HBV Response to Tenofovir or Lamivudine-Based ART in HIV-HBV Co-Infected Chinese

描述（由申请人提供）：大多数慢性B型肝炎病毒（HBV）感染者生活在资源有限的环境（RLS）中，例如中国，780，000例HIV感染患者中有10-20%合并HBV感染。来自北京协和医院的数据显示，最近所有艾滋病毒感染者死亡的一半可归因于肝功能衰竭，其中最常见的是HBV。因此，HIV-HBV合并感染是中国和其他RLS的主要公共卫生问题。替诺福韦作为抗逆转录病毒治疗（ART）的一部分，被推荐用于治疗RLS中的HIV-HBV合并感染患者，但由于其成本和可用性，该建议并不总是被遵循。RLS最近的研究表明，高达一半的HIV-HBV合并感染患者的HBV DNA水平较低;因此，以拉米夫定为基础的ART治疗，这是便宜得多，广泛可用，可能是有效的，在这样的合并感染的患者。这项研究提出的新假设是，拉米夫定为基础的ART对一部分患者（如HBV DNA水平低的患者）具有长期疗效。 在目标1中，我们将比较约100例接受拉米夫定为基础的ART和约100例接受替诺福韦为基础的ART的中国HIV-HBV合并感染患者的HBV病毒学应答和副作用。我们假设，在治疗前HBV DNA水平较低时，这两种治疗方案相似，但在较高水平时，替诺福韦将具有上级优势。为此，受试者将每6个月接受一次血清检测，以检测各种HBV和HIV参数。我们还将进行全基因组HBV测序，以寻找治疗前存在的突变，因此可能影响治疗结果或治疗中出现的突变。我们还将比较方案的副作用。目的2比较拉米夫定和替诺福韦抗病毒治疗方案的HBV特异性免疫应答。在该目的中，每个治疗组中的20名受试者将在治疗前和治疗后24、48和96周对一组HBV肽进行HBV特异性T细胞应答（包括多功能性）测试。本目标还将使用所有200例受试者来比较这两个治疗组之间的细胞因子产生。我们预计免疫应答在两组之间不会有显著差异，特别是在那些HBV DNA水平低的患者中。 完成拟议的目标将提供拉米夫定为基础的ART在RLS中的疗效急需的数据。这些数据是重要的，因为替诺福韦是昂贵的，如果一个子集的患者，如那些低HBV DNA，响应拉米夫定，然后在RLS治疗方案可以根据拉米夫定响应的可能性个性化。这将使更好地利用替诺福韦，这是显着更昂贵，使更多的病人可以治疗一定数量的钱。这是美国和中国研究者之间的一个合作项目，其中美国PI Thio博士具有HBV病毒学方面的专业知识，中国PI Li博士具有免疫学方面的专业知识。

DESCRIPTION (provided by applicant): The majority of persons with chronic hepatitis B virus (HBV) infection live in resource-limited settings (RLS) such as China where 10-20% of the 780,000 HIV-infected patients are co-infected with HBV. Data from the Peking Union Medical College Hospital shows that half of all recent deaths in HIV-infected patients are attributable to liver failure, which is most commonly from HBV. Thus, HIV-HBV co-infection is a major public health problem in China and other RLS. Tenofovir as part of antiretroviral therapy (ART) is recommended for treatment of HIV-HBV co-infected patients in RLS, but this recommendation is not always followed due its cost and availability. Recent studies from RLS demonstrate that up to half of the HIV-HBV co-infected patients have low levels of HBV DNA; thus, therapy with lamivudine-based ART, which is much less expensive and widely available, may be efficacious in such co-infected patients. The novel hypothesis proposed in this study is that lamivudine-based ART has long-term efficacy in a subset of patients such as those with low HBV DNA. In Aim 1, we will compare the HBV virologic response and side effects in ~100 Chinese HIV-HBV co- infected patients who received lamivudine-based ART to ~100 who received tenofovir-based ART. We hypothesize that at low pre-treatment HBV DNA levels, these two treatment regimens will be similar but at higher levels, tenofovir will be superior. For this Aim, subjects will have serum tested for various HBV and HIV parameters every six months. We will also perform full genome HBV sequencing to look for mutations that exist prior to therapy and therefore may affect treatment outcomes or that emerge on therapy. We will also compare side effects of the regimens. Aim 2 compares the HBV-specific immunological response in lamivudine-based and tenofovir-based ART regimens. In this Aim, 20 subjects in each treatment group will have their HBV- specific T cell responses, including polyfunctionality, tested to a panel of HBV peptides prior to therapy and at 24, 48, and 96 weeks after therapy. This Aim will also use all 200 subjects to compare the cytokine production between these two treatment groups. We expect that the immunological response will not differ significantly between the groups especially in those who have low HBV DNA levels. Completion of the proposed Aims will provide much-needed data on the efficacy of lamivudine-based ART in a RLS. Such data are important since tenofovir is expensive and if a subset of patients, such as those with low HBV DNA, respond well to lamivudine, then treatment regimens in RLS can be individualized based upon the likelihood of response to lamivudine. This would allow better utilization of tenofovir, which is significantly more expensive, so that a greater number of patients can be treated for a given amount of money. This is a collaborative project between U.S. and China investigators where Dr. Thio, the U.S. PI, has expertise in HBV virology and Dr. Li, the China PI, has expertise in immunology.