AIDS Clinical Trials Group Study Research Articles

Integrative Analysis of Site-Specific Parameters with Nuisance Parameters on the Common Support

AbstractHigh-throughput technologies in bioscience have pushed us into an era with high dimensionality. Swamped by thousands of predictors, detecting the valuable signal from the noise in clinical studies becomes challenging. As a common strategy, integrative analysis utilizing similarities across multiple studies might help lift the curse of dimensionality and enhance statistical power. However, due to the growing concern about individual data privacy, data-sharing constraints are often imposed in integrative analysis. These might lead to results inequivalent to ones without sharing constraints and reduce statistical power in integrative analyses. In this paper, built on Abess, we propose an integrative analysis method to estimate the site-specific parameters in the presence of high dimensional nuisance parameters in multi-site studies. Implemented with a carefully designed $$L_{2,0}$$ L 2 , 0 penalization on nuisance parameters, the proposed method satisfies both the DataSHIELD constraint, which only allows the transmission of summary statistics from sites, and the equivalence property that the solution is exactly the same as the solution merging all datasets into one on a single location. Assuming the nuisance parameters share a common support, the proposed method has support recovery and selection consistency with high probability and exhibits improved estimation accuracy on the site-specific parameters and low computational cost in numerical experiments. We demonstrate the merit of the proposed method by investigating the relationship between the CD8 T cell count and the treatment effect of zidovudine-incorporated therapy in the AIDS Clinical Trials Group Study 175.

Design and analysis considerations for early phase clinical trials in hepatitis B (HBV) cure research: the ACTG A5394 study in persons with both HIV and HBV

With growing interest and efforts to achieve a hepatitis B (HBV) cure, HBV therapeutics have increasingly entered the clinical testing phase. In designing an early phase clinical trial aimed at HBV cure, the heterogeneity in participants and the choice of a biomarker endpoint that signals a cure requires careful consideration. We describe the key elements to consider during the development of HBV clinical trials aimed at a functional cure, and how we have addressed them in the design of a phase II AIDS Clinical Trials Group (ACTG) study, A5394 (NCT05551273). The trial we present is for persons with both HIV and HBV, a unique population that has much to gain from an HBV cure. Our decisions on the design elements are specific to the study agent and the targeted population, but our deliberations may be informative in the emerging field of early phase HBV trials aimed at cure.

Pharmacogenetic interactions of efavirenz or rifampin and isoniazid with levonorgestrel emergency contraception during treatment of HIV or tuberculosis.

In AIDS Clinical Trials Group study A5375, a pharmacokinetic trial of levonorgestrel emergency contraception, double-dose levonorgestrel (3 mg, versus standard dose 1.5 mg) offset the induction effects of efavirenz or rifampin on plasma levonorgestrel exposure over 8 h post-dose (AUC 0-8h ). We characterized the pharmacogenetics of these interactions. Cisgender women receiving efavirenz- or dolutegravir-based HIV therapy, or on isoniazid-rifampin for tuberculosis, were followed after a single oral dose of levonorgestrel. Linear regression models, adjusted for BMI and age, characterized associations of CYP2B6 and NAT2 genotypes (which affect plasma efavirenz and isoniazid exposure, respectively) with levonorgestrel pharmacokinetic parameters. Of 118 evaluable participants, 17 received efavirenz/levonorgestrel 1.5 mg, 35 efavirenz/levonorgestrel 3 mg, 34 isoniazid-rifampin/levonorgestrel 3 mg, and 32 (control group) dolutegravir/levonorgestrel 1.5 mg. There were 73 Black and 33 Asian participants. Regardless of genotype, women on efavirenz and isoniazid-rifampin had higher levonorgestrel clearance. In the efavirenz/levonorgestrel 3 mg group, CYP2B6 normal/intermediate metabolizers had levonorgestrel AUC 0-8h values similar to controls, while CYP2B6 poor metabolizers had AUC 0-8h values of 40% lower than controls. In the isoniazid-rifampin group, NAT2 rapid/intermediate acetylators had levonorgestrel AUC 0-8h values similar to controls, while NAT2 slow acetylators had AUC 0-8h values 36% higher than controls. CYP2B6 poor metabolizer genotypes exacerbate the efavirenz-levonorgestrel interaction, likely by increased CYP3A induction with higher efavirenz exposure, making the interaction more difficult to overcome. NAT2 slow acetylator genotypes attenuate the rifampin-levonorgestrel interaction, likely by increased CYP3A inhibition with higher isoniazid exposure.

Prevention of the Vertical Transmission of HIV; A Recap of the Journey so Far.

