Weight-based dosing of ribavirin improves outcomes for patients with hepatitis C

Patients with hepatitis C treated with combination therapy of pegylated interferon and ribavirin had better outcomes when taking a weight-based dosage of ribavirin compared to a flat dosage.

This treatment technique also improved the response rates of African American patients, whose outcomes have lagged behind those of Caucasian patients. These findings are in the October issue of Hepatology, a journal published by John Wiley & Sons on behalf of the American Association for the Study of Liver Diseases (AASLD). The articles and an accompanying editorial are also available online at Wiley Interscience (http://www.interscience.wiley.com/journal/hepatology).

Combination therapy of pegylated interferon and ribavirin is the standard of care for patients with chronic hepatitis C, allowing more than half to achieve a sustained viral response. However, previous studies have suggested that a weight-based dose of ribavirin might lead to even better results. To examine this possibility, researchers, led by Ira Jacobson of Cornell University, conducted a large, multi-center, randomized, prospective, open-label study between December 2000 and June 2005.

They enrolled 5,027 patients with hepatitis C from more than 200 centers around the country. All participants were 18 to 70 years old, weighed less than 125 kg, had detectable HCV RNA in their blood, and had never been treated for it. They were randomly assigned to receive interferon and a flat dose of ribavirin (800 mg/day), or interferon and a weight-based dose of ribavirin, which started at 800 mg/day for patients weighing under 65 kg, and increased by 200 mg/day for up to each additional 20 kg of weight up to a maxiumum dose of 1400 mg. Those with HCV genotype 2 or 3, which is more responsive to interferon-based therapy, also tested treatment durations of 24 and 48 weeks. Each patient was followed up for 24 weeks after treatment.

“A sustained viral response was achieved by significantly more patients who received a weight-based dose (44.2 percent) than fixed dose (40.5 percent) ribavirin,” the authors report. “Overall, response rates decreased as weight increased when a fixed dose was used but remained unaltered with a weight-based dose.” Discontinuation rates and reported adverse events did not differ significantly between the two treatment schemes, and relapse rates were lower for patients who had received weight-based dosing. The researchers also found that 48 weeks of treatment offered no additional benefit compared to 24 weeks for patients with genotypes 2 or 3..

Another group of researchers from the same study, also lead by Jacobson, used the study data to understand the impact of weight-based ribavirin with peginterferon alfa-2b in African American patients with HCV genotype 1. Genotype 1 is the hardest to treat, and it afflicts African Americans disproportionately.

Three hundred eighty seven African American patients with genotype 1 were included in the analysis: of those weighing 65 kg or more, and therefore receiving different doses of ribavirin in each arm, 188 had received flat-dose ribavirin, and 174 had received weight-based dosing. Significantly fewer patients in the flat-dose group (10 percent) attained a sustained virological response, compared to 21 percent in the flat-dose group. Relapse rates were 30 percent and 22 percent, respectively.

“An unexpected finding of our study was the increase in efficacy with an increase in ribavirin dose in heavier patients,” the authors report. That is, sustained viral response rates increased as body weight increased, suggesting that “ribavirin distribution may be more complex than realized and body weight may only approximate the marker for size required to dose RBV consistently,” the authors say.

In conclusion, weight-based dosing of ribavirin offered a significant advantage in efficacy of treatment for African American patients, however, the rate of sustained viral response in this population remains low. “Further studies are needed to elucidate the fundamental basis for the impaired responsiveness in this population,” they say.

In an accompanying editorial, Steven-Huy Han, MD and Jason Smith, PharmD of Los Angeles, report that this study adds significantly to our understanding of interferon therapy in African American patients. It will change the approach to ribavirin dosing and will benefit a difficult-to-treat population.

They suggest that the larger question of whether true weight-based dosing of ribavirin is superior to the currently approved standard dosing schemes still awaits head-to-head studies to answer. “At the minimum,” they conclude, “the traditional notion that ribavirin dosage should be fixed has now been sidelined by the idea that we should tailor ribavirin dosing to our patients.”