Hector Bolivar

Atazanavir Plus Ritonavir or Efavirenz as Part of a 3-Drug Regimen for Initial Treatment of HIV-1: A Randomized Trial

BACKGROUND Limited data compare once-daily options for initial therapy for HIV-1. OBJECTIVE To compare time to virologic failure; first grade-3 or -4 sign, symptom, or laboratory abnormality (safety); and change or discontinuation of regimen (tolerability) for atazanavir plus ritonavir with efavirenz-containing initial therapy for HIV-1. DESIGN A randomized equivalence trial accrued from September 2005 to November 2007, with median follow-up of 138 weeks. Regimens were assigned by using a central computer, stratified by screening HIV-1 RNA level less than 100 000 copies/mL or 100 000 copies/mL or greater; blinding was known only to the site pharmacist. (ClinicalTrials.gov registration number: NCT00118898) SETTING 59 AIDS Clinical Trials Group sites in the United States and Puerto Rico. PATIENTS Antiretroviral-naive patients. INTERVENTION Open-label atazanavir plus ritonavir or efavirenz, each given with with placebo-controlled abacavir-lamivudine or tenofovir disoproxil fumarate (DF)-emtricitabine. MEASUREMENTS Primary outcomes were time to virologic failure, safety, and tolerability events. Secondary end points included proportion of patients with HIV-1 RNA level less than 50 copies/mL, emergence of drug resistance, changes in CD4 cell counts, calculated creatinine clearance, and lipid levels. RESULTS 463 eligible patients were randomly assigned to receive atazanavir plus ritonavir and 465 were assigned to receive efavirenz, both with abacavir-lamivudine; 322 (70%) and 324 (70%), respectively, completed follow-up. The respective numbers of participants in each group who received tenofovir DF-emtricitabine were 465 and 464; 342 (74%) and 343 (74%) completed follow-up. Primary efficacy was similar in the group that received atazanavir plus ritonavir and and the group that received efavirenz and did not differ according to whether abacavir-lamivudine or tenofovir DF-emtricitabine was also given. Hazard ratios for time to virologic failure were 1.13 (95% CI, 0.82 to 1.56) and 1.01 (CI, 0.70 to 1.46), respectively, although CIs did not meet prespecified criteria for equivalence. The time to safety (P = 0.048) and tolerability (P < 0.001) events was longer in persons given atazanavir plus ritonavir than in those given efavirenz with abacavir-lamivudine but not with tenofovir DF-emtricitabine. LIMITATIONS Neither HLA-B*5701 nor resistance testing was the standard of care when A5202 enrolled patients. The third drugs, atazanavir plus ritonavir and efavirenz, were open-label; the nucleoside reverse transcriptase inhibitors were prematurely unblinded in the high viral load stratum; and 32% of patients modified or discontinued treatment with their third drug. CONCLUSION Atazanavir plus ritonavir and efavirenz have similar antiviral activity when used with abacavir-lamivudine or tenofovir DF-emtricitabine. PRIMARY FUNDING SOURCE National Institutes of Health.

Atazanavir Plus Ritonavir or Efavirenz as Part of a 3-Drug Regimen for Initial Treatment of HIV-1

Few studies have compared once-daily treatment regimens for HIV-1. This randomized trial in antiretroviral-naive patients with HIV-1 showed that a once-daily ritonavir-boosted protease inhibitor re...

Fractures after antiretroviral initiation.

