HBV HIV Coinfection Research Network

描述（由申请人提供）：自1996年引入高效抗逆转录病毒疗法（ART）以来，艾滋病毒感染者的发病率和死亡率显著降低。然而，由于合并感染乙型肝炎（HBV）或丙型肝炎（HCV）病毒而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。HBV感染的自然史在HIV感染者中发生改变。目前的指南建议大多数合并感染的患者使用包括替诺福韦（TDF）在内的抗逆转录病毒药物联合治疗HIV和HBV感染。尽管在美国广泛采用，但该方案对HBV疾病的长期结局（如组织学严重程度、进展、出现耐药HBV变异的风险）的影响以及TDF治疗的长期风险仍未得到解答。需要进一步的研究来解决以下重要问题：(1)在TDF上病毒抑制不完全的hiv合并感染患者的比例是多少？(2)在HIV合并感染者中不完全抑制HBV是否可以接受，如果可以，什么阈值HBV DNA水平构成足够的临床目标？(3)鉴于HIV从业者对肝活检缺乏接受度，无创标志物能否准确评估HBV疾病活动性和ART对疾病进展的影响？(4)以tdf为基础的治疗HBV合并HIV感染的长期风险是什么？简而言之，以tdf为基础的治疗合并HIV感染的CHB患者的风险和益处是什么？美国国立卫生研究院乙型肝炎研究网络（HBRN）是阐明美国慢性乙型肝炎患者的自然史和治疗结果的第一个主要努力。HBRN将不解决HIV感染者中HBV肝病进展的关键问题，因为合并HIV感染的患者将被排除在外。目前的提案是一项批准的HBRN辅助研究，提供了一个独特的机会来填补HBV- hiv知识的主要空白，并将HBV- hiv感染者与参与HBRN的HBV单感染患者进行比较。在北美，没有其他资助的研究网络具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。定义问题。我们将在临床、组织学、血清学和病毒学上以横断面方式对北美一组明确的HBV-HIV患者进行表征；2. 明确长期治疗的益处。我们将通过配对活检和2a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。确定与疾病进展相关的HBV DNA阈值水平；2 b。建立无创肝纤维化评估与活检比较的实用性；和2 c。确定长期治疗中基因型和表型TDF耐药的频率；最后是3。明确长期治疗的风险。我们将评估基于tdf的治疗在HBV-HIV队列中的长期肾脏和骨骼影响。总的来说，这项研究将满足NIH HBV-HIV合并感染肝病行动计划中列出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.