Optimizing Care for HIV/HCV-Coinfected Patients in the New HCV Treatment Era

 描述(由申请者提供)：这一K01奖项将为我提供培训和指导研究经验，使我成为一名独立研究员，专注于改善慢性病毒感染患者或有慢性病毒感染风险的患者的健康结果。在美国，慢性丙型肝炎病毒感染影响着300多万人，估计每年有8万人死于与丙型肝炎病毒相关的疾病。丙型肝炎病毒对健康的影响在人类免疫缺陷病毒(HIV)患者中更为严重，在这些患者中，丙型肝炎相关肝病是非艾滋病相关死亡的主要原因。艾滋病毒/丙型肝炎病毒混合感染也与肝外结局的风险增加有关，包括心血管和肾脏疾病。随着无干扰素疗法的出现，大多数丙型肝炎患者现在都可以治愈，无论艾滋病毒状态如何。然而，关键的问题仍然存在：1)丙型肝炎病毒治疗的时机对丙型肝炎病毒相关预后的影响，以及2)丙型肝炎病毒治愈后丙型肝炎病毒相关预后的持续风险。这项建议解决了这些紧迫的临床问题，重点放在艾滋病毒/丙型肝炎合并感染的患者身上。艾滋病毒/丙型肝炎病毒混合感染患者的高危人群是研究这些疾病的理想人群 这些问题有两个原因。首先，由于艾滋病毒/丙型肝炎病毒混合感染患者是丙型肝炎病毒治疗的优先群体，他们将在一系列肝脏疾病阶段接受治疗，这为调查推迟治疗的风险提供了独特的机会。其次，在艾滋病毒/丙型肝炎病毒混合感染的患者中，可能更容易检测到丙型肝炎病毒治愈后与丙型肝炎病毒相关的结果的持续风险，这些患者可能会因为艾滋病毒/丙型肝炎病毒感染期间免疫激活和炎症的增加而经历持久的损害。这项拟议的研究将包括对北加州凯撒永久医院成员的队列研究。这一环境的优势包括330万成员的多样化和普适性人口，内部单一感染丙型肝炎病毒和单一感染艾滋病毒的对照组，以及来自电子健康记录的大量临床数据。其具体目的是：1)确定早期和延迟治疗丙型肝炎病毒对艾滋病毒/丙型肝炎病毒混合感染和丙型肝炎病毒单一感染患者的肝脏和肝外结局的影响，以及2)评估丙型肝炎病毒治愈后艾滋病毒/丙型肝炎病毒混合感染者和丙型肝炎病毒单一感染者以及从未感染过丙型肝炎病毒的匹配组艾滋病毒患者的肝脏和肝外结局的风险。拟议的研究将通过使用边缘结构模型等方法得到加强，这些方法克服了标准方法的局限性。该职业发展奖将提供以下领域的培训：1)丙型肝炎病毒感染和艾滋病毒/丙型肝炎病毒混合感染的流行病学和发病机制，2)艾滋病毒和肝脏相关结果，3)丙型肝炎病毒和艾滋病毒/丙型肝炎患者的临床管理，以及4)强调因果推断的先进生物统计方法。这种有指导的研究和培训将直接为艾滋病毒/丙型肝炎患者的临床护理提供信息，并奠定我作为该领域独立研究员的职业生涯。

 DESCRIPTION (provided by applicant): This K01 award will provide the training and mentored research experience needed for me to become an independent researcher with a focus on improving the health outcomes of patients with or at risk for chronic viral infections. Chronic hepatitis C virus (HCV) infection affects over 3 million people in the U.S., with an estimated 80,000 HCV-related deaths per year. The health impacts of HCV are more severe in human immunodeficiency virus (HIV) patients, in whom HCV-associated liver disease is the leading cause of non-AIDS-related death. HIV/HCV coinfection has also been linked to an increased risk of extrahepatic outcomes, including cardiovascular and kidney disease. With the emergence of interferon-free regimens, most HCV patients can now be cured, regardless of HIV status. However, critical questions remain about 1) the effect of the timing of HCV treatment on HCV-related outcomes and 2) ongoing risk for HCV-related outcomes after HCV cure. This proposal addresses these pressing clinical questions with a focus on HIV/HCV-coinfected patients. The high-risk population of HIV/HCV- coinfected patients is ideal for investigating these questions for two reasons. First, because HIV/HCV- coinfected patients are a priority group for HCV treatment, they will have been treated over a range of liver disease stages, offering a unique opportunity to investigate the risks of treatment deferral. Second, ongoing risk of HCV-related outcomes after HCV cure may be more readily detectable in HIV/HCV- coinfected patients, who may experience lasting damage from increased immune activation and inflammation during HIV/HCV coinfection. The proposed research will consist of cohort studies among members of Kaiser Permanente Northern California. The strengths of this setting include a diverse and generalizable population of 3.3 million members, internal HCV-monoinfected and HIV-monoinfected comparison groups, and extensive clinical data from an electronic health record. The specific aims are to 1) determine the effect of early versus deferred HCV treatment on hepatic and extrahepatic outcomes among HIV/HCV-coinfected and HCV-monoinfected patients, and 2) evaluate the risk of hepatic and extrahepatic outcomes among HIV/HCV-coinfected and HCV-monoinfected patients after HCV cure, and in a matched group of HIV patients who never had HCV infection. The proposed research will be strengthened by the use of methods such as marginal structural models that overcome limitations of standard approaches. This career development award will provide training in the following areas: 1) epidemiology and pathogenesis of HCV infection and HIV/HCV coinfection, 2) HIV and liver- related outcomes, 3) clinical management of HCV and HIV/HCV patients, and 4) advanced biostatistical methods with an emphasis on causal inference. This mentored research and training will directly inform the clinical care of HIV/HCV patients and establish my career as an independent researcher in the field.