BACKGROUND: WHO recommends treating hepatitis C infection with one of three antiviral combinations for 8-12 weeks. No randomised trials have compared these regimens, and high cure rates might be achievable with shorter durations of therapy. We aimed to compare sofosbuvir-daclatasvir with sofosbuvir-velpatasvir, and to evaluate potential novel treatment strategies. METHODS: We conducted a multi-arm, open-label, randomised controlled non-inferiority trial in two public hospitals in Viet Nam. Adults (aged ≥18 years) with chronic hepatitis C infection and mild-to-moderate liver fibrosis were eligible. Recruitment was stratified by centre and viral genotype (1-5 vs 6) with 1:1 random allocation to an oral fixed-dose combination of sofosbuvir 400 mg plus daclatasvir 60 mg (sofosbuvir-daclatasvir) or sofosbuvir 400 mg plus velpatasvir 100 mg (sofosbuvir-velpatasvir). Participants were simultaneously factorially randomly assigned to one of four treatment strategies: 12 weeks' standard of care (SOC)
4 weeks' therapy with four weekly PEGylated interferon alfa-2a subcutaneous injections
induction and maintenance therapy with 2 weeks' standard therapy followed by 10 weeks' therapy 5 days a week
and response-guided therapy (RGT) for 4, 8, or 12 weeks determined by viral load on day 7. The primary outcome was sustained virological response (SVR) 12 weeks after treatment completion, analysed in all evaluable participants regardless of actual treatment received. We chose a 5% non-inferiority margin for the drug comparison, and a 10% non-inferiority margin for the treatment strategy comparisons. Safety was assessed in all randomised participants. This trial is registered with ISRCTN, 61522291, and is completed. FINDINGS: Between June 19, 2020, and May 10, 2023, 624 participants were randomised (470 [75%] were male and 154 [25%] were female). 296 (47%) had genotype 6 and 328 (53%) had genotypes 1-5. The primary outcome was assessable in 609 (98%) participants. SVR occurred in 294 (97%) of 302 participants in the sofosbuvir-daclatasvir group and 292 (95%) of 307 participants in the sofosbuvir-velpatasvir group (risk difference 2·2%, 90% credible interval [CrI] -0·2 to 4·8, within the 5% non-inferiority margin
93% probability that sofosbuvir-daclatasvir is superior to sofosbuvir-velpatasvir). SVR occurred in 148 (99%) of 150 in the SOC group, 143 (94%) of 152 in the 4-week antiviral plus interferon group (-4·5%, 90% CrI -8·3 to -1·3), 151 (99%) of 152 in the induction-maintenance group (0·6%, -1·1 to 2·7), and 144 (93%) of 155 in the RGT group (-5·7%, -9·6 to -2·3)
all risk differences were within the 10% non-inferiority margin. Serious adverse events were rare (11 [4%] of 313 participants in the sofosbuvir-velpatasvir group vs six [2%] of 311 in the sofosbuvir-daclatasvir group
risk difference -1·6% [95% CrI -4·2 to 0·8]) with no evidence of differences between regimens or strategies, but adverse reactions were very common in the 4-week antiviral plus interferon group compared with the other treatment strategies (risk difference vs SOC group, 66·8% [59·2 to 74·0]
p<
0·0002). INTERPRETATION: Sofosbuvir-daclatasvir was non-inferior to sofosbuvir-velpatasvir. High efficacy was seen with novel strategies, which might help to inform approaches to treatment for harder-to-reach populations. FUNDING: Wellcome Trust.