Hepatitis B treatment and HIV Infection in resources limited settings

描述（由申请人提供）：慢性乙型肝炎（CH-B）是世界范围内终末期肝病和肝细胞癌的主要原因，约影响10%的hiv感染者。目前治疗CH- B的方法疗效较差。随着抗逆转录病毒治疗被引入CH-B负担最重的地区，确定hiv感染者的HBV治疗非常重要。为此，本提案检验的总体假设是，具有更高效力和更高耐药阈值的抗hbv方案优于没有这两种特征的方案。这一假设将在现有的国际ACTG抗逆转录病毒治疗（ART）试验中的一项临床试验中得到检验，在该试验中，参与者被随机分配到三种抗逆转录病毒治疗方案中的一种。一种方案在一粒药丸中含有两种抗hbv药物，因此可能比其他两种方案具有更大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HBV复制量之间的关系来研究hiv感染者CH-B的免疫控制。第二个目的是验证一个假设，即使用病毒抑制作为主要结果的抗hbv方案是有效的，具有高抵抗屏障，优于其他两种具有低抵抗屏障的方案。病毒抑制是用HBV DNA测定来确定的，每6个月测量一次，至少30个月。次要结果包括HBV DNA下降、HBeAg血清转化和ALT正常化。这一目的还确定了与抗HBV治疗反应相关的HBV和HIV因素。第三个目的是检验病毒学反弹和缺乏抑制是由于耐药病毒的发展的假设。为了实现这一目标，将在复发时对整个HBV基因组进行测序，并对代偿性突变的发展进行前瞻性跟踪。将测试这些突变病毒的抗病毒药物敏感性和复制能力。这项建议与公共卫生直接相关，因为它涉及艾滋病毒感染者CH-B的最佳治疗，这是一个重大的全球问题。考虑到调查小组的经验、随机临床试验设计和现有研究的嵌套，该建议有很高的成功可能性。

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.