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We evaluated early virological response as a means of shortening treatment and explored host, viral and pharmacokinetic contributors to treatment outcome.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec id=\"abs2\">\n                    <jats:title>Methods:<\/jats:title>\n                    <jats:p>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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec id=\"abs3\">\n                    <jats:title>Results:<\/jats:title>\n                    <jats:p>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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec id=\"abs4\">\n                    <jats:title>Conclusions:<\/jats:title>\n                    <jats:p>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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec id=\"abs5\">\n                    <jats:title>Funding:<\/jats:title>\n                    <jats:p>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).<\/jats:p>\n                  <\/jats:sec>","DOI":"10.7554\/elife.81801","type":"journal-article","created":{"date-parts":[[2023,1,9]],"date-time":"2023-01-09T06:01:17Z","timestamp":1673244077000},"update-policy":"https:\/\/doi.org\/10.7554\/elife.81801","source":"Crossref","is-referenced-by-count":17,"title":["Efficacy of ultra-short, response-guided sofosbuvir and daclatasvir therapy for hepatitis C in a single-arm mechanistic pilot 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