Weight-adjusted dosing of ribavirin and importance of hepatitis C virus RNA below 1000 IU/mL by day 7 in short-term peginterferon therapy for chronic genotype 2/3 hepatitis C virus infection


  • Potential conflict of interest: Dr. Lagging is a consultant for and is on the speakers' bureau of Roche. He is a consultant for Schering-Plough and Abbott. Dr. Hellstrand owns stock in, is a consultant for, and holds intellectual property rights for Epicet. Dr. Westin is a consultant for Roche and Schering-Plough. Dr.Christensen advises and received grants from Roche.

Weight-Adjusted Dosing of Ribavirin and Importance of Hepatitis C Virus RNA Below 1000 IU/mL by Day 7 in Short-Term Peginterferon Therapy for Chronic Genotype 2/3 Hepatitis C Virus Infection

To the Editor:

Dalgard and Mangia address an important issue in the treatment of infections with hepatitis C virus (HCV) genotype 2/3, that is, the putative benefit of adjusting the ribavirin dose for weight rather than, as in our NORDynamIC trial, using a fixed dose. The authors specifically point to a higher relapse rate in patients receiving short-term pegylated interferon (peg-IFN) and ribavirin in the NORDynamIC trial than that observed in their own studies.1–3 These divergent relapse rates may reflect a superiority of weight-adjusted dosing of ribavirin, but may also be explained by differences in demographic characteristics of participating patients. For example, 53% of our patients had bridging fibrosis or cirrhosis, compared to 18% in the study by Mangia et al.,3 and 23% in the pilot study by Dalgard et al.1; in the North-C trial, 17% of patients had an aspartate aminotransferase-to-platelet ratio index score >2, indicating significant fibrosis.2

In support of weight-adjusted ribavirin dosing, as proposed by Dalgard et al., the patients in the NORDynamIC trial who achieved sustained virologic response (SVR) after 24 weeks of therapy had a significantly lower body weight than patients not achieving SVR in the per protocol analysis (mean 75.4 kg versus 84.0 kg, P = 0.016, Mann-Whitney U-test), and a similar albeit nonsignificant trend was observed in patients treated for 12 weeks (78.6 kg versus 83.2 kg, P = 0.11). On the other hand, the larger prospectively randomized trial by Hadziyannis et al. noted no such significant differences between 800 mg and standard weight-based dosing (1000 mg or 1200 mg) of ribavirin for patients infected with genotype 2/3 who were treated for 24 or 48 weeks.4

It is conceivable that weight adjustment of the ribavirin dose may be preferable in short-term therapy for genotype 2/3 infection. However, it is of note that in studies utilizing weight adjustment as well as fixed dosing of the ribavirin, patients achieving rapid virologic response had consistently higher SVR rates and lower relapse rates following standard 24 weeks of therapy compared to patients who had 12-16 weeks of therapy.2, 5, 6 We wish to point out, however, that the NORDynamIC trial identified patients in whom short-term treatment appeared to be acceptably efficacious, that is, the group of patients infected with genotype 2/3 with HCV RNA below 1000 IU/mL already by day 7 (that is, immediately prior to the second dose of peg-IFN). In these patients (which constituted 30% of the intention-to-treat population), 12 weeks of combination therapy using a fixed dose of 800 mg ribavirin daily yielded SVR rates of 92% and 90% in the intention-to-treat analysis in the 12-week and 24-week arms, respectively, and in the per protocol analysis, the SVR rates were 97% and 98% (Fig. 1). Short-term treatment thus appears to be suitable as a response-guided therapy for patients infected with genotype 2/3 with a very rapid virologic response, especially if they are adherent to combination therapy.

Figure 1.

Histogram displaying the percent of patients with HCV RNA below 1000 IU/mL by day 7 who achieved (gray bars) or did not achieve (black bars) SVR; 360 patients in the intention-to-treat analysis and 286 patients in the per protocol analysis had plasma HCV RNA samples available by day 7.

Martin Lagging*, Nina Langeland†, Court Pedersen‡, Martti Färkkilä?, Mads Rauning Buhl?, Kristine Mørch†, Amar P. Dhillon**, Åsa Alsiö*, Kristoffer Hellstrand*, Johan Westin*, Peer Christensen‡, Peter Leutscher?, Gunnar Norkrans*, * Department of Infectious Diseases, Göteborg University, Göteborg, Sweden, † Department of Infectious Diseases, Haukeland University Hospital and Institute of Medicine, University of Bergen, Bergen, Norway, ‡ Department of Infectious Diseases, University of Southern Denmark, Denmark, ? Department of Gastroenterology, Helsinki University, Helsinki, Finland, ? Department of Infectious Diseases, Aarhus University, Aarhus, Denmark, ** Department of Histopathology, Royal Free Hospital, London, UK.