In 1989, one in four (25%) infants born to women living with HIV were infected; by the age of 2 years, there was 25% mortality among them due to HIV. These and other pieces of data prompted the development of interventions to offset vertical transmission, including the landmark Pediatric AIDS Clinical Trial Group Study (PACTG 076) in 1994. This study reported a 67.5% reduction in perinatal HIV transmission with prophylactic antenatal, intrapartum, and postnatal zidovudine. Numerous studies since then have provided compelling evidence to further optimize interventions, such that annual transmission rates of 0% are now reported by many health departments in the US and elimination has been validated in several countries around the world. Despite this success, the elimination of HIV's vertical transmission on the global scale remains a work in progress, limited by socioeconomic factors such as the prohibitive cost of antiretrovirals. Here, we review some of the key trials underpinning the development of guidelines in the US as well as globally, and discuss the evidence through a historic lens.

1248. Relationship Between ALT and New HBV Biomarkers in HBV/HIV Coinfected Persons Started on Antiviral Therapy

Abstract Background While HBV DNA has served as a primary biomarker of HBV infection, newer biomarkers including pre-genomic HBV RNA (pgRNA) and quantitative HBV surface antigen (qHBsAg) may prognosticate treatment responses better. We analyzed the changes in these biomarkers over time following initiation of antiviral therapy in persons living with HIV (PLWH) to determine the relationship to ALT, a key marker of liver injury. FigureBiomarker changes Methods NIH AIDS Clinical Trials Group Study 5127 enrolled HBV/HIV PLWH into a Phase 2 treatment trial that randomized them to receive 48 weeks of either tenofovir (TDF) or adefovir (ADV). ALT and HBV DNA were evaluated as measures of treatment response. Stored samples were tested for HBV pgRNA and qHBsAg at baseline, 4, 12, 24, 36, and 48 weeks. HBV pgRNA was isolated using RNA-selective extraction chemistry followed by a multiplex RT-qPCR that targets the HBV X and core targets on the m2000 system (Abbott Molecular, Des Plaines, Illinois). A sensitive second-generation assay with a lower limit of quantification (LLOQ) of 10 copies/mL was utilized. Quantitative HBsAg was determined by Abbott ARCHITECT (List# 6C36) with a LLOQ of 0.05 IU/mL. Data were analyzed using SAS® version 9.4. Results Overall, 47 study participants had sufficient samples for biomarker testing. Participants were predominantly male (93.6%) and identified as white, non-Hispanic (55.3%) or black (34%). Groups were evenly randomized to receive either TDF (n=23) or ADV (n=24). Baseline ALT mean was 64.9 U/L, and HBV DNA was 9.1 (+1.6) copies/mL. Pre-treatment pgRNA serum concentration was 7.0 (+1.3) log U/mL, and qHBsAg was 195,574 (+272,190) IU/mL. Over the course of treatment, pgRNA was significantly correlated with the change in serum ALT levels (r=0.48; p=0.0035) but not HBV DNA (r=0.21; p=0.226). ALT was negatively correlated with qHBsAg (r=-0.52; p=0.02). pgRNA was also highly negatively correlated with qHBsAg (r=-0.49l; p=0.03) but not HBV DNA (r=0.13; p=0.59). (Figure). Conclusion HBV pgRNA is a better predictor of ALT change – a key measure of hepatocyte injury – than HBV DNA in PLWH who are initiated on nucleotide/nucleoside therapy. Quantitative HBsAg is inversely associated with ALT levels, supporting the hypothesis that HBsAg inhibits immune mediated injury to hepatocytes. Disclosures Michael E. Stec, MSc, Abbott Laboratories: Employee of Abbott|Abbott Laboratories: Stocks/Bonds mark C. Anderson, PhD, Abbott Laboratories: Employment|Abbott Laboratories: Stocks/Bonds Marion G. Peters, MD, Aligos: Advisor/Consultant|antios: Advisor/Consultant|Excision Biotherapeutics: DSMB Gavin Cloherty, PhD, Abbott: Employee|Abbott: Stocks/Bonds|Abbott Labs: Employee.

Comparative sensitivity of automated (Abbott M2000) and manual plasma HIV-1 RNA PCR assays for the detection of persistent viremia after long-term antiretroviral therapy

