Showing papers by "Jeffrey L. Lennox published in 2015"

Healthy HIV-1-Infected Individuals on Highly Active Antiretroviral Therapy Harbor HIV-1 in Their Alveolar Macrophages

Abstract: In a prospective cross-sectional study we quantified HIV viral load within the alveolar macrophage in a cohort of healthy HIV-infected subjects who did not have medical comorbidities or smoke cigarettes to determine if alveolar macrophage proviral DNA was associated with alveolar macrophage phagocytic immune dysfunction. We enrolled 23 subjects who underwent bronchoscopy and bronchoalveolar lavage. Alveolar macrophages were isolated and HIV-1 RNA was quantified in the cells using the Abbott RealTime HIV-1 Assay. Proviral DNA was qualitatively measured using a modified version of the HIV-1 RNA assay. Phagocytosis measured by incubating alveolar macrophages with FITC-labeled Staphylococcus aureus and determining fluorescence with a Zeiss inverted microscope. Phagocytic index was calculated as (% positive cells×mean channel fluorescence)/100. Sixteen subjects had (+) proviral DNA and seven had (−) proviral DNA in their alveolar macrophages. Of all subjects 100% in both groups were on highly active a...

Comparison of the Metabolic Effects of Ritonavir-Boosted Darunavir or Atazanavir Versus Raltegravir, and the Impact of Ritonavir Plasma Exposure: ACTG 5257

Abstract: Background. Metabolic effects following combination antiretroviral therapy (cART) vary by regimen type. Changes in metabolic effects were assessed following cART in the AIDS Clinical Trials Group (ACTG) A5257 study, and correlated with plasma ritonavir trough concentrations (C24). Methods. Treatment-naive adult subjects were randomized to ritonavir-boosted atazanavir or darunavir, or raltegravir-based cART. Changes in lipids and other metabolic outcomes over time were estimated. Differences between arms were estimated with 97.5% confidence intervals and compared using pairwise Student t tests. Associations between ritonavir C24 and lipid changes at week 48 were evaluated via linear regression. Results. Analyses included 1797 subjects with baseline fasting data. Baseline lipid profiles and metabolic syndrome rates (approximately 21%) were similar across arms. Comparable increases occurred in total cholesterol, triglycerides, and low-density lipoprotein cholesterol with the boosted protease inhibitors (PIs); each PI had greater increases relative to raltegravir (all P ≤ .001 at week 96). Metabolic syndrome incident rates by week 96 (approximately 22%) were not different across arms. Ritonavir C24 was not different by arm (P = .89) (median, 69 ng/mL and 74 ng/mL in the atazanavir and darunavir arms, respectively) and were not associated with changes in lipid measures (all P > .1). Conclusions. Raltegravir produced the most favorable lipid profile. Metabolic syndrome rates were high at baseline and increased to the same degree in all arms. Ritonavir C24 was not different in the PI arms and had no relationship with the modest but comparable increases in lipids observed with either atazanavir or darunavir. The long-term clinical significance of the lipid changes noted with the PIs relative to raltegravir deserves further evaluation. Clinical Trials Registration. {"type":"clinical-trial","attrs":{"text":"NCT 00811954","term_id":"NCT00811954"}}NCT 00811954.

Screening for UGT1A1 Genotype in Study A5257 Would Have Markedly Reduced Premature Discontinuation of Atazanavir for Hyperbilirubinemia

