“True” weight‐based dosing versus “flat” dosing of ribavirin: Will the WIN‐R please come forward?

Since the introduction of ribavirin in combination with interferon for the treatment of chronic infection with hepatitis C virus (HCV), the optimal dose of ribavirin has become the Holy Grail for investigators interested in slaying HCV. Prior to 2001, flat doses (FDs) of ribavirin (800 mg daily) were used in combination with interferon alfa-2b or interferon alfa-2a. The concept of weight-based dosing (WBD) of ribavirin originated from a retrospective finding in the pivotal trial of Manns et al.1 The authors found that patients receiving 10.6 mg/kg body weight of ribavirin in combination with peginterferon alfa-2b were more likely to respond to therapy. They postulated that dosing ribavirin according to the patient’s total body weight would improve sustained virological response (SVR). Indeed, subsequent studies2,3 revealed improved SVR in genotype 1 patients receiving ribavirin according to a “standard” WBD scheme (that is, 1000 mg daily for patients weighing 75 kg and 1200 mg daily for patients weighing 75 kg). Further studies examining WBD of ribavirin have used a similar “standard” WBD scheme.4-6 However, the concept of “true” WBD of ribavirin over multiple or continuous weight ranges remained unproven. Accordingly, currently approved therapies recommend “standard” WBD of ribavirin in combination with peginterferon alfa-2a or alfa-2b. The idea of increasing the dosage of ribavirin has been studied in other ways since the registration trials. A recent pilot study of 10 chronic HCV patients investigated ribavirin dosing determined by measuring serum ribavirin concentrations rather than dosing according to body weight.7 Very high doses of ribavirin were administered to achieve a steady-state plasma concentration of 15 mol/L of ribavirin (equivalent to an average 2540 mg ribavirin/ day, with a range of 1600-3600 mg/day). This concentration was chosen empirically based on the knowledge that a standard daily dose of 800-1200 mg ribavirin would result in a plasma concentration of 8.2 mol/L. An SVR was achieved in an impressive 9 of 10 patients, although 2 patients required red blood cell transfusions and all required growth factors. Another alternative to dosing ribavirin explored adjusting ribavirin dose to creatinine clearance. This approach is based on the observation that ribavirin is predominantly excreted renally. Separate investigators studied population-based ribavirin pharmacokinetics in relation to renal function. Bruchfeld et al.8 found that ribavirin clearance was linearly dependent on renal function. They proposed a ribavirin dosing scheme based mainly on renal function and body weight. However, conflicting data was reported by Wade et al.9, who could not find an association between ribavirin concentration and creatinine clearance, except possibly at creatinine clearance rates 34 mL/minute. Therefore, further research will be necessary before creatinine clearance– based dosing of ribavirin can be recommended. During the time that WBD of ribavirin was evolving, a tandem quandary was challenging investigators in regards to the observation that interferon therapy for chronic HCV infection was not as effective in African American patients as compared to Caucasian patients. In their seminal article from 1999, Reddy et al.10 retrospectively analyzed data from a large consensus interferon trial. When compared to Caucasian patients, African American patients treated for the same duration with consensus interferon monotherapy achieved a lower end-of-treatment response and SVR (end-of-treatment 5% versus 33%, P 0.04 and SVR 2% versus 12%, P 0.07). They hypothesized that the lower response rates seen in African American patients were attributable to a significantly greater number of genotype 1 African American versus Caucasian patients in their study (88% versus 66%, P 0.004). Shortly thereafter, the National Institutes of Health (NIH) responded to the growing body of evidence indicating lower SVRs in African American patients with HCV infection11 by organizing a workshop designed to enumerate the discrepancies between Caucasian and African American patients in order to facilitate the development of strategies directed toward a solution. Results from 5 trials (1 NIH trial and 4 published trials) were reviewed with respect to their African American representation (Table 1). 11-14 The understanding gained from this workshop cast a light on the disparity between HCV infections in African American versus Abbreviations: FD, flat dose; HCC, hepatocellular carcinoma; HCV, hepatitis C virus; NIH, National Institutes of Health; SVR, sustained virologic response; WBD, weight-based dosing. Address reprint requests to: Steven-Huy Han, M.D. AGAF, Pfleger Liver Institute, 200 UCLA Medical Plaza, Suite 214, Los Angeles, CA 90095. E-mail: steven.han@ucla.edu; fax: 310-206-4197. Copyright © 2007 by the American Association for the Study of Liver Diseases. Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/hep.21890 Potential conflict of interest: Nothing to report.