Efficacy of ultra-short, response-guided sofosbuvir and daclatasvir therapy for hepatitis C in a single-arm mechanistic pilot study
Barnaby Flower, Le Manh Hung, Leanne McCabe, M. Azim Ansari, Châu Lê Ngọc, Thu Vo Thi, Hang Vu Thi Kim, Phuong Nguyen Thi Ngoc, Le Thanh Phuong, Vo Minh Quang, Thuận Đặng Trọng, Thao Le Thi, Tran Nguyen Bao, Cherry Kingsley, David A. Smith, Richard M. Hoglund, Joel Tärning, Evelyne Kestelyn, Sarah Pett, H. Rogier van Doorn, Jennifer Ilo Van Nuil, Hugo C. Turner, Guy Thwaites, Eleanor Barnes, Motiur Rahman, A. Sarah Walker, Jeremy Day, Nguyen VV Chau, Graham Cooke
Abstract
Background: World Health Organization has called for research into predictive factors for selecting persons who could be successfully treated with shorter durations of direct-acting antiviral (DAA) therapy for hepatitis C. We evaluated early virological response as a means of shortening treatment and explored host, viral and pharmacokinetic contributors to treatment outcome. Methods: Duration of sofosbuvir and daclatasvir (SOF/DCV) was determined according to day 2 (D2) virologic response for HCV genotype (gt) 1- or 6-infected adults in Vietnam with mild liver disease. Participants received 4- or 8-week treatment according to whether D2 HCV RNA was above or below 500 IU/ml (standard duration is 12 weeks). Primary endpoint was sustained virological response (SVR12). Those failing therapy were retreated with 12 weeks SOF/DCV. Host IFNL4 genotype and viral sequencing was performed at baseline, with repeat viral sequencing if virological rebound was observed. Levels of SOF, its inactive metabolite GS-331007 and DCV were measured on days 0 and 28. Results: Of 52 adults enrolled, 34 received 4 weeks SOF/DCV, 17 got 8 weeks and 1 withdrew. SVR12 was achieved in 21/34 (62%) treated for 4 weeks, and 17/17 (100%) treated for 8 weeks. Overall, 38/51 (75%) were cured with first-line treatment (mean duration 37 days). Despite a high prevalence of putative NS5A-inhibitor resistance-associated substitutions (RASs), all first-line treatment failures cured after retreatment (13/13). We found no evidence treatment failure was associated with host IFNL4 genotype, viral subtype, baseline RAS, SOF or DCV levels. Conclusions: Shortened SOF/DCV therapy, with retreatment if needed, reduces DAA use in patients with mild liver disease, while maintaining high cure rates. D2 virologic response alone does not adequately predict SVR12 with 4-week treatment. Funding: Funded by the Medical Research Council (Grant MR/P025064/1) and The Global Challenges Research 70 Fund (Wellcome Trust Grant 206/296/Z/17/Z).