Jeffrey T. Schouten

Effects of metformin and rosiglitazone in HIV-infected patients with hyperinsulinemia and elevated waist/hip ratio.

Objective:To evaluate the effects of metformin and rosiglitazone, alone or in combination, on fat distribution, insulin sensitivity, and lipids in HIV-infected patients with insulin resistance and changes in fat distribution. Methods:A total of 105 subjects were randomly assigned to receive metformin (500 mg twice a day increasing to 1000 mg twice a day after 2 weeks) with rosiglitazone placebo (Met/P, N = 26); rosiglitazone (4 mg/day) with metformin placebo (Rosi/P, N = 27); rosiglitazone (4 mg/day) plus metformin (500 mg twice a day increasing to 1000 mg twice a day after 2 weeks; Met/Rosi, N = 25); or dual placebo (P/P, N = 27) for 16 weeks. Efficacy assessments included oral glucose tolerance testing, abdominal computed tomography, whole-body dual-energy X-ray absorptiometry, and the measurement of fasting lipids and other biochemical indices. Safety was monitored throughout. Intent-to-treat analyses were performed using non-parametric methods. Results:The median insulin area under the curve (AUC) decreased significantly compared with baseline in both groups randomly assigned to rosiglitazone (Rosi/P −25.7 μIU/ml, P = 0.012; Met/Rosi −17.7 μIU/ml, P = 0.002); and tended to decrease in the Met/P group (−11.1 μIU/ml, P = 0.058). The change in AUC with combination therapy was significant compared with placebo (P = 0.032). No treatment was associated with significant changes in visceral or subcutaneous abdominal fat. Leg fat increased in subjects on Rosi/P compared with placebo (+4.8 versus −8.3%, P = 0.034). Rosiglitazone, but not metformin, increased adiponectin but also increased LDL-cholesterol and decreased HDL-cholesterol. Gastrointestinal effects occurred frequently in subjects on metformin. Conclusion:Both treatments improved insulin sensitivity, but neither reduced visceral fat. Rosiglitazone may increase subcutaneous fat in some individuals.

Evaluating Research and Impact: A Bibliometric Analysis of Research by the NIH/NIAID HIV/AIDS Clinical Trials Networks

Evaluative bibliometrics uses advanced techniques to assess the impact of scholarly work in the context of other scientific work and usually compares the relative scientific contributions of research groups or institutions. Using publications from the National Institute of Allergy and Infectious Diseases (NIAID) HIV/AIDS extramural clinical trials networks, we assessed the presence, performance, and impact of papers published in 2006–2008. Through this approach, we sought to expand traditional bibliometric analyses beyond citation counts to include normative comparisons across journals and fields, visualization of co-authorship across the networks, and assess the inclusion of publications in reviews and syntheses. Specifically, we examined the research output of the networks in terms of the a) presence of papers in the scientific journal hierarchy ranked on the basis of journal influence measures, b) performance of publications on traditional bibliometric measures, and c) impact of publications in comparisons with similar publications worldwide, adjusted for journals and fields. We also examined collaboration and interdisciplinarity across the initiative, through network analysis and modeling of co-authorship patterns. Finally, we explored the uptake of network produced publications in research reviews and syntheses. Overall, the results suggest the networks are producing highly recognized work, engaging in extensive interdisciplinary collaborations, and having an impact across several areas of HIV-related science. The strengths and limitations of the approach for evaluation and monitoring research initiatives are discussed.

A prospective study of hearing changes after beginning zidovudine or didanosine in HIV-1 treatment-naïve people

BackgroundWhile hearing loss in HIV-infected people after beginning nucleoside reverse transcriptase inhibitors (NRTIs) has been reported, there have been no prospective studies that measured hearing changes longitudinally in treatment-naïve HIV-infected subjects following initiation of regimens containing NRTIs. The goal of this study was to conduct a prospective assessment of the contribution of zidovudine (ZDV) and didanosine (ddI) to hearing lossMethods/designA prospective observational pilot study to determine whether ZDV or ddI, alone or in combination, are associated with sensorineural hearing loss in HIV-infected persons. Changes in hearing levels at all frequencies and in low and high frequency pure tone averages were measured at baseline, 16, and 32 weeks after initiating antiretroviral therapy.DiscussionTreatment with ZDV and ddI did not result in loss of hearing, even after taking into account noise exposure, immune status and age. The results of this prospective pilot study do not support the notion that treatment with nucleoside antiretrovirals damages hearing.