Abstract: Background. Some patients are not prescribed atazanavir because of concern about possible jaundice. Atazanavir-associated hyperbilirubinemia correlates with UGT1A1 rs887829 genotype. We examined bilirubin-related discontinuation of atazanavir in participants from AIDS Clinical Trials Group Study A5257. Methods. Discriminatory properties of UGT1A1 T/T genotype for predicting bilirubin-related atazanavir discontinuation through 96 weeks after antiretroviral initiation were estimated. Results. Genetic analyses involved 1450 participants, including 481 who initiated randomized atazanavir/ritonavir. Positive predictive values of rs887829 T/T for bilirubin-related discontinuation of atazanavir (with 95% confidence intervals [CIs]) were 20% (CI, 9%-36%) in Black, 60% (CI, 32%-84%) in White, and 29% (CI, 8%-58%) in Hispanic participants; negative predictive values were 97% (CI, 93%-99%), 95% (CI, 90%-98%), and 97% (CI, 90%-100%), respectively. Conclusions. Bilirubin-related discontinuation of atazanavir was rare in participants not homozygous for rs887829 T/T, regardless of race or ethnicity. We hypothesize that the higher rate of discontinuation among White participants homozygous for rs887829 T/T may reflect differences in physical manifestations of jaundice by race and ethnicity. Selective avoidance of atazanavir initiation among individuals with T/T genotypes would markedly reduce the likelihood of bilirubin-related discontinuation of atazanavir while allowing atazanavir to be prescribed to the majority of individuals. This genetic association will also affect atazanavir/cobicistat.

Three Nonnucleoside Reverse Transcriptase Inhibitor–Sparing Antiretroviral Regimens for Treatment-Naive Volunteers Infected With HIV-1

Abstract: IN RESPONSE: Dr. Stephan proposes a potential bias against ritonavir-boosted atazanavir due to the necessity to reimburse ritonavir copayments. He also suggests that efforts to ensure adequate representation of women may have enriched the study for impoverished participants predisposed to discontinue ritonavir-containing regimens to avoid costs. We did not target any particular socioeconomic subgroup of women for enrollment nor have we suggested that we did so. The potential biases associated with ritonavir use during the study were anticipated and addressed during trial design. As noted in the article, all participants not receiving ritonavir from a federal insurance program were reimbursed in a timely manner. Furthermore, the protocol encouraged sites to make within-class regimen switches; as a result, 72% of those who discontinued ritonavir-boosted atazanavir switched to ritonavir-boosted darunavir. Dr. Stephan also cites 3 studies in which hyperbilirubinemia was not a common reason for atazanavir cessation. One of these studies (ACTG A5142) did not include atazanavir. Another study (ACTG A5202) placed stringent limitations on regimen switching because it compared not only ritonavir-boosted atazanavir with efavirenz but also separate nucleoside reverse transcriptase inhibitor combinations. The third study (CASTLE [Comparing the Antiviral Efficacy and Safety of Atazanavir/Ritonavir With Lopinavir/Ritonavir, Each in Combination With Fixed-Dose TenofovirEmtricitabine in HIV-1Infected Treatment-Naive Subjects]) compared a 3-pill, once-daily boosted atazanavir regimen with a 6-pill, twice-daily boosted lopinavir regimen, a design that may have discouraged regimen changes. Our study shows that some participants who develop cosmetically intolerable hyperbilirubinemia will choose to change therapy if equally effective and convenient options are available. We agree with Drs. Lapadula and Gori that careful planning is essential for studies that include discontinuation of treatment due to toxicity as an end point. For this reason, toxicity end points in our study were predefined and strictly categorized according to the Division of AIDS toxicity table. Tolerability was also strictly defined as the intent of the participant to discontinue the treatment because of toxicity. We believe that participant-driven tolerability discontinuations for toxicity are a necessary and useful measure for comparing commercially available medications. However, we agree with Drs. Lapadula and Gori that study of observational cohorts can further inform results from randomized studies. In a recent analysis, 11.7% of Korean patients discontinued atazanavir because of jaundice (1) compared with 7.8% of participants in our study. This rate of discontinuation took place despite Koreans' having a lower frequency of a polymorphism in uridine 5'-diphosphate glucuronosyltransferase 1A1 associated with atazanavir-induced hyperbilirubinemia than the HIV-1infected population in the United States (2, 3). Our study population may therefore have facilitated our ability to detect this important tolerability difference between ritonavir-boosted protease inhibitors recommended by the U.S. Department of Health and Human Services.