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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 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

  15. 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

  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

    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

  1. 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

  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

    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

  10. 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

  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

    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

  6. 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

  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 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

  15. 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

  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. 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

  17. 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.

  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. 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

  2. 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

  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. 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

  18. 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

  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

    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 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

  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. 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

  10. 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

  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. 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

  16. 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

  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. 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...

  19. 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.

  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

    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 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

  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 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

  1. 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

  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