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

 描述（由申请人提供）：这个K 01奖将提供我成为一名独立研究人员所需的培训和指导研究经验，重点是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。慢性丙型肝炎病毒（HCV）感染影响美国超过300万人，估计每年有8万人死于HCV相关疾病。在人类免疫缺陷病毒（HIV）患者中，HCV对健康的影响更为严重，其中HCV相关肝病是非艾滋病相关死亡的主要原因。HIV/HCV合并感染也与肝外结局风险增加有关，包括心血管和肾脏疾病。随着无干扰素治疗方案的出现，大多数HCV患者现在可以治愈，无论HIV状态如何。然而，关键问题仍然是1）HCV治疗的时间对HCV相关结局的影响和2）HCV治愈后HCV相关结局的持续风险。该提案解决了这些紧迫的临床问题，重点关注HIV/HCV合并感染患者。HIV/HCV合并感染的高危人群是研究这些疾病的理想人群。 提问有两个原因。首先，由于HIV/HCV合并感染患者是HCV治疗的优先群体，他们将在一系列肝病阶段接受治疗，这为研究治疗延迟的风险提供了独特的机会。其次，在HIV/HCV合并感染患者中，HCV治愈后HCV相关结局的持续风险可能更容易检测到，这些患者可能在HIV/HCV合并感染期间因免疫激活和炎症增加而遭受持久损害。拟议中的研究将包括北方加州凯撒医疗机构成员的队列研究。这种设置的优势包括330万成员的多样化和可推广的人口，内部HCV单感染和HIV单感染的比较组，以及来自电子健康记录的广泛临床数据。具体目的是：1）确定早期与延迟HCV治疗对HIV/HCV合并感染和HCV单一感染患者的肝脏和肝外结局的影响; 2）评价HCV治愈后HIV/HCV合并感染和HCV单一感染患者以及从未感染过HCV的匹配HIV患者组的肝脏和肝外结局风险。拟议的研究将通过使用边际结构模型等克服标准方法局限性的方法得到加强。该职业发展奖将提供以下领域的培训：1）HCV感染和HIV/HCV合并感染的流行病学和发病机制，2）HIV和肝脏相关结果，3）HCV和HIV/HCV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。这种指导研究和培训将直接告知HIV/HCV患者的临床护理，并建立我作为该领域独立研究人员的职业生涯。

 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.