Treatment options to support the elimination of Hepatitis C: an open label, factorial randomised controlled trial
Cooke G., Le Manh H., Flower B., McCabe L., Vu Thu Kim H., Vo Thi T., Dang Trong T., Nguyen Thanh D., Le Thanh P., Dao Bach K., Nguyen Thi Chau A., Pham Ngoc T., Vu Thu Thu H., Dang Thi B., Nguyen Kim T., Ansari M., Le Ngoc C., Vo Minh Q., Nguyen Thi Ngoc P., Le Thi T., Nguyen Bao T., Kestelyn E., Kingsley C., Van Doorn R., Rahman M., Pett S., Thwaites G., Barnes E., Day J., Nguyen Van Vinh C., Walker AS.
Background: WHO recommends treating Hepatitis C infection with one of three antiviral combinations for 8 to 12 weeks. No randomised trials have compared these regimens and high cure rates may be achievable with shorter durations of therapy. Methods: We conducted a multi-arm, randomised controlled trial in Vietnamese adults with chronic hepatitis C infection, with mild-moderate liver fibrosis. Recruitment was stratified by viral genotype (1-5 versus 6) with 1:1 random allocation to sofosbuvir 400mg/daclatasvir 60mg (SOF/DCV) or sofosbuvir 400mg/velpatasvir 100mg (SOF/VEL). Participants were simultaneously factorially randomised to one of four treatment strategies: 12 weeks standard-of-care (SOC); four weeks’ initial therapy with additional weekly PEGylated interferon (4w-DAA/IFN); induction/maintenance therapy with two weeks’ standard therapy followed by 10 weeks’ therapy 5 days/week; and response-guided therapy for 4,8 or 12 weeks determined by viral load on day 7. The primary outcome was sustained virological response 12 weeks after treatment completion (SVR12). Findings: 624 participants were randomised: 296 (47.4%) genotype 6, 328 (52.6%) genotypes 1-5). Primary outcome was assessable for 609 (97.6%). SVR12 was 294/302 (97.4%) for SOF/DCV and 292/307 (95.1%) for SOF/VEL (difference +2.2% (90% Credible Interval (CrI) -0.2%,+4.8%) vs 5% non-inferiority margin; 93% probability SOF/DCV superior to SOF/VEL). SVR12 was 148/150 (98.7%) in SOC, 143/152 (94.1%) with 4wDAA/IFN (-4.5% (-8.3%,-1.3%) vs 10% non-inferiority margin), 151/152 (99.3%) with induction/maintenance (+0.6% (-1.1%,+2.7%)), and 144/155 (92.9%) with response-guided therapy (-5.7% (-9.6%,-2.3%)). Serious adverse events were rare (2.7%) with no evidence of differences between regimens or strategies. Interpretation: SOF/DCV is non-inferior to SOF/VEL. High efficacy was seen with novel strategies that help to inform approaches to treatment for harder-to-reach populations. Funding: Wellcome Trust (ISRCTN 61522291).