Science.gov

Sample records for hiv virological suppression

  1. Incomplete Immune Reconstitution Despite Virologic Suppression in HIV-1 Infected Children and Adolescents

    PubMed Central

    Krogstad, Paul; Patel, Kunjal; Karalius, Brad; Hazra, Rohan; Abzug, Mark J.; Oleske, James; Seage, George R.; Williams, Paige; Borkowsky, William; Wiznia, Andrew; Pinto, Jorge; Van Dyke, Russell B.

    2015-01-01

    Objectives Some perinatally infected children do not regain normal CD4 T cell counts despite suppression of HIV-1 plasma viremia by antiretroviral therapy (ART), The frequency, severity, and significance of these discordant treatment responses remain unclear. Design We examined the persistence of CD4 lymphocytopenia despite virologic suppression (VS) in 933 children (>5 years of age) in the US, Latin America, and the Caribbean. Methods CD4 T-cell trajectories were examined and Kaplan Meier methods used to estimate median time to CD4 T cell count ≥ 500 cells/μL. Results After 1 year of VS, most (99%) children achieved a CD4 T cell count of ≥200 cells/μl, but CD4 T cell counts remained below 500 cells/μL after 1 and 2 years of VS in 14% and 8%. Median times to first CD4 T cell count ≥ 500 cells/μl were 1.29, 0.78, and 0.46 years for children with <200, 200–349, and 350–499 cells/μL at the start of VS. New AIDS-defining events occurred in 9 children, including 4 in the first 6 months of VS. Other infectious and HIV-related diagnoses occurred more frequently and across a wide range of CD4 counts. Conclusions ART improved CD4 counts in most children, but the time to CD4 count of ≥ 500 cells was highly dependent upon baseline immunological status. Some children did not reach a CD4 T cell count of 500 cells/μl despite 2 years of VS. AIDS defining events occurred in 1% of the population, including children in whom VS and improved CD4 T cell counts were achieved. PMID:25849832

  2. Coinfection with Human Herpesvirus 8 Is Associated with Persistent Inflammation and Immune Activation in Virologically Suppressed HIV-Infected Patients

    PubMed Central

    Masiá, Mar; Robledano, Catalina; Ortiz de la Tabla, Victoria; Antequera, Pedro; Lumbreras, Blanca; Hernández, Ildefonso; Gutiérrez, Félix

    2014-01-01

    Objectives Infection with co-pathogens is one of the postulated factors contributing to persistent inflammation and non-AIDS events in virologically-suppressed HIV-infected patients. We aimed to investigate the relationship of human herpesvirus-8 (HHV-8), a vasculotropic virus implicated in the pathogenesis of Kaposi's sarcoma, with inflammation and subclinical atherosclerosis in HIV-infected patients. Methods Prospective study including virologically suppressed HIV-infected patients. Several blood biomarkers (highly-sensitive C-reactive protein [hsCRP], tumour necrosis factor-α, interleukin-6, monocyte chemoattractant protein-1, vascular cell adhesion molecule-1, intercellular cell adhesion molecule-1, malondialdehyde, plasminogen activator inhibitor [PAI-1], D-dimer, sCD14, sCD163, CD4/CD38/HLA-DR, and CD8/CD38/HLA-DR), serological tests for HHV-8 and the majority of herpesviruses, carotid intima-media thickness, and endothelial function through flow-mediated dilatation of the brachial artery were measured. Results A total of 136 patients were included, 34.6% of them infected with HHV-8. HHV-8-infected patients were more frequently co-infected with herpes simplex virus type 2 (HSV-2) (P<0.001), and less frequently with hepatitis C virus (HCV) (P = 0.045), and tended to be older (P = 0.086). HHV-8-infected patients had higher levels of hsCRP (median [interquartile range], 3.63 [1.32–7.54] vs 2.08 [0.89–4.11] mg/L, P = 0.009), CD4/CD38/HLA-DR (7.67% [4.10–11.86]% vs 3.86% [2.51–7.42]%, P = 0.035) and CD8/CD38/HLA-DR (8.02% [4.98–14.09]% vs 5.02% [3.66–6.96]%, P = 0.018). After adjustment for the traditional cardiovascular risk factors, HCV and HSV-2 infection, the associations remained significant: adjusted difference between HHV-8 positive and negative patients (95% confidence interval) for hsCRP, 74.19% (16.65–160.13)%; for CD4/CD38/HLA-DR, 89.65% (14.34–214.87)%; and for CD8/CD38/HLA-DR, 58.41% (12.30–123.22)%. Flow

  3. Trends and Disparities in Antiretroviral Therapy Initiation and Virologic Suppression Among Newly Treatment-Eligible HIV-Infected Individuals in North America, 2001–2009

    PubMed Central

    Hanna, David B.; Buchacz, Kate; Gebo, Kelly A.; Hessol, Nancy A.; Horberg, Michael A.; Jacobson, Lisa P.; Kirk, Gregory D.; Kitahata, Mari M.; Korthuis, P. Todd; Moore, Richard D.; Napravnik, Sonia; Patel, Pragna; Silverberg, Michael J.; Sterling, Timothy R.; Willig, James H.; Lau, Bryan; Althoff, Keri N.; Crane, Heidi M.; Collier, Ann C.; Samji, Hasina; Thorne, Jennifer E.; Gill, M. John; Klein, Marina B.; Martin, Jeffrey N.; Rodriguez, Benigno; Rourke, Sean B.; Gange, Stephen J.; Benson, A.; Bosch, Ronald J.; Collier, Ann C.; Boswell, Stephen; Grasso, Chris; Mayer, Ken; Hogg, Robert S.; Harrigan, Richard; Montaner, Julio; Cescon, Angela; Brooks, John T.; Buchacz, Kate; Gebo, Kelly A.; Moore, Richard D.; Rodriguez, Benigno; Horberg, Michael A.; Silverberg, Michael J.; Thorne, Jennifer E.; Goedert, James J.; Jacobson, Lisa P.; Klein, Marina B.; Rourke, Sean B.; Burchell, Ann; Rachlis, Anita R.; Hunter-Mellado, Robert F.; Mayor, Angel M.; Gill, M. John; Deeks, Steven G.; Martin, Jeffrey N.; Saag, Michael S.; Mugavero, Michael J.; Willig, James; Eron, Joseph J.; Napravnik, Sonia; Kitahata, Mari M.; Crane, Heidi M.; Justice, Amy C.; Dubrow, Robert; Fiellin, David; Sterling, Timothy R.; Haas, David; Bebawy, Sally; Turner, Megan; Gange, Stephen J.; Anastos, Kathryn; Moore, Richard D.; Saag, Michael S.; Gange, Stephen J.; Kitahata, Mari M.; McKaig, Rosemary G.; Justice, Amy C.; Freeman, Aimee M.; Moore, Richard D.; Freeman, Aimee M.; Lent, Carol; Platt, Aaron; Kitahata, Mari M.; Van Rompaey, Stephen E.; Crane, Heidi M.; Webster, Eric; Morton, Liz; Simon, Brenda; Gange, Stephen J.; Abraham, Alison G.; Lau, Bryan; Althoff, Keri N.; Zhang, Jinbing; Jing, Jerry; Golub, Elizabeth; Modur, Shari; Hanna, David B.; Rebeiro, Peter; Wong, Cherise; Mendes, Adell

    2013-01-01

    Background. Since the mid-1990s, effective antiretroviral therapy (ART) regimens have improved in potency, tolerability, ease of use, and class diversity. We sought to examine trends in treatment initiation and resulting human immunodeficiency virus (HIV) virologic suppression in North America between 2001 and 2009, and demographic and geographic disparities in these outcomes. Methods. We analyzed data on HIV-infected individuals newly clinically eligible for ART (ie, first reported CD4+ count <350 cells/µL or AIDS-defining illness, based on treatment guidelines during the study period) from 17 North American AIDS Cohort Collaboration on Research and Design cohorts. Outcomes included timely ART initiation (within 6 months of eligibility) and virologic suppression (≤500 copies/mL, within 1 year). We examined time trends and considered differences by geographic location, age, sex, transmission risk, race/ethnicity, CD4+ count, and viral load, and documented psychosocial barriers to ART initiation, including non–injection drug abuse, alcohol abuse, and mental illness. Results. Among 10 692 HIV-infected individuals, the cumulative incidence of 6-month ART initiation increased from 51% in 2001 to 72% in 2009 (Ptrend < .001). The cumulative incidence of 1-year virologic suppression increased from 55% to 81%, and among ART initiators, from 84% to 93% (both Ptrend < .001). A greater number of psychosocial barriers were associated with decreased ART initiation, but not virologic suppression once ART was initiated. We found significant heterogeneity by state or province of residence (P < .001). Conclusions. In the last decade, timely ART initiation and virologic suppression have greatly improved in North America concurrent with the development of better-tolerated and more potent regimens, but significant barriers to treatment uptake remain, both at the individual level and systemwide. PMID:23315317

  4. A Randomized, Placebo-Controlled Trial of Abacavir Intensification in HIV-1–Infected Adults With Virologic Suppression on a Protease Inhibitor–Containing Regimen

    PubMed Central

    Hammer, Scott M.; Ribaudo, Heather; Bassett, Roland; Mellors, John W.; Demeter, Lisa M.; Coombs, Robert W.; Currier, Judith; Morse, Gene D.; Gerber, John G.; Martinez, Ana I.; Spreen, William; Fischl, Margaret A.; Squires, Kathleen E.

    2011-01-01

    Background and Objective Maximizing the durability of viral suppression is a key goal of antiretroviral therapy. The objective of AIDS Clinical Trials Group Study 372A was to determine whether the intensification strategy of adding abacavir to an effective indinavir-dual nucleoside regimen would delay the time to virologic failure. Methods Zidovudine-experienced subjects (n=229) on therapy with indinavir + zidovudine + lamivudine with plasma HIV-1 RNA levels <500 copies/mL were randomized to abacavir 300 mg twice daily or placebo. The primary endpoint was the time to treatment failure, defined as a composite of confirmed virologic failure (2 consecutive HIV-1 RNAs >200 copies/mL) and treatment discontinuation. Results At baseline, the study population was 88% male with a median age of 41 years and median CD4 cell count of 250/mm3. Median follow-up was 4.4 years. The primary endpoint was reached in 61/116 of abacavir versus 62/113 of placebo recipients (P = .77); virologic failure occurred in 34/116 and 42/113 patients, respectively (P = .22). There were no differences in the proportions of subjects with plasma HIV-1 RNA levels below 50 copies/mL, in CD4 cell count increases, nor adverse events between the arms. In the study, 17% of subjects developed nephrolithiasis, 2% experienced abacavir hypersensitivity, and 4.8% experienced at least 1 serious cardiovascular event (7 [6%] in the abacavir arm, 4 [3.5%] in the placebo arm). In additional secondary and post hoc analyses, rates of intermittent viremia, suppression below a plasma HIV-1 RNA level of 6 copies/mL, and HIV-1 proviral DNA levels in peripheral blood mononuclear cells were not significantly different in the 2 arms. Conclusions The strategy of intensification with abacavir in patients who are virologically suppressed on a stable antiretroviral regimen does not confer a clinical or virologic benefit. As antiretroviral regimens have become more potent since this trial was completed, it will be even more

  5. Quantitative Assessment of Intra-Patient Variation in CD4+ T Cell Counts in Stable, Virologically-Suppressed, HIV-Infected Subjects

    PubMed Central

    Gordon, Claire L.; Cheng, Allen C.; Cameron, Paul U.; Bailey, Michael; Crowe, Suzanne M.; Mills, John

    2015-01-01

    Objectives Counts of absolute CD4+ T lymphocytes (CD4+ T cells) are known to be highly variable in untreated HIV-infected individuals, but there are no data in virologically-suppressed individuals. We investigated CD4+ T cell variability in stable, virologically-suppressed, HIV-1 infected adults on combination antiretroviral therapy (cART). Methods From a large hospital database we selected patients with stable virological suppression on cART for >3 years with >10 CD4+ T cell measurements performed over a further >2 years; and a control group of 95 patients not on cART. Results We identified 161 HIV-infected patients on cART without active HCV or HBV infection, with stable virological suppression for a median of 6.4 years. Over the study period 88 patients had reached a plateau in their absolute CD4+ T cell counts, while 65 patients had increasing and 8 patients had decreasing absolute CD4+ T cell counts. In patients with plateaued CD4+ T cell counts, variability in absolute CD4+ T cell counts was greater than in percent CD4+ T cells (median coefficient of variation (CV) 16.6% [IQR 13.8-20.1%] and CV 9.6% [IQR 7.4-13.0%], respectively). Patients with increasing CD4+ T cell counts had greater variability in absolute CD4+ T cell counts than those with plateaued CD4 T cell counts (CV 19.5% [IQR 16.1-23.8%], p<0.001) while there was no difference in percent CD4+ T cell variability between the two groups. As previously reported, untreated patients had CVs significantly higher than patients on cART (CVs of 21.1% [IQR 17.2-32.0%], p<0.001 and 15.2% (IQR 10.7-20.0%), p<0.001, respectively). Age or sex did not affect the degree of CD4+ variation. Conclusions Adults with stable, virologically-suppressed HIV infection continue to have significant variations in individual absolute CD4+ T cell and percent CD4+ T cell counts; this variation can be of clinical relevance especially around CD4+ thresholds. However, the variation seen in individuals on cART is substantially less

  6. Nevirapine Concentration in Hair Samples Is a Strong Predictor of Virologic Suppression in a Prospective Cohort of HIV-Infected Patients

    PubMed Central

    Baxi, Sanjiv M.; Greenblatt, Ruth M.; Bacchetti, Peter; Jin, Chengshi; French, Audrey L.; Keller, Marla J.; Augenbraun, Michael H.; Gange, Stephen J.; Liu, Chenglong; Mack, Wendy J.; Gandhi, Monica

    2015-01-01

    Effective antiretroviral (ARV) therapy depends on adequate drug exposure, yet methods to assess ARV exposure are limited. Concentrations of ARV in hair are the product of steady-state pharmacokinetics factors and longitudinal adherence. We investigated nevirapine (NVP) concentrations in hair as a predictor of treatment response in women receiving ARVs. In participants of the Women’s Interagency HIV Study, who reported NVP use for >1 month from 2003–2008, NVP concentrations in hair were measured via liquid-chromatography-tandem mass-spectrometry. The outcome was virologic suppression (plasma HIV RNA below assay threshold) at the time of hair sampling and the primary predictor was nevirapine concentration categorized into quartiles. We controlled for age, race/ethnicity, pre-treatment HIV RNA, CD4 cell count, and self-reported adherence over the 6-month visit interval (categorized ≤ 74%, 75%–94% or ≥ 95%). We also assessed the relation of NVP concentration with changes in hepatic transaminase levels via multivariate random intercept logistic regression and linear regression analyses. 271 women contributed 1089 person-visits to the analysis (median 3 of semi-annual visits). Viral suppression was least frequent in concentration quartile 1 (86/178 (48.3%)) and increased in higher quartiles (to 158/204 (77.5%) for quartile 4). The odds of viral suppression in the highest concentration quartile were 9.17 times (95% CI 3.2–26, P < 0.0001) those in the lowest. African-American race was associated with lower rates of virologic suppression independent of NVP hair concentration. NVP concentration was not significantly associated with patterns of serum transaminases. Concentration of NVP in hair was a strong independent predictor of virologic suppression in women taking NVP, stronger than self-reported adherence, but did not appear to be strongly predictive of hepatotoxicity. PMID:26053176

  7. Persistently Elevated C-Reactive Protein Level in the First Year of Antiretroviral Therapy, Despite Virologic Suppression, Is Associated With HIV Disease Progression in Resource-Constrained Settings.

    PubMed

    Shivakoti, Rupak; Yang, Wei-Teng; Berendes, Sima; Mwelase, Noluthando; Kanyama, Cecilia; Pillay, Sandy; Samaneka, Wadzanai; Santos, Breno; Poongulali, Selvamuthu; Tripathy, Srikanth; Riviere, Cynthia; Lama, Javier R; Cardoso, Sandra W; Sugandhavesa, Patcharaphan; Balagopal, Ashwin; Gupte, Nikhil; Semba, Richard D; Campbell, Thomas B; Bollinger, Robert C; Gupta, Amita

    2016-04-01

    A case-cohort analysis of human immunodeficiency virus (HIV)-infected individuals receiving antiretroviral therapy (ART) was performed within a multicountry randomized trial (PEARLS) to assess the prevalence of persistently elevated C-reactive protein (CRP) levels, based on serial measurements of CRP levels, and their association with HIV clinical failure. A persistently elevated CRP level in plasma (defined as ≥ 5 mg/L at both baseline and 24 weeks after ART initiation) was observed in 50 of 205 individuals (24%). A persistently elevated CRP level but not an elevated CRP level only at a single time point was independently associated with increased clinical failure, compared with a persistently low CRP level, despite achievement of virologic suppression. Serial monitoring of CRP levels could identify individuals who are at highest risk of HIV progression and may benefit from future adjunct antiinflammatory therapies. PMID:26621909

  8. Efficacy and safety of switching to abacavir/lamivudine (ABC/3TC) plus rilpivirine (RPV) in virologically suppressed HIV-infected patients on HAART.

    PubMed

    Palacios, R; Pérez-Hernández, I A; Martínez, M A; Mayorga, M L; González-Domenech, C M; Omar, M; Olalla, J; Romero, A; Romero, J M; Pérez-Camacho, I; Hernández-Quero, J; Santos, J

    2016-05-01

    We analysed the efficacy and safety of switching from a regimen based on nonnucleoside reverse transcriptase inhibitors (NNRTI) or integrase inhibitors (INI) to ABC/3TC + RPV in virologically suppressed HIV-infected patients. This multicentre, retrospective study comprised asymptomatic HIV-infected patients who switched from 2 NRTI + NNRTI or 2 NRTI + INI to ABC/3TC + RPV between February 2013 and December 2013; all had undetectable HIV viral load prior to switching. Efficacy and safety, and changes in lipids and cardiovascular risk (CVR) were analysed at 48 weeks. Of 85 patients (74.1 % men, mean age 49.5 years), 83 (97.6 %) switched from a regimen based on NNRTI (EFV 74, RPV 5, ETV 2, NVP 2), and 45 (53 %) switched from TDF/FTC to ABC/3TC. The main reasons for switching were toxicity (58.8 %) and convenience (29.4 %). At 48 weeks, 78 (91.8 %) patients continued taking the same regimen; efficacy was 88 % by intention to treat, and 96 % by per protocol. Two patients were lost to follow-up and five ceased the new regimen (4 due to adverse effects and 1 virologic failure). Mean CD4 cell counts increased (744 vs. 885 cells/μL; p = 0.0001), and there were mean decreases in fasting total cholesterol (-15.9 mg/dL; p < 0.0001) and LDL-cholesterol (-11.0 mg/dL; p < 0.004), with no changes in HDL-cholesterol, triglycerides, total cholesterol:HDL-cholesterol ratio, and CVR. ABC/3TC + RPV is effective and safe in virologically-suppressed patients on antiretroviral therapy (ART). Forty-eight weeks after switching the lipid profile improved with decreases in total and LDL cholesterol. PMID:26879392

  9. Patient-reported outcomes in virologically suppressed, HIV-1-Infected subjects after switching to a simplified, single-tablet regimen of efavirenz, emtricitabine, and tenofovir DF.

    PubMed

    Hodder, Sally L; Mounzer, Karam; Dejesus, Edwin; Ebrahimi, Ramin; Grimm, Kristy; Esker, Stephen; Ecker, Janet; Farajallah, Awny; Flaherty, John F

    2010-02-01

    A randomized, open-label, multicenter study was conducted to evaluate the therapeutic switch to a single-tablet formulation of efavirenz/emtricitabine/tenofovir DF (EFV/FTC/TDF) among virologically suppressed, HIV-1-infected subjects. Eligible subjects on stable antiretroviral therapy (ART) with HIV-1 RNA less than 200 copies per milliliter for 3 months or more were stratified by prior protease inhibitor (PI)- or non-nucleoside reverse transcriptase inhibitor (NNRTI)-based therapy and randomized (2:1) to EFV/FTC/TDF or to stay on their baseline regimen (SBR). Patient-reported measures were quality of life (QOL; SF-36 [version 2]), treatment adherence (visual analogue scale), preference of medication (POM), perceived ease of the regimen for condition (PERC), and a 20-item HIV symptom index. Overall, 203 subjects were randomized to EFV/FTC/TDF and 97 to SBR. Fifty-three percent of subjects had previously received a PI-based regimen; 47% an NNRTI-based therapy. Throughout the study, SF-36 summary scores did not differ significantly from baseline, regardless of previous ART or treatment allocation. Adherence was 96% or more in both groups at baseline and all subsequent study visits. At study conclusion, the EFV/FTC/TDF regimen was considered easier to follow than prior regimens by 97% and 96% of subjects previously receiving PI-based and NNRTI-based therapies, respectively. Overall, 91% of subjects switched to EFV/FTC/TDF indicated a preference over their prior therapy. Switching to EFV/FTC/TDF was associated with transient worsening/emergence of dizziness and sustained improvements in several other HIV-related symptoms. In conclusion, switching virologically suppressed, HIV-1-infected subjects from PI-based or NNRTI-based regimens to EFV/FTC/TDF was associated with maintained QOL and treatment adherence, and improved ease of use and treatment satisfaction. PMID:20156091

  10. Administration of a Toll-like receptor 9 agonist decreases the proviral reservoir in virologically suppressed HIV-infected patients.

    PubMed

    Winckelmann, Anni A; Munk-Petersen, Lærke V; Rasmussen, Thomas A; Melchjorsen, Jesper; Hjelholt, Thomas J; Montefiori, David; Østergaard, Lars; Søgaard, Ole S; Tolstrup, Martin

    2013-01-01

    Toll-like receptor (TLR) agonists can reactivate HIV from latently infected cells in vitro. We aimed to investigate the TLR-9 agonist, CPG 7909's in vivo effect on the proviral HIV reservoir and HIV-specific immunity. This was a post-hoc analysis of a double-blind randomized controlled vaccine trial. HIV-infected adults were randomized 1:1 to receive pneumococcal vaccines with or without 1 mg CPG 7909 as adjuvant at 0, 3 and 9 months. In patients on suppressive antiretroviral therapy we quantified proviral DNA at 0, 3, 4, 9, and 10 months (31 subjects in the CPG group and 37 in the placebo-adjuvant group). Furthermore, we measured HIV-specific antibodies, characterized T cell phenotypes and HIV-specific T cell immunity. We observed a mean reduction in proviral DNA in the CPG group of 12.6% (95% CI: -23.6-0.0) following each immunization whereas proviral DNA in the placebo-adjuvant group remained largely unchanged (6.7% increase; 95% CI: -4.2-19.0 after each immunization, p = 0.02). Among participants with additional cryo-preserved PBMCs, HIV-specific CD8+ T cell immunity as indicated by increased expression of degranulation marker CD107a and macrophage inflammatory protein 1β (MIP1β) tended to be up-regulated following immunization with CPG 7909 compared with placebo as adjuvant. Further, increasing proportion of HIV-specific CD107a and MIP1β-expressing CD8+ T cells were strongly correlated with decreasing proviral load. No changes were observed in T cell phenotype distribution, HIV-specific CD4+ T cell immunity, or HIV-specific antibodies. TLR9-adjuvanted pneumococcal vaccination decreased proviral load. Reductions in proviral load correlated with increasing levels of HIV specific CD8+ T cells. Further investigation into the potential effect of TLR9 agonists on HIV latency is warranted. PMID:23637967

  11. Brief Report: Switch to Ritonavir-Boosted Atazanavir Plus Raltegravir in Virologically Suppressed Patients With HIV-1 Infection: A Randomized Pilot Study

    PubMed Central

    van Lunzen, Jan; Pozniak, Anton; Gatell, Jose M.; Antinori, Andrea; Serrano, Oscar; Baakili, Adyb; Osiyemi, Olayemi; Sevinsky, Heather; Girard, Pierre-Marie

    2016-01-01

    Abstract: This open-label, multinational, pilot study randomized (1:2 ratio) adults with HIV-1 RNA <40 copies per milliliter and nucleos(t)ide-related safety/tolerability issues to switch to ritonavir-boosted atazanavir (ATV/r) plus tenofovir disoproxil fumarate/emtricitabine (n = 37) or the nucleos(t)ide reverse transcriptase inhibitor-sparing regimen of ATV/r plus raltegravir (RAL) (n = 72). At 24 weeks, 35/37 (94.6%) and 58/72 (80.6%) of patients, respectively, maintained virological suppression, the primary endpoint, and 1 (2.7%) and 7 (9.7%), respectively, experienced virological rebound. Corresponding 48-week proportions were 86.5%, 69.4%, 2.7%, and 12.5%, respectively. Adherence was lower and treatment discontinuation was higher with ATV/r+RAL. In conclusion, switching to ATV/r+RAL resulted in a higher virological rebound rate than switching to ATV/r plus tenofovir disoproxil fumarate/emtricitabine. PMID:26605505

  12. Brief Report: Switch to Ritonavir-Boosted Atazanavir Plus Raltegravir in Virologically Suppressed Patients With HIV-1 Infection: A Randomized Pilot Study.

    PubMed

    van Lunzen, Jan; Pozniak, Anton; Gatell, Jose M; Antinori, Andrea; Klauck, Isabelle; Serrano, Oscar; Baakili, Adyb; Osiyemi, Olayemi; Sevinsky, Heather; Girard, Pierre-Marie

    2016-04-15

    This open-label, multinational, pilot study randomized (1:2 ratio) adults with HIV-1 RNA <40 copies per milliliter and nucleos(t)ide-related safety/tolerability issues to switch to ritonavir-boosted atazanavir (ATV/r) plus tenofovir disoproxil fumarate/emtricitabine (n = 37) or the nucleos(t)ide reverse transcriptase inhibitor-sparing regimen of ATV/r plus raltegravir (RAL) (n = 72). At 24 weeks, 35/37 (94.6%) and 58/72 (80.6%) of patients, respectively, maintained virological suppression, the primary endpoint, and 1 (2.7%) and 7 (9.7%), respectively, experienced virological rebound. Corresponding 48-week proportions were 86.5%, 69.4%, 2.7%, and 12.5%, respectively. Adherence was lower and treatment discontinuation was higher with ATV/r+RAL. In conclusion, switching to ATV/r+RAL resulted in a higher virological rebound rate than switching to ATV/r plus tenofovir disoproxil fumarate/emtricitabine. PMID:26605505

  13. Switch to Stribild versus continuation of NVP or RPV with FTC and TDF in virologically suppressed HIV adults: a STRATEGY-NNRTI subgroup analysis

    PubMed Central

    Stellbrink, Hans-Juergen; Antinori, Andrea; Pozniak, Anton; Flamm, Jason; Bredeek, Fritz; Patel, Kiran; Garner, Will; Piontkowsky, David

    2014-01-01

    Introduction Switch to Stribild (STB) was non-inferior to continuation of a non-nucleoside reverse transcriptase inhibitor (NNRTI) with emtricitabine and tenofovir DF (FTC/TDF) at week 48 in virologically suppressed HIV adults [1]. We report the Week 48 efficacy and safety of STB versus nevirapine (NVP) or rilpivirine (RPV) with FTC/TDF in suppressed subjects. Materials and Methods Virologically suppressed subjects on an NNRTI with FTC/TDF regimens for ≥6 months were randomized (2:1) to switch to STB versus continue their NNRTI regimen. Eligibility criteria included no documented resistance to FTC and TDF, no history of virologic failure and eGFR ≥70 mL/min. The primary endpoint was the proportion of subjects in the modified ITT population who maintained HIV-1 RNA <50 copies(c)/mL at Week 48 by FDA snapshot algorithm (12% non-inferiority margin). Subgroup analysis by non-EFV NNRTI use (NVP [74]; RPV [19]; etravirine [3]) at screening was pre-specified. Results The mITT population included 433 subjects who were randomized and treated. In the non-EFV NNRTI subgroup, 59 switched to STB; 37 continued a non-EFV NNRTI (27 NVP, 10 RPV) with FTC/TDF. At week 48, 97% STB versus 95% non-EFV NNRTI maintained HIV-1 RNA <50 c/mL. No emergent resistance was detected in either group. No difference in median increases from baseline in CD4 count at week 48 (cells/µL): 25 STB versus 55 non-EFV NNRTI (p=0.78). No discontinuation due to adverse events; no cases of proximal renal tubulopathy. As expected, there were no significant changes in the frequency of neuropsychiatric symptoms (i.e. anxiety, insomnia, dizziness, vivid dreams, weird/intense dreams, and nightmares) reported on the HIV Symptom Index at week 48 compared to baseline after switching to STB. There was a greater but non-progressive decrease from baseline in eGFR in the STB versus non-EFV NNRTI group; median changes (mL/min) at week 48: −9.1 versus −1.4. Switch to STB was associated with a higher treatment ease

  14. When to Monitor CD4 Cell Count and HIV RNA to Reduce Mortality and AIDS-Defining Illness in Virologically Suppressed HIV-Positive Persons on Antiretroviral Therapy in High-Income Countries: A Prospective Observational Study

    PubMed Central

    Caniglia, Ellen C.; Sabin, Caroline; Robins, James M.; Logan, Roger; Cain, Lauren E.; Abgrall, Sophie; Mugavero, Michael J.; Hernandez-Diaz, Sonia; Meyer, Laurence; Seng, Remonie; Drozd, Daniel R.; Seage, George R.; Bonnet, Fabrice; Dabis, Francois; Moore, Richard R.; Reiss, Peter; van Sighem, Ard; Mathews, William C.; del Amo, Julia; Moreno, Santiago; Deeks, Steven G.; Muga, Roberto; Boswell, Stephen L.; Ferrer, Elena; Eron, Joseph J.; Napravnik, Sonia; Jose, Sophie; Phillips, Andrew; Olson, Ashley; Justice, Amy C.; Tate, Janet P.; Bucher, Heiner C.; Egger, Matthias; Touloumi, Giota; Sterne, Jonathan A.; Costagliola, Dominique; Saag, Michael; Hernán, Miguel A.

    2016-01-01

    Objective: To illustrate an approach to compare CD4 cell count and HIV-RNA monitoring strategies in HIV-positive individuals on antiretroviral therapy (ART). Design: Prospective studies of HIV-positive individuals in Europe and the USA in the HIV-CAUSAL Collaboration and The Center for AIDS Research Network of Integrated Clinical Systems. Methods: Antiretroviral-naive individuals who initiated ART and became virologically suppressed within 12 months were followed from the date of suppression. We compared 3 CD4 cell count and HIV-RNA monitoring strategies: once every (1) 3 ± 1 months, (2) 6 ± 1 months, and (3) 9–12 ± 1 months. We used inverse-probability weighted models to compare these strategies with respect to clinical, immunologic, and virologic outcomes. Results: In 39,029 eligible individuals, there were 265 deaths and 690 AIDS-defining illnesses or deaths. Compared with the 3-month strategy, the mortality hazard ratios (95% CIs) were 0.86 (0.42 to 1.78) for the 6 months and 0.82 (0.46 to 1.47) for the 9–12 month strategy. The respective 18-month risk ratios (95% CIs) of virologic failure (RNA >200) were 0.74 (0.46 to 1.19) and 2.35 (1.56 to 3.54) and 18-month mean CD4 differences (95% CIs) were −5.3 (−18.6 to 7.9) and −31.7 (−52.0 to −11.3). The estimates for the 2-year risk of AIDS-defining illness or death were similar across strategies. Conclusions: Our findings suggest that monitoring frequency of virologically suppressed individuals can be decreased from every 3 months to every 6, 9, or 12 months with respect to clinical outcomes. Because effects of different monitoring strategies could take years to materialize, longer follow-up is needed to fully evaluate this question. PMID:26895294

  15. Reducing Viral Load Measurements to Once a Year in Patients on Stable, Virologically Suppressive Cart Regimen: Findings from the Australian HIV Observational Database

    PubMed Central

    Rafiee, Mahshid; Kariminia, Azar; Wright, Stephen; Mills, Graham; Woolley, Ian; Smith, Don; Templeton, David J.; Law, Matthew G.; Petoumenos, Kathy

    2015-01-01

    Reducing viral-load measurements to annual testing in virologically suppressed patients increases the estimated mean time those patients remain on a failing regimen by 6 months. This translates to an increase in the proportion of patients with at least one Thymidine Analogue Mutation from 10% to 32% over one year. PMID:26618053

  16. Measures of site resourcing predict virologic suppression, immunologic response and HIV disease progression following highly active antiretroviral therapy (HAART) in the TREAT Asia HIV Observational Database (TAHOD)

    PubMed Central

    Oyomopito, R; Lee, MP; Phanuphak, P; Lim, PL; Ditangco, R; Zhou, J; Sirisanthana, T; Chen, YMA; Pujari, S; Kumarasamy, N; Sungkanuparph, S; Lee, CKC; Kamarulzaman, A; Oka, S; Zhang, FJ; Mean, CV; Merati, T; Tau, G; Smith, J; Li, PCK

    2010-01-01

    Objectives Surrogate markers of HIV disease progression are HIV RNA in plasma viral load (VL) and CD4 cell count (immune function). Despite improved international access to antiretrovirals, surrogate marker diagnostics are not routinely available in resource-limited settings. Therefore, the objective was to assess effects of economic and diagnostic resourcing on patient treatment outcomes. Methods Analyses were based on 2333 patients initiating highly active antiretroviral therapy (HAART) from 2000 onwards. Sites were categorized by World Bank country income criteria (high/low) and annual frequency of VL (≥ 3, 1–2 or <1) or CD4 (≥ 3 or <3) testing. Endpoints were time to AIDS/death and change in CD4 cell count and VL suppression (<400 HIV-1 RNA copies/mL) at 12 months. Demographics, Centers for Disease Control and Prevention (CDC) classification, baseline VL/CD4 cell counts, hepatitis B/C coinfections and HAART regimen were covariates. Time to AIDS/death was analysed by proportional hazards models. CD4 and VL endpoints were analysed using linear and logistic regression, respectively. Results Increased disease progression was associated with site-reported VL testing less than once per year [hazard ratio (HR)=1.4; P=0.032], severely symptomatic HIV infection (HR=1.4; P=0.003) and hepatitis C virus coinfection (HR=1.8; P=0.011). A total of 1120 patients (48.2%) had change in CD4 cell count data. Smaller increases were associated with older age (P<0.001) and `Other' HIV source exposures, including injecting drug use and blood products (P=0.043). A total of 785 patients (33.7%) contributed to the VL suppression analyses. Patients from sites with VL testing less than once per year [odds ratio (OR)=0.30; P<0.001] and reporting `Other' HIV exposures experienced reduced suppression (OR=0.28; P<0.001). Conclusion Low measures of site resourcing were associated with less favourable patient outcomes, including a 35% increase in disease progression in patients from sites

  17. Relationships Among Neurocognitive Status, Medication Adherence Measured by Pharmacy Refill Records, and Virologic Suppression in HIV-infected Persons

    PubMed Central

    Andrade, Adriana S.A.; Deutsch, Reena; Celano, Shivaun; Duarte, Nichole A.; Marcotte, Thomas D.; Umlauf, Anya; Atkinson, J. Hampton; McCutchan, J. Allen; Franklin, Donald; Alexander, Terry J.; McArthur, Justin; Marra, Christina; Grant, Igor; Collier, Ann C

    2013-01-01

    Background Optimal antiretroviral therapy (ART) effectiveness depends upon medication adherence, which is a complex behavior with many contributing factors including neurocognitive function. Pharmacy refill records offer a promising and practical tool to assess adherence. Methods A substudy of the CHARTER (CNS HIV Anti-Retroviral Therapy Effects Research) study was conducted at the Johns Hopkins University (JHU) and the University of Washington (UW). Pharmacy refill records were the primary method to measure ART adherence, indexed to a “sentinel” drug with the highest central nervous system penetration effectiveness score. Standardized neuromedical, neuropsychological, psychiatric and substance use assessments were performed at enrollment and at 6 months. Regression models were used to determine factors associated with adherence and the relationships between adherence and change in plasma and cerebrospinal fluid HIV RNA concentrations between visits. Results Among 80 (33 JHU, 47 UW) participants, the mean adherence score was 86.4% with no difference by site. In the final multivariable model, better neurocognitive function was associated with better adherence, especially among participants who were at JHU, male, and HIV-infected for a longer time-period. Worse performance on working memory tests was associated with worse adherence. Better adherence predicted greater decreases in cerebrospinal fluid HIV RNA between visits. Conclusion Poorer global neurocognitive functioning and deficits in working memory were associated with lower adherence defined by a pharmacy refill record measure, suggesting that assessments of cognitive function, and working memory in particular, may identify patients at risk for poor ART adherence who would benefit from adherence support. PMID:23202813

  18. Simplification to atazanavir/ritonavir+lamivudine in virologically suppressed HIV-infected patients: 24-weeks interim analysis from ATLAS-M trial

    PubMed Central

    Fabbiani, Massimiliano; Di Giambenedetto, Simona; Quiros-Roldan, Eugenia; Latini, Alessandra; Vullo, Vincenzo; Antinori, Andrea; Castagna, Antonella; Orofino, Giancarlo; Francisci, Daniela; Grilli, Elisabetta; Madeddu, Giordanu; Grima, Pierfrancesco; Rusconi, Stefano; Del Pin, Barbara; Mondi, Annalisa; Borghetti, Alberto; Focà, Emanuele; Colafigli, Manuela; De Luca, Andrea; Cauda, Roberto

    2014-01-01

    Introduction We report interim 24-weeks efficacy data of ATLAS-M trial, a phase IV, multicentre, open-label, randomized study designed to show 48-weeks, non-inferior efficacy (margin of −12%) of treatment simplification to atazanavir/ritonavir (ATV/r)+lamivudine (3TC) versus maintaining 3-drugs ATV/r-based cART. Methods Subjects on ATV/r+2 NRTIs, without previous treatment failure (TF), with HIV-RNA <50copies/mL for >3 months and CD4>200 cells/mm3 for >6 months were eligible. At baseline, patients were randomized to switch to ATV/r+3TC (arm one) or to maintain the original 3-drug regimen (arm two). Primary endpoint: proportion of patients free of TF at week 48. TF was defined as treatment modification for any reason, including virological failure (VF=two consecutive HIV-RNA>50 copies/mL or a single value >1000 copies/mL). Enrollment of 266 patients was planned. Results A total of 266 patients (78% males, median age 44 years, median CD4 603 cells/µL, 79% treated with a tenofovir-containing backbone) were enrolled. At the time of analysis, 24 weeks data were available for 84 and 87 patients in arm one and two, respectively. At baseline, subjects in the two arms did not differ for the main characteristics. At 24 weeks, at the intention to treat analysis the proportion of patients free of TF was 91.7% (95% CI 85.8–97.6) and 85.1% (95% CI 77.6–92.6) in arm one and two, respectively (difference +6.6%, 95% CI −2.9/+16.1). VF was observed in two patients randomized to arm one (one at baseline, before treatment simplification) and one to arm two without resistance mutations. Clinical and laboratory adverse events occurred at similar rates in the two arms. At week 24, patients in arm one showed a greater increase in CD4 (mean change +90 vs +10 cells/µL, p=0.007). A greater increase in total cholesterol (+18 vs −2 mg/dL, p<0.001), HDL (+4 vs +0 mg/dL, p=0.001) and LDL (+12 vs +0 mg/dL, p=0.001) was also observed in arm one without differences in other lipid

  19. [Virological diagnosis of HIV infection in children].

    PubMed

    Muñoz Fernández, M A

    1998-01-01

    The laboratory diagnosis of HIV-1 infection in newborns should be carried out using virological methods, viral isolation or molecular methods for the detection of proviral DNA by PCR. Serological methods have poor sensitivity in the first months of life because the IgG of the seropositive mother crosses the placenta. Once HIV-1 infection is diagnosed, other assays are available which indicate the clinical progression of the infection, the genetic variability of the virus, its biological behavior and sensitivity to different antiretroviral medications. These studies can be used independently of the clinical manifestations in order to assess disease progression. Different immunological markers and virological markers of disease progression have been described, but the CD4+ T lymphocyte count is used routinely as an immunological marker and as a virological marker of the virus load. In HIV-1 newborns and children, the largest decrease in the number of CD4+ T lymphocytes is due to the combined effect of infection progression and a natural decrease in CD4+ T lymphocytes with age. In newborns, low viral load levels suggest that the infection was acquired shortly before birth or that maternal and/or placental factors inhibited viral replication before birth, or that the child was infected at birth. In children, viral loads are greater than in adult patients during the primary infection and throughout their evolution. Because of advances in the treatment of HIV-1 infection, the study of resistance to antiretroviral agents by phenotypical and genotypical methods is important. Increased viral load suggests the loss of effectiveness of a treatment and should be monitored. PMID:9675394

  20. 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 Central

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

    2016-01-01

    Objective 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. Methods 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. Results 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. Conclusions The potential benefits of dual therapy regimens include reduced toxicity, improved tolerability and adherence, and reduced cost. Although the data reviewed here

  1. Monotherapy with lopinavir/ritonavir versus standard of care in HIV-infected patients virologically suppressed while on treatment with protease inhibitor-based regimens: results from the MoLo study.

    PubMed

    Gianotti, Nicola; Poli, Andrea; Galli, Massimo; Pan, Angelo; Rizzardini, Giuliano; Soria, Alessandro; Viale, Pierluigi; Di Biagio, Antonio; Quirino, Tiziana; Viganò, Paolo; Bonfanti, Paolo; d'Arminio Monforte, Antonella; Fortino, Ida; Lazzarin, Adriano

    2014-10-01

    This study compared the cost-efficacy ratios of lopinavir/ritonavir monotherapy (LPV/r-MT) and of standard of care in virologically suppressed HIV-infected patients. The results of the efficacy and safety analyses are presented. We conducted a multicentre, randomised, open-label trial of HIV-infected adults on stable treatment, with HIV- RNA <50 copies/mL, randomised to continue the ongoing regimen (cART-arm) or to switch to LPV/r (400/100 mg BID) MT (MT-arm). Time to virological rebound (VR = confirmed HIV-RNA ?50 copies/mL) was estimated by Ka- plan-Meier method and changes in laboratory values during follow-up were evaluated by univariate mixed-linear models. Ninety-four patients were randomised and analysed (43 in the MT-arm and 51 in the cART-arm). Five (four in the MT and 1 in the cART-arm; p=0.175) had VR, but time to VR did not statistically differ between the two arms (p=0.143). Major PI mutations were not detected at VR. Patients on MT had significant increases in total choles- terol [difference in mean change between MT and cART arm: 0.77 (±0.30) mg/dL per month; p=0.012] and eGFR [difference in mean change between MT and cART arm: 0.24 (±0.11) mL/min/1.73 m2 per month; p=0.029]. LPV/r-MT seems safe in most patients and should be considered in patients who have developed kidney toxicity from tenofovir. PMID:25387282

  2. Lipid Changes in Virologically Suppressed HIV-Infected Patients Switching from any Antiretroviral Therapy to the Emtricitabine/Rilpivirine/Tenofovir Single Tablet: GeSida Study 8114.

    PubMed

    Palacios, Rosario; Mayorga, Marisa; Pérez-Hernández, Isabel A; Rivero, Antonio; Arco, Alfonso Del; Lozano, Fernando; Santos, Jesús

    2016-05-01

    We carried out a retrospective, multicenter study of a cohort of 298 asymptomatic HIV-infected patients who switched from a regimen based on 2 nucleoside reverse transcriptase inhibitors + protease inhibitor (PI)/nonnucleoside reverse transcriptase inhibitor or ritonavir-boosted PI monotherapy to emtricitabine/rilpivirine/tenofovir disoproxil fumarate (FTC/RPV/TDF) to analyze lipid changes. At 24 weeks, 284 (95.3%) patients were still taking the same regimen, maintaining similar CD4 counts as at baseline (651 versus 672 cells/mm(3), P = .08), and 98.9% of them with an undetectable viral load. Eight of the other 14 patients were lost to follow up and 6 (2.0%) ceased the new regimen: 3 due to adverse effects, 2 due to virologic failure, and 1 due to abandonment. The mean levels of fasting total cholesterol (TC), low-density lipoprotein cholesterol, high-density lipoprotein cholesterol (HDL-C), and triglycerides fell at 12 and 24 weeks, with no changes detected in the TC to HDL-C ratio. PMID:26858314

  3. Switching to darunavir/ritonavir 800/100 mg once-daily containing regimen maintains virological control in fully suppressed pre-treated patients infected with HIV-1.

    PubMed

    Ghosn, Jade; Slama, Laurence; Chermak, Aziza; Houssaini, Allal; Lambert-Niclot, Sidonie; Schneider, Luminita; Fourn, Erwan; Duvivier, Claudine; Simon, Anne; Courbon, Eve; Murphy, Robert; Flandre, Philippe; Peytavin, Gilles; Katlama, Christine

    2013-01-01

    The objective of this study was to evaluate the switch to once-daily darunavir/ritonavir 800/100 mg in treatment-experienced patients with suppressed HIV-1 replication on a twice-daily ritonavir-boosted protease-inhibitor (bid PI/r) containing regimen, that is in a setting where genotypic resistance test cannot be performed. In this open label, non-comparative, multicenter study, patients on a bid PI/r-containing triple combination, with suppressed viral replication, were switched to once-daily darunavir/r 800/100 mg containing triple combination. The primary endpoint was the proportion of patients with plasma HIV-RNA < 50 copies/ml 24 weeks after the switch. Intensive darunavir pharmacokinetic evaluation was performed at Week 4 (W4) in 11 patients. Eighty-five patients were enrolled. All had HIV-RNA < 50 copies/ml at screening with a pre-exposure to a median of 2 PI/r (1-5). By intent-to-treat analysis (missing = failure), 78/85 patients (92%, 95% CI [83;96]) maintained an HIV-RNA < 50 copies/ml at W24. Seven patients experienced protocol-defined treatment failure between baseline and W24: Two had confirmed low-level viral rebound, one discontinued study treatment for adverse event, three withdrew their consent, and one was lost to follow-up. By on-treatment analysis, 78/80 patients (97%, 95% CI [91;99]) maintained an HIV-RNA < 50 copies/ml at W24. Results were similar at Week 48. The median area under the darunavir plasma concentration-time curve measured in 11 patients was 61,380 ng hr/ml; darunavir median trough concentration 1,340 ng/ml and darunavir half-life was 12.2 hr. Tolerability of once-daily darunavir/r 800/100 mg was excellent. Optimally suppressed, treatment-experienced patients can switch safely from a twice-daily PI/r regimen to a once-daily darunavir/r 800/100 mg containing regimen. PMID:23024008

  4. HIV controllers with different viral load cut-off levels have distinct virologic and immunologic profiles

    PubMed Central

    Bello, Gonzalo; Teixeira, Sylvia LM; Vorsatz, Carla; Babic, Dunja; Sharkey, Mark; Grinsztejn, Beatriz; Veloso, Valdilea; Stevenson, Mario; Morgado, Mariza G

    2015-01-01

    Background The mechanisms behind natural control of HIV replication are still unclear, and several studies pointed that elite controllers are a heterogeneous group. Methods We performed analyses of virologic, genetic and immunologic parameters of HIV-1 controllers groups: 1) Elite Controllers (EC; VL <80 copies/mL); 2) Ebbing Elite Controllers (EEC; transient viremia/blips); and Viremic Controllers (VC; detectable viremia <5,000 copies/mL). Untreated non-controllers (NC), patients under suppressive HAART and HIV-1 negative individuals were analyzed as controls. Results Total and integrated HIV-1 DNA for EC were significantly lower than for NC and HAART groups. 2-LTR circles were detected in EEC (3/5) and VC (6/7) but not in EC. While EC and EEC maintain normal T cell counts over time, some VC displayed negative CD4+ T cells slopes. VC and EEC showed a higher percentage of activated CD8+ T cells and microbial translocation than HIV-1 negative controls. EC displayed a weaker Gag/Nef IFN-γ T cell response and a significantly lower proportion of anti-HIV IgG antibodies than EEC, VC and NC groups. Conclusion Transient/persistent low level viremia in HIV controllers may have an impact on immunologic and virologic profiles. Classify HIV controllers patients taking into account their virologic profile may decrease the heterogeneity of HIV controllers cohorts, which may help to clarify the mechanisms associated to the elite control of HIV. PMID:25564106

  5. Virologic suppression among HIV-infected US Air Force members in a highly-structured programme with free access to care.

    PubMed

    Matthews, P E; Le, T; Delmar, J; Okulicz, J F

    2015-11-01

    SummaryThe United States Air Force HIV programme has several features that may enhance antiretroviral therapy outcomes, including free access to healthcare and mandatory clinical visits every six months at a single centre. We evaluated viral load suppression (<50 copies/ml) after 12 months of initial antiretroviral therapy, with extension to 18 and 24 months. Active duty Air Force members were categorised by year of antiretroviral therapy initiation: 2000-2005 (n = 95, 36.1%) and 2006-2011 (n = 168, 63.9%). The median months from HIV diagnosis to initial antiretroviral therapy were shorter in the 2000-2005 group (2.4, IQR 1.2-5.9) compared with the 2006-2011 group (12.6, IQR 2.6-29.0; p < 0.001). Viral load suppression was greater in the 2006-2011 group compared with the 2000-2005 group at 12 months (93.2% versus 78.6%, p = 0.002) and 18 months (91.8% versus 80.3%, p = 0.03), and trended higher at 24 months (90.8% versus 82.5%; p = 0.15). Factors associated with viral load suppression at 12 months in multivariate models included antiretroviral therapy initiation during 2006-2011 (OR 5.22, 95% CI 1.50-18.18) and CD4 count at antiretroviral therapy initiation (OR 2.29, 95% CI 1.19-14.43 per 100 cells/µl increase). Structured programmes that minimise traditional barriers to care combined with the use of contemporary antiretroviral therapy regimens can achieve clinic-wide viral load suppression in >90% of patients. PMID:25505041

  6. Novel Use of Surveillance Data to Detect HIV-Infected Persons with Sustained High Viral Load and Durable Virologic Suppression in New York City

    PubMed Central

    Terzian, Arpi S.; Bodach, Sara D.; Wiewel, Ellen W.; Sepkowitz, Kent; Bernard, Marie-Antoinette; Braunstein, Sarah L.; Shepard, Colin W.

    2012-01-01

    Background Monitoring of the uptake and efficacy of ART in a population often relies on cross-sectional data, providing limited information that could be used to design specific targeted intervention programs. Using repeated measures of viral load (VL) surveillance data, we aimed to estimate and characterize the proportion of persons living with HIV/AIDS (PLWHA) in New York City (NYC) with sustained high VL (SHVL) and durably suppressed VL (DSVL). Methods/Principal Findings Retrospective cohort study of all persons reported to the NYC HIV Surveillance Registry who were alive and ≥12 years old by the end of 2005 and who had ≥2 VL tests in 2006 and 2007. SHVL and DSVL were defined as PLWHA with 2 consecutive VLs ≥100,000 copies/mL and PLWHA with all VLs ≤400 copies/mL, respectively. Logistic regression models using generalized estimating equations were used to model the association between SHVL and covariates. There were 56,836 PLWHA, of whom 7% had SHVL and 38% had DSVL. Compared to those without SHVL, persons with SHVL were more likely to be younger, black and have injection drug use (IDU) risk. PLWHA with SHVL were more likely to die by 2007 and be younger by nearly ten years, on average. Conclusions/Significance Nearly 60% of PLWHA in 2005 had multiple VLs, of whom almost 40% had DSVL, suggesting successful ART uptake. A small proportion had SHVL, representing groups known to have suboptimal engagement in care. This group should be targeted for additional outreach to reduce morbidity and secondary transmission. Measures based on longitudinal analyses of surveillance data in conjunction with cross-sectional measures such as community viral load represent more precise and powerful tools for monitoring ART effectiveness and potential impact on disease transmission than cross-sectional measures alone. PMID:22291892

  7. CD4:CD8 ratio as a frontier marker for clinical outcome, immune dysfunction and viral reservoir size in virologically suppressed HIV-positive patients

    PubMed Central

    Lu, Wei; Mehraj, Vikram; Vyboh, Kishanda; Cao, Wei; Li, Taisheng; Routy, Jean-Pierre

    2015-01-01

    Introduction Absolute CD4 T cell count and plasma viral load have been established as predictors of HIV disease progression, and CD4 T cell count is used as an indicator for initiation of antiretroviral therapy. Following long-term therapy, patients generally present with significant CD4 T cell recovery contrasting with persistently elevated CD8 T cell counts, which leads to a partial restoration of CD4:CD8 ratio. This review focuses on the relevance of the CD4:CD8 ratio on clinical outcomes, immune dysfunction and HIV reservoir size in long-term treated patients. Method We conducted a comprehensive literature review of publications in English language using major electronic databases. Our search was focused on factors contributing to CD4:CD8 T cell ratio and clinical outcome in adult HIV-positive patients in the context of treated infection. Discussion Low CD4:CD8 ratio has been linked to ageing and acts as a predictor of mortality in the general population. This ratio may represent the combined effects of inflammation and immunological changes called “inflammaging.” Although the mechanisms underlying partial correction of the CD4:CD8 ratio and persistently elevated CD8 T cell count in long-term treated patients remain poorly understood, it has been recently indicated that patients with optimal CD4 T cell recovery and low CD4:CD8 ratio still harbour increased immune activation, an immune senescent phenotype and have a higher risk of non-AIDS morbidity and mortality. This review reconsiders CD4:CD8 ratio in the light of advances in the understanding of immune dysfunction and examines its pathophysiological features and implications on clinical outcome and HIV reservoir size in long-term treated HIV-positive adults. Conclusion The CD4:CD8 ratio can contribute to the immunological evaluation of treated patients in a long-term follow-up and may be applied for monitoring both immune dysfunction and viral reservoir size in immune-based clinical trials. PMID:26130226

  8. Effect of HIV type 1 subtype on virological and immunological response to combination antiretroviral therapy: evidence for a more rapid viral suppression for subtype A than subtype B-infected Greek individuals.

    PubMed

    Paraskevis, Dimirios; Touloumi, Giota; Bakoyannis, Giorgos; Paparizos, Vassilios; Lazanas, Marios; Gargalianos, Panagiotis; Chryssos, Georgios; Antoniadou, Anastasia; Psichogiou, Mina; Panos, Georgios; Katsarou, Olga; Sambatakou, Helen; Kordossis, Theodoros; Hatzakis, Angelos

    2013-03-01

    Whether response to combination antiretroviral therapy (cART) differs between those infected with HIV-1 subtype A or B remains unclear. We compared virological and immunological response to cART in individuals infected with subtype A or B in an ethnically homogeneous population. Data derived from the Athens Multicenter AIDS Cohort Study (AMACS) and analysis were restricted to those of Greek origin. Time to virological response (confirmed HIV-RNA <500 copies/ml) and time to failure (>500 copies/ml at any time or no response by month 6) were analyzed using survival models and CD4 changes after cART initiation using piecewise linear mixed effects models. Of the 571 subjects included in the analysis, 412 (72.2%) were infected with subtype B and 159 (27.8%) with subtype A. After adjusting for various prognostic factors, the rate of virological response was higher for those infected with subtype A versus B (adjusted HR: 1.35; 95% CI: 1.08-1.68; p=0.009). Subtype A was also marginally associated with a lower hazard of virological failure compared to subtype B (HR=0.73; 95% CI: 0.53-1.02; p=0.062). Further adjustment for treatment adherence did not substantially changed the main results. No significant differences were observed in the rates of CD4 increases by subtype. The overall median (95% CI) CD4 increase at 2 years of cART was 193 (175, 212) cells/μl. Our study, based on one of the largest homogeneous groups of subtype A and B infections in Europe, showed that individuals infected with subtype A had an improved virological but similar immunological response to cART compared to those infected with subtype B. PMID:23034083

  9. Magnitude of Virologic Blips Is Associated With a Higher Risk for Virologic Rebound in HIV-Infected Individuals: A Recurrent Events Analysis

    PubMed Central

    Grennan, J. Troy; Loutfy, Mona R.; Su, DeSheng; Harrigan, P. Richard; Cooper, Curtis; Klein, Marina; Machouf, Nima; Montaner, Julio S. G.; Rourke, Sean; Tsoukas, Christos; Hogg, Bob

    2012-01-01

    (See the editorial commentary by Taiwo and Bosch, on pages 1189–91.) Background. The importance of human immunodeficiency virus (HIV) blip magnitude on virologic rebound has been raised in clinical guidelines relating to viral load assays. Methods. Antiretroviral-naive individuals initiating combination antiretroviral therapy (cART) after 1 January 2000 and achieving virologic suppression were studied. Negative binomial models were used to identify blip correlates. Recurrent event models were used to determine the association between blips and rebound by incorporating multiple periods of virologic suppression per individual. Results. 3550 participants (82% male; median age, 40 years) were included. In a multivariable negative binomial regression model, the Amplicor assay was associated with a lower blip rate than branched DNA (rate ratio, 0.69; P < .01), controlling for age, sex, region, baseline HIV-1 RNA and CD4 count, AIDS-defining illnesses, year of cART initiation, cART type, and HIV-1 RNA testing frequency. In a multivariable recurrent event model controlling for age, sex, intravenous drug use, cART start year, cART type, assay type, and HIV-1 RNA testing frequency, blips of 500–999 copies/mL were associated with virologic rebound (hazard ratio, 2.70; P = .002), whereas blips of 50–499 were not. Conclusions. HIV-1 RNA assay was an important determinant of blip rates and should be considered in clinical guidelines. Blips ≥500 copies/mL were associated with increased rebound risk. PMID:22438396

  10. Lamivudine Concentration in Hair and Prediction of Virologic Failure and Drug Resistance among HIV Patients Receiving Free ART in China

    PubMed Central

    Wang, Zhe; Wu, Jianjun; Zhang, Jiafeng; Ruan, Yuhua; Hsi, Jenny; Liao, Lingjie; Shao, Yiming; Xing, Hui

    2016-01-01

    Background The assessment of adherence to antiretroviral therapy (ART) is important in order to predict treatment outcomes. Lamivudine (3TC) is one of the most widely used NRTIs in China, but its concentrations in hair and association with virologic failure and drug resistance have not been studied. Methods We conducted a cross-sectional survey to investigate 3TC concentrations in hair as a predictor of virologic failure and drug resistance among HIV patients receiving free ART. We also compared the capacity of hair 3TC concentrations with self-reported adherence in predicting virologic responses. Hair 3TC concentrations were detected through the LC-MS/MS system. Results In patients without HIV drug resistance (HIVDR), with a threshold hair 3TC concentration of 260 ng/g, the sensitivity and specificity in predicting virologic suppression were 76.9% and 89.9%, respectively. Some factors, including CD4+ cell counts, initial treatment regimens with 3TC, and current regimens with second-line drugs, influenced the association between hair 3TC concentrations and virologic suppression. In patients who experienced virologic failure with HIVDR, with a threshold of 180 ng/g, the sensitivity and specificity were 70.0% and 74.4%, respectively. Hair 3TC concentrations had higher sensitivity and specificity in predicting virologic failure and drug resistance than self-reported adherence. Conclusions The hair 3TC concentration was a stronger indicator than self-reported adherence in predicting virologic failure and drug resistance in HIV patients receiving free ART. PMID:27119346

  11. Age at Virologic Control Influences Peripheral Blood HIV Reservoir Size and Serostatus in Perinatally-Infected Adolescents

    PubMed Central

    Persaud, Deborah; Patel, Kunjal; Karalius, Brad; Rainwater-Lovett, Kaitlin; Ziemniak, Carrie; Ellis, Angela; Chen, Ya Hui; Richman, Douglas; Siberry, George K.; Van Dyke, Russell B.; Burchett, Sandra; Seage, George R.; Luzuriaga, Katherine

    2014-01-01

    Importance Combination antiretroviral therapy (cART) initiated within several weeks of HIV infection in adults limits proviral reservoirs that preclude HIV cure. Biomarkers of restricted proviral reservoirs may aid in the monitoring of HIV remission or cure. Objectives To quantify peripheral blood proviral reservoir size in perinatally HIV-infected adolescents and to identify correlates of limited proviral reservoirs. Design, Setting, and Participants A cross-sectional study including 144 perinatally HIV-infected (PHIV+) youth (median age: 14.3 years), enrolled in the US-based Pediatric HIV/AIDS Cohort Study, on durable (median: 10.2 years) cART, stratified by age at virologic control. Main Outcome and Measures The primary endpoint was peripheral blood mononuclear cell (PBMC) proviral load following virologic control at different ages. Correlations between proviral load and markers of active HIV production (HIV-specific antibodies, 2-long terminal repeat (2-LTR) circles), and markers of immune activation and inflammation were also assessed. Results Proviral reservoir size was markedly reduced in the PHIV+ youth who achieved virologic control by age 1 year (4.2 [interquartile range, 2.6-8 6] copies per 1 million PBMCs) compared to those who achieved virologic control between 1-5 years of age (19.4 [interquartile range, 5.5-99.8] copies per 1 million PBMCs) or after age 5 years (−(70.7 [interquartile range, 23.2-209.4] copies per 1 million PBMCs; P < .00l). A proviral burden <10 copies/million PBMCs was measured in 11 (79%), 20 (40%), and 13 (18%) participants with virologic control at ages <1 year, 1-5 years, and >5 years, respectively (p<0.001). Lower proviral load was associated with undetectable 2-LTR circles (p<0.001) and HIV negative or indeterminate serostatus (p<0.001), but not with concentrations of soluble immune activation markers CD14 and CD163. Conclusions and Relevance Early effective cART along with prolonged virologic suppression after perinatal HIV

  12. Primary Relationships, HIV Treatment Adherence, and Virologic Control

    PubMed Central

    Dilworth, Samantha E.; Taylor, Jonelle M.; Darbes, Lynae A.; Comfort, Megan L.; Neilands, Torsten B.

    2013-01-01

    To identify factors associated with antiretroviral therapy (ART) adherence and virologic control among HIV-positive men on ART in primary relationships, data were collected from 210 male couples (420 men). Dyadic actor–partner analyses investigated associations with three levels of adherence-related dependent variables: self-efficacy (ASE), self-reported adherence, and virologic control. Results indicated that higher patient ASE was related to his own positive beliefs about medications, higher relationship autonomy and intimacy, and fewer depressive symptoms. Fewer depressive symptoms and less relationship satisfaction in the partner were linked to higher ASE in the patient. Better self-reported adherence was related to the patient’s positive appraisal of the relationship and the partner’s positive treatment efficacy beliefs. Greater medication concerns of both patient and partner were associated with less adherence. The partner’s higher relationship commitment was associated with lower viral load in the patient. Findings suggest that depressive symptoms, treatment beliefs, and relationship quality factors of both partners may influence adherence-related outcomes. PMID:21811842

  13. Performance and Logistical Challenges of Alternative HIV-1 Virological Monitoring Options in a Clinical Setting of Harare, Zimbabwe

    PubMed Central

    Bronze, Michelle; Wellington, Maureen; Boender, Tamara Sonia; Manting, Corry; Steegen, Kim; Luethy, Rudi; Rinke de Wit, Tobias

    2014-01-01

    We evaluated a low-cost virological failure assay (VFA) on plasma and dried blood spot (DBS) specimens from HIV-1 infected patients attending an HIV clinic in Harare. The results were compared to the performance of the ultrasensitive heat-denatured p24 assay (p24). The COBAS AmpliPrep/COBAS TaqMan HIV-1 test, version 2.0, served as the gold standard. Using a cutoff of 5,000 copies/mL, the plasma VFA had a sensitivity of 94.5% and specificity of 92.7% and was largely superior to the VFA on DBS (sensitivity = 61.9%; specificity = 99.0%) or to the p24 (sensitivity = 54.3%; specificity = 82.3%) when tested on 302 HIV treated and untreated patients. However, among the 202 long-term ART-exposed patients, the sensitivity of the VFA decreased to 72.7% and to 35.7% using a threshold of 5,000 and 1,000 RNA copies/mL, respectively. We show that the VFA (either on plasma or on DBS) and the p24 are not reliable to monitor long-term treated, HIV-1 infected patients. Moreover, achieving acceptable assay sensitivity using DBS proved technically difficult in a less-experienced laboratory. Importantly, the high level of virological suppression (93%) indicated that quality care focused on treatment adherence limits virological failure even when PCR-based viral load monitoring is not available. PMID:25025031

  14. Performance and logistical challenges of alternative HIV-1 virological monitoring options in a clinical setting of Harare, Zimbabwe.

    PubMed

    Ondoa, Pascale; Shamu, Tinei; Bronze, Michelle; Wellington, Maureen; Boender, Tamara Sonia; Manting, Corry; Steegen, Kim; Luethy, Rudi; Rinke de Wit, Tobias

    2014-01-01

    We evaluated a low-cost virological failure assay (VFA) on plasma and dried blood spot (DBS) specimens from HIV-1 infected patients attending an HIV clinic in Harare. The results were compared to the performance of the ultrasensitive heat-denatured p24 assay (p24). The COBAS AmpliPrep/COBAS TaqMan HIV-1 test, version 2.0, served as the gold standard. Using a cutoff of 5,000 copies/mL, the plasma VFA had a sensitivity of 94.5% and specificity of 92.7% and was largely superior to the VFA on DBS (sensitivity = 61.9%; specificity = 99.0%) or to the p24 (sensitivity = 54.3%; specificity = 82.3%) when tested on 302 HIV treated and untreated patients. However, among the 202 long-term ART-exposed patients, the sensitivity of the VFA decreased to 72.7% and to 35.7% using a threshold of 5,000 and 1,000 RNA copies/mL, respectively. We show that the VFA (either on plasma or on DBS) and the p24 are not reliable to monitor long-term treated, HIV-1 infected patients. Moreover, achieving acceptable assay sensitivity using DBS proved technically difficult in a less-experienced laboratory. Importantly, the high level of virological suppression (93%) indicated that quality care focused on treatment adherence limits virological failure even when PCR-based viral load monitoring is not available. PMID:25025031

  15. T cell virological synapses and HIV-1 pathogenesis.

    PubMed

    Chen, Benjamin K

    2012-12-01

    Human immunodeficiency virus type 1 is the cause of a modern global pandemic associated with progressive acquired immune deficiency. The infection is characterized by the loss of the primary target of viral infection, the CD4+ T cell. The measurement of plasma viremia in patients can predict the rate of CD4+ cell decline; however, it is not clear whether this cell-free plasma virus represents the engine that drives viral spread. Active viral replication is mainly observed within lymphoid tissues that are hotbeds of cell-cell interactions that initiate and organize immune responses. It is well established that cell-cell interactions enhance viral spread in vitro. Dendritic cell-T cell interactions, which lie at the heart of adaptive immune responses, enhance viral infection in vitro. Interactions between infected and uninfected CD4+ T cells are a dominant route of viral spread in vitro and are likely to play a central role in viral dissemination in vivo. Future studies will test existing paradigms of HIV-1 dissemination to determine whether virus-transmitting contacts between infected and uninfected T cells called virological synapses are the dominant mode of viral spread in vivo. Here, we review the status of our understanding of this mode of infection with a focus on T cell-T cell interactions and examine how it may explain resistance to neutralizing antibodies and or the generation of genetic diversity of HIV. PMID:22477441

  16. Factors Influencing Antiretroviral Adherence and Virological Outcomes in People Living with HIV in the Highlands of Papua New Guinea.

    PubMed

    Gare, Janet; Kelly-Hanku, Angela; Ryan, Claire E; David, Matthew; Kaima, Petronia; Imara, Ulato; Lote, Namarola; Crowe, Suzanne M; Hearps, Anna C

    2015-01-01

    Adherence to antiretroviral therapy (ART) is paramount for virological suppression and positive treatment outcomes. ART has been rapidly scaled up in Papua New Guinea (PNG) in recent years, however clinical monitoring of HIV+ individuals on ART is limited. A cross-sectional study was conducted at two major sexual health clinics in high HIV prevalence provinces in the Highlands Region of PNG to assess ART adherence, factors affecting adherence and the relationship between ART adherence and virological outcomes. Ninety-five HIV+ individuals were recruited and administered a questionnaire to gather demographic and ART adherence information whilst clinical data and pill counts were extracted from patient charts and blood was collected for viral load testing. Bivariate analysis was performed to identify independent predictors of ART adherence. Fourteen percent (n = 12) of participants showed evidence of virological failure. Although the majority of participants self-reported excellent ART adherence in the last seven days (78.9%, 75/91), pill count measurements indicated only 40% (34/84) with >95% adherence in the last month. Taking other medications while on ART (p = 0.01) and taking ART for ≥1 year (p = 0.037) were positively associated with adherence by self-report and pill count, respectively. Participants who had never heard of drug resistance were more likely to show virological failure (p = 0.033). Misconception on routes of HIV transmission still persists in the studied population. These findings indicate that non-adherence to ART is high in this region of PNG and continued education and strategies to improve adherence are required to ensure the efficacy of ART and prevent HIV drug resistance. PMID:26244516

  17. Is Primary Mycobacterium avium Complex Prophylaxis Necessary in Patients with CD4 < 50 Cells/μL Who Are Virologically Suppressed on cART?

    PubMed Central

    Yangco, Bienvenido G.; Buchacz, Kate; Baker, Rose; Palella, Frank J.; Armon, Carl; Brooks, John T.

    2015-01-01

    We analyzed 369 patients with no prior Mycobacterium avium complex (MAC) infection and CD4 < 50 cells/ μL (baseline), while on combination antiretroviral therapy(cART), for incidence rates of primary MAC infection during the 6 months after baseline, by prophylaxis status. Of participants (median age, 40 years old), most were male (81%) and about half were non-white; at baseline, 81% of participants were on cART > 60 days and 19% had HIV RNA < 1000 copies/mL, whereas 65% had HIV RNA > 10,000 copies/mL. Eleven patients had MAC infection within 6 months baseline (rate = 0.6/100 person months): 4/175 on MAC prophylaxis vs. 7/194, no MAC prophylaxis (p = 0.64). Of the 11 patients, seven had HIV RNA > 10,000, and three > 1000–9999 copies/mL at baseline (one missing). Median time to MAC infection was 62 days (IQR 43–126, maximum 139 days). No MAC infection occurred among 71 (19%) patients virologically suppressed (HIV RNA < 1000 copies/mL) at baseline, including 41 patients with no MAC prophylaxis during follow-up. A small number of eligible virologically suppressed participants and the lack of data on cART/MAC prophylaxis adherence limited our observational nonrandomized study. Primary MAC prophylaxis may not be required for cART-virologically suppressed patients with CD4 < 50 cells/mL. PMID:24833016

  18. Is primary mycobacterium avium complex prophylaxis necessary in patients with CD4 <50 cells/μL who are virologically suppressed on cART?

    PubMed

    Yangco, Bienvenido G; Buchacz, Kate; Baker, Rose; Palella, Frank J; Armon, Carl; Brooks, John T

    2014-06-01

    We analyzed 369 patients with no prior Mycobacterium avium complex (MAC) infection and CD4 <50 cells/μL (baseline), while on combination antiretroviral therapy(cART), for incidence rates of primary MAC infection during the 6 months after baseline, by prophylaxis status. Of participants (median age, 40 years old), most were male (81%) and about half were non-white; at baseline, 81% of participants were on cART >60 days and 19% had HIV RNA <1000 copies/mL, whereas 65% had HIV RNA >10,000 copies/mL. Eleven patients had MAC infection within 6 months baseline (rate=0.6/100 person months): 4/175 on MAC prophylaxis vs. 7/194, no MAC prophylaxis (p=0.64). Of the 11 patients, seven had HIV RNA >10,000, and three >1000-9999 copies/mL at baseline (one missing). Median time to MAC infection was 62 days (IQR 43-126, maximum 139 days). No MAC infection occurred among 71 (19%) patients virologically suppressed (HIV RNA <1000 copies/mL) at baseline, including 41 patients with no MAC prophylaxis during follow-up. A small number of eligible virologically suppressed participants and the lack of data on cART/MAC prophylaxis adherence limited our observational nonrandomized study. Primary MAC prophylaxis may not be required for cART-virologically suppressed patients with CD4 <50 cells/mL. PMID:24833016

  19. Virology, Immunology, and Clinical Course of HIV Infection.

    ERIC Educational Resources Information Center

    McCutchan, J. Allen

    1990-01-01

    Presents overview of medical aspects of human immunodeficiency virus Type 1 (HIV-1) disease. Addresses structure and replication of virus, current methods for detecting HIV-1 in infected persons, effects of the virus on immune system, and clinical course of HIV-1 disease. Emphasizes variable causes of progression through HIV-1 infection stages;…

  20. HIV-1 DNA predicts disease progression and post-treatment virological control.

    PubMed

    Williams, James P; Hurst, Jacob; Stöhr, Wolfgang; Robinson, Nicola; Brown, Helen; Fisher, Martin; Kinloch, Sabine; Cooper, David; Schechter, Mauro; Tambussi, Giuseppe; Fidler, Sarah; Carrington, Mary; Babiker, Abdel; Weber, Jonathan; Koelsch, Kersten K; Kelleher, Anthony D; Phillips, Rodney E; Frater, John

    2014-01-01

    In HIV-1 infection, a population of latently infected cells facilitates viral persistence despite antiretroviral therapy (ART). With the aim of identifying individuals in whom ART might induce a period of viraemic control on stopping therapy, we hypothesised that quantification of the pool of latently infected cells in primary HIV-1 infection (PHI) would predict clinical progression and viral replication following ART. We measured HIV-1 DNA in a highly characterised randomised population of individuals with PHI. We explored associations between HIV-1 DNA and immunological and virological markers of clinical progression, including viral rebound in those interrupting therapy. In multivariable analyses, HIV-1 DNA was more predictive of disease progression than plasma viral load and, at treatment interruption, predicted time to plasma virus rebound. HIV-1 DNA may help identify individuals who could safely interrupt ART in future HIV-1 eradication trials. PMID:25217531

  1. Clinical and Virological Outcome of European Patients Infected With HIV

    ClinicalTrials.gov

    2016-02-29

    HIV; Hepatitis B; Hepatitis C; AIDS; Coinfection; Cardiovascular Diseases; Diabetes Mellitus; Acidosis, Lactic; Renal Insufficiency; Fractures, Bone; End Stage Liver Disease; Kidney Failure, Chronic; Proteinuria

  2. 3D visualization of HIV transfer at the virological synapse between dendritic cells and T cells

    PubMed Central

    Felts, Richard L.; Narayan, Kedar; Estes, Jacob D.; Shi, Dan; Trubey, Charles M.; Fu, Jing; Hartnell, Lisa M.; Ruthel, Gordon T.; Schneider, Douglas K.; Nagashima, Kunio; Bess, Julian W.; Bavari, Sina; Lowekamp, Bradley C.; Bliss, Donald; Lifson, Jeffrey D.; Subramaniam, Sriram

    2010-01-01

    The efficiency of HIV infection is greatly enhanced when the virus is delivered at conjugates between CD4+ T cells and virus-bearing antigen-presenting cells such as macrophages or dendritic cells via specialized structures known as virological synapses. Using ion abrasion SEM, electron tomography, and superresolution light microscopy, we have analyzed the spatial architecture of cell-cell contacts and distribution of HIV virions at virological synapses formed between mature dendritic cells and T cells. We demonstrate the striking envelopment of T cells by sheet-like membrane extensions derived from mature dendritic cells, resulting in a shielded region for formation of virological synapses. Within the synapse, filopodial extensions emanating from CD4+ T cells make contact with HIV virions sequestered deep within a 3D network of surface-accessible compartments in the dendritic cell. Viruses are detected at the membrane surfaces of both dendritic cells and T cells, but virions are not released passively at the synapse; instead, virus transfer requires the engagement of T-cell CD4 receptors. The relative seclusion of T cells from the extracellular milieu, the burial of the site of HIV transfer, and the receptor-dependent initiation of virion transfer by T cells highlight unique aspects of cell-cell HIV transmission. PMID:20624966

  3. Ezrin Is a Component of the HIV-1 Virological Presynapse and Contributes to the Inhibition of Cell-Cell Fusion

    PubMed Central

    Roy, Nathan H.; Lambelé, Marie; Chan, Jany; Symeonides, Menelaos

    2014-01-01

    ABSTRACT During cell-to-cell transmission of HIV-1, viral and cellular proteins transiently accumulate at the contact zone between infected (producer) and uninfected (target) cells, forming the virological synapse. Rearrangements of the cytoskeleton in producer and target cells are required for proper targeting of viral and cellular components during synapse formation, yet little is known about how these processes are regulated, particularly within the producer cell. Since ezrin-radixin-moesin (ERM) proteins connect F-actin with integral and peripheral membrane proteins, are incorporated into virions, and interact with cellular components of the virological presynapse, we hypothesized that they play roles during the late stage of HIV-1 replication. Here we document that phosphorylated (i.e., active) ezrin specifically accumulates at the HIV-1 presynapse in T cell lines and primary CD4+ lymphocytes. To investigate whether ezrin supports virus transmission, we sought to ablate ezrin expression in producer cells. While cells did not tolerate a complete knockdown of ezrin, even a modest reduction of ezrin expression (∼50%) in HIV-1-producing cells led to the release of particles with impaired infectivity. Further, when cocultured with uninfected target cells, ezrin-knockdown producer cells displayed reduced accumulation of the tetraspanin CD81 at the synapse and fused more readily with target cells, thus forming syncytia. Such an outcome likely is not optimal for virus dissemination, as evidenced by the fact that, in vivo, only relatively few infected cells form syncytia. Thus, ezrin likely helps secure efficient virus spread not only by enhancing virion infectivity but also by preventing excessive membrane fusion at the virological synapse. IMPORTANCE While viruses, in principal, can propagate through successions of syncytia, HIV-1-infected cells in the majority of cases do not fuse with potential target cells during viral transmission. This mode of spread is

  4. Abacavir/lamivudine versus tenofovir/emtricitabine in virologically suppressed patients switching from ritonavir-boosted protease inhibitors to raltegravir.

    PubMed

    Martínez, Esteban; d'Albuquerque, Polyana M; Pérez, Ignacio; Pich, Judit; Gatell, José M

    2013-02-01

    There are few clinical data on the combination abacavir/lamivudine plus raltegravir. We compared the outcomes of patients from the SPIRAL trial receiving either abacavir/lamivudine or tenofovir/emtricitabine at baseline who had taken at least one dose of either raltegravir or ritonavir-boosted protease inhibitors. For the purpose of this analysis, treatment failure was defined as virological failure (confirmed HIV-1 RNA ≥50 copies/ml) or discontinuation of abacavir/lamivudine or tenofovir/emtricitabine because of adverse events, consent withdrawal, or lost to follow-up. There were 143 (72.59%) patients with tenofovir/emtricitabine and 54 (27.41%) with abacavir/lamivudine. In the raltegravir group, there were three (11.11%) treatment failures with abacavir/lamivudine and eight (10.96%) with tenofovir/emtricitabine (estimated difference 0.15%; 95% CI -17.90 to 11.6). In the ritonavir-boosted protease inhibitor group, there were four (14.81%) treatment failures with abacavir/lamivudine and 12 (17.14%) with tenofovir/emtricitabine (estimated difference -2.33%; 95% CI -16.10 to 16.70). Triglycerides decreased and HDL cholesterol increased through the study more pronouncedly with abacavir/lamivudine than with tenofovir/emtricitabine and differences in the total-to-HDL cholesterol ratio between both combinations of nucleoside reverse transcriptase inhibitors (NRTIs) tended to be higher in the raltegravir group, although differences at 48 weeks were not significant. While no patient discontinued abacavir/lamivudine due to adverse events, four (2.80%) patients (all in the ritonavir-boosted protease inhibitor group) discontinued tenofovir/emtricitabine because of adverse events (p=0.2744). The results of this analysis do not suggest that outcomes of abacavir/lamivudine are worse than those of tenofovir/emtricitabine when combined with raltegravir in virologically suppressed HIV-infected adults. PMID:22916715

  5. Three-Dimensional Imaging of HIV-1 Virological Synapses Reveals Membrane Architectures Involved in Virus Transmission

    PubMed Central

    Do, Thao; Murphy, Gavin; Earl, Lesley A.; Del Prete, Gregory Q.; Grandinetti, Giovanna; Li, Guan-Han; Estes, Jacob D.; Rao, Prashant; Trubey, Charles M.; Thomas, James; Spector, Jeffrey; Bliss, Donald; Nath, Avindra; Lifson, Jeffrey D.

    2014-01-01

    ABSTRACT HIV transmission efficiency is greatly increased when viruses are transmitted at virological synapses formed between infected and uninfected cells. We have previously shown that virological synapses formed between HIV-pulsed mature dendritic cells (DCs) and uninfected T cells contain interdigitated membrane surfaces, with T cell filopodia extending toward virions sequestered deep inside invaginations formed on the DC membrane. To explore membrane structural changes relevant to HIV transmission across other types of intercellular conjugates, we used a combination of light and focused ion beam scanning electron microscopy (FIB-SEM) to determine the three-dimensional (3D) architectures of contact regions between HIV-1-infected CD4+ T cells and either uninfected human CD4+ T cells or human fetal astrocytes. We present evidence that in each case, membrane extensions that originate from the uninfected cells, either as membrane sheets or filopodial bridges, are present and may be involved in HIV transmission from infected to uninfected cells. We show that individual virions are distributed along the length of astrocyte filopodia, suggesting that virus transfer to the astrocytes is mediated, at least in part, by processes originating from the astrocyte itself. Mechanisms that selectively disrupt the polarization and formation of such membrane extensions could thus represent a possible target for reducing viral spread. IMPORTANCE Our findings lead to new insights into unique aspects of HIV transmission in the brain and at T cell-T cell synapses, which are thought to be a predominant mode of rapid HIV transmission early in the infection process. PMID:24965444

  6. HIV-1 DNA predicts disease progression and post-treatment virological control

    PubMed Central

    Williams, James P; Hurst, Jacob; Stöhr, Wolfgang; Robinson, Nicola; Brown, Helen; Fisher, Martin; Kinloch, Sabine; Cooper, David; Schechter, Mauro; Tambussi, Giuseppe; Fidler, Sarah; Carrington, Mary; Babiker, Abdel; Weber, Jonathan

    2014-01-01

    In HIV-1 infection, a population of latently infected cells facilitates viral persistence despite antiretroviral therapy (ART). With the aim of identifying individuals in whom ART might induce a period of viraemic control on stopping therapy, we hypothesised that quantification of the pool of latently infected cells in primary HIV-1 infection (PHI) would predict clinical progression and viral replication following ART. We measured HIV-1 DNA in a highly characterised randomised population of individuals with PHI. We explored associations between HIV-1 DNA and immunological and virological markers of clinical progression, including viral rebound in those interrupting therapy. In multivariable analyses, HIV-1 DNA was more predictive of disease progression than plasma viral load and, at treatment interruption, predicted time to plasma virus rebound. HIV-1 DNA may help identify individuals who could safely interrupt ART in future HIV-1 eradication trials. Clinical trial registration: ISRCTN76742797 and EudraCT2004-000446-20 DOI: http://dx.doi.org/10.7554/eLife.03821.001 PMID:25217531

  7. Contact-Induced Mitochondrial Polarization Supports HIV-1 Virological Synapse Formation

    PubMed Central

    Groppelli, Elisabetta; Starling, Shimona

    2014-01-01

    ABSTRACT Rapid HIV-1 spread between CD4 T lymphocytes occurs at retrovirus-induced immune cell contacts called virological synapses (VS). VS are associated with striking T cell polarization and localized virus budding at the site of contact that facilitates cell-cell spread. In addition to this, spatial clustering of organelles, including mitochondria, to the contact zone has been previously shown. However, whether cell-cell contact specifically induces dynamic T cell remodeling during VS formation and what regulates this process remain unclear. Here, we report that contact between an HIV-1-infected T cell and an uninfected target T cell specifically triggers polarization of mitochondria concomitant with recruitment of the major HIV-1 structural protein Gag to the site of cell-cell contact. Using fixed and live-cell imaging, we show that mitochondrial and Gag polarization in HIV-1-infected T cells occurs within minutes of contact with target T cells, requires the formation of stable cell-cell contacts, and is an active, calcium-dependent process. We also find that perturbation of mitochondrial polarization impairs cell-cell spread of HIV-1 at the VS. Taken together, these data suggest that HIV-1-infected T cells are able to sense and respond to contact with susceptible target cells and undergo dynamic cytoplasmic remodeling to create a synaptic environment that supports efficient HIV-1 VS formation between CD4 T lymphocytes. IMPORTANCE HIV-1 remains one of the major global health challenges of modern times. The capacity of HIV-1 to cause disease depends on the virus's ability to spread between immune cells, most notably CD4 T lymphocytes. Cell-cell transmission is the most efficient way of HIV-1 spread and occurs at the virological synapse (VS). The VS forms at the site of contact between an infected cell and an uninfected cell and is characterized by polarized assembly and budding of virions and clustering of cellular organelles, including mitochondria. Here, we

  8. Multiple proviral integration events after virological synapse-mediated HIV-1 spread

    SciTech Connect

    Russell, Rebecca A.; Martin, Nicola; Mitar, Ivonne; Jones, Emma; Sattentau, Quentin J.

    2013-08-15

    HIV-1 can move directly between T cells via virological synapses (VS). Although aspects of the molecular and cellular mechanisms underlying this mode of spread have been elucidated, the outcomes for infection of the target cell remain incompletely understood. We set out to determine whether HIV-1 transfer via VS results in productive, high-multiplicity HIV-1 infection. We found that HIV-1 cell-to-cell spread resulted in nuclear import of multiple proviruses into target cells as seen by fluorescence in-situ hybridization. Proviral integration into the target cell genome was significantly higher than that seen in a cell-free infection system, and consequent de novo viral DNA and RNA production in the target cell detected by quantitative PCR increased over time. Our data show efficient proviral integration across VS, implying the probability of multiple integration events in target cells that drive productive T cell infection. - Highlights: • Cell-to-cell HIV-1 infection delivers multiple vRNA copies to the target cell. • Cell-to-cell infection results in productive infection of the target cell. • Cell-to-cell transmission is more efficient than cell-free HIV-1 infection. • Suggests a mechanism for recombination in cells infected with multiple viral genomes.