Background:Bone mineral density declines by 2–6% within 1–2 years after initiation of antiretroviral therapy (ART); however, it is uncertain whether this results in an immediate or cumulative increase in fracture rates. Methods:We evaluated the incidence and predictors of fracture in 4640 HIV-positive participants from 26 randomized ART studies followed in the AIDS Clinical Trials Group (ACTG) Longitudinal-Linked Randomized Trial study for a median of 5 years. Fragility and nonfragility fractures were recorded prospectively at semiannual visits. Incidence was calculated as fractures/total person-years. Cox proportional hazards models evaluated effects of traditional fracture risks, HIV disease characteristics, and ART exposure on fracture incidence. Results:Median (interquartile range) age was 39 (33, 45) years; 83% were men, 48% white, and median nadir CD4 cell count was 187 (65, 308) cells/&mgr;l. Overall, 116 fractures were reported in 106 participants with median time-to-first fracture of 2.3 years. Fracture incidence was 0.40 of 100 person-years among all participants and 0.38 of 100 person-years among 3398 participants who were ART naive at enrollment into ACTG parent studies. Among ART-naive participants, fracture rates were higher within the first 2 years after ART initiation (0.53/100 person-years) than subsequent years (0.30/100 person-years). In a multivariate analysis of ART-naive participants, increased hazard of fracture was associated with current smoking and glucocorticoid use but not with exposure to specific antiretrovirals. Conclusion:Fracture rates were higher within the first 2 years after ART initiation, relative to subsequent years. However, continuation of ART was not associated with increasing fracture rates in these relatively young HIV-positive individuals.

Immune Activation in HIV-Infected Aging Women on Antiretrovirals—Implications for Age-Associated Comorbidities: A Cross-Sectional Pilot Study

Background Persistent immune activation and microbial translocation associated with HIV infection likely place HIV-infected aging women at high risk of developing chronic age-related diseases. We investigated immune activation and microbial translocation in HIV-infected aging women in the post-menopausal ages. Methods Twenty-seven post-menopausal women with HIV infection receiving antiretroviral treatment with documented viral suppression and 15 HIV-negative age-matched controls were enrolled. Levels of immune activation markers (T cell immune phenotype, sCD25, sCD14, sCD163), microbial translocation (LPS) and biomarkers of cardiovascular disease and impaired cognitive function (sVCAM-1, sICAM-1 and CXCL10) were evaluated. Results T cell activation and exhaustion, monocyte/macrophage activation, and microbial translocation were significantly higher in HIV-infected women when compared to uninfected controls. Microbial translocation correlated with T cell and monocyte/macrophage activation. Biomarkers of cardiovascular disease and impaired cognition were elevated in women with HIV infection and correlated with immune activation. Conclusions HIV-infected antiretroviral-treated aging women who achieved viral suppression are in a generalized status of immune activation and therefore are at an increased risk of age-associated end-organ diseases compared to uninfected age-matched controls.

Reply to: “ CCL3L1 and HIV/AIDS susceptibility” and “Experimental aspects of copy number variant assays at CCL3L1 ”

Reply to: “ CCL3L1 and HIV/AIDS susceptibility” and “Experimental aspects of copy number variant assays at CCL3L1 ”

Reply to: "Experimental aspects of copy number variant assays at CCL3L1".

Reply to: “ CCL3L1 and HIV/AIDS susceptibility” and “Experimental aspects of copy number variant assays at CCL3L1 ”

Randomized study of dual versus single ritonavir-enhanced protease inhibitors for protease inhibitor-experienced patients with HIV.

Abstract Purpose: To compare activity and safety of a regimen containing lopinavir/ritonavir (LPV/r) + fosamprenavir (FPV) to regimens with LPV/r or FPV + r and to test the hypothesis that a ritonavir-enhanced dual protease inhibitor (PI) regimen has better antiviral activity. Method: This study was a multicenter, open-label, randomized study. HIV-infected adults with prior PI failure were selectively randomized based on prior PI experience to either LPV/r, FPV + r, or LPV/r + FPV. All patients received tenofovir DF and 1 to 2 nucleoside reverse transcriptase inhibitors. Results: Baseline characteristics were similar across arms. Study enrollment and follow-up were stopped early (N = 56) because pharmacokinetic analyses showed significantly lower LPV and FPV exposures in the dual-PI arm. At Week 24, proportions achieving >1 log10 decline in HIV RNA or <50 copies/mL in the dual-PI versus single-PI arms combined were 75% vs. 61% in intent-to-treat (ITT, p = .17) and 100% vs. 64% in as-treated (AT) analyses (p = .02), respectively. Median CD4+ T cell/mm3 increases were 81 vs. 41 (ITT, p = .4) and 114 vs. 43 (AT, p = .08), respectively. Clinical events and toxicity rates were not different between arms. Conclusion: The trial was unable to show a difference between dual versus single PIs in ITT analyses but favored dual PIs in AT analyses.

