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

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. 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. 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. 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. 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).) Clinical trial number ISRCTN17100273

COVID-19 and ASEAN responses: Comparative policy analysis.

Scholars and policy-makers agree that cross-border and multi-sector cooperation are essential components of coordinated efforts to contain the spread of COVID-19 infections. This paper examines the responses of ASEAN (Association of Southeast Asian Nation) member countries to the COVID-19 pandemic, including the limits of regional cooperation. ASEAN has pre-existing cooperative frameworks in place, including regional health security measures, which, at least theoretically, could assist the region's efforts to formulate cooperative responses to containing a global pandemic. With its overarching "One Vision, One Identity, One Community", ASEAN cooperation has extended to include region-wide disaster responses, framed as "One Asean, One Response". Using content analysis, this paper examines media statements and policies from ASEAN member states and the ASEAN Secretariat to assess the collective response to COVID-19 during the period from January to August 2020. By identifying gaps and opportunities in government responses to COVID-19 as the virus spread throughout Southeast Asia, this paper provides new insights as well as recommendations for the future.