  9. Time of HIV Diagnosis and Engagement in Prenatal Care Impact Virologic Outcomes of Pregnant Women with HIV

    PubMed Central

    Momplaisir, Florence M.; Brady, Kathleen A.; Fekete, Thomas; Thompson, Dana R.; Diez Roux, Ana; Yehia, Baligh R.

    2015-01-01

    Background HIV suppression at parturition is beneficial for maternal, fetal and public health. To eliminate mother-to-child transmission of HIV, an understanding of missed opportunities for antiretroviral therapy (ART) use during pregnancy and HIV suppression at delivery is required. Methodology We performed a retrospective analysis of 836 mother-to-child pairs involving 656 HIV-infected women in Philadelphia, 2005-2013. Multivariable regression examined associations between patient (age, race/ethnicity, insurance status, drug use) and clinical factors such as adequacy of prenatal care measured by the Kessner index which classifies prenatal care as inadequate, intermediate, or adequate prenatal care; timing of HIV diagnosis; and the outcomes: receipt of ART during pregnancy and viral suppression at delivery. Results Overall, 25% of the sample was diagnosed with HIV during pregnancy; 39%, 38%, and 23% were adequately, intermediately, and inadequately engaged in prenatal care. Eight-five percent of mother-to-child pairs received ART during pregnancy but only 52% achieved suppression at delivery. Adjusting for patient factors, pairs diagnosed with HIV during pregnancy were less likely to receive ART (AOR 0.39, 95% CI 0.25-0.61) and achieve viral suppression (AOR 0.70, 95% CI 0.49-1.00) than those diagnosed before pregnancy. Similarly, women with inadequate prenatal care were less likely to receive ART (AOR 0.06, 95% CI 0.03-0.11) and achieve viral suppression (AOR 0.31, 95% CI 0.20-0.47) than those with adequate prenatal care. Conclusions Targeted interventions to diagnose HIV prior to pregnancy and engage HIV-infected women in prenatal care have the potential to improve HIV related outcomes in the perinatal period. PMID:26132142

  10. Mitochondrial DNA variation and virologic and immunological HIV outcomes in African Americans

    PubMed Central

    Aissani, Brahim; Shrestha, Sadeep; Wiener, Howard W.; Tang, Jianming; Kaslow, Richard A.; Wilson, Craig M.

    2016-01-01

    Objective To evaluate the impact of mitochondrial DNA (mtDNA) haplogroups on virologic and immunological outcomes of HIV infection. Design HAART-naive African American adolescent participants to the Reaching for Excellence in Adolescent Care and Health study. Methods The mtDNA haplogroups were inferred from sequenced mtDNA hypervariable regions HV1 and HV2 and their predictive value on HIV outcomes were evaluated in linear mixed models, controlled for human leukocyte antigen (HLA)-B27, HLA-B57 and HLA-B35-Px alleles and other covariates. Results We report data showing that the mtDNA L2 lineage, a group composed of L2a, L2b and L2e mtDNA haplogroups in the studied population, is significantly associated (beta=−0.08; Bonferroni-adjusted P=0.004) with decline of CD4+ T cells (median loss of 8 ± 1 cells per month) in HAART-naive HIV-infected individuals of African American descent (n=133). No significant association (P<0.05) with set-point viral load was observed with any of the tested mtDNA haplogroups. The present data concur with previous findings in the AIDS Clinical Trials Group study 384, implicating the L2 lineage with slower CD4+ T-cell recovery after antiretroviral therapy in African Americans. Conclusions Whereas the L2 lineage showed an association with unfavorable immunological outcomes of HIV infection, its phylogenetic divergence from J and U5a, two lineages associated with accelerated HIV progression in European Americans, raises the possibility that interactions with common nucleus-encoded variants drive HIV progression. Disentangling the effects of mitochondrial and nuclear gene variants on the outcomes of HIV infection is an important step to be taken toward a better understanding of HIV/AIDS pathogenesis and pharmacogenomics. PMID:24932613

  11. HIV-1 Virological Synapse is not Simply a Copycat of the Immunological Synapse

    PubMed Central

    Vasiliver-Shamis, Gaia; Dustin, Michael L.; Hioe, Catarina E.

    2010-01-01

    The virological synapse (VS) is a tight adhesive junction between an HIV-infected cell and an uninfected target cell, across which virus can be efficiently transferred from cell to cell in the absence of cell-cell fusion. The VS has been postulated to resemble, in its morphology, the well-studied immunological synapse (IS). This review article discusses the structural similarities between IS and VS and the shared T cell receptor (TCR) signaling components that are found in the VS. However, the IS and the VS display distinct kinetics in disassembly and intracellular signaling events, possibly leading to different biological outcomes. Hence, HIV-1 exploits molecular components of IS and TCR signaling machinery to trigger unique changes in cellular morphology, migration, and activation that facilitate its transmission and cell-to-cell spread. PMID:20890395

  12. Antiretroviral Genotypic Resistance Mutations in HIV-1 Infected Korean Patients with Virologic Failure

    PubMed Central

    Chin, Bum Sik; Choi, Ju-Yeon; Choi, Jin Young; Kim, Gab Jung; Kee, Mee-Kyung; Kim, June Myung

    2009-01-01

    Resistance assays are useful in guiding decisions for patients experiencing virologic failure (VF) during highly-active antiretroviral therapy (HAART). We investigated antiretroviral resistance mutations in 41 Korean human immunodeficiency virus type 1 (HIV-1) infected patients with VF and observed immunologic/virologic response 6 months after HAART regimen change. Mean HAART duration prior to resistance assay was 45.3±27.5 months and commonly prescribed HAART regimens were zidovudine/lamivudine/nelfinavir (22.0%) and zidovudine/lamivudine/efavirenz (19.5%). Forty patients (97.6%) revealed intermediate to high-level resistance to equal or more than 2 antiretroviral drugs among prescribed HAART regimen. M184V/I mutation was observed in 36 patients (87.7%) followed by T215Y/F (41.5%) and M46I/L (34%). Six months after resistance assay and HAART regimen change, median CD4+ T cell count increased from 168 cells/µL (interquartile range [IQR], 62-253) to 276 cells/µL (IQR, 153-381) and log viral load decreased from 4.65 copies/mL (IQR, 4.18-5.00) to 1.91 copies/mL (IQR, 1.10-3.60) (P<0.001 for both values). The number of patients who accomplished viral load <400 copies/mL was 26 (63.4%) at 6 months follow-up. In conclusion, many Korean HIV-1 infected patients with VF are harboring strains with multiple resistance mutations and immunologic/virologic parameters are improved significantly after genotypic resistance assay and HAART regimen change. PMID:19949656

  13. Antiretroviral therapy, Interferon Sensitivity, and Virologic Set Point in HIV-Hepatitis C Virus Co-infected Patients

    PubMed Central

    Balagopal, A; Kandathil, AJ; Higgins, YH; Wood, J; Richer, J; Quinn, J; Eldred, L; Li, Z; Ray, SC; Sulkowski, MS; Thomas, DL

    2014-01-01

    HIV and hepatitis C virus (HCV) cause substantial mortality, especially in persons chronically infected with both viruses. HIV infection raises plasma HCV RNA levels and diminishes the response to exogenous alfa interferon (IFN). The degree to which antiretroviral (ART) control of infection overcomes these HIV effects is unknown. Participants with HIV-HCV co-infection were enrolled in a trial to measure HCV viral kinetics after IFN administration (ΔHCVIFN) twice: initially before (pre-ART) and then after (post-ART) HIV RNA suppression. Liver tissue was obtained 2–4 hours before each IFN injection to measure interferon stimulated genes (ISGs). Following ART, the ΔHCVIFN at 72 hours (ΔHCVIFN,72) increased in 15/19 (78.9%) participants by a median (IQR) of 0.11 log10 IU/mL (0.00–0.40;p<0.05). Increases in ΔHCVIFN,72 post-ART were associated with decreased hepatic expression of several ISGs (r=−0.68; p=0.001); a 2-fold reduction in a 4-gene ISG signature predicted an increase in ΔHCVIFN,72 of 0.78 log10 IU/mL (95%CI 0.36,1.20). Pre- and post-ART ΔHCVIFN,72 were closely associated (r=0.87;p<0.001). HCV virologic setpoint also changed after ART (ΔHCVART): transient median increases of 0.28 log10 IU/ml were followed by median decreases from baseline of 0.21 log10 IU/mL (p=0.002). A bivariate model of HIV RNA control (p<0.05) and increased expression of a 9-gene ISG signature (p<0.001) predicted the decreased ΔHCVART. Conclusion: ART is associated with lower post-IFN HCV RNA levels and that change is linked to reduced hepatic ISG expression. These data support recommendations to provide ART prior to IFN based treatment of HCV and may provide insights into the pathogenesis of HIV-HCV co-infection. PMID:24706559

  14. Virological and Immunological Status of the People Living with HIV/AIDS Undergoing ART Treatment in Nepal.

    PubMed

    Ojha, Chet Raj; Shakya, Geeta; Dumre, Shyam Prakash

    2016-01-01

    Antiretroviral therapy (ART) has increased the life span of the people living with HIV (PLHIV), but their virological and immunological outcomes are not well documented in Nepal. The study was conducted at a tertiary care center including 826 HIV-1 seropositive individuals undergoing ART for at least six months. Plasma viral load (HIV-1 RNA) was detected by Real Time PCR and CD4(+) T-lymphocyte (CD4(+)) counts were estimated by flow cytometry. The mean CD4(+) count of patients was 501 (95% CI = 325-579) cells/cumm, but about 35% of patients had CD4(+) T cell counts below 350 cells/cumm. With increasing age, average CD4(+) count was found to be decreasing (p = 0.005). Of the total cases, 82 (9.92%) were found to have virological failure (viral load: >1000 copies/ml). Tenofovir/Lamivudine/Efavirenz (TDF/3TC/EFV), the frequently used ART regimen in Nepal, showed virological failure in 11.34% and immunological failure in 37.17% of patients. Virological failure rate was higher among children < 15 years (14.5%) (p = 0.03); however, no association was observed between ART outcomes and gender or route of transmission. The study suggests there are still some chances of virological and immunological failures despite the success of highly active ART (HAART). PMID:27547761

  15. Virological and Immunological Status of the People Living with HIV/AIDS Undergoing ART Treatment in Nepal

    PubMed Central

    Dumre, Shyam Prakash

    2016-01-01

    Antiretroviral therapy (ART) has increased the life span of the people living with HIV (PLHIV), but their virological and immunological outcomes are not well documented in Nepal. The study was conducted at a tertiary care center including 826 HIV-1 seropositive individuals undergoing ART for at least six months. Plasma viral load (HIV-1 RNA) was detected by Real Time PCR and CD4+ T-lymphocyte (CD4+) counts were estimated by flow cytometry. The mean CD4+ count of patients was 501 (95% CI = 325–579) cells/cumm, but about 35% of patients had CD4+ T cell counts below 350 cells/cumm. With increasing age, average CD4+ count was found to be decreasing (p = 0.005). Of the total cases, 82 (9.92%) were found to have virological failure (viral load: >1000 copies/ml). Tenofovir/Lamivudine/Efavirenz (TDF/3TC/EFV), the frequently used ART regimen in Nepal, showed virological failure in 11.34% and immunological failure in 37.17% of patients. Virological failure rate was higher among children < 15 years (14.5%) (p = 0.03); however, no association was observed between ART outcomes and gender or route of transmission. The study suggests there are still some chances of virological and immunological failures despite the success of highly active ART (HAART). PMID:27547761

  16. Alternative methods to analyse the impact of HIV mutations on virological response to antiviral therapy

    PubMed Central

    Wittkop, Linda; Commenges, Daniel; Pellegrin, Isabelle; Breilh, Dominique; Neau, Didier; Lacoste, Denis; Pellegrin, Jean-Luc; Chêne, Geneviève; Dabis, François; Thiébaut, Rodolphe

    2008-01-01

    Background Principal component analysis (PCA) and partial least square (PLS) regression may be useful to summarize the HIV genotypic information. Without pre-selection each mutation presented in at least one patient is considered with a different weight. We compared these two strategies with the construction of a usual genotypic score. Methods We used data from the ANRS-CO3 Aquitaine Cohort Zephir sub-study. We used a subset of 87 patients with a complete baseline genotype and plasma HIV-1 RNA available at baseline and at week 12. PCA and PLS components were determined with all mutations that had prevalences >0. For the genotypic score, mutations were selected in two steps: 1) p-value < 0.01 in univariable analysis and prevalences between 10% and 90% and 2) backwards selection procedure based on the Cochran-Armitage Test. The predictive performances were compared by means of the cross-validated area under the receiver operating curve (AUC). Results Virological failure was observed in 46 (53%) patients at week 12. Principal components and PLS components showed a good performance for the prediction of virological response in HIV infected patients. The cross-validated AUCs for the PCA, PLS and genotypic score were 0.880, 0.868 and 0.863, respectively. The strength of the effect of each mutation could be considered through PCA and PLS components. In contrast, each selected mutation contributes with the same weight for the calculation of the genotypic score. Furthermore, PCA and PLS regression helped to describe mutation clusters (e.g. 10, 46, 90). Conclusion In this dataset, PCA and PLS showed a good performance but their predictive ability was not clinically superior to that of the genotypic score. PMID:18945369

  17. Low-frequency drug-resistant HIV-1 and risk of virological failure to first-line NNRTI-based ART: a multicohort European case–control study using centralized ultrasensitive 454 pyrosequencing

    PubMed Central

    Cozzi-Lepri, Alessandro; Noguera-Julian, Marc; Di Giallonardo, Francesca; Schuurman, Rob; Däumer, Martin; Aitken, Sue; Ceccherini-Silberstein, Francesca; D'Arminio Monforte, Antonella; Geretti, Anna Maria; Booth, Clare L.; Kaiser, Rolf; Michalik, Claudia; Jansen, Klaus; Masquelier, Bernard; Bellecave, Pantxika; Kouyos, Roger D.; Castro, Erika; Furrer, Hansjakob; Schultze, Anna; Günthard, Huldrych F.; Brun-Vezinet, Francoise; Paredes, Roger; Metzner, Karin J.; Paredes, Roger; Metzner, Karin J.; Cozzi-Lepri, Alessandro; Schuurman, Rob; Brun-Vezinet, Francoise; Günthard, Huldrych; Ceccherini-Silberstein, Francesca; Kaiser, Rolf; Geretti, Anna Maria; Brockmeyer, Norbert; Masquelier, Bernard; Dabis, F.; Bruyand, M.; Chêne, G.; Dabis, F.; Lawson-Ayayi, S.; Thiébaut, R.; Wittkop, L.; André, K.; Bonnal, F.; Bonnet, F.; Bernard, N.; Caunègre, L.; Cazanave, C.; Ceccaldi, J.; Chossat, I.; Courtaud, K.; Dauchy, F. A.; De Witte, S.; Dupon, M.; Dupont, A.; Duffau, P.; Dutronc, H.; Farbos, S.; Gaborieau, V.; Gemain, M. C.; Gerard, Y.; Greib, C.; Hessamfar, M.; Lacoste, D.; Lataste, P.; Lazaro, E.; Longy-Boursier, M.; Malvy, D.; Meraud, J. P.; Mercié, P.; Monlun, E.; Morlat, P.; Neau, D.; Ochoa, A.; Pellegrin, J. L.; Pistone, T.; Receveur, M. C.; Schmeltz, J. Roger; Tchamgoué, S.; Vandenhende, M. A.; Vareil, M.O.; Viallard, J. F.; Moreau, J. F.; Pellegrin, I.; Fleury, H.; Lafon, M. E.; Masquelier, B.; Reigadas, S.; Trimoulet, P.; Bouchet, S.; Breilh, D.; Molimard, M.; Titier, K.; Haramburu, F.; Miremont-Salamé., G.; Blaizeau, M. J.; Decoin, M.; Delaune, J.; Delveaux, S.; D'Ivernois, C.; Hanapier, C.; Leleux, O.; Lenaud, E.; Uwamaliya-Nziyumvira, B.; Sicard, X.; Geffard, S.; Le Marec, F.; Conte, V.; Frosch, A.; Leray, J.; Palmer, G.; Touchard, D.; Bonnet, F.; Breilh, D.; Chêne, G.; Dabis, F.; Dupon, M.; Fleury, H.; Malvy, D.; Mercié, P.; Morlat, P.; Neau, D.; Pellegrin, I.; Pellegrin, J. L.; Bouchet, S.; Gaborieau, V.; Lacoste, D.; Tchamgoué, S.; Thiébaut, R.; Losso, M.; Kundro, M.; Ramos Mejia, J. M.; Vetter, N.; Zangerle, R.; Karpov, I.; Vassilenko, A.; Mitsura, V. M.; Suetnov, O.; Clumeck, N.; De Wit, S.; Delforge, M.; Florence, E.; Vandekerckhove, L.; Hadziosmanovic, V.; Kostov, K.; Begovac, J.; Machala, L.; Jilich, D.; Sedlacek, D.; Nielsen, J.; Kronborg, G.; Benfield, T.; Larsen, M.; Gerstoft, J.; Katzenstein, T.; Hansen, A.-B. E.; Skinhøj, P.; Pedersen, C.; Ostergaard, L.; Dragsted, U. B.; Nielsen, L. N.; Zilmer, K.; Smidt, Jelena; Ristola, M.; Katlama, C.; Viard, J. P.; Girard, P. M.; Vanhems, P.; Pradier, C.; Dabis, F.; Neau, D.; Duvivier, C.; Rockstroh, J.; Schmidt, R.; van Lunzen, J.; Degen, O.; Stellbrink, H. J.; Bickel, M.; Bogner, J.; Fätkenheuer, G.; Kosmidis, J.; Gargalianos, P.; Xylomenos, G.; Perdios, J.; Sambatakou, H.; Banhegyi, D.; Gottfredsson, M.; Mulcahy, F.; Yust, I.; Turner, D.; Burke, M.; Pollack, S.; HassounRambam, G.; Elinav, H.; HaouziHadassah, M.; EspositoI, R.; Mazzotta, F.; Vullo, V.; Moroni, M.; Andreoni, M.; Angarano, G.; Antinori, A.; Castelli, F.; Cauda, R.; Di Perri, G.; Galli, M.; Iardino, R.; Ippolito, G.; Lazzarin, A.; Perno, C. F.; von Schloesser, F.; Viale, P.; Monforte, A. D'Arminio; Antinori, A.; Castagna, A.; Ceccherini-Silberstein, F.; Cozzi-Lepri, A.; Girardi, E.; Lo Caputo, S.; Mussini, C.; Puoti, M.; Andreoni, M.; Ammassari, A.; Antinori, A.; Balotta, C.; Bonfanti, P.; Bonora, S.; Borderi, M.; Capobianchi, M. R.; Castagna, A.; Ceccherini-Silberstein, F.; Cingolani, A.; Cinque, P.; Cozzi-Lepri, A.; De Luca, A.; Di Biagio, A.; Girardi, E.; Gianotti, N.; Gori, A.; Guaraldi, G.; Lapadula, G.; Lichtner, M.; Lo Caputo, S.; Madeddu, G.; Maggiolo, F.; Marchetti, G.; Marcotullio, S.; Monno, L.; Mussini, C.; Puoti, M.; Quiros Roldan, E.; Rusconi, S.; Cozzi-Lepri, A.; Cicconi, P.; Fanti, I.; Formenti, T.; Galli, L.; Lorenzini, P.; Carletti, F.; Carrara, S.; Castrogiovanni, A.; Di Caro, A.; Petrone, F.; Prota, G.; Quartu, S.; Giacometti, A.; Costantini, A.; Mazzoccato, S.; Angarano, G.; Monno, L.; Santoro, C.; Maggiolo, F.; Suardi, C.; Viale, P.; Vanino, E.; Verucchi, G.; Castelli, F.; Quiros Roldan, E.; Minardi, C.; Quirino, T.; Abeli, C.; Manconi, P. E.; Piano, P.; Vecchiet, J.; Falasca, K.; Sighinolfi, L.; Segala, D.; Mazzotta, F.; Lo Caputo, S.; Cassola, G.; Viscoli, C.; Alessandrini, A.; Piscopo, R.; Mazzarello, G.; Mastroianni, C.; Belvisi, V.; Bonfanti, P.; Caramma, I.; Chiodera, A.; Castelli, A. P.; Galli, M.; Lazzarin, A.; Rizzardini, G.; Puoti, M.; D'Arminio Monforte, A.; Ridolfo, A. L.; Piolini, R.; Castagna, A.; Salpietro, S.; Carenzi, L.; Moioli, M. C.; Tincati, C.; Marchetti, G.; Mussini, C.; Puzzolante, C.; Gori, A.

    2015-01-01

    Objectives It is still debated if pre-existing minority drug-resistant HIV-1 variants (MVs) affect the virological outcomes of first-line NNRTI-containing ART. Methods This Europe-wide case–control study included ART-naive subjects infected with drug-susceptible HIV-1 as revealed by population sequencing, who achieved virological suppression on first-line ART including one NNRTI. Cases experienced virological failure and controls were subjects from the same cohort whose viraemia remained suppressed at a matched time since initiation of ART. Blinded, centralized 454 pyrosequencing with parallel bioinformatic analysis in two laboratories was used to identify MVs in the 1%–25% frequency range. ORs of virological failure according to MV detection were estimated by logistic regression. Results Two hundred and sixty samples (76 cases and 184 controls), mostly subtype B (73.5%), were used for the analysis. Identical MVs were detected in the two laboratories. 31.6% of cases and 16.8% of controls harboured pre-existing MVs. Detection of at least one MV versus no MVs was associated with an increased risk of virological failure (OR = 2.75, 95% CI = 1.35–5.60, P = 0.005); similar associations were observed for at least one MV versus no NRTI MVs (OR = 2.27, 95% CI = 0.76–6.77, P = 0.140) and at least one MV versus no NNRTI MVs (OR = 2.41, 95% CI = 1.12–5.18, P = 0.024). A dose–effect relationship between virological failure and mutational load was found. Conclusions Pre-existing MVs more than double the risk of virological failure to first-line NNRTI-based ART. PMID:25336166

  18. Systematic Review of HIV Transmission between Heterosexual Serodiscordant Couples where the HIV-Positive Partner Is Fully Suppressed on Antiretroviral Therapy

    PubMed Central

    Loutfy, Mona R.; Wu, Wei; Letchumanan, Michelle; Bondy, Lise; Antoniou, Tony; Margolese, Shari; Zhang, Yimeng; Rueda, Sergio; McGee, Frank; Peck, Ryan; Binder, Louise; Allard, Patricia; Rourke, Sean B.; Rochon, Paula A.

    2013-01-01

    Background The risk of sexual HIV transmission in serodiscordant couples when the HIV-positive partner has full virologic suppression on combination antiretroviral therapy (cART) is debated. This study aims to systematically review observational studies and randomized controlled trials (RCTs), evaluating rates of sexual HIV transmission between heterosexual serodiscordant couples when the HIV-positive partner has full suppression on cART. Methods and Findings We searched major bibliographic databases to November 2012 for relevant observational studies and RCTs without language restrictions. Conference proceedings, key journals and bibliographies were also searched. Studies reporting HIV transmission rates, cART histories and viral loads of the HIV-positive partners were included. Two reviewers extracted methodologic characteristics and outcomes. Of 20,252 citations, 3 studies met all eligibility criteria with confirmed full virologic suppression in the HIV-positive partner. We included 3 additional studies (2 cohort studies, 1 RCT) that did not confirm viral suppression in the HIV-positive partner at transmission in a secondary meta-analysis. Methodologic quality was reasonable. The rate of transmission in the 3 studies confirming virologic suppression was 0 per 100 person-years (95% CI = 0–0.05), with low heterogeneity (I2 = 0%). When we included the 3 studies that did not confirm virologic suppression, the rate of transmission was 0.14 per 100 person-years (95%CI = 0.04–0.31) (I2 = 0%). In a sensitivity analysis including all 6 studies, the rate of transmission was 0 per 100 person-years (95%CI = 0–0.01) after omitting all transmissions with known detectable or unconfirmed viral loads, as full suppression in these cases was unlikely. Limitations included lack of data on same-sex couples, type of sexual intercourse (vaginal vs. anal), direction of HIV transmission, exact viral load at the time of transmission, sexually transmitted

  19. NRTI Sparing Therapy in Virologically Controlled HIV-1 Infected Subjects: Results of a Controlled, Randomized Trial (Probe).

    PubMed

    Maggiolo, Franco; Di Filippo, Elisa; Valenti, Daniela; Ortega, Paula S; Callegaro, Annapaola

    2016-05-01

    Dual treatments could help clinicians to avoid drawbacks and toxicities due to the nucleosidic backbone, while maintaining the efficacy and convenience of robust combination antiretroviral therapy (cART). We explored the combination of rilpivirine plus boosted darunavir (DRV) as an option when switching from standard cART in patients who are virologically suppressed. In this randomized, open-label, proof-of-concept, noninferiority trial, we recruited patients aged 18 years or older with chronic HIV-1 infection and on a stable, effective (>6 months) protease inhibitor-based cART including a nucleosidic backbone. The primary endpoint was noninferiority of the virological response between treatment groups, according to FDA snapshot approach. Sixty patients were randomly allocated to dual treatment with rilpivirine plus boosted DRV or to continue their ongoing triple treatment. Noninferiority was shown at the prespecified level of -12% both at 24 and 48 weeks. At week 24, 100% of patients in the dual arm presented a blood HIV-RNA level <50 copies per milliliter compared with 90.1% in the triple drug arm (difference 9.9%, 95% CI: -0.7 to 20.7), whereas, at 48 weeks, the same proportions were 96.7% and 93.4%, respectively (difference 3.3%, 95% CI: -7.15 to 13.5). The mean change in CD4 cell count from baseline was 6.0 cells per microliter (SD, 184) for dual treatment and 16.5 cells per microliter (SD, 142) for triple treatment. A relevant decrement in CD838HLADR cells was observed in both arms. The reduction was, however, significantly more pronounced in the dual-therapy arm. At week 48, the CD838HLADR cell count was 3.4% (SD, 2.2) in the dual-therapy arm and 5.2% (SD, 3.1) in the triple arm (P = 0.018). None of the patients developed severe adverse events nor had to stop treatment because of adverse events or presented grade 3-4 laboratory abnormalities. A greater reduction of bone stiffness (-2.25; SD, 7.1) was observed in patients randomized to continue triple therapy

  20. Comparison of Adherence Monitoring Tools and Correlation to Virologic Failure in a Pediatric HIV Clinical Trial

    PubMed Central

    Intasan, Jintana; Vonthanak, Saphonn; Kosalaraksa, Pope; Hansudewechakul, Rawiwan; Kanjanavanit, Suparat; Ngampiyaskul, Chaiwat; Wongsawat, Jurai; Luesomboon, Wicharn; Apornpong, Tanakorn; Kerr, Stephen; Ananworanich, Jintanat; Puthanakit, Thanyawee

    2014-01-01

    Abstract There is no consensus on a gold standard for monitoring adherence to antiretroviral therapy (ART). We compared different adherence monitoring tools in predicting virologic failure as part of a clinical trial. HIV-infected Thai and Cambodian children aged 1–12 years (N=207) were randomized to immediate-ART or deferred-ART until CD4% <15%. Virologic failure (VF) was defined as HIV-RNA >1000 copies/mL after ≥6 months of ART. Adherence monitoring tools were: (1) announced pill count, (2) PACTG adherence questionnaire (form completed by caregivers), and (3) child self-report (self-reporting from children or caregivers to direct questioning by investigators during the clinic visit) of any missed doses in the last 3 days and in the period since the last visit. The Kappa statistic was used to describe agreement between each tool. The median age at ART initiation was 7 years with median CD4% 17% and HIV-RNA 5.0 log10copies/mL and 92% received zidovudine/lamivudine/nevirapine. Over 144 weeks, 13% had VF. Mean adherence by announced pill count before VF in VF children was 92% compared to 98% in children without VF (p=0.03). Kappa statistics indicated slight to fair agreement between tools. In multivariate analysis adjusting for gender, treatment arm ethnicity and caregiver education, significant predictors of VF were poor adherence by announced pill count (OR 4.56; 95%CI 1.78–11.69), reporting any barrier to adherence in the PACTG adherence questionnaire (OR 7.08; 95%CI 2.42–20.73), and reporting a missed dose in the 24 weeks since the last HIV-RNA assessment (OR 8.64; 95%CI 1.96–38.04). In conclusion, we recommend the child self-report of any missed doses since last visit for use in HIV research and in routine care settings, because it is easy and quick to administer and a strong association with development of VF. PMID:24901463

  1. Comparison of adherence monitoring tools and correlation to virologic failure in a pediatric HIV clinical trial.

    PubMed

    Intasan, Jintana; Bunupuradah, Torsak; Vonthanak, Saphonn; Kosalaraksa, Pope; Hansudewechakul, Rawiwan; Kanjanavanit, Suparat; Ngampiyaskul, Chaiwat; Wongsawat, Jurai; Luesomboon, Wicharn; Apornpong, Tanakorn; Kerr, Stephen; Ananworanich, Jintanat; Puthanakit, Thanyawee

    2014-06-01

    There is no consensus on a gold standard for monitoring adherence to antiretroviral therapy (ART). We compared different adherence monitoring tools in predicting virologic failure as part of a clinical trial. HIV-infected Thai and Cambodian children aged 1-12 years (N=207) were randomized to immediate-ART or deferred-ART until CD4% <15%. Virologic failure (VF) was defined as HIV-RNA >1000 copies/mL after ≥6 months of ART. Adherence monitoring tools were: (1) announced pill count, (2) PACTG adherence questionnaire (form completed by caregivers), and (3) child self-report (self-reporting from children or caregivers to direct questioning by investigators during the clinic visit) of any missed doses in the last 3 days and in the period since the last visit. The Kappa statistic was used to describe agreement between each tool. The median age at ART initiation was 7 years with median CD4% 17% and HIV-RNA 5.0 log(10)copies/mL and 92% received zidovudine/lamivudine/nevirapine. Over 144 weeks, 13% had VF. Mean adherence by announced pill count before VF in VF children was 92% compared to 98% in children without VF (p=0.03). Kappa statistics indicated slight to fair agreement between tools. In multivariate analysis adjusting for gender, treatment arm ethnicity and caregiver education, significant predictors of VF were poor adherence by announced pill count (OR 4.56; 95%CI 1.78-11.69), reporting any barrier to adherence in the PACTG adherence questionnaire (OR 7.08; 95%CI 2.42-20.73), and reporting a missed dose in the 24 weeks since the last HIV-RNA assessment (OR 8.64; 95%CI 1.96-38.04). In conclusion, we recommend the child self-report of any missed doses since last visit for use in HIV research and in routine care settings, because it is easy and quick to administer and a strong association with development of VF. PMID:24901463

  2. Durability and Effectiveness of Maraviroc-Containing Regimens in HIV-1-Infected Individuals with Virological Failure in Routine Clinical Practice

    PubMed Central

    Potard, Valérie; Reynes, Jacques; Ferry, Tristan; Aubin, Céline; Finkielsztejn, Laurent; Yazdanpanah, Yazdan; Costagliola, Dominique

    2015-01-01

    Introduction Limited data are available on the durability and effectiveness of maraviroc in routine clinical practice. We assessed the durability of maraviroc-containing regimens during a 30-month period, as well as their immunovirological and clinical efficacy, according to viral tropism in treatment-experienced individuals with viral load (VL) >50 copies/ml in the French Hospital Database on HIV. Methods Virological success was defined as VL<50 copies/ml, immunological success as a confirmed increase of at least 100 CD4 cells/mm3 measured twice at least one month apart, and clinical failure as hospitalization for a non-AIDS event, an AIDS event, or death. Multivariable Cox regression models adjusted for potential confounders were used to assess the influence of viral tropism on durability, the immunovirological responses, and clinical outcome. Results 356 individuals started maraviroc with VL>50 copies/ml of whom 223 harbored R5 viruses, 44 non-R5 viruses and 89 viruses of unknown tropism. Individuals with non-R5 viruses were more likely than individuals with R5 viruses to discontinue maraviroc (75% vs 34%, p<0.0001). At 30 months, the estimated rates of virological and immunological success were respectively 89% and 51% in individuals with R5 viruses and 48% and 23% in individuals with non-R5 viruses. In multivariable analysis, non-R5 viruses were associated with a lower likelihood of both virological success (hazard ratio (HR): 0.42; 95% confidence interval (CI), 0.25–0.70) and immunological success (HR: 0.37; 95% CI, 0.18–0.77). No difference in clinical outcome was found between individuals with R5 and non-R5 viruses. The effectiveness of maraviroc-containing regimens in individuals with unknown viral tropism was not significantly different from that in individuals with R5 viruses. A limitation of the study is the absence of genotypic susceptibility score. Conclusion In this observational study, maraviroc-containing regimens yielded high rates of viral

  3. Everything fine so far? Physical and mental health in HIV-infected patients with virological success and long-term exposure to antiretroviral therapy

    PubMed Central

    Erdbeer, Gesa; Sabranski, Michael; Sonntag, Ina; Stoehr, Albrecht; Horst, Heinz-A.; Plettenberg, Andreas; Schewe, Knud; Unger, Stefan; Stellbrink, Hans-J.; Fenske, Stefan; Hoffmann, Christian

    2014-01-01

    Introduction Little is known about the well-being on long-term exposure to antiretroviral therapy. The ACTG Augmented Symptoms Distress Module (ASDM) is a validated tool which measures the presence of a total of 22 symptoms seen with HIV and quantifies the extent to which they cause distress to the patient. Methods ELBE was a cross-sectional study that consecutively included adult HIV-infected patients presenting with viral suppression (<50 HIV RNA copies/mL) and ART exposure for at least five years. Patients were evaluated by four different questionnaires, including ASDM. Results Of a total of 894 patients included in the three participating ELBE centres, complete data on ASDM were available for 698 patients (626 male, 69 female, 3 transsexual). Median age was 49.7 years (range, 23.3–82.5 years) and median exposure to ART was 11.5 years (range, 5–28 years). Median CD4 T-cell counts had increased from a CD4 nadir of 180 to currently 640 cells/µL. Despite immunological and virological success, a high degree of symptom-related distress was noted in this patient population. In total, 63.8% and 36.3% of the patients had at least one “bothersome” or one “very bothersome” symptom, respectively. The symptoms most frequently reported to be “bothersome” or “very bothersome” were fatigue and energy loss (18.5% and 11.0% respectively), insomnia (12.8% and 11.6%), sadness and depression (13.0% and 10.0%), sexual dysfunction (12.0% and 10.0%), and changes in body appearance (11.0% and 10.9%). There was no association between the degree of symptom-related distress and gender, age or CD4 T-cell nadir. However, the history of AIDS-defining illnesses, comorbidities such as depression but also the duration of ART were significantly associated with a higher overall symptom summary score and with a higher frequency of symptoms. For example, in patients with at least 15 years of ART exposure, only 27.3% of the patients did not report at least one

  4. Clinical and Virological Efficacy of Etravirine Plus Two Active Nucleos(t)ide Analogs in an Heterogeneous HIV-Infected Population

    PubMed Central

    López-Cortés, Luis F.; Viciana, Pompeyo; Girón-González, José A.; Romero-Palacios, Alberto; Márquez-Solero, Manuel; Martinez-Perez, Maria A.; López-Ruz, Miguel A.; de la Torre-Lima, Javier; Téllez-Pérez, Francisco; Delgado-Fernández, Marcial; Garcia-Lázaro, Milagros; Lozano, Fernando; Mohamed-Balghata, Mohamed O.

    2014-01-01

    Etravirine (ETV) is recommended in combination with a boosted protease inhibitor plus an optimized background regimen for salvage therapy, but there is limited experience with its use in combination with two nucleos(t)ide reverse-transcriptase inhibitors (NRTIs). This multicenter study aimed to assess the efficacy of this combination in two scenarios: group A) subjects without virologic failure on or no experience with non-nucleoside reverse-transcriptase inhibitors (NNRTIs) switched due to adverse events and group B) subjects switched after a virologic failure on an efavirenz- or nevirapine-based regimen. The primary endpoint was efficacy at 52 weeks analysed by intention-to-treat. Virologic failure was defined as the inability to suppress plasma HIV-RNA to <50 copies/mL after 24 weeks on treatment, or a confirmed viral load >200 copies/mL in patients who had previously achieved a viral suppression or had an undetectable viral load at inclusion. Two hundred eighty seven patients were included. Treatment efficacy rates in group A and B were 88.0% (CI95, 83.9–92.1%) and 77.4% (CI95, 65.0–89.7%), respectively; the rates reached 97.2% (CI95, 95.1–99.3%) and 90.5% (CI95, 81.7–99.3), by on-treatment analysis. The once-a-day ETV treatment was as effective as the twice daily dosing regimen. Grade 1–2 adverse events were observed motivating a treatment switch in 4.2% of the subjects. In conclusion, ETV (once- or twice daily) plus two analogs is a suitable, well-tolerated combination both as a switching strategy and after failure with first generation NNRTIs, ensuring full drug activity. Trial registration ClinicalTrials.gov NCT01437241 PMID:24836963

  5. HIV-1 Reservoirs During Suppressive Therapy.

    PubMed

    Barton, Kirston; Winckelmann, Anni; Palmer, Sarah

    2016-05-01

    The introduction of antiretroviral therapy (ART) 20 years ago has dramatically reduced morbidity and mortality associated with HIV-1. Initially there was hope that ART would be curative, but it quickly became clear that even though ART was able to restore CD4(+) T cell counts and suppress viral loads below levels of detection, discontinuation of treatment resulted in a rapid rebound of infection. This is due to persistence of a small reservoir of latently infected cells with a long half-life, which necessitates life-long ART. Over the past few years, significant progress has been made in defining and characterizing the latent reservoir of HIV-1, and here we review how understanding the latent reservoir during suppressive therapy will lead to significant advances in curative approaches for HIV-1. PMID:26875617

  6. Early virological failure and the development of antiretroviral drug resistance mutations in HIV-infected Ugandan children

    PubMed Central

    Ruel, Theodore D.; Kamya, Moses R.; Li, Pelin; Pasutti, William; Charlebois, Edwin D.; Liegler, Teri; Dorsey, Grant; Rosenthal, Philip J.; Havlir, Diane V.; Wong, Joseph K.; Achan, Jane

    2011-01-01

    Background Without virologic testing, HIV-infected African children starting antiretroviral (ARV)-therapy are at risk for undetected virological failure and the development of ARV-resistance. We sought to determine the prevalence of early virologic failure (EVF), to characterize the evolution of ARV-resistance mutations, and to predict the impact on second-line therapy. Methods The prevalence of EVF (HIV-RNA >400 copies/mL on sequential visits after 6 months of therapy) was identified among 120 HIV-infected Ugandan children starting ARV-therapy. ARV-mutations were identified by population sequencing of HIV-1 pol in sequential archived specimens. Composite discrete genotypic susceptibility scores (dGSS) were determined for second-line ARV-regimens. Results EVF occurred in 16 (13%) children and persisted throughout a median (IQR) 938 (760-1066) days of follow-up. M184V and non-nucleoside-reverse-transcriptase-inhibitor-associated mutations emerged within 6 months of EVF; thymidine-analog-mutations arose after 12 months. Worse dGSS scores correlated with increasing duration of failure (Spearman R = −0.47, p=0.001). Only 1 child met World Health Organization CD4 criteria for ARV-failure at the time of EVF or during the follow-up period. Conclusions A significant portion of HIV-infected African children experience EVF that would be undetected using CD4/clinical monitoring and resulted in the accumulation of ARV-mutations that could compromise second line therapy options. PMID:21099693

  7. High-Multiplicity HIV-1 Infection and Neutralizing Antibody Evasion Mediated by the Macrophage-T Cell Virological Synapse

    PubMed Central

    Duncan, Christopher J. A.; Williams, James P.; Schiffner, Torben; Gärtner, Kathleen; Ochsenbauer, Christina; Kappes, John; Russell, Rebecca A.; Frater, John

    2014-01-01

    ABSTRACT Macrophage infection is considered to play an important role in HIV-1 pathogenesis and persistence. Using a primary cell-based coculture model, we show that monocyte-derived macrophages (MDM) efficiently transmit a high-multiplicity HIV-1 infection to autologous CD4+ T cells through a viral envelope glycoprotein (Env) receptor- and actin-dependent virological synapse (VS), facilitated by interactions between ICAM-1 and LFA-1. Virological synapse (VS)-mediated transmission by MDM results in high levels of T cell HIV-1 integration and is 1 to 2 orders of magnitude more efficient than cell-free infection. This mode of cell-to-cell transmission is broadly susceptible to the activity of CD4 binding site (CD4bs) and glycan or glycopeptide epitope-specific broadly neutralizing monoclonal antibodies (bNMAbs) but shows resistance to bNMAbs targeting the Env gp41 subunit membrane-proximal external region (MPER). These data define for the first time the structure and function of the macrophage-to-T cell VS and have important implications for bNMAb activity in HIV-1 prophylaxis and therapy. IMPORTANCE in vivo PMID:24307588

  8. Replication Capacity in Relation to Immunologic and Virologic Outcomes in HIV-1 infected, Treatment-Naïve Subjects

    PubMed Central

    Skowron, Gail; Spritzler, John G.; Weidler, Jodi; Robbins, Gregory K.; Johnson, Victoria A.; Chan, Ellen S.; Asmuth, David M.; Gandhi, Rajesh T.; Lie, Yolanda; Bates, Michael; Pollard, Richard B.

    2012-01-01

    Objectives To evaluate the association between baseline (BL) replication capacity (RC) [RCBL] and immunologic/virologic parameters (at BL and after 48 weeks on therapy) in HIV-1 infected subjects initiating antiretroviral therapy. Methods RCBL was determined using a modified Monogram PhenoSense HIV drug susceptibility assay on plasma HIV-1 from 321 treatment-naïve subjects from ACTG384. Univariate and multivariable analyses were performed to determine the association of RCBL with BL and on-therapy virologic and immunologic outcomes. Results Higher RCBL was associated with lower baseline CD4 (CD4BL) (r=−0.23, p<0.0001), higher baseline HIV-1 (RNABL) (r=0.25, p<0.0001), higher CD4BL activation percent (r=0.23, p<0.0001) and lower CD4BL memory count (r=−0.21, p=0.0002). In a multivariable model, week 48 CD4 increase (ΔCD448) was associated with lower CD4BL memory count and higher CD4BL naive percent (p=0.004, p=0.015, respectively). The interaction between CD4BL and RCBL was significant (p=0.018), with a positive association between RCBL and ΔCD448 in subjects with higher CD4BL, and a negative association at lower absCD4BL. Conclusions At baseline, higher RC was significantly associated with higher HIV-1 RNA, higher CD4 cell activation, lower CD4 cell count, and lower CD4 memory cell count. These factors may interact, directly or indirectly, to modify the extent to which CD4 recovery occurs in patients starting antiretroviral therapy at different baseline CD4 counts. PMID:19194319

  9. Full Viral Suppression, Low-Level Viremia, and Quantifiable Plasma HIV-RNA at the End of Pregnancy in HIV-Infected Women on Antiretroviral Treatment

    PubMed Central

    Baroncelli, Silvia; Pirillo, Maria F.; Tamburrini, Enrica; Guaraldi, Giovanni; Pinnetti, Carmela; Antoni, Anna Degli; Galluzzo, Clementina M.; Stentarelli, Chiara; Amici, Roberta

    2015-01-01

    Abstract There is limited information on full viral suppression and low-level HIV-RNA viremia in HIV-infected women at the end of pregnancy. We investigated HIV-RNA levels close to delivery in women on antiretroviral treatment in order to define rates of complete suppression, low-level viremia, and quantifiable HIV-RNA, exploring as potential determinants some clinical and viroimmunological variables. Plasma samples from a national study in Italy, collected between 2003 and 2012, were used. According to plasma HIV-RNA levels, three groups were defined: full suppression (target not detected), low-level viremia (target detected but <37 copies/ml), and quantifiable HIV-RNA (≥37 copies/ml). Multivariable logistic regression was used to define determinants of full viral suppression and of quantifiable HIV-RNA. Among 107 women evaluated at a median gestational age of 35 weeks, 90 (84.1%) had HIV-RNA <37 copies/ml. Most of them (59/90, 65.6%) had full suppression, with the remaining (31/90, 34.4%) showing low-level viremia (median: 11.9 copies/ml; IQR 7.4–16.3). Among the 17 women with quantifiable viral load, median HIV-RNA was 109 copies/ml (IQR 46–251), with only one case showing resistance (mutation M184V; rate: 9.1%). In multivariable analyses, women with higher baseline HIV-RNA levels and with hepatitis C virus (HCV) coinfection were significantly more likely to have quantifiable HIV-RNA in late pregnancy. Full viral suppression was significantly more likely with nonnucleoside reverse transcriptase inhibitor (NNRTI)-based regimens and significantly less likely with higher HIV-RNA in early pregnancy. No cases of HIV transmission occurred. In conclusion, HIV-infected pregnant women showed a high rate of viral suppression and a low resistance rate before delivery. In most cases no target HIV-RNA was detected in plasma, suggesting a low risk of subsequent virological rebound and development of resistance. Women with high levels of HIV-RNA in early pregnancy and

  10. Virological Response and Drug Resistance 1 and 2 Years Post-Partum in HIV-Infected Women Initiated on Life-Long Antiretroviral Therapy in Malawi.

    PubMed

    Mancinelli, Sandro; Galluzzo, Clementina Maria; Andreotti, Mauro; Liotta, Giuseppe; Jere, Haswel; Sagno, Jean-Baptiste; Amici, Roberta; Pirillo, Maria Franca; Scarcella, Paola; Marazzi, Maria Cristina; Vella, Stefano; Palombi, Leonardo; Giuliano, Marina

    2016-08-01

    The objective of this study was to determine the virological response and the possible emergence of drug resistance at 1 and 2 years postpartum in HIV-positive pregnant women enrolled under the Option B approach and meeting the criteria for treatment. In the study, women with baseline CD4(+) <350/mm(3) received a combination of stavudine, lamivudine, and nevirapine during pregnancy (from week 25 of gestation) and continued it indefinitely after delivery. HIV-RNA was measured at 12 and 24 months postpartum. Drug resistance mutations were assessed in those with HIV-RNA >50 copies/ml. Baseline resistance mutations were assessed in the entire cohort. A total of 107 women were studied. At baseline, resistance mutations were seen in 6.6% of the women. At 12 months, 26.7% of the women had >50 copies/ml and among them 12.9% had virological failure (HIV-RNA >1,000 copies/ml). At 24 months, detectable HIV-RNA was seen in 28.3% of the women and virological failure in 10.1% of the women. Resistance mutations (mainly non-nucleoside reverse transcriptase inhibitors mutations) were seen in 40% of the women with detectable HIV-RNA. Baseline mutations did not correlate with virological failure or the emergence of resistance at later time points. Virological failure 2 years postpartum and emergence of resistance were rare in this cohort of HIV-infected women. These findings are reassuring in the light of the new strategies for the prevention of mother-to-child HIV transmission, recommending life-long antiretroviral therapy administration. PMID:27067142

  11. Viral suppression in adolescents on antiretroviral treatment: A review of the literature and critical appraisal of methodological challenges

    PubMed Central

    Ferrand, Rashida A; Briggs, Datonye; Ferguson, Jane; Penazzato, Martina; Armstrong, Alice; MacPherson, Peter; Ross, David A; Kranzer, Katharina

    2016-01-01

    Background Medication adherence is often sub-optimal for adolescents with HIV, and establishing correct weight-based antiretroviral therapy dosing is difficult, contributing to virological failure. This review aimed to determine the proportion of adolescents achieving virological suppression after initiating ART. Methods MEDLINE, EMBASE and Web of Science databases were searched. Studies published between January 2004 and September 2014 including ≥ 50 adolescents taking ART and reporting on the proportion of virological suppressed participants were included. Results From a total of 5316 potentially relevant citations, 20 studies were included. Only 8 studies reported the proportion of adolescents that were virologically suppressed at a specified time point. The proportion of adolescents with virological suppression at 12 months ranged from 27%-89%. Conclusion Adolescent achievement of HIV virological suppression was highly variable. Improved reporting of virological outcomes from a wider range of settings is required to support efforts to improve HIV care and treatment for adolescents. PMID:26681359

  12. Pretreatment HIV-1 drug resistance is strongly associated with virologic failure in HIV-infected patients receiving partly active antiretroviral regimens

    PubMed Central

    Parikh, Urvi M; Mellors, John W

    2016-01-01

    The scale-up of antiretroviral therapy in sub-Saharan Africa has significantly reduced mortality from AIDS. Hamers et al. explores the impact of pretreatment HIV-1 drug resistance on virologic failure, immunologic response, and acquisition of drug resistance after 1 year of first-line antiretroviral therapy by longitudinally evaluating 2579 participants with pretreatment drug resistance results from the PharmAccess African Studies to Evaluate Resistance Monitoring (PASER-M) cohort. Participants with pretreatment drug resistance who were given a treatment regimen with reduced activity to at least one prescribed drug had a significantly greater risk of virologic failure and acquired drug resistance compared with both participants without pretreatment drug resistance, and participants with pretreatment drug resistance who were prescribed fully active regimens. This paper by Hamers et al. validates the need for at least three fully active antiretroviral drugs to prevent the acquisition of drug resistance and to optimize treatment success in resource limited settings. PMID:22913352

  13. HIV multi-drug resistance at first-line antiretroviral failure and subsequent virological response in Asia

    PubMed Central

    Jiamsakul, Awachana; Sungkanuparph, Somnuek; Law, Matthew; Kantor, Rami; Praparattanapan, Jutarat; Li, Patrick CK; Phanuphak, Praphan; Merati, Tuti; Ratanasuwan, Winai; Lee, Christopher KC; Ditangco, Rossana; Mustafa, Mahiran; Singtoroj, Thida; Kiertiburanakul, Sasisopin

    2014-01-01

    Introduction First-line antiretroviral therapy (ART) failure often results from the development of resistance-associated mutations (RAMs). Three patterns, including thymidine analogue mutations (TAMs), 69 Insertion (69Ins) and the Q151M complex, are associated with resistance to multiple-nucleoside reverse transcriptase inhibitors (NRTIs) and may compromise treatment options for second-line ART. Methods We investigated patterns and factors associated with multi-NRTI RAMs at first-line failure in patients from The TREAT Asia Studies to Evaluate Resistance – Monitoring study (TASER-M), and evaluated their impact on virological responses at 12 months after switching to second-line ART. RAMs were compared with the IAS-USA 2013 mutations list. We defined multi-NRTI RAMs as the presence of either Q151M; 69Ins; ≥2 TAMs; or M184V+≥1 TAM. Virological suppression was defined as viral load (VL) <400 copies/ml at 12 months from switch to second-line. Logistic regression was used to analyze (1) factors associated with multi-NRTI RAMs at first-line failure and (2) factors associated with virological suppression after 12 months on second-line. Results A total of 105 patients from 10 sites in Thailand, Hong Kong, Indonesia, Malaysia and Philippines were included. There were 97/105 (92%) patients harbouring ≥1 RAMs at first-line failure, 39/105 with multi-NRTI RAMs: six with Q151M; 24 with ≥2 TAMs; and 32 with M184V+≥1 TAM. Factors associated with multi-NRTI RAMs were CD4 ≤200 cells/µL at genotyping (OR=4.43, 95% CI [1.59–12.37], p=0.004) and ART duration >2 years (OR=6.25, 95% CI [2.39–16.36], p<0.001). Among 87/105 patients with available VL at 12 months after switch to second-line ART, virological suppression was achieved in 85%. The median genotypic susceptibility score (GSS) for the second-line regimen was 2.00. Patients with ART adherence ≥95% were more likely to be virologically suppressed (OR=9.33, 95% CI (2.43–35.81), p=0.001). Measures of patient

  14. “Risk factors associated with virologic failure in HIV-infected patients receiving antiretroviral therapy at a public hospital in Peru”

    PubMed Central

    Jorge, Alave R; Jorge, Paz B; Elsa, Gonzalez L; Miguel, Campos S; Rodriguez, Martin; Willig, James; Juan, Echevarría Z

    2013-01-01

    OBJECTIVE To describe clinical and biological characteristics of subjects with virologic failure who participated in the sexually transmitted diseases HIV/AIDS National Program from a Peruvian public hospital. MATERIALS AND METHODS An exploratory descriptive study was performed with data from subjects older than 18 who started high activity antiretroviral therapy (HAART) between May 2004 and December 2009 and who had a viral load control after 24 weeks of HAART. Virologic failure was defined as a viral load value above 1000 copies/mL on follow up after 24 weeks on HAART. RESULTS Of 1 478 records of patients on HAART analized, the median age was 35 years [IQR, 29-41] and 69.6% were male. Also, virologic failure occurred in 24% and 3.7% died. Of subjects with virologic failure, 9.5% died. On multivariate analysis, age, history of antiretroviral use before starting HAART, change of antiretroviral therapy due to toxicity, opportunistic infections during HAART, level of CD4 + lymphocytes below 100 cells/ml at start of HAART, adherence and clinical stage were independently associated with virologic failure. In the group of patient with no history of antiretroviral use before starting HAART, age, opportunistic infections during HAART were associated with virologic failure. CONCLUSION This study identified factors associated with virologic failure. Further studies are needed to evaluate whether the use of these factors can help to identify prospectively patients at high risk of failure, and to design interventions aimed to reduce this risk. PMID:23450408

  15. Low rate of sustained virological response in an outbreak of acute hepatitis C in HIV-infected patients.

    PubMed

    Laguno, Montserrat; Martínez-Rebollar, Maria; Perez, Iñaki; Costa, Josep; Larrousse, Maria; Calvo, Marta; Loncá, Montse; Muñoz, Ana; González-Cordón, Ana; Blanco, José Luís; Martínez, Esteban; Gatell, Josep Maria; Mallolas, Josep

    2012-10-01

    Recent reports have suggested an increased risk of acute hepatitis C (AHC) infection in homosexual HIV-infected men and that early treatment with interferon-alfa, alone or associated with ribavirin, significantly reduces the risk of chronic evolution. A retrospective analysis of 38 HIV-infected patients who were consecutively diagnosed as developing AHC, defined by both seroconversion of anti-hepatitis C virus (HCV) antibodies and detection of serum HCV-RNA in those with previous negative results. Thirty-six patients were men with history of unprotected sexual intercourse with men and two were women with sexual and nosocomial risk factors. AHC infection was asymptomatic in 26 patients; asthenia and jaundice were the most frequent symptoms. HCV genotype 1 was present in 19 patients and genotype 4 in 14 patients. Thirty-five patients received early antiviral treatment with pegylated interferon-alfa associated with ribavirin; 15 of the 32 patients who completed the follow-up (47%) achieved a sustained virological response, as defined by undetectable HCV-RNA 6 months after the end of therapy. There is a risk of sexual transmission of HCV in HIV-infected men who have sex with men. In our experience, early treatment of AHC with pegylated interferon-alfa plus ribavirin in HIV patients achieves poor results. PMID:22428909

  16. Clinical Outcome of HIV-Infected Patients with Sustained Virologic Response to Antiretroviral Therapy: Long-Term Follow-Up of a Multicenter Cohort

    PubMed Central

    Gutierrez, Félix; Padilla, Sergio; Masiá, Mar; Iribarren, José A.; Moreno, Santiago; Viciana, Pompeyo; Muñoz, Leopoldo; Sirvent, José L. Gómez; Vidal, Francesc; López-Aldeguer, José; Blanco, José R.; Leal, Manuel; Rodríguez-Arenas, María Angeles; Hoyos, Santiago Perez

    2006-01-01

    Background Limited information exists on long-term prognosis of patients with sustained virologic response to antiretroviral therapy. We aimed to assess predictors of unfavorable clinical outcome in patients who maintain viral suppression with HAART. Methods Using data collected from ten clinic-based cohorts in Spain, we selected all antiretroviral-naive adults who initiated HAART and maintained plasma HIV-1 RNA levels <500 copies/mL throughout follow-up. Factors associated with disease progression were determined by Cox proportional-hazards models. Results Of 2,613 patients who started HAART, 757 fulfilled the inclusion criteria. 61% of them initiated a protease inhibitor-based HAART regimen, 29.7% a nonnucleoside reverse-transcriptase inhibitor-based regimen, and 7.8% a triple-nucleoside regimen. During 2,556 person-years of follow-up, 22 (2.9%) patients died (mortality rate 0.86 per 100 person-years), and 40 (5.3%) died or developed a new AIDS-defining event. The most common causes of death were neoplasias and liver failure. Mortality was independently associated with a CD4-T cell response <50 cells/L after 12 months of HAART (adjusted hazard ratio [AHR], 4.26 [95% confidence interval {CI}, 1.68–10.83]; P = .002), and age at initiation of HAART (AHR, 1.06 per year; 95% CI, 1.02–1.09; P = .001). Initial antiretroviral regimen chosen was not associated with different risk of clinical progression. Conclusions Patients with sustained virologic response on HAART have a low mortality rate over time. Long-term outcome of these patients is driven by immunologic response at the end of the first year of therapy and age at the time of HAART initiation, but not by the initial antiretroviral regimen selected. PMID:17183720

  17. The Perilous Road from HIV Diagnosis in the Hospital to Viral Suppression in the Outpatient Clinic.

    PubMed

    Colasanti, Jonathan; Goswami, Neela D; Khoubian, Jonathan J; Pennisi, Eugene; Root, Christin; Ziemer, Dorothy; Armstrong, Wendy S; Del Rio, Carlos

    2016-08-01

    The HIV care continuum has received considerable attention in recent years, however, few care continua focus on the population of patients who are diagnosed during an inpatient hospital admission. We aimed to describe the HIV care continuum for patients newly diagnosed during hospitalization through 24-month follow-up. A retrospective chart review of HIV patients diagnosed at Grady Memorial Hospital from 2011 to 2012 was performed and records were matched to Georgia Department of Public Health HIV/AIDS surveillance data. Descriptive statistics and statistical tests of independence were utilized. Ninety-four new diagnoses were confirmed during the 2-year study period. Median age was 43 years (interquartile range [IQR] 30-51), 77% were male, 72% were non-Hispanic Black, 31% were men who have sex with men (MSM), and 77% were uninsured. Median CD4 count at diagnosis was 134 cells/μL (IQR 30-307). Eighty-four percent received their diagnosis before hospital discharge, 68% linked to care by 90 days, 73% were retained for 12 months, 48% were virologically suppressed by 12 months, 58% were retained for 24 continuous months, and 38% achieved continuous viral suppression (VS) during the initial 24 months after diagnosis. Late diagnosis is a persistent problem in hospitalized patients. Despite relative success with linkage to care and 12-month retention in care, a minority of patients maintained retention and VS for 24 continuous months. PMID:27005488

  18. Neutralization resistance of virological synapse-mediated HIV-1 Infection is regulated by the gp41 cytoplasmic tail.

    PubMed

    Durham, Natasha D; Yewdall, Alice W; Chen, Ping; Lee, Rebecca; Zony, Chati; Robinson, James E; Chen, Benjamin K

    2012-07-01

    Human immunodeficiency virus type 1 (HIV-1) infection can spread efficiently from infected to uninfected T cells through adhesive contacts called virological synapses (VSs). In this process, cell-surface envelope glycoprotein (Env) initiates adhesion and viral transfer into an uninfected recipient cell. Previous studies have found some HIV-1-neutralizing patient sera to be less effective at blocking VS-mediated infection than infection with cell-free virus. Here we employ sensitive flow cytometry-based infection assays to measure the inhibitory potency of HIV-1-neutralizing monoclonal antibodies (MAb) and HIV-1-neutralizing patient sera against cell-free and VS-mediated infection. To various degrees, anti-Env MAbs exhibited significantly higher 50% inhibitory concentration (IC(50)s) against VS-mediated infection than cell-free infection. Notably, the MAb 17b, which binds a CD4-induced (CD4i) epitope on gp120, displayed a 72-fold reduced efficacy against VS-mediated inocula compared to cell-free inocula. A mutant with truncation mutation in the gp41 cytoplasmic tail (CT) which is unable to modulate Env fusogenicity in response to virus particle maturation but which can still engage in cell-to-cell infection was tested for the ability to resist neutralizing antibodies. The ΔCT mutation increased cell surface staining by neutralizing antibodies, significantly enhanced neutralization of VS-mediated infection, and had reduced or no effect on cell-free infection, depending upon the antibody. Our results suggest that the gp41 CT regulates the exposure of key neutralizing epitopes during cell-to-cell infection and plays an important role in immune evasion. Vaccine strategies should consider immunogens that reflect Env conformations exposed on the infected cell surface to enhance protection against VS-mediated HIV-1 spread. PMID:22553332

  19. Pretreatment HIV Drug Resistance and HIV-1 Subtype C Are Independently Associated With Virologic Failure: Results From the Multinational PEARLS (ACTG A5175) Clinical Trial

    PubMed Central

    Kantor, Rami; Smeaton, Laura; Vardhanabhuti, Saran; Hudelson, Sarah E.; Wallis, Carol L.; Tripathy, Srikanth; Morgado, Mariza G.; Saravanan, Shanmugham; Balakrishnan, Pachamuthu; Reitsma, Marissa; Hart, Stephen; Mellors, John W.; Halvas, Elias; Grinsztejn, Beatriz; Hosseinipour, Mina C.; Kumwenda, Johnstone; La Rosa, Alberto; Lalloo, Umesh G.; Lama, Javier R.; Rassool, Mohammed; Santos, Breno R.; Supparatpinyo, Khuanchai; Hakim, James; Flanigan, Timothy; Kumarasamy, Nagalingeswaran; Campbell, Thomas B.; Eshleman, Susan H.

    2015-01-01

    Background. Evaluation of pretreatment HIV genotyping is needed globally to guide treatment programs. We examined the association of pretreatment (baseline) drug resistance and subtype with virologic failure in a multinational, randomized clinical trial that evaluated 3 antiretroviral treatment (ART) regimens and included resource-limited setting sites. Methods. Pol genotyping was performed in a nested case-cohort study including 270 randomly sampled participants (subcohort), and 218 additional participants failing ART (case group). Failure was defined as confirmed viral load (VL) >1000 copies/mL. Cox proportional hazards models estimated resistance–failure association. Results. In the representative subcohort (261/270 participants with genotypes; 44% women; median age, 35 years; median CD4 cell count, 151 cells/µL; median VL, 5.0 log10 copies/mL; 58% non-B subtypes), baseline resistance occurred in 4.2%, evenly distributed among treatment arms and subtypes. In the subcohort and case groups combined (466/488 participants with genotypes), used to examine the association between resistance and treatment failure, baseline resistance occurred in 7.1% (9.4% with failure, 4.3% without). Baseline resistance was significantly associated with shorter time to virologic failure (hazard ratio [HR], 2.03; P = .035), and after adjusting for sex, treatment arm, sex–treatment arm interaction, pretreatment CD4 cell count, baseline VL, and subtype, was still independently associated (HR, 2.1; P = .05). Compared with subtype B, subtype C infection was associated with higher failure risk (HR, 1.57; 95% confidence interval [CI], 1.04–2.35), whereas non-B/C subtype infection was associated with longer time to failure (HR, 0.47; 95% CI, .22–.98). Conclusions. In this global clinical trial, pretreatment resistance and HIV-1 subtype were independently associated with virologic failure. Pretreatment genotyping should be considered whenever feasible. Clinical Trials

  20. Clinical, Virologic, Immunologic Outcomes and Emerging HIV Drug Resistance Patterns in Children and Adolescents in Public ART Care in Zimbabwe

    PubMed Central

    Makadzange, A. T.; Higgins-Biddle, M.; Chimukangara, B.; Birri, R.; Gordon, M.; Mahlanza, T.; McHugh, G.; van Dijk, J. H.; Bwakura-Dangarembizi, M.; Ndung’u, T.; Masimirembwa, C.; Phelps, B.; Amzel, A.; Ojikutu, B. O.; Walker, B. D.; Ndhlovu, C. E.

    2015-01-01

    Objective To determine immunologic, virologic outcomes and drug resistance among children and adolescents receiving care during routine programmatic implementation in a low-income country. Methods A cross-sectional evaluation with collection of clinical and laboratory data for children (0-<10 years) and adolescents (10–19 years) attending a public ART program in Harare providing care for pediatric patients since 2004, was conducted. Longitudinal data for each participant was obtained from the clinic based medical record. Results Data from 599 children and adolescents was evaluated. The participants presented to care with low CD4 cell count and CD4%, median baseline CD4% was lower in adolescents compared with children (11.0% vs. 15.0%, p<0.0001). The median age at ART initiation was 8.0 years (IQR 3.0, 12.0); median time on ART was 2.9 years (IQR 1.7, 4.5). On ART, median CD4% improved for all age groups but remained below 25%. Older age (≥ 5 years) at ART initiation was associated with severe stunting (HAZ <-2: 53.3% vs. 28.4%, p<0.0001). Virologic failure rate was 30.6% and associated with age at ART initiation. In children, nevirapine based ART regimen was associated with a 3-fold increased risk of failure (AOR: 3.5; 95% CI: 1.3, 9.1, p = 0.0180). Children (<10y) on ART for ≥4 years had higher failure rates than those on ART for <4 years (39.6% vs. 23.9%, p = 0.0239). In those initiating ART as adolescents, each additional year in age above 10 years at the time of ART initiation (AOR 0.4 95%CI: 0.1, 0.9, p = 0.0324), and each additional year on ART (AOR 0.4, 95%CI 0.2, 0.9, p = 0.0379) were associated with decreased risk of virologic failure. Drug resistance was evident in 67.6% of sequenced virus isolates. Conclusions During routine programmatic implementation of HIV care for children and adolescents, delayed age at ART initiation has long-term implications on immunologic recovery, growth and virologic outcomes. PMID:26658814

  1. Is long-term virological response related to CCR5 Δ32 deletion in HIV-1-infected patients started on highly active antiretroviral therapy?

    PubMed Central

    Laurichesse, Jean-Jacques; Taieb, Audrey; Capoulade-Metay, Corinne; Katlama, Christine; Villes, Virginie; Drobacheff-Thiebaud, Marie-Christine; Raffi, François; Chêne, Genevieve; Theodorou, Ioannis; Leport, Catherine

    2010-01-01

    Objective To examine whether CCR5 Δ32 deletion is associated with long-term response to combination antiretroviral treatment (cART) in HIV-1 infected patients. Methods The genetic sub-study of ANRS CO8 APROCO-COPILOTE cohort included 609 patients who started a protease inhibitor-containing cART in 1997–99. Patients were considered to have a sustained virological response if all plasma HIV-RNA measurements between month 4 and years 3–5 were <500 copies/ml, allowing for a single blip. Virological response was compared between patients heterozygous for CCR5 Δ32 (Δ32/wt) and wild-type patients (wt/wt) from month 4 to year 3 and month 4 to year 5. Logistic regression analysis was used to adjust for baseline demographical data, HIV-RNA, CD4 cell counts, antiretroviral naive status, time spent on antiretroviral therapy at year 3 and 5 and adherence to treatment (month 4 to year 3 and 5). Results Sustained virological response was better in Δ32/wt than in wt/wt patients: 66% versus 52% up to year 3 (p=0.02), nearly significant after adjustment to potential cofounders (p=0.07). Δ32/wt patients had a better virological response, up to year 5, 48% versus 35% (p=0.01), and remained significantly better, after adjustment, associated with a better virological response up to 5 years post initiation of cART (p=0.04). There was no association with CD4 response. Conclusion Δ32/wt deletion is associated with a beneficial virological response to cART on the long-term. Whether this association can be a direct effect of Δ32/wt deletion remains questionable and needs confirmation in other observational studies. PMID:20050936

  2. Immunologic and Virologic Progression in HIV Controllers: The Role of Viral “Blips” and Immune Activation in the ANRS CO21 CODEX Study

    PubMed Central

    Lécuroux, Camille; Goujard, Cécile; Venet, Alain; Saez-Cirion, Asier; Avettand-Fenoël, Veronique; Meyer, Laurence; Boufassa, Faroudy; Lambotte, Olivier

    2015-01-01

    Some HIV controllers (HICs) experience CD4+T cell count loss and/or lose their ability to control HIV. In this study, we investigated the rate of immunologic and/or virologic progression (ImmP/VirP) and its determinants in the ANRS CO21/CODEX cohort. Immunologic progression was defined as a lasting fall in CD4+T cell count below 350/mm3 or more than 200/mm3 with a baseline count below 600/mm3. Virologic progression was defined as a HIV viral load (VL) above 2000 copies/mL on two consecutive determinations. Clinical characteristics, immune activation, ultrasensitive HIV VL and total HIV DNA were analyzed. Disease progression was observed in 15 of the 217 patients followed up between 2009 and 2013 (ImmP, n = 10; VirP, n = 5). Progressors had higher ultrasensitive HIV RNA levels at inclusion (i.e. 1-2 years before progression) than non-progressors. ImmP had also lower CD4+T cell nadir and CD4+T cell count at inclusion, and VirP had higher HIV DNA levels in blood. T cell activation and IP10 levels at inclusion were significantly higher in ImmP than in non-progressors. In summary, the lasting loss of CD4+T cells, residual HIV replication and basal levels of immune activation appear to be major determinants of progression in HICs. These factors should be considered for adjusting their follow-up. PMID:26146823

  3. K65R-associated virologic failure in HIV-infected patients receiving tenofovir-containing triple nucleoside/nucleotide reverse transcriptase inhibitor regimens.

    PubMed

    Ruane, Peter J; Luber, Andrew D

    2004-01-01

    High rates of early virologic failure associated with the emergence of the K65R mutation in HIV-1 reverse transcriptase (RT) have been reported among HIV-infected patients who received novel, tenofovir-containing, triple-nucleoside/nucleotide reverse transcriptase inhibitor (NRTI/NtRTI) regimens as their initial therapy. This review surveys the findings of prospective and retrospective studies in this regard, examines the significance of the K65R mutation and other factors associated with reports of early virologic failure among patients receiving tenofovir-containing NRTI/NtRTI regimens, and discusses clinical approaches to preventing and managing HIV drug resistance and treatment failure associated with the K65R mutation. PMID:15266257

  4. Brief Report: Effect of CMV and HIV Transcription on CD57 and PD-1 T-Cell Expression During Suppressive ART

    PubMed Central

    Massanella, Marta; Smith, Davey M.; Spina, Celsa A.; Schrier, Rachel; Daar, Eric S.; Dube, Michael P.; Morris, Sheldon R.; Gianella, Sara

    2016-01-01

    Abstract: HIV-infected men who have sex with men are nearly universally coinfected with cytomegalovirus (CMV). In this study of 45 HIV-infected men who have sex with men virologically suppressed on ART, we found that presence of seminal CMV DNA shedding and higher levels of systemic cellular HIV RNA transcription were both independently associated with increased PD-1 expression on circulating CD4+ T cells, but not with higher levels of senescent (CD57+) T cells. In addition, greater HIV RNA transcription was associated with lower CD57 expression on CD8 T cells. Although causality cannot be inferred from this retrospective study, these results suggest that asymptomatic CMV replication and residual cellular HIV transcription may contribute to persistent immune dysregulation during suppressive ART. PMID:26818740

  5. Brief Report: Effect of CMV and HIV Transcription on CD57 and PD-1 T-Cell Expression During Suppressive ART.

    PubMed

    Dan, Jennifer M; Massanella, Marta; Smith, Davey M; Spina, Celsa A; Schrier, Rachel; Daar, Eric S; Dube, Michael P; Morris, Sheldon R; Gianella, Sara

    2016-06-01

    HIV-infected men who have sex with men are nearly universally coinfected with cytomegalovirus (CMV). In this study of 45 HIV-infected men who have sex with men virologically suppressed on ART, we found that presence of seminal CMV DNA shedding and higher levels of systemic cellular HIV RNA transcription were both independently associated with increased PD-1 expression on circulating CD4 T cells, but not with higher levels of senescent (CD57) T cells. In addition, greater HIV RNA transcription was associated with lower CD57 expression on CD8 T cells. Although causality cannot be inferred from this retrospective study, these results suggest that asymptomatic CMV replication and residual cellular HIV transcription may contribute to persistent immune dysregulation during suppressive ART. PMID:26818740

  6. Biochemical and virological analysis of the 18-residue C-terminal tail of HIV-1 integrase

    PubMed Central

    Dar, Mohd J; Monel, Blandine; Krishnan, Lavanya; Shun, Ming-Chieh; Di Nunzio, Francesca; Helland, Dag E; Engelman, Alan

    2009-01-01

    Background The 18 residue tail abutting the SH3 fold that comprises the heart of the C-terminal domain is the only part of HIV-1 integrase yet to be visualized by structural biology. To ascertain the role of the tail region in integrase function and HIV-1 replication, a set of deletion mutants that successively lacked three amino acids was constructed and analyzed in a variety of biochemical and virus infection assays. HIV-1/2 chimers, which harbored the analogous 23-mer HIV-2 tail in place of the HIV-1 sequence, were also studied. Because integrase mutations can affect steps in the replication cycle other than integration, defective mutant viruses were tested for integrase protein content and reverse transcription in addition to integration. The F185K core domain mutation, which increases integrase protein solubility, was furthermore analyzed in a subset of mutants. Results Purified proteins were assessed for in vitro levels of 3' processing and DNA strand transfer activities whereas HIV-1 infectivity was measured using luciferase reporter viruses. Deletions lacking up to 9 amino acids (1-285, 1-282, and 1-279) displayed near wild-type activities in vitro and during infection. Further deletion yielded two viruses, HIV-11-276 and HIV-11-273, that displayed approximately two and 5-fold infectivity defects, respectively, due to reduced integrase function. Deletion mutant HIV-11-270 and the HIV-1/2 chimera were non-infectious and displayed approximately 3 to 4-fold reverse transcription in addition to severe integration defects. Removal of four additional residues, which encompassed the C-terminal β strand of the SH3 fold, further compromised integrase incorporation into virions and reverse transcription. Conclusion HIV-11-270, HIV-11-266, and the HIV-1/2 chimera were typed as class II mutant viruses due to their pleiotropic replication defects. We speculate that residues 271-273 might play a role in mediating the known integrase-reverse transcriptase interaction, as

  7. Determination of the influence of home delivery of HIV therapy on virological outcomes and adherence.

    PubMed

    Castelino, Sheena; Miah, Hamida; Auyeung, Vivian; Vogt, Florian

    2015-02-01

    The aim of this study was to evaluate whether the change in the mode of supply of HIV medicines to a homecare model was associated with any change in adherence and patient outcomes. We conducted a retrospective analysis of medical records of 100 patients who received supplies from a clinic-based hospital HIV pharmacy and 100 patients who were started on home delivery over a three-month period and were followed up over six months. Data on patient demographics, type of HIV drug regimen, HIV viral load, CD4% and adherence status were analysed. The mode of delivery had no significant effect on CD4% (p > 0.05), HIV viral load status (p > 0.05) or adherence status (p > 0.05). There was a significant increase in CD4% over time for both groups (p < 0.01). This study suggests that expanding home delivery as a model of care in London HIV clinics is safe and does not affect adherence and patient outcomes as indicated by HIV viral load and CD4%. PMID:24733153

  8. Immunologic, Virologic, and Pharmacologic Characterization of the Female Upper Genital Tract in HIV-infected women

    PubMed Central

    Rahangdale, Lisa; De Paris, Kristina; Kashuba, Angela DM; Nelson, Julie AE; Cottrell, Mackenzie; Sykes, Craig; Emerson, Cindi; Young, Steven L; Stevens, Trenton; Patterson, Kristine B; Cohen, Myron S.

    2014-01-01

    A comparative analysis of cellular and soluble markers of immune activation in HIV-infected women on combination antiretroviral therapy (cART) showed that the upper (UGT) compared to the lower female genital (LGT) tract was characterized by higher frequencies of potential HIV target cells and increased inflammatory molecules. Despite the activated UGT milieu, HIV RNA could not be detected in paired samples of plasma, cervicovaginal (CVL) or endometrial lavage (EML). As ARV concentrations were ≥3 fold higher in the endometrium than the in the lower genital tract, high ARV penetration and/or metabolism may limit viral replication in the UGT. PMID:25501615

  9. Brief Report: Food Insufficiency Is Associated With Lack of Sustained Viral Suppression Among HIV-Infected Pregnant and Breastfeeding Ugandan Women

    PubMed Central

    Natureeba, Paul; Nyafwono, Dorcas; Plenty, Albert; Mwesigwa, Julia; Nzarubara, Bridget; Clark, Tamara D.; Ruel, Theodore D.; Achan, Jane; Charlebois, Edwin D.; Cohan, Deborah; Kamya, Moses R.; Havlir, Diane V.; Young, Sera L.

    2016-01-01

    Abstract: Food insecurity is associated with poor virologic outcomes, but this has not been studied during pregnancy and breastfeeding. We assessed sustained viral suppression from 8 weeks on antiretroviral therapy to 48 weeks postpartum among 171 pregnant and breastfeeding Ugandan women; 74.9% experienced food insufficiency. In multivariable analysis, food insufficiency [adjusted odds ratio (aOR) 0.38, 95% confidence interval (CI): 0.16 to 0.91], higher pretreatment HIV-1 RNA (aOR 0.55 per 10-fold increase, 95% CI: 0.37 to 0.82), and lopinavir/ritonavir versus efavirenz (aOR 0.49, 95% CI: 0.24 to 0.96) were associated with lower odds of sustained viral suppression. Interventions to address food security may improve virologic outcomes among HIV-infected women. PMID:26397935

  10. Brief Report: Food Insufficiency Is Associated With Lack of Sustained Viral Suppression Among HIV-Infected Pregnant and Breastfeeding Ugandan Women.

    PubMed

    Koss, Catherine A; Natureeba, Paul; Nyafwono, Dorcas; Plenty, Albert; Mwesigwa, Julia; Nzarubara, Bridget; Clark, Tamara D; Ruel, Theodore D; Achan, Jane; Charlebois, Edwin D; Cohan, Deborah; Kamya, Moses R; Havlir, Diane V; Young, Sera L

    2016-03-01

    Food insecurity is associated with poor virologic outcomes, but this has not been studied during pregnancy and breastfeeding. We assessed sustained viral suppression from 8 weeks on antiretroviral therapy to 48 weeks postpartum among 171 pregnant and breastfeeding Ugandan women; 74.9% experienced food insufficiency. In multivariable analysis, food insufficiency [adjusted odds ratio (aOR) 0.38, 95% confidence interval (CI): 0.16 to 0.91], higher pretreatment HIV-1 RNA (aOR 0.55 per 10-fold increase, 95% CI: 0.37 to 0.82), and lopinavir/ritonavir versus efavirenz (aOR 0.49, 95% CI: 0.24 to 0.96) were associated with lower odds of sustained viral suppression. Interventions to address food security may improve virologic outcomes among HIV-infected women. PMID:26397935

  11. Elevated CD8 T-cell counts and virological failure in HIV-infected patients after combination antiretroviral therapy

    PubMed Central

    Ku, Nam Su; Jiamsakul, Awachana; Ng, Oon Tek; Yunihastuti, Evy; Cuong, Do Duy; Lee, Man Po; Sim, Benedict Lim Heng; Phanuphak, Praphan; Wong, Wing-Wai; Kamarulzaman, Adeeba; Zhang, Fujie; Pujari, Sanjay; Chaiwarith, Romanee; Oka, Shinichi; Mustafa, Mahiran; Kumarasamy, Nagalingeswaran; Van Nguyen, Kinh; Ditangco, Rossana; Kiertiburanakul, Sasisopin; Merati, Tuti Parwati; Durier, Nicolas; Choi, Jun Yong

    2016-01-01

    Abstract Elevated CD8 counts with combination antiretroviral therapy (cART) initiation may be an early warning indicator for future treatment failure. Thus, we investigated whether elevated CD8 counts were associated with virological failure (VF) in the first 4 years of cART in Asian HIV-infected patients in a multicenter regional cohort. We included patients from the TREAT Asia HIV Observational Database (TAHOD). Patients were included in the analysis if they started cART between 1996 and 2013 with at least one CD8 measurement within 6 months prior to cART initiation and at least one CD8 and viral load (VL) measurement beyond 6 months after starting cART. We defined VF as VL ≥400 copies/mL after 6 months on cART. Elevated CD8 was defined as CD8 ≥1200 cells/μL. Time to VF was modeled using Cox regression analysis, stratified by site. In total, 2475 patients from 19 sites were included in this analysis, of whom 665 (27%) experienced VF in the first 4 years of cART. The overall rate of VF was 12.95 per 100 person-years. In the multivariate model, the most recent elevated CD8 was significantly associated with a greater hazard of VF (HR = 1.35, 95% CI 1.14–1.61; P = 0.001). However, the sensitivity analysis showed that time-lagged CD8 measured at least 6 months prior to our virological endpoint was not statistically significant (P = 0.420). This study indicates that the relationship between the most recent CD8 count and VF was possibly due to the CD8 cells reacting to the increase in VL rather than causing the VL increase itself. However, CD8 levels may be a useful indicator for VF in HIV-infected patients after starting cART. PMID:27512885

  12. Elevated CD8 T-cell counts and virological failure in HIV-infected patients after combination antiretroviral therapy.

