sexual function without therapeutic impairment. Lasers Surg. Med. © 2015 Wiley Periodicals, Inc. © 2015 Wiley Periodicals, Inc.

[Hysterectomy and intraepithelial neoplasia of the lower female genital tract].

PubMed

Spuhler, S; De Grandi, P

1992-01-01

Delimiting the place of hysterectomy in cases of lower genital tract intraepithelial neoplasias in women. The laser and colposcopy centre (CCL) of a maternity unit in Lausanne in the Vaudois University Hospital Centre (CHUV). THE TYPE OF STUDY: Retrospective on 1,303 patients between 1986 and 1990. THE SUBJECTS AND TREATMENT: 853 cases of cervical intraepithelial neoplasia (CIN) and 79 cases of vaginal intraepithelial neoplasia (VAIN) were treated with CO2 laser. The situations in which hysterectomy could be considered in the course of treatment are discussed. They are: 1) Dysplasia persisting after treatment, 2) when pathological tissue is found on examining slides from conisation specimens, 3) micro-invasive carcinoma, 4) post-operative obstructive stenosis. The multiple location of dysplasia lesions of the lower genital tract was calculated for all the patients examined. It shows that hysterectomy itself will be insufficient to remove all dysplasias since frequently (9.2%) of lesions are found in the vagina in cases that have dysplasia of the cervix. Residual lesions after hysterectomy are shown up by VAIN which are responsible for the persistence of changes in the control smears (in which there were 9 cases of VAIN3 after hysterectomy in this series). Treatment therefore is hazardous and only poorly successful because the site of these lesions is often hidden in the scar through the top of the vagina. Furthermore their discovery in uncertain since there is a tendency at present to avoid out cytological screening of these patients once they have undergone hysterectomy. The high incidence of multifocal lesions and the possibility that is very real of residual dysplasia after hysterectomy has made the authors limit the place of hysterectomy in these cases, preferring to use conservative treatments and emphasizing the need to continue cytological controls for after treatment.

Evaluation of a multimodal, distance learning HIV management course for clinical care providers in India.

PubMed

Chang, Larry William; Kadam, Dileep B; Sangle, Shashi; Narayanan, Shivakumar; Borse, Rohidas T; McKenzie-White, Jane; Bowen, Craig W; Sisson, Stephen D; Bollinger, Robert C

2012-01-01

Distance learning is an important tool for training HIV health workers. However, there is limited evidence on design and evaluation of distance learning HIV curricula and tools. We therefore designed, implemented, and evaluated a distance learning course on HIV management for clinical care providers in India. After course completion, participant scores rose significantly from a pretest (78.4% mean correct) compared with the posttest (87.5%, P < .001). After course completion, participants were more likely to be confident in starting an initial antiretroviral (ARV) regimen, understanding ARV toxicities, encouraging patient adherence, diagnosing immune reconstitution syndrome, and monitoring patients on ARV medications (P ≤ .05). All participants (100%) strongly agreed/agreed that they would recommend this course to others, and most of them (96%) strongly agreed/agreed that they would take a course in this format again. A pragmatic approach to HIV curriculum development and evaluation resulted in reliable learning outcomes, as well as learner satisfaction and improvement in knowledge.

Use of Complementary/Alternative Medicines and Supplements by Mexican-Origin Patients in a U.S.-Mexico Border HIV Clinic

PubMed Central

Shedlin, Michele G.; Anastasi, Joyce K.; Decena, Carlos U.; Rivera, José O.; Beltran, Oscar; Smith, Kaitlyn

2012-01-01

This article draws from a study investigating the influence of institutional and psychosocial factors on adherence to antiretroviral (ARV) medications by Mexican-origin persons living with HIV (PWLA) on the U.S.-Mexico border and seeking treatment at a clinic in El Paso, Texas. Among 113 participants, many individuals reported using complementary and alternative medicines (CAM) to support general health and their immune systems and to address symptoms of HIV-related diseases and ARV side effects. CAM was seen as complementing ARV treatment; however, its use was often unreported to health care providers out of concerns about disapproval and loss of care privileges. This finding challenges researchers and providers to seriously consider how Hispanic populations, with their CAM use, may exhibit the hybridization of health and healing. Information on CAM use needs to be available to providers to assess the benefits and contraindications of use and to develop realistic and effective care strategies. PMID:23122906

Herbicides and forest ecosystems - approaches to risk communication

Treesearch

Charles K. McMahon

1992-01-01

Abstract.It has become apparent to many risk experts that without good communication, risk assessment and risk management efforts may be largely in vain. For the public, perception is reality when it comes to the interpretation of risk information and the shaping of regulatory policy. The findings of several- risk communication experts are reviewed...

The US Food and Drug Administration's tentative approval process and the global fight against HIV.

PubMed

Chahal, Harinder Singh; Murray, Jeffrey S; Shimer, Martin; Capella, Peter; Presto, Ryan; Valdez, Mary Lou; Lurie, Peter G

2017-12-01

In 2004, the US government began to utilize the Food and Drug Administration's (USFDA) tentative approval process (tFDA) as a basis to determine which HIV drugs are appropriate to be purchased and used in resource-constrained settings. This process permits products that are not approved for marketing in the US, including medicines with active patents or marketing restrictions in the US, to be purchased and distributed in resource-constrained settings. Although the tFDA was originally intended to support the United States' President's Emergency Plan for AIDS Relief (PEPFAR), the USFDA list has become a cornerstone of international HIV programmes that support procurement of ARVs, such as the World Health Organization and the Global Fund to Fight AIDS, Tuberculosis, and Malaria. Our objective in this article is to help the global HIV policy makers and implementers of HIV programmes better understand the benefits and limitations of the tFDA by providing an in-depth review of the relevant legal and regulatory processes. USFDA's dedicated tFDA process for ARVs used by the PEPFAR programme has a wide impact globally; however, the implementation and the regulatory processes governing the programme have not been thoroughly described in the medical literature. This paper seeks to help stakeholders better understand the legal and regulatory aspects associated with review of ARVs under the tFDA by describing the following: (1) the tFDA and its importance to global ARV procurement; (2) the regulatory pathways for applications under tFDA for the PEPFAR programme, including modifications to applications, review timelines and costs; (3) the role of US patents, US marketing exclusivity rights, and the Medicines Patents Pool in tFDA; and (4) an overview of how applications for PEPFAR programme are processed through the USFDA. We also provide a case study of a new ARV, tenofovir alafenamide fumarate (TAF), not yet reviewed by USFDA for PEPFAR use. In this paper, we describe the

HIV treatment and reproductive health in the health system in Burkina Faso: resource allocation and the need for integration.

PubMed

Windisch, Ricarda; de Savigny, Don; Onadja, Geneviève; Somda, Antoine; Wyss, Kaspar; Sié, Ali; Kouyaté, Bocar

2011-11-01

Organizational changes, increased funding and the demands of HIV antiretroviral (ARV) treatment create particular challenges for governance in the health sector. We assess resource allocation, policy making and integration of the national responses to ARV provision and reproductive health in Burkina Faso, using national and district budgets related to disease burden, policy documents, organizational structures, and coordination and implementation processes. ARV provision represents the concept of a "crisis scenario", in which reforms are pushed due to a perception of urgent need, whereas the national reproductive health programme, which is older and more integrated, represents a "politics-as-usual scenario". Findings show that the early years of the national response to HIV and AIDS were characterized by new institutions with overlapping functions, and failure to integrate with and strengthen existing structures. National and district budget allocations for HIV compared to other interventions were disproportionately high when assessed against burden of disease. Strategic documents for ARV provision were relatively less developed and referred to, compared to those of the Ministry of Health Directorates for HIV and for Family Health and district health planning teams for reproductive health services. Imbalances and new structures potentially trigger important adverse effects which are difficult to remedy and likely to increase due to the dynamics they create. It therefore becomes crucial, from the outset, to integrate HIV/AIDS funding and responses into health systems. Copyright © 2011 Reproductive Health Matters. Published by Elsevier Ltd. All rights reserved.

The relationship between dietary salt intake and ambulatory blood pressure variability in non-diabetic hypertensive patients.

PubMed

Ozkayar, Nihal; Dede, Fatih; Ates, Ihsan; Akyel, Fatma; Yildirim, Tolga; Altun, Bulent

High dietary salt intake was reported to increase blood pressure by numerous studies, but no study has investigated the effect of dietary salt intake on blood pressure variability (BPV). This study aimed to determine if daily salt intake is related to ambulatory BPV. The study included 136 primary hypertensive patients (92 male, 44 female) with a mean age of 50.7±11.1 years. All the patients underwent 24-h ambulatory blood pressure monitoring to determine both the 24-h systolic and 24-h diastolic BPV. 24-h urine sodium was measured. The correlation between BPV and 24-h urinary sodium was investigated. Logarithmic transformation of 24-h urinary sodium [log(24-h urinary sodium)] was positively correlated with the mean 24-h systolic ARV, and nighttime systolic ARV (r=0.371 and p=0.001, r=0.329 and p=0.028, respectively). Similarly, log(24-h urinary sodium) was positively correlated with mean 24-h diastolic ARV and nighttime diastolic ARV (r=0.381 and p=0.001, r=0.320 and p=0.020 respectively). Log(24-h urinary sodium) was an independent predictor of BPV based on multivariate regression analysis. Dietary salt intake might play a role in the pathogenesis of ambulatory BPV. Copyright © 2016 Sociedad Española de Nefrología. Published by Elsevier España, S.L.U. All rights reserved.

Alpharetroviral self-inactivating vectors produced by a superinfection-resistant stable packaging cell line allow genetic modification of primary human T lymphocytes.

PubMed

Labenski, Verena; Suerth, Julia D; Barczak, Elke; Heckl, Dirk; Levy, Camille; Bernadin, Ornellie; Charpentier, Emmanuelle; Williams, David A; Fehse, Boris; Verhoeyen, Els; Schambach, Axel

2016-08-01

Primary human T lymphocytes represent an important cell population for adoptive immunotherapies, including chimeric-antigen and T-cell receptor applications, as they have the capability to eliminate non-self, virus-infected and tumor cells. Given the increasing numbers of clinical immunotherapy applications, the development of an optimal vector platform for genetic T lymphocyte engineering, which allows cost-effective high-quality vector productions, remains a critical goal. Alpharetroviral self-inactivating vectors (ARV) have several advantages compared to other vector platforms, including a more random genomic integration pattern and reduced likelihood for inducing aberrant splicing of integrated proviruses. We developed an ARV platform for the transduction of primary human T lymphocytes. We demonstrated functional transgene transfer using the clinically relevant herpes-simplex-virus thymidine kinase variant TK.007. Proof-of-concept of alpharetroviral-mediated T-lymphocyte engineering was shown in vitro and in a humanized transplantation model in vivo. Furthermore, we established a stable, human alpharetroviral packaging cell line in which we deleted the entry receptor (SLC1A5) for RD114/TR-pseudotyped ARVs to prevent superinfection and enhance genomic integrity of the packaging cell line and viral particles. We showed that superinfection can be entirely prevented, while maintaining high recombinant virus titers. Taken together, this resulted in an improved production platform representing an economic strategy for translating the promising features of ARVs for therapeutic T-lymphocyte engineering. Copyright © 2016 Elsevier Ltd. All rights reserved.

Antiretroviral Resistance and Pregnancy Characteristics of Women with Perinatal and Nonperinatal HIV Infection

PubMed Central

Mmeje, Okeoma; Fisher, Barbra M.; Weinberg, Adriana; Aaron, Erika K.; Keating, Maria; Luque, Amneris E.; Willers, Denise; Cohan, Deborah; Money, Deborah

2016-01-01

Objective. To compare HIV drug resistance in pregnant women with perinatal HIV (PHIV) and those with nonperinatal HIV (NPHIV) infection. Methods. We conducted a multisite cohort study of PHIV and NPHIV women from 2000 to 2014. Sample size was calculated to identify a fourfold increase in antiretroviral (ARV) drug resistance in PHIV women. Continuous variables were compared using Student's t-test and Wilcoxon rank-sum tests. Categorical variables were compared using χ 2 and Fisher's exact tests. Univariate analysis was used to determine factors associated with antiretroviral drug resistance. Results. Forty-one PHIV and 41 NPHIV participants were included. Women with PHIV were more likely to have drug resistance than those with NPHIV ((55% versus 17%, p = 0.03), OR 6.0 (95% CI 1.0–34.8), p = 0.05), including multiclass resistance (15% versus 0, p = 0.03), and they were more likely to receive nonstandard ARVs during pregnancy (27% versus 5%, p = 0.01). PHIV and NPHIV women had similar rates of preterm birth (11% versus 28%, p = 0.08) and cesarean delivery (47% versus 46%, p = 0.9). Two infants born to a single NPHIV woman acquired HIV infection. Conclusions. PHIV women have a high frequency of HIV drug resistance mutations, leading to nonstandard ARVs use during pregnancy. Despite nonstandard ARV use during pregnancy, PHIV women did not experience increased rates of adverse pregnancy outcomes. PMID:27413359

Serum lactate levels in infants exposed peripartum to antiretroviral agents to prevent mother-to-child transmission of HIV: Agence Nationale de Recherches Sur le SIDA et les Hépatites Virales 1209 study, Abidjan, Ivory Coast

PubMed Central

Ekouevi, Didier Koumavi; Touré, Ramata; Becquet, Renaud; Viho, Ida; Sakarovitch, Charlotte; Rouet, François; Towne-Gold, Besigin; Fassinou, Patricia; Leroy, Valériane; Blanche, Stéphane; Dabis, François

2006-01-01

Background Mitochondrial toxicity was described in infants exposed to long-term antiretroviral regimens (ARVs) containing nucleoside analogues for the prevention of mother-to-child transmission of HIV (PMTCT). We measured the serum lactate levels in children born to HIV-1 infected (HIV+) African women receiving short-term ARV PMTCT regimens. Methods A prospective study was conducted in women-child pairs from the third trimester of pregnancy to three months of life. The exposed group was formed by children exposed in utero to nucleoside analogue ARVs, zidovudine (ZDV) or ZDV + lamivudine (3TC) from 32–36 weeks of amenorrhea until delivery. All these women received nevirapine single-dose (NVPsd) at the beginning of labor. The children received ZDV during the first 7 days of life and a NVPsd at day 3. The control group was formed by infants born to HIV+ women who had received NVPsd only and not exposed to nucleoside analogue ARVs. Serum lactate levels were measured at 4, 6 and 12 weeks of life by Cobas Integra 400™. Results A total of 836 blood samples from 338 infants were collected (262 exposed and 76 controls). Median lactacidemia was 1.8 mmol/l, Interquartile Range [1.2–2.7 mmol/l]). Overall serum lactate levels ≥2.5 mmol/l, defining hyperlactatemia were observed in 39 of the 292 infants who had at least two serum lactate measurements, 13.4%, 95% confidence Interval [9.6–17.8%]. The three-month period prevalence of hyperlactatemia did not differ between the exposed group (13.1%) and the control group (14.3%) (p=0.84). All serum lactate levels returned to normal values in all subsequent samples No case of symptomatic hyperlactatemia was detected during the study period. Conclusion Increased lactate levels were identified equally in infants whose mother received a short-term of nucleoside analogues or NVPsd for PMTCT. Although not rare, hyperlactatemia was not related to short-term exposure to nucleoside analogue ARVs PMID:16950945

Preexposure prophylaxis (PrEP) of HIV infection in France: a nationwide cross-sectional study (PREVIC study).

PubMed

Rosenthal, E; Piroth, L; Cua, E; Joulié, A; Ravaux, I; Chauveau, M; Lacombe, K; Cotte, L; Bonnard, P; Weiss, L; Longuet, M; Pradier, C; Cacoub, P

2014-02-01

Although preliminary studies showed that preexposure prophylaxis (PrEP) lowers the HIV transmission in individuals with HIV, confirmative trials are ongoing and PrEP is not routinely recommended. The aim of this study was to assess whether individuals with HIV share antiretroviral (ARV) drugs for PrEP and to describe awareness and discussion on PrEP in this population. A cross-sectional survey was conducted in France in 23 representative departments of infectious diseases and internal medicine. Physicians administered an anonymous standardized questionnaire to all individuals with HIV receiving ARVs and followed between 24 and 31 October 2011. The questionnaire included items regarding PrEP (awareness; discussion with their close circle, physician or patients' association; experience), personal sociodemographic characteristics, risk behaviors and HIV status of the participants. Five hundred and ninety three participants were recruited: male 74.2% (men who have sex with men 52.4%, heterosexuals 21.6%), member of patient's association 9.8%. Half of them (50.6%) lived with a stable partner and 35.2% with an HIV-negative partner. Almost half (41.8%) were aware and 29.5% had had discussion about PrEP. In logistic regression, awareness and discussion on PrEP were more frequent: (1) among males, in patients' association members (p< 0.001 for both) and in nonheterosexuals (p=0.023 and 0.057, respectively); (2) among women, in those not living with a stable partner (p=0.035 and p=0.03, respectively) or living with an HIV-negative partner (p=0.049 and p=0.083, respectively). One percent of the participants declared having shared ARVs with someone and 8.3% reported PrEP in their close circle. Men reporting PrEP in their close circle shared ARVs more frequently than those who did not (10.3% vs. 0.2%, p < 0.001). Today, individuals with HIV do not seem to widely share personal ARVs for PrEP with seronegative people. A significant number of individuals with HIV are aware of and

Expression of Genes for Drug Transporters in the Human Female Genital Tract and Modulatory Effect of Antiretroviral Drugs.

PubMed

Hijazi, Karolin; Cuppone, Anna M; Smith, Kieron; Stincarelli, Maria A; Ekeruche-Makinde, Julia; De Falco, Giulia; Hold, Georgina L; Shattock, Robin; Kelly, Charles G; Pozzi, Gianni; Iannelli, Francesco

2015-01-01

Anti-retroviral (ARV) -based microbicides are one of the strategies pursued to prevent HIV-1 transmission. Delivery of ARV drugs to subepithelial CD4+ T cells at concentrations for protection is likely determined by drug transporters expressed in the cervicovaginal epithelium. To define the role of drug transporters in mucosal disposition of topically applied ARV-based microbicides, these must be tested in epithelial cell line-based biopharmaceutical assays factoring the effect of relevant drug transporters. We have characterised gene expression of influx and efflux drug transporters in a panel of cervicovaginal cell lines and compared this to expression in cervicovaginal tissue. We also investigated the effect of dapivirine, darunavir and tenofovir, currently at advanced stages of microbicides development, on expression of drug transporters in cell lines. Expression of efflux ABC transporters in cervical tissue was best represented in HeLa, Ect1/E6E7 and End1/E6E7 cell lines. Expression of influx OCT and ENT transporters in ectocervix matched expression in Hela while expression of influx SLCO transporters in vagina was best reflected in VK2/E6E7 cell line. Stimulation with darunavir and dapivirine upregulated MRP transporters, including MRP5 involved in transport of tenofovir. Dapivirine also significantly downregulated tenofovir substrate MRP4 in cervical cell lines. Treatment with darunavir and dapivirine showed no significant effect on expression of BCRP, MRP2 and P-glycoprotein implicated in efflux of different ARV drugs. Darunavir strongly induced expression in most cell lines of CNT3 involved in cell uptake of nucleotide/nucleoside analogue reverse transcriptase inhibitors and SLCO drug transporters involved in cell uptake of protease inhibitors. This study provides insight into the suitability of cervicovaginal cell lines for assessment of ARV drugs in transport kinetics studies. The modulatory effect of darunavir and dapivirine on expression of drug

Expression of Genes for Drug Transporters in the Human Female Genital Tract and Modulatory Effect of Antiretroviral Drugs

PubMed Central

Hijazi, Karolin; Cuppone, Anna M.; Smith, Kieron; Stincarelli, Maria A.; Ekeruche-Makinde, Julia; De Falco, Giulia; Hold, Georgina L.; Shattock, Robin; Kelly, Charles G.; Pozzi, Gianni; Iannelli, Francesco

2015-01-01

Anti-retroviral (ARV) –based microbicides are one of the strategies pursued to prevent HIV-1 transmission. Delivery of ARV drugs to subepithelial CD4+ T cells at concentrations for protection is likely determined by drug transporters expressed in the cervicovaginal epithelium. To define the role of drug transporters in mucosal disposition of topically applied ARV-based microbicides, these must be tested in epithelial cell line-based biopharmaceutical assays factoring the effect of relevant drug transporters. We have characterised gene expression of influx and efflux drug transporters in a panel of cervicovaginal cell lines and compared this to expression in cervicovaginal tissue. We also investigated the effect of dapivirine, darunavir and tenofovir, currently at advanced stages of microbicides development, on expression of drug transporters in cell lines. Expression of efflux ABC transporters in cervical tissue was best represented in HeLa, Ect1/E6E7 and End1/E6E7 cell lines. Expression of influx OCT and ENT transporters in ectocervix matched expression in Hela while expression of influx SLCO transporters in vagina was best reflected in VK2/E6E7 cell line. Stimulation with darunavir and dapivirine upregulated MRP transporters, including MRP5 involved in transport of tenofovir. Dapivirine also significantly downregulated tenofovir substrate MRP4 in cervical cell lines. Treatment with darunavir and dapivirine showed no significant effect on expression of BCRP, MRP2 and P-glycoprotein implicated in efflux of different ARV drugs. Darunavir strongly induced expression in most cell lines of CNT3 involved in cell uptake of nucleotide/nucleoside analogue reverse transcriptase inhibitors and SLCO drug transporters involved in cell uptake of protease inhibitors. This study provides insight into the suitability of cervicovaginal cell lines for assessment of ARV drugs in transport kinetics studies. The modulatory effect of darunavir and dapivirine on expression of drug

Risk-Based Sampling: I Don't Want to Weight in Vain.

PubMed

Powell, Mark R

2015-12-01

Recently, there has been considerable interest in developing risk-based sampling for food safety and animal and plant health for efficient allocation of inspection and surveillance resources. The problem of risk-based sampling allocation presents a challenge similar to financial portfolio analysis. Markowitz (1952) laid the foundation for modern portfolio theory based on mean-variance optimization. However, a persistent challenge in implementing portfolio optimization is the problem of estimation error, leading to false "optimal" portfolios and unstable asset weights. In some cases, portfolio diversification based on simple heuristics (e.g., equal allocation) has better out-of-sample performance than complex portfolio optimization methods due to estimation uncertainty. Even for portfolios with a modest number of assets, the estimation window required for true optimization may imply an implausibly long stationary period. The implications for risk-based sampling are illustrated by a simple simulation model of lot inspection for a small, heterogeneous group of producers. © 2015 Society for Risk Analysis.

Teaching for Ethical Reasoning

ERIC Educational Resources Information Center

Sternberg, Robert J.

2012-01-01

This article argues for the importance of teaching for ethical reasoning. Much of our teaching is in vain if it is not applied to life in an ethical manner. The article reviews lapses in ethical reasoning and the great costs they have had for society. It proposes that ethical reasoning can be taught across the curriculum. It presents an eight-step…

Proceedings of the Annual Conference on Manual Control (18th) Held at Dayton, Ohio on 8-10 June 1982

DTIC Science & Technology

1983-01-01

frequency of the disturbance the probability to cross the borderline becomes larger, and corrective action (moving average value further away-,_. from the...pupillometer. The prototypical data was the average of 10 records from 5 normal subjects who showed similar responses. The different amplitudes of light...following orders touch, position, temperature , and vain. Our subjects sometimes reported numbness in the fingertips, dulled pinprick sensations

Real-time imaging of cerebral infarction in rabbits using electrical impedance tomography.

PubMed

Yang, Bin; Shi, Xuetao; Dai, Meng; Xu, Canhua; You, Fushen; Fu, Feng; Liu, Ruigang; Dong, Xiuzhen

2014-02-01

To investigate the possible use of electrical impedance tomography (EIT) in monitoring focal cerebral infarction in a rabbit model. A model of focal cerebral infarction was established in eight New Zealand rabbits using a photochemical method without craniectomy. Focal cerebral infarction was confirmed by histopathological examination. Intracranial impedance variation was measured using 16 electrodes placed in a circle on the scalp. EIT images were obtained using a damped least-squares reconstruction algorithm. The average resistivity value (ARV) of the infarct region on EIT images was calculated to quantify relative resistivity changes. A symmetry index was calculated to evaluate the relative difference in resistivity between the two sides of the cerebrum. EIT images and ARV curves showed that impedance changes caused by cerebral infarction increased linearly with irradiation time. A difference in ARV was found between measurements taken before and after infarct induction. Focal cerebral infarction can be monitored by EIT in the proposed animal model. The results are sufficiently encouraging that the authors plan to extend this study to humans, after further technical improvements.

High HIV-1 Diversity and Prevalence of Transmitted Drug Resistance Among Antiretroviral-Naive HIV-Infected Pregnant Women from Rio de Janeiro, Brazil.

PubMed

Delatorre, Edson; Silva-de-Jesus, Carlos; Couto-Fernandez, José Carlos; Pilotto, Jose H; Morgado, Mariza G

2017-01-01

Antiretroviral (ARV) resistance mutations in human immunodeficiency virus type 1 (HIV-1) infection may reduce the efficacy of prophylactic therapy to prevent mother-to-child transmission (PMTCT) and future treatment options. This study evaluated the diversity and the prevalence of transmitted drug resistance (TDR) in protease (PR) and reverse transcriptase (RT) regions of HIV-1 pol gene among 87 ARV-naive HIV-1-infected pregnant women from Rio de Janeiro, Brazil, between 2012 and 2015. The viral diversity comprised HIV-1 subtypes B (67.8%), F1 (17.2%), and C (4.6%); the circulating recombinant forms 12_BF (2.3%), 28/29_BF, 39_BF, 02_AG (1.1% each) and unique recombinants forms (4.5%). The overall prevalence of any TDR was 17.2%, of which 5.7% for nucleoside RT inhibitors, 5.7% for non-nucleoside RT inhibitors, and 8% for PR inhibitors. The TDR prevalence found in this population may affect the virological outcome of the standard PMTCT ARV-regimens, reinforcing the importance of continuous monitoring.

Antiretrovirals and safer conception for HIV-serodiscordant couples

PubMed Central

Matthews, Lynn T.; Smit, Jennifer A.; Cu-Uvin, Susan; Cohan, Deborah

2013-01-01

Purpose of review Many men and women living with HIV and their uninfected partners attempt to conceive children. HIV-prevention science can be applied to reduce sexual transmission risk while respecting couples’ reproductive goals. Here we discuss antiretrovirals as prevention in the context of safer conception for HIV-serodiscordant couples. Recent findings Antiretroviral therapy (ART) for the infected partner and pre-exposure prophylaxis (PrEP) for the uninfected partner reduce the risk of heterosexual HIV transmission. Several demonstration projects suggest the feasibility and acceptability of antiretroviral (ARV)s as periconception HIV-prevention for HIV-serodiscordant couples. The application of ARVs to periconception risk reduction may be limited by adherence. Summary For male-infected (M+F−) couples who cannot access sperm processing and female-infected (F+M−) couples unwilling to carry out insemination without intercourse, ART for the infected partner, PrEP for the uninfected partner, combined with treatment for sexually transmitted infections, sex limited to peak fertility, and medical male circumcision (for F+M couples) provide excellent, well tolerated options for reducing the risk of periconception HIV sexual transmission. PMID:23032734

Antiretroviral drug resistance and phylogenetic diversity of HIV-1 in Chile.

PubMed

Ríos, Maritza; Delgado, Elena; Pérez-Alvarez, Lucía; Fernández, Jorge; Gálvez, Paula; de Parga, Elena Vázquez; Yung, Verónica; Thomson, Michael M; Nájera, Rafael

2007-06-01

This study reports the analysis of human immunodeficiency virus type 1 (HIV-1) protease (PR) and reverse transcriptase (RT) coding sequences from 136 HIV-1-infected subjects from Chile, 66 (49%) of them under antiretroviral (ARV) treatment. The prevalence of mutations conferring high or intermediate resistance levels to ARVs was 77% among treated patients and 2.5% among drug-naïve subjects. The distribution of resistance prevalence in treated patients by drug class was 61% to nucleoside RT inhibitors, 84% to nonnucleoside RT inhibitors, and 46% to PR inhibitors. Phylogenetic analysis revealed that 115 (85%) subjects were infected with subtype B viruses, 1 with a subtype F1 virus, and 20 (15%) carried BF intersubtype recombinants. Most BF recombinants grouped into two clusters, one related to CRF12_BF, while the other could represent a new circulating recombinant form (CRF). In conclusion, this is the first report analysing the prevalence of ARV resistance which includes patients under HAART from Chile. Additionally, phylogenetic analysis of the PR-RT coding sequences reveals the presence of BF intersubtype recombinants. (c) 2007 Wiley-Liss, Inc.

A survey of the syntheses of active pharmaceutical ingredients for antiretroviral drug combinations critical to access in emerging nations.

PubMed

Pinheiro, Eloan Dos Santos; Antunes, Octavio Augusto Ceva; Fortunak, Joseph M D

2008-09-01

It has been roughly 25 years since the threat posed by human immunodeficiency virus type 1 (HIV-1) became widely known. The cumulative death toll from HIV/AIDS is now greater than 25 million. There are approximately 33 million people living worldwide with this disease, of whom about 68% (22.5 million) live in sub-Saharan Africa (http://www.avert.org/worldstats.htm). A number of antiretroviral (ARV) drugs have been approved for treatment of HIV/AIDS. Inhibitors of HIV reverse transcriptase (RTIs) include the nucleoside/nucleotide drugs zidovudine, lamivudine, abacavir, didanosine, stavudine, emtricitabine and tenofovir disoproxil fumarate. Non-nucleoside RTIs include nevirapine, efavirenz and etravirine. Inhibitors of HIV protease (PIs) include saquinavir, ritonavir, lopinavir, nelfinavir, indinavir, fosamprenavir and atazanavir. Enfuvirtide inhibits the HIV fusion protein. The CCR5 chemokine antagonist maraviroc and the integrase inhibitor raltegravir were very recently approved by the US FDA. Fixed-dose combinations (FDCs) have been formulated to increase tolerability, convenience and compliance. First-line drug combinations are offered to treatment-naive patients, while second-line drugs are reserved for those who no longer respond adequately to first-line therapy. In developing countries a modest but increasing fraction of those infected have access to ARVs. The Clinton HIV/AIDS Initiative estimates that 2.4 million of the nearly 8 million individuals needing treatment in developing nations have access to some drugs. First-line FDCs used in resource-poor settings are largely combinations of two nucleoside RTIs and a non-nucleoside RTI or PI. The effectiveness of these combinations decreases over time, requiring a switch to combinations that retain potency in the presence of viral resistance. Increasing access to second-line FDCs and new developments in first-line ARV therapy are cost challenges. In high-income countries the cost of ARV therapy is largely

Trends in procurement costs for HIV commodities: a 7-year retrospective analysis of global fund data across 125 countries.

PubMed

Wafula, Francis; Agweyu, Ambrose; Macintyre, Kate

2014-04-01

Nearly 40% of Global Fund money goes toward procurement. However, no analyses have been published to show how costs vary across regions and time, despite the availability of procurement data collected through the Global Fund's price and quality reporting system. We analyzed data for the 3 most widely procured commodities for the prevention, diagnosis, and treatment of HIV. These were male condoms, HIV rapid tests, and the antiretroviral (ARV) combination of lamivudine/nevirapine/zidovudine. The compared costs, first across time (2005-2012), then across regions, and finally, between individual procurement reported through the price and quality reporting and pooled procurement reported through the Global Fund's voluntary pooled procurement system. All costs were adjusted for inflation and reported in US dollars. There were 2337 entries from 578 grants in 125 countries. The procurement cost for the ARV dropped substantially over the period, whereas those for condoms and HIV tests remained relatively stable. None of the commodity prices increased. Regional variations were pronounced for HIV tests, but minimal for condoms and the ARV. The unit cost for the 3-table ARV combination, for instance, varied between US$0.15 and US$0.23 in South Asia and the Eastern Europe/Central Asia regions, respectively, compared with a range of $0.23 (South Asia)-$1.50 (Eastern Europe/Central Asia) for a single diagnostic test. Pooled procurement lowered costs for condoms but not the other commodities. We showed how global procurement costs vary by region and time. Such analyses should be done more often to identify and correct market insufficiencies.

Short Communication: Transplacental Nucleoside Analogue Exposure and Mitochondrial Parameters in HIV-Uninfected Children

PubMed Central

Brogly, Susan B.; DiMauro, Salvatore; Van Dyke, Russell B.; Williams, Paige L.; Naini, Ali; Libutti, Daniel E.; Choi, Julia; Chung, Michelle

2011-01-01

Abstract Transplacental nucleoside analogue exposure can affect infant mitochondrial DNA (mtDNA). We evaluated mitochondria in peripheral blood mononuclear cells of children with and without clinical signs of mitochondrial dysfunction (MD) and antiretroviral (ARV) exposure. We previously identified 20 children with signs of MD (cases) among 1037 HIV-uninfected children born to HIV-infected women. We measured mtDNA copies/cell and oxidative phosphorylation (OXPHOS) NADH dehydrogenase (complex I) and cytochrome c oxidase (complex IV) protein levels and enzyme activities, determined mtDNA haplogroups and deletions in 18 of 20 cases with stored samples and in sex- and age-matched HIV-uninfected children, both ARV exposed and unexposed, (1) within 18 months of birth and (2) at the time of presentation of signs of MD. In specimens drawn within 18 months of birth, mtDNA levels were higher and OXPHOS protein levels and enzyme activities lower in cases than controls. In contrast, at the time of MD presentation, cases and ARV-exposed controls had lower mtDNA levels, 214 and 215 copies/cell, respectively, than ARV-unexposed controls, 254 copies/cell. OXPHOS protein levels and enzyme activities were lower in cases than exposed controls, and higher in cases than unexposed controls, except for complex IV activity, which was higher in cases. Haplotype H was less frequent among cases (6%) than controls (31%). No deletions were found. The long-term significance of these small but potentially important alterations should continue to be studied as these children enter adolescence and adulthood. PMID:21142587

A Review of the Toxicity of HIV Medications II: Interactions with Drugs and Complementary and Alternative Medicine Products.

PubMed

Stolbach, Andrew; Paziana, Karolina; Heverling, Harry; Pham, Paul

2015-09-01

For many patients today, HIV has become a chronic disease. For those patients who have access to and adhere to lifelong antiretroviral (ARV) therapy, the potential for drug-drug interactions has become a real and life-threatening concern. It is known that most ARV drug interactions occur through the cytochrome P450 (CYP) pathway. Medications for comorbid medical conditions, holistic supplements, and illicit drugs can be affected by CYP inhibitors and inducers and have the potential to cause harm and toxicity. Protease inhibitors (PIs) tend to inhibit CYP3A4, while most non-nucleoside reverse transcriptase inhibitors (NNRTIs) tend to induce the enzyme. As such, failure to adjust the dose of co-administered medications, such as statins and steroids, may lead to serious complications including rhabdomyolysis and hypercortisolism, respectively. Similarly, gastric acid blockers can decrease several ARV absorption, and warfarin doses may need to be adjusted to maintain therapeutic concentrations. Illicit drugs such as methylenedioxymethamphetamine (MDMA, "ecstasy") in combination with PIs lead to increased toxicity, while the concomitant administration of sedative drugs such as midazolam and alprazolam in patients taking PIs can result in prolonged sedation, delayed recovery, and increased length of stay. Even supplements like St. John's Wort can alter PI concentrations. In theory, any drug that is metabolized by CYP has potential for a pharmacokinetic drug-drug interaction with all PIs, cobicistat, and most NNRTIs. When adding a new medication to an ARV regimen, use of a drug-drug interaction software and/or consultation with a clinical pharmacist/pharmacologist or HIV specialist is recommended.

Evolving Human Rights and the Science of Antiretroviral Medicine.

PubMed

Kavanagh, Matthew; Cohn, Jennifer; Mabote, Lynette; Meier, Benjamin Mason; Williams, Brian; Russell, Asia; Sikwese, Kenly; Baker, Brook

2015-06-11

Recent years have seen significant advances in the science of using antiretroviral medicines (ARVs) to fight HIV. Where not long ago ARVs were used late in disease to prevent sick people from dying, today people living with HIV can use ARVs to achieve viral suppression early in the course of disease. This article reviews the mounting new scientific evidence of major clinical and prevention ARV benefits. This has changed the logic of the AIDS response, eliminating competition between "treatment" and "prevention" and encouraging early initiation of treatment for individual and public health benefit. These breakthroughs have implications for the health-related human rights duties of States. With medical advance, the "highest attainable standard" of health has taken a leap, and with it the rights obligations of States. We argue that access to early treatment for all is now a core State obligation and restricting access to, or failing to provide accurate information about, it violates both individual and collective rights. In a context of real political and technical challenges, however, in this article we review the policy implications of evolving human rights obligations given the new science. National and international legal standards require action on budget, health and intellectual property policy, which we outline. Copyright 2015 Kavanagh et al. This is an open access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/), which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original author and source are credited.

Longitudinal development of cognitive, visuomotor and adaptive behavior skills in HIV uninfected children, aged 3-5 years of age, exposed pre- and perinatally to anti-retroviral medications.

PubMed

Smith, Mary Lou; Puka, Klajdi; Sehra, Ramandeep; Read, Stanley E; Bitnun, Ari

2017-10-01

Little is known about the neurodevelopmental outcomes of children older than 3 years of age born to HIV infected mother but who are HIV-uninfected (HEU), and who have been exposed in utero and early in life to HIV and to antiretroviral medications (ARVs). We conducted a longitudinal study of cognitive, visuomotor and adaptive function of HEU children, who were assessed at two ages, 3.5 and 5.5 years. Sixty-four children (33 female) were assessed. In comparison with population norms for their age, at 3.5 years of age they had scores significantly below age expectations on aspects of adaptive behavior, but at age 5.5 years, their scores did not significantly diverge from the population norms on any of the measures. Verbal intelligence was lower at age 5.5 than at age 3.5 years, although there were also improvements in some features of adaptive behavior. Exposure to PI-based ARVs (compared to NNRTIs) was associated with higher Performance IQ, visuomotor and communication scores at age 5.5 years. Birth, early growth, and sociodemographic variables were predictive of outcomes. This study is important in tracking the trajectory of neurocognitive development across the pre-school and early school age years. The findings suggest that the full impact of early ARV exposure may not be evident until a considerable period of development has occurred. The results raise the possibility of negative effects of early ARV exposure on neurodevelopment that emerge over time, and reiterate the importance of sociodemographic and early health variables for optimal development.

Activation of plantar flexor muscles is constrained by multiple muscle synergies rather than joint torques

PubMed Central

Suzuki, Takahito; Kinugasa, Ryuta; Fukashiro, Senshi

2017-01-01

Behavioral evidence has suggested that a small number of muscle synergies may be responsible for activating a variety of muscles. Nevertheless, such dimensionality reduction may also be explained using the perspective of alternative hypotheses, such as predictions based on linear combinations of joint torques multiplied by corresponding coefficients. To compare the explanatory capacity of these hypotheses for describing muscle activation, we enrolled 12 male volunteers who performed isometric plantar flexor contractions at 10–100% of maximum effort. During each plantar flexor contraction, the knee extensor muscles were isometrically contracted at 0%, 50%, or 100% of maximum effort. Electromyographic activity was recorded from the vastus lateralis, medial gastrocnemius (MG), lateral gastrocnemius (LG), and soleus muscles and quantified using the average rectified value (ARV). At lower plantar flexion torque, regression analysis identified a clear linear relationship between the MG and soleus ARVs and between the MG and LG ARVs, suggesting the presence of muscle synergy (r2 > 0.65). The contraction of the knee extensor muscles induced a significant change in the slope of this relationship for both pairs of muscles (MG × soleus, P = 0.002; MG × LG, P = 0.006). Similarly, the slope of the linear relationship between the plantar flexion torque and the ARV of the MG or soleus changed significantly with knee extensor contraction (P = 0.031 and P = 0.041, respectively). These results suggest that muscle synergies characterized by non-mechanical constraints are selectively recruited according to whether contraction of the knee extensor muscles is performed simultaneously, which is relatively consistent with the muscle synergy hypothesis. PMID:29107958

Operational issues and barriers to implementation of prevention of mother-to-child transmission of HIV (PMTCT) interventions in Sub-Saharan Africa.

PubMed

Aizire, Jim; Fowler, Mary G; Coovadia, Hoosen M

2013-03-01

Over the past 10 years substantial progress has been made in the implementation of prevention of mother-to-child transmission of HIV (PMTCT) interventions in Sub-Saharan Africa (SSA). In spite of this, new pediatric infections remain unacceptably high, contributing the majority (>90%) of the estimated 390,000 infections globally in 2010; and yet prolonged breastfeeding remains the norm and crucial to overall infant survival. However, there is reason for optimism given the 2010 World Health Organization PMTCT recommendations: to start HIV infected pregnant women with CD4 cell counts less than 350 cells/mm(3) on lifelong antiretroviral therapy (ART); and for mothers not eligible for ART to provide efficacious maternal and/or infant PMTCT antiretroviral (ARV) regimens to be taken during pregnancy, labor/delivery and through breastfeeding. Current attention is on whether to extend maternal ARVs for life once triple ARV PMTCT regimens are started. To dramatically reduce new pediatric infections, individual countries need to politically commit to rapid scale-up of a multi-pronged PMTCT effort: including primary prevention to reduce HIV incidence among women of reproductive age; increased access to family planning services; HIV screening of all pregnant and breastfeeding women followed by ART or ARVs for PMTCT; and comprehensive care for HIV affected families. Efforts to achieve population-level success in SSA need to critically address operational issues and challenges to implementation (health system) and utilization (social, economic and cultural barriers), at the country, health centre and client level that have led to the relatively slow progress in the scale-up of PMTCT strategies.

