Strategic treatment optimization for HCV (STOPHCV1): a randomised controlled trial of ultrashort duration therapy for chronic hepatitis C

Abstract

Background: The world health organization (WHO) has identified the need for a better understanding of which patients with hepatitis C virus (HCV) can be cured with ultrashort course HCV therapy. Methods: A total of 202 individuals with chronic HCV were randomised to fixed-duration shortened therapy (8 weeks) vs variable-duration ultrashort strategies (VUS1/2). Participants not cured following first-line treatment were retreated with 12 weeks’ sofosbuvir/ledipasvir/ribavirin. The primary outcome was sustained virological response 12 weeks (SVR12) after first-line treatment and retreatment. Participants were factorially randomised to receive ribavirin with first-line treatment. Results: All evaluable participants achieved SVR12 overall (197/197, 100% [95% CI 98-100]) demonstrating non-inferiority between fixed-duration and variable-duration strategies (difference 0% [95% CI -3.8%, +3.7%], 4% pre-specified non-inferiority margin). First-line SVR12 was 91% [86%-97%] (92/101) for fixed-duration vs 48% [39%-57%] (47/98) for variable-duration, but was significantly higher for VUS2 (72% [56%-87%] (23/32)) than VUS1 (36% [25%-48%] (24/66)). Overall, first-line SVR12 was 72% [65%-78%] (70/101) without ribavirin and 68% [61%-76%] (69/98) with ribavirin (p=0.48). At treatment failure, the emergence of viral resistance was lower with ribavirin (12% [2%-30%] (3/26)) than without (38% [21%-58%] (11/29), p=0.01). Conclusions: Unsuccessful first-line short-course therapy did not compromise retreatment with sofosbuvir/ledipasvir/ribavirin (100% SVR12). SVR12 rates were significantly increased when ultrashort treatment varied between 4-7 weeks rather than 4-6 weeks. Ribavirin significantly reduced resistance emergence in those failing first-line therapy. ISRCTN Registration: 37915093 (11/04/2016).

Rise in alanine aminotransferase after HCV treatment is a highly sensitive screen for treatment failure

“…In a second study population, we tested the hypothesis that any increase in ALT or AST between EOT and EOT + 12 is a sensitive marker of treatment failure. STOPHCV1 (UK) was a randomized trial that assessed variable ultrashort-course treatment (4–8 weeks based on pretreatment viral load) versus 8 weeks of fixed-duration therapy with ombitasvir, paritaprevir, ritonavir +/− dasabuvir, +/− ribavirin (1:1) 14. Of 199 individuals under follow-up until EOT + 12, SVR12 was achieved in 141 (71%), with 58 individuals experiencing virological rebound at or before this time point (Supplemental Figures S2 and S4, http://links.lww.com/XCL/A8).…”

“…Trial registrations and ethical permissions are provided with both published manuscripts. [11,12] In SEARCH-1 (Vietnam), genotype 1 or 6-infected adults with mild liver disease (FibroScan score ≤ 7.1 kPa) received 4 or 8 weeks of sofosbuvir and daclatasvir therapy according to whether HCV RNA was below or above 500 IU/mL after 2 days of treatment. HCV RNA was measured at regular intervals until end of follow-up (EOT + 12 wk) or until treatment failure if it occurred first (Supplemental Figures S1 and S3, http://links.lww.com/ XCL/A8).…”

“…This diagnostic accuracy study was STARD compliant10 (Supplemental Table S1, http://links.lww.com/XCL/A8). Trial registrations and ethical permissions are provided with both published manuscripts 11,12…”