BackgroundThe ability of automated, FDA-cleared plasma HIV-1 RNA assays to detect low-level viremia, compared to manual, highly sensitive research-only methods, is not well-defined. We therefore tested paired plasma samples from people with HIV-1 (PWH) on long-term antiretroviral therapy (ART) with both the Abbott M2000 RealTime HIV-1 Viral Load assay (Abbott) and a quantitative reverse transcriptase (RT)-initiated PCR assay that has a reported 95% detection limit of 1 HIV-1 RNA copy/ml (single copy assay, SCA). MethodsPlasma samples from 309 participants in the AIDS Clinical Trials Group study A5321 were tested by both Abbott and SCA. Participants were mostly men (82%). All were on stable ART for a median of 7 years with HIV-1 RNA <40 copies/mL by Abbott. Pooled plasma from each donor was divided and tested. Abbott results were reported as target detected <40 copies/mL but not quantifiable (target detected <40) or target not detected (TND), and SCA results were classified as HIV-1 RNA detected or not detected. ResultsBy Abbott, 17% (51/309) of sample results were target detected <40, whereas 83% (258/309) were TND. Of the samples that were target detected <40 by Abbott, 73% (37/51) had HIV-1 RNA detected by SCA. By contrast, 43% of samples that were TND by Abbott (110/258) had HIV-1 RNA detected by SCA (p < 0.001). ConclusionPlasma samples from PWH with HIV-1 RNA detected but <40 copies/ml by the automated Abbott M2000 assay are likely (73% of 51 samples) to have HIV-1 RNA detected by an optimized manual assay with single copy sensitivity. An Abbott HIV-1 RNA result of target not detected did not exclude low-level viremia: 43% of 258 samples had HIV-1 RNA detected by the single copy assay. These findings indicate that the Abbott M2000 assay cannot exclude the persistence of viremia on ART and thus may have less utility, compared to a manual single copy assay, for assessing the impact of experimental interventions designed to eliminate low-level viremia as a step towards achieving ART-free HIV-1 remission.

Associations of L-Ferritin and Tim-1 with frailty measures in people with HIV: a cross-sectional and longitudinal study

BackgroundPeople with HIV are at high risk of frailty. Iron transport is key to energy production and is dysregulated by HIV and inflammation. We previously linked higher cerebrospinal fluid levels of the iron transporter heavy-chain-ferritin (Fth1) to better cognition in people with HIV. Here, we evaluated whether higher levels of serum Fth1 and light-chain-ferritin (Ftl), and lower levels of urine T-cell immunoglobulin-and-mucin domain (Tim)-1 (Fth1 receptor) are associated with better frailty measures in people with HIV. MethodsSerum Fth1, Ftl, inflammation markers (IL-6, sTNFR2), and urine Tim-1 were quantified by ELISA in 324 AIDS Clinical Trials Group Study A5322 enrollees at entry. Prefrailty and frailty were assessed using Fried's criteria. Relationships among baseline biomarker concentrations, HIV clinical variables and demographic variables were tested using Pearson's χ2 test, non-parametric tests for trend, or Spearman's correlations. Multivariable regression models evaluated cross-sectional and longitudinal Fth1, Ftl, and Tim-1 associations with prefrail and frail status, average 4-metre walk time, and grip strength in all people with HIV and by sex. FindingsAt study entry, 127 (40%) of 321 participants were prefrail and 15 (4%) of 321 were frail (mean age 52 years [SD 7·3]]; 61 (19%) of 321 were female and 260 (81%) of 321 were male; and 306 (96%) of 319 were virally suppressed). Serum Fth1 was correlated with Ftl (rho 0·14; p<0·01), but not to urine Tim-1. In univariate analyses, Tim-1 was higher (ptrend=0·06) and Ftl lower (ptrend=0·02) across non-frail, prefrail, and frail groups. Higher Tim-1 was associated with prefrailty (odds ratio [OR] 1·5; p<0·01) and combined prefrailty and frailty (OR 2·3; p=0·01) versus non-frail people with HIV. Higher Ftl was associated with faster 4 m walk time (β –0·045; p<0·01), lower odds of weak grip (OR 0·49; p<0·01), and less frailty, particularly in female participants (OR 0·28; p=0·03). In multivariable-adjusted analyses, higher Ftl was associated with faster 4 m walk time and better grip strength (both p<0·05), reduced odds of combined prefrailty and frailty versus non-frailty (adjusted OR 0·56 in all people with HIV and 0·29 in female participants, both p<0·05 for levels greater than or equal to the median versus less than the median) and lower odds of weak grip (OR 0·50; p<0·05). Ftl concentrations in the highest versus lowest quartile were associated with lower odds of slow 4 m walk time in female participants (OR 0·060; p<0·05). Higher Tim-1 was associated with combined prefrailty and frailty versus non-frailty (OR 2·6; p<0·05). Serum Fth1 was not associated with frailty measures. InterpretationIncreased urine Tim-1 is a marker of risk for prefrailty and frailty in people with HIV. Higher serum Ftl is associated with preserved motor function and less prefrailty or frailty, particularly in female individuals. Future studies will explore causal pathways. FundingNational Institutes of Health grant (to AK): 5R03 MH123291-02; National Institute of Allergy and Infectious Diseases, National Institute of Mental Health, National Institute on Aging, and National Institute of Diabetes and Digestive and Kidney Diseases.

