IRUS Total

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

File Description SizeFormat 
elife-81801-v2.pdfPublished version3.85 MBAdobe PDFView/Open
Title: Efficacy of ultra-short, response-guided sofosbuvir and daclatasvir therapy for hepatitis C in a single-arm mechanistic pilot study.
Authors: Flower, B
Hung, LM
Mccabe, L
Ansari, MA
Le Ngoc, C
Vo Thi, T
Vu Thi Kim, H
Nguyen Thi Ngoc, P
Phuong, LT
Quang, VM
Dang Trong, T
Le Thi, T
Nguyen Bao, T
Kingsley, C
Smith, D
Hoglund, RM
Tarning, J
Kestelyn, E
Pett, SL
Van Doorn, R
Van Nuil, JI
Turner, H
Thwaites, GE
Barnes, E
Rahman, M
Walker, AS
Day, JN
Chau, NVV
Cooke, GS
Item Type: Journal Article
Abstract: BACKGROUND: World Health Organization 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-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. RESULTS: 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. 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-week treatment. FUNDING: 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).
Issue Date: 9-Jan-2023
Date of Acceptance: 23-Dec-2022
URI: http://hdl.handle.net/10044/1/102638
DOI: 10.7554/eLife.81801
ISSN: 2050-084X
Publisher: eLife Sciences Publications Ltd
Start Page: 1
End Page: 30
Journal / Book Title: eLife
Volume: 12
Copyright Statement: Copyright © 2023, Flower et al. This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use and redistribution provided that the original author and source are credited.
Publication Status: Published
Conference Place: England
Online Publication Date: 2023-01-09
Appears in Collections:Department of Infectious Diseases
School of Public Health

This item is licensed under a Creative Commons License Creative Commons