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In an analysis of randomized trials, use of efavirenz for treatment of human immunodeficiency virus (HIV) infection was associated with increased suicidal thoughts/behaviors. However, analyses of observational data have found no evidence of increased risk. To assess whether population differences might explain this divergence, we transported the effect of efavirenz use from these trials to a specific target population. Using inverse odds weights and multiple imputation, we transported the effect of efavirenz on suicidal thoughts/behaviors in these randomized trials (participants were enrolled in 2001-2007) to a trials-eligible cohort of US adults initiating antiretroviral therapy while receiving HIV clinical care at medical centers between 1999 and 2015. Overall, 8,291 cohort participants and 3,949 trial participants were eligible. Prescription of antidepressants (19% vs. 13%) and injection drug history (16% vs. 10%) were more frequent in the cohort than in the trial participants. Compared with the effect in trials, the estimated hazard ratio for efavirenz on suicidal thoughts/behaviors was attenuated in our target population (trials: hazard ratio (HR) = 2.3 (95% confidence interval (CI): 1.2, 4.4); transported: HR = 1.8 (95% CI: 0.9, 4.4)), whereas the incidence rate difference was similar (trials: HR = 5.1 (95% CI: 1.6, 8.7); transported: HR = 5.4 (95% CI: -0.4, 11.4)). In our target population, there was greater than 20% attenuation of the hazard ratio estimate as compared with the trials-only estimate. Transporting results from trials to a target population is informative for addressing external validity.

The AIDS Clinical Trials Group (ACTG) A5345 study included an intensively monitored antiretroviral pause (IMAP), during which a cohort of participants temporarily stopped antiretroviral treatment during chronic HIV infection. We surveyed participant perceptions and understanding of A5345 using a cross-sectional sociobehavioral questionnaire. Participants completed the baseline questionnaire either before or after initiating the study's IMAP. Questionnaire responses were linked to existing demographic data. Quantitative responses were analyzed overall and stratified by IMAP status. Open-ended responses were analyzed using conventional content analysis. Thirty-two participants completed the baseline sociobehavioral questionnaire. Half (n = 16) completed it before (i.e., pre-IMAP initiation group) and half (n = 16) after IMAP initiation (i.e., post-IMAP initiation group). Eight pre-IMAP initiation respondents (50%) and 11 post-IMAP respondents (69%) responded "yes" when asked if they perceived any direct benefits from participating in A5345. Perceived societal-level benefits included furthering HIV cure-related research and helping the HIV community. Perceived personal-level benefits included the opportunity to learn about the body's response to IMAP and financial compensation. The majority of respondents-13 from each group (81% of each)-reported risks from participation, for example, viral load becoming detectable. A5345 participants perceived both societal- and personal-level benefits of study participation. While the majority of survey respondents perceived participatory risks, nearly one in five did not. Key messages pertaining to study-related risks and benefits may need to be clarified or reiterated periodically throughout follow-up in HIV cure-related studies with IMAPs. Clinical Trail Registration Number: NCT03001128.

BackgroundPersistent HIV infection of long-lived resting CD4 T cells, despite antiretroviral therapy (ART), remains a barrier to HIV cure. Women have a more robust type 1 interferon response during HIV infection relative to men, contributing to lower initial plasma viremia. As lower viremia during acute infection is associated with reduced frequency of latent HIV infection, we hypothesized that women on ART would have a lower frequency of latent HIV compared to men.MethodsART-suppressed, HIV seropositive women (n = 22) were matched 1:1 to 22 of 39 ART-suppressed men. We also compared the 22 women to all 39 men, adjusting for age and race as covariates. We measured the frequency of latent HIV using the quantitative viral outgrowth assay, the intact proviral DNA assay, and total HIV gag DNA. We also performed activation/exhaustion immunophenotyping on peripheral blood mononuclear cells and quantified interferon-stimulated gene (ISG) expression in CD4 T cells.ResultsWe did not observe evident sex differences in the frequency of persistent HIV in resting CD4 T cells. Immunophenotyping and CD4 T-cell ISG expression analysis revealed marginal differences across the sexes.ConclusionsDifferences in HIV reservoir frequency and immune activation appear to be small across sexes during long-term suppressive therapy.

