Modulating the Impact of Critical Events in Early HIV Infection: Effect of ART Initiation and Alcohol Use

Overview

The overall objective is to determine the influence of timing of ART initiation and alcohol consumption on HIV disease course. ART initiation immediately after HIV infection 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 intestinal microbiome dysbiosis, 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 study will be conducted in Lima, Peru, in a cohort of 180 MSM and transgender women (TW) with acute (Ab-, HIV RNA+) or recent (≤ 3 months) HIV infection. Alcohol use disorder (AUDIT score ≥8) is present in \~50% of HIV + participants in our cohort, 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. 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 at 24 weeks after diagnosis. The investigators will study outcomes after 2 and 4 years in MSM and TW diagnosed with acute or recent HIV infection. 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.

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. Early ART initiation is, however, associated with preservation of CD4+ T cells and lower levels of total HIV DNA and cell-associated RNA 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. 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. 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). 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) and TW, in whom high-level alcohol use is common. They will study outcomes after 2 and 4 years in MSM and TW diagnosed with acute (Ab-, HIV RNA+) or recent (≤3 months) HIV infection. Three groups based on time since estimated date of detectible HIV infection (EDDI) to ART initiation will be studied: a) EDDI-to-ART: ≤ 30 days b) EDDI-to-ART: 31-90 days and c) EDDI-to-ART: \>90 days 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 within 30 days will have the greatest benefit. 2. Irrespective of the time of ART initiation, alcohol use will compound the negative effects of HIV. SPECIFIC AIM 1) To determine the relative long-term benefits of immediate vs. early vs. delayed initiation of ART. Initiation of ART within 30 days of infection, while theoretically appealing, is infeasible in clinical practice because antibody-based tests, used almost world-wide, are unable to diagnose very early infection. Six months of ART initiated shortly after seroconversion can improve many immune parameters, although not to the near normal level seen when ART is initiated earlier.. Longer-term follow-up of seropositive participants who started ART \~2-8 months after HIV acquisition compared to those initiating ART within 30 days 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 4 years of ART, comparing viral load, CD4 counts, time to reach undetectable VL, the GI microbiota, and inflammatory markers. Specimens from uninfected and chronically infected subjects are available as controls for some outcomes. They will model the size and persistence of the viral reservoir across all ART-compliant study subjects, measuring total HIV DNA, integrated HIV DNA and multi-spliced HIV RNA via TILDA (Tat/Rev Induced Limiting Dilution Assay) assay. In a subset of individuals from each group, the proviral integration sites will be defined at ART initiation and after 2 and 4 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.. Dysbiosis is present in many HIV-infected patients. Methods: Investigators will compare outcomes between subjects by their reported alcohol use or by assessing alcohol use blood biomarkers (Phosphatidylethanol; PEth) at specified timepoints.. 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 2 and 4 years after ART initiation.