    PubMed

    Ku, Nam Su; Jiamsakul, Awachana; Ng, Oon Tek; Yunihastuti, Evy; Cuong, Do Duy; Lee, Man Po; Sim, Benedict Lim Heng; Phanuphak, Praphan; Wong, Wing-Wai; Kamarulzaman, Adeeba; Zhang, Fujie; Pujari, Sanjay; Chaiwarith, Romanee; Oka, Shinichi; Mustafa, Mahiran; Kumarasamy, Nagalingeswaran; Van Nguyen, Kinh; Ditangco, Rossana; Kiertiburanakul, Sasisopin; Merati, Tuti Parwati; Durier, Nicolas; Choi, Jun Yong

    2016-08-01

    Elevated CD8 counts with combination antiretroviral therapy (cART) initiation may be an early warning indicator for future treatment failure. Thus, we investigated whether elevated CD8 counts were associated with virological failure (VF) in the first 4 years of cART in Asian HIV-infected patients in a multicenter regional cohort.We included patients from the TREAT Asia HIV Observational Database (TAHOD). Patients were included in the analysis if they started cART between 1996 and 2013 with at least one CD8 measurement within 6 months prior to cART initiation and at least one CD8 and viral load (VL) measurement beyond 6 months after starting cART. We defined VF as VL ≥400 copies/mL after 6 months on cART. Elevated CD8 was defined as CD8 ≥1200 cells/μL. Time to VF was modeled using Cox regression analysis, stratified by site.In total, 2475 patients from 19 sites were included in this analysis, of whom 665 (27%) experienced VF in the first 4 years of cART. The overall rate of VF was 12.95 per 100 person-years. In the multivariate model, the most recent elevated CD8 was significantly associated with a greater hazard of VF (HR = 1.35, 95% CI 1.14-1.61; P = 0.001). However, the sensitivity analysis showed that time-lagged CD8 measured at least 6 months prior to our virological endpoint was not statistically significant (P = 0.420).This study indicates that the relationship between the most recent CD8 count and VF was possibly due to the CD8 cells reacting to the increase in VL rather than causing the VL increase itself. However, CD8 levels may be a useful indicator for VF in HIV-infected patients after starting cART. PMID:27512885

  13. Contribution of immunological and virological factors to extremely severe primary HIV-1 infection

    PubMed Central

    Dalmau, Judith; Puertas, Maria Carmen; Azuara, Marta; Mariño, Ana; Frahm, Nicole; Mothe, Beatriz; Izquierdo-Useros, Nuria; Buzón, Maria José; Paredes, Roger; Matas, Lourdes; Allen, Todd M.; Brander, Christian; Rodrigo, Carlos; Clotet, Bonaventura; Martinez-Picado, Javier

    2009-01-01

    Background During acute HIV infection, high viral loads and the induction of host immune responses typically coincide with the onset of clinical symptoms. However, clinically severe presentations during acute HIV-1 infection, including AIDS-defining symptoms, are unusual. Methods Virus isolates were tested for clade, drug susceptibility, coreceptor usage, and growth rate for two cases of clinically severe sexual transmission. HLA genotype was determined, and HIV-1-specific CTL responses to an overlapping peptide set spanning the entire HIV clade A and clade B proteome were assayed. Results The virus isolated from the two unrelated cases of severe primary HIV-1 infection showed R5/X4 dual/mixed tropism, belonged to clade B and CRF02-AG, and were highly replicative in peripheral blood mononuclear cell culture. Impaired humoral responses were paralleled by a profound absence of HIV-1-specific CTL responses to the entire viral proteome in the two study cases. One case for which the virus source was available, showed a remarkable HLA similarity between the transmission pair as all 4 HLA-A and -B alleles were HLA supertype-matched between the subjects involved in the transmission case. Conclusions The data suggest that concurrence of viral and host factors contribute to the clinical severity of primary HIV-1 infection and that subjects infected with highly replicative dual tropic viruses are more prone to develop AIDS-defining symptoms during acute infection if they are unable to mount humoral and cellular HIV-1-specific immune responses. Concordant HLA supertypes might facilitate the preferential transmission of HLA-adapted viral variants, further accelerating disease progression. PMID:19093810

  14. A Prognostic Model for Estimating the Time to Virologic Failure in HIV-1 Infected Patients Undergoing a New Combination Antiretroviral Therapy Regimen

    PubMed Central

    2011-01-01

    Background HIV-1 genotypic susceptibility scores (GSSs) were proven to be significant prognostic factors of fixed time-point virologic outcomes after combination antiretroviral therapy (cART) switch/initiation. However, their relative-hazard for the time to virologic failure has not been thoroughly investigated, and an expert system that is able to predict how long a new cART regimen will remain effective has never been designed. Methods We analyzed patients of the Italian ARCA cohort starting a new cART from 1999 onwards either after virologic failure or as treatment-naïve. The time to virologic failure was the endpoint, from the 90th day after treatment start, defined as the first HIV-1 RNA > 400 copies/ml, censoring at last available HIV-1 RNA before treatment discontinuation. We assessed the relative hazard/importance of GSSs according to distinct interpretation systems (Rega, ANRS and HIVdb) and other covariates by means of Cox regression and random survival forests (RSF). Prediction models were validated via the bootstrap and c-index measure. Results The dataset included 2337 regimens from 2182 patients, of which 733 were previously treatment-naïve. We observed 1067 virologic failures over 2820 persons-years. Multivariable analysis revealed that low GSSs of cART were independently associated with the hazard of a virologic failure, along with several other covariates. Evaluation of predictive performance yielded a modest ability of the Cox regression to predict the virologic endpoint (c-index≈0.70), while RSF showed a better performance (c-index≈0.73, p < 0.0001 vs. Cox regression). Variable importance according to RSF was concordant with the Cox hazards. Conclusions GSSs of cART and several other covariates were investigated using linear and non-linear survival analysis. RSF models are a promising approach for the development of a reliable system that predicts time to virologic failure better than Cox regression. Such models might represent a

  15. Suppression of HIV-1 Infectivity by Human Glioma Cells.

    PubMed

    Hoque, Sheikh Ariful; Tanaka, Atsushi; Islam, Salequl; Ahsan, Gias Uddin; Jinno-Oue, Atsushi; Hoshino, Hiroo

    2016-05-01

    HIV-1 infection to the central nervous system (CNS) is very common in AIDS patients. The predominant cell types infected in the brain are monocytes and macrophages, which are surrounded by several HIV-1-resistant cell types, such as astrocytes, oligodendrocytes, neurons, and microvascular cells. The effect of these HIV-1-resistant cells on HIV-1 infection is largely unknown. In this study, we examined the stability of HIV-1 cultured with several human glioblastoma cell lines, for example, NP-2, U87MG, T98G, and A172, to determine whether these HIV-1-resistant brain cells could enhance or suppress HIV-1 infection and thus modulate HIV-1 infection in the CNS. The HIV-1 titer was determined using the MAGIC-5A indicator cell line as well as naturally occurring CD4(+) T cells. We found that the stability of HIV-1 incubated with NP-2 or U87MG cells at 37°C was significantly shorter (half-life, 2.5-4 h) compared to that of HIV-1 incubated with T98G or A172 cells or in culture medium without cells (half-life, 8-18 h). The spent culture media (SCM) of NP-2 and U87MG cells had the ability to suppress both R5- and X4-HIV-1 infection by inhibiting HIV-1 attachment to target cells. This inhibitory effect was eliminated by the treatment of the SCM with chondroitinase ABC but not heparinase, suggesting that the inhibitory factor(s) secreted by NP-2 and U87MG cells was chiefly mediated by chondroitin sulfate (CS) or CS-like moiety. Thus, this study reveals that some but not all glioma cells secrete inhibitory molecules to HIV-1 infection that may contribute in lowering HIV-1 infection in the CNS in vivo. PMID:26650729

  16. CD4+ and viral load outcomes of antiretroviral therapy switch strategies after virologic failure of combination antiretroviral therapy in perinatally HIV-infected youth in the United States

    PubMed Central

    Fairlie, Lee; Karalius, Brad; Patel, Kunjal; van Dyke, Russell B.; Hazra, Rohan; Hernán, Miguel A.; Siberry, George K.; Seage, George R.; Agwu, Allison; Wiznia, Andrew

    2015-01-01

    Objective: This study compared 12-month CD4+ and viral load outcomes in HIV-infected children and adolescents with virological failure, managed with four treatment switch strategies. Design: This observational study included perinatally HIV-infected (PHIV) children in the Pediatric HIV/AIDS Cohort Study (PHACS) and Pediatric AIDS Clinical Trials (PACTG) Protocol 219C. Methods: Treatment strategies among children with virologic failure were compared: continue failing combination antiretroviral therapy (cART); switch to new cART; switch to drug-sparing regimen; and discontinue all ART. Mean changes in CD4+% and viral load from baseline (time of virologic failure) to 12 months follow-up in each group were evaluated using weighted linear regression models. Results: Virologic failure occurred in 939 out of 2373 (40%) children. At 12 months, children switching to new cART (16%) had a nonsignificant increase in CD4+% from baseline, 0.59 percentage points [95% confidence interval (95% CI) −1.01 to 2.19], not different than those who continued failing cART (71%) (−0.64 percentage points, P = 0.15) or switched to a drug-sparing regimen (5%) (1.40 percentage points, P = 0.64). Children discontinuing all ART (7%) experienced significant CD4+% decline −3.18 percentage points (95% CI −5.25 to −1.11) compared with those initiating new cART (P = 0.04). All treatment strategies except discontinuing ART yielded significant mean decreases in log10VL by 12 months, the new cART group having the largest drop (−1.15 log10VL). Conclusion: In PHIV children with virologic failure, switching to new cART was associated with the best virological response, while stopping all ART resulted in the worst immunologic and virologic outcomes and should be avoided. Drug-sparing regimens and continuing failing regimens may be considered with careful monitoring. PMID:26182197

  17. Virological and immunological characteristics of HIV-infected individuals at the earliest stage of infection

    PubMed Central

    Ananworanich, Jintanat; Sacdalan, Carlo P.; Pinyakorn, Suteeraporn; Chomont, Nicolas; de Souza, Mark; Luekasemsuk, Tassanee; Schuetz, Alexandra; Krebs, Shelly J; Dewar, Robin; Jagodzinski, Linda; Ubolyam, Sasiwimol; Trichavaroj, Rapee; Tovanabutra, Sodsai; Spudich, Serena; Valcour, Victor; Sereti, Irini; Michael, Nelson; Robb, Merlin; Phanuphak, Praphan; Kim, Jerome H.; Phanuphak, Nittaya

    2016-01-01

    Background The challenges of identifying acute HIV infection (AHI) have resulted in a lack of critical information on early AHI that constrains the development of therapeutics that are designed to eradicate HIV from the infected host. Methods AHI participants were recruited from the Thai Red Cross Anonymous Clinic in Bangkok, Thailand into the RV254/SEARCH010 protocol and categorised according to Fiebig stages as follows: Fiebig I (HIV-RNA+, p24 Ag−, HIV IgM−) and Fiebig II–IV (HIV-RNA+, p24 Ag + or −, HIV IgM− or +, Western blot- or indeterminate). Proviral and viral burden and immune activation levels were compared between Fiebig stage groups at the time of AHI. CD4 and CD4/CD8 ratio were also compared between groups before and up to 96 weeks of ART. Results Median age was 27 years and 96% were male. Fiebig I individuals had lower median HIV-DNA in mononuclear cells from blood (3 vs. 190 copies/106 cells) and gut (0 vs. 898 copies/106 cells), and lower HIV-RNA in blood (4.2 vs. 6.2 log10 copies/mL), gut (1.7 vs. 3.1 log10 copies/mg) and cerebrospinal fluid (2.0 vs. 3.8 log10 copies/mL), when compared to Fiebig II–IV individuals (all P<0.01). Median plasma sCD14 level was lower (1.1 vs. 1.6 μg/mL) in Fiebig I individuals as was the frequency of CD8+HLADR+CD38+ T cells in blood (7.6 vs. 14.9%, both P<0.05). The median plasma interleukin 6 levels were similar between stages (0.6 in Fiebig I vs. 0.5 pg/mL in Fiebig II–IV, P>0.05). The frequencies of CD4+HLA-DR+CD38+ T cells were also similar between these stages (2.1 vs. 2.6%, P>0.05). Median CD4 count and CD4/CD8 ratio were higher in Fiebig I: 508 vs. 340 cells/mm3 and 1.1 vs. 0.7, respectively (both P<0.001). After ART, CD4 cell count normalised by week 24 in Fiebig I and week 48 in Fiebig II–IV. However, CD4/CD8 ratio was lower in both groups after 96 weeks of ART compared to healthy Thais (P=0.02). Conclusions Compared to later AHI stages, Fiebig I was associated with lower HIV burden in blood

  18. Virologic and Clinical Outcomes of Hepatitis B Virus Infection in HIV-HBV Coinfected Transplant Recipients

    PubMed Central

    Coffin, C.S.; Stock, P.G.; Dove, L.M.; Berg, C.L.; Nissen, N.N.; Curry, M.P.; Ragni, M.; Regenstein, F.G.; Sherman, K.E.; Roland, M.E.; Terrault, N.A.

    2010-01-01

    Liver transplantation (LT) is the treatment of choice for endstage liver disease, but is controversial in patients with human immunodeficiency virus (HIV) infection. Using a prospective cohort of HIV-HBV coinfected patients transplanted between 2001–2007; outcomes including survival and HBV clinical recurrence were determined. Twenty-two coinfected patients underwent LT; 45% had detectable HBV DNA pre-LT and 72% were receiving anti-HBV drugs with efficacy against lamivudine-resistant HBV. Post-LT, all patients received hepatitis B immune globulin (HBIG) plus nucleos(t)ide analogues and remained HBsAg negative without clinical evidence of HBV recurrence, with a median follow-up 3.5 years. Low-level HBV viremia (median 108 IU/ml, range 9–789) was intermittently detected in 7/13 but not associated with HBsAg detection or ALT elevation. Compared with 20 HBV monoinfected patients on similar HBV prophylaxis and median follow-up of 4.0 years, patient and graft survival were similar: 100% vs. 85% in HBV mono- vs coinfected patients (p=0.08, log rank test). LT is effective for HIV-HBV coinfected patients with complications of cirrhosis, including those who are HBV DNA positive at the time of LT. Combination HBIG and antivirals is effective as prophylaxis with no clinical evidence of HBV recurrence but low level HBV DNA is detectable in ~50% of recipients. PMID:20346065

  19. Impact of insertions in the HIV-1 p6 PTAPP region on the virological response to amprenavir.

    PubMed

    Lastere, Stephane; Dalban, Cecile; Collin, Gilles; Descamps, Diane; Girard, Pierre-Marie; Clavel, Francois; Costagliola, Dominique; Brun-Vezinet, Francoise

    2004-04-01

    We evaluated the impact of genetic changes within p6Gag gene on the virological response (VR, mean decrease in plasma viral load at week 12) to unboosted amprenavir (APV). Gag-protease fragments, including gag p2, p7, p1, p6 regions and whole protease (PR) were sequenced from baseline plasma specimens of 84 highly pre-treated but APV-naive patients included in the NARVAL (ANRS 088) trial. The correlation between baseline p6Gag polymorphism, PR mutations, baseline characteristics and VR to APV was analysed in univariate analysis. Insertions (P459Ins) within p6 protein, leading to partial or complete duplication of the PTAPP motif, were significantly associated with a decreased VR (P459Ins versus wild-type; -0.3 +/- 0.8 vs -1.1 +/- 1.2 log copies/ml, P=0.007) and were more frequent when the V82A/F/T/S PR mutation was present (P=0.020). In multivariate analysis, after adjustment on the predictive factors of the VR in the NARVAL trial and on the PR mutations linked with response, there was a strong trend to an association (P=0.058) between the presence of P459Ins and an altered VR. In conclusion, these results suggest that insertions in the p6 region of HIV-1 gag gene may affect the VR, in highly pre-treated patients receiving an unboosted APV-containing regimen. PMID:15134184

  20. Selective Serotonin Reuptake Inhibitor Suppression of HIV Infectivity and Replication

    PubMed Central

    Benton, Tami; Lynch, Kevin; Dubé, Benoit; Gettes, David R.; Tustin, Nancy B.; Lai, Jian Ping; Metzger, David S.; Blume, Joshua; Douglas, Steven D.; Evans, Dwight L.

    2010-01-01

    Objective To test the hypothesis that the selective serotonin reuptake inhibitor (SSRI) citalopram would down regulate HIV infectivity and that the greatest effects would be seen in people with depression. Depression is a risk factor for morbidity and mortality in HIV/AIDS. Serotonin (5-HT) neurotransmission has been implicated in the pathobiology of depression, and pharmacologic therapies for depression target this system. The 5-HT transporter and 5-HT receptors are widely distributed throughout the central nervous and immune systems. Depression has been associated with suppression of natural killer cells (NK) cells and CD8+ lymphocytes, key regulators of HIV infection. Methods Ex-vivo models for acute and chronic HIV infection were used to study the effects of citalopram on HIV viral infection and replication, in 48 depressed and non-depressed women. For both the acute and chronic infection models, HIV reverse transcriptase (RT) activity was measured in the citalopram treatment condition and the control condition. Results The SSRI significantly downregulated the RT response in both the acute and chronic infection models. Specifically, citalopram significantly decreased the acute HIV infectivity of macrophages. Citalopram also significantly decreased HIV viral replication in the latently infected T-cell line and in the latently infected macrophage cell line. There was no difference in down-regulation by depression status. Conclusions These studies suggest that an SSRI enhances NK/CD8 non-cytolytic HIV suppression in HIV/AIDS and decreases HIV viral infectivity of macrophages, ex vivo, suggesting the need for in vivo studies to determine a potential role for agents targeting serotonin in the host defense against HIV. PMID:20947783

  1. Etravirine as a Switching Option for Patients with HIV RNA Suppression: A Review of Recent Trials

    PubMed Central

    Nelson, Mark; Hill, Andrew; van Delft, Yvon; Moecklinghoff, Christiane

    2014-01-01

    Unlike other nonnucleoside reverse transcriptase inhibitors, etravirine is only approved for use in treatment-experienced patients. In the DUET 1 and 2 trials, 1203 highly treatment-experienced patients were randomized to etravirine or placebo, in combination with darunavir/ritonavir and optimized background treatment. In these trials, etravirine showed significantly higher rates of HIV RNA suppression when compared with placebo (61% versus 40% at Week 48). There was no significant rise of lipids or neuropsychiatric adverse events, but there was an increase in the risk of rash with etravirine treatment. In the SENSE trial, which evaluated etravirine and efavirenz in 157 treatment-naïve patients in combination with 2 nucleoside analogues, there was a lower risk of lipid elevations and neuropsychiatric adverse events with etravirine when compared to efavirenz. Etravirine has been evaluated in three randomized switching studies. In the SSAT029 switch trial, 38 patients who had neuropsychiatric adverse events possibly related to efavirenz showed an improvement in these after switching to etravirine. The Swiss Switch-EE recruited 58 individuals without neuropsychiatric adverse events who were receiving efavirenz, and no benefit was shown when switching to etravirine. In the Spanish ETRA-SWITCH trial (n = 46), there were improvements in lipids when individuals switched from a protease inhibitor to etravirine. These switching trials were conducted in patients with full HIV RNA suppression: <50 copies/mL and with no history of virological failure or resistance to therapy. The results from these three randomized switching studies suggest a possible new role for etravirine, in combination with two nucleoside analogues, as a switching option for those with HIV RNA suppression but who are reporting adverse events possibly related to antiretroviral therapy. However a large well-powered trial would need to be conducted to strengthen the evidence from the pilot studies conducted

  2. Influence of Hepatitis C Virus Sustained Virological Response on Immunosuppressive Tryptophan Catabolism in ART-Treated HIV/HCV Coinfected Patients

    PubMed Central

    Jenabian, Mohammad-Ali; Mehraj, Vikram; Costiniuk, Cecilia T.; Vyboh, Kishanda; Kema, Ido; Rollet, Kathleen; Paulino Ramirez, Robert; Klein, Marina B.

    2016-01-01

    Background: We previously reported an association between tryptophan (Trp) catabolism and immune dysfunction in HIV monoinfection. Coinfection with HIV is associated with more rapid evolution of hepatitis C virus (HCV)–associated liver disease despite antiretroviral therapy (ART), possibly due to immune dysregulation. We hypothesized that liver fibrosis in HIV/HCV coinfection would be associated with immune dysfunction and alterations in Trp metabolism. Methods: Trp catabolism and inflammatory soluble markers were assessed in plasma samples from ART-treated HIV/HCV-coinfected patients (n = 90) compared with ART-treated HIV-monoinfected patients and noninfected subjects. Furthermore, 17 additional coinfected patients with sustained virological response (SVR) were assessed longitudinally 6 months after completion of interferon-α/ribavirin treatment. Results: HIV/HCV patients had higher Trp catabolism compared with HIV-monoinfected and healthy individuals. Elevated kynurenine levels in HIV/HCV patients with liver fibrosis correlated with the prognostic aspartate aminotransaminase to platelet ratio (APRI scores) and insulin levels. Furthermore, HIV/HCV patients had elevated levels of disease progression markers interleukin-6 and induced protein 10 and shared similar levels of markers of microbial translocation (intestinal fatty acid-binding protein, soluble CD14 and lipopolysaccharide-binding protein) compared with HIV-monoinfected and healthy individuals. Successful HCV treatment improved APRI score and markers of disease progression and microbial translocation although elevated Trp catabolism remained unchanged 6 months after SVR. Conclusion: ART-treated HIV/HCV-coinfected patients had elevated immunosuppressive Trp catabolism when compared with monoinfected HIV-treated patients, which did not normalize after SVR. These findings suggest that a necroinflammatory liver syndrome persists through inflammation by Trp catabolism after 6 month of SVR. PMID:26436613

  3. Long-term immunologic and virologic responses on raltegravir-containing regimens among ART-experienced participants in the HIV Outpatient Study

    PubMed Central

    Buchacz, Kate; Wiegand, Ryan; Armon, Carl; Chmiel, Joan S.; Wood, Kathleen; Brooks, John T.; Palella, Frank J.

    2015-01-01

    Objectives Raltegravir (RAL)-containing antiretroviral therapy (ART) produced better immunologic and virologic responses than optimized background ART in clinical trials of heavily ART-experienced patients, but few data exist on long-term outcomes in routine HIV care. Methods We studied ART-experienced HIV outpatient study (HOPS) participants seen at 10 US HIV-specialty clinics during 2007–2011. We identified patients who started (baseline date) either continuous ≥30 days of RAL-containing or RAL-sparing ART, and used propensity score (PS) matching methods to account for baseline clinical and demographic differences. We used Kaplan–Meier methods and log-rank tests for the matched subsets to evaluate probability of death, achieving HIV RNA <50 copies/ml, and CD4 cell count (CD4) increase of ≥50 cells mm−3 during follow-up. Results Among 784 RAL-exposed and 1062 RAL-unexposed patients, 472 from each group were matched by PS. At baseline, the 472 RAL-exposed patients (mean nadir CD4, 205 cells mm−3; mean baseline CD4, 460 cells mm−3; HIV RNA <50 copies ml−1 in 61%; mean years on prescribed ART, 7.5) were similar to RAL unexposed. During a mean follow-up of over 3 years, mortality rates and immunologic and virologic trajectories did not differ between the two groups. Among patients with detectable baseline HIV RNA levels, 76% of RAL-exposed and 63% of RAL-unexposed achieved HIV RNA <50 copies ml−1 (P=0.51); 69 and 58%, respectively, achieved a CD4 increase ≥50 cells mm−3 (P=0.70). Discussion In our large cohort of US ART-experienced patients with a wide spectrum of clinical history, similar outcomes were observed when prescribed RAL containing versus other contemporary ART. PMID:26126549

  4. High rates of virological failure and drug resistance in perinatally HIV-1-infected children and adolescents receiving lifelong antiretroviral therapy in routine clinics in Togo

    PubMed Central

    Salou, Mounerou; Dagnra, Anoumou Y; Butel, Christelle; Vidal, Nicole; Serrano, Laetitia; Takassi, Elom; Konou, Abla A; Houndenou, Spero; Dapam, Nina; Singo-Tokofaï, Assetina; Pitche, Palokinam; Atakouma, Yao; Prince-David, Mireille; Delaporte, Eric; Peeters, Martine

    2016-01-01

    Introduction Antiretroviral treatment (ART) has been scaled up over the last decade but compared to adults, children living with HIV are less likely to receive ART. Moreover, children and adolescents are more vulnerable than adults to virological failure (VF) and emergence of drug resistance. In this study we determined virological outcome in perinatally HIV-1-infected children and adolescents receiving ART in Togo. Methods HIV viral load (VL) testing was consecutively proposed to all children and adolescents who were on ART for at least 12 months when attending HIV healthcare services for their routine follow-up visit (June to September 2014). Plasma HIV-1 VL was measured using the m2000 RealTime HIV-1 assay (Abbott Molecular, Des Plaines, IL, USA). Genotypic drug resistance was done for all samples with VL>1000 copies/ml. Results and discussion Among 283 perinatally HIV-1-infected children and adolescents included, 167 (59%) were adolescents and 116 (41%) were children. The median duration on ART was 48 months (interquartile range: 28 to 68 months). For 228 (80.6%), the current ART combination consisted of two nucleoside reverse transcriptase inhibitors (NRTIs) (zidovudine and lamivudine) and one non-nucleoside reverse transcriptase inhibitor (NNRTI) (nevirapine or efavirenz). Only 28 (9.9%) were on a protease inhibitor (PI)-based regimen. VL was below the detection limit (i.e. 40 copies/ml) for 102 (36%), between 40 and 1000 copies/ml for 35 (12.4%) and above 1000 copies/ml for 146 (51.6%). Genotypic drug-resistance testing was successful for 125/146 (85.6%); 110/125 (88.0%) were resistant to both NRTIs and NNRTIs, 1/125 (0.8%) to NRTIs only, 4/125 (3.2%) to NNRTIs only and three harboured viruses resistant to reverse transcriptase and PIs. Overall, 86% (108/125) of children and adolescents experiencing VF and successfully genotyped, corresponding thus to at least 38% of the study population, had either no effective ART or had only a single effective drug in

  5. A lymphomagenic role for HIV beyond immune suppression?

    PubMed Central

    Dolcetti, Riccardo; Gloghini, Annunziata; Caruso, Arnaldo

    2016-01-01

    Despite the immune reconstitution promoted by combined antiretroviral therapy (cART), lymphomas still represent the most common type of cancer in HIV-infected individuals. Cofactors related to immunodeficiency such as oncogenic viruses, chronic antigenic stimulation, and cytokine overproduction are thought to be the main drivers of HIV lymphomagenesis, although the current scenario does not convincingly explain the still-high incidence of lymphomas and the occurrence of peculiar lymphoma histotypes in HIV-infected patients under cART. Recent findings are challenging the current view of a mainly indirect role of HIV in lymphoma development and support the possibility that HIV may directly contribute to lymphomagenesis. In fact, mechanisms other than immune suppression involve biologic effects mediated by HIV products that are secreted and accumulate in lymphoid tissues, mainly within lymph node germinal centers. Notably, HIV-infected patients with lymphomas, but not those not affected by these tumors, were recently shown to carry HIV p17 protein variants with enhanced B-cell clonogenic activity. HIV p17 protein variants were characterized by the presence of distinct insertions at the C-terminal region of the protein responsible for a structural destabilization and the acquisition of novel biologic properties. These data are changing the current paradigm assuming that HIV is only indirectly related to lymphomagenesis. Furthermore, these recent findings are consistent with a role of HIV as a critical microenvironmental factor promoting lymphoma development and pave the way for further studies that may lead to the design of more effective strategies for an early identification and improved control of lymphomas in the HIV setting. PMID:26773045

  6. A lymphomagenic role for HIV beyond immune suppression?

    PubMed

    Dolcetti, Riccardo; Gloghini, Annunziata; Caruso, Arnaldo; Carbone, Antonino

    2016-03-17

    Despite the immune reconstitution promoted by combined antiretroviral therapy (cART), lymphomas still represent the most common type of cancer in HIV-infected individuals. Cofactors related to immunodeficiency such as oncogenic viruses, chronic antigenic stimulation, and cytokine overproduction are thought to be the main drivers of HIV lymphomagenesis, although the current scenario does not convincingly explain the still-high incidence of lymphomas and the occurrence of peculiar lymphoma histotypes in HIV-infected patients under cART. Recent findings are challenging the current view of a mainly indirect role of HIV in lymphoma development and support the possibility that HIV may directly contribute to lymphomagenesis. In fact, mechanisms other than immune suppression involve biologic effects mediated by HIV products that are secreted and accumulate in lymphoid tissues, mainly within lymph node germinal centers. Notably, HIV-infected patients with lymphomas, but not those not affected by these tumors, were recently shown to carry HIV p17 protein variants with enhanced B-cell clonogenic activity. HIV p17 protein variants were characterized by the presence of distinct insertions at the C-terminal region of the protein responsible for a structural destabilization and the acquisition of novel biologic properties. These data are changing the current paradigm assuming that HIV is only indirectly related to lymphomagenesis. Furthermore, these recent findings are consistent with a role of HIV as a critical microenvironmental factor promoting lymphoma development and pave the way for further studies that may lead to the design of more effective strategies for an early identification and improved control of lymphomas in the HIV setting. PMID:26773045

  7. GADD45 proteins inhibit HIV-1 replication through specific suppression of HIV-1 transcription.

    PubMed

    Liang, Zhibin; Liu, Ruikang; Zhang, Hui; Zhang, Suzhen; Hu, Xiaomei; Tan, Juan; Liang, Chen; Qiao, Wentao

    2016-06-01

    GADD45 proteins are a group of stress-induced proteins and participate in various cellular pathways including cell cycle regulation, cell survival and death, DNA repair and demethylation. It was recently shown that HIV-1 infection induces the expression of GADD45 proteins. However, the effect of GADD45 on HIV-1 replication has not been studied. Here, we report that overexpression of GADD45 proteins reduces HIV-1 production through suppressing transcription from the HIV-1 LTR promoter. This inhibitory effect is specific to HIV-1, since GADD45 proteins neither inhibit the LTR promoters from other retroviruses nor reduce the production of these viruses. Knockdown of endogenous GADD45 modestly activates HIV-1 in the J-Lat A72 latency cell line, which suggests GADD45 proteins might play a role in maintaining HIV-1 latency. PMID:26994425

  8. Cell-to-Cell Transfer of HIV-1 via Virological Synapses Leads to Endosomal Virion Maturation that Activates Viral Membrane Fusion

    PubMed Central

    Dale, Benjamin M.; McNerney, Gregory P.; Thompson, Deanna L.; Hubner, Wolfgang; de los Reyes, Kevin; Chuang, Frank Y.S.; Huser, Thomas; Chen, Benjamin K.

    2012-01-01

    SUMMARY HIV-1 can infect T cells by cell-free virus or by direct virion transfer between cells through cell contact-induced structures called virological synapses (VS). During VS-mediated infection, virions accumulate within target cell endosomes. We show that after crossing the VS, the transferred virus undergoes both maturation and viral membrane fusion. Following VS transfer, viral membrane fusion occurs with delayed kinetics and transferred virions display reduced sensitivity to patient antisera compared to mature, cell-free virus. Furthermore, particle fusion requires that the transferred virions undergo proteolytic maturation within acceptor cell endosomes, which occurs over several hours. Rapid, live cell confocal microscopy demonstrated that viral fusion can occur in compartments that have moved away from the VS. Thus, HIV particle maturation activates viral fusion in target CD4+ T cell endosomes following transfer across the VS and may represent a pathway by which HIV evades antibody neutralization. PMID:22177560

  9. HIV Drug Resistance Mutations (DRMs) Detected by Deep Sequencing in Virologic Failure Subjects on Therapy from Hunan Province, China

    PubMed Central

    He, Jianmei; Zheng, Jun; Chiarella, Jennifer; Kozal, Michael J.

    2016-01-01

    Objective Determine HIV drug resistance mutations (DRMs) prevalence at low and high levels in ART-experienced patients experiencing virologic failure (VF). Methods 29 subjects from 18 counties in Hunan Province that experienced VF were evaluated for the prevalence of DRMs (Stanford DRMs with an algorithm value ≥15, include low-, intermediate and high-level resistance) by both Sanger sequencing (SS) and deep sequencing (DS) to 1% frequency levels. Results DS was performed on samples from 29 ART-experienced subjects; the median viral load 4.95×104 c/ml; 82.76% subtype CRF01_AE. 58 DRMs were detected by DS. 18 DRMs were detected by SS. Of the 58 mutations detected by DS, 40 were at levels <20% frequency (26 NNRTI, 12 NRTI and 2 PI) and the majority of these 95.00% (38/40) were not detected by standard genotyping. Of these 40 low-level DRMs, 16 (40%) were detected at frequency levels of 1–4% and 24 (60%) at levels of 5–19%. SS detected 15 of 17 (88.24%) DRMs at levels ≥ 20% that were detected by DS. The only variable associated with the detection of DRMs by DS was ART adherence (missed doses in the prior 7 days); all patients that reported missing a dose in the last 7 days had DRMs detected by DS. Conclusions DS of VF samples from treatment experienced subjects infected with primarily AE subtype frequently identified Stanford HIVdb NRTI and NNRTI resistance mutations with an algorithm value 15. Low frequency level resistant variants detected by DS were frequently missed by standard genotyping in VF specimens from antiretroviral-experienced subjects. PMID:26895182

  10. The Effect of Malnutrition on the Pharmacokinetics and Virologic Outcomes of Lopinavir, Efavirenz and Nevirapine in Food Insecure HIV-Infected Children in Tororo, Uganda

    PubMed Central

    Bartelink, Imke H.; Savic, Rada M.; Dorsey, Grant; Ruel, Theodore; Gingrich, David; Scherpbier, Henriette J.; Capparelli, Edmund; Jullien, Vincent; Young, Sera L.; Achan, Jane; Plenty, Albert; Charlebois, Edwin; Kamya, Moses; Havlir, Diane; Aweeka, Francesca

    2014-01-01

    Background Malnutrition may impact the pharmacokinetics (PK) of antiretroviral medications and virologic responses in HIV-infected children. We therefore evaluated the PK of nevirapine (NVP), efavirenz (EFV) and lopinavir (LPV) in associations with nutritional status in a cohort of HIV-infected Ugandan children. Methods Sparse dried blood spot (DBS) samples from Ugandan children were used to estimate plasma concentrations. Historical PK data from children from three resource-rich countries (RRC) were utilized to develop the PK models. Results Concentrations in 330 DBS from 163 Ugandan children aged 0.7–7 years were analyzed in reference to plasma PK data (1189 samples) from 204 children from RRC aged 0.5–12 years. Among Ugandan children 48% was malnourished (underweight, thin or stunted). Compared to RRC, Ugandan children exhibited reduced bioavailability of EFV and LPV; 11% (P=0.045) and 18% (P=0.008) respectively. In contrast, NVP bioavailability was 46% higher in Ugandan children (P<0.001) with a trend towards greater bioavailability when malnourished. Children receiving LPV, EFV or NVP had comparable risk of virologic failure. Among children on NVP, low height and weight for age Z-scores were associated with reduced risk of virologic failure (p=0.034, p=0.068 respectively). Conclusions Ugandan children demonstrated lower EFV and LPV and higher NVP exposure compared to children in RRC, perhaps reflecting the consequence of malnutrition on bioavailability. In children receiving NVP, the relation between exposure, malnutrition and outcome turned out to be marginally significant. Further investigations are warranted using more intensive PK measurements and adequate adherence assessements, to further assess causes of virologic failure in Ugandan children. PMID:25742090

  11. Early Viral Suppression Improves Neurocognitive Outcomes in HIV-infected Children

    PubMed Central

    CROWELL, Claudia S.; HUO, Yanling; TASSIOPOULOS, Katherine; MALEE, Kathleen M.; YOGEV, Ram; HAZRA, Rohan; RUTSTEIN, Richard M.; NICHOLS, Sharon L.; SMITH, Renee A.; WILLIAMS, Paige L.; OLESKE, James; MULLER, William J.

    2014-01-01

    Objective To estimate the association of age of viral suppression and central nervous system penetration effectiveness (CPE) score with neurocognitive functioning among school-age children with perinatally-acquired HIV infection (PHIV+). Design We analyzed data from two U.S.-based multisite prospective cohort studies. Methods Multivariable general linear regression models were used to evaluate associations of age at viral suppression and CPE scores [of initial ART regimen and weighted average] with WISC-III or WISC-IV neurocognitive assessments [full scale IQ (FSIQ); performance IQ/ perceptual reasoning index (PIQ/PRI); and verbal IQ/ verbal comprehension index (VIQ/VCI)], adjusted for demographic and clinical covariates. Sensitivity analyses were stratified by birth cohort (before vs after 1996). Results 396 PHIV+ children were included. Estimated differences in mean FSIQ (comparing virally suppressed vs. unsuppressed children) by each age cutoff were 3.7, 2.2, 3.2, 4.4, and 3.9 points at ages 1, 2, 3, 4, and 5, respectively. For PIQ/PRI, estimated mean differences were 3.7, 2.4, 2.2, 4.6, and 4.5 at ages 1 through 5 respectively. In both cases, these differences were significant only at the age 4 and 5 thresholds. After stratifying by birth cohort the association between age at suppression and cognitive function persisted only among those born after 1996. Age at viral suppression was not associated with VIQ/VCI; CPE score was not associated with FSIQ, verbal comprehension or perceptual reasoning indices. Conclusions Virologic suppression during infancy or early childhood is associated with improved neurocognitive outcomes in school-aged PHIV+ children. In contrast, CPE scores showed no association with neurocognitive outcomes. PMID:25686678

  12. Development and Evaluation of an Affordable Real-Time Qualitative Assay for Determining HIV-1 Virological Failure in Plasma and Dried Blood Spots

    PubMed Central

    Kliphuis, Aletta; Bronze, Michelle; Wallis, Carole L.; Kityo, Cissy; Balinda, Sheila; Stevens, Wendy; Spieker, Nicole; de Oliveira, Tulio; Rinke de Wit, Tobias F.; Schuurman, Rob

    2013-01-01

    Virological failure (VF) has been identified as the earliest, most predictive determinant of HIV-1 antiretroviral treatment (ART) failure. Due to the high cost and complexity of virological monitoring, VF assays are rarely performed in resource-limited settings (RLS). Rather, ART failure is determined by clinical monitoring and to a large extent immunological monitoring. This paper describes the development and evaluation of a low-cost, dried blood spot (DBS)-compatible qualitative assay to determine VF, in accordance with current WHO guideline recommendations for therapy switching in RLS. The assay described here is an internally controlled qualitative real-time PCR targeting the conserved long terminal repeat domain of HIV-1. This assay was applied to HIV-1 subtypes A to H and further evaluated on HIV-1 clinical plasma samples from South Africa (n = 191) and Tanzania (n = 42). Field evaluation was performed in Uganda using local clinical plasma samples (n = 176). Furthermore, assay performance was evaluated for DBS. This assay is able to identify VF for all major HIV-1 group M subtypes with equal specificity and has a lower detection limit of 1.00E+03 copies/ml for plasma samples and 5.00E+03 copies/ml for DBS. Comparative testing yielded accurate VF determination for therapy switching in 89% to 96% of samples compared to gold standards. The assay is robust and flexible, allowing for “open platform” applications and producing results comparable to those of commercial assays. Assay design enables application in laboratories that can accommodate real-time PCR equipment, allowing decentralization of testing to some extent. Compatibility with DBS extends access of sampling and thus access to this test to remote settings. PMID:23596235

  13. Circulating HIV DNA Correlates With Neurocognitive Impairment in Older HIV-infected Adults on Suppressive ART

    PubMed Central

    Oliveira, Michelli Faria de; Murrel, Ben; Pérez-Santiago, Josué; Vargas, Milenka; Ellis, Ronald J.; Letendre, Scott; Grant, Igor; Smith, Davey M.; Woods, Steven Paul; Gianella, Sara

    2015-01-01

    Older HIV-infected adults have a higher risk of neurocognitive impairment, but the underlying mechanisms are poorly understood. Here, we investigated the associations between levels of HIV DNA in peripheral blood, soluble markers of inflammation and cellular trafficking in blood and cerebrospinal fluid (CSF) and neurocognitive functioning among 18 younger (22–40 years) and 26 older (50–71 years) HIV-infected subjects, who were administered a comprehensive neurocognitive battery. Older HIV-infected individuals presented higher levels of inflammation in CSF and blood compared to younger individuals, but no difference was observed in HIV DNA levels. Among older participants, higher HIV DNA levels were significantly associated with more severe neurocognitive impairment (p = 0.005), particularly in the Executive Functions domain (p = 0.004). No association was observed between HIV DNA and neurocognition among younger individuals. Despite significantly increased inflammation observed in the older group, none of the inflammatory markers were associated with neurocognitive impairment among older HIV+ individuals (p > 0.05). Our study supports the involvement of peripheral HIV DNA reservoir in the pathogenesis of neurocognitive disorder during suppressive ART. Correlates of neurocognitive impairment might differ between younger and older adults, suggesting that future treatment and prevention strategies for HIV-associated neurocognitive disorders likely need to be tailored based on age. PMID:26603568

  14. Rapid HIV Viral Load Suppression in those Initiating Antiretroviral Therapy at First Visit after HIV Diagnosis.

    PubMed

    Hoenigl, Martin; Chaillon, Antoine; Moore, David J; Morris, Sheldon R; Mehta, Sanjay R; Gianella, Sara; Amico, K Rivet; Little, Susan J

    2016-01-01

    Expert guidelines for antiretroviral therapy (ART) now recommend ART as soon as possible in all HIV infected persons to reduce the risk of disease progression and prevent transmission. The goal of this observational study was to evaluate the impact of very early ART initiation and regimen type on time to viral suppression. We evaluated time to viral suppression among 86 persons with newly-diagnosed HIV infection who initiated ART within 30 days of diagnosis. A total of 36 (42%) had acute, 27 (31%) early, and 23 (27%) had established HIV infection. The median time from an offer of immediate ART to starting ART was 8 days. A total of 56/86 (65%) initiated an integrase inhibitor-based regimen and 30/86 (35%) a protease inhibitor-based regimen. The time to viral suppression was significantly shorter in those receiving an integrase inhibitor- versus a protease inhibitor-based regimen (p = 0.022). Twenty-two (26%) initiated ART at their HIV care intake visit and 79% of these participants achieved viral suppression at week 12, 82% at week 24 and 88% at week 48. ART initiated at the intake visit led to rapid and reliable viral suppression in acute, early and chronic HIV infection, in particular when integrase inhibitor-based regimens were used. PMID:27597312

  15. Rapid HIV Viral Load Suppression in those Initiating Antiretroviral Therapy at First Visit after HIV Diagnosis

    PubMed Central

    Hoenigl, Martin; Chaillon, Antoine; Moore, David J.; Morris, Sheldon R.; Mehta, Sanjay R.; Gianella, Sara; Amico, K. Rivet; Little, Susan J.

    2016-01-01

    Expert guidelines for antiretroviral therapy (ART) now recommend ART as soon as possible in all HIV infected persons to reduce the risk of disease progression and prevent transmission. The goal of this observational study was to evaluate the impact of very early ART initiation and regimen type on time to viral suppression. We evaluated time to viral suppression among 86 persons with newly-diagnosed HIV infection who initiated ART within 30 days of diagnosis. A total of 36 (42%) had acute, 27 (31%) early, and 23 (27%) had established HIV infection. The median time from an offer of immediate ART to starting ART was 8 days. A total of 56/86 (65%) initiated an integrase inhibitor-based regimen and 30/86 (35%) a protease inhibitor-based regimen. The time to viral suppression was significantly shorter in those receiving an integrase inhibitor- versus a protease inhibitor-based regimen (p = 0.022). Twenty-two (26%) initiated ART at their HIV care intake visit and 79% of these participants achieved viral suppression at week 12, 82% at week 24 and 88% at week 48. ART initiated at the intake visit led to rapid and reliable viral suppression in acute, early and chronic HIV infection, in particular when integrase inhibitor-based regimens were used. PMID:27597312

  16. On the front line of HIV virological monitoring: barriers and facilitators from a provider perspective in resource-limited settings.

    PubMed

    Rutstein, S E; Golin, C E; Wheeler, S B; Kamwendo, D; Hosseinipour, M C; Weinberger, M; Miller, W C; Biddle, A K; Soko, A; Mkandawire, M; Mwenda, R; Sarr, A; Gupta, S; Mataya, R

    2016-01-01

    Scale-up of viral load (VL) monitoring for HIV-infected patients on antiretroviral therapy (ART) is a priority in many resource-limited settings, and ART providers are critical to effective program implementation. We explored provider-perceived barriers and facilitators of VL monitoring. We interviewed all providers (n = 17) engaged in a public health evaluation of dried blood spots for VL monitoring at five ART clinics in Malawi. All ART clinics were housed within district hospitals. We grouped themes at patient, provider, facility, system, and policy levels. Providers emphasized their desire for improved ART monitoring strategies, and frustration in response to restrictive policies for determining which patients were eligible to receive VL monitoring. Although many providers pled for expansion of monitoring to include all persons on ART, regardless of time on ART, the most salient provider-perceived barrier to VL monitoring implementation was the pressure of work associated with monitoring activities. The work burden was exacerbated by inefficient data management systems, highlighting a critical interaction between provider-, facility-, and system-level factors. Lack of integration between laboratory and clinical systems complicated the process for alerting providers when results were available, and these communication gaps were intensified by poor facility connectivity. Centralized second-line ART distribution was also noted as a barrier: providers reported that the time and expenses required for patients to collect second-line ART frequently obstructed referral. However, provider empowerment emerged as an unexpected facilitator of VL monitoring. For many providers, this was the first time they used an objective marker of ART response to guide clinical management. Providers' knowledge of a patient's virological status increased confidence in adherence counseling and clinical decision-making. Results from our study provide unique insight into provider

  17. Boosted Lopinavir– Versus Boosted Atazanavir–Containing Regimens and Immunologic, Virologic, and Clinical Outcomes: A Prospective Study of HIV-Infected Individuals in High-Income Countries

    PubMed Central

    2015-01-01

    Background. Current clinical guidelines consider regimens consisting of either ritonavir-boosted atazanavir or ritonavir-boosted lopinavir and a nucleoside reverse transcriptase inhibitor (NRTI) backbone among their recommended and alternative first-line antiretroviral regimens. However, these guidelines are based on limited evidence from randomized clinical trials and clinical experience. Methods. We compared these regimens with respect to clinical, immunologic, and virologic outcomes using data from prospective studies of human immunodeficiency virus (HIV)-infected individuals in Europe and the United States in the HIV-CAUSAL Collaboration, 2004–2013. Antiretroviral therapy–naive and AIDS-free individuals were followed from the time they started a lopinavir or an atazanavir regimen. We estimated the ‘intention-to-treat’ effect for atazanavir vs lopinavir regimens on each of the outcomes. Results. A total of 6668 individuals started a lopinavir regimen (213 deaths, 457 AIDS-defining illnesses or deaths), and 4301 individuals started an atazanavir regimen (83 deaths, 157 AIDS-defining illnesses or deaths). The adjusted intention-to-treat hazard ratios for atazanavir vs lopinavir regimens were 0.70 (95% confidence interval [CI], .53–.91) for death, 0.67 (95% CI, .55–.82) for AIDS-defining illness or death, and 0.91 (95% CI, .84–.99) for virologic failure at 12 months. The mean 12-month increase in CD4 count was 8.15 (95% CI, −.13 to 16.43) cells/µL higher in the atazanavir group. Estimates differed by NRTI backbone. Conclusions. Our estimates are consistent with a lower mortality, a lower incidence of AIDS-defining illness, a greater 12-month increase in CD4 cell count, and a smaller risk of virologic failure at 12 months for atazanavir compared with lopinavir regimens. PMID:25567330

  18. Pharmacology and immuno-virologic efficacy of once-a-day HAART in African HIV-infected children: ANRS 12103 phase II trial

    PubMed Central

    Nacro, Boubacar; Zoure, Emmanuelle; Hien, Hervé; Tamboura, Hassane; Rouet, François; Ouiminga, Adama; Drabo, Ali; Yameogo, Souleymane; Hien, Alain; Peyriere, Hélène; Mathieu, Olivier; Hirt, Deborah; Treluyer, Jean-Marc; Nicolas, Joëlle; Foulongne, Vincent; Segondy, Michel; van de Perre, Philippe; Diagbouga, Serge

    2011-01-01

    Abstract Objective To assess 12-month survival, pharmacokinetics, immunologic and virologic efficacy, tolerance, compliance and drug resistance in HIV-infected children in Bobo-Dioulasso, Burkina Faso, receiving once-daily highly-active antiretroviral therapy as a combination of didanosine (DDI), lamivudine (3TC) and efavirenz (EFV). Methods In the ANRS 12103 open phase II trial, HIV-infected children were examined at inclusion and monthly thereafter. CD4+ T-lymphocyte (CD4) count, plasma concentration of ribonucleic acid (RNA) of human immunodeficiency virus type 1 (HIV-1) and haematologic and biochemical parameters were measured at baseline and every trimester. HIV-1 resistance testing was performed in case of viral escape. Drug plasma concentrations were determined with high-performance liquid chromatography. Findings From February 2006 to November 2007, 51 children (39% girls) with a mean age of 6.8 years were enrolled and treated for 12 months. At baseline, Z scores for mean weight-for-age and mean height-for-age were −2.01 and −2.12, respectively. Mean CD4% was 9.0. Median plasma HIV-1 RNA viral load was 5.51 log10 copies per millilitre (cp/ml). Two children (3.9%) died and another 11 (22%) suffered 13 severe clinical events. At month 12, mean WAZ had improved by 0.63 (P < 0.001) and mean HAZ by 0.57 (P < 0.001). Mean CD4% had risen to 24 (P < 0.001). Viral load was below 300 RNA cp/ml in 81% of the children; HIV resistance mutations were detected in 11 (21.6%). Conclusion The once-a-day combination of DDI + 3TC + EFV is an alternative first-line treatment for HIV-1-infected children. Dose adjustment should further improve efficacy. PMID:21673861

  19. Innate immune reconstitution with suppression of HIV-1

    PubMed Central

    Scully, Eileen P.; Lockhart, Ainsley; Garcia-Beltran, Wilfredo; Palmer, Christine D.; Musante, Chelsey; Rosenberg, Eric; Allen, Todd M.; Chang, J. Judy; Bosch, Ronald J.; Altfeld, Marcus

    2016-01-01

    Progressive HIV-1 infection leads to both profound immune suppression and pathologic inflammation in the majority of infected individuals. While adaptive immune dysfunction, as evidenced by CD4+ T cell depletion and exhaustion, has been extensively studied, less is known about the functional capacity of innate immune cell populations in the context of HIV-1 infection. Given the broad susceptibility to opportunistic infections and the dysregulated inflammation observed in progressive disease, we hypothesized that there would be significant changes in the innate cellular responses. Using a cohort of patients with multiple samplings before and after antiretroviral therapy (ART) initiation, we demonstrated increased responses to innate immune stimuli following viral suppression, as measured by the production of inflammatory cytokines. Plasma viral load itself had the strongest association with this change in innate functional capacity. We further identified epigenetic modifications in the TNFA promoter locus in monocytes that are associated with viremia, suggesting a molecular mechanism for the observed changes in innate immune function following initiation of ART. These data indicate that suppression of HIV-1 viremia is associated with changes in innate cellular function that may in part determine the restoration of protective immune responses. PMID:27158667

  20. Undergraduate Virology Exercises Demonstrate Conventional and Real-Time PCR Using Commercially Available HIV Primers and Noninfectious Target

    ERIC Educational Resources Information Center

    Sulzinski, Michael A.; Wasilewski, Melissa A.; Farrell, James C.; Glick, David L.

    2009-01-01

    It is an extraordinary challenge to offer an undergraduate laboratory course in virology that teaches hands-on, relevant molecular biology techniques using nonpathogenic models of human virus detection. To our knowledge, there exists no inexpensive kits or reagent sets that are appropriate for demonstrating real-time PCR (RT-PCR) in an…

  1. Low rate of virological failure and maintenance of susceptibility to HIV-1 protease inhibitors with first-line lopinavir/ritonavir-based antiretroviral treatment in clinical practice.

    PubMed

    Prosperi, Mattia C F; Zazzi, Maurizio; Punzi, Grazia; Monno, Laura; Colao, Grazia; Corsi, Paola; Di Giambenedetto, Simona; Meini, Genny; Ghisetti, Valeria; Bonora, Stefano; Pecorari, Monica; Gismondo, Maria Rita; Bagnarelli, Patrizia; Carli, Tiziana; De Luca, Andrea

    2010-12-01

    Protease inhibitor (PI)-resistant HIV-1 has hardly ever been detected at failed boosted PI-based first-line antiretroviral regimens in clinical trials. However, this phenomenon has not been investigated in clinical practice. To address this gap, data from patients starting a first-line lopinavir/ritonavir (LPV/rtv)-based therapy with available baseline HIV-1 RNA load, a viral genotype and follow-up viral load after 3 and 6 months of treatment were extracted from the Italian Antiretroviral Resistance Cohort Analysis (ARCA) observational database. Based on survival analysis, 39 (7.1%) and 43 (7.8%) of the 548 examined patient cases had an HIV-1 RNA >500 and >50 copies/ml, respectively, after 6 months of treatment. Cox proportional hazard models detected baseline HIV-1 RNA (RH 1.79, 95%CI 1.10-2.92 per 1-log(10) increase, P=0.02) and resistance to the nucleoside backbone (RH 1.04, 95%CI 1.02-1.06 per 10-point increase using the Stanford HIVdb algorithm, P<0.001) as independent predictors of HIV-1 RNA at >500 copies/ml, but not at the >50 copies/ml cutoff criteria. Higher baseline viral load, older patient age, heterosexual route of infection and use of tenofovir/emtricitabine were predictors of failure at month 3 using the 50-copy and/or 500-copy threshold. Resistance to LPV/rtv did not occur or increase in any of the available 36 follow-up HIV-1 genotypes. Resistance to the nucleoside backbone (M184V) developed in four cases. Despite the likely differences in patient population and adherence, both the low rate of virological failure and the lack of development of LPV/rtv resistance documented in clinical trials are thus confirmed in clinical practice. PMID:20981785

  2. Effect of directly observed antiretroviral therapy compared to self-administered antiretroviral therapy on adherence and virological outcomes among HIV-infected prisoners: a randomized controlled pilot study.

    PubMed

    White, Becky L; Golin, Carol E; Grodensky, Catherine A; Kiziah, C Nichole; Richardson, Amy; Hudgens, Michael G; Wohl, David A; Kaplan, Andrew H

    2015-01-01

    The effect of directly observed therapy (DOT) versus self-administered therapy (SAT) on antiretroviral (ART) adherence and virological outcomes in prison has never been assessed in a randomized, controlled trial. Prisoners were randomized to receive ART by DOT or SAT. The primary outcome was medication adherence [percent of ART doses measured by the medication event monitoring system (MEMS) and pill counts] at the end of 24 weeks. The changes in the plasma viral loads from baseline and proportion of participants virological suppressed (<400 copies/mL) at the end of 24 weeks were assessed. Sixty-six percent (90/136) of eligible prisoners declined participation. Participants in the DOT arm (n = 20) had higher viral loads than participants in the SAT (n = 23) arm (p = 0.23). Participants, with complete data at 24 weeks, were analyzed as randomized. There were no significant differences in median ART adherence between the DOT (n = 16, 99% MEMS [IQR 93.9, 100], 97.1 % pill count [IQR 95.1, 99.3]) and SAT (n = 21, 98.3 % MEMS [IQR 96.0, 100], 98.5 % pill count [95.8, 100]) arms (p = 0.82 MEMS, p = 0.40 Pill Count) at 24 weeks. Participants in the DOT arm had a greater reduction in viral load of approximately -1 log 10 copies/mL [IQR -1.75, -0.05] compared to -0.05 [IQR -0.45, 0.51] in the SAT arm (p value = 0.02) at 24 weeks. The proportion of participants achieving virological suppression in the DOT vs SAT arms was not statistically different at 24 weeks (53 % vs 32 %, p = 0.21). These findings suggest that DOT ART programs in prison settings may not offer any additional benefit on adherence than SAT programs. PMID:25055766

  3. A single tablet regimen is associated with higher adherence and viral suppression than multiple tablet regimens in HIV+ homeless and marginally housed people

    PubMed Central

    Bangsberg, David R; Ragland, Kathleen; Monk, Alex; Deeks, Steven G

    2013-01-01

    Although, single tablet regimen (STR) efavirenz, emtricibine, and tenofovir disoproxil fumarate (EFV/FTC/TDF) may be appealing in HIV infected persons who are at high risk for non-adherence, the degree to which this simplified formulation affects adherence is not known. The virologic effectiveness of this STR in a potentially non-adherent population remains a concern, given the rapid selection of drug-resistance seen with these drugs. We performed a prospective observational study assessing adherence and virologic response to EFV/FTC/TDF STR among a cohort of homeless and marginally housed individuals. We compared adherence and viral suppression to historical controls followed in the same cohort. Adherence was higher in EFV/FTC/TDF STR regimen compared to non-one-pill once daily therapy (p=0.0060) after controlling for multiple confounders. Viral suppression (HIV RNA <50 c/ml) was greater in EFV/FTC/TDF STR than non-one pill daily regimens (69.2% vs 46.5%; p=0.02), but there was no difference in viral suppression after controlling for adherence. Once daily EFV/TNF/FTC STR appears to be a reasonable option for individuals with multiple barriers to adherence. Randomized clinical trials addressing various therapeutic strategies for this patient population are needed. PMID:21045636

  4. Pediatric Virology

    PubMed Central

    Portnoy, Bernard

    1965-01-01

    Pediatric virology is not an isolàted discipline. Rather, the syndromes associated with viral infection are modified by the unique characteristics of infancy and childhood. Fortunately for the pediatrician, and certainly for children, viral infections in childhood are rarely fatal, and are almost never serious. Future efforts of the pediatrician and virologist should be directed toward increased fetal salvage as with rubella and the prevention of severe, viral lower respiratory tract disease. PMID:14298871

  5. (1→3)-β-D-Glucan Levels Correlate With Neurocognitive Functioning in HIV-Infected Persons on Suppressive Antiretroviral Therapy: A Cohort Study.

    PubMed

    Hoenigl, Martin; de Oliveira, Michelli Faria; Pérez-Santiago, Josué; Zhang, Yonglong; Morris, Sheldon; McCutchan, Allen J; Finkelman, Malcolm; Marcotte, Thomas D; Ellis, Ronald J; Gianella, Sara

    2016-03-01

    Microbial translocation from the gut is associated with immune dysfunction, persistent inflammation, and likely plays a role in the pathogenesis of neurocognitive dysfunction during HIV infection. (1→3)-β-D-Glucan (BDG) is a component of most fungal cell walls and might be a useful indicator of gut mucosal barrier impairment. The objective of this study was to evaluate whether higher blood BDG levels correlate with impaired neurocognitive functioning in a cohort of HIV-infected adults with suppressed levels of HIV RNA in blood plasma. In this cross-sectional cohort study, we measured levels of BDG in blood plasma and cerebrospinal fluid (CSF) supernatant samples in a cohort of adults with acute/early HIV infection, who initiated antiretroviral therapy (ART) during the earliest phase of infection and achieved suppressed levels of HIV RNA in blood plasma (<50 copies/mL) thereafter. We compared BDG with established biomarkers of microbial translocation, immune activation, and cognitive dysfunction (evaluated by global deficit score). We found that higher blood BDG levels were significantly related to higher global deficit scores, reflecting worse neurocognitive performance (Spearman r = 0.47; P = 0.042) among HIV-infected adults with suppressed viral loads who initiated ART early in infection. Two CSF samples presented elevated BDG levels. Interestingly, these 2 samples originated from the 2 subjects with the highest global deficit scores of the cohort. BDG may be a promising independent biomarker associated with neurocognitive functioning in virologically suppressed HIV-infected individuals. PMID:26986173

  6. (1→3)-β-D-Glucan Levels Correlate With Neurocognitive Functioning in HIV-Infected Persons on Suppressive Antiretroviral Therapy

    PubMed Central

    Hoenigl, Martin; de Oliveira, Michelli Faria; Pérez-Santiago, Josué; Zhang, Yonglong; Morris, Sheldon; McCutchan, Allen J.; Finkelman, Malcolm; Marcotte, Thomas D.; Ellis, Ronald J.; Gianella, Sara

    2016-01-01

    Abstract Microbial translocation from the gut is associated with immune dysfunction, persistent inflammation, and likely plays a role in the pathogenesis of neurocognitive dysfunction during HIV infection. (1→3)-β-D-Glucan (BDG) is a component of most fungal cell walls and might be a useful indicator of gut mucosal barrier impairment. The objective of this study was to evaluate whether higher blood BDG levels correlate with impaired neurocognitive functioning in a cohort of HIV-infected adults with suppressed levels of HIV RNA in blood plasma. In this cross-sectional cohort study, we measured levels of BDG in blood plasma and cerebrospinal fluid (CSF) supernatant samples in a cohort of adults with acute/early HIV infection, who initiated antiretroviral therapy (ART) during the earliest phase of infection and achieved suppressed levels of HIV RNA in blood plasma (<50 copies/mL) thereafter. We compared BDG with established biomarkers of microbial translocation, immune activation, and cognitive dysfunction (evaluated by global deficit score). We found that higher blood BDG levels were significantly related to higher global deficit scores, reflecting worse neurocognitive performance (Spearman r = 0.47; P = 0.042) among HIV-infected adults with suppressed viral loads who initiated ART early in infection. Two CSF samples presented elevated BDG levels. Interestingly, these 2 samples originated from the 2 subjects with the highest global deficit scores of the cohort. BDG may be a promising independent biomarker associated with neurocognitive functioning in virologically suppressed HIV-infected individuals. PMID:26986173

  7. Exploring the limits of optical microscopy: live cell and superresolution fluorescence microscopy of HIV-1 Transfer Between T lymphocytes Across the Virological Synapse

    NASA Astrophysics Data System (ADS)

    McNerney, Gregory Paul

    Human immunodeficiency virus 1 (HIV-1) is a human retrovirus that efficiently, albeit gradually, overruns the immune system. An already infected T lymphocyte can latch onto another T lymphocyte whereby creating a virological synapse (VS); this junction drives viral assembly and transfer to the target cell in batches in an efficient, protective manor. My Ph.D. doctoral thesis focused on studying this transmission mechanism using advanced optical imaging modalities and the fully infectious fluorescent clone HIV Gag-iGFP. T lymphocytes are non-adherent cells (˜10 um thick) and the viral transmission process is fairly dynamic, hence we employed a custom spinning disk confocal microscope that revealed many interesting characteristics of this cooperative event. This methodology has low throughput as cell contact and transfer is at random. Optical tweezers was then added to the microscope to directly initiate cell contact at will. To assess when viral maturation occurs post-transfer, an optical assay based off of Forster resonance energy transfer was developed to monitor maturation. Structured illumination microscopy was further used to image the process at higher resolution and it showed that viral particles are not entering existing degradative compartments. Non-HIV-1 applications of the optical technologies are also reviewed.

  8. Suppression of HIV Replication by Lymphoid Tissue CD8+ Cells Correlates with the Clinical State of HIV-Infected Individuals

    NASA Astrophysics Data System (ADS)

    Blackbourn, David J.; Mackewicz, Carl E.; Barker, Edward; Hunt, Thomas K.; Herndier, Brian; Haase, Ashley T.; Levy, Jay A.

    1996-11-01

    Lymphoid tissues from asymptomatic HIV-infected individuals, as compared with symptomatic HIV-infected subjects, show limited histopathological changes and lower levels of HIV expression. In this report we correlate the control of HIV replication in lymph nodes to the non-cytolytic anti-HIV activity of lymphoid tissue CD8+ cells. Five subjects at different stages of HIV-related disease were studied and the ability of their CD8+ cells, isolated from both lymphoid tissue and peripheral blood, to inhibit HIV replication was compared. CD8+ cells from lymphoid tissue and peripheral blood of two HIV-infected long-term survivors suppressed HIV replication at a low CD8+:CD4+ cell ratio of 0.1. The CD8+ cells from the lymphoid tissue of a third asymptomatic subject suppressed HIV replication at a CD8+:CD4+ cell ratio of 0.25; the subject's peripheral blood CD8+ cells showed this antiviral response at a lower ratio of 0.05. The lymphoid tissue CD8+ cells from two AIDS patients were not able to suppress HIV replication, and the peripheral blood CD8+ cells of only one of them suppressed HIV replication. The plasma viremia, cellular HIV load as well as the extent of pathology and virus expression in the lymphoid tissue of the two long-term survivors, were reduced compared with these parameters in the three other subjects. The data suggest that the extent of anti-HIV activity by CD8+ cells from lymphoid tissue relative to peripheral blood correlates best with the clinical state measured by lymphoid tissue pathology and HIV burden in lymphoid tissues and blood. The results and further emphasis to the importance of this cellular immune response in controlling HIV pathogenesis.

  9. [Detection of the viral load and its use as a virological marker in the follow-up of HIV-1-positive patients].

    PubMed

    Hodara, V L; Monticelli, A; Benetucci, J; Lasala, M; Jauregui Rueda, H; Libonatti, O; García Messina, O; Reboredo, G; Bogdanowicz, E; Bases, O; Pampuro, S; Salomón, H

    1998-01-01

    The evaluation of viral load as virological marker and its clinical and immunological correlation are presented. The first viral load studies were performed during 1996 at the National Reference Center for AIDS in Argentina in HIV-1 positive patients derived from different Hospitals in Buenos Aires. The study included 216 HIV-1 positive patients, 49 females and 167 males. Plasma was used for evaluating viral load and a second sample was obtained in 25 of the 216 patients for their monitoring. Viral load was performed using bDNA technique (Quantiplex HIV RNA assay 2.0, Chiron Corporation, USA). Other parameters such as CD4 count determined by flow cytometry and clinical stages according to CDC classification were obtained in order to correlate clinical and immunological status of the patients. When CD4 count was compared with viral load, the results showed a trend of viral RNA increase in plasma along with a decrease in CD4+ lymphocytes. This trend was also observed to correlate with the progression to AIDS disease. In all groups of patients, considering either CD4 counts or clinical status, ranges of viral load values were broad. Thus, as shown by percentiles 25 and 75, patients with CD4 counts < 200/ml, presented viral load values between 18,395 c/ml to 215,425 c/ml and patients with > 200/ml viral RNA showed values from < 10,000 to 35,180 c/ml. Patients with CDC's A and B stages presented values from < 10,000 to 45,160 c/ml and 87,000 c/ml respectively, while patients classified as C had 10,582 to 215,000 c/ml. Results of two consecutive samples in the 25 patients showed the usefulness of this technique for monitoring antiretroviral therapy. Nevertheless, despite the tendency of viral load to increase along with the progression of the disease, the broad range of values suggested the importance of using both virological and immunological parameters for the management of HIV infected patients. PMID:9629601

  10. Comparison of Three Different FDA-Approved Plasma HIV-1 RNA Assay Platforms Confirms the Virologic Failure Endpoint of 200 Copies per Milliliter Despite Improved Assay Sensitivity

    PubMed Central

    Jennings, Cheryl; Johnson, Victoria A.; Coombs, Robert W.; McKinnon, John E.; Bremer, James W.; Cobb, Bryan R.; Cloherty, Gavin A.; Mellors, John W.; Ribaudo, Heather J.

    2015-01-01

    Discrepancies between HIV-1 RNA results assayed by different FDA-approved platforms have been reported. Plasma samples collected from 332 randomly selected clinical trial participants during the second year of antiretroviral treatment were assayed with three FDA-approved platforms: UltraSensitive Roche Amplicor Monitor, v1.5 (Monitor), the Abbott RealTime HIV-1 test on the m2000 system (Abbott), and the Roche TaqMan HIV-1 test, v2.0 (TaqMan). Samples from 61 additional participants with confirmed HIV-1 RNA levels of >50 copies/ml during trial follow-up were also included. Endpoints were HIV-1 RNA quantification of ≤50 copies/ml versus >50 copies/ml at an individual-sample level (primary) and determination of confirmed virologic failure (VF) from longitudinal samples. A total of 389 participants had results obtained from all assays on at least one sample (median = 6). Proportions of results of >50 copies/ml were 19% (Monitor), 22% (TaqMan), and 25% (Abbott). Despite indication of strong agreement (Cohen's kappa, 0.76 to 0.82), Abbott was more likely to detect HIV-1 RNA levels of >50 copies/ml than Monitor (matched-pair odds ratio [mOR] = 4.2; modified Obuchowski P < 0.001) and TaqMan (mOR = 2.1; P < 0.001); TaqMan was more likely than Monitor (mOR = 2.6; P < 0.001). Despite strong agreement in classifying VF across assay comparisons (kappa, 0.75 to 0.92), at a 50-copies/ml threshold, differences in the probability of VF classification (in the same direction as primary) were apparent (all McNemar's P < 0.007). At a 200-copies/ml VF threshold, no differences between assays were apparent (all P > 0.13). Despite strong agreement among assays, significant differences were observed with respect to detecting HIV-1 RNA levels of >50 copies/ml and identifying VF at the 50-copies/ml threshold. This has important implications for the definition of VF in clinical trials and clinical practice. PMID:26063861

  11. Comparison of Three Different FDA-Approved Plasma HIV-1 RNA Assay Platforms Confirms the Virologic Failure Endpoint of 200 Copies per Milliliter Despite Improved Assay Sensitivity.

    PubMed

    Lalama, Christina M; Jennings, Cheryl; Johnson, Victoria A; Coombs, Robert W; McKinnon, John E; Bremer, James W; Cobb, Bryan R; Cloherty, Gavin A; Mellors, John W; Ribaudo, Heather J

    2015-08-01

    Discrepancies between HIV-1 RNA results assayed by different FDA-approved platforms have been reported. Plasma samples collected from 332 randomly selected clinical trial participants during the second year of antiretroviral treatment were assayed with three FDA-approved platforms: UltraSensitive Roche Amplicor Monitor, v1.5 (Monitor), the Abbott RealTime HIV-1 test on the m2000 system (Abbott), and the Roche TaqMan HIV-1 test, v2.0 (TaqMan). Samples from 61 additional participants with confirmed HIV-1 RNA levels of >50 copies/ml during trial follow-up were also included. Endpoints were HIV-1 RNA quantification of ≤50 copies/ml versus >50 copies/ml at an individual-sample level (primary) and determination of confirmed virologic failure (VF) from longitudinal samples. A total of 389 participants had results obtained from all assays on at least one sample (median = 6). Proportions of results of >50 copies/ml were 19% (Monitor), 22% (TaqMan), and 25% (Abbott). Despite indication of strong agreement (Cohen's kappa, 0.76 to 0.82), Abbott was more likely to detect HIV-1 RNA levels of >50 copies/ml than Monitor (matched-pair odds ratio [mOR] = 4.2; modified Obuchowski P < 0.001) and TaqMan (mOR = 2.1; P < 0.001); TaqMan was more likely than Monitor (mOR = 2.6; P < 0.001). Despite strong agreement in classifying VF across assay comparisons (kappa, 0.75 to 0.92), at a 50-copies/ml threshold, differences in the probability of VF classification (in the same direction as primary) were apparent (all McNemar's P < 0.007). At a 200-copies/ml VF threshold, no differences between assays were apparent (all P > 0.13). Despite strong agreement among assays, significant differences were observed with respect to detecting HIV-1 RNA levels of >50 copies/ml and identifying VF at the 50-copies/ml threshold. This has important implications for the definition of VF in clinical trials and clinical practice. PMID:26063861

  12. A cohort study of treatment-experienced HIV-1-infected patients treated with raltegravir: factors associated with virological response and mutations selected at failure.

    PubMed

    Marcelin, Anne-Geneviève; Delaugerre, Constance; Beaudoux, Céline; Descamps, Diane; Morand-Joubert, Laurence; Amiel, Corinne; Schneider, Veronique; Ferre, Virginie; Izopet, Jacques; Si-Mohamed, Ali; Maillard, Anne; Henquell, Cécile; Desbois, Delphine; Lazrek, Mouna; Signori-Schmuck, Anne; Rogez, Sylvie; Yerly, Sabine; Trabaud, Mary-Anne; Plantier, Jean-Christophe; Fourati, Slim; Houssaini, Allal; Masquelier, Bernard; Calvez, Vincent; Flandre, Philippe

    2013-07-01

    This study aimed to identify factors associated with virological response (VR) to raltegravir (RAL)-containing regimens in 468 treatment-experienced but integrase inhibitor-naive HIV-1 patients receiving a RAL-containing regimen. VR was defined at Month 6 (M6) as HIV-1 RNA viral load (VL) <50 copies/mL. The impacts on VR of baseline integrase mutations, VL, CD4 count, genotypic sensitivity score for nucleoside reverse transcriptase inhibitors, non-nucleoside reverse transcriptase inhibitors and protease inhibitors, and the number of new antiretrovirals used for the first time associated with RAL were investigated. For patients with VL >50 copies/mL at M6, integrase mutations selected were characterised. Median baseline VL was 4.2 log(10)copies/mL (IQR 3.3-4.9 log(10) copies/mL) and CD4 count was 219 cells/mm(3) (IQR 96-368 cells/mm(3)). At M6, 71% of patients were responders. In multivariate analysis, baseline VL and CD4 count and ≥ 2 new antiretrovirals among darunavir, etravirine, maraviroc and enfuvirtide were associated with VR to RAL. Neither HIV-1 subtype nor baseline integrase polymorphisms were associated with VR to RAL. Among 63 failing patients at M6, selection of ≥ 1 change in the integrase gene was observed in 49 (77.8%), and 27/63 (42.9%) were considered as RAL-associated resistance mutations. Factors independently associated with the occurrence of ≥ 1 RAL-associated resistance mutation were VL at failure >3 log(10) and having no new drugs associated with RAL. RAL showed great potency in treatment-experienced patients. The number of new drugs associated with RAL was an important factor associated with VR. HIV-1 subtype and baseline integrase polymorphisms do not influence the RAL VR. PMID:23562640

  13. Potential Impact of a Free Online HIV Treatment Response Prediction System for Reducing Virological Failures and Drug Costs after Antiretroviral Therapy Failure in a Resource-Limited Setting

    PubMed Central

    Revell, Andrew D.; Wang, Dechao; Pozniak, Anton; Montaner, Julio S.; Lane, H. Clifford; Larder, Brendan A.

    2013-01-01

    Objective. Antiretroviral drug selection in resource-limited settings is often dictated by strict protocols as part of a public health strategy. The objective of this retrospective study was to examine if the HIV-TRePS online treatment prediction tool could help reduce treatment failure and drug costs in such settings. Methods. The HIV-TRePS computational models were used to predict the probability of response to therapy for 206 cases of treatment change following failure in India. The models were used to identify alternative locally available 3-drug regimens, which were predicted to be effective. The costs of these regimens were compared to those actually used in the clinic. Results. The models predicted the responses to treatment of the cases with an accuracy of 0.64. The models identified alternative drug regimens that were predicted to result in improved virological response and lower costs than those used in the clinic in 85% of the cases. The average annual cost saving was $364 USD per year (41%). Conclusions. Computational models that do not require a genotype can predict and potentially avoid treatment failure and may reduce therapy costs. The use of such a system to guide therapeutic decision-making could confer health economic benefits in resource-limited settings. PMID:24175292

  14. Virologic and Immunologic Correlates With the Magnitude of Antibody Responses to the Hepatitis A Vaccine in HIV-Infected Children on Highly Active Antiretroviral Treatment

    PubMed Central

    Weinberg, Adriana; Huang, Sharon; Fenton, Terence; Patterson-Bartlett, Julie; Gona, Philimon; Read, Jennifer S.; Dankner, Wayne M.; Nachman, Sharon

    2010-01-01

    Background HIV-infected individuals mount poor antibody responses to vaccines. We sought to identify the immunologic and virologic factors associated with a robust response to hepatitis Avirus (HAV) vaccine in children on highly active antiretroviral treatment. Methods One hundred fifty-two pediatric highly active antiretroviral treatment recipients immunized against HAV at weeks 0 and 24 had anti-HAV antibodies, CD4+, CD8+, and CD19+ cell percent assessed at weeks 0 and 32. Subgroups had HIV viremia, B- and T-cell subpopulations, and cell-mediated immunity (CMI) to HAV and other stimulants measured. Results Anti-HAV antibodies after complete vaccination correlated positively with CD4+ percent and CD19+ percent and negatively with viremia and CD8+ percent at baseline, but not at 32 weeks. There were no significant correlations between anti-HAV antibodies and B- or T-cell-naïve, memory, or activated subpopulations or non-HAV CMI. Compared with children who remained HAV-CMI-negative, those who mounted HAV-CMI in response to vaccination had higher anti-HAV antibody titers and CD19+ CD21+ CD27+ memory B cell percent at 32 weeks, but no other differences. Conclusions In HIV-infected children on highly active antiretroviral treatment, control of viral replication and conserved or reconstituted CD19+ and CD4+ cell numbers and function determine a robust antibody response to anti-HAV primary immunization. Our data support a bidirectional B- and T-cell cooperation in the response to the HAV vaccine. PMID:19617848

  15. The HIV Care Continuum: Changes over Time in Retention in Care and Viral Suppression

    PubMed Central

    Yehia, Baligh R.; Stephens-Shields, Alisa J.; Fleishman, John A.; Berry, Stephen A.; Agwu, Allison L.; Metlay, Joshua P.; Moore, Richard D.; Christopher Mathews, W.; Nijhawan, Ank; Rutstein, Richard; Gaur, Aditya H.; Gebo, Kelly A.

    2015-01-01

    Background The HIV care continuum (diagnosis, linkage to care, retention in care, receipt of antiretroviral therapy (ART), viral suppression) has been used to identify opportunities for improving the delivery of HIV care. Continuum steps are typically calculated in a conditional manner, with the number of persons completing the prior step serving as the base population for the next step. This approach may underestimate the prevalence of viral suppression by excluding patients who are suppressed but do not meet standard definitions of retention in care. Understanding how retention in care and viral suppression interact and change over time may improve our ability to intervene on these steps in the continuum. Methods We followed 17,140 patients at 11 U.S. HIV clinics between 2010-2012. For each calendar year, patients were classified into one of five categories: (1) retained/suppressed, (2) retained/not-suppressed, (3) not-retained/suppressed, (4) not-retained/not-suppressed, and (5) lost to follow-up (for calendar years 2011 and 2012 only). Retained individuals were those completing ≥2 HIV medical visits separated by ≥90 days in the year. Persons not retained completed ≥1 HIV medical visit during the year, but did not meet the retention definition. Persons lost to follow-up had no HIV medical visits in the year. HIV viral suppression was defined as HIV-1 RNA ≤200 copies/mL at the last measure in the year. Multinomial logistic regression was used to determine the probability of patients’ transitioning between retention/suppression categories from 2010 to 2011 and 2010 to 2012, adjusting for age, sex, race/ethnicity, HIV risk factor, insurance status, CD4 count, and use of ART. Results Overall, 65.8% of patients were retained/suppressed, 17.4% retained/not-suppressed, 10.0% not-retained/suppressed, and 6.8% not-retained/not-suppressed in 2010. 59.5% of patients maintained the same status in 2011 (kappa=0.458) and 53.3% maintained the same status in 2012

  16. Physical virology

    NASA Astrophysics Data System (ADS)

    Roos, W. H.; Bruinsma, R.; Wuite, G. J. L.

    2010-10-01

    Viruses are nanosized, genome-filled protein containers with remarkable thermodynamic and mechanical properties. They form by spontaneous self-assembly inside the crowded, heterogeneous cytoplasm of infected cells. Self-assembly of viruses seems to obey the principles of thermodynamically reversible self-assembly but assembled shells (`capsids') strongly resist disassembly. Following assembly, some viral shells pass through a sequence of coordinated maturation steps that progressively strengthen the capsid. Nanoindentation measurements by atomic force microscopy enable tests of the strength of individual viral capsids. They show that concepts borrowed from macroscopic materials science are surprisingly relevant to viral shells. For example, viral shells exhibit `materials fatigue' and the theory of thin-shell elasticity can account - in part - for atomic-force-microscopy-measured force-deformation curves. Viral shells have effective Young's moduli ranging from that of polyethylene to that of plexiglas. Some of them can withstand internal osmotic pressures that are tens of atmospheres. Comparisons with thin-shell theory also shed light on nonlinear irreversible processes such as plastic deformation and failure. Finally, atomic force microscopy experiments can quantify the mechanical effects of genome encapsidation and capsid protein mutations on viral shells, providing virological insight and suggesting new biotechnological applications.

  17. Randomized trial of DRV/r or LPV/r QD monotherapy vs maintaining a PI/r-based antiretroviral regimen in persons with suppressed HIV replication

    PubMed Central

    Pinnetti, Carmela; Lorenzini, Patrizia; Cozzi-Lepri, Alessandro; Sandrine, Ottou; Tommasi, Chiara; Zaccarelli, Mauro; Federico Perno, Carlo; Rosaria Capobianchi, Maria; Girardi, Enrico; Antinori, Andrea; Ammassari, Adriana

    2014-01-01

    Introduction PI/r monotherapy has been suggested as an attainable maintenance strategy in patients achieving stable HIV suppression in plasma. The objective of trial was to compare the virological outcome of two different PI/r QD monotherapy strategies (LPV/r or DRV/r) with maintaining a triple PI/r-based ARV regimen. Material and Methods Phase III, open-label, non-inferiority (−12% margin), randomized trial of HIV adults with HIV-RNA <50 cp/mL for at least 48 weeks while on PI/r-based cART, CD4 nadir >100 cell/mm3, without previous PIs virological failure. Eligible patients were randomized to continue PI/r+2NRTIs (Arm A), to switch to LPV/r 800/200 mg QD monotherapy (Arm B), or to switch to DRV/r 800/100 mg QD monotherapy (Arm C). Primary endpoint was proportion of patients with plasma HIV-1 RNA <50 cp/mL (TLOVR) at 48w by intent to treat (ITT) analysis (missing/re-induction=failure). FDA snapshot and ITT switch-included analysis (ITT-SI) were also used. In ITT-SI, patients who had <50 copies/mL at 96w were counted as successes even if they had confirmed HIV-RNA elevations and had subsequently successfully intensified by NRTI. Results Due to slow recruitment, only 103 patients were included. No differences were observed between the three arms with respect to gender, age, HIV transmission, CD4 nadir and at screening. At randomization, 61 patients were receiving TDF/FTC (60%), 19 ZDV/3TC (18%), 8 ABV/3TC (8%), 75 LPV/r (73%), 13 ATV/r (13%), 4 DRV/r (4%). Differences in proportion of virological success by groups using Arm A as comparator according to FDA TLOVR were reported in Figure 1. Similar results were obtained by Snapshot analysis. Of 14 patients with virological failure, 8 patients restarted triple therapy with 2NRTI and 7/8 regained a VL <50 cp/mL over time. According to ITT-SI analysis, 96 week differences [95% CI] were −5.7 [−29.6; +18.2] in Arm B, and +19.6 [−1.6; +40.8] in Arm C. A GRT was performed in 6/14 patients (one not amplifiable; four

  18. Incidence and predictors of cardiovascular disease, chronic kidney disease, and diabetes in HIV/HCV-coinfected patients who achieved sustained virological response.

    PubMed

    Leone, S; Prosperi, M; Costarelli, S; Nasta, P; Maggiolo, F; Di Giambenedetto, S; Saracino, A; Di Pietro, M; Gori, A

    2016-09-01

    Data on the effects of sustained virologic response (SVR) to hepatitis C virus (HCV) therapy on the outcome of extrahepatic complications are scarce. We conducted this study to assess the impact of SVR on the occurrence of chronic kidney disease (CKD), diabetes mellitus (DM), and cardiovascular disease (CVD) in a cohort of human immunodeficiency virus (HIV)-infected patients. We analyzed coinfected HIV/HCV patients in the Management of Standardized Evaluation of Retroviral HIV Infection (MASTER) cohort. Only event-free patients with a serum HCV-RNA determination at baseline were included. Patients were divided into four groups: INF-exposed with SVR; INF-exposed without SVR; spontaneous HCV clearance; untreated viremic patients. We estimated the incidence of extrahepatic complications and employed Kaplan-Meier curves and Cox regression to assess the association of SVR/INF strata adjusted for a series of confounders. Data from 1676 patients were analyzed (20.29 % started an INF-based regimen). Overall, the incidence of CKD, DM, CVD, and death was 5.32 [95 % confidence interval (CI) 3.99-6.98], 10.13 (95 % CI 8.20-12.37), 6.79 (95 % CI 5.26-8.65), and 13.49 (95 % CI 11.29-16.0) per 1000 person-years of follow-up, respectively. In the Cox model for treated patients, SVR was not associated with a lower risk of CKD, DM, CVD, and death compared to non-SVR. Cirrhosis was significantly associated with a higher risk of CKD [hazard ratio (HR) 2.13; 95 % CI 1.06-4.31], DM (HR 3.48; 95 % CI 2.18-5.57), and death (HR 6.18; 95 % CI 4.1-9.31), but not of CVD (HR 1.14; 95 % CI 0.57-2.3). There are still many unknowns regarding the impact of SVR on the occurrence of extrahepatic complications in coinfected HIV/HCV patients. Further investigations are needed in order to elucidate the role of SVR as an independent prognostic factor for extrahepatic events. PMID:27272121

  19. Higher Levels of Osteoprotegerin and Immune Activation/Immunosenescence Markers Are Correlated with Concomitant Bone and Endovascular Damage in HIV-Suppressed Patients

    PubMed Central

    D’Abramo, Alessandra; Zingaropoli, Maria Antonella; Oliva, Alessandra; D’Agostino, Claudia; Al Moghazi, Samir; De Luca, Giulia; Iannetta, Marco; d’Ettorre, Gabriella; Ciardi, Maria Rosa; Mastroianni, Claudio Maria; Vullo, Vincenzo

    2016-01-01

    HIV-infected patients appear to have a significantly greater risk of non-AIDS comorbidities such as osteoporosis and atherosclerosis. Subjects with osteoporosis are at a higher risk of developing cardiovascular disease than those with normal bone mass, therefore a possible relation between these two conditions can be hypothesized. In the setting of HIV infection, several factors might contribute to bone disease and endothelial dysfunction. The aim of our study was to evaluate the relationship between bone and cardiovascular disease and to investigate the role of traditional factors, T-cell phenotype and osteoprotegerin in HIV positive subjects on effective antiretroviral therapy. We included 94 HIV positive subjects on antiretroviral therapy with virological suppression and 41 healthy subjects matched for age and gender as a control group. Carotid-Intima Media Thickness (c-IMT) and bone mineral density (BMD) were performed by ultrasound and DEXA, respectively. CD4+/CD8+ T-cell activation, senescence and osteoprotegerin plasma levels were measured by flow-cytometry and ELISA, respectively. Among HIV positive patients, 56.4% had osteopenia/osteoporosis and 45.7% had pathological c-IMT (>0.9mm). Subjects with pathological c-IMT and BMD exhibited higher CD4+ and CD8+ activated, CD8+ senescent and osteoprotegerin than subjects with normal c-IMT and BMD. HIV positive subjects with osteopenia/osteoporosis had higher c-IMT than subjects with normal BMD, and linear regression analysis showed a negative correlation between BMD and c-IMT. Several factors are implicated in the pathogenesis of non-AIDS comorbidities in HIV positive patients. Osteoprotegerin together with inflammation and immunosenescence in HIV positive patients could affect bone and vascular system and could be considered as a possible common link between these two diseases. PMID:26913505

  20. Higher Levels of Osteoprotegerin and Immune Activation/Immunosenescence Markers Are Correlated with Concomitant Bone and Endovascular Damage in HIV-Suppressed Patients.

    PubMed

    D'Abramo, Alessandra; Zingaropoli, Maria Antonella; Oliva, Alessandra; D'Agostino, Claudia; Al Moghazi, Samir; De Luca, Giulia; Iannetta, Marco; d'Ettorre, Gabriella; Ciardi, Maria Rosa; Mastroianni, Claudio Maria; Vullo, Vincenzo

    2016-01-01

    HIV-infected patients appear to have a significantly greater risk of non-AIDS comorbidities such as osteoporosis and atherosclerosis. Subjects with osteoporosis are at a higher risk of developing cardiovascular disease than those with normal bone mass, therefore a possible relation between these two conditions can be hypothesized. In the setting of HIV infection, several factors might contribute to bone disease and endothelial dysfunction. The aim of our study was to evaluate the relationship between bone and cardiovascular disease and to investigate the role of traditional factors, T-cell phenotype and osteoprotegerin in HIV positive subjects on effective antiretroviral therapy. We included 94 HIV positive subjects on antiretroviral therapy with virological suppression and 41 healthy subjects matched for age and gender as a control group. Carotid-Intima Media Thickness (c-IMT) and bone mineral density (BMD) were performed by ultrasound and DEXA, respectively. CD4+/CD8+ T-cell activation, senescence and osteoprotegerin plasma levels were measured by flow-cytometry and ELISA, respectively. Among HIV positive patients, 56.4% had osteopenia/osteoporosis and 45.7% had pathological c-IMT (>0.9 mm). Subjects with pathological c-IMT and BMD exhibited higher CD4+ and CD8+ activated, CD8+ senescent and osteoprotegerin than subjects with normal c-IMT and BMD. HIV positive subjects with osteopenia/osteoporosis had higher c-IMT than subjects with normal BMD, and linear regression analysis showed a negative correlation between BMD and c-IMT. Several factors are implicated in the pathogenesis of non-AIDS comorbidities in HIV positive patients. Osteoprotegerin together with inflammation and immunosenescence in HIV positive patients could affect bone and vascular system and could be considered as a possible common link between these two diseases. PMID:26913505

  1. Increased risk of virologic failure to the first antiretroviral regimen in HIV-infected migrants compared to natives: data from the ICONA cohort.

