HIV, HCV and Liver Disease Among Injection Drug Users in Chennai, India

描述（由申请人提供）：提议的申请是响应PA-09-020“药物成瘾国际研究合作”，该合作将约翰霍普金斯大学和YR Gaitonde艾滋病研究和教育中心联合起来，表征金奈注射吸毒者（IDUs）中艾滋病毒、丙型肝炎病毒（HCV）、结核病（TB）、酒精和肝脏疾病之间的相互作用。为未来的治疗举措和干预措施提供信息，以减轻多重肝毒性因素人群的肝病负担。在发达国家，肝病已成为感染艾滋病毒的注射吸毒者发病的主要原因。然而，在注射吸毒者中艾滋病毒流行增长最快的发展中国家所做的工作很少。丙型肝炎病毒治疗在发展中国家没有得到广泛应用；然而，这种差异将会改变，这提高了了解印度特有的暴露如何影响肝病的流行和形式的紧迫性，以及是否可以用新的、文化上可接受的工具来识别风险最大的人。因此，我们的目标是：目的1：确定脂肪肝疾病（如脂肪变性、脂肪性肝炎）的患病率，并调查使用4t、HCV基因型3、胰岛素抵抗和酒精使用是否独立相关的假设；AIM 1.1：验证脂肪变性和纤维化的现有诊断算法，并比较现有面板（例如，APRI, FIB-4）与使用低成本测试和当地风险因素的新面板的预测准确性；目的2：确定脂肪变性和肝纤维化是否影响与抗逆转录病毒治疗（ART）和抗结核治疗（ATT）相关的未来肝脏不良事件的发生率；目标3：开始试点干预措施，以减轻印度注射吸毒者的肝病负担；目标3.1。量化印度注射吸毒者中HCV治疗反应的可接受性和潜力（IL28b基因单核苷酸多态性[snp]的患病率）；和AIM 3.2。进行双盲安慰剂对照随机临床试验，以确定维生素E治疗脂肪变性的疗效。我们将通过横断面研究、纵向队列随访和基于两个现有队列的双盲安慰剂对照随机临床试验来实现这些目标。对于Aim 1，我们将使用超声检查脂肪变性和纤维扫描(R)检查纤维化。对于目标2，我们将每半年对患者进行随访，以确定ART和ATT的新开始者，并在开始后进行强化随访，以确定肝脏耐受性。在目标3中，我们将通过问卷调查评估HCV治疗的可接受性，并通过宿主基因检测评估潜在的治疗反应。Aim - 3试验将在基线时患有组织学脂肪性肝炎的100名注射者中进行。我们有一个很小的机会窗口，为发展中国家注射吸毒者中即将发生的肝病流行病做好准备。由于注射吸毒对包括非洲在内的发展中国家的艾滋病毒流行的影响越来越大，艾滋病毒-丙型肝炎病毒合并感染的流行率继续上升，这些发现还将为PEPFAR和GFATM等捐助者提供有关治疗决策的信息。

DESCRIPTION (provided by applicant): Proposed is an application in response to PA-09-020, "International Research Collaboration on Drug Addiction." that brings together Johns Hopkins University and the YR Gaitonde Centre for AIDS Research and Education to characterize interactions between HIV, hepatitis C virus (HCV), tuberculosis (TB), alcohol and liver disease among injection drug users (IDUs) in Chennai, India and to inform future treatment initiatives and interventions to reduce the burden of liver disease in a population with a confluence of hepatotoxic factors. In the developed world, liver disease has emerged as a leading cause of morbidity among HIV-infected IDUs. However, little work has been done in developing countries which represent the fastest growing HIV epidemics among IDUs. HCV treatment is not widely available in the developing world; however this disparity will change raising the urgency of understanding how exposures unique to India affect prevalence and forms of liver disease and whether those at greatest risk can be identified with novel, culturally acceptable tools. Accordingly, our aims are: AIM 1: To ascertain the prevalence of fatty liver disease (e.g., steatosis, steatohepatitis) and investigate the hypothesis d4T use, HCV genotype 3, insulin resistance and alcohol use are independently associated; AIM 1.1: To validate existing diagnostic algorithms for steatosis and fibrosis and to compare the predictive accuracy of existing panels (e.g., APRI, FIB-4) with new panels that use low-cost tests and local risk factors; AIM 2: To determine whether steatosis and liver fibrosis impact the incidence of future hepatic adverse events associated with antiretroviral therapy (ART) and anti-tuberculosis therapy (ATT); AIM 3: To begin to pilot interventions to reduce the burden of liver disease among IDUs in India; AIM 3.1. To quantify the acceptability and potential for HCV treatment response (prevalence of single nucleotide polymorphisms [SNPs] in the IL28b gene) among IDUs in India; and AIM 3.2. To conduct a double-blinded placebo controlled randomized clinical trial to determine the efficacy of Vitamin E for the treatment of steatosis. We will achieve these aims through a mix of cross-sectional studies, longitudinal cohort follow-up and a double-blinded placebo controlled randomized clinical trial building on two existing cohorts. For Aim 1, we will use ultrasonography for steatosis and Fibroscan(R) for fibrosis. For Aim 2, we will follow persons semi-annually to identify new initiates of ART and ATT and conduct intensive follow-up after initiation to determine hepatic tolerability. In Aim 3, we will assess acceptability of HCV treatment via questionnaire and potential treatment response via host genetic testing. The Aim 3 trial will be conducted among 100 IDUs with histologic steatohepatitis at baseline. We have a small window of opportunity to prepare for the impending epidemic of liver disease among IDUs in the developing world. These findings will also inform donors such as PEPFAR and GFATM regarding treatment decisions as the prevalence of HIV-HCV co-infection continues to rise as a result of the increasing contribution of injection drug use to the HIV epidemic in the developing countries including Africa. PUBLIC HEALTH RELEVANCE: Injection drug users (IDUs) are at high risk for HIV and hepatitis infections and the long-term complications of these infections, including liver disease, drug-related hepatotoxicity and mortality. The findings from this study will help to inform interventions to reduce the morbidity and mortality associated with drug use, HIV and hepatitis C. to inform interventions to reduce the morbidity and mortality associated with drug use, HIV and hepatitis C.