Evaluation of operational chronic infection endpoints for HCV vaccine trials.
Evaluation of operational chronic infection endpoints for HCV vaccine trials.
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HCV 疫苗试验的操作性慢性感染终点评估。
DOI：
10.1016/j.cct.2008.03.006
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发表时间：
2008
影响因子：
2.2
通讯作者：
Nicolay,Uwe
中科院分区：
文献类型：
--
作者：
Kang,Minhee;Nicolay,Uwe
丙型肝炎病毒（HCV）是慢性肝病的主要原因。HCV感染的自然史是异质性的，感染HCV的人可以清除病毒或进展为慢性感染。慢性感染可在肝硬化和/或肝癌发展之前保持无症状数十年。目前，还没有可以区分短暂感染（可以清除的急性感染）和慢性感染的检测方法，并且使用系列HCV RNA检测来操作性地定义慢性丙型肝炎（例如，超过6个月的可检测HCV）。因此，HCV疫苗试验计划可以受益于针对慢性感染的终点候选者的评估。基于研究访视时病毒学检测的操作定义终点先前已在人乳头瘤病毒（HPV）疫苗试验的背景下进行了研究。然而，HCV的自然史与HPV不同，需要单独考虑。在这项工作中，几个定义的慢性感染的基础上定期观察到的HCV RNA的状态进行评估，使用多状态，时间齐次马尔可夫模型的瞬时和慢性感染下的各种感染设置。我们的研究结果表明，在存在与短暂感染相关的疫苗效力的情况下，在对疫苗对慢性感染效力的对数秩检验中，I型错误出现了一些膨胀。在一个设置中观察到的I类错误几乎是计划率5%的四倍。总体而言，简单操作终点产生的把握度高于更复杂的终点，但最简单的终点受I类错误膨胀和试验不完善导致的误分类错误的影响最大。
Hepatitis C virus (HCV) is a leading cause of chronic liver disease. The natural history of HCV infection is heterogeneous, and a person infected with HCV can clear the virus or progress to a chronic infection. The chronic infection can remain asymptomatic for decades before the development of liver cirrhosis and/or carcinoma. Currently, there are no assays that can differentiate a transient infection (an acute infection that would clear) from a chronic infection, and serial HCV RNA testing is used to operationally define chronic hepatitis C (e.g. detectable HCV over 6 months). Therefore, HCV vaccine trial planning can benefit from the assessment of the endpoint candidates that are aimed at the chronic infection. Operationally defined endpoints based on the virological tests at study visits have been previously studied in the context of human papillomavirus (HPV) vaccine trials. However, HCV natural history is different from HPV, requiring separate considerations. In this work, several definitions of chronic infection that are based on the periodically observed HCV RNA statuses are evaluated, using a multi-state, time-homogeneous Markov model for transient and chronic infections under various infection settings. Our results show some inflation in the type I error in the log-rank test on the vaccine efficacy against chronic infections in the presence of vaccine efficacy related to transient infections. A type I error up to almost four times the planned rate of 5% is observed in one setting. Overall, simple operational endpoints yield higher power than more complex endpoints, but the simplest endpoint is most affected by the type I error inflation and misclassification error due to the assay imperfection.