    PubMed

    Saracino, A; Lorenzini, P; Lo Caputo, S; Girardi, E; Castelli, F; Bonfanti, P; Rusconi, S; Caramello, P; Abrescia, N; Mussini, C; Monno, L; d'Arminio Monforte, A

    2016-03-01

    Migrant and Italian HIV-infected patients (n = 5773) enrolled in the ICONA cohort in 2004-2014 were compared for disparities in access to an initial antiretroviral regimen and/or risk of virologic failure (VF), and determinants of failure were evaluated. Variables associated with initiating antiretroviral therapy (ART) were analysed. Primary endpoint was time to failure after at least 6 months of ART and was defined as: VF, first of two consecutive virus loads (VL) >200 copies/mL; treatment discontinuation (TD) for any reason; and treatment failure as confirmed VL >200 copies/mL or TD. A Poisson multivariable analysis was performed to control for confounders. Migrants presented significantly lower CD4 counts and more frequent AIDS events at baseline. When adjusting for baseline confounders, migrants presented a lower likelihood to begin ART (odds ratio 0.80, 95% confidence interval (CI) 0.67-0.95, p 0.012). After initiating ART, the incidence VF rate was 6.4 per 100 person-years (95% CI 4.8-8.5) in migrants and 2.7 in natives (95% CI 2.2-3.3). Multivariable analysis confirmed that migrants had a higher risk of VF (incidence rate ratio 1.90, 95% CI 1.25-2.91, p 0.003) and treatment failure (incidence rate ratio 1.16, 95% CI 1.01-1.33, p 0.031), with no differences for TD. Among migrants, variables associated with VF were age, unemployment and use of a boosted protease inhibitor-based regimen versus nonnucleoside reverse transcriptase inhibitors. Despite the use of more potent and safer drugs in the last 10 years, and even in a universal health care setting, migrants living with HIV still present barriers to initiating ART and an increased risk of VF compared to natives. PMID:26551839

  2. Regression of liver fibrosis is progressive after sustained virological response to HCV therapy in patients with hepatitis C and HIV coinfection.

    PubMed

    Casado, J L; Quereda, C; Moreno, A; Pérez-Elías, M J; Martí-Belda, P; Moreno, S

    2013-12-01

    There are few data about the long-term histological outcome of HIV-/HCV-coinfected patients after therapy with interferon and ribavirin. We performed an observational study of 216 patients who received therapy against HCV and who had at least three successive transient elastographies (TE) during the follow-up. The primary endpoint was confirmed fibrosis regression, defined as a reduction of at least 1 point in Metavir fibrosis score, confirmed and without worsening in successive TE. At baseline, 23% had fibrosis stage 4 or cirrhosis. Overall, 82 (38%) achieved sustained virological response (SVR), without differences in baseline fibrosis or time of follow-up. Confirmed fibrosis regression was observed in 55% of patients, higher for SVR (71% vs 44%; P < 0.01), and the likelihood of achieving fibrosis regression at 3, 5 and 7 years was 0.17, 0.51 and 0.67, respectively, for SVR patients, in comparison with 0.02, 0.23 and 0.41 for no SVR patients (P < 0.01, log-rank test at any time point). Progressive regression, defined as continuous improvement in successive TE, was observed in 62% of patients with advanced liver fibrosis or cirrhosis who achieved SVR. In a Cox regression model, only SVR (HR, 4.01; 95% CI, 2.33-7.57; P < 0.01) and a younger age (HR, 1.14; 95% CI, 1.05-1.25; P < 0.01; per year) were associated with fibrosis regression. This study confirms that the rate of liver fibrosis regression increases during the follow-up after SVR to interferon therapy in HIV-/HCV-coinfected patients. PMID:24304452

  3. HIV sexual transmission risks in the context of clinical care: a prospective study of behavioural correlates of HIV suppression in a community sample, Atlanta, GA, USA

    PubMed Central

    Kalichman, Seth C; Cherry, Chauncey; Kalichman, Moira O; Washington, Christopher; Grebler, Tamar; Merely, Cindy; Welles, Brandi; Pellowski, Jennifer; Kegler, Christopher

    2015-01-01

    Introduction Antiretroviral therapy (ART) improves the health of people living with HIV and has the potential to reduce HIV infectiousness, thereby preventing HIV transmission. However, the success of ART for HIV prevention hinges on sustained ART adherence and avoiding sexually transmitted infections (STI). Objectives To determine the sexual behaviours and HIV transmission risks of individuals with suppressed and unsuppressed HIV replication (i.e., viral load). Methods Assessed HIV sexual transmission risks among individuals with clinically determined suppressed and unsuppressed HIV. Participants were 760 men and 280 women living with HIV in Atlanta, GA, USA, who completed behavioural assessments, 28-daily prospective sexual behaviour diaries, one-month prospective unannounced pill counts for ART adherence, urine screening for illicit drug use and medical record chart abstraction for HIV viral load. Results Individuals with unsuppressed HIV demonstrated a constellation of behavioural risks for transmitting HIV to uninfected sex partners that included symptoms of STI and substance use. In addition, 15% of participants with suppressed HIV had recent STI symptoms/diagnoses, indicating significant risks for sexual infectiousness despite their HIV suppression in blood plasma. Overall, 38% of participants were at risk for elevated sexual infectiousness and just as many engaged in unprotected sexual intercourse with non-HIV-infected partners. Conclusions Implementation strategies for using HIV treatments as HIV prevention requires enhanced behavioural interventions that extend beyond ART to address substance use and sexual health that will otherwise undermine the potential preventive impact of early ART. PMID:26249127

  4. Short Communication: HIV-1 Infection Suppresses Circulating Viral Restriction microRNAs.

    PubMed

    Zhou, Yu; Sun, Li; Wang, Xu; Liang, Hao; Ye, Li; Zhou, Li; Liang, Bing-Yu; Li, Jie-Liang; Liu, Man-Qing; Peng, Jin-Song; Zhou, Dun-Jin; Gui, Xi-En; Ho, Wen-Zhe

    2016-04-01

    MicroRNAs (miRNAs) participate in host innate immunity against HIV-1 infection. We examined the impact of HIV-1 infection on viral restriction miRNAs in plasma of HIV-1-infected subjects. HIV-1-infected subjects had significantly lower plasma levels of HIV-1 restriction miRNAs (miRs-29a, -29b, -125b, -223, -198, and -382) than control subjects. Further in vitro studies showed that HIV-1 infection of macrophages suppressed production of the extracellular miRs-29b, -125b, and -223. These data demonstrate the compelling evidence that HIV-1 infection impairs host innate immunity by inhibiting antiviral miRNAs, which provide a possible mechanism for HIV-1 persistence in the host. PMID:26607272

  5. Natural Killer KIR3DS1 Is Closely Associated with HCV Viral Clearance and Sustained Virological Response in HIV/HCV Patients

    PubMed Central

    Rivero-Juarez, Antonio; Gonzalez, Rafael; Camacho, Angela; Manzanares-Martin, Barbara; Caruz, Antonio; Martinez-Peinado, Antonio; Torre-Cisneros, Julian; Pineda, Juan A.; Peña, José; Rivero, Antonio

    2013-01-01

    Aim To evaluate the influence of the presence of the killer cell immunoglobulin-like receptor (KIR) 3DS1 on HCV treatment response in HIV/HCV genotype 1 co-infected patients Methods HIV/HCV co-infected patients were included. KIR3DS1, their specific HLA-B ligands and IL28B gene were genotyped. Reductions of plasma HCV RNA levels between baseline and week 1, week 2 and week 4 were analyzed for IL28B genotype and KIR3DS1 (HLA Bw4 or Bw6). Rapid and sustained virological response (RVR and SVR) rates were also analyzed. Results Sixty HIV/HCV genotype 1 co-infected patients were included. Patients with KIR3DS1 and Bw4 had higher rates of HCV viral decline than those who were not carriers of KIR3DS1 (week1: p = 0.01; week2: p = 0.038; week 4: p = 0.03). Patients carrying KIR3DS1/Bw4 had higher rates of RVR and SVR than those who did not carry KIR3DS1 (RVR: 46.15% versus 17.02%, p = 0.012; SVR: 63.6% versus 13 26.5%, p = 0.031). With respect to patients carrying the IL28B-CC genotype, those with KIR3DS1/Bw4 had greater rates of HCV viral clearance (week1: p<0.001; week2: p = 0.01; week 4: p = 0.02), RVR (p = 0.015) and SVR (p = 0.029) than those not carrying KIR3DS1. Conclusion Our results show that the KIR3DS1 genotype has a positive effect on HCV viral clearance during the first weeks of Peg-IFN/RBV treatment in HCV/HCV co-infected patients bearing genotype 1, and higher RVR and SVR rates. PMID:23613999

  6. Short Communication: CXCL12 rs1029153 Polymorphism Is Associated with the Sustained Virological Response in HIV/Hepatitis C Virus-Coinfected Patients on Hepatitis C Virus Therapy.

    PubMed

    Pineda-Tenor, Daniel; Jiménez-Sousa, María A; Rallón, Norma; Berenguer, Juan; Soriano, Vicente; Aldámiz-Echevarria, Teresa; García-Álvarez, Mónica; Diez, Cristina; Fernández-Rodríguez, Amanda; Benito, Jose Miguel; Resino, Salvador

    2016-03-01

    The immune response against HIV and hepatitis C virus (HCV) infection partly depends on chemokine-mediated recruitment of specific T cells. CXCL12 polymorphisms have been associated with AIDS progression and survival, but there are no data related to HCV infection. The aim of this study was to determine whether CXCL12 polymorphisms are related so as to achieve sustained virological response (SVR) after HCV therapy with pegylated-interferon-alpha/ribavirin (pegIFN-α/ribavirin) in HIV/HCV-coinfected patients. We carried out a retrospective study in 319 naive patients who started HCV treatment. The CXCL12 (rs266093, rs1029153, and rs1801157) and IL28B (rs12980275) polymorphisms were genotyped by using the GoldenGate assay. Genetic data were analyzed under an additive inheritance model. The overall rates of the SVR were 54.9% (175/319) and 41.5% (90/217) in GT1/4 patients and 83.2% (84/101) in GT2/3 patients. Patients with a favorable CXCL12 rs1029153 T allele had higher SVR rates than patients with the rs1029153 CC genotype (44% CC, 49% CT, and 61.3% TT; p = 0.025). No significant results for the rs266093 and rs1801157 polymorphisms were found. Patients harboring the favorable rs1029153 T allele had significantly increased odds of achieving SVR [adjusted odds ratio (aOR) = 1.55; 95% confidence interval (95% CI) = 1.01; 2.40; p = 0.047]. Moreover, no significant association was found when the study population was stratified by HCV genotype (data not shown), possibly due to the low number of patients in each group. In conclusion, in this study we found that the favorable CXCL12 rs1029153 T allele seems to be related so as to achieve an SVR in HIV/HCV-coinfected patients on pegIFN-α/ribavirin therapy. PMID:26499461

  7. Postpartum Loss to HIV Care and HIV Viral Suppression among Previously Diagnosed HIV-Infected Women with a Live Birth in New York State

    PubMed Central

    2016-01-01

    Mother-to-child-transmission of HIV in the United States has been greatly reduced, with clear benefits for the child. However, little is known about factors that predict maternal loss to HIV care in the postpartum year. This retrospective cohort study included 980 HIV-positive women, diagnosed with HIV at least one year before pregnancy, who had a live birth during 2008–2010 in New York State. Women who did not meet the following criterion in the 12 months after the delivery-related hospital discharge were considered to be lost to HIV care: two or more laboratory tests (CD4 or HIV viral load), separated by at least 90 days. Adjusted relative risks (aRR) and 95% confidence intervals (CI) for predictors of postpartum loss to HIV care were identified with Poisson regression, solved using generalized estimating equations. Having an unsuppressed (>200 copies/mL) HIV viral load in the postpartum year was also evaluated. Overall, 24% of women were loss to HIV care during the postpartum year. Women with low participation in HIV care during preconception were more likely to be lost to HIV care during the postpartum year (aRR: 2.70; 95% CI: 2.09–3.49). In contrast, having a low birth weight infant was significantly associated with a decreased likelihood of loss to HIV care (aRR: 0.72; 95% CI: 0.53–0.98). While 75% of women were virally suppressed at the last viral load before delivery only 44% were continuously suppressed in the postpartum year; 12% had no viral load test reported in the postpartum year and 44% had at least one unsuppressed viral load test. Lack of engagement in preconception HIV-related health care predicts postpartum loss to HIV care for HIV-positive parturient women. Many women had poor viral control during the postpartum period, increasing the risk of disease progression and infectivity. PMID:27513953

  8. Association of Efavirenz Hypersusceptibility with Virologic Response in ACTG 368, a Randomized Trial of Abacavir (ABC) in Combination with Efavirenz (EFV) and Indinavir (IDV) in HIV-infected Subjects with Prior Nucleoside Analog Experience

    PubMed Central

    Demeter, Lisa M.; DeGruttola, Victor; Lustgarten, Stephanie; Bettendorf, Daniel; Fischl, Margaret; Eshleman, Susan; Spreen, William; Nguyen, Bach-Yen; Koval, Christine E.; Eron, Joseph J.; Hammer, Scott; Squires, Kathleen

    2010-01-01

    Purpose To evaluate the association of efavirenz hypersusceptibility (EFV-HS) with clinical outcome in a double-blind, placebo-controlled, randomized trial of EFV plus indinavir (EFV+IDV) vs. EFV+IDV plus abacavir (ABC) in 283 nucleoside-experienced HIV-infected patients. Methods and Results Rates of virologic failure were similar in the 2 arms at week 16 (p=0.509). Treatment discontinuations were more common in the ABC arm (p=0.001). Using logistic regression, there was no association between virologic failure and either baseline ABC resistance or regimen sensitivity score. Using 3 different genotypic scoring systems, EFV-HS was significantly associated with reduced virologic failure at week 16, independent of treatment assignment. In some patients on the nucleoside-sparing arm, the nucleoside-resistant mutant L74V was selected for in combination with the uncommonly occurring EFV-resistant mutant K103N+L100I; L74V was not detected as a minority variant, using clonal sequence analysis, when the nucleoside-sparing regimen was initiated. Conclusions Premature treatment discontinuations in the ABC arm and the presence of EFV-hypersusceptible HIV variants in this patient population likely made it difficult to detect a benefit of adding ABC to EFV+IDV. In addition, L74V, when combined with K103N+L100I, may confer a selective advantage to the virus that is independent of its effects on nucleoside resistance. PMID:18215978

  9. Activation of HIV Transcription with Short-Course Vorinostat in HIV-Infected Patients on Suppressive Antiretroviral Therapy

    PubMed Central

    Solomon, Ajantha; Ghneim, Khader; Ahlers, Jeffrey; Cameron, Mark J.; Smith, Miranda Z.; Spelman, Tim; McMahon, James; Velayudham, Pushparaj; Brown, Gregor; Roney, Janine; Watson, Jo; Prince, Miles H.; Hoy, Jennifer F.; Chomont, Nicolas; Fromentin, Rémi; Procopio, Francesco A.; Zeidan, Joumana; Palmer, Sarah; Odevall, Lina; Johnstone, Ricky W.; Martin, Ben P.; Sinclair, Elizabeth; Deeks, Steven G.; Hazuda, Daria J.; Cameron, Paul U.; Sékaly, Rafick-Pierre; Lewin, Sharon R.

    2014-01-01

    Human immunodeficiency virus (HIV) persistence in latently infected resting memory CD4+ T-cells is the major barrier to HIV cure. Cellular histone deacetylases (HDACs) are important in maintaining HIV latency and histone deacetylase inhibitors (HDACi) may reverse latency by activating HIV transcription from latently infected CD4+ T-cells. We performed a single arm, open label, proof-of-concept study in which vorinostat, a pan-HDACi, was administered 400 mg orally once daily for 14 days to 20 HIV-infected individuals on suppressive antiretroviral therapy (ART). The primary endpoint was change in cell associated unspliced (CA-US) HIV RNA in total CD4+ T-cells from blood at day 14. The study is registered at ClinicalTrials.gov (NCT01365065). Vorinostat was safe and well tolerated and there were no dose modifications or study drug discontinuations. CA-US HIV RNA in blood increased significantly in 18/20 patients (90%) with a median fold change from baseline to peak value of 7.4 (IQR 3.4, 9.1). CA-US RNA was significantly elevated 8 hours post drug and remained elevated 70 days after last dose. Significant early changes in expression of genes associated with chromatin remodeling and activation of HIV transcription correlated with the magnitude of increased CA-US HIV RNA. There were no statistically significant changes in plasma HIV RNA, concentration of HIV DNA, integrated DNA, inducible virus in CD4+ T-cells or markers of T-cell activation. Vorinostat induced a significant and sustained increase in HIV transcription from latency in the majority of HIV-infected patients. However, additional interventions will be needed to efficiently induce virus production and ultimately eliminate latently infected cells. Trial Registration ClinicalTrials.gov NCT01365065 PMID:25393648

  10. Evaluation of the Genotypic Prediction of HIV-1 Coreceptor Use versus a Phenotypic Assay and Correlation with the Virological Response to Maraviroc: the ANRS GenoTropism Study▿

    PubMed Central

    Recordon-Pinson, Patricia; Soulié, Cathia; Flandre, Philippe; Descamps, Diane; Lazrek, Mouna; Charpentier, Charlotte; Montes, Brigitte; Trabaud, Mary-Anne; Cottalorda, Jacqueline; Schneider, Véronique; Morand-Joubert, Laurence; Tamalet, Catherine; Desbois, Delphine; Macé, Muriel; Ferré, Virginie; Vabret, Astrid; Ruffault, Annick; Pallier, Coralie; Raymond, Stéphanie; Izopet, Jacques; Reynes, Jacques; Marcelin, Anne-Geneviève; Masquelier, Bernard

    2010-01-01

    Genotypic algorithms for prediction of HIV-1 coreceptor usage need to be evaluated in a clinical setting. We aimed at studying (i) the correlation of genotypic prediction of coreceptor use in comparison with a phenotypic assay and (ii) the relationship between genotypic prediction of coreceptor use at baseline and the virological response (VR) to a therapy including maraviroc (MVC). Antiretroviral-experienced patients were included in the MVC Expanded Access Program if they had an R5 screening result with Trofile (Monogram Biosciences). V3 loop sequences were determined at screening, and coreceptor use was predicted using 13 genotypic algorithms or combinations of algorithms. Genotypic predictions were compared to Trofile; dual or mixed (D/M) variants were considered as X4 variants. Both genotypic and phenotypic results were obtained for 189 patients at screening, with 54 isolates scored as X4 or D/M and 135 scored as R5 with Trofile. The highest sensitivity (59.3%) for detection of X4 was obtained with the Geno2pheno algorithm, with a false-positive rate set up at 10% (Geno2pheno10). In the 112 patients receiving MVC, a plasma viral RNA load of <50 copies/ml was obtained in 68% of cases at month 6. In multivariate analysis, the prediction of the X4 genotype at baseline with the Geno2pheno10 algorithm including baseline viral load and CD4 nadir was independently associated with a worse VR at months 1 and 3. The baseline weighted genotypic sensitivity score was associated with VR at month 6. There were strong arguments in favor of using genotypic coreceptor use assays for determining which patients would respond to CCR5 antagonist. PMID:20530226

  11. Substance abuse, violence, and HIV/AIDS (SAVA) syndemic effects on viral suppression among HIV positive women of color.

    PubMed

    Sullivan, Kristen A; Messer, Lynne C; Quinlivan, E Byrd

    2015-01-01

    The combined epidemics of substance abuse, violence, and HIV/AIDS, known as the SAVA syndemic, contribute to the disproportionate burden of disease among people of color in the US. To examine the association between HIV viral load suppression and SAVA syndemic variables, we used baseline data from 563 HIV+ women of color treated at nine HIV medical and ancillary care sites participating in HRSA's Special Project of National Significance Women of Color (WOC) Initiative. Just under half the women (n=260) were virally suppressed. Five psychosocial factors contributing to the SAVA syndemic were examined in this study: substance abuse, binge drinking, intimate partner violence, poor mental health, and sexual risk taking. Associations among the psychosocial factors were assessed and clustering confirmed. A SAVA score was created by summing the dichotomous (present/absent) psychosocial measures. Using generalized estimating equation (GEE) models to account for site-level clustering and individual-covariates, a higher SAVA score (0 to 5) was associated with reduced viral suppression; OR (adjusted)=0.81, 95% CI: 0.66, 0.99. The syndemic approach represents a viable framework for understanding viral suppression among HIV positive WOC, and suggests the need for comprehensive interventions that address the social/environmental contexts of patients' lives. PMID:25397666

  12. Substance Abuse, Violence, and HIV/AIDS (SAVA) Syndemic Effects on Viral Suppression Among HIV Positive Women of Color

    PubMed Central

    Messer, Lynne C.; Quinlivan, E. Byrd

    2015-01-01

    Abstract The combined epidemics of substance abuse, violence, and HIV/AIDS, known as the SAVA syndemic, contribute to the disproportionate burden of disease among people of color in the US. To examine the association between HIV viral load suppression and SAVA syndemic variables, we used baseline data from 563 HIV+ women of color treated at nine HIV medical and ancillary care sites participating in HRSA's Special Project of National Significance Women of Color (WOC) Initiative. Just under half the women (n=260) were virally suppressed. Five psychosocial factors contributing to the SAVA syndemic were examined in this study: substance abuse, binge drinking, intimate partner violence, poor mental health, and sexual risk taking. Associations among the psychosocial factors were assessed and clustering confirmed. A SAVA score was created by summing the dichotomous (present/absent) psychosocial measures. Using generalized estimating equation (GEE) models to account for site-level clustering and individual-covariates, a higher SAVA score (0 to 5) was associated with reduced viral suppression; OR (adjusted)=0.81, 95% CI: 0.66, 0.99. The syndemic approach represents a viable framework for understanding viral suppression among HIV positive WOC, and suggests the need for comprehensive interventions that address the social/environmental contexts of patients' lives. PMID:25397666

  13. A Single Quantifiable Viral Load Is Predictive of Virological Failure in Human Immunodeficiency Virus (HIV)-Infected Patients on Combination Antiretroviral Therapy: The Austrian HIV Cohort Study

    PubMed Central

    Leierer, Gisela; Grabmeier-Pfistershammer, Katharina; Steuer, Andrea; Sarcletti, Mario; Geit, Maria; Haas, Bernhard; Taylor, Ninon; Kanatschnig, Manfred; Rappold, Michaela; Ledergerber, Bruno; Zangerle, Robert

    2016-01-01

    Background. Viral loads (VLs) detectable at low levels are not uncommon in patients on combination antiretroviral therapy (cART). We investigated whether a single quantifiable VL predicted virological failure (VF). Methods. We analyzed patients receiving standard regimens with at least 1 VL measurement below the limit of quantification (BLQ) in their treatment history. The first VL measurement after 6 months of unmodified cART served as baseline VL for the subsequent analyses of the time to reach single VL levels of ≥200, ≥400, and ≥1000 copies/mL. Roche TaqMan 2.0 was used to quantify human immunodeficiency virus-1 ribonucleic acid. Factors associated with VF were determined by Cox proportional hazards models. Results. Of 1614 patients included in the study, 68, 44, and 34 experienced VF ≥200, ≥400, and ≥1000 copies/mL, respectively. In multivariable analyses, compared with patients who were BLQ, a detectable VL ≤ 50 and VL 51–199 copies/mL predicted VF ≥ 200 copies/mL (hazards ratio [HR] = 2.19, 95% confidence interval [CI] = 1.06–4.55 and HR = 4.21, 95% CI = 2.15–8.22, respectively). In those with VL 51–199 copies/mL, a trend for an increased risk of VF ≥400 and VF ≥1000 copies/mL could be found (HR = 2.13, 95% CI = 0.84–5.39 and HR = 2.52, 95% CI = 0.96–6.60, respectively). Conclusions. These findings support closer monitoring and adherence counseling for patients with a single measurement of quantifiable VL <200 copies/mL. PMID:27419163

  14. The impact of transient combination antiretroviral treatment in early HIV infection on viral suppression and immunologic response in later treatment

    PubMed Central

    Pantazis, Nikos; Touloumi, Giota; Meyer, Laurence; Olson, Ashley; Costagliola, Dominique; Kelleher, Anthony D.; Lutsar, Irja; Chaix, Marie-Laure; Fisher, Martin; Moreno, Santiago; Porter, Kholoud

    2016-01-01

    Objective: Effects of transient combination antiretroviral treatment (cART) initiated during early HIV infection (EHI) remain unclear. We investigate whether this intervention affects viral suppression and CD4+ cell count increase following its reinitiation in chronic infection (CHI). Design: Longitudinal observational study. Methods: We identified adult patients from Concerted Action of Seroconversion to AIDS and Death in Europe who seroconverted after 1/1/2000, had a 12 months or less HIV test interval and initiated cART from naive. We classified individuals as ‘pretreated in EHI’ if treated within 6 months of seroconversion, interrupted for at least 12 weeks, and reinitiated during CHI. Statistical analysis was performed using survival analysis methods and mixed models. Results: Pretreated and initiated in CHI groups comprised 202 and 4263 individuals, with median follow-up after CHI treatment 4.5 and 3 years, respectively. Both groups had similar virologic response and relapse rates (P = 0.585 and P = 0.206) but pretreated individuals restarted treatment with higher baseline CD4+ cell count (∼80 cells/μl; P < 0.001) and retained significantly higher CD4+ cell count for more than 3 years after treatment (re)initiation. Assuming common baseline CD4+ cell count, differences in CD4+ cell count slopes were nonsignificant. Immunovirologic response to CHI treatment was not associated with timing or duration of the transient treatment. Conclusion: Although treatment interruptions are not recommended, stopping cART initiated in EHI does not seem to reduce the chance of a successful outcome of treatment in CHI. PMID:26636925

  15. A Re-Examination of Global Suppression of RNA Interference by HIV-1

    PubMed Central

    Sanghvi, Viraj R.; Steel, Laura F.

    2011-01-01

    The nature of the interaction between replicating HIV-1 and the cellular RNAi pathway has been controversial, but it is clear that it can be complex and multifaceted. It has been proposed that the interaction is bi-directional, whereby cellular silencing pathways can restrict HIV-1 replication, and in turn, HIV-1 can suppress silencing pathways. Overall suppression of RNAi has been suggested to occur via direct binding and inhibition of Dicer by the HIV-1 Tat protein or through sequestration of TRBP, a Dicer co-factor, by the structured TAR element of HIV-1 transcripts. The role of Tat as an inhibitor of Dicer has been questioned and our results support and extend the conclusion that Tat does not inhibit RNAi that is mediated by either exogenous or endogenous miRNAs. Similarly, we find no suppression of silencing pathways in cells with replicating virus, suggesting that viral products such as the TAR RNA elements also do not reduce the efficacy of cellular RNA silencing. However, knockdown of Dicer does allow increased viral replication and this occurs at a post-transcriptional level. These results support the idea that although individual miRNAs can act to restrict HIV-1 replication, the virus does not counter these effects through a global suppression of RNAi synthesis or processing. PMID:21386885

  16. Factors associated with retention and viral suppression among a cohort of HIV+ women of color.

    PubMed

    Blank, Arthur E; Fletcher, Jason; Verdecias, Niko; Garcia, Iliana; Blackstock, Oni; Cunningham, Chinazo

    2015-01-01

    Access to sustained HIV medical care is critical to achieving viral suppression. However, a variety of factors may impede or facilitate retention in care or becoming virally suppressed. Though retention and suppression are often treated separately, this study examined both in a cohort of 921 HIV+ women of color who participated in eight demonstration programs across the US. For women who met the inclusion criteria, 83% (n = 587) were retained and 73% (n = 357) were virally suppressed. Average age of women retained was 40.9, and 41.9 for those virally suppressed. The majority were African American/Black or Hispanic/Latina, single, and had no children less than 18 years of age, had health insurance, a high school degree or higher, were stably housed, and unemployed. Some factors associated with retention in care were indecision about seeking HIV medical care (AOR = 0.42) and having children under the age of 18 (AOR = 0.59). Some factors associated with being virally suppressed were living with others (AOR = 0.58), current substance abuse (AOR = 0.38), and fair/poor health (AOR = 0.40). The findings suggest different processes and social mechanisms may influence retention and viral suppression. Interventions seeking to improve retention in care may require tailored program components and strategies that focus on improving viral suppression. PMID:25458205

  17. An omitted level: an examination of relational orientations and viral suppression among HIV serodiscordant male couples.

    PubMed

    Gamarel, Kristi E; Neilands, Torsten B; Golub, Sarit A; Johnson, Mallory O

    2014-06-01

    Couples' adopting a relational orientation, when partners regard themselves as a collective unit, is associated with optimal health. HIV-positive men and their HIV-negative partners (N = 116 serodiscordant male couples) were surveyed. Logistic regression showed greater relational orientations of HIV-positive [adjusted odds ratio (aOR) = 7.87; 95% confidence interval (CI): 1.63 to 38.05] and HIV-negative partners (aOR = 6.16; 95% CI: 1.43 to 26.59) and HIV-positive partners' higher income (aOR = 2.95; 95% CI: 1.13 to 7.70) and lower depression (aOR = 0.39; 95% CI: 0.15 to 0.97) were associated with viral suppression with no evidence of mediation by adherence. Incorporating relationship dynamics into biomedical strategies is a promising avenue for research and intervention. PMID:24662295

  18. Decreased HIV Type 1 Transcription in CCR5-Δ32 Heterozygotes During Suppressive Antiretroviral Therapy

    PubMed Central

    Wang, Charlene; Abdel-Mohsen, Mohamed; Strain, Matthew C.; Lada, Steven M.; Yukl, Steven; Cockerham, Leslie R.; Pilcher, Christopher D.; Hecht, Frederick M.; Sinclair, Elizabeth; Liegler, Teri; Richman, Douglas D.; Deeks, Steven G.; Pillai, Satish K.

    2014-01-01

    Individuals who are heterozygous for the CCR5-Δ32 mutation provide a natural model to examine the effects of reduced CCR5 expression on human immunodeficiency virus (HIV) persistence. We evaluated the HIV reservoir in 18 CCR5-Δ32 heterozygotes and 54 CCR5 wild-type individuals during suppressive antiretroviral therapy. Cell-associated HIV RNA levels (P = .035), RNA to DNA transcriptional ratios (P = .013), and frequency of detectable HIV 2–long terminal repeat circular DNA (P = .013) were significantly lower in CD4+ T cells from CCR5-Δ32 heterozygotes. Cell-associated HIV RNA was significantly correlated with CCR5 surface expression on CD4+ T cells (r2 = 0.136; P = .002). Our findings suggest that curative strategies should further explore manipulation of CCR5. PMID:24935955

  19. Antiretroviral Therapy and Efficacy After Virologic Failure on First-line Boosted Protease Inhibitor Regimens

    PubMed Central

    Zheng, Yu; Hughes, Michael D.; Lockman, Shahin; Benson, Constance A.; Hosseinipour, Mina C.; Campbell, Thomas B.; Gulick, Roy M.; Daar, Eric S.; Sax, Paul E.; Riddler, Sharon A.; Haubrich, Richard; Salata, Robert A.; Currier, Judith S.

    2014-01-01

    Background. Virologic failure (VF) on a first-line ritonavir-boosted protease inhibitor (PI/r) regimen is associated with low rates of resistance, but optimal management after failure is unknown. Methods. The analysis included participants in randomized trials who experienced VF on a first-line regimen of PI/r plus 2 nucleoside reverse transcriptase inhibitors (NRTIs) and had at least 24 weeks of follow-up after VF. Antiretroviral management and virologic suppression (human immunodeficiency virus type 1 [HIV-1] RNA <400 copies/mL) after VF were assessed. Results. Of 209 participants, only 1 participant had major PI-associated treatment-emergent mutations at first-line VF. The most common treatment approach after VF (66%) was to continue the same regimen. The virologic suppression rate 24 weeks after VF was 64% for these participants, compared with 72% for those who changed regimens (P = .19). Participants remaining on the same regimen had lower NRTI resistance rates (11% vs 30%; P = .003) and higher CD4+ cell counts (median, 275 vs 213 cells/µL; P = .005) at VF than those who changed. Among participants remaining on their first-line regimen, factors at or before VF significantly associated with subsequent virologic suppression were achieving HIV-1 RNA <400 copies/mL before VF (odds ratio [OR], 3.39 [95% confidence interval {CI}, 1.32–8.73]) and lower HIV-1 RNA at VF (OR for <10 000 vs ≥10 000 copies/mL, 3.35 [95% CI, 1.40–8.01]). Better adherence after VF was also associated with subsequent suppression (OR for <100% vs 100%, 0.38 [95% CI, .15–.97]). For participants who changed regimens, achieving HIV-1 RNA <400 copies/mL before VF also predicted subsequent suppression. Conclusions. For participants failing first-line PI/r with no or limited drug resistance, remaining on the same regimen is a reasonable approach. Improving adherence is important to subsequent treatment success. PMID:24842909

  20. Clinical, virological and biochemical evidence supporting the association of HIV-1 reverse transcriptase polymorphism R284K and thymidine analogue resistance mutations M41L, L210W and T215Y in patients failing tenofovir/emtricitabine therapy

    PubMed Central

    2012-01-01

    Background Thymidine analogue resistance mutations (TAMs) selected under treatment with nucleoside analogues generate two distinct genotypic profiles in the HIV-1 reverse transcriptase (RT): (i) TAM1: M41L, L210W and T215Y, and (ii) TAM2: D67N, K70R and K219E/Q, and sometimes T215F. Secondary mutations, including thumb subdomain polymorphisms (e.g. R284K) have been identified in association with TAMs. We have identified mutational clusters associated with virological failure during salvage therapy with tenofovir/emtricitabine-based regimens. In this context, we have studied the role of R284K as a secondary mutation associated with mutations of the TAM1 complex. Results The cross-sectional study carried out with >200 HIV-1 genotypes showed that virological failure to tenofovir/emtricitabine was strongly associated with the presence of M184V (P < 10-10) and TAMs (P < 10-3), while K65R was relatively uncommon in previously-treated patients failing antiretroviral therapy. Clusters of mutations were identified, and among them, the TAM1 complex showed the highest correlation coefficients. Covariation of TAM1 mutations and V118I, V179I, M184V and R284K was observed. Virological studies showed that the combination of R284K with TAM1 mutations confers a fitness advantage in the presence of zidovudine or tenofovir. Studies with recombinant HIV-1 RTs showed that when associated with TAM1 mutations, R284K had a minimal impact on zidovudine or tenofovir inhibition, and in their ability to excise the inhibitors from blocked DNA primers. However, the mutant RT M41L/L210W/T215Y/R284K showed an increased catalytic rate for nucleotide incorporation and a higher RNase H activity in comparison with WT and mutant M41L/L210W/T215Y RTs. These effects were consistent with its enhanced chain-terminated primer rescue on DNA/DNA template-primers, but not on RNA/DNA complexes, and can explain the higher fitness of HIV-1 having TAM1/R284K mutations. Conclusions Our study shows the association

  1. Regulatory T Cells Expanded from HIV-1-Infected Individuals Maintain Phenotype, TCR Repertoire and Suppressive Capacity

    PubMed Central

    Angin, Mathieu; Klarenbeek, Paul L.; King, Melanie; Sharma, Siddhartha M.; Moodley, Eshia S.; Rezai, Ashley; Piechocka-Trocha, Alicja; Toth, Ildiko; Chan, Andrew T.; Goulder, Philip J.; Ndung'u, Thumbi; Kwon, Douglas S.; Addo, Marylyn M.

    2014-01-01

    While modulation of regulatory T cell (Treg) function and adoptive Treg transfer are being explored as therapeutic modalities in the context of autoimmune diseases, transplantation and cancer, their role in HIV-1 pathogenesis remains less well defined. Controversy persists regarding their beneficial or detrimental effects in HIV-1 disease, which warrants further detailed exploration. Our objectives were to investigate if functional CD4+ Tregs can be isolated and expanded from HIV-1-infected individuals for experimental or potential future therapeutic use and to determine phenotype and suppressive capacity of expanded Tregs from HIV-1 positive blood and tissue. Tregs and conventional T cell controls were isolated from blood and gut-associated lymphoid tissue of individuals with HIV-1 infection and healthy donors using flow-based cell-sorting. The phenotype of expanded Tregs was assessed by flow-cytometry and quantitative PCR. T-cell receptor ß-chain (TCR-β) repertoire diversity was investigated by deep sequencing. Flow-based T-cell proliferation and chromium release cytotoxicity assays were used to determine Treg suppressive function. Tregs from HIV-1 positive individuals, including infants, were successfully expanded from PBMC and GALT. Expanded Tregs expressed high levels of FOXP3, CTLA4, CD39 and HELIOS and exhibited a highly demethylated TSDR (Treg-specific demethylated region), characteristic of Treg lineage. The TCRß repertoire was maintained following Treg expansion and expanded Tregs remained highly suppressive in vitro. Our data demonstrate that Tregs can be expanded from blood and tissue compartments of HIV-1+ donors with preservation of Treg phenotype, function and TCR repertoire. These results are highly relevant for the investigation of potential future therapeutic use, as currently investigated for other disease states and hold great promise for detailed studies on the role of Tregs in HIV-1 infection. PMID:24498287

  2. Regulatory T cells expanded from HIV-1-infected individuals maintain phenotype, TCR repertoire and suppressive capacity.

    PubMed

    Angin, Mathieu; Klarenbeek, Paul L; King, Melanie; Sharma, Siddhartha M; Moodley, Eshia S; Rezai, Ashley; Piechocka-Trocha, Alicja; Toth, Ildiko; Chan, Andrew T; Goulder, Philip J; Ndung'u, Thumbi; Kwon, Douglas S; Addo, Marylyn M

    2014-01-01

    While modulation of regulatory T cell (Treg) function and adoptive Treg transfer are being explored as therapeutic modalities in the context of autoimmune diseases, transplantation and cancer, their role in HIV-1 pathogenesis remains less well defined. Controversy persists regarding their beneficial or detrimental effects in HIV-1 disease, which warrants further detailed exploration. Our objectives were to investigate if functional CD4(+) Tregs can be isolated and expanded from HIV-1-infected individuals for experimental or potential future therapeutic use and to determine phenotype and suppressive capacity of expanded Tregs from HIV-1 positive blood and tissue. Tregs and conventional T cell controls were isolated from blood and gut-associated lymphoid tissue of individuals with HIV-1 infection and healthy donors using flow-based cell-sorting. The phenotype of expanded Tregs was assessed by flow-cytometry and quantitative PCR. T-cell receptor ß-chain (TCR-β) repertoire diversity was investigated by deep sequencing. Flow-based T-cell proliferation and chromium release cytotoxicity assays were used to determine Treg suppressive function. Tregs from HIV-1 positive individuals, including infants, were successfully expanded from PBMC and GALT. Expanded Tregs expressed high levels of FOXP3, CTLA4, CD39 and HELIOS and exhibited a highly demethylated TSDR (Treg-specific demethylated region), characteristic of Treg lineage. The TCRß repertoire was maintained following Treg expansion and expanded Tregs remained highly suppressive in vitro. Our data demonstrate that Tregs can be expanded from blood and tissue compartments of HIV-1+ donors with preservation of Treg phenotype, function and TCR repertoire. These results are highly relevant for the investigation of potential future therapeutic use, as currently investigated for other disease states and hold great promise for detailed studies on the role of Tregs in HIV-1 infection. PMID:24498287

  3. CD8 T-Cells from Most HIV-Infected Patients Lack Ex Vivo HIV-Suppressive Capacity during Acute and Early Infection

    PubMed Central

    Chéret, Antoine; Versmisse, Pierre; Nembot, Georges; Meyer, Laurence; Rouzioux, Christine; Pancino, Gianfranco; Venet, Alain; Sáez-Cirión, Asier

    2013-01-01

    The strong CD8+ T-cell-mediated HIV-1-suppressive capacity found in a minority of HIV-infected patients in chronic infection is associated with spontaneous control of viremia. However, it is still unclear whether such capacities were also present earlier in the CD8+ T cells from non controller patients and then lost as a consequence of uncontrolled viral replication. We studied 50 patients with primary HIV-1-infection to determine whether strong CD8+ T-cell-mediated HIV suppression is more often observed at that time. Despite high frequencies of polyfunctional HIV-specific CD8+ T-cells and a strong CD4+ T-helper response, CD8+ T-cells from 48 patients lacked strong HIV-suppressive capacities ex vivo. This indicates that the superior HIV-suppressive capacity of CD8+ T-cells from HIV controllers is not a general characteristic of the HIV-specific CD8+ T cell response in primary HIV infection. PMID:23555774

  4. HIV prevention: integrating biomedical and behevioral interventions.

    PubMed

    Del Rio, Carlos

    Recommendations for HIV prevention in clinical care settings by an IAS-USA panel were recently published. They include recommendations on HIV testing, antiretroviral therapy initiation, risk-reduction counseling, and antiretroviral therapy adherence counseling for HIV-infected individuals. For individuals at risk for HIV infection, recommendations for preexposure prophylaxis, other risk-reduction strategies, adherence counseling, and postexposure prophylaxis are included. Many HIV-infected individuals in the United States are not fully engaged in HIV care and are not virologically suppressed, thus a crucial component of efforts to reduce HIV transmission is moving patients through the HIV care continuum. This article summarizes an IAS-USA continuing education webinar presented by Carlos del Rio, MD, in September 2014. PMID:25612180

  5. 80% Viral Suppression by 2020? Understanding the Concept of Engagement in HIV Care and A Call to Action for Nursing.

    PubMed

    Mignano, Jamie L

    2016-01-01

    An updated National HIV/AIDS Strategy released in July 2015 emphasized closing the gaps in the HIV care continuum and a goal of 80% viral suppression by 2020. Engagement in HIV care describes an individual's interaction with the health care system to achieve key clinical and behavioral outcomes along the HIV care continuum. The goal of this concept analysis is to explicate engagement in HIV care by defining the concept, and identifying its antecedents, consequences, and research-related gaps. Research, practice, and policy implications involve leveraging the multiple entry points in the health care system where nurses encounter persons living with HIV. PMID:27301911

  6. Influence of Jail Incarceration and Homelessness Patterns on Engagement in HIV Care and HIV Viral Suppression among New York City Adults Living with HIV/AIDS

    PubMed Central

    Lim, Sungwoo; Nash, Denis; Hollod, Laura; Harris, Tiffany G.; Lennon, Mary Clare; Thorpe, Lorna E.

    2015-01-01

    Objectives Both homelessness and incarceration are associated with housing instability, which in turn can disrupt continuity of HIV medical care. Yet, their impacts have not been systematically assessed among people living with HIV/AIDS (PLWHA). Methods We studied a retrospective cohort of 1,698 New York City PLWHA with both jail incarceration and homelessness during 2001–05 to evaluate whether frequent transitions between jail incarceration and homelessness were associated with a lower likelihood of continuity of HIV care during a subsequent one-year follow-up period. Using matched jail, single-adult homeless shelter, and HIV registry data, we performed sequence analysis to identify trajectories of these events and assessed their influence on engagement in HIV care and HIV viral suppression via marginal structural modeling. Results Sequence analysis identified four trajectories; 72% of the cohort had sporadic experiences of both brief incarceration and homelessness, whereas others experienced more consistent incarceration or homelessness during early or late months. Trajectories were not associated with differential engagement in HIV care during follow-up. However, compared with PLWHA experiencing early bouts of homelessness and later minimal incarceration/homelessness events, we observed a lower prevalence of viral suppression among PLWHA with two other trajectories: those with sporadic, brief occurrences of incarceration/homelessness (0.67, 95% CI = 0.50,0.90) and those with extensive incarceration experiences (0.62, 95% CI = 0.43,0.88). Conclusions Housing instability due to frequent jail incarceration and homelessness or extensive incarceration may exert negative influences on viral suppression. Policies and services that support housing stability should be strengthened among incarcerated and sheltered PLWHA to reduce risk of adverse health conditions. PMID:26599877

  7. Suppression of HIV-1 replication by propolis and its immunoregulatory effect.

    PubMed

    Harish, Z; Rubinstein, A; Golodner, M; Elmaliah, M; Mizrachi, Y

    1997-01-01

    In the current study we show that propolis, a non-toxic natural bee-hive product, suppresses HIV-1 replication and modulates in vitro immune responses. CEM cells were treated with propolis at nontoxic concentrations prior to or following infection with HIV-1. Propolis abolished syncytium formation at 4.5 micrograms/ml and inhibited it at lower doses in a concentration-dependent manner. Propolis decreased p24 antigen production by as much as 90-100% in a concentration-dependent manner. Furthermore, modulation of peripheral blood mononuclear cells (PBMCs) mitogenic responses upon the addition of propolis was noted, reducing the elevated responses to Concanavalin A (Con A) and enhancing suppressed mitogenic responses to pokeweed mitogen (PWM). In summary, propolis may constitute a non-toxic natural product with both anti HIV-1 and immunoregulatory effects. PMID:9309384

  8. Mortality and Long-Term Virologic Outcomes in Children and Infants Treated with Lopinavir/Ritonavir

    PubMed Central

    Estripeaut, Dora; Mosser, Jon; Doherty, Meg; Acosta, William; Shah, Harita; Castaño, Elizabeth; Luciani, Kathia; Pascale, Juan Miguel; Bollinger, Robert C.; Page, Kathleen R.

    2013-01-01

    Background There is scant data on young children receiving protease inhibitor (PI)-based therapy in real-life resource-limited settings and on the optimal timing of therapy among children who survive infancy. Our aim was to evaluate outcomes at the Hospital del Niño, Panama, where children have been routinely treated with lopinavir/ritonavir (LPV/r)-based therapy since 2002. Methods Retrospective cohort analysis of all HIV-infected children enrolled in care between January 1, 1991 and June 1, 2011. Kaplan-Meier method and Cox proportional hazards regression were used to evaluate death, virologic suppression, and virologic rebound. Results Of 399 children contributing 1,944 person-years of follow-up, 254 (63.7%) were treated with LPV/r and 94 (23.6%) were never treated with antiretrovirals (ARVs). Among infants, improved survival was associated with male gender (HRdeath 0.54, 95% CI 0.32–0.92) and treatment with highly active antiretroviral therapy (HAART) (HRdeath 0.32, 95% CI 0.12–0.83), while residence outside of Panama City was associated with poorer survival (HRdeath 1.72, 95% CI 1.01–2.94). Among children who survived to 1 year of age without exposure to ARVs, LPV/r-based therapy improved survival (HRdeath 0.07, 95% CI 0.01–0.33). Virologic suppression was achieved in 42.1%, 70.5%, and 85.1% by 12, 24 and 60 months of follow up among children treated with LPV/r. Virologic suppression was not associated with prior ARV exposure or age at initiation of therapy but was associated with residence outside of Panama City (HRsuppression 1.93, 95% CI 1.19–3.14). Patients with a baseline viral load > 100,000 copies/mL were less likely to achieve suppression (HRsuppression 0.37, 95% CI 0.21–0.66). No children who achieved virologic suppression after initiating LPV/r died. Conclusions LPV/r-based therapy improved survival not only in infants but also in children over 1 year of age. Age at initiation of LPV/r-based therapy or prior ARVs did not impact virologic

  9. Psychiatric Distress, Drug Use, and HIV Viral Load Suppression in Russia.

    PubMed

    Ustinov, A; Suvorova, A; Belyakov, A; Makhamatova, A; Levina, O; Krupitsky, E; Lioznov, D; Niccolai, L; Heimer, R

    2016-08-01

    To explore the influence of psychiatric distress and substance use on viral load suppression in HIV-infected patients taking ART we analyzed socio-demographic characteristics, CD4+ cells count and viral loads, the Symptom Check List-90 and the Addiction Severity Index of 75 patients who had taken ART for at least 6 month. Using viral load data as the marker of ART success, we divided the sample into two groups. Comparison of the groups showed that education, marriage, and female gender are predictors of optimal viral load suppression. Overall results failed to demonstrate substance use and psychiatric distress as predictors of viral load suppression. PMID:26809193

  10. Functional Mechanisms of Treg in the Context of HIV Infection and the Janus Face of Immune Suppression

    PubMed Central

    López-Abente, Jacobo; Correa-Rocha, Rafael; Pion, Marjorie

    2016-01-01

    Regulatory T cells (Tregs) play an important role in infections, by modulating host immune responses and avoiding the overreactive immunity that in the case of human immunodeficiency virus (HIV) infection leads to a marked erosion and deregulation of the entire immune system. Therefore, the suppressive function of Treg in HIV-infected patients is critical because of their implication on preventing the immune hyperactivation, even though it could also have a detrimental effect by suppressing HIV-specific immune responses. In recent years, several studies have shown that HIV-1 can directly infect Treg, disturbing their phenotype and suppressive capacity via different mechanisms. These effects include Foxp3 and CD25 downregulation, and the impairment of suppressive capacity. This review describes the functional mechanisms of Treg to modulate immune activation during HIV infection, and how such control is no longer fine-tune orchestrated once Treg itself get infected. We will review the current knowledge about the HIV effects on the Treg cytokine expression, on pathways implying the participation of different ectoenzymes (i.e., CD39/CD73 axis), transcription factors (ICER), and lastly on cyclic adenosine monophosphate (cAMP), one of the keystones in Treg-suppressive function. To define which are the HIV effects upon these regulatory mechanisms is crucial not only for the comprehension of immune deregulation in HIV-infected patients but also for the correct understanding of the role of Tregs in HIV infection. PMID:27242797

  11. Speaking of sex workers: How suppression of research has distorted the United States' domestic HIV response.

    PubMed

    Forbes, Anna

    2015-05-01

    Sex workers remain a vulnerable population at risk for HIV acquisition and transmission. Research suggests that interventions at the individual level, such as condom distribution, are less effective in preventing HIV among sex workers than structural changes such as allowing safer work settings and reducing the harassment and abuse of sex workers by clients and police. In the US, HIV incidence has not declined in the last decade. This may be due in part to its policy of wilful ignorance about sex work, but the data to resolve the question simply do not exist. Political actions such as PEPFAR's prostitution pledge and a congressional campaign against "waste, fraud and abuse" in research are products of an ideological environment that suppresses research on HIV prevention and treatment needs of sex workers. Even basic prevalence data are missing because there is no "sex worker" category in the US National HIV Behavior Surveillance System. However, international efforts are taking a public health approach and are calling for decriminalization of sex work, as the most effective public health strategy for reducing HIV incidence among sex workers. Although such an approach is not yet politically feasible in the US, some urgent practical policy changes can be implemented to improve data collection and generation of evidence to support HIV prevention and treatment programs targeting sex workers. PMID:26278830

  12. 3BNC117 a Broadly Neutralizing Antibody Suppresses Viremia in HIV-1-Infected Humans

    PubMed Central

    Caskey, Marina; Klein, Florian; Lorenzi, Julio C. C.; Seaman, Michael S.; West, Anthony P.; Buckley, Noreen; Kremer, Gisela; Nogueira, Lilian; Braunschweig, Malte; Scheid, Johannes F.; Horwitz, Joshua A.; Shimeliovich, Irina; Ben Avraham-Shulman, Sivan; Witmer-Pack, Maggi; Platten, Martin; Lehmann, Clara; Burke, Leah A.; Hawthorne, Thomas; Gorelick, Robert J.; Walker, Bruce D.; Keler, Tibor; Gulick, Roy M.; Fätkenheuer, Gerd; Schlesinger, Sarah J.; Nussenzweig, Michel C.

    2016-01-01

    HIV-1 immunotherapy with a combination of first generation monoclonal antibodies was largely ineffective in pre-clinical and clinical settings and was therefore abandoned1–3. However, recently developed single cell based antibody cloning methods have uncovered a new generation of far more potent broadly neutralizing antibodies (bNAbs) to HIV-14,5. These antibodies can prevent infection and suppress viremia in humanized mice (hu-mice) and nonhuman primates, but their potential for human HIV-1 immunotherapy has not been evaluated6–10. Here we report the results of a first-in-man dose escalation phase 1 clinical trial of 3BNC117, a potent human CD4 binding site antibody11, in uninfected and HIV-1-infected individuals. 3BNC117 infusion was well tolerated and demonstrated favorable pharmacokinetics. A single 30 mg/kg infusion of 3BNC117 reduced the viral load (VL) in HIV-1-infected individuals by 0.8 – 2.5 log10 and viremia remained significantly reduced for 28 days. Emergence of resistant viral strains was variable, with some individuals remaining sensitive to 3BNC117 for a period of 28 days. We conclude that as a single agent 3BNC117 is safe and effective in reducing HIV-1 viremia, and that immunotherapy should be explored as a new modality for HIV-1 prevention, therapy, and cure. PMID:25855300

  13. Adherence to Antiretroviral Therapy and Virologic Failure

    PubMed Central

    Bezabhe, Woldesellassie M.; Chalmers, Leanne; Bereznicki, Luke R.; Peterson, Gregory M.

    2016-01-01

    Abstract The often cited need to achieve ≥95% (nearly perfect) adherence to antiretroviral therapy (ART) for successful virologic outcomes in HIV may present a barrier to initiation of therapy in the early stages of HIV. This meta-analysis synthesized 43 studies (27,905 participants) performed across >26 countries, to determine the relationship between cut-off point for optimal adherence to ART and virologic outcomes. Meta-analysis was performed using a random-effect model to calculate pooled odds ratios with corresponding 95% confidence intervals. The mean rate of patients reporting optimal adherence was 63.4%. Compared with suboptimal adherence, optimal adherence was associated with a lower risk of virologic failure (0.34; 95% CI: 0.26–0.44). There were no significant differences in the pooled odds ratios among different optimal adherence thresholds (≥98–100%, ≥95%, ≥80–90%). Study design (randomized controlled trial vs observational study) (regression coefficient 0.74, 95% CI: 0.04–1.43, P < 0.05) and study region (developing vs developed countries; regression coefficient 0.56, 95% CI: 0.01–1.12, P < 0.05) remained as independent predictors of between-study heterogeneity, with more patients with optimal adherence from developing countries or randomized controlled trials experiencing virologic failure. The threshold for optimal adherence to achieve better virologic outcomes appears to be wider than the commonly used cut-off point (≥95% adherence). The cut-off point for optimal adherence could be redefined to a slightly lower level to encourage the prescribing ART at an early stage of HIV infection. PMID:27082595

  14. Cocaine Enhances HIV-1 Infectivity in Monocyte Derived Dendritic Cells by Suppressing microRNA-155

    PubMed Central

    Napuri, Jessica; Pilakka-Kanthikeel, Sudheesh; Raymond, Andrea; Agudelo, Marisela; Yndart-Arias, Adriana; Saxena, Shailendra K.; Nair, Madhavan

    2013-01-01

    Cocaine and other drugs of abuse increase HIV-induced immunopathogenesis; and neurobiological mechanisms of cocaine addiction implicate a key role for microRNAs (miRNAs), single-stranded non-coding RNAs that regulate gene expression and defend against viruses. In fact, HIV defends against miRNAs by actively suppressing the expression of polycistronic miRNA cluster miRNA-17/92, which encodes miRNAs including miR-20a. IFN-g production by natural killer cells is regulated by miR-155 and this miRNA is also critical to dendritic cell (DC) maturation. However, the impact of cocaine on miR-155 expression and subsequent HIV replication is unknown. We examined the impact of cocaine on two miRNAs, miR-20a and miR-155, which are integral to HIV replication, and immune activation. Using miRNA isolation and analysis, RNA interference, quantitative real time PCR, and reporter assays we explored the effects of cocaine on miR-155 and miR-20 in the context of HIV infection. Here we demonstrate using monocyte-derived dendritic cells (MDCCs) that cocaine significantly inhibited miR-155 and miR-20a expression in a dose dependent manner. Cocaine and HIV synergized to lower miR-155 and miR-20a in MDDCs by 90%. Cocaine treatment elevated LTR-mediated transcription and PU.1 levels in MDCCs. But in context of HIV infection, PU.1 was reduced in MDDCs regardless of cocaine presence. Cocaine increased DC-SIGN and and decreased CD83 expression in MDDC, respectively. Overall, we show that cocaine inhibited miR-155 and prevented maturation of MDDCs; potentially, resulting in increased susceptibility to HIV-1. Our findings could lead to the development of novel miRNA-based therapeutic strategies targeting HIV infected cocaine abusers. PMID:24391808

  15. Suppression of HIV Replication by CD8+ Regulatory T-Cells in Elite Controllers

    PubMed Central

    Lu, Wei; Chen, Song; Lai, Chunhui; Lai, Mingyue; Fang, Hua; Dao, Hong; Kang, Jun; Fan, Jianhua; Guo, Weizhong; Fu, Linchun; Andrieu, Jean-Marie

    2016-01-01

    We previously demonstrated in the Chinese macaque model that an oral vaccine made of inactivated SIV and Lactobacillus plantarum induced CD8+ regulatory T-cells, which suppressed the activation of SIV+CD4+ T-cells, prevented SIV replication, and protected macaques from SIV challenges. Here, we sought whether a similar population of CD8+ T-regs would induce the suppression of HIV replication in elite controllers (ECs), a small population (3‰) of HIV-infected patients with undetectable HIV replication. For that purpose, we investigated the in vitro antiviral activity of fresh CD8+ T-cells on HIV-infected CD4+ T-cells taken from 10 ECs. The 10 ECs had a classical genomic profile: all of them carried the KIR3DL1 gene and 9 carried at least 1 allele of HLA-B:Bw4-80Ile (i.e., with an isoleucine residue at position 80). In the nine HLA-B:Bw4-80Ile-positive patients, we demonstrated a strong viral suppression by KIR3DL1-expressing CD8+ T-cells that required cell-to-cell contact to switch off the activation signals in infected CD4+ T-cells. KIR3DL1-expressing CD8+ T-cells withdrawal and KIR3DL1 neutralization by a specific anti-killer cell immunoglobulin-like receptor (KIR) antibody inhibited the suppression of viral replication. Our findings provide the first evidence for an instrumental role of KIR-expressing CD8+ regulatory T-cells in the natural control of HIV-1 infection. PMID:27148256

  16. Structural Determinants of Antiretroviral Therapy Use, HIV Care Attendance, and Viral Suppression among Adolescents and Young Adults Living with HIV

    PubMed Central

    Kahana, Shoshana Y.; Jenkins, Richard A.; Bruce, Douglas; Fernandez, Maria I.; Hightow-Weidman, Lisa B.; Bauermeister, Jose A.

    2016-01-01

    Background The authors examined associations between structural characteristics and HIV disease management among a geographically diverse sample of behaviorally and perinatally HIV-infected adolescents and young adults in the United States. Methods The sample included 1891 adolescents and young adults living with HIV (27.8% perinatally infected; 72.2% behaviorally infected) who were linked to care through 20 Adolescent Medicine Trials Network for HIV/AIDS Interventions Units. All completed audio computer–assisted self-interview surveys. Chart abstraction or blood draw provided viral load data. Geographic-level variables were extracted from the United States Census Bureau (e.g., socioeconomic disadvantage, percent of Black and Latino households, percent rural) and Esri Crime (e.g., global crime index) databases as Zip Code Tabulation Areas. AIDSVu data (e.g., prevalence of HIV among youth) were extracted at the county-level. Using HLM v.7, the authors conducted means-as-outcomes random effects multi-level models to examine the association between structural-level and individual-level factors and (1) being on antiretroviral therapy (ART) currently; (2) being on ART for at least 6 months; (3) missed HIV care appointments (not having missed any vs. having missed one or more appointments) over the past 12 months; and (4) viral suppression (defined by the corresponding assay cutoff for the lower limit of viral load at each participating site which denoted nondetectability vs. detectability). Results Frequencies for the 4 primary outcomes were as follows: current ART use (n = 1120, 59.23%); ART use for ≥6 months (n = 861, 45.53%); at least one missed HIV care appointment (n = 936, 49.50); and viral suppression (n = 577, 30.51%). After adjusting for individual-level factors, youth living in more disadvantaged areas (defined by a composite score derived from 2010 Census indicators including percent poverty, percent receiving public assistance, percent of female, single

  17. An analog of the natural steroidal alkaloid Cortistatin A potently suppresses Tat dependent HIV transcription

    PubMed Central

    Mousseau, Guillaume; Clementz, Mark A.; Bakeman, Wendy N.; Nagarsheth, Nisha; Cameron, Michael; Shi, Jun; Baran, Phil; Fromentin, Rémi; Chomont, Nicolas; Valente, Susana T.

    2012-01-01

    The human immunodeficiency virus type I (HIV) Tat protein, a potent activator of HIV gene expression, is essential for integrated viral genome expression and represents a potential antiviral target. Tat binds the 5′ terminal region of HIV mRNA’s stem-bulge-loop structure, the Trans-activation Responsive (TAR) element to activate transcription. We find that didehydro-Cortistatin A (dCA), an analogue of a natural steroidal alkaloid from a marine sponge inhibits Tat-mediated trans-activation of the integrated provirus by binding specifically to the TAR-binding domain of Tat. Working at subnanomolar concentrations, dCA reduces Tat mediated transcriptional initiation/elongation from the viral promoter to inhibit HIV-1 and HIV-2 replication in acutely and chronically infected cells. Importantly, dCA abrogates spontaneous viral particle release from CD4+T cells from virally suppressed subjects on highly active antiretroviral therapy (HAART). Thus, dCA defines a unique class of anti-HIV drugs that may inhibit viral production from stable reservoirs and reduce residual viremia during HAART. PMID:22817991

  18. Sexual risk behaviour and viral suppression among HIV-infected adults receiving medical care in the United States

    PubMed Central

    Mattson, Christine L.; Freedman, Mark; Fagan, Jennifer L.; Frazier, Emma L.; Beer, Linda; Huang, Ping; Valverde, Eduardo E.; Johnson, Christopher; Sanders, Catherine; McNaghten, A.D.; Sullivan, Patrick; Lansky, Amy; Mermin, Jonathan; Heffelfinger, James; Skarbinski, Jacek

    2014-01-01

    Objective: To describe the prevalence and association of sexual risk behaviours and viral suppression among HIV-infected adults in the United States. Design: Cross-sectional analysis of weighted data from a probability sample of HIV-infected adults receiving outpatient medical care. The facility and patient response rates were 76 and 51%, respectively. Methods: We analysed 2009 interview and medical record data. Sexual behaviours were self-reported in the past 12 months. Viral suppression was defined as all viral load measurements in the medical record during the past 12 months less than 200 copies/ml. Results: An estimated 98 022 (24%) HIV-infected adults engaged in unprotected vaginal or anal sex; 50 953 (12%) engaged in unprotected vaginal or anal sex with at least one partner of negative or unknown HIV status; 23 933 (6%) did so while not virally suppressed. Persons who were virally suppressed were less likely than persons who were not suppressed to engage in vaginal or anal sex [prevalence ratio, 0.88; 95% confidence interval (CI), 0.82–0.93]; unprotected vaginal or anal sex (prevalence ratio, 0.85; 95% CI, 0.73–0.98); and unprotected vaginal or anal sex with a partner of negative or unknown HIV status (prevalence ratio, 0.79; 95% CI, 0.64–0.99). Conclusion: The majority of HIV-infected adults receiving medical care in the U.S. did not engage in sexual risk behaviours that have the potential to transmit HIV, and of the 12% who did, approximately half were not virally suppressed. Persons who were virally suppressed were less likely than persons who were not suppressed to engage in sexual risk behaviours. PMID:25000558

  19. Improvements in HIV Care Engagement and Viral Load Suppression Following Enrollment in a Comprehensive HIV Care Coordination Program

    PubMed Central

    Irvine, Mary K.; Chamberlin, Stephanie A.; Robbins, Rebekkah S.; Myers, Julie E.; Braunstein, Sarah L.; Mitts, Beau J.; Harriman, Graham A.; Nash, Denis

    2015-01-01

    Background. Substantial evidence gaps remain regarding human immunodeficiency virus (HIV) intervention strategies that improve engagement in care (EiC) and viral load suppression (VLS). We assessed EiC and VLS before and after enrollment in a comprehensive intervention for persons at risk of poor HIV care outcomes. Methods. New York City's Ryan White Part A HIV Care Coordination Program (CCP), launched at 28 agencies in 2009, applies multiple strategies to promote optimal utilization of medical and social services. Using laboratory test records from an HIV surveillance registry, we examined pre–post outcomes among 3641 CCP clients enrolled before April 2011. For the year before and after enrollment, we assessed EiC (defined as ≥2 tests, ≥90 days apart, with ≥1 in each half-year) and VLS (defined as viral load [VL] ≤200 copies/mL on latest VL test in the second half of the year). We estimated relative risks (RRs), comparing pre- and postenrollment proportions achieving EiC and VLS. Results. Among newly diagnosed clients, 90.5% (95% confidence interval [CI], 87.9%–93.2%) and 66.2% (95% CI, 61.9%–70.6%) achieved EiC and VLS, respectively. Among previously diagnosed clients, EiC increased from 73.7% to 91.3% (RR = 1.24; 95% CI, 1.21–1.27) and VLS increased from 32.3% to 50.9% (RR = 1.58; 95% CI, 1.50–1.66). Clients without evidence of HIV care during the 6 months preenrollment contributed most to overall improvements. Pre–post improvements were robust, retaining statistical significance within most sociodemographic and clinical subgroups, and in 89% (EiC) and 75% (VLS) of CCP agencies. Conclusions. Clients in comprehensive HIV care coordination for persons with evident barriers to care showed substantial and consistent improvement in short-term outcomes. PMID:25301208

  20. Dimethyl fumarate, an immune modulator and inducer of the antioxidant response, suppresses HIV replication and macrophage-mediated neurotoxicity; a novel candidate for HIV-neuroprotection1

    PubMed Central

    Cross, Stephanie A.; Cook, Denise R.; Chi, Anthony W.S.; Vance, Patricia J.; Kolson, Lorraine L.; Wong, Bethany J.; Jordan-Sciutto, Kelly L.; Kolson, Dennis L.

    2011-01-01

    Despite antiretroviral therapy (ART), HIV infection promotes cognitive dysfunction and neurodegeneration through persistent inflammation and neurotoxin release from infected and/or activated macrophages/microglia. Furthermore, inflammation and immune activation within both the central nervous system (CNS) and periphery correlate with disease progression and morbidity in ART-treated individuals. Accordingly, drugs targeting these pathological processes in the CNS and systemic compartments are needed for effective, adjunctive therapy. Using our in vitro model of HIV-mediated neurotoxicity, in which HIV infected monocyte-derived macrophages (MDM) release excitatory neurotoxins, we show that HIV infection dysregulates the macrophage antioxidant response and reduces levels of heme oxygenase-1 (HO-1). Furthermore, restoration of HO-1 expression in HIV-infected MDM reduces neurotoxin release without altering HIV replication. Given these novel observations, we have identified dimethyl fumarate (DMF), used to treat psoriasis and showing promising results in clinical trials for multiple sclerosis, as a potential neuroprotectant and HIV disease-modifying agent. DMF, an immune modulator and inducer of the antioxidant response, suppresses HIV replication and neurotoxin release. Two distinct mechanisms are proposed; inhibition of NF-κB nuclear translocation and signaling, which could contribute to the suppression of HIV replication, and induction of HO-1, which is associated with decreased neurotoxin release. Finally, we found that DMF attenuates CCL2-induced monocyte chemotaxis, suggesting that DMF could decrease recruitment of activated monocytes to the CNS in response to inflammatory mediators. We propose that dysregulation of the antioxidant response during HIV infection drives macrophage-mediated neurotoxicity and that DMF could serve as an adjunctive neuroprotectant and HIV disease modifier in ART-treated individuals. PMID:21976775

  1. HIV-1 antibody 3BNC117 suppresses viral rebound in humans during treatment interruption.

    PubMed

    Scheid, Johannes F; Horwitz, Joshua A; Bar-On, Yotam; Kreider, Edward F; Lu, Ching-Lan; Lorenzi, Julio C C; Feldmann, Anna; Braunschweig, Malte; Nogueira, Lilian; Oliveira, Thiago; Shimeliovich, Irina; Patel, Roshni; Burke, Leah; Cohen, Yehuda Z; Hadrigan, Sonya; Settler, Allison; Witmer-Pack, Maggi; West, Anthony P; Juelg, Boris; Keler, Tibor; Hawthorne, Thomas; Zingman, Barry; Gulick, Roy M; Pfeifer, Nico; Learn, Gerald H; Seaman, Michael S; Bjorkman, Pamela J; Klein, Florian; Schlesinger, Sarah J; Walker, Bruce D; Hahn, Beatrice H; Nussenzweig, Michel C

    2016-07-28

    Interruption of combination antiretroviral therapy in HIV-1-infected individuals leads to rapid viral rebound. Here we report the results of a phase IIa open label clinical trial evaluating 3BNC117,a broad and potent neutralizing antibody against the CD4 binding site of the HIV-1 Env protein, during analytical treatment interruption in 13 HIV-1-infected individuals. Participants with 3BNC117-sensitive virus outgrowth cultures were enrolled. Results show that two or four 30 mg kg(-1) 3BNC117 infusions,separated by 3 or 2 weeks, respectively, are generally well tolerated.Infusions are associated with a delay in viral rebound of 5-9 weeks after two infusions, and up to 19 weeks after four infusions, or an average of 6.7 and 9.9 weeks, respectively, compared with 2.6 weeks for historical controls (P < 0.00001). Rebound viruses arise predominantly from a single provirus. In most individuals,emerging viruses show increased resistance, indicating escape.However, 30% of participants remained suppressed until antibody concentrations waned below 20 μg ml(-1), and the viruses emerging in all but one of these individuals showed no apparent resistance to 3BCN117, suggesting failure to escape over a period of 9-19 weeks.We conclude that the administration of 3BNC117 exerts strong selective pressure on HIV-1 emerging from latent reservoirs during analytical treatment interruption in humans. PMID:27338952

  2. Robust Suppression of HIV Replication by Intracellularly Expressed Reverse Transcriptase Aptamers Is Independent of Ribozyme Processing

    PubMed Central

    Lange, Margaret J; Sharma, Tarun K; Whatley, Angela S; Landon, Linda A; Tempesta, Michael A; Johnson, Marc C; Burke, Donald H

    2012-01-01

    RNA aptamers that bind human immunodeficiency virus 1 (HIV-1) reverse transcriptase (RT) also inhibit viral replication, making them attractive as therapeutic candidates and potential tools for dissecting viral pathogenesis. However, it is not well understood how aptamer-expression context and cellular RNA pathways govern aptamer accumulation and net antiviral bioactivity. Using a previously-described expression cassette in which aptamers were flanked by two “minimal core” hammerhead ribozymes, we observed only weak suppression of pseudotyped HIV. To evaluate the importance of the minimal ribozymes, we replaced them with extended, tertiary-stabilized hammerhead ribozymes with enhanced self-cleavage activity, in addition to noncleaving ribozymes with active site mutations. Both the active and inactive versions of the extended hammerhead ribozymes increased inhibition of pseudotyped virus, indicating that processing is not necessary for bioactivity. Clonal stable cell lines expressing aptamers from these modified constructs strongly suppressed infectious virus, and were more effective than minimal ribozymes at high viral multiplicity of infection (MOI). Tertiary stabilization greatly increased aptamer accumulation in viral and subcellular compartments, again regardless of self-cleavage capability. We therefore propose that the increased accumulation is responsible for increased suppression, that the bioactive form of the aptamer is one of the uncleaved or partially cleaved transcripts, and that tertiary stabilization increases transcript stability by reducing exonuclease degradation. PMID:22948672

  3. Viral Suppression and Resistance in a Cohort of Perinatally-HIV Infected (PHIV+) Pregnant Women

    PubMed Central

    Cruz, Maria Letícia; Santos, Edwiges; Benamor Teixeira, Maria de Lourdes; Poletti, Monica; Sousa, Carolina; Gouvea, Maria Isabel; Nielsen-Saines, Karin; João, Esaú

    2016-01-01

    Our objective was to describe viral suppression and antiretroviral (ARV) resistance mutations in an ongoing cohort of perinatally-infected HIV+ (PHIV+) pregnant women. Descriptive analysis was performed using SPSS 18.0. From 2011 to 2014, we followed 22 PHIV+ pregnant women. Median age at prenatal entry was 19 years (Interquartile range (IQR) 17.6–21.0); 86% had an AIDS diagnosis; 81% had disclosed their HIV status to partner 11. The median age at HIV diagnosis was 8.3 y (IQR 4.0–13.6), the median age at sexual debut was 16 years (IQR 14–18). At the time of prenatal care initiation, four (18%) were on their first antiretroviral treatment (ART), eight (36%) in their second regimen and nine (41%) in their third regimen or beyond, and one had no data. Seventeen of 22 (77%) had HIV-viral load (VL) > 50 copies/mL at prenatal care entry, 16 had a genotyping exam performed. Seventeen of 22 PHIV+ had VL results near delivery: 7/17 (41%) had VL < 50 copies/mL. Among those who had genotyping at prenatal entry, 11/16 (69%) had mutations associated with ARV resistance. The most frequent major mutations were K103N, M184V, T215, M41L, D67N at reverse transcriptase gene and M46, I54V and V82A at protease gene. No vertical transmissions occurred. Management of pregnancy among PHIV+ is challenging. Individualized ART are needed to achieve viral suppression in a highly ART-exposed subpopulation. PMID:27338425

  4. Viral Suppression and Resistance in a Cohort of Perinatally-HIV Infected (PHIV+) Pregnant Women.

    PubMed

    Cruz, Maria Letícia; Santos, Edwiges; Benamor Teixeira, Maria de Lourdes; Poletti, Monica; Sousa, Carolina; Gouvea, Maria Isabel; Nielsen-Saines, Karin; João, Esaú

    2016-01-01

    Our objective was to describe viral suppression and antiretroviral (ARV) resistance mutations in an ongoing cohort of perinatally-infected HIV+ (PHIV+) pregnant women. Descriptive analysis was performed using SPSS 18.0. From 2011 to 2014, we followed 22 PHIV+ pregnant women. Median age at prenatal entry was 19 years (Interquartile range (IQR) 17.6-21.0); 86% had an AIDS diagnosis; 81% had disclosed their HIV status to partner 11. The median age at HIV diagnosis was 8.3 y (IQR 4.0-13.6), the median age at sexual debut was 16 years (IQR 14-18). At the time of prenatal care initiation, four (18%) were on their first antiretroviral treatment (ART), eight (36%) in their second regimen and nine (41%) in their third regimen or beyond, and one had no data. Seventeen of 22 (77%) had HIV-viral load (VL) > 50 copies/mL at prenatal care entry, 16 had a genotyping exam performed. Seventeen of 22 PHIV+ had VL results near delivery: 7/17 (41%) had VL < 50 copies/mL. Among those who had genotyping at prenatal entry, 11/16 (69%) had mutations associated with ARV resistance. The most frequent major mutations were K103N, M184V, T215, M41L, D67N at reverse transcriptase gene and M46, I54V and V82A at protease gene. No vertical transmissions occurred. Management of pregnancy among PHIV+ is challenging. Individualized ART are needed to achieve viral suppression in a highly ART-exposed subpopulation. PMID:27338425

  5. Updates and achievements in virology.

    PubMed

    Buonaguro, Franco M; Campadelli-Fiume, Gabriella; De Giuli Morghen, Carlo; Palù, Giorgio

    2010-07-01

    The 4th European Congress of Virology, hosted by the Italian Society for Virology, attracted approximately 1300 scientists from 46 countries worldwide. It also represented the first conference of the European Society for Virology, which was established in Campidoglio, Rome, Italy in 2009. The main goal of the meeting was to share research activities and results achieved in European virology units/institutes and to strengthen collaboration with colleagues from both western and developing countries. The worldwide representation of participants is a testament to the strength and attraction of European virology. The 5-day conference brought together the best of current virology; topics covered all three living domains (bacteria, archaea and eucarya), with special sessions on plant and veterinary virology as well as human virology, including two oral presentations on mimiviruses. The conference included five plenary sessions, 31 workshops, one hepatitis C virus roundtable, ten special workshops and three poster sessions, as well as 45 keynote lectures, 191 oral presentations and 845 abstracts. Furthermore, the Gesellschaft fur Virologie Loeffler-Frosch medal award was given to Peter Vogt for his long-standing career and achievements; the Gardner Lecture of the European Society for Clinical Virology was presented by Yoshihiro Kawaoka, and the Pioneer in Virology Lecture of the Italian Society for Virology was presented by Ulrich Koszinowski. PMID:20624042

  6. PHARMACOKINETIC EXPOSURE AND VIROLOGIC RESPONSE IN HIV-1 INFECTED PREGNANT WOMEN TREATED WITH LOPINAVIR/RITONAVIR: AIDS CLINICAL TRIALS GROUP PROTOCOL A5153S: A SUBSTUDY TO A5150

    PubMed Central

    Sha, Beverly E.; Tierney, Camlin; Sun, Xin; Stek, Alice; Cohn, Susan E.; Coombs, Robert W.; Bastow, Barbara; Aweeka, Francesca T.

    2015-01-01

    Objective We studied the pharmacokinetics and pharmacodynamics of boosted soft-gel lopinavir/ritonavir to assess if the area under the plasma concentration versus time curve (AUC) is altered in pregnancy and whether changes in AUC impacted HIV-1 control. Methods We enrolled pregnant women ≥13 years of age between 22 to 30 weeks gestation who expected to be on stable lopinavir/ritonavir for ≥8 weeks pre-delivery and ≥24 weeks post-delivery. Pharmacokinetic evaluations for lopinavir and ritonavir occurred at 36 weeks gestation and 6 and 24 weeks postpartum. Results Ten women underwent intensive pharmacokinetic evaluations for lopinavir and ritonavir at 36 weeks gestation and at 6 and 24 weeks postpartum. Estimated geometric mean (GM) AUC 0–6h (95% CI) for lopinavir were not significantly different at 26.5 (17.0, 41.4) and 41.9 (26.1, 67.5) mcg*hr/mL at 36 weeks gestation and 6 weeks postpartum, respectively (within-subject GM ratio 0.60 (0.25, 1.43); p=0.19). At 36 weeks gestation, 5 of 10 women had viral load <50 copies/mL and at 6 weeks postpartum 5 of 9 had viral load <50 copies/mL. Nine of ten infants for whom data were available were HIV negative. Conclusion Despite below target lopinavir levels (< 52 mcg*hr/mL except at 2 postpartum measurements), women maintained virologic control postpartum. Higher doses of lopinavir/ritonavir during pregnancy may not be necessary in all women. PMID:26878071

  7. CD4+ cell count recovery in naïve patients initiating cART, who achieved and maintained plasma HIV-RNA suppression

    PubMed Central

    Costagliola, Dominique; Lacombe, Jean-Marc; Ghosn, Jade; Delaugerre, Constance; Pialoux, Gilles; Cuzin, Lise; Launay, Odile; Ménard, Amélie; de Truchis, Pierre; Mary-Krause, Murielle; Weiss, Laurence; Delfraissy, Jean-François

    2014-01-01

    Introduction A key objective of combined antiretroviral therapy (cART) is to reach and maintain high CD4 cell counts to provide long-term protection against AIDS-defining opportunistic infections and malignancies, as well as other comorbidities. However, a high proportion of patients present late for care. Our objective was to assess CD4 cell count recovery up to seven years in naïve patients initiating cART with at least three drugs in usual clinical care. Methods From the French Hospital Database on HIV, we selected naïve individuals initiating cART from 2000 with at least two years of follow-up. Participants were further required to have achieved viral load suppression by six months after initiating cART and were censored in case of virological failure. We calculated the proportion of patients (Kaplan-Meier estimates) who achieved CD4 recovery to >500/mm3 according to baseline CD4 cell count. Results A total of 15,025 patients were analyzed with a median follow-up on ART of 65.5 months (IQR: 42.3–96.0). At cART initiation, the median age was 38.6 years (IQR: 32.2–46.0), 9734 (64.8%) were men, median CD4 cell count was 239 (IQR: 130–336) and 2668 (17.8%) had a prior AIDS event. Results are presented in the Table 1. Conclusions This study shows that CD4 cell counts continue to increase seven years after cART initiation, whatever the baseline CD4 cell count. Failing to achieve CD4 recovery with continuous viral load suppression is rare for naïve patients initiating cART in routine clinical practice, but takes substantially longer in patients who initiate antiretroviral therapy at low CD4 cell counts. PMID:25393990

  8. Violence Screening and Viral Load Suppression Among HIV-Positive Women of Color

    PubMed Central

    Fletcher, Jason; Precht, Allison; Matoff-Stepp, Sabrina

    2015-01-01

    Abstract Recent research suggests intimate partner violence (IPV) is commonly experienced by many people living with HIV/AIDS, which can complicate their care. We introduce a novel approach to screening for history of violence among 102 women of color living with HIV and receiving care at an outpatient public health clinic. Using a composite measure composed of data from a variety of screening tools, we were able to determine that 70.6% of the women had a history of violence using the composite measure, and that 43% screened positive using multiple screening tools. Although overall viral load suppression rate was high at 81.4%, women with a history of violence were less likely to be virally suppressed when compared to those without such a history (76.4% versus 93.3%, p<0.05). Our findings suggest using a variety of screening questions at entry and at follow-up care appointments may be key to identifying and supporting women survivors who may not disclose violence when first asked. Future research should foster further development, analysis, and use of a variety of screening tools such as those used in this study. PMID:25561308

  9. Increased Intrathecal Immune Activation in Virally Suppressed HIV-1 Infected Patients with Neurocognitive Impairment

    PubMed Central

    Edén, Arvid; Marcotte, Thomas D.; Heaton, Robert K.; Nilsson, Staffan; Zetterberg, Henrik; Fuchs, Dietmar; Franklin, Donald; Price, Richard W.; Grant, Igor; Letendre, Scott L.; Gisslén, Magnus

    2016-01-01

    Objective Although milder forms of HIV-associated neurocognitive disorder (HAND) remain prevalent, a correlation to neuronal injury has not been established in patients on antiretroviral therapy (ART). We examined the relationship between mild HAND and CSF neurofilament light protein (NFL), a biomarker of neuronal injury; and CSF neopterin, a biomarker of CNS immunoactivation, in virally suppressed patients on antiretroviral therapy (ART). Design and Methods We selected 99 subjects on suppressive ART followed longitudinally from the CNS HIV Anti-Retroviral Therapy Effects Research (CHARTER) study. Based on standardized comprehensive neurocognitive performance (NP) testing, subjects were classified as neurocognitively normal (NCN; n = 29) or impaired (NCI; n = 70). The NCI group included subjects with asymptomatic (ANI; n = 37) or mild (MND; n = 33) HAND. CSF biomarkers were analyzed on two occasions. Results Geometric mean CSF neopterin was 25% higher in the NCI group (p = 0.04) and NFL and neopterin were significantly correlated within the NCI group (r = 0.30; p<0.001) but not in the NCN group (r = -0.13; p = 0.3). Additionally, a trend towards higher NFL was seen in the NCI group (p = 0.06). Conclusions Mild HAND was associated with increased intrathecal immune activation, and the correlation between neopterin and NFL found in NCI subjects indicates an association between neurocognitive impairment, CNS inflammation and neuronal damage. Together these findings suggest that NCI despite ART may represent an active pathological process within the CNS that needs further characterization in prospective studies. PMID:27295036

  10. Linker-Region Modified Derivatives of the Deoxyhypusine Synthase Inhibitor CNI-1493 Suppress HIV-1 Replication.

    PubMed

    Schröder, Marcus; Kolodzik, Adrian; Windshügel, Björn; Krepstakies, Marcel; Priyadarshini, Poornima; Hartjen, Philip; van Lunzen, Jan; Rarey, Matthias; Hauber, Joachim; Meier, Chris

    2016-02-01

    The inhibition of cellular factors that are involved in viral replication may be an important alternative to the commonly used strategy of targeting viral enzymes. The guanylhydrazone CNI-1493, a potent inhibitor of the deoxyhypusine synthase (DHS), prevents the activation of the cellular factor eIF-5A and thereby suppresses HIV replication and a number of other diseases. Here, we report on the design, synthesis and biological evaluation of a series of CNI-1493 analogues. The sebacoyl linker in CNI-1493 was replaced by different alkyl or aryl dicarboxylic acids. Most of the tested derivatives suppress HIV-1 replication efficiently in a dose-dependent manner without showing toxic side effects. The unexpected antiviral activity of the rigid derivatives point to a second binding mode as previously assumed for CNI-1493. Moreover, the chemical stability of CNI-1493 was analysed, showing a successive hydrolysis of the imino bonds. By molecular dynamics simulations, the behaviour of the parent CNI-1493 in solution and its interactions with DHS were investigated. PMID:26725082

  11. Retention in Care and Viral Suppression Among Persons Living With HIV/AIDS in New York City, 2006–2010

    PubMed Central

    Xia, Qiang; Wiewel, Ellen W.

    2014-01-01

    Objectives. We estimated the proportions of persons living with HIV/AIDS (PLWHA) in New York City (NYC) retained in care and virally suppressed. Methods. We used routinely reported laboratory surveillance data to measure trends in retention in care and viral suppression in PLWHA in NYC from 2006 through 2010. Our denominator excluded persons lacking any HIV-related laboratory tests during the 5 years prior to the year of analysis. Results. The proportion of patients retained in care (≥ 1 care visit in a calendar year) was stable, at 82.5% in 2006 and 81.8% in 2010. However, the proportion of persons with evidence of viral suppression increased significantly, from 44.3% to 59.1%. Blacks were least likely to have viral suppression (adjusted prevalence ratio [APR] = 0.89; 95% confidence interval [CI] = 0.87, 0.90). A U-shaped relationship between age and viral suppression was observed, with the 20- to 29-year age group least likely to have a suppressed viral load. Conclusions. Higher and more plausible proportions retained in care and virally suppressed than national estimates may reflect the difference in methodology and our comprehensive HIV-related laboratory reporting system. PMID:25033144

  12. Natural conception in HIV-serodiscordant couples with the infected partner in suppressive antiretroviral therapy: A prospective cohort study.

    PubMed

    Del Romero, Jorge; Baza, María Begoña; Río, Isabel; Jerónimo, Adrián; Vera, Mar; Hernando, Victoria; Rodríguez, Carmen; Castilla, Jesús

    2016-07-01

    The potential of antiretroviral treatment (ART) to prevent the sexual transmission of HIV has increased the number of serodiscordant couples who are considering natural conception. We aim to describe the results of a protocol for reproductive counseling aimed at HIV serodiscordant couples who desire natural conception, in which the infected partner, the index case, is receiving suppressive antiretroviral treatment.A prospective cohort included all HIV serodiscordant couples attended a counseling program in the period 2002 to 2013 who opted for natural conception and met the following criteria: index case on ART with persistent plasma viral suppression for at least the previous 6 months, ART compliance over 95%, preserved immune status, undetectable HIV viral and proviral load in semen in male index cases, and absence of genitourinary infections and fertility problems in both members of the couple.Of the 161 HIV serodiscordant couples included, 133 with male index cases, 66% achieved at least 1 pregnancy, 18% a second one, and 5% a third pregnancy. A total of 144 natural pregnancies occurred and 107 babies were born. The pregnancy rate was 1.9 for each 100 acts of vaginal intercourse, and the mean time to conception was 6.1 months, both independently of the sex of the index case. No case of sexual or vertical HIV transmission occurred.In the absence of fertility problems and under controlled conditions, natural conception might be a safe and effective reproductive method for those HIV serodiscordant couples who choose this reproductive option. PMID:27472733

  13. Entry-Level Competencies Required of Primary Care Nurse Practitioners Providing HIV Specialty Care: A National Practice Validation Study.