Bacterial vaginosis is associated with loss of gamma delta T cells in the female reproductive tract in women in the Miami Women Interagency HIV Study (WIHS): A cross sectional study

Bacterial vaginosis (BV) is the most common female reproductive tract infection and is associated with an increased risk of acquiring and transmitting HIV by a mechanism that is not well understood. Gamma delta (GD) T cells are essential components of the adaptive and innate immune system, are present in the female reproductive tract, and play an important role in epithelial barrier protection. GD1 cells predominate in the mucosal tissue and are important in maintaining mucosal integrity. GD2 cells predominate in peripheral blood and play a role in humoral immunity and in the immune response to pathogens. HIV infection is associated with changes in GD T cells frequencies in the periphery and in the female reproductive tract. The objective of this study is to evaluate if changes in vaginal flora occurring with BV are associated with changes in endocervical GD T cell responses, which could account for increased susceptibility to HIV. Seventeen HIV-infected (HIV+) and 17 HIV-uninfected (HIV-) pre-menopausal women underwent collection of vaginal swabs and endocervical cytobrushes. Vaginal flora was assessed using the Nugent score. GD T cells were assessed in cytobrush samples by flow cytometry. Median Nugent score was 5.0 and 41% of women had abnormal vaginal flora. In HIV uninfected women there was a negative correlation between Nugent score and cervical GD1 T cells (b for interaction = - 0.176, p<0.01); cervical GD1 T cells were higher in women with normal vaginal flora than in those with abnormal flora (45.00% vs 9.95%, p = 0.005); and cervical GD2 T cells were higher in women with abnormal flora than in those with normal flora (1.70% vs 0.35%, p = 0.023). GD T cells in the genital tract are protective (GD1) and are targets for HIV entry (GD2). The decrease in cervical GD1 and increase in GD2 T cells among women with abnormal vaginal flora predisposes women with BV to HIV acquisition. We propose to use GD T cell as markers of female genital tract vulnerability to HIV.

Loss of Intra-Epithelial Endocervical Gamma Delta (GD) 1 T Cells in HIV-Infected Women.

Human gamma delta (GD) T cells play a well‐documented role in epithelial barrier surveillance and protection. Two subsets of GD T cells, defined by the use of either the Vdelta2 (GD2) or Vdelta1 (GD1) TCR, predominate. We hypothesized that endocervical GD T cells play important role in lower genital tract anti‐HIV immune responses.

Cognitive trajectories over 4 years among HIV-infected women with optimal viral suppression

Objective: To determine whether persistent viral suppression alters cognitive trajectories among HIV-infected (HIV+) women on combination antiretroviral therapy (cART) by investigating performance longitudinally in uninfected (HIV−) and 3 groups of HIV+ women: those with consistent viral suppression after continuous cART use (VS), those without consistent virologic suppression despite continuous cART use (NVS), and those without consistent virologic suppression after intermittent cART use (Int NVS). Methods: Two hundred thirty-nine VS, 220 NVS, 172 Int NVS, and 301 HIV− women from the Womens Interagency HIV Study (WIHS) completed neuropsychological testing every 2 years for 3 visits between 2009 and 2013. Mixed-effects regressions were used to examine group differences on continuous T scores and categorical measures of impairment (T score <40). Results: On global function, VS women demonstrated lower scores and were more likely to score in the impaired range than HIV− women (p = 0.01). These differences persisted over time (group × time, p > 0.39). VS women demonstrated lower learning and memory scores than HIV− women (p < 0.05) and lower attention/working memory and fluency scores than HIV− and NVS women (p < 0.05). Group differences in scores persisted over time. Categorically, VS women were more likely to be impaired on attention/working memory and executive function than HIV− women (p < 0.05). On motor skills, VS and NVS women showed a greater decline and were more likely to be impaired than HIV− women (p < 0.05). Conclusions: Cognitive difficulties remain among HIV+ women despite persistent viral suppression. In some instances, VS women are worse than NVS women, reinforcing the need for novel adjunctive therapies to attenuate cognitive problems.