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Ritonavir-boosted danoprevir-based regimens in treatment-naive and prior null responders with HCV genotype 1 or 4 and compensated cirrhosis

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Abstract

Background and aim

Effective and safe antiviral treatment regimens are needed for patients with chronic hepatitis C (CHC) and cirrhosis.

Methods

An international open-label trial was conducted in CHC patients with genotype (G)1/4 infection, compensated cirrhosis, HCV RNA ≥ 50,000 IU/mL and body mass index 18–35 kg/m2. Treatment-naive patients (Cohort 1) received a triple therapy regimen [danoprevir/r 100/100 mg twice daily (bid), ribavirin 1000/1200 mg/day and peginterferon alfa-2a 180 µg/week] for 24 weeks. Prior null responders (Cohort 2) received a quadruple therapy regimen (danoprevir/r 100/100 mg bid, mericitabine 1000 mg bid and peginterferon alfa-2a/ribavirin). The primary efficacy outcome was sustained virological response (HCV RNA < limit of quantification, target not detected) at end of the 24-week follow-up period (SVR24).

Results

In Cohort 1 (n = 23), 73.9 and 65.2 % of patients had a virological response at Weeks 4 and 24, respectively; 39.1 % achieved SVR24 (G1a = 1/13; G1b = 8/9; G4 = 0/1). In Cohort 2 (n = 20), 100 % achieved virological response at Weeks 4 and 24; 65 % achieved SVR24 (G1a = 4/8; G1b = 7/10; G4 = 2/2). Treatment failure was more common in G1a than G1b-infected patients and less common in patients receiving quadruple therapy. Treatment failure was associated with emergence of resistance to danoprevir, but not mericitabine. The safety profile was typical of that associated with peginterferon alfa-2a/ribavirin. No deaths/episodes of hepatic decompensation occurred.

Conclusions

Treatment with danoprevir/r-based regimens for 24 weeks is safe and well tolerated in CHC patients with compensated cirrhosis. A quadruple therapy regimen (danoprevir/r, mericitabine, peginterferon alfa/ribavirin) produced high SVR24 rates in prior null responders, particularly among G1b patients.

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Abbreviations

ACTG:

AIDS Clinical Trial Group

AE:

Adverse event

AUC:

Area under the plasma-concentration time curve

AUC0–τ :

Area under the plasma-concentration time curve from time 0 to the last measurement during the dosing interval

C max :

Maximum observed plasma concentration

C min :

Minimum observed plasma concentration

CHC:

Chronic hepatitis C

CLss/F:

Apparent total oral clearance at steady-state

G:

Genotype

HCV:

Hepatitis C virus

LOQ:

Limit of quantification

RVR:

Rapid virological response

SAE:

Serious adverse event

SVR:

Sustained virological response

t max :

Time to attain C max

t 1/2 :

Terminal elimination half-life

ULN:

Upper limit of normal

Vdss/F:

Apparent volume of distribution at steady-state

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Acknowledgements

This research was funded by F. Hoffmann-La Roche Ltd. Support for third-party writing assistance for this manuscript, furnished by Blair Jarvis, was provided by F. Hoffmann-La Roche Ltd.

Author contributions

E. J. Gane—study concept and design; acquisition of data; analysis and interpretation of data; drafting of the manuscript; critical revision of the manuscript for important intellectual content; study supervision. R. Rouzier—acquisition of data; analysis and interpretation of data; critical revision of the manuscript for important intellectual content. T. Hassanein—acquisition of data; analysis and interpretation of data; critical revision of the manuscript for important intellectual content. C. A. Stedman—acquisition of data; analysis and interpretation of data; critical revision of the manuscript for important intellectual content. W. Mazur—acquisition of data; analysis and interpretation of data; critical revision of the manuscript for important intellectual content. V. Kupcova—acquisition of data; analysis and interpretation of data; critical revision of the manuscript for important intellectual content. S. Le Pogam—study concept and design; analysis and interpretation of data; drafting of the manuscript; critical revision of the manuscript for important intellectual content; study supervision. S. Eng—study concept and design; analysis and interpretation of data; drafting of the manuscript; critical revision of the manuscript for important intellectual content; study supervision. A. Voulgari—study concept and design; analysis and interpretation of data; drafting of the manuscript; critical revision of the manuscript for important intellectual content; study supervision. P. Morcos—study concept and design; analysis and interpretation of data; drafting of the manuscript; critical revision of the manuscript for important intellectual content; study supervision. B. J. Brennan—study concept and design; analysis and interpretation of data; drafting of the manuscript; critical revision of the manuscript for important intellectual content; study supervision. A. Scalori—study concept and design; analysis and interpretation of data; drafting of the manuscript; critical revision of the manuscript for important intellectual content; study supervision. J. Thommes—study concept and design; analysis and interpretation of data; drafting of the manuscript; critical revision of the manuscript for important intellectual content; study supervision.