HIV infection induces a robust T cell response that is sustained by high viremia, but falls following the onset of antiretroviral therapy (ART). Relatively little has been reported on the subsequent stability of the HIV-specific T cell response in individuals on durable therapy. Such data are critical for powering clinical trials testing T cell-based immunotherapies. In a cross-sectional study, HIV-specific T cell responses were detectable by ex vivo interferon (IFN)-γ ELISpot (average ∼1,100 spot-forming units [SFUs]/106 peripheral blood mononuclear cells) in persons living with HIV (PLWH; n = 34), despite median durable ART suppression of 5.0 years. No substantial association was detected between the summed HIV-specific T cell response and the size of the replication-competent HIV reservoir. T cell responses were next measured in participants sampled weekly, monthly, or yearly. HIV-specific T cell responses were highly stable over the time periods examined; within-individual variation ranged from 16% coefficient of variation (CV) for weekly to 27% CV for yearly sampling. These data were used to generate power calculations for future immunotherapy studies. The stability of the HIV-specific T cell response in suppressed PLWH will enable powered studies of small sizes (e.g., n = 6-12), facilitating rapid and iterative testing for T cell-based immunotherapies against HIV.

IntroductionPeople who inject drugs (PWID) experience high HIV incidence and face significant barriers to engagement in HIV care and substance use treatment. Strategies for HIV treatment as prevention and substance use treatment present unique challenges in PWID that may vary regionally. Understanding differences in the risk structure for HIV transmission and disease progression among PWID is essential in developing and effectively targeting intervention strategies of HIV treatment as prevention.MethodsWe present a baseline analysis of HIV Prevention Trials Network (HPTN) 074, a two-arm, randomized controlled trial among PWID in Indonesia (n = 258), Ukraine (n = 457) and Vietnam (n = 439). HPTN 074 was designed to determine the feasibility, barriers and uptake of an integrated intervention combining health systems navigation and psychosocial counselling for the early engagement of antiretroviral therapy (ART) and substance use treatment for PWID living with HIV. Discordant PWID networks were enrolled, consisting of an HIV-positive index and their HIV-negative network injection partner(s). Among the enrolled cohort of 1154 participants (502 index participants and 652 network partners), we examine regional differences in the baseline risk structure, including sociodemographics, HIV and substance use treatment history, and injection and sexual risk behaviours.ResultsThe majority of participants were male (87%), with 82% of the enrolled females coming from Ukraine. The overall mean age was 34 (IQR: 30, 38). Most commonly injected substances included illegally manufactured methadone in Ukraine (84.2%), and heroin in Indonesia (81.8%) and Vietnam (99.5%). Injection network sizes varied by region: median number of people with whom participants self-reported injecting drugs was 3 (IQR: 2, 5) in Indonesia, 5 (IQR: 3, 10) in Ukraine and 3 (IQR: 2, 4) in Vietnam. Hazardous alcohol use, assessed using the Alcohol Use Disorders Identification Test - Alcohol Consumption Questions (AUDIT-C), was prominent in Ukraine (54.7%) and Vietnam (26.4%). Reported sexual risk behaviours in the past month, including having two or more sex partners and giving/receiving money or drugs in exchange for sex, were uncommon among all participants and regions.ConclusionsWhile regional differences in risk structure exist, PWID particularly in Ukraine need immediate attention for risk reduction strategies. Substantial regional differences in risk structure will require flexible, tailored treatment as prevention interventions for distinct PWID populations.

BackgroundPeople who inject drugs (PWID) have a high incidence of HIV, little access to antiretroviral therapy (ART) and medication-assisted treatment (MAT), and high mortality. We aimed to assess the feasibility of a future controlled trial based on the incidence of HIV, enrolment, retention, and uptake of the intervention, and the efficacy of an integrated and flexible intervention on ART use, viral suppression, and MAT use.MethodsThis randomised, controlled vanguard study was run in Kyiv, Ukraine (one community site), Thai Nguyen, Vietnam (two district health centre sites), and Jakarta, Indonesia (one hospital site). PWID who were HIV infected (index participants) and non-infected injection partners were recruited as PWID network units and were eligible for screening if they were aged 18-45 years (updated to 18-60 years 8 months into study), and active injection drug users. Further eligibility criteria for index participants included a viral load of 1000 copies per mL or higher, willingness and ability to recruit at least one injection partner who would be willing to participate. Index participants were randomly assigned via a computer generated sequence accessed through a secure web portal (3:1) to standard of care or intervention, stratified by site. Masking of assignment was not possible due to the nature of intervention. The intervention comprised systems navigation, psychosocial counselling, and ART at any CD4 count. Local ART and MAT services were used. Participants were followed up for 12-24 months. The primary objective was to assess the feasibility of a future randomised controlled trial. To achieve this aim we looked at the following endpoints: HIV incidence among injection partners in the standard of care group, and enrolment and retention of HIV-infected PWID and their injection partners and the uptake of the integrated intervention. The study was also designed to assess the feasibility, barriers, and uptake of the integrated intervention. Endpoints were assessed in a modified intention-to-treat popualtion after exclusion of ineligible participants. This trial is registered on ClinicalTrials.gov, NCT02935296, and is active but not recruiting new participants.FindingsBetween Feb 5, 2015, and June 3, 2016, 3343 potential index participants were screened, of whom 502 (15%) were eligible and enrolled. 1171 injection partners were referred, and 806 (69%) were eligible and enrolled. Index participants were randomly assigned to intervention (126 [25%]) and standard of care (376 [75%]) groups. At week 52, most living index participants (389 [86%] of 451) and partners (567 [80%] of 710) were retained, and self-reported ART use was higher among index participants in the intervention group than those in the standard of care group (probability ratio [PR] 1·7, 95% CI 1·4-1·9). Viral suppression was also higher in the intervention group than in the standard of care group (PR 1·7, 95% CI 1·3-2·2). Index participants in the intervention group reported more MAT use at 52 weeks than those in the standard of care group (PR 1·7, 95% CI 1·3-2·2). Seven incident HIV infections occurred, and all in injection partners in the standard of care group (intervention incidence 0·0 per 100 person-years, 95% CI 0·0-1·7; standard of care incidence 1·0 per 100 person-years, 95% CI 0·4-2·1; incidence rate difference -1·0 per 100 person-years, 95% CI -2·1 to 1·1). No severe adverse events due to the intervention were recorded.InterpretationThis vanguard study provides evidence that a flexible, scalable intervention increases ART and MAT use and reduces mortality among PWID. The low incidence of HIV in both groups impedes a future randomised, controlled trial, but given the strength of the effect of the intervention, its implementation among HIV-infected PWID should be considered.FundingUS National Institutes of Health.

