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

 描述（由申请人提供）：我们的总体目标是确定ART启动时间和饮酒对HIV病程的影响，包括详细分析HIV感染后不久发生的重要事件。艾滋病毒感染后立即开始ART（在Fiebig I-II期期间）在很大程度上导致艾滋病毒储存库较小和艾滋病毒相关全身炎症较低，这与非艾滋病发病率和死亡率有关。立即ART还减少了HIV相关的细菌易位，并可能预防生态失调，这是一种与全身炎症增加有关的肠道微生物群的改变。然而，立即干预通常是不可行的，需要更多关于在晚些时候开始抗逆转录病毒治疗的后果的信息，但仍然是在获得后的早期。拟定的研究将在秘鲁利马进行，在我们的180例急性（Ab-，HIV RNA+）或近期（= 3个月）HIV感染的MSM队列中进行。在我们的队列中，酒精使用障碍存在于约50%的艾滋病毒感染的男男性行为者中，这比秘鲁普通人群中的男性高出四倍。尽管饮酒在艾滋病发病机制和病程中的作用尚不清楚，但一些研究表明与加速疾病进展相关。在动物模型和临床研究中，急性和慢性饮酒都与细菌移位和先天免疫系统的激活有关，这可能导致促炎细胞因子的增加。酒精的影响类似于HIV诱导的细菌易位和促炎细胞因子的感染后早期变化，其对ART启动前后HIV病程的影响尚未探讨。 具体目标1：确定立即与早期与延迟ART启动的相对长期益处。我们将研究1.5年和3.5年后的结果在MSM诊断为急性或最近的艾滋病毒感染。我们将根据ART启动时间检查3组的结局：a）立即：FI-II期间（N~30），B）早期：FIII-V期间（N~50）或c）延迟：诊断后24周（N~80）。我们预计FIII-V组和延迟组中的CD 4 + T细胞计数和外周炎性标志物将随着时间的推移接近立即治疗组（FI-II）;相反，我们预计在“早期”或“延迟”时间点开始ART的患者将在GI微生物组和HIV储库中发生持续变化。 具体目标二：为了确定酒精使用的影响，相对的长期利益，立即与早期与延迟启动抗逆转录病毒治疗。我们将研究酒精使用的影响，在艾滋病毒感染的关键事件。我们假设，剂量依赖性酒精诱导的变化将加剧艾滋病毒的负面影响，并导致更高水平的生态失调和炎症，更高的早期血浆HIV RNA，以及更大的“播种”和高水平酒精使用参与者中HIV DNA的持久性。我们将评估病毒载量、GI微生物组和宏基因组学、促炎细胞因子、msRNA的产生，并分析ART启动前所有受试者和持续病毒抑制的ART依从受试者中酒精使用的影响。

 DESCRIPTION (provided by applicant): Our 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 our 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. We will study outcomes after 1.5 and 3.5 years in MSM diagnosed with acute or recent HIV infection. We 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). We 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, we expect that those started ART at "early" or "delayed" time point 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. We will examine the impact of alcohol use on critical events in HIV infection. We 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. We 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.