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

描述(由申请人提供)：大多数慢性乙肝病毒感染者生活在资源有限的环境中，例如中国，在那里，78万名艾滋病毒感染者中有10%-20%是同时感染乙肝病毒的。来自北京协和医院的数据显示，最近艾滋病患者死亡的一半可归因于肝功能衰竭，这是最常见的乙肝病毒引起的。因此，艾滋病毒和乙肝病毒混合感染是中国和其他RLS的主要公共卫生问题。替诺福韦作为抗逆转录病毒疗法(ART)的一部分，被推荐用于治疗RLS中艾滋病毒和乙肝病毒合并感染的患者，但由于其成本和可用性，这一建议并不总是得到遵守。RLS最近的研究表明，多达一半的艾滋病毒和乙肝病毒混合感染患者的HBVdna水平较低；因此，基于拉米夫定的抗逆转录病毒疗法可能对这类联合感染患者有效，这种疗法成本低得多，而且可以广泛获得。这项研究中提出的新假设是，基于拉米夫定的抗逆转录病毒疗法对部分患者(如低HBVDNA患者)具有长期疗效。在目标1中，我们将比较大约100名接受拉米夫定为基础的ART和大约100名接受替诺福韦为基础的ART的中国HIV-HBVe混合感染患者的乙肝病毒学应答和副作用。我们假设，在治疗前HBVDNA水平较低的情况下，这两种治疗方案将相似，但在较高水平时，替诺福韦将更好。为此，受试者将每六个月进行一次血清检测，以检测各种乙肝病毒和艾滋病毒参数。我们还将进行全基因组乙肝病毒测序，以寻找治疗前存在的突变，因此可能会影响治疗结果或在治疗中出现。我们还将比较这些方案的副作用。目的比较拉米夫定和替诺福韦ART方案对乙肝病毒特异性免疫应答的影响。为了实现这一目标，每个治疗组中的20名受试者将在治疗前以及治疗后24、48和96周对其乙肝病毒特异性T细胞反应进行测试，包括多功能。这一目标还将使用所有200名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不同组之间不会有显着差异，特别是在那些HBVDNA水平较低的人群中。拟议目标的完成将为基于拉米夫定的ART在RLS中的疗效提供亟需的数据。这样的数据很重要，因为替诺福韦价格昂贵，如果一部分患者，如那些HBVDNA低的患者，对拉米夫定有良好的反应，那么RLS的治疗方案可以根据对拉米夫定的反应的可能性进行个体化。这将使替诺福韦得到更好的利用，而替诺福韦的价格要高得多，这样就可以用给定的金额治疗更多的患者。这是美国和中国调查人员之间的一个合作项目，其中美国派的Thio博士拥有乙肝病毒学方面的专业知识，而中国派的李博士拥有免疫学专业知识。

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.