In patients with chronic Hepatitis C virus (HCV) infection, a sustained viral response to treatment regimens 12 weeks after therapy (SVR12) is a good indicator that the response will be maintained until week 24 (SVR 24), based on an analysis of pooled clinical trial data published in the June issue of Gastroenterology. Therefore SVR12 can be used instead of SVR24 as a primary end point for registration trials.
A SVR24 (undetectable levels of HCV RNA in serum 24 weeks after completion of therapy) is considered to indicate successful treatment—most patients who achieve SVR24 maintain their serum-negative status and have reduced complications from liver disease and increased survival times. It is therefore the primary endpoint of HCV therapy trials for regulatory approval—efficacies of all HCV therapies approved by the US Food and Drug Administration have been based on the proportion of patients attaining SVR24. However, earlier time points could increase efficiency of drug development.
Jianmeng Chen et al. assessed data from 15 phase 2 and 3 trials, 3 pediatric studies, and 5 drug-development programs to determine the concordance between SVR24 and SVR12, and even SVR4. They analyzed data from groups of subjects who received various combinations and regimens with interferon, ribavirin, and direct-acting antiviral agents.
Of the 13,599 adult subjects in the database analyzed, 50.6% achieved SVR24 and 51.8% achieved SVR12. These appeared to be mostly the same patients—the positive predictive value of SVR12 for SVR24 was 98% and the negative predictive value was 99% among subjects with genotype 1 HCV infection. A similar level of concordance was observed in subjects with HCV genotype 2 or 3 infections, as well as in pediatric studies.
The positive predictive value of SVR4 for SVR24 was 91% and the negative predictive value was 98% in subjects with genotype 1 HCV infection. Chen et al. observed similar values regardless of subjects’ race, sex, treatment experience, genotype 1a vs 1b, or presence of cirrhosis.
Why is there such a high level of agreement between SVR12 and SVR24, and to a lesser extent SVR4 and SVR24? Chen et al. explained that 65% of subjects who relapsed had detectable viral load by week 4 after treatment and 95% had detectable viral load by week 12. So if the virus is going to reappear, in generally does so within 12 weeks after the treatment ends.
The authors conclude that individual patients should be followed for 24 weeks or longer after treatment to confirm their responses. But SVR12, which is currently used as supportive information for registration trial design, can also be appropriate for regulatory approval of treatment regimens.
More Information on HCV Infection
- The CDC Website on Hepatitis C
- The US National Library of Medicine Website on HCV
- The World Health Organization Website on HCV
Read the article online.
Chen J, Florian J, Carter W, et al. Earlier sustained virologic response end points for regulatory approval and dose selection of hepatitis c therapies. Gastroenterology 2013;144:1450–1455.e2.