Understanding factors, outcomes and reasons for loss to follow-up among women in Option B+ PMTCT programme in Lilongwe, Malawi.

PubMed

Tweya, Hannock; Gugsa, Salem; Hosseinipour, Mina; Speight, Colin; Ng'ambi, Wingston; Bokosi, Mphatso; Chikonda, Janet; Chauma, Annie; Khomani, Patricia; Phoso, Malocho; Mtande, Tiwonge; Phiri, Sam

2014-11-01

To assess factors, outcomes and reasons for loss to follow-up (LTFU) among pregnant and breastfeeding women initiated on a lifelong antiretroviral therapy (ART) for PMTCT in a large antenatal clinic in Malawi. We identified all pregnant and breastfeeding women who were initiated on ART between September 2011 and September 2013 and had missed their clinic appointment by at least 3 weeks at Bwaila Hospital, the largest antenatal clinic in Malawi. These women were traced by phone or home visits. Their true status and reasons for ART discontinuation were documented during tracing. A total of 2930 women started ART for PMTCT; 2458 (84%) pregnant and 472 (16%) breastfeeding, of which, 577 (20%) missed a scheduled clinic appointment. LTFU was associated with younger age, being pregnant, and earlier year of ART initiation. We successfully traced 229 (40%), of whom, 10 (4%) had died. Of the 219 women found alive, 118 (54%) had stopped taking ARV drugs, 67 (30%) had self-transferred to another ART clinic, 13 (6%) had collected drugs from other sources, 9 (4%) had treatment interruptions and 12 (5%) had other outcomes. Reasons cited for stopping ART were travel (38%), lack of transport money (16%), not understanding the initial ARV education session (10%), being too weak/sick (10%), ARV side effects (10%) and other reasons. Approximately half of the women who were traced were taking ARVs. The study emphasises the need for enhanced post-test counselling strategies, ongoing psychosocial support, provision of incentives and further decentralisation efforts of PMTCT services. © 2014 John Wiley & Sons Ltd.

CO2 laser surgery for vulvar intraepithelial neoplasia. Excisional, destructive and combined techniques.

PubMed

Penna, Carlo; Fallani, M Grazia; Fambrini, Massimiliano; Zipoli, Elisa; Marchionni, Mauro

2002-11-01

To evaluate CO2 laser excision, vaporization and combined techniques for treatment of vulvar intraepithelial neoplasia (VIN). Thirty-nine cases of VIN 3, 15 cases of VIN 2 and 9 of VIN 1, for a total of 63 patients with histologically proven VIN, underwent laser excision or vaporization under colposcopic guidance, using local anesthesia, in an outpatient setting or after day-surgery admission. Clinical aspects, cervical intraepithelial neoplasia (CIN) and vaginal intraepithelial neoplasia (VaIN) association, types of CO2 laser treatment, follow-up, recurrences and second treatments were evaluated. Twenty-seven (41.3%) patients underwent laser vaporization, and 37 (58.7%) with VIN 3, underwent laser excision or the combined technique. Colposcopic and biopsy examinations of patients with VIN revealed three cases of CIN 3 and nine cases of VaIN 3; two patients had concomitant VIN 3, CIN 3 and VaIN 3. Local anesthesia, using 2% carbocaine, and outpatient or day-surgery treatments were possible in all cases. A small incidence of intraoperative complications (4.8%) and absence of postoperative complications were observed. A single session was curative in 76.9% of patients treated with laser vaporization and in 78.4% of those treated with laser excision. Eleven cases of recurrent VIN and two cases of invasive vulvar carcinoma were observed during follow-up. A second laser procedure was carred out in all cases of relapsed VIN, with an overall cure rate of 96.8% after two treatments. Radical vulvectomy associated with inguinal-femoral lymphadenectomy was performed in the two cases of invasive carcinoma. CO2 laser surgery permits treatment of VIN in an outpatient or day-surgery setting under local anesthesia with excellent cosmetic and functional results. The treatment can also be adjusted to the patient's specific needs, with the possibility of calibrating the depth of the vaporized and removed tissues. Excisional treatment is the preferred method because it permits

Vestibular involvement in adults with HIV/AIDS.

PubMed

Heinze, Barbara M; Vinck, Bart M; Hofmeyr, Louis M; Swanepoel, De Wet

2014-04-01

HIV/AIDS is responsible for widespread clinical manifestations involving the head, and neck. The prevalence and nature of vestibular involvement is still largely unknown. This study, aimed to describe and compare the occurrence and nature of vestibular involvement among a group of, adults infected with HIV compared to a control group. It also aimed to compare the vestibular function, of symptomatic and asymptomatic HIV positive adults who receive antiretroviral (ARV) therapies to, subjects not receiving ARV. A cross-sectional study was conducted on 53 adults (29 male, 24 female, aged 23-49 years, mean=38.5, SD=4.4) infected with HIV, compared to a control group of 38 HIV negative adults (18, male, 20 female, aged 20-49 years, mean=36.9, SD=8.2). A structured interview probed the subjective, perception of vestibular symptoms. Medical records were reviewed for CD4+ cell counts and the use of, ARV medication. An otologic assessment and a comprehensive vestibular assessment (bedside, assessments, vestibular evoked myogenic potentials, ocular motor and positional tests and bithermal, caloric irrigation) were conducted. Vestibular involvement occurred in 79.2% of subjects with HIV in all categories of disease, progression, compared to 18.4% in those without HIV. Vestibular involvement increased from 18.9% in CDC category 1 to 30.2% in category 2. Vestibular involvement was 30.1% in category 3. There were, vestibular involvement in 35.9% of symptomatic HIV positive subjects, and 41.5% in asymptomatic, HIV positive subjects. There was no significant difference in the occurrence of vestibular involvement, in subjects receiving ARV therapies compared to those not receiving ARV therapies (p=.914; chi-square, test). The odds ratio indicates that individuals with HIV have a 16.61 times higher risk of developing, vestibular involvement during their lifetime of living with the disease and that it may occur despite, being asymptomatic. Vestibular involvement was significantly more

LB01.06: VISIT-TO-VISIT BLOOD PRESSURE VARIABILITY AND CARDIOVASCULAR OUTCOMES IN FELODIPINE EVENT REDUCTION STUDY.

PubMed

Zhang, Y; Zhang, X; Liu, L; Zanchetti, A

2015-06-01

Many antihypertensive outcome trials have shown that visit-to-visit blood pressure variability is correlated closely with clinical outcomes in hypertensive patients. The objective of the study was to investigate the relationship between visit-to-visit blood pressure variability (BPV) and the major cardiovascular outcomes in the Chinese hypertensive patients. Felodipine Event Reduction (FEVER) study was a double-blind, randomized trial on 9711 Chinese hypertensive patients, in whom cardiovascular outcomes were significantly reduced by more intense therapy achieving a mean of 138 mmHg SBP compared with less-intense therapy achieving a mean of 142 mmHg. Visit-to-visit BPV during the follow-up period [defined as standard deviation (SD), coefficient of variation (CV), and average real variability(ARV)] was derived from casual cuff BP measures after six months follow-up until the end of the study. Hazard ratios (HRs), for the incidence of CVD associated with SD, CV, and ARV of SBP and DBP were calculated using Cox proportional hazard models. Overall predictive power [area under receiver operating characteristic (AUC ROC) curve] of the level of blood pressure, blood pressure variability and other baseline characteristics was calculated. In FEVER study, visit-to-visit variability in SBP were significant predictors of subsequent stroke [eg, hazard ratios [HR] for ARV, SD and CV was 1.071 (95% CI: 1.025-1.118), 1.373 (95% CI: 1.159-1.626) and 0.572 (95% CI: 0.451-0,726)]. Visit-to-visit variability in DBP were also showed similar trend [eg, HR for ARV, SD and CV was 1.066 (95% CI: 0.992-1.145), 1.931 (95% CI: 1.435-2.598) and 0.558 (95% CI: 0.438-0,710)]. However, using the analysis of AUC ROC analysis, the risk importance sequence of the stroke events in this cohort was level of SBP, age, level of DBP ARV, SD, sex, CV and treatment. Visit-to-visit blood pressure variability has some effects on the cardiovascular outcomes in the Chinese hypertensive patents in the cohort in

Relationships between 24-h blood pressure variability and 24-h central arterial pressure, pulse wave velocity and augmentation index in hypertensive patients.

PubMed

Omboni, Stefano; Posokhov, Igor N; Rogoza, Anatoly N

2017-04-01

Twenty-four-h blood pressure variability (BPV) predicts cardiovascular complications in hypertension, but its association with pulse wave indices (central arterial pressure, pulse wave velocity (PWV) and augmentation index (AIx)) is poorly understood. In the present study, we assessed the degree of the effect of 24-h BPV on 24-h pulse wave indices. Brachial blood pressure was measured non-invasively over the 24 h with an electronic, oscillometric, automated device (BPLab) in 661 uncomplicated treated or untreated hypertensive patients. Digitalized oscillometric waveforms were analyzed with a validated algorithm to obtain pulse wave indices. Twenty-four-h BPV was calculated as the unweighted (SDu) or weighted s.d. (SDw) of the mean blood pressure or as the average real variability (ARV). Twenty-four-h systolic BPV showed a direct and significant relationship with the central arterial systolic pressure (r=0.28 SDu, r=0.40 SDw, r=0.34 ARV), PWV (r=0.10 SDu, r=0.21 SDw, r=0.19 ARV) and AIx (r=0.17 SDu, r=0.27 SDw, r=0.23 ARV). After adjustment for age, sex, body mass index, antihypertensive treatment and 24-h systolic blood pressure, the relationship lost some power but was still significant for all measures, except for the AIx. Pulse wave indices were higher in patients with high BPV than in those with low BPV: after adjustment, these differences were abolished for the AIx. The diastolic BPV showed a weak association with the pulse wave indices. In conclusion, in hypertensive patients, 24-h systolic BPV is moderately and independently associated with 24-h central arterial pressure and stiffness.

Results of antiretroviral treatment interruption and intensification in advanced multi-drug resistant HIV infection from the OPTIMA trial.

PubMed

Holodniy, Mark; Brown, Sheldon T; Cameron, D William; Kyriakides, Tassos C; Angus, Brian; Babiker, Abdel; Singer, Joel; Owens, Douglas K; Anis, Aslam; Goodall, Ruth; Hudson, Fleur; Piaseczny, Mirek; Russo, John; Schechter, Martin; Deyton, Lawrence; Darbyshire, Janet

2011-03-31

Guidance is needed on best medical management for advanced HIV disease with multidrug resistance (MDR) and limited retreatment options. We assessed two novel antiretroviral (ARV) treatment approaches in this setting. We conducted a 2×2 factorial randomized open label controlled trial in patients with a CD4 count≤300 cells/µl who had ARV treatment (ART) failure requiring retreatment, to two options (a) re-treatment with either standard (≤4 ARVs) or intensive (≥5 ARVs) ART and b) either treatment starting immediately or after a 12-week monitored ART interruption. Primary outcome was time to developing a first AIDS-defining event (ADE) or death from any cause. Analysis was by intention to treat. From 2001 to 2006, 368 patients were randomized. At baseline, mean age was 48 years, 2% were women, median CD4 count was 106/µl, mean viral load was 4.74 log(10) copies/ml, and 59% had a prior AIDS diagnosis. Median follow-up was 4.0 years in 1249 person-years of observation. There were no statistically significant differences in the primary composite outcome of ADE or death between re-treatment options of standard versus intensive ART (hazard ratio 1.17; CI 0.86-1.59), or between immediate retreatment initiation versus interruption before re-treatment (hazard ratio 0.93; CI 0.68-1.30), or in the rate of non-HIV associated serious adverse events between re-treatment options. We did not observe clinical benefit or harm assessed by the primary outcome in this largest and longest trial exploring both ART interruption and intensification in advanced MDR HIV infection with poor retreatment options. Clinicaltrials.gov NCT00050089.

Blood pressure variability of two ambulatory blood pressure monitors.

PubMed

Kallem, Radhakrishna R; Meyers, Kevin E C; Cucchiara, Andrew J; Sawinski, Deirdre L; Townsend, Raymond R

2014-04-01

There are no data on the evaluation of blood pressure (BP) variability comparing two ambulatory blood pressure monitoring monitors worn at the same time. Hence, this study was carried out to compare variability of BP in healthy untreated adults using two ambulatory BP monitors worn at the same time over an 8-h period. An Accutorr device was used to measure office BP in the dominant and nondominant arms of 24 participants.Simultaneous 8-h BP and heart rate data were measured in 24 untreated adult volunteers by Mobil-O-Graph (worn for an additional 16 h after removing the Spacelabs monitor) and Spacelabs with both random (N=12) and nonrandom (N=12) assignment of each device to the dominant arm. Average real variability (ARV), SD, coefficient of variation, and variation independent of mean were calculated for systolic blood pressure, diastolic blood pressure, mean arterial pressure, and pulse pressure (PP). Whether the Mobil-O-Graph was applied to the dominant or the nondominant arm, the ARV of mean systolic (P=0.003 nonrandomized; P=0.010 randomized) and PP (P=0.009 nonrandomized; P=0.005 randomized) remained significantly higher than the Spacelabs device, whereas the ARV of the mean arterial pressure was not significantly different. The average BP readings and ARVs for systolic blood pressure and PP obtained by the Mobil-O-Graph were considerably higher for the daytime than the night-time. Given the emerging interest in the effect of BP variability on health outcomes, the accuracy of its measurement is important. Our study raises concerns about the accuracy of pooling international ambulatory blood pressure monitoring variability data using different devices.

Pharmacokinetics of Tenofovir Alafenamide When Co-administered With Other HIV Antiretrovirals.

PubMed

Begley, Rebecca; Das, Moupali; Zhong, Lijie; Ling, John; Kearney, Brian P; Custodio, Joseph M

2018-04-10

Tenofovir alafenamide (TAF), a prodrug of the nucleotide analogue tenofovir (TFV), is an antiretroviral (ARV) agent approved either as a complete regimen (elvitegravir/cobicistat/emtricitabine (F)/tenofovir alafenamide (TAF), rilpivirine/F/TAF, bictegravir/F/TAF), or for use with other ARVs (F/TAF), for treatment of HIV. TAF is a substrate of P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) transporters. Disposition of TAF may be altered by co-medications that can inhibit or induce P-gp or BCRP transporters. The effects of ARVs on the pharmacokinetics (PK) of TAF were evaluated in 3 studies. Healthy participants received TAF administered alone or with rilpivirine (RPV) in study 1; with dolutegravir (DTG), ritonavir boosted atazanavir (ATV+RTV), lopinavir (LPV/RTV), or darunavir (DRV+RTV) in study 2; and with the pharmacokinetic enhancer cobicistat (COBI), or efavirenz (EFV) in study 3. Across the three studies, 98 participants received treatment with TAF and a coadministered agent (n=10-34/cohort). All study treatments were well tolerated. TAF and TFV exposures were unaffected following co-administration with RPV and DTG. Co-administration with Pgp/BCRP inhibitors such as COBI or PI based regimens (ATV+RTV, LPV/r or DRV+RTV) resulted in a range of 6% to 183% increases in TAF and 105% to 316% increases in TFV exposure, while co-administration with a Pgp inducer, EFV, resulted in a 15% to 24% decrease in TAF and TFV exposure. Evaluation of the drug interaction between TAF and other commonly prescribed boosted and unboosted ARVs provides characterization of the susceptibility of TAF and/or TFV PK to inhibitors or inducers of Pgp/BCRP transporters.

Global Fund-supported programmes contribution to international targets and the Millennium Development Goals: an initial analysis.

PubMed

Komatsu, Ryuichi; Low-Beer, Daniel; Schwartländer, Bernhard

2007-10-01

The Global Fund to Fight AIDS, Tuberculosis and Malaria is one of the largest funders to fight these diseases. This paper discusses the programmatic contribution of Global Fund-supported programmes towards achieving international targets and Millennium Development Goals, using data from Global Fund grants. Results until June 2006 of 333 grants supported by the Global Fund in 127 countries were aggregated and compared against international targets for HIV/AIDS, tuberculosis and malaria. Progress reports to the Global Fund secretariat were used as a basis to calculate results. Service delivery indicators for antiretrovirals (ARV) for HIV/AIDS, case detection under the DOTS strategy for tuberculosis (DOTS) and insecticide-treated nets (ITNs) for malaria prevention were selected to estimate programmatic contributions to international targets for the three diseases. Targets of Global Fund-supported programmes were projected based on proposals for Rounds 1 to 4 and compared to international targets for 2009. Results for Global Fund-supported programmes total 544,000 people on ARV, 1.4 million on DOTS and 11.3 million for ITNs by June 2006. Global Fund-supported programmes contributed 18% of international ARV targets, 29% of DOTS targets and 9% of ITNs in sub-Saharan Africa by mid-2006. Existing Global Fund-supported programmes have agreed targets that are projected to account for 19% of the international target for ARV delivery expected for 2009, 28% of the international target for DOTS and 84% of ITN targets in sub-Saharan Africa. Global Fund-supported programmes have already contributed substantially to international targets by mid-2006, but there is a still significant gap. Considerably greater financial support is needed, particularly for HIV, in order to achieve international targets for 2009.

No effect of interleukin-2 on IgE levels given in addition to antiretroviral therapy in HIV-infected adults with CD4 >300 cells/mm3.

PubMed

Ananworanich, Jintanat; Chantaphakul, Hiroshi; Teeratakulpisarn, Somsong; Siangphoe, Umaporn; Ubolyam, Sasiwimol; Chuenyam, Theshinee; Ungsedhaphan, Chaiwat; Lange, Joep; Cooper, David; Phanuphak, Praphan; Ruxrungtham, Kiat

2005-03-01

HIV-infected patients may have frequent atopy caused by an imbalance of Th1 and Th2 cytokines. The objective of the present study was to investigate whether IL-2 given in addition to antiretrovirals (ARV) would result in lower IgE levels and less allergic symptoms. Patients naive to IL-2 (n=28) began IL-2 plus ARV and were followed for 12 months. IgE, eosinophil and CD4 counts, HIV RNA, symptom scoring, PFT and skin prick test (SPT) were performed. It was found that the baseline median CD4 and IgE were 386.5 cells/mm3 and 63.5 IU/ml, respectively. Four patients had allergic rhinitis (AR) and 61% had a positive SPT to at least 1 antigen. At month 12, patients had higher CD4 counts (p < 0.001) compared to the baseline; however, there were no differences in IgE levels, allergic symptom scores or HIV RNA. The eosinophil count was higher after IL-2 administration. It was concluded that IL-2 plus ARV resulted in higher CD4 counts but had no effect on atopy.

Cost Considerations in the Current ARV Era

PubMed Central

Eaton, Ellen F; Tamhane, Ashutosh; Saag, Michael; Mugavero, Michael J; Kilgore, Meredith L

2018-01-01

Summary Of five commonly prescribed regimens for treatment-naïve HIV patients in one clinic (2007–2012), Emtricitabine and Tenofovir with Efavirenz and Raltegravir were the only consistently cost-effective options; the Rilpivirine-based regimen was valuable in limited scenarios. Further data on the comparative effectiveness of Efavirenz and Rilpivirine are needed before they are abandoned. PMID:27088319

The Malaysian Eagle Aerial Reconnaissance Vehicle (ARV)

DTIC Science & Technology

2002-06-01

Santa Monica, CA Report Documentation Page Form ApprovedOMB No . 0704-0188 Public reporting burden for the collection of information is estimated to...Jefferson Davis Highway, Suite 1204, Arlington VA 22202-4302. Respondents should be aware that notwithstanding any other provision of law, no person

19th Century Christian Benevolence and the Unwritten Constitution

DTIC Science & Technology

2007-05-01

indispensable supports. In vain would that man claim the tribute of Patriotism, who should labour to subvert these great Pillars of human happiness...Brought on by disestablishment and buoyed by the energy from the Second Great Awakening, ecumenical Protestantism jettisoned the artificial barriers of the...highest to the lowest, as coworkers in the same labour of love.’’ 23 Efficiency in distribution, however, required accurate communication between the

Is Your Love in Vain? Another Look at Premarital Cohabitation and Divorce

ERIC Educational Resources Information Center

Svarer, Michael

2004-01-01

In this paper we provide an empirical investigation of the association between premarital cohabitation and subsequent risk of divorce. Theoretically couples who cohabit before marriage should have a lower subsequent risk of divorce since cohabitation enables you to gather information about the match quality, and only good matches evolve into…

Climatic change effects on hydro-metereological variables in the Alps: a case study on the upper Arve catchment at Chamonix (France) over the last 50 years

NASA Astrophysics Data System (ADS)

Viani, Alessandra; Condom, Thomas; Bacchi, Baldassare; Zin, Isabella; Six, Delphine; Gottardi, Frederic; Rabatel, Antoine; Morin, Samuel

2016-04-01

Hydrological changes in partially glaciated catchments are expected under future climate scenarios, with consequences for water availability and management at catchment and regional scales. In order to correctly predict the magnitude of such changes and envisage adaptation and/or mitigation measures against water related hazards, a good understanding of the water cycle dynamics at different spatial and temporal scales is needed. The Upper Arve catchment in Chamonix (202 square kilometers), situated in the French Northern Alps, between the two massifs of Mont Blanc and Aiguilles Rouges, is a perfect case study for evaluating the sensitivity of the alpine water cycle to climate change. It is highly glaciated (32% of the total area in 2012) with three important glaciers: Glacier du Tour, Glacier d'Argentiere and Glacier de la Mer de Glace. Its elevation ranges from 1025 up to 4295 m a.s.l. and the exposure of the ice cover is generally north and east oriented. Long term time-series exist of (i) glacier mass balance, (ii) meteorological (in-situ and reanalyses) and (iii) hydrological data. The objectives of the presented study were: 1 - To characterize the inter-annual regimes of the different climatological and hydrological variables: precipitation, temperature and discharge; 2 - To estimate trends on the previous variables, at different temporal scales (annual and monthly) for different altitudes, and compare them to usually observed values in alpine regions; 3 - To infer from the previous statistical analyses and from a cross-analysis between the different considered variables the catchment's hydrological evolution during the last 50 years. Results showed precipitation, temperature and discharge regimes typical of high mountainous partially glaciated catchments. In the long term period, this catchment is characterized by an evident retreat of glacier. Long term trends over the past five decades show no significant change in the annual amount of precipitation. At the

Stepped-Wedge Cluster Randomized Controlled Trial to Promote Option B+ Retention in Central Mozambique.

PubMed

Pfeiffer, James T; Napúa, Manuel; Wagenaar, Bradley H; Chale, Falume; Hoek, Roxanne; Micek, Mark; Manuel, João; Michel, Cathy; Cowan, Jessica Greenberg; Cowan, James F; Gimbel, Sarah; Sherr, Kenneth; Gloyd, Stephen; Chapman, Rachel R

2017-11-01

This randomized trial studied performance of Option B+ in Mozambique and evaluated an enhanced retention package in public clinics. The study was conducted at 6 clinics in Manica and Sofala Provinces in central Mozambique. Seven hundred sixty-one pregnant women tested HIV+, immediately initiated antiretroviral (ARV) therapy, and were followed to track retention at 6 clinics from May 2014 to May 2015. Clinics were randomly allocated within a stepped-wedge fashion to intervention and control periods. The intervention included (1) workflow modifications and (2) active patient tracking. Retention was defined as percentage of patients returning for 30-, 60-, and 90-day medication refills within 25-35 days of previous refills. During control periods, 52.3% of women returned for 30-day refills vs. 70.8% in intervention periods [odds ratio (OR): 1.80; 95% confidence interval (CI): 1.05 to 3.08]. At 60 days, 46.1% control vs. 57.9% intervention were retained (OR: 1.82; CI: 1.06 to 3.11), and at 90 days, 38.3% control vs. 41.0% intervention (OR: 1.04; CI: 0.60 to 1.82). In prespecified subanalyses, birth before pickups was strongly associated with failure-women giving birth before ARV pickup were 33.3 times (CI: 4.4 to 250.3), 7.5 times (CI: 3.6 to 15.9), and 3.7 times (CI: 2.2 to 6.0) as likely to not return for ARV pickups at 30, 60, and 90 days, respectively. The intervention was effective at 30 and 60 days, but not at 90 days. Combined 90-day retention (40%) and adherence (22.5%) were low. Efforts to improve retention are particularly important for women giving birth before ARV refills.

In Utero Exposure to Antiretroviral Drugs: Effect on Birth Weight and Growth Among HIV-Exposed Uninfected Children in Brazil

PubMed Central

Hofer, Cristina Barroso; Keiser, Olivia; Zwahlen, Marcel; Lustosa, Carla Sepulveda; CisneFrota, Ana Cristina; de Oliveira, Ricardo Hugo; Abreu, Thalita F; Carvalho, Alice Weber; Araujo, Lucia Evangelista; Egger, Matthias

2015-01-01

Context There are concerns about the effects of in utero exposure to antiretroviral drugs (ARVs) on the development of HIV exposed but uninfected (HEU) children. Objectives To evaluate whether in utero exposure to ARVs is associated with lower birth weight/height and reduced growth during the first two years of life. Design Cohort study of HEU infants. Setting Tertiary children's hospital in Rio de Janeiro, Brazil. Study population HEU infants born 1996-2010. Main outcome measures Weight measured by mechanical scale, height measured by measuring board. Z-scores for weight-for-age (WAZ), length-for-age (LAZ) and weight-for-length (WLZ) were calculated. We modeled trajectories by mixed-effects models and adjusted for mother's age, CD4 cell count, viral load, year of birth and family income. Results A total of 588 HEU infants were included of whom 155 (26%) were not exposed to ARVs, 114 (19%) were exposed early (first trimester) and 319 (54%) later. WAZ were lower among infants exposed early compared to infants exposed later: adjusted differences were −0.52 (95% CI −0.99 to −0.04, P=0.02) at birth and −0.22 (95% CI −0.47 to 0.04, P=0.10) during follow-up. LAZ were lower during follow-up: −0.35 (95% CI −0.63 to −0.08, P=0.01). There were no differences in WLZ scores. Z-scores of infants exposed late during pregnancy were similar to unexposed infants. Conclusions In HEU children early exposure to ARVs was associated with lower WAZ at birth and lower LAZ up to 2 years of life. Growth of HEU children needs to be monitored closely. PMID:26741583

The make or buy debate: Considering the limitations of domestic production in Tanzania

PubMed Central

2012-01-01

Background In order to ensure their population’s regular access to essential medicines, many least developed countries and developing countries are faced with the policy question of whether to import or manufacture drugs locally, in particular for life-saving antiretroviral medicines for HIV/AIDS patients. In order for domestic manufacturing to be viable and cost-effective, the local industry must be able to compete with international suppliers of medicines by producing sufficiently low cost ARVs. Methods This paper considers the ‘make-or-buy’ dilemma by using Tanzania as a case study. Key informant interviews, event-driven observation, and purposive sampling of documents were used to evaluate the case study. The case study focused on Tanzania’s imitation technology transfer agreement to locally manufacture a first-line ARV (3TC + d4T + NVP), reverse engineering the ARV. Results Tanzania is limited by weak political support for the use of TRIPS flexibilities, limited production capacity for ARVs and limited competitiveness in both domestic and regional markets. The Ministry of Health and Social Welfare encourages the use of flexibilities while others push for increased IP protection. Insufficient production capacity and lack of access to donor-financed tenders make it difficult to obtain economies of scale and provide competitive prices. Conclusions Within the “make-or-buy” context, it was determined that there are significant limitations in domestic manufacturing for developing countries. The case study highlights the difficulty of governments to make use of economies of scale and produce low-cost medicines, attract technology transfer, and utilize the flexibilities of the WTO Agreement on Trade-Related Aspects of Intellectual Property Rights (TRIPS). The results demonstrate the importance of evaluating barriers to the use of TRIPS flexibilities and long-term planning across sectors in future technology transfer and manufacturing initiatives

Impact of a systems engineering intervention on PMTCT service delivery in Côte d’Ivoire, Kenya, Mozambique: a cluster randomized trial

PubMed Central

Rustagi, Alison Silvis; Gimbel, Sarah; Nduati, Ruth; de Fatima Cuembelo, Maria; Wasserheit, Judith N.; Farquhar, Carey; Gloyd, Stephen; Sherr, Kenneth

2016-01-01

BACKGROUND Efficacious interventions to prevent mother-to-child HIV transmission (PMTCT) have not translated well into effective programs. Prior studies of systems engineering applications to PMTCT lacked comparison groups or randomization. METHODS Thirty-six health facilities in Côte d’Ivoire, Kenya, and Mozambique were randomized to usual care or a systems engineering intervention, stratified by country and volume. The intervention guided facility staff to iteratively identify and then rectify barriers to PMTCT implementation. Registry data quantified coverage of HIV testing during first antenatal care visit, antiretrovirals (ARVs) for HIV-positive pregnant women, and screening HIV-exposed infants (HEI) for HIV by 6–8 weeks. We compared the change between baseline (January 2013–January 2014) and post-intervention (January–March 2015) periods using t-tests. All analyses were intent-to-treat. RESULTS ARV coverage increased 3-fold (+13.3 percentage points [95% CI: 0.5, 26.0] in intervention vs. +4.1 [−12.6, 20.7] in control facilities) and HEI screening increased 17-fold (+11.6 [−2.6, 25.7] in intervention vs. +0.7 [−12.9, 14.4] in control facilities). In pre-specified sub-group analyses, ARV coverage increased significantly in Kenya (+20.9 [−3.1, 44.9] in intervention vs. −21.2 [−52.7, 10.4] in controls; p=0.02). HEI screening increased significantly in Mozambique (+23.1 [10.3, 35.8] in intervention vs. +3.7 [−13.1, 20.6] in controls; p=0.04). HIV testing did not differ significantly between arms. CONCLUSIONS In this first randomized trial of systems engineering to improve PMTCT, we saw substantially larger improvements in ARV coverage and HEI screening in intervention facilities compared to controls, which were significant in pre-specified sub-groups. Systems engineering could strengthen PMTCT service delivery and protect infants from HIV. PMID:27082507

Maternal anaemia and duration of zidovudine in antiretroviral regimens for preventing mother-to-child transmission: a randomized trial in three African countries.

PubMed

Sartorius, Benn K D; Chersich, Matthew F; Mwaura, Mary; Meda, Nicolas; Temmerman, Marleen; Newell, Marie Louise; Farley, Timothy M M; Luchters, Stanley

2013-11-06

Although substantiated by little evidence, concerns about zidovudine-related anaemia in pregnancy have influenced antiretroviral (ARV) regimen choice for preventing mother-to-child transmission of HIV-1, especially in settings where anaemia is common. Eligible HIV-infected pregnant women in Burkina Faso, Kenya and South Africa were followed from 28 weeks of pregnancy until 12-24 months after delivery (n = 1070). Women with a CD4 count of 200-500 cells/mm(3) and gestational age 28-36 weeks were randomly assigned to zidovudine-containing triple-ARV prophylaxis continued during breastfeeding up to 6-months, or to zidovudine during pregnancy plus single-dose nevirapine (sd-NVP) at labour. Additionally, two cohorts were established, women with CD4 counts: <200 cells/mm(3) initiated antiretroviral therapy, and >500 cells/mm(3) received zidovudine during pregnancy plus sd-NVP at labour. Mild (haemoglobin 8.0-10.9 g/dl) and severe anaemia (haemoglobin < 8.0 g/dl) occurrence were assessed across study arms, using Kaplan-Meier and multivariable Cox proportional hazards models. At enrolment (corresponded to a median 32 weeks gestation), median haemoglobin was 10.3 g/dl (IQR = 9.2-11.1). Severe anaemia occurred subsequently in 194 (18.1%) women, mostly in those with low baseline haemoglobin, lowest socio-economic category, advanced HIV disease, prolonged breastfeeding (≥ 6 months) and shorter ARV exposure. Severe anaemia incidence was similar in the randomized arms (equivalence P-value = 0.32). After 1-2 months of ARV's, severe anaemia was significantly reduced in all groups, though remained highest in the low CD4 cohort. Severe anaemia occurs at a similar rate in women receiving longer triple zidovudine-containing regimens or shorter prophylaxis. Pregnant women with pre-existing anaemia and advanced HIV disease require close monitoring. ISRCTN71468401.

Access to hepatitis C virus treatment: Lessons from implementation of strategies for increasing access to antiretroviral treatment.

PubMed

Assefa, Yibeltal; Hill, Peter S; Williams, Owain D

2018-05-01

At September's 2017 United Nations General Assembly, a state-of-the-art HIV medicine was announced to be made available at just $75 per person per year. There have been a number of strategies that the global AIDS community and countries have utilized to reduce prices and make antiretrovirals (ARVs) accessible for people living with HIV/AIDS. There appears to be an opportunity for the treatment of hepatitis C virus infection using direct-acting antivirals (DAAs) to benefit from the often painful and laboured history of driving down the prices of ARVs. In general, the success of lowering prices for ARVs has stemmed from the politics needed to initially support generic entry into the on-patent market. The use of flexibilities present in the World Trade Organization's Agreement on Trade-Related Aspects of Intellectual Property Rights (TRIPS) have been used to overcome patent barriers, with the use of compulsory licenses and/or the threat of their use as instruments for strengthening the bargaining power in price negotiations. These strategies have been combined with new financing mechanisms that have promoted more effective procurement and price negotiations. Partnership among the different stakeholders has also been critical in this regard. Countries have also invested in their health systems and implemented several strategies to reduce stigma and discrimination to increase access to and improve utilization of ARVs. This article suggests that any future international initiatives to increase access to DAAs can learn from these lessons surrounding price reduction, improved financing, advocacy, as well as health systems strengthening and stigma reduction. Adopting and reconfiguring these strategies will also incur substantial savings in time, money and lives. Crown Copyright © 2018. Published by Elsevier Ltd. All rights reserved.

Implementation and Operational Research: Impact of a Systems Engineering Intervention on PMTCT Service Delivery in Côte d'Ivoire, Kenya, Mozambique: A Cluster Randomized Trial.

PubMed

Rustagi, Alison Silvis; Gimbel, Sarah; Nduati, Ruth; Cuembelo, Maria de Fatima; Wasserheit, Judith N; Farquhar, Carey; Gloyd, Stephen; Sherr, Kenneth

2016-07-01

Efficacious interventions to prevent mother-to-child HIV transmission (PMTCT) have not translated well into effective programs. Previous studies of systems engineering applications to PMTCT lacked comparison groups or randomization. Thirty-six health facilities in Côte d'Ivoire, Kenya, and Mozambique were randomized to usual care or a systems engineering intervention, stratified by country and volume. The intervention guided facility staff to iteratively identify and then rectify barriers to PMTCT implementation. Registry data quantified coverage of HIV testing during first antenatal care visit, antiretrovirals (ARVs) for HIV-positive pregnant women, and screening HIV-exposed infants (HEI) for HIV by 6-8 weeks. We compared the change between baseline (January 2013-January 2014) and postintervention (January 2015-March 2015) periods using t-tests. All analyses were intent-to-treat. ARV coverage increased 3-fold [+13.3% points (95% CI: 0.5 to 26.0) in intervention vs. +4.1 (-12.6 to 20.7) in control facilities] and HEI screening increased 17-fold [+11.6 (-2.6 to 25.7) in intervention vs. +0.7 (-12.9 to 14.4) in control facilities]. In prespecified subgroup analyses, ARV coverage increased significantly in Kenya [+20.9 (-3.1 to 44.9) in intervention vs. -21.2 (-52.7 to 10.4) in controls; P = 0.02]. HEI screening increased significantly in Mozambique [+23.1 (10.3 to 35.8) in intervention vs. +3.7 (-13.1 to 20.6) in controls; P = 0.04]. HIV testing did not differ significantly between arms. In this first randomized trial of systems engineering to improve PMTCT, we saw substantially larger improvements in ARV coverage and HEI screening in intervention facilities compared with controls, which were significant in prespecified subgroups. Systems engineering could strengthen PMTCT service delivery and protect infants from HIV.

Morning pressor surge, blood pressure variability, and arterial stiffness in essential hypertension.

PubMed

Pucci, Giacomo; Battista, Francesca; Anastasio, Fabio; Schillaci, Giuseppe

2017-02-01

An excess morning blood pressure surge (MBPS) may portend an increased cardiovascular risk, but the mechanisms thereof have been little investigated. The link between MBPS, short-term blood pressure (BP) variability, and arterial stiffness has not been entirely defined. In 602 consecutive untreated hypertensive patients (48 ± 12 years, 61% men, office BP 149/93 ± 17/10 mmHg), we measured carotid-femoral pulse wave velocity (cf-PWV, SphygmoCor) and 24-h ambulatory BP. Using self-reported sleep and wake times, MBPS was defined as sleep-trough (ST-MBPS), prewaking, rising. Short-term BP variability was calculated as weighted 24-h SBP SD and average real variability of 24-h SBP (ARV), that is, average of absolute differences between consecutive SBP readings. ST-MBPS (r = 0.16, P < 0.001) and rising MBPS (r = 0.12, P = 0.003) showed a direct correlation with cf-PWV, whereas prewaking MBPS had no such relation (r = 0.06, P = 0.14). Only ST-MBPS was independently associated with cf-PWV (t = 1.96, P = 0.04) after adjustment for age, sex, height, office mean arterial pressure, heart rate, and renal function. This association was lost after further adjustment for weighted 24-h SBP SD (P = 0.13) or ARV (P = 0.24). ARV was a significant mediator of the relationship between ST-MBPS and cf-PWV (P = 0.003). In untreated hypertension, ST-MBPS has a direct relation with aortic stiffness, which is mediated by an increased ARV. The adverse effects of MBPS may be partly explained by its link with arterial stiffness, mediated by short-term SBP variability.

Results of Antiretroviral Treatment Interruption and Intensification in Advanced Multi-Drug Resistant HIV Infection from the OPTIMA Trial

PubMed Central

Holodniy, Mark; Brown, Sheldon T.; Cameron, D. William; Kyriakides, Tassos C.; Angus, Brian; Babiker, Abdel; Singer, Joel; Owens, Douglas K.; Anis, Aslam; Goodall, Ruth; Hudson, Fleur; Piaseczny, Mirek; Russo, John; Schechter, Martin; Deyton, Lawrence; Darbyshire, Janet

2011-01-01

Background Guidance is needed on best medical management for advanced HIV disease with multidrug resistance (MDR) and limited retreatment options. We assessed two novel antiretroviral (ARV) treatment approaches in this setting. Methods and Findings We conducted a 2×2 factorial randomized open label controlled trial in patients with a CD4 count ≤300 cells/µl who had ARV treatment (ART) failure requiring retreatment, to two options (a) re-treatment with either standard (≤4 ARVs) or intensive (≥5 ARVs) ART and b) either treatment starting immediately or after a 12-week monitored ART interruption. Primary outcome was time to developing a first AIDS-defining event (ADE) or death from any cause. Analysis was by intention to treat. From 2001 to 2006, 368 patients were randomized. At baseline, mean age was 48 years, 2% were women, median CD4 count was 106/µl, mean viral load was 4.74 log10 copies/ml, and 59% had a prior AIDS diagnosis. Median follow-up was 4.0 years in 1249 person-years of observation. There were no statistically significant differences in the primary composite outcome of ADE or death between re-treatment options of standard versus intensive ART (hazard ratio 1.17; CI 0.86–1.59), or between immediate retreatment initiation versus interruption before re-treatment (hazard ratio 0.93; CI 0.68–1.30), or in the rate of non-HIV associated serious adverse events between re-treatment options. Conclusions We did not observe clinical benefit or harm assessed by the primary outcome in this largest and longest trial exploring both ART interruption and intensification in advanced MDR HIV infection with poor retreatment options. Trial Registration Clinicaltrials.gov NCT00050089 PMID:21483491

The make or buy debate: considering the limitations of domestic production in Tanzania.

PubMed

Wilson, Kinsley Rose; Kohler, Jillian Clare; Ovtcharenko, Natalia

2012-06-29

In order to ensure their population's regular access to essential medicines, many least developed countries and developing countries are faced with the policy question of whether to import or manufacture drugs locally, in particular for life-saving antiretroviral medicines for HIV/AIDS patients. In order for domestic manufacturing to be viable and cost-effective, the local industry must be able to compete with international suppliers of medicines by producing sufficiently low cost ARVs. This paper considers the 'make-or-buy' dilemma by using Tanzania as a case study. Key informant interviews, event-driven observation, and purposive sampling of documents were used to evaluate the case study. The case study focused on Tanzania's imitation technology transfer agreement to locally manufacture a first-line ARV (3TC + d4T + NVP), reverse engineering the ARV. Tanzania is limited by weak political support for the use of TRIPS flexibilities, limited production capacity for ARVs and limited competitiveness in both domestic and regional markets. The Ministry of Health and Social Welfare encourages the use of flexibilities while others push for increased IP protection. Insufficient production capacity and lack of access to donor-financed tenders make it difficult to obtain economies of scale and provide competitive prices. Within the "make-or-buy" context, it was determined that there are significant limitations in domestic manufacturing for developing countries. The case study highlights the difficulty of governments to make use of economies of scale and produce low-cost medicines, attract technology transfer, and utilize the flexibilities of the WTO Agreement on Trade-Related Aspects of Intellectual Property Rights (TRIPS). The results demonstrate the importance of evaluating barriers to the use of TRIPS flexibilities and long-term planning across sectors in future technology transfer and manufacturing initiatives.

