eprintid: 10203644 rev_number: 19 eprint_status: archive userid: 699 dir: disk0/10/20/36/44 datestamp: 2025-01-21 10:09:24 lastmod: 2025-06-02 12:17:50 status_changed: 2025-01-21 10:09:24 type: article metadata_visibility: show sword_depositor: 699 creators_name: Cooke, Graham creators_name: Le Manh, Hung creators_name: Flower, Barnaby creators_name: McCabe, Leanne creators_name: Vu Thi Kim, Hang creators_name: Vo Thi, Thu creators_name: Dang Trong, Thuan creators_name: Nguyen Thanh, Dung creators_name: Le Thanh, Phuong creators_name: Dao Bach, Khoa creators_name: Nguyen Thu Chau, An creators_name: Pham Ngoc, Thach creators_name: Vu Thu Thu, Huong creators_name: Dang Thu, Bich creators_name: Nguyen Kim, Tuyen creators_name: Ansari, Azim creators_name: Le Ngoc, Chau creators_name: Vo Minh, Quang creators_name: Nguyen Thi Ngoc, Phuong creators_name: Le Thi, Thao creators_name: Nguyen Bao, Tran creators_name: Kestelyn, Evelyne creators_name: Kingsley, Cherry creators_name: Van Doorn, Rogier creators_name: Rahman, Motiur creators_name: Pett, Sarah creators_name: Thwaites, Guy creators_name: Barnes, Eleanor creators_name: Day, Jeremy creators_name: Nguyen Van Vinh, Chau creators_name: Walker, Ann Sarah title: Treatment Options to Support the Elimination of Hepatitis C: an open label, factorial randomised controlled trial ispublished: pub divisions: UCL divisions: B02 divisions: D65 divisions: J38 note: Copyright © 2025 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. abstract: 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. date: 2025-03-14 date_type: published publisher: Elsevier official_url: https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(25)00097-2/fulltext oa_status: green full_text_type: pub language: eng primo: open primo_central: open_green verified: verified_manual elements_id: 2353908 lyricists_name: Walker, Ann lyricists_id: ASWAL40 actors_name: Walker, Ann actors_id: ASWAL40 actors_role: owner full_text_status: public publication: The Lancet volume: 405 pagerange: 1769-1780 issn: 0140-6736 citation: Cooke, Graham; Le Manh, Hung; Flower, Barnaby; McCabe, Leanne; Vu Thi Kim, Hang; Vo Thi, Thu; Dang Trong, Thuan; ... Walker, Ann Sarah; + view all <#> Cooke, Graham; Le Manh, Hung; Flower, Barnaby; McCabe, Leanne; Vu Thi Kim, Hang; Vo Thi, Thu; Dang Trong, Thuan; Nguyen Thanh, Dung; Le Thanh, Phuong; Dao Bach, Khoa; Nguyen Thu Chau, An; Pham Ngoc, Thach; Vu Thu Thu, Huong; Dang Thu, Bich; Nguyen Kim, Tuyen; Ansari, Azim; Le Ngoc, Chau; Vo Minh, Quang; Nguyen Thi Ngoc, Phuong; Le Thi, Thao; Nguyen Bao, Tran; Kestelyn, Evelyne; Kingsley, Cherry; Van Doorn, Rogier; Rahman, Motiur; Pett, Sarah; Thwaites, Guy; Barnes, Eleanor; Day, Jeremy; Nguyen Van Vinh, Chau; Walker, Ann Sarah; - view fewer <#> (2025) Treatment Options to Support the Elimination of Hepatitis C: an open label, factorial randomised controlled trial. The Lancet , 405 pp. 1769-1780. Green open access document_url: https://discovery.ucl.ac.uk/id/eprint/10203644/17/Walker_PIIS0140673625000972.pdf