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

Abstract

Background: WHO 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. <br />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 weeks 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 day 0 and 28. <br />Results: Of 52 adults enrolled, 34 received 4 weeks SOF/DCV, 17 got 8 weeks and one 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 (RAS), 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 or DCV levels. SOF metabolite levels were higher in those failing 4-week therapy. <br />Conclusions: Shortened SOF/DCV therapy, with retreatment if needed, reduces DAA use while maintaining high cure rates. D2 virologic response alone does not adequately predict SVR12 with 4 weeks treatment. <br />Funding: Funded by the Medical Research Council (grant MR/P025064/1) and The Global Challenges Research Fund (Wellcome Trust Grant 206/296/Z/17/Z).) <br />Clinical trial number: ISRCTN17100273

Rise in alanine aminotransferase after HCV treatment is a highly sensitive screen for treatment failure

“…Trial registrations and ethical permissions are provided with both published manuscripts. [11,12] In SEARCH-1 (Vietnam), genotype 1 or 6-infected adults with mild liver disease (FibroScan score ≤ 7.1 kPa) received 4 or 8 weeks of sofosbuvir and daclatasvir therapy according to whether HCV RNA was below or above 500 IU/mL after 2 days of treatment. HCV RNA was measured at regular intervals until end of follow-up (EOT + 12 wk) or until treatment failure if it occurred first (Supplemental Figures S1 and S3, http://links.lww.com/ XCL/A8).…”