Contribution of different antiretroviral regimens containing zidovudine, lamivudine and ritonavir-boosted lopinavir on HIV viral load reduction during pregnancy.

PubMed

Sripan, Patumrat; Le Coeur, Sophie; Ingsrisawang, Lily; Cressey, Tim R; Bouazza, Naïm; Foissac, Frantz; Ngo-Giang-Huong, Nicole; Traisathit, Patrinee; Srirompotong, Ussanee; Ayudhaya, Orada Patamasingh Na; Puangsombat, Achara; Jungpipun, Jantana; Jittayanun, Kanokwan; Tréluyer, Jean-Marc; Jourdain, Gonzague; Lallemant, Marc; Urien, Saïk

2016-01-01

Antiretroviral (ARV) regimens used for the prevention of mother-to-child transmission of HIV have evolved over time. We evaluated the contribution of different ARV regimens on the reduction of the plasma HIV RNA viral load (VL) during pregnancy. A total of 1,833 VL measurements from ARV-naive pregnant women participating in perinatal prevention trials in Thailand were included. Women received either zidovudine (ZDV) monotherapy, ZDV plus lopinavir/ritonavir (LPV/r), or ZDV plus lamivudine (3TC) plus LPV/r. VL time-course during pregnancy was described as a function of pretreatment VL and treatment duration using an Emax non-linear mixed-effect model. VL reduction and median time to achieve a VL<50 copies/ml were estimated for each regimen. Among 745 women, 279 (37%), 145 (20%) and 321 (43%) received ZDV monotherapy, ZDV+LPV/r and ZDV+3TC+LPV/r, respectively. The predicted VL reduction from baseline to delivery after a median of 10 weeks of treatment were 0.5, 2.7 and 2.9 log10 copies/ml with ZDV monotherapy, ZDV+LPV/r and ZDV+3TC+LPV/r, respectively. At delivery, 1%, 57% and 63% of women receiving ZDV monotherapy, ZDV+LPV/r or ZDV+3TC+LPV/r had a VL<50 copies/ml. The addition of 3TC to ZDV+LPV/r reduced the time to achieve a VL<50 copies/ml and the higher the pretreatment VL, the larger the effect 3TC had on reducing the time to VL<50 copies/ml. The addition of 3TC to ZDV+LPV/r was associated with a slight further VL reduction but the time to reach a VL<50 copies/ml was shorter. This beneficial effect of 3TC is crucial for prevention of mother-to-child transmission in women who receive ARVs late and with high pretreatment VL.

Lack of pre-antiretroviral care and competition from traditional healers, crucial risk factors for very late initiation of antiretroviral therapy for HIV--a case-control study from eastern Uganda.

PubMed

Muhamadi, Lubega; Tumwesigye, Nazarius Mbona; Kadobera, Daniel; Marrone, Gaetano; Wabwire-Mangen, Fred; Pariyo, George; Peterson, Stefan; Ekström, Anna Mia

2011-01-01

Although WHO recommends starting antiretroviral treatment at a CD4 count of 350 cells/[µ]L, many Ugandan districts still struggle with large proportions of clients initiating ART very late at CD4<50 cells/[µ]L. This study seeks to establish crucial risk factors for very late ART initiation in eastern Uganda. All adult HIV-infected clients on ART in Iganga who enrolled between 2005 and 2009 were eligible for this case-control study. Clients who started ART at CD4 cell count of <50 cells/[µ]L (very late initiators) were classified as cases and 50-200 cells/[µ]L (late initiators) as control subjects. A total of 152 cases and 202 controls were interviewed. Multivariate analyses were performed to calculate adjusted odds ratios and 95% confidence intervals. Reported health system-related factors associated with very late ART initiation were stock-outs of antiretroviral drugs stock-outs (affecting 70% of the cases and none of the controls), competition from traditional/spiritual healers (AOR 7.8, 95 CI% 3.7-16.4), and lack of pre-ARV care (AOR 4.6, 95% CI: 2.3-9.3). Men were 60% more likely and subsistence farmers six times more likely (AOR 6.3, 95% CI: 3.1-13.0) to initiate ART very late. Lack of family support tripled the risk of initiating ART very late (AOR 3.3, 95% CI: 1.6-6.6). Policy makers should prevent ARV stock-outs though effective ARV procurement and supply chain management. New HIV clients should seek pre-ARV care for routine monitoring and determination of ART eligibility. ART services should be more affordable, accessible and user-friendly to make them more attractive than traditional healers.

Geographic and Temporal Trends in the Molecular Epidemiology and Genetic Mechanisms of Transmitted HIV-1 Drug Resistance: An Individual-Patient- and Sequence-Level Meta-Analysis

PubMed Central

Rhee, Soo-Yon; Blanco, Jose Luis; Jordan, Michael R.; Taylor, Jonathan; Lemey, Philippe; Varghese, Vici; Hamers, Raph L.; Bertagnolio, Silvia; de Wit, Tobias F. Rinke; Aghokeng, Avelin F.; Albert, Jan; Avi, Radko; Avila-Rios, Santiago; Bessong, Pascal O.; Brooks, James I.; Boucher, Charles A. B.; Brumme, Zabrina L.; Busch, Michael P.; Bussmann, Hermann; Chaix, Marie-Laure; Chin, Bum Sik; D’Aquin, Toni T.; De Gascun, Cillian F.; Derache, Anne; Descamps, Diane; Deshpande, Alaka K.; Djoko, Cyrille F.; Eshleman, Susan H.; Fleury, Herve; Frange, Pierre; Fujisaki, Seiichiro; Harrigan, P. Richard; Hattori, Junko; Holguin, Africa; Hunt, Gillian M.; Ichimura, Hiroshi; Kaleebu, Pontiano; Katzenstein, David; Kiertiburanakul, Sasisopin; Kim, Jerome H.; Kim, Sung Soon; Li, Yanpeng; Lutsar, Irja; Morris, Lynn; Ndembi, Nicaise; NG, Kee Peng; Paranjape, Ramesh S.; Peeters, Martine; Poljak, Mario; Price, Matt A.; Ragonnet-Cronin, Manon L.; Reyes-Terán, Gustavo; Rolland, Morgane; Sirivichayakul, Sunee; Smith, Davey M.; Soares, Marcelo A.; Soriano, Vincent V.; Ssemwanga, Deogratius; Stanojevic, Maja; Stefani, Mariane A.; Sugiura, Wataru; Sungkanuparph, Somnuek; Tanuri, Amilcar; Tee, Kok Keng; Truong, Hong-Ha M.; van de Vijver, David A. M. C.; Vidal, Nicole; Yang, Chunfu; Yang, Rongge; Yebra, Gonzalo; Ioannidis, John P. A.; Vandamme, Anne-Mieke; Shafer, Robert W.

2015-01-01

Background Regional and subtype-specific mutational patterns of HIV-1 transmitted drug resistance (TDR) are essential for informing first-line antiretroviral (ARV) therapy guidelines and designing diagnostic assays for use in regions where standard genotypic resistance testing is not affordable. We sought to understand the molecular epidemiology of TDR and to identify the HIV-1 drug-resistance mutations responsible for TDR in different regions and virus subtypes. Methods and Findings We reviewed all GenBank submissions of HIV-1 reverse transcriptase sequences with or without protease and identified 287 studies published between March 1, 2000, and December 31, 2013, with more than 25 recently or chronically infected ARV-naïve individuals. These studies comprised 50,870 individuals from 111 countries. Each set of study sequences was analyzed for phylogenetic clustering and the presence of 93 surveillance drug-resistance mutations (SDRMs). The median overall TDR prevalence in sub-Saharan Africa (SSA), south/southeast Asia (SSEA), upper-income Asian countries, Latin America/Caribbean, Europe, and North America was 2.8%, 2.9%, 5.6%, 7.6%, 9.4%, and 11.5%, respectively. In SSA, there was a yearly 1.09-fold (95% CI: 1.05–1.14) increase in odds of TDR since national ARV scale-up attributable to an increase in non-nucleoside reverse transcriptase inhibitor (NNRTI) resistance. The odds of NNRTI-associated TDR also increased in Latin America/Caribbean (odds ratio [OR] = 1.16; 95% CI: 1.06–1.25), North America (OR = 1.19; 95% CI: 1.12–1.26), Europe (OR = 1.07; 95% CI: 1.01–1.13), and upper-income Asian countries (OR = 1.33; 95% CI: 1.12–1.55). In SSEA, there was no significant change in the odds of TDR since national ARV scale-up (OR = 0.97; 95% CI: 0.92–1.02). An analysis limited to sequences with mixtures at less than 0.5% of their nucleotide positions—a proxy for recent infection—yielded trends comparable to those obtained using the complete dataset. Four

Geographic and temporal trends in the molecular epidemiology and genetic mechanisms of transmitted HIV-1 drug resistance: an individual-patient- and sequence-level meta-analysis.

PubMed

Rhee, Soo-Yon; Blanco, Jose Luis; Jordan, Michael R; Taylor, Jonathan; Lemey, Philippe; Varghese, Vici; Hamers, Raph L; Bertagnolio, Silvia; Rinke de Wit, Tobias F; Aghokeng, Avelin F; Albert, Jan; Avi, Radko; Avila-Rios, Santiago; Bessong, Pascal O; Brooks, James I; Boucher, Charles A B; Brumme, Zabrina L; Busch, Michael P; Bussmann, Hermann; Chaix, Marie-Laure; Chin, Bum Sik; D'Aquin, Toni T; De Gascun, Cillian F; Derache, Anne; Descamps, Diane; Deshpande, Alaka K; Djoko, Cyrille F; Eshleman, Susan H; Fleury, Herve; Frange, Pierre; Fujisaki, Seiichiro; Harrigan, P Richard; Hattori, Junko; Holguin, Africa; Hunt, Gillian M; Ichimura, Hiroshi; Kaleebu, Pontiano; Katzenstein, David; Kiertiburanakul, Sasisopin; Kim, Jerome H; Kim, Sung Soon; Li, Yanpeng; Lutsar, Irja; Morris, Lynn; Ndembi, Nicaise; Ng, Kee Peng; Paranjape, Ramesh S; Peeters, Martine; Poljak, Mario; Price, Matt A; Ragonnet-Cronin, Manon L; Reyes-Terán, Gustavo; Rolland, Morgane; Sirivichayakul, Sunee; Smith, Davey M; Soares, Marcelo A; Soriano, Vincent V; Ssemwanga, Deogratius; Stanojevic, Maja; Stefani, Mariane A; Sugiura, Wataru; Sungkanuparph, Somnuek; Tanuri, Amilcar; Tee, Kok Keng; Truong, Hong-Ha M; van de Vijver, David A M C; Vidal, Nicole; Yang, Chunfu; Yang, Rongge; Yebra, Gonzalo; Ioannidis, John P A; Vandamme, Anne-Mieke; Shafer, Robert W

2015-04-01

Regional and subtype-specific mutational patterns of HIV-1 transmitted drug resistance (TDR) are essential for informing first-line antiretroviral (ARV) therapy guidelines and designing diagnostic assays for use in regions where standard genotypic resistance testing is not affordable. We sought to understand the molecular epidemiology of TDR and to identify the HIV-1 drug-resistance mutations responsible for TDR in different regions and virus subtypes. We reviewed all GenBank submissions of HIV-1 reverse transcriptase sequences with or without protease and identified 287 studies published between March 1, 2000, and December 31, 2013, with more than 25 recently or chronically infected ARV-naïve individuals. These studies comprised 50,870 individuals from 111 countries. Each set of study sequences was analyzed for phylogenetic clustering and the presence of 93 surveillance drug-resistance mutations (SDRMs). The median overall TDR prevalence in sub-Saharan Africa (SSA), south/southeast Asia (SSEA), upper-income Asian countries, Latin America/Caribbean, Europe, and North America was 2.8%, 2.9%, 5.6%, 7.6%, 9.4%, and 11.5%, respectively. In SSA, there was a yearly 1.09-fold (95% CI: 1.05-1.14) increase in odds of TDR since national ARV scale-up attributable to an increase in non-nucleoside reverse transcriptase inhibitor (NNRTI) resistance. The odds of NNRTI-associated TDR also increased in Latin America/Caribbean (odds ratio [OR] = 1.16; 95% CI: 1.06-1.25), North America (OR = 1.19; 95% CI: 1.12-1.26), Europe (OR = 1.07; 95% CI: 1.01-1.13), and upper-income Asian countries (OR = 1.33; 95% CI: 1.12-1.55). In SSEA, there was no significant change in the odds of TDR since national ARV scale-up (OR = 0.97; 95% CI: 0.92-1.02). An analysis limited to sequences with mixtures at less than 0.5% of their nucleotide positions—a proxy for recent infection—yielded trends comparable to those obtained using the complete dataset. Four NNRTI SDRMs—K101E, K103N, Y181C, and G190A�

Cumulative Antiretroviral Exposure Measured in Hair Is Not Associated With Measures of HIV Persistence or Inflammation Among Individuals on Suppressive ART.

PubMed

Gandhi, Monica; Gandhi, Rajesh T; Stefanescu, Andrei; Bosch, Ronald J; Cyktor, Joshua C; Horng, Howard; Louie, Alexander; Phung, Nhi; Eron, Joseph J; Hogg, Evelyn; Macatangay, Bernard J C; Hensel, Christopher; Fletcher, Courtney V; Mellors, John W; McMahon, Deborah K

2018-06-20

Data on the relationship of antiretroviral exposure to measures of human immunodeficiency virus (HIV) persistence are limited. To address this gap, multiple viral, immunologic, and pharmacologic measures were analyzed from individuals with sustained virologic suppression on therapy (median 7 years) in the AIDS Clinical Trials Group A5321 cohort. Among 110 participants on tenofovir-(TFV)-disoproxil-fumarate (TDF)/emtricitabine (FTC)-containing regimens, we found no significant correlation between hair concentrations of individual antiretrovirals (ARVs) in the regimen and measures of HIV persistence (plasma HIV-1 RNA by single copy assay, cell-associated-DNA, cell-associated RNA) or soluble markers of inflammation. These findings suggest that higher systemic ARV exposure may not impact HIV persistence or inflammation.

[Initial antiretroviral treatment in human immunodeficiency virus-infected patients in Spain: Decisions made in relation to particular immunovirological characteristics (PERFIL-es study)].

PubMed

Viciana, Pompeyo; Ocampo, Antonio; Hevia, Henar; Palazuelos, Marta; Ledesma, Francisco

2014-02-01

The purpose of Perfil-es study was to identify the proportion of patients starting ARV treatment based on NNRTIs or PI/r, and to identify the variables involved in the therapeutic decision-making in standard clinical practice. An observational retrospective study performed in 65 Spanish hospitals. Was a total of 1,687 starts: 53% with NNRTI-based regimen and 42% with PI/r, and of the 642 patients analyzed, 72% had a CD4 count<350 cells/μl. The initiation of ARV treatment is still late in Spain. NNRTIs are the more frequent choice, although PI/r plays an important role. Copyright © 2012 Elsevier España, S.L. All rights reserved.

Perinatal exposure of patas monkeys to antiretroviral nucleoside reverse-transcriptase inhibitors induces genotoxicity persistent for up to 3 years of age.

PubMed

Olivero, Ofelia A; Torres, Lorangelly Rivera; Gorjifard, Sayeh; Momot, Dariya; Marrogi, Eryney; Divi, Rao L; Liu, Yongmin; Woodward, Ruth A; Sowers, Marsha J; Poirier, Miriam C

2013-07-15

Erythrocebus patas (patas) monkeys were used to model antiretroviral (ARV) drug in human immunodeficiency virus type 1-infected pregnant women. Pregnant patas dams were given human-equivalent doses of ARVs daily during 50% of gestation. Mesenchymal cells, cultured from bone marrow of patas offspring obtained at birth and at 1 and 3 years of age, were examined for genotoxicity, including centrosomal amplification, micronuclei, and micronuclei containing whole chromosomes. Compared with controls, statistically significant increases (P < .05) in centrosomal amplification, micronuclei, and micronuclei containing whole chromosomes were found in mesenchymal cells from most groups of offspring at the 3 time points. Transplacental nucleoside reverse-transcriptase inhibitor exposures induced fetal genotoxicity that was persistent for 3 years.

JPRS Report, East Europe

DTIC Science & Technology

1990-11-29

subject of parliamentary debate. At that time there was serious talk about recognizing the Jewry as a minority. And another reminder: The Lauder Javne...assimilating group will protest in vain, because judging by the statement and instant success of the Lauder Javne school there indeed exists a Jewry in...Szabo] Money , money , money . [Verebelyi] I know, everyone would want to milk the Treasury. Of course, central aid is also needed, but we have much

Behavioral Variability, Learning Processes, and Creativity

DTIC Science & Technology

1992-03-01

socio- logiques, 6conomiques ou iddologiques auxquels n𔄀chappent pas les entreprises dducatives. Nous retrouvons IA trois themes de d~bat assez courants...pour ne pas dire traditionnels, dans les milieux pidagogiques, trois arguments que I’on pourrait reforinuler de la maniere suivante: 1 . Les...vain de concevoir I’enseignement comme un domaine d’ap- plication de la psychologie de I’apprentissage. Sans doute aucune de ces trois propositions ne

[Antiretroviral drug supply in Argentina: National Program to Combat Human Retroviruses, AIDS, and STDs].

PubMed

Colautti, Marisel; Luppi, Irene; Salamano, Mercedes; Traverso, María Luz; Botta, Carina; Palchik, Valeria

2009-01-01

To evaluate the supply cycle of antiretroviral (ARV) drugs, overseen by the National Program to Combat Human Retroviruses, AIDS, and STDs, through its order fulfillment indicators, and to obtain input from supply chain stakeholders. A study was carried out from April-September 2005 in the pharmacies of two hospitals in Rosario, Argentina, involving both a quantitative analysis of indicators and secondary sources and a qualitative evaluation using semistructured interviews. The indicators reveal the impact that interruptions in ARV supply stream from the Program (central level) have and the overstocking that takes place at the pharmacies (local level) to manage the shortages. Changes in ARV treatment account for over 50% of the prescriptions. Fulfillments fall short of the reference value. The interviewees shared possible strategies for overcoming the communication gaps between levels, for building-up stock, for guaranteeing availability, and for shortening waiting times; reached informal agreements to deal with the lack of policies and the shortage of staff; acknowledged the challenges facing the jurisdictions (central, intermediate, and local/community); and recognized local efforts to improve management. These challenges could be the starting point for building teams to work on effectively decentralizing the entire supply chain and allowing the Program to fulfill its much-needed oversight role.

Optimizing content for pre-exposure prophylaxis (PrEP) counseling for men who have sex with men: Perspectives of PrEP users and high-risk PrEP naïve men.

PubMed

Wade Taylor, S; Mayer, Kenneth H; Elsesser, Steven M; Mimiaga, Matthew J; O'Cleirigh, Conall; Safren, Steven A

2014-05-01

Existing trials of antiretroviral (ARV) medication as chemoprophylaxis against HIV reveal that the degree of protection is primarily dependent on product adherence. However, there is a lack of data on targets for behavioral interventions to improve adherence to ARV as prevention. Information from individuals who have used ARV as pre-exposure prophylaxis (PrEP) can inform behavioral intervention development. Thirty-nine HIV-uninfected MSM at high risk for HIV acquisition participated in one of four semi-structured focus groups. Two of the focus groups consisted of MSM who had been prescribed and used PrEP in the context of a clinical trial; the other two consisted of high-risk MSM who had not previously used PrEP. An in-depth, within-case/across-case content analysis resulted in six descriptive themes potentially salient for a PrEP adherence behavioral intervention: (1) motivations to use PrEP, (2) barriers to PrEP use, (3) facilitators to PrEP use, (4) sexual decision-making in the context of PrEP, (5) prospective PrEP education content, and, (6) perceived effective characteristics of PrEP delivery personnel. Addressing these themes in behavioral interventions in the context of prescribing PrEP may result in the optimal "packaging" public health programs that implement PrEP for high-risk MSM.

Correlation between Lymphocyte CD4 Count, Treatment Duration, Opportunistic Infection and Cognitive Function in Human Immunodeficiency Virus-Acquired Immunodeficiency Syndrome (HIV-AIDS) Patients.

PubMed

Fitri, Fasihah Irfani; Rambe, Aldy Safruddin; Fitri, Aida

2018-04-15

Human immunodeficiency virus (HIV) infection is an epidemic worldwide, despite the marked benefits of antiretroviral therapy (ARV) in reducing severe HIV-associated dementia. A milder form of neurocognitive disorders are still prevalent and remain a challenge. This study aimed to determine the correlation between plasma cluster of differentiation 4 (CD4) lymphocyte, duration of ARV treatment, opportunistic infections, and cognitive function in HIV-AIDS patients. A cross-sectional study involving 85 HIV-AIDS patients was conducted at Adam Malik General Hospital Medan, Indonesia. All subjects were subjected to physical, neurologic examination and Montreal Cognitive Assessment-Indonesian Version (MoCA-INA) to assess cognitive function and measurement of lymphocyte CD4 counts. Out of the 85 subjects evaluated, the proportion concerning sexes include 52 males (61.2 %) and 33 females (38.8%). The mean age was 38.53 ± 9.77 years old. There was a significant correlation between CD4 lymphocyte counts and MoCA-INA score (r = 0.271, p = 0.012), but there was no significant correlation between duration of ARV treatment and MoCA-INA score. There was also no difference in MoCA-INA score based on the presence of opportunistic infection. Lymphocyte CD4 count was independently correlated with cognitive function in HIV-AIDS patients.

Economic modeling of HIV treatments.

PubMed

Simpson, Kit N

2010-05-01

To review the general literature on microeconomic modeling and key points that must be considered in the general assessment of economic modeling reports, discuss the evolution of HIV economic models and identify models that illustrate this development over time, as well as examples of current studies. Recommend improvements in HIV economic modeling. Recent economic modeling studies of HIV include examinations of scaling up antiretroviral (ARV) in South Africa, screening prior to use of abacavir, preexposure prophylaxis, early start of ARV in developing countries and cost-effectiveness comparisons of specific ARV drugs using data from clinical trials. These studies all used extensively published second-generation Markov models in their analyses. There have been attempts to simplify approaches to cost-effectiveness estimates by using simple decision trees or cost-effectiveness calculations with short-time horizons. However, these approaches leave out important cumulative economic effects that will not appear early in a treatment. Many economic modeling studies were identified in the 'gray' literature, but limited descriptions precluded an assessment of their adherence to modeling guidelines, and thus to the validity of their findings. There is a need for developing third-generation models to accommodate new knowledge about adherence, adverse effects, and viral resistance.

Production of antiretroviral drugs in middle- and low-income countries.

PubMed

Pinheiro, Eloan dos Santos; Brüning, Karin; Macedo, M Fernanda; Siani, Antonio C

2014-01-01

This review outlines the main issues concerning the production of antiretroviral (ARV) drugs in middle- and low-income countries and the relevant political, legal and technical requirements for supporting such production. The requirements for efficient local production, including the manufacture of generic and branded products and public demand, have been considered from economic, market and socio-political perspectives. A steady and consistent government policy is crucial to success. Additional crucial factors in establishing local production are adequate infrastructure, qualified human resources in technical and managerial areas, and production-distribution logistics systems. The creation or strengthening of a national drug regulatory agency is a basic requirement. Production of ARVs relies on the structure of the international market for active pharmaceutical ingredients (APIs), which are highly monopolized for inclusion in branded or patented drugs, or are concentrated in a few Asian generic companies. Countries seeking to begin local production must develop strategies to overcome the various barriers. For instance, sub-Saharan African countries may benefit from developing multilateral health agreements with neighbouring countries. Such agreements are recommended and should be complemented by technology transfers, especially for the manufacture of APIs. Achieving a production level that is sustainable in the long term is crucial to maintaining patients' access to ARVs.

Individualized texting for adherence building (iTAB): improving antiretroviral dose timing among HIV-infected persons with co-occurring bipolar disorder.

PubMed

Moore, David J; Poquette, Amelia; Casaletto, Kaitlin B; Gouaux, Ben; Montoya, Jessica L; Posada, Carolina; Rooney, Alexandra S; Badiee, Jayraan; Deutsch, Reena; Letendre, Scott L; Depp, Colin A; Grant, Igor; Atkinson, J Hampton

2015-03-01

HIV+ persons with co-occurring bipolar disorder (HIV+/BD+) have elevated rates of medication nonadherence. We conducted a 30-day randomized controlled trial of a two-way, text messaging system, iTAB (n = 25), compared to an active comparison (CTRL) (n = 25) to improve antiretroviral (ARV) and psychotropic (PSY) adherence and dose timing. Both groups received medication adherence psychoeducation and daily texts assessing mood. The iTAB group additionally received personalized medication reminder texts. Participants responded to over 90 % of the mood and adherence text messages. Mean adherence, as assessed via electronic monitoring caps, was high and comparable between groups for both ARV (iTAB 86.2 % vs. CTRL 84.8 %; p = 0.95, Cliff's d = 0.01) and PSY (iTAB 78.9 % vs. CTRL 77.3 %; p = 0.43, Cliff's d = -0.13) medications. However, iTAB participants took ARVs significantly closer to their intended dosing time than CTRL participants (iTAB: 27.8 vs. CTRL: 77.0 min from target time; p = 0.02, Cliff's d = 0.37). There was no group difference on PSY dose timing. Text messaging interventions may represent a low-burden approach to improving timeliness of medication-taking behaviors among difficult-to-treat populations. The benefits of improved dose timing for long-term medication adherence require additional investigation.

Synergistic vulnerabilities: antiretroviral treatment among women in Uganda.

PubMed

Winchester, Margaret S

2015-01-01

Despite being an early success story in the reduction of HIV infection rates, Uganda faces myriad challenges in the recent era of accelerated antiretroviral treatment (ARV) scale-up. For those able to access treatment, ongoing vulnerabilities of poverty and violence compound treatment-related costs and concerns. This paper explores experiences of one particularly vulnerable population - women on ARVs who have also experienced intimate partner violence (IPV). Data were collected over 12 months in Uganda. They include ethnographic interviews (n = 40) drawn from a larger sample of women on ARV and semi-structured interviews with policy-makers and service providers (n = 42), examining the intersection of experiences and responses to treatment from multiple perspectives. Women's narratives show that due to treatment, immediate health concerns take on secondary importance, while other forms of vulnerability, including IPV and poverty, can continue to shape treatment experiences and the decision to stay in violent relationships. Providers likewise face difficulties in overburdened clinics, though they recognise women's concerns and the importance of considering other forms of vulnerability in treatment. This analysis makes the case for integrating treatment with other types of social services and demonstrates the importance of understanding the ways in which synergistic and compounding vulnerabilities confound treatment scale-up efforts.

The role of drugs in HIV prevention

NASA Astrophysics Data System (ADS)

Kembaren, T.

2018-03-01

WHO reports 36.7 million people are living with Human Immunodeficiency Virus (HIV) worldwide by 2016 with about 1.8 million new infections each year. It will be a specific health problem for the world in both developed and developing countries so it is necessary strategies to reduce HIV transmission to the community. HIV transmission in people with risk factors is largely determined by the amount of virus in the blood of people who are the source of infection. Antiretroviral (ARV) therapy has long been used in HIV patients, which serves to suppress viral replication so that the patient’s immunity increases; opportunistic infections are resolved and prolong the lifespan and lower transmission rates. In the HIV Prevention Trials Network (HPTN) study 052 there was a 96% reduction in transmission in earlier antiretroviral. ARV is also used in the prevention of transmission in people exposed to HIV virus that is Postexposure Prophylaxis as well as in people at risk before exposure (Pre-exposure Prophylaxis). Three prevention strategies with the provision of ARV is expected to be guided as a means of prevention of transmission in addition to behavioral changes has long been declared since the beginning of the HIV epidemic.

Towards nanomedicines for neuro-AIDS

PubMed Central

Sagar, Vidya; Pilakka-Kanthikeel, Sudheesh; Pottathil, Ravi; Saxena, Shailendra K; Nair, Madhavan

2014-01-01

Although Highly Active Antiretroviral Therapy (HAART) has resulted in remarkable decline in the morbidity and mortality in AIDS Patients, controlling HIV infections still remain a global health priority. HIV access to the central nervous system (CNS) serves as the natural viral preserve because most anti-retro viral (ARV) drugs possess inadequate or zero delivery across the brain barriers. Thus, development of target-specific, effective, safe and controllable drug-delivery approach is an important health priority for global elimination of AIDS progression. Emergence of nanotechnology in medicine has shown exciting prospect for development of novel drug delivery systems to administer the desired therapeutic levels of ARV drugs in the CNS. Neuron-resuscitating and/or anti-dependence agents may also be delivered in the brain though nanocarriers to countercheck the rate of neuronal degradation during HIV infection. Several nanovehicles such as liposomes, dendrimers, polymeric nanoparticles, micelles, solid lipid nanoparticles, etc. have been intensively explored. Recently, magnetic nanoparticles and monocytes/macrophages have also been used as carrier to improve the delivery of nanoformulated ARV drugs across the blood-brain barrier (BBB). Nevertheless, more rigorous research-homework has to be elucidated to sort out the shortcomings that affect the target specificity, delivery, release and/or bioavailability of desired amount of drugs for treatment of neuroAIDS. PMID:24395761

Human papillomavirus prevalence, viral load and pre-cancerous lesions of the cervix in women initiating highly active antiretroviral therapy in South Africa: a cross-sectional study.

PubMed

Moodley, Jennifer R; Constant, Deborah; Hoffman, Margaret; Salimo, Anna; Allan, Bruce; Rybicki, Ed; Hitzeroth, Inga; Williamson, Anna-Lise

2009-08-07

Cervical cancer and infection with human immunodeficiency virus (HIV) are both important public health problems in South Africa (SA). The aim of this study was to determine the prevalence of cervical squamous intraepithelial lesions (SILs), high-risk human papillomavirus (HR-HPV), HPV viral load and HPV genotypes in HIV positive women initiating anti-retroviral (ARV) therapy. A cross-sectional survey was conducted at an anti-retroviral (ARV) treatment clinic in Cape Town, SA in 2007. Cervical specimens were taken for cytological analysis and HPV testing. The Digene Hybrid Capture 2 (HC2) test was used to detect HR-HPV. Relative light units (RLU) were used as a measure of HPV viral load. HPV types were determined using the Roche Linear Array HPV Genotyping test. Crude associations with abnormal cytology were tested and multiple logistic regression was used to determine independent risk factors for abnormal cytology. The median age of the 109 participants was 31 years, the median CD4 count was 125/mm3, 66.3% had an abnormal Pap smear, the HR-HPV prevalence was 78.9% (Digene), the median HPV viral load was 181.1 RLU (HC2 positive samples only) and 78.4% had multiple genotypes. Among women with abnormal smears the most prevalent HR-HPV types were HPV types 16, 58 and 51, all with a prevalence of 28.5%. On univariate analysis HR-HPV, multiple HPV types and HPV viral load were significantly associated with the presence of low and high-grade SILs (LSIL/HSIL). The multivariate logistic regression showed that HPV viral load was associated with an increased odds of LSIL/HSIL, odds ratio of 10.7 (95% CI 2.0 - 57.7) for those that were HC2 positive and had a viral load of 181.1 RLU. Women initiating ARVs have a high prevalence of abnormal Pap smears and HR-HPV. Our results underscore the need for locally relevant, rigorous screening protocols for

Superior Efficacy of a Human Immunodeficiency Virus Vaccine Combined with Antiretroviral Prevention in Simian-Human Immunodeficiency Virus-Challenged Nonhuman Primates.

PubMed

Le Grand, Roger; Dereuddre-Bosquet, Nathalie; Dispinseri, Stefania; Gosse, Leslie; Desjardins, Delphine; Shen, Xiaoying; Tolazzi, Monica; Ochsenbauer, Christina; Saidi, Hela; Tomaras, Georgia; Prague, Mélanie; Barnett, Susan W; Thiebaut, Rodolphe; Cope, Alethea; Scarlatti, Gabriella; Shattock, Robin J

2016-06-01

Although vaccines and antiretroviral (ARV) prevention have demonstrated partial success against human immunodeficiency virus (HIV) infection in clinical trials, their combined introduction could provide more potent protection. Furthermore, combination approaches could ameliorate the potential increased risk of infection following vaccination in the absence of protective immunity. We used a nonhuman primate model to determine potential interactions of combining a partially effective ARV microbicide with an envelope-based vaccine. The vaccine alone provided no protection from infection following 12 consecutive low-dose intravaginal challenges with simian-HIV strain SF162P3, with more animals infected compared to naive controls. The microbicide alone provided a 68% reduction in the risk of infection relative to that of the vaccine group and a 45% reduction relative to that of naive controls. The vaccine-microbicide combination provided an 88% reduction in the per-exposure risk of infection relative to the vaccine alone and a 79% reduction relative to that of the controls. Protected animals in the vaccine-microbicide group were challenged a further 12 times in the absence of microbicide and demonstrated a 98% reduction in the risk of infection. A total risk reduction of 91% was observed in this group over 24 exposures (P = 0.004). These important findings suggest that combined implementation of new biomedical prevention strategies may provide significant gains in HIV prevention. There is a pressing need to maximize the impact of new biomedical prevention tools in the face of the 2 million HIV infections that occur each year. Combined implementation of complementary biomedical approaches could create additive or synergistic effects that drive improved reduction of HIV incidence. Therefore, we assessed a combination of an untested vaccine with an ARV-based microbicide in a nonhuman primate vaginal challenge model. The vaccine alone provided no protection (and may have

Superior Efficacy of a Human Immunodeficiency Virus Vaccine Combined with Antiretroviral Prevention in Simian-Human Immunodeficiency Virus-Challenged Nonhuman Primates

PubMed Central

Le Grand, Roger; Dereuddre-Bosquet, Nathalie; Dispinseri, Stefania; Gosse, Leslie; Desjardins, Delphine; Shen, Xiaoying; Tolazzi, Monica; Ochsenbauer, Christina; Saidi, Hela; Tomaras, Georgia; Prague, Mélanie; Barnett, Susan W.; Thiebaut, Rodolphe; Scarlatti, Gabriella

2016-01-01

ABSTRACT Although vaccines and antiretroviral (ARV) prevention have demonstrated partial success against human immunodeficiency virus (HIV) infection in clinical trials, their combined introduction could provide more potent protection. Furthermore, combination approaches could ameliorate the potential increased risk of infection following vaccination in the absence of protective immunity. We used a nonhuman primate model to determine potential interactions of combining a partially effective ARV microbicide with an envelope-based vaccine. The vaccine alone provided no protection from infection following 12 consecutive low-dose intravaginal challenges with simian-HIV strain SF162P3, with more animals infected compared to naive controls. The microbicide alone provided a 68% reduction in the risk of infection relative to that of the vaccine group and a 45% reduction relative to that of naive controls. The vaccine-microbicide combination provided an 88% reduction in the per-exposure risk of infection relative to the vaccine alone and a 79% reduction relative to that of the controls. Protected animals in the vaccine-microbicide group were challenged a further 12 times in the absence of microbicide and demonstrated a 98% reduction in the risk of infection. A total risk reduction of 91% was observed in this group over 24 exposures (P = 0.004). These important findings suggest that combined implementation of new biomedical prevention strategies may provide significant gains in HIV prevention. IMPORTANCE There is a pressing need to maximize the impact of new biomedical prevention tools in the face of the 2 million HIV infections that occur each year. Combined implementation of complementary biomedical approaches could create additive or synergistic effects that drive improved reduction of HIV incidence. Therefore, we assessed a combination of an untested vaccine with an ARV-based microbicide in a nonhuman primate vaginal challenge model. The vaccine alone provided no

The Coast Artillery Journal. Volume 83, Number 3, May-June 1940

DTIC Science & Technology

1940-06-01

remembers But the badly shattered rankswere incapable of immediate his troops and issues a Special Order: "The Major Gen - consolidation, so the...popular fanc )’ was a boule- vardier who wore a waxy black mus- tache and a pointed black beard; he was an effeminate, vain, and to Eng- lish and American...D. C. Lieutcnant Colonel \\V. C. Footc, to Gen - eral Staff Corps, 6th Corps Arca. l.ieutenant Colonel Ferdinand F. Gallag- her, to instructor

Train in vain: the role of the self in claimed self-handicapping strategies.

PubMed

Finez, Lucie; Sherman, David K

2012-10-01

Two field studies investigate the role of self in the tendency of athletes to engage in claimed handicapping strategies during training (anticipatively claiming that handicaps may interfere with their performance). Study 1 tested the relationship between trait self-esteem and athletes' engagement in claimed self-handicapping. As hypothesized, low physical self-esteem athletes claimed more handicaps than high physical self-esteem athletes. For stronger evidence for the causal role of the self, Study 2 tested whether securing athletes' self-worth through self-affirmation would lead to decreased claimed self-handicapping by using a mixed model design that allows for both between-subjects (affirmation vs. control condition) and within-subject comparisons (before vs. after self-affirmation intervention). Self-affirmed athletes had decreased levels of claimed self-handicapping. Studies 1 and 2 also demonstrate that athletes engage in claimed self-handicapping during training, which could have deleterious effects on subsequent performance. Discussion centers on theoretical implications and applications for coaches, sport teachers, and sport psychologists.

The sacrifice of knowledge: vain debates in the social scientific study of religion.

PubMed

Kramp, Joseph M

2013-03-01

Since its inception, the social scientific study of religion has been a battleground for scholars advocating for the advantages of one sort of methodology over against the other. I argue that these debates have more to do with the personalities of the researchers rather than any kind of justifiable proof that one method is better than another. I argue that the process by which scholars quarrel over methods is a sign of stagnation or regression in the academy; I draw broad implications for the health of the discipline of religious studies.

"Uproar, bulk, rage, suffocation, effort unceasing, frenzied and vain": Beckett's Transports of Rage.

PubMed

Smith, Russell

2016-06-01

In a 1961 interview, Beckett warded off philosophical interpretations of his work: 'I'm no intellectual. All I am is feeling'. Despite the emotional intensity of Beckett's post-war writing, Beckett criticism has tended to ignore this claim, preferring the kinds of philosophical readings that Beckett here rejects. In particular, Beckett criticism underestimates the element of rage in his work. This paper argues that Beckett's post-war breakthrough is enabled by a radical reconsideration of the nature of feeling and of rage in particular. It involves the rejection of the idea of rage as pathological and the embrace of a positive conception of rage as drive or compulsion, a locus of energy and even pleasure.This paper reads the 'Moran' section of Molloy as a kind of 'rage fable', drawing on the ancient Greek concept of thymos, of anger as a virtue. It draws on Alfred Adler's theory of the 'masculine protest', with which Beckett was familiar from his extensive note-taking on Adler in 1934-5, and Sianne Ngai's discussion of the distinction between irritation and rage. According to this reading, Moran's report charts a narrative of thymotic liberation from the irritations of servitude, prefiguring the Unnamable's abandonment to impersonal affective intensities. It ends by suggesting that the prose of the Trilogy might be better understood, not as a 'syntax of weakness' but as a 'syntax of rage', a stylistic correlative of the imperious drive of thymos. We might then begin to understand the Trilogy as the epic of a heroic, impersonal, implacable and liberated rage.

