HBV HIV Coinfection Research Network

描述(申请人提供)：自1996年采用高效抗逆转录病毒疗法(ART)以来，艾滋病毒携带者的发病率和死亡率大幅下降。然而，与乙肝病毒(乙肝病毒)或丙型肝炎病毒(丙型肝炎病毒)混合感染引起的慢性肝病已成为艾滋病毒感染者死亡的第二大原因。艾滋病毒携带者的乙肝病毒感染的自然病史会发生改变。目前的指南建议大多数合并感染的患者同时使用包括替诺福韦(TDF)在内的ART治疗艾滋病毒和乙肝病毒感染。尽管在美国被广泛采用，但该方案对乙肝疾病的长期结果的影响，如组织学严重程度、进展和出现耐药变异的风险，以及TDF治疗的长期风险仍未得到回答。需要进一步的研究来解决以下重要问题：(1)HIV合并感染患者对TDF的病毒抑制不完全的比例是多少？(2)不完全抑制HBVDNA在HIV合并感染者中是可以接受的，如果是，什么水平的HBVDNA水平构成了一个足够的临床目标？(3)鉴于HIV从业者缺乏接受肝活检，非侵入性标记物能否准确地评估HBV病活动性和ART对疾病进展的影响？(4)基于TDF的治疗HIV合并感染的乙肝病毒的长期风险是什么？简而言之，在HIV合并感染的患者中，基于TDF的CHB治疗的风险和好处是什么？美国国立卫生研究院乙肝研究网络(HBRN)是美国第一个阐明慢性乙肝患者的自然病史和治疗结果的重大努力。HBRN将不会解决艾滋病毒感染者中乙肝病毒肝病进展的关键问题，因为艾滋病毒合并感染的患者将被排除在外。目前的建议是HBRN的一项已获批准的辅助研究，它提供了一个独特的机会来填补乙肝病毒-艾滋病毒知识的主要空白，并将乙肝病毒-艾滋病毒感染者与参与HBRN的乙肝病毒单一感染者进行比较。在北美，没有其他资助的研究网络拥有开展拟议研究的专业知识、患者群体和结构。具体目标是：1.界定问题。我们将在临床、组织学、血清学和病毒学方面以横断面的方式对北美明确界定的乙肝病毒感染者队列进行特征描述；2.确定长期治疗的益处。我们将通过配对活检和2a来纵向确定完全和不完全病毒抑制对临床和血清学结果以及组织学进展的影响。定义与疾病进展相关的HBVDNA水平阈值；2b。建立肝纤维化的无创性评估与活组织检查相比的实用性；确定长期治疗的遗传型和表型TDF耐药的频率；最后3.确定长期治疗的风险。我们将评估在HBV-HIV队列中基于TDF的治疗的长期肾脏和骨骼效应。总而言之，这项研究将实现NIH肝病治疗乙肝病毒-艾滋病毒混合感染行动计划中概述的许多关键优先事项。

DESCRIPTION (provided by applicant): Since the introduction of highly active antiretroviral therapy (ART) in 1996, there has been a dramatic reduction in morbidity and mortality among those living with HIV. However, chronic liver disease due to coinfection with hepatitis B (HBV) or C (HCV) virus has emerged as the second leading cause of mortality among HIV-infected persons. The natural history of HBV infection is altered in those with HIV. Current guidelines recommend that most coinfected patients be treated for both HIV and HBV infection using combinations of ART that include tenofovir (TDF). Despite widespread adoption in the US, the effect of this regimen on long-term outcomes of HBV disease such as histologic severity, progression, and risk of emergence of resistant HBV variants, and the long term risks of TDF therapy remains unanswered. Further investigation is required to address the following important questions: (1) what is the proportion of HIV-coinfected patients who have incomplete viral suppression on TDF? (2) is incomplete suppression of HBV acceptable in HIV coinfected persons and if so, what threshold HBV DNA level constitutes an adequate clinical goal? (3) in view of the lack of acceptance of liver biopsy among HIV practitioners, can noninvasive markers accurately assess HBV disease activity and the impact of ART on disease progression? (4) What are the long term risks of TDF-based therapy for HBV in HIV coinfection? In short, what are the risks and benefits of TDF-based therapy for CHB in patients with HIV coinfection? The NIH Hepatitis B Research Network (HBRN) is the first major effort to elucidate the natural history and treatment outcomes of persons with chronic HBV the US. The HBRN will not address the critical issue of HBV liver disease progression in HIV-infected persons because patients with HIV coinfection will be excluded. The current proposal, an approved ancillary study of the HBRN, offers a unique opportunity to fill major gaps in HBV-HIV knowledge and to compare HBV-HIV infected persons to those with HBV monoinfection participating in the HBRN. No other funded research network in North America has the expertise, patient population, and structure to carry out the proposed studies. The Specific Aims are: 1. Define the problem. We will clinically, histologically, serologically, and virologically characterize a well-defined cohort of HBV-HIV patients in North America in a cross-sectional manner; 2. Define the benefit of long term therapy. We will longitudinally determine the impact of complete vs. incomplete viral suppression on clinical and serologic outcomes, and histologic progression by paired biopsy and 2a. Define a threshold HBV DNA level associated with disease progression; 2b. Establish the utility of noninvasive assessment of hepatic fibrosis compared with biopsy; and 2c. Define the frequency of genotypic and phenotypic TDF resistance with long term therapy; and finally 3. Define the risk of long term therapy. We will assess the long term renal and bone effects of TDF-based therapy in the HBV-HIV cohort. Collectively, this study will fulfill many of the key priorities outlined in the NIH Action Plan fo Liver Disease for HBV-HIV coinfection.