Liver Disease and HIV-HBV Coinfection in the HAART era

描述(申请人提供)：慢性乙肝(CH-B)在艾滋病毒感染者中很常见，艾滋病毒会加速与乙肝相关的肝病的进展速度。在多中心艾滋病队列研究(MACS)中，与单独感染CH-B病毒的人相比，与肝脏相关的死亡风险在合并感染HIV-HBV者中几乎高出18倍。此外，与1996年引入高效抗逆转录病毒疗法(HAART)之前相比，这一比率高出两倍。这些数据支持了研究HAART对HIV-HBV共感染者肝脏疾病进展的影响的必要性。 这项提案调查了接受HAART的HIV感染者中的CH-B，接受HAART的是来自MACS的HIV-HBV共感染患者队列和两个具有良好特征的澳大利亚队列，一个在墨尔本，一个在悉尼。第一个目的是验证这样一种假设，即长期有效地抗乙肝病毒的HAART将改变HIV-乙肝混合感染者中与HAART相关的肝毒性的比率。我们将确定HAART启动后五年内的肝毒性比率。在第二个目标中，HBVHAART方案抑制HBVDNA的幅度和持久性将通过前瞻性地跟踪HBVDNA水平来确定。第三个目的是研究在乙肝病毒活性的HAART中没有持久抑制HBVDNA的人发生的耐药性突变的演变。在复发时，将对整个乙肝病毒基因组进行测序，然后随后进行代偿突变的开发。这些突变病毒将接受抗病毒药物敏感性和复制能力的测试。这些目标被整合到第四个目标中，该目标验证了有效的乙肝病毒活性HAART方案将减缓肝病进展速度的假设。为此，将检查成对的肝脏活检，以确定肝脏疾病的进展率，并分析维持持久的HBVDNA应答的能力，耐药突变株的发展，以及肝内HBVDNA和CCC DNA的水平。鉴于调查小组的经验和所涉及的特征良好的队列，这项提案的结果将为艾滋病毒-乙肝合并感染患者的管理提供洞察力。

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.