Comparison of the therapeutic dose of warfarin in HIV-infected and HIV-uninfected patients: a study of clinical practice

PubMed Central

Jackson, B S; Mokoena, T

2017-01-01

Background People infected with HIV are prone to venous thrombosis. Treatment of thrombosis is primarily with warfarin. No studies have addressed the effects of HIV infection on warfarin dose. The aims of this study were to determine whether the therapeutic dose of warfarin and induction time to therapeutic dose in HIV-infected patients differ from that in HIV-uninfected patients. Methods A prospective and retrospective descriptive study of induction time to therapeutic warfarin dose, as well as of ambulant therapeutic warfarin dose, was performed. HIV-infected and HIV-uninfected patients being treated after deep venous thrombosis with or without pulmonary embolism were compared. Sex and use of antiretroviral drugs (ARVs) were also compared in the groups. Results 234 patients were entered into the study. Induction time to therapeutic warfarin dose did not differ between the 2 groups. The mean therapeutic dose of warfarin was higher in the HIV-infected than the HIV-uninfected group: 6.06 vs 5.72 mg/day, but this was not statistically significant (p=0.29). There was no difference in therapeutic warfarin dose between ARV-naïve groups—HIV-uninfected and HIV-infected patients not on ARVs. Conclusions There appears to be little effect of HIV infection on warfarin dosing. Warfarin therapy should be administered conventionally in HIV-infected patients. PMID:28179414

Efficacy and safety of darunavir (Prezista®) with low-dose ritonavir and other antiretroviral medications in subtype F HIV-1 infected, treatment-experienced subjects in Romania: a post-authorization, open-label, one-cohort, non-interventional, prospective study

PubMed Central

Benea, Otilia Elisabeta; Streinu-Cercel, Adrian; Dorobăţ, Carmen; Rugină, Sorin; Negruţiu, Lucian; Cupşa, Augustin; Duiculescu, Dan; Chiriac, Carmen; Itu, Corina; Prisăcariu, Liviu Jany; Iosif, Ionel

2014-01-01

Introduction The aim of the study was to assess the safety and efficacy of darunavir (Prezista®) used in subtype F human immunodeficiency virus – type 1 (HIV-1) infected, antiretroviral therapy (ART)-experienced patients in Romania in routine clinical practice. Methods This was a post-authorization, open-label, one-cohort, non-interventional, prospective study conducted at multiple sites in Romania to assess efficacy (CD4 cell count, viral load, and treatment compliance) and safety ([serious] adverse events, clinical laboratory evaluation, and vital signs) of darunavir in combination with low-dose ritonavir (DRV/r) and other antiretroviral (ARV) medications in subtype F HIV-1 infected subjects in naturalistic settings. Seventy-eight subjects were recruited by 9 investigational sites and received 600/100 mg DRV/r twice daily. Results Treatment with DRV/r administered with other ARV medications resulted in the expected, statistically relevant improvement of CD4 cell count and viral load in subjects eligible for such treatment. In addition, adherence to treatment was high and the treatment-emergent safety profile observed during this study was consistent with the established safety profile of darunavir. Conclusion DRV/r administered in combination with other ARV medications in subtype F HIV-1 infected subjects in naturalistic settings proved to be an effective and safe treatment in Romania. Trial registration NCT01253967 PMID:25276665

Acceptability and preferences for safer conception HIV prevention strategies: A qualitative study

PubMed Central

Schwartz, Sheree; West, Nora; Phofa, Rebecca; Yende, Nompumelelo; Sanne, Ian; Bassett, Jean; Van Rie, Annelies

2016-01-01

Safer conception strategies to reduce HIV transmission risk include antiretroviral therapy (ART) for HIV-positive partners, pre-exposure prophylaxis (PrEP) for HIV-negative partners, condomless sex limited to fertile periods, and home-based self-insemination. Resistance to taking treatment or cultural concerns may limit uptake of strategies and intervention success. Understanding the acceptability and preferences between different approaches is important to optimize service delivery. Between February-July 2013, 42 adults (21 HIV-positive and 21 HIV-negative) receiving primary care at Witkoppen Health and Welfare Centre in Johannesburg, South Africa, participated in focus group discussions or in-depth interviews. Themes were analyzed using a grounded theory approach. Acceptability of antiretroviral-based (ARV) strategies varied. Concerns over side effects, ARV treatment duration, and beliefs that treatment is only for the sick were common barriers, however desperation for a child was noted as a facilitator for uptake. HIV-negative men and HIV-positive women had favorable attitudes towards self-insemination, though paternity and safety concerns were raised. Self-insemination was generally preferred over PrEP by HIV-negative men, and ARV-based strategies were preferred by couples with HIV-negative female partners, despite concerns raised about condomless sex while virally suppressed. Knowledge about the fertile window was low. A strong counselling component will be required for effective uptake and adherence to safer conception services. PMID:26384950

[HIV drug resistance in ART-experienced patients in Cali, Colombia, 2008-2010].

PubMed

Martínez-Cajas, Jorge L; Mueses-Marín, Héctor F; Galindo-Orrego, Pablo; Agudelo, Juan F; Galindo-Quintero, Jaime

2013-01-01

Little has been published in Colombia on HIV drug resistance in patients taking antiretroviral treatment (ART). Currently, the Colombian guidelines do not recommend the use of genotypic antiretroviral resistance tests (GART) for treatment-naive patients or for those experiencing a first therapeutic failure. To determine the frequency of relevant resistance mutations and the degree of susceptibility/ resistance of HIV to antiretroviral drugs (ARVs) in ART-experienced patients. A non-random sample of 170 ART-experienced HIV patients with virologic failure and who underwent GART was recruited. A study of HIV drug resistance was carried out in two groups of patients: one group that underwent early GART and the other group that received late GART testing. The most frequent type of resistance affected the non-nucleoside class (76%). The late-GART group had higher risk of nucleoside analog and protease inhibitor drug resistance, a higher number of resistance mutations and more complex mutational profiles than the early-GART group. A high cross resistance level (30%) was found in the nucleoside analog class. The least affected medications were tenofovir and darunavir. Our results suggest that performing GART late is associated with levels of ARV resistance that could restrict the use of an important number of essential ARV in subsequent regimens. There is a need to revise the current recommendations to include GART prior to start of treatment and after the first virologic failure.

Access to antiretroviral drugs and AIDS management in Senegal.

PubMed

Desclaux, Alice; Ciss, Mounirou; Taverne, Bernard; Sow, Papa S; Egrot, Marc; Faye, Mame A; Lanièce, Isabelle; Sylla, Omar; Delaporte, Eric; Ndoye, Ibrahima

2003-07-01

Description and analysis of the Senegalese Antiretroviral Drug Access Initiative (ISAARV), the first governmental highly active antiretroviral therapy (HAART) treatment programme in Africa, launched in 1998. ISAARV was initially an experimental project designed to evaluate the feasibility, efficacy and acceptability of HAART in an African context. It was based on four principles: collective definition of the strategy, with involvement of the health professionals who would be called on to execute the programme; matching the objectives to available means (gradual enrollment according to drug availability); monitoring by several research programmes; and ongoing adaptation of treatment and follow-up according to the latest international recommendations. Persons qualifying for antiretroviral (ARV) therapy are selected on the basis of immunological and clinical criteria, regardless of economic and social considerations. A system of subsidies was created to favor access to ARV. Following the ARV price reductions that occurred in November 2000, 100% subsidies were created for the poorest participants. Optimal adherence was ensured by monthly follow-up by pharmacists and support groups held by social workers and patient associations. The chosen supply and distribution system allowed drug dispensing to be strictly controlled. The ISAARV programme demonstrates that HAART can be successfully prescribed in Africa. This experience has served as the basis for the creation of a national treatment programme in Senegal planned to treat 7000 patients by 2006.

Individualized Texting for Adherence Building (iTAB): Improving Antiretroviral Dose Timing Among HIV-Infected Persons with Co-occurring Bipolar Disorder

PubMed Central

Poquette, Amelia; Casaletto, Kaitlin B.; Gouaux, Ben; Montoya, Jessica L.; Posada, Carolina; Rooney, Alexandra S.; Badiee, Jayraan; Deutsch, Reena; Letendre, Scott L.; Depp, Colin A.; Grant, Igor; Atkinson, J. Hampton

2015-01-01

HIV+ persons with co-occurring bipolar disorder (HIV+/BD+) have elevated rates of medication nonadherence. We conducted a 30-day randomized controlled trial of a two-way, text messaging system, iTAB (n = 25), compared to an active comparison (CTRL) (n = 25) to improve antiretroviral (ARV) and psychotropic (PSY) adherence and dose timing. Both groups received medication adherence psychoeducation and daily texts assessing mood. The iTAB group additionally received personalized medication reminder texts. Participants responded to over 90 % of the mood and adherence text messages. Mean adherence, as assessed via electronic monitoring caps, was high and comparable between groups for both ARV (iTAB 86.2 % vs. CTRL 84.8 %; p = 0.95, Cliff’s d = 0.01) and PSY (iTAB 78.9 % vs. CTRL 77.3 %; p = 0.43, Cliff’s d = −0.13) medications. However, iTAB participants took ARVs significantly closer to their intended dosing time than CTRL participants (iTAB: 27.8 vs. CTRL: 77.0 min from target time; p = 0.02, Cliff’s d = 0.37). There was no group difference on PSY dose timing. Text messaging interventions may represent a low-burden approach to improving timeliness of medication-taking behaviors among difficult-to-treat populations. The benefits of improved dose timing for long-term medication adherence require additional investigation. PMID:25504449

Asteroid Redirect Mission: EVA and Sample Collection

NASA Technical Reports Server (NTRS)

Abell, Paul; Stich, Steve

2015-01-01

Asteroid Redirect Mission (ARM) Overview (1) Notional Development Schedule, (2) ARV Crewed Mission Accommodations; Asteroid Redirect Crewed Mission (ARCM) Mission Summary; ARCM Accomplishments; Sample collection/curation plan (1) CAPTEM Requirements; SBAG Engagement Plan

Novel methods to estimate antiretroviral adherence: protocol for a longitudinal study.

PubMed

Saberi, Parya; Ming, Kristin; Legnitto, Dominique; Neilands, Torsten B; Gandhi, Monica; Johnson, Mallory O

2018-01-01

There is currently no gold standard for assessing antiretroviral (ARV) adherence, so researchers often resort to the most feasible and cost-effective methods possible (eg, self-report), which may be biased or inaccurate. The goal of our study was to evaluate the feasibility and acceptability of innovative and remote methods to estimate ARV adherence, which can potentially be conducted with less time and financial resources in a wide range of clinic and research settings. Here, we describe the research protocol for studying these novel methods and some lessons learned. The 6-month pilot study aimed to examine the feasibility and acceptability of a remotely conducted study to evaluate the correlation between: 1) text-messaged photographs of pharmacy refill dates for refill-based adherence; 2) text-messaged photographs of pills for pill count-based adherence; and 3) home-collected hair sample measures of ARV concentration for pharmacologic-based adherence. Participants were sent monthly automated text messages to collect refill dates and pill counts that were taken and sent via mobile telephone photographs, and hair collection kits every 2 months by mail. At the study end, feasibility was calculated by specific metrics, such as the receipt of hair samples and responses to text messages. Participants completed a quantitative survey and qualitative exit interviews to examine the acceptability of these adherence evaluation methods. The relationship between the 3 novel metrics of adherence and self-reported adherence will be assessed. Investigators conducting adherence research are often limited to using either self-reported adherence, which is subjective, biased, and often overestimated, or other more complex methods. Here, we describe the protocol for evaluating the feasibility and acceptability of 3 novel and remote methods of estimating adherence, with the aim of evaluating the relationships between them. Additionally, we note the lessons learned from the protocol

High prevalence of HIV-1 drug resistance among patients on first-line antiretroviral treatment in Lomé, Togo.

PubMed

Dagnra, Anoumou Y; Vidal, Nicole; Mensah, Akovi; Patassi, Akouda; Aho, Komi; Salou, Mounerou; Monleau, Marjorie; Prince-David, Mireille; Singo, Assétina; Pitche, Palokinam; Delaporte, Eric; Peeters, Martine

2011-06-10

With widespread use of antiretroviral (ARV) drugs in Africa, one of the major potential challenges is the risk of emergence of ARV drug-resistant HIV strains. Our objective is to evaluate the virological failure and genotypic drug-resistance mutations in patients receiving first-line highly active antiretroviral therapy (HAART) in routine clinics that use the World Health Organization public health approach to monitor antiretroviral treatment (ART) in Togo. Patients on HAART for one year (10-14 months) were enrolled between April and October 2008 at three sites in Lomé, the capital city of Togo. Plasma viral load was measured with the NucliSENS EasyQ HIV-1 assay (Biomérieux, Lyon, France) and/or a Generic viral load assay (Biocentric, Bandol, France). Genotypic drug-resistance testing was performed with an inhouse assay on plasma samples from patients with viral loads of more than 1000 copies/ml. CD4 cell counts and demographic data were also obtained from medical records. A total of 188 patients receiving first-line antiretroviral treatment were enrolled, and 58 (30.8%) of them experienced virologic failure. Drug-resistance mutations were present in 46 patients, corresponding to 24.5% of all patients enrolled in the study. All 46 patients were resistant to non-nucleoside reverse-transcriptase inhibitors (NNRTIs): of these, 12 were resistant only to NNRTIs, 25 to NNRTIs and lamivudine/emtricitabine, and eight to all three drugs of their ARV regimes. Importantly, eight patients were already predicted to be resistant to etravirine, the new NNRTI, and three patients harboured the K65R mutation, inducing major resistance to tenofovir. In Togo, efforts to provide access to ARV therapy for infected persons have increased since 2003, and scaling up of ART started in 2007. The high number of resistant strains observed in Togo shows clearly that the emergence of HIV drug resistance is of increasing concern in countries where ART is now widely used, and can compromise the

Anaemia in HIV-infected pregnant women receiving triple antiretroviral combination therapy for prevention of mother-to-child transmission: a secondary analysis of the Kisumu breastfeeding study (KiBS).

PubMed

Odhiambo, Collins; Zeh, Clement; Angira, Frank; Opollo, Valarie; Akinyi, Brenda; Masaba, Rose; Williamson, John M; Otieno, Juliana; Mills, Lisa A; Lecher, Shirley Lee; Thomas, Timothy K

2016-03-01

The prevalence of anaemia during pregnancy is estimated to be 35-75% in sub-Saharan Africa and is associated with an increased risk of maternal mortality. We evaluated the frequency and factors associated with anaemia in HIV-infected women undergoing antiretroviral (ARV) therapy for prevention of mother-to-child transmission (PMTCT) enrolled in The Kisumu Breastfeeding Study 2003-2009. Maternal haematological parameters were monitored from 32 to 34 weeks of gestation to 2 years post-delivery among 522 enrolled women. Clinical and laboratory assessments for causes of anaemia were performed, and appropriate management was initiated. Anaemia was graded using the National Institutes of Health Division of AIDS 1994 Adult Toxicity Tables. Data were analysed using SAS software, v 9.2. The Wilcoxon two-sample rank test was used to compare groups. A logistic regression model was fitted to describe the trend in anaemia over time. At enrolment, the prevalence of any grade anaemia (Hb < 9.4 g/dl) was 61.8%, but fell during ARV therapy, reaching a nadir (7.4%) by 6 months post-partum. A total of 41 women (8%) developed severe anaemia (Hb < 7 g/dl) during follow-up; 2 (4.9%) were hospitalised for blood transfusion, whereas 3 (7.3%) were transfused while hospitalised (for delivery). The greatest proportion of severe anaemia events occurred around delivery (48.8%; n = 20). Anaemia (Hb ≥ 7 and < 9.4 g/dl) at enrolment was associated with severe anaemia at delivery (OR 5.87; 95% CI: 4.48, 7.68, P < 0.01). Few cases of severe anaemia coincided with clinical malaria (24.4%; n = 10) and helminth (7.3%; n = 3) infections. Resolution of anaemia among most participants during study follow-up was likely related to receipt of ARV therapy. Efforts should be geared towards addressing common causes of anaemia in HIV-infected pregnant women, prioritising initiation of ARV therapy and management of peripartum blood loss. © 2016 John Wiley & Sons Ltd.

Existing capacity to manage pharmaceuticals and related commodities in East Africa: an assessment with specific reference to antiretroviral therapy

PubMed Central

Waako, Paul J; Odoi-adome, Richard; Obua, Celestino; Owino, Erisa; Tumwikirize, Winnie; Ogwal-okeng, Jasper; Anokbonggo, Willy W; Matowe, Lloyd; Aupont, Onesky

2009-01-01

Background East African countries have in the recent past experienced a tremendous increase in the volume of antiretroviral drugs. Capacity to manage these medicines in the region remains limited. Makerere University, with technical assistance from the USAID supported Rational Pharmaceutical Management Plus (RPM Plus) Program of Management Sciences for Health (MSH) established a network of academic institutions to build capacity for pharmaceutical management in the East African region. The initiative includes institutions from Uganda, Tanzania, Kenya and Rwanda and aims to improve access to safe, effective and quality-assured medicines for the treatment of HIV/AIDS, TB and Malaria through spearheading in-country capacity. The initiative conducted a regional assessment to determine the existing capacity for the management of antiretroviral drugs and related commodities. Methods Heads and implementing workers of fifty HIV/AIDS programs and institutions accredited to offer antiretroviral services in Uganda, Kenya, Tanzania and Rwanda were key informants in face-to-face interviews guided by structured questionnaires. The assessment explored categories of health workers involved in the management of ARVs, their knowledge and practices in selection, quantification, distribution and use of ARVs, nature of existing training programs, training preferences and resources for capacity building. Results Inadequate human resource capacity including, inability to select, quantify and distribute ARVs and related commodities, and irrational prescribing and dispensing were some of the problems identified. A competence gap existed in all the four countries with a variety of healthcare professionals involved in the supply and distribution of ARVs. Training opportunities and resources for capacity development were limited particularly for workers in remote facilities. On-the-job training and short courses were the preferred modes of training. Conclusion There is inadequate capacity for

Plasma and breast-milk selenium in HIV-infected Malawian mothers are positively associated with infant selenium status but are not associated with maternal supplementation: results of the Breastfeeding, Antiretrovirals, and Nutrition study.

PubMed

Flax, Valerie L; Bentley, Margaret E; Combs, Gerald F; Chasela, Charles S; Kayira, Dumbani; Tegha, Gerald; Kamwendo, Debbie; Daza, Eric J; Fokar, Ali; Kourtis, Athena P; Jamieson, Denise J; van der Horst, Charles M; Adair, Linda S

2014-04-01

Selenium is found in soils and is essential for human antioxidant defense and immune function. In Malawi, low soil selenium and dietary intakes coupled with low plasma selenium concentrations in HIV infection could have negative consequences for the health of HIV-infected mothers and their exclusively breastfed infants. We tested the effects of lipid-based nutrient supplements (LNS) that contained 1.3 times the Recommended Dietary Allowance of sodium selenite and antiretroviral drugs (ARV) on maternal plasma and breast-milk selenium concentrations. HIV-infected Malawian mothers in the Breastfeeding, Antiretrovirals, and Nutrition study were randomly assigned at delivery to receive: LNS, ARV, LNS and ARV, or a control. In a subsample of 526 mothers and their uninfected infants, we measured plasma and breast-milk selenium concentrations at 2 or 6 (depending on the availability of infant samples) and 24 wk postpartum. Overall, mean (± SD) maternal (range: 81.2 ± 20.4 to 86.2 ± 19.9 μg/L) and infant (55.6 ± 16.3 to 61.0 ± 15.4 μg/L) plasma selenium concentrations increased, whereas breast-milk selenium concentrations declined (14.3 ± 11.5 to 9.8 ± 7.3 μg/L) from 2 or 6 to 24 wk postpartum (all P < 0.001). Compared with the highest baseline selenium tertile, low and middle tertiles were positively associated with a change in maternal plasma or breast-milk selenium from 2 or 6 to 24 wk postpartum (both P < 0.001). With the use of linear regression, we showed that LNS that contained selenium and ARV were not associated with changes in maternal plasma and breast-milk selenium, but maternal selenium concentrations were positively associated with infant plasma selenium at 2 or 6 and 24 wk postpartum (P < 0.001) regardless of the study arm. Selenite supplementation of HIV-infected Malawian women was not associated with a change in their plasma or breast-milk selenium concentrations. Future research should examine effects of more readily incorporated forms of

Association of Dyslipidemia and Glucose Abnormalities with Antiretroviral Treatment in a Cohort of HIV-infected Latin American Children

PubMed Central

Paganella, MP; Cohen, RA; Harris, DR; Kuchenbecker, RS; Sperhacke, RD; Kato, SK; Silva, CLO; Sturzbecher, FT; Oliveira, RHS; Pavía Ruz, N; Hazra, R

2016-01-01

Objective(s) To estimate the incidence of lipid and glucose abnormalities and assess their association with exposure to antiretroviral (ARV) regimens among perinatally HIV-infected Latin American children. Design Longitudinal cohort study. Methods Data were analyzed from the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) International Site Development Initiative (NISDI) Pediatric Latin American Countries Epidemiologic Study (PLACES). The incidence of dyslipidemia (total cholesterol>200mg/dL, HDL<35mg/dL, LDL≥130mg/dL, triglycerides>110mg/dL [age<10 years] or >150mg/dL [≥10 years]) and fasting glucose abnormalities (homeostasis model assessment of insulin resistance >2.5 [Tanner Stage 1] or >4.0 [Tanner Stage>1]; impaired glucose: 110 to <126mg/dL; diabetes: ≥126 mg/dL) was estimated. Proportional hazards regression was used to evaluate the risk of abnormalities associated with ARV regimen, adjusted for covariates. Results There were 385 children eligible for analysis (mean age 6.6 years). Incident cholesterol abnormalities were reported in 18.1% of participants (95% confidence interval [CI] 14.1–22.8%), HDL and LDL cholesterol abnormalities in 19.6% (15.1–24.7%) and 15.0% (11.3–19.5%), respectively, and triglyceride abnormalities in 44.2% (37.7–50.8%). In multivariable analysis, ARV regimen was only associated with triglyceride abnormalities; participants receiving a protease inhibitor-containing (PI) regimen were 3.6 times as likely to experience a triglyceride abnormality as those receiving no ARVs (95% CI: 1.3–10.5; p=0.0167). The cumulative incidence of insulin resistance was 3.8% (1.8–7.1%); there were no incident cases of diabetes and only two of impaired fasting glucose. Conclusions Children receiving PI-containing regimens were at increased risk of developing triglyceride abnormalities. Continued monitoring of lipid levels in children receiving PI-containing regimens appears warranted. PMID:27570910

APMP.T-K3.4: key comparison of realizations of the ITS-90 over the range -38.8344 °C to 419.527 °C

NASA Astrophysics Data System (ADS)

Joung, W.; Gam, K. S.; Achmadi, A.; Trisna, B. A.

2016-01-01

The APMP bilateral key comparison APMP.T-K3.4 was initiated on the request from RCM-LIPI (Indonesia) to link their national standards to the average reference values (ARVs) of the CCT-K3. Korea Research Institute of Standards and Science (KRISS, Republic of Korea) provided the linkage to the CCT-K3 for temperatures ranging from -38.8344 °C to 419.527 °C. In the APMP.T-K3.4, two standard platinum resistance thermometers (SPRTs) were chosen as the transfer instruments and were calibrated at the ITS-90 fixed-points in the comparison range. The fixed-points in this comparison included Zn freezing point (419.527 °C), Sn freezing point (231.928 °C), In freezing point (156.5985 °C), Ga melting point (29.7646 °C), and Hg triple point (-38.8344 °C). The comparison was carried out in a participant-pilot-participant sequence where KRISS served as the pilot. The linkage was based on the fixed-point resistance ratios of RCM-LIPI relative to the ARVs of the CCT-K3 via the difference between the fixed-point resistance ratios of KRISS and the ARVs of the CCT-K3. The temperature differences between the national standards of RCM-LIPI and the ARVs of the CCT-K3 were within the evaluated comparison uncertainties of the ATPM.T-K3.4. This report provides detailed information on the comparison results, linkage mechanism, and the Degree of Equivalence of the RCM-LIPI relative to the institutes having participated in the CCT-K3. Main text To reach the main text of this paper, click on Final Report. Note that this text is that which appears in Appendix B of the BIPM key comparison database kcdb.bipm.org/. The final report has been peer-reviewed and approved for publication by the CCT, according to the provisions of the CIPM Mutual Recognition Arrangement (CIPM MRA).

Novel methods to estimate antiretroviral adherence: protocol for a longitudinal study

PubMed Central

Saberi, Parya; Ming, Kristin; Legnitto, Dominique; Neilands, Torsten B; Gandhi, Monica; Johnson, Mallory O

2018-01-01

Background There is currently no gold standard for assessing antiretroviral (ARV) adherence, so researchers often resort to the most feasible and cost-effective methods possible (eg, self-report), which may be biased or inaccurate. The goal of our study was to evaluate the feasibility and acceptability of innovative and remote methods to estimate ARV adherence, which can potentially be conducted with less time and financial resources in a wide range of clinic and research settings. Here, we describe the research protocol for studying these novel methods and some lessons learned. Methods The 6-month pilot study aimed to examine the feasibility and acceptability of a remotely conducted study to evaluate the correlation between: 1) text-messaged photographs of pharmacy refill dates for refill-based adherence; 2) text-messaged photographs of pills for pill count-based adherence; and 3) home-collected hair sample measures of ARV concentration for pharmacologic-based adherence. Participants were sent monthly automated text messages to collect refill dates and pill counts that were taken and sent via mobile telephone photographs, and hair collection kits every 2 months by mail. At the study end, feasibility was calculated by specific metrics, such as the receipt of hair samples and responses to text messages. Participants completed a quantitative survey and qualitative exit interviews to examine the acceptability of these adherence evaluation methods. The relationship between the 3 novel metrics of adherence and self-reported adherence will be assessed. Discussion Investigators conducting adherence research are often limited to using either self-reported adherence, which is subjective, biased, and often overestimated, or other more complex methods. Here, we describe the protocol for evaluating the feasibility and acceptability of 3 novel and remote methods of estimating adherence, with the aim of evaluating the relationships between them. Additionally, we note the lessons

Drug transporter gene expression in human colorectal tissue and cell lines: modulation with antiretrovirals for microbicide optimization.

PubMed

Mukhopadhya, Indrani; Murray, Graeme I; Berry, Susan; Thomson, John; Frank, Bruce; Gwozdz, Garry; Ekeruche-Makinde, Julia; Shattock, Robin; Kelly, Charles; Iannelli, Francesco; Pozzi, Gianni; El-Omar, Emad M; Hold, Georgina L; Hijazi, Karolin

2016-02-01

The objectives of this study were to comprehensively assess mRNA expression of 84 drug transporters in human colorectal biopsies and six representative cell lines, and to investigate the alteration of drug transporter gene expression after exposure to three candidate microbicidal antiretroviral (ARV) drugs (tenofovir, darunavir and dapivirine) in the colorectal epithelium. The outcome of the objectives informs development of optimal ARV-based microbicidal formulations for prevention of HIV-1 infection. Drug transporter mRNA expression was quantified from colorectal biopsies and cell lines by quantitative real-time PCR. Relative mRNA expression was quantified in Caco-2 cells and colorectal explants after induction with ARVs. Data were analysed using Pearson's product moment correlation (r), hierarchical clustering and principal component analysis (PCA). Expression of 58 of the 84 transporters was documented in colorectal biopsies, with genes for CNT2, P-glycoprotein (P-gp) and MRP3 showing the highest expression. No difference was noted between individual subjects when analysed by age, gender or anatomical site (rectum or recto-sigmoid) (r = 0.95-0.99). High expression of P-gp and CNT2 proteins was confirmed by immunohistochemical staining. Similarity between colorectal tissue and cell-line drug transporter gene expression was variable (r = 0.64-0.84). PCA showed distinct clustering of human colorectal biopsy samples, with the Caco-2 cells defined as the best surrogate system. Induction of Caco-2 cell lines with ARV drugs suggests that darunavir-based microbicides incorporating tenofovir may result in drug-drug interactions likely to affect distribution of individual drugs to sub-epithelial target cells. These findings will help optimize complex formulations of rectal microbicides to realize their full potential as an effective approach for pre-exposure prophylaxis against HIV-1 infection. © The Author 2015. Published by Oxford University Press on behalf of the

Polymorphisms in the HIV-1 gp41 env gene, natural resistance to enfuvirtide (T-20) and pol resistance among pregnant Brazilian women.

PubMed

Reis, Mônica Nogueira da Guarda; de Alcântara, Keila Correa; Cardoso, Ludimila Paula Vaz; Stefani, Mariane Martins Araújo

2014-01-01

The selective pressure of antiretroviral drugs (ARVs) targeting HIV-1 pol can promote drug resistance mutations in other genomic regions, such as env. Drug resistance among women should be monitored to avoid horizontal and mother-to-child transmission. To describe natural resistance to T-20 (enfuvirtide), gp41 env polymorphisms, mutations in pol and HIV-1 subtypes, 124 pregnant women were recruited. For 98 patients, the gp41 env, protease (PR) and reverse transcriptase (RT) fragments were sequenced. The patients were ARV naïve (n = 30), taking mother-to-child transmission prophylaxis (n = 50), or being treated with highly active ARV therapy/HAART (n = 18). The Stanford and IAS/USA databases and other sources were used to analyze PR/RT, gp41 env resistance mutations. The HIV-1 genetic diversity was analyzed by REGA/phylogenetic analyses. The patients' median age was 25 years (range, 16-42), 18.4% had AIDS. The frequency of natural resistance to T-20 (N42D, L44M, and R46M-low-impact mutations) was 6.1% (6/98); 20.4% (20/98) had compensatory mutations in HR2. The prevalence of transmitted drug resistance in the pol was 13.3% (4/30), and the prevalence of secondary drug resistance was 33.3% (6/18). Two patients were infected with multidrug resistant/MDR viruses. The analysis of HIV-1 subtypes (PR/RT/gp41) revealed that 61.2% (60/98) were subtype B, 12.2% (12/98) were subtype C, 4.1% (4/98) were subtype F1, and 22.4% (22/98) were possible recombinants (BF1 = 20.4%; BC = 2%). Natural resistance to T-20 was not associated with pol resistance or previous ARV use. The high rate of secondary resistance, including MDR, indicates that the number of women that may need T-20 salvage therapy may be higher than anticipated. © 2013 Wiley Periodicals, Inc.

[Asymmetry in international relations, industrial property rights and anti-HIV medication].

PubMed

Costa-Couto, Maria Helena; Nascimento, Alvaro César

2008-01-01

This paper analyzes the asymmetry in the international relations as refers to the recognition of industrial property rights in the pharmaceutical industry. It focuses on the impact of such relations upon the access to ARV medication, an issue of worldwide interest due to its connection with the development of the nations. Clashing interests and the position taken by some countries in their patent laws point to a scenario less favorable for the access of peripheral countries to anti-HIV/AIDS medication. On the other hand, it seems that the success of the Brazilian STD/AIDS program in negotiating ARV prices will open new possibilities. The solution may be the internal strengthening of the National States and the active role played by the Agencies of the United Nations System in defense of the collective human interests.

Assessment of quality of life in people living with HIV in Georgia.

PubMed

Karkashadze, Ekaterine; Gates, Margaret A; Chkhartishvili, Nikoloz; DeHovitz, Jack; Tsertsvadze, Tengiz

2017-06-01

The purpose of our study was to assess quality of life (QoL) among Georgian HIV-infected individuals and to examine factors associated with QoL. Our cross-sectional study sample consisted of 201 HIV-infected adult outpatients recruited at the National AIDS Center in Tbilisi, Georgia. WHOQOL-HIV-BREF was used to measure QoL. Data about other variables of interest were obtained from medical records. Modified Poisson regression with robust variance estimates was performed to create a predictive model of factors that influenced QoL. The study results showed the following factors as predictors of good general QoL: antiretroviral (ARV) treatment (prevalence ratio (PR)=2.87 (95% CI: 1.45, 5.67)); higher education level (PR = 1.51 (95% CI: 1.05, 2.17)); CD4 cells ≥200 cells/mm 3 (PR = 1.83 (95% CI: 1.13, 2.94)); and age ≥40 years (PR = 1.60 (95% CI: 1.09, 2.36)). However, all factors examined were associated with at least one QoL domain. Our study suggests that HIV-infected individuals younger than 40 years and those with lower education level are more likely to have poorer QoL, while those receiving ARV treatment tend to have better QoL. This highlights the importance of educational interventions and ARV treatment in HIV patients. Future research should seek to implement additional evidence-based actions to improve QoL in this population.

Comparison of the therapeutic dose of warfarin in HIV-infected and HIV-uninfected patients: a study of clinical practice.

PubMed

Jackson, B S; Mokoena, T

2017-02-08

People infected with HIV are prone to venous thrombosis. Treatment of thrombosis is primarily with warfarin. No studies have addressed the effects of HIV infection on warfarin dose. The aims of this study were to determine whether the therapeutic dose of warfarin and induction time to therapeutic dose in HIV-infected patients differ from that in HIV-uninfected patients. A prospective and retrospective descriptive study of induction time to therapeutic warfarin dose, as well as of ambulant therapeutic warfarin dose, was performed. HIV-infected and HIV-uninfected patients being treated after deep venous thrombosis with or without pulmonary embolism were compared. Sex and use of antiretroviral drugs (ARVs) were also compared in the groups. 234 patients were entered into the study. Induction time to therapeutic warfarin dose did not differ between the 2 groups. The mean therapeutic dose of warfarin was higher in the HIV-infected than the HIV-uninfected group: 6.06 vs 5.72 mg/day, but this was not statistically significant (p=0.29). There was no difference in therapeutic warfarin dose between ARV-naïve groups-HIV-uninfected and HIV-infected patients not on ARVs. There appears to be little effect of HIV infection on warfarin dosing. Warfarin therapy should be administered conventionally in HIV-infected patients. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.

[High activity antiretroviral therapy change associated to adverse drug reactions in a specialized center in Venezuela].

PubMed

Subiela, José D; Dapena, Elida

2016-03-01

Adverse drug reactions (ADRs) represent the first cause of change of the first-line highly active antiretroviral therapy (HAART) regimen, therefore, they constitute the main limiting factor in the long-term follow up of HIV patients in treatment. A retrospective study was carried out in a specialized center in Lara State, Venezuela, including 99 patients over 18 years of age who had change of first-line HAART regimen due to ADRs, between 2010 and 2013. The aims of this research were to describe the sociodemographic and clinical variables, frequency of ADRs related to change of HAART, duration of the first-line HAART regimen, to determine the drugs associated with ARVs and to identify the risk factors. The ADRs constituted 47.5% of all causes of change of first-line HAART regimen, the median duration was 1.08±0.28 years. The most frequent ADRs were anemia (34.3%), hypersensitivity reactions (20.2%) and gastrointestinal intolerance (13.1%). The most frequent ARV regimen type was the protease inhibitors-based regimen (59.6%), but zidovudine was the ARV most linked to ADRs (41.4%). The regression analysis showed increased risk of ADRs in singles and students in the univariate analysis and heterosexuals and homosexuals in multivariate analysis; and decreased risk in active workers. The present work shows the high prevalence of ADRs in the studied population and represents the first case-based study that describes the pharmacoepidemiology of a cohort of HIV-positive patients treated in Venezuela.

Timely antiretroviral prophylaxis during pregnancy effectively reduces HIV mother-to-child transmission in eight counties in China: a prospective study during 2004-2011.

PubMed

Wang, Qian; Wang, Linhong; Fang, Liwen; Wang, Ailing; Jin, Xi; Wang, Fang; Wang, Xiaoyan; Qiao, Yaping; Sullivan, Sheena G; Rutherford, Shannon; Zhang, Lei

2016-10-10

This study investigates the improvement of the prevention of mother-to-child transmission (PMTCT) of Human Immunodeficiency Virus (HIV) in China during 2004-2011. A clinic-based prospective study was conducted among HIV-positive pregnant women and their children in eight counties across China. Associated factors of mother-to-child transmission were analyzed using regression analysis. A total of 1,387 HIV+ pregnant women and 1,377 HIV-exposed infants were enrolled. The proportion of pregnant women who received HIV testing increased significantly from 45.1% to 98.9% during 2004-2011. Among whom, the proportion that received antiretroviral (ARV) prophylaxis increased from 61% to 96%, and the corresponding coverage in children increased from 85% to 97% during the same period. In contrast, single-dose nevirapine treatment during delivery declined substantially from 97.9% to 12.7%. Vertical transmission of HIV declined from 11.1% (95% confidence interval [CI]: 5.7-23.3%) in 2004 to 1.2% (95% CI: 0.1-5.8%) in 2011. Women who had a vaginal delivery (compared to emergency caesarian section (odds ratio [OR] = 0.46; 0.23-0.96)) and mothers on multi-ARVs (OR = 0.11; 0.04-0.29) were less likely to transmit HIV to their newborns. Increasing HIV screening enabled timely HIV care and prophylaxis to reduce vertical transmission of HIV. Early and consistent treatment with multi-ARVs during pregnancy is vital for PMTCT.

Antiretroviral Therapy and Pre-exposure Prophylaxis: Combined Impact on HIV Transmission and Drug Resistance in South Africa

PubMed Central

Abbas, Ume L.; Glaubius, Robert; Mubayi, Anuj; Hood, Gregory; Mellors, John W.

2013-01-01

Background. The potential impact of antiretroviral therapy (ART) and pre-exposure prophylaxis (PrEP) with overlapping and nonoverlapping antiretrovirals (ARVs) on human immunodeficiency virus (HIV) transmission and drug resistance is unknown. Methods. A detailed mathematical model was used to simulate the epidemiological impact of ART alone, PrEP alone, and combined ART + PrEP in South Africa. Results. ART alone initiated at a CD4 lymphocyte cell count <200 cells/µL (80% coverage and 96% effectiveness) prevents 20% of HIV infections over 10 years but increases drug resistance prevalence to 6.6%. PrEP alone (30% coverage and 75% effectiveness) also prevents 21% of infections but with lower resistance prevalence of 0.5%. The ratio of cumulative infections prevented to prevalent drug-resistant cases after 10 years is 7-fold higher for PrEP than for ART. Combined ART + PrEP with overlapping ARVs prevents 35% of infections but increases resistance prevalence to 8.2%, whereas ART + PrEP with nonoverlapping ARVs prevents slightly more infections (37%) and reduces resistance prevalence to 7.2%. Conclusions. Combined ART + PrEP is likely to prevent more HIV infections than either strategy alone, but with higher prevalence of drug resistance. ART is predicted to contribute more to resistance than is PrEP. Optimizing both ART and PrEP effectiveness and delivery are the keys to preventing HIV transmission and drug resistance. PMID:23570850

Sensitivity analysis of the parameters of an HIV/AIDS model with condom campaign and antiretroviral therapy

NASA Astrophysics Data System (ADS)

Marsudi, Hidayat, Noor; Wibowo, Ratno Bagus Edy

2017-12-01

In this article, we present a deterministic model for the transmission dynamics of HIV/AIDS in which condom campaign and antiretroviral therapy are both important for the disease management. We calculate the effective reproduction number using the next generation matrix method and investigate the local and global stability of the disease-free equilibrium of the model. Sensitivity analysis of the effective reproduction number with respect to the model parameters were carried out. Our result shows that efficacy rate of condom campaign, transmission rate for contact with the asymptomatic infective, progression rate from the asymptomatic infective to the pre-AIDS infective, transmission rate for contact with the pre-AIDS infective, ARV therapy rate, proportion of the susceptible receiving condom campaign and proportion of the pre-AIDS receiving ARV therapy are highly sensitive parameters that effect the transmission dynamics of HIV/AIDS infection.

Patient Experience and Views on Antiretroviral Treatment—Findings from the Positive Perspectives Survey

PubMed Central

Young, Benjamin; Spire, Bruno; Morcillo, Diego Garcia; Muchenje, 
Marvelous; Parkinson, Kneeshe; Krehl, Moritz; Marcotullio, Simone; Allan, Brent; Punekar, Yogesh; Namiba, Angelina; deRuiter, Annemiek; Barthel, Sophie; Koteff, Justin; Garris, Cindy; Nguyen, Christopher; Ustianowski, Andrew; Ferrer, Pedro Eitz; Murungi, Andrew

2017-01-01

Abstract Background While advances in treatment have dramatically improved the life-expectancy of people living with HIV (PLHIV), a number of unmet needs remain. We conducted an international survey of PLHIV to explore their level of satisfaction with current treatment and potential areas of improvement for ARVs. Methods Qualitative in-depth interviews were performed with PLHIV to identify key hypotheses. A steering group developed the survey questions which was fielded online from November 2016 to April 2017 in 9 countries across North America, Europe and Australia. A mixed sampling/recruitment approach was used to ensure a broad cross-section of PLHIV. Respondents were screened for eligibility prior to receiving access to the online survey Results Overall 1085 PLHIV completed the survey with 40% of respondents from North America. The demographic breakdown was 25% women, 34% >50 years, 49% diagnosed >10 years ago, 76 % with co-morbidities. 40% had a college degree or higher, 33% were in full-time employment and 62% lived in a large city. Majority (98%) were currently taking ARVs with 53% taking a Single Tablet Regimen (STR). 87% of those diagnosed within last 2 years had started treatment within 6 months of diagnosis, compared with 40% of those diagnosed > 10 years ago. Of those on treatment, 87% were satisfied with their current ARV regimen. 33% had changed treatment in the last 12 months with the main reasons for switching being reducing severity or frequency of side effects (43%) and reducing the pill burden (31%). 73% of those on treatment were worried about the long-term effects of ARVs. Reducing these long-term effects (25%) and the potential availability of longer lasting treatments (21%) were identified as the 2 most important potential improvements to current regimens. 62% were open to changing to an ARV regimen with fewer drugs as long as their HIV remained suppressed. Demographics and results for the North American cohort were generally similar to the

View of Apollo 16 lunar sample no. 68815

NASA Image and Video Library

1972-04-30

A closeup view or "mug shot" of Apollo 16 lunar sample no. 68815, a dislodged fragment from a parent boulder roughly four feet high and five feet long encountered at Station 8. The crew tried in vain to overturn the parent boulder. A fillet-soil sample was taken close to the boulder, allowing for study of the type and rate of erosion acting on lunar rocks. The fragment itself is very hard, has many veticles and a variety of inclusions. In addition, numerous metallic particles were observed in the black matrix.

Gestational trophoblastic neoplasia and human immunodeficiency virus infection: a 10-year review.

