Randomized Trial Evaluating the Impact of Ribavirin Mono-Therapy and Double Dosing on Viral Kinetics, Ribavirin Pharmacokinetics and Anemia in Hepatitis C Virus Genotype 1 Infection

Jesper Waldenström; Johan Westin; Kristina Nyström; Peer Christensen; Olav Dalgard; Martti Färkkilä; Karin Lindahl; Staffan Nilsson; Gunnar Norkrans; Henrik Krarup; Hans Norrgren; Mads Rauning Buhl; Stephan Stenmark; Martin Lagging

doi:10.1371/journal.pone.0155142

Randomized Trial Evaluating the Impact of Ribavirin Mono-Therapy and Double Dosing on Viral Kinetics, Ribavirin Pharmacokinetics and Anemia in Hepatitis C Virus Genotype 1 Infection

PLoS One. 2016 May 11;11(5):e0155142. doi: 10.1371/journal.pone.0155142. eCollection 2016.

Authors

Affiliations

¹ Department of Infectious Medicine, Institute of Biomedicine at Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
² Department of Infectious Diseases, University of Southern Denmark, Odense, Denmark.
³ Department of Infectious Diseases, Akershus University Hospital, Oslo, Norway.
⁴ Department of Gastroenterology, Helsinki University, Helsinki, Finland.
⁵ Department of Infectious Diseases, Karolinska University Hospital Huddinge, Karolinska Institute, Stockholm, Sweden.
⁶ Department of Mathematical Sciences, Chalmers University of Technology, Gothenburg, Sweden.
⁷ Section of Molecular Diagnostics, Clinical Biochemistry, Aalborg University Hospital, Aalborg, Denmark.
⁸ Department of Infectious Diseases, Skåne University Hospital, Lund, Sweden.
⁹ Department of Infectious Diseases, Aarhus University, Aarhus, Denmark.
¹⁰ Department of Communicable Disease Control Västerbotten, Umeå, Sweden.

Abstract

In this pilot study (RibaC), 58 hepatitis C virus (HCV) genotype 1 infected treatment-naïve patients were randomized to (i) 2 weeks ribavirin double dosing concomitant with pegylated interferon-α (pegIFN-α), (ii) 4 weeks ribavirin mono-therapy prior to adding pegIFN-α, or (iii) standard-of-care (SOC) ribavirin dosing concurrent with pegIFN-α. Four weeks of ribavirin mono-therapy resulted in a mean 0.46 log(10) IU/mL HCV RNA reduction differentially regulated across IL28B genotypes (0.89 vs. 0.21 log(10) IU/mL for CC and CT/TT respectively; P = 0.006), increased likelihood of undetectable HCV RNA week 4 after initiating pegIFN-α and thus shortened treatment duration (P<0.05), and decreased median IP-10 concentration from 550 to 345 pg/mL (P<0.001). Both experimental strategies impacted on ribavirin concentrations, and high levels were achieved after one week of double dosing. However, by day 14, double dosing entailed a greater hemoglobin decline as compared to SOC (2.2 vs. 1.4 g/dL; P = 0.03). Conclusion: Ribavirin down-regulates IP-10, and may have an anti-viral effect differently regulated across IL28B genotypes.

Trial registration: ClinicalTrials.gov NCT01226771.

Publication types

Randomized Controlled Trial
Research Support, Non-U.S. Gov't

MeSH terms

Adult
Alanine Transaminase / metabolism
Anemia / complications*
Chemokine CXCL10 / blood
Chemokine CXCL10 / metabolism
Dose-Response Relationship, Drug
Female
Genotype
Hemoglobins / metabolism
Hepacivirus / drug effects
Hepacivirus / genetics*
Hepatitis C, Chronic / blood
Hepatitis C, Chronic / drug therapy*
Hepatitis C, Chronic / virology*
Humans
Kinetics
Male
Middle Aged
RNA, Viral / metabolism
Ribavirin / administration & dosage
Ribavirin / blood
Ribavirin / pharmacokinetics*
Ribavirin / therapeutic use*
Treatment Outcome

Substances

Chemokine CXCL10
Hemoglobins
RNA, Viral
Ribavirin
Alanine Transaminase

Associated data

ClinicalTrials.gov/NCT01226771

Grants and funding

This work was supported by the Swedish Medical Research Council (Vetenskapsrådet; Diarienr 2008:2427 and 2011:3821), and ALF Funds at the Sahlgrenska University Hospital (Diarienr ALFGBG-143271). An unrestricted grant from Roche affiliates in the Nordic region also supported this study. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.