Prevalence and risk of residual viremia after ART in low- and middle-income countries: A cross-sectional study.

In order to design effective strategies to eradicate the HIV, an understanding of persistent viral reservoirs is needed. Many studies have demonstrated HIV residual viremia prevalence in high income countries, data from low- and middle-income countries (LMIC) are limited. We assessed the prevalence, and factors associated with residual viremia in people with HIV (PWH), who were virally-suppressed on antiretroviral therapy (ART) in LMIC. We also compared residual viremia prevalence between the LMIC and US.This is a cross-sectional, retrospective study that utilized stored specimen samples from the AIDS clinical trials group (ACTG) studies A5175 and A5208. The last available sample among participants with plasma HIV RNA < 400 copies/mL for ≥3 years were tested by the HIV molecular and monitoring core gag (HMMCgag) single copy assay (SCA). Residual viremia was defined as detectable if ≥1 copy/mL. Spearman's correlation and multivariable stepwise logistic regression were used to assess associations of various factors with SCA.A total of 320 participants, 246 (77%) from LMIC and 74 (23%) from US, were analyzed. Median (IQR) age was 33 (2840) years; baseline CD4 166 (88,230) cells/mm3; HIV RNA 5.0 (4.5, 5.3) log10 copies/mL; duration of viral suppression 3.4 (3.1, 4.0) years and 48% were male. In 85 participants with information available, 53% were subtype C, 42% subtype B and 5% other subtypes. Overall prevalence of residual viremia was 57% [95% CI, 52–63] with 51% [40–63] in US and 59% [53–65] in LMIC. Among participants with detectable SCA, the median (IQR) HIV RNA was 3.8 (2.2, 8.1) copies/mL. The multivariable model conducted in LMIC participants showed that higher baseline HIV RNA was associated with detectable residual RNA (OR 2.9, 95% CI 1.8, 4.6 for every log10 increase, P < .001). After including both US and LMIC in the final model, baseline HIV RNA remained significant. No difference in SCA detestability was found between US and LMIC sites (OR 1.1 [0.6, 2.0], P = .72) after adjusting for baseline RNA and parent study.The prevalence of residual viremia between both groups were not different and more than half of the participants had detectable viremia. Higher baseline HIV RNA was independently associated with residual viremia.

A bias-adjusted estimator in quantile regression for clustered data

Quantile regression models with random effects are useful for studying associations between covariates and quantiles of the response distribution for clustered data. Parameter estimation is examined for a class of mixed-effects quantile regression models, with focus on settings with many but small clusters. The main contributions are the following: (i) documenting that existing methods may lead to severely biased estimators for fixed effects parameters; (ii) proposing a new two-step estimation methodology where predictions of the random effects are first computed by a pseudo likelihood approach (the LQMM method) and then used as offsets in standard quantile regression; (iii) proposing a novel bootstrap sampling procedure in order to reduce bias of the two-step estimator and compute confidence intervals. The proposed estimation and associated inference is assessed numerically through rigorous simulation studies and applied to an AIDS Clinical Trial Group (ACTG) study.

Cardiovascular Risk and Health Among People With Human Immunodeficiency Virus (HIV) Eligible for Primary Prevention: Insights From the REPRIEVE Trial.

BackgroundIn addition to traditional cardiovascular (CV) risk factors, antiretroviral therapy, lifestyle, and human immunodeficiency virus (HIV)-related factors may contribute to future CV events in persons with HIV (PWH).MethodsAmong participants in the global REPRIEVE randomized trial, we characterized demographics and HIV characteristics relative to ACC/AHA pooled cohort equations (PCE) for atherosclerotic CV disease predicted risk and CV health evaluated by Life’s Simple 7 (LS7; includes smoking, diet, physical activity, body mass index, blood pressure, total cholesterol, and glucose).ResultsAmong 7382 REPRIEVE participants (31% women, 45% Black), the median PCE risk score was 4.5% (lower and upper quartiles Q1, Q3: 2.2, 7.2); 29% had a PCE score <2.5%, and 9% scored above 10%. PCE score was related closely to known CV risk factors and modestly (<1% difference in risk score) to immune function and HIV parameters. The median LS7 score was 9 (Q1, Q3: 7, 10) of a possible 14. Only 24 participants (0.3%) had 7/7 ideal components, and 36% had ≤2 ideal components; 90% had <5 ideal components. The distribution of LS7 did not vary by age or natal sex, although ideal health was more common in low sociodemographic index countries and among Asians. Poor dietary and physical activity patterns on LS7 were seen across all PCE scores, including the lowest risk categories.ConclusionsPoor CV health by LS7 was common among REPRIEVE participants, regardless of PCE. This suggests a critical and independent role for lifestyle interventions in conjunction with conventional treatment to improve CV outcomes in PWH. Clinical Trials Registration: NCT02344290. AIDS Clinical Trials Group study number: A5332.

