The overall objective is to determine the influence of timing of ART initiation and alcohol consumption on HIV disease course, including detailed analysis of important events occurring shortly after HIV acquisition. ART initiation immediately after HIV infection (during Fiebig stages I-II) largely results in smaller HIV reservoir and lower HIV-associated systemic inflammation, which has been linked to non-AIDS morbidity and mortality. Immediate ART also reduces HIV-associated bacterial translocation and may prevent dysbiosis, an alteration of the intestinal microbiota that has been linked to increased systemic inflammation. Immediate intervention is not, however, generally feasible and more information is required about the consequences of starting ART at later time-points, but still early after acquisition. The proposed study will be conducted in Lima, Peru, in the cohort of 180 MSM with acute (Ab-, HIV RNA+) or recent (≤ 3 months) HIV infection. Alcohol use disorder is present in ~50% of HIV-infected MSM in our cohort, which is four times higher than that seen among males in the general Peruvian population. Although the role of alcohol use in HIV pathogenesis and disease course remains unclear, some studies show a correlation with accelerated disease progression. In animal models and clinical studies, both acute and chronic alcohol consumption have been linked to bacterial translocation and activation of the innate immune system, which can lead to increases in pro-inflammatory cytokines. The effects of alcohol resemble early post-infection changes in bacterial translocation and pro-inflammatory cytokines induced by HIV and their impact on HIV disease course before and after ART initiation remain unexplored.
Specific Aim 1: To determine the relative long-term benefits of immediate vs. early vs. delayed ART initiation. The investigators will study outcomes after 1.5 and 3.5 years in MSM diagnosed with acute or recent HIV infection. The investigators will examine outcomes in 3 groups based on time of ART initiation: a) immediate: during FI-II (N~30), b) early: during FIII-V (N~50) or c) delayed: at 24 weeks after diagnosis (N~80). The investigators anticipate that CD4+ T cell counts and peripheral inflammatory markers in the FIII-V group and the delayed group will approach those in the immediate treatment group (FI-II) over time; in contrast, they expect that those started ART at "early" or "delayed" time points will have persistent changes in the GI microbiome and in the HIV reservoir.
Specific Aim 2: To determine the impact of alcohol use on the relative long-term benefits of immediate vs. early vs. delayed initiation of ART. The investigators will examine the impact of alcohol use on critical events in HIV infection. They hypothesize that dose-dependent alcohol-induced changes will compound the negative effects of HIV and lead to greater levels of dysbiosis and inflammation, higher early plasma HIV RNA, and greater "seeding" and persistence of HIV DNA in participants with high-level alcohol use. The investigators will assess viral load, GI microbiome and metagenomics, pro-inflammatory cytokines, production of msRNA and analyze the impact on alcohol use in all subjects prior to ART initiation and among ART-adherent participants with persistent viral suppression.
- Study Type: Interventional
- Study Design
- Allocation: Randomized
- Intervention Model: Parallel Assignment
- Primary Purpose: Treatment
- Masking: None (Open Label)
- Study Primary Completion Date: August 2020
Specific Aims: Recent studies suggest that very early initiation of ART (prior to seroconversion) does not prevent the establishment of HIV reservoirs, which eventually expand when ART is discontinued (1, 2). Early ART initiation is, however, associated with preservation of CD4+ T cells and lower levels of total HIV DNA and cell-associated RNA (3) as well as preservation of gut Th17 cells, thereby averting a major driver of HIV-related immune activation and limiting the size of the HIV reservoir (4). When, by contrast, ART is initiated in Fiebig III (FIII) or later, many HIV-associated changes have already occurred, including seeding of HIV reservoirs, damage to GI mucosa, and initiation of inflammatory cascades (4). Some if not all of these effects may be related to the development of dysbiosis (a markedly different composition of the gut microbiota that might itself drive continued inflammation). Since ART initiation within weeks of HIV acquisition is not a viable public health strategy, it is important to more completely understand the relative long-term benefits of initiating ART at very early times after infection (FI-II) as opposed to after a short (during FIII-V) or longer delay (at 24 weeks). The effects of alcohol on microbial translocation and pro-inflammatory cytokines are not unlike early changes after HIV infection (5-7); however, alcohol's role in HIV pathogenesis and progression is not well defined. Since the possibility that high-level alcohol use can mitigate the benefits of early ART is emerging as a potentially important public health issue, the investigators will evaluate the impact of time of ART initiation as well as alcohol use on HIV pathogenesis in Peruvian men who have sex with men (MSM), in whom high-level alcohol use is common. They will study outcomes after 1.5 and 3.5 years in MSM diagnosed with acute (Ab-, HIV RNA+) or recent (≤3 months) HIV infection. Three groups based on time of ART initiation will be studied: a) immediate: during FI-II (N~30), b) early: during FIII-V (N~50) or c) delayed: at 24 weeks after diagnosis (N~80).