    PubMed

    Relf, Michael V; Harmon, James L

    2016-01-01

    In the United States, only 30% of HIV-infected persons are diagnosed, engaged in care, provided antiretroviral therapy, and virologically suppressed. Competent HIV care providers are needed to achieve optimal clinical outcomes for all people living with HIV, but 69% of Ryan White Clinics in the United States report difficulty recruiting HIV clinicians, and one in three current HIV specialty physicians are expected to retire in the next decade. Nurse practitioners who specialize in HIV and have caseloads with large numbers of HIV-infected patients have care outcomes that are equal to or better than that provided by physicians, especially generalist non-HIV specialist physicians. We designed a national practice validation study to help prepare the next generation of primary care nurse practitioners who desire to specialize in HIV. This manuscript reports the results of the national study and identifies entry-level competencies for entry-level primary care nurse practitioners specializing in HIV. PMID:26803386

  14. An Evolved RNA Recognition Motif That Suppresses HIV-1 Tat/TAR-Dependent Transcription.

    PubMed

    Crawford, David W; Blakeley, Brett D; Chen, Po-Han; Sherpa, Chringma; Le Grice, Stuart F J; Laird-Offringa, Ite A; McNaughton, Brian R

    2016-08-19

    Potent and selective recognition and modulation of disease-relevant RNAs remain a daunting challenge. We previously examined the utility of the U1A N-terminal RNA recognition motif as a scaffold for tailoring new RNA hairpin recognition and showed that as few as one or two mutations can result in moderate affinity (low μM dissociation constant) for the human immunodeficiency virus (HIV) trans-activation response element (TAR) RNA, an RNA hairpin controlling transcription of the human immunodeficiency virus (HIV) genome. Here, we use yeast display and saturation mutagenesis of established RNA-binding regions in U1A to identify new synthetic proteins that potently and selectively bind TAR RNA. Our best candidate has truly altered, not simply broadened, RNA-binding selectivity; it binds TAR with subnanomolar affinity (apparent dissociation constant of ∼0.5 nM) but does not appreciably bind the original U1A RNA target (U1hpII). It specifically recognizes the TAR RNA hairpin in the context of the HIV-1 5'-untranslated region, inhibits the interaction between TAR RNA and an HIV trans-activator of transcription (Tat)-derived peptide, and suppresses Tat/TAR-dependent transcription. Proteins described in this work are among the tightest TAR RNA-binding reagents-small molecule, nucleic acid, or protein-reported to date and thus have potential utility as therapeutics and basic research tools. Moreover, our findings demonstrate how a naturally occurring RNA recognition motif can be dramatically resurfaced through mutation, leading to potent and selective recognition-and modulation-of disease-relevant RNA. PMID:27253715

  15. Atazanavir/ritonavir monotherapy as maintenance strategy in HIV-1 treated subjects with viral suppression: 96-week analysis results of the MODAT study

    PubMed Central

    Spagnuolo, Vincenzo; Galli, Laura; Bigoloni, Alba; Nozza, Silvia; d'Arminio Monforte, Antonella; Antinori, Andrea; Di Biagio, Antonio; Rusconi, Stefano; Guaraldi, Giovanni; Di Giambenedetto, Simona; Lazzarin, Adriano; Castagna, Antonella

    2014-01-01

    Introduction The 48-week interim analysis of the MODAT study showed that confirmed virologic failure (CVF) was more frequent in patients simplifying to ATV/r monotherapy compared to maintaining ATV/r-based triple therapy. The DSMB recommended stopping study enrollment but continuing follow-up of enrolled patients. We present the 96-week efficacy analysis. Material and Methods Multicentre, randomized, open-label, non-inferiority trial (non-inferiority margin −10%). Treatment failure (TF) was defined as CVF (two consecutive HIV-RNA >50 cp/mL) or discontinuation for any cause. In the monotherapy arm, patients with CVF re-introduced their previous NRTIs and remained in the study if HIV-RNA <50 copies/mL within 12 weeks of re-intensification. Results 101 patients evaluated (Figure 1): 85% males, 21% HCV-positive, median (IQR) age of 42 (36–48) years, baseline CD4+ 576 (447–743) cells/µL. In the 96-week analysis (ITT; TF=failure), efficacy was 64% (32/50) in the monotherapy arm and 63% (32/51) in the triple-therapy arm (difference +1.3%, 95% CI −17.5–20.1). Fourteen patients in monotherapy and two in triple-therapy arm had CVF; median HIV-RNA was 136 (72–376) copies/mL. In monotherapy arm, no PI or NRTI associated resistance mutations were observed at CVF. All patients who re-intensified re-suppressed. In monotherapy arm, TF was more frequent in HCV-co-infected patients (64% vs 28%; p=0.041). In the secondary analysis (ITT; re-intensification=success), 82% (41/50) in monotherapy arm and 63% (32/51) in triple-therapy arm were on study at week 96 (difference +19.3%, 95% CI 2.2–36.3). SAEs occurred in four (8%) patients in the monotherapy arm (one left basal pneumonia, one acute coronary stenosis, one traumatic lesion, one nephrolithiasis) and two (4%) in the triple therapy arm (one sepsis, one renal failure). Drug-related adverse events (AEs) leading to discontinuation were three (6%) in the monotherapy arm (two AEs occurred in patients after successful re

  16. Dolutegravir-based monotherapy or dual therapy maintains a high proportion of viral suppression even in highly experienced HIV-1-infected patients

    PubMed Central

    Gubavu, Camelia; Prazuck, Thierry; Niang, Mohamadou; Buret, Jennifer; Mille, Catherine; Guinard, Jérôme; Avettand-Fènoël, Véronique; Hocqueloux, Laurent

    2016-01-01

    Background Dolutegravir is a powerful, well-tolerated integrase inhibitor with a high genetic barrier to resistance and may thus constitute the backbone of lightened regimens. Methods This was a monocentric, retrospective study. HIV-1-infected patients receiving dolutegravir as monotherapy (mDGV) or dual therapy (dDGV) were systematically identified. The primary outcome was the proportion of patients who maintained undetectable (<50 copies/mL) plasma HIV RNA [plasma viral load (PVL)]. Results We identified 21 patients on mDGV (50 mg/day) and 31 on dDGV (50 or 100 mg/day, with atazanavir ± ritonavir, n = 12; rilpivirine, n = 11; maraviroc, n = 3; lamivudine, n = 3; darunavir/ritonavir, n = 1; or abacavir, n = 1). All of the patients were treatment experienced and 48% had experienced at least one virological failure. The baseline characteristics were as follows (for the mDGV/dDGV patients, respectively): 5%/29% had a history of AIDS; the median (IQR) highest PVL was 4.5 (4.3–5.5)/5.3 (4.7–5.6) log copies/mL; the median (IQR) nadir CD4+ count was 310 (280–468)/199 (134–281) cells/mm3; 100% had undetectable PVL before the mDGV for a median (IQR) duration of 5.9 (3.5–9.9) years/81% had undetectable PVL before the dDGV for a median (IQR) duration of 3.7 (1.4–8.3) years; and the median (IQR) HIV DNA level was 2.7 (2.1–3.1)/2.9 (2.7–3) log copies/106 PBMCs. At the last follow-up visit, 100% and 97% of patients showed undetectable PVL following mDGV and dDGV, respectively [median (IQR) follow-up of 32 (29–45) and 50 (30–74) weeks, respectively]. Conclusions In our experience, dolutegravir-based lightened regimens provided a high proportion of viral suppression, even in highly treatment-experienced patients. PMID:26712907

  17. Psychiatric Diagnoses among an HIV-Infected Outpatient Clinic Population.

    PubMed

    Shacham, Enbal; Önen, Nur F; Donovan, Michael F; Rosenburg, Neal; Overton, E Turner

    2016-01-01

    As individuals with HIV infection are living longer, the management of psychiatric disorders has increasingly been incorporated into comprehensive care. Individuals were recruited from an outpatient HIV clinic to assess the prevalence and related associations of current psychiatric disorders and biomarkers. Of the 201 participants who completed the interviews, the median age was 43.5 years, and the majority was male and African American. Most were receiving HIV therapy and 78% of those had achieved virologic suppression. Prevalent psychiatric diagnoses included major depressive disorder, generalized anxiety, and agoraphobia. Alcohol and cocaine/crack abuse and dependence were common substance use disorders. Current receipt of HIV therapy was less common among those diagnosed with generalized anxiety disorder. Agoraphobia was the only disorder associated with unsuppressed viral load. Psychiatric and substance use disorders are highly prevalent among an urban HIV clinic population, although we identified few associations between psychiatric diagnoses and HIV diseases status. PMID:25348798

  18. Estimating the fraction of progeny virions that must incorporate APOBEC3G for suppression of productive HIV-1 infection

    SciTech Connect

    Thangavelu, Pulari U.; Gupta, Vipul; Dixit, Narendra M.

    2014-01-20

    The contest between the host factor APOBEC3G (A3G) and the HIV-1 protein Vif presents an attractive target of intervention. The extent to which the A3G–Vif interaction must be suppressed to tilt the balance in favor of A3G remains unknown. We employed stochastic simulations and mathematical modeling of the within-host dynamics and evolution of HIV-1 to estimate the fraction of progeny virions that must incorporate A3G to render productive infection unsustainable. Using three different approaches, we found consistently that a transition from sustained infection to suppression of productive infection occurred when the latter fraction exceeded ∼0.8. The transition was triggered by A3G-induced hypermutations that led to premature stop codons compromising viral production and was consistent with driving the basic reproductive number, R{sub 0}, below unity. The fraction identified may serve as a quantitative guideline for strategies targeting the A3G–Vif axis. - Highlights: • We perform simulations and mathematical modeling of the role of APOBEC3G in suppressing HIV-1 infection. • In three distinct ways, we estimate that when over 80% of progeny virions carry APOBEC3G, productive HIV-1 infection would be suppressed. • Our estimate of this critical fraction presents quantitative guidelines for strategies targeting the APOBEC3G–Vif axis.

  19. Food insecurity, CD4 counts, and incomplete viral suppression among HIV+ patients from Texas Children's Hospital: A pilot study

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Our goal was to determine the relationship between food insecurity and CD4 counts and viral suppression among pediatric HIV-positive patients. Food insecurity was assessed by validated survey. CD4 counts and viral load were abstracted from patients’ charts. We used linear regression for the dependen...

  20. Antiretroviral Therapy (ART) Use, Human Immunodeficiency Virus (HIV)-1 RNA Suppression, and Medical Causes of Hospitalization Among HIV-Infected Intravenous Drug Users in the Late ART Era

    PubMed Central

    Vallecillo, Gabriel; Mojal, Sergio; Torrens, Marta; Muga, Roberto

    2014-01-01

    Background.  Antiretroviral therapy (ART) has reduced the rates and changed the causes of hospital admission. However, human immunodeficiency virus-positive intravenous drug users (HIV-IDU) continue to have increased hospitalizations and discharge diagnosis are less defined in the late ART era. Our aim was to examine ART use, HIV-1 RNA suppression, and hospital discharge diagnoses among HIV-IDU admitted to an urban hospital. Methods.  A retrospective analysis was made of HIV-IDU admitted for medical causes for the first time (2006–2010). Surgical, obstetric, or mental (except HIV-associated neurocognitive disorder) diagnoses were excluded. Clinical characteristics, number of admissions, and primary discharge diagnoses were determined for each patient. Results.  Three hundred and seventy-five admissions were recorded among 197 hospitalized HIV-IDU. Lifetime prevalence of ART use was 83.2% (164 of 197) and the rate of HIV-1 RNA <50 copies/mL was 38.1% (75 of 197). Primary discharge diagnosis groups were as follows: bacterial infections (59.2%), chronic end-organ damage (16.8%), complications derived from injected drug use (16.8%), malignancies (9.1%), and opportunistic infections (6.6%). Chronic end-organ damage was diagnosed more frequently in patients with HIV-1 RNA <50 copies/mL (36% vs 4.9%; P < .000), and complications derived from injected drug use (23.8% vs 5.3%; P < .0008) and acquired immune deficiency syndrome (AIDS) opportunistic infections (19.8% vs 1.3% P < .019) were usually diagnosed in patients with HIV-1 RNA detectable viral load. Conclusions.  Human immunodeficiency virus-positive intravenous drug users are admitted to hospitals mainly for non-AIDS-related illnesses; however, sustained HIV-1 RNA viral load suppression is poor and determines hospital discharge diagnoses. Providers need to be aware of the management of HIV-related comorbidities and reinforce strategies to improve ART retention in this population. PMID:25734084

  1. Antiretroviral Therapy and Viral Suppression Among Foreign-Born HIV-Infected Persons Receiving Medical Care in the United States

    PubMed Central

    Myers, Tanya R.; Lin, Xia; Skarbinski, Jacek

    2016-01-01

    Abstract Immigrants to the United States are more likely to be diagnosed with human immunodeficiency virus (HIV) infection compared with native-born persons. Navigating access to healthcare in the United States can be challenging for foreign-born persons, and HIV treatment outcomes may be suboptimal for these persons. We compared characteristics of and assessed disparities in clinical outcomes of foreign-born persons in care for HIV in the United States. The Medical Monitoring Project is a complex sample, cross-sectional survey designed to be nationally representative of HIV-infected adults receiving medical care in the United States. Using data from 2009, 2010, and 2011, we conducted descriptive analyses and multivariable logistic regression to assess associations between foreign-born status and antiretroviral therapy (ART) prescription, and between foreign-born status and viral suppression. In all, 13.4% of HIV-infected persons were self-identified as foreign-born; the most common regions of birth were Central America and Mexico (45.4%) and the Caribbean (16.0%). Nearly 90% of foreign-born persons were diagnosed with HIV after entry into the United States. Compared with US-born persons, foreign-born persons were more likely to be younger, Hispanic, less educated, and uninsured. The prevalence of ART prescription (prevalence ratio 1.00; 95% confidence interval 0.98–1.02) was not significantly different between foreign-born and US-born persons. A higher percentage of foreign-born persons achieved viral suppression compared with US-born persons (prevalence ratio 1.05; 95% confidence interval 1.00–1.09). No major disparities in ART prescription and viral suppression were found between foreign-born and US-born HIV-infected persons receiving medical care, despite higher percentages being uninsured. PMID:26986128

  2. Dextran Sulfate Suppression of Viruses in the HIV Family: Inhibition of Virion Binding to CD4+ Cells

    NASA Astrophysics Data System (ADS)

    Mitsuya, Hiroaki; Looney, David J.; Kuno, Sachiko; Ueno, Ryuji; Wong-Staal, Flossie; Broder, Samuel

    1988-04-01

    The first step in the infection of human T lymphocytes by human immunodeficiency virus type 1 (HIV-1) is attachment to the target cell receptor, the CD4 antigen. This step may be vulnerable to attack by antibodies, chemicals, or small peptides. Dextran sulfate (molecular weight approximately 8000), which has been given to patients as an anticoagulant or antilipemic agent for more than two decades, was found to block the binding of virions to various target T lymphocytes, inhibit syncytia formation, and exert a potent inhibitory effect against HIV-1 in vitro at concentrations that may be clinically attainable in human beings. This drug also suppressed the replication of HIV-2 in vitro. These observations could have theoretical and clinical implications in the strategy to develop drugs against HIV types 1 and 2.

  3. Benefits of a Routine Opt-Out HIV Testing and Linkage to Care Program for Previously Diagnosed Patients in Publicly Funded Emergency Departments in Houston, TX

    PubMed Central

    Flash, Charlene A.; Pasalar, Siavash; Hemmige, Vagish; Davila, Jessica A.; Hallmark, Camden J.; McNeese, Marlene; Miertschin, Nancy; Ruggerio, Michael C.; Giordano, Thomas P.

    2015-01-01

    Background The Routine Universal Screening for HIV (RUSH) program provides opt-out HIV testing and linkage to care for emergency department (ED) patients in Harris Health System, Houston, TX. Seventy-five percent of patients testing positive in this program have been previously diagnosed. Whether linkage to care is increased among these patients is unknown. Methods We conducted a retrospective cohort study of persons tested for HIV in the ED between 2008–2012 but had a previously documented positive HIV test ≥1 year prior. Outcomes were engagement in care (≥1 HIV outpatient visits in 6 months), retention in care (≥2 HIV outpatient visits in 12 months, at least 3 months apart) and virologic suppression (<200 c/ml in 12 months) compared before and after the ED visit. Analysis was conducted using McNemar’s test and multivariate conditional logistic regression. Results A total of 202,767 HIV tests identified 2068 previously diagnosed patients. The mean age was 43 years with 65% male and 87% racial and ethnic minorities. Engagement in care increased from 41.3% pre-visit to 58.8% post-visit (P<0.001). Retention in care increased from 32.6% pre-visit to 47.1% post-visit (P<0.001). Virologic suppression increased from 22.8% pre-visit to 34.0% post-visit (P<0.001). Analyses revealed that engagement in care after visit improved most among younger participants (ages 16 to 24), retention improved across all groups, and virologic suppression improved most among participants 25 to 34 years old. Conclusions Routine opt-out HIV testing in an ED paired with standardized service linkage improves engagement, retention, and virologic suppression in previously diagnosed patients. PMID:25867782

  4. Informal Caregiver Characteristics Associated with Viral Load Suppression Among Current or Former Injection Drug Users Living with HIV/AIDS.

    PubMed

    Mitchell, Mary M; Robinson, Allysha C; Nguyen, Trang Q; Knowlton, Amy R

    2015-11-01

    Few studies have examined the association between having an informal (unpaid) caregiver and viral suppression among persons living with HIV/AIDS (PLHIV) who are on antiretroviral therapy. The current study examined relationships between caregivers' individual and social network characteristics and care recipient viral suppression. Baseline data were from the BEACON study caregivers and their HIV seropositive former or current drug using care recipients, of whom 89 % were African American (N = 258 dyads). Using adjusted logistic regression, care recipient's undetectable viral load was positively associated with caregiver's limited physical functioning and negatively associated with caregivers having few family members to turn to for problem solving, a greater number of current drug users in their network, and poorer perceptions of the care recipient's mental health. Results further understandings of interpersonal relationship factors important to PLHIV's health outcomes, and the need for caregiving relationship-focused intervention to promote viral suppression among PLHIV. PMID:25969180

  5. Management of HIV Infection during Pregnancy in the United States: Updated Evidence-Based Recommendations and Future Potential Practices

    PubMed Central

    Haddad, Lisa; Chakraborty, Rana

    2016-01-01

    All HIV-infected women contemplating pregnancy should initiate combination antiretroviral therapy (cART), with a goal to achieve a maternal serum HIV RNA viral load beneath the laboratory level of detection prior to conceiving, as well as throughout their pregnancy. Successfully identifying HIV infection during pregnancy through screening tests is essential in order to prevent in utero and intrapartum transmission of HIV. Perinatal HIV transmission can be less than 1% when effective cART, associated with virologic suppression of HIV, is given during the ante-, intra-, and postpartum periods. Perinatal HIV guidelines, developed by organizations such as the World Health Organization, American College of Obstetricians and Gynecologists, and the US Department of Health and Human Services, are constantly evolving, and hence the aim of our review is to provide a useful concise review for medical providers caring for HIV-infected pregnant women, summarizing the latest and current recommendations in the United States. PMID:27504071

  6. Management of HIV Infection during Pregnancy in the United States: Updated Evidence-Based Recommendations and Future Potential Practices.

    PubMed

    Rimawi, Bassam H; Haddad, Lisa; Badell, Martina L; Chakraborty, Rana

    2016-01-01

    All HIV-infected women contemplating pregnancy should initiate combination antiretroviral therapy (cART), with a goal to achieve a maternal serum HIV RNA viral load beneath the laboratory level of detection prior to conceiving, as well as throughout their pregnancy. Successfully identifying HIV infection during pregnancy through screening tests is essential in order to prevent in utero and intrapartum transmission of HIV. Perinatal HIV transmission can be less than 1% when effective cART, associated with virologic suppression of HIV, is given during the ante-, intra-, and postpartum periods. Perinatal HIV guidelines, developed by organizations such as the World Health Organization, American College of Obstetricians and Gynecologists, and the US Department of Health and Human Services, are constantly evolving, and hence the aim of our review is to provide a useful concise review for medical providers caring for HIV-infected pregnant women, summarizing the latest and current recommendations in the United States. PMID:27504071

  7. HIV-1 Genital Shedding is Suppressed in the Setting of High Genital Antiretroviral Drug Concentrations Throughout the Menstrual Cycle

    PubMed Central

    Sheth, Anandi N.; Evans-Strickfaden, Tammy; Haaland, Richard; Martin, Amy; Gatcliffe, Chelsea; Adesoye, Adebola; Omondi, Michael W.; Lupo, L. Davis; Danavall, Damien; Easley, Kirk; Chen, Cheng-Yen; Pau, Chou-Pong; Hart, Clyde; Ofotokun, Igho

    2014-01-01

    Background. It is not known if fluctuations in genital tract antiretroviral drug concentrations correlate with genital virus shedding in human immunodeficiency virus (HIV)–infected women on antiretroviral therapy (ART). Methods. Among 20 HIV-infected women on ART (tenofovir [TFV], emtricitabine [FTC], and ritonavir-boosted atazanavir [ATV]) with suppressed plasma virus loads, blood and cervicovaginal samples collected twice weekly for 3 weeks were tested for antiretroviral concentrations, HIV-1 RNA, and proviral DNA. Results. Cervicovaginal:plasma antiretroviral concentration ratios were highest for FTC (11.9, 95% confidence interval [CI], 8.66–16.3), then TFV (3.52, 95% CI, 2.27–5.48), and ATV (2.39, 95% CI, 1.69–3.38). Within- and between-person variations in plasma and genital antiretroviral concentrations were observed. Low amounts of genital HIV-1 RNA (<50 copies/mL) were detected in 45% of women at 16% of visits. Genital HIV-1 DNA was detected in 70% of women at 35% of visits. Genital virus detection was associated with higher concentrations of mucosal leukocytes but not with genital antiretroviral concentrations, menstrual cycle phase, bacterial vaginosis, genital bleeding, or plasma virus detection. Conclusions. Standard doses of ART achieved higher genital than plasma concentrations across the menstrual cycle. Therapeutic ART suppresses genital virus shedding throughout the menstrual cycle, even in the presence of factors reported to increase virus shedding. PMID:24643223

  8. Deep Sequencing: Becoming a Critical Tool in Clinical Virology

    PubMed Central

    QUIÑONES-MATEU, Miguel E.; AVILA, Santiago; REYES-TERAN, Gustavo; MARTINEZ, Miguel A.

    2014-01-01

    Population (Sanger) sequencing has been the standard method in basic and clinical DNA sequencing for almost 40 years; however, next-generation (deep) sequencing methodologies are now revolutionizing the field of genomics, and clinical virology is no exception. Deep sequencing is highly efficient, producing an enormous amount of information at low cost in a relatively short period of time. High-throughput sequencing techniques have enabled significant contributions to multiples areas in virology, including virus discovery and metagenomics (viromes), molecular epidemiology, pathogenesis, and studies of how viruses to escape the host immune system and antiviral pressures. In addition, new and more affordable deep sequencing-based assays are now being implemented in clinical laboratories. Here we review the use of the current deep sequencing platforms in virology, focusing on three of the most studied viruses: human immunodeficiency virus (HIV), hepatitis C virus (HCV), and influenza virus. PMID:24998424

  9. Biomarkers of inflammation in HIV-infected Peruvian men and women before and during suppressive antiretroviral therapy

    PubMed Central

    Ticona, Eduardo; Bull, Marta E.; Soria, Jaime; Tapia, Kenneth; Legard, Jillian; Styrchak, Sheila M.; Williams, Corey; Mitchell, Caroline; Rosa, Alberto L.A.; Coombs, Robert W.; Frenkel, Lisa M.

    2016-01-01

    Objective Inflammatory biomarkers associated with cardiovascular disease are elevated in HIV-infected persons. These biomarkers improve with antiretroviral therapy (ART) but do not normalize to values observed in HIV-uninfected adults. Little is known regarding biomarkers of inflammation in HIV-infected Peruvians, in whom an increased burden of infectious diseases may exacerbate inflammation, and women, in whom sex difference may alter inflammation compared with men. Methods Peruvians initiating first-line ART were enrolled in a prospective observational study. Individuals with suppression of HIV RNA plasma loads to less than 30 copies/ml when determined quarterly over 24 months of ART, had biomarkers of inflammation and cellular activation measured pre-ART and at 24-months of ART, and evaluated for associations with sex and clinical parameters. Results Pre-ART high-sensitivity C-reactive protein (hsCRP) values of men were in the high-risk cardiovascular disease category (>3.0mg/l) more frequently compared with women (P = 0.02); most women’s values were in the low/average-risk categories. At 24 months of suppressive ART, hsCRP concentrations decreased in men (P = 0.03), but tended to increase in women, such that the proportion with high-risk hsCRP did not differ by sex. Pre-ART, soluble CD163 concentrations were higher in women compared with men (P = 0.02), and remained higher after 24 months of suppressive ART (P = 0.02). All other inflammatory biomarkers (P < 0.03) decreased across sexes. Biomarker concentrations were not associated with BMI or coinfections. Conclusion Elevated inflammatory biomarkers persisted despite 24 months of suppressive ART in a subset of Peruvians, and to a greater extent in women compared with men. These findings suggest that lifestyle or pharmacologic interventions may be required to optimize the health of HIV-infected Peruvians, particularly women. PMID:26372272

  10. Early diagnosis and retention in care of HIV-infected patients through rapid salivary testing: a test-and-treat fast track pilot study.

    PubMed

    Parisi, Maria Rita; Soldini, Laura; Negri, Silvia; Vidoni, Gian Marino; Gianotti, Nicola; Nozza, Silvia; Schlusnus, Karin; Dorigatti, Fernanda; Lazzarin, Adriano

    2016-01-01

    Aim of this study was to evaluate the efficacy and the retention-in-care of individuals diagnosed during six years of salivary HIV testing (EASY-test project). Among those linked-to-care at the Infectious Diseases Department of San Raffaele Hospital (Milan, Italy), the proportion of patients engaged, retained in care and virologically suppressed after the antiretroviral treatment was 96%, 100% and 95.2%, respectively. Results from our study suggest that salivary HIV testing may help bring to light cases of HIV infection otherwise undiagnosed, and thus favour a more rapid and wider reduction of the HIV infection burden at the population level. PMID:26922986

  11. Prevalence of low bone mineral density among HIV patients on long-term suppressive antiretroviral therapy in resource limited setting of western India

    PubMed Central

    Dravid, Ameet; Kulkarni, Milind; Borkar, Amit; Dhande, Sachin

    2014-01-01

    Introduction Bone mineral density (BMD) assessment in HIV patients is sparsely done in resource limited settings. Materials and Methods We conducted a cross-sectional study of BMD amongst HIV patients following up in our clinic from 1 June to 1 December 2013 by performing dual-energy X-ray absorptiometry scan (Lunar Prodigy Advanced DXA System, GE Healthcare) of lumbar spine and hip. Patients on long term (≥12 months), virologically suppressive antiretroviral therapy (ART) were included. Patients who were ART naïve were included as control population. Virologic failures were excluded. Low BMD was defined by WHO T-score criteria (normal: T score ≥−1;osteopenia: T score between −1 and −2.5 SD; osteoporosis: T score ≤−2.5 SD). Baseline risk factors associated with low BMD like age, low BMI, lipoatrophy, diabetes mellitus, current smoking, current alcohol intake, steroid exposure and menopause were recorded. ART-related factors associated with low BMD like ART duration, exposure to tenofovir and exposure to protease inhibitors (PI) were studied. Results A total of 536 patients (66% males, 496 ART experienced and 40 ART naïve) were included in this analysis. Median age was 42 years, mean BMI 23.35 kg/m2 and median CD4 count 146 cells/mm3. All ART experienced patients had plasma viral load<400 copies/ml. Prevalence of low BMD amongst ART naive and ART experienced patients was 67% (osteopenia: 70.4%, osteoporosis: 29.6%) and 80.4% (osteopenia: 63.4%, osteoporosis: 36.6%), respectively (p=0.05). Mean T scores at lumbar spine and hip for ART naive and ART experienced patients were −1.37 and −0.9 versus −1.56 and −1.48 (p=0.05), respectively. Age, low BMI, current smoking, menopause, baseline CD4 count and exposure to ART were factors significantly associated with low overall BMD on univariate regression analysis. On multivariable logistic regression analysis age (p<0.001), low BMI (p<0.001), current smoking (0.05) and menopause (0.03) were associated

  12. HIV outcomes at a Canadian remand centre.

    PubMed

    Subramanian, Yazhini; Khan, Muhammad Naeem; Berger, Sara; Foisy, Michelle; Singh, Ameeta; Woods, Dan; Pyne, Diane; Ahmed, Rabia

    2016-09-12

    Purpose The purpose of this paper is to assess the impact of short-term incarceration on antiretroviral therapy (ART) adherence, virologic suppression, and engagement and retention in community care post-release. Design/methodology/approach A retrospective chart review of patients who attended the human immunodeficiency virus (HIV) Outreach Clinic at a Canadian remand center between September 2007 and December 2011 was carried out. Data extraction included CD4 lymphocyte count, HIV viral load, ART prescription refills, and community engagement and retention during and one-year pre- and post-incarceration. Findings Outpatient engagement increased by 23 percent ( p=0.01), as did ART adherence (55.2-70.7 percent, p=0.01), following incarceration. Retention into community care did not significantly improve following incarceration (22.4 percent pre-incarceration to 25.9 percent post-release, p=0.8). There was a trend toward improved virologic suppression (less than 40 copies/ml; 50-77.8 percent ( p=0.08)) during incarceration and 70. 4 percent sustained this one-year post-incarceration ( p=0.70). Originality/value The impact of short-term incarceration in a Canadian context of universal health coverage has not been previously reported and could have significant implications in optimizing HIV patient outcomes given the large number of HIV-positive patients cycling through short-term remand centers. PMID:27548017

  13. HIV Infection Care and Viral Suppression Among People Who Inject Drugs, 28 U.S. Jurisdictions, 2012-2013

    PubMed Central

    Karch, Debra L.; Gray, Kristen Mahle; Shi, Jing; Hall, H. Irene

    2016-01-01

    Objectives: Assess outcomes along the care continuum for HIV-infected people who inject drugs (PWID), by type of facility and stage of infection at diagnosis. Methods: Data reported by 28 jurisdictions to the National HIV Surveillance System by December 2014 were used to identify PWID aged ≥13 years, diagnosed with HIV infection before December 31, 2013. Analyses used the CDC definition of linkage to care (LTC), retention in care (RIC), and viral suppression (VS), and are stratified by age, sex, race/ethnicity, and type of facility and stage of HIV infection at diagnosis. Results: Of 1,409 PWID diagnosed with HIV in 2013, 1,116 (79.2%) were LTC with the lowest percentages among males (78.4%); blacks (77.5%) ages 13-24 years (69.0%); those diagnosed in early stage infection (71.6%); and at screening, diagnostic, or referral agencies (60.0%). Of 80,958 PWID living with HIV in 2012, 40,234 (49.7%) were RIC and 34,665 (42.8%) achieved VS. The lowest percentages for RIC and VS were among males (47.1% and 41.3% respectively); those diagnosed with late stage disease (47.1% and 42.4%); and young people. Whites had the lowest RIC (47.0%) while blacks had the lowest VS (41.1%). Conclusion: Enhanced LTC activities are needed for PWID diagnosed at screening, diagnostic or referral agencies versus those diagnosed at inpatient or outpatient settings, especially among young people and blacks diagnosed in early stage infection. Less than half of PWID are retained in care or reach viral suppression indicating the need for continued engagement and return to care activities over the long term. PMID:27386014

  14. Summary of the 9th annual meeting of the Italian Society for Virology.

    PubMed

    Salata, Cristiano; Calistri, Arianna; Parolin, Cristina; Palù, Giorgio

    2011-01-01

    The 9th annual meeting of the Italian Society for Virology (SIV) comprised seven plenary sessions focused on: General virology and viral genetics; Virus-Host interaction and pathogenesis; Viral oncology; Emerging viruses and zoonotic, foodborne, and environmental pathways of transmission; Viral immunology and vaccines; Medical virology and antiviral therapy; Viral biotechnologies and gene therapy. Moreover, four hot topics were discussed in special lectures: the Pioneer in human virology lecture regarding the control of viral epidemics with particular emphasis on the human immunodeficiency virus (HIV), the Pioneer in plant virology lecture focused on cell responses to plant virus infection, a Keynote lecture on the epidemiology and genetic diversity of Crimea-Congo Hemorrhagic Fever virus, and the G.B. Rossi lecture on the molecular basis and clinical implications of human cytomegalovirus tropism for endothelial/epithelial cells. The meeting had an attendance of about 160 virologists. A summary of the plenary lectures and oral selected presentations is reported. PMID:20799282

  15. Assessing the HIV Care Continuum in Latin America: progress in clinical retention, cART use and viral suppression

    PubMed Central

    Rebeiro, Peter F; Cesar, Carina; Shepherd, Bryan E; De Boni, Raquel B; Cortés, Claudia P; Rodriguez, Fernanda; Belaunzarán-Zamudio, Pablo; Pape, Jean W; Padgett, Denis; Hoces, Daniel; McGowan, Catherine C; Cahn, Pedro

    2016-01-01

    Introduction We assessed trends in HIV Care Continuum outcomes associated with delayed disease progression and reduced transmission within a large Latin American cohort over a decade: clinical retention, combination antiretroviral therapy (cART) use and viral suppression (VS). Methods Adults from Caribbean, Central and South America network for HIV epidemiology clinical cohorts in seven countries contributed data between 2003 and 2012. Retention was defined as two or more HIV care visits annually, >90 days apart. cART was defined as prescription of three or more antiretroviral agents annually. VS was defined as HIV-1 RNA <200 copies/mL at last measurement annually. cART and VS denominators were subjects with at least one visit annually. Multivariable modified Poisson regression was used to assess temporal trends and examine associations between age, sex, HIV transmission mode, cohort, calendar year and time in care. Results Among 18,799 individuals in retention analyses, 14,380 in cART analyses and 13,330 in VS analyses, differences existed between those meeting indicator definitions versus those not by most characteristics. Retention, cART and VS significantly improved from 2003 to 2012 (63 to 77%, 74 to 91% and 53 to 82%, respectively; p<0.05, each). Female sex (risk ratio (RR)=0.97 vs. males) and injection drug use as HIV transmission mode (RR=0.83 vs. male sexual contact with males (MSM)) were significantly associated with lower retention, but unrelated with cART or VS. MSM (RR=0.96) significantly decreased the probability of cART compared with heterosexual transmission. Conclusions HIV Care Continuum outcomes improved over time in Latin America, though disparities for vulnerable groups remain. Efforts must be made to increase retention, cART and VS, while engaging in additional research to sustain progress in these settings. PMID:27065108

  16. HIV Disease: Current Concepts.

    ERIC Educational Resources Information Center

    Keeling, Richard P.

    1993-01-01

    Describes human immunodeficiency virus (HIV), newly characterized human retrovirus which causes chronic, progressive, immune deficiency disease, the most severe phase of which is Acquired Immune Deficiency Syndrome (AIDS). Reviews most important current epidemiologic, clinical, and virologic information about HIV and HIV disease and provides…

  17. The HIV Care Cascade Before, During, and After Incarceration: A Systematic Review and Data Synthesis

    PubMed Central

    Iroh, Princess A.; Mayo, Helen

    2015-01-01

    We conducted a systematic literature review of the data on HIV testing, engagement in care, and treatment in incarcerated persons, and estimated the care cascade in this group. We identified 2706 titles in MEDLINE, EBSCO, and Cochrane Library databases for studies indexed to January 13, 2015, and included 92 for analysis. We summarized HIV testing results by type (blinded, opt-out, voluntary); reviewed studies on HIV care engagement, treatment, and virological suppression; and synthesized these results into an HIV care cascade before, during, and after incarceration. The HIV care cascade following diagnosis increased during incarceration and declined substantially after release, often to levels lower than before incarceration. Incarceration provides an opportunity to address HIV care in hard-to-reach individuals, though new interventions are needed to improve postrelease care continuity. PMID:25973818

  18. The HIV Care Cascade Before, During, and After Incarceration: A Systematic Review and Data Synthesis.

    PubMed

    Iroh, Princess A; Mayo, Helen; Nijhawan, Ank E

    2015-07-01

    We conducted a systematic literature review of the data on HIV testing, engagement in care, and treatment in incarcerated persons, and estimated the care cascade in this group. We identified 2706 titles in MEDLINE, EBSCO, and Cochrane Library databases for studies indexed to January 13, 2015, and included 92 for analysis. We summarized HIV testing results by type (blinded, opt-out, voluntary); reviewed studies on HIV care engagement, treatment, and virological suppression; and synthesized these results into an HIV care cascade before, during, and after incarceration. The HIV care cascade following diagnosis increased during incarceration and declined substantially after release, often to levels lower than before incarceration. Incarceration provides an opportunity to address HIV care in hard-to-reach individuals, though new interventions are needed to improve postrelease care continuity. PMID:25973818

  19. Long-Term Efficacy and Safety of Atazanavir/Ritonavir Treatment in a Real-Life Cohort of Treatment-Experienced Patients with HIV Type 1 Infection

    PubMed Central

    Sönnerborg, Anders; Brockmeyer, Norbert; Thalme, Anders; Svedhem, Veronica; Dupke, Stephan; Eychenne, Jean-Luc; Nakonz, Tina; Jimenez-Exposito, Maria Jesus; Pugliese, Pascal

    2013-01-01

    Abstract Atazanavir-based regimens have established efficacy and safety in both antiretroviral (ARV)-naive and -experienced patients. However, data evaluating effectiveness beyond 2 years is sparse. Therefore, we assessed the long-term outcomes of ritonavir-boosted atazanavir (ATV/r)-containing regimens in ARV-experienced patients in a clinical setting in a noncomparative, retrospective, observational study collecting data from three European HIV databases on ARV-experienced adults with HIV-1 infection starting an ATV/r-based regimen. Data were extracted every 6 months (maximum follow-up 5 years). Primary outcome was the proportion of patients remaining on ATV/r by baseline HIV-1 RNA (<500 or ≥500 copies/ml). Secondary outcomes included time to virologic failure, reasons for discontinuation, and long-term safety profile. The duration of treatment and time to virologic failure were analyzed using the Kaplan–Meier method. Data were analyzed for 1,294 ARV-experienced patients (male 74%; mean ART exposure 5.7 years). After 3 years, 56% (95% CI: 52%, 60%) of patients with baseline HIV-1 RNA <500 copies/ml and 53% (95% CI: 49%, 58%) of those with HIV-1 RNA ≥500 copies/ml remained on ATV/r. After 3 years, 75% (95% CI: 69%, 80%) of patients with baseline HIV-1 RNA <50 copies/ml remained suppressed and 51% (95% CI: 47%, 55%) of those with baseline HIV-1 RNA ≥50 copies/ml achieved and maintained virologic suppression. Although adverse events (AEs) were the main known reason for discontinuation, no unexpected AEs were observed. In a real-life setting ATV/r-based regimens demonstrated sustained virologic suppression in ARV-experienced patients. After long-term therapy the majority of patients remained on treatment and no unexpected AEs were observed. PMID:23016535

  20. Virological Outcomes and Drug Resistance in Chinese Patients after 12 Months of 3TC-Based First-Line Antiretroviral Treatment, 2011–2012

    PubMed Central

    Xu, Xiaoqin; Liu, Yong; He, Jianmei; Ling, Hua; Ding, Ping; Tong, Yi; Zou, Xiaobai; Zhou, Quanhua; Liao, Lingjie; Wang, Xia; Ruan, Yuhua; Shao, Yiming; Xing, Hui

    2014-01-01

    Objective To determine the prevalence of virological failure and HIV drug resistance among Chinese patients one year after initiating lamivudine-based first-line antiretroviral treatment. Methods A prospective cohort study with follow-up at 12 months was conducted in four urban sentinel sites in China. Antiretroviral naive patients ≥18 years old were recruited. Blood samples were collected for testing CD4 cell count, viral load, and (for samples with HIV-1 RNA ≥1000 copies/ml) genotyping of drug resistance. Results A total of 513 patients were enrolled in this cohort, of whom 448 (87.3%) were retained at 12 months. The median final CD4 cell count was 313 cells/mm3, which increased from 192 cells/mm3 at baseline (P<0.0001). Of the 448 remaining subjects, 394 (87.9%) had successful virological suppression (HIV RNA <1000 copies/ml). Among 54 samples with viral load ≥1000 copies/ml, 40 were successfully genotyped, and 11 were found with detectable HIV drug resistance mutations. Of these, the proportions of drug resistance to NNRTIs, NRTIs and PIs were 100%, 81.8% and 0%, respectively. Injecting drug use (AOR = 0.40, 95% CI: 0.19,0.84; P = 0.0154), CD4 count at baseline ≥350 cells/mm3 (AOR = 0.32, 95% CI: 0.14,0.72; P = 0.0056), and missed doses in the past month (AOR = 0.30, 95% CI: 0.15,0.60; P = 0.0006) were significantly negatively associated with HIV RNA <1000 copies/ml. Conclusions Our study demonstrates effective virological and immunological outcomes at 12 months among these who initiated first-line ART treatment. However, patients infected through drug injection, who missed doses, or with higher CD4 count at baseline are at increased risk for poor virological response. PMID:24516631

  1. D-Dimer Levels before HIV Seroconversion Remain Elevated Even after Viral Suppression and Are Associated with an Increased Risk of Non-AIDS Events

    PubMed Central

    Freiberg, Matthew S.; Bebu, Ionut; Tracy, Russell; So-Armah, Kaku; Okulicz, Jason; Ganesan, Anuradha; Armstrong, Adam; O’Bryan, Thomas; Rimland, David; Justice, Amy C.; Agan, Brian K.

    2016-01-01

    The mechanism underlying the excess risk of non-AIDS diseases among HIV infected people is unclear. HIV associated inflammation/hypercoagulability likely plays a role. While antiretroviral therapy (ART) may return this process to pre-HIV levels, this has not been directly demonstrated. We analyzed data/specimens on 249 HIV+ participants from the US Military HIV Natural History Study, a prospective, multicenter observational cohort of >5600 active duty military personnel and beneficiaries living with HIV. We used stored blood specimens to measure D-dimer and Interleukin-6 (IL-6) at three time points: pre-HIV seroconversion, ≥6 months post-HIV seroconversion but prior to ART initiation, and ≥6 months post-ART with documented HIV viral suppression on two successive evaluations. We evaluated the changes in biomarker levels between time points, and the association between these biomarker changes and future non-AIDS events. During a median follow-up of 3.7 years, there were 28 incident non-AIDS diseases. At ART initiation, the median CD4 count was 361cells/mm3; median duration of documented HIV infection 392 days; median time on ART was 354 days. Adjusted mean percent increase in D-dimer levels from pre-seroconversion to post-ART was 75.1% (95% confidence interval 24.6–148.0, p = 0.002). This increase in D-dimer was associated with a significant 22% increase risk of future non-AIDS events (p = 0.03). Changes in IL-6 levels across time points were small and not associated with future non-AIDS events. In conclusion, ART initiation and HIV viral suppression does not eliminate HIV associated elevation in D-dimer levels. This residual pathology is associated with an increased risk of future non-AIDS diseases. PMID:27088215

  2. D-Dimer Levels before HIV Seroconversion Remain Elevated Even after Viral Suppression and Are Associated with an Increased Risk of Non-AIDS Events.

    PubMed

    Freiberg, Matthew S; Bebu, Ionut; Tracy, Russell; So-Armah, Kaku; Okulicz, Jason; Ganesan, Anuradha; Armstrong, Adam; O'Bryan, Thomas; Rimland, David; Justice, Amy C; Agan, Brian K

    2016-01-01

    The mechanism underlying the excess risk of non-AIDS diseases among HIV infected people is unclear. HIV associated inflammation/hypercoagulability likely plays a role. While antiretroviral therapy (ART) may return this process to pre-HIV levels, this has not been directly demonstrated. We analyzed data/specimens on 249 HIV+ participants from the US Military HIV Natural History Study, a prospective, multicenter observational cohort of >5600 active duty military personnel and beneficiaries living with HIV. We used stored blood specimens to measure D-dimer and Interleukin-6 (IL-6) at three time points: pre-HIV seroconversion, ≥6 months post-HIV seroconversion but prior to ART initiation, and ≥6 months post-ART with documented HIV viral suppression on two successive evaluations. We evaluated the changes in biomarker levels between time points, and the association between these biomarker changes and future non-AIDS events. During a median follow-up of 3.7 years, there were 28 incident non-AIDS diseases. At ART initiation, the median CD4 count was 361cells/mm3; median duration of documented HIV infection 392 days; median time on ART was 354 days. Adjusted mean percent increase in D-dimer levels from pre-seroconversion to post-ART was 75.1% (95% confidence interval 24.6-148.0, p = 0.002). This increase in D-dimer was associated with a significant 22% increase risk of future non-AIDS events (p = 0.03). Changes in IL-6 levels across time points were small and not associated with future non-AIDS events. In conclusion, ART initiation and HIV viral suppression does not eliminate HIV associated elevation in D-dimer levels. This residual pathology is associated with an increased risk of future non-AIDS diseases. PMID:27088215

  3. 42 CFR 493.1205 - Condition: Virology.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... 42 Public Health 5 2013-10-01 2013-10-01 false Condition: Virology. 493.1205 Section 493.1205 Public Health CENTERS FOR MEDICARE & MEDICAID SERVICES, DEPARTMENT OF HEALTH AND HUMAN SERVICES....1205 Condition: Virology. If the laboratory provides services in the subspecialty of Virology,...

  4. 42 CFR 493.919 - Virology.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... 42 Public Health 5 2012-10-01 2012-10-01 false Virology. 493.919 Section 493.919 Public Health... Proficiency Testing Programs by Specialty and Subspecialty § 493.919 Virology. (a) Types of services offered by laboratories. In virology, there are two types of laboratories for proficiency testing...

  5. 42 CFR 493.1205 - Condition: Virology.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... 42 Public Health 5 2012-10-01 2012-10-01 false Condition: Virology. 493.1205 Section 493.1205 Public Health CENTERS FOR MEDICARE & MEDICAID SERVICES, DEPARTMENT OF HEALTH AND HUMAN SERVICES....1205 Condition: Virology. If the laboratory provides services in the subspecialty of Virology,...

  6. 42 CFR 493.1205 - Condition: Virology.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... 42 Public Health 5 2014-10-01 2014-10-01 false Condition: Virology. 493.1205 Section 493.1205 Public Health CENTERS FOR MEDICARE & MEDICAID SERVICES, DEPARTMENT OF HEALTH AND HUMAN SERVICES....1205 Condition: Virology. If the laboratory provides services in the subspecialty of Virology,...

  7. 42 CFR 493.1205 - Condition: Virology.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 42 Public Health 5 2010-10-01 2010-10-01 false Condition: Virology. 493.1205 Section 493.1205 Public Health CENTERS FOR MEDICARE & MEDICAID SERVICES, DEPARTMENT OF HEALTH AND HUMAN SERVICES....1205 Condition: Virology. If the laboratory provides services in the subspecialty of Virology,...

  8. 42 CFR 493.919 - Virology.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 42 Public Health 5 2010-10-01 2010-10-01 false Virology. 493.919 Section 493.919 Public Health... Proficiency Testing Programs by Specialty and Subspecialty § 493.919 Virology. (a) Types of services offered by laboratories. In virology, there are two types of laboratories for proficiency testing...

  9. 42 CFR 493.1205 - Condition: Virology.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 42 Public Health 5 2011-10-01 2011-10-01 false Condition: Virology. 493.1205 Section 493.1205 Public Health CENTERS FOR MEDICARE & MEDICAID SERVICES, DEPARTMENT OF HEALTH AND HUMAN SERVICES....1205 Condition: Virology. If the laboratory provides services in the subspecialty of Virology,...

  10. Cellular HIV-1 DNA quantitation in patients during simplification therapy with protease inhibitor-sparing regimens.

    PubMed

    Sarmati, Loredana; Parisi, Saverio Giuseppe; Nicastri, Emanuele; d'Ettorre, Gabriella; Andreoni, Carolina; Dori, Luca; Gatti, Francesca; Montano, Marco; Buonomini, Anna Rita; Boldrin, Caterina; Palù, Giorgio; Vullo, Vincenzo; Andreoni, Massimo

    2007-07-01

    Simplified regimens containing protease-inhibitors (PI)-sparing combinations were used in patients with virological suppression after prolonged highly active antiretroviral therapy. This study evaluated the total HIV-1 DNA quantitation as a predictor of long-term success for PI-sparing simplified therapy. Sixty-two patients were enrolled in a prospective non-randomized cohort. All patients have been receiving a triple-therapy regimen, two nucleoside reverse transcriptase inhibitors (NRTIs) plus one PI, for at least 9 months and were characterized by undetectable plasma HIV-1 RNA levels (<50 cp/ml) for at least 6 months. Patients were changed to a simplified PI-sparing regimen to overcome PI-associated adverse effects. HIV-DNA levels in peripheral blood mononuclear cells (PBMCs) were evaluated at baseline and at the end of follow-up. Patients with proviral DNA levels below the median value (226 copies/10(6) PBMCs) had a significant higher CD4 cell count at nadir (P = 0.003) and at enrolment (P = 0.001) with respect to patients with HIV-DNA levels above the median value. At month 18, 53 out of 62 (85%) patients on simplified regimen showed virological success, 4 (6.4%) patients experienced virological failure and 5 (8%) patients showed viral blip. At logistic regression analysis, HIV-DNA levels below 226 copies/10(6) PBMCs at baseline were associated independently to a reduced risk of virological failure or viral blip during simplified therapy (OR 0.002, 95% CI 0.001-0.46, P = 0.025). The substitution of PI with NRTI or non-NRTIs may represent an effective treatment option. Indeed, treatment failure or viral blip were experienced by 6% and 8% of the patients on simplified therapy, respectively. In addition, sustained suppression of the plasma viral load was significantly correlated with low levels of proviral DNA before treatment simplification. PMID:17516532

  11. Pseudotyping human immunodeficiency virus type 1 (HIV-1) by the glycoprotein of vesicular stomatitis virus targets HIV-1 entry to an endocytic pathway and suppresses both the requirement for Nef and the sensitivity to cyclosporin A.

    PubMed Central

    Aiken, C

    1997-01-01

    Human immunodeficiency virus type 1 (HIV-1) normally enters cells by direct fusion with the plasma membrane. In this report, HIV-1 particles capable of infecting cells through an endocytic pathway are described. Chimeric viruses composed of the HIV-1 core and the envelope glycoprotein of vesicular stomatitis virus (VSV-G) were constructed and are herein termed HIV-1(VSV) pseudotypes. HIV-1(VSV) pseudotypes were 20- to 130-fold more infectious than nonpseudotyped HIV-1. Infection by HIV-1(VSV) pseudotypes was markedly diminished by ammonium chloride and concanamycin A, a selective inhibitor of vacuolar H+ ATPases, demonstrating that these viruses require endosomal acidification to achieve productive infection. HIV-1 is thus capable of performing all of the viral functions necessary for infection when entry is targeted to an endocytic route. Maximal HIV-1 infectivity requires the presence of the viral Nef protein and the cellular protein cyclophilin A (CyPA) during virus assembly. Pseudotyping by VSV-G markedly suppressed the requirement for Nef. HIV-1(VSV) particles were also resistant to inhibition by cyclosporin A; however, the deleterious effect of a gag mutation inhibiting CyPA incorporation was not relieved by VSV-G. These results suggest that Nef acts at a step of the HIV-1 life cycle that is either circumvented or facilitated by targeting virus entry to an endocytic pathway. The findings also support the hypothesis that Nef and CyPA enhance HIV-1 infectivity through independent processes and demonstrate a mechanistic difference between reduction of HIV-1 infectivity by cyclosporin A and gag mutations that decrease HIV-1 incorporation of CyPA. PMID:9223476

  12. Long-term virological outcome in children on antiretroviral therapy in the UK and Ireland

    PubMed Central

    Duong, Trinh; Judd, Ali; Collins, Intira Jeannie; Doerholt, Katja; Lyall, Hermione; Foster, Caroline; Butler, Karina; Tookey, Pat; Shingadia, Delane; Menson, Esse; Dunn, David T.; Gibb, Di M.

    2014-01-01

    Objective: To assess factors at the start of antiretroviral therapy (ART) associated with long-term virological response in children. Design: Multicentre national cohort. Methods: Factors associated with viral load below 400 copies/ml by 12 months and virologic failure among children starting 3/4-drug ART in the UK/Irish Collaborative HIV Paediatric Study were assessed using Poisson models. Results: Nine hundred and ninety-seven children started ART at a median age of 7.7 years (inter-quartile range 2.9–11.7), 251 (25%) below 3 years: 411 (41%) with efavirenz and two nucleoside reverse transcriptase inhibitors (EFV + 2NRTIs), 264 (26%) with nevirapine and two NRTIs (NVP + 2NRTIs), 119 (12%; 106 NVP, 13 EFV) with non-nucleoside reverse transcriptase inhibitor and three NRTIs (NNRTI + 3NRTIs), and 203 (20%) with boosted protease inhibitor-based regimens. Median follow-up after ART initiation was 5.7 (3.0–8.8) years. Viral load was less than 400 copies/ml by 12 months in 92% [95% confidence interval (CI) 91–94%] of the children. Time to suppression was similar across regimens (P = 0.10), but faster over calendar time, with older age and lower baseline viral load. Three hundred and thirty-nine (34%) children experienced virological failure. Although progression to failure varied by regimen (P < 0.001) and was fastest for NVP + 2NRTIs regimens, risk after 2 years on therapy was similar for EFV + 2NRTIs and NVP + 2NRTIs, and lowest for NNRTI + 3NRTIs regimens (P-interaction = 0.03). Older age, earlier calendar periods and maternal ART exposure were associated with increased failure risk. Early treatment discontinuation for toxicity occurred more frequently for NVP-based regimens, but 5-year cumulative incidence was similar: 6.1% (95% CI 3.9–8.9%) NVP, 8.3% (95% CI 5.6–11.6) EFV, and 9.8% (95% CI 5.7–15.3%) protease inhibitor-based regimens (P = 0.48). Conclusion: Viral load suppression by 12 months was high with

  13. Sustained Elite Suppression of Replication Competent HIV-1 in a Patient Treated With Rituximab Based Chemotherapy

    PubMed Central

    Gaillard, Stephanie; Dinoso, Jason B.; Marsh, Julia A.; DeZern, Amy E.; O’Connell, Karen A; Spivak, Adam M.; Alwood, Karla; Durand, Christine M.; Ambinder, Richard F.; Blankson, Joel N.

    2011-01-01

    The mechanism of elite control of HIV-1 replication is not fully understood. While immunosuppression due to rituximab based chemotherapy has been associated with increased replication of HBV, CMV, and HIV-1, control of replication-competent HIV-1 was maintained in an elite controller/suppressor treated with a regimen that included vincristine, cyclophosphamide, prednisone, four rounds of plasmapheresis and ten cycles of rituximab. The data suggests that de-novo antibody responses do not play a significant role in the control of viral replication in these patients. PMID:21550842

  14. Effects of CD4 monitoring frequency on clinical endpoints in clinically stable HIV-infected patients with viral suppression

    PubMed Central

    Ahn, Jin Young; Boettiger, David; Law, Matthew; Kumarasamy, Nagalingeswaran; Yunihastuti, Evy; Chaiwarith, Romanee; Lee, Man Po; Sim, Benedict LH; Oka, Shinichi; Wong, Wingwai; Kamarulzaman, Adeeba; Kantipong, Pacharee; Phanuphak, Praphan; Ng, Oon Tek; Kiertiburanakul, Sasisopin; Zhang, Fujie; Pujari, Sanjay; Ditangco, Rossana; Ratanasuwan, Winai; Merati, Tuti Parwati; Saphonn, Vonthanak; Sohn, Annette H.; Choi, Jun Yong

    2015-01-01

    Background Current treatment guidelines for HIV infection recommend routine CD4+ lymphocyte (CD4) count monitoring in patients with viral suppression. This may have a limited impact on influencing care as clinically meaningful CD4 decline rarely occurs during viral suppression. Methods In a regional HIV observational cohort in the Asia-Pacific, patients with viral suppression (2 consecutive viral loads <400 copies/mL) and a CD4 count ≥200 cells/μL who had CD4 testing 6 monthly were analyzed. Main study endpoints were occurrence of one CD4 count <200 cells/μL (single CD4<200) and two CD4 counts <200 cells/μL within a 6-month period (confirmed CD4<200). A comparison of time to single and confirmed CD4<200 with biannual or annual CD4 assessment was performed by generating a hypothetical group comprised of the same patients with annual CD4 testing by removing every second CD4 count. Results Among 1538 patients, the rate of single CD4<200 was 3.45/100 patient-years, and of confirmed CD4<200 was 0.77/100 patient-years. During 5 years of viral suppression, patients with baseline CD4 200-249 cells/μL were significantly more likely to experience confirmed CD4<200 compared with patients with higher baseline CD4 (hazard ratio 55.47 [95% confidence interval 7.36–418.20], p<0.001 versus baseline CD4 ≥500 cells/μL). Cumulative probabilities of confirmed CD4<200 was also higher in patients with baseline CD4 200-249 cells/μL compared with patients with higher baseline CD4. There was no significant difference in time to confirmed CD4<200 between biannual and annual CD4 measurement (p=0.336). Conclusions Annual CD4 monitoring in virally suppressed HIV patients with a baseline CD4 ≥250 cells/μL may be sufficient for clinical management. PMID:25850606

  15. Off-label use of maraviroc in HIV-1-infected paediatric patients in clinical practice.

    PubMed

    Palladino, Claudia; Gómez, María Luisa Navarro; Soler-Palacín, Pere; González-Tomé, María Isabel; De Ory, Santiago J; Espiau, María; Hoyos, Santiago Pérez; León-Leal, Juan Antonio; Méndez, María; Moreno-Pérez, David; Guasch, Claudia Fortuny; Sierra, Antoni Mur; Guruceta, Itziar Pocheville; Guillén, Santiago Moreno; Briz, Verónica

    2015-10-23

    Maraviroc (MVC) is not approved for HIV-1-infected paediatric patients. This is the first assessment of the use of MVC-based salvage therapy in vertically HIV-1-infected paediatric patients in clinical settings. The results suggest that MVC-based salvage therapy is useful in children and adolescents with extensive resistance profile leading to maintained virological suppression in up to 88% of the patients with CCR5-tropic virus. The likelihood of treatment success might increase when MVC is combined with other active drugs. PMID:26544580

  16. The Factors Related to CD4+ T-Cell Recovery and Viral Suppression in Patients Who Have Low CD4+ T Cell Counts at the Initiation of HAART: A Retrospective Study of the National HIV Treatment Sub-Database of Zhejiang Province, China, 2014

    PubMed Central

    He, Lin; Pan, Xiaohong; Dou, Zhihui; Huang, Peng; Zhou, Xin; Peng, Zhihang; Zheng, Jinlei; Zhang, Jiafeng; Yang, Jiezhe; Xu, Yun; Jiang, Jun; Chen, Lin; Jiang, Jianmin; Wang, Ning

    2016-01-01

    Background Since China has a unique system of delivering HIV care that includes all patients’ records. The factors related to CD4+ T-cell recovery and viral suppression in patients who have low CD4+ T cell counts at the initiation of HAART are understudied in the China despite subsequent virological suppression (viral load < 50 copies/mL) is unknown. Methods The authors conducted a retrospective cohort study using data from the national HIV treatment sub-database of Zhejiang province to identify records of HIV+ patients. Patient records were included if they were ≥ 16 years of age, had an initial CD4 count < 100 cells/μL, were on continuous HAART for at least one year by the end of December 31, 2014; and achieved and maintained continued maximum virological suppression (MVS) (< 50 copies/ml) by 9 months after starting HAART. The primary endpoint for analysis was time to first CD4+ T cell count recovery (≥ 200, 350, 500 cells/μL). Cox proportional hazard regression was used to identify the risk factors for CD4+ T cell count recovery to key thresholds (200–350, 350–500, ≥ 500 cells/μL) by the time of last clinical follow-up (whichever occurred first), key thresholds (follow-up date for analysis), with patients still unable to reach the endpoints being censored by the end December 31, 2014 (follow-up date for analysis). Results Of the 918 patients who were included in the study, and the median CD4+ T cell count was 39 cells/μL at the baseline. At the end of follow-up, 727 (79.2%), 363 (39.5%) and 149 (16.2%) patients had return to ≥ 200, 350, and 500 cells/μL, respectively. Kaplan-Meier analysis demonstrated that the rate of patients with CD4+ count recovery to ≥ 200, 350, and 500 cells/μL after 1 year on HAART was 43.6, 8.6, and 2.5%, respectively, after 3 years on treatment was 90.8, 46.3, and 17.9%, respectively, and after 5 years on HAART was 97.1, 72.2, and 36.4%, respectively. The median time to return to 200–350, 350–500, ≥ 500cells

  17. Histone Deacetylase Inhibitor Romidepsin Induces HIV Expression in CD4 T Cells from Patients on Suppressive Antiretroviral Therapy at Concentrations Achieved by Clinical Dosing

    PubMed Central

    Wei, Datsen George; Chiang, Vicki; Fyne, Elizabeth; Balakrishnan, Mini; Barnes, Tiffany; Graupe, Michael; Hesselgesser, Joseph; Irrinki, Alivelu; Murry, Jeffrey P.; Stepan, George; Stray, Kirsten M.; Tsai, Angela; Yu, Helen; Spindler, Jonathan; Kearney, Mary; Spina, Celsa A.; McMahon, Deborah; Lalezari, Jacob; Sloan, Derek; Mellors, John; Geleziunas, Romas; Cihlar, Tomas

    2014-01-01

    Persistent latent reservoir of replication-competent proviruses in memory CD4 T cells is a major obstacle to curing HIV infection. Pharmacological activation of HIV expression in latently infected cells is being explored as one of the strategies to deplete the latent HIV reservoir. In this study, we characterized the ability of romidepsin (RMD), a histone deacetylase inhibitor approved for the treatment of T-cell lymphomas, to activate the expression of latent HIV. In an in vitro T-cell model of HIV latency, RMD was the most potent inducer of HIV (EC50 = 4.5 nM) compared with vorinostat (VOR; EC50 = 3,950 nM) and other histone deacetylase (HDAC) inhibitors in clinical development including panobinostat (PNB; EC50 = 10 nM). The HIV induction potencies of RMD, VOR, and PNB paralleled their inhibitory activities against multiple human HDAC isoenzymes. In both resting and memory CD4 T cells isolated from HIV-infected patients on suppressive combination antiretroviral therapy (cART), a 4-hour exposure to 40 nM RMD induced a mean 6-fold increase in intracellular HIV RNA levels, whereas a 24-hour treatment with 1 µM VOR resulted in 2- to 3-fold increases. RMD-induced intracellular HIV RNA expression persisted for 48 hours and correlated with sustained inhibition of cell-associated HDAC activity. By comparison, the induction of HIV RNA by VOR and PNB was transient and diminished after 24 hours. RMD also increased levels of extracellular HIV RNA and virions from both memory and resting CD4 T-cell cultures. The activation of HIV expression was observed at RMD concentrations below the drug plasma levels achieved by doses used in patients treated for T-cell lymphomas. In conclusion, RMD induces HIV expression ex vivo at concentrations that can be achieved clinically, indicating that the drug may reactivate latent HIV in patients on suppressive cART. PMID:24722454

  18. Immune Suppression by Myeloid Cells in HIV Infection: New Targets for Immunotherapy

    PubMed Central

    Mehraj, Vikram; Jenabian, Mohammad-Ali; Vyboh, Kishanda; Routy, Jean-Pierre

    2014-01-01

    Over thirty years of extensive research has not yet solved the complexity of HIV pathogenesis leading to a continued need for a successful cure. Recent immunotherapy-based approaches are aimed at controlling the infection by reverting immune dysfunction. Comparatively less appreciated than the role of T cells in the context of HIV infection, the myeloid cells including macrophages monocytes, dendritic cells (DCs) and neutrophils contribute significantly to immune dysfunction. Host restriction factors are cellular proteins expressed in these cells which are circumvented by HIV. Guided by the recent literature, the role of myeloid cells in HIV infection will be discussed highlighting potential targets for immunotherapy. HIV infection, which is mainly characterized by CD4 T cell dysfunction, also manifests in a vicious cycle of events comprising of inflammation and immune activation. Targeting the interaction of programmed death-1 (PD-1), an important regulator of T cell function; with PD-L1 expressed mainly on myeloid cells could bring promising results. Macrophage functional polarization from pro-inflammatory M1 to anti-inflammatory M2 and vice versa has significant implications in viral pathogenesis. Neutrophils, recently discovered low density granular cells, myeloid derived suppressor cells (MDSCs) and yolk sac macrophages provide new avenues of research on HIV pathogenesis and persistence. Recent evidence has also shown significant implications of neutrophil extracellular traps (NETs), antimicrobial peptides and opsonizing antibodies. Further studies aimed to understand and modify myeloid cell restriction mechanisms have the potential to contribute in the future development of more effective anti-HIV interventions that may pave the way to viral eradication. PMID:25624956

  19. Relationship Dynamics and Partner Beliefs About Viral Suppression: A Longitudinal Study of Male Couples Living with HIV/AIDS (The Duo Project).

    PubMed

    Conroy, Amy A; Gamarel, Kristi E; Neilands, Torsten B; Dilworth, Samantha E; Darbes, Lynae A; Johnson, Mallory O

    2016-07-01

    Accurate beliefs about partners' viral suppression are important for HIV prevention and care. We fit multilevel mixed effects logistic regression models to examine associations between partners' viral suppression beliefs and objective HIV RNA viral load tests, and whether relationship dynamics were associated with accurate viral suppression beliefs over time. Male couples (N = 266 couples) with at least one HIV-positive partner on antiretroviral therapy completed five assessments over 2 years. Half of the 407 HIV-positive partners were virally suppressed. Of the 40 % who had inaccurate viral load beliefs, 80 % assumed their partner was suppressed. The odds of having accurate viral load beliefs decreased over time (OR = 0.83; p = 0.042). Within-couple differences in dyadic adjustment (OR = 0.66; p < 0.01) and commitment (OR = 0.82; p = 0.022) were negatively associated with accurate viral load beliefs. Beliefs about a partner's viral load may factor into sexual decision-making and social support. Couple-based approaches are warranted to improve knowledge of partners' viral load. PMID:27150895

  20. Methamphetamine Use in HIV-infected Individuals Affects T-cell Function and Viral Outcome during Suppressive Antiretroviral Therapy.

    PubMed

    Massanella, Marta; Gianella, Sara; Schrier, Rachel; Dan, Jennifer M; Pérez-Santiago, Josué; Oliveira, Michelli F; Richman, Douglas D; Little, Susan J; Benson, Constance A; Daar, Eric S; Dube, Michael P; Haubrich, Richard H; Smith, Davey M; Morris, Sheldon R

    2015-01-01

    We investigated the associations between methamphetamine (meth) use, immune function, and the dynamics of HIV and cytomegalovirus [CMV] in the blood and genital tract of HIV-infected ART-suppressed subjects. Self-reported meth use was associated with increased CD4(+) and CD8(+) T-cell proliferation (Ki67(+), p < 0.005), CD4(+) T-cell activation (CD45RA(-)CD38(+), p = 0.005) and exhaustion (PD-1(+), p = 0.0004) in blood, compared to non-meth users. Meth use was also associated with a trend towards higher blood HIV DNA levels (p = 0.09) and more frequent shedding of CMV in seminal plasma (p = 0.002). To explore possible mechanisms, we compared ex vivo spontaneous and antigen-specific proliferation in PBMC collected from subjects with and without positive meth detection in urine (Utox+ vs. Utox-). Despite higher levels of spontaneous proliferation, lymphocytes from Utox+ meth users had a significantly lower proliferative capacity after stimulation with a number of pathogens (CMV, candida, mycobacterium, toxoplasma, HIV, p < 0.04 in all cases), compared to Utox- participants. Our findings suggest that meth users have greater proliferation and exhaustion of the immune system. Meth use is also associated with a loss of control of CMV replication, which could be related to loss of immune response to pathogens. Future studies should consider meth use as a potential modulator of T-cell responses. PMID:26299251

  1. Methamphetamine Use in HIV-infected Individuals Affects T-cell Function and Viral Outcome during Suppressive Antiretroviral Therapy

    PubMed Central

    Massanella, Marta; Gianella, Sara; Schrier, Rachel; Dan, Jennifer M.; Pérez-Santiago, Josué; Oliveira, Michelli F.; Richman, Douglas D.; Little, Susan J.; Benson, Constance A.; Daar, Eric S.; Dube, Michael P.; Haubrich, Richard H.; Smith, Davey M.; Morris, Sheldon R.

    2015-01-01

    We investigated the associations between methamphetamine (meth) use, immune function, and the dynamics of HIV and cytomegalovirus [CMV] in the blood and genital tract of HIV-infected ART-suppressed subjects. Self-reported meth use was associated with increased CD4+ and CD8+ T-cell proliferation (Ki67+, p < 0.005), CD4+ T-cell activation (CD45RA–CD38+, p = 0.005) and exhaustion (PD-1+, p = 0.0004) in blood, compared to non-meth users. Meth use was also associated with a trend towards higher blood HIV DNA levels (p = 0.09) and more frequent shedding of CMV in seminal plasma (p = 0.002). To explore possible mechanisms, we compared ex vivo spontaneous and antigen-specific proliferation in PBMC collected from subjects with and without positive meth detection in urine (Utox+ vs. Utox-). Despite higher levels of spontaneous proliferation, lymphocytes from Utox+ meth users had a significantly lower proliferative capacity after stimulation with a number of pathogens (CMV, candida, mycobacterium, toxoplasma, HIV, p < 0.04 in all cases), compared to Utox- participants. Our findings suggest that meth users have greater proliferation and exhaustion of the immune system. Meth use is also associated with a loss of control of CMV replication, which could be related to loss of immune response to pathogens. Future studies should consider meth use as a potential modulator of T-cell responses. PMID:26299251

  2. The HIV care continuum in Latin America: challenges and opportunities.

    PubMed

    Piñeirúa, Alicia; Sierra-Madero, Juan; Cahn, Pedro; Guevara Palmero, Rafael Napoleón; Martínez Buitrago, Ernesto; Young, Benjamin; Del Rio, Carlos

    2015-07-01

    Combination antiretroviral therapy (ART), also known as highly active antiretroviral therapy, provides clinical and immunological benefits for people living with HIV and is an effective strategy to prevent HIV transmission at the individual level. Early initiation of ART as part of a test and treat approach might decrease HIV transmission at the population level, but to do so the HIV continuum of care, from diagnosis to viral suppression, should be optimised. Access to ART has improved greatly in Latin America, and about 600,000 people are on treatment. However, health-care systems are deficient in different stages of the HIV continuum of care, and in some cases only a small proportion of individuals achieve the desired outcome of virological suppression. At present, data for most Latin American countries are not sufficient to build reliable metrics. Available data and estimates show that many people living with HIV in Latin America are unaware of their status, are diagnosed late, and enter into care late. Stigma, administrative barriers, and economic limitations seem to be important determinants of late diagnosis and failure to be linked to and retained in care. Policy makers need reliable data to optimise the HIV care continuum and improve individual-based and population-based outcomes of ART in Latin America. PMID:26122456

  3. CD4+ T cell recovery during suppression of HIV replication: an international comparison of the immunological efficacy of antiretroviral therapy in North America, Asia and Africa

    PubMed Central

    Geng, Elvin H; Neilands, Torsten B; Thièbaut, Rodolphe; Bosco Bwana, Mwebesa; Nash, Denis; Moore, Richard D; Wood, Robin; Marcel Zannou, Djimon; Althoff, Keri N; Lian Lim, Poh; Nachega, Jean B; Easterbrook, Philippa J; Kambugu, Andrew; Little, Francesca; Nakigozi, Gertrude; Nakanjako, Damalie; Kiggundu, Valerian; Chung Ki Li, Patrick; Bangsberg, David R; Fox, Matthew P; Prozesky, Hans W; Hunt, Peter W; Davies, Mary-Ann; Reynolds, Steven J; Egger, Matthias; Yiannoutsos, Constantin T; Vittinghoff, Eric V; Deeks, Steven G; Martin, Jeffrey N

    2015-01-01

    Background: Even among HIV-infected patients who fully suppress plasma HIV RNA replication on antiretroviral therapy, genetic (e.g. CCL3L1 copy number), viral (e.g. tropism) and environmental (e.g. chronic exposure to microbial antigens) factors influence CD4 recovery. These factors differ markedly around the world and therefore the expected CD4 recovery during HIV RNA suppression may differ globally. Methods: We evaluated HIV-infected adults from North America, West Africa, East Africa, Southern Africa and Asia starting non-nucleoside reverse transcriptase inhibitor-based regimens containing efavirenz or nevirapine, who achieved at least one HIV RNA level <500/µl in the first year of therapy and observed CD4 changes during HIV RNA suppression. We used a piecewise linear regression to estimate the influence of region of residence on CD4 recovery, adjusting for socio-demographic and clinical characteristics. We observed 28 217 patients from 105 cohorts over 37 825 person-years. Results: After adjustment, patients from East Africa showed diminished CD4 recovery as compared with other regions. Three years after antiretroviral therapy initiation, the mean CD4 count for a prototypical patient with a pre-therapy CD4 count of 150/µl was 529/µl [95% confidence interval (CI): 517–541] in North America, 494/µl (95% CI: 429–559) in West Africa, 515/µl (95% CI: 508–522) in Southern Africa, 503/µl (95% CI: 478–528) in Asia and 437/µl (95% CI: 425–449) in East Africa. Conclusions: CD4 recovery during HIV RNA suppression is diminished in East Africa as compared with other regions of the world, and observed differences are large enough to potentially influence clinical outcomes. Epidemiological analyses on a global scale can identify macroscopic effects unobservable at the clinical, national or individual regional level. PMID:25859596

  4. Oligomerization Requirements for MX2-Mediated Suppression of HIV-1 Infection

    PubMed Central

    Dicks, Matthew D. J.; Goujon, Caroline; Pollpeter, Darja; Betancor, Gilberto; Apolonia, Luis; Bergeron, Julien R. C.

    2015-01-01

    ABSTRACT Human myxovirus resistance 2 (MX2/MXB) is an interferon-stimulated gene (ISG) and was recently identified as a late postentry suppressor of human immunodeficiency virus type 1 (HIV-1) infection, inhibiting the nuclear accumulation of viral cDNAs. Although the HIV-1 capsid (CA) protein is believed to be the viral determinant of MX2-mediated inhibition, the precise mechanism of antiviral action remains unclear. The MX family of dynamin-like GTPases also includes MX1/MXA, a well-studied inhibitor of a range of RNA and DNA viruses, including influenza A virus (FLUAV) and hepatitis B virus but not retroviruses. MX1 and MX2 are closely related and share similar domain architectures and structures. However, MX2 possesses an extended N terminus that is essential for antiviral function and confers anti-HIV-1 activity on MX1 [MX1(NMX2)]. Higher-order oligomerization is required for the antiviral activity of MX1 against FLUAV, with current models proposing that MX1 forms ring structures that constrict around viral nucleoprotein complexes. Here, we performed structure-function studies to investigate the requirements for oligomerization of both MX2 and chimeric MX1(NMX2) for the inhibition of HIV-1 infection. The oligomerization state of mutated proteins with amino acid substitutions at multiple putative oligomerization interfaces was assessed using a combination of covalent cross-linking and coimmunoprecipitation. We show that while monomeric MX2 and MX1(NMX2) mutants are not antiviral, higher-order oligomerization does not appear to be required for full antiviral activity of either protein. We propose that lower-order oligomerization of MX2 is sufficient for the effective inhibition of HIV-1. IMPORTANCE Interferon plays an important role in the control of virus replication during acute infection in vivo. Recently, cultured cell experiments identified human MX2 as a key effector in the interferon-mediated postentry block to HIV-1 infection. MX2 is a member of a family

  5. Pharmacologic Boosting of Atazanavir in Maintenance HIV-1 Therapy: The COREYA Propensity-Score Adjusted Study

    PubMed Central

    Hocqueloux, Laurent; Choisy, Philippe; Le Moal, Gwenaël; Borsa-Lebas, Françoise; Plainchamp, David; Legac, Eric; Prazuck, Thierry; de la Tribonnière, Xavier; Yazdanpanah, Yazdan; Parienti, Jean-Jacques

    2012-01-01

    Background Among HIV-1 infected patients who achieved virologic suppression, the use of atazanavir without pharmacologic boosting is debated. We evaluated the efficacy and tolerance of maintenance therapy with unboosted atazanavir in clinical practice. Methods and Results This multicenter retrospective cohort study evaluated the efficacy of switching HIV-1-infected patients controlled on triple therapy to unboosted (ATV0, n = 98) versus ritonavir-boosted atazanavir (ATV/r, n = 254) +2 nucleos(t)ide reverse transcriptase inhibitors. The primary endpoint was time to virologic failure (VF, >200 copies/mL). ATV groups were compared controlling for potential confounding bias by inverse probability weighted Cox analysis and propensity-score matching. Overall and adjusted VF rates were similar for both strategies. Both strategies improved dyslipidemia and creatininemia, with less jaundice in the ATV0 group. Conclusion In previously well-suppressed patients, within an observational cohort setting, ATV0–based triple-therapy appeared as effective as ATV/r- based triple-therapy to maintain virologic suppression, even if co-administered with TDF, but was better tolerated. PMID:23152890

  6. Baseline Natural Killer and T Cell Populations Correlation with Virologic Outcome after Regimen Simplification to Atazanavir/Ritonavir Alone (ACTG 5201)

    PubMed Central

    McKinnon, John E.; Mailliard, Robbie B.; Swindells, Susan; Wilkin, Timothy J.; Borowski, LuAnn; Roper, Jillian M.; Bastow, Barbara; Kearney, Mary; Wiegand, Ann; Mellors, John W.; Rinaldo, Charles R.

    2014-01-01

    Objectives Simplified maintenance therapy with ritonavir-boosted atazanavir (ATV/r) provides an alternative treatment option for HIV-1 infection that spares nucleoside analogs (NRTI) for future use and decreased toxicity. We hypothesized that the level of immune activation (IA) and recovery of lymphocyte populations could influence virologic outcomes after regimen simplification. Methods Thirty-four participants with virologic suppression ≥48 weeks on antiretroviral therapy (2 NRTI plus protease inhibitor) were switched to ATV/r alone in the context of the ACTG 5201 clinical trial. Flow cytometric analyses were performed on PBMC isolated from 25 patients with available samples, of which 24 had lymphocyte recovery sufficient for this study. Assessments included enumeration of T-cells (CD4/CD8), natural killer (NK) (CD3+CD56+CD16+) cells and cell-associated markers (HLA-DR, CD's 38/69/94/95/158/279). Results Eight of the 24 patients had at least one plasma HIV-1 RNA level (VL) >50 copies/mL during the study. NK cell levels below the group median of 7.1% at study entry were associated with development of VL >50 copies/mL following simplification by regression and survival analyses (p = 0.043 and 0.023), with an odds ratio of 10.3 (95% CI: 1.92–55.3). Simplification was associated with transient increases in naïve and CD25+ CD4+ T-cells, and had no impact on IA levels. Conclusions Lower NK cell levels prior to regimen simplification were predictive of virologic rebound after discontinuation of nucleoside analogs. Regimen simplification did not have a sustained impact on markers of IA or T lymphocyte populations in 48 weeks of clinical monitoring. Trial Registration ClinicalTrials.gov NCT00084019 PMID:24802242

  7. Maraviroc intensification in patients with suppressed HIV viremia has limited effects on CD4+ T cell recovery and gene expression

    PubMed Central

    Beliakova-Bethell, Nadejda; Jain, Sonia; Woelk, Christopher H.; Witt, Mallory D.; Sun, Xiaoying; Lada, Steven M.; Spina, Celsa A.; Goicoechea, Miguel; Rought, Steffney E.; Haubrich, Richard; Dubé, Michael P.

    2014-01-01

    Addition of the CCR5 inhibitor Maraviroc (MVC) to ongoing antiretroviral therapy increases CD4+ T cell counts in some virologically suppressed patients with suboptimal CD4+ T cell recovery. To understand the mechanisms by which MVC elicits increases in CD4+ T cell counts, the present study was undertaken to identify host factors (i.e. genes) that are modulated and are correlated with CD4+ T cell recovery during the 24 weeks of MVC intensification in 32 subjects. Median changes of CD4+ T cell counts over 24 weeks of MVC compared to baseline were 38 cells/mm3 (p < 0.001). The median slope of CD4+ T cell recovery was 39 cells/mm3 per year before initiation of MVC and 76 cells/mm3 per year during MVC intensification, however, this increase was not statistically significant (p = 0.33). Microarray analysis (N = 31,426 genes) identified a single differentially expressed gene, tumor necrosis factor alpha (TNF), which was modestly (1.44-fold, p < 0.001) downregulated by MVC at week 24 compared to baseline. TNF differential expression was evaluated using an independent method of droplet digital PCR, but the difference was not significant (p = 0.6). Changes in gene expression did not correlate with CD4+ T cell recovery or any changes in the CD4+ T cell maturation, proliferation and activation phenotypes. In summary, our data suggest that modest improvements of CD4+ T cell counts during MVC intensification cannot be explained by changes in gene expression elicited by MVC. However, the modest changes in T cell composition, including reduction of the percentages of Tregs, proliferating CD4+ T cells and senescent CD8+ T cells, suggest immunologically favorable effects of MVC. PMID:24769244

  8. The History of Tumor Virology

    PubMed Central

    Javier, Ronald T.; Butel, Janet S.

    2012-01-01

    In the century since its inception, the field of tumor virology has provided groundbreaking insights into the causes of human cancer. Peyton Rous founded this scientific field in 1911 by discovering an avian virus that induced tumors in chickens; however, it took 40 years for the scientific community to comprehend the effect of this seminal finding. Later identification of mammalian tumor viruses in the 1930s by Richard Shope and John Bittner, and in the 1950s by Ludwik Gross, sparked the first intense interest in tumor virology by suggesting the possibility of a similar causal role for viruses in human cancers. This change in attitude opened the door in the 1960s and 1970s for the discovery of the first human tumor viruses—EBV, hepatitis B virus, and the papillomaviruses. Such knowledge proved instrumental to the development of the first cancer vaccines against cancers having an infectious etiology. Tumor virologists additionally recognized that viruses could serve as powerful discovery tools, leading to revolutionary breakthroughs in the 1970s and 1980s that included the concept of the oncogene, the identification of the p53 tumor suppressor, and the function of the retinoblastoma tumor suppressor. The subsequent availability of more advanced molecular technologies paved the way in the 1980s and 1990s for the identification of additional human tumor viruses—human T-cell leukemia virus type 1, hepatitis C virus, and Kaposi’s sarcoma virus. In fact, current estimates suggest that viruses are involved in 15% to 20% of human cancers worldwide. Thus, viruses not only have been shown to represent etiologic agents for many human cancers but have also served as tools to reveal mechanisms that are involved in all human malignancies. This rich history promises that tumor virology will continue to contribute to our understanding of cancer and to the development of new therapeutic and preventive measures for this disease in the 21st century. PMID:18829521

  9. Effectiveness of Ritonavir-Boosted Protease Inhibitor Monotherapy in Clinical Practice Even with Previous Virological Failures to Protease Inhibitor-Based Regimens

    PubMed Central

    López-Cortés, Luis F.; Castaño, Manuel A.; López-Ruz, Miguel A.; Rios-Villegas, María J.; Hernández-Quero, José; Merino, Dolores; Jiménez-Aguilar, Patricia; Marquez-Solero, Manuel; Terrón-Pernía, Alberto; Tellez-Pérez, Francisco; Viciana, Pompeyo; Orihuela-Cañadas, Francisco; Palacios-Baena, Zaira; Vinuesa-Garcia, David; Fajardo-Pico, Jose M.; Romero-Palacios, Alberto; Ojeda-Burgos, Guillermo; Pasquau-Liaño, Juan

    2016-01-01

    Background and Objective Significant controversy still exists about ritonavir-boosted protease inhibitor monotherapy (mtPI/rtv) as a simplification strategy that is used up to now to treat patients that have not experienced previous virological failure (VF) while on protease inhibitor (PI) -based regimens. We have evaluated the effectiveness of two mtPI/rtv regimens in an actual clinical practice setting, including patients that had experienced previous VF with PI-based regimens. Methods This retrospective study analyzed 1060 HIV-infected patients with undetectable viremia that were switched to lopinavir/ritonavir or darunavir/ritonavir monotherapy. In cases in which the patient had previously experienced VF while on a PI-based regimen, the lack of major HIV protease resistance mutations to lopinavir or darunavir, respectively, was mandatory. The primary endpoint of this study was the percentage of participants with virological suppression after 96 weeks according to intention-to-treat analysis (non-complete/missing = failure). Results A total of 1060 patients were analyzed, including 205 with previous VF while on PI-based regimens, 90 of whom were on complex therapies due to extensive resistance. The rates of treatment effectiveness (intention-to-treat analysis) and virological efficacy (on-treatment analysis) at week 96 were 79.3% (CI95, 76.8−81.8) and 91.5% (CI95, 89.6–93.4), respectively. No relationships were found between VF and earlier VF while on PI-based regimens, the presence of major or minor protease resistance mutations, the previous time on viral suppression, CD4+ T-cell nadir, and HCV-coinfection. Genotypic resistance tests were available in 49 out of the 74 patients with VFs and only four patients presented new major protease resistance mutations. Conclusion Switching to mtPI/rtv achieves sustained virological control in most patients, even in those with previous VF on PI-based regimens as long as no major resistance mutations are present for

  10. Antiretroviral Therapy and Viral Suppression Among Foreign-Born HIV-Infected Persons Receiving Medical Care in the United States: A Complex Sample, Cross-Sectional Survey.

