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

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.

Conflict of interest statement

Competing Interests: The funding from the commercial source, i.e. Roche affiliates, does not alter the authors' adherence to PLOS ONE policies on sharing data and materials, and none of the authors have any relevant declarations relating to employment, consultancy, patents, products in development, marketed products, etc. regarding the commercial funder.

Figures

Fig 1. Flow diagram of the RibaC study trial showing enrollment and disposition of patients.

Patients were randomized to arm A “loading” (2 weeks of ribavirin double dosing concomitant with pegIFN-α), arm B “priming” (4 weeks ribavirin mono-therapy prior to adding pegIFN-α), or arm C “standard-of-care”.

Fig 2

Impact of “loading” (2 weeks of ribavirin double dosing concomitant with pegIFN-α), “priming” (4 weeks ribavirin mono-therapy prior to adding pegIFN-α), and “standard-of-care” on plasma ribavirin concentrations (A), hemoglobin (B), decline in HCV RNA (C), and ALT (D). Mean with standard error of the mean shown.

Fig 3

Impact in arm B “priming” (i.e. 4 weeks ribavirin mono-therapy prior to adding pegIFN-α) of interleukin 28B (IL28B, also known as IFNL4) genetic variant CC (n = 8) vs. CT/TT (n = 13) on decline in HCV RNA (A) and ribavirin concentration day 0 (B), as well as correlation between decline in HCV RNA and ribavirin concentration day 0 (C). White squares showing IL28B CC patients and black dots showing CT/TT carriage. Mean with standard deviation in (A and B). P values obtained using Mann-Whitney U test/Welch T test (3A), Mann-Whitney U test (3B) and Spearman correlation (3C).

Fig 4. Impact of ribavirin mono-therapy for four weeks on plasma IP-10 concentrations.

Box plots displaying the 10th, 25th, 50th, 75th, and 90th percentiles. P values obtained using Wilcoxon matched-pairs signed rank test.

Fig 5. Proportion of patients achieving HCV RNA below 1000 IU/mL day 7 (VRVR), undetectable HCV RNA at week 4 (RVR), week 12 (Week 12), at end-of-treatment (EOT), and 24 weeks post treatment (SVR24).