The overarching hypotheses are: 1. Initiation of ART soon after HIV infection will dampen perturbations of GI microbiota, reduce HIV-induced inflammatory changes, and decrease seeding of the reservoir. Initiation of ART in FI-II will have the greatest benefit. The investigators anticipate that CD4 counts and peripheral inflammatory markers in the FIII-V group and the group treated at 24 weeks will approach those in the FI-II group at 1.5 and 3.5 years; in contrast, the investigators expect changes in the GI microbiome and the HIV reservoir over time will be more modest. 2. Irrespective of the time of ART initiation, alcohol use will compound the negative effects of HIV to generate greater levels of dysbiosis, microbial translocation, up-regulation of inflammatory pathways, and seeding of the HIV reservoir. To investigate these hypotheses, they will address the following two specific aims:
SPECIFIC AIM 1) To determine the relative long-term benefits of immediate vs. early vs. delayed initiation of ART. Initiation of ART during Fiebig I-II, while theoretically appealing, is infeasible in clinical practice because the duration of FI-II is very short (10 days) and because antibody-based tests, used almost world-wide, are unable to diagnose FI-II. Six months of ART initiated shortly after seroconversion (FIII) can improve many immune parameters, although not to the near normal level seen when ART is initiated during FI-II (4). Longer-term follow-up of seropositive participants who started ART ~2-8 months after HIV acquisition compared to those initiating ART during FI-II is needed to see whether markers of inflammation and residual viral load might continue to improve after 6 months, decreasing the difference between the groups. Methods: the investigators will evaluate the 3 groups using specimens from equivalent times after ART initiation for a total of 3.5 years of ART, comparing CD4 counts, time to reach undetectable VL, the GI microbiota, and inflammatory markers. The size of the replication-competent reservoir in PBMCs will be compared using measurements of multiply spliced viral RNA (msRNA) and the degree of low-level infection of new cells by assessing the production of circular viral DNA (2LTR HIV DNA). They will model the size and persistence of the viral reservoir across all ART-compliant study subjects. In a subset of individuals from each group, the proviral integration sites will be defined at ART initiation and after 1.5 and 3.5 years to assess the maintenance of the reservoir by proliferating CD4 cells.
SPECIFIC AIM 2) To determine the impact of high-level alcohol use on the relative long-term benefits of immediate vs. early vs. delayed ART initiation. High-level alcohol use results in changes in the GI microbiome, increasing dysbiosis and gut permeability, and these changes are associated with up-regulation of inflammatory pathways (8-13). Dysbiosis is present in many HIV-infected patients. The extent of dysbiosis correlates with established markers of HIV disease progression and the consequent inflammatory processes contribute to HIV disease progression, even in treated individuals. Methods: The investigators will use monthly data on alcohol use to assess alcohol consumption as a continuous, time-varying predictor. In all participants at the time of diagnosis, and at multiple timepoints prior to ART in those enrolled into the deferred group, they will assess VL, GI microbiota and metagenomics, pro-inflammatory cytokines, and production of msRNA. They will compare these factors between subjects by their reported alcohol use, focusing on events occurring shortly after HIV acquisition. Specimens from uninfected and chronically infected subjects are available as controls. Finally, among ART-adherent subjects with persistent viral suppression, the investigators will assess inflammatory markers and HIV reservoirs in those with and without high-level alcohol use at 1.5 and 3.5 years after ART initiation.
- Drug: ART initiation at time of HIV diagnosis
- Immediate ART initiation
- Drug: ART at 24 weeks
- ART initiation 24 weeks after enrollment
Arms, Groups and Cohorts
- Other: Early ART initiation
- Immediate ART initiation at the time of HIV diagnosis; daily dose of combination ART (one pill/day)
- Other: Deferred ART initiation
- ART initiation at 24 weeks after HIV diagnosis; daily dose of combination ART (one pill/day)
Clinical Trial Outcome Measures
- HIV reservoir
- Time Frame: 3.5 years
- HIV reservoir measured a several time points after ART initiation
- GI microbiome
- Time Frame: 3.5 years
- GI microbiome characterized at multiple time points after ART initiation
- DNA integration sites
- Time Frame: 3.5 years
- HIV integration sites measured after 3 1/2 years of VL suppression on ART
Participating in This Clinical Trial
- Men who have sex with men or transgender women HIV-infected with prior participation in SABES study in Lima Peru OR Established HIV infection OR HIV uninfected
- counter-indication for use of study antiretroviral drugs
Gender Eligibility: Male
Minimum Age: 18 Years
Maximum Age: N/A
Are Healthy Volunteers Accepted: Accepts Healthy Volunteers
- Lead Sponsor
- Fred Hutchinson Cancer Research Center
- University of California, San Francisco
- Provider of Information About this Clinical Study
- Principal Investigator: Ann C Duerr, Member – Fred Hutchinson Cancer Research Center
- Overall Official(s)
- Ann Duerr, Principal Investigator, Fred Hutchinson Cancer Research Center
- Overall Contact(s)
- Ann C Duerr, MD, PhD, MPH, 206 667 7938, email@example.com
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