PubMed

Tayib, Shahila; van Wijk, Leon; Denny, Lynette

2011-12-01

The objective of the study was to describe the management of gestational trophoblastic neoplasia (GTN), with particular reference to concurrent human immunodeficiency virus (HIV) infection. This retrospective descriptive study comprised all cases of GTN managed at Groote Schuur Hospital over a 10-year period (1999-2008). Seventy-six patients, with a median age of 30 years at presentation, were included in the study. Only 36 patients (47.4%) had known HIV status. Fourteen (18.4%) were HIV positive, and of these, 4 (28.6%) were on antiretroviral treatment (ARV). The mean CD4 count was 142 cells/μL for those on ARV and 543 cells/μL for those not on ARV (P = 0.001). Histologically, 44 patients (58%) had hydatidiform mole, and 21 (28%) had choriocarcinoma. In the remaining 10 cases, a clinical diagnosis was made. Based on the revised International Federation of Gynecology and Obstetrics (FIGO)/modified World Health Organization scoring, 43 patients (56.6%) were low risk, and 33 (43.4%) were high risk. Thirty-eight patients (50%) were staged as FIGO stage I. Of 73 patients who received chemotherapy, 56 (76.7%) achieved complete remission, 9 (12.3%) did not achieve any remission, 7 (9.6%) had a relapse, and 1 (1.4%) was lost to follow-up. Patients who never went into remission had frequent treatment delays due to poor compliance or inadequate blood counts. The overall survival at 60 months was 81.9%. Of the 13 patients (17.1%) who have died, 5 (38.5%) were HIV positive. The overall 5-year survival rates for FIGO stages I, II, III, and IV were 97.4%, 66.7%, 77.8%, and 46.2%, respectively. The overall 5-year survival for HIV-positive patients was 64.3% versus more than 85% for both the HIV-negative and HIV-unknown groups. Apart from more advanced stage, HIV seropositivity and poor compliance with treatment also portend poorer outcome in GTN patients. In HIV-positive patients with poor CD4, little clarity is available whether ARV should be commenced speedily, and the

Longitudinal Detection and Persistence of Minority Drug-Resistant Populations and Their Effect on Salvage Therapy

PubMed Central

Nishizawa, Masako; Matsuda, Masakazu; Hattori, Junko; Shiino, Teiichiro; Matano, Tetsuro; Heneine, Walid; Johnson, Jeffrey A.; Sugiura, Wataru

2015-01-01

Background Drug-resistant HIV are more prevalent and persist longer than previously demonstrated by bulk sequencing due to the ability to detect low-frequency variants. To clarify a clinical benefit to monitoring minority-level drug resistance populations as a guide to select active drugs for salvage therapy, we retrospectively analyzed the dynamics of low-frequency drug-resistant population in antiretroviral (ARV)-exposed drug resistant individuals. Materials and Methods Six HIV-infected individuals treated with ARV for more than five years were analyzed. These individuals had difficulty in controlling viremia, and treatment regimens were switched multiple times guided by standard drug resistance testing using bulk sequencing. To detect minority variant populations with drug resistance, we used a highly sensitive allele-specific PCR (AS-PCR) with detection thresholds of 0.3–2%. According to ARV used in these individuals, we focused on the following seven reverse transcriptase inhibitor-resistant mutations: M41L, K65R, K70R, K103N, Y181C, M184V, and T215F/Y. Results of AS-PCR were compared with bulk sequencing data for concordance and presence of additional mutations. To clarify the genetic relationship between low-frequency and high-frequency populations, AS-PCR amplicon sequences were compared with bulk sequences in phylogenetic analysis. Results The use of AS-PCR enabled detection of the drug-resistant mutations, M41L, K103N, Y181C, M184V and T215Y, present as low-frequency populations in five of the six individuals. These drug resistant variants persisted for several years without ARV pressure. Phylogenetic analysis indicated that pre-existing K103N and T215I variants had close genetic relationships with high-frequency K103N and T215I observed during treatment. Discussion and Conclusion Our results demonstrate the long-term persistence of drug-resistant viruses in the absence of drug pressure. The rapid virologic failures with pre-existing mutant viruses

Growth Inhibition by Testosterone in an Androgen Receptor Splice Variant-Driven Prostate Cancer Model.

PubMed

Nakata, Daisuke; Nakayama, Kazuhide; Masaki, Tsuneo; Tanaka, Akira; Kusaka, Masami; Watanabe, Tatsuya

2016-12-01

Castration resistance creates a significant problem in the treatment of prostate cancer. Constitutively active splice variants of androgen receptor (AR) have emerged as drivers for resistance to androgen deprivation therapy, including the next-generation androgen-AR axis inhibitors abiraterone and enzalutamide. In this study, we describe the characteristics of a novel castration-resistant prostate cancer (CRPC) model, designated JDCaP-hr (hormone refractory). JDCaP-hr was established from an androgen-dependent JDCaP xenograft model after surgical castration. The expression of AR and its splice variants in JDCaP-hr was evaluated by immunoblotting and quantitative reverse transcription-polymerase chain reaction. The effects of AR antagonists and testosterone on JDCaP-hr were evaluated in vivo and in vitro. The roles of full-length AR (AR-FL) and AR-V7 in JDCaP-hr cell growth were evaluated using RNA interference. JDCaP-hr acquired a C-terminally truncated AR protein during progression from the parental JDCaP. The expression of AR-FL and AR-V7 mRNA was upregulated by 10-fold in JDCaP-hr compared with that in JDCaP, indicating that the JDCaP and JDCaP-hr models simulate castration resistance with some clinical features, such as overexpression of AR and its splice variants. The AR antagonist bicalutamide did not affect JDCaP-hr xenograft growth, and importantly, testosterone induced tumor regression. In vitro analysis demonstrated that androgen-independent prostate-specific antigen secretion and cell proliferation of JDCaP-hr were predominantly mediated by AR-V7. JDCaP-hr cell growth displayed a bell-shaped dependence on testosterone, and it was suppressed by physiological concentrations of testosterone. Testosterone induced rapid downregulation of both AR-FL and AR-V7 expression at physiological concentrations and suppressed expression of the AR target gene KLK3. Our findings support the clinical value of testosterone therapy, including bipolar androgen therapy, in the

ART access-related barriers faced by HIV-positive persons linked to care in southern Ghana: a mixed method study.

PubMed

Ankomah, Augustine; Ganle, John Kuumuori; Lartey, Margaret Yaa; Kwara, Awewura; Nortey, Priscilla Awo; Okyerefo, Michael Perry Kweku; Laar, Amos Kankponang

2016-12-07

Timely and enduring access to antiretroviral therapy (ART) by HIV-infected individuals has been shown to substantially reduce HIV transmission risk, HIV-related morbidity and mortality. However, there is evidence that in addition to limited supply of antiretrovirals (ARVs) and linkage to ART in many low-income countries, HIV+ persons often encounter barriers in accessing ART-related services even in contexts where these services are freely available. In Ghana, limited research evidence exists regarding the barriers HIV+ persons already linked to ART face. This paper explores ART access-related barriers that HIV+ persons linked to care in southern Ghana face. A mixed method study design, involving a cross-sectional survey and qualitative in-depth interviews, was conducted to collect data from four healthcare providers and a total of 540 adult HIV+ persons receiving ART at four treatment centres in Ghana. We used univariate analysis to generate descriptive tabulations for key variables from the survey. Data from qualitative in-depth interviews were thematically analysed. Results from the survey and in-depth interviews were brought together to illuminate the challenges of the HIV+ persons. All (100%) the HIV+ persons interviewed were ARV-exposed and linked to ART. Reasons for taking ARVs ranged from beliefs that they will suppress the HIV virus, desire to maintain good health and prolong life, and desire to prevent infection in unborn children, desire both to avoid death and to become good therapeutic citizens (abide by doctors' advice). Despite this, more than half of the study participants (63.3%) reported seven major factors as barriers hindering access to ART. These were high financial costs associated with accessing and receiving ART (26%), delays associated with receiving care from treatment centres (24%), shortage of drugs and other commodities (23%), stigma (8.8%), fear of side effects of taking ARVs (7.9%), job insecurity arising from regular leave of absence

Retention in care, resource utilization, and costs for adults receiving antiretroviral therapy in Zambia: a retrospective cohort study

PubMed Central

2014-01-01

Background Of the estimated 800,000 adults living with HIV in Zambia in 2011, roughly half were receiving antiretroviral therapy (ART). As treatment scale up continues, information on the care provided to patients after initiating ART can help guide decision-making. We estimated retention in care, the quantity of resources utilized, and costs for a retrospective cohort of adults initiating ART under routine clinical conditions in Zambia. Methods Data on resource utilization (antiretroviral [ARV] and non-ARV drugs, laboratory tests, outpatient clinic visits, and fixed resources) and retention in care were extracted from medical records for 846 patients who initiated ART at ≥15 years of age at six treatment sites between July 2007 and October 2008. Unit costs were estimated from the provider’s perspective using site- and country-level data and are reported in 2011 USD. Results Patients initiated ART at a median CD4 cell count of 145 cells/μL. Fifty-nine percent of patients initiated on a tenofovir-containing regimen, ranging from 15% to 86% depending on site. One year after ART initiation, 75% of patients were retained in care. The average cost per patient retained in care one year after ART initiation was $243 (95% CI, $194-$293), ranging from $184 (95% CI, $172-$195) to $304 (95% CI, $290-$319) depending on site. Patients retained in care one year after ART initiation received, on average, 11.4 months’ worth of ARV drugs, 1.5 CD4 tests, 1.3 blood chemistry tests, 1.4 full blood count tests, and 6.5 clinic visits with a doctor or clinical officer. At all sites, ARV drugs were the largest cost component, ranging from 38% to 84% of total costs, depending on site. Conclusions Patients initiate ART late in the course of disease progression and a large proportion drop out of care after initiation. The quantity of resources utilized and costs vary widely by site, and patients utilize a different mix of resources under routine clinical conditions than if they were

Plasma and breast-milk selenium in HIV-infected Malawian mothers are positively associated with infant selenium status but are not associated with maternal supplementation: results of the Breastfeeding, Antiretrovirals, and Nutrition study123

PubMed Central

Flax, Valerie L; Bentley, Margaret E; Combs, Gerald F; Chasela, Charles S; Kayira, Dumbani; Tegha, Gerald; Kamwendo, Debbie; Daza, Eric J; Fokar, Ali; Kourtis, Athena P; Jamieson, Denise J; van der Horst, Charles M; Adair, Linda S

2014-01-01

Background: Selenium is found in soils and is essential for human antioxidant defense and immune function. In Malawi, low soil selenium and dietary intakes coupled with low plasma selenium concentrations in HIV infection could have negative consequences for the health of HIV-infected mothers and their exclusively breastfed infants. Objective: We tested the effects of lipid-based nutrient supplements (LNS) that contained 1.3 times the Recommended Dietary Allowance of sodium selenite and antiretroviral drugs (ARV) on maternal plasma and breast-milk selenium concentrations. Design: HIV-infected Malawian mothers in the Breastfeeding, Antiretrovirals, and Nutrition study were randomly assigned at delivery to receive: LNS, ARV, LNS and ARV, or a control. In a subsample of 526 mothers and their uninfected infants, we measured plasma and breast-milk selenium concentrations at 2 or 6 (depending on the availability of infant samples) and 24 wk postpartum. Results: Overall, mean (±SD) maternal (range: 81.2 ± 20.4 to 86.2 ± 19.9 μg/L) and infant (55.6 ± 16.3 to 61.0 ± 15.4 μg/L) plasma selenium concentrations increased, whereas breast-milk selenium concentrations declined (14.3 ± 11.5 to 9.8 ± 7.3 μg/L) from 2 or 6 to 24 wk postpartum (all P < 0.001). Compared with the highest baseline selenium tertile, low and middle tertiles were positively associated with a change in maternal plasma or breast-milk selenium from 2 or 6 to 24 wk postpartum (both P < 0.001). With the use of linear regression, we showed that LNS that contained selenium and ARV were not associated with changes in maternal plasma and breast-milk selenium, but maternal selenium concentrations were positively associated with infant plasma selenium at 2 or 6 and 24 wk postpartum (P < 0.001) regardless of the study arm. Conclusions: Selenite supplementation of HIV-infected Malawian women was not associated with a change in their plasma or breast-milk selenium concentrations. Future research should examine

Microbicides: Topical Prevention against HIV

PubMed Central

Shattock, Robin J.; Rosenberg, Zeda

2012-01-01

Microbicides represent a potential intervention strategy for preventing HIV transmission. Vaginal microbicides would meet the need for a discreet method that women could use to protect themselves against HIV. Although early-generation microbicides failed to demonstrate efficacy, newer candidates are based on more potent antiretroviral (ARV) products. Positive data from the CAPRISA 004 trial of tenofovir gel support use in women and represent a turning point for the field. This article reviews current progress in development of ARV-based microbicides. We discuss the consensus on selection criteria, the potential for drug resistance, rationale for drug combinations, and the use of pharmacokinetic (PK)/pharmacodynamic (PD) assessment in product development. The urgent need for continued progress in development of formulations for sustained delivery is emphasized. Finally, as the boundaries between different prevention technologies become increasingly blurred, consideration is given to the potential synergy of diverse approaches across the prevention landscape. PMID:22355798

An Intravaginal Ring for the Simultaneous Delivery of an HIV-1 Maturation Inhibitor and Reverse-Transcriptase Inhibitor for Prophylaxis of HIV Transmission.

PubMed

Ugaonkar, Shweta R; Clark, Justin T; English, Lexie B; Johnson, Todd J; Buckheit, Karen W; Bahde, Robert J; Appella, Daniel H; Buckheit, Robert W; Kiser, Patrick F

2015-10-01

Nucleocapsid 7 (NCp7) inhibitors have been investigated extensively for their role in impeding the function of HIV-1 replication machinery and their ability to directly inactivate the virus. A class of NCp7 zinc finger inhibitors, S-acyl-2-mercaptobenzamide thioesters (SAMTs), was investigated for topical drug delivery. SAMTs are inherently unstable because of their hydrolytically labile thioester bond, thus requiring formulation approaches that can lend stability. We describe the delivery of N-[2-(3,4,5-trimethoxybenzoylthio)benzoyl]-β-alaninamide (SAMT-10), as a single agent antiretroviral (ARV) therapeutic and in combination with the HIV-1 reverse-transcriptase inhibitor pyrimidinedione IQP-0528, from a hydrophobic polyether urethane (PEU) intravaginal ring (IVR) for a month. The physicochemical stability of the ARV-loaded IVRs was confirmed after 3 months at 40°C/75% relative humidity. In vitro, 25 ± 3 mg/IVR of SAMT-10 and 86 ± 13 mg/IVR of IQP-0528 were released. No degradation of the hydrolytically labile SAMT-10 was observed within the matrix. The combination of ARVs had synergistic antiviral activity when tested in in vitro cell-based assays. Toxicological evaluations performed on an organotypic EpiVaginal(™) tissue model demonstrated a lack of formulation toxicity. Overall, SAMT-10 and IQP-0528 were formulated in a stable PEU IVR for sustained release. Our findings support the need for further preclinical evaluation. © 2015 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 104:3426-3439, 2015. © 2015 Wiley Periodicals, Inc. and the American Pharmacists Association.

Cultural conundrums: the ethics of epidemiology and the problems of population in implementing pre-exposure prophylaxis.

PubMed

Fiereck, Kirk

2015-04-01

The impending implementation of pre-exposure prophylaxis (PrEP) has prompted complicated bioethical and public health ethics concerns regarding the moral distribution of antiretroviral medications (ARVs) to ostensibly healthy populations as a form of HIV prevention when millions of HIV-positive people still lack access to ARVs globally. This manuscript argues that these questions are, in part, concerns over the ethics of the knowledge production practices of epidemiology. Questions of distribution, and their attendant cost-benefit calculations, will rely on a number of presupposed, and therefore, normatively cultural assumptions within the science of epidemiology specifically regarding the ability of epidemiologic surveillance to produce accurate maps of HIV throughout national populations. Specifically, ethical questions around PrEP will focus on who should receive ARVs given the fact that global demand will far exceed supply. Given that sexual transmission is one of the main modes of HIV transmission, these questions of 'who' are inextricably linked to knowledge about sexual personhood. As a result, the ethics of epidemiology, and how the epidemiology of HIV in particular conceives, classifies and constructs sexual populations will become a critical point of reflection and contestation for bioethicists, health activists, physicians, nurses, and researchers in the multi-disciplinary field of global health. This paper examines how cultural conundrums within the fields of bioethics and public health ethics are directly implicated within the ethics of PrEP, by analyzing the problems of population inaugurated by the construction of the men who have sex with men (MSM) epidemiologic category in the specific national context of South Africa. © 2013 John Wiley & Sons Ltd.

Perceptions among Dutch men who have sex with men and their willingness to use rectal microbicides and oral pre-exposure prophylaxis to reduce HIV risk--a preliminary study.

PubMed

Marra, Elske; Hankins, Catherine A

2015-01-01

Oral pre-exposure prophylaxis (PrEP) with antiretroviral (ARV) tablets and topical PrEP or microbicides containing ARV drugs could help to reduce HIV incidence. These methods hold promise for men who have sex with men (MSM) who are at higher risk of acquiring HIV. This mixed-methods study in the Netherlands explored perceptions of MSM and their willingness to use oral PrEP and rectal microbicides (RM) if made available. Recruited through social media (Facebook and Twitter), 108 MSM completed online questionnaires. Seven of them consented to discuss the survey results in semi-structured interviews. Survey participants preferred a RM that could be applied before and after anal intercourse (60.8%) to daily oral PrEP (20.3%). This preference was based on anticipated user friendliness, hypothetically fewer expected adverse events, and perceptions that RM would be less likely to be confused with ARVs for treatment. Those who preferred oral PrEP had stronger beliefs in the effectiveness of pills, perceived its use as easy, and viewed not requiring sexual partner awareness as advantages. No predictive factors were found for the choice of one prevention method over the other. Although Dutch MSM perceive both oral and topical PrEP positively, many barriers exist to the introduction of these products in the Netherlands. These include lack of regulatory approval of oral PrEP, no proven efficacy as yet for RM, and strong HIV stigma within the MSM population. In-depth qualitative research is needed to further explore the perceptions of MSM to inform implementation of programmes should these HIV prevention methods become available.

Cultural Conundrums: The Ethics of Epidemiology and the Problems of Population in Implementing Pre-Exposure Prophylaxis

PubMed Central

2013-01-01

The impending implementation of pre-exposure prophylaxis (PrEP) has prompted complicated bioethical and public health ethics concerns regarding the moral distribution of antiretroviral medications (ARVs) to ostensibly healthy populations as a form of HIV prevention when millions of HIV-positive people still lack access to ARVs globally. This manuscript argues that these questions are, in part, concerns over the ethics of epidemiological science and knowledge production practices. Questions of distribution, and their attendant cost-benefit calculations, will rely on a number of presupposed, and therefore, normatively cultural assumptions within the science of epidemiology specifically regarding the ability of epidemiological surveillance to produce accurate maps of HIV throughout national populations. Specifically, ethical questions around PrEP will focus on who should receive ARVs given the fact that global demand will far exceed supply. Given that sexual transmission is one of the main modes of HIV transmission, these questions of “who” are inextricably linked to knowledge about sex, gender and sexuality. As a result, the ethics of epidemiology, and how the epidemiology of HIV in particular conceives, classifies and constructs sexual populations will become a critical point of reflection and contestation for bioethicists, health activists, physicians, nurses, and researchers in the medical humanities and biomedicine. This paper examines how cultural conundrums within the fields of bio- and public health ethics are directly implicated within the ethics of PrEP, by analyzing the problems of population inaugurated by the construction of the men who have sex with men (MSM) epidemiological category in the specific national context of South Africa. PMID:24373050

Effectiveness and Safety of Generic Fixed-Dose Combination of Tenofovir/Emtricitabine/Efavirenz in HIV-1-Infected Patients in Western India

PubMed Central

Pujari, Sanjay; Dravid, Ameet; Gupte, Nikhil; Joshi, Kedar; Bele, Vivek

2008-01-01

Objective To assess effectiveness and safety of a generic fixed-dose combination of tenofovir (TDF)/emtricitabine (FTC)/efavirenz (EFV) among HIV-1-infected patients in Western India. Methods Antiretroviral (ARV)-naive and experienced (thymidine analog nucleoside reverse transcriptase inhibitor [tNRTI] replaced by TDF) patients were started on a regimen of 1 TDF/FTC/EFV pill once a day. They were followed clinically on a periodic basis, and viral loads and CD4 counts were measured at 6 and 12 months. Creatinine clearance was calculated at baseline and at 6 months and/or as clinically indicated. Effectiveness was defined as not having to discontinue the regimen due to failure or toxicity. Results One hundred forty-one patients who started TDF/FTC/EFV before 1 June 2007 were eligible. Of these, 130 (92.2%) and 44 (31.2%) had 6- and 12-months follow-up, respectively. Thirty-five percent of the patients were ARV-naive. Eleven patients discontinued treatment (4 for virologic failure, 1 for grade 3-4 central nervous system disturbances, 4 for grade 3-4 renal toxicity, and 2 for cost). Ninety-six percent of patients were virologically suppressed at 6 months. Frequency of TDF-associated grade 3-4 renal toxicity was 2.8%; however, 3 of these patients had comorbid conditions associated with renal dysfunction. Conclusion A fixed-dose combination of generic TDF/FTC/EFV is effective in ARV-naive and experienced patients. Although frequency of severe renal toxicity was higher than has been reported in the literature, it was safe in patients with no comorbid renal conditions. PMID:18924648

Effectiveness and safety of generic fixed-dose combination of tenofovir/emtricitabine/efavirenz in HIV-1-infected patients in Western India.

PubMed

Pujari, Sanjay; Dravid, Ameet; Gupte, Nikhil; Joshi, Kedar; Bele, Vivek

2008-01-01

To assess effectiveness and safety of a generic fixed-dose combination of tenofovir (TDF)/emtricitabine (FTC)/efavirenz (EFV) among HIV-1-infected patients in Western India. Antiretroviral (ARV)-naive and experienced (thymidine analog nucleoside reverse transcriptase inhibitor [tNRTI] replaced by TDF) patients were started on a regimen of 1 TDF/FTC/EFV pill once a day. They were followed clinically on a periodic basis, and viral loads and CD4 counts were measured at 6 and 12 months. Creatinine clearance was calculated at baseline and at 6 months and/or as clinically indicated. Effectiveness was defined as not having to discontinue the regimen due to failure or toxicity. One hundred forty-one patients who started TDF/FTC/EFV before 1 June 2007 were eligible. Of these, 130 (92.2%) and 44 (31.2%) had 6- and 12-months follow-up, respectively. Thirty-five percent of the patients were ARV-naive. Eleven patients discontinued treatment (4 for virologic failure, 1 for grade 3-4 central nervous system disturbances, 4 for grade 3-4 renal toxicity, and 2 for cost). Ninety-six percent of patients were virologically suppressed at 6 months. Frequency of TDF-associated grade 3-4 renal toxicity was 2.8%; however, 3 of these patients had comorbid conditions associated with renal dysfunction. A fixed-dose combination of generic TDF/FTC/EFV is effective in ARV-naive and experienced patients. Although frequency of severe renal toxicity was higher than has been reported in the literature, it was safe in patients with no comorbid renal conditions.

Effectiveness and Safety of Generic Fixed-Dose Combination of Tenofovir/Emtricitabine/Efavirenz in HIV-1-Infected Patients in Western India.

PubMed

Pujari, Sanjay; Dravid, Ameet; Gupte, Nikhil; Joshix, Kedar; Bele, Vivek

2008-08-20

To assess effectiveness and safety of a generic fixed-dose combination of tenofovir (TDF)/emtricitabine (FTC)/efavirenz (EFV) among HIV-1-infected patients in Western India. Antiretroviral (ARV)-naive and experienced (thymidine analog nucleoside reverse transcriptase inhibitor [tNRTI] replaced by TDF) patients were started on a regimen of 1 TDF/FTC/EFV pill once a day. They were followed clinically on a periodic basis, and viral loads and CD4 counts were measured at 6 and 12 months. Creatinine clearance was calculated at baseline and at 6 months and/or as clinically indicated. Effectiveness was defined as not having to discontinue the regimen due to failure or toxicity. One hundred forty-one patients who started TDF/FTC/EFV before 1 June 2007 were eligible. Of these, 130 (92.2%) and 44 (31.2%) had 6- and 12-months follow-up, respectively. Thirty-five percent of the patients were ARV-naive. Eleven patients discontinued treatment (4 for virologic failure, 1 for grade 3-4 central nervous system disturbances, 4 for grade 3-4 renal toxicity, and 2 for cost). Ninety-six percent of patients were virologically suppressed at 6 months. Frequency of TDF-associated grade 3-4 renal toxicity was 2.8%; however, 3 of these patients had comorbid conditions associated with renal dysfunction. A fixed-dose combination of generic TDF/FTC/EFV is effective in ARV-naive and experienced patients. Although frequency of severe renal toxicity was higher than has been reported in the literature, it was safe in patients with no comorbid renal conditions.

NASA's asteroid redirect mission: Robotic boulder capture option

NASA Astrophysics Data System (ADS)

Abell, P.; Nuth, J.; Mazanek, D.; Merrill, R.; Reeves, D.; Naasz, B.

2014-07-01

NASA is examining two options for the Asteroid Redirect Mission (ARM), which will return asteroid material to a Lunar Distant Retrograde Orbit (LDRO) using a robotic solar-electric-propulsion spacecraft, called the Asteroid Redirect Vehicle (ARV). Once the ARV places the asteroid material into the LDRO, a piloted mission will rendezvous and dock with the ARV. After docking, astronauts will conduct two extravehicular activities (EVAs) to inspect and sample the asteroid material before returning to Earth. One option involves capturing an entire small (˜4--10 m diameter) near-Earth asteroid (NEA) inside a large inflatable bag. However, NASA is also examining another option that entails retrieving a boulder (˜1--5 m) via robotic manipulators from the surface of a larger (˜100+ m) pre-characterized NEA. The Robotic Boulder Capture (RBC) option can leverage robotic mission data to help ensure success by targeting previously (or soon to be) well-characterized NEAs. For example, the data from the Japan Aerospace Exploration Agency's (JAXA) Hayabusa mission has been utilized to develop detailed mission designs that assess options and risks associated with proximity and surface operations. Hayabusa's target NEA, Itokawa, has been identified as a valid target and is known to possess hundreds of appropriately sized boulders on its surface. Further robotic characterization of additional NEAs (e.g., Bennu and 1999 JU_3) by NASA's OSIRIS REx and JAXA's Hayabusa 2 missions is planned to begin in 2018. This ARM option reduces mission risk and provides increased benefits for science, human exploration, resource utilization, and planetary defense.

Development and validation of the first liquid chromatography-tandem mass spectrometry assay for simultaneous quantification of multiple antiretrovirals in meconium.

PubMed

Himes, Sarah K; Scheidweiler, Karl B; Tassiopoulos, Katherine; Kacanek, Deborah; Hazra, Rohan; Rich, Kenneth; Huestis, Marilyn A

2013-02-05

A novel method for the simultaneous quantification of 16 antiretroviral (ARV) drugs and 4 metabolites in meconium was developed and validated. Quantification of 6 nucleoside/nucleotide reverse transcriptase inhibitors, 2 non-nucleoside reverse transcriptase inhibitors, 7 protease inhibitors, and 1 integrase inhibitor was achieved in 0.25 g of meconium. Specimen preparation included methanol homogenization and solid-phase extraction. Separate positive and negative polarity multiple reaction monitoring mode injections were required to achieve sufficient sensitivity. Linearity ranged from 10 to 75 ng/g up to 2500 ng/g for most analytes and 100-500 ng/g up to 25,000 ng/g for some; all correlation coefficients were ≥0.99. Extraction efficiencies from meconium were 32.8-119.5% with analytical recovery of 80.3-108.3% and total imprecision of 2.2-11.0% for all quantitative analytes. Two analytes with analytical recovery (70.0-138.5%) falling outside the 80-120% criteria range were considered semiquantitative. Matrix effects were -98.3-47.0% and -98.0-67.2% for analytes and internal standards, respectively. Analytes were stable (>75%) at room temperature for 24 h, 4 °C for 3 days, -20 °C for 3 freeze-thaw cycles over 3 days, and on the autosampler. Method applicability was demonstrated by analyzing meconium from HIV-uninfected infants born to HIV-positive mothers on ARV therapy. This method can be used as a tool to investigate the potential effects of in utero ARV exposure on childhood health and neurodevelopmental outcomes.

Antiretroviral therapeutic drug monitoring in HIV-infected pregnant women: maternal immunovirological outcome at delivery and during the 18 month follow-up period.

PubMed

Nicastri, Emanuele; Ivanovic, Jelena; Signore, Fabrizio; Tempestilli, Massimo; Bellagamba, Rita; Viscione, Magdalena; Pisani, Giuseppe; Vallone, Cristina; Tommasi, Chiara; Gallo, Anna L; De Nardo, Pasquale; Pucillo, Paolo L; Narciso, Pasquale

2012-10-01

No data are available on the long-term immunovirological outcome of HIV-positive pregnant women experiencing sub-therapeutic antiretroviral drug (ARV) concentrations during pregnancy. The objective of our study was to assess the long-term virological outcome in pregnant women treated with HAART. A prospective, multi-center study enrolled 60 HIV-infected pregnant women stratified into 3 groups according to the response to HAART. Group A, women successfully treated with HAART; Group B, women with confirmed virological failure during HAART; Group C, women successfully treated with HAART during pregnancy for prevention of vertical transmission only. Smoking, alcohol use, low adherence to therapy, and increased viral load at delivery were significantly associated to virological failure at univariate analysis. At multivariate regression analysis, only adherence to therapy was reported as an independent variable related to the virological response (p < 0.001). Virological failure during follow-up was reported in 2 (25.0%) of the 8 women with sub therapeutic Ctrough and in 4 of the 33 (12.1%) women with therapeutic Ctrough (p=0.33). In group C, the viro-immunological set points during follow-up did not differ from those observed before HAART initiation. No significantly increased rate of virological failure after delivery was reported in women with sub-therapeutic ARV concentrations during pregnancy and long-term follow-up. The long-term virological outcome was independently associated to reduced adherence to therapy. Evaluation of the clinical impact of the low plasma ARV concentrations during pregnancy on the long-term virological outcome deserves further larger studies.

Intimate partner violence and challenges facing women living with HIV/AIDS in accessing antiretroviral treatment at Singida Regional Hospital, central Tanzania

PubMed Central

Kosia, Agnes; Kakoko, Deodatus; Semakafu, Ave Maria Emilius; Nyamhanga, Tumaini; Frumence, Gasto

2016-01-01

Background Human immunodeficiency virus (HIV) remains a global public health problem. Sub-Saharan Africa is the region most affected by HIV/AIDS in the world. Globally, and in Tanzania in particular, women are more affected by HIV/AIDS than men. Tanzania has been reported to be among the countries with the highest burden of intimate partner violence (IPV). This study explored the challenges facing women living with HIV/AIDS (LWHA) attending the care and treatment clinic (CTC) in Singida Regional Hospital in Tanzania. Design A qualitative study was performed in which data were collected through in-depth interviews with 35 women LWHA who also experienced IPV. Content analysis was used to analyse the data. Results The study findings showed that women LWHA experienced challenges from their male partners in the form of lack of fare to attend CTC, delayed attendance to CTC, verbal threats and intimidation, mistrust partner resulting in changed antiretroviral (ARV) dosing time. Also, systemic challenges such as malfunction of CD4 count testing apparatus contributed to mistrust from their male partners which led to IPV. Conclusion In this study, women LWHA experienced IPV challenges that resulted in poor adherence to ARV medication and CTC attendance, as well as insufficient time to collect ARV medication. It is recommended that the government address systemic challenges faced by women LWHA, introduce multiple approaches to address the needs of women LWHA experiencing IPV, and develop strong policies to prevent IPV against women in Tanzania, regardless of their HIV status. PMID:27987296

In-vitro photo-translocation of antiretroviral drug delivery into TZMbl cells

NASA Astrophysics Data System (ADS)

Malabi, Rudzani; Manoto, Sello; Ombinda-Lemboumba, Saturnin; Maaza, Malik; Mthunzi-Kufa, Patience

2017-02-01

The current human immunodeficiency virus (HIV) treatment regime possesses the ability to diminish the viral capacity to unnoticeable levels; however complete eradication of the virus cannot be achieved while latent HIV-1 reservoirs go unchallenged. Therapeutic targeting of HIV therefore requires further investigation and current therapies need modification in order to address HIV eradication. This deflects research towards investigating potential novel antiretroviral drug delivery systems. The use of femtosecond (fs) laser pulses in promoting targeted optical drug delivery of antiretroviral drugs (ARVs) into TZMbl cells revolves around using ultrafast laser pulses that have high peak powers, which precisely disrupt the cell plasma membrane in order to allow immediate transportation and expression of exogenous material into the live mammalian cells. A photo-translocation optical setup was built and validated by characterisation of the accurate parameters such as wavelength (800 nm) and pulse duration (115 fs). Optimisation of drug translocation parameters were done by performing trypan blue translocation studies. Cellular responses were determined via cell viability (Adenosine Triphosphate activity) and cell cytotoxicity (Lactate Dehydrogenase) assays which were done to study the influence of the drugs and laser exposure on the cells. After laser irradiation, high cell viability was observed and low toxicity levels were observed after exposure of the cells to both the ARVs and the laser. Our results confirmed that, with minimal damage and high therapeutic levels of ARVs, the fs laser assisted drug delivery system is efficient with benefits of non-invasive and non-toxic treatment to the cells.

Knowledge of antiretrovirals in preventing parentto-child-transmission of HIV: a cross-sectional study among women living with HIV in Tamil Nadu, India.

PubMed

Rastogi, Saumya; Charles, Bimal; Sam, Asirvatham E

2012-01-01

India is amongst the top 10 countries in the world currently with the highest burden of pregnant women living with HIV and nearly 80% of these women do not receive antiretroviral (ARV) drugs to prevent parent-to-child transmission (PTCT) of HIV. The aim of this study was to estimate HIV-infected women's awareness on PTCT and knowledge of ARVs as a measure to prevent PTCT. This was a descriptive, cross-sectional study in which a total of 986 women with HIV aged 18 years and above were interviewed in 13 high HIV prevalence districts of Tamil Nadu, South India. Data were analysed using descriptive, bivariate and multivariate methods. Nearly one fifth (18.8%) of the women with HIV had not heard of PTCT and 40% did not know that ARVs could prevent PTCT. In addition, 39.3% were not aware of the timing of PTCT; 50.4% reported intrauterine and intrapartum and 13.7% mentioned breastfeeding period as the possible timings of PTCT of HIV. Multivariate analysis showed that single/never married women had lower knowledge of PTCT. Also, those who had undergone a prior training on reproductive and child health (RCH) and those who discussed RCH issues with their partners were more likely to have higher knowledge. Considering the risk of HIV transmission from HIV-infected women to their children, the knowledge level of PTCT among them is low. Appropriate strategies to generate awareness among women with HIV need be introduced to help them make informed decisions.

Evaluation of Two New Indices of Blood Pressure Variability Using Postural Change in Older Fallers.

PubMed

Goh, Choon-Hian; Ng, Siew-Cheok; Kamaruzzaman, Shahrul B; Chin, Ai-Vyrn; Poi, Philip J H; Chee, Kok Han; Imran, Z Abidin; Tan, Maw Pin

2016-05-01

To evaluate the utility of blood pressure variability (BPV) calculated using previously published and newly introduced indices using the variables falls and age as comparators.While postural hypotension has long been considered a risk factor for falls, there is currently no documented evidence on the relationship between BPV and falls.A case-controlled study involving 25 fallers and 25 nonfallers was conducted. Systolic (SBPV) and diastolic blood pressure variability (DBPV) were assessed using 5 indices: standard deviation (SD), standard deviation of most stable continuous 120 beats (staSD), average real variability (ARV), root mean square of real variability (RMSRV), and standard deviation of real variability (SDRV). Continuous beat-to-beat blood pressure was recorded during 10 minutes' supine rest and 3 minutes' standing.Standing SBPV was significantly higher than supine SBPV using 4 indices in both groups. The standing-to-supine-BPV ratio (SSR) was then computed for each subject (staSD, ARV, RMSRV, and SDRV). Standing-to-supine ratio for SBPV was significantly higher among fallers compared to nonfallers using RMSRV and SDRV (P = 0.034 and P = 0.025). Using linear discriminant analysis (LDA), 3 indices (ARV, RMSRV, and SDRV) of SSR SBPV provided accuracies of 61.6%, 61.2%, and 60.0% for the prediction of falls which is comparable with timed-up and go (TUG), 64.4%.This study suggests that SSR SBPV using RMSRV and SDRV is a potential predictor for falls among older patients, and deserves further evaluation in larger prospective studies.

Analysis of Antiretrovirals in Single Hair Strands for Evaluation of Drug Adherence with Infrared-Matrix-Assisted Laser Desorption Electrospray Ionization Mass Spectrometry Imaging.

PubMed

Rosen, Elias P; Thompson, Corbin G; Bokhart, Mark T; Prince, Heather M A; Sykes, Craig; Muddiman, David C; Kashuba, Angela D M

2016-01-19

Adherence to a drug regimen can be a strong predictor of health outcomes, and validated measures of adherence are necessary at all stages of therapy from drug development to prescription. Many of the existing metrics of drug adherence (e.g., self-report, pill counts, blood monitoring) have limitations, and analysis of hair strands has recently emerged as an objective alternative. Traditional methods of hair analysis based on LC-MS/MS (segmenting strands at ≥1 cm length) are not capable of preserving a temporal record of drug intake at higher resolution than approximately 1 month. Here, we evaluated the detectability of HIV antiretrovirals (ARVs) in hair from a range of drug classes using infrared matrix-assisted laser desorption electrospray ionization (IR-MALDESI) mass spectrometry imaging (MSI) with 100 μm resolution. Infrared laser desorption of hair strands was shown to penetrate into the strand cortex, allowing direct measurement by MSI without analyte extraction. Using optimized desorption conditions, a linear correlation between IR-MALDESI ion abundance and LC-MS/MS response was observed for six common ARVs with estimated limits of detection less than or equal to 1.6 ng/mg hair. The distribution of efavirenz (EFV) was then monitored in a series of hair strands collected from HIV infected, virologically suppressed patients. Because of the role hair melanin plays in accumulation of basic drugs (like most ARVs), an MSI method to quantify the melanin biomarker pyrrole-2,3,5-tricarboxylic acid (PTCA) was evaluated as a means of normalizing drug response between patients to develop broadly applicable adherence criteria.

76 FR 2683 - Notice of a Project Waiver of Section 1605: (Buy American Requirement) of the American Recovery...

Federal Register 2010, 2011, 2012, 2013, 2014

2011-01-14

... Water State Revolving Fund (CWSRF)/ARRA loan recipient, for the purchase of Air Release Vacuum (ARV... CONTACT: Abimbola Odusoga, Environmental Engineer, Water Division, Infrastructure Office (WTR-4), (415... provides drinking water and waste water treatment services to municipalities in the Chino Basin. The Church...

Expression of the Broad Autism Phenotype in Simplex Autism Families from the Simons Simplex Collection

ERIC Educational Resources Information Center

Davidson, Julie; Goin-Kochel, Robin P.; Green-Snyder, Lee Anne; Hundley, Rachel J.; Warren, Zachary; Peters, Sarika U.

2014-01-01

The broad autism phenotype (BAP) refers to the phenotypic expression of an underlying genetic liability to autism, manifest in non-autistic relatives. This study examined the relationship among the "Broad Autism Phenotype Questionnaire" (BAPQ), "Social Responsiveness Scale: Adult Research Version" (SRS:ARV), and "Family…

Reovirus infections

USDA-ARS?s Scientific Manuscript database

Avian reoviruses (ARV) are widespread worldwide and may infect turkeys, chickens and other avian species, including domestic waterfowl and game birds. The virus is non-enveloped double-stranded RNA, therefore is environmentally stable and due to its segmented genome can generate variants easily. A...

The Political Demography of Bangladesh,

DTIC Science & Technology

1972-04-13

ment by expanding the bureaucracy?) page seven d. The impact of population grcwth on gnera:tional cleavanges. Arv there division between political ... socialization experiences ancd therefore di1vergent pol.itical outlooKs%? To what extent are the cleavagecs in Bengalx politics - between the Auami League

Patients' Ways of Speaking about Antiretroviral Medications and Possible Implications for Adherence

ERIC Educational Resources Information Center

Delbene, Roxana

2012-01-01

The medical literature reports that antiretrovirals (ARVs) are considered attitudinal objects (Dunbar-Jacob, 1995). Drawing on the pragmatics of emotion (Caffi & Janney, 1994), this study analyzes how patients' stances about their ARTs shape their emotional relationships with their treatments. The data, collected in a public hospital in…

The effects of a lipid-based nutrient supplement and antiretroviral therapy in a randomized controlled trial on iron, copper, and zinc in milk from HIV+ Malawian mothers and associations with maternal and infant biomarkers

USDA-ARS?s Scientific Manuscript database

We evaluated effects of antiretroviral (ARV) therapy and lipid-based nutrient supplements (LNS) on iron, copper and zinc in milk of exclusively breastfeeding HIV-infected Malawian mothers, and their correlations with maternal and infant biomarkers. Breast milk at 2, 6, and 24 weeks (wk) postpartum a...

