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

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 ### Competing Interest Statement The authors have declared no competing interest. ### Clinical Trial The trial was registered at ISRCTN registration number is ISRCTN17100273 ### Clinical Protocols ### Funding Statement This work was supported by the Medical Research Council (grant MR/P025064/1) and The Global Challenges Research Fund (Wellcome Trust Grant 206/296/Z/17/Z). GC is supported in part by the NIHR Biomedical Research Centre of Imperial College NHS Trust and an NIHR Professorship. BF received a travel grant to attend AASLD conference in Washington DC from Gilead Sciences in 2017. HCT acknowledges funding from the MRC Centre for Global Infectious Disease Analysis (reference MR/R015600/1), jointly funded by the UK Medical Research Council (MRC) and the UK Foreign, Commonwealth & Development Office (FCDO), under the MRC/FCDO Concordat agreement and is also part of the EDCTP2 programme supported by the European Union. EB acknowledges support from Oxford NIHR Biomedical Research Centre. MAA is supported by a Sir Henry Dale Fellowship jointly funded by the Royal Society and Wellcome Trust (220171/Z/20/Z). ASW and EB are NIHR Senior Investigators. LM, SLP and ASW are supported by core support from the Medical Research Council UK to the MRC Clinical Trials Unit [MC\_UU\_00004/03]. The views expressed are those of the author(s) and not necessarily those of the NIHR or the Department of Health and Social Care. No authors report conflicts of interest relating to this work. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The trial was approved by the research ethics committees of The Hospital for Tropical Diseases Vietnam Ministry of Health Imperial College London and Oxford University Tropical Research Ethics Committee. The studys conduct and reporting is fully compliant with the World Medical Associations Declaration of Helsinki on Ethical Principles for Medical Research Involving Human Subjects. The trial was registered at ISRCTN registration number is [ISRCTN1710027334][1]. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes TThe study protocol and processed study data have been uploaded to the ISRCTN registry ([ISRCTN17100273][2]; https://doi.org/10.1186/[ISRCTN17100273][2]). The data are available under unrestricted access. The raw data are protected and are not available due to data privacy laws. The virus sequencing dataset has been uploaded to Dryad (https://datadryad.org) and is available here: doi:10.5061/dryad.x0k6djhnp. All data generated in this study is provided in the main text or appendix 1. [1]: /external-ref?link_type=ISRCTN&access_num=ISRCTN1710027334 [2]: /external-ref?link_type=ISRCTN&access_num=ISRCTN17100273