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大幅下降。然而，由于与乙型肝炎B（HBV）或丙型肝炎（HCV）病毒的共感染引起的慢性肝病已经成为HIV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）的ART组合治疗HIV和HBV感染。尽管该方案在美国被广泛采用，但该方案对HBV疾病长期结局的影响，如组织学严重程度、进展和出现耐药HBV变异的风险，以及TDF治疗的长期风险，仍然没有答案。需要进一步研究以解决以下重要问题：（1）TDF治疗后病毒抑制不完全的HIV合并感染患者的比例是多少？(2)在HIV合并感染者中，HBV的不完全抑制是否可以接受？如果可以，HBV DNA水平的阈值是多少？(3)鉴于HIV从业者不接受肝活检，非侵入性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)在HIV合并感染者中，以TDF为基础的HBV治疗的长期风险是什么？ 简而言之，对于HIV合并感染的CHB患者，基于TDF的治疗有哪些风险和益处？美国国立卫生研究院的B型肝炎研究网络（HBRN）是第一个主要的努力，以阐明自然史和治疗结果的人与慢性HBV在美国。 HBRN不会解决HIV感染者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。目前的建议，一个批准的HBRN辅助研究，提供了一个独特的机会，以填补HBV-HIV知识的主要差距，并比较HBV-HIV感染者与那些与HBV单一感染参与HBRN。北美没有其他受资助的研究网络拥有开展拟议研究的专业知识、患者人群和结构。具体目标是：1。定义问题。我们将以横断面的方式对北美一组明确的HBV-HIV患者进行临床、组织学、血清学和病毒学特征分析; 2.定义长期治疗的益处。我们将通过配对活检和2a纵向确定完全与不完全病毒抑制对临床和血清学结局以及组织学进展的影响。定义与疾病进展相关的阈值HBV DNA水平; 2b.建立肝纤维化的非侵入性评估与活检相比的效用;和2c.定义长期治疗的基因型和表型TDF抗性的频率;最后3.定义长期治疗的风险。我们将在HBV-HIV队列中评估基于TDP的治疗对肾脏和骨骼的长期影响。 总的来说，这项研究将实现NIH肝病HBV-HIV合并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.