    PubMed

    Myers, Tanya R; Lin, Xia; Skarbinski, Jacek

    2016-03-01

    Immigrants to the United States are more likely to be diagnosed with human immunodeficiency virus (HIV) infection compared with native-born persons. Navigating access to healthcare in the United States can be challenging for foreign-born persons, and HIV treatment outcomes may be suboptimal for these persons. We compared characteristics of and assessed disparities in clinical outcomes of foreign-born persons in care for HIV in the United States. The Medical Monitoring Project is a complex sample, cross-sectional survey designed to be nationally representative of HIV-infected adults receiving medical care in the United States. Using data from 2009, 2010, and 2011, we conducted descriptive analyses and multivariable logistic regression to assess associations between foreign-born status and antiretroviral therapy (ART) prescription, and between foreign-born status and viral suppression. In all, 13.4% of HIV-infected persons were self-identified as foreign-born; the most common regions of birth were Central America and Mexico (45.4%) and the Caribbean (16.0%). Nearly 90% of foreign-born persons were diagnosed with HIV after entry into the United States. Compared with US-born persons, foreign-born persons were more likely to be younger, Hispanic, less educated, and uninsured. The prevalence of ART prescription (prevalence ratio 1.00; 95% confidence interval 0.98-1.02) was not significantly different between foreign-born and US-born persons. A higher percentage of foreign-born persons achieved viral suppression compared with US-born persons (prevalence ratio 1.05; 95% confidence interval 1.00-1.09). No major disparities in ART prescription and viral suppression were found between foreign-born and US-born HIV-infected persons receiving medical care, despite higher percentages being uninsured. PMID:26986128

  11. HIV-1 Tat Protein Suppresses Cholangiocyte Toll-Like Receptor 4 Expression and Defense against Cryptosporidium parvum

    PubMed Central

    O’Hara, Steven P.; Small, Aaron J.; Gajdos, Gabriella B.; Badley, Andrew D.; Chen, Xian-Ming; LaRusso, Nicholas F.

    2009-01-01

    Biliary cryptosporidiosis is associated with acquired immunodeficiency syndrome (AIDS) cholangiopathy and occurs almost exclusively in adult patients with AIDS. Infection of biliary epithelial cells (cholangiocytes) with Cryptosporidium parvum induces Toll-like receptor (TLR) 4 expression and stimulates a TLR-dependent response against infection. Here, we tested whether human immunodeficiency virus type 1 (HIV-1) Tat affects TLR expression and, hence, anti–C. parvum defense responses. Using an in vitro model of human biliary cryptosporidiosis, we found that recombinant Tat protein increased TLR4 mRNA expression in both uninfected and C. parvum–infected cholangiocytes. Conversely, Tat decreased TLR4 protein levels and suppressed C. parvum–induced TLR4 protein expression. Using actinomycin to inhibit transcription, we found that Tat increased the half-life of TLR4 mRNA from ~25 to 60 min, and RNA gel-shift assays demonstrated direct binding of Tat to TLR4 mRNA. In vitro transcription/translation studies suggested that Tat does not affect transcription but does decrease TLR4 translation. Importantly, more parasites were found in Tat-treated cells than in control cells 48h after infection. These findings suggest that Tat inhibits cholangiocyte TLR4protein expression through translational inhibition. These events appear to diminish the ability of cholangiocytes to initsiate an innate immune response to C. parvum. We suggest that these findings may contribute to the unusual susceptibility of HIV-infected individuals to biliary cryptosporidiosis. PMID:19265483

  12. HIV-1 Rev protein specifies the viral RNA export pathway by suppressing TAP/NXF1 recruitment.

    PubMed

    Taniguchi, Ichiro; Mabuchi, Naoto; Ohno, Mutsuhito

    2014-06-01

    Nuclear RNA export pathways in eukaryotes are often linked to the fate of a given RNA. Therefore, the choice of export pathway should be well-controlled to avoid an unfavorable effect on gene expression. Although some RNAs could be exported by more than one pathway, little is known about how the choice is regulated. This issue is highlighted when the human immunodeficiency virus type 1 (HIV-1) Rev protein induces the export of singly spliced and unspliced HIV-1 transcripts. How these RNAs are exported is not well understood because such transcripts should have the possibility of utilizing CRM1-dependent export via Rev or cellular TAP/NXF1-dependent export via the transcription/export (TREX) complex, or both. Here we found that Rev suppressed TAP/NXF1-dependent export of model RNA substrates that recapitulated viral transcripts. In this effect, Rev interacted with the cap-binding complex and inhibited the recruitment of the TREX complex. Thus, Rev controls the identity of the factor occupying the cap-proximal region that determines the RNA export pathway. This ribonucleoprotein remodeling activity of Rev may favor viral gene expression. PMID:24753416

  13. Simulating Patterns of Patient Engagement, Treatment Adherence, and Viral Suppression: A System Dynamics Approach to Evaluating HIV Care Management

    PubMed Central

    Schwartz, Brian; Palma, Anton

    2015-01-01

    Abstract System dynamics (SD) modeling belongs to the rapidly evolving, interdisciplinary field of system science research. This field adds value to more traditional health research by contributing to the design and testing of complex integrated models of change, to examine health system performance and patient outcomes. Using selected milestones in HIV care management to frame our simulation research, we created a SD model to examine three patient subgroups of women of color (WOC) represented in our multi-site cohort, classified by their health care seeking status at baseline. Asked to reflect on their circumstance 6 months prior to enrollment in the MSE cohort, 53% noted they were receiving some care (In Care, n=341), 31% that they had been seeking care (Seeking Care, n=201), and 16% that they were undecided about seeking care (i.e., answered that they may or may not look for care) for treatment of their HIV (May or May Not Seek Care, n=103). Our SD model compared simulated patterns of patient retention over 24 months in relation to: (1) access to antiretroviral therapy (ART), (2) adherence to ART, and (3) viral suppression. Assessed patterns yielded insights about system capacities and constraints in the context of the SPNS initiative under evaluation. PMID:25561309

  14. Detectable HIV Viral Load in Kenya: Data from a Population-Based Survey

    PubMed Central

    Cherutich, Peter; Kim, Andrea A.; Kellogg, Timothy A.; Sherr, Kenneth; Waruru, Anthony; De Cock, Kevin M.; Rutherford, George W.

    2016-01-01

    Introduction At the individual level, there is clear evidence that Human Immunodeficiency Virus (HIV) transmission can be substantially reduced by lowering viral load. However there are few data describing population-level HIV viremia especially in high-burden settings with substantial under-diagnosis of HIV infection. The 2nd Kenya AIDS Indicator Survey (KAIS 2012) provided a unique opportunity to evaluate the impact of antiretroviral therapy (ART) coverage on viremia and to examine the risks for failure to suppress viral replication. We report population-level HIV viral load suppression using data from KAIS 2012. Methods Between October 2012 to February 2013, KAIS 2012 surveyed household members, administered questionnaires and drew serum samples to test for HIV and, for those found to be infected with HIV, plasma viral load (PVL) was measured. Our principal outcome was unsuppressed HIV viremia, defined as a PVL ≥ 550 copies/mL. The exposure variables included current treatment with ART, prior history of an HIV diagnosis, and engagement in HIV care. All point estimates were adjusted to account for the KAIS 2012 cluster sampling design and survey non-response. Results Overall, 61·2% (95% CI: 56·4–66·1) of HIV-infected Kenyans aged 15–64 years had not achieved virological suppression. The base10 median (interquartile range [IQR]) and mean (95% CI) VL was 4,633 copies/mL (0–51,596) and 81,750 copies/mL (59,366–104,134), respectively. Among 266 persons taking ART, 26.1% (95% CI: 20.0–32.1) had detectable viremia. Non-ART use, younger age, and lack of awareness of HIV status were independently associated with significantly higher odds of detectable viral load. In multivariate analysis for the sub-sample of patients on ART, detectable viremia was independently associated with younger age and sub-optimal adherence to ART. Discussion This report adds to the limited data of nationally-representative surveys to report population- level virological

  15. Select Host Restriction Factors Are Associated with HIV Persistence During Antiretroviral Therapy

    PubMed Central

    ABDEL-MOHSEN, Mohamed; WANG, Charlene; STRAIN, Matthew C.; LADA, Steven M.; DENG, Xutao; COCKERHAM, Leslie R.; PILCHER, Christopher D.; HECHT, Frederick M.; LIEGLER, Teri; RICHMAN, Douglas D.; DEEKS, Steven G.; PILLAI, Satish K.

    2015-01-01

    Objective The eradication of HIV necessitates elimination of the HIV latent reservoir. Identifying host determinants governing latency and reservoir size in the setting of antiretroviral therapy (ART) is an important step in developing strategies to cure HIV infection. We sought to determine the impact of cell-intrinsic immunity on the HIV latent reservoir. Design We investigated the relevance of a comprehensive panel of established anti-HIV-1 host restriction factors to multiple established virologic and immunologic measures of viral persistence in HIV-1-infected, ART-suppressed individuals. Methods We measured the mRNA expression of 42 anti-HIV-1 host restriction factors, levels of cell-associated HIV-1 RNA, levels of total pol and 2-LTR circle HIV-1 DNA, and immunophenotypes of CD4+ T cells in 72 HIV-1-infected subjects on suppressive ART (23 subjects initiated ART <1 year post-infection, and 49 subjects initiated ART >1 year post-infection). Correlations were analyzed using non-parametric tests. Results The enhanced expression of a few select host restriction factors, p21, schlafen 11, and PAF1, was strongly associated with reduced CD4+ T cell-associated HIV RNA during ART (p<0.001). In addition, our data suggested that ART perturbs the regulatory relationship between CD4+ T cell activation and restriction factor expression. Lastly, cell-intrinsic immune responses were significantly enhanced in subjects who initiated ART during early versus chronic infection, and may contribute to the reduced reservoir size observed in these individuals. Conclusions Intrinsic immune responses modulate HIV persistence during suppressive ART, and may be manipulated to enhance the efficacy of ART and promote viral eradication through reversal of latency in vivo. PMID:25602681

  16. 42 CFR 493.1265 - Standard: Virology.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... 42 Public Health 5 2012-10-01 2012-10-01 false Standard: Virology. 493.1265 Section 493.1265 Public Health CENTERS FOR MEDICARE & MEDICAID SERVICES, DEPARTMENT OF HEALTH AND HUMAN SERVICES... Systems § 493.1265 Standard: Virology. (a) When using cell culture to isolate or identify viruses,...

  17. 42 CFR 493.831 - Standard; Virology.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... 42 Public Health 5 2014-10-01 2014-10-01 false Standard; Virology. 493.831 Section 493.831 Public Health CENTERS FOR MEDICARE & MEDICAID SERVICES, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED... Tests § 493.831 Standard; Virology. (a) Failure to attain an overall testing event score of at least...

  18. 42 CFR 493.1265 - Standard: Virology.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... 42 Public Health 5 2013-10-01 2013-10-01 false Standard: Virology. 493.1265 Section 493.1265 Public Health CENTERS FOR MEDICARE & MEDICAID SERVICES, DEPARTMENT OF HEALTH AND HUMAN SERVICES... Systems § 493.1265 Standard: Virology. (a) When using cell culture to isolate or identify viruses,...

  19. 42 CFR 493.1265 - Standard: Virology.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... 42 Public Health 5 2014-10-01 2014-10-01 false Standard: Virology. 493.1265 Section 493.1265 Public Health CENTERS FOR MEDICARE & MEDICAID SERVICES, DEPARTMENT OF HEALTH AND HUMAN SERVICES... Systems § 493.1265 Standard: Virology. (a) When using cell culture to isolate or identify viruses,...

  20. 42 CFR 493.831 - Standard; Virology.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... 42 Public Health 5 2013-10-01 2013-10-01 false Standard; Virology. 493.831 Section 493.831 Public Health CENTERS FOR MEDICARE & MEDICAID SERVICES, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED... Tests § 493.831 Standard; Virology. (a) Failure to attain an overall testing event score of at least...

  1. 42 CFR 493.831 - Standard; Virology.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... 42 Public Health 5 2012-10-01 2012-10-01 false Standard; Virology. 493.831 Section 493.831 Public Health CENTERS FOR MEDICARE & MEDICAID SERVICES, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED... Tests § 493.831 Standard; Virology. (a) Failure to attain an overall testing event score of at least...

  2. 42 CFR 493.831 - Standard; Virology.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 42 Public Health 5 2011-10-01 2011-10-01 false Standard; Virology. 493.831 Section 493.831 Public Health CENTERS FOR MEDICARE & MEDICAID SERVICES, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED... Tests § 493.831 Standard; Virology. (a) Failure to attain an overall testing event score of at least...

  3. Integrative Virology for Senior Medical Students.

    ERIC Educational Resources Information Center

    Koment, Roger W.

    1991-01-01

    The article describes a senior elective in virology developed at the University of South Dakota School of Medicine. Students work independently through a series of course units, selecting 12 study topics from a catalog of 35 topics in medical virology and discussing their reading daily with the professor. (DB)

  4. 42 CFR 493.1265 - Standard: Virology.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 42 Public Health 5 2011-10-01 2011-10-01 false Standard: Virology. 493.1265 Section 493.1265 Public Health CENTERS FOR MEDICARE & MEDICAID SERVICES, DEPARTMENT OF HEALTH AND HUMAN SERVICES... Systems § 493.1265 Standard: Virology. (a) When using cell culture to isolate or identify viruses,...

  5. Influence of CD4+ T cell counts on viral evolution in HIV-infected individuals undergoing suppressive HAART.

    PubMed

    Lorenzo, Eric; Colon, Maria C; Almodovar, Sharilyn; Maldonado, Irvin M; Gonzalez, Sandra; Costa, Sonia E; Hill, Martin D; Mendoza, Rafael; Sepulveda, Gladys; Yanagihara, Richard; Nerurkar, Vivek; Kumar, Rakesh; Yamamura, Yasuhiro; Scott, Walter A; Kumar, Anil

    2004-12-01

    We analyzed the viral C2-V4 envelope diversity, glycosylation patterns, and dS/dN ratios of plasma HIV-1 in an attempt to better understand the complex interaction between viral quasispecies and the host-selective pressures pre- and post-HAART. Phylogenetic analysis of the envelope gene of five patients revealed monophyletic clustering in patients with higher CD4+ T cell counts and sequence intermingling in those with lower CD4+ T cells in relation to the stage of HAART. Our analyses also showed clear shifts in N-linked glycosylation patterns in patients with higher CD4+ T cells, suggesting possible distinct immunological pressures pre- and post-HAART. The relative preponderance of synonymous/nonsynonymous changes in the envelope region suggested a positive selection in patients with higher CD4+ T cells, whereas lack of evidence for positive selection was found in the patients with lower CD4+ T cells. An exception to the last analysis occurred in the only patient who reached complete viral suppression, maybe due to drug pressure exerted over the pol gene that may obscure the immune pressure/selection at the envelope in this analysis. All these indications may suggest that even when HAART generates viral suppression, quasispecies evolve in the envelope gene probably resulting from host-selective pressure. PMID:15527839

  6. HSV vector-mediated GAD67 suppresses neuropathic pain induced by perineural HIV gp120 in rats through inhibition of ROS and Wnt5a

    PubMed Central

    Kanda, Hirotsugu; Kanao, Megumi; Liu, Shue; Yi, Hyun; Iida, Takafumi; Levitt, Roy C; Candiotti, Keith A; Lubarsky, David A; Hao, Shuanglin

    2016-01-01

    Human immunodeficiency virus (HIV)-related neuropathic pain is a debilitating chronic condition that is severe and unrelenting. Despite the extensive research, the exact neuropathological mechanisms remain unknown, which hinders our ability to develop effective treatments. Loss of GABAergic tone may play an important role in the neuropathic pain state. Glutamic acid decarboxylase 67 (GAD67) is one of isoforms that catalyze GABA synthesis. Here, we used recombinant herpes simplex virus (HSV-1) vectors that encode gad1 gene to evaluate the therapeutic potential of GAD67 in peripheral HIV gp120-induced neuropathic pain in rats. We found that 1) subcutaneous inoculation of the HSV vectors expressing GAD67 attenuated mechanical allodynia in the model of HIV gp120-induced neuropathic pain, 2) the anti-allodynic effect of GAD67 was reduced by GABA-A and-B receptors antagonists, 3) HSV vectors expressing GAD67 reversed the lowered GABA-IR expression, and 4) the HSV vectors expressing GAD67 suppressed the upregulated mitochondrial superoxide and Wnt5a in the spinal dorsal horn. Taken together, our studies support the concept that recovering GABAergic tone by the HSV vectors may reverse HIV-associated neuropathic pain through suppressing mitochondrial superoxide and Wnt5a. Our studies provide validation of HSV-mediated GAD67 gene therapy in the treatment of HIV-related neuropathic pain. PMID:26752351

  7. Increases in brain white matter abnormalities and subcortical gray matter are linked to CD4 recovery in HIV infection.

    PubMed

    Fennema-Notestine, Christine; Ellis, Ronald J; Archibald, Sarah L; Jernigan, Terry L; Letendre, Scott L; Notestine, Randy J; Taylor, Michael J; Theilmann, Rebecca J; Julaton, Michelle D; Croteau, David J; Wolfson, Tanya; Heaton, Robert K; Gamst, Anthony C; Franklin, Donald R; Clifford, David B; Collier, Ann C; Gelman, Benjamin B; Marra, Christina; McArthur, Justin C; McCutchan, J Allen; Morgello, Susan; Simpson, David M; Grant, Igor

    2013-08-01

    MRI alterations in the cerebral white (WM) and gray matter (GM) are common in HIV infection, even during successful combination antiretroviral therapy (CART), and their pathophysiology and clinical significance are unclear. We evaluated the association of these alterations with recovery of CD4+ T cells. Seventy-five HIV-infected (HIV+) volunteers in the CNS HIV Anti-Retroviral Therapy Effects Research study underwent brain MRI at two visits. Multi-channel morphometry yielded volumes of total cerebral WM, abnormal WM, cortical and subcortical GM, and ventricular and sulcal CSF. Multivariable linear regressions were used to predict volumetric changes with change in current CD4 and detectable HIV RNA. On average, the cohort (79 % initially on CART) demonstrated loss of total cerebral WM alongside increases in abnormal WM and ventricular volumes. A greater extent of CD4 recovery was associated with increases in abnormal WM and subcortical GM volumes. Virologic suppression was associated with increased subcortical GM volume, independent of CD4 recovery. These findings suggest a possible link between brain alterations and immune recovery, distinct from the influence of virologic suppression. The association of increasing abnormal WM and subcortical GM volumes with CD4+ T cell recovery suggests that neuroinflammation may be one mechanism in CNS pathogenesis. PMID:23838849

  8. Understanding Cross-Sectional Racial, Ethnic, and Gender Disparities in Antiretroviral Use and Viral Suppression Among HIV Patients in the United States

    PubMed Central

    Beer, Linda; Mattson, Christine L.; Bradley, Heather; Skarbinski, Jacek

    2016-01-01

    Abstract To examine racial/ethnic and gender disparities in antiretroviral (ART) use and viral suppression among HIV-infected persons in care and identify factors that might account for observed disparities. The Medical Monitoring Project (MMP) is a complex sample survey of HIV-infected adults receiving medical care in the United States. We used weighted interview and medical record data collected 06/2009 to 05/2012 to estimate the prevalence of ART use and viral suppression among gender-stratified racial/ethnic groups. We used χ2 tests to identify significant differences in outcomes between white men versus other groups, and logistic regression models to identify the most parsimonious set of factors that could account for each observed difference. We found no significant disparity in ART use between white and Hispanic men, and no disparities between white men and white and Hispanic women after adjustment for disease stage, age, and poverty. Disparities in ART use between white men and black persons persisted after adjusting for other factors, but the observed differences were relatively small. Differences in ART use and adherence, demographic characteristics, and social determinants of health such as poverty, education, and insurance accounted for the observed disparities in viral suppression between white men and all groups except black men. In our model, accounting for these factors reduced the prevalence difference in viral suppression between white and black men by almost half. We found that factors associated with disparities differed among men and women of the same race/ethnicity, lending support to the assertion that gender affects access to care and health status among HIV-infected patients. In addition to supporting efforts to increase ART use and adherence among persons living with HIV, our analysis provides evidence for the importance of social determinants of health in understanding racial/ethnic and gender differences in ART use and viral suppression

  9. Understanding Cross-Sectional Racial, Ethnic, and Gender Disparities in Antiretroviral Use and Viral Suppression Among HIV Patients in the United States.

    PubMed

    Beer, Linda; Mattson, Christine L; Bradley, Heather; Skarbinski, Jacek

    2016-03-01

    To examine racial/ethnic and gender disparities in antiretroviral (ART) use and viral suppression among HIV-infected persons in care and identify factors that might account for observed disparities. The Medical Monitoring Project (MMP) is a complex sample survey of HIV-infected adults receiving medical care in the United States. We used weighted interview and medical record data collected 06/2009 to 05/2012 to estimate the prevalence of ART use and viral suppression among gender-stratified racial/ethnic groups. We used χ² tests to identify significant differences in outcomes between white men versus other groups, and logistic regression models to identify the most parsimonious set of factors that could account for each observed difference. We found no significant disparity in ART use between white and Hispanic men, and no disparities between white men and white and Hispanic women after adjustment for disease stage, age, and poverty. Disparities in ART use between white men and black persons persisted after adjusting for other factors, but the observed differences were relatively small. Differences in ART use and adherence, demographic characteristics, and social determinants of health such as poverty, education, and insurance accounted for the observed disparities in viral suppression between white men and all groups except black men. In our model, accounting for these factors reduced the prevalence difference in viral suppression between white and black men by almost half. We found that factors associated with disparities differed among men and women of the same race/ethnicity, lending support to the assertion that gender affects access to care and health status among HIV-infected patients. In addition to supporting efforts to increase ART use and adherence among persons living with HIV, our analysis provides evidence for the importance of social determinants of health in understanding racial/ethnic and gender differences in ART use and viral suppression. PMID

  10. Amniocentesis in the HIV-infected pregnant woman: Is there still cause for concern in the era of combination antiretroviral therapy?

    PubMed Central

    Andany, Nisha; Letchumanan, Michelle; Bondy, Lise; Murphy, Kellie; Loutfy, Mona R

    2013-01-01

    The current standard of care in Canadian obstetrical practice is to offer pregnant women the opportunity for prenatal investigation to diagnose congenital abnormalities. Prenatal amniocentesis is Canada’s most commonly practiced invasive procedure for the diagnosis of chromosomal and single gene disorders. The potential risk of intrapartum HIV transmission during amniocentesis raises several ethical concerns and limits the availability of prenatal genetic testing for HIV-positive pregnant women. Complete virological suppression with antiretroviral therapy may alleviate the risk of mother-to-child transmission during amniocentesis and increase accessibility of this important diagnostic tool in the HIV-positive population. The present report describes a case involving a 32-year-old HIV-positive pregnant woman whose plasma viral load was undetectable on antiretroviral therapy; she underwent successful prenatal amniocentesis without transmission of HIV to her infant. PMID:24421839

  11. Hepatitis B and C Co-Infection in HIV Patients from the TREAT Asia HIV Observational Database: Analysis of Risk Factors and Survival

    PubMed Central

    Chen, Marcelo; Wong, Wing-Wai; Law, Matthew G.; Kiertiburanakul, Sasisopin; Yunihastuti, Evy; Merati, Tuti Parwati; Lim, Poh Lian; Chaiwarith, Romanee; Phanuphak, Praphan; Lee, Man Po; Kumarasamy, Nagalingeswaran; Saphonn, Vonthanak; Ditangco, Rossana; Sim, Benedict L. H.; Nguyen, Kinh Van; Pujari, Sanjay; Kamarulzaman, Adeeba; Zhang, Fujie; Pham, Thuy Thanh; Choi, Jun Yong; Oka, Shinichi; Kantipong, Pacharee; Mustafa, Mahiran; Ratanasuwan, Winai; Durier, Nicolas; Chen, Yi-Ming Arthur

    2016-01-01

    Background We assessed the effects of hepatitis B (HBV) or hepatitis C (HCV) co-infection on outcomes of antiretroviral therapy (ART) in HIV-infected patients enrolled in the TREAT Asia HIV Observational Database (TAHOD), a multi-center cohort of HIV-infected patients in the Asia-Pacific region. Methods Patients testing HBs antigen (Ag) or HCV antibody (Ab) positive within enrollment into TAHOD were considered HBV or HCV co-infected. Factors associated with HBV and/or HCV co-infection were assessed by logistic regression models. Factors associated with post-ART HIV immunological response (CD4 change after six months) and virological response (HIV RNA <400 copies/ml after 12 months) were also determined. Survival was assessed by the Kaplan-Meier method and log rank test. Results A total of 7,455 subjects were recruited by December 2012. Of patients tested, 591/5656 (10.4%) were HBsAg positive, 794/5215 (15.2%) were HCVAb positive, and 88/4966 (1.8%) were positive for both markers. In multivariate analysis, HCV co-infection, age, route of HIV infection, baseline CD4 count, baseline HIV RNA, and HIV-1 subtype were associated with immunological recovery. Age, route of HIV infection, baseline CD4 count, baseline HIV RNA, ART regimen, prior ART and HIV-1 subtype, but not HBV or HCV co-infection, affected HIV RNA suppression. Risk factors affecting mortality included HCV co-infection, age, CDC stage, baseline CD4 count, baseline HIV RNA and prior mono/dual ART. Shortest survival was seen in subjects who were both HBV- and HCV-positive. Conclusion In this Asian cohort of HIV-infected patients, HCV co-infection, but not HBV co-infection, was associated with lower CD4 cell recovery after ART and increased mortality. PMID:26933963

  12. The Clinical Impact of Continuing to Prescribe Antiretroviral Therapy in Patients with Advanced AIDS Who Manifest No Virologic or Immunologic Benefit

    PubMed Central

    Wohl, David A.; Kendall, Michelle A.; Feinberg, Judith; Alston-Smith, Beverly; Owens, Susan; Chafey, Suzette; Marco, Michael; Maxwell, Sharon; Benson, Constance; Keiser, Philip; van der Horst, Charles; Jacobson, Mark A.

    2013-01-01

    Introduction Despite the efficacy and tolerability of modern antiretroviral therapy (ART), many patients with advanced AIDS prescribed these regimens do not achieve viral suppression or immune reconstitution as a result of poor adherence, drug resistance, or both. The clinical outcomes of continued ART prescription for such patients have not been well characterized. Methods We examined the causes and predictors of all-cause mortality, AIDS-defining conditions, and serious non-AIDS-defining events among a cohort of participants in a clinical trial of pre-emptive therapy for CMV disease. We focused on participants who, despite ART had failed to achieve virologic suppression and substantive immune reconstitution. Results 233 ART-receiving participants entered with a median baseline CD4+ T cell count of 30/mm3 and plasma HIV RNA of 5 log10 copies/mL. During a median 96 weeks of follow-up, 24.0% died (a mortality rate of 10.7/100 patient-years); 27.5% reported a new AIDS-defining condition, and 22.3% a new serious non-AIDS event. Of the deaths, 42.8% were due to an AIDS-defining condition, 44.6% were due to a non-AIDS-defining condition, and 12.5% were of unknown etiology. Decreased risk of mortality was associated with baseline CD4+ T cell count ≥25/mm3 and lower baseline HIV RNA. Conclusions Among patients with advanced AIDS prescribed modern ART who achieve neither virologic suppression nor immune reconstitution, crude mortality percentages appear to be lower than reported in cohorts of patients studied a decade earlier. Also, in contrast to the era before modern ART became available, nearly half of the deaths in our modern-era study were caused by serious non-AIDS-defining events. Even among the most advanced AIDS patients who were not obtaining apparent immunologic and virologic benefit from ART, continued prescription of these medications appears to alter the natural history of AIDS—improving survival and shifting the causes of death from AIDS- to non

  13. Recovery of CD4+ T Cells in HIV patients with a stable virologic response to antiretroviral therapy is associated with polymorphisms of interleukin-6 and central major histocompatibility complex genes.

    PubMed

    Fernandez, Sonia; Rosenow, Ann A; James, Ian R; Roberts, Steven G; Nolan, Richard C; French, Martyn A; Price, Patricia

    2006-01-01

    We investigated whether polymorphisms in genes associated with HIV disease progression and/or immune activation affect CD4+ T-cell recovery in HIV patients who began combination antiretroviral therapy (ART) with advanced immunodeficiency and achieved stable control of plasma viremia. Patients with CD4 T-cell counts <300 cells/microL (n = 33) and >400 cells/microL (n = 37) on ART were compared. A multiple case-control logistic regression associated carriage of BAT1(1,2) or interleukin (IL)6-174(2,2) with low CD4 T-cell counts (P = 0.012). BAT1*2 uniquely marks the central major histocompatibility complex region of a conserved haplotype (HLA-A1,B8,BAT1*2,TNFA-308*2,DR3,DQ2). There was no association between alleles carried at CCR5Delta32, CCR5 59029, CCR5 59353, CCR2+190 (V64I), SDF1 3'UTR, IL1A+4845, IL1B+3953, IL4-589, IL10-592, IL10-R1+536, IL10-R1+1112, IL12B 3'UTR, TNFA-308, or TNFA-1031 and CD4 T-cell counts. We suggest that immune activation and/or CD4 T-cell apoptosis in HIV patients on effective ART is influenced by genetic factors. PMID:16340466

  14. ART influences HIV persistence in the female reproductive tract and cervicovaginal secretions

    PubMed Central

    Olesen, Rikke; Swanson, Michael D.; Kovarova, Martina; Nochi, Tomonori; Chateau, Morgan; Honeycutt, Jenna B.; Long, Julie M.; Denton, Paul W.; Hudgens, Michael G.; Richardson, Amy; Tolstrup, Martin; Østergaard, Lars; Wahl, Angela; Garcia, J. Victor

    2016-01-01

    The recently completed HIV prevention trials network study 052 is a landmark collaboration demonstrating that HIV transmission in discordant couples can be dramatically reduced by treating the infected individual with antiretroviral therapy (ART). However, the cellular and virological events that occur in the female reproductive tract (FRT) during ART that result in such a drastic decrease in transmission were not studied and remain unknown. Here, we implemented an in vivo model of ART in BM/liver/thymus (BLT) humanized mice in order to better understand the ability of ART to prevent secondary HIV transmission. We demonstrated that the entire FRT of BLT mice is reconstituted with human CD4+ cells that are shed into cervicovaginal secretions (CVS). A high percentage of the CD4+ T cells in the FRT and CVS expressed CCR5 and therefore are potential HIV target cells. Infection with HIV increased the numbers of CD4+ and CD8+ T cells in CVS of BLT mice. Furthermore, HIV was present in CVS during infection. Finally, we evaluated the effect of ART on HIV levels in the FRT and CVS and demonstrated that ART can efficiently suppress cell-free HIV-RNA in CVS, despite residual levels of HIV-RNA+ cells in both the FRT and CVS. PMID:26854925

  15. Hemorrhagic Stroke in an Adolescent Female with HIV-Associated Thrombotic Thrombocytopenic Purpura

    PubMed Central

    Rakhmanina, Natella; Wong, Edward CC; Davis, Jeremiah C; Ray, Patricio E

    2014-01-01

    HIV-1 infection can trigger acute episodes of Idiopathic Thrombocytoponic Purpura (ITP), and Thrombotic Thrombocytopenic Purpura (TTP), particularly in populations with advanced disease and poor adherence to antiretroviral therapy (ART). These diseases should be distinguished because they respond to different treatments. Previous studies done in adults with HIV-TTP have recommended the prompt initiation or re-initiation of ART in parallel with plasma exchange therapy to improve the clinical outcome of these patients. Here, we describe a case of HIV-TTP resulting in an acute hemorrhagic stroke in a 16 year old female with perinatally acquired HIV infection and non-adherence to ART, who presented with severe thrombocytopenia, microangiopathic hemolytic anemia, and a past medical history of HIV-ITP. Both differential diagnosis and treatments for HIV-ITP and HIV-TTP were considered simultaneously. A decrease in plasma ADAMTS13 activity (<5%) without detectable inhibitory antibodies confirmed the diagnosis of HIV-TTP. Re-initiation of ART and plasma exchange resulted in a marked decrease in the HIV-RNA viral load, recovery of the platelet count, and complete recovery was achieved with sustained virologic suppression. PMID:25429351

  16. Early Combination Antiretroviral Therapy Limits Exposure to HIV-1 Replication and Cell-Associated HIV-1 DNA Levels in Infants

    PubMed Central

    McManus, Margaret; Mick, Eric; Hudson, Richard; Mofenson, Lynne M.; Sullivan, John L.; Somasundaran, Mohan; Luzuriaga, Katherine

    2016-01-01

    The primary aim of this study was to measure HIV-1 persistence following combination antiretroviral therapy (cART) in infants and children. Peripheral blood mononuclear cell (PBMC) HIV-1 DNA was quantified prior to and after 1 year of cART in 30 children, stratified by time of initiation (early, age <3 months, ET; late, age >3 months-2 years, LT). Pre-therapy PBMC HIV-1 DNA levels correlated with pre-therapy plasma HIV-1 levels (r = 0.59, p<0.001), remaining statistically significant (p = 0.002) after adjustment for prior perinatal antiretroviral exposure and age at cART initiation. PBMC HIV-1 DNA declined significantly after 1 year of cART (Overall: -0.91±0.08 log10 copies per million PBMC, p<0.001; ET: -1.04±0.11 log10 DNA copies per million PBMC, p<0.001; LT: -0.74 ±0.13 log10 DNA copies per million PBMC, p<0.001) but rates of decline did not differ significantly between ET and LT. HIV-1 replication exposure over the first 12 months of cART, estimated as area-under-the-curve (AUC) of circulating plasma HIV-1 RNA levels, was significantly associated with PBMC HIV-1 DNA at one year (r = 0.51, p = 0.004). In 21 children with sustained virologic suppression after 1 year of cART, PBMC HIV-1 DNA levels continued to decline between years 1 and 4 (slope -0.21 log10 DNA copies per million PBMC per year); decline slopes did not differ significantly between ET and LT. PBMC HIV-1 DNA levels at 1 year and 4 years of cART correlated with age at cART initiation (1 year: p = 0.04; 4 years: p = 0.03) and age at virologic control (1 and 4 years, p = 0.02). Altogether, these data indicate that reducing exposure to HIV-1 replication and younger age at cART initiation are associated with lower HIV-1 DNA levels at and after one year of age, supporting the concept that HIV-1 diagnosis and cART initiation in infants should occur as early as possible. PMID:27104621

  17. Early Combination Antiretroviral Therapy Limits Exposure to HIV-1 Replication and Cell-Associated HIV-1 DNA Levels in Infants.

    PubMed

    McManus, Margaret; Mick, Eric; Hudson, Richard; Mofenson, Lynne M; Sullivan, John L; Somasundaran, Mohan; Luzuriaga, Katherine

    2016-01-01

    The primary aim of this study was to measure HIV-1 persistence following combination antiretroviral therapy (cART) in infants and children. Peripheral blood mononuclear cell (PBMC) HIV-1 DNA was quantified prior to and after 1 year of cART in 30 children, stratified by time of initiation (early, age <3 months, ET; late, age >3 months-2 years, LT). Pre-therapy PBMC HIV-1 DNA levels correlated with pre-therapy plasma HIV-1 levels (r = 0.59, p<0.001), remaining statistically significant (p = 0.002) after adjustment for prior perinatal antiretroviral exposure and age at cART initiation. PBMC HIV-1 DNA declined significantly after 1 year of cART (Overall: -0.91±0.08 log10 copies per million PBMC, p<0.001; ET: -1.04±0.11 log10 DNA copies per million PBMC, p<0.001; LT: -0.74 ±0.13 log10 DNA copies per million PBMC, p<0.001) but rates of decline did not differ significantly between ET and LT. HIV-1 replication exposure over the first 12 months of cART, estimated as area-under-the-curve (AUC) of circulating plasma HIV-1 RNA levels, was significantly associated with PBMC HIV-1 DNA at one year (r = 0.51, p = 0.004). In 21 children with sustained virologic suppression after 1 year of cART, PBMC HIV-1 DNA levels continued to decline between years 1 and 4 (slope -0.21 log10 DNA copies per million PBMC per year); decline slopes did not differ significantly between ET and LT. PBMC HIV-1 DNA levels at 1 year and 4 years of cART correlated with age at cART initiation (1 year: p = 0.04; 4 years: p = 0.03) and age at virologic control (1 and 4 years, p = 0.02). Altogether, these data indicate that reducing exposure to HIV-1 replication and younger age at cART initiation are associated with lower HIV-1 DNA levels at and after one year of age, supporting the concept that HIV-1 diagnosis and cART initiation in infants should occur as early as possible. PMID:27104621

  18. The EPIICAL project: an emerging global collaboration to investigate immunotherapeutic strategies in HIV-infected children

    PubMed Central

    Palma, P; Foster, C; Rojo, P; Zangari, P; Yates, A; Cotugno, N; Klein, N; Luzuriaga, K; Pahwa, S; Nastouli, E; Gibb, DM; Borkowsky, W; Bernardi, S; Calvez, V; Manno, E; Mora, Nadia; Compagnucci, A; Wahren, B; Muñoz-Fernández, MÁ; De Rossi, A; Ananworanich, J; Pillay, D; Giaquinto, C; Rossi, P

    2016-01-01

    Short summary The EPIICAL (Early-treated Perinatally HIV-infected Individuals: Improving Children’s Actual Life with Novel Immunotherapeutic Strategies) project arises from the firm belief that perinatally infected children treated with suppressive antiretroviral therapy (ART) from early infancy represent the optimal population model in which to study novel immunotherapeutic strategies aimed at achieving ART-free remission. This is because HIV-infected infants treated within 2–3 months of life have a much reduced viral reservoir size, and rarely show HIV-specific immunity but preserve normal immune development. The goal of EPIICAL is the establishment of an international collaboration to develop a predictive platform using this model to select promising HIV therapeutic vaccine candidates, leading to prioritisation or deprioritisation of novel immunotherapeutic strategies. To establish this platform, the EPIICAL Consortium aims to: develop predictive models of virological and immunological dynamics associated with response to early ART and to treatment interruption using available data from existing cohorts/studies of early-treated perinatally HIV-infected children; optimise methodologies to better characterise immunological, virological and genomic correlates/profiles associated with viral control; test novel immunotherapeutic strategies using in vivo proof-of-concept (PoC) studies with the aim of inducing virological, immunological and transcriptomic correlates/profiles equivalent to those defined by the predictive model. This approach will strengthen the capacity for discovery, development and initial testing of new therapeutic vaccine strategies through the integrated efforts of leading international scientific groups, with the aim of improving the health of HIV-infected individuals. PMID:26893908

  19. Association of pol Diversity with Antiretroviral Treatment Outcomes among HIV-Infected African Children

    PubMed Central

    Chen, Iris; Khaki, Leila; Lindsey, Jane C.; Fry, Carrie; Cousins, Matthew M.; Siliciano, Robert F.; Violari, Avy; Palumbo, Paul; Eshleman, Susan H.

    2013-01-01

    Background In HIV-infected children, viral diversity tends to increase with age in the absence of antiretroviral treatment (ART). We measured HIV diversity in African children (ages 6–36 months) enrolled in a randomized clinical trial comparing two ART regimens (Cohort I of the P1060 trial). Children in this cohort were exposed to single dose nevirapine (sdNVP) at birth. Methods HIV diversity was measured retrospectively using a high resolution melting (HRM) diversity assay. Samples were obtained from 139 children at the enrollment visit prior to ART initiation. Six regions of the HIV genome were analyzed: two in gag, one in pol, and three in env. A single numeric HRM score that reflects HIV diversity was generated for each region; composite HRM scores were also calculated (mean and median for all six regions). Results In multivariable median regression models using backwards selection that started with demographic and clinical variables, older age was associated with higher HRM scores (higher HIV diversity) in pol (P = 0.005) and with higher mean (P = 0.014) and median (P<0.001) HRM scores. In multivariable models adjusted for age, pre-treatment HIV viral load, pre-treatment CD4%, and randomized treatment regimen, higher HRM scores in pol were associated with shorter time to virologic suppression (P = 0.016) and longer time to study endpoints (virologic failure [VF], VF/death, and VF/off study treatment; P<0.001 for all measures). Conclusions In this cohort of sdNVP-exposed, ART-naïve African children, higher levels of HIV diversity in the HIV pol region prior to ART initiation were associated with better treatment outcomes. PMID:24312277

  20. CNS safety at 48-week of switching to ATV/r plus 3TC or two nucleos(t)ides in HIV-suppressed patients on stable ART: the SALT neurocognitive sub-study

    PubMed Central

    Pérez Valero, Ignacio; Pasquau, Juan; Rubio, Rafael; Ribero, Antonio; Santos, Jose; Sanz, Jesus; Mariño, Ana; Crespo, Manel; Hernandez, Jose; Antonio Iribarren, Jose; Gutierrez, Felix; Terron, Alberto; Esteban, Herminia; Antonio Pérez-Molina, Jose

    2014-01-01

    Introduction Due to their low CNS penetrance, there are concerns about the capacity of non-conventional PI-based ART (monotherapy and dual therapies) to preserve neurocognitive performance (NP). Methods We evaluated the NP change of aviremic participants of the SALT clinical trial [1] switching therapy to dual therapy (DT: ATV/r+3TC) or triple therapy (TT: ATV/r+2NRTI) who agreed to perform an NP assessment (NPZ-5) at baseline and W48. Neurocognitive impairment and NP were assessed using AAN-2007 criteria [2] and global deficit scores (GDS) [3]. Neurocognitive change (GDS change: W48 – baseline) and the effect of DT on NP evolution crude and adjusted by significant confounders were determined using ANCOVA. Results A total of 158 patients were included (Table 1). They had shorter times because HIV diagnosis, ART initiation and HIV-suppression and their virologic outcome at W48 by snapshot was higher (79.1% vs 72.7%; p=0.04) compared to the 128 patients not included in the sub-study. By AAN-2007 criteria, 51 patients in each ART group (68% vs 63%) were neurocognitively impaired at baseline (p=0.61). Forty-seven patients were not reassessed at W48: 30 lost of follow-up (16 DT-14 TT) and 17 had non-evaluable data (6 DT-11 TT). Patients retested were more likely to be men (78.9% vs 61.4%) and had neurological cofounders (9.6% vs 0%) than patients non-retested. At W48, 3 out of 16 (5.7%) patients on DT and 6 out of 21 (10.5%) on TT who were non-impaired at baseline became impaired (p=0.49) while 10 out of 37 (18.9%) on DT and 7 out of 36 (12.3%) on TT who were neurocognitively impaired at baseline became non-impaired (p=0.44). Mean GDS changes (95% CI) were: Overall −0.2 (−0.3 to −0.04): DT −0.26 (−0.4 to −0.07) and TT −0.08 (−0.2 to 0.07). NP was similar between DT and TT (0.15). This absence of differences was also observed in all cognitive tests. Effect of DT: −0.16 [−0.38 to 0.06]) (r2=0.16) on NP evolution was similar to TT (reference), even

  1. Adherence to Antiretroviral Therapy and Virologic Failure: A Meta-Analysis.

    PubMed

    Bezabhe, Woldesellassie M; Chalmers, Leanne; Bereznicki, Luke R; Peterson, Gregory M

    2016-04-01

    The often cited need to achieve ≥95% (nearly perfect) adherence to antiretroviral therapy (ART) for successful virologic outcomes in HIV may present a barrier to initiation of therapy in the early stages of HIV.This meta-analysis synthesized 43 studies (27,905 participants) performed across >26 countries, to determine the relationship between cut-off point for optimal adherence to ART and virologic outcomes.Meta-analysis was performed using a random-effect model to calculate pooled odds ratios with corresponding 95% confidence intervals.The mean rate of patients reporting optimal adherence was 63.4%. Compared with suboptimal adherence, optimal adherence was associated with a lower risk of virologic failure (0.34; 95% CI: 0.26-0.44). There were no significant differences in the pooled odds ratios among different optimal adherence thresholds (≥98-100%, ≥95%, ≥80-90%). Study design (randomized controlled trial vs observational study) (regression coefficient 0.74, 95% CI: 0.04-1.43, P < 0.05) and study region (developing vs developed countries; regression coefficient 0.56, 95% CI: 0.01-1.12, P < 0.05) remained as independent predictors of between-study heterogeneity, with more patients with optimal adherence from developing countries or randomized controlled trials experiencing virologic failure.The threshold for optimal adherence to achieve better virologic outcomes appears to be wider than the commonly used cut-off point (≥95% adherence). The cut-off point for optimal adherence could be redefined to a slightly lower level to encourage the prescribing ART at an early stage of HIV infection. PMID:27082595

  2. Finding our roots and celebrating our shoots: Plant virology in Virology, 1955-1964.

    PubMed

    Scholthof, Karen-Beth G

    2015-05-01

    To celebrate the sixtieth anniversary of Virology a survey is made of the plant viruses, virologists and their institutions, and tools and technology described in the first decade of plant virus publications in Virology. This was a period when plant viruses increasingly became tools of discovery as epistemic objects and plant virology became a discipline discrete from plant pathology and other life sciences. PMID:25842010

  3. Stem-loop 1 of the U1 snRNP plays a critical role in the suppression of HIV-1 polyadenylation.

    PubMed Central

    Ashe, M P; Furger, A; Proudfoot, N J

    2000-01-01

    The inactivity or occlusion of the HIV-1 poly(A) signal when in the 5' long terminal repeat (LTR) has been mechanistically investigated. First we show that neither the homologous HIV-1 promoter nor the close proximity of this RNA processing signal to the transcript initiation site is required for the occlusion effect. Instead we demonstrate that the major splice donor (MSD) site positioned about 200 bp downstream maintains the poly(A) site in an inactive state. Although mutation of MSD results in activation of the 5' LTR poly(A) signal, this effect can be suppressed by targeting U1 snRNAs near to the mutated MSD by base pairing. We show that hybrid U7-U1 snRNAs can also suppress the poly(A) signal and that this suppression is dependent on the U1 stem-loop 1. In particular the binding site for the U1 snRNP protein 70K that binds to the loop structure of stem-loop 1 is associated with poly(A) site occlusion. These experiments were carried out with an HIV-1 proviral construct and as such emphasize the physiological importance of this splice donor-poly(A) site interaction. PMID:10688356

  4. HIV

    PubMed Central

    Chawla, Sumit; Sahoo, Soumya Swaroop; Jain, Rambilas; Khanna, Pardeep; Mehta, Bharti; Singh, Inderjeet

    2014-01-01

    Getting to zero: zero new HIV infections, zero deaths from AIDS-related illness, zero discrimination is the theme of World AIDS Day 2012. Given the spread of the epidemic today, getting to zero may sound difficult, but significant progress is underway. The total annual loss for the entire country due to HIV is 7% of GDP, which exceeds India’s annual health expenditure in 2004. The additional loss due to loss of labor income and increased medical expenditure as measured by the external transfers, account for 5% of the country’s health expenditure and 0.23% of GDP. Given that the HIV incidence rate is only 0.27% in India, these losses are quite staggering. Despite the remarkable achievements in development of anti-retroviral therapies against HIV and the recent advances in new prevention technologies, the rate of new HIV infections continue to outpace efforts on HIV prevention and control. Thus, the development of a safe and effective vaccine for prevention and control of AIDS remains a global public health priority and the greatest opportunity to eventually end the AIDS pandemic. PMID:24056755

  5. Introducing Virological Concepts Using an Insect Virus.

    ERIC Educational Resources Information Center

    Sheppard, Roger F.

    1980-01-01

    A technique is presented which utilizes wax moth larvae in a laboratory investigation of an insect virus. Describes how an insect virus can be used to introduce undergraduate biology students to laboratory work on viruses and several virological concepts. (SA)

  6. Reactivation of HIV latency by a newly modified Ingenol derivative via protein kinase Cδ–NF-κB signaling

    PubMed Central

    Jiang, Guochun; Mendes, Erica A.; Kaiser, Philipp; Sankaran-Walters, Sumathi; Tang, Yuyang; Weber, Mariana G.; Melcher, Greg P.; Thompson, George R.; Tanuri, Amilcar; Pianowski, Luiz F.; Wong, Joseph K.; Dandekar, Satya

    2016-01-01

    Objective Although HAART effectively suppresses viral replication, it fails to eradicate latent viral reservoirs. The ‘shock and kill’ strategy involves the activation of HIV from latent reservoirs and targeting them for eradication. Our goal was to develop new approaches for activating HIV from latent reservoirs. Design We investigated capacity of Ingenol B (IngB), a newly modified derivative of Ingenol ester that was originally isolated from a Brazilian plant in Amazon, for its capacity and mechanisms of HIV reactivation. Methods Reactivation of HIV-1 by IngB was evaluated in J-Lat A1 cell culture model of HIV latency as well as in purified primary CD4+ T cells from long-term HAART-treated virologically-suppressed HIV-infected individuals. The underlining molecular mechanisms of viral reactivation were investigated using flow cytometry, RT-qPCR and chromatin immunoprecipitation. Results IngB is highly effective in reactivating HIV in J-Lat A1 cells with relatively low cellular toxicity. It is also able to reactivate latent HIV in purified CD4+ T cells from HAART-treated HIV-positive individuals ex vivo. Our data show that IngB may reactivate HIV expression by both activating protein kinase C (PKC)δ–nuclear factor kappalight-chain-enhancer of activated B cells (NF-κB) pathway and directly inducing NF-κB protein expression. Importantly, IngB has a synergistic effect with JQ1, a BET bromodomain inhibitor, in latent HIV reactivation. Conclusions IngB is a new promising compound to activate latent HIV reservoirs. Our data suggest that formulating novel derivatives from Ingenol esters may be an innovative approach to develop new lead compounds to reactivate latent HIV. PMID:24804860

  7. Implementation and Operational Research: Engagement in HIV Care Among Persons Enrolled in a Clinical HIV Cohort in Ontario, Canada, 2001–2011

    PubMed Central

    Burchell, Ann N.; Gardner, Sandra; Light, Lucia; Ellis, Brooke M.; Antoniou, Tony; Bacon, Jean; Benoit, Anita; Cooper, Curtis; Kendall, Claire; Loutfy, Mona; McGee, Frank; Raboud, Janet; Rachlis, Anita; Wobeser, Wendy; Rourke, Sean B.

    2015-01-01

    Background: Ensuring that people living with HIV are accessing and staying in care is vital to achieving optimal health outcomes including antiretroviral therapy (ART) success. We sought to characterize engagement in HIV care among participants of a large clinical cohort in Ontario, Canada, from 2001 to 2011. Methods: The Ontario HIV Treatment Network Cohort Study (OCS) is a multisite HIV clinical cohort, which conducts record linkage with the provincial public health laboratory for viral load tests. We estimated the annual proportion meeting criteria for being in care (≥1 viral load per year), in continuous care (≥2 viral load per year ≥90 days apart), on ART, and with suppressed viral load <200 copies per milliliter. Ratios of proportions according to socio-demographic and clinical characteristics were examined using multivariable generalized estimating equations with a log-link. Results: A total of 5380 participants were followed over 44,680 person-years. From 2001 to 2011, we observed high and constant proportions of patients in HIV care (86.3%–88.8%) and in continuous care (76.4%–79.5%). There were statistically significant rises over time in the proportions on ART and with suppressed viral load; by 2011, a majority of patients were on ART (77.3%) and had viral suppression (76.2%). There was minimal variation in HIV engagement indicators by socio-demographic and HIV risk characteristics. Conclusions: In a setting with universal health care, we observed high proportions of HIV care engagement over time and an increased proportion of patients attaining successful virologic suppression, likely due to improvements in ART regimens and changing guidelines. PMID:26322672

  8. HMBA Enhances Prostratin-Induced Activation of Latent HIV-1 via Suppressing the Expression of Negative Feedback Regulator A20/TNFAIP3 in NF-κB Signaling

    PubMed Central

    Chen, Duchu; Wang, Huiping; Aweya, Jude Juventus; Chen, Yanheng; Chen, Meihua; Wu, Xiaomeng; Chen, Xiaonan; Lu, Jing

    2016-01-01

    In the past decade, much emphasis has been put on the transcriptional activation of HIV-1, which is proposed as a promised strategy for eradicating latent HIV-1 provirus. Two drugs, prostratin and hexamethylene bisacetamide (HMBA), have shown potent effects as inducers for releasing HIV-1 latency when used alone or in combination, although their cellular target(s) are currently not well understood, especially under drug combination. Here, we have shown that HMBA and prostratin synergistically release HIV-1 latency via different mechanisms. While prostratin strongly stimulates HMBA-induced HIV-1 transcription via improved P-TEFb activation, HMBA is capable of boosting NF-κB-dependent transcription initiation by suppressing prostratin-induced expression of the deubiquitinase A20, a negative feedback regulator in the NF-κB signaling pathway. In addition, HMBA was able to increase prostratin-induced phosphorylation and degradation of NF-κB inhibitor IκBα, thereby enhancing and prolonging prostratin-induced nuclear translocation of NF-κB, a prerequisite for stimulation of transcription initiation. Thus, by blocking the negative feedback circuit, HMBA functions as a signaling enhancer of the NF-κB signaling pathway. PMID:27529070

  9. Targeting of mTOR catalytic site inhibits multiple steps of the HIV-1 lifecycle and suppresses HIV-1 viremia in humanized mice.

    PubMed

    Heredia, Alonso; Le, Nhut; Gartenhaus, Ronald B; Sausville, Edward; Medina-Moreno, Sandra; Zapata, Juan C; Davis, Charles; Gallo, Robert C; Redfield, Robert R

    2015-07-28

    HIV necessitates host factors for successful completion of its life cycle. Mammalian target of rapamycin (mTOR) is a conserved serine/threonine kinase that forms two complexes, mTORC1 and mTORC2. Rapamycin is an allosteric inhibitor of mTOR that selectively inhibits mTORC1. Rapamycin interferes with viral entry of CCR5 (R5)-tropic HIV and with basal transcription of the HIV LTR, potently inhibiting replication of R5 HIV but not CXCR4 (X4)-tropic HIV in primary cells. The recently developed ATP-competitive mTOR kinase inhibitors (TOR-KIs) inhibit both mTORC1 and mTORC2. Using INK128 as a prototype TOR-KI, we demonstrate potent inhibition of both R5 and X4 HIV in primary lymphocytes (EC50 < 50 nM), in the absence of toxicity. INK128 inhibited R5 HIV entry by reducing CCR5 levels. INK128 also inhibited both basal and induced transcription of HIV genes, consistent with inhibition of mTORC2, whose activity is critical for phosphorylation of PKC isoforms and, in turn, induction of NF-κB. INK128 enhanced the antiviral potency of the CCR5 antagonist maraviroc, and had favorable antiviral interactions with HIV inhibitors of reverse transcriptase, integrase and protease. In humanized mice, INK128 decreased plasma HIV RNA by >2 log10 units and partially restored CD4/CD8 cell ratios. Targeting of cellular mTOR with INK128 (and perhaps others TOR-KIs) provides a potential strategy to inhibit HIV, especially in patients with drug resistant HIV strains. PMID:26170311

  10. Establishment and Replenishment of the Viral Reservoir in Perinatally HIV-1-infected Children Initiating Very Early Antiretroviral Therapy

    PubMed Central

    Martínez-Bonet, Marta; Puertas, Maria Carmen; Fortuny, Claudia; Ouchi, Dan; Mellado, Maria José; Rojo, Pablo; Noguera-Julian, Antoni; Muñoz-Fernández, Ma Angeles; Martinez-Picado, Javier

    2015-01-01

    Background. Combination antiretroviral therapy (cART) generally suppresses the replication of the human immunodeficiency virus type 1 (HIV-1) but does not cure the infection, because proviruses persist in stable latent reservoirs. It has been proposed that low-level proviral reservoirs might predict longer virologic control after discontinuation of treatment. Our objective was to evaluate the impact of very early initiation of cART and temporary treatment interruption on the size of the latent HIV-1 reservoir in vertically infected children. Methods. This retrospective study included 23 perinatally HIV-1-infected children who initiated very early treatment within 12 weeks after birth (n = 14), or early treatment between week 12 and 1 year (n = 9). We measured the proviral reservoir (CD4+ T-cell–associated HIV-1 DNA) in blood samples collected beyond the first year of sustained virologic suppression. Results. There is a strong positive correlation between the time to initiation of cART and the size of the proviral reservoir. Children who initiated cART within the first 12 weeks of life showed a proviral reservoir 6-fold smaller than children initiating cART beyond this time (P < .01). Rapid virologic control after initiation of cART also limits the size of the viral reservoir. However, patients who underwent transient treatment interruptions showed a dramatic increase in the size of the viral reservoir after discontinuation. Conclusions. Initiation of cART during the first 12 weeks of life in perinatally HIV-1-infected children limits the size of the viral reservoir. Treatment interruptions should be undertaken with caution, as they might lead to fast and irreversible replenishment of the viral reservoir. PMID:26063721

  11. Cerebrovascular disease in children with HIV-1 infection.

    PubMed

    Hammond, Charles K; Eley, Brian; Wieselthaler, Nicky; Ndondo, Alvin; Wilmshurst, Jo M

    2016-05-01

    An estimated 3.2 million children worldwide have human immunodeficiency virus (HIV) infection. Antiretroviral therapy (ART) has resulted in prolonged survival, leading to an increase in complications previously recognized in adults. Children with HIV infection have increased risk of cerebrovascular disease from multiple aetiologies including HIV-associated vasculopathy, opportunistic vasculitis, cardioembolism or coagulopathy, all of which may be secondary to the infection. Prevalence of cerebrovascular disease in HIV-infected children is underestimated because of limited neuroimaging in low and middle income countries, silent events without overt motor manifestations, and mislabeling as HIV encephalopathy for non-motor manifestations such as behavioural and cognitive difficulties. No management guidelines for cerebrovascular disease in HIV-infected children exist but common practices target risk factors for stroke in low and middle income countries. Where capacity permits, screening for opportunistic infections, vasculitis, coagulopathy and cardioembolism is important. Optimising virological suppression, correction of anaemia, control of seizures and aspirin prophylaxis are management priorities. Neurosurgical interventions may have a role. PMID:26890389

  12. Deep sequencing of HIV: clinical and research applications.

    PubMed

    Chabria, Shiven B; Gupta, Shaili; Kozal, Michael J

    2014-01-01

    Human immunodeficiency virus (HIV) exhibits remarkable diversity in its genomic makeup and exists in any given individual as a complex distribution of closely related but nonidentical genomes called a viral quasispecies, which is subject to genetic variation, competition, and selection. This viral diversity clinically manifests as a selection of mutant variants based on viral fitness in treatment-naive individuals and based on drug-selective pressure in those on antiretroviral therapy (ART). The current standard-of-care ART consists of a combination of antiretroviral agents, which ensures maximal viral suppression while preventing the emergence of drug-resistant HIV variants. Unfortunately, transmission of drug-resistant HIV does occur, affecting 5% to >20% of newly infected individuals. To optimize therapy, clinicians rely on viral genotypic information obtained from conventional population sequencing-based assays, which cannot reliably detect viral variants that constitute <20% of the circulating viral quasispecies. These low-frequency variants can be detected by highly sensitive genotyping methods collectively grouped under the moniker of deep sequencing. Low-frequency variants have been correlated to treatment failures and HIV transmission, and detection of these variants is helping to inform strategies for vaccine development. Here, we discuss the molecular virology of HIV, viral heterogeneity, drug-resistance mutations, and the application of deep sequencing technologies in research and the clinical care of HIV-infected individuals. PMID:24821496

  13. Evaluating mental health difficulties and associated outcomes among HIV-positive adolescents in Tanzania.

    PubMed

    Dow, Dorothy E; Turner, Elizabeth L; Shayo, Aisa M; Mmbaga, Blandina; Cunningham, Coleen K; O'Donnell, Karen

    2016-07-01

    AIDS-related mortality among HIV-positive adolescents has risen by 50% despite the scale up of antiretroviral therapy (ART). ART maladherence likely plays a role in the increase of AIDS-related deaths among adolescents and has shown to be associated with psychosocial and mental health difficulties. Addressing the specific mental health needs of HIV-positive adolescents is critical to ending the HIV epidemic. This cross-sectional study prospectively enrolled HIV-positive adolescents (12-24 years) in Moshi, Tanzania. A structured questionnaire was administered that included questions about home, school, adherence, and measures of stigma (Berger Stigma Scale) and mental health. Mental health measures included depression (Patient Health Questionnaire-9), emotional/behavioral difficulties (Strengths and Difficulties Questionnaire), and traumatic experiences/post-traumatic stress symptoms (The University of California Los Angeles-post-traumatic stress disorder-Reaction Index). Mental health difficulties were prevalent among HIV-positive adolescents and were associated with incomplete adherence and stigma. Resources are needed to reduce HIV stigma and address mental health among HIV-positive adolescents in low-resource settings. This will improve not only mental health, but may also improve ART adherence and virologic suppression, improving overall health of the individual and reducing the risk of HIV transmission to others. PMID:26837437

  14. Patterns of homelessness and implications for HIV health after release from jail.

    PubMed

    Zelenev, Alexei; Marcus, Ruthanne; Kopelev, Artem; Cruzado-Quinones, Jacqueline; Spaulding, Anne; Desabrais, Maureen; Lincoln, Tom; Altice, Frederick L

    2013-10-01

    This empirical study examines the association between substance abuse, mental illness, health behaviors and different patterns of homelessness among recently released, HIV-infected jail detainees. Using longitudinal data from a 10-site study, we examine correlates of homelessness, transitions to and from stable housing and the effect of housing on HIV treatment outcomes. Based on our analysis, we found evidence that the transitions from homelessness are closely associated with a reduction in the use of alcohol and illicit drugs, a decline in drug addiction severity, and an improvement in mental health. In addition, we found evidence that disparities in the housing status contributed substantially to the observed gap in the HIV treatment outcomes between homeless and non-homeless patients, including in achievement of virological suppression over time. PMID:23657757

  15. Progressive Proximal-to-Distal Reduction in Expression of the Tight Junction Complex in Colonic Epithelium of Virally-Suppressed HIV+ Individuals

    PubMed Central

    Chung, Charlotte Y.; Alden, Stephanie L.; Funderburg, Nicholas T.; Fu, Pingfu; Levine, Alan D.

    2014-01-01

    Effective antiretroviral therapy (ART) dramatically reduces AIDS-related complications, yet the life expectancy of long-term ART-treated HIV-infected patients remains shortened compared to that of uninfected controls, due to increased risk of non-AIDS related morbidities. Many propose that these complications result from translocated microbial products from the gut that stimulate systemic inflammation – a consequence of increased intestinal paracellular permeability that persists in this population. Concurrent intestinal immunodeficiency and structural barrier deterioration are postulated to drive microbial translocation, and direct evidence of intestinal epithelial breakdown has been reported in untreated pathogenic SIV infection of rhesus macaques. To assess and characterize the extent of epithelial cell damage in virally-suppressed HIV-infected patients, we analyzed intestinal biopsy tissues for changes in the epithelium at the cellular and molecular level. The intestinal epithelium in the HIV gut is grossly intact, exhibiting no decreases in the relative abundance and packing of intestinal epithelial cells. We found no evidence for structural and subcellular localization changes in intestinal epithelial tight junctions (TJ), but observed significant decreases in the colonic, but not terminal ileal, transcript levels of TJ components in the HIV+ cohort. This result is confirmed by a reduction in TJ proteins in the descending colon of HIV+ patients. In the HIV+ cohort, colonic TJ transcript levels progressively decreased along the proximal-to-distal axis. In contrast, expression levels of the same TJ transcripts stayed unchanged, or progressively increased, from the proximal-to-distal gut in the healthy controls. Non-TJ intestinal epithelial cell-specific mRNAs reveal differing patterns of HIV-associated transcriptional alteration, arguing for an overall change in intestinal epithelial transcriptional regulation in the HIV colon. These findings suggest that

  16. Treatment options after virological failure of first-line tenofovir-based regimens in South Africa: an analysis by deep sequencing.

    PubMed

    Casadellà, Maria; Noguera-Julian, Marc; Sunpath, Henry; Gordon, Michelle; Rodriguez, Cristina; Parera, Mariona; Kuritzkes, Daniel R; Marconi, Vincent C; Paredes, Roger

    2016-04-24

    In a South African cohort of participants living with HIV developing virological failure on first-line tenofovir disoproxyl fumarate (TDF)-based regimens, at least 70% of participants demonstrated TDF resistance according to combined Sanger and MiSeq genotyping. Sanger sequencing missed the K65R mutation in 30% of samples. Unless HIV genotyping is available to closely monitor epidemiological HIV resistance to TDF, its efficacy as second-line therapy will be greatly compromised. PMID:26807968

  17. Effect of HIV Housing Services on Engagement in Care and Treatment, New York City, 2011.

    PubMed

    Terzian, Arpi S; Irvine, Mary K; Hollod, Laura M; Lim, Sungwoo; Rojas, John; Shepard, Colin W

    2015-11-01

    The federal Housing Opportunities for Persons with AIDS (HOPWA) program addresses housing needs of low-income persons living with HIV/AIDS (PLWHA). The New York City (NYC) Department of Health and Mental Hygiene oversees 22 HOPWA contracts for over 2,400 clients, and manages the NYC HIV Registry. HOPWA clients (N = 1,357) were matched to a random 20 % sample of other PLWHA (N = 13,489). Groups were compared on HIV care retention, viral suppression, and rebound. HOPWA clients were, on average, 3 years younger and more likely to be concurrently diagnosed with HIV and AIDS. While HOPWA clients were more likely to be retained in care (94 vs. 82 %; mOR = 2.97, 95 % CI 2.35-3.74), they were no more likely to achieve suppression (84 vs. 86 %; mOR = 0.85, 95 % 0.70-1.03) and were more likely to rebound (11 vs. 7 %; mOR = 1.45; 95 % CI 1.10-1.91). HIV care retention does not fully translate to virologic suppression in this low-income service population. PMID:25631320

  18. Co-receptor switch during HAART is independent of virological success.

    PubMed

    Saracino, Annalisa; Monno, Laura; Cibelli, Donatella C; Punzi, Grazia; Brindicci, Gaetano; Ladisa, Nicoletta; Tartaglia, Alessandra; Lagioia, Antonella; Angarano, Gioacchino

    2009-12-01

    The influence of antiretroviral therapy on co-receptor tropism remains controversial. To verify if co-receptor tropism shift was affected by HAART, the evolution of proviral DNA V3 genotype after 12 months of a new antiretroviral regimen was compared between responder and non-responder patients. Baseline blood samples were collected from 36 patients infected with HIV-1 subtype-B (18 naïve and 18 experienced) for virus isolation and env V3 genotyping from plasma HIV-1 RNA and PBMC DNA. DNA V3 genotyping was repeated after 12 months from initiating HAART. WebPSSM was used for categorizing V3 sequences into X4 or R5; for analysis purposes, dual/mixed viruses were considered as X4. From the 10 (28%) patients changing their proviral DNA V3 genotype during therapy, six shifted from R5-to-X4 and four from X4-to-R5. The lack of reaching virological suppression was not associated with an X4-to-R5 (P = 0.25) or R5-to-X4 (P = 0.14) shift; time-to-viral suppression and CD4 increase were similar in both groups. No association was found between tropism shift and patient baseline characteristics including age, sex, CDC stage, CD4 count, viral load, exposure and length of previous HAART, enfuvirtide use in the new regimen, number of reverse transcriptase and protease resistance-associated mutations. Conversely, CD4 nadir was correlated to emergence of X4 virus in proviral DNA (mean 27.2 +/- 30.6 in R5-to-X4 shifting patients vs. 161.6 +/- 150.6 in non-shifting patients, P = 0.02). The occurrence of a tropism shift in both directions was independent of HAART use, irrespective of its efficacy. The CD4 count nadir was the only baseline characteristic able to predict an R5-to-X4 viral shift. PMID:19856465

  19. Darunavir: a review of its use in the management of HIV-1 infection.

    PubMed

    Deeks, Emma D

    2014-01-01

    The latest HIV-1 protease inhibitor (PI) darunavir (Prezista™) has a high genetic barrier to resistance development and is active against wild-type HIV and HIV strains no longer susceptible to some older PIs. Ritonavir-boosted darunavir, as a component of antiretroviral therapy (ART), is indicated for the treatment of HIV-1 infection in adult and paediatric patients (aged ≥3 years), with or without treatment experience (details vary depending on region of approval). Several open-label or partially-blinded trials have evaluated the efficacy of ritonavir-boosted darunavir ART regimens for up to 192 weeks in these settings. In treatment-naïve adults, once-daily boosted darunavir was no less effective in establishing virological suppression than once- or twice-daily boosted lopinavir, yet was more effective at maintaining suppression long term. Moreover, treatment-experienced adults with no darunavir resistance-associated mutations (RAMs) had no less effective viral load suppression with once-daily than with twice-daily boosted darunavir. In treatment-experienced adults, including some with multiple major PI RAMs, twice-daily boosted darunavir was more effective than twice-daily boosted lopinavir or boosted control PIs in reducing viral load, and provided virological benefit as part of a salvage regimen in those with few remaining treatment options. Boosted darunavir also reduced viral load when administered once-daily in treatment-naïve adolescents or twice-daily in treatment-experienced children and adolescents. Boosted darunavir is generally well tolerated, with gastrointestinal disturbances and lipid abnormalities among the most common tolerability issues. It has a lipid profile more favourable than that of boosted lopinavir in terms of total cholesterol and triglyceride changes and, when administered once daily, its lipid effects are generally similar to those of boosted atazanavir. Thus, boosted darunavir is a useful option for the ART regimens of adult

  20. Emtricitabine/rilpivirine/tenofovir disoproxil fumarate single-tablet regimen: a review of its use in HIV infection.

    PubMed

    Deeks, Emma D

    2014-11-01

    The nucleos(t)ide reverse transcriptase inhibitors, emtricitabine and tenofovir disoproxil fumarate (tenofovir DF), and the non-nucleoside reverse transcriptase inhibitor, rilpivirine, are now available as a fixed-dose single-tablet regimen (emtricitabine/rilpivirine/tenofovir DF; Complera(®), Eviplera(®)) for the treatment of adults infected with HIV-1. In treatment-naïve adults, once-daily emtricitabine/rilpivirine/tenofovir DF was noninferior to once-daily emtricitabine/efavirenz/tenofovir DF with regard to establishing virological suppression over 96 weeks of therapy in a randomized, open-label, phase IIIb study (STaR). These data confirmed the findings of a pooled subset analysis of two earlier 96-week, double-blind, phase III trials (ECHO and THRIVE) in which treatment-naïve adults received either rilpivirine or efavirenz in combination with emtricitabine/tenofovir DF. However, the virological benefit of emtricitabine/rilpivirine/tenofovir DF in this setting appeared limited in patients with low CD4+ cell counts or high viral loads at baseline. In 48-week phase IIIb (SPIRIT) and IIb (Study 111) trials in treatment-experienced patients already virologically suppressed with a single- or multiple-tablet antiretroviral regimen and without prior virological failure, switching to once-daily emtricitabine/rilpivirine/tenofovir DF maintained virological suppression and was noninferior to remaining on a more complex multiple-tablet regimen in this regard. Emtricitabine/rilpivirine/tenofovir DF is generally well tolerated and appears to have a more favourable tolerability profile than emtricitabine/efavirenz/tenofovir DF. Thus, emtricitabine/rilpivirine/tenofovir DF is a welcome addition to the other single-tablet regimens currently available for the treatment of HIV-1 infection, providing a convenient and effective option for some adults who are treatment-naïve, as well as those who are already virologically suppressed on their current treatment regimen and

  1. Biological Aspects of Computer Virology

    NASA Astrophysics Data System (ADS)

    Vlachos, Vasileios; Spinellis, Diomidis; Androutsellis-Theotokis, Stefanos

    Recent malware epidemics proved beyond any doubt that frightful predictions of fast-spreading worms have been well founded. While we can identify and neutralize many types of malicious code, often we are not able to do that in a timely enough manner to suppress its uncontrolled propagation. In this paper we discuss the decisive factors that affect the propagation of a worm and evaluate their effectiveness.

  2. Five years' real-life experience with raltegravir in a large HIV centre.

    PubMed

    van Halsema, Clare; Whitfield, Thomas; Lin, Naomi; Ashton, Kathryn; Torkington, Adele; Ustianowski, Andrew

    2016-04-01

    Raltegravir was the first licensed integrase inhibitor. Real-life experience is informative and complements trial data. We therefore evaluated raltegravir use in adults in a large HIV treatment centre. From pharmacy and departmental HIV database records, we identified all adults taking ≥1 dose of raltegravir from first availability to the end of November 2012. Data were collected using a standardised case report form. Two hundred and fifteen individuals provided 502 patient-years (median 2.6 years/person) of raltegravir use. Of 215 individuals, 166 (77%) were male, median age 43 years; 189 (88%) were antiretroviral therapy (ART)-experienced and 26 (12%) ART-naive, with median baseline CD4 counts of 324 and 54 cells/µL, respectively. Of ten individuals using once-daily raltegravir, four, with good adherence remained virologically suppressed after a median 28 months, four stopped against medical advice, one stopped to simplify and one failed virologically. In hepatitis co-infection, 35 individuals (92 patient-years) took raltegravir without evidence of hepatotoxicity. Six women started raltegravir during pregnancy for intensification (5/6) or switch for tolerability without complications. Of ten individuals stopping raltegravir after virological failure, 2/4 with successful sequencing showed resistance. Raltegravir appears safe and effective, without evidence of toxicity above that in published trials, including in pregnancy and co-infections. Once-daily dosing seems effective where adherence is good. PMID:25931236

  3. Comparative Value of Four Measures of Retention in Expert Care in Predicting Clinical Outcomes and Health Care Utilization in HIV Patients

    PubMed Central

    Reveles, Kelly R.; Juday, Timothy R.; Labreche, Matthew J.; Mortensen, Eric M.; Koeller, Jim M.; Seekins, Daniel; Oramasionwu, Christine U.; Bollinger, Mary; Copeland, Laurel A.; Jones, Xavier; Frei, Christopher R.

    2015-01-01

    This study compared the ability of four measures of patient retention in HIV expert care to predict clinical outcomes. This retrospective study examined Veterans Health Administration (VHA) beneficiaries with HIV (ICD-9-CM codes 042 or V08) receiving expert care (defined as HIV-1 RNA viral load and CD4 cell count tests occurring within one week of each other) at VHA facilities from October 1, 2006, to September 30, 2008. Patients were ≥18 years old and continuous VHA users for at least 24 months after entry into expert care. Retention measures included: Annual Appointments (≥2 appointments annually at least 60 days apart), Missed Appointments (missed ≥25% of appointments), Infrequent Appointments (>6 months without an appointment), and Missed or Infrequent Appointments (missed ≥25% of appointments or >6 months without an appointment). Multivariable nominal logistic regression models were used to determine associations between retention measures and outcomes. Overall, 8,845 patients met study criteria. At baseline, 64% of patients were virologically suppressed and 37% had a CD4 cell count >500 cells/mm3. At 24 months, 82% were virologically suppressed and 46% had a CD4 cell count >500 cells/mm3. During follow-up, 13% progressed to AIDS, 48% visited the emergency department (ED), 28% were hospitalized, and 0.3% died. All four retention measures were associated with virologic suppression and antiretroviral therapy initiation at 24 months follow-up. Annual Appointments correlated positively with CD4 cell count >500 cells/mm3. Missed Appointments was predictive of all primary and secondary outcomes, including CD4 cell count ≤500 cells/mm3, progression to AIDS, ED visit, and hospitalization. Missed Appointments was the only measure to predict all primary and secondary outcomes. This finding could be useful to health care providers and public health organizations as they seek ways to optimize the health of HIV patients. PMID:25794182

  4. Frequencies of Circulating MAIT Cells Are Diminished in Chronic HCV, HIV and HCV/HIV Co-Infection and Do Not Recover during Therapy

    PubMed Central

    Spaan, Michelle; Hullegie, Sebastiaan J.; Beudeker, Boris J. B.; Kreefft, Kim; van Oord, Gertine W.; Groothuismink, Zwier M. A.; van Tilborg, Marjolein; Rijnders, Bart; de Knegt, Robert J.; Claassen, Mark A. A.; Boonstra, Andre

    2016-01-01

    Objective Mucosal-associated invariant T (MAIT) cells comprise a subpopulation of T cells that can be activated by bacterial products and cytokines to produce IFN-γ. Since little is known on MAIT cells during HCV infection, we compared their phenotype and function in comparison to HIV and HCV/HIV co-infected patients, and determined the effect of IFN-α-based and direct-acting antiviral therapy on MAIT cells of HCV patients. Methods Blood samples from patients with chronic HCV (CHCV), virologically suppressed HIV, acute HCV/HIV co-infection (AHCV/HIV) and healthy individuals were examined by flowcytometry for phenotype and function of MAIT and NK cells. Results and Conclusions Compared to healthy individuals, the frequency of CD161+Vα7.2+ MAIT cells was significantly decreased in patients with CHCV, HIV and AHCV/HIV co-infection. CD38 expression on MAIT cells was increased in AHCV/HIV patients. MAIT cells were responsive to IFN-α in vitro as evidenced by enhanced frequencies of IFN-γ producing cells. IFN-α-based therapy for CHCV decreased the frequency of IFN-γ+ MAIT cells, which was still observed 24 weeks after successful therapy. Importantly, even after successful IFN-α-based as well as IFN-α-free therapy for CHCV, decreased frequencies of MAIT cells persisted. We show that the frequencies of MAIT cells are reduced in blood of patients with CHCV, HIV and in AHCV/HIV co-infection compared to healthy individuals. Successful therapy for CHCV did not normalize MAIT cell frequencies at 24 weeks follow up. The impact of HIV and HCV infection on the numbers and function of MAIT cells warrant further studies on the impact of viral infections and the antimicrobial function of MAIT cells. PMID:27416100

  5. HIV-1 integrase inhibitor resistance and its clinical implications.

    PubMed

    Blanco, Jose-Luis; Varghese, Vici; Rhee, Soo-Yon; Gatell, Jose M; Shafer, Robert W

    2011-05-01

    With the approval in 2007 of the first integrase inhibitor (INI), raltegravir, clinicians became better able to suppress virus replication in patients infected with human immunodeficiency virus type 1 (HIV-1) who were harboring many of the most highly drug-resistant viruses. Raltegravir also provided clinicians with additional options for first-line therapy and for the simplification of regimens in patients with stable virological suppression. Two additional INIs in advanced clinical development-elvitegravir and S/GSK1349572-may prove equally versatile. However, the INIs have a relatively low genetic barrier to resistance in that 1 or 2 mutations are capable of causing marked reductions in susceptibility to raltegravir and elvitegravir, the most well-studied INIs. This perspective reviews the genetic mechanisms of INI resistance and their implications for initial INI therapy, the treatment of antiretroviral-experienced patients, and regimen simplification. PMID:21459813

  6. 42 CFR 493.919 - Virology.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... 42 Public Health 5 2013-10-01 2013-10-01 false Virology. 493.919 Section 493.919 Public Health CENTERS FOR MEDICARE & MEDICAID SERVICES, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) STANDARDS AND CERTIFICATION LABORATORY REQUIREMENTS Proficiency Testing Programs for Nonwaived Testing Proficiency Testing Programs by Specialty...

  7. 42 CFR 493.919 - Virology.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 42 Public Health 5 2011-10-01 2011-10-01 false Virology. 493.919 Section 493.919 Public Health CENTERS FOR MEDICARE & MEDICAID SERVICES, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) STANDARDS AND CERTIFICATION LABORATORY REQUIREMENTS Proficiency Testing Programs for Nonwaived Testing Proficiency Testing Programs by Specialty...

  8. Estimates of global research productivity in virology.

    PubMed

    Falagas, Matthew E; Karavasiou, Antonia I; Bliziotis, Ioannis A

    2005-06-01

    The quantity and quality of published research in the field of Virology by different world regions was estimated in this study. Using the PubMed database, articles from journals included in the "Virology" category of the "Journal Citation Reports" database of the Institute for Scientific Information for the period 1995-2003 were retrieved. The world was divided into nine regions based on geographic, economic, and scientific criteria. Data on the country of origin of the research was available for 33,425 out of 33,712 articles (99.2% of all articles from the included journals). USA exceeds all other world regions in research production for the period studied (42% of total articles), with Western Europe ranking second (35.7%). The mean impact factor in articles published in Virology journals was highest for the USA (4.60), while it was 3.90 for Western Europe and 3.22 for the rest of the world (seven regions combined). USA and Canada ranked first in research productivity when both gross national income per capita (GNIPC) and population were taken into account. The results of this analysis show a distressing fact; the absolute and relative production of research in the field of Virology by the developing regions is very low, although viral diseases cause considerable morbidity and mortality in these areas. It is evident from this study that developing regions need more help from the developed regions to enhance research infrastructure. PMID:15834885

  9. 42 CFR 493.919 - Virology.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... 42 Public Health 5 2014-10-01 2014-10-01 false Virology. 493.919 Section 493.919 Public Health CENTERS FOR MEDICARE & MEDICAID SERVICES, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) STANDARDS AND CERTIFICATION LABORATORY REQUIREMENTS Proficiency Testing Programs for Nonwaived Testing Proficiency Testing Programs by Specialty...

  10. 42 CFR 493.1265 - Standard: Virology.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 42 Public Health 5 2010-10-01 2010-10-01 false Standard: Virology. 493.1265 Section 493.1265 Public Health CENTERS FOR MEDICARE & MEDICAID SERVICES, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) STANDARDS AND CERTIFICATION LABORATORY REQUIREMENTS Quality System for Nonwaived Testing...

  11. Emerging Role and Characterization of Immunometabolism: Relevance to HIV Pathogenesis, Serious Non-AIDS Events, and a Cure.