Incidence of Non-AIDS-Defining Cancer in Antiretroviral Treatment-Naïve Subjects after Antiretroviral Treatment Initiation: An ACTG Longitudinal Linked Randomized Trials Analysis

Background: Prospective data on factors associated with the non-AIDS-defining cancer (NADC) incidence in HIV-infected individuals are limited. Methods: We examined the NADC incidence in 3,158 antiretroviral treatment (ART)-naïve subjects after ART initiation in AIDS Clinical Trials Group trials; extended follow-up was available for 2,122 subjects. Poisson regression was used to examine the associations between covariates and incident NADC. Results: At ART initiation, subjects (median age 37 years) were 40% non-Hispanic whites, and 82% were male; 23% had CD4+ T cell count ≤50 cells/mm3 and 25% had CD4 >350 cells/mm3. Median follow-up was 3.8 years. Among 64 incident NADCs, the most common were 8 anal cancers, 8 basal cell carcinomas, 8 Hodgkin’s disease, and 6 lung cancers. In univariate models, age, smoking and recent (time-updated) CD4 were associated with incident NADC. There was no association between initial ART drug class (protease inhibitor, nucleoside reverse transcriptase inhibitor and nonnucleoside reverse transcriptase inhibitor) and NADC. After adjusting for age, race and sex: smoking [relative risk = 2.12 (95% CI = 1.1–4.08)] and recent CD4 (≤50 cells/mm3: 3.58, 1.22–10.45; 51–200 cells/mm3: 2.54, 1.30–5.0; 201–350 cells/mm3: 2.37, 1.32–4.26 vs. >350 cells/mm3) were associated with NADC. Conclusion: Smoking and lower recent CD4 levels, but not initial ART drug class, were associated with NADC. Strategies for maintaining higher CD4 cell counts and successful smoking cessation may reduce the NADC incidence in the HIV-infected population.

Metabolic syndrome before and after initiation of antiretroviral therapy in treatment-naïve HIV-infected individuals

Background:Metabolic syndrome (MetS) is a cluster of risk factors for cardiovascular disease and diabetes, many of which are associated with HIV and antiretroviral therapy (ART). We examined prevalence and incidence of MetS and risk factors for MetS in ART-naive HIV-infected individuals starting ART. Methods:MetS, defined by the Adult Treatment Panel III criteria, was assessed at and after ART initiation in HIV-infected individuals who enrolled in selected AIDS Clinical Trials Group trials and were followed long-term after these trials as part of the AIDS Clinical Trials Group Longitudinal Linked Randomized Trials cohort. Cox proportional hazards models were used to examine risk factors of incident MetS. Adjusted hazard ratios (aHRs) and 95% confidence intervals (CI) are reported. Results:At ART initiation, the prevalence of MetS was 20%. After ART initiation, the incidence of MetS was 8.5 per 100 person-years. After adjusting for demographics and body mass index, the risk of MetS was decreased for CD4+ T-cell counts >50 cells per cubic millimeter (aHR = 0.62, 95% CI = 0.43 to 0.90 for CD4 >500), and the risk was increased for HIV-1 RNA >400 copies per milliliter (aHR = 1.55 (95% CI = 1.25 to 1.92) and use of a protease-inhibitor (PI)–based regimen [relative to no PI use, aHR = 1.25 (95% CI = 1.04 to 1.51) for any PI use]. Conclusions:In HIV-infected individuals on ART, virologic suppression and maintenance of high CD4+ T-cell counts may be potentially modifiable factors that can reduce the risk of MetS. The effect of MetS on the risk of cardiovascular disease and diabetes needs to be evaluated.

Substitution of nevirapine because of efavirenz toxicity in AIDS Clinical Trials Group A5095.

In AIDS Clinical Trials Group A5095, 9% of participants who experienced an adverse event related to efavirenz substituted nevirapine. Most adverse events resolved; 15 participants ultimately discontinued nevirapine therapy. Grade 3/4 hepatotoxicity was observed in 14% of individuals who substituted nevirapine, compared with 6% who continued efavirenz therapy. Substitution of nevirapine because of efavirenz toxicity was generally safe and efficacious. Clinical trials registration. NCT00013520 .

