Zinc for HIV Disease among Alcohol Users -An RCT in the Russia ARCH Cohort

描述（由申请人提供）：大量饮酒和HIV感染的结合与死亡率增加、HIV疾病进展、急性心肌梗死（AMI）和以炎症生物标志物水平升高为特征的促炎症状态相关。大量饮酒和艾滋病毒感染都是微生物易位的原因，这是胃肠道细菌产物通过胃肠道膜渗漏到门静脉循环的过程。微生物易位引起免疫激活，导致终末器官损伤。酒精可以通过缺锌导致微生物移位。缺锌在艾滋病毒阳性的酗酒者中很常见，并与高死亡率有关。锌补充剂是负担得起的，可获得的，不干扰抗逆转录病毒治疗，并且有最小的药物不良反应。在动物模型中，锌可以减少乙醇相关的微生物易位。在人体研究中，锌减缓了HIV疾病的进展，降低了与死亡率密切相关的炎症生物标志物的水平。鉴于锌的潜在功效，我们建议开展锌治疗HIV炎症和慢性疾病（zinc HIV），这是一项双盲随机对照试验，在250名HIV+俄罗斯人中评估锌补充剂与安慰剂的疗效，这些人在入组时未接受art治疗，并且最近有大量饮酒史。我们将从乌干达-俄罗斯-波士顿酒精网络艾滋病毒/艾滋病酒精研究合作（URBAN ARCH）联盟研究的俄罗斯队列中招募大多数参与者。我们的具体目标是测试锌补充剂的功效，与安慰剂相比：(1)改善由VACS指数测量的死亡率指标；(2) CD4细胞计数检测HIV疾病进展缓慢；(3)改善Reynolds风险评分中AMI风险指标；(4)血清生物标志物测量的微生物易位和炎症水平较低。我们假设，与安慰剂相比，通过VACS指数和Reynolds风险评分测量，接受锌补充剂的患者AMI和死亡风险显著降低；CD4细胞计数较高；微生物易位和炎症的生物标志物水平较低。重要的是，如果我们的假设是正确的，即使在资源有限的环境中，锌补充剂最终也可能成为HIV+患者酒精干预的标准辅助疗法。

DESCRIPTION (provided by applicant): The combination of heavy alcohol consumption and HIV infection is associated with increased mortality, HIV disease progression, acute myocardial infarction (AMI) and a proinflammatory state characterized by increased biomarker levels of inflammation. Heavy alcohol use and HIV infection are both causes of microbial translocation, the process by which bacterial products from the gastrointestinal (GI) tract leak across the GI membrane to the portal circulation. Microbial translocation causes immune activation leading to end organ damage. Alcohol can cause microbial translocation via zinc deficiency. Zinc deficiency is common among HIV+ heavy drinkers and linked to high mortality rates. Zinc supplementation is affordable, available, does not interfere with ART, and has minimal adverse drug reactions. In animal models zinc reduces ethanol associated microbial translocation. In human studies zinc slows HIV disease progression and reduces levels of inflammatory biomarkers which are strongly linked to mortality. Given zinc's potential efficacy we propose to conduct Zinc for INflammation and Chronic disease in HIV (ZINC HIV), a double-blinded randomized controlled trial to assess the efficacy of zinc supplementation vs. placebo among 250 HIV+ Russians, who are ART-naive at enrollment and have a recent history of heavy drinking. We will recruit most of our participants from the Russia cohort within the Uganda Russia Boston Alcohol Network for Alcohol Research Collaboration on HIV/AIDS (URBAN ARCH) Consortium study. Our specific aims will test the efficacy of zinc supplementation, compared to placebo to (1) improve markers of mortality as measured by the VACS index; (2) slow HIV disease progression as measured by CD4 cell count; (3) improve markers of AMI risk as measured by the Reynolds risk score; and (4) lower levels of microbial translocation and inflammation as measured by serum biomarkers. We hypothesize that as compared with placebo, patients receiving zinc supplementation will have significantly lower AMI and mortality risk as measured by the VACS index and Reynolds risk scores; higher CD4 cell counts; lower levels of biomarkers for microbial translocation and inflammation. Importantly, if our hypotheses are true, zinc supplementation could ultimately become a standard adjunctive therapy complementing alcohol interventions among HIV+ persons even in resource limited environments.