Impact of dedicated women’s outreach workers (WOWs) on recruitment of women in ACTG clinical studies

Background: Despite efforts by the AIDS Clinical Trials Group (ACTG) to enroll representative numbers of diverse women, participation in ACTG studies in the United States remains largely white and male. To address this gap in women’s participation in ACTG research, a one-year pilot study of dedicated women’s outreach workers (WOWs) was proposed. Objectives: included demonstrating that targeted recruitment efforts can expand community awareness of ACTG research and ensuring successful enrollment of women at the respective clinical research sites. Methods: The pilot study was conducted at two U.S. sites (Rutgers New Jersey Medical School and Emory Ponce de Leon Center in Atlanta, Georgia). The WOWs worked with site personnel to identify and reach out to women living with HIV and/or Hepatitis B or C at their respective sites and encourage them to join a clinical trial registry for those interested in participating in future clinical trials. Results: The Rutgers WOW approached 127 potential participants (of whom 100 joined the WOW registry) and screened 35 participants for open ACTG studies. The Emory WOW approached 120 participants, enrolling 86 into the WOW registry, and screened 51 potential participants for open ACTG studies during the WOW’s tenure. The majority of women screened at both sites were women of color. Conclusions: The WOW study team identified several lessons learned that can inform future efforts to engage women living with HIV in clinical research. First, success in engaging women is proportional to level of funding and institutional support. Second, there is a need for a more gender-inclusive scientific agenda as women are more likely to participate if studies address topics of interest to them. Third, meaningful engagement is a two-way street.

David Katzenstein and James Hakim-In Memoriam.

The world lost two wonderful doctors who devoted their lives to the fight against HIV/AIDS in Africa. Ironically, they both died of COVID-19 within hours of each other in late January in Zimbabwe. David Katzenstein, MD, began his career in the early 1980 s working with underserved populations at a Native Tribal clinic in New Mexico and with persons suffering from AIDS at the Haight Ashbury Clinic in San Francisco, conducted CMV research at the University of Minnesota, and then took a position working as a microbiologist at the University of Zimbabwe in Harare between 1985 and 1987. In 1989, David joined the faculty at Stanford University where he remained until his retirement in 2017. Dr Katzenstein, led many important clinical and translational research studies related to HIV. With his colleagues in the AIDS Clinical Trials Group (ACTG), he led studies that resulted in the approval of life-saving antiretroviral medications. David dedicated a major portion of his academic endeavors to study HIV drug resistance, serving as director of one of the Virology Specialty Laboratories for the ACTG for many years. He was a protocol team member and leader on several ACTG studies and served on numerous ACTG committees, including the Performance Evaluation Committee and the original Virology Committee. He was co-chair of ACTG 384 that dealt with protease and/or non-nucleoside reverse transcriptase inhibitors, and was one of the first investigators to call attention to the issues of drug resistance in Africa. Recognizing the disparate impact of HIV in resource limited settings, David was a pioneer in Global HIV Research, in the fields of perinatal HIV transmission prevention, and studying different approaches to optimize antiretroviral treatment and laboratory monitoring in various settings around the world. He worked diligently to bring laboratory technology to Zimbabwe. Following his retirement from Stanford in 2017, David became the director of the Biomedical Research Training Institute in Zimbabwe where he led the molecular diagnostics laboratory to support laboratory monitoring of community-based treatment programs. In all his work, David engaged researchers and trainees from different parts of the world. Generous with his time, effort and ideas, David was a cherished mentor for many young and mid-career physicians and scientists, now scattered throughout different academic institutions and agencies in the U.S. He nurtured careers of clinicians, basic and social scientists, while encouraging multidisciplinary efforts to tackle the global HIV pandemic. He worked tirelessly and with great joy, giving of himself without reserve. James Gita Hakim, MRCP-UK, Professor of Medicine, University of Zimbabwe College of Health Sciences, to COVID-19. Dr Hakim was an accomplished investigator who made seminal contributions in HIV treatment and prevention research. He was known internationally for his accomplishments as a research leader, a builder of African research capacity, a leader of modernizing medical education in Africa, and as a mentor of young African investigators. Dr Hakim was at the forefront of clinical research on HIV/AIDS in Africa for over 20 years. He founded the University of Zimbabwe Clinical Research Centre (UZ-CRC) in 2001 as a site for international clinical trials on HIV treatment and prevention. He was a leader in pivotal international clinical trials including the landmark HIV ‘treatment as prevention’ trial HPTN 052, the MRC-funded “Development of Anti-Retroviral Therapy in Africa” (DART) trial, and the ACTG “Prospective Evaluation of Antiretroviral Therapy in Resource Limited Settings” (PEARLS) study. These studies contributed to the knowledge needed for successful implementation of antiretroviral therapy in southern Africa. Dr Hakim was as Principal Investigator of the University of Zimbabwe's program, the Medical Education Partnership Initiative (MEPI) which serves as a model for medical education in Africa. He was as a representative on the International AIDS Society (IAS) Governing Council from 2016 to 2020 and on the World Health Organization Guidelines Review Committee, the UNAIDS Advisory Committee, and on program committees for IAS Conference on HIV Science, the Conference on Retroviruses and Opportunistic Infections (CROI). Dr Hakim was Co-chair of the World AIDS Conference, Amsterdam, Netherlands in 2018. James Hakim's life demonstrated how investment in biomedical research and modern medical education can pay large dividends and be transformative for Africa. The world is better for the lives you lived, David and James. May light perpetual shine upon you.