Evidence for Limited Genetic Compartmentalization of HIV-1 between Lung and Blood

Background HIV-1 is frequently detected in the lungs of infected individuals and is likely important in the development of pulmonary opportunistic infections. The unique environment of the lung, rich in alveolar macrophages and with specialized local immune responses, may contribute to differential evolution or selection of HIV-1. Methodology and Findings We characterized HIV-1 in the lung in relation to contemporaneous viral populations in the blood. The C2-V5 region of HIV-1 env was sequenced from paired lung (induced sputum or bronchoalveolar lavage) and blood (plasma RNA and proviral DNA from sorted or unsorted PBMC) from 18 subjects. Compartmentalization between tissue pairs was assessed using 5 established tree or distance-based methods, including permutation tests to determine statistical significance. We found statistical evidence of compartmentalization between lung and blood in 10/18 subjects, although lung and blood sequences were intermingled on phylogenetic trees in all subjects. The subject showing the greatest compartmentalization contained many nearly identical sequences in BAL sample, suggesting clonal expansion may contribute to reduced viral diversity in the lung in some cases. However, HIV-1 sequences in lung were not more homogeneous overall, nor were we able to find a lung-specific genotype associated with macrophage tropism in V3. In all four subjects in whom predicted X4 genotypes were found in blood, predicted X4 genotypes were also found in lung. Conclusions Our results support a picture of continuous migration of HIV-1 between circulating blood and lung tissue, with perhaps a very limited degree of localized evolution or clonal replication.

Efavirenz-Based Regimens in Treatment-Naive Patients with a Range of Pretreatment HIV-1 RNA Levels and CD4 Cell Counts

The potency of 2 nucleoside reverse transcriptase inhibitors (NRTIs) and efavirenz in patients with higher viral loads (VLs) or low CD4 cell counts remains uncertain. Virologic failure and changes in CD4 count in relation to pretreatment VL and CD4 count were evaluated in treatment-naive patients randomized to treatment groups that received 2 or 3 NRTIs with efavirenz. Over 3 years, the risk of virologic failure was not significantly different among subgroups categorized according to pretreatment VL or CD4 count. No significant differences among subgroups were observed for CD4 count changes, except in patients with high pretreatment VL. There were no significant differences among subgroups with respect to treatment responses. These results demonstrate the potency of efavirenz-containing regimens across a spectrum of pretreatment VLs and CD4 counts.

Intensification of a triple-nucleoside regimen with tenofovir or efavirenz in HIV-1-infected patients with virological suppression.

Objective:To compare a quadruple-nucleoside with an efavirenz-containing regimen for treatment of HIV-1 infection. Design:A randomized, open-label study of the AIDS Clinical Trials Group (ACTG). Methods:Subjects receiving zidovudine/lamivudine/abacavir on ACTG 5095 with HIV-1 RNA less than 200 copies/ml were randomly assigned to intensify either with tenofovir or efavirenz. Subjects were followed for time to treatment failure, defined as either virological failure or treatment discontinuation. Analyses were intent-to-treat. Results:One hundred and seventy subjects (21% women; 56% non-white) entered the study. At baseline, 95 and 73% had HIV-1-RNA levels less than 200 and 50 copies/ml, respectively; the median CD4 cell count was 453 cells/μl. Over a median 79 weeks follow-up, 165 (97%) completed the study, three (2%) discontinued, and two (1%) died. Treatment failure occurred in 31 subjects: 18 (21%) (quadruple nucleosides) and 13 (15%) (efavirenz-containing regimen); however the failure–time curves crossed and demonstrated a non-constant treatment effect over time, characterized by more early treatment failures on the efavirenz-containing regimen and more late treatment failures on the four-nucleoside regimen. HIV-1 RNA remained suppressed in more than 88% of subjects to less than 200 copies/ml and in more than 78% to less than 50 copies/ml at weeks 24, 48, and 72, without differences by treatment arm. There were no significant differences between the regimens in CD4 cell increases, time to new grade 3/4 adverse events, or adherence. Conclusion:The safety, tolerability, and efficacy of the four-nucleoside regimen were not significantly different from the efavirenz-containing regimen. These pilot data support further investigation of the quadruple-nucleoside regimen.

Modeling the dissemination and uptake of clinical trials results

A select set of highly cited publications from the National Institutes of Health (NIH) HIV/AIDS Clinical Trials Networks was used to illustrate the integration of time interval and citation data, modeling the progression, dissemination, and uptake of primary research findings. Following a process marker approach, the pace of initial utilization of this research was measured as the time from trial conceptualization, development and implementation, through results dissemination and uptake. Compared to earlier studies of clinical research, findings suggest that select HIV/AIDS trial results are disseminated and utilized relatively rapidly. Time-based modeling of publication results as they meet specific citation milestones enabled the observation of points at which study results were present in the literature summarizing the evidence in the field. Evaluating the pace of clinical research, results dissemination, and knowledge uptake in synthesized literature can help establish realistic expectations for the time course of clinical trials research and their relative impact toward influencing clinical practice.