Hepatitis B treatment and HIV Infection in resources limited settings

描述(申请人提供)：慢性乙型肝炎(CH-B)是全球终末期肝病和肝细胞癌的主要原因，估计有10%的艾滋病毒感染者受到影响。目前治疗慢性乙型病毒性肝炎的方法疗效不佳。随着抗逆转录病毒疗法被引入到CH-B病毒负担最重的地区，确定艾滋病毒感染者对乙肝病毒的治疗是重要的。为此，在这项建议中检验的总体假设是，具有更大效力和更高耐药阈值的抗乙肝方案优于没有这两个特征的方案。这一假设将在一项嵌套在现有国际ACTG抗逆转录病毒疗法(ART)试验中的临床试验中得到验证，在该试验中，参与者被随机分成三种抗逆转录病毒方案之一。一种方案在一片药片中包含两种抗乙肝药物，因此可能比另外两种方案具有更强的效力和更高的耐药阈值。第一个目的是通过确定免疫抑制程度与病毒复制量之间的关系来研究CH-B对HIV感染者的免疫控制。第二个目的是验证这样的假设，即以病毒抑制为主要结果，有效且耐药屏障高的抗乙肝方案优于其他两种耐药屏障较低的方案。病毒抑制是使用HBVDNA分析来定义的，并且每6个月测量一次，至少30个月。次要结果包括HBVDNA下降、HBeAg血清转换和ALT正常化。这一目的也决定了与抗乙肝治疗反应相关的乙肝病毒和艾滋病毒因素。第三个目的是验证病毒学反弹和缺乏抑制是由于抗药性病毒的发展的假设。为了实现这一目标，将在复发时对整个乙肝病毒基因组进行测序，并前瞻性地进行跟踪，以发展代偿性突变。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。这项建议与公共卫生直接相关，因为它涉及对艾滋病毒感染者进行最佳治疗的问题，这是一个重大的全球问题。考虑到研究团队的经验、随机临床试验设计和现有研究的嵌套，这项建议成功的可能性很高。

DESCRIPTION (provided by applicant): Chronic hepatitis B (CH-B), which is the leading cause of end stage liver disease and hepatocellular carcinoma worldwide, affects an estimated 10% of HIV-infected persons. The current options for treating CH- B have poor efficacy. As antiretroviral therapy is introduced into areas with the greatest burden of CH-B, it is important to determine the treatment for HBV in the HIV-infected person. To this end, the overall hypothesis tested in this proposal is that an anti-HBV regimen that has greater potency and higher resistance threshold is superior to one without both those characteristics. This hypothesis will be tested in a clinical trial nested within an existing international ACTG antiretroviral therapy (ART) trial in which participants are randomized to one of three antiretroviral regimens. One regimen contains two anti-HBV drugs in one pill and thus may have greater potency and higher resistance threshold than the other two arms. The first aim investigates the immunologic control of CH-B in HIV-infected persons by determining the relationship between the degree of immunosuppression and the amount of HBV replication. The second aim tests the hypothesis that the anti-HBV regimen that is potent and has a high barrier to resistance is superior to the other two regimens that have a lower barrier to resistance using viral suppression as the primary outcome. Viral suppression is defined using the HBV DNA assay and is measured every 6 months for 30 months minimum. Secondary outcomes include decline in HBV DNA, HBeAg seroconversion, and ALT normalization. This aim also determines HBV and HIV factors associated with response to anti-HBV treatment. The third aim tests the hypothesis that virological rebound and lack of suppression are due to development of drug-resistant virus. To accomplish this aim the entire HBV genome will be sequenced at the time of relapse and followed prospectively for the development of compensatory mutations. These mutant viruses will be tested for anti-viral drug sensitivity and replication competence. This proposal is directly relevant to public health since it addresses optimal treatment of CH-B in HIV- infected persons, which is a major global problem. This proposal has a high likelihood for success given the investigative team's experience, the randomized clinical trial design, and the nesting in an existing study.