Efavirenz Pharmacogenetics and Weight Gain Following Switch to Integrase Inhibitor-Containing Regimens.

Unwanted weight gain affects some people living with human immunodeficiency virus (HIV) who are prescribed integrase strand transfer inhibitors (INSTIs). Mechanisms and risk factors are incompletely understood. We utilized 2 cohorts to study pharmacogenetics of weight gain following switch from efavirenz- to INSTI-based regimens. In an observational cohort, we studied weight gain at 48 weeks following switch from efavirenz- to INSTI-based regimens among patients who had been virologically suppressed for at least 2 years at a clinic in the United States. Associations were characterized with CYP2B6 and UGT1A1 genotypes that affect efavirenz and INSTI metabolism, respectively. In a clinical trials cohort, we studied weight gain at 48 weeks among treatment-naive participants who were randomized to receive efavirenz-containing regimens in AIDS Clinical Trials Group studies A5095, A5142, and A5202 and did not receive INSTIs. In the observational cohort (n = 61), CYP2B6 slow metabolizers had greater weight gain after switch (P = .01). This was seen following switch to elvitegravir or raltegravir, but not dolutegravir. UGT1A1 genotype was not associated with weight gain. In the clinical trials cohort (n = 462), CYP2B6 slow metabolizers had lesser weight gain at week 48 among participants receiving efavirenz with tenofovir disoproxil fumarate (P = .001), but not those receiving efavirenz with abacavir (P = .65). Findings were consistent when stratified by race/ethnicity and by sex. Among patients who switched from efavirenz- to INSTI-based therapy, CYP2B6 genotype was associated with weight gain, possibly reflecting withdrawal of the inhibitory effect of higher efavirenz concentrations on weight gain. The difference by concomitant nucleoside analogue is unexplained.

Association of Male Sex and Obesity With Residual Plasma Human Immunodeficiency Virus 1 Viremia in Persons on Long-Term Antiretroviral Therapy.

Although adipose tissue has been proposed to harbor part of the human immunodeficiency virus 1 (HIV-1) reservoir, the influence of host characteristics, including sex and body mass index (BMI), on measures of HIV-1 persistence during antiretroviral therapy (ART) are incompletely understood. We evaluated age, sex, BMI, waist circumference, years on ART, pre-ART HIV-1 RNA, pre-ART CD4+ T-cell count, and initial ART regimen with measures of HIV-1 persistence in blood (residual viremia, cellular HIV-1 DNA and RNA) in a cohort of 295 individuals with well-documented long-term virologic suppression (HIV-1 RNA <50 copies/mL) on ART (AIDS Clinical Trials Group study A5321). Men were more likely than women to have detectable plasma HIV-1 RNA by single-copy assay (52% vs 29%; P = .003), and the proportion of participants with detectable residual viremia increased in a stepwise fashion by BMI category (normal weight or underweight, 38%; overweight, 50%; and obese, 55%). ART regimen type was not associated with measures of HIV-1 persistence after controlling for ART duration. Sex and obesity are independently associated with residual viremia in people on long-term ART. Additional studies to confirm these relationships and to define the mechanisms by which sex and obesity affect HIV-1 persistence are needed to inform HIV-1 cure strategies.

