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

描述(申请人提供)：大量饮酒和艾滋病毒感染的组合与死亡率增加、艾滋病毒疾病进展、急性心肌梗死(AMI)和以炎症生物标记物水平增加为特征的促炎状态有关。大量饮酒和艾滋病毒感染都是微生物移位的原因，微生物移位是胃肠道(GI)的细菌产物通过GI膜泄漏到门静脉循环的过程。微生物易位导致免疫激活，最终导致器官损伤。酒精可通过缺锌引起微生物移位。缺锌在HIV+酗酒者中很常见，并与高死亡率有关。补锌是负担得起的，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，锌减少了与乙醇相关的微生物易位。在人体研究中，锌可以减缓HIV疾病的进展，降低与死亡率密切相关的炎性生物标志物的水平。鉴于锌的潜在疗效，我们建议进行锌对HIV中的炎症和慢性病(HIV锌)的治疗，这是一项双盲随机对照试验，在250名HIV+俄罗斯人中评估补锌和安慰剂的疗效，这些人在登记时很幼稚，最近有大量饮酒史。我们将从乌干达、俄罗斯、波士顿酒精网络酒精研究合作艾滋病毒/艾滋病(城市ARCH)联盟研究的俄罗斯队列中招募大多数参与者。我们的具体目标将测试锌补充剂与安慰剂相比的有效性：(1)通过Vacs指数衡量的死亡标志物；(2)通过CD4细胞计数衡量的HIV疾病进展缓慢；(3)通过雷诺风险评分衡量的急性心肌梗死风险标志物；以及(4)通过血清生物标志物衡量的更低的微生物易位和炎症水平。我们假设，与安慰剂相比，接受锌补充的患者将显著降低急性心肌梗死和死亡风险，这是通过Vacs指数和雷诺风险评分来衡量的；更高的CD4细胞计数；更低的微生物易位和炎症生物标志物水平。重要的是，如果我们的假设属实，即使在资源有限的环境中，补锌最终也可能成为补充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.