Ultra-short response-guided Hepatitis C treatment with sofosbuvir and daclatasvir: the SEARCH study HCV sequence data

Background WHO has called for research into predictive factors for
selecting persons who could be successfully treated with shorter durations
of antiviral 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 weeks of
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. Findings 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
of 37 days). Despite a high prevalence of putative NS5A-inhibitor
resistance-associated substitutions (RAS), all first-line treatment
failures were 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. Interpretation 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
of treatment.