Pharmacogenetic interactions between antiretroviral drugs and vaginally administered hormonal contraceptives

In AIDS Clinical Trials Group study A5316, efavirenz lowered plasma concentrations of etonogestrel and ethinyl estradiol, given as a vaginal ring, while atazanavir/ritonavir increased etonogestrel and lowered ethinyl estradiol concentrations. We characterized the pharmacogenetics of these interactions. In A5316, women with HIV enrolled into control (no antiretrovirals), efavirenz [600 mg daily with nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs)], and atazanavir/ritonavir (300/100 mg daily with NRTIs) groups. On day 0, a vaginal ring was inserted, releasing etonogestrel/ethinyl estradiol 120/15 μg/day. Intensive plasma sampling for antiretrovirals was obtained on days 0 and 21, and single samples for etonogestrel and ethinyl estradiol on days 7, 14, and 21. Seventeen genetic polymorphisms were analyzed. The 72 participants in this analysis included 25, 24 and 23 in the control, efavirenz, and atazanavir/ritonavir groups, respectively. At day 21 in the efavirenz group, CYP2B6 genotype was associated with increased plasma efavirenz exposure (P = 3.2 × 10), decreased plasma concentrations of etonogestrel (P = 1.7 × 10), and decreased ethinyl estradiol (P = 6.7 × 10). Compared to controls, efavirenz reduced median etonogestrel concentrations by at least 93% in CYP2B6 slow metabolizers versus approximately 75% in normal and intermediate metabolizers. Efavirenz reduced median ethinyl estradiol concentrations by 75% in CYP2B6 slow metabolizers versus approximately 41% in normal and intermediate metabolizers. CYP2B6 slow metabolizer genotype worsens the pharmacokinetic interaction of efavirenz with hormonal contraceptives administered by vaginal ring. Efavirenz dose reduction in CYP2B6 slow metabolizers may reduce, but will likely not eliminate, this interaction.

Circulating CD30+CD4+ T Cells Increase Before Human Immunodeficiency Virus Rebound After Analytical Antiretroviral Treatment Interruption.

Identification of nonviral markers of human immunodeficiency virus (HIV) infection that increase before viral rebound during analytical treatment interruption (ATI) may affect HIV persistence research. We previously showed that HIV ribonucleic acid (RNA) is enriched in CD30+CD4+ T cells in many individuals. Here, we studied CD30+CD4+ T-cell dynamics before ATI, during ATI (before detectable plasma RNA), and after HIV rebound. Peripheral blood mononuclear cells from 23 participants collected longitudinally from 5 Adult AIDS Clinical Trials Group studies incorporating ATI were included in this study. Flow cytometric characterization of expression of CD30 and markers of T-cell activation and exhaustion were performed along with HIV-1 RNA and deoxyribonucleic acid quantification and measurement of soluble plasma CD30 and CD30 ligand. The percentage of CD4+ T cells expressing CD30 significantly increased from pre-ATI to postinterruption time points before detectible viremia (1.65 mean relative increase, P = .005). Seventy-seven percent of participants experienced an increase in CD30+ cells before viral rebound. In contrast, there were no significant differences between pre-ATI and postinterruption pre-rebound time points in percentages of lymphocytes expressing CD69, CD38/HLA-DR, or PD-1 until after HIV recrudescence. CD30 may be a surrogate marker of early replication or viral transcriptional activity before detection by routine peripheral blood sampling.

Exploration of Heterogeneous Treatment Effects via Concave Fusion.

Understanding treatment heterogeneity is essential to the development of precision medicine, which seeks to tailor medical treatments to subgroups of patients with similar characteristics. One of the challenges of achieving this goal is that we usually do not have a priori knowledge of the grouping information of patients with respect to treatment effect. To address this problem, we consider a heterogeneous regression model which allows the coefficients for treatment variables to be subject-dependent with unknown grouping information. We develop a concave fusion penalized method for estimating the grouping structure and the subgroup-specific treatment effects, and derive an alternating direction method of multipliers algorithm for its implementation. We also study the theoretical properties of the proposed method and show that under suitable conditions there exists a local minimizer that equals the oracle least squares estimator based on a priori knowledge of the true grouping information with high probability. This provides theoretical support for making statistical inference about the subgroup-specific treatment effects using the proposed method. The proposed method is illustrated in simulation studies and illustrated with real data from an AIDS Clinical Trials Group Study.

Relationships Between Adipose Mitochondrial Function, Serum Adiponectin, and Insulin Resistance in Persons With HIV After 96 Weeks of Antiretroviral Therapy.

