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

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.

The following data sets were generated

Article and author information

Author details

  1. Barnaby Flower Dr

    Oxford University Clinical Research Unit, Ho Chi Minh City, Viet Nam
    For correspondence
    bflower@oucru.org
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-2659-544X
  2. Le Manh Hung

    Hospital for Tropical Diseases, Ho Chi Minh City, Viet Nam
    Competing interests
    No competing interests declared.
  3. Leanne Mccabe

    MRC Clinical Trials Unit, University College London, London, United Kingdom
    Competing interests
    Leanne Mccabe, has received a grant from the Medical Research Council UK to the MRC Clinical Trials Unit [MC_UU_00004/03]. The author has no other competing interests to declare..
  4. M Azim Ansari

    Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom
    Competing interests
    No competing interests declared.
  5. Chau Le Ngoc

    Oxford University Clinical Research Unit, Ho Chi Minh City, Viet Nam
    Competing interests
    No competing interests declared.
  6. Thu Vo Thi

    Oxford University Clinical Research Unit, Ho Chi Minh City, Viet Nam
    Competing interests
    No competing interests declared.
  7. Hang Vu Thi Kim

    Oxford University Clinical Research Unit, Ho Chi Minh City, Viet Nam
    Competing interests
    No competing interests declared.
  8. Phuong Nguyen Thi Ngoc

    Oxford University Clinical Research Unit, Ho Chi Minh City, Viet Nam
    Competing interests
    No competing interests declared.
  9. Le Thanh Phuong

    Hospital for Tropical Diseases, Ho Chi Minh City, Viet Nam
    Competing interests
    No competing interests declared.
  10. Vo Minh Quang

    Hospital for Tropical Diseases, Ho Chi Minh City, Viet Nam
    Competing interests
    No competing interests declared.
  11. Thuan Dang Trong

    Oxford University Clinical Research Unit, Ho Chi Minh City, Viet Nam
    Competing interests
    No competing interests declared.
  12. Thao Le Thi

    Oxford University Clinical Research Unit, Ho Chi Minh City, Viet Nam
    Competing interests
    No competing interests declared.
  13. Tran Nguyen Bao

    Oxford University Clinical Research Unit, Ho Chi Minh City, Viet Nam
    Competing interests
    No competing interests declared.
  14. Cherry Kingsley

    Department of Infectious Disease, Imperial College London, London, United Kingdom
    Competing interests
    No competing interests declared.
  15. David Smith

    Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom
    Competing interests
    No competing interests declared.
  16. Richard M Hoglund

    Mahidol Oxford Tropical Medicine Research Unit, Mahidol University, Bangkok, Thailand
    Competing interests
    No competing interests declared.
  17. Joel Tarning

    Mahidol-Oxford Tropical Medicine Research Unit, Mahidol University, Bangkok, Thailand
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-4566-4030
  18. Evelyne Kestelyn

    Oxford University Clinical Research Unit, Ho Chi Minh City, Viet Nam
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-5728-0918
  19. Sarah L Pett

    MRC Clinical Trials Unit, University College London, London, United Kingdom
    Competing interests
    Sarah L Pett, has received grants from Gilead Sciences, ViiV Healthcare, Janssen-Cilag, Academy of Medical Sciences, EDCTP, NIHR, NIH, and is a member of the TIPAL (Treating people with idiopathic pulmonary fibrosis with the addition of lansoprazole trial, ISRCTN13526307) DSMB. The author has no other competing interests to declare..
  20. Rogier van Doorn

    Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom
    Competing interests
    No competing interests declared.
  21. Jennifer Ilo Van Nuil

    Oxford University Clinical Research Unit, Ho Chi Minh City, Viet Nam
    Competing interests
    No competing interests declared.
  22. Hugo Turner

    MRC Centre for Global Infectious Disease Analysis, Imperial College London, London, United Kingdom
    Competing interests
    No competing interests declared.
  23. Guy E Thwaites

    Oxford University Clinical Research Unit, Ho Chi Minh City, Viet Nam
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-2858-2087
  24. Eleanor Barnes

    Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom
    Competing interests
    No competing interests declared.
  25. Motiur Rahman

    Oxford University Clinical Research Unit, Ho Chi Minh City, Viet Nam
    Competing interests
    No competing interests declared.
  26. Ann Sarah Walker

    Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-0412-8509
  27. Jeremy N Day

    Oxford University Clinical Research Unit, Ho Chi Minh City, Viet Nam
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-7843-6280
  28. Nguyen VV Chau

    Hospital for Tropical Diseases, Ho Chi Minh CIty, Viet Nam
    Competing interests
    No competing interests declared.
  29. Graham S Cooke

    Department of Infectious Disease, Imperial College London, London, United Kingdom
    Competing interests
    Graham S Cooke, is a board member of MHRA. The author has no other competing interests to declare..

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.

Reviewing Editor

  1. Harel Dahari, Loyola University Chicago, Stritch School of Medicine, United States

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.

Version history

  1. Received: July 12, 2022
  2. Preprint posted: August 17, 2022 (view preprint)
  3. Accepted: December 23, 2022
  4. Accepted Manuscript published: January 9, 2023 (version 1)
  5. Version of Record published: January 23, 2023 (version 2)

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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  1. Barnaby Flower Dr
  2. Le Manh Hung
  3. Leanne Mccabe
  4. M Azim Ansari
  5. Chau Le Ngoc
  6. Thu Vo Thi
  7. Hang Vu Thi Kim
  8. Phuong Nguyen Thi Ngoc
  9. Le Thanh Phuong
  10. Vo Minh Quang
  11. Thuan Dang Trong
  12. Thao Le Thi
  13. Tran Nguyen Bao
  14. Cherry Kingsley
  15. David Smith
  16. Richard M Hoglund
  17. Joel Tarning
  18. Evelyne Kestelyn
  19. Sarah L Pett
  20. Rogier van Doorn
  21. Jennifer Ilo Van Nuil
  22. Hugo Turner
  23. Guy E Thwaites
  24. Eleanor Barnes
  25. Motiur Rahman
  26. Ann Sarah Walker
  27. Jeremy N Day
  28. Nguyen VV Chau
  29. Graham S Cooke
(2023)
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

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https://doi.org/10.7554/eLife.81801

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