12 Weeks Post-Treatment Is Appropriate Endpoint for Measuring Response to Hepatitis C Regimen

Emerging data from a clinical trial on triple direct-acting antiviral (DAA) therapy plus ribavirin (RBV) in hepatitis C (HCV) genotype 1 (GT1) patients shows that the low rate of relapse during and after treatment leads to high concordance rates between measurements of sustained viral response (SVR) at 4, 12, and 24 weeks post-treatment.

Those findings were presented by Fred Poordad, MD, of the Texas Liver Institute and the University of Texas Health Science Center in San Antonio, TX, and his coauthors during a poster session at the 2013 annual meeting of the American Association for the Study of Liver Diseases, held November 1-5 in Washington, DC.

For the randomized, open-label, multicenter phase 2b AVIATOR study, both treatment-naïve and treatment-experienced patients received an all-oral, interferon -free treatment regimen for HCV GT1. Enrolled in the study were adults with chronic HCV GT 1 and HCV RNA >50,000IU/ml at screening, but without cirrhosis or co-infection with HIV or hepatitis B. Patients received the triple DAA (3D) treatment + RBV for either 12 or 24 weeks.

Overall, high percentages of patients in both the treatment-naïve and treatment-experienced groups achieved rapid virologic response (99.4%), as well as SVR at 4 weeks (96.4%), 12 weeks (95.5%), and 24 weeks (93.9%).

An intention-to-treat (ITT) analysis measured individuals whose HCV RNA was below the lower limit of quantitation (LLOQ) within 4 weeks of treatment, as well as at 4 (SVR4), 12 (SVR12), and 24 (SVR24) weeks post-treatment. Positive and negative predictive values (PPV/NPV), sensitivity, and specificity were also calculated.

For the purposes of the analysis, “true positive” patients were defined as those who achieved SVR at 24 weeks or an earlier time point, while “true negative” patients were those who had quantifiable HCV at 24 weeks post-treatment and at an earlier time point. Patients with missing data were also included as “true negatives.”

PPV was reported as a ratio of true positives/total with SVR12; by contrast, NPV was reported as the ratio of true negatives/total without SVR12. Sensitivity was calculated as the ratio of true positives/total with SVR24, and specificity as the ratio of true negatives/total without SVR24.

Analysis showed PPVs of 94 to 98%, and outcomes at each earlier time point had a 100% NPV for SVR24. Further analysis showed that when patients lost to follow-up were excluded, all patients achieving SVR4 or SVR12 also achieved SVR24, which accounted for all of the discordance. To further refine the reliability of their results, the investigators used Cohen’s kappa, a calculation that accounts for the rate of agreement that might be expected by chance. Higher Cohen’s kappa values indicate higher reliability, with values >0.80 indicating a high degree of reliability. According to the poster authors, the Cohen’s kappa between SVR12 and SVR24 in this analysis was 0.84.

Poordad and his coauthors concluded that SVR12 is an appropriate endpoint to measure efficacy of an 3D + RBV regimen in a group of patients with HCV GT1, as none of the patients who achieved SVR4 relapsed by the end of 24 weeks post-treatment. Additionally, all discordance was accounted for by loss to follow-up.