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Background: The restricted mean survival time (RMST) measures have not been used as primary measure of efficacy in HIV/AIDS clinical trials. In this work, we aim to compare analysis based on the difference in RMST ([DELTA]-RMST) measure and 2 other treatment-effect measures in a recent HIV equivalence trial, and to investigate the performance and characteristics of [DELTA]-RMST-based analysis in a simulation study. Setting and Methods: We reanalyzed a recent HIV equivalence trial (ACTG A5257 trial) with hazard ratio and [DELTA]-RMST, and then compared the results with the original analysis based on risk difference estimated by Kaplan-Meier curves (RDKM). In a simulation study, we investigated the performance and operating characteristics of [DELTA]-RMST-based analysis in the setting of non-proportional hazards (PH) ratio. Results: In the ACTG A5257 trial, analyses based on [DELTA]-RMST globally led to similar conclusions as the published finding based on RDKM. By contrast, analyses based on hazard ratio provided some discordant equivalence conclusions compared both with the initial analyses based on RDKM and the [DELTA]-RMST. Results of simulation study indicate that the violation of the PH assumption has an impact on [DELTA]-RMST-based analysis regarding the probability of declaring equivalence. Conclusions: Although the RMST-based analysis is an alternative measure of efficacy in HIV/AIDS, clinical trials such an analysis can be strongly impacted by departures from the PH assumption. [ABSTRACT FROM AUTHOR]

The article presents medical research into racial differences in virologic failure associated with quality of life and patient compliance on initial HIV infection therapy with efavirenz. This is a placebo-controlled clinical trial of HIV-positive black, white, and Hispanic persons randomized to zidovudine/lamivudine/abacavir plus efavirenz, zidovudine/lamivudine plus efavirenz, or zidovudine/lamivudine/abacavir without efavirenz.

Prior candidate gene studies have associated CYP2B6 516G→T [rs3745274] and 983T→C [rs28399499] with increased plasma efavirenz exposure. We sought to identify novel variants associated with efavirenz pharmacokinetics.Antiretroviral therapy-naive AIDS Clinical Trials Group studies A5202, A5095, and ACTG 384 included plasma sampling for efavirenz pharmacokinetics. Log-transformed trough efavirenz concentrations (Cmin) were previously estimated by population pharmacokinetic modeling. Stored DNA was genotyped with Illumina HumanHap 650Y or 1MDuo platforms, complemented by additional targeted genotyping of CYP2B6 and CYP2A6 with MassARRAY iPLEX Gold. Associations were identified by linear regression, which included principal component vectors to adjust for genetic ancestry.Among 856 individuals, CYP2B6 516G→T was associated with efavirenz estimated Cmin (P=8.5×10-41). After adjusting for CYP2B6 516G→T, CYP2B6 983T→C was associated (P=9.9×10-11). After adjusting for both CYP2B6 516G→T and 983T→C, a CYP2B6 variant (rs4803419) in intron 3 was associated (P=4.4×10-15). After adjusting for all the three variants, non-CYP2B6 polymorphisms were associated at P-value less than 5×10-8. In a separate cohort of 240 individuals, only the three CYP2B6 polymorphisms replicated. These three polymorphisms explained 34% of interindividual variability in efavirenz estimated Cmin. The extensive metabolizer phenotype was best defined by the absence of all three polymorphisms.Three CYP2B6 polymorphisms were independently associated with efavirenz estimated Cmin at genome-wide significance, and explained one-third of interindividual variability. These data will inform continued efforts to translate pharmacogenomic knowledge into optimal efavirenz utilization. [ABSTRACT FROM AUTHOR]

Background: Hepatic steatosis, including nonalcoholic fatty liver disease (NAFLD), is common among people with HIV (PWH). We present baseline steatosis prevalence and cardiometabolic characteristics among REPRIEVE substudy participants., Methods: REPRIEVE is an international, primary cardiovascular disease prevention, randomized, controlled trial of pitavastatin calcium vs. placebo among 7769 PWH ages 40-75 years on antiretroviral therapy (ART) and with low-to-moderate cardiovascular risk. A subset of participants underwent noncontrast computed tomography, with hepatic steatosis defined as mean hepatic attenuation less than 40 HU or liver/spleen ratio less than 1.0, and NAFLD defined as steatosis in the absence of frequent alcohol use or viral hepatitis., Results: Of 687 evaluable persons, median age was 51 years, BMI 27 kg/m 2 , CD4 + T-cell count 607 cells/μl; 17% natal female sex, 36% Black, 24% Hispanic, and 98% HIV-1 RNA less than 400 copies/ml. Hepatic steatosis prevalence was 22% (149/687), and NAFLD 21% (96/466). Steatosis/NAFLD prevalence was higher in men and with older age, non-Black race, and higher BMI and waist circumference. Both were associated with BMI greater than 30 kg/m 2 , metabolic syndrome components, higher atherosclerotic cardiovascular disease (ASCVD) risk score, HOMA-IR, LpPLA-2 and hs-CRP, and lower high-density lipoprotein cholesterol. Of HIV-specific/ART-specific characteristics, only history of an AIDS-defining illness was more common among persons with steatosis/NAFLD. After adjusting for age, sex and race/ethnicity, BMI greater than 30 kg/m 2 , HOMA-IR greater than 2.0, Metabolic syndrome and each of its components were associated with NAFLD prevalence., Conclusion: In this cohort with controlled HIV and low-to-moderate cardiovascular risk, hepatic steatosis and NAFLD were common and associated with clinically relevant metabolic and inflammatory disturbances but not current HIV-related or ART-related factors., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

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/microl. 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.

Objectives: Efavirenz is an effective antiretroviral agent, but central nervous system side effects occur commonly, and population (racial) differences in pharmacokinetics and response have been reported. Efavirenz is metabolized by cytochrome P4502B6 (CYP2B6). We investigated whether polymorphisms in CYP2B6, CYP3A4, CYP3A5, and MDR1 were associated with efavirenz central nervous system side effects and pharmacokinetics., Design: Twenty-four week cohort from a randomized study., Methods: Adult AIDS Clinical Trials Group study A5097s examined relationships between central nervous system side effects and efavirenz plasma concentration-time profiles in HIV-infected subjects. Efavirenz plasma pharmacokinetics were estimated by a population-based method. Central nervous system symptoms were assessed by questionnaires and neuropsychological testing., Results: Study subjects included 89 (57%) European-Americans, 50 (32%) African-Americans, and 15 (10%) Hispanics. The CYP2B6 T/T genotype at position 516 (GlnHis) was more common in African-Americans (20%) than in European-Americans (3%), and was associated with greater efavirenz plasma exposure (P < 0.0001). The median efavirenz [area-under-the-curve] (0-24 h) according to G/G, G/T, and T/T genotype was 44 (n = 78), 60 (n = 60), and 130 (n = 14) mug.h/ml, respectively (P < 0.0001). The CYP2B6 G516T genotype was also associated with central nervous system symptoms at week 1 (P = 0.036). Analysis of DNA from other subjects confirmed population differences in frequency of the G516T variant. No associations were apparent with the other polymorphisms studied., Conclusions: A CYP2B6 allelic variant that is more common in African-Americans than in Europeans-Americans was associated with significantly greater efavirenz plasma exposure during HIV therapy. Inter-individual differences in metabolism may, in part, explain susceptibility to efavirenz central nervous system side effects.