Ribavirin Retains Role with Improved Dosing for HCV

JANUARY 11, 2018
Kenneth Bender
Ribavirin (RBV) continues to be a necessary adjunct to direct-acting antiviral (DAA) regimens for difficult-to-cure hepatitis C virus (HCV) infection. A new large cohort study has confirmed the RBV steady-state serum levels that correspond to high rates of efficacy and low adverse effect.

Faydra Lieveld, MD, University Medical Center Utrecht, The Netherlands, and Marjolein van Tilborg, MD, PhD, Erasmus MC University Medical Center, The Netherlands, co-lead authors on behalf of the HepNed Study Group, 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 presence of cirrhosis, genotype 3 infection, presence of resistance-associated substitutes, previous antiviral treatment failure and/or in specific DAA regimens to increase treatment efficacy," researchers wrote.

In an essay commenting on the HepNed Study Group findings, Martin Lagging, MD, PhD and Jesper Waldenström, MD, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Sweden, elaborated on the role of RBV.
 
Martin Lagging, MD, PhDMartin Lagging, MD, PhD
"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.

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.

Lieveld, 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," researchers wrote. 

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. They also suggested an additional step to reduce the occurrence of  hemolytic anemia: 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," Lagging and Waldenström concluded.

The study, "Ribavirin steady-state plasma level is a predictor of sustained virological response in hepatitis C–infected patients treated with direct-acting antivirals," was published online in Alimentary Pharmacology and Therapeutics in November. 

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