Earlier Sustained Virologic Response End Points for Regulatory Approval and Dose Selection of Hepatitis C Therapies
Earlier Sustained Virologic Response End Points for Regulatory Approval and Dose Selection of Hepatitis C Therapies
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DOI：
10.1053/j.gastro.2013.02.039
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发表时间：
2013-06-01
期刊：
影响因子：
29.4
通讯作者：
Birnkrant, Debra
中科院分区：
文献类型：
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作者：
Chen, Jianmeng;Florian, Jeffry;Birnkrant, Debra
背景和目的：慢性丙型肝炎治疗试验以随访第 24 周丙型肝炎病毒 (HCV) 检测（持续病毒学应答 [SVR] 24）作为主要终点。然而，越来越多的证据表明，大多数在早期时间点（例如 SVR12）获得 SVR 的患者将其维持到第 24 周。使用早期时间点进行关键监管决策（SVR12）和剂量选择（SVR4）可以促进 HCV 药物开发。方法：我们评估了 15 项 II 期和 III 期试验、3 项儿科研究和 5 个药物开发项目的数据，以确定 SVR24 与 SVR12 或 SVR4 之间的一致性。对接受干扰素、聚乙二醇化干扰素、利巴韦林和直接作用抗病毒药物的各种组合和方案的受试者组的数据进行了分析。结果：在基因 1 型 HCV 感染受试者中，SVR12 的阳性预测值 (PPV) 为 98%，SVR24 的阴性预测值 (NPV) 为 99%。在 HCV 基因型 2 或 3 感染受试者以及儿科研究中也观察到了类似的一致性水平。大约 2% 达到 SVR12 的受试者随后在第 24 周复发（未达到 SVR24）。此外，SVR12 和 SVR24 受试者的治疗效果大小（治疗组与主动对照组之间的差异）相似。在基因型 1 HCV 感染受试者中，SVR4 的 PPV 为 91%，SVR24 的 NPV 为 98%。结论：在参与不同治疗方案和持续时间的临床试验的大量 HCV 感染受试者中，SVR12 和 SVR24 测量结果是一致的。 SVR12 适合作为监管部门批准的主要终点。 SVR4 可用于指导试验中的剂量和治疗策略。
BACKGROUND & AIMS: Trials of therapies for chronic hepatitis C have used detection of hepatitis C virus (HCV) at week 24 of follow-up (sustained virologic response [SVR] 24) as a primary end point. However, there is increasing evidence that most patients who have an SVR at earlier time points (such as SVR12) maintain it until week 24. Use of earlier time points for key regulatory decisions (SVR12) and dose selection (SVR4) could facilitate HCV drug development. METHODS: We assessed data from 15 phase II and III trials, 3 pediatric studies, and 5 drug-development programs to determine the concordance between SVR24 and SVR12 or SVR4. Data were analyzed from groups of subjects who received various combinations and regimens with interferon, pegylatedinterferon, ribavirin, and direct-acting antivirals. RESULTS: The positive predictive value (PPV) of SVR12 was 98% and the negative predictive value (NPV) was 99% for SVR24 among subjects with genotype 1 HCV infection. A similar level of concordance was observed for subjects with HCV genotype 2 or 3 infections, as well as in pediatric studies. About 2% of subjects who achieved an SVR12 subsequently relapsed by week 24 (did not achieve an SVR24). Furthermore, the treatment effect size (difference between treatment and active control arms) was similar for subjects with SVR12 and SVR24. The PPV of SVR4 was 91% and the NPV was 98% for SVR24 in subjects with genotype 1 HCV infection. CONCLUSIONS: SVR12 and SVR24 measurements were concordant in a large population of subjects with HCV infection who participated in clinical trials with various treatment regimens and durations. SVR12 is suitable as a primary end point for regulatory approval. SVR4 might be used to guide dose and treatment strategies in trials.