A phase III study of the safety and efficacy of viramidine versus ribavirin in treatment-naïve patients with chronic hepatitis C: ViSER1 results #

Abstract

Pegylated interferon (peg-IFN) and ribavirin (RBV) are effective in eradicating the hepatitis C virus in more than half of patients. However, anemia arising from RBV-induced hemolysis can prompt dose reductions and lower sustained virologic response (SVR) rates. In early clinical trials, Viramidine (VRD, renamed taribavirin), an RBV prodrug, was associated with less anemia and VRD given at 600 mg twice daily (BID) appeared to provide the best safety with comparable efficacy to RBV. The phase III Viramidine's Safety and Efficacy versus Ribavirin 1 (ViSER1) study randomized 972 treatment-naïve patients with chronic hepatitis C to fixed-dose VRD (600 mg BID) or weight-based RBV (1000 or 1200 mg/day), each given with peg-IFN alfa-2b at 1.5 g/kg/week. The primary efficacy endpoint was SVR rate, and the primary safety endpoint was hemoglobin (Hb) event rate (percent of patients with Hb < 10 g/dL or at least a 2.5-g/dL decrease from baseline). SVR rates were 37.7% with VRD (244/647) and 52.3% with RBV (170/325). Thus, the ViSER1 study failed to demonstrate the primary noninferiority efficacy endpoint. Significantly fewer patients had Hb events with VRD (353/647; 54.6%) compared to those with RBV (272/325; 83.7%) (P < 0.001), and significantly fewer developed anemia (Hb < 10 g/dL) with VRD (34/647; 5.3%) compared to those with RBV (76/325; 23.5%) (P < 0.001). Conclusion: Fixed doses of VRD failed to demonstrate noninferiority to RBV in producing SVR rates. The incidence of anemia was approximately four-fold significantly lower with VRD than with RBV. These results suggest fixed-dose VRD given 600 mg BID is insufficient to treat patients with chronic hepatitis C; a weight-based dosing trial of viramidine is currently under way. (HEPATOLOGY 2009;50:717-726.) C ombination therapy with pegylated interferon alfa (peg-IFN) and ribavirin (RBV) is the standard of care for the treatment of patients with chronic hepatitis C, resulting in overall sustained virologic response (SVR) rates of 54%-56%. 1,2 However, adherence to the prescribed regimen of peg-IFN and RBV, especially during the first 12 weeks of treatment, is critical to viral clearance. 3 A recent study showed that when patients infected with hepatitis C virus (HCV) genotype 1 maintained less than 80% of their cumulative RBV dose, the SVR rate was 52% compared with 67% for those who maintained more than 97% of their RBV dose. 4 Patient characteristics such as ethnicity (African American) and coinfection with human immunodeficiency virus, as well as viral genotype (1, 4, 5, or 6) and adverse effects, may impair treatment outcomes and lower SVR

Safety and efficacy of viramidine versus ribavirin in ViSER2: Randomized, double-blind study in therapy-naive hepatitis C patients

“…N = number of patients in weight group; n = number of patients with hemoglobin concentrations <10 g/dl. non-inferiority for the primary efficacy variable (SVR rate at 24-week follow-up) [15]. These results may be explained by suboptimal VRD dosing.…”

Host-Based Ribavirin Resistance Influences Hepatitis C Virus Replication and Treatment Response

“…The addition of RBV to IFN therapy doubled response rates, illustrating the importance of RBV in HCV treatment (37). Efforts to replace RBV with taribavirin, a RBV prodrug formerly known as viramidine, have been unsuccessful (1). Although HCV protease and polymerase inhibitors are promising new antivirals, RBV will continue to be a critical part of combination therapy because eliminating RBV from telaprevir-IFN therapy significantly reduced response rates (26,43).…”

Review: New direct-acting antivirals in the development for hepatitis C virus infection

“…Taribavirin did not meet the noninferiority to ribavirin efficacy endpoint on intent-to-treat basis. It did demonstrate a superior safety profile with anemia rates (Hb < 100 g/L) being significantly less (5 versus 24%) [Benhamou et al 2009]. VISER 2 compared taribavirin plus pegylated interferon alpha-2a versus ribavirin plus pegylated interferon alpha-2a and produced similar results as VISER 1 with SVR rates of 40% in taribavirin-treated patients and 55% in ribavirin-treated patients.…”