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Authors and Affiliations

  1. Auckland Clinical Studies, Grafton, New Zealand

    Edward J. Gane

  2. Centre Cap, Centre Médical Odysséum, Montpellier, France

    Régine Rouzier

  3. Southern California Liver Centers, Coronado, CA, USA

    Tarek Hassanein

  4. Christchurch Clinical Studies and University of Otago, Christchurch, New Zealand

    Catherine A. Stedman

  5. Department of Infectious Diseases, Medical University of Silesia, Katowice, Poland

    Wlodzimierz Mazur

  6. Medical Faculty of Comenius University, Dérer’s Hospital, Bratislava, Slovakia

    Viera Kupcova

  7. Hoffmann-La Roche Inc, Nutley, NJ, USA

    Sophie Le Pogam, Peter N. Morcos & Barbara J. Brennan

  8. Genentech, South San Francisco, CA, USA

    Simon Eng & James Thommes

  9. Roche Products Ltd, Welwyn, UK

    Athina Voulgari & Astrid Scalori

  10. Auckland City Hospital, Auckland, 1442, New Zealand

    Edward J. Gane

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  1. Edward J. Gane
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Corresponding author

Correspondence to Edward J. Gane.

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Conflict of interest

E. J. Gane—advisory boards for Gilead, AbbVie, Idenix, Achillion, Novartis, Janssen and Roche; R. Rouzier—None to declare; T. Hassanein—Research Grants: AbbVie, Boehringer Ingelheim, Bristol-Myers Squibb, Eisai, Gilead Sciences, Janssen, Idenix, Ikaria, Mochida, Roche, Ocera, Taigen, Takeda, Salix, Sundise, Vertex. Speaker: Baxter, Bristol-Myers Squibb, Gilead, Salix; Advisory Board: AbbVie, Bristol-Myers Squibb; C. A. Stedman—advisory boards for Roche, MSD, Gilead Sciences and Janssen; W. Mazur—has received lecture fees from Gilead, Roche, Bristol-Myers Squibb, Janssen, and AbbVie; consulting fees from MSD, Gilead, Roche, Bristol-Myers Squibb and Abbott; has participated as an investigator in clinical trials for GlaxoSmithKline, Roche, Gilead, Janssen, AbbVie, and Bristol-Myers Squibb; V. Kupcova—None to declare; S. Le Pogam—Hoffmann La Roche employee at the time of the study; S. Eng—Genentech/Roche employee at the time of the study; A. Voulgari—Employee of Roche; P. Morcos—Employee of Roche; B. J. Brennan—Employee of Roche; A. Scalori—Employee of Roche; J. Thommes—Employee of Genentech.

Ethical approval

Ethical approval was attained et al. sites prior to patient recruitment. All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. This article does not contain any studies with animals performed by any of the authors. The study was conducted in accordance with the principles of the Declaration of Helsinki and amendments and in compliance with Guidelines for Good Clinical Practice and EU Directive 2001/20/EC. The protocol was approved by the research ethics committee at each participating centre and each patient provided written informed consent before undergoing any study procedures.

Informed consent

Informed consent was obtained from all individual participants included in the study.

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Gane, E.J., Rouzier, R., Hassanein, T. et al. Ritonavir-boosted danoprevir-based regimens in treatment-naive and prior null responders with HCV genotype 1 or 4 and compensated cirrhosis. Hepatol Int 10, 478–487 (2016). https://doi.org/10.1007/s12072-015-9699-9

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