Reducing Ribavirin Dose Raises Relapse Risk for Chronic Hepatitis C Patients, but Pegylated Interferon May be Decreased after Week 12

Reducing the dose of ribavirin in combination therapy for chronic hepatitis C (HCV) virus infection below 12 mg/kg/day led to an increased likelihood of relapse, researchers reported in the August 2009 Journal of Viral Hepatitis. However, if an adequate ribavirin level was maintained, pegylated interferon doses could be safely reduced after 12 weeks without increased risk of treatment failure.

By Liz Highleyman

Ribavirin, which has both antiviral and immune-modulating activity, has been shown to reduce the risk of relapse for patients receiving interferon-based therapy. Standard therapy calls for weight-based ribavirin dosing, to ensure that even heavier patients achieve adequate levels, but optimal timing, dose regimens, and ideal drug exposures are not fully defined.

In the present study, investigators evaluated the impact of ribavirin exposure on virological relapse in 984 chronic C patients with HCV genotype 1 who were treated with pegylated interferon alpha-2b (PegIntron) plus ribavirin. The drug exposure of each medication was calculated by averaging doses actually taken.

Results

	Stepwise reduction of ribavirin doses was associated with a stepwise increase in relapse rates, from 11% to 60%.
	For patients with complete early virological response (EVR) -- defined as undetectable HCV RNA at week 12 -- only 4% of patients who received ribavirin doses of 12 mg/kg/day or more experienced viral relapse.
	Ribavirin exposure continued to influence relapse rates even after week 12.
	Pegylated interferon doses, however, could be reduced to 0.6 mcg/kg/week after week 12 without increase the risk of relapse.
	For the 472 patients who had undetectable HCV viral load at week 24 and week 48, a multivariate analysis showed that the factors significantly associated with viral relapse were:
	- Degree of liver fibrosis (P = 0.002); - Time at which a person became HCV RNA negative (P < 0.001); - Mean dose of ribavirin (P < 0.001).
	In contrast, pegylated interferon dose did not significantly predict relapse.

Based on these findings, the study authors concluded, "Maintaining as high a ribavirin dose as possible (> or = 12 mg/kg/day) during the full treatment period can lead to suppression of the relapse [rate] in HCV genotype 1 patients responding to [pegylated interferon alpha-2b] plus ribavirin, especially in complete EVR patients."

Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Osaka, Japan; Osaka Medical Center for Cancer and Cardiovascular Diseases, Osaka, Japan; NTT West Osaka Hospital, Osaka, Japan; Osaka Police Hospital, Osaka, Japan; Higashiosaka City Central Hospital, Osaka, Japan; National Hospital Organization Osaka National Hospital, Osaka, Japan; Suita Municipal Hospital, Osaka, Japan; Kansai Rousai Hospital, Hyogo, Japan; Hyogo Prefectural Nishinomiya Hospital, Hyogo, Japan; National Hospital Organization Osaka Minami Medical Center, Osaka, Japan; Osaka Koseinenkin Hospital, Osaka, Japan; Minoh City Hospital, Osaka, Japan; Osaka Rousai Hospital, Osaka, Japan; Ikeda Municipal Hospital, Osaka, Japan; National Hospital Organization Minami Wakayama Medical Center, Wakayama, Japan.

10/16/09

Reference
N Hiramatsu, T Oze, T Yakushijin, and others. Ribavirin dose reduction raises relapse rate dose-dependently in genotype 1 patients with hepatitis C responding to pegylated interferon alpha-2b plus ribavirin. Journal of Viral Hepatitis 16(8): 586-594. August 2009. (Abstract).