Some antiretroviral therapy (ART) and HIV itself confer metabolic risk, perhaps through altered mitochondrial function and adipokines. In AIDS Clinical Trials Group study A5224s, adipose mitochondrial DNA (mtDNA) levels decreased on ART, and electron transport chain complex I (CI) and complex IV (CIV) activity decreased. Another study found decreased serum adiponectin on ART with mtDNA mutation m.10398A>G. We hypothesized that decreased adipose tissue mitochondrial function would be associated with lower adiponectin and insulin sensitivity on ART, and m.10398G would influence these changes. Retrospective analysis of an ART-naive substudy population from A5224s. Analyses included adipose mtDNA levels, CI and CIV activity by immunoassay, visceral adipose tissue by computed tomography, and fasting serum glucose at week 0 and week 96 of ART. Fasting insulin and adiponectin were measured from cryopreserved serum using multiplex bead array. Homeostasis model assessment-2 (HOMA2)-IR and HOMA2-%B estimated insulin resistance and β-cell function, respectively. The m.10398A>G mtDNA variant was available from existing genetic data. Thirty-seven participants had adipose biopsies at week 0 and week 96. Percent decreases in CIV activity and adiponectin were correlated (Spearman rho 0.41; P = 0.01); this association persisted after controlling for age, sex, body mass index, or visceral adipose tissue in single-covariate regression. HOMA2-IR correlated with decreased CIV (-0.44; P = 0.01) and CI (-0.34; P = 0.05) activity. Among 12 non-Hispanic white persons, m.10398G was associated with decreased adiponectin (P = 0.04). Decreased adipose mitochondrial activity correlated with changes in adiponectin and glucose homeostasis on ART. Previous findings that a mtDNA mutation modulates adiponectin levels in persons with HIV were replicated.

Persistence of Human Immunodeficiency Virus-1 Drug Resistance Mutations in Proviral Deoxyribonucleic Acid After Virologic Failure of Efavirenz-Containing Antiretroviral Regimens.

BackgroundEfavirenz (EFV)-based regimens select broad drug resistance to nonnucleoside reverse-transcriptase inhibitors (NNRTIs), limiting the effectiveness of EFV and other NNRTIs. The duration, persistence, and decay of drug resistance mutations (DRMs) in the proviral reservoir is not well defined.MethodsParticipants with virologic failure of EFV-based regimens and drug-resistant viremia with the K103N mutation in plasma ribonucleic acid (RNA) were identified from AIDS Clinical Trials Group (ACTG) studies A364 and A5095. These individuals received a second-line, boosted protease inhibitor-based regimen with suppression of viremia for up to10 years during long-term follow-up (median = 3.6 years; interquartile range, 2.1–6.9 years). Proviral deoxyribonucleic acid (DNA) from cryopreserved peripheral blood mononuclear cells was sequenced to identify the persistence of DRM.ResultsTwenty-eight participants from ACTG 364 and ACTG 5095 were evaluated. Sanger sequencing of proviral DNA detected K103N as well as additional reverse-transcriptase inhibitor (RTI) mutations. Ultradeep sequencing confirmed persistence of K103N in 71% of participants with minimal decay over time. In an adjusted model including years since suppression, persistent proviral K103N was 2.6 times more likely (95% confidence interval, 1.0–6.4) per log10 higher human immunodeficiency virus RNA at EFV failure.ConclusionsPersistence of RTI mutations in proviral DNA after virologic failure has implications for the effectiveness of future drug regimens and the recycling of RTI drugs.

Parenting Desires Among Individuals Living With Human Immunodeficiency Virus in the United States.

BackgroundIn 1988, 1 of 3 women (W) and heterosexual men living with human immunodeficiency virus (HIV) reported wanting children, but little is known about parenting desires of men who have sex with men (MSM) living with HIV. We examined parenting desires among persons initiating antiretroviral therapy (ART).MethodsOf 1809 participants in the AIDS Clinical Trials Group (ACTG) Study 5257, 1425 W aged ≤45 years or men completed questionnaires about parenting desires at baseline and 96 weeks after initiating ART. Self-reported desires for children in the future (yes/unsure vs no) and associations between baseline sociodemographics and parenting desires at 96 weeks were examined using multivariable logistic regression, overall and within subgroups.ResultsThe 1425 participants were as follows: 36% white, 39% black, 22% Hispanic; median age 36 (interquartile range, 28–44); 70% MSM, 13% men reported sex only with W (MSW), 17% W. At baseline, 42% may want children in the future (42% MSM, 37% MSW, 43% W); at 96 weeks, 41% may want children (41% MSM, 37% MSW, 43% W). At follow-up, approximately 10% of responses changed in each direction. In multivariable analyses, education greater than high school, <30 years, and having no children were significantly associated with future parenting desires among all subgroups. Among MSM, being black was associated with desiring children.ConclusionsApproximately 40% of MSM, W, and MSW with HIV may want children, both at baseline and 96 weeks after ART initiation. These results highlight the need to regularly assess parenting goals, provide access to comprehensive reproductive services, and address prevention of vertical and heterosexual HIV transmission.