BackgroundEvidence about the effect of initiating efavirenz-containing combination antiretroviral therapy (ART) as the first-line therapy on suicidal thoughts remains conflicting.MethodsUsing data from a cohort of HIV-infected adults enrolled in routine care across 5 sites in the United States, we included participants with a baseline patient-reported outcome measure and detectable viral load who initiated ART between 2011 and 2014. Participants were followed until the earliest of the following: first suicidal thoughts, discontinuation of initial ART regimen, death, loss to care (>12 months with no HIV appointments), or administrative censoring (2014-2015). Suicidal thoughts were measured using a Patient Health Questionnaire-9 item. We used weighted marginal structural Cox models to estimate the effect of initiating efavirenz-containing ART, versus efavirenz-free ART, on the hazard of active or passive suicidal thoughts after ART initiation, accounting for confounding by channeling bias.ResultsOverall, 597 participants were followed for a median of 19 months (13,132 total person-months); 147 (25%) initiated efavirenz-containing ART. At ART initiation, 38% of participants reported suicidal thoughts or depressive symptoms. Initiating efavirenz-based ART was associated with a hazard ratio (HR) for suicidal thoughts below the null in the crude analysis [HR, 0.88; 95% confidence interval (CI): 0.53 to 1.45] and above the null in the weighted analysis (HR, 1.21; 95% CI: 0.66 to 2.28). Among those with a prior mental health issue, the weighted HR was 1.76 (95% CI: 0.45 to 6.86).ConclusionsAfter accounting for measured channeling bias, we observed no strong evidence that initiating efavirenz-containing ART increased the hazard of suicidal thoughts.

BackgroundThe worldwide increase in life expectancy has been associated with an increase in age-related morbidities. The underlying mechanisms resulting in immunosenescence are only incompletely understood. Chronic viral infections, in particular infection with human cytomegalovirus (HCMV), have been suggested as a main driver in immunosenescence. Here, we propose that rhesus macaques could serve as a relevant model to define the impact of chronic viral infections on host immunity in the aging host. We evaluated whether chronic rhesus CMV (RhCMV) infection, similar to HCMV infection in humans, would modulate normal immunological changes in the aging individual by taking advantage of the unique resource of rhesus macaques that were bred and raised to be Specific Pathogen Free (SPF-2) for distinct viruses.ResultsOur results demonstrate that normal age-related immunological changes in frequencies, activation, maturation, and function of peripheral blood cell lymphocytes in humans occur in a similar manner over the lifespan of rhesus macaques. The comparative analysis of age-matched SPF-2 and non-SPF macaques that were housed under identical conditions revealed distinct differences in certain immune parameters suggesting that chronic pathogen exposure modulated host immune responses. All non-SPF macaques were infected with RhCMV, suggesting that chronic RhCMV infection was a major contributor to altered immune function in non-SPF macaques, although a causative relationship was not established and outside the scope of these studies. Further, we showed that immunological differences between SPF-2 and non-SPF macaques were already apparent in adolescent macaques, potentially predisposing RhCMV-infected animals to age-related pathologies.ConclusionsOur data validate rhesus macaques as a relevant animal model to study how chronic viral infections modulate host immunity and impact immunosenescence. Comparative studies in SPF-2 and non-SPF macaques could identify important mechanisms associated with inflammaging and thereby lead to new therapies promoting healthy aging in humans.