Vulvar and vaginal cancers and dysplasia in France--an analysis of the hospital medical information system (PMSI) database.

PubMed

Rémy, Vanessa; Mathevet, Patrice; Vainchtock, Alexandre

2009-12-01

Literature on the epidemiology of vulvar and vaginal cancers is scarce. The incidence of these diseases seems to be increasing. It has been reported that about 40% of vulvar and 70% of vaginal cancers may be linked to human papillomavirus (HPV). This study aimed to assess the medical burden associated with hospitalizations and management of vulvar and vaginal cancers and dysplasia (VIN and VaIN) in France. A retrospective analysis using the French national hospital database (PMSI) was performed to assess the annual number of patients hospitalized for vulvar and vaginal cancers and VIN/VaIN, based on hospital admissions in 2006. Data for all stays and chemotherapy/radiotherapy sessions were extracted. SAE database (Statistiques annuelles des établissements de santé) was used to take into account patients who had radiotherapy sessions performed in the private sector which are not reported in the PMSI. In 2006, 1237 and 623 patients were hospitalized for vulvar cancer and VIN, respectively. There were also 728 and 244 patients hospitalized for vaginal cancer and VaIN, respectively. Overall, about 35% of all patients were hospitalized in the private setting. For all lesions except vaginal cancer, surgery was the most common type of management. For vaginal cancer, medical care was the most prevalent (52%), followed by surgery (31%). The burden of hospitalizations due to vulvar and vaginal cancers is substantial. Further research is needed to assess the outpatient burden due to these diseases especially for precancerous dysplasia which may be mostly managed in an outpatient setting.

Getting into the brain: Potential of nanotechnology in the management of NeuroAIDS.

PubMed

Nair, Madhavan; Jayant, Rahul Dev; Kaushik, Ajeet; Sagar, Vidya

2016-08-01

In spite of significant advances in antiretroviral (ARV) therapy, the elimination of human immunodeficiency virus (HIV) reservoirs from the periphery and the central nervous system (CNS) remains a formidable task. The incapability of ARV to go across the blood-brain barrier (BBB) after systemic administration makes the brain one of the dominant HIV reservoirs. Thus, screening, monitoring, and elimination of HIV reservoirs from the brain remain a clinically daunting and key task. The practice and investigation of nanomedicine possesses potentials for therapeutics against neuroAIDS. This review highlights the advancements in nanoscience and nanotechnology to design and develop specific size therapeutic cargo for efficient navigation across BBB so as to recognize and eradicate HIV brain reservoirs. Different navigation and drug release strategies, their biocompatibility and efficacy with related challenges and future prospects are also discussed. This review would be an excellent platform to understand nano-enable multidisciplinary research to formulate efficient nanomedicine for the management of neuroAIDS. Copyright © 2016 Elsevier B.V. All rights reserved.

HIV and the moral economy of survival in an East African City.

PubMed

Prince, Ruth

2012-12-01

Based on fieldwork in the city of Kisumu, Kenya, the article examines the survival of HIV-positive people on antiretroviral (ARV) medicines and situates this within broader moral economies of their lives-in matters of food, hunger, social relationships, and networks of care, including NGOs. Through locating survival at the level of individual adherence to medication, ARV programs medicalize it. Yet their focus on the intimate relation between medicine and food also opens up spaces in which the material conditions of life can be articulated. The article follows these spaces, from the clinic to the economy of NGO interventions and community-based groups, paying attention to how hunger and material needs are visible in some spaces and invisible in others, and to how people have learned to articulate their "needs." In this economy, HIV identities accrue moral and economic value, as through them people become visible to the flow of funds and the distribution of goods organized by NGOs. © 2012 by the American Anthropological Association.

Different intracellular distribution of avian reovirus core protein sigmaA in cells of avian and mammalian origin

DOE Office of Scientific and Technical Information (OSTI.GOV)

Vazquez-Iglesias, Lorena; Lostale-Seijo, Irene; Martinez-Costas, Jose

2012-10-25

A comparative analysis of the intracellular distribution of avian reovirus (ARV) core protein sigmaA in cells of avian and mammalian origin revealed that, whereas the viral protein accumulates in the cytoplasm and nucleolus of avian cells, most sigmaA concentrates in the nucleoplasm of mammalian cells in tight association with the insoluble nuclear matrix fraction. Our results further showed that sigmaA becomes arrested in the nucleoplasm of mammalian cells via association with mammalian cell-specific factors and that this association prevents nucleolar targeting. Inhibition of RNA polymerase II activity, but not of RNA polymerase I activity, in infected mammalian cells induces nucleus-to-cytoplasmmore » sigmaA translocation through a CRM1- and RanGTP-dependent mechanism, yet a heterokaryon assay suggests that sigmaA does not shuttle between the nucleus and cytoplasm. The scarcity of sigmaA in cytoplasmic viral factories of infected mammalian cells could be one of the factors contributing to limited ARV replication in mammalian cells.« less

Strategies to improve HIV treatment adherence in developed countries: clinical management at the individual level

PubMed Central

Enriquez, Maithe; McKinsey, David S

2011-01-01

Remarkable advances in the treatment of human immunodeficiency virus (HIV) disease have been blunted by widespread suboptimal adherence (ie, nonadherence), which has emerged as a major barrier to achieving the primary goal of antiretroviral (ARV) therapy: suppression of HIV viral load. Nonsuppressed HIV viral load is associated with drug resistance, increased morbidity and mortality, and a higher risk of person-to-person HIV transmission. For HIV-infected individuals who are failing HIV treatment due to nonadherence, becoming adherent is a life-saving behavior change. However, overcoming nonadherence is one of the most daunting challenges in the successful management of HIV disease. The purpose of this paper is to provide clinicians with a better understanding of nonadherence to ARV treatment and to review the various factors that have been associated with either adherence or nonadherence. Strategies are presented that may help the nonadherent individual become ready to take HIV medications as prescribed. PMID:22096406

Chylothorax after left side pneumothorax surgery managed by OK-432 pleurodesis: an effective alternative.

PubMed

Huang, Sheng-Yang; Yeh, Chou-Ming; Chou, Chia-Man; Chen, Hou-Chuan

2014-12-01

Chylothorax, a relatively rare complication of thoracic surgery, mostly occurs on the right side. We present a 16-year-old male who received thoracoscopic surgery for left spontaneous pneumothorax. Chylothorax developed on the postoperative 2(nd) day and resolved after diet control on the 4(th) day. Unfortunately, chylothorax recurred 2 weeks later. Chest drainage and nil per os with total parental nutrition were given but in vain. Thereafter, chemical pleurodesis with OK-432 was performed. Chylothorax resolved on the next day. The relevant literature is reviewed and possible pathogenesis clarified. Copyright © 2014. Published by Elsevier Taiwan.

Floquet Topological Insulators in Uranium Compounds

NASA Astrophysics Data System (ADS)

Pi, Shu-Ting; Savrasov, Sergey

2014-03-01

A major issue regarding the Uranium based nuclear fuels is to conduct the heat from the core area to its outer area. Unfortunately, those materials are notorious for their extremely low thermal conductivity due to the phonon-dominated-heat-transport properties in insulating states. Although metallic Uranium compounds are helpful in increasing the thermal conductivity, their low melting point still make those efforts in vain. In this report, we will figure out potential Uranium based Floquet topological insulators where the insulating bulk states accompanied with metallic surface states is achieved by applying periodic electrical fields which makes the coexistence of both benefits possible.

Problems associated with substandard and counterfeit drugs in developing countries: a review article on global implications of counterfeit drugs in the era of antiretroviral (ARVs) drugs in a free market economy.

PubMed

Nsimba, Stephen E D

2008-12-01

To review the global implications associated with the use of substandard and or counterfeit drugs in developing and may be developed countries. The focus of this review is particularly on antiretroviral (ARVs), antimalarials and other drugs. Review of various literatures through Pub-Med, Medline, Google and Internet search to retrieve and download published materials was done by the author of this review paper. When patients receive a counterfeit medicines, they are subjected to multiple risks. They often suffer more than just an inconvenience; as they become victims of fraud medicines and are all put at risk of adverse effects from unprescribed medicines or substandard ingredients. Additionally, patients may lose confidence in health care professionals including their physician and pharmacist, and potentially modern medicine or the pharmaceutical industry in general. Counterfeit or substandard (poor quality) drugs pose threats to society; not only to the individual in terms of the health side effects experienced, but also to the public in terms of trade relations, economic implications, and the effects on global pandemics. It is vital for suppliers, providers, and patients to be aware of current trends in counterfeiting in order to best prepare for encounters with suspicious products. Furthermore, this is an issue that needs to be continually dealt with on national and international policy levels. Developing countries should try their level best to establish good laboratories for monitoring and checking quality of all pharmaceuticals manufactured locally and those imported or donated to these countries. The Ministries of Health and all stakeholders involved in this issue must ensure that all drugs meet the set or established international standards and national standards. Failure to do so will be to misuse the hard earned forex that is normally borrowed from banks for the procurement and distribution of drugs to its people. Indeed sub-standard medications do more

An adherence trilogy is essential for long-term HAART success.

PubMed

Garcia, Rosa; Schooley, Robert T; Badaró, Roberto

2003-10-01

Adherence is the milestone of a successful therapy. Over the last decade several authors have addressed the importance of adherence for optimal results of antiretroviral (ARV) therapy. Many health care systems are investing substantial resources to make available contemporary antiretroviral therapy. Despite the large investment in medications, insufficient investments have been made into an integrated adherence component to maximize the impact of these medications. Adherence, unlike drug therapy, cannot be defined as a single method with a defined prescription or formula. Instead, it is the result of a complex interaction between the patient, a prescribed medication and the health system. Many reports are available analyzing each of these components. We have found that critical elements of adherence include the patient's knowledge about the disease and how medications will help achieve a longer and healthier life, together with the motivation to adapt to a new style of life. A trilogy composed of information, motivation and behavioral skills is essential to achieve the maximum desired level of adherence. We have computerized this trilogy in a software program for self-administration in which each of the three components is provided to the patient as many times as necessary to transmit an understanding of the problem and to help make a rational decision to adhere to the ARV treatment program. In this review we analyze several efforts and techniques to improve adherence to any recommended medication that may interfere with the patient's lifestyle and outline how the adherence trilogy can be best used to optimize the ability of ARV therapy to durably suppress plasma HIV RNA to undetectable levels.

Islamic perspectives on HIV/AIDS and antiretroviral treatment: the case of Nigeria.

PubMed

Balogun, Amusa Saheed

2010-12-01

Some religious reactions to the HIV epidemic in Africa unwittingly contributed to the expansion of the epidemic in its early years. This was because many religious people regarded the emergence of HIV and AIDS as divine punishment for man's sins as a result of people's sexual promiscuity. Some also opposed public promotion of the use of condoms for HIV prevention. However, religious bodies have made positive contributions to HIV/AIDS responses in many African countries in recent times. Though Christian bodies are taking the lead in faith-based responses to HIV and AIDS in Africa, Islamic bodies have also been major partners in HIV/AIDS interventions in several countries. Against this background, this article examines some Islamic perceptions of HIV and AIDS, and especially the impact of antiretroviral treatment (ART) for people living with HIV in Africa, with particular emphasis on Nigeria. In spite of the emergence of antiretroviral (ARV) drugs in Africa, Islam still emphasises the prevention of new infections and care for people living with HIV or AIDS. The article discusses basic issues associated with ARVs, such as health, sickness, life-prolongation and death, from an Islamic viewpoint, as well as some Islamic measures to prevent HIV-risk-taking behaviours in an era of ARVs. It also looks at the nature and extent of Islamic involvement in the national HIV/AIDS response in Nigeria. The paper concludes that while Islam sees HIV and AIDS and other diseases as 'tests' from Allah, the religion is not opposed to ART. Thus, efforts need to be intensified by Islamic bodies and Muslim leaders in Nigeria for an improved response to HIV and AIDS in the country.

Abasic Phosphorothioate Oligomers Inhibit HIV-1 Reverse Transcription and Block Virus Transmission across Polarized Ectocervical Organ Cultures

PubMed Central

Fraietta, Joseph A.; Mueller, Yvonne M.; Lozenski, Karissa L.; Ratner, Deena; Boesteanu, Alina C.; Hancock, Aidan S.; Lackman-Smith, Carol; Zentner, Isaac J.; Chaiken, Irwin M.; Chung, Suhman; LeGrice, Stuart F. J.; Snyder, Beth A.; Mankowski, Marie K.; Jones, Natalie M.; Hope, Jennifer L.; Gupta, Phalguni; Anderson, Sharon H.; Wigdahl, Brian

2014-01-01

In the absence of universally available antiretroviral (ARV) drugs or a vaccine against HIV-1, microbicides may offer the most immediate hope for controlling the AIDS pandemic. The most advanced and clinically effective microbicides are based on ARV agents that interfere with the earliest stages of HIV-1 replication. Our objective was to identify and characterize novel ARV-like inhibitors, as well as demonstrate their efficacy at blocking HIV-1 transmission. Abasic phosphorothioate 2′ deoxyribose backbone (PDB) oligomers were evaluated in a variety of mechanistic assays and for their ability to inhibit HIV-1 infection and virus transmission through primary human cervical mucosa. Cellular and biochemical assays were used to elucidate the antiviral mechanisms of action of PDB oligomers against both lab-adapted and primary CCR5- and CXCR4-utilizing HIV-1 strains, including a multidrug-resistant isolate. A polarized cervical organ culture was used to test the ability of PDB compounds to block HIV-1 transmission to primary immune cell populations across ectocervical tissue. The antiviral activity and mechanisms of action of PDB-based compounds were dependent on oligomer size, with smaller molecules preventing reverse transcription and larger oligomers blocking viral entry. Importantly, irrespective of molecular size, PDBs potently inhibited virus infection and transmission within genital tissue samples. Furthermore, the PDB inhibitors exhibited excellent toxicity and stability profiles and were found to be safe for vaginal application in vivo. These results, coupled with the previously reported intrinsic anti-inflammatory properties of PDBs, support further investigations in the development of PDB-based topical microbicides for preventing the global spread of HIV-1. PMID:25224013

Effectiveness and Safety of Generic Fixed-Dose Combination of Tenofovir/Emtricitabine/Efavirenz in HIV-1-Infected Patients in Western India

PubMed Central

2008-01-01

Objective To assess effectiveness and safety of a generic fixed-dose combination of tenofovir (TDF)/emtricitabine (FTC)/efavirenz (EFV) among HIV-1-infected patients in Western India. Methods Antiretroviral (ARV)-naive and experienced (thymidine analog nucleoside reverse transcriptase inhibitor [tNRTI] replaced by TDF) patients were started on a regimen of 1 TDF/FTC/EFV pill once a day. They were followed clinically on a periodic basis, and viral loads and CD4 counts were measured at 6 and 12 months. Creatinine clearance was calculated at baseline and at 6 months and/or as clinically indicated. Effectiveness was defined as not having to discontinue the regimen due to failure or toxicity. Results One hundred forty-one patients who started TDF/FTC/EFV before 1 June 2007 were eligible. Of these, 130 (92.2%) and 44 (31.2%) had 6- and 12-months follow-up, respectively. Thirty-five percent of the patients were ARV-naive. Eleven patients discontinued treatment (4 for virologic failure, 1 for grade 3–4 central nervous system disturbances, 4 for grade 3–4 renal toxicity, and 2 for cost). Ninety-six percent of patients were virologically suppressed at 6 months. Frequency of TDF-associated grade 3–4 renal toxicity was 2.8%; however, 3 of these patients had comorbid conditions associated with renal dysfunction. Conclusion A fixed-dose combination of generic TDF/FTC/EFV is effective in ARV-naive and experienced patients. Although frequency of severe renal toxicity was higher than has been reported in the literature, it was safe in patients with no comorbid renal conditions. PMID:19825144

Challenges in infant and young child nutrition in the context of HIV.

PubMed

Sint, Tin Tin; Lovich, Ronnie; Hammond, Wendy; Kim, Maria; Melillo, Sara; Lu, Lydia; Ching, Pamela; Marcy, Jennifer; Rollins, Nigel; Koumans, Emilia H; Heap, Amie N; Brewinski-Isaacs, Margaret

2013-11-01

There is consensus on the benefits for all infants of exclusive breastfeeding for 6 months and introduction of appropriate complementary foods at 6 months, followed by continued breastfeeding. However, guidelines on infant and young child feeding (IYCF) for HIV-positive mothers have changed continually since 2000. This article explores issues and evidence related to IYCF for the prevention and care of paediatric HIV in resource-limited settings in light of new HIV treatment guidelines, implementation challenges and knowledge gaps.In 2010 the impact of antiretroviral drugs (ARVs) on reducing the risk of mother-to-child transmission of HIV moved WHO to urge countries to endorse either avoidance of all breastfeeding or exclusive breastfeeding for the first 6 months while taking ARVs, depending on which strategy could give their infants the greatest chance of HIV-free survival. Implementation of the 2010 recommendations is challenged by lack of healthcare provider training, weak clinic-community linkages to support mother/infant pairs and lack of national monitoring and reporting on infant feeding indicators.More evidence is needed to inform prevention and treatment of malnutrition among HIV-exposed and HIV-infected children. Knowledge gaps include the effects of prolonged ARV exposure, the cause of HIV-associated growth faltering, the effects of early infant testing on continuation of breastfeeding and specific nutrition interventions needed for HIV-infected children.Significant progress has been made toward keeping mothers alive and reducing paediatric HIV infection, but sustained political, financial and scientific commitment are required to ensure meaningful interventions to eliminate postnatal transmission and meet the nutritional needs of HIV-exposed and HIV-infected children.

Meconium Atazanavir Concentrations and Early Language Outcomes in HIV-Exposed Uninfected Infants With Prenatal Atazanavir Exposure.

PubMed

Himes, Sarah K; Huo, Yanling; Siberry, George K; Williams, Paige L; Rice, Mabel L; Sirois, Patricia A; Frederick, Toni; Hazra, Rohan; Huestis, Marilyn A

2015-06-01

To investigate whether prenatal atazanavir (ATV) exposure, assessed by meconium antiretroviral (ARV) quantification, predicts early child language outcomes. Prenatal ATV exposure previously was associated with poorer language development in 1-year olds. Pregnant women with HIV and their uninfected infants enrolled in the Surveillance Monitoring of Antiretroviral Therapy Toxicities study. Meconium ARV concentrations were quantified by liquid chromatography-tandem mass spectrometry. Language development at 1 year was assessed with MacArthur-Bates Communicative Development Inventory (CDI) and Bayley Scales of Infant and Toddler Development-Third Edition (Bayley-III). Late language emergence was defined as ≥ 1 of 4 CDI scores ≤ 10th percentile for age. Associations between fetal ATV exposure timing and duration, meconium ATV concentration, and language outcomes were evaluated, adjusting for potential confounders. Through 2013, meconium samples were available from 175 of 432 infants with prenatal ATV exposure. Valid Bayley-III (n = 93) and CDI (n = 106) assessments also were available. After adjustment for potential confounders, higher ATV meconium concentrations were associated with lower late language emergence risk (P = 0.04) and cumulative ATV exposure duration also was associated with higher Bayley-III Language scores (P = 0.03). Maternal ATV duration and initiation week correlated with ATV meconium concentrations (positively and negatively, respectively). Higher meconium ATV concentrations were protective against developmental language delays at 1 year, suggesting the importance of fetal ATV detoxification into meconium. This information supports ATV exposure safety for infant language development. ATV is a preferred ARV for pregnant women with HIV, suggesting the importance of ATV safety investigations. Additionally, further pursuit of the influences on language development in HIV-exposed uninfected infants is required.

Correlation of Respiratory Activity of Contralateral Diaphragm Muscles for Evaluation of Recovery Following Hemiparesis

PubMed Central

Dow, Douglas E.; Zhan, Wen-Zhi; Sieck, Gary C.; Mantilla, Carlos B.

2014-01-01

Respiration is impaired by disruption of the central drive for inspiration to the diaphragm muscle (DIAm). Some function may recover involving nerve regeneration, reinnervation or neuroplasticity. A research animal model involves inducing hemiparesis of the DIAm and monitoring any recovery under different conditions. Methods to accurately track the level of functional recovery are needed. In this study, an algorithm was developed and tested to quantify the relative amount of electromyogram (EMG) activity that temporally correlated for an experimental (EXP) hemi-DIAm with its intact contralateral hemi-DIAm. An average rectified value (ARV) trace was calculated. A template was formed of the ARV trace of the intact hemi-DIAm, with higher positive values corresponding with periods of inspirations and lower negative values corresponding with quiet periods. This template was multiplied by the EXP ARV trace to reward (more positive) periods of correlating activity, and punish (more negative) periods of high activity on the EXP side that corresponded with quiet periods on the intact side. The average integrated value was the index of correlating contralateral activity (ICCA). A negative ICCA value indicated no net correlation of activity, and a positive value indicated a net correlation of activity. The algorithm was tested on rats having the conditions of control or hemi-paresis induced by denervatation (DNV), tetrodotoxin administration (TTX) or cervical spinal hemi-section (SH). Control had high positive ICCA values, and DNV had negative values. TTX maintained negative ICCA values at 3, 7 and 14 days, indicating a lack of functional recovery. SH maintained negative values at 3 and 7 days, but a subset had positive values at 14 days indicating some functional recovery. PMID:19965125

HIV salvage therapy does not require nucleoside reverse transcriptase inhibitors: a randomized trial

PubMed Central

Tashima, Karen T; Smeaton, Laura M; Fichtenbaum, Carl J; Andrade, Adriana; Eron, Joseph J; Gandhi, Rajesh T; Johnson, Victoria A; Klingman, Karin L; Ritz, Justin; Hodder, Sally; Santana, Jorge L; Wilkin, Timothy; Haubrich, Richard H

2015-01-01

Background Nucleoside reverse transcriptase inhibitors (NRTIs) are often included in antiretroviral (ARV) regimens in treatment-experienced patients in the absence of data from randomized trials. Objective To compare treatment success between participants who omit versus Add NRTIs to an optimized ARV regimen of three or more agents. Design Multisite, randomized, controlled trial. Setting Outpatient HIV clinics. Participants HIV-infected patients with three-class ARV experience and/or viral resistance. Intervention Open-label optimized regimens (not including NRTIs) were selected based upon treatment history and susceptibility testing. Participants were randomized to Omit or Add NRTIs. Measurements The primary efficacy outcome was regimen failure through week 48, using a non-inferiority margin of 15%. The primary safety outcome was time to initial episode of severe sign/symptom or laboratory abnormality prior to discontinuation of NRTI assignment. Results 360 participants were randomized and 93% completed a week 48 visit. The cumulative probability of regimen failure was 29.8% in the Omit NRTI arm versus 25.9% in the Add NRTI arm (difference= 3.2%: 95% CI, −6.1 to 12.5). There were no significant differences in the primary safety endpoints or the proportion of participants with HIV RNA <50 copies/mL between arms. No deaths occurred in the Omit NRTIs arm, compared with 7 deaths in the Add NRTIs arm. Limitations Non-blinded study design and may not be applicable to resource poor settings. Conclusion HIV-infected treatment-experienced patients starting a new optimized regimen can safely omit NRTIs without compromising virologic efficacy. Omitting NRTIs will reduce pill burden, cost, and toxicity in this patient population. PMID:26595748

Blood pressure variability is increasing from the first to the second day of the interdialytic interval in hemodialysis patients.

PubMed

Karpetas, Antonios; Loutradis, Charalampos; Bikos, Athanasios; Tzanis, Georgios; Koutroumpas, Georgios; Lazaridis, Antonios A; Mavromatidis, Konstantinos; Liakopoulos, Vassilios; Papagianni, Aikaterini; Zebekakis, Pantelis; Ruilope, Luis M; Parati, Gianfranco; Sarafidis, Pantelis A

2017-12-01

Patients with end-stage renal-disease under hemodialysis have increased cardiovascular risk and experience severe blood pressure (BP) fluctuations during the dialysis session and the subsequent interdialytic period. BP variability (BPV) may be an additional risk factor for cardiovascular events and preliminary data suggest increased BPV with advancing stages of chronic kidney disease. This is the first study to examine BPV during the whole intradialytic and interdialytic period in hemodialysis patients with ambulatory BP monitoring. A total of 160 patients receiving maintenance hemodialysis had 48-h ambulatory BP monitoring with the Mobil-O-Graph device during a regular dialysis session and the subsequent interdialytic interval. Brachial and aortic BPV were calculated with validated formulas and were compared between Days 1 and 2 of the interdialytic period (44-h), Days 1 and 2 of the total 48-h interval (including the dialysis session), and between the two respective daytime periods and night-time periods. All brachial SBPV indices [SD: 14.75 ± 4.38 vs. 15.91 ± 4.41, P = 0.001; weighted SD: 13.80 ± 4.00 vs. 14.89 ± 3.90, P < 0.001; coefficient of variation (CV): 11.34 ± 2.91 vs. 11.93 ± 2.94, P = 0.011; average real variability (ARV): 11.38 ± 3.44 vs. 12.32 ± 3.65, P < 0.001)] were increasing from Days 1 to 2 of the 44-h interdialytic period. Similarly, all indexes of DBPV were significantly increased in Day 2, except for CV. Aortic SBPV and DBPV indices displayed a similar pattern. Furthermore, all studied brachial SBPV and DBPV indexes were also lower during daytimes 1 than 2 (systolic ARV 11.56 ± 3.98 vs. 12.44 ± 4.03, P = 0.002); systolic ARV was lower in night-time 1 compared with night-time 2 (11.20 ± 5.09 vs. 12.18 ± 4.66, P = 0.045). In multivariate regression analysis prehemodialysis SBP, age and diabetes were independently associated with increased SBP ARV. BPV is

Use of Antiretroviral HIV Post-Exposure Prophylaxis in Sexually Abused Children and Adolescents Treated in an Inner-City Pediatric Emergency Department

ERIC Educational Resources Information Center

Fajman, Nancy; Wright, Richelle

2006-01-01

Background: In 2002, Georgia had the United States' eighth highest number of persons living with AIDS. Human immunodeficiency virus (HIV) transmission as a result of sexual abuse is uncommon but definitely occurs. In certain circumstances of sexual abuse, antiretroviral post-exposure prophylaxis (ARV-PEP) has been suggested as a means to decrease…

The Ethiopian Orphanage Project

ERIC Educational Resources Information Center

LaVecchia, Antoinette

2010-01-01

The Ethiopian Orphanage Project was the brainchild of a prominent pediatrician who, through her foundation and private practice, has been saving the physical and emotional lives of children for years, both in the United States and abroad, with a focus on HIV+ orphans in developing countries. Three years ago, after introducing ARVs (antiretroviral…

HIV-Positive Status Disclosure and Use of Essential PMTCT and Maternal Health Services in Rural Kenya

PubMed Central

Spangler, Sydney A.; Onono, Maricianah; Bukusi, Elizabeth A.; Cohen, Craig R.

2014-01-01

Background: In sub-Saharan Africa, women's disclosure of HIV-positive status to others may affect their use of services for prevention of mother-to-child transmission of HIV (PMTCT) of HIV and maternal and child health—including antenatal care, antiretroviral drugs (ARVs) for PMTCT, and skilled birth attendance. Methods: Using data from the Migori and AIDS Stigma Study conducted in rural Nyanza Province, Kenya, we compared the use of PMTCT and maternal health services for all women by HIV status and disclosure category (n = 390). Among HIV-infected women (n = 145), associations between disclosure of HIV-positive status and the use of services were further examined with bivariate and multivariate logistic regression analyses. Results: Women living with HIV who had not disclosed to anyone had the lowest levels of maternity and PMTCT service utilization. For example, only 21% of these women gave birth in a health facility, compared with 35% of HIV-negative women and 49% of HIV-positive women who had disclosed (P < 0.001). Among HIV-positive women, the effect of disclosure to anyone on ARV drug use [odds ratio (OR) = 5.8; 95% confidence interval (CI): 1.9 to 17.8] and facility birth (OR = 2.9; 95% CI: 1.4 to 5.7) remained large and significant after adjusting for confounders. Disclosure to a male partner had a particularly strong effect on the use of ARVs for PMTCT (OR = 7.9; 95% CI: 3.7 to 17.1). Conclusions: HIV-positive status disclosure seems to be a complex yet critical factor for the use of PMTCT and maternal health services in this setting. The design of interventions to promote such disclosure must recognize the impact of HIV-related stigma on disclosure decisions and protect women's rights, autonomy, and safety. PMID:25436823

Hematological parameters of human immunodeficiency virus positive pregnant women on antiretroviral therapy in Aminu Kano Teaching Hospital Kano, North Western Nigeria.

PubMed

Abdulqadir, Ibrahim; Ahmed, Sagir Gumel; Kuliya, Aisha Gwarzo; Tukur, Jamilu; Yusuf, Aminu Abba; Musa, Abubakar Umar

2018-01-01

Human immunodeficiency virus (HIV) scourge continues to affect young women within the reproductive age group and pregnancy is a recognized indication for the use antiretroviral (ARV) drugs among HIV-positive women. The aim is to determine the combined effect of pregnancy, HIV and ARV drugs on the hematological parameters of the pregnant women. This was a comparative cross-sectional study conducted among 70 each of HIV-positive and negative pregnant women. Bio-demographic and clinical data were extracted from the client folder and 4 ml of blood sample was obtained from each participant. Full blood count was generated using Swelab automatic hematology analyzer while reticulocyte count and erythrocyte sedimentation rate (ESR) were conducted manually. Data analysis was performed using SPSS version software 16 while P < 0.05 was considered statistically significant. Pregnant women with HIV had statistically significant lower hematocrit and white blood cell (WBC) and higher ESR than pregnant women without HIV ( P < 0.000). There was no statistically significant difference between the two groups in terms of platelet and reticulocyte ( P > 0.05). However, among HIV positive pregnant women, those with CD4 count <350/μL had statistically significant lower WBC and lymphocyte count than those with CD4 count ≥350/μL ( P < 0.05), whereas, those on zidovudine (AZT)-containing treatment had statistically significant lower hematocrit and higher mean cell volume than those on non-AZT-containing treatment ( P < 0.05), but there was no statistically significant difference in any of the hematological parameters ( P > 0.050) between women on first- and second-line ARV regimens. There is a significant difference in terms of hematological parameters between HIV-positive and HIV-negative pregnant women in this environment.

Factors associated with conception among a sample of HIV-positive women at a hospital in Uganda.

PubMed

Kisakye, Peter; Akena, Wilfred Owot; Kikampikaho, G; Kaye, Dan K

2009-09-01

Conception among HIV-positive individuals is an important health and social issue. However, the proportion of HIV-positive women who conceive while being aware of their serostatus and the factors that influence this decision is not well documented. In a cross-sectional study, 385 HIV-positive women in the labour ward at Mulago Hospital, Uganda, were interviewed using a structured questionnaire. Data were collected on socio-demographic characteristics, contraception ever used, knowledge of antiretrovirals (ARVs), and ARVs ever used. To assess factors associated with conception among women who know their HIV-positive status, the variables were compared for women in two groups: those who conceived while knowing their HIV-positive status and those who discovered their HIV status during pregnancy. Bivariate and logistic regression analyses were used to assess confounding variables and interactions. The data show that one in every three HIV-positive women in the study population (37.1%) conceived despite being HIV-positive. Women who conceived while knowing they were HIV-positive differed from those who conceived without knowing their HIV status in regard to employment status, marital status, the employment status of their spouse/partner, and their intention to conceive. Logistic regression showed that factors independently associated with conception in this sample of HIV-positive women were: age below 25 years (odds ratio [OR] 2.06; 95% confidence interval [CI]: 1.18-3.62); unemployment (OR 2.7; 95% CI: 1.42-5.04); carrying a first pregnancy (OR 4.53; 95% CI: 2.02-9.94), being unaware of her partner's HIV status (OR 0.26; 95% CI: 0.15-0.44); having an awareness of ARVs (OR 3.66; 95% CI: 2.15-6.25); and having regrets about conceiving while being HIV-positive (OR 0.21; 95% CI: 0.09-0.46).

Menstrual cycle phase and single tablet antiretroviral medication adherence in women with HIV.

PubMed

Hessol, Nancy A; Holman, Susan; Minkoff, Howard; Cohen, Mardge H; Golub, Elizabeth T; Kassaye, Seble; Karim, Roksana; Sosanya, Oluwakemi; Shaheen, Christopher; Merhi, Zaher

2016-01-01

Suboptimal adherence to antiretroviral (ARV) therapy among HIV-infected individuals is associated with increased risk of progression to AIDS and the development of HIV resistance to ARV medications. To examine whether the luteal phase of the menstrual cycle is independently associated with suboptimal adherence to single tablet regimen (STR) ARV medication, data were analyzed from a multicenter cohort study of HIV-infected women who reported regular menstrual cycles and were taking an STR. In a cross-sectional analysis, suboptimal adherence to an STR among women in their follicular phase was compared with suboptimal adherence among women in their luteal phase. In two-way crossover analyses, whereby the same woman was assessed for STR medication adherence in both her follicular and luteal phases, the estimated exact conditional odds of non-adherence to an STR was measured. In adjusted logistic regression analysis of the cross-sectional data (N=327), women with ≤12 years of education were more than three times more likely to have suboptimal adherence (OR=3.6, p=.04) compared to those with >12 years of education. Additionally, women with Center for Epidemiological Studies Depression Scale (CES-D) scores ≥23 were 2.5-times more likely to have suboptimal adherence (OR=2.6, p=.02) compared to those with CES-D scores <23. In conditional logistic regression analyses of the crossover data (N=184), having childcare responsibilities was associated with greater odds of ≤95% adherence. Menstrual cycle phase was not associated with STR adherence in either the cross-sectional or crossover analyses. The lack of association between phase of the menstrual cycle and adherence to an STR in HIV-infected women means attention can be given to other more important risk factors for suboptimal adherence, such as depression, level of education, and childcare responsibilities.

Incident Hypertension in Older Women and Men with or at-risk for HIV Infection

PubMed Central

Factor, SH; Lo, Y; Schoenbaum, EE; Klein, RS

2015-01-01

Objectives Antiretroviral (ARV) therapy has prolonged the life expectancy of HIV-infected persons, increasing their risk of age-associated diseases including atherosclerosis (AS). Decreased risk of AS has been associated with the prevention and control of hypertension (HTN). We conducted a cohort study of perimenopausal women and older men with or at-risk of HIV infection to identify risk factors for incident HTN. Methods Standardized interviews, physical examinations, and laboratory examinations were scheduled at 6-month intervals. Interview data included demographics, medical, family, sexual behavior, and drug use histories, and physical activity. Results There were 330 women and 329 men eligible persons; 27% and 35% of participants developed HTN during a median follow-up of 1080 and 1071 days, respectively. In gender-stratified analysis, adjusting for traditional HTN risk factors (age, race, BMI, smoking, diabetes, family history of HTN, alcohol dependence, physical activity, and high cholesterol), HIV infection was not associated with incident HTN in women or men [HR= 1.31, 95%CI (0.56, 3.06); HR = 1.67, 95%CI (0.75, 3.74), respectively]. Among HIV-infected women, although exposure to ARV's was not significantly associated with incident HTN [HR=0.72, 95%CI (0.26, 1.99)], CD4+ T-cell count was positively associated with incident HTN [HR=1.15 per 100 cells, 95%CI (1.03, 1.28)]. Among physically active HIV-infected men, exposure to ARV's was negatively associated with incident HTN [HR=0.15, 95%CI (0.03, 0.78)]. Conclusions HIV infection was not associated with incident HTN in older men or women. This study provides additional evidence supporting a causal relationship between immune function and incident HTN, which warrants further study. PMID:23294666

HIV-positive status disclosure and use of essential PMTCT and maternal health services in rural Kenya.

PubMed

Spangler, Sydney A; Onono, Maricianah; Bukusi, Elizabeth A; Cohen, Craig R; Turan, Janet M

2014-12-01

In sub-Saharan Africa, women's disclosure of HIV-positive status to others may affect their use of services for prevention of mother-to-child transmission of HIV (PMTCT) of HIV and maternal and child health-including antenatal care, antiretroviral drugs (ARVs) for PMTCT, and skilled birth attendance. Using data from the Migori and AIDS Stigma Study conducted in rural Nyanza Province, Kenya, we compared the use of PMTCT and maternal health services for all women by HIV status and disclosure category (n = 390). Among HIV-infected women (n = 145), associations between disclosure of HIV-positive status and the use of services were further examined with bivariate and multivariate logistic regression analyses. Women living with HIV who had not disclosed to anyone had the lowest levels of maternity and PMTCT service utilization. For example, only 21% of these women gave birth in a health facility, compared with 35% of HIV-negative women and 49% of HIV-positive women who had disclosed (P < 0.001). Among HIV-positive women, the effect of disclosure to anyone on ARV drug use [odds ratio (OR) = 5.8; 95% confidence interval (CI): 1.9 to 17.8] and facility birth (OR = 2.9; 95% CI: 1.4 to 5.7) remained large and significant after adjusting for confounders. Disclosure to a male partner had a particularly strong effect on the use of ARVs for PMTCT (OR = 7.9; 95% CI: 3.7 to 17.1). HIV-positive status disclosure seems to be a complex yet critical factor for the use of PMTCT and maternal health services in this setting. The design of interventions to promote such disclosure must recognize the impact of HIV-related stigma on disclosure decisions and protect women's rights, autonomy, and safety.

Clinically relevant transmitted drug resistance to first line antiretroviral drugs and implications for recommendations.

PubMed

Monge, Susana; Guillot, Vicente; Alvarez, Marta; Chueca, Natalia; Stella, Natalia; Peña, Alejandro; Delgado, Rafael; Córdoba, Juan; Aguilera, Antonio; Vidal, Carmen; García, Federico

2014-01-01

The aim was to analyse trends in clinically relevant resistance to first-line antiretroviral drugs in Spain, applying the Stanford algorithm, and to compare these results with reported Transmitted Drug Resistance (TDR) defined by the 2009 update of the WHO SDRM list. We analysed 2781 sequences from ARV naive patients of the CoRIS cohort (Spain) between 2007-2011. Using the Stanford algorithm "Low-level resistance", "Intermediate resistance" and "High-level resistance" categories were considered as "Resistant". 70% of the TDR found using the WHO list were relevant for first-line treatment according to the Stanford algorithm. A total of 188 patients showed clinically relevant resistance to first-line ARVs [6.8% (95%Confidence Interval: 5.8-7.7)], and 221 harbored TDR using the WHO list [7.9% (6.9-9.0)]. Differences were due to a lower prevalence in clinically relevant resistance for NRTIs [2.3% (1.8-2.9) vs. 3.6% (2.9-4.3) by the WHO list] and PIs [0.8% (0.4-1.1) vs. 1.7% (1.2-2.2)], while it was higher for NNRTIs [4.6% (3.8-5.3) vs. 3.7% (3.0-4.7)]. While TDR remained stable throughout the study period, clinically relevant resistance to first line drugs showed a significant trend to a decline (p = 0.02). Prevalence of clinically relevant resistance to first line ARVs in Spain is decreasing, and lower than the one expected looking at TDR using the WHO list. Resistance to first-line PIs falls below 1%, so the recommendation of screening for TDR in the protease gene should be questioned in our setting. Cost-effectiveness studies need to be carried out to inform evidence-based recommendations.

