Efficacy of ultra-short, response-guided sofosbuvir and daclatasvir therapy for hepatitis C in a single-arm mechanistic pilot study

• DOI: 10.7554/elife.81801
• Publication Date: 2023-01-09T11:01:17Z
• Authors: Barnaby Flower; Le Manh Hung; Leanne Mccabe; M Azim Ansari; Chau Le Ngoc; Thu Vo Thi; Hang Vu Thi Kim; Phuong Nguyen Thi...; Le Thanh Phuong; Vo Minh Quang; Thuan Dang Trong; Thao Le Thi; Tran Nguyen Bao; Cherry Kingsley; David Smith; Richard M Hoglund; Joel Tarning; Evelyne Kestelyn; Sarah L Pett; Rogier van Doorn; Jennifer Ilo Van ...; Hugo Turner; Guy E Thwaites; Eleanor Barnes; Motiur Rahman; Ann Sarah Walker; Jeremy N Day; Nguyen VV Chau; Graham S Cooke
• Keywords: Daclatasvir; Sofosbuvir; Clinical endpoint; NS5A; Hepatitis C

Background: World Health Organization has called for research into predictive factors selecting persons who could be successfully treated with shorter durations of direct-acting antiviral (DAA) therapy hepatitis C. We evaluated early virological response as a means shortening treatment and explored host, viral pharmacokinetic contributors to outcome. Methods: Duration sofosbuvir daclatasvir (SOF/DCV) was determined according day 2 (D2) virologic HCV genotype (gt) 1- or 6-infected adults in Vietnam mild liver disease. Participants received 4- 8-week whether D2 RNA above below 500 IU/ml (standard duration is 12 weeks). Primary endpoint sustained (SVR12). Those failing were retreated weeks SOF/DCV. Host IFNL4 sequencing performed at baseline, repeat if rebound observed. Levels SOF, its inactive metabolite GS-331007 DCV measured on days 0 28. Results: Of 52 enrolled, 34 4 SOF/DCV, 17 got 8 1 withdrew. SVR12 achieved 21/34 (62%) weeks, 17/17 (100%) weeks. Overall, 38/51 (75%) cured first-line (mean 37 days). Despite high prevalence putative NS5A-inhibitor resistance-associated substitutions (RASs), all failures after retreatment (13/13). found no evidence failure associated host genotype, subtype, baseline RAS, SOF levels. Conclusions: Shortened SOF/DCV therapy, needed, reduces DAA use patients disease, while maintaining cure rates. alone does not adequately predict 4-week treatment. Funding: Funded by the Medical Research Council (Grant MR/P025064/1) The Global Challenges 70 Fund (Wellcome Trust Grant 206/296/Z/17/Z).