Gastroenterology
Volume 144, Issue 7 , Pages 1450-1455.e2, June 2013
Jianmeng Chen, Jeffry Florian, Wendy Carter, Russell D. Fleischer, Thomas S. Hammerstrom, Pravin R. Jadhav, Wen Zeng, Jeffrey Murray, Debra Birnkrant,
Received 18 December 2012; accepted 27 February 2013. published online 07 March 2013.
Absrtact
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, pegylated-interferon, 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.
Keywords: Therapy, Outcome, Effectiveness, Quantification
Abbreviations used in this paper: AIMS, Antiviral Information Management System, CHC, chronic hepatitis C, DAA, direct-acting antiviral, HCV, hepatitis C virus, NPV, negative predictive value, PPV, positive predictive value, SVR, sustained virologic response
Author names in bold designate shared co-first authorship.
Conflicts of interest This authors disclose the following: Jadhav Pravin was employed by Merck after completion of this study. The remaining authors disclose no conflicts.
Funding This project was supported by funding through a critical path grant and in part by an appointment to the ORISE Research Participation Program at the Center for Drug Evaluation and Research administered by the Oak Ridge Institute for Science and Education through an agreement between the US Department of Energy and Center for Drug Evaluation and Research.
PII: S0016-5085(13)00288-6
doi:10.1053/j.gastro.2013.02.039
© 2013 AGA Institute. Published by Elsevier Inc. All rights reserved.
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