Clinically Relevant Transmitted Drug Resistance to First Line Antiretroviral Drugs and Implications for Recommendations

PubMed Central

Monge, Susana; Guillot, Vicente; Alvarez, Marta; Chueca, Natalia; Stella, Natalia; Peña, Alejandro; Delgado, Rafael; Córdoba, Juan; Aguilera, Antonio; Vidal, Carmen; García, Federico; CoRIS

2014-01-01

Background The aim was to analyse trends in clinically relevant resistance to first-line antiretroviral drugs in Spain, applying the Stanford algorithm, and to compare these results with reported Transmitted Drug Resistance (TDR) defined by the 2009 update of the WHO SDRM list. Methods We analysed 2781 sequences from ARV naive patients of the CoRIS cohort (Spain) between 2007–2011. Using the Stanford algorithm “Low-level resistance”, “Intermediate resistance” and “High-level resistance” categories were considered as “Resistant”. Results 70% of the TDR found using the WHO list were relevant for first-line treatment according to the Stanford algorithm. A total of 188 patients showed clinically relevant resistance to first-line ARVs [6.8% (95%Confidence Interval: 5.8–7.7)], and 221 harbored TDR using the WHO list [7.9% (6.9–9.0)]. Differences were due to a lower prevalence in clinically relevant resistance for NRTIs [2.3% (1.8–2.9) vs. 3.6% (2.9–4.3) by the WHO list] and PIs [0.8% (0.4–1.1) vs. 1.7% (1.2–2.2)], while it was higher for NNRTIs [4.6% (3.8–5.3) vs. 3.7% (3.0–4.7)]. While TDR remained stable throughout the study period, clinically relevant resistance to first line drugs showed a significant trend to a decline (p = 0.02). Conclusions Prevalence of clinically relevant resistance to first line ARVs in Spain is decreasing, and lower than the one expected looking at TDR using the WHO list. Resistance to first-line PIs falls below 1%, so the recommendation of screening for TDR in the protease gene should be questioned in our setting. Cost-effectiveness studies need to be carried out to inform evidence-based recommendations. PMID:24637804

Short Communication: Interferon/Ribavirin Treatment for HCV Is Associated with the Development of Hypophosphatemia in HIV/Hepatitis C Virus-Coinfected Patients

PubMed Central

Funk, Emily K.; Shaffer, Ashton; Shivakumar, Bhavana; Sneller, Michael; Polis, Michael A.; Masur, Henry; Heytens, Laura; Nelson, Amy; Kwan, Richard; Kottilil, Shyam

2013-01-01

Abstract One-third of all HIV-infected individuals in the United States are estimated to be coinfected with the hepatitis C virus (HCV). Treatment of chronic hepatitis C in patients coinfected with HIV is a complex problem associated with toxicities and drug interactions between HIV antiretrovirals and interferon and ribavirin. In recent HCV treatment studies, we observed a previously unreported development of hypophosphatemia in HIV/HCV-coinfected patients treated with interferon/ribavirin (IFN/RBV). To further investigate this observation, we retrospectively reviewed 61 HIV/HCV-coinfected patients on antiretrovirals (ARVs) during treatment with IFN/RBV as well as 154 HIV-infected patients treated with ARVs alone. We found that HIV/HCV-coinfected patients on IFN/RBV therapy were more likely to develop frequent (57% vs. 13%, IFN/RBV-treated patients vs. no IFN/RBV; χ2=0.001) and higher-grade hypophosphatemia (67.0% Grade 2, 33.3% Grade 3 vs. 94.7% Grade 2, 5.3% Grade 3, IFN/RBV-treated patients vs. no IFN/RBV; χ2<0.001) than untreated patients. In addition, we found that the new onset of hypophosphatemia after IFN/RBV treatment initiation was followed by a diminished frequency of this toxicity upon cessation of IFN/RBV, supporting the idea that a drug–drug interaction may increase the risk of this toxicity. To understand the risks of developing this toxicity, we evaluated the association between individual ARV use and hypophosphatemia incidence. Our data suggest that concomitant tenofovir (TDF) use may be a risk factor for the development of hypophosphatemia in HIV/HCV-coinfected patients treated with IFN/RBV. Although the etiology of this abnormality is likely multifactorial, clinicians should be aware of hypophosphatemia as a potential marker of renal toxicity in HIV/HCV-coinfected patients being treated with IFN/RBV regimens. PMID:23701022

Short communication: Interferon/ribavirin treatment for HCV is associated with the development of hypophosphatemia in HIV/hepatitis C virus-coinfected patients.

PubMed

Funk, Emily K; Shaffer, Ashton; Shivakumar, Bhavana; Sneller, Michael; Polis, Michael A; Masur, Henry; Heytens, Laura; Nelson, Amy; Kwan, Richard; Kottilil, Shyam; Kohli, Anita

2013-09-01

One-third of all HIV-infected individuals in the United States are estimated to be coinfected with the hepatitis C virus (HCV). Treatment of chronic hepatitis C in patients coinfected with HIV is a complex problem associated with toxicities and drug interactions between HIV antiretrovirals and interferon and ribavirin. In recent HCV treatment studies, we observed a previously unreported development of hypophosphatemia in HIV/HCV-coinfected patients treated with interferon/ribavirin (IFN/RBV). To further investigate this observation, we retrospectively reviewed 61 HIV/HCV-coinfected patients on antiretrovirals (ARVs) during treatment with IFN/RBV as well as 154 HIV-infected patients treated with ARVs alone. We found that HIV/HCV-coinfected patients on IFN/RBV therapy were more likely to develop frequent (57% vs. 13%, IFN/RBV-treated patients vs. no IFN/RBV; χ(2)=0.001) and higher-grade hypophosphatemia (67.0% Grade 2, 33.3% Grade 3 vs. 94.7% Grade 2, 5.3% Grade 3, IFN/RBV-treated patients vs. no IFN/RBV; χ(2)<0.001) than untreated patients. In addition, we found that the new onset of hypophosphatemia after IFN/RBV treatment initiation was followed by a diminished frequency of this toxicity upon cessation of IFN/RBV, supporting the idea that a drug-drug interaction may increase the risk of this toxicity. To understand the risks of developing this toxicity, we evaluated the association between individual ARV use and hypophosphatemia incidence. Our data suggest that concomitant tenofovir (TDF) use may be a risk factor for the development of hypophosphatemia in HIV/HCV-coinfected patients treated with IFN/RBV. Although the etiology of this abnormality is likely multifactorial, clinicians should be aware of hypophosphatemia as a potential marker of renal toxicity in HIV/HCV-coinfected patients being treated with IFN/RBV regimens.

Strand transfer inhibitors of HIV-1 integrase: bringing IN a new era of antiretroviral therapy.

PubMed

McColl, Damian J; Chen, Xiaowu

2010-01-01

HIV-1 integrase (IN) is one of three essential enzymes (along with reverse transcriptase and protease) encoded by the viral pol gene. IN mediates two critical reactions during viral replication; firstly 3'-end processing (3'EP) of the double-stranded viral DNA ends and then strand transfer (STF) which joins the viral DNA to the host chromosomal DNA forming a functional integrated proviral DNA. IN is a 288 amino acid protein containing three functional domains, the N-terminal domain (NTD), catalytic core domain (CCD) and the C-terminal domain (CTD). The CCD contains three conserved catalytic residues, Asp64, Asp116 and Glu152, which coordinate divalent metal ions essential for the STF reaction. Intensive research over the last two decades has led to the discovery and development of small molecule inhibitors of the IN STF reaction (INSTIs). INSTIs are catalytic inhibitors of IN, and act to chelate the divalent metal ions in the CCD. One INSTI, raltegravir (RAL, Merck Inc.) was approved in late 2007 for the treatment of HIV-1 infection in patients with prior antiretroviral (ARV) treatment experience and was recently approved also for first line therapy. A second INSTI, elvitegravir (EVG, Gilead Sciences, Inc.) is currently undergoing phase 3 studies in ARV treatment-experienced patients and phase 2 studies in ARV naïve patients as part of a novel fixed dose combination. Several additional INSTIs are in early stage clinical development. This review will discuss the discovery and development of this novel class of antiretrovirals. This article forms part of a special issue of Antiviral Research marking the 25th anniversary of antiretroviral drug discovery and development, Vol 85, issue 1, 2010. Copyright 2009. Published by Elsevier B.V.

Food Insecurity is Associated with Incomplete HIV RNA Suppression Among Homeless and Marginally Housed HIV-infected Individuals in San Francisco

PubMed Central

Frongillo, Edward A.; Ragland, Kathleen; Hogg, Robert S.; Riley, Elise D.; Bangsberg, David R.

2008-01-01

Background and Objectives There is growing international concern that food insecurity may negatively impact antiretroviral (ARV) treatment outcomes, but no studies have directly evaluated the effect of food insecurity on viral load suppression and antiretroviral adherence. We hypothesized that food insecurity would be associated with poor virologic response among homeless and marginally housed HIV-positive ARV-treated patients. Design This is a cross-sectional study. Participants and Setting Participants were ARV-treated homeless and marginally housed persons receiving adherence monitoring with unannounced pill counts in the Research on Access to Care in the Homeless (REACH) Cohort. Measurements Food insecurity was measured by the Household Food Insecurity Access Scale (HFIAS). The primary outcome was suppression of HIV viral RNA to <50 copies/ml. We used multivariate logistic regression to assess whether food insecurity was associated with viral suppression. Results Among 104 participants, 51% were food secure, 24% were mildly or moderately food insecure and 25% were severely food insecure. Severely food insecure participants were less likely to have adherence >=80%. In adjusted analyses, severe food insecurity was associated with a 77% lower odds of viral suppression (95% CI = 0.06–0.82) when controlling for all covariates. In analyses stratified by adherence level, severe food insecurity was associated with an 85% lower odds of viral suppression (95% CI = 0.02–0.99) among those with <=80% adherence and a 66% lower odds among those with >80% adherence (95% CI = 0.06–1.81). Conclusions Food insecurity is present in half of the HIV-positive urban poor in San Francisco, one of the best resourced settings for HIV-positive individuals in the United States, and is associated with incomplete viral suppression. These findings suggest that ensuring access to food should be an integral component of public health HIV programs serving impoverished

The Effect of Viral Suppression on Cross Sectional Incidence Testing in the Johns Hopkins Hospital Emergency Department

PubMed Central

Laeyendecker, Oliver; Rothman, Richard E.; Henson, Charlamaine; Jo Horne, Bobbi; Ketlogetswe, Kerunne S.; Kraus, Chadd K.; Shahan, Judy; Kelen, Gabor. D.; Quinn, Thomas C.

2009-01-01

Objective(s) To determine the effect of viral suppression on cross sectional incidence testing. Methods In 2001 and 2003, patients entering the Johns Hopkins Hospital Emergency Department (JHHED) were enrolled into an interview based, identity unlinked serosurvey. All HIV positive samples were tested by the Vironostika-less sensitive (LS) EIA and an avidity assay to determine recent HIV infection. Additionally 16 samples from 8 previously characterized elite suppressors (ES) were tested by cross sectional incidence assays. Results HIV prevalence was 12% for the 2001 survey and 11% for the 2003 survey. Of the HIV infected subjects 18% did not know they were infected. Vironostika-LS EIA determined that 6% (11/183) and 7% (17/243) of HIV+ individuals in 2001and 2003, respectively, were recently infected. Avidity testing confirmed 6 of 11 in 2001, and 5 of 17 in 2003 were newly infected, leaving 17 discrepant samples. All 17 discrepant samples were western blot positive, viral load undetectable and 7/17 had antiretroviral drugs (ARVs) in their serum. Ten individuals were virally suppressed without ARVs, appeared incident by Vironostika-LS EIA but chronic by avidity. These 10 subjects had similar testing profiles to the known 16 ES samples, as 9 of 16 were incident by Vironostika-LS EIA, and 0/16 were incident by avidity. Conclusions By removing the viral load negative individuals and by confirming the initial Vironostika-LS EIA results by avidity, the incidence estimate was lowered from 1.73 to 0.94 percent/year in 2001 and from 1.90 to 0.56 percent/year in 2003. Viral suppression affects the performance of the cross sectional incidence tests which rely on antibody titer. In additional 2% (10/426) of all HIV infected individuals who use the JHHED for medical care appear to suppress HIV to undetectable levels without ARVs. PMID:18520680

Costing Analysis of National HIV Treatment and Care Program in Vietnam

PubMed Central

Duong, Anh Thuy; Bales, Sarah; Do, Nhan Thi; Minh Nguyen, Thu Thi; Thanh Cao, Thuy Thi; Nguyen, Long Thanh

2014-01-01

Background: Vietnam achieved rapid scale-up of antiretroviral therapy (ART), although external funds are declining sharply. To achieve and sustain universal access to HIV services, evidence-based planning is essential. To date, there had been limited HIV treatment and care cost data available in Vietnam. Methods: Cost data of outpatient and inpatient HIV care were extracted at 21 sentinel facilities (17 adult and 4 pediatric) that epitomize the national program. Step-down costing for administration costs and bottom-up resource costing for drugs, diagnostics, and labor were used. Records of 1401 adults and 527 pediatric patients were reviewed. Results: Median outpatient care costs per patient-year for pre-ART, first year ART, later year ART, and second-line ART were US $100, US $316, US $303, and US $1557 for adults; and US $171, US $387, US $320, and US $1069 for children, respectively. Median inpatient care cost per episode was US $162 for adults and US $142 for children. Non-antiretroviral (ARV) costs in adults at stand-alone facilities were 44% (first year ART) and 24% (later year ART) higher than those at integrated facilities. Adults who started ART with CD4 count ≤100 cells per cubic millimeter had 47% higher non-ARV costs in the first year ART than those with CD4 count >100 cells per cubic millimeter. Adult ARV drug costs at government sites were from 66% to 85% higher than those at donor-supported sites in the first year ART. Conclusions: The study found that HIV treatment and care costs in Vietnam are economical, yet there is potential to further promote efficiency through strengthening competitive procurement, integrating HIV services, and promoting earlier ART initiation. PMID:23846564

Use of Lipid-Based Nutrient Supplements by HIV-Infected Malawian Women during Lactation Has No Effect on Infant Growth from 0 to 24 Weeks1234

PubMed Central

Flax, Valerie L.; Bentley, Margaret E.; Chasela, Charles S.; Kayira, Dumbani; Hudgens, Michael G.; Knight, Rodney J.; Soko, Alice; Jamieson, Denise J.; van der Horst, Charles M.; Adair, Linda S.

2012-01-01

The Breastfeeding, Antiretrovirals, and Nutrition Study evaluated the effect of daily consumption of lipid-based nutrient supplements (LNS) by 2121 lactating, HIV-infected mothers on the growth of their exclusively breast-fed, HIV-uninfected infants from 0 to 24 wk. The study had a 2 × 3 factorial design. Malawian mothers with CD4+ ≥250 cells/mm3, hemoglobin ≥70 g/L, and BMI ≥17 kg/m2 were randomized within 36 h of delivery to receive either no LNS or 140 g/d of LNS to meet lactation energy and protein needs, and mother-infant pairs were assigned to maternal antiretroviral drugs (ARV), infant ARV, or no ARV. Sex-stratified, longitudinal, random effects models were used to estimate the effect of the 6 study arms on infant weight, length, and BMI. Logistic regression models were used to calculate the odds of growth faltering [decline in weight-for-age Z-score (WAZ) or length-for-age Z-score (LAZ) >0.67] using the control arm as the reference. Although some differences between study arms emerged with increasing infant age in boys, there were no consistent effects of the maternal supplement across the 3 growth outcomes in longitudinal models. At the ages where differences were observed, the effects on weight and BMI were quite small (≤200 g and ≤0.4 kg/m2) and unlikely to be of clinical importance. Overall, 21 and 34% of infants faltered in WAZ and LAZ, respectively. Maternal supplementation did not reduce the odds of infant weight or length faltering from 0 to 24 wk in any arm. These results indicate that blanket supplementation of HIV-infected lactating women may have little impact on infant growth. PMID:22649265

HIV-1 Drug Resistance and Resistance Testing

PubMed Central

Clutter, Dana S; Jordan, Michael R; Bertagnolio, Silvia; Shafer, Robert W

2016-01-01

The global scale-up of antiretroviral (ARV) therapy (ART) has led to dramatic reductions in HIV-1 mortality and incidence. However, HIV drug resistance (HIVDR) poses a potential threat to the long-term success of ART and is emerging as a threat to the elimination of AIDS as a public health problem by 2030. In this review we describe the genetic mechanisms, epidemiology, and management of HIVDR at both individual and population levels across diverse economic and geographic settings. To describe the genetic mechanisms of HIVDR, we review the genetic barriers to resistance for the most commonly used ARVs and describe the extent of cross-resistance between them. To describe the epidemiology of HIVDR, we summarize the prevalence and patterns of transmitted drug resistance (TDR) and acquired drug resistance (ADR) in both high-income and low- and middle-income countries (LMICs). We also review to two categories of HIVDR with important public health relevance: (i) pre-treatment drug resistance (PDR), a World Health Organization-recommended HIVDR surveillance metric and (ii) and pre-exposure prophylaxis (PrEP)-related drug resistance, a type of ADR that can impact clinical outcomes if present at the time of treatment initiation. To summarize the implications of HIVDR for patient management, we review the role of genotypic resistance testing and treatment practices in both high-income and LMIC settings. In high-income countries where drug resistance testing is part of routine care, such an understanding can help clinicians prevent virological failure and accumulation of further HIVDR on an individual level by selecting the most efficacious regimens for their patients. Although there is reduced access to diagnostic testing and to many ARVs in LMIC, understanding the scientific basis and clinical implications of HIVDR is useful in all regions in order to shape appropriate surveillance, inform treatment algorithms, and manage difficult cases. PMID:27587334

Optimising research to speed up availability of paediatric antiretroviral drugs and formulations

PubMed Central

Penazzato, M; Gnanashanmugam, D; Rojo, P; Lallemant, M; Lewis, L; Rocchi, F; Saint Raymond, A; Ford, N; Hazra, R; Giaquinto, C; Gibb, D; Abrams, Elaine J

2018-01-01

Globally 1.8 million children are estimated to be living with HIV, yet only 51% of those eligible actually start treatment. The completion of research and development (R&D) for paediatric antiretrovirals (ARVs) is a lengthy process and licensing of new paediatric ARVs continues to lag considerably behind adults. Providing safe, effective, and well-tolerated drugs for children remains critical to ensuring scale-up of paediatric treatment globally. In this manuscript we review current approaches to R&D for paediatric ARVs and suggest innovations to enable simplified, faster, and more comprehensive strategies to develop optimal formulations. Several approaches could be adopted, including enrolment of multiple age-cohorts concurrently and the early introduction of dosing approaches for both single and fixed-dose combination (FDC) drug formulations (preferably scored and dispersible) that match WHO weight-bands. Efforts to speed up development of optimal drugs and formulations for children should focus on a limited number of prioritised formulations. This work should build upon existing partnerships and collaborations to ensure that paediatric investigation plans are developed early in the drug development process but can be modified in a streamlined manner as more information becomes available. In addition, simplified and more efficient mechanisms to undertake R&D need to be put in place, and financing mechanisms must be made more efficient and sustainable. Registration, implementation, and strategic use of drugs should not be seen as a sequential process, with research designed to address multiple questions simultaneously to respond to the needs of HIV-infected children where they live. It is imperative that lessons learned from HIV should be shared to support progress in developing paediatric formulations for other diseases with similar treatment challenges, including tuberculosis and viral hepatitis. PMID:29190337

Potential pharmacokinetic interactions between antiretrovirals and medicinal plants used as complementary and African traditional medicines.

PubMed

Müller, Adrienne C; Kanfer, Isadore

2011-11-01

The use of traditional/complementary/alternate medicines (TCAMs) in HIV/AIDS patients who reside in Southern Africa is quite common. Those who use TCAMs in addition to antiretroviral (ARV) treatment may be at risk of experiencing clinically significant pharmacokinetic (PK) interactions, particularly between the TCAMs and the protease inhibitors (PIs) and non-nucleoside reverse transcriptase inhibitors (NNRTIs). Mechanisms of PK interactions include alterations to the normal functioning of drug efflux transporters, such as P-gp and/or CYP isoenzymes, such a CYP3A4 that mediate the absorption and elimination of drugs in the small intestine and liver. Specific mechanisms include inhibition and activation of these proteins and induction via the pregnane X receptor (PXR). Several clinical studies and case reports involving ARV-herb PK interactions have been reported. St John's Wort, Garlic and Cat's Claw exhibited potentially significant interactions, each with a PI or NNRTI. The potential for these herbs to induce PK interactions with drugs was first identified in reports of in vitro studies. Other in vitro studies have shown that several African traditional medicinal (ATM) plants and extracts may also demonstrate PK interactions with ARVs, through effects on CYP3A4, P-gp and PXR. The most complex effects were exhibited by Hypoxis hemerocallidea, Sutherlandia frutescens, Cyphostemma hildebrandtii, Acacia nilotica, Agauria salicifolia and Elaeodendron buchananii. Despite a high incidence of HIV/AIDs in the African region, only one clinical study, between efavirenz and Hypoxis hemerocallidea has been conducted. However, several issues/concerns still remain to be addressed and thus more studies on ATMs are warranted in order for more meaningful data to be generated and the true potential for such interactions to be determined. Copyright © 2011 John Wiley & Sons, Ltd.

Pre-treatment drug resistance among patients initiating antiretroviral therapy (ART) in Zimbabwe: 2008-2010.

PubMed

Mungati, More; Mhangara, Mutsa; Gonese, Elizabeth; Mugurungi, Owen; Dzangare, Janet; Ngwende, Stella; Musasa, Patience; Wellington, Maureen; Shambira, Gerald; Apollo, Tsitsilina; Yang, Chunfu; DeVos, Joshua; Sabatier, Jennifer; Kilmarx, Peter; Chakanyuka-Musanhu, Christine; Tshimanga, Mufuta

2016-06-10

Zimbabwe set up 12 sentinel sites to monitor HIV drug resistance (HIVDR) following the international standards for prevention of HIVDR from 2008 to 2010. Participants were consecutively enrolled. Blood was collected and used for CD4 count, viral load (VL) and pre-treatment DR (PDR) tests besides routine baseline tests. We analyzed the characteristics of participants enrolled into the survey and estimated the point prevalence of PDR and its associated factors among ART initiators in a cross-sectional analysis using the baseline data collected from a prospective cohort in 12 purposefully selected sentinel sites. A total of 1728 participants (96 % response rate) were enrolled and 1610 had complete data. Of the 1610 there were more females (68.7 %) than males (31.3 %). The median CD4 count was 168 cells/mm(3) with males having lower values (P = 0.003). Ninety-six percent of participants had a VL ≥ 1000 copies/ml and the median VL was 128,000. Previous exposure to antiretroviral drugs (ARVs) was mainly through PMTCT (5 % of the participants). Overall, PDR mutations were detected in 6.3 % (95 % CI 5.2-7.7) of the 1480 successfully genotyped participants. However, the prevalence of PDR mutations was double for those with previous exposure (12.1 %) to ARVs compared with those without previous exposure (5.7 %, P = 0.002). The results show a moderate level of PDR prevalence among ART initiators. To maintain the efficacy of the current first-line regimens, there is need to strengthen all HIVDR prevention efforts and to conduct further studies to investigate optimal strategies that can prolong the efficacy of first-line ARV regimens in the country.

Developing visual images for communicating information aboutantiretroviral side effects to a low-literate population.

PubMed

Dowse, Ros; Ramela, Thato; Barford, Kirsty-Lee; Browne, Sara

2010-09-01

The side effects of antiretroviral (ARV) therapy are linked to altered quality of life and adherence. Poor adherence has also been associated with low health-literacy skills, with an uninformed patient more likely to make ARV-related decisions that compromise the efficacy of the treatment. Low literacy skills disempower patients in interactions with healthcare providers and preclude the use of existing written patient information materials, which are generally written at a high reading level. Visual images or pictograms used as a counselling tool or included in patient information leaflets have been shown to improve patients' knowledge, particularly in low-literate groups. The objective of this study was to design visuals or pictograms illustrating various ARV side effects and to evaluate them in a low-literate South African Xhosa population. Core images were generated either from a design workshop or from posed photos or images from textbooks. The research team worked closely with a graphic artist. Initial versions of the images were discussed and assessed in group discussions, and then modified and eventually evaluated quantitatively in individual interviews with 40 participants who each had a maximum of 10 years of schooling. The familiarity of the human body, its facial expressions, postures and actions contextualised the information and contributed to the participants' understanding. Visuals that were simple, had a clear central focus and reflected familiar body experiences (e.g. vomiting) were highly successful. The introduction of abstract elements (e.g. fever) and metaphorical images (e.g. nightmares) presented problems for interpretation, particularly to those with the lowest educational levels. We recommend that such visual images should be designed in collaboration with the target population and a graphic artist, taking cognisance of the audience's literacy skills and culture, and should employ a multistage iterative process of modification and

Combination treatment with docetaxel and histone deacetylase inhibitors downregulates androgen receptor signaling in castration-resistant prostate cancer.

PubMed

Park, Sang Eun; Kim, Ha-Gyeong; Kim, Dong Eun; Jung, Yoo Jung; Kim, Yunlim; Jeong, Seong-Yun; Choi, Eun Kyung; Hwang, Jung Jin; Kim, Choung-Soo

2018-04-01

Backgrounds Since most patients with castration-resistant prostate cancer (CRPC) develop resistance to its standard therapy docetaxel, many studies have attempted to identify novel combination treatment to meet the large clinical unmet need. In this study, we examined whether histone deacetylase inhibitors (HDACIs) enhanced the effect of docetaxel on AR signaling in CRPC cells harboring AR and its splice variants. Methods HDACIs (vorinostat and CG200745) were tested for their ability to enhance the effects of docetaxel on cell viability and inhibition of AR signaling in CRPC 22Rv1 and VCaP cells by using CellTiter-Glo™ Luminescent cell viability assay, synergy index analysis and Western blotting. The nuclear localization of AR was examined via immunocytochemical staining in 22Rv1 cells and primary tumor cells from a patient with CRPC. Results Combination treatment with HDACIs (vorinostat or CG200745) and docetaxel synergistically inhibited the growth of 22Rv1 and VCaP cells. Consistently, the combination treatment decreased the levels of full-length AR (AR-FL), AR splice variants (AR-Vs), prostate-specific antigen (PSA), and anti-apoptotic Bcl-2 proteins more efficiently compared with docetaxel or vorinostat alone. Moreover, the combination treatment accelerated the acetylation and bundling of tubulin, which significantly inhibited the nuclear accumulation of AR in 22Rv1 cells. The cytoplasmic colocalization of AR-FL and AR-V7 with microtubule bundles increased after combination treatment in primary tumor cells from a patient with CRPC. Conclusions The results suggested that docetaxel, in combination with HDACIs, suppressed the expression and nuclear translocation of AR-FL and AR-Vs and showed synergistic anti-proliferative effect in CRPC cells. This combination therapy may be useful for the treatment of patients with CRPC.

Blood pressure response to renal denervation is correlated with baseline blood pressure variability: a patient-level meta-analysis.

PubMed

Persu, Alexandre; Gordin, Daniel; Jacobs, Lotte; Thijs, Lutgarde; Bots, Michiel L; Spiering, Wilko; Miroslawska, Atena; Spaak, Jonas; Rosa, Ján; de Jong, Mark R; Berra, Elena; Fadl Elmula, Fadl Elmula M; Wuerzner, Gregoire; Taylor, Alison H M; Olszanecka, Agnieszka; Czarnecka, Danuta; Mark, Patrick B; Burnier, Michel; Renkin, Jean; Kjeldsen, Sverre E; Widimský, Jiří; Elvan, Arif; Kahan, Thomas; Steigen, Terje K; Blankestijn, Peter J; Tikkanen, Ilkka; Staessen, Jan A

2018-02-01

Sympathetic tone is one of the main determinants of blood pressure (BP) variability and treatment-resistant hypertension. The aim of our study was to assess changes in BP variability after renal denervation (RDN). In addition, on an exploratory basis, we investigated whether baseline BP variability predicted the BP changes after RDN. We analyzed 24-h BP recordings obtained at baseline and 6 months after RDN in 167 treatment-resistant hypertension patients (40% women; age, 56.7 years; mean 24-h BP, 152/90 mmHg) recruited at 11 expert centers. BP variability was assessed by weighted SD [SD over time weighted for the time interval between consecutive readings (SDiw)], average real variability (ARV), coefficient of variation, and variability independent of the mean (VIM). Mean office and 24-h BP fell by 15.4/6.6 and 5.5/3.7 mmHg, respectively (P < 0.001). In multivariable-adjusted analyses, systolic/diastolic SDiw and VIM for 24-h SBP/DBP decreased by 1.18/0.63 mmHg (P ≤ 0.01) and 0.86/0.42 mmHg (P ≤ 0.05), respectively, whereas no significant changes in ARV or coefficient of variation occurred. Furthermore, baseline SDiw (P = 0.0006), ARV (P = 0.01), and VIM (P = 0.04) predicted the decrease in 24-h DBP but not 24-h SBP after RDN. RDN was associated with a decrease in BP variability independent of the BP level, suggesting that responders may derive benefits from the reduction in BP variability as well. Furthermore, baseline DBP variability estimates significantly correlated with mean DBP decrease after RDN. If confirmed in younger patients with less arterial damage, in the absence of the confounding effect of drugs and drug adherence, baseline BP variability may prove a good predictor of BP response to RDN.

Differences in Optimal Growth Equations For White Oak in the Interior Highlands

Treesearch

Don C. Bragg; James M. Guldin

2003-01-01

Optimal growth equations are fundamental to many ecological simulators, but few have been critically examined. This paper reviews some of the behavior of the Potential Relative Increment (PRI) approach. Models for white oak were compared for Arkansas River Valley (ARV), Boston Mountains (BoM), Ouachita Mountains (OM), and Ozark Highlands (OH) ecological sections of the...

Differential Splicing of Oncogenes and Tumor Suppressor Genes in African- and Caucasian-American Populations: Contributing Factor in Prostate Cancer Disparities

DTIC Science & Technology

2016-10-01

Clinical cancer research : an official journal of the American Association for Cancer...kinase isoform p110delta impairs growth and survival in neuroblastoma cells. Clinical cancer research : an official journal of the American...Regulation of AR and AR-V7: Implications for Racial Disparity of Prostate Cancer. Clinical cancer research : an official journal of the

The cost of accessing infant HIV medications and health services in Uganda.

PubMed

Bergmann, Julie N; Wanyenze, Rhoda K; Stockman, Jamila K

2017-11-01

Patient costs are a critical barrier to the elimination of mother to child HIV transmission. Despite the Ugandan government providing free public HIV services, infant antiretroviral (ARV) prophylaxis coverage remains low (25%). To understand costs mothers incur in accessing ARV prophylaxis for their infants, we conducted a mixed methods study to quantify and identify their direct costs. We used cross-sectional survey data and focus group discussions from 49 HIV-positive mothers in Uganda. Means and standard deviations were calculated for the direct costs (e.g., transportation, caretaker, services/medications) involved in accessing infant HIV services. The direct cost of attending HIV clinic visits averaged $3.71 (SD = $3.52). Focus group discussions identified two costs hindering access to infant HIV services: transportation costs and informal service charges. All participants reported significant costs associated with accessing infant HIV services - the equivalent of 2-3 days' income. To address transportation costs, community and home care models should be explored. Additionally, stricter policies and oversight should be implemented to prevent informal HIV service charges.

ACK1/TNK2 Regulates Histone H4 Tyr88-phosphorylation and AR Gene Expression in Castration-Resistant Prostate Cancer.

PubMed

Mahajan, Kiran; Malla, Pavani; Lawrence, Harshani R; Chen, Zhihua; Kumar-Sinha, Chandan; Malik, Rohit; Shukla, Sudhanshu; Kim, Jongphil; Coppola, Domenico; Lawrence, Nicholas J; Mahajan, Nupam P

2017-06-12

The androgen receptor (AR) is critical for the progression of prostate cancer to a castration-resistant (CRPC) state. AR antagonists are ineffective due to their inability to repress the expression of AR or its splice variant, AR-V7. Here, we report that the tyrosine kinase ACK1 (TNK2) phosphorylates histone H4 at tyrosine 88 upstream of the AR transcription start site. The WDR5/MLL2 complex reads the H4-Y88-phosphorylation marks and deposits the transcriptionally activating H3K4-trimethyl marks promoting AR transcription. Reversal of the pY88-H4 epigenetic marks by the ACK1 inhibitor (R)-9bMS-sensitized naive and enzalutamide-resistant prostate cancer cells and reduced AR and AR-V7 levels to mitigate CRPC tumor growth. Thus, a feedforward ACK1/pY88-H4/WDR5/MLL2/AR epigenetic circuit drives CRPC and is necessary for maintenance of the malignant state. Copyright © 2017 Elsevier Inc. All rights reserved.

The male genital tract is not a pharmacological sanctuary from efavirenz.

PubMed

Avery, L B; Bakshi, R P; Cao, Y J; Hendrix, C W

2011-07-01

Many antiretroviral (ARV) drugs have large blood plasma-to-seminal plasma (BP/SP) concentration ratios. Concern exists that these drugs do not adequately penetrate the male genital tract (MGT), resulting in the MGT becoming a "pharmacological sanctuary" from these agents, with ineffective MGT concentrations despite effective blood concentrations. Efavirenz (EFV) is the most highly protein-bound ARV drug, with >99% binding in blood plasma and the largest BP/SP total EFV concentration ratio, reportedly ranging from 11 to 33. To evaluate protein binding as an explanation for the differences between the drug concentrations in blood and semen, we developed a novel ultrafiltration method, corrected for the duration of centrifugation, to measure protein binding in the two matrices. In six subjects, protein-free EFV concentrations were the same in blood and semen; the median (interquartile range (IQR)) protein-free EFV SP/BP ratio was 1.21 (0.99-1.35); EFV protein binding was 99.82% (99.79-99.86) in BP and 95.26% (93.24-96.67) in SP. This shows that the MGT is not a sanctuary from EFV.

Different intracellular distribution of avian reovirus core protein sigmaA in cells of avian and mammalian origin.

PubMed

Vázquez-Iglesias, Lorena; Lostalé-Seijo, Irene; Martínez-Costas, José; Benavente, Javier

2012-10-25

A comparative analysis of the intracellular distribution of avian reovirus (ARV) core protein sigmaA in cells of avian and mammalian origin revealed that, whereas the viral protein accumulates in the cytoplasm and nucleolus of avian cells, most sigmaA concentrates in the nucleoplasm of mammalian cells in tight association with the insoluble nuclear matrix fraction. Our results further showed that sigmaA becomes arrested in the nucleoplasm of mammalian cells via association with mammalian cell-specific factors and that this association prevents nucleolar targeting. Inhibition of RNA polymerase II activity, but not of RNA polymerase I activity, in infected mammalian cells induces nucleus-to-cytoplasm sigmaA translocation through a CRM1- and RanGTP-dependent mechanism, yet a heterokaryon assay suggests that sigmaA does not shuttle between the nucleus and cytoplasm. The scarcity of sigmaA in cytoplasmic viral factories of infected mammalian cells could be one of the factors contributing to limited ARV replication in mammalian cells. Copyright © 2012 Elsevier Inc. All rights reserved.

Foreign Aid: An Introduction to U.S. Programs and Policy

DTIC Science & Technology

2009-02-10

additionally meeting U.S. humanitarian objectives. Microcredit programs may help develop local economies while at the same time providing food and...training and expertise to fledgling microcredit institutions. In recent years, antiretroviral drugs (ARVs) provided through PEPFAR programs to...For instance, grants are sometimes provided to microcredit organizations which in turn provide loans to microentrepreneurs. Through the USAID-funded

Foreign Aid: An Introduction to U.S. Programs and Policy

DTIC Science & Technology

2009-04-09

Microcredit programs may help develop local economies while at the same time providing food and education to the children of entrepreneurs...and expertise to fledgling microcredit institutions. In recent years, antiretroviral drugs (ARVs) provided through PEPFAR programs to individuals...instance, grants are sometimes provided to microcredit organizations which in turn provide loans to microentrepreneurs. Through the USAID-funded Eurasia

Developing Novel Therapeutics Targeting Undifferentiated and Castration-Resistant Prostate Cancer Stem Cells

DTIC Science & Technology

2015-10-01

LNCaP-CRPC cells expressed AR protein and its 4 targets, i.e., PSA, FKBP5, PAP (prostate alkaline phosphatase), and PSMA (prostate-specific membrane...LNCaP GAPDH FKBP5 PSA 75 - 50 - PAP AR *** 100 - 75 - AR-V7100 -75 - PSMA 100 - 250 - 150 - 37 - 25 - 50 - 36 - A B C CDSS CDSS+Bica Re lat ive m

Patients with Parkinson disease present high ambulatory blood pressure variability.

PubMed

Kanegusuku, Hélcio; Silva-Batista, Carla; Peçanha, Tiago; Silva-Junior, Natan; Queiroz, Andreia; Costa, Luiz; Mello, Marco; Piemonte, Maria; Ugrinowitsch, Carlos; Forjaz, Cláudia

2017-09-01

Patients with Parkinson disease (PD) present blunted nocturnal blood pressure fall and similar ambulatory blood pressure variability (ABPV) measured by standard deviation (SD) and coefficient of variation (CV) compared with healthy subjects. However, these classical indices of ABPV have limited validity in individuals with circadian blood pressure alterations. New indices, such as the average of daytime and night-time standard deviation weighted by the duration of the daytime and night-time intervals (SD dn ) and the average real variability (ARV), remove the influence of the daytime and the night-time periods on ABPV. This study assessed ABPV by SD dn and ARV in PD. Twenty-one patients with PD (11 men, 66 ± 2 years, stages 2-3 of modified Hoehn & Yahr) and 21 matched controls without Parkinson disease (9 men, 64 ± 1 years old) underwent blood pressure monitoring for 24 h. ABPV was analysed by 24 h, daytime and night-time SD and CV, and by the SD dn and ARV. Systolic/diastolic 24-h and night-time SD and CV were similar between the patients with PD and the controls. The patients with PD presented higher daytime systolic/diastolic CV and SD than the controls (10·4 ± 0·9/12·3 ± 0·8 versus 7·0 ± 0·3/9·9 ± 0·5%, P<0·05; 12·6 ± 1·0/9·1 ± 0·5 versus 8·6 ± 0·4/7·5 ± 0·3 mmHg, P<0·05, respectively) as well as higher systolic/diastolic SD dn (10·9 ± 0·8/8·2 ± 0·5 versus 8·2 ± 0·3/7·1 ± 0·2 mmHg, P<0·05, respectively) and ARV (8·8 ± 0·6/6·9 ± 0·3 versus 7·2 ± 0·2/6·0 ± 0·2 mmHg, P<0·05, respectively). In conclusion, patients with PD have higher ABPV than control subjects as assessed by SD d , CV d , SD dn and AVR. © 2016 Scandinavian Society of Clinical Physiology and Nuclear Medicine. Published by John Wiley & Sons Ltd.

Cutting Your Losses: Could Best-Practice Pedagogy Involve Acknowledging that Even Robust Hope May Be Vain?

ERIC Educational Resources Information Center

Schuurmans-Stekhoven, James

2009-01-01

A recent special issue of "Asia-Pacific Journal of Teacher Education" (Vol. 35, Issue 3, 2007) championed "robust hope" as fundamental to achieving educational utopias, and yet key features of hope were largely overlooked. Although hope feels good and has utility in some circumstances, in other situations different…

Risk Factors, Health Care Resource Utilization, and Costs Associated with Nonadherence to Antiretrovirals in Medicaid-Insured Patients with HIV.

PubMed

Dunn, Keith; Lafeuille, Marie-Hélène; Jiao, Xiaolong; Romdhani, Hela; Emond, Bruno; Woodruff, Kimberly; Pesa, Jacqueline; Tandon, Neeta; Lefebvre, Patrick

2018-06-07

Adherence to antiretrovirals (ARVs) is critical to achieving durable virologic suppression. To investigate risk factors of poor adherence and the effect of suboptimal adherence on health care resource utilization (HCRU) and costs in Medicaid patients. A retrospective longitudinal study was conducted using Medicaid data. Adults (aged ≥ 18 years) with human immunodeficiency virus (HIV)-1 initiating selected ARVs (index date) were identified. Adherence was measured using medication possession ratio (MPR) and proportion of days covered (PDC) at 6 and 12 months post-index. Risk factors of poor adherence (PDC < 80%) were assessed using a logistic regression. HCRU and costs were compared between suboptimal (80% ≤ PDC < 95%) and optimal (PDC ≥ 95%) adherence groups using Poisson and ordinary least square models, respectively. In total, 3,477 patients were identified. Using MPR, 1,282 (39.0%) of the evaluable patients had poor adherence; 667 (20.2%) had suboptimal adherence; and 1,342 (40.8%) had optimal adherence versus 1,342 (51.1%), 509 (19.0%), and 804 (30.0%), respectively, using PDC at 6 months. PDC at 12 months was even lower. Younger age (OR = 1.58; 95% CI = 1.18-2.11; P = 0.002), noncapitated coverage (OR = 1.40; 95% CI = 1.16-1.69; P < 0.001), dual Medicaid/Medicare coverage (OR = 5.98; 95% CI = 4.39-8.16; P < 0.001), no baseline ARV treatment (OR = 1.98; 95% CI = 1.62-2.41; P < 0.001), and baseline asymptomatic HIV (OR = 1.37; 95% CI = 1.13-1.68; P = 0.002) were associated with higher risk of poor adherence. Suboptimal adherence patients had higher total number of days spent in a hospital (incidence rate ratio [IRR] = 1.62; 95% CI = 1.13-2.19; P = 0.008), total number of long-term care admissions (IRR = 3.11; 95% CI = 1.26-7.39; P = 0.008), total medical costs (mean monthly cost difference = $339; 95% CI = $153-$536; P < 0.001), and inpatient costs (mean monthly cost difference = $259; 95% CI = $122-$418; P < 0.001) compared with patients with optimal

Yield of Cytology Surveillance After High-Grade Vulvar Intraepithelial Neoplasia or Cancer.

