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).
Highlights
The recent and rapid development of treatment for hepatitis C virus (HCV) has enabled an ambitious strategy for the elimination of viral hepatitis as a global public health threat by 2030, with the target of treating 80% of those chronically infected with HCV1
Secondary outcomes were sustained virological response 12 weeks (SVR12) after first-line treatment, SVR12 after the end of the combined first and any re-treatment phases, SVR24 (24 weeks) after the end of the combined first and any re-treatment phases, SVR24 after first-line treatment only, lack of initial virological response, viral load rebound after becoming undetectable, serious adverse events, grade 3/4 adverse events, grade 3/4 adverse events judged definitely/probably related to interventions, treatment-modifying adverse events, grade 3/4 anaemia and emergence of resistanceassociated HCV variants
70 (70%) receiving VUS1/VUS2 vs 72 (71%) receiving fixed-duration were included in the per-protocol population and 68 (68%) receiving ribavirin vs 74 (73%) not receiving ribavirin
Summary
The recent and rapid development of treatment for hepatitis C virus (HCV) has enabled an ambitious strategy for the elimination of viral hepatitis as a global public health threat by 2030, with the target of treating 80% of those chronically infected with HCV1. Licensed durations of 8–12 weeks’ therapy with directly acting antivirals (DAAs) are significantly shorter, more tolerable and more effective than previous interferon-based therapies, there are patients who still find it challenging to complete a full treatment course. In vitro evidence suggests the addition of ribavirin, a generically available guanosine analogue, may improve rates of virological cure with shorter treatment courses and could reduce the emergence of resistance in those failing treatment when added to short-course therapy. In vitro evidence suggests the addition of ribavirin, a generically available guanosine analogue, may improve rates of virological cure with shorter treatment courses and could reduce the emergence of resistance in those failing treatment when added to short-course therapy13 These hypotheses have not been tested in a randomised trial. We performed a strategic post-licensing randomised controlled trial in HCV-infected participants with mild liver disease to evaluate strategies for short-course treatment, the impact of treatment failure on retreatment and the role of adjunctive ribavirin in short-course therapy
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