Liver Disease and HIV-HBV Coinfection in the HAART era

描述（由申请人提供）：慢性B型肝炎（CH-B）在HIV感染者中很常见，HIV加速了乙型肝炎相关肝病进展的速度。在多中心艾滋病队列研究（MACS）中，合并感染HIV-HBV的患者的肝脏相关死亡风险比单独感染CH-B的患者高出近18倍。此外，在1996年采用高效抗逆转录病毒疗法之后，这一比率比1996年之前高出两倍。这些数据支持需要研究HAART对HIV-HBV合并感染者肝脏疾病进展的影响。 该提案调查了接受HAART的HIV-HBV合并感染患者队列中的CH-B，这些患者来自MACS和两个特征良好的澳大利亚队列，一个在墨尔本，一个在悉尼。第一个目的是检验长期抗HBV HAART治疗是否会改变HIV-HBV合并感染者HAART相关肝毒性的发生率。我们将确定HAART开始后5年内的肝毒性发生率。在第二个目标中，将通过前瞻性随访HBV DNA水平来确定HBV活性HAART方案对HBV DNA抑制的程度和持久性。第三个目的是研究在HBV活性HAART没有持久抑制HBV DNA的人中发生的耐药突变的演变。将在复发时对整个HBV基因组进行测序，然后随后进行代偿性突变的发展。将检测这些突变病毒的抗病毒药物敏感性和复制能力。这些目标被整合到第四个目标中，该目标测试了有效的HBV活性HAART方案将减缓肝病进展速度的假设。为此，将检查成对肝活检以确定肝病进展率，并分析维持持久HBV DNA应答的能力、耐药突变体的形成以及HBV DNA和ccc DNA的肝内水平。鉴于研究小组的经验和所涉及的特征良好的队列，该提案的结果将为HIV-HBV合并感染患者的管理提供见解。

DESCRIPTION (provided by applicant): Chronic hepatitis B (CH-B) is common in HIV-infected persons, and HIV accelerates the rate of hepatitis B-related liver disease progression. In the Multicenter AIDS Cohort Study (MACS), the risk of liver-related death was nearly 18 times higher in those coinfected with HIV-HBV compared to those with CH-B alone. Furthermore, the rate was two times higher after compared to before 1996, the time of the introduction of highly active antiretroviral therapy (HAART). These data support the need to study the effects of HAART on liver disease progression in HIV-HBV coinfected persons. This proposal investigates CH-B in HIV-infected persons receiving HAART in a cohort of HIV-HBV coinfected patients from the MACS and two well-characterized Australian cohorts, one in Melbourne and one in Sydney. The first aim will test the hypothesis that long-term HAART active against HBV will alter the rate of HAART-related hepatotoxicity in HIV-HBV coinfected persons. We will determine the rates of hepatotoxicity over a five-year period following HAART initiation. In the second aim the magnitude and durability of HBV DNA suppression with a HBV active HAART regimen will be determined by prospectively following HBV DNA levels. The third aim is designed to study the evolution of resistance mutations that occur in persons who do not have a durable suppression of their HBV DNA with HBV-active HAART. The entire HBV genome will be sequenced at the time of relapse and then followed subsequently for the development of compensatory mutations. These mutant viruses will be tested for anti-viral drug sensitivity and replication competence. These aims are integrated in the fourth aim, which tests the hypothesis that an effective HBV active HAART regimen will slow the rate of liver disease progression. In this aim, paired liver biopsies will be examined to determine the rates of liver disease progression and analyzed with respect to the ability to maintain a durable HBV DNA response, to the development of drug-resistant mutants, and to intrahepatic levels of HBV DNA and ccc DNA. Given the experience of the investigative team and the well-characterized cohorts involved, the results from this proposal will yield insights into the management of HIV-HBV co-infected patients.