Ribavirin Remains Pivotal Component of Hepatitis C Treatment

We’re living in an era where there are highly effective direct-acting antivirals (DAA) available for the treatment of chronic hepatitis C virus, but ribavirin (RBV) continues to be a necessary adjunct to DAA regimens for the virus.

A new cohort study published online in Alimentary Pharmacology and Therapeutics in November confirmed the RBV steady-state serum levels that correspond to high rates of efficacy and low adverse effect.

Co-lead authors of the study Faydra Lieveld, MD, University Medical Center Utrecht, The Netherlands, and Marjolein van Tilborg, MD, PhD, Erasmus MC University Medical Center, The Netherlands, determined the RBV steady-state plasma level at 8 weeks that correspond to a sustained virologic response (SVR) to the RBV-DAA regimen at 12 weeks.

"RBV has not left the therapeutic arena and still used as an additive under certain circumstances such as the presence of cirrhosis, genotype 3 infection, the presence of resistance-associated substitutes, previous antiviral treatment failure and/or in specific DAA regimens to increase treatment efficacy," the authors wrote.

In an essay commenting on the study’s findings, Martin Lagging, MD, PhD and Jesper Waldenström, MD, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Sweden, elaborated on the role of RBV.

"In the setting of decompensated cirrhosis (Child-Pugh B or C), RBV likely will remain a pivotal component of HCV therapy as protease inhibitors should not be used and re-treatment options are limited," they wrote.

Drs. Lagging and Waldenström illustrated that point by citing the ASTRAL-4 trial of sofosbuvir and velpatasvir (Epclusa) treatment of HCV genotype 1-6 infected patients with decompensated cirrhosis, in which the highest SVR rate was achieved in those additionally receiving RBV.

Dr. Lieveld, Dr. vanTilborg, and colleagues identified 183 patients treated with DAAs plus RBV from 4 Dutch academic medical centers. Eighty-five percent of the patients were characterized as difficult-to-cure, with such characteristics as previous treatment experience, HCV genotype 3 and/or cirrhosis.

Most were treated with a sofosbuvir-based regimen, and the majority (89%) achieved SVR at 12 weeks.

The median RBV steady-state plasma level attained at 8 weeks was 2.66mg/L (95% CI; 1.95-3.60) with a median dose of 12.9mg/kg/day (11.2-14.7). Multivariable analyses revealed that a higher RBV steady-state plasma level was an independent predictor of SVR (OR 1.79; 95% CI; 1.09-2.93).

The investigators reported that the optimal RBV lowest level for achieving SVR was 2.28mg/L and the optimal ceiling to attain efficacy while minimizing the incidence of hemolytic anemia was 3.61mg/L.

Their findings counter a lack of association between RBV steady-state plasma levels and SVR found in a previous study, but argue that this is likely to due to the smaller size of that study (N=47), that cohort predominately comprised of genotype 1-infected, non-cirrhotic patients, and the retrospective analysis of the RBV plasma samples.

"Our study represents a large real-world cohort of mainly difficult-to-cure patients on various DAA combinations with prospectively analyzed plasma samples and SVR rates similar to clinical trials and real-world cohorts," the authors wrote.

Dr. Lagging and Waldenström accepted the investigators' recommended therapeutic range of 2.28-3.61mg/L for optimal dosing of RBV with DAAs in treating HCV infection. In order to reduce the occurrence of hemolytic anemia, the researchers suggested an additional step: screening for patients who are more refractory to the adverse effect (approximately one-third) by virtue of carrying genetic variants entailing reduced inosine triphosphate pyrophosphatase (ITPase) activity.

"Based on these findings, in patients continuing to receive ribavirin containing treatment, it may be of interest to tailor therapy by means of on-treatment monitoring of ribavirin concentrations, and/or performing pre-treatment ITPA genetic profiling in order to optimize the likelihood of achieving SVR while minimizing the risk of adverse effects," the doctors concluded.