Efficacy of ultra-short, response-guided sofosbuvir and daclatasvir therapy for Hepatitis C: a single arm mechanistic pilot study
- Oxford University Clinical Research Unit, Viet Nam
- Hospital for Tropical Diseases, Viet Nam
- University College London, United Kingdom
- University of Oxford, United Kingdom
- Imperial College London, United Kingdom
- Mahidol University, Thailand
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, SOF or DCV levels.
Conclusions: 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 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
Data availability
The study protocol and processed study data have been uploaded to the ISRCTN registry (ISRCTN17100273; https://doi.org/10.1186/ISRCTN17100273). The data are available under unrestricted access. The raw, pseudo-anonymised viral load data is available in Source Data File 1. 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, appendix 1 and Source Data File 1.
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Ultra-short response-guided Hepatitis C treatment with sofosbuvir and daclatasvir: the SEARCH study HCV sequence dataDryad Digital Repository, doi:10.5061/dryad.x0k6djhnp.
Article and author information
Author details
Funding
Medical Research Council (MR/P025064/1)
- Graham S Cooke
Wellcome Trust (206/296/Z/17/Z)
- Graham S Cooke
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Human subjects: In METHODS section we state: Patients referred to the trial were initially enrolled into an observational study which included fibroscan assessment and genotyping. Individuals in this cohort found to be potentially eligible for the trial were invited for further screening. All patients provided written informed consent.In Ethics subsection we state: The trial was approved by the research ethics committees of The Hospital for Tropical Diseases31 (ref: CS/BND/18/25), Vietnam Ministry of Health32 (ref: 6172/QĐ-BYTtnam MoH), Imperial College London33 (ref: 17IC4238), and Oxford University Tropical Research Ethics Committee34 (ref: 43-17). The study's conduct and reporting is fully compliant with the World Medical Association's Declaration of Helsinki on Ethical Principles for Medical Research Involving Human Subjects.35 The trial was registered at ISRCTN, registration number is ISRCTN1710027336.
Copyright
© 2023, Flower et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Efficacy of ultra-short, response-guided sofosbuvir and daclatasvir therapy for Hepatitis C: a single arm mechanistic pilot study
eLife 12:e81801.
https://doi.org/10.7554/eLife.81801