PubMed

Kuroki, Lindsay M; Frolova, Antonina I; Wu, Ningying; Liu, Jingxia; Powell, Matthew; Thaker, Premal H; Massad, L Stewart

2017-07-01

The aim of the study was to estimate the risk of high-grade cervical and vaginal intraepithelial neoplasia (CIN/VAIN 2+) and cancer among women treated surgically for high-grade vulvar intraepithelial neoplasia (HGVIN) and vulvar cancer. We performed a retrospective cohort study of women who underwent surgery for HGVIN/vulvar cancer between 2006 and 2010. Univariate and multivariate analyses using stepwise selection were used to identify correlates of abnormal cytology after treatment for VIN and vulvar cancer. Among 191 women under surveillance for a median of 3.7 years who underwent treatment for HGVIN/vulvar cancer, primary vulvar lesions included VIN 2 (10, 5%), VIN 3 (102, 53%), and carcinoma (79, 41%). During follow-up, 71 (37%) had abnormal cytology, including 47 (25%) low grade, 23 (12%) high grade, and 1 (0.5%) carcinoma. Subsequent risk for VAIN 2+ was 11% (6/57) after previous hysterectomy and 8% for CIN 2+ (10/124) with intact cervix. Overall risk for CIN 3+ was 5%. Correlates of high-grade cytology after treatment for HGVIN/vulvar cancer included nonwhite race (odds ratio [OR] = 3.3, 95% CI = 1.50-7.36), immunodeficiency (OR = 4.2, 95% CI = 1.76-9.94), and previous abnormal cytology (OR = 2.7, 95% CI = 1.29-5.78). Stepwise multivariate analysis revealed immunosuppression as the only significant correlate of high-grade cytology after vulvar treatment (adjusted OR = 3.7, 95% CI = 1.26-10.83). Women with HGVIN/cancer should have cervical/vaginal cytology before vulvar surgery. Those with a negative cervical or vaginal cytology result should undergo cytology testing at 1- to 3-year intervals, based on the threshold for CIN 3+ set forth by the American Society for Colposcopy and Cervical Pathology.

A systematic review of the prevalence and attribution of human papillomavirus types among cervical, vaginal, and vulvar precancers and cancers in the United States.

PubMed

Insinga, Ralph P; Liaw, Kai-Li; Johnson, Lisa G; Madeleine, Margaret M

2008-07-01

To describe prevalence and estimated attribution of human papillomavirus (HPV) types in U.S. cervical, vaginal, and vulvar precancers and cancers. U.S. studies reporting HPV typing for cervical intraepithelial neoplasia (CIN), vulvar intraepithelial neoplasia (VIN), and vaginal intraepithelial neoplasia (VaIN) and/or invasive cancers of those sites were gathered from the PubMed database (http://www.ncbi.nlm.nih.gov/sites/entrez/). Selected studies had PCR testing data for > or =10 cases for a disease endpoint. Analytic methods augmented prior reviews of cervical disease with an updated and expanded analysis (including vulvar and vaginal disease), new selection criteria for specimens, and adjustment for histologic type, where possible, among pooled cancer cases. In addition, for analyses of estimated attribution of HPV types, we incorporated accounting methods for lesions infected with multiple HPV types. Data from 22 U.S. studies meeting review eligibility criteria were tabulated. Following adjustment for the presence of multiple HPV types in a single specimen, the top two HPV types contributing to disease were CIN 1 (HPV 16/66; 15.3%), CIN 2/3 (HPV 16/31; 61.9%), cervical cancer (HPV 16/18; 79.2%), VIN 1 (HPV 6/11; 41.7%), VIN 3 (HPV 16/18; 84.0%), vulvar cancer (HPV 16/33; 55.5%), VaIN 3 (HPV 16/18; 65.1%), and vaginal cancer (HPV 16/18; 72.7%). The HPV type distribution and proportion of cases testing positive for any HPV type were observed to vary among U.S. cervical, vulvar, and vaginal neoplasias and by grade of disease. Adjustment for the presence of multitype HPV infections can have an important effect on the estimated attribution of HPV types to disease, particularly for types other than HPV 16.

A Systematic Review of the Prevalence and Attribution of Human Papillomavirus Types Among Cervical, Vaginal and Vulvar Pre-cancers and Cancers in the United States

PubMed Central

Insinga, Ralph P.; Liaw, Kai-Li; Johnson, Lisa G.; Madeleine, Margaret M.

2008-01-01

Objectives To describe (1) prevalence and (2) estimated attribution of human papillomavirus (HPV) types in U.S. cervical, vaginal and vulvar precancers and cancers. Methods U.S. studies reporting HPV typing for cervical (CIN), vulvar (VIN) and vaginal (VaIN) intraepithelial neoplasias and/or invasive cancers of those sites were gathered from the PubMed database (http://www.ncbi.nlm.nih.gov/sites/entrez/). Selected studies had polymerase chain reaction testing data for ≥10 cases for a disease endpoint. Analytic methods augmented prior reviews of cervical disease with an updated and expanded analysis (including vulvar and vaginal disease), new selection criteria for specimens, and adjustment for histologic type, where possible, among pooled cancer cases. In addition, for analyses of estimated attribution of HPV types, we incorporated accounting methods for lesions infected with multiple HPV types. Results Data from 22 U.S. studies meeting review eligibility criteria were tabulated. Following adjustment for the presence of multiple HPV types in a single specimen, the top two HPV types contributing to disease were: CIN 1 (HPV 16/66) [15.3%], CIN 2/3 (16/31) [61.9%], cervical cancer (16/18) [79.2%], VIN 1 (6/11) [41.7%], VIN 3 (16/18) [84.0%], vulvar cancer (16/33) [55.5%], VaIN 3 (16/18) [65.1%], vaginal cancer (16/18) [72.7%]. Conclusions The HPV type distribution and proportion of cases testing positive for any HPV type were observed to vary among U.S. cervical, vulvar and vaginal neoplasias and by grade of disease. Adjustment for the presence of multi-type HPV infections can have an important impact on the estimated attribution of HPV types to disease, particularly for types other than HPV 16. PMID:18628412

Georg Friedrich Kordenbusch and astronomy in Nuremberg in the second half of the 18th century. (German Title: Georg Friedrich Kordenbusch und die Astronomie in Nürnberg in der zweiten Hälfte des 18. Jahrhunderts)

NASA Astrophysics Data System (ADS)

Gaab, Hans

In the second half of the 18th century, Georg Friedrich Kordenbusch (1731 - 1802) was the best-known living mathematician and astronomer in Nuremberg. Being a physician by training, he obtained, in 1769, the post of lecturer in mathematics and physics at the Egidien secondary school. Subsequently, he tried in vain to re-erect the observatory, torn down in 1751. In the early 1770s, he became famous for preparing the second edition of Johann Leonhard Rost's Astronomisches Handbuch that was, in its first edition of 1718, the first compendium of astronomy written in German, and which had a wide circulation. In 1790, Kordenbusch was raised to the nobility for his achievements.

The economic-impact fallacy

NASA Astrophysics Data System (ADS)

Moriarty, Philip

2009-06-01

Before the UK budget was announced in April, there had been excited expectations of an "Obama-style" £1bn stimulus package for science. That prospect prompted research councils and learned societies in the UK to rush to identify "shovel-ready" projects that could benefit from a fresh injection of funds. However, their efforts were in vain - the stimulus did not arrive. Instead, John Denham, secretary of state for Innovation, Universities and Skills, has had to put a brave face on an immensely disappointing budget settlement for science. The Department for Innovation, Universities and Skills (DIUS), which Denham runs, must now make £0.5bn in savings over the next two years.

HIV Immune Recovery Inflammatory Syndrome and Central Nervous System Paracoccidioidomycosis.

PubMed

de Almeida, Sérgio Monteiro; Roza, Thiago Henrique

2017-04-01

The immune reconstitution inflammatory syndrome (IRIS) is a deregulated inflammatory response to invading microorganisms. It is manifested when there is an abrupt change in host immunity from an anti-inflammatory and immunosuppressive state to a pro-inflammatory state as a result of rapid depletion or removal of factors that promote immune suppression or inhibition of inflammation. The aim of this paper is to discuss and re-interpret the possibility of association of paracoccidioidomycosis (PCM) with IRIS in the central nervous system (CNS) in a case from Brazil published by Silva-Vergara ML. et al. (Mycopathologia 177:137-141, 6). An AIDS patient who was not receiving medical care developed pulmonary PCM successfully treated with itraconazole. The patient developed central nervous system PCM (NPCM) after starting the ARV therapy with recovery of immunity and control of HIV viral load, although it was not interpreted as IRIS by the authors, it fulfills the criteria for CNS IRIS. This could be the first case of NPCM associated with IRIS described. Although not frequent, IRIS must be considered in PCM patients and HIV, from endemic areas or patients that traveled to endemic areas, receiving ARV treatment and with worsening symptoms.

New Patterns of Disclosure: How HIV-Positive Support Group Members from KwaZulu-Natal Speak of their Status in Oral Narratives

PubMed Central

Denis, Philippe

2014-01-01

This paper examines the representations and emotions associated with disclosure and stigma in Pietermaritzburg, KwaZulu-Natal, seven years after the start of the South African government’s ARV roll-out programme on the basis of in-depth oral history interviews of HIV-positive support group members. It argues that the wider availability of ARV treatment, the ensuing reduced fatality rate and the increased number of people, including men, who receive counselling and testing, may mean that HIV/AIDS is less stigmatised and that disclosure has become easier. This does not mean that stigma has disappeared and that the confusion created by competing world-views and belief systems has dissipated. Yet the situation of extreme denial and ideological confusion observed, for example, by Deborah Posel and her colleagues in 2003 and 2004 in the Mpumalanga province seems to have lessened. The interviews hint at the possibility that people living with HIV may have, more than a decade before, a language to express the emotions and feelings associated with HIV/AIDS. They were also found to be more assertive in matters of gender relations. These new attitudes would make disclosure easier and stigma more likely to recede. PMID:24775433

Intellectual property rights, market competition and access to affordable antiretrovirals.

PubMed

Pascual, Fernando

2014-01-01

The number of patients receiving antiretroviral therapy (ART) has increased from around half a million in 2003 to almost 10 million in only 10 years, and will continue to increase in the coming years. Over 16 million more are eligible to start ART according to the last World Health Organization (WHO) guidelines. The demand is also switching from the less expensive antiretrovirals (ARVs) that allowed such scale-up to newer more expensive ones with fewer side effects or those that can be used by people who have developed resistance to first-line treatment. However, patents on these new drugs can delay robust generic competition and, consequently, price reduction made possible by economies of scale. Various ways to address this issue have been envisaged or implemented, including the use of the flexibilities available under the Agreement on Trade-Related Aspects of Intellectual Property Rights (TRIPS), systematic widespread voluntary licensing, of which the Medicines Patent Pool (MPP) is an example, and the application of different prices in different countries, called tiered pricing. This paper helps explain the impact of patents on market competition for ARVs and analyses various approaches available today to minimize this impact.

Preclinical discovery and development of maraviroc for the treatment of HIV.

PubMed

Veljkovic, Nevena; Vucicevic, Jelica; Tassini, Sabrina; Glisic, Sanja; Veljkovic, Veljko; Radi, Marco

2015-06-01

Maraviroc is a first-in-class antiretroviral (ARV) drug acting on a host cell target (CCR5), which blocks the entry of the HIV virus into the cell. Maraviroc is currently indicated for combination ARV treatment in adults infected only with CCR5-tropic HIV-1. This drug discovery case history focuses on the key studies that led to the discovery and approval of maraviroc, as well as on post-launch clinical reports. The article is based on the data reported in published preclinical and clinical studies, conference posters and on drug package data. The profound understanding of HIV's entry mechanisms has provided a strong biological rationale for targeting the chemokine receptor CCR5. The CCR5-antagonist mariviroc, with its unique mode of action and excellent safety profile, is an important therapeutic option for HIV patients. In general, the authors believe that targeting host factors is a useful approach for combating new and re-emerging transmissible diseases, as well as pathogens that easily become resistant to common antiviral drugs. Maraviroc, offering a potent and safe cellular receptor-mediated pharmacological response to HIV, has paved the way for the development of a new generation of host-targeting antivirals.

Optimizing Research to Speed Up Availability of Pediatric Antiretroviral Drugs and Formulations.

PubMed

Penazzato, Martina; Gnanashanmugam, Devasena; Rojo, Pablo; Lallemant, Marc; Lewis, Linda L; Rocchi, Francesca; Saint Raymond, Agnes; Ford, Nathan; Hazra, Rohan; Giaquinto, Carlo; Belew, Yodit; Gibb, Diana M; Abrams, Elaine J

2017-06-01

Globally 1.8 million children are living with human immunodeficiency virus (HIV), yet only 51% of those eligible actually start treatment. Research and development (R&D) for pediatric antiretrovirals (ARVs) is a lengthy process and lags considerably behind drug development in adults. Providing safe, effective, and well-tolerated drugs for children remains critical to ensuring scale-up globally. We review current approaches to R&D for pediatric ARVs and suggest innovations to enable simplified, faster, and more comprehensive strategies to develop optimal formulations. Several approaches could be adopted, including focusing on a limited number of prioritized formulations and strengthening existing partnerships to ensure that pediatric investigation plans are developed early in the drug development process. Simplified and more efficient mechanisms to undertake R&D need to be put in place, and financing mechanisms must be made more sustainable. Lessons learned from HIV should be shared to support progress in developing pediatric formulations for other diseases, including tuberculosis and viral hepatitis. © The Author 2017. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.

Risk factors of HIV-1 vertical transmission (VT) and the influence of antiretroviral therapy (ART) in pregnancy outcome.

PubMed

Barral, Maria F M; de Oliveira, Gisele R; Lobato, Rubens C; Mendoza-Sassi, Raul A; Martínez, Ana M B; Gonçalves, Carla V

2014-01-01

In the absence of intervention, the rate of vertical transmission of HIV can range from 15-45%. With the inclusion of antiretroviral drugs during pregnancy and the choice of delivery route this amounts to less than 2%. However ARV use during pregnancy has generated several questions regarding the adverse effects of the gestational and neonatal outcome. This study aims to analyze the risk factors for vertical transmission of HIV-1 seropositive pregnant women living in Rio Grande and the influence of the use of ARVs in pregnancy outcome. Among the 262 pregnant women studied the rate of vertical transmission of HIV was found to be 3.8%. Regarding the VT, there was a lower risk of transmission when antiretroviral drugs were used and prenatal care was conducted at the referral service. However, the use of ART did not influence the outcome of pregnancy. However, initiation of prenatal care after the first trimester had an influence on low birth weight, as well as performance of less than six visits increased the risk of prematurity. Therefore, the risk factors analyzed in this study appear to be related to the realization of inadequate pre-natal and maternal behavior.

Design Study for the Asteroid Redirect Vehicle (ARV) Composite Primary Bulkhead

NASA Technical Reports Server (NTRS)

Cressman, Thomas O.; Paddock, David A.

2017-01-01

A design study was undertaken of a carbon fiber primary bulkhead for a large solar electric propulsion (SEP) spacecraft. The bulkhead design, supporting up to 16 t of xenon propellant, progressed from one consisting of many simple parts with many complex joints, to one consisting of a few complex parts with a few simple joints. The unique capabilities of composites led to a topology that transitioned loads from bending to in-plane tension and shear, with low part count. This significantly improved bulkhead manufacturability, cost, and mass. The stiffness-driven structure utilized high-modulus M55J fiber unidirectional prepregs. A full-scale engineering demonstration unit (EDU) of the concept was used to demonstrate manufacturability of the concept. Actual labor data was obtained, which could be extrapolated to a full bulkhead. The effort demonstrated the practicality of using high-modulus fiber (HMF) composites for unique shape topologies that minimize mass and cost. The lessons are applicable to primary and secondary aerospace structures that are stiffness driven.

Engineering Evaluation and Analysis for the Improvement of Military Standard Generators. Volume 1.

DTIC Science & Technology

1987-05-29

Heights, MI 48077 Schenectady, NY 12301-1058 (32) Peter Diesels, Inc. (44) Snyder Industries, Inc. 4761 Hugh Howell Road 4700 FreemontTucker, GA 30084 Box...Aaisi-icns 7 ;s:ems Marazeen: :e 1 an 30 k. o -. -e e aco se i o’*.: -- c-.weerA Ica i 1 -re 7h3. ~e .1arv e:mres zec an :nrterast to r-asoive -.e

The HIV-1 integrase-LEDGF allosteric inhibitor MUT-A: resistance profile, impairment of virus maturation and infectivity but without influence on RNA packaging or virus immunoreactivity.

PubMed

Amadori, Céline; van der Velden, Yme Ubeles; Bonnard, Damien; Orlov, Igor; van Bel, Nikki; Le Rouzic, Erwann; Miralles, Laia; Brias, Julie; Chevreuil, Francis; Spehner, Daniele; Chasset, Sophie; Ledoussal, Benoit; Mayr, Luzia; Moreau, François; García, Felipe; Gatell, José; Zamborlini, Alessia; Emiliani, Stéphane; Ruff, Marc; Klaholz, Bruno P; Moog, Christiane; Berkhout, Ben; Plana, Montserrat; Benarous, Richard

2017-11-09

HIV-1 Integrase (IN) interacts with the cellular co-factor LEDGF/p75 and tethers the HIV preintegration complex to the host genome enabling integration. Recently a new class of IN inhibitors was described, the IN-LEDGF allosteric inhibitors (INLAIs). Designed to interfere with the IN-LEDGF interaction during integration, the major impact of these inhibitors was surprisingly found on virus maturation, causing a reverse transcription defect in target cells. Here we describe the MUT-A compound as a genuine INLAI with an original chemical structure based on a new type of scaffold, a thiophene ring. MUT-A has all characteristics of INLAI compounds such as inhibition of IN-LEDGF/p75 interaction, IN multimerization, dual antiretroviral (ARV) activities, normal packaging of genomic viral RNA and complete Gag protein maturation. MUT-A has more potent ARV activity compared to other INLAIs previously reported, but similar profile of resistance mutations and absence of ARV activity on SIV. HIV-1 virions produced in the presence of MUT-A were non-infectious with the formation of eccentric condensates outside of the core. In studying the immunoreactivity of these non-infectious virions, we found that inactivated HIV-1 particles were captured by anti-HIV-specific neutralizing and non-neutralizing antibodies (b12, 2G12, PGT121, 4D4, 10-1074, 10E8, VRC01) with efficiencies comparable to non-treated virus. Autologous CD4 + T lymphocyte proliferation and cytokine induction by monocyte-derived dendritic cells (MDDC) pulsed either with MUT-A-inactivated HIV or non-treated HIV were also comparable. Although strongly defective in infectivity, HIV-1 virions produced in the presence of the MUT-A INLAI have a normal protein and genomic RNA content as well as B and T cell immunoreactivities comparable to non-treated HIV-1. These inactivated viruses might form an attractive new approach in vaccine research in an attempt to study if this new type of immunogen could elicit an immune response

NASA's Asteroid Redirect Mission: The Boulder Capture Option

NASA Technical Reports Server (NTRS)

Abell, Paul A.; Nuth, J.; Mazanek, D.; Merrill, R.; Reeves, D.; Naasz, B.

2014-01-01

NASA is examining two options for the Asteroid Redirect Mission (ARM), which will return asteroid material to a Lunar Distant Retrograde Orbit (LDRO) using a robotic solar-electric-propulsion spacecraft, called the Asteroid Redirect Vehicle (ARV). Once the ARV places the asteroid material into the LDRO, a piloted mission will rendezvous and dock with the ARV. After docking, astronauts will conduct two extravehicular activities (EVAs) to inspect and sample the asteroid material before returning to Earth. One option involves capturing an entire small (approximately 4-10 m diameter) near-Earth asteroid (NEA) inside a large inflatable bag. However, NASA is examining another option that entails retrieving a boulder (approximately 1-5 m) via robotic manipulators from the surface of a larger (approximately 100+ m) pre-characterized NEA. This option can leverage robotic mission data to help ensure success by targeting previously (or soon to be) well-characterized NEAs. For example, the data from the Hayabusa mission has been utilized to develop detailed mission designs that assess options and risks associated with proximity and surface operations. Hayabusa's target NEA, Itokawa, has been identified as a valid target and is known to possess hundreds of appropriately sized boulders on its surface. Further robotic characterization of additional NEAs (e.g., Bennu and 1999 JU3) by NASA's OSIRIS REx and JAXA's Hayabusa 2 missions is planned to begin in 2018. The boulder option is an extremely large sample-return mission with the prospect of bringing back many tons of well-characterized asteroid material to the Earth-Moon system. The candidate boulder from the target NEA can be selected based on inputs from the world-wide science community, ensuring that the most scientifically interesting boulder be returned for subsequent sampling. This boulder option for NASA's ARM can leverage knowledge of previously characterized NEAs from prior robotic missions, which provides more

The cost-effectiveness in the use of HIV counselling and testing-mobile outreaches in reaching men who have sex with men (MSM) in northern Nigeria.

PubMed

Ifekandu, Chiedu; Suleiman, Aliyu; Aniekwe, Ogechukwu

2014-01-01

Men who have sex with men (MSM) are at increased risk of HIV and other STI infections in Nigeria. This is because MSM are afraid to seek medical help because the healthcare workers in various facilities are afraid of the consequences if they provide services for MSM citing the law as a reason not to intervene. MSM in northern states of Nigeria are facing double-jeopardy because the few international partners working in MSM in Nigeria are pulling out of these volatile areas because of the fear of attacks by the Boko Haram and the Nigerian law enforcement agencies. The intervention was conducted to promote affordable and sustainable HIV care and treatment for MSM in Nigeria. This intervention was conducted in the Boko Haram ravaged cities of Kano and Maiduguri (North-East Nigeria). Twenty MSM-key influencers from the two cities were identified and trained on HIV counselling and testing, caregivers, case managers and on initiation process for ARV treatment for new HIV+MSM as well as ethical considerations. The mean age of the key influencers was 24 years +/-SD. Each of the trained 20 key influencers reached 20 MSM-peer with condom promotion, HCT, referral to identified MSM-community health centers and follow-up/caregiving within the space of one month. The project was able to reach 400 MSM in the two cities. 89% of the peers consented to HCT. HIV prevalence among the participants was at 18%. The project recorded ARV-successful referral to healthcare facilities for the respondents that tested positive. The key influencers have been following up for ARV-adherence. Use of community members should be promoted for sustainability and ownership. It also helps in eradicating socio-cultural barrier to HIV intervention for MSM. Moreover, this proves to be one of the safest and affordable methods of reaching MSM in Nigeria in this ugly time of legalization of homophobia in the country's constitution.

Transporters for Antiretroviral Drugs in Colorectal CD4+ T Cells and Circulating α4β7 Integrin CD4+ T Cells: Implications for HIV Microbicides.

PubMed

Mukhopadhya, Indrani; Murray, Graeme I; Duncan, Linda; Yuecel, Raif; Shattock, Robin; Kelly, Charles; Iannelli, Francesco; Pozzi, Gianni; El-Omar, Emad M; Hold, Georgina L; Hijazi, Karolin

2016-09-06

CD4+ T lymphocytes in the colorectal mucosa are key in HIV-1 transmission and dissemination. As such they are also the primary target for antiretroviral (ARV)-based rectal microbicides for pre-exposure prophylaxis. Drug transporters expressed in mucosal CD4+ T cells determine ARV distribution across the cell membrane and, most likely, efficacy of microbicides. We describe transporters for antiretroviral drugs in colorectal mucosal CD4+ T lymphocytes and compare gene expression with circulating α4β7+CD4+ T cells, which traffic to the intestine and have been shown to be preferentially infected by HIV-1. Purified total CD4+ T cells were obtained from colorectal tissue and blood samples by magnetic separation. CD4+ T cells expressing α4β7 integrin were isolated by fluorescence-activated cell sorting from peripheral blood mononuclear cells of healthy volunteers. Expressions of 15 efflux and uptake drug transporter genes were quantified using Taqman qPCR assays. Expression of efflux transporters MRP3, MRP5, and BCRP and uptake transporter CNT2 were significantly higher in colorectal CD4+ T cells compared to circulating CD4+ T cells (p = 0.01-0.03). Conversely, circulating α4β7+CD4+ T cells demonstrated significantly higher expression of OATPD compared to colorectal CD4+ T cells (p = 0.001). To the best of our knowledge this is the first report of drug transporter gene expression in colorectal CD4+ and peripheral α4β7+CD4+ T cells. The qualitative and quantitative differences in drug transporter gene expression profiles between α4β7+CD4+ T cells and total mucosal CD4+ T cells may have significant implications for the efficacy of rectally delivered ARV-microbicides. Most notably, we have identified efflux drug transporters that could be targeted by selective inhibitors or beneficial drug-drug interactions to enhance intracellular accumulation of antiretroviral drugs.

HIV-1 drug resistance and resistance testing.

PubMed

Clutter, Dana S; Jordan, Michael R; Bertagnolio, Silvia; Shafer, Robert W

2016-12-01

The global scale-up of antiretroviral (ARV) therapy (ART) has led to dramatic reductions in HIV-1 mortality and incidence. However, HIV drug resistance (HIVDR) poses a potential threat to the long-term success of ART and is emerging as a threat to the elimination of AIDS as a public health problem by 2030. In this review we describe the genetic mechanisms, epidemiology, and management of HIVDR at both individual and population levels across diverse economic and geographic settings. To describe the genetic mechanisms of HIVDR, we review the genetic barriers to resistance for the most commonly used ARVs and describe the extent of cross-resistance between them. To describe the epidemiology of HIVDR, we summarize the prevalence and patterns of transmitted drug resistance (TDR) and acquired drug resistance (ADR) in both high-income and low- and middle-income countries (LMICs). We also review to two categories of HIVDR with important public health relevance: (i) pre-treatment drug resistance (PDR), a World Health Organization-recommended HIVDR surveillance metric and (ii) and pre-exposure prophylaxis (PrEP)-related drug resistance, a type of ADR that can impact clinical outcomes if present at the time of treatment initiation. To summarize the implications of HIVDR for patient management, we review the role of genotypic resistance testing and treatment practices in both high-income and LMIC settings. In high-income countries where drug resistance testing is part of routine care, such an understanding can help clinicians prevent virological failure and accumulation of further HIVDR on an individual level by selecting the most efficacious regimens for their patients. Although there is reduced access to diagnostic testing and to many ARVs in LMIC, understanding the scientific basis and clinical implications of HIVDR is useful in all regions in order to shape appropriate surveillance, inform treatment algorithms, and manage difficult cases. Copyright © 2016 Elsevier B

Maternal anaemia and duration of zidovudine in antiretroviral regimens for preventing mother-to-child transmission: a randomized trial in three African countries

PubMed Central

2013-01-01

Background Although substantiated by little evidence, concerns about zidovudine-related anaemia in pregnancy have influenced antiretroviral (ARV) regimen choice for preventing mother-to-child transmission of HIV-1, especially in settings where anaemia is common. Methods Eligible HIV-infected pregnant women in Burkina Faso, Kenya and South Africa were followed from 28 weeks of pregnancy until 12–24 months after delivery (n = 1070). Women with a CD4 count of 200-500cells/mm3 and gestational age 28–36 weeks were randomly assigned to zidovudine-containing triple-ARV prophylaxis continued during breastfeeding up to 6-months, or to zidovudine during pregnancy plus single-dose nevirapine (sd-NVP) at labour. Additionally, two cohorts were established, women with CD4 counts: <200 cells/mm3 initiated antiretroviral therapy, and >500 cells/mm3 received zidovudine during pregnancy plus sd-NVP at labour. Mild (haemoglobin 8.0-10.9 g/dl) and severe anaemia (haemoglobin < 8.0 g/dl) occurrence were assessed across study arms, using Kaplan-Meier and multivariable Cox proportional hazards models. Results At enrolment (corresponded to a median 32 weeks gestation), median haemoglobin was 10.3 g/dl (IQR = 9.2-11.1). Severe anaemia occurred subsequently in 194 (18.1%) women, mostly in those with low baseline haemoglobin, lowest socio-economic category, advanced HIV disease, prolonged breastfeeding (≥6 months) and shorter ARV exposure. Severe anaemia incidence was similar in the randomized arms (equivalence P-value = 0.32). After 1–2 months of ARV’s, severe anaemia was significantly reduced in all groups, though remained highest in the low CD4 cohort. Conclusions Severe anaemia occurs at a similar rate in women receiving longer triple zidovudine-containing regimens or shorter prophylaxis. Pregnant women with pre-existing anaemia and advanced HIV disease require close monitoring. Trial registration number ISRCTN71468401 PMID:24192332

HIV-1-associated inflammation and antiretroviral therapy regulate astrocyte endoplasmic reticulum stress responses.

PubMed

Nooka, Shruthi; Ghorpade, Anuja

2017-01-01

Antiretroviral (ARV) therapy (ART) has effectively suppressed the incidence of human immunodeficiency virus (HIV)-associated dementia in HIV-1 positive individuals. However, the prevalence of more subtle forms of neurocognitive dysfunction continues to escalate. Recently, endoplasmic reticulum (ER) stress has been linked to many neurological diseases; yet, its role in HIV/neuroAIDS remains largely unexplored. Furthermore, upregulation of astrocyte elevated gene-1 ( AEG-1 ), a novel HIV-1 inducible gene, along with ER stress markers in a Huntington's disease model, suggests a possible role in HIV-associated ER stress. The current study is focused on unfolded protein responses (UPRs) and AEG-1 regulation in primary human astrocytes exposed to HIV-associated neurocognitive disorders (HAND)-relevant stimuli (HIV-1 virions, inflammation and ARV drugs). Interleukin (IL)-1 β and the nucleoside reverse transcriptase inhibitor abacavir upregulated expression of ER stress markers in human astrocytes, including binding immunoglobulin protein (BiP), C/EBP homologous protein (CHOP), and calnexin. In addition, IL-1 β activated all three well-known UPR pathways: protein kinase RNA-like ER kinase (PERK); activating transcription factor 6 (ATF-6); and inositol-requiring enzyme 1 α (IRE1 α ). AEG-1 upregulation correlated to ER stress and demonstrated astrocyte AEG-1 interaction with the calcium-binding chaperone, calnexin. IL-1 β and abacavir enhanced intracellular calcium signaling in astrocytes in the absence of extracellular calcium, illustrating ER-associated calcium release. Alternatively, calcium evoked in response to HAND-relevant stimuli led to mitochondrial permeability transition pore (mPTP) opening in human astrocytes. Importantly, IL-1 β - and abacavir-induced UPR and mPTP opening were inhibited by the intracellular calcium chelation, indicating the critical role of calcium signaling in HAND-relevant ER stress in astrocytes. In summary, our study highlights that

Combination antiretroviral therapy improves cognitive performance and functional connectivity in treatment-naïve HIV-infected individuals.

PubMed

Zhuang, Yuchuan; Qiu, Xing; Wang, Lu; Ma, Qing; Mapstone, Mark; Luque, Amneris; Weber, Miriam; Tivarus, Madalina; Miller, Eric; Arduino, Roberto C; Zhong, Jianhui; Schifitto, Giovanni

2017-10-01

Our study aimed to investigate the short-term effect of combination antiretroviral therapy (cART) on cognitive performance and functional and structural connectivity and their relationship to plasma levels of antiretroviral (ARV) drugs. Seventeen ARV treatment-naïve HIV-infected individuals (baseline mean CD4 cell count, 479 ± 48 cells/mm 3 ) were age matched with 17 HIV-uninfected individuals. All subjects underwent a detailed neurocognitive and functional assessment and magnetic resonance imaging. HIV-infected subjects were scanned before starting cART and 12 weeks after initiation of treatment. Uninfected subjects were assessed once at baseline. Functional connectivity (FC) was assessed within the default mode network while structural connectivity was assessed by voxel-wise analysis using tract-based spatial statistics (TBSS) and probabilistic tractography within the DMN. Tenofovir and emtricitabine blood concentration were measured at week 12 of cART. Prior to cART, HIV-infected individuals had significantly lower cognitive performance than control subjects as measured by the total Z-score from the neuropsychological tests assessing six cognitive domains (p = 0.020). After 12 weeks of cART treatment, there remained only a weak cognitive difference between HIV-infected and HIV-uninfected subjects (p = 0.057). Mean FC was lower in HIV-infected individuals compared with those uninfected (p = 0.008), but FC differences became non-significant after treatment (p = 0.197). There were no differences in DTI metrics between HIV-infected and HIV-uninfected individuals using the TBSS approach and limited evidence of decreased structural connectivity within the DMN in HIV-infected individuals. Tenofovir and emtricitabine plasma concentrations did not correlate with either cognitive performance or imaging metrics. Twelve weeks of cART improves cognitive performance and functional connectivity in ARV treatment-naïve HIV-infected individuals with relatively

Low Prevalence of Antiretroviral Resistance Among HIV Type 1-Positive Prisoners in the Southeast United States

PubMed Central

Rosen, David; Wohl, David A.; Kiziah, Nichole; Sebastian, Joseph; Eron, Joseph J.; White, Becky

2013-01-01

Abstract Drug-resistant HIV complicates management of HIV infection. Although an estimated 14% of all HIV-positive persons pass through a prison or jail in the United States each year, little is known about the overall prevalence of antiretroviral (ARV) resistance in incarcerated persons. All genotypic sequence data on HIV-positive prisoners in the North Carolina (NC) Department of Corrections (DOC) were obtained from LabCorp. Screening for major resistance mutations in protease (PI) and reverse transcriptase (NRTI and NNRTI) was done using Genosure and the Stanford HIV Database. For subjects with multiple genotype reports, each mutation was counted only once and considered present on all subsequent genotypes. Between October 2006 and February 2010, the NC DOC incarcerated 1,911 HIV+ individuals of whom 19.2% (n=367) had at least one genotype performed. The overall prevalence of a major resistance mutation was 28.3% (95% CI 23.7, 33.0). Among prisoners ever exposed to an ARV during incarceration (n=329) prevalence of a major resistance mutation was 29.8% (95% CI 24.9, 34.7); resistance by class was 20.4% (95% CI 16.0, 24.7) for NRTIs, 19.8% (95% CI 15.5, 24.1) for NNRTIs, and 8.8% (95% CI 5.8,11.9) for PIs. Single class drug resistance was most prevalent at 14.2% (10.2,17.7) followed by dual 12.5% (I8.9,16.0) and triple class 3.3% (1.4,5.3) resistance. The three most prevalent mutations were K103N 15.8% (12.0, 20.2), M184V 14.3% (10.7,18.5), and M41L 4.9% (2.8,7.8). In the NC DOC ARV resistance prevalence, dual and triple class drug resistance was moderate over the study period. Resistance to PIs was lower than NNRTIs and NRTIs, likely reflecting higher usage of these two classes or a lower barrier to resistance. PMID:22966822

Development of written information for antiretroviral therapy: comprehension in a Tanzanian population.

PubMed

Mwingira, Betty; Dowse, Ros

2007-06-01

To design and develop a simple, easily readable patient information leaflet (PIL) for a commonly used antiretroviral (ARV) regimen and to evaluate its readability and acceptability in a Tanzanian population. A PIL incorporating simple text and pictograms was designed for the antiretroviral regimen of stavudine, lamivudine and efavirenz. The PIL was designed according to established good design guidelines, modified during a multi-stage iterative testing process and piloted in a South African Xhosa population. The PIL was made available in both English and Kiswahili. Sixty Tanzanian participants who were not taking ARVs were interviewed. They were asked to read the PIL in the language of their choice and were then asked a series of two-part questions; the first part required participants to locate the information in the PIL, after which they were asked to explain the information in their own words. Acceptability was assessed through close-ended questions and open-ended feedback. The influence of selected patient characteristics on comprehension of the PIL was investigated using one-way ANOVA and t-tests for independent samples with a significance level set at 0.05. Comprehension of the written information in an overall percentage understanding. The overall average percentage comprehension of the PIL was 95%. The target set by the EC guideline that at least 80% of participants correctly locate and understand the information was achieved for 19 of the 20 questions. Five of the six instructions illustrated by pictograms were correctly understood by all participants. The only patient characteristics significantly associated with comprehension were educational level and self-reported ease of reading the PIL. Acceptability of the PIL was high and positive comments were associated with simplicity, good design, easy readability and user-friendliness, the latter enhanced by the inclusion of pictograms. The PIL designed for this study was shown to be effective in communicating

Psychosocial needs of perinatally HIV-infected youths in Thailand: lessons learnt from instructive counseling.

PubMed

Manaboriboon, B; Lolekha, R; Chokephaibulkit, K; Leowsrisook, P; Naiwatanakul, T; Tarugsa, J; Durier, Y; Aunjit, N; Punpanich Vandepitte, W; Boon-Yasidhi, V

2016-12-01

Identifying psychosocial needs of perinatally HIV-infected (pHIV) youth is a key step in ensuring good mental health care. We report psychosocial needs of pHIV youth identified using the "Youth Counseling Needs Survey" (YCS) and during individual counseling (IC) sessions. pHIV youth receiving care at two tertiary-care hospitals in Bangkok or at an orphanage in Lopburi province were invited to participate IC sessions. The youths' psychosocial needs were assessed using instructive IC sessions in four main areas: general health, reproductive health, mood, and psychosocial concerns. Prior to the IC session youth were asked to complete the YCS in which their concerns in the four areas were investigated. Issues identified from the YCS and the IC sessions were compared. During October 2010-July 2011, 150 (68.2%) of 220 eligible youths participated in the IC sessions and completed the YCS. Median age was 14 (range 11-18) years and 92 (61.3%) were female. Mean duration of the IC sessions was 36.5 minutes. One-hundred and thirty (86.7%) youths reported having at least one psychosocial problem discovered by either the IC session or the YCS. The most common problems identified during the IC session were poor health attitude and self-care (48.0%), lack of life skills (44.0%), lack of communication skills (40.0%), poor antiretroviral (ARV) adherence (38.7%), and low self-value (34.7%). The most common problems identified by the YCS were lack of communication skills (21.3%), poor health attitude and self-care (14.0%), and poor ARV adherence (12.7%). Youth were less likely to report psychosocial problems in the YCS than in the IC session. Common psychosocial needs among HIV-infected youth were issues about life skills, communication skills, knowledge on self-care, ARV adherence, and self-value. YCS can identify pHIV youths' psychosocial needs but might underestimate issues. Regular IC sessions are useful to detect problems and provide opportunities for counseling.

Molecular Indicators of Castration-Resistant Prostate Cancer

DTIC Science & Technology

2015-12-01

hypothesis- generating. To evaluate the clinical utility of AR-V7/AR- FL ratio measurement, a more in-depth investigation will be necessary but would be...V7, supporting expanded validation studies aimed at evaluating the clinical utility of this blood-based treatment selection marker. References...engl j med 371;11 nejm.org september 11, 2014 1035 mained marginally predictive of shorter clinical or radiographic progression–free survival (hazard

Do Androgen Receptor Splice Variants Facilitate Growth of Bone Metastases

DTIC Science & Technology

2016-11-01

therapy is expression of constitutively active AR splice variants, which lack the carboxyl terminal hormone binding domain. The best characterized...resistance is expression of constitutively active AR splice variants, which lack the carboxyl terminal hormone binding domain. Of these, the most...removes hormone , but also many other factors. We plan to retest the effects of AR-V7 in the complete medium to determine whether effects would be

Muscle fibre conduction velocity during a 30-s Wingate anaerobic test.

PubMed

Stewart, David; Farina, Dario; Shen, Chao; Macaluso, Andrea

2011-06-01

Ten male volunteers (age 29.2 ± 5.2 years, mean ± SD) were recruited to test the hypothesis that muscle fibre conduction velocity (MFCV) would decrease with power output during a 30-s Wingate test on a mechanically-braked cycle ergometer. Prior to the main test, the optimal pre-fixed load corresponding to the highest power output was selected following a random series of six 10-s sprints. Surface electromyographic (EMG) signals were detected from the right vastus lateralis with linear adhesive arrays of eight electrodes. Power output decreased significantly from 6-s until the end of the test (860.9 ± 207.8 vs. 360.9 ± 11.4 W, respectively) and was correlated with MFCV (R=0.543, P<0.01), which also declined significantly by 26.8 ± 11% (P<0.05). There was a tendency for the mean frequency of the EMG power spectrum (MNF) to decrease, but average rectified values (ARV) remained unchanged throughout the test. The parallel decline of MFCV with power output suggests changes in fibre membrane properties. The unaltered ARV, together with the declined MFCV, would indicate either a decrease in discharge rate, de-recruitment of fatigued motor units or elongation of still present motor unit action potentials. Copyright © 2011 Elsevier Ltd. All rights reserved.

Quantitative mass spectrometry imaging of emtricitabine in cervical tissue model using infrared matrix-assisted laser desorption electrospray ionization

PubMed Central

Bokhart, Mark T.; Rosen, Elias; Thompson, Corbin; Sykes, Craig; Kashuba, Angela D. M.; Muddiman, David C.

2015-01-01

A quantitative mass spectrometry imaging (QMSI) technique using infrared matrix-assisted laser desorption electrospray ionization (IR-MALDESI) is demonstrated for the antiretroviral (ARV) drug emtricitabine in incubated human cervical tissue. Method development of the QMSI technique leads to a gain in sensitivity and removal of interferences for several ARV drugs. Analyte response was significantly improved by a detailed evaluation of several cationization agents. Increased sensitivity and removal of an isobaric interference was demonstrated with sodium chloride in the electrospray solvent. Voxel-to-voxel variability was improved for the MSI experiments by normalizing analyte abundance to a uniformly applied compound with similar characteristics to the drug of interest. Finally, emtricitabine was quantified in tissue with a calibration curve generated from the stable isotope-labeled analog of emtricitabine followed by cross-validation using liquid chromatography tandem mass spectrometry (LC-MS/MS). The quantitative IR-MALDESI analysis proved to be reproducible with an emtricitabine concentration of 17.2±1.8 μg/gtissue. This amount corresponds to the detection of 7 fmol/voxel in the IR-MALDESI QMSI experiment. Adjacent tissue slices were analyzed using LC-MS/MS which resulted in an emtricitabine concentration of 28.4±2.8 μg/gtissue. PMID:25318460