%0 Journal Article
%@ 0140-6736
%A Cooke, Graham
%A Le Manh, Hung
%A Flower, Barnaby
%A McCabe, Leanne
%A Vu Thi Kim, Hang
%A Vo Thi, Thu
%A Dang Trong, Thuan
%A Nguyen Thanh, Dung
%A Le Thanh, Phuong
%A Dao Bach, Khoa
%A Nguyen Thu Chau, An
%A Pham Ngoc, Thach
%A Vu Thu Thu, Huong
%A Dang Thu, Bich
%A Nguyen Kim, Tuyen
%A Ansari, Azim
%A Le Ngoc, Chau
%A Vo Minh, Quang
%A Nguyen Thi Ngoc, Phuong
%A Le Thi, Thao
%A Nguyen Bao, Tran
%A Kestelyn, Evelyne
%A Kingsley, Cherry
%A Van Doorn, Rogier
%A Rahman, Motiur
%A Pett, Sarah
%A Thwaites, Guy
%A Barnes, Eleanor
%A Day, Jeremy
%A Nguyen Van Vinh, Chau
%A Walker, Ann Sarah
%D 2025
%F discovery:10203644
%I Elsevier
%J The Lancet
%P 1769-1780
%T Treatment Options to Support the Elimination of Hepatitis C: an open label, factorial randomised controlled trial
%U https://discovery.ucl.ac.uk/id/eprint/10203644/
%V 405
%X 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<0·0001).  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.
%Z Copyright © 2025 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0  license.