    PubMed

    Palmer, Clovis S; Henstridge, Darren C; Yu, Di; Singh, Amit; Balderson, Brad; Duette, Gabriel; Cherry, Catherine L; Anzinger, Joshua J; Ostrowski, Matias; Crowe, Suzanne M

    2016-06-01

    Immune cells cycle between a resting and an activated state. Their metabolism is tightly linked to their activation status and, consequently, functions. Ag recognition induces T lymphocyte activation and proliferation and acquisition of effector functions that require and depend on cellular metabolic reprogramming. Likewise, recognition of pathogen-associated molecular patterns by monocytes and macrophages induces changes in cellular metabolism. As obligate intracellular parasites, viruses manipulate the metabolism of infected cells to meet their structural and functional requirements. For example, HIV-induced changes in immune cell metabolism and redox state are associated with CD4(+) T cell depletion, immune activation, and inflammation. In this review, we highlight how HIV modifies immunometabolism with potential implications for cure research and pathogenesis of comorbidities observed in HIV-infected patients, including those with virologic suppression. In addition, we highlight recently described key methods that can be applied to study the metabolic dysregulation of immune cells in disease states. PMID:27207806

  12. Twelve-Month Antiretroviral Therapy Suppresses Plasma and Genital Viral Loads but Fails to Alter Genital Levels of Cytokines, in a Cohort of HIV-Infected Rwandan Women

    PubMed Central

    Ondoa, Pascale; Gautam, Raju; Rusine, John; Lutter, Rene; Jurriaans, Suzanne; Kootstra, Neeltje; Karita, Etienne; van de Wijgert, Janneke

    2015-01-01

    Background Genital viral load (GVL) is the main determinant of sexual transmission of human immune-deficiency virus (HIV). The effect of antiretroviral therapy (ART) on local cervico-vaginal immunological factors associated with GVL is poorly described. We aimed to identify the risk factors of detectable GVL, and the impact of ART on HIV genital shedding and its correlates in a cohort of HIV-infected women, attending HIV care in Kigali, Rwanda. Materials and Methods All participants were evaluated for GVL, plasma viral load (PVL), CD4 count, various sexually-transmitted infections (STIs) at baseline and at month 12. Genital concentration of 19 cytokines and mRNA expression of APOBEC3G and BST2, two host HIV restriction factors, were evaluated at baseline in all participants. Cytokine levels were re-assessed at month 12 only in participants eligible for ART at baseline. Risk factors of GVL ≥40copies/mL at baseline and month 12 were assessed using logistic regression. Effect of 12-month ART on various local and systemic immunological parameters was examined using a paired t-test and McNemar as appropriate. Results 96 of the 247 women enrolled in the study were eligible for ART. After 12 months of ART, PVL and GVL decreased to undetectable level in respectively 74 and 88% of treated participants. ART did not affect cytokine levels. HIV genital shedding occurred only when PVL was detectable. At baseline, GVL was independently associated with IL-1β after controlling for PVL, age and N. gonorrhea infection (95% CI 1.32-2.15) and at month 12 with MIP-1β (95% CI 0.96-21.32) after controlling for baseline GVL, PVL and month 12 IL-8. Conclusion Suppressive ART does not necessarily reduce genital level of immune activation. Minimizing all conditions favoring genital inflammation, including active detection and treatment of STIs, might reduce the risk of HIV transmission as supplement to the provision of potent ART. PMID:26010956

  13. Virologic response and breakthrough in chronic hepatitis B Egyptian patients receiving lamivudine therapy

    PubMed Central

    Ismail, Sohair; Hafez, Hanan Abdel; Darweesh, Samar K.; Kamal, Kamal Hassan; Esmat, Gamal

    2014-01-01

    Background Lamivudine monotherapy is effective in suppressing hepatitis B virus (HBV) replication to undetectable levels by PCR, in ameliorating liver disease and to some extent in achieving HBsAg seroconversion. This study aimed at assessing the virological and biochemical responses as well as breakthrough in HBeAg-negative chronic HBV (CHB) Egyptian patients receiving lamivudine therapy. Methods This retrospective study included 140 CHB patients with positive serum HBV-DNA by quantitative PCR assays and negative HBeAg who had never received prior anti-viral therapy for HBV. According to duration of lamivudine therapy (100 mg/day) patients were grouped into: group I (n=59) who received lamivudine for 1 year, group II (n=50) who received lamivudine for 2 years, and group III (n=31) who received lamivudine for 3 years. Results In group I, 76.3% patients had virologic response but this was reduced in group II and group III to 72% and 67.7% respectively. None of the patients in group I developed virologic breakthrough, whereas 12% and 25.8% in groups II and III respectively developed breakthrough. In group I, 25% of patients having high pre-treatment viremia showed virologic response compared to 84.6% and 83.3% having mild and moderate viremia respectively (P<0.01). However, in groups II and III, there was no significant relationship between pre-treatment viremia and virologic response. No significant relationship was found between pre-treatment viral load and incidence of breakthrough within each group. Conclusion Lamivudine remains one of the antiviral therapies for HBeAg negative CHB patients. The rates of maintained virologic and biochemical responses to lamivudine decrease in time due to selection of drug-resistant mutants and, hence, breakthrough. PMID:25331321

  14. Prediction of virologic response to tenofovir mono-rescue therapy for multidrug resistant chronic hepatitis B.

    PubMed

    Lee, Sangheun; Park, Jun Yong; Kim, Do Young; Kim, Beom Kyung; Kim, Seung Up; Song, Kijun; Ku, Hye Jin; Han, Kwang-Hyub; Ahn, Sang Hoon

    2016-06-01

    Most guidelines suggest combination therapy including nucleoside and nucleotide analogues for the treatment of chronic hepatitis B (CHB) with multidrug resistance (MD-R). However, long-term combination treatment can evoke high costs and safety problems. Therefore, we investigated the efficacy of tenofovir disoproxil fumarate (TDF) mono-rescue therapy for viral suppression in patients with CHB exhibiting MD-R. We reviewed patients with CHB exhibiting antiviral drug resistance treated by TDF mono-rescue therapy from December 2012 to June 2014. The patients were categorized into three groups: lamivudine-resistance (LAM-R) group (n = 290), and LAM-R + adefovir-resistance (ADV-R) group (n = 43), and LAM-R + entecavir-resistance (ETV-R) group (n = 113). We compared the virologic response rate according to the multiplicity of resistance and investigated the predictive factors of a virologic response. For a median of 15 months (range, 6-24 months) of TDF mono-rescue therapy, the cumulative virologic response rates were 82.8, 81.4, and 84.1% in the LAM-R, LAM-R + ADV-R, and LAM-R + ETV-R groups, respectively (P = 0.239). Multivariate analysis revealed that multiplicity of resistance did not influence the achievement of a virologic response (P = 0.218). However, the baseline HBV DNA level significantly influenced the achievement of a virologic response for the treatment of CHB with MD-R (P < 0.001). TDF mono-rescue therapy is an appropriate treatment for CHB with MD-R, and the baseline HBV DNA level is a significant predictive factor for a virologic response. These factors should be considered before treating CHB with MD-R. J. Med. Virol. 88:1027-1034, 2016. © 2015 Wiley Periodicals, Inc. PMID:26538234

  15. Burden of HIV Infection Among Children Aged 18 Months to 14 Years in Kenya: Results From a Nationally Representative Population-Based Cross-sectional Survey

    PubMed Central

    Ng’eno, Bernadette; Mwangi, Ann; Ng’ang’a, Lucy; Kim, Andrea A.; Waruru, Anthony; Mukui, Irene; Ngugi, Evelyn W.; Rutherford, George W.

    2016-01-01

    Backgrounds In Kenya, mathematical models estimate that there are approximately 220,000 children aged less than 15 years infected with HIV. We analyzed data from the second Kenya AIDS Indicator Survey (KAIS 2012) to estimate the prevalence of HIV infection among children aged 18 months to 14 years. Methods KAIS 2012 was a nationally representative 2-stage cluster sample household survey. We studied children aged 18 months to 14 years whose parents or guardians answered questions pertaining to their children by interview. Blood specimens were collected for HIV serology and viral load measurement. Results We identified 5162 children who were eligible for the study. Blood was obtained for 3681 (71.3%) children. Among child participants, 16.4% had been tested for HIV infection in the past, and among children with parents or guardians who self-reported HIV-positive status, 52.9% had been tested for HIV infection. Twenty-eight (0.9%) children tested HIV-positive in the survey. Of these, 11 had been previously diagnosed with HIV infection before the survey. All 11 children were in HIV care and receiving cotrimoxazole; 8 were on antiretorivral therapy (ART). Among those on ART, 4 were virologically suppressed. Conclusions HIV causes a substantial burden of disease in the Kenyan pediatric population. Although most children who had been diagnosed with HIV before the survey were engaged in care and treatment, they represented less than half of HIV-infected children identified in the survey. Future efforts should focus on identifying infected children and getting them into care and on suppressive ART as early as possible. PMID:24732823

  16. Comparative virology and AIDS (review).

    PubMed

    Kodama, M; Kodama, T

    1996-03-01

    The scientific debate between pros and cons of the HIV criminal theory of AIDS still remains unsettled. The purpose of this review is to promote resolution of the problem by extracting a common principle of the host-virus relation using data resources for each of 4 viruses as follows: a) polyoma virus, b) Marek's disease virus, c) Ebola virus, d) Korean hemorrhagic fever virus. Conclusions drawn from this study are given as follows: i) Environment emerged as the cardinal factor to modify the process of virus infection in all of the 4 viruses studied. Above all, an accelerating effect of environmental stress on the progression of virus infection was noted in vivo in the majority of viral diseases. ii) Evidence is available to indicate that a healthy cell (or a healthy individual) may harbor virus genes of multiple species without manifesting any pathologic sign. iii) Evidence also suggests that the biological property as well as morphological structure of a virus may vary in reponse to a change of the bioenvironment. On the basis of the above information, we propose to renounce 2 assumptions of classical infection model: a) the hereditarily determined virulence of a microorganism (including virus) be the sole determinant of infection to the effect that its invasion into the host should automatically complete the programmed course of infection; b) virus, a quasi-living creature, should reserve its behavioral independence irrespective of a change of the bioenvironment. The new infection model was constructed on the basis of the selfish gene concept that had been invented by Richard Dawkins to explain the altruistic behavior of an individual. That is, the fate of an exogenous or endogenous virus is under the dual control of the host genome (selfish gene) and the outer environment. The progression of virus infection is conditioned by a crosstalk between them. The selfish gene may use virus (a lifeless substance) as a magic bullet to induce a designated host response. In

  17. HIV treatment as prevention: the key to an AIDS-free generation.

    PubMed

    Hull, Mark W; Montaner, Julio S G

    2013-12-01

    The presence of elevated HIV viral load within blood and genital secretions is a critical driver of transmission events. Long-term suppression of viral load to undetectable levels through the use of antiretroviral therapy is now standard practice for clinical management of HIV. Antiretroviral therapy therefore can play a key role as a means to curb HIV transmission. Results of a randomized clinical trial, in conjunction with several observational studies, have now confirmed that antiretroviral therapy markedly decreases HIV transmission risk. Mathematical models and population-based ecologic studies suggest that further expansion of antiretroviral coverage within current guidelines can play a major role in controlling the spread of HIV. Expansion of so-called "Treatment as Prevention" initiatives relies upon maximal uptake of the HIV continuum-of-care cascade to allow for successful identification of those not yet known to be HIV-infected, engagement of patients in appropriate care, and subsequently achieving sustained virologic suppression in patients with the use of antiretroviral therapy. Since 2010, the Joint United Nations AIDS (UNAIDS) program has called for the inclusion of antiretroviral treatment as a key pillar in the global strategy to control the spread of HIV infection. This has now been invigorated by the release of the World Health Organization's 2013 Consolidated Antiretroviral Therapy Guidelines, recommending treatment to be offered to all HIV-infected individuals with CD4 cell counts below 500/mm(3), and, regardless of CD4 cell count, to serodiscordant couples, TB and HBV co-infected individuals, pregnant women, and children below the age of 5 years. PMID:25214752

  18. Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Alafenamide: A Review in HIV-1 Infection.

    PubMed

    Greig, Sarah L; Deeks, Emma D

    2016-06-01

    Tenofovir alafenamide (tenofovir AF) is a novel oral prodrug of the nucleos(t)ide reverse transcriptase inhibitor (NRTI) tenofovir that has several pharmacological advantages over tenofovir disoproxil fumarate (tenofovir DF), including increased plasma stability and reduced tenofovir systemic exposure. Tenofovir AF has been coformulated with elvitegravir, cobicistat and emtricitabine as a once-daily, single-tablet regimen (elvitegravir/cobicistat/emtricitabine/tenofovir AF; Genvoya(®)) for the treatment of adults and adolescents with HIV-1 infection. With regard to establishing and/or maintaining virological suppression over 48 weeks in randomized, phase III trials, elvitegravir/cobicistat/emtricitabine/tenofovir AF was noninferior to elvitegravir/cobicistat/emtricitabine/tenofovir DF in antiretroviral therapy (ART)-naive adults, and statistically superior (subsequent to established noninferiority) to ongoing treatment with tenofovir DF-containing regimens in ART-experienced adults with virological suppression. In single-arm, phase III trials, elvitegravir/cobicistat/emtricitabine/tenofovir AF also provided high rates of virological suppression among ART-naive adolescents and ART-experienced adults with stable renal impairment. In general, elvitegravir/cobicistat/emtricitabine/tenofovir AF was well tolerated and associated with more favourable renal and bone parameters, but a less favourable lipid profile, than tenofovir DF-containing regimens. Thus, elvitegravir/cobicistat/emtricitabine/tenofovir AF is an alternative single-tablet regimen for adults and adolescents with HIV-1 infection, particularly those with an estimated creatinine clearance of ≥30 to <50 mL/min or an increased risk of tenofovir DF-related bone toxicity. PMID:27189707

  19. High-risk oncogenic HPV genotype infection associates with increased immune activation and T cell exhaustion in ART-suppressed HIV-1-infected women.

    PubMed

    Papasavvas, Emmanouil; Surrey, Lea F; Glencross, Deborah K; Azzoni, Livio; Joseph, Jocelin; Omar, Tanvier; Feldman, Michael D; Williamson, Anna-Lise; Siminya, Maureen; Swarts, Avril; Yin, Xiangfan; Liu, Qin; Firnhaber, Cynthia; Montaner, Luis J

    2016-05-01

    Persistence of human papillomavirus (HPV) and cervical disease in the context of HIV co-infection can be influenced by introduction of antiretroviral therapy (ART) and sustained immune activation despite ART. We conducted a cross-sectional study in order to evaluate immune activation/exhaustion in ART-suppressed HIV(+) women with or without high-risk (HR) HPV-related cervical intraepithelial neoplasia (CIN). 55 South African women were recruited in three groups: HR (-) (n = 16) and HR (+) (n = 15) HPV with negative cervical histopathology, and HR (+) HPV with CIN grade 1/2/3 (n = 24). Sampling included endocervical brushing (HPV DNA genotyping), Pap smear (cytology), colposcopic punch biopsy (histopathology, histochemical evaluation of immune cells), and peripheral blood (clinical assessment, flow cytometry-based immune subset characterization). Statistics were done using R2.5.1. Irrespective of the presence of CIN, HR (+) HPV women had higher circulating levels of T cells expressing markers of activation/exhaustion (CD38, PD1, CTLA-4, BTLA, CD160), Tregs, and myeloid subsets expressing corresponding ligands (PDL1, PDL2, CD86, CD40, HVEM) than HR (-) HPV women. A decrease in circulating NK cells was associated with CIN grade. CD4(+) T cell count associated negatively with T cell exhaustion and expression of negative regulators on myeloid cells. Women with CIN when compared to HR (-) HPV women, had higher cervical cell density in stroma and epithelium for CD4(+), CD68(+), and CD11c(+) cells, and only in stroma for CD8(+) cells. We conclude that in ART-suppressed HIV-infected women with HPV co-infection the levels of T and myeloid cell activation/exhaustion are associated with the presence of HR HPV genotypes. PMID:27467943

  20. The Association of Individual and Systemic Barriers to Optimal Medical Care in People Living with HIV/AIDS (PLWHA) in Miami-Dade County

    PubMed Central

    Wawrzyniak, Andrew J.; Rodríguez, Allan E.; Falcon, Anthony E.; Chakrabarti, Anindita; Parra, Alexa; Park, Jane; Mercogliano, Kathleen; Villamizar, Kira; Kolber, Michael A.; Feaster, Daniel J.; Metsch, Lisa R.

    2015-01-01

    Barriers to retention in HIV care are detrimental to patients’ progress along the HIV continuum of care. Previous literature has focused on individual, client-level barriers and interventions to address them. In contrast, less work has examined the role of system-level barriers on HIV care outcomes. The present study seeks to understand how individual and systemic barriers individually are associated with clinic appointment attendance and virologic suppression in HIV-infected patients attending the largest HIV clinic in Miami-Dade, Florida. In addition, we examined the synergistic effects of these barriers as potential syndemic factors on these health outcomes. Barriers to clinic attendance were determined in a face-to-face study interview with 444 HIV-infected outpatients (187 regular attenders, 191 irregular attenders, 66 non-attenders) identified from electronic medical records. Compared to the other attendance groups, non-attenders had higher viral loads, were less likely to be virologically suppressed, had lower CD4 counts, had higher depressive symptoms, life chaos, lower quality of life, and higher rates of food insecurity and recent drug use. Additionally, non-attenders compared to regular attenders had lower physician relationship ratings, had lower medical information clarity, and more often reported transportation as a barrier to clinic attendance. When viewed as a syndemic, compared to patients not reporting any barriers, patients with three or more individual-level barriers were more likely to have a detectable viral load (OR = 3.60, 95%CI [1.71, 7.61]). Our findings suggest that patients presenting to the clinic with multiple barriers should be prioritized for assistance and future interventions to improve retention in care. Interventions should address multiple individual and system level barriers simultaneously with particular attention to addressing depressive symptoms, organizational skills, relationship with the physician, and HIV

  1. Association of individual and systemic barriers to optimal medical care in people living with HIV/AIDS in Miami-Dade County.

    PubMed

    Wawrzyniak, Andrew J; Rodríguez, Allan E; Falcon, Anthony E; Chakrabarti, Anindita; Parra, Alexa; Park, Jane; Mercogliano, Kathleen; Villamizar, Kira; Kolber, Michael A; Feaster, Daniel J; Metsch, Lisa R

    2015-05-01

    Barriers to retention in HIV care are detrimental to patients' progress along the HIV continuum of care. Previous literature has focused on individual, client-level barriers, and interventions to address them. In contrast, less work has examined the role of system-level barriers on HIV care outcomes. This study seeks to understand how individual and systemic barriers individually are associated with clinic appointment attendance and virologic suppression in HIV-infected patients attending the largest HIV clinic in Miami-Dade, FL. In addition, we examined the synergistic effects of these barriers as potential syndemic factors on these health outcomes. Barriers to clinic attendance were determined in a face-to-face study interview with 444 HIV-infected outpatients (187 regular attenders, 191 irregular attenders, and 66 nonattenders) identified from electronic medical records. Compared with the other attendance groups, nonattenders had higher viral loads, were less likely to be virologically suppressed, had lower CD4 counts, had higher depressive symptoms, life chaos, lower quality of life, and higher rates of food insecurity, and recent drug use. Additionally, nonattenders compared with regular attenders had lower physician relationship ratings, had lower medical information clarity and more often reported transportation as a barrier to clinic attendance. When viewed as a syndemic, compared with patients not reporting any barriers, patients with 3 or more individual-level barriers were more likely to have a detectable viral load (odds ratio = 3.60, 95% CI: 1.71 to 7.61). Our findings suggest that patients presenting to the clinic with multiple barriers should be prioritized for assistance and future interventions to improve retention in care. Interventions should address multiple individual and system-level barriers simultaneously with particular attention to addressing depressive symptoms, organizational skills, relationship with the physician, and HIV

  2. Elevated Plasma Viral Loads in Romidepsin-Treated Simian Immunodeficiency Virus-Infected Rhesus Macaques on Suppressive Combination Antiretroviral Therapy.

    PubMed

    Del Prete, Gregory Q; Oswald, Kelli; Lara, Abigail; Shoemaker, Rebecca; Smedley, Jeremy; Macallister, Rhonda; Coalter, Vicky; Wiles, Adam; Wiles, Rodney; Li, Yuan; Fast, Randy; Kiser, Rebecca; Lu, Bing; Zheng, Jim; Alvord, W Gregory; Trubey, Charles M; Piatak, Michael; Deleage, Claire; Keele, Brandon F; Estes, Jacob D; Hesselgesser, Joseph; Geleziunas, Romas; Lifson, Jeffrey D

    2016-03-01

    Replication-competent human immunodeficiency virus (HIV) persists in infected people despite suppressive combination antiretroviral therapy (cART), and it represents a major obstacle to HIV functional cure or eradication. We have developed a model of cART-mediated viral suppression in simian human immunodeficiency virus (SIV) mac239-infected Indian rhesus macaques and evaluated the impact of the histone deacetylase inhibitor (HDACi) romidepsin (RMD) on viremia in vivo. Eight macaques virologically suppressed to clinically relevant levels (<30 viral RNA copies/ml of plasma), using a three-class five-drug cART regimen, received multiple intravenous infusions of either RMD (n = 5) or saline (n = 3) starting 31 to 54 weeks after cART initiation. In vivo RMD treatment resulted in significant transient increases in acetylated histone levels in CD4(+) T cells. RMD-treated animals demonstrated plasma viral load measurements for each 2-week treatment cycle that were significantly higher than those in saline control-treated animals during periods of treatment, suggestive of RMD-induced viral reactivation. However, plasma virus rebound was indistinguishable between RMD-treated and control-treated animals for a subset of animals released from cART. These findings suggest that HDACi drugs, such as RMD, can reactivate residual virus in the presence of suppressive antiviral therapy and may be a valuable component of a comprehensive HIV functional cure/eradication strategy. PMID:26711758

  3. HIV Drug Resistance Mutations in Proviral DNA from a Community Treatment Program

    PubMed Central

    Derache, Anne; Shin, Hyoung-Shik; Balamane, Maya; White, Elizabeth; Israelski, Dennis; Klausner, Jeffrey D.; Freeman, Alexandra H.; Katzenstein, David

    2015-01-01

    Background Drug resistance mutations archived in resting memory CD4+ cells may persist despite suppression of HIV RNA to <50 copies/ml. We sequenced pol gene from proviral DNA among viremic and suppressed patients to identify drug resistance mutations. Methods The Peninsula AIDS Research Cohort study enrolled and followed over 2 years 120 HIV infected patients from San Mateo and San Francisco Counties. HIV-1 pol genotyping by bulk sequencing was performed on 38 DNA and RNA from viremic patients and DNA only among 82 suppressed patients at baseline. Antiretroviral susceptibility was predicted by HIVDB.stanford.edu. Results Among 120 subjects, 81% were on antiretroviral therapy and had been treated for a median time of 7 years. Thirty-two viremic patients showed concordant RNA and DNA genotypes (84%); the discordant profiles were mainly observed in patients with low-level viremia. Among suppressed patients, 21 had drug resistance mutations in proviral DNA (26%) with potential resistance to one, two or three ARV classes in 16, 4 and 1 samples respectively. Conclusions The high level of genotype concordance between DNA and RNA in viremic patients suggested that DNA genotyping might be used to assess drug resistance in resource-limited settings, and further investigation of extracted DNA from dried blood spots is needed. Drug resistance mutations in proviral DNA in 26% of subjects with less than 50 copies/ml pose a risk for the transmission of drug resistant virus with virologic failure, treatment interruption or decreased adherence. PMID:25635815

  4. Innate Lymphoid Cells Are Depleted Irreversibly during Acute HIV-1 Infection in the Absence of Viral Suppression.

    PubMed

    Kløverpris, Henrik N; Kazer, Samuel W; Mjösberg, Jenny; Mabuka, Jenniffer M; Wellmann, Amanda; Ndhlovu, Zaza; Yadon, Marisa C; Nhamoyebonde, Shepherd; Muenchhoff, Maximilian; Simoni, Yannick; Andersson, Frank; Kuhn, Warren; Garrett, Nigel; Burgers, Wendy A; Kamya, Philomena; Pretorius, Karyn; Dong, Krista; Moodley, Amber; Newell, Evan W; Kasprowicz, Victoria; Abdool Karim, Salim S; Goulder, Philip; Shalek, Alex K; Walker, Bruce D; Ndung'u, Thumbi; Leslie, Alasdair

    2016-02-16

    Innate lymphoid cells (ILCs) play a central role in the response to infection by secreting cytokines crucial for immune regulation, tissue homeostasis, and repair. Although dysregulation of these systems is central to pathology, the impact of HIV-1 on ILCs remains unknown. We found that human blood ILCs were severely depleted during acute viremic HIV-1 infection and that ILC numbers did not recover after resolution of peak viremia. ILC numbers were preserved by antiretroviral therapy (ART), but only if initiated during acute infection. Transcriptional profiling during the acute phase revealed upregulation of genes associated with cell death, temporally linked with a strong IFN acute-phase response and evidence of gut barrier breakdown. We found no evidence of tissue redistribution in chronic disease and remaining circulating ILCs were activated but not apoptotic. These data provide a potential mechanistic link between acute HIV-1 infection, lymphoid tissue breakdown, and persistent immune dysfunction. PMID:26850658

  5. Single-Cell Genomics for Virology.

    PubMed

    Ciuffi, Angela; Rato, Sylvie; Telenti, Amalio

    2016-01-01

    Single-cell sequencing technologies, i.e., single cell analysis followed by deep sequencing investigate cellular heterogeneity in many biological settings. It was only in the past year that single-cell sequencing analyses has been applied in the field of virology, providing new ways to explore viral diversity and cell response to viral infection, which are summarized in the present review. PMID:27153082

  6. Single-Cell Genomics for Virology

    PubMed Central

    Ciuffi, Angela; Rato, Sylvie; Telenti, Amalio

    2016-01-01

    Single-cell sequencing technologies, i.e., single cell analysis followed by deep sequencing investigate cellular heterogeneity in many biological settings. It was only in the past year that single-cell sequencing analyses has been applied in the field of virology, providing new ways to explore viral diversity and cell response to viral infection, which are summarized in the present review. PMID:27153082

  7. Early antiretroviral therapy in children perinatally infected with HIV: a unique opportunity to implement immunotherapeutic approaches to prolong viral remission.

    PubMed

    Klein, Nigel; Palma, Paolo; Luzuriaga, Katherine; Pahwa, Savita; Nastouli, Eleni; Gibb, Diane M; Rojo, Pablo; Borkowsky, William; Bernardi, Stefania; Zangari, Paola; Calvez, Vincent; Compagnucci, Alexandra; Wahren, Britta; Foster, Caroline; Munoz-Fernández, María Ángeles; De Rossi, Anita; Ananworanich, Jintanat; Pillay, Deenan; Giaquinto, Carlo; Rossi, Paolo

    2015-09-01

    From the use of antiretroviral therapy to prevent mother-to-child transmission to the possibility of HIV cure hinted at by the Mississippi baby experience, paediatric HIV infection has been pivotal to our understanding of HIV pathogenesis and management. Daily medication and indefinite antiretroviral therapy is recommended for children infected with HIV. Maintenance of life-long adherence is difficult and the incidence of triple-class virological failure after initiation of antiretroviral therapy increases with time. This challenge shows the urgent need to define novel strategies to provide long-term viral suppression that will allow safe interruption of antiretroviral therapy without viral rebound and any associated complications. HIV-infected babies treated within a few days of birth have a unique combination of a very small pool of integrated viruses, a very high proportion of relatively HIV resistant naive T cells, and an unparalleled capacity to regenerate an immune repertoire. These features make this group the optimum model population to investigate the potential efficacy of immune-based therapies. If successful, these investigations could change the way we manage HIV infection. PMID:26187030

  8. Association of Neisseria gonorrhoeae Opa(CEA) with dendritic cells suppresses their ability to elicit an HIV-1-specific T cell memory response.

    PubMed

    Yu, Qigui; Chow, Edith M C; McCaw, Shannon E; Hu, Ningjie; Byrd, Daniel; Amet, Tohti; Hu, Sishun; Ostrowski, Mario A; Gray-Owen, Scott D

    2013-01-01

    Infection with Neisseria gonorrhoeae (N. gonorrhoeae) can trigger an intense local inflammatory response at the site of infection, yet there is little specific immune response or development of immune memory. Gonococcal surface epitopes are known to undergo antigenic variation; however, this is unlikely to explain the weak immune response to infection since individuals can be re-infected by the same serotype. Previous studies have demonstrated that the colony opacity-associated (Opa) proteins on the N. gonorrhoeae surface can bind human carcinoembryonic antigen-related cellular adhesion molecule 1 (CEACAM1) on CD4⁺ T cells to suppress T cell activation and proliferation. Interesting in this regard, N. gonorrhoeae infection is associated with impaired HIV-1 (human immunodeficiency virus type 1)-specific cytotoxic T-lymphocyte (CTL) responses and with transient increases in plasma viremia in HIV-1-infected patients, suggesting that N. gonorrhoeae may also subvert immune responses to co-pathogens. Since dendritic cells (DCs) are professional antigen presenting cells (APCs) that play a key role in the induction of an adaptive immune response, we investigated the effects of N. gonorrhoeae Opa proteins on human DC activation and function. While morphological changes reminiscent of DC maturation were evident upon N. gonorrhoeae infection, we observed a marked downregulation of DC maturation marker CD83 when the gonococci expressing CEACAM1-specific Opa(CEA), but not other Opa variants. Consistent with a gonococcal-induced defect in maturation, Opa(CEA) binding to CEACAM1 reduced the DCs' capacity to stimulate an allogeneic T cell proliferative response. Moreover, Opa(CEA)-expressing N. gonorrhoeae showed the potential to impair DC-dependent development of specific adaptive immunity, since infection with Opa(CEA)-positive gonococci suppressed the ability of DCs to stimulate HIV-1-specific memory CTL responses. These results reveal a novel mechanism to explain why

  9. Prevalence and Outcomes of Recycling NNRTIs Despite Documented NNRTI Resistance in HIV-Infected Children and Youth

    PubMed Central

    Chang, Jennifer Y.; Wiegand, Ryan E.; Wheeling, John T.; Bohannon, Beverly A.; Dominguez, Kenneth L.

    2014-01-01

    Abstract Non-nucleoside reverse transcriptase inhibitors (NNRTIs) are commonly used in pediatric patients; however, rapid development of resistance, due to non-adherence and cross-resistance, results in their discontinuation and limits their recycling. We evaluated the clinical experience of recycling NNRTIs despite documented NNRTI resistance (NNRTI-R), and examined virologic and CD4 cell count outcomes among participants enrolled in Longitudinal Epidemiologic Study to Gain Insight into HIV/AIDS in Children and Youth (LEGACY), a national HIV-infected pediatric cohort. We conducted a retrospective analysis of LEGACY participants with major NNRTI-R. Using chi-square analyses and logistic regression, we examined demographic and clinical factors associated with prescription of NNRTIs despite documented NNRTI-R, and associated changes in plasma HIV RNA viral load and CD4 cell counts. Sixteen of 133 (12%) participants with documented NNRTI-R re-started NNRTIs for a median of 370 days (IQR 105–919) with a median 402 days (IQR 70–841) between documentation of NNRTI-R to NNRTI recycling. Participants recycling NNRTIs were less likely to have documented past non-adherence (40.0% vs. 69.2%; p=0.02). Among twelve patients with virologic data at 24 (±8) weeks; seven (58.3%) experienced virologic suppression while on the recycled NNRTI-based regimens. Of the five who failed to suppress, three with subsequent genotyping developed additional NNRTI-R mutations compromising higher generation NNRTIs. While NNRTI's were recycled in only a small fraction of LEGACY participants harboring NNRTI-R mutations, such recycling increased the risk of inducing further resistance mutations that compromised use of higher generation NNRTIs. PMID:24428795

  10. Relevance of Interleukin-6 and D-Dimer for Serious Non-AIDS Morbidity and Death among HIV-Positive Adults on Suppressive Antiretroviral Therapy

    PubMed Central

    Baker, Jason V; Deeks, Steven G.; Wolfson, Julian; Wentworth, Deborah; Cozzi-Lepri, Alessandro; Cohen, Calvin J.; Phillips, Andrew; Lundgren, Jens D.; Neaton, James D.

    2016-01-01

    Background Despite effective antiretroviral treatment (ART), HIV-positive individuals are at increased risk of serious non-AIDS conditions (cardiovascular, liver and renal disease, and cancers), perhaps due in part to ongoing inflammation and/or coagulation. To estimate the potential risk reduction in serious non-AIDS conditions or death from any cause that might be achieved with treatments that reduce inflammation and/or coagulation, we examined associations of interleukin-6 (IL-6), D-dimer, and high-sensitivity C-reactive protein (hsCRP) levels with serious non-AIDS conditions or death in 3 large cohorts. Methods In HIV-positive adults on suppressive ART, associations of IL-6, D-dimer, and hsCRP levels at study entry with serious non-AIDS conditions or death were studied using Cox regression. Hazard ratios (HR) adjusted for age, gender, study, and regression dilution bias (due to within-person biomarker variability) were used to predict risk reductions in serious non-AIDS conditions or death associated with lower “usual” levels of IL-6 and D-dimer. Results Over 4.9 years of mean follow-up, 260 of the 3766 participants experienced serious non-AIDS conditions or death. IL-6, D-dimer and hsCRP were each individually associated with risk of serious non-AIDS conditions or death, HR = 1.45 (95% CI: 1.30 to 1.63), 1.28 (95% CI: 1.14 to 1.44), and 1.17 (95% CI: 1.09 to 1.26) per 2x higher biomarker levels, respectively. In joint models, IL-6 and D-dimer were independently associated with serious non-AIDS conditions or death, with consistent results across the 3 cohorts and across serious non-AIDS event types. The association of IL-6 and D-dimer with serious non-AIDS conditions or death was graded and persisted throughout follow-up. For 25% lower “usual” IL-6 and D-dimer levels, the joint biomarker model estimates a 37% reduction (95% CI: 28 to 46%) in the risk of serious non-AIDS conditions or death if the relationship is causal. Conclusions Both IL-6 and D

  11. HIV-1 suppression and durable control by combining single broadly neutralizing antibodies and antiretroviral drugs in humanized mice

    PubMed Central

    Horwitz, Joshua A.; Halper-Stromberg, Ariel; Mouquet, Hugo; Gitlin, Alexander D.; Tretiakova, Anna; Eisenreich, Thomas R.; Malbec, Marine; Gravemann, Sophia; Billerbeck, Eva; Dorner, Marcus; Büning, Hildegard; Schwartz, Olivier; Knops, Elena; Kaiser, Rolf; Seaman, Michael S.; Wilson, James M.; Rice, Charles M.; Ploss, Alexander; Bjorkman, Pamela J.; Klein, Florian; Nussenzweig, Michel C.

    2013-01-01

    Effective control of HIV-1 infection in humans is achieved using combinations of antiretroviral therapy (ART) drugs. In humanized mice (hu-mice), control of viremia can be achieved using either ART or by immunotherapy using combinations of broadly neutralizing antibodies (bNAbs). Here we show that treatment of HIV-1–infected hu-mice with a combination of three highly potent bNAbs not only resulted in complete viremic control but also led to a reduction in cell-associated HIV-1 DNA. Moreover, lowering the initial viral load by coadministration of ART and immunotherapy enabled prolonged viremic control by a single bNAb after ART was withdrawn. Similarly, a single injection of adeno-associated virus directing expression of one bNAb produced durable viremic control after ART was terminated. We conclude that immunotherapy reduces plasma viral load and cell-associated HIV-1 DNA and that decreasing the initial viral load enables single bNAbs to control viremia in hu-mice. PMID:24043801

  12. Brief Report: Apparent Antiretroviral Overadherence by Pill Count is Associated With HIV Treatment Failure in Adolescents.

    PubMed

    Okatch, Harriet; Beiter, Kaylin; Eby, Jessica; Chapman, Jennifer; Marukutira, Tafireyi; Tshume, Ontibile; Matshaba, Mogomotsi; Anabwani, Gabriel M; Gross, Robert; Lowenthal, Elizabeth

    2016-08-15

    Pill counts with calculated adherence percentages are used in many settings to monitor adherence, but can be undermined by patients discarding pills to hide nonadherence. Pill counts suggesting that >100% of prescribed doses were taken can signal "pill dumping." We defined "overadherence" among a cohort of 300 HIV-infected adolescents as having greater than one-third of pill counts with >100% adherence during a year of follow-up. Apparent overadherence was more common in those with virologic failure than in those with suppressed viral loads (33% vs 13%, χ P = 0.001). Pill count adherence repeatedly >100% may identify HIV-infected adolescents at increased risk of treatment failure. PMID:26990822

  13. Genotypic Changes in Human Immunodeficiency Virus Type 1 Associated with Loss of Suppression of Plasma Viral RNA Levels in Subjects Treated with Ritonavir (Norvir) Monotherapy

    PubMed Central

    Eastman, P. Scott; Mittler, John; Kelso, Reed; Gee, Chris; Boyer, Eric; Kolberg, Janice; Urdea, Mickey; Leonard, John M.; Norbeck, Daniel W.; Mo, Hongmei; Markowitz, Martin

    1998-01-01

    Ten subjects received 600 to 1,200 mg of the human immunodeficiency virus type 1 (HIV-1) protease inhibitor ritonavir per day. Following 2 weeks of therapy, plasma HIV RNA levels decreased by a mean of 1.57 (range, 0.89 to 1.96) log units. With continued therapy, HIV RNA levels began to rise in eight subjects. The initial rise in plasma RNA levels was temporally associated with the development and quantitative increase in the V82 resistance mutation. Doubling times of the V82A mutant virus were estimated to be 2.4 to 4.8 days. An L63P/A mutation was commonly present at baseline even in subjects with a durable virologic response. The concomitant acquisition of an L63P/A mutation with the V82A/F mutation at the time when plasma RNA levels rebounded suggests a role for the L63P/A mutation in improving the fitness of the V82A/F mutation. Subsequent additional genotypic changes at codons 54 and 84 were often associated with further increases in plasma RNA levels. Ongoing viral replication in the presence of drugs resulted in the appearance of additional genotypic changes, including the L90M saquinavir resistance mutation, and decreased phenotypic susceptibility. The relative fitness of the protease V82A ritonavir resistance mutation and reverse transcriptase T215Y/F zidovudine resistance mutation following drug withdrawal were estimated to be 96 to 98% that of the wild type. Durability of the virologic response was associated with plasma RNA levels at the nadir. A virologic response beyond 60 days was not observed unless plasma HIV RNA levels were suppressed below 2,000 copies/ml, consistent with estimates from V82A doubling times for selection of a single resistance mutation to dominate the replicating population. PMID:9573287

  14. Progressive cerebral injury in the setting of chronic HIV infection and antiretroviral therapy.

    PubMed

    Gongvatana, Assawin; Harezlak, Jaroslaw; Buchthal, Steven; Daar, Eric; Schifitto, Giovanni; Campbell, Thomas; Taylor, Michael; Singer, Elyse; Algers, Jeffrey; Zhong, Jianhui; Brown, Mark; McMahon, Deborah; So, Yuen T; Mi, Deming; Heaton, Robert; Robertson, Kevin; Yiannoutsos, Constantin; Cohen, Ronald A; Navia, Bradford

    2013-06-01

    Emerging evidence suggests that CNS injury and neurocognitive impairment persist in the setting of chronic HIV infection and combination antiretroviral therapy (CART). Yet, whether neurological injury can progress in this setting remains uncertain. Magnetic resonance spectroscopy and neurocognitive and clinical assessments were performed over 2 years in 226 HIV-infected individuals on stable CART, including 138 individuals who were neurocognitively asymptomatic (NA). Concentrations of N-acetylaspartate (NAA), creatine (Cr), choline (Cho), myoinositol, and glutamate/glutamine (Glx) were measured in the midfrontal cortex (MFC), frontal white matter (FWM), and basal ganglia (BG). Longitudinal changes in metabolite levels were determined using linear mixed effect models, as were metabolite changes in relation to global neurocognitive function. HIV-infected subjects showed significant annual decreases in brain metabolite levels in all regions examined, including NAA (2.95 %) and Cho (2.61 %) in the FWM; NAA (1.89 %), Cr (1.84 %), Cho (2.19 %), and Glx (6.05 %) in the MFC; and Glx (2.80 %) in the BG. Similar metabolite decreases were observed in the NA and subclinically impaired subgroups, including subjects with virologic suppression in plasma and CSF. Neurocognitive decline was associated with longitudinal decreases in Glx in the FWM and the BG, and in NAA in the BG. Widespread progressive changes in the brain, including neuronal injury, occur in chronically HIV-infected persons despite stable antiretroviral treatment and virologic suppression and can lead to neurocognitive declines. The basis for these findings is poorly understood and warrants further study. PMID:23613008

  15. High prevalence of low skeletal muscle mass associated with male gender in midlife and older HIV-infected persons despite CD4 cell reconstitution and viral suppression.

    PubMed

    Wasserman, Peter; Segal-Maurer, Sorana; Rubin, David S

    2014-01-01

    Therapeutic goals for HIV-infected patients receiving antiretroviral therapy include minimizing risk of future physical disability. Presarcopenia and sarcopenia precede age-associated physical disability. We investigated their prevalence and the predictive value of patient mid-upper arm circumference (MUAC) for them. Eighty community-dwelling patients ≥45 years old demonstrating durable viral suppression were evaluated. Sarcopenia was defined as low skeletal muscle index (SMI, skeletal muscle kg/height m(2)) and either low strength or poor performance by handgrip dynamometry and gait speed, respectively. Presarcopenia was defined as low SMI only. MUAC was interpreted according to National Health Statistics percentile. Prevalence of sarcopenia and presarcopenia was 5.0% and 20.0%, respectively. Male gender (odds ratio [OR] 10.72; P < .026), recreational psychoactive substance use (OR 5.13; P < .037), and intravenous drug use transmission category (OR 6.94; P <.0327) were associated with presarcopenia. Higher body mass index (OR 0.80; P < .0007), MUAC (OR 0.83; P < .024), and large skeletal frame (OR 0.09; P < .003) were negatively associated with presarcopenia. Finding that a participant did not have a MUAC <25th percentile on physical examination had a 90.4% negative predictive value for presarcopenia. Although sarcopenia was uncommon, presarcopenia was highly prevalent in midlife and older HIV-infected males. Determination of MUAC percentile may identify those least likely to demonstrate skeletal muscle deficit and improve patient selection for mass and function testing. PMID:24067494

  16. 'I Know that I Do Have HIV but Nobody Saw Me': Oral HIV Self-Testing in an Informal Settlement in South Africa.

    PubMed

    Martínez Pérez, Guillermo; Cox, Vivian; Ellman, Tom; Moore, Ann; Patten, Gabriela; Shroufi, Amir; Stinson, Kathryn; Van Cutsem, Gilles; Ibeto, Maryrene

    2016-01-01

    Reaching universal HIV-status awareness is crucial to ensure all HIV-infected patients access antiretroviral treatment (ART) and achieve virological suppression. Opportunities for HIV testing could be enhanced by offering self-testing in populations that fear stigma and discrimination when accessing conventional HIV Counselling and Testing (HCT) in health care facilities. This qualitative research aims to examine the feasibility and acceptability of unsupervised oral self-testing for home use in an informal settlement of South Africa. Eleven in-depth interviews, two couple interviews, and two focus group discussions were conducted with seven healthcare workers and thirteen community members. Thematic analysis was done concurrently with data collection. Acceptability to offer home self-testing was demonstrated in this research. Home self-testing might help this population overcome barriers to accepting HCT; this was particularly expressed in the male and youth groups. Nevertheless, pilot interventions must provide evidence of potential harm related to home self-testing, intensify efforts to offer quality counselling, and ensure linkage to HIV/ART-care following a positive self-test result. PMID:27044006

  17. ‘I Know that I Do Have HIV but Nobody Saw Me’: Oral HIV Self-Testing in an Informal Settlement in South Africa

    PubMed Central

    Cox, Vivian; Ellman, Tom; Moore, Ann; Patten, Gabriela; Shroufi, Amir; Stinson, Kathryn; Van Cutsem, Gilles

    2016-01-01

    Reaching universal HIV-status awareness is crucial to ensure all HIV-infected patients access antiretroviral treatment (ART) and achieve virological suppression. Opportunities for HIV testing could be enhanced by offering self-testing in populations that fear stigma and discrimination when accessing conventional HIV Counselling and Testing (HCT) in health care facilities. This qualitative research aims to examine the feasibility and acceptability of unsupervised oral self-testing for home use in an informal settlement of South Africa. Eleven in-depth interviews, two couple interviews, and two focus group discussions were conducted with seven healthcare workers and thirteen community members. Thematic analysis was done concurrently with data collection. Acceptability to offer home self-testing was demonstrated in this research. Home self-testing might help this population overcome barriers to accepting HCT; this was particularly expressed in the male and youth groups. Nevertheless, pilot interventions must provide evidence of potential harm related to home self-testing, intensify efforts to offer quality counselling, and ensure linkage to HIV/ART-care following a positive self-test result. PMID:27044006

  18. Adoption of the chronic care model to improve HIV care

    PubMed Central

    Tu, David; Belda, Patricia; Littlejohn, Doreen; Pedersen, Jeanette Somlak; Valle-Rivera, Juan; Tyndall, Mark

    2013-01-01

    Abstract Objective To measure the effectiveness of implementing the chronic care model (CCM) in improving HIV clinical outcomes. Design Multisite, prospective, interventional cohort study. Setting Two urban community health centres in Vancouver and Prince George, BC. Participants Two hundred sixty-nine HIV-positive patients (18 years of age or older) who received primary care at either of the study sites. Intervention Systematic implementation of the CCM during an 18-month period. Main outcome measures Documented pneumococcal vaccination, documented syphilis screening, documented tuberculosis screening, antiretroviral treatment (ART) status, ART status with undetectable viral load, CD4 cell count of less than 200 cells/mL, and CD4 cell count of less than 200 cells/mL while not taking ART compared during a 36-month period. Results Overall, 35% of participants were women and 59% were aboriginal persons. The mean age was 45 years and most participants had a history of injection drug use that was the presumed route of HIV transmission. During the study follow-up period, 39 people died, and 11 transferred to alternate care providers. Compared with their baseline clinical status, study participants showed statistically significant (P < .001 for all) increases in pneumococcal immunization (54% vs 84%), syphilis screening (56% vs 91%), tuberculosis screening (23% vs 38%), and antiretroviral uptake (47% vs 77%), as well as increased viral load suppression rates among those receiving ART (72% vs 90%). Stable housing at baseline was associated with a 4-fold increased probability of survival. Aboriginal ethnicity was not associated with better or worse outcomes at baseline or at follow-up. Conclusion Application of the CCM approach to HIV care in a marginalized, largely aboriginal patient population led to improved disease screening, immunization, ART uptake, and virologic suppression rates. In addition to addressing underlying social determinants of health, a paradigm shift

  19. Impact of HIV-1 tropism on the emergence of non-AIDS events in HIV-infected patients receiving fully suppressive antiretroviral therapy

    PubMed Central

    Maffongelli, Gaetano; Alteri, Claudia; Gentilotti, Elisa; Bertoli, Ada; Ricciardi, Alessandra; Malagnino, Vincenzo; Svicher, Valentina; Santoro, Maria M.; Dori, Luca; Perno, Carlo F.; Andreoni, Massimo; Sarmati, Loredana

    2016-01-01

    Objective: The impact of HIV-1 tropism on the emergence of non-AIDS events was evaluated in a cohort of 116 antiretroviral therapy (ART) responder patients. Methods: The patients were followed for the emergence of hypertension, renal impairment, metabolic and bone disorders (defined as non-AIDS events) each 8 weeks at standard visits. A V3 plasma sequence genotype analysis was performed at the time of ART initiation and the geno2pheno algorithm with the results that defines the false-positive rate (FPR) was used to infer HIV tropism. The associations between the non-AIDS events and the FPR at baseline were evaluated using the χ2 test for trend. A Cox-regression analysis using the counting process formulation of Andersen and Gill was performed to define whether the emergence of non-AIDS events was correlated to FPR. Results: The prevalence of at least one non-AIDS event resulted higher in patients with a FPR below 10% than in patients with a R5 virus (P = 0.033). Patients with a FPR below 5.0% most frequently developed non-AIDS events during ART (P = 0.01). A higher prevalence of patients with at least two AIDS events was found in the group of patients with a FPR below 5.0% with respect to the others (P < 0.001). At multivariate Cox-regression analysis, having an X4 virus and age were independently associated with a higher probability of non-AIDS event development. Conclusion: This study shows that an X4 virus, particularly a FPR less than 5%, is related to non-AIDS events development. Further studies are warranted to understand the mechanisms underlying this phenomenon. PMID:26595543

  20. Predicting virological decay in patients starting combination antiretroviral therapy

    PubMed Central

    2016-01-01

    Objective: Model trajectories of viral load measurements from time of starting combination antiretroviral therapy (cART), and use the model to predict whether patients will achieve suppressed viral load (≤200 copies/ml) within 6-months of starting cART. Design: Prospective cohort study including HIV-positive adults (UK Collaborative HIV Cohort Study). Methods: Eligible patients were antiretroviral naive and started cART after 1997. Random effects models were used to estimate viral load trends. Patients were randomly selected to form a validation dataset with those remaining used to fit the model. We evaluated predictions of suppression using indices of diagnostic test performance. Results: Of 9562 eligible patients 6435 were used to fit the model and 3127 for validation. Mean log10 viral load trajectories declined rapidly during the first 2 weeks post-cART, moderately between 2 weeks and 3 months, and more slowly thereafter. Higher pretreatment viral load predicted steeper declines, whereas older age, white ethnicity, and boosted protease inhibitor/non-nucleoside reverse transcriptase inhibitors based cART-regimen predicted a steeper decline from 3 months onwards. Specificity of predictions and the diagnostic odds ratio substantially improved when predictions were based on viral load measurements up to the 4-month visit compared with the 2 or 3-month visits. Diagnostic performance improved when suppression was defined by two consecutive suppressed viral loads compared with one. Conclusions: Viral load measurements can be used to predict if a patient will be suppressed by 6-month post-cART. Graphical presentations of this information could help clinicians decide the optimum time to switch treatment regimen during the first months of cART. PMID:27124894

  1. Ability of Two Commercially Available Assays (Abbott RealTime HIV-1 and Roche Cobas AmpliPrep/Cobas TaqMan HIV-1 Version 2.0) To Quantify Low HIV-1 RNA Levels (<1,000 Copies/Milliliter): Comparison with Clinical Samples and NIBSC Working Reagent for Nucleic Acid Testing Assays

    PubMed Central

    Marsella, Patrizia; Bloisi, Maria; Forbici, Federica; Angeletti, Claudio; Capobianchi, Maria R.

    2014-01-01

    Concordance between molecular assays may be suboptimal at low HIV-1 viremia levels (<1,000 copies/ml); therefore, it may be difficult to define and compare virologic endpoints for successful and failed therapy. We compared two commercial assays (the Abbott RealTime HIV-1 and the Roche Cobas AmpliPrep/TaqMan HIV-1 version 2.0) for their ability to detect and quantify low viral loads. A comparison was performed using 167 residual clinical samples (with values ranging from “not detected” to 1,000 copies/ml, as measured by the Abbott assay) and the National Institute and Biological Standards and Control (NIBSC) HIV-1 RNA working reagent 1 for nucleic acid amplification techniques (NAT) assays (serially diluted to a range from 1 to 1,000 copies/ml). Quantitative results were compared using Lin's concordance correlation coefficient and a Bland-Altman plot. Concordance with the qualitative results was measured by Cohen's kappa statistic. With clinical samples, the degree of interassay concordance of the qualitative results at a 40-copies/ml HIV-1 RNA threshold was substantial (κ = 0.762); the correlation among the quantified samples was suboptimal (concordance correlation coefficient, 0.728; P < 0.0001); the mean difference of the values between the Roche and Abbott assays was 0.193 log10 copies/ml. Using the HIV-1 RNA working reagent 1 for NAT assays, the results provided by the Roche assay were, on average, 3 times higher than expected, while the Abbott assay showed high accuracy. The Roche assay was highly sensitive, being able to detect a level as low as 3.5 copies/ml HIV-1 RNA with 95% probability. The performance characteristics of each molecular assay should be taken into account when HIV-1 RNA threshold values for “virologic suppression,” “virologic failure,” “persistent low viral loads,” etc., are defined and indicated in the support of clinical decisions. PMID:24671791

  2. Raman spectroscopy: the gateway into tomorrow's virology.

    PubMed

    Lambert, Phelps J; Whitman, Audy G; Dyson, Ossie F; Akula, Shaw M

    2006-01-01

    In the molecular world, researchers act as detectives working hard to unravel the mysteries surrounding cells. One of the researchers' greatest tools in this endeavor has been Raman spectroscopy. Raman spectroscopy is a spectroscopic technique that measures the unique Raman spectra for every type of biological molecule. As such, Raman spectroscopy has the potential to provide scientists with a library of spectra that can be used to unravel the makeup of an unknown molecule. However, this technique is limited in that it is not able to manipulate particular structures without disturbing their unique environment. Recently, a novel technology that combines Raman spectroscopy with optical tweezers, termed Raman tweezers, evades this problem due to its ability to manipulate a sample without physical contact. As such, Raman tweezers has the potential to become an incredibly effective diagnostic tool for differentially distinguishing tissue, and therefore holds great promise in the field of virology for distinguishing between various virally infected cells. This review provides an introduction for a virologist into the world of spectroscopy and explores many of the potential applications of Raman tweezers in virology. PMID:16805914

  3. Raman spectroscopy: the gateway into tomorrow's virology

    PubMed Central

    Lambert, Phelps J; Whitman, Audy G; Dyson, Ossie F; Akula, Shaw M

    2006-01-01

    In the molecular world, researchers act as detectives working hard to unravel the mysteries surrounding cells. One of the researchers' greatest tools in this endeavor has been Raman spectroscopy. Raman spectroscopy is a spectroscopic technique that measures the unique Raman spectra for every type of biological molecule. As such, Raman spectroscopy has the potential to provide scientists with a library of spectra that can be used to unravel the makeup of an unknown molecule. However, this technique is limited in that it is not able to manipulate particular structures without disturbing their unique environment. Recently, a novel technology that combines Raman spectroscopy with optical tweezers, termed Raman tweezers, evades this problem due to its ability to manipulate a sample without physical contact. As such, Raman tweezers has the potential to become an incredibly effective diagnostic tool for differentially distinguishing tissue, and therefore holds great promise in the field of virology for distinguishing between various virally infected cells. This review provides an introduction for a virologist into the world of spectroscopy and explores many of the potential applications of Raman tweezers in virology. PMID:16805914

  4. Synthetic Virology: Engineering Viruses for Gene Delivery

    PubMed Central

    Guenther, Caitlin M.; Kuypers, Brianna E.; Lam, Michael T.; Robinson, Tawana M.; Zhao, Julia; Suh, Junghae

    2014-01-01

    The success of gene therapy relies heavily on the performance of vectors that can effectively deliver transgenes to desired cell populations. As viruses have evolved to deliver genetic material into cells, a prolific area of research has emerged over the last several decades to leverage the innate properties of viruses as well as to engineer new features into them. Specifically, the field of synthetic virology aims to capitalize on knowledge accrued from fundamental virology research in order to design functionally enhanced gene delivery vectors. The enhanced viral vectors, or “bionic” viruses, feature engineered components, or “parts”, that are natural (intrinsic to viruses or from other organisms) and synthetic (such as man-made polymers or inorganic nanoparticles). Various design strategies – rational, combinatorial, and pseudo-rational – have been pursued to create the hybrid viruses. The gene delivery vectors of the future will likely criss-cross the boundaries between natural and synthetic domains to harness the unique strengths afforded by the various functional parts that can be grafted onto virus capsids. Such research endeavours will further expand and enable enhanced control over the functional capacity of these nanoscale devices for biomedicine. PMID:25195922

  5. Paediatric Virology in the Hippocratic Corpus

    PubMed Central

    Mammas, Ioannis N.; Spandidos, Demetrios A.

    2016-01-01

    Hippocrates (Island of Kos, 460 B.C.-Larissa, 370 B.C.) is the founder of the most famous Medical School of the classical antiquity. In acknowledgement of his pioneering contribution to the new scientific field of Paediatric Virology, this article provides a systematic analysis of the Hippocratic Corpus, with particular focus on viral infections predominating in neonates and children. A mumps epidemic, affecting the island of Thasos in the 5th century B.C., is described in detail. ‘Herpes’, a medical term derived from the ancient Greek word ‘ἕρπειν’, meaning ‘to creep’ or ‘crawl’, is used to describe the spreading of cutaneous lesions in both childhood and adulthood. Cases of children with exanthema ‘resembling mosquito bites’ are presented in reference to varicella or smallpox infection. A variety of upper and lower respiratory tract viral infections are described with impressive accuracy, including rhinitis, pharyngitis, tonsillitis, laryngitis, bronchiolitis and bronchitis. The ‘cough of Perinthos’ epidemic, an influenza-like outbreak in the 5th century B.C., is also recorded and several cases complicated with pneumonia or fatal outcomes are discussed. Hippocrates, moreover, describes conjunctivitis, otitis, lymphadenitis, meningoencephalitis, febrile convulsions, gastroenteritis, hepatitis, poliomyelitis and skin warts, along with proposed treatment directions. Almost 2,400 years later, Hippocrates' systematic approach and methodical innovations can inspire paediatric trainees and future Paediatric Virology subspecialists. PMID:27446241

  6. End-Stage Renal Disease Among HIV-Infected Adults in North America

    PubMed Central

    Abraham, Alison G.; Althoff, Keri N.; Jing, Yuezhou; Estrella, Michelle M.; Kitahata, Mari M.; Wester, C. William; Bosch, Ronald J.; Crane, Heidi; Eron, Joseph; Gill, M. John; Horberg, Michael A.; Justice, Amy C.; Klein, Marina; Mayor, Angel M.; Moore, Richard D.; Palella, Frank J.; Parikh, Chirag R.; Silverberg, Michael J.; Golub, Elizabeth T.; Jacobson, Lisa P.; Napravnik, Sonia; Lucas, Gregory M.; Kirk, Gregory D.; Benson, Constance A.; Bosch, Ronald J.; Collier, Ann C.; Boswell, Stephen; Grasso, Chris; Mayer, Ken; Hogg, Robert S.; Harrigan, Richard; Montaner, Julio; Cescon, Angela; Brooks, John T.; Buchacz, Kate; Gebo, Kelly A.; Moore, Richard D.; Moore, Richard D.; Carey, John T.; Rodriguez, Benigno; Horberg, Michael A.; Silverberg, Michael J.; Thorne, Jennifer E.; Goedert, James J.; Jacobson, Lisa P.; Klein, Marina B.; Rourke, Sean B.; Burchell, Ann; Rachlis, Anita R.; Hunter-Mellado, Robert F.; Mayor, Angel M.; Gill, M. John; Deeks, Steven G.; Martin, Jeffrey N.; Saag, Michael S.; Mugavero, Michael J.; Willig, James; Eron, Joseph J.; Napravnik, Sonia; Kitahata, Mari M.; Crane, Heidi M.; Justice, Amy C.; Dubrow, Robert; Fiellin, David; Sterling, Timothy R.; Haas, David; Bebawy, Sally; Turner, Megan; Gange, Stephen J.; Anastos, Kathryn; Moore, Richard D.; Saag, Michael S.; Gange, Stephen J.; Althoff, Keri N.; Kitahata, Mari M.; McKaig, Rosemary G.; Justice, Amy C.; Freeman, Aimee M.; Moore, Richard D.; Freeman, Aimee M.; Lent, Carol; Kitahata, Mari M.; Van Rompaey, Stephen E.; Crane, Heidi M.; Webster, Eric; Morton, Liz; Simon, Brenda; Gange, Stephen J.; Althoff, Keri N.; Abraham, Alison G.; Lau, Bryan; Zhang, Jinbing; Jing, Jerry; Golub, Elizabeth; Modur, Shari; Hanna, David B.; Rebeiro, Peter; Wong, Cherise; Mendes, Adell

    2015-01-01

    Background. Human immunodeficiency virus (HIV)-infected adults, particularly those of black race, are at high-risk for end-stage renal disease (ESRD), but contributing factors are evolving. We hypothesized that improvements in HIV treatment have led to declines in risk of ESRD, particularly among HIV-infected blacks. Methods. Using data from the North American AIDS Cohort Collaboration for Research and Design from January 2000 to December 2009, we validated 286 incident ESRD cases using abstracted medical evidence of dialysis (lasting >6 months) or renal transplant. A total of 38 354 HIV-infected adults aged 18–80 years contributed 159 825 person-years (PYs). Age- and sex-standardized incidence ratios (SIRs) were estimated by race. Poisson regression was used to identify predictors of ESRD. Results. HIV-infected ESRD cases were more likely to be of black race, have diabetes mellitus or hypertension, inject drugs, and/or have a prior AIDS-defining illness. The overall SIR was 3.2 (95% confidence interval [CI], 2.8–3.6) but was significantly higher among black patients (4.5 [95% CI, 3.9–5.2]). ESRD incidence declined from 532 to 303 per 100 000 PYs and 138 to 34 per 100 000 PYs over the time period for blacks and nonblacks, respectively, coincident with notable increases in both the prevalence of viral suppression and the prevalence of ESRD risk factors including diabetes mellitus, hypertension, and hepatitis C virus coinfection. Conclusions. The risk of ESRD remains high among HIV-infected individuals in care but is declining with improvements in virologic suppression. HIV-infected black persons continue to comprise the majority of cases, as a result of higher viral loads, comorbidities, and genetic susceptibility. PMID:25409471

  7. Immune activation and IL-12 production during acute/early HIV infection in the absence and presence of highly active, antiretroviral therapy.

    PubMed

    Byrnes, Adriana A; Harris, David M; Atabani, Sowsan F; Sabundayo, Beulah P; Langan, Susan J; Margolick, Joseph B; Karp, Christopher L

    2008-12-01

    Suppressed IL-12 production and maladaptive immune activation, both of which are ameliorated by successful highly active antiretroviral therapy (HAART), are thought to play important roles in the immunopathogenesis of chronic HIV infection. Despite the important effects of the immunological and virological events of early HIV infection on subsequent disease progression, IL-12 production and immune activation in early infection remain under-defined. To quantify IL-12 production and immune activation during acute/early HIV infection, in the presence and absence of HAART, we performed a prospective, longitudinal study of participants in the Baltimore site of the Acute Infection and Early Disease Research Program, with cross-sectional comparison to healthy control subjects. PBMC cytokine productive capacity and plasma immune activation markers [soluble CD8 (sCD8), sCD4, granzyme B, neopterin, beta2-microglobulin, sIL-2R, sTNFRI, sTNFRII, and IL-12p70] were quantified by ELISA. Notably, PBMC from patients with acute/early HIV infection exhibited in vivo IL-12p70 production along with increased, maximal in vitro IL-12 production. Further, despite evidence from plasma markers of generalized immune activation, no elevation in plasma levels of sCD4 was observed, suggesting relative blunting of in vivo CD4+ T cell activation from the beginning of HIV infection. Finally, despite successful virological responses to HAART, heightened in vivo CD8+ T cell activation, IL-12 production, and IFN activity were sustained for at least 6 months during primary HIV infection. These data underscore the need for comparative mechanistic analysis of the immunobiology of early and chronic HIV infection. PMID:18806124

  8. Retention in Early Care at an HIV Outpatient Clinic in Rio de Janeiro, Brazil, 2000-2013.

    PubMed

    Silva, Daniel S; De Boni, Raquel B; Lake, Jordan E; Cardoso, Sandra W; Ribeiro, Sayonara; Moreira, Ronaldo I; Clark, Jesse L; Veloso, Valdilea G; Grinsztejn, Beatriz; Luz, Paula M

    2016-05-01

    Retention in early HIV care has been associated with virologic suppression and improved survival, but remains understudied in Brazil. We estimated retention in early HIV care for the period 2000-2013, and identified socio-demographic and clinical factors associated with good retention in an urban cohort from Rio de Janeiro, Brazil. Antiretroviral therapy-naïve, HIV-infected persons ≥18 years old linked to care between 2000 and 2011 were included. Retention in the first 2 years post-linkage (i.e. early care) was defined by the proportion of 6-month intervals with ≥1 HIV laboratory result. "Good" retention was defined as ≥1 HIV laboratory result recorded in at least three intervals. Overall, 80 % of participants met criteria for good retention and retention significantly improved over the study period. Older age, higher education level and early antiretroviral therapy initiation were associated with good retention. Efforts to improve retention in early care in this population should target younger and less-educated HIV-infected persons. PMID:26525222

  9. CD4 criteria improves the sensitivity of a clinical algorithm developed to identify viral failure in HIV-positive patients on antiretroviral therapy

    PubMed Central

    Evans, Denise H; Fox, Matthew P; Maskew, Mhairi; McNamara, Lynne; MacPhail, Patrick; Mathews, Christopher; Sanne, Ian

    2014-01-01

    Introduction Several studies from resource-limited settings have demonstrated that clinical and immunologic criteria are poor predictors of virologic failure, confirming the need for viral load monitoring or at least an algorithm to target viral load testing. We used data from an electronic patient management system to develop an algorithm to identify patients at risk of viral failure using a combination of accessible and inexpensive markers. Methods We analyzed data from HIV-positive adults initiated on antiretroviral therapy (ART) in Johannesburg, South Africa, between April 2004 and February 2010. Viral failure was defined as ≥2 consecutive HIV-RNA viral loads >400 copies/ml following suppression ≤400 copies/ml. We used Cox-proportional hazards models to calculate hazard ratios (HR) and 95% confidence intervals (CI). Weights for each predictor associated with virologic failure were created as the sum of the natural logarithm of the adjusted HR and dichotomized with the optimal cut-off at the point with the highest sensitivity and specificity (i.e. ≤4 vs. >4). We assessed the diagnostic accuracy of predictor scores cut-offs, with and without CD4 criteria (CD4 <100 cells/mm3; CD4 < baseline; >30% drop in CD4), by calculating the proportion with the outcome and the observed sensitivity, specificity, positive and negative predictive value of the predictor score compared to the gold standard of virologic failure. Results We matched 919 patients with virologic failure (1:3) to 2756 patients without. Our predictor score included variables at ART initiation (i.e. gender, age, CD4 count <100 cells/mm3, WHO stage III/IV and albumin) and laboratory and clinical follow-up data (drop in haemoglobin, mean cell volume (MCV) <100 fl, CD4 count <200 cells/mm3, new or recurrent WHO stage III/IV condition, diagnosis of new condition or symptom and regimen change). Overall, 51.4% had a score 51.4% had a score ≥4 and 48.6% had a score <4. A predictor score including CD4

  10. Treatment intensification with maraviroc (CCR5 antagonist) leads to declines in CD16-expressing monocytes in cART-suppressed chronic HIV-infected subjects and is associated with improvements in neurocognitive test performance: implications for HIV-associated neurocognitive disease (HAND)

    PubMed Central

    Ndhlovu, Lishomwa C.; Umaki, Tracie; Chew, Glen M.; Chow, Dominic C.; Agsalda, Melissa; Kallianpur, Kalpana J.; Paul, Robert; Zhang, Guangxiang; Ho, Erika; Hanks, Nancy; Nakamoto, Beau; Shiramizu, Bruce T.; Shikuma, Cecilia M.

    2014-01-01

    HIV-associated neurocognitive disorders (HAND) continues to be prevalent (30–50 %) despite plasma HIVRNA suppression with combination antiretroviral therapy (cART). There is no proven therapy for individuals on suppressive cARTwith HAND. We have shown that the degree of HIV reservoir burden (HIV DNA) in monocytes appear to be linked to cognitive outcomes. HIV infection of monocytes may therefore be critical in the pathogenesis of HAND. A single arm, open-labeled trial was conducted to examine the effect of maraviroc (MVC) intensification on monocyte inflammation and neuropsychological (NP) performance in 15 HIV subjects on stable 6-month cART with undetectable plasma HIV RNA (<48 copies/ml) and detectable monocyte HIV DNA (>10 copies/106 cells). MVC was added to their existing cART regimen for 24 weeks. Post-intensification change in monocytes was assessed using multiparametric flow cytometry, monocyte HIV DNA content by PCR, soluble CD163 (sCD163) by an ELISA, and NP performance over 24 weeks. In 12 evaluable subjects, MVC intensification resulted in a decreased proportion of circulating intermediate (median; 3.06 % (1.93, 6.45) to 1.05 % (0.77, 2.26)) and nonclassical (5.2 % (3.8, 7.9) to 3.2 % (1.8, 4.8)) CD16-expressing monocytes, a reduction in monocyte HIV DNA content to zero log10 copies/106 cells and in levels of sCD163 of 43 % by 24 weeks. This was associated with significant improvement in NP performance among six subjects who entered the study with evidence of mild to moderate cognitive impairment. The results of this study suggest that antiretroviral therapy with potency against monocytes may have efficacy against HAND. PMID:25227930

  11. The effect of efavirenz versus nevirapine-containing regimens on immunologic, virologic and clinical outcomes in a prospective observational study

    PubMed Central

    2013-01-01

    Objective To compare regimens consisting of either efavirenz or nevirapine and two or more nucleoside reverse transcriptase inhibitors (NRTIs) among HIV-infected, antiretroviral-naive, and AIDS-free individuals with respect to clinical, immunologic, and virologic outcomes. Design Prospective studies of HIV-infected individuals in Europe and the US included in the HIV-CAUSAL Collaboration. Methods Antiretroviral therapy-naive and AIDS-free individuals were followed from the time they started an NRTI, efavirenz or nevirapine, classified as following one or both types of regimens at baseline, and censored when they started an ineligible drug or at 6 months if their regimen was not yet complete. We estimated the ‘intention-to-treat’ effect for nevirapine versus efavirenz regimens on clinical, immunologic, and virologic outcomes. Our models included baseline covariates and adjusted for potential bias introduced by censoring via inverse probability weighting. Results A total of 15 336 individuals initiated an efavirenz regimen (274 deaths, 774 AIDS-defining illnesses) and 8129 individuals initiated a nevirapine regimen (203 deaths, 441 AIDS-defining illnesses). The intention-to-treat hazard ratios [95% confidence interval (CI)] for nevirapine versus efavirenz regimens were 1.59 (1.27, 1.98) for death and 1.28 (1.09, 1.50) for AIDS-defining illness. Individuals on nevirapine regimens experienced a smaller 12-month increase in CD4 cell count by 11.49 cells/μl and were 52% more likely to have virologic failure at 12 months as those on efavirenz regimens. Conclusions Our intention-to-treat estimates are consistent with a lower mortality, a lower incidence of AIDS-defining illness, a larger 12-month increase in CD4 cell count, and a smaller risk of virologic failure at 12 months for efavirenz compared with nevirapine. PMID:22546987

  12. Pharmacy and self-report adherence measures to predict virological outcomes for patients on free antiretroviral therapy in Tamil Nadu, India

    PubMed Central

    McMahon, James H.; Manoharan, Anand; Wanke, Christine A.; Mammen, Shoba; Jose, Hepsibah; Malini, Thabeetha; Kadavanu, Tony; Jordan, Michael R.; Elliott, Julian H.; Lewin, Sharon R.; Mathai, Dilip

    2013-01-01

    Over 480,000 individuals receive free antiretroviral therapy (ART) in India yet data associating ART adherence with HIV viral load for populations exclusively receiving free ART are not available. Additionally estimates of adherence using pharmacy data on ART pick-up are not available for any population in India. After 12-months ART we found self-reported estimates of adherence were not associated with HIV viral load. Individuals with < 100% adherence using pharmacy data predicted HIV viral load, and estimates combining pharmacy data and self-report were also predictive. Pharmacy adherence measures proved a feasible method to estimate adherence in India and appear more predictive of virological outcomes than self-report. Predictive adherence measures identified in this study warrant further investigation in populations receiving free ART in India to allow for identification of individuals at risk of virological failure and in need of adherence support. PMID:23435750

  13. Gender Differences in Psychosocial Factors Associated with HIV Viral Suppression Among African-American Injection Drug Users.

    PubMed

    Robinson, Allysha C; Knowlton, Amy R

    2016-02-01

    Research suggests gender differences exist in achieving undetectable viral load (UVL) among persons living with HIV (PLHIV), and that psychosocial health factors may play a role. The present study examined these factors among African-American PLHIV enrolled in the BEACON study. Participants completed self-report surveys and gave biomarker data. Poisson regression with robust standard errors was implemented. Men with moderate religious activity had 1.3 times the likelihood of UVL as men with low religious activity (p < 0.10; N = 199). Men with 1-2 mental illness diagnoses had 1.3 times the likelihood of UVL as men with none (p < 0.05). Women using 1-2 substances had 28 % lower likelihood of UVL than non-using women (N = 122; p < 0.10). Finally, women with frequent doctor-patient communication had 35 % higher likelihood of UVL as women with less doctor-patient communication (p < 0.05). Results suggest that social support, substance use, and mental illness function differently among men and women. Healthcare professionals should employ gender-specific interventions to address and improve HIV health outcomes. PMID:26143248

  14. Second-line protease inhibitor-based highly active antiretroviral therapy after failing non-nucleoside reverse transcriptase inhibitors-based regimens in Asian HIV-infected children

    PubMed Central

    Bunupuradah, Torsak; Puthanakit, Thanyawee; Fahey, Paul; Kariminia, Azar; Yusoff, Nik Khairulddin Nik; Khanh, Truong Huu; Sohn, Annette H.; Chokephaibulkit, Kulkanya; Lumbiganon, Pagakrong; Hansudewechakul, Rawiwan; Razali, Kamarul; Kurniati, Nia; Huy, Bui Vu; Sudjaritruk, Tavitiya; Kumarasamy, Nagalingeswaran; Fong, Siew Moy; Saphonn, Vonthanak; Ananworanich, Jintanat

    2013-01-01

    Background The WHO recommends boosted protease inhibitor (bPI)-based highly active antiretroviral therapy (HAART) after failing non-nucleoside reverse transcriptase inhibitor (NNRTI) treatment. We examined outcomes of this regimen in Asian HIV-infected children. Methods Children from five Asian countries in the TREAT Asia Pediatric HIV Observational Database (TApHOD) with ≥24 weeks of NNRTI-based HAART followed by ≥24 weeks of bPI-based HAART were eligible. Primary outcomes were the proportions with virologic suppression (HIV-RNA <400 copies/ml) and immune recovery (CD4% ≥25% if age <5 years and CD4 count ≥500 cells/mm3 if age ≥5 years) at 48 and 96 weeks. Results Of 3422 children, 153 were eligible; 52% were female. At switch, median age was 10 years, 26% were in WHO stage 4. Median weight-for-age z-score (WAZ) was −1.9 (n=121), CD4% was 12.5% (n=106), CD4 count was 237 (n=112) cells/mm3, and HIV-RNA was 4.6 log10copies/ml (n=61). The most common PI was lopinavir/ritonavir (83%). At 48 weeks, 61% (79/129) had immune recovery, 60% (26/43) had undetectable HIV-RNA and 73% (58/79) had fasting triglycerides ≥130mg/dl. By 96 weeks, 70% (57/82) achieved immune recovery, 65% (17/26) virologic suppression, and hypertriglyceridemia occurred in 66% (33/50). Predictors for virologic suppression at week 48 were longer duration of NNRTI-based HAART (p=0.006), younger age (p=0.007), higher WAZ (p=0.020), and HIV-RNA at switch <10,000 copies/ml (p=0.049). Conclusion In this regional cohort of Asian children on bPI-based second-line HAART, 60% of children tested had immune recovery by one year, and two-thirds had hyperlipidemia, highlighting difficulties in optimizing second-line HAART with limited drug options. PMID:23296119

  15. Gender-specific risk factors for virologic failure in KwaZulu-Natal: Automobile ownership and financial insecurity

    PubMed Central

    HARE, Anna Q.; ORDÓÑEZ, Claudia E.; JOHNSON, Brent A.; RIO, Carlos DEL; KEARNS, Rachel A.; WU, Baohua; HAMPTON, Jane; WU, Peng; SUNPATH, Henry; MARCONI, Vincent C.

    2014-01-01

    We sought to examine which socioeconomic indicators are risk factors for virologic failure among HIV-1 infected patients receiving antiretroviral therapy in KwaZulu-Natal, South Africa. A case-control study of virologic failure was conducted among patients recruited from the outpatient clinic at McCord Hospital in Durban, South Africa between October 1, 2010 and June 30, 2012. Cases were those failing first-line antiretroviral therapy (ART), defined as viral load > 1000 copies/mL. Univariate logistic regression was performed on sociodemographic data for the outcome of virologic failure. Variables found significant (p<.05) were used in multivariate models and all models were stratified by gender. Of 158 cases and 300 controls, 35% were male and median age was 40 years. Gender stratification of models revealed automobile ownership was a risk factor among males, while variables of financial insecurity (unemployment, non-spouse family paying for care, staying with family) were risk factors for women. In this cohort, financial insecurity among women and automobile ownership among men were risk factors for virologic failure. Risk factor differences between genders demonstrate limitations of generalized risk factor analysis. PMID:25037488

  16. Immune Compromise in HIV-1/HTLV-1 Coinfection With Paradoxical Resolution of CD4 Lymphocytosis During Antiretroviral Therapy: A Case Report.

    PubMed

    Rockwood, N; Cook, L; Kagdi, H; Basnayake, S; Bangham, C R M; Pozniak, A L; Taylor, G P

    2015-12-01

    Human immunodeficiency virus type-1 (HIV-1) and human T lymphotropic virus type-1 (HTLV-1) infections have complex effects on adaptive immunity, with specific tropism for, but contrasting effects on, CD4 T lymphocytes: depletion with HIV-1, proliferation with HTLV-1. Impaired T lymphocyte function occurs early in HIV-1 infection but opportunistic infections (OIs) rarely occur in the absence of CD4 lymphopenia. In the unusual case where a HIV-1 infected individual with a high CD4 count presents with recurrent OIs, a clinician is faced with the possibility of a second underlying comorbidity. We present a case of pseudo-adult T cell leukemia/lymphoma (ATLL) in HIV-1/HTLV-1 coinfection where the individual fulfilled Shimoyama criteria for chronic ATLL and had pulmonary Mycobacterium kansasii, despite a high CD4 lymphocyte count. However, there was no evidence of clonal T-cell proliferation by T-cell receptor gene rearrangement studies nor of monoclonal HTLV-1 integration by high-throughput sequencing. Mutually beneficial interplay between HIV-1 and HTLV-1, maintaining high level HIV-1 and HTLV-1 viremia and proliferation of poorly functional CD4 cells despite chronicity of infection is a postulated mechanism. Despite good microbiological response to antimycobacterial therapy, the patient remained systemically unwell with refractory anemia. Subsequent initiation of combined antiretroviral therapy led to paradoxical resolution of CD4 T lymphocytosis as well as HIV-1 viral suppression and decreased HTLV-1 proviral load. This is proposed to be the result of attenuation of immune activation post-HIV virological control. This case illustrates the importance of screening for HTLV-1 in HIV-1 patients with appropriate clinical presentation and epidemiological risk factors and explores mechanisms for the complex interactions on HIV-1/HTLV-1 adaptive immunity. PMID:26683952

  17. Aptamers in Virology: Recent Advances and Challenges

    PubMed Central

    Binning, Jennifer M.; Leung, Daisy W.; Amarasinghe, Gaya K.

    2012-01-01

    Aptamers generated from randomized libraries of nucleic acids have found utility in a wide variety of fields and in the clinic. Aptamers can be used to target both intracellular and extracellular components, including small molecules, proteins, cells, and viruses. With recent technological developments in stringent selection and rapid isolation strategies, it is likely that aptamers will continue to make an impact as useful tools and reagents. Although many recently developed aptamers are intended for use as therapeutic and diagnostic agents, use of aptamers for basic research, including target validation, remains an active area with high potential to impact our understanding of molecular mechanisms and for drug discovery. In this brief review, we will discuss recent aptamer discoveries, their potential role in structural virology, as well as challenges and future prospects. PMID:22347221

  18. Overview of HIV.

    PubMed

    Klimas, Nancy; Koneru, Anne O'Brien; Fletcher, Mary Ann

    2008-06-01

    This article provides an overview and reviews the HIV pandemic, the basic biology and immunology of the virus (e.g., genetic diversity of HIV and the viral life cycle), the phases of disease progression, modes of HIV transmission, HIV testing, immune response to the infection, and current therapeutic strategies. HIV is occurring in epidemic proportions, especially in Sub-Saharan Africa. In the US, men who have sex with men account for over half of AIDS diagnoses; racial and ethnic minorities are disproportionally affected. Factors influencing the progression and severity of HIV infection include type of immune response, coinfection (e.g., another sexually transmitted infection, including hepatitis B or C), age and behavioral and psychosocial factors. Antiretroviral therapies can achieve reduction in blood levels of the HIV virus below the limits of detection by current technology. However, effective treatment requires adherence to therapy. Patient failure to adhere to treatment regimens results in detectible circulating virus and in HIV disease progression, and is the primary cause of drug resistance. In addition to research on the immunology and virology of the disease, other studies focus on behavioral and psychosocial factors that may affect medication adherence and risk behaviors. PMID:18541903

  19. Transgender women, hormonal therapy and HIV treatment: a comprehensive review of the literature and recommendations for best practices

    PubMed Central

    Radix, Asa; Sevelius, Jae; Deutsch, Madeline B

    2016-01-01

    Introduction Studies have shown that transgender women (TGW) are disproportionately affected by HIV, with an estimated HIV prevalence of 19.1% among TGW worldwide. After receiving a diagnosis, HIV-positive TGW have challenges accessing effective HIV treatment, as demonstrated by lower rates of virologic suppression and higher HIV-related mortality. These adverse HIV outcomes have been attributed to the multiple sociocultural and structural barriers that negatively affect their engagement within the HIV care continuum. Guidelines for feminizing hormonal therapy among TGW recommend combinations of oestrogens and androgen blockers. Pharmacokinetic studies have shown that certain antiretroviral therapy (ART) agents, such as protease inhibitors (PIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs) and cobicistat, interact with ethinyl estradiol, the key oestrogen component of oral contraceptives (OCPs). The goal of this article is to provide an overview of hormonal regimens used by TGW, to summarize the known drug-drug interactions (DDIs) between feminizing hormonal regimens and ART, and to provide clinical care recommendations. Methods The authors identified English language articles examining DDIs between oestrogen therapy, androgen blockers and ART published between 1995 and 2015 using PubMed, Cumulative Index to Nursing and Allied Health Literature and EBSCOhost. Results and Discussion Published articles predominantly addressed interactions between ethinyl estradiol and NNRTIs and PIs. No studies examined interactions between ART and the types and doses of oestrogens found in feminizing regimens. DDIs that may have the potential to result in loss of virologic suppression included ethinyl estradiol and amprenavir, unboosted fosamprenavir and stavudine. No clinically significant DDIs were noted with other anti-retroviral agents or androgen blockers Conclusions There are insufficient data to address DDIs between ART and feminizing hormone regimens used by TGW

  20. Characterizing Class-Specific Exposure-Viral Load Suppression Response of HIV Antiretrovirals Using A Model-Based Meta-Analysis.

    PubMed

    Xu, Y; Li, Y F; Zhang, D; Dockendorf, M; Tetteh, E; Rizk, M L; Grobler, J A; Lai, M-T; Gobburu, J; Ankrom, W

    2016-08-01

    We applied model-based meta-analysis of viral suppression as a function of drug exposure and in vitro potency for short-term monotherapy in human immunodeficiency virus type 1 (HIV-1)-infected treatment-naïve patients to set pharmacokinetic targets for development of nonnucleoside reverse transcriptase inhibitors (NNRTIs) and integrase strand transfer inhibitors (InSTIs). We developed class-specific models relating viral load kinetics from monotherapy studies to potency normalized steady-state trough plasma concentrations. These models were integrated with a literature assessment of doses which demonstrated to have long-term efficacy in combination therapy, in order to set steady-state trough concentration targets of 6.17- and 2.15-fold above potency for NNRTIs and InSTIs, respectively. Both the models developed and the pharmacokinetic targets derived can be used to guide compound selection during preclinical development and to predict the dose-response of new antiretrovirals to inform early clinical trial design. PMID:27171172

  1. Human Immunodeficiency Virus Type 1 Monoclonal Antibodies Suppress Acute Simian-Human Immunodeficiency Virus Viremia and Limit Seeding of Cell-Associated Viral Reservoirs

    PubMed Central

    Pegu, Amarendra; Wang, Keyun; McGinnis, Kathleen; Nason, Martha; Foulds, Kathryn; Letukas, Valerie; Schmidt, Stephen D.; Chen, Xuejun; Todd, John Paul; Lifson, Jeffrey D.; Rao, Srinivas; Michael, Nelson L.; Robb, Merlin L.; Mascola, John R.; Koup, Richard A.

    2015-01-01

    ABSTRACT Combination antiretroviral therapy (cART) administered shortly after human immunodeficiency virus type 1 (HIV-1) infection can suppress viremia and limit seeding of the viral reservoir, but lifelong treatment is required for the majority of patients. Highly potent broadly neutralizing HIV-1 monoclonal antibodies (MAbs) can reduce plasma viremia when administered during chronic HIV-1 infection, but the therapeutic potential of these antibodies during acute infection is unknown. We tested the ability of HIV-1 envelope glycoprotein-specific broadly neutralizing MAbs to suppress acute simian-human immunodeficiency virus (SHIV) replication in rhesus macaques. Four groups of macaques were infected with SHIV-SF162P3 and received (i) the CD4-binding-site MAb VRC01; (ii) a combination of a more potent clonal relative of VRC01 (VRC07-523) and a V3 glycan-dependent MAb (PGT121); (iii) daily cART, all on day 10, just prior to expected peak plasma viremia; or (iv) no treatment. Daily cART was initiated 11 days after MAb administration and was continued for 13 weeks in all treated animals. Over a period of 11 days after a single administration, MAb treatment significantly reduced peak viremia, accelerated the decay slope, and reduced total viral replication compared to untreated controls. Proviral DNA in lymph node CD4 T cells was also diminished after treatment with the dual MAb. These data demonstrate the virological effect of potent MAbs and support future clinical trials that investigate HIV-1-neutralizing MAbs as adjunctive therapy with cART during acute HIV-1 infection. IMPORTANCE Treatment of chronic HIV-1 infection with potent broadly neutralizing HIV-1 MAbs has been shown to significantly reduce plasma viremia. However, the antiviral effect of MAb treatment during acute HIV-1 infection is unknown. Here, we demonstrate that MAbs targeting the HIV-1 envelope glycoprotein both suppress acute SHIV plasma viremia and limit CD4 T cell-associated viral DNA. These

  2. Discordant responses to cART in HIV-1 patients in the era of high potency antiretroviral drugs: clinical evaluation, classification, management prospects.

    PubMed

    Cenderello, Giovanni; De Maria, Andrea

    2016-01-01

    The goal of antiretroviral treatment (ART) in HIV-1 patients is immune reconstitution following control of viral replication. CD4+ cell number/proportions are a crude but essential correlate of immune reconstitution. Despite suppression of HIV replication, a fraction of ART-treated patients still fails to fully reconstitute CD4+ T cell numbers (immunological nonresponders, INRs). New drugs, regimens and treatment strategies led to increased efficacy, lower side effects and higher virological success rates in clinical practice. The multitude of described immune defects and clinical events accompanying INR opposed to the marginal effect of antiretroviral intensification or immunotherapy trials underline the need for continuing efforts at understanding the mechanisms that underlie INR. Here, we reassess INR definition, frequency, and the achievements of active clinical and translational research suggesting a shared definition for insufficient, partial and complete CD4+ cell number recovery thus improving homogeneity in patient selection and mechanism identification. PMID:26513236

  3. Glucose Metabolism in T Cells and Monocytes: New Perspectives in HIV Pathogenesis

    PubMed Central

    Palmer, Clovis S.; Cherry, Catherine L.; Sada-Ovalle, Isabel; Singh, Amit; Crowe, Suzanne M.

    2016-01-01

    Activation of the immune system occurs in response to the recognition of foreign antigens and receipt of optimal stimulatory signals by immune cells, a process that requires energy. Energy is also needed to support cellular growth, differentiation, proliferation, and effector functions of immune cells. In HIV-infected individuals, persistent viral replication, together with inflammatory stimuli contributes to chronic immune activation and oxidative stress. These conditions remain even in subjects with sustained virologic suppression on antiretroviral therapy. Here we highlight recent studies demonstrating the importance of metabolic pathways, particularly those involving glucose metabolism, in differentiation and maintenance of the activation states of T cells and monocytes. We also discuss how changes in the metabolic status of these cells may contribute to ongoing immune activation and inflammation in HIV- infected persons and how this may contribute to disease progression, establishment and persistence of the HIV reservoir, and the development of co-morbidities. We provide evidence that other viruses such as Epstein–Barr and Flu virus also disrupt the metabolic machinery of their host cells. Finally, we discuss how redox signaling mediated by oxidative stress may regulate metabolic responses in T cells and monocytes during HIV infection. PMID:27211546

  4. TB-HIV co-infection: a catastrophic comradeship.

    PubMed

    Narendran, G; Swaminathan, S

    2016-04-01

    The symbiotic association of tuberculosis (TB) and HIV poses a challenge to human survival. HIV complicates every aspect of TB including presentation, diagnosis and treatment. HIV-TB patients encounter unique problems like drug-drug interactions, cumulative toxicity, immune reconstitution inflammatory syndrome (IRIS), lower plasma drug levels and emergence of drug resistance during treatment despite adherence. TB may also be overdiagnosed in HIV due to a number of diseases that closely resemble TB. Notable among them are non-tuberculous mycobacteria, Pneumocystis Jirovecii and Nocardia. Even though diagnostic procedures have improved over the years, patients in developing countries usually seek health care at later stage of the disease. Research data ascertains the duration of therapy for TB to be 6 months with rifampicin and isoniazid, reinforced with ethambutol and pyrazinamide in the first 2 months. The schedule of therapy is still debatable with daily regimens being preferred in the context of HIV. Many reasons exist for persistence of Mycobacterium Tuberculosis (M.TB) in sputum, or delayed-clearance of TB from sputum smears in HIV, apart from emergence of drug resistance and non-compliance. Acquired rifampicin resistance (ARR) is a unique phenomenon complicating HIV-associated TB when an intermittent regimen of antituberculosis therapy (ATT) is used without timely initiation of highly active antiretroviral therapy (HAART), especially in patients harbouring isoniazid-resistant strains Immune restoration is often incomplete ('swiss cheese' pattern) even with effective HAART if not started early. Immune reconstitution inflammatory syndrome (IRIS) is the paradoxical worsening of the patient's condition often with radiological deterioration, due to an enhanced immune response with HAART. IRIS occurs despite an effective virological suppression and a favourable response to ATT. The incidence of IRIS in HIV has reached up to 54%, requiring utilization of experts

  5. Virtual support for paediatric HIV treatment decision making

    PubMed Central

    Le Doare, Kirsty; Mackie, N E; Kaye, S; Bamford, A; Walters, S; Foster, C

    2015-01-01

    Objective The objective of this study is to review clinical outcomes of recommendations made by a multidisciplinary paediatric virtual clinic (PVC) for complex case management of paediatric HIV as a model of care within a tertiary network. Design A retrospective review of the clinical outcomes of paediatric and adolescent (0–21 years) referrals to the PVC at St. Mary's Hospital, Imperial College Healthcare NHS Trust, London was performed between October 2009 and November 2013. Results 234 referrals were made for 182 children from 37 centres, discussed in 42 meetings (median age 13 years, IQR 10–15 years). Reasons for referral included virological failure (44%), simplification of the current regimen (24%) and antiretroviral drug complications (24%). At latest follow-up, PVC advice had been instituted in 80% of referrals. Suppression following virological failure was achieved in 48% following first referral and 57% following subsequent discussions and was maintained in 95% of children referred for regimen simplification. Following advice, dyslipidaemia resolved in 42% and liver function normalised in 73% with biochemical hepatitis. Adherence support aided resolution of viraemia in nine children and 12% of referrals resulted in additional support, including psychology, social services and mental health input. Conclusions Combined multidisciplinary virtual input with adult expertise in resistance and newer agents, paediatric knowledge of pill swallowing, childhood formulations/weight banding and parental support, assists complex treatment decision making in paediatric HIV infection. The Virtual Clinic model could be applied to the management of other rare complex diseases of childhood within a clinical network. PMID:25549664

  6. Engagement in HIV care and sexual transmission risk behavior among men who have sex with men using online social/sexual networking in Latin America.

    PubMed

    Magidson, Jessica F; Biello, Katie B; Safren, Steven A; Rosenberger, Joshua G; Novak, David S; Mayer, Kenneth H; Mimiaga, Matthew J

    2015-01-01

    HIV/AIDS in Latin America is concentrated among men who have sex with men (MSM). However, accurate estimates of engagement in HIV care in this population can be difficult to ascertain because many do not self-identify as MSM. Given evidence of decreased HIV transmissibility in the context of antiretroviral therapy (ART) adherence, identifying individuals not in care who are engaging in HIV transmission risk behavior is crucial for secondary prevention. Primary aims of this study were to examine engagement in care from testing to ART adherence among MSM using online social/sexual networking across Latin America, and whether individuals not in care at each step reported greater sexual transmission risk behavior than those in care. In the overall sample (n=28,779), approximately 75% reported ever being tested for HIV, and 9% reported having received an HIV diagnosis. Among known HIV-infected individuals, 20% reported not being in care, 30% reported not taking ART, and 55% reported less than 100% ART adherence. Over one-third of HIV-infected individuals reported sexual HIV transmission risk behavior, defined as unprotected anal intercourse (UAI) with a male partner of different/unknown HIV serostatus in the past three months. HIV-infected individuals not engaged in care more often reported UAI compared to those in care (OR=1.29; 95% CI=1.01-1.66). Although not statistically significant, HIV-infected individuals not on ART more often reported UAI compared to those on ART (OR=1.18; 95% CI=0.94-1.47). Individuals who reported less than 100% ART adherence more often reported UAI compared to individuals with 100% adherence (OR=1.55; 95% CI=1.26-1.90). Findings demonstrate that a substantial portion of HIV-infected MSM in Latin America who are likely not virologically suppressed from lack of ART use or adherence report sexual HIV transmission risk. Tailoring secondary HIV prevention for MSM in Latin America who are not in HIV care or adherent to ART may be warranted. PMID

  7. Levels of circulating myeloid subpopulations and of heme oxygenase-1 do not predict CD4+ T cell recovery after the initiation of antiretroviral therapy for HIV disease

    PubMed Central

    2014-01-01

    The level (or frequency) of circulating monocyte subpopulations such as classical (CD14hiCD16-) and non-classical (CD14dimCD16+) monocytes varies during the course of HIV disease progression and antiretroviral therapy (ART). We hypothesized that such variation and/or differences in the degree to which these cells expressed the immunoregulatory enzyme, heme oxygenase-1 (HO-1), would be associated with CD4+ T cell recovery after the initiation of ART. This hypothesis was tested in a cross-sectional study of four groups of HIV-infected subjects, including those who were seronegative, untreated virologic controllers [detectable viral load (VL) of <1000 copies/mL], untreated virologic non-controllers [VL > 10,000 copies/mL], and ART-mediated virologic controllers [VL < 75 copies/mL]. A longitudinal analysis of ART-treated subjects was also performed along with regression analysis to determine which biomarkers were associated with and/or predictive of CD4+ T cell recovery. Suppressive ART was associated with increased levels of classical monocyte subpopulations (CD14hiCD16-) and decreased levels of non-classical monocyte populations (CD14dimCD16+). Among peripheral blood mononuclear cells (PBMCs), HO-1 was found to be most highly up-regulated in CD14+ monocytes after ex vivo stimulation. Neither the levels of monocyte subpopulations nor of HO-1 expression in CD14+ monocytes were significantly associated with the degree of CD4+ T cell recovery. Monocyte subpopulations and HO-1 gene expression were, however, restored to normal levels by suppressive ART. These results suggest that the level of circulating monocyte subpopulations and their expression of HO-1 have no evident relationship to CD4+ T cell recovery after the initiation of ART. PMID:25180041

  8. Antiretroviral Drugs for Treatment and Prevention of HIV Infection in Adults

    PubMed Central

    Günthard, Huldrych F.; Saag, Michael S.; Benson, Constance A.; del Rio, Carlos; Eron, Joseph J.; Gallant, Joel E.; Hoy, Jennifer F.; Mugavero, Michael J.; Sax, Paul E.; Thompson, Melanie A.; Gandhi, Rajesh T.; Landovitz, Raphael J.; Smith, Davey M.; Jacobsen, Donna M.; Volberding, Paul A.

    2016-01-01

    IMPORTANCE New data and therapeutic options warrant updated recommendations for the use of antiretroviral drugs (ARVs) to treat or to prevent HIV infection in adults. OBJECTIVE To provide updated recommendations for the use of antiretroviral therapy in adults (aged ≥18 years) with established HIV infection, including when to start treatment, initial regimens, and changing regimens, along with recommendations for using ARVs for preventing HIV among those at risk, including preexposure and postexposure prophylaxis. EVIDENCE REVIEW A panel of experts in HIV research and patient care convened by the International Antiviral Society-USA reviewed data published in peer-reviewed journals, presented by regulatory agencies, or presented as conference abstracts at peer-reviewed scientific conferences since the 2014 report, for new data or evidence that would change previous recommendations or their ratings. Comprehensive literature searches were conducted in the PubMed and EMBASE databases through April 2016. Recommendations were by consensus, and each recommendation was rated by strength and quality of the evidence. FINDINGS Newer data support the widely accepted recommendation that antiretroviral therapy should be started in all individuals with HIV infection with detectable viremia regardless of CD4 cell count. Recommended optimal initial regimens for most patients are 2 nucleoside reverse transcriptase inhibitors (NRTIs) plus an integrase strand transfer inhibitor (InSTI). Other effective regimens include nonnucleoside reverse transcriptase inhibitors or boosted protease inhibitors with 2 NRTIs. Recommendations for special populations and in the settings of opportunistic infections and concomitant conditions are provided. Reasons for switching therapy include convenience, tolerability, simplification, anticipation of potential new drug interactions, pregnancy or plans for pregnancy, elimination of food restrictions, virologic failure, or drug toxicities. Laboratory

  9. Evaluating immunologic response and clinical deterioration in treatment-naïve patients initiating first-line therapies infected with HIV-1 CRF01_AE and subtype B

    PubMed Central

    Oyomopito, Rebecca A.; Li, Patrick CK.; Sungkanuparph, Somnuek; Phanuphak, Praphan; Tee, Kok Keng; Sirisanthana, Thira; Kantipong, Pacharee; Oka, Shinichi; Lee, Chris KC.; Kamarulzaman, Adeeba; Choi, Jun Yong; Sohn, Annette H.; Law, Matthew; Chen, Yi-Ming A.

    2012-01-01

    Background HIV-1 group M viruses diverge 25%–35% in envelope, important for viral attachment during infection, and 10–15% in the pol region, under selection pressure from common antiretrovirals. In Asia, subtypes B and CRF01_AE are common genotypes. Our objectives were to determine whether clinical, immunologic or virologic treatment responses differed by genotype in treatment-naïve patients initiating first-line therapy. Methods Prospectively collected, longitudinal data from patients in Thailand, Hong Kong, Malaysia, Japan, Taiwan and South Korea were provided for analysis. Covariates included demographics, hepatitis B and C coinfections, baseline CD4 T lymphocyte count and plasma HIV-1 RNA levels. Clinical deterioration (a new diagnosis of CDC category B/AIDS-defining illness or death) was assessed by proportional hazards models. Surrogate endpoints were 12-month change in CD4 cell count and virologic suppression post-therapy, evaluated by linear and logistic regression, respectively. Results Of 1105 patients, 1036 (93.8%) infected with CRF01_AE or subtype B were eligible for inclusion in clinical deterioration analyses and contributed 1546.7 person-years of follow-up (median:413 days, IQR:169–672 days). Patients >40 years demonstrated smaller immunological increases (p=0.002) and higher risk of clinical deterioration (HR=2.17; p=0.008). Patients with baseline CD4 cell counts >200 cells/μL had lower risk of clinical deterioration (HR=0.373; p=0.003). A total of 532 patients (48.1% of eligible) had CD4 counts available at baseline and 12 months post-therapy for inclusion in immunolgic analyses. Patients infected with subtype B had larger increases in CD4 counts at 12 months (p=0.024). A total of 530 patients (48.0% of eligible) were included in virologic analyses with no differences in response found between genotypes. Conclusions Results suggest that patients infected with CRF01_AE have reduced immunologic response to therapy at 12 months, compared to

  10. A case cluster demonstrating the relationship between HLA concordance and virologic and disease outcomes in human immunodeficiency virus infection.

    PubMed

    Chaillon, A; Gianella, S; Massanella Luna, M; Little, S J; Richman, D D; Mehta, S R

    2014-01-20

    We present a detailed analysis of sexual HIV transmission from one source partner to two recipients. The HLA haplotypes between the source partner and one recipient were very similar with 7 out of 8 HLA alleles from four loci (HLA A, B, C and DRB) shared, while the other recipient shared only one allele. The immunologic outcomes between the two recipients differed dramatically, despite the absence of apparent virologic differences in their inoculums. We suggest that non-viral factors, which might be related to differences in the HLA profile, played a role in determining different CD4+ T-cells dynamics for these two recipients. PMID:24418543

  11. Long-Term Antiretroviral Treatment Initiated at Primary HIV-1 Infection Affects the Size, Composition, and Decay Kinetics of the Reservoir of HIV-1-Infected CD4 T Cells

    PubMed Central

    Buzon, Maria J.; Martin-Gayo, Enrique; Pereyra, Florencia; Ouyang, Zhengyu; Sun, Hong; Li, Jonathan Z.; Piovoso, Michael; Shaw, Amy; Dalmau, Judith; Zangger, Nadine; Martinez-Picado, Javier; Zurakowski, Ryan; Yu, Xu G.; Telenti, Amalio; Walker, Bruce D.; Rosenberg, Eric S.

    2014-01-01

    ABSTRACT Initiation of antiretroviral therapy during the earliest stages of HIV-1 infection may limit the seeding of a long-lasting viral reservoir, but long-term effects of early antiretroviral treatment initiation remain unknown. Here, we analyzed immunological and virological characteristics of nine patients who started antiretroviral therapy at primary HIV-1 infection and remained on suppressive treatment for >10 years; patients with similar treatment duration but initiation of suppressive therapy during chronic HIV-1 infection served as controls. We observed that independently of the timing of treatment initiation, HIV-1 DNA in CD4 T cells decayed primarily during the initial 3 to 4 years of treatment. However, in patients who started antiretroviral therapy in early infection, this decay occurred faster and was more pronounced, leading to substantially lower levels of cell-associated HIV-1 DNA after long-term treatment. Despite this smaller size, the viral CD4 T cell reservoir in persons with early treatment initiation consisted more dominantly of the long-lasting central-memory and T memory stem cells. HIV-1-specific T cell responses remained continuously detectable during antiretroviral therapy, independently of the timing of treatment initiation. Together, these data suggest that early HIV-1 treatment initiation, even when continued for >10 years, is unlikely to lead to viral eradication, but the presence of low viral reservoirs and durable HIV-1 T cell responses may make such patients good candidates for future interventional studies aiming at HIV-1 eradication and cure. IMPORTANCE Antiretroviral therapy can effectively suppress HIV-1 replication to undetectable levels; however, HIV-1 can persist despite treatment, and viral replication rapidly rebounds when treatment is discontinued. This is mainly due to the presence of latently infected CD4 T cells, which are not susceptible to antiretroviral drugs. Starting treatment in the earliest stages of HIV-1

  12. Occurrence of etravirine/rilpivirine-specific resistance mutations selected by efavirenz and nevirapine in Kenyan patients with non-B HIV-1 subtypes failing antiretroviral therapy.

    PubMed

    Crawford, Keith W; Njeru, Dorothy; Maswai, Jonah; Omondi, Milton; Apollo, Duncan; Kimetto, Jane; Gitonga, Lawrence; Munyao, James; Langat, Raphael; Aoko, Appolonia; Tarus, Jemutai; Khamadi, Samoel; Hamm, Tiffany E

    2014-01-28

    Resistance to efavirenz and nevirapine has not been associated with mutations at position 138 of reverse transcriptase. In an evaluation of virologic suppression rates in PEPFAR (President's Emergency Plan For AIDS Relief) clinics in Kenya among patients on first-line therapy (RV288), 63% (617/975) of randomly selected patients on antiretroviral therapy were suppressed (HIV RNA<400 copies/ml). Among those with non-nucleoside reverse transcriptase inhibitor resistance (n = 101), 14 (13.8%) had substitutions at 138 (A, G, K or Q), mutations selected only by etravirine and rilpivirine in subtype B viruses. All 14 patients received efavirenz or nevirapine, not etravirine or rilpivirine, and were predominantly subtype A1. This may be the first report of efavirenz and nevirapine selecting these mutations in these subtypes. PMID:24670527

  13. Kaposi's-sarcoma-associated-herpesvirus-activated dendritic cells promote HIV-1 trans-infection and suppress CD4{sup +} T cell proliferation

    SciTech Connect

    Liu, Wan; Qin, Yan; Bai, Lei; Lan, Ke; Wang, Jian-Hua

    2013-06-05

    Infection of Kaposi's sarcoma-associated herpesvirus (KSHV) is commonly occurred in AIDS patients. KSHV and HIV-1 act cooperatively in regulating infection with each other and in human carcinogenesis. Dendritic cells (DCs), as the pivotal cells in host immunity, may be modulated by both viruses, for immunoevasion and dissemination, therefore, the interaction between DCs and each virus has been a prior focus for pathogenesis elucidation. Here, we assessed the potential effect of KSHV on DC–HIV-1 interaction. We found that KSHV stimulation could promote maturation of monocyte-derived DCs (MDDCs) and impaired the ability of MDDCs to drive proliferation of resting CD4{sup +} T cells, demonstrating the immunosuppression induced by KSHV. More importantly, KSHV-stimulated MDDCs could capture more HIV-1 and efficiently transferred these infectious viruses to Hut/CCR5 T cell line. Our results reveal the novel modulation of DC-mediated HIV-1 dissemination by KSHV, and highlight the importance of studying DC–HIV-1 interaction to elucidate HIV/AIDS pathogenesis. - Highlights: ► KSHV impaired the ability of MDDCs to drive proliferation of resting CD4{sup +} T cells. ► KSHV stimulation matured MDDCs and enhanced HIV-1 endocytosis. ► KSHV stimulated MDDCs increased ICAM-1 expression and tighten contact with T cells. ► KSHV-stimulated MDDCs promoted HIV-1 trans-infection of CD4{sup +} T cells.

  14. Reducing mortality in HIV-infected infants and achieving the 90–90–90 target through innovative diagnosis approaches

    PubMed Central

    Essajee, Shaffiq; Vojnov, Lara; Penazzato, Martina; Jani, Ilesh; Siberry, George K; Fiscus, Susan A; Markby, Jessica

    2015-01-01

    Introduction Despite significant gains in access to early infant diagnosis (EID) over the past decade, most HIV-exposed infants still do not get tested for HIV in the first two months of life. For those who are tested, the long turnaround time between when the sample is drawn and when the results are returned leads to a high rate of loss to follow-up, which in turn means that few infected infants start antiretroviral treatment. Consequently, there continues to be high mortality from perinatally acquired HIV, and the ambitious goals of 90% of infected children identified, 90% of identified children treated and 90% of treated children with sustained virologic suppression by 2020 seem far beyond our reach. The objective of this commentary is to review recent advances in the field of HIV diagnosis in infants and describe how these advances may overcome long-standing barriers to access to testing and treatment. Discussion Several innovative approaches to EID have recently been described. These include point-of-care testing, use of SMS printers to connect the central laboratory and the health facility through a mobile phone network, expanding paediatric testing to other entry points where children access the health system and testing HIV-exposed infants at birth as a rapid way to identify in utero infection. Each of these interventions is discussed here, together with the opportunities and challenges associated with scale-up. Point-of-care testing has the potential to provide immediate results but is less cost-effective in settings where test volumes are low. Virological testing at birth has been piloted in some countries to identify those infants who need urgent treatment, but a negative test at birth does not obviate the need for additional testing at six weeks. Routine testing of infants in child health settings is a useful strategy to identify exposed and infected children whose mothers were not enrolled in programmes for the prevention of mother

  15. Raltegravir and Abacavir/Lamivudine in Japanese Treatment-Naïve and Treatment-Experienced Patients with HIV Infection: a 48-Week Retrospective Pilot Analysis.

    PubMed

    Suzuki, Akihito; Uehara, Yuki; Saita, Mizue; Inui, Akihiro; Isonuma, Hiroshi; Naito, Toshio

    2016-01-01

    Abacavir/lamivudine (ABC/3TC) is a nucleoside reverse transcriptase inhibitor used for treating human immunodeficiency viral (HIV) infections. Hypersensitivity reactions such as skin eruptions caused by ABC are well-known, but rarely occur in Asians. Raltegravir (RAL) is an integrase strand transfer inhibitor, that is now increasingly, used for treating HIV infections because it has few adverse effects. This retrospective analysis assessed the efficacy and safety of combined ABC/3TC and RAL in both treatment-naïve and -experienced Japanese patients with HIV infections. In all 11 treatment-naïve patients (100%), virological suppression to undetectable level was achieved. Liver transaminases, renal function, and serum lipid profiles showed no exacerbations up to 48 weeks of treatment. In 12 patients who were switched from previous regimens to ABC/3TC and RAL, HIV viral load was undetectable in 11 patients (91.6%), but remained detectable in 1 patient with poor adherence. Major reasons for switching regimens to ABC/3TC and RAL were hyperlipidemia and nausea. After switching, these adverse effects improved, and no new adverse effects were observed. Despite the small number of participants in this study, the results support the combination of ABC/3TC and RAL as a possible treatment choice in Japanese individuals with HIV-infection. PMID:25971320

  16. Evaluation of patient care cascade for HIV-positive patients diagnosed in La Romana, Dominican Republic in 2011: a retrospective cohort study.

    PubMed

    Bowman, Alex S; Lerebours, Leonel; Amesty, Silvia; de la Rosa, Milagros; Gil, Elizabeth; Halpern, Mina; Nicholas, Stephen; Lamb, Matthew R

    2016-04-01

    The Caribbean has the highest adult HIV prevalence in the world after sub-Saharan Africa (2011). One sub-population in the Dominican Republic is the migratory Batey community primarily comprised of Haitian immigrants with limited access to healthcare and HIV prevalence rates of between 3.0% and 9.0%, compared to 0.7% nationally. This retrospective cohort study describes the cumulative retention from diagnosis to virological suppression for newly-diagnosed HIV-infected adults presenting to the Clínica de Familia and its Batey programme in La Romana, during 2011. Of the patients diagnosed with HIV, 65% entered into care, 59% completed immunologic testing, 53% were eligible for antiretroviral therapy (ART) initiation, 36% initiated ART within three months of eligibility and 27% were retained in care. Seventeen per cent of those retained on ART with a 12-month viral load measure had undetectable viral load. Attrition primarily occurred before ART initiation. The Batey programme had a first step lost-to-follow-up of 88% compared to 20% at the clinic (p < 0.001). This retrospective study details the continuum of care and indicates where structural changes must occur to increase continuity between steps. The manuscript results are important to help implement programmes to enhance engagement and retention in HIV primary care. PMID:25941055

  17. Tenofovir-based alternate therapies for chronic hepatitis B patients with partial virological response to entecavir.

    PubMed

    Lu, L; Yip, B; Trinh, H; Pan, C Q; Han, S-H B; Wong, C C; Li, J; Chan, S; Krishnan, G; Wong, C C; Nguyen, M H

    2015-08-01

    Entecavir (ETV) is a first-line antiviral therapy for treating chronic hepatitis B (CHB); however, some patients have suboptimal response to ETV. Currently, there are limited data on how to approach these patients. Therefore, our aim was to compare the effectiveness of two alternate therapies--tenofovir (TDF) monotherapy and combination therapy of ETV+TDF--in CHB patients with ETV partial virological response. We conducted a retrospective study of 68 patients who had partial virological response to ETV, defined as having detectable HBV DNA following at least 12 months of ETV, and were switched to TDF monotherapy (n = 25) or ETV+TDF (n = 43). Patients were seen in seven US liver/community-based clinics and started on ETV between 2005 and 2009. The majority of patients were male; the vast majority were Asian and had positive hepatitis B e antigen (HBeAg). Patients in both groups had similar pretreatment characteristics. Complete viral suppression (CVS) rates with TDF monotherapy and ETV+TDF were similar after 6 months (71% vs 83%, P = 0.23) and 12 months (86% vs 84%, P = 0.85), and there was no statistically significant difference in CVS rates even when only patients with higher HBV DNA levels at switch (>1000 IU/mL) were evaluated. Multivariate analysis indicated that ETV+TDF was not an independent predictor of CVS compared to TDF monotherapy (OR = 1.19, P = 0.63). In conclusion, TDF monotherapy and ETV+TDF are comparable in achieving CVS in CHB patients with partial virological response to ETV. Long-term alternate therapy with one pill (TDF monotherapy) vs two pills (ETV+TDF) could lead to lower nonadherence rates and better treatment outcomes. PMID:25417914

  18. The road to success. Long-term prognosis for persons living with HIV in Denmark - time trends and risk factors.

    PubMed

    Lohse, Nicolai

    2016-02-01

    The work on this thesis began in 2003 when the global HIV epidemic was out of control. A minority of persons with HIV were benefitting fully from the recently introduced highly efficacious antiretroviral therapy (ART) combinations. Among the global challenges were lack of access to good healthcare, drug toxicity, and emergence of drug-resistant virus. It was unknown how long the drugs could maintain their efficacy in the individual even if administered as intended, and there was a fear that the increased drug pressure would increase the prevalence of drug resistance, subsequently leading to transmission of resistant virus from one individual to another, and thereby waning the treatment options available. Hence, we were far from the ideal conditions where an HIV-infected individual gets to know immediately that he/she is infected, has access to specialized medical and social support, receives a drug combination which effectively suppresses the virus and has no side effects, and is free of co-morbid conditions both before and after he/she gets infected. The nine papers on which this thesis is based each aimed to provide new knowledge to aspects of the above. Late diagnosis and late presentation to clinical care continue to be major barriers to improved HIV management. We used nation-wide hospital registries to explore the potential for an indicator disease-based HIV testing strategy. A range of conditions that were manifestations of the HIV infection itself were found to be associated with highly increased risk of HIV diagnosis during the coming year, but less so three to five years later. Other conditions were associated with an almost constant five-year long increased risk of being diagnosed with HIV because they share behavioural risk factors with HIV, making them indicators of not only current HIV but also of future HIV acquisition. Hence, indicator condition-based testing should be adapted to the local epidemic and could be a valuable addition to the existing

  19. Evaluating the efficacy of therapeutic HIV vaccines through analytical treatment interruptions

    PubMed Central

    Graziani, Gina M; Angel, Jonathan B

    2015-01-01

    Introduction The development of an effective therapeutic HIV vaccine that induces immunologic control of viral replication, thereby eliminating or reducing the need for antiretroviral therapy (ART), would be of great value. Besides the obvious challenges of developing a therapeutic vaccine that would generate effective, sustained anti-HIV immunity in infected individuals is the issue of how to best assess the efficacy of vaccine candidates. Discussion This review discusses the various outcome measures assessed in therapeutic HIV vaccine clinical trials involving individuals receiving suppressive ART, with a particular focus on the role of analytical treatment interruption (ATI) as a way to assess the virologic control induced by an immunotherapy. This strategy is critical given that there are otherwise no readily available measures to determine the ability of a vaccine-induced immune response to effectively control HIV replication. The various outcome measures that have been used to assess vaccine efficacy in published therapeutic HIV vaccine clinical trials will also be discussed. Outcome measures have included the kinetics of viral rebound, the new viral set point and changes in the size of the viral reservoir. Clinically relevant outcomes such as the CD4 decline, the time to resume therapy or the time to meet the criterion to resume therapy, the proportion of participants who resume therapy and/or the development of clinical symptoms such as acute retroviral syndrome are also measures of vaccine efficacy. Conclusions Given the lack of consistency between therapeutic HIV vaccine trials in how efficacy is assessed, comparing vaccines has been difficult. It would, therefore, be beneficial to determine the most clinically relevant measure for use in future studies. Other recommendations for future clinical trials also include studying compartments in addition to blood and replacing ATIs with single-copy assays in situations in which the use of an ATI is not ideal

  20. Acceptance of the Use of HIV Surveillance Data for Care Engagement: National and Local Community Perspectives

    PubMed Central

    Evans, David; Van Gorder, Dana; Morin, Stephen F.; Steward, Wayne T.; Gaffney, Stuart; Charlebois, Edwin D.

    2015-01-01

    Background Use of surveillance data including laboratory results (e.g. CD4 and HIV RNA) by public health departments to facilitate linkage, retention, and re-engagement of HIV-infected individuals in health care is on the rise. This is part of the goal of increasing the proportion of infected persons achieving virologic suppression. However, this use of surveillance data is not without controversy, particularly among some providers and people living with HIV. Methods We conducted informal discussions with key stakeholders and a literature search, and held a national think tank in November 2012, bringing together 31 representatives of the federal government, county and state officials, health care providers, and community-based organizations. A follow-up community consultation specific to San Francisco was held January 24, 2014, with 10 participants. Notes from these activities were used as data for this analysis. Results The think tank identified three strategies utilizing HIV surveillance data to aid in care engagement: 1) provider-mediated – where health department staff work with the provider of record on re-engagement, 2) electronic linkages between surveillance databases and medical records databases, and 3) direct outreach – where trained health department staff reach out to persons out of care. Participants also developed recommendations for minimizing harm, guidance on meaningful stakeholder involvement, and a consensus statement in support of the use of HIV surveillance data in care engagement. Conclusions Acceptance of the use of surveillance data for HIV care linkage, retention, and re-engagement is achievable, particularly if stakeholders have been engaged in the design, conduct, and evaluation of programs. PMID:25867776

  1. Adherence to Antiretroviral Therapy for the Success of Emerging Interventions to Prevent HIV Transmission: A Wake up Call

    PubMed Central

    Nachega, Jean B; Uthman, Olalekan A; Mills, Edward J; Quinn, Thomas C

    2012-01-01

    Despite recent successes in several HIV prevention trials, the epidemic continues to increase in many countries. The most successful biomedical interventions to prevent HIV have been the use of Antiretroviral Therapy (ART) to Prevent Mother-To-Child Transmission (PMTCT), and sexual transmission via microbicides, PreExposure Prophylaxis (PrEP), and treatment of the infected person within discordant couples. In addition medical male circumcision has also been shown to be highly effective in prevention of HIV acquisition. However, emerging data demonstrate that adherence to several of these prevention interventions is critical. ART adherence during and after pregnancy has been shown to be significantly below that recommended for adequate virologic suppression, particularly during the postpartum period. Five recent PrEP trials also demonstrate that the success of PrEP as a public health intervention will necessitate monitoring ART adherence and will include additional interventions to improve or maintain adherence to optimal levels. New successes in HIV prevention research have been tempered by suboptimal adherence. There is a critical need to define practical and effective adherence monitoring strategies as well as controlled trials of adherence interventions in the era of PrEP, Treatment as Prevention (TasP), and PMTCT to maximize their benefit. PMID:24032088

  2. Thank you to Virology Journal's peer reviewers in 2013

    PubMed Central

    2014-01-01

    The editors of Virology Journal would like to thank all our reviewers who have contributed to the journal in Volume 10 (2013). The success of any scientific journal depends on an effective and strict peer review process and Virology Journal could not operate without your contribution. We are grateful to the large number of reviewers (1026 to be exact!), who have done a great job in not only lifting the quality of the journal’s scientific peer reviewing process, but also helped us to achieve our goal of a median time to first decision of just 35 days. Our record time from submission to online, open access, publication in 2013 was 22 days for a Research Article [1] and 28 days for a Review [2]. This is a great achievement by any standard. We look forward to your continuous support of Virology Journal either as an invited reviewer or a contributing author in the years to come.

  3. HIV-1 Infection-Induced Suppression of the Let-7i/IL-2 Axis Contributes to CD4+ T Cell Death

    PubMed Central

    Zhang, Yijun; Yin, Yue; Zhang, Shaoying; Luo, Haihua; Zhang, Hui

    2016-01-01

    The mechanisms underlying HIV-1-mediated CD4+ T cell depletion are highly complicated. Interleukin-2 (IL-2) is a key cytokine that maintains the survival and proliferation of activated CD4+ T cells. IL-2 levels are disturbed during HIV-1 infection, but the underlying mechanism(s) requires further investigation. We have reported that cellular microRNA (miRNA) let-7i upregulates IL-2 expression by targeting the promoter TATA-box region, which functions as a positive regulator. In this study, we found that HIV-1 infection decreases the expression of let-7i in CD4+ T cells by attenuating its promoter activity. The reduced let-7i miRNA expression led to a decline in IL-2 levels. A let-7i mimic increased IL-2 expression and subsequently enhanced the resistance of CD4+ T cells to HIV-1-induced apoptosis. By contrast, the blockage of let-7i with a specific inhibitor resulted in elevated CD4+ T cell apoptosis during HIV-1 infection. Furthermore, by knocking down the expression of IL-2, we found that the let-7i-mediated CD4+ T cell resistance to apoptosis during HIV-1 infection was dependent on IL-2 signaling rather than an alternative CD95-mediated cell-death pathway. Taken together, our findings reveal a novel pathway for HIV-1-induced dysregulation of IL-2 cytokines and depletion of CD4+ T-lymphocytes. PMID:27145859

  4. Minocycline attenuates HIV-1 infection and suppresses chronic immune activation in humanized NOD/LtsZ-scidIL-2Rγnull mice

    PubMed Central

    Singh, Maneesh; Singh, Pratibha; Vaira, Dolores; Amand, Mathieu; Rahmouni, Souad; Moutschen, Michel

    2014-01-01

    More than a quarter of a century of research has established chronic immune activation and dysfunctional T cells as central features of chronic HIV infection and subsequent immunodeficiency. Consequently, the search for a new immunomodulatory therapy that could reduce immune activation and improve T-cell function has been increased. However, the lack of small animal models for in vivo HIV study has hampered progress. In the current study, we have investigated a model of cord blood haematopoietic progenitor cells (CB-HPCs) -transplanted humanized NOD/LtsZ-scidIL-2Rγnull mice in which progression of HIV infection is associated with widespread chronic immune activation and inflammation. Indeed, HIV infection in humanized NSG mice caused up-regulation of several T-cell immune activation markers such as CD38, HLA-DR, CD69 and co-receptor CCR5. T-cell exhaustion markers PD-1 and CTLA-4 were found to be significantly up-regulated on T cells. Moreover, increased plasmatic levels of lipopolysaccharide, sCD14 and interleukin-10 were also observed in infected mice. Treatment with minocycline resulted in a significant decrease of expression of cellular and plasma immune activation markers, inhibition of HIV replication and improved T-cell counts in HIV-infected humanized NSG mice. The study demonstrates that minocycline could be an effective, low-cost adjunctive treatment to regulate chronic immune activation and replication of HIV. PMID:24409837

  5. Dried-Plasma Transport Using a Novel Matrix and Collection System for Human Immunodeficiency Virus and Hepatitis C Virus Virologic Testing▿

    PubMed Central

    Lloyd, R. M.; Burns, D. A.; Huong, J. T.; Mathis, R. L.; Winters, M. A.; Tanner, M.; De La Rosa, A.; Yen-Lieberman, B.; Armstrong, W.; Taege, A.; McClernon, D. R.; Wetshtein, J. L.; Friedrich, Brian M.; Ferguson, Monique R.; O'Brien, William; Feorino, P. M.; Holodniy, M.

    2009-01-01

    A novel method for the collection and transportation of dried-blood-plasma samples, SampleTanker (ST), was developed and compared to standard shipping protocols for frozen-plasma specimens containing human immunodeficiency virus type 1 (HIV-1) and/or hepatitis C virus (HCV). Matched frozen and dried 1-ml EDTA-containing plasma samples were collected and analyzed by several molecular-based virologic assays. After addition of 1.175 ml of reconstitution buffer, 1.035 ml of dried plasma was recovered. Mean intra-assay variances were 0.05, 0.05, and 0.06 log10 copies/ml for the Versant, Amplicor, and NucliSens QT HIV-1 load assays, respectively (P, not significant). However, mean HIV-1 viral load was consistently reduced in dried samples by 0.32 to 0.51 log10 copies/ml, depending on assay type (P < 0.05). Infectious HIV-1 was not recovered from dried ST plasma. There was no significant difference in HIV-1 viral load results obtained using ST after 8 weeks of storage at ambient temperature. Compared to frozen plasma, HIV-1 genotypic results were >99% concordant at the nucleotide and amino acid levels, as well as for resistance-associated mutations. We further demonstrated successful detection of multiple analytes, including HIV-1 viral load, HIV-1 antiretroviral resistance genotype, and HCV genotype, from a single ST unit. Dried plasma collected with ST yielded comparable results to frozen samples for multiple-analyte clinical testing. As such, ST could be a useful alternative for virologic tests and clinical trials worldwide by significantly diminishing transportation cost and the sample volume restrictions associated with dried-blood-spot technology. PMID:19321732

  6. Treatment outcomes among HIV-1 and HIV-2 infected children initiating antiretroviral therapy in a concentrated low prevalence setting in West Africa

    PubMed Central

    2012-01-01

    610; P = 0.0196) and 615 cells/mm3 (250 – 1060; P = 0.0180) respectively. The proportions of children achieving undetectable HIV-1 viral load at 6-, 12-, 24- and 36 months of treatment were 24/38 (63.2%), 20/36 (55.6%), 8/22 (36.4%) and 7/12 (58.3%) respectively. The probability of survival among HIV-1 infected children after 12 months on ART was 89.9% (95% CI 78.8 – 95.3). CD4 T cell recovery was sub-optimal in all the HIV-2 infected children and none achieved virologic suppression. Two of the HIV-2 infected children died within 6 months of starting treatment while the remaining three were lost to follow-up. Conclusions The beneficial effects of cART among HIV-1 infected children in our setting are sustained in the first 24 months of treatment with a significant improvement in survival experience up to 36 months; however the outcome was poor in the few HIV-2 infected children initiated on cART. PMID:22770231

  7. Integrated Delivery of Antiretroviral Treatment and Pre-exposure Prophylaxis to HIV-1–Serodiscordant Couples: A Prospective Implementation Study in Kenya and Uganda

    PubMed Central

    Baeten, Jared M.; Heffron, Renee; Kidoguchi, Lara; Mugo, Nelly R.; Katabira, Elly; Bukusi, Elizabeth A.; Asiimwe, Stephen; Haberer, Jessica E.; Ngure, Kenneth; Bulya, Nulu; Odoyo, Josephine; Hendrix, Craig; Marzinke, Mark A.; Ware, Norma C.; Wyatt, Monique A.; Morrison, Susan; Mujugira, Andrew; Donnell, Deborah; Celum, Connie

    2016-01-01

    Background Antiretroviral-based interventions for HIV-1 prevention, including antiretroviral therapy (ART) to reduce the infectiousness of HIV-1 infected persons and pre-exposure prophylaxis (PrEP) to reduce the susceptibility of HIV-1 uninfected persons, showed high efficacy for HIV-1 protection in randomized clinical trials. We conducted a prospective implementation study to understand the feasibility and effectiveness of these interventions in delivery settings. Methods and Findings Between November 5, 2012, and January 5, 2015, we enrolled and followed 1,013 heterosexual HIV-1-serodiscordant couples in Kenya and Uganda in a prospective implementation study. ART and PrEP were offered through a pragmatic strategy, with ART promoted for all couples and PrEP offered until 6 mo after ART initiation by the HIV-1 infected partner, permitting time to achieve virologic suppression. One thousand thirteen couples were enrolled, 78% of partnerships initiated ART, and 97% used PrEP, during a median follow-up of 0.9 years. Objective measures of adherence to both prevention strategies demonstrated high use (≥85%). Given the low HIV-1 incidence observed in the study, an additional analysis was added to compare observed incidence to incidence estimated under a simulated counterfactual model constructed using data from a prior prospective study of HIV-1-serodiscordant couples. Counterfactual simulations predicted 39.7 HIV-1 infections would be expected in the population at an incidence of 5.2 per 100 person-years (95% CI 3.7–6.9). However, only two incident HIV-1 infections were observed, at an incidence of 0.2 per 100 person-years (95% CI 0.0–0.9, p < 0.0001 versus predicted). The use of a non-concurrent comparison of HIV-1 incidence is a potential limitation of this approach; however, it would not have been ethical to enroll a contemporaneous population not provided access to ART and PrEP. Conclusions Integrated delivery of time-limited PrEP until sustained ART use in

  8. CD4 Cell Count and the Risk of AIDS or Death in HIV-Infected Adults on Combination Antiretroviral Therapy with a Suppressed Viral Load: A Longitudinal Cohort Study from COHERE

    PubMed Central

    2012-01-01

    Background Most adults infected with HIV achieve viral suppression within a year of starting combination antiretroviral therapy (cART). It is important to understand the risk of AIDS events or death for patients with a suppressed viral load. Methods and Findings Using data from the Collaboration of Observational HIV Epidemiological Research Europe (2010 merger), we assessed the risk of a new AIDS-defining event or death in successfully treated patients. We accumulated episodes of viral suppression for each patient while on cART, each episode beginning with the second of two consecutive plasma viral load measurements <50 copies/µl and ending with either a measurement >500 copies/µl, the first of two consecutive measurements between 50–500 copies/µl, cART interruption or administrative censoring. We used stratified multivariate Cox models to estimate the association between time updated CD4 cell count and a new AIDS event or death or death alone. 75,336 patients contributed 104,265 suppression episodes and were suppressed while on cART for a median 2.7 years. The mortality rate was 4.8 per 1,000 years of viral suppression. A higher CD4 cell count was always associated with a reduced risk of a new AIDS event or death; with a hazard ratio per 100 cells/µl (95% CI) of: 0.35 (0.30–0.40) for counts <200 cells/µl, 0.81 (0.71–0.92) for counts 200 to <350 cells/µl, 0.74 (0.66–0.83) for counts 350 to <500 cells/µl, and 0.96 (0.92–0.99) for counts ≥500 cells/µl. A higher CD4 cell count became even more beneficial over time for patients with CD4 cell counts <200 cells/µl. Conclusions Despite the low mortality rate, the risk of a new AIDS event or death follows a CD4 cell count gradient in patients with viral suppression. A higher CD4 cell count was associated with the greatest benefit for patients with a CD4 cell count <200 cells/µl but still some slight benefit for those with a CD4 cell count ≥500 cells/µl. Please see later in the article for the

  9. Origin of Rebound Plasma HIV Includes Cells with Identical Proviruses That Are Transcriptionally Active before Stopping of Antiretroviral Therapy

    PubMed Central

    Wiegand, Ann; Shao, Wei; Coffin, John M.; Mellors, John W.; Lederman, Michael; Gandhi, Rajesh T.; Keele, Brandon F.

    2015-01-01

    ABSTRACT Understanding the origin of HIV variants during viral rebound may provide insight into the composition of the HIV reservoir and has implications for the design of curative interventions. HIV single-genome sequences were obtained from 10 AIDS Clinical Trials Group participants who underwent analytic antiretroviral therapy (ART) interruption (ATI). Rebounding variants were compared with those in pre-ART plasma in all 10 participants and with on-ART peripheral blood mononuclear cell (PBMC)-associated DNA and RNA (CA-RNA) in 7/10 participants. The highest viral diversities were found in the DNA and CA-RNA populations. In 3 of 7 participants, we detected multiple, identical DNA and CA-RNA sequences during suppression on ART that exactly matched plasma HIV sequences. Hypermutated DNA and CA-RNA were detected in four participants, contributing to diversities in these compartments that were higher than in the pre-ART and post-ATI plasma. Shifts in the viral rebound populations could be detected in some participants over the 2- to 3-month observation period. These findings suggest that a source of initial rebound viremia could be populations of infected cells that clonally expanded prior to and/or during ART, some of which were already expressing HIV RNA before treatment was interrupted. These clonally expanding populations of HIV-infected cells may represent an important target for strategies aimed at achieving reservoir reduction and sustained virologic remission. IMPORTANCE Antiretroviral therapy alone cannot eradicate the HIV reservoir, and viral rebound is generally rapid after treatment interruption. It has been suggested that clonal expansion of HIV-infected cells is an important mechanism of HIV reservoir persistence, but the contribution of these clonally proliferating cells to the rebounding virus is unknown. We report a study of AIDS Clinical Trials Group participants who underwent treatment interruption and compared rebounding plasma virus with that

  10. Computational virology: From the inside out.

    PubMed

    Reddy, Tyler; Sansom, Mark S P

    2016-07-01

    Viruses typically pack their genetic material within a protein capsid. Enveloped viruses also have an outer membrane made up of a lipid bilayer and membrane-spanning glycoproteins. X-ray diffraction and cryoelectron microscopy provide high resolution static views of viral structure. Molecular dynamics (MD) simulations may be used to provide dynamic insights into the structures of viruses and their components. There have been a number of simulations of viral capsids and (in some cases) of the inner core of RNA or DNA packaged within them. These simulations have generally focussed on the structural integrity and stability of the capsid and/or on the influence of the nucleic acid core on capsid stability. More recently there have been a number of simulation studies of enveloped viruses, including HIV-1, influenza A, and dengue virus. These have addressed the dynamic behaviour of the capsid, the matrix, and/or of the outer envelope. Analysis of the dynamics of the lipid bilayer components of the envelopes of influenza A and of dengue virus reveals a degree of biophysical robustness, which may contribute to the stability of virus particles in different environments. Significant computational challenges need to be addressed to aid simulation of complex viruses and their membranes, including the need to integrate structural data from a range of sources to enable us to move towards simulations of intact virions. This article is part of a Special Issue entitled: Membrane Proteins edited by J.C. Gumbart and Sergei Noskov. PMID:26874202

  11. Albuminuria is associated with elevated acute phase reactants and proinflammatory markers in HIV-infected patients receiving suppressive combination antiretroviral therapy.

    PubMed

    O-charoen, Pichaya; Ndhlovu, Lishomwa C; Gangcuangco, Louie Mar A; Keating, Sheila M; Norris, Philip J; Ng, Roland C K; Mitchell, Brooks I; Shikuma, Cecilia M; Chow, Dominic C

    2014-12-01

    Albuminuria among HIV-infected individuals has been found to be associated with cardiovascular disease (CVD) and mortality. Inflammation has been associated with albuminuria. The pathophysiology of albuminuria in HIV-infected individuals is poorly understood. We investigated the association of albuminuria with inflammatory biomarkers among HIV-infected individuals on combination antiretroviral therapy (cART). This is a cross-sectional analysis of participants enrolled in the Hawaii Aging with HIV-Cardiovascular Cohort. Plasma inflammatory biomarkers were assessed using the Milliplex Human Cardiovascular disease multiplex assays. A random urine sample was collected for albumin measurement. Albuminuria was defined as urine albumin-to-creatinine ratio of ≥30 mg/g. Framingham risk score was calculated and divided into three classes. Simple and multivariable logistic regression analyses were utilized to assess the correlation between plasma inflammatory biomarkers and albuminuria and were adjusted for Framingham risk category. Among 111 HIV-infected patients [median (IQR) age of 52 (46-57) years, 86% male, median (IQR) CD4 count of 489 (341-638) cells/mm(3), 85% with HIV RNA <50 copies/ml], 18 subjects (16.2%) had moderately increased albuminuria (albuminuria range between 30 and 300 mg/g) and 2 subjects (1.8%) had severely increased albuminuria (albuminuria more than 300 mg/g). In multivariable logistic models, sE-selectin, sVCAM-1, CRP, SAA, and SAP remained significantly associated with albuminuria after adjustment of CVD risk factors. This study showed an association between inflammation and albuminuria independent of previously reported risk factors for albuminuria in HIV-infected subjects who were on combination antiretroviral therapy (cART). Chronic inflammation despite potent antiretroviral treatment may contribute to higher rates of albuminuria among HIV-infected patients. PMID:25205472

  12. Serious Non-AIDS Events: Therapeutic Targets of Immune Activation and Chronic Inflammation in HIV Infection.

    PubMed

    Hsu, Denise C; Sereti, Irini

    2016-04-01

    In the antiretroviral therapy (ART) era, serious non-AIDS events (SNAEs) have become the major causes of morbidity and mortality in HIV-infected persons. Early ART initiation has the strongest evidence for reducing SNAEs and mortality. Biomarkers of immune activation, inflammation and coagulopathy do not fully normalize despite virologic suppression and persistent immune activation is an important contributor to SNAEs. A number of strategies aimed to reduce persistent immune activation including ART intensification to reduce residual viremia; treatment of co-infections to reduce chronic antigen stimulation; the use of anti-inflammatory agents, reducing microbial translocation as well as interventions to improve immune recovery through cytokine administration and reducing lymphoid tissue fibrosis, have been investigated. To date, there is little conclusive evidence on which strategies beyond treatment of hepatitis B and C co-infections and reducing cardiovascular risk factors will result in clinical benefits in patients already on ART with viral suppression. The use of statins seems to show early promise and larger clinical trials are underway to confirm their efficacy. At this stage, clinical care of HIV-infected patients should therefore focus on early diagnosis and prompt ART initiation, treatment of active co-infections and the aggressive management of co-morbidities until further data are available. PMID:26915027

  13. Superior virologic and treatment outcomes when viral load is measured at 3 months compared to 6 months on antiretroviral therapy

    PubMed Central

    Kerschberger, Bernhard; Boulle, Andrew M; Kranzer, Katharina; Hilderbrand, Katherine; Schomaker, Michael; Coetzee, David; Goemaere, Eric; Van Cutsem, Gilles

    2015-01-01

    Introduction Routine viral load (VL) monitoring is utilized to assess antiretroviral therapy (ART) adherence and virologic failure, and it is currently scaled-up in many resource-constrained settings. The first routine VL is recommended as late as six months after ART initiation for early detection of sub-optimal adherence. We aimed to assess the optimal timing of first VL measurement after initiation of ART. Methods This was a retrospective, cohort analysis of routine monitoring data of adults enrolled at three primary care clinics in Khayelitsha, Cape Town, between January 2002 and March 2009. Primary outcomes were virologic failure and switch to second-line ART comparing patients in whom first VL done was at three months (VL3M) and six months (VL6M) after ART initiation. Adjusted hazard ratios (aHR) were estimated using Cox proportional hazard models. Results In total, 6264 patients were included for the time to virologic failure and 6269 for the time to switch to second-line ART analysis. Patients in the VL3M group had a 22% risk reduction of virologic failure (aHR 0.78, 95% CI 0.64–0.95; p=0.016) and a 27% risk reduction of switch to second-line ART (aHR 0.73, 95% CI 0.58–0.92; p=0.008) when compared to patients in the VL6M group. For each additional month of delay of the first VL measurement (up to nine months), the risk of virologic failure increased by 9% (aHR 1.09, 95% CI 1.02–1.15; p=0.008) and switch to second-line ART by 13% (aHR 1.13, 95% CI 1.05–1.21; p<0.001). Conclusions A first VL at three months rather than six months with targeted adherence interventions for patients with high VL may improve long-term virologic suppression and reduce switches to costly second-line ART. ART programmes should consider the first VL measurement at three months after ART initiation. PMID:26403636

  14. Integrated Design of a Virology Course Develops Lifelong Learners

    ERIC Educational Resources Information Center

    Mester, Joseph C.

    2009-01-01

    This article describes the author's first attempt at integrated course design. Students in the author's virology course helped set the learning goals, and the design and content of the exams, and developed rubrics for individual and group projects. The result was that they learned how to direct their own learning. Integrated course design and…

  15. Relapse of visceral leishmaniasis in an HIV-infected patient successfully treated with a combination of miltefosine and amphotericin B.

    PubMed

    McQuarrie, Shauna; Kasper, Ken; Moffatt, Dana C; Marko, Daniel; Keynan, Yoav

    2015-01-01

    The present report documents a 49-year-old HIV-infected man receiving antiretroviral therapy with a suboptimal immune response and a CD4 count of 95 cells/mm(3), despite virological suppression. Investigation of bone marrow was conducted and yielded a diagnosis of visceral leishmaniasis. The clinical course was complicated by gastrointestinal involvment and relapse occurred after amphotericin B therapy. With the addition of miltefosine, the patient no longer presented with bone marrow amastigotes, and displayed an increased CD4 count and negative Leishmania polymerase chain reaction results. The present case highlights atypical presentation of visceral leishmaniasis, including poor immune reconstitution and gastrointestinal involvement. The high likelihood of relapse and response to combination therapy are illustrated. PMID:26744591

  16. Relapse of visceral leishmaniasis in an HIV-infected patient successfully treated with a combination of miltefosine and amphotericin B

    PubMed Central

    McQuarrie, Shauna; Kasper, Ken; Moffatt, Dana C; Marko, Daniel; Keynan, Yoav

    2015-01-01

    The present report documents a 49-year-old HIV-infected man receiving antiretroviral therapy with a suboptimal immune response and a CD4 count of 95 cells/mm3, despite virological suppression. Investigation of bone marrow was conducted and yielded a diagnosis of visceral leishmaniasis. The clinical course was complicated by gastrointestinal involvment and relapse occurred after amphotericin B therapy. With the addition of miltefosine, the patient no longer presented with bone marrow amastigotes, and displayed an increased CD4 count and negative Leishmania polymerase chain reaction results. The present case highlights atypical presentation of visceral leishmaniasis, including poor immune reconstitution and gastrointestinal involvement. The high likelihood of relapse and response to combination therapy are illustrated. PMID:26744591

  17. Virological Response and Muscular Adverse Events during Long-Term Clevudine Therapy in Chronic Hepatitis B Patients

    PubMed Central

    Kim, Byung Kook; Ko, Soon Young; Kwon, So Young; Park, Eugene; Kim, Jeong Han; Choe, Won Hyeok; Lee, Chang Hong

    2013-01-01

    Background Recently, several reports issued clevudine induced myopathy in the long term use. Objectives The aim of this study was to investigate antiviral effects and adverse events of clevudine monotherapy in patients with chronic hepatitis B (CHB). Patients and Methods The subjects were 110 treatment-naïve CHB patients. They were treated with 30 mg clevudine/day for more than six months. Virological and biochemical tests, including that for serum creatine kinase (CK), were monitored at baseline and at 3-month intervals during treatment period. Results In HBeAg-positive patients, the cumulative rates of virological response were 74.0 %, 68.5 %, and 67.3 % after one, two, and three years of clevudine treatment, respectively. Cumulative rates of HBeAg loss or seroconversion were 17.8 %, 30 %, and 31.5 % after one, two and, three years of clevudine treatment, respectively. In HBeAg-negative patients, the cumulative rates of virological response were 97.3 %, 100 %, and 94.6 %, respectively. Virological breakthrough occurred in 27 patients. The rtM204I mutation in HBV polymerase was predominantly detected. Muscular adverse events were observed in 15 patients. All patients with myopathy recovered after the cessation of clevudine monotherapy. Fluctuations in CK level during the clevudine treatment period were frequently observed irrespective of development of myopathy. Multiple episodes of CK elevation were significantly related to the development of myopathy. Conclusions Long-term clevudine monotherapy is effective for suppression of serum HBV DNA level and normalization of serum alanine amino transaminase levels, but associated with occurrence of rtM204I mutation. Clevudine-induced muscular adverse events are not uncommon, although they are totally reversible after cessation of the treatment. Muscular adverse events and serum CK level should be carefully monitored during long-term treatment with clevudine. PMID:23805155

  18. Long-Term Efficacy, Tolerability, and Renal Safety of Atazanavir/Ritonavir-based Antiretroviral Therapy in a Cohort of Treatment-Naïve Patients with HIV-1 Infection: the REMAIN Study

    PubMed Central

    Teófilo, Eugénio; Rocha-Pereira, Nuno; Kuhlmann, Birger; Antela, Antonio; Knechten, Heribert; Santos, Jesús; Jiménez-Expósito, Maria Jesús

    2016-01-01

    Background: Boosted protease inhibitors (PIs), including ritonavir-boosted atazanavir (ATV/r), are a recommended option for the initial treatment of HIV-1 infection based upon clinical trial data; however, long-term real-life clinical data are limited. Objective: We evaluated the long-term use of ATV/r as a component of antiretroviral combination therapy in the real-life setting in the REMAIN study. Methods: This was an observational cohort study conducted at sites across Germany, Portugal, and Spain. Retrospective historical and prospective longitudinal follow-up data were extracted every six months from medical records of HIV-infected treatment-naïve patients aged ≥ 18 years initiating a first-line ATV/r-containing regimen. Results: Eligible patients (n = 517) were followed up for a median of 3.4 years. The proportion remaining on ATV/r at 5 years was 51.5% with an estimated Kaplan-Meier median time to treatment discontinuation of 4.9 years. Principal reasons for discontinuation were adverse events (15.9%; 8.9% due to hyperbilirubinemia) and virologic failure (6.8%). The Kaplan-Meier probability of not having virologic failure (HIV-1 RNA < 50 copies/mL) was 0.79 (95% CI: 0.75, 0.83) at five years. No treatment-emergent major PI resistance occurred. ATV/r was generally well tolerated during long-term treatment with no significant changes in estimated glomerular filtration rate over five years. Conclusions: In a real-life clinical setting over five years, treatment-naïve patients with HIV-1 infection initiating an ATV/r-based regimen showed sustained virologic suppression, an overall treatment persistence rate of 51.5%, an absence of treatment-emergent major PI resistance mutations at virologic failure, a long-term safety profile consistent with that observed in clinical trials, and no significant decline in renal function. PMID:26899539

  19. Modeling the Impact of Interventions Along the HIV Continuum of Care in Newark, New Jersey

    PubMed Central

    Birger, Ruthie B.; Hallett, Timothy B.; Sinha, Anushua; Grenfell, Bryan T.; Hodder, Sally L.

    2014-01-01

    Background. The human immunodeficiency virus (HIV) epidemic in Newark, New Jersey, is among the most severe in the United States. Prevalence ranges up to 3.3% in some groups. The aim of this study is to use a mathematical model of the epidemic in Newark to assess the impact of interventions along the continuum of care, leading to virologic suppression. Methods. A model was constructed of HIV infection including specific care-continuum steps. The model was calibrated to HIV/AIDS cases in Newark among different populations over a 10-year period. Interventions applied to model fits were increasing proportions tested, linked and retained in care, linked and adherent to treatment, and increasing testing frequency, high-risk-group testing, and adherence. Impacts were assessed by measuring incidence and death reductions 10 years postintervention. Results. The most effective interventions for reducing incidence were improving treatment adherence and increasing testing frequency and coverage. No single intervention reduced incidence in 2023 by >5%, and the most effective combination of interventions reduced incidence by approximately 16% (2%–24%). The most efficacious interventions for reducing deaths were increasing retention, linkage to care, testing coverage, and adherence. Increasing retention reduced deaths by approximately 27% (24%–29%); the most efficacious combination of interventions reduced deaths in 2023 by approximately 52% (46%–57%). Conclusions. Reducing HIV deaths in Newark over a 10-year period may be a realizable goal, but reducing incidence is less likely. Our results highlight the importance of addressing leaks across the entire continuum of care and reinforcing efforts to prevention new HIV infections with additional interventions. PMID:24140971

  20. HIV-1 Genetic Variation Resulting in the Development of New Quasispecies Continues to Be Encountered in the Peripheral Blood of Well-Suppressed Patients

    PubMed Central

    Dampier, Will; Nonnemacher, Michael R.; Mell, Joshua; Earl, Joshua; Ehrlich, Garth D.; Pirrone, Vanessa; Aiamkitsumrit, Benjamas; Zhong, Wen; Kercher, Katherine; Passic, Shendra; Williams, Jean W.; Jacobson, Jeffrey M.; Wigdahl, Brian

    2016-01-01

    As a result of antiretroviral therapeutic strategies, human immunodeficiency virus type 1 (HIV-1) infection has become a long-term clinically manageable chronic disease for many infected individuals. However, despite this progress in therapeutic control, including undetectable viral loads and CD4+ T-cell counts in the normal range, viral mutations continue to accumulate in the peripheral blood compartment over time, indicating either low level reactivation and/or replication. Using patients from the Drexel Medicine CNS AIDS Research and Eradication Study (CARES) Cohort, whom have been sampled longitudinally for more than 7 years, genetic change was modeled against to the dominant integrated proviral quasispecies with respect to selection pressures such as therapeutic interventions, AIDS defining illnesses, and other factors. Phylogenetic methods based on the sequences of the LTR and tat exon 1 of the HIV-1 proviral DNA quasispecies were used to obtain an estimate of an average mutation rate of 5.3 nucleotides (nt)/kilobasepair (kb)/year (yr) prior to initiation of antiretroviral therapy (ART). Following ART the baseline mutation rate was reduced to an average of 1.02 nt/kb/yr. The post-ART baseline rate of genetic change, however, appears to be unique for each patient. These studies represent our initial steps in quantifying rates of genetic change among HIV-1 quasispecies using longitudinally sampled sequences from patients at different stages of disease both before and after initiation of combination ART. Notably, while long-term ART reduced the estimated mutation rates in the vast majority of patients studied, there was still measurable HIV-1 mutation even in patients with no detectable virus by standard quantitative assays. Determining the factors that affect HIV-1 mutation rates in the peripheral blood may lead to elucidation of the mechanisms associated with changes in HIV-1 disease severity. PMID:27195985

  1. HIV-1 Genetic Variation Resulting in the Development of New Quasispecies Continues to Be Encountered in the Peripheral Blood of Well-Suppressed Patients.

    PubMed

    Dampier, Will; Nonnemacher, Michael R; Mell, Joshua; Earl, Joshua; Ehrlich, Garth D; Pirrone, Vanessa; Aiamkitsumrit, Benjamas; Zhong, Wen; Kercher, Katherine; Passic, Shendra; Williams, Jean W; Jacobson, Jeffrey M; Wigdahl, Brian

    2016-01-01

    As a result of antiretroviral therapeutic strategies, human immunodeficiency virus type 1 (HIV-1) infection has become a long-term clinically manageable chronic disease for many infected individuals. However, despite this progress in therapeutic control, including undetectable viral loads and CD4+ T-cell counts in the normal range, viral mutations continue to accumulate in the peripheral blood compartment over time, indicating either low level reactivation and/or replication. Using patients from the Drexel Medicine CNS AIDS Research and Eradication Study (CARES) Cohort, whom have been sampled longitudinally for more than 7 years, genetic change was modeled against to the dominant integrated proviral quasispecies with respect to selection pressures such as therapeutic interventions, AIDS defining illnesses, and other factors. Phylogenetic methods based on the sequences of the LTR and tat exon 1 of the HIV-1 proviral DNA quasispecies were used to obtain an estimate of an average mutation rate of 5.3 nucleotides (nt)/kilobasepair (kb)/year (yr) prior to initiation of antiretroviral therapy (ART). Following ART the baseline mutation rate was reduced to an average of 1.02 nt/kb/yr. The post-ART baseline rate of genetic change, however, appears to be unique for each patient. These studies represent our initial steps in quantifying rates of genetic change among HIV-1 quasispecies using longitudinally sampled sequences from patients at different stages of disease both before and after initiation of combination ART. Notably, while long-term ART reduced the estimated mutation rates in the vast majority of patients studied, there was still measurable HIV-1 mutation even in patients with no detectable virus by standard quantitative assays. Determining the factors that affect HIV-1 mutation rates in the peripheral blood may lead to elucidation of the mechanisms associated with changes in HIV-1 disease severity. PMID:27195985

  2. Addressing the Achilles' Heel in the HIV Care Continuum for the Success of a Test-and-Treat Strategy to Achieve an AIDS-Free Generation

    PubMed Central

    Nachega, Jean B.; Uthman, Olalekan A.; del Rio, Carlos; Mugavero, Michael J.; Rees, Helen; Mills, Edward J.

    2014-01-01

    Mathematical models and recent data from ecological, observational, and experimental studies show that antiretroviral therapy (ART) is effective for both treatment and prevention of HIV, validating the treatment as prevention (TasP) approach. Data from a variety of settings, including resource-rich and -limited sites, show that patient attrition occurs at each stage of the human immunodeficiency virus (HIV) treatment cascade, starting with the percent unaware of their HIV infection in a population and linkage to care after diagnosis, assessment of ART readiness, receipt of ART, and finally long-term virologic suppression. Therefore, in order to implement TasP, we must first define practical and effective linkage to care, acceptability of treatment, and adherence and retention monitoring strategies, as well as the cost-effectiveness of such strategies. Ending this pandemic will require the combination of political will, resources, and novel effective interventions that are not only feasible and cost effective but also likely to be used in combination across successive steps on the HIV treatment cascade. PMID:24926028

  3. Human genetic variability and HIV treatment response.

    PubMed

    Haas, David W

    2006-07-01

    Access to potent antiretroviral medications greatly reduces morbidity and mortality due to HIV/AIDS, but drug toxicity limits treatment success in many individuals. The field of pharmacogenomics strives to understand the influence of human genetic variants in response to medications. Investigators have begun to identify associations among human genetic variants, predisposition to HIV drug toxicities, and likelihood of virologic response. These include associations among abacavir hypersensitivity reactions, HLA type, and hsp70-hom genotypes, and among CYP2B6 polymorphisms, efavirenz pharmacokinetics, and central nervous system symptoms. Pharmacogenomics also holds great promise to suggest novel targets for drug development. The discovery that a naturally occurring, nonfunctional variant of the HIV receptor gene CCR5 protected against HIV infection encouraged the development of CCR5 antagonists. Through continued translational and applied research, pharmacogenomics will ultimately benefit persons living with HIV worldwide by identifying new therapeutic targets and through individualized drug prescribing that is informed by human genetic testing. PMID:16608660

  4. Prothymosin α Variants Isolated From CD8+ T Cells and Cervicovaginal Fluid Suppress HIV-1 Replication Through Type I Interferon Induction

    PubMed Central

    Teixeira, Avelino; Yen, Benjamin; Gusella, Gabriele Luca; Thomas, Albert G.; Mullen, Michael P.; Aberg, Judith; Chen, Xintong; Hoshida, Yujin; van Bakel, Harm; Schadt, Eric; Basler, Christopher F.; García-Sastre, Adolfo; Mosoian, Arevik

    2015-01-01

    Soluble factors from CD8+ T cells and cervicovaginal mucosa of women are recognized as important in controlling human immunodeficiency virus type 1 (HIV-1) infection and transmission. Previously, we have shown the strong anti-HIV-1 activity of prothymosin α (ProTα) derived from CD8+ T cells. ProTα is a small acidic protein with wide cell distribution, to which several functions have been ascribed, depending on its intracellular or extracellular localization. To date, activities of ProTα have been attributed to a single protein known as isoform 2. Here we report the isolation and identification of 2 new ProTα variants from CD8+ T cells and cervicovaginal lavage with potent anti-HIV-1 activity. The first is a splice variant of the ProTα gene, known as isoform CRA_b, and the second is the product of a ProTα gene, thus far classified as a pseudogene 7. Native or recombinant ProTα variants potently restrict HIV-1 replication in macrophages through the induction of type I interferon. The baseline expression of interferon-responsive genes in primary human cervical tissues positively correlate with high levels of intracellular ProTα, and the knockdown of ProTα variants by small interfering RNA leads to downregulation of interferon target genes. Overall, these findings suggest that ProTα variants are innate immune mediators involved in immune surveillance. PMID:25404520

  5. The Diagnosis of HIV Infection in Infants and Children.

    PubMed

    Abdollahi, Alireza; Saffar, Hana

    2016-01-01

    It is estimated that the number of HIV infected children globally has increased from 1.6 million in 2001 to 3.3 million in 2012. The number of children below 15 years of age living with HIV has increased worldwide. Published data from recent studies confirmed dramatic survival benefit for infants started anti-retroviral therapy (ART) as early as possible after diagnosis of HI. Early confirmation of HIV diagnosis is required in order to identify infants who need immediate ART. WHO has designed recommendations to improve programs for both early diagnoses of HIV infection and considering ART whenever indicated? It is strongly recommended that HIV virologocal assays for diagnosis of HIV have sensitivity of at least 95% and ideally greater than 98% and specificity of 98% or more under standardized and validated conditions. Timing of virological testing is also important. Infants infected at or around delivery may take short time to have detectable virus. Therefore, sensitivity of virological tests is lower at birth. In utero HIV infection, HIV DNA or RNA can be detected within 48 h of birth and in infants with peripartum acquisition it needs one to two weeks. Finally it is emphasized that all laboratories performing HIV tests should follow available services provided by WHO or CDC for quality assurance programs. Both clinicians and staffs providing laboratory services need regular communications, well-defined SOPs and nationally validated algorithms for optimal use of laboratory tests. Every country should use assays that have been validated by national reference laboratory. PMID:27499768

  6. The Diagnosis of HIV Infection in Infants and Children

    PubMed Central

    Abdollahi, Alireza; Saffar, Hana

    2016-01-01

    It is estimated that the number of HIV infected children globally has increased from 1.6 million in 2001 to 3.3 million in 2012. The number of children below 15 years of age living with HIV has increased worldwide. Published data from recent studies confirmed dramatic survival benefit for infants started anti-retroviral therapy (ART) as early as possible after diagnosis of HI. Early confirmation of HIV diagnosis is required in order to identify infants who need immediate ART. WHO has designed recommendations to improve programs for both early diagnoses of HIV infection and considering ART whenever indicated? It is strongly recommended that HIV virologocal assays for diagnosis of HIV have sensitivity of at least 95% and ideally greater than 98% and specificity of 98% or more under standardized and validated conditions. Timing of virological testing is also important. Infants infected at or around delivery may take short time to have detectable virus. Therefore, sensitivity of virological tests is lower at birth. In utero HIV infection, HIV DNA or RNA can be detected within 48 h of birth and in infants with peripartum acquisition it needs one to two weeks. Finally it is emphasized that all laboratories performing HIV tests should follow available services provided by WHO or CDC for quality assurance programs. Both clinicians and staffs providing laboratory services need regular communications, well-defined SOPs and nationally validated algorithms for optimal use of laboratory tests. Every country should use assays that have been validated by national reference laboratory.

  7. [Detection of local influenza outbreaks and role of virological diagnostics].

    PubMed

    Schweiger, B; Buda, S

    2013-01-01

    For many years, the Working Group on Influenza (AGI) has been the most important influenza surveillance system in Germany. An average sample of the population is covered by both syndromic and virological surveillance, which provides timely data regarding the onset and course of the influenza wave as well as its burden of disease. However, smaller influenza outbreaks cannot be detected by the AGI sentinel system. This is achieved by the information reported by the mandatory notification system (Protection Against Infection Act, IfSG), which serves as the second pillar of the national influenza surveillance. Approaches to recognize such outbreaks are based either on reported influenza virus detection and subsequent investigations by local health authorities or by notification of an accumulation of respiratory diseases or nosocomial infections and subsequent laboratory investigations. In this context, virological diagnostics plays an essential role. This has been true particularly for the early phase of the 2009 pandemic, but generally timely diagnostics is essential for the identification of outbreaks. Regarding potential future outbreaks, it is also important to keep an eye on animal influenza viruses that have repeatedly infected humans. This mainly concerns avian influenza viruses of the subtypes H5, H7, and H9 as well as porcine influenza viruses for which a specific PCR has been established at the National Influenza Reference Centre. An increased incidence of respiratory infections, both during and outside the season, should always encourage virological laboratory diagnostics to be performed as a prerequisite of further extensive investigations and an optimal outbreak management. PMID:23275953

  8. HIV cell-to-cell transmission: effects on pathogenesis and antiretroviral therapy

    PubMed Central

    Agosto, Luis M.; Uchil, Pradeep D.; Mothes, Walther

    2015-01-01

    The human immunodeficiency virus (HIV) spreads more efficiently in vitro when infected cells directly contact uninfected cells to form virological synapses. A hallmark of virological synapses is that viruses can be transmitted at a higher multiplicity of infection (MOI) that, in vitro, results in a higher number of proviruses. Whether HIV also spreads by cell-cell contact in vivo is a matter of debate. Here we discuss recent data that suggest that contact-mediated transmission largely manifests itself in vivo as CD4+ T cell depletion. The assault of a cell by a large number of incoming particles is likely efficiently sensed by the innate cellular surveillance to trigger cell death. The large number of particles transferred across virological synapses has also been implicated in reduced efficacy of antiretroviral therapies. Thus, antiretroviral therapies must remain effective against the high MOI observed during cell-to-cell transmission to inhibit both viral replication and the pathogenesis associated with HIV infection. PMID:25766144

  9. Chronic hepatitis B: Virology, natural history, current management and a glimpse at future opportunities.

    PubMed

    Gish, Robert G; Given, Bruce D; Lai, Ching-Lung; Locarnini, Stephen A; Lau, Johnson Y N; Lewis, David L; Schluep, Thomas

    2015-09-01

    The host immune system plays an important role in chronic hepatitis B (CHB), both in viral clearance and hepatocellular damage. Advances in our understanding of the natural history of the disease have led to redefining the major phases of infection, with the "high replicative, low inflammatory" phase now replacing what was formerly termed the "immune tolerant" phase, and the "nonreplicative phase" replacing what was formerly termed the "inactive carrier" phase. As opposed to the earlier view that HBV establishes chronic infection by exploiting the immaturity of the neonate's immune system, new findings on trained immunity show that the host is already somewhat "matured" following birth, and is actually very capable of responding immunologically, potentially altering future hepatitis B treatment strategies. While existing therapies are effective in reducing viral load and necroinflammation, often restoring the patient to near-normal health, they do not lead to a cure except in very rare cases and, in many patients, viremia rebounds after cessation of treatment. Researchers are now challenged to devise therapies that will eliminate infection, with a particular focus on eliminating the persistence of viral cccDNA in the nuclei of hepatocytes. In the context of chronic hepatitis B, new definitions of 'cure' are emerging, such as 'functional' and 'virological' cure, defined by stable off-therapy suppression of viremia and antigenemia, and the normalization of serum ALT and other liver-related laboratory tests. Continued advances in the understanding of the complex biology of chronic hepatitis B have resulted in the development of new, experimental therapies targeting viral and host factors and pathways previously not accessible to therapy, approaches which may lead to virological cures in the near term and functional cures upon long term follow-up. This article forms part of a symposium in Antiviral Research on "An unfinished story: from the discovery of the Australia

  10. Pre-antiretroviral therapy serum selenium concentrations predict WHO stages 3, 4 or death but not virologic failure post-antiretroviral therapy.

    PubMed

    Shivakoti, Rupak; Gupte, Nikhil; Yang, Wei-Teng; Mwelase, Noluthando; Kanyama, Cecilia; Tang, Alice M; Pillay, Sandy; Samaneka, Wadzanai; Riviere, Cynthia; Berendes, Sima; Lama, Javier R; Cardoso, Sandra W; Sugandhavesa, Patcharaphan; Semba, Richard D; Christian, Parul; Campbell, Thomas B; Gupta, Amita

    2014-11-01

    A case-cohort study, within a multi-country trial of antiretroviral therapy (ART) efficacy (Prospective Evaluation of Antiretrovirals in Resource Limited Settings (PEARLS)), was conducted to determine if pre-ART serum selenium deficiency is independently associated with human immunodeficiency virus (HIV) disease progression after ART initiation. Cases were HIV-1 infected adults with either clinical failure (incident World Health Organization (WHO) stage 3, 4 or death by 96 weeks) or virologic failure by 24 months. Risk factors for serum selenium deficiency (<85 μg/L) pre-ART and its association with outcomes were examined. Median serum selenium concentration was 82.04 μg/L (Interquartile range (IQR): 57.28-99.89) and serum selenium deficiency was 53%, varying widely by country from 0% to 100%. In multivariable models, risk factors for serum selenium deficiency were country, previous tuberculosis, anemia, and elevated C-reactive protein. Serum selenium deficiency was not associated with either clinical failure or virologic failure in multivariable models. However, relative to people in the third quartile (74.86-95.10 μg/L) of serum selenium, we observed increased hazards (adjusted hazards ratio (HR): 3.50; 95% confidence intervals (CI): 1.30-9.42) of clinical failure but not virologic failure for people in the highest quartile. If future studies confirm this relationship of high serum selenium with increased clinical failure, a cautious approach to selenium supplementation might be needed, especially in HIV-infected populations with sufficient or unknown levels of selenium. PMID:25401501

  11. Early Warning Indicators for First-Line Virologic Failure Independent of Adherence Measures in a South African Urban Clinic

    PubMed Central

    Wu, Baohua; Hampton, Jane; Ordóñez, Claudia E.; Johnson, Brent A.; Singh, Dinesh; John, Sally; Gordon, Michelle; Hare, Anna; Murphy, Richard; Nachega, Jean; Kuritzkes, Daniel R.; del Rio, Carlos; Sunpath, Henry

    2013-01-01

    Abstract We sought to develop individual-level Early Warning Indicators (EWI) of virologic failure (VF) for clinicians to use during routine care complementing WHO population-level EWI. A case-control study was conducted at a Durban clinic. Patients after≥5 months of first-line antiretroviral therapy (ART) were defined as cases if they had VF [HIV-1 viral load (VL)>1000 copies/mL] and controls (2:1) if they had VL≤1000 copies/mL. Pharmacy refills and pill counts were used as adherence measures. Participants responded to a questionnaire including validated psychosocial and symptom scales. Data were also collected from the medical record. Multivariable logistic regression models of VF included factors associated with VF (p<0.05) in univariable analyses. We enrolled 158 cases and 300 controls. In the final multivariable model, male gender, not having an active religious faith, practicing unsafe sex, having a family member with HIV, not being pleased with the clinic experience, symptoms of depression, fatigue, or rash, low CD4 counts, family recommending HIV care, and using a TV/radio as ART reminders (compared to mobile phones) were associated with VF independent of adherence measures. In this setting, we identified several key individual-level EWI associated with VF including novel psychosocial factors independent of adherence measures. PMID:24320011

  12. Factors associated with poor CD4 and viral load outcomes in patients with HIV/AIDS.

    PubMed

    Syed, Imran Ahmed; Sulaiman, Syed Azhar Syed; Hassali, Mohammad Azmi; Syed, Shahzad Hasan; Shan, Lau Hui; Lee, Christopher K C

    2016-05-01

    Suboptimal viral suppression and CD4 response to antiretroviral treatment (HAART) is known to cause poor outcomes with the increase cost of treatment. We aimed to assess factors associated with such control among HIV/AIDS patients in Malaysia. Four hundred and six HIV/AIDS patients, using Antiretroviral Therapy (ART) for at least the past three months, treated as outpatients at medication therapy adherence clinics (MTAC) were recruited. CD4 cell counts, viral load readings along with co-variants such as socio-demographic factors, adverse drug reactions, comorbidities, and medication record were obtained. Statistical Package for Social Sciences (SPSS(®)) version 18 and STATA IC(®) version 12 were used for data analysis. CD4 counts were found highest among those within the age category 41-50 years (390.43 ± 272.28), female (402.64 ± 276.14), other ethnicities (400.20 ± 278.04), and participants with no formal education (414.87 ± 290.90). Patients experiencing adverse effects had a 2.28 (95%CI:1.25-4.18) fold greater risk of poor CD4 control, while patients with comorbidities had 2.46 (95%CI:1.02-5.91) fold greater risk of mild viral suppression. Adverse drug reactions, co-morbidities were found to be significantly associated with poor immunological and virological outcomes in HIV/AIDS patients. However, a comprehensive evaluation is needed to better understand other confounders. PMID:26399724

  13. [Immunopathogenesis of HIV infection].

    PubMed

    Alcamí, José; Coiras, Mayte

    2011-03-01

    Killing of CD4 lymphocytes and systemic immune suppression are the hallmarks of HIV infection. These milestones are produced by different mechanisms that draw a complex picture of AIDS immunopathogenesis. The role of the GALT system as a preferential target for HIV, chronic activation of the immune system and viral escape mechanisms are recent challenges that have changed our current view on the mechanisms leading to immune destruction and development of AIDS. In this article, the mechanisms of immune suppression, the evolution of immune response throughout the infection and the mechanisms of viral escape are analysed. PMID:21388715

  14. No Need for Lopinavir Dose Adjustment during Pregnancy: a Population Pharmacokinetic and Exposure-Response Analysis in Pregnant and Nonpregnant HIV-Infected Subjects.

    PubMed

    Salem, Ahmed Hamed; Jones, Aksana Kaefer; Santini-Oliveira, Marilia; Taylor, Graham P; Patterson, Kristine B; Nilius, Angela M; Klein, Cheri Enders

    2016-01-01

    Lopinavir-ritonavir is frequently prescribed to HIV-1-infected women during pregnancy. Decreased lopinavir exposure has been reported during pregnancy, but the clinical significance of this reduction is uncertain. This analysis aimed to evaluate the need for lopinavir dose adjustment during pregnancy. We conducted a population pharmacokinetic analysis of lopinavir and ritonavir concentrations collected from 84 pregnant and 595 nonpregnant treatment-naive and -experienced HIV-1-infected subjects enrolled in six clinical studies. Lopinavir-ritonavir doses in the studies ranged between 400/100 and 600/150 mg twice daily. In addition, linear mixed-effect analysis was used to compare the area under the concentration-time curve from 0 to 12 h (AUC0-12) and concentration prior to dosing (Cpredose) in pregnant women and nonpregnant subjects. The relationship between lopinavir exposure and virologic suppression in pregnant women and nonpregnant subjects was evaluated. Population pharmacokinetic analysis estimated 17% higher lopinavir clearance in pregnant women than in nonpregnant subjects. Lopinavir clearance values postpartum were 26.4% and 37.1% lower than in nonpregnant subjects and pregnant women, respectively. As the tablet formulation was estimated to be 20% more bioavailable than the capsule formulation, no statistically significant differences between lopinavir exposure in pregnant women receiving the tablet formulation and nonpregnant subjects receiving the capsule formulation were identified. In the range of lopinavir AUC0-12 or Cpredose values observed in the third trimester, there was no correlation between lopinavir exposure and viral load or proportion of subjects with virologic suppression. Similar efficacy was observed between pregnant women and nonpregnant subjects receiving lopinavir-ritonavir at 400/100 mg twice daily. The pharmacokinetic and pharmacodynamic results support the use of a lopinavir-ritonavir 400/100-mg twice-daily dose during pregnancy

  15. No Need for Lopinavir Dose Adjustment during Pregnancy: a Population Pharmacokinetic and Exposure-Response Analysis in Pregnant and Nonpregnant HIV-Infected Subjects

    PubMed Central

    Jones, Aksana Kaefer; Santini-Oliveira, Marilia; Taylor, Graham P.; Patterson, Kristine B.; Nilius, Angela M.; Klein, Cheri Enders

    2015-01-01

    Lopinavir-ritonavir is frequently prescribed to HIV-1-infected women during pregnancy. Decreased lopinavir exposure has been reported during pregnancy, but the clinical significance of this reduction is uncertain. This analysis aimed to evaluate the need for lopinavir dose adjustment during pregnancy. We conducted a population pharmacokinetic analysis of lopinavir and ritonavir concentrations collected from 84 pregnant and 595 nonpregnant treatment-naive and -experienced HIV-1-infected subjects enrolled in six clinical studies. Lopinavir-ritonavir doses in the studies ranged between 400/100 and 600/150 mg twice daily. In addition, linear mixed-effect analysis was used to compare the area under the concentration-time curve from 0 to 12 h (AUC0–12) and concentration prior to dosing (Cpredose) in pregnant women and nonpregnant subjects. The relationship between lopinavir exposure and virologic suppression in pregnant women and nonpregnant subjects was evaluated. Population pharmacokinetic analysis estimated 17% higher lopinavir clearance in pregnant women than in nonpregnant subjects. Lopinavir clearance values postpartum were 26.4% and 37.1% lower than in nonpregnant subjects and pregnant women, respectively. As the tablet formulation was estimated to be 20% more bioavailable than the capsule formulation, no statistically significant differences between lopinavir exposure in pregnant women receiving the tablet formulation and nonpregnant subjects receiving the capsule formulation were identified. In the range of lopinavir AUC0–12 or Cpredose values observed in the third trimester, there was no correlation between lopinavir exposure and viral load or proportion of subjects with virologic suppression. Similar efficacy was observed between pregnant women and nonpregnant subjects receiving lopinavir-ritonavir at 400/100 mg twice daily. The pharmacokinetic and pharmacodynamic results support the use of a lopinavir-ritonavir 400/100-mg twice-daily dose during pregnancy

  16. HIV-1 Drug Resistance and Second-line Treatment in Children Randomized to Switch at Low versus Higher RNA Thresholds

    PubMed Central

    Harrison, Linda; Melvin, Ann; Fiscus, Susan; Saidi, Yacine; Nastouli, Eleni; Harper, Lynda; Compagnucci, Alexandra; Babiker, Abdel; McKinney, Ross; Gibb, Diana; Tudor-Williams, Gareth

    2015-01-01

    Background The PENPACT-1 trial compared virologic thresholds to determine when to switch to second-line antiretroviral therapy (ART). Using PENPACT-1 data, we aimed to describe HIV-1 drug resistance accumulation on first-line ART by virologic threshold. Methods PENPACT-1 had a 2x2 factorial design, randomizing HIV-infected children to start protease inhibitor (PI) versus non-nucleoside reverse transcriptase inhibitor (NNRTI) based ART, and switch at a 1000c/ml versus 30000c/ml threshold. Switch-criteria were: not achieving the threshold by week 24, confirmed rebound above the threshold thereafter, or CDC-C event. Resistance tests were performed on samples ≥1000c/ml before switch, re-suppression and at 4-year/trial-end. Results Sixty-seven children started PI-based ART and were randomized to switch at 1000c/ml (PI-1000), 64 PIs and 30000c/ml (PI-30000), 67 NNRTIs and 1000c/ml (NNRTI-1000), and 65 NNRTI and 30000c/ml (NNRTI-30000). Ninety-four (36%) children reached the 1000c/ml switch-criteria during 5 years follow-up. In 30000c/ml threshold arms, median time from 1000c/ml to 30000c/ml switch-criteria was 58 (PI) versus 80 (NNRTI) weeks (P=0.81). In NNRTI-30000 more NRTI resistance mutations accumulated than other groups. NNRTI mutations were selected before switching at 1000c/ml (23% NNRTI-1000, 27% NNRTI-30000). Sixty-two children started abacavir+lamivudine, 166 lamivudine+zidovudine or stavudine, and 35 other NRTIs. The abacavir+lamivudine group acquired fewest NRTI mutations. Of 60 switched to second-line, 79% PI-1000, 63% PI-30000, 64% NNRTI-1000 and 100% NNRTI-30000 were <400c/ml 24 weeks later. Conclusion Children on first-line NNRTI-based ART who were randomized to switch at a higher virologic threshold developed the most resistance, yet re-suppressed on second-line. An abacavir+lamivudine NRTI combination seemed protective against development of NRTI resistance. PMID:26322666

  17. HIV-associated neurocognitive disorders.

    PubMed

    Sanmarti, Montserrat; Ibáñez, Laura; Huertas, Sonia; Badenes, Dolors; Dalmau, David; Slevin, Mark; Krupins