Weight-based Ribavirin Is Superior to the Standard Fixed Dose in Combination with Pegylated Interferon for Treatment of Genotype 1 Hepatitis C

By Liz Highleyman

The current standard of care for the treatment of chronic hepatitis C is a combination of pegylated interferon (Pegasys or PegIntron) plus ribavirin. Although its mechanism of action against hepatitis C virus (HCV) is not fully understood, studies have shown than an adequate dose of ribavirin helps prevent relapse after treatment is completed.

When the pegylated interferon/ribavirin combination was first approved, the usual ribavirin dose was a fixed 800 mg/day. But research suggested this wasn't sufficient, especially for overweight patients, and a standard weight-based dose was approved. Patients who weighed less than 75 kg (about 165 lb) received 1000 mg/day, while heavier patients received 1200 mg/day.

The WIN-R was designed to test fixed versus "true" weight-based ribavirin dosing, allowing higher doses for the heaviest subjects. With just over 5000 previously untreated chronic hepatitis C patients at more than 200 U.S. sites, it was the largest hepatitis C clinical trial to date.

All participants received 1.5 mcg/kg pegylated interferon alpha 2-b (PegIntron) once per week. In addition, they were randomly assigned to received 800 to 1400 mg ribavirin per day, according to body weight:

• < 65 kg (about 140 lb): 800 mg/day;
• 65 to 84 kg (about 185 lb): 1000 mg/day;
• 85 to 104 kg (about 225 lb): 1200 mg/day;
• 105-125 kg (about 275 lb): 1400 mg/day.

Since ribavirin can cause anemia, the dose was reduced if a patient's hemoglobin level fell below 10 gm/dL, and the drug was discontinued if it fell below 8.5 gm/dL. (Normal hemoglobin is 12-15 gm/dL for women and 14-17 gm/dL for men.) However, erythropoietin (Procrit) could be used to manage anemia before dose reduction.

Participants with hard-to-treat HCV genotype 1 (also the few patients with genotypes 4, 5, or 6) were treated for 48 weeks, while those with genotype 2 or 3 were randomized to receive therapy for 24 or 48 weeks.

HCV RNA was measured using a PCR test with a limit of detection of 125 IU/mL. HCV viral load was measured as weeks 24, 48, and 72. Sustained virological response (SVR) was defined as continued undetectable viral load 24 weeks after completion of treatment.

Results were described in 2 reports in the September 2007 issue of Hepatology.

Report 1: Overall Results

In the first report, Ira Jacobson and colleagues provided overall results for the 5,027 total participants enrolled in WIN-R.

Results

• The rate of sustained virological response, but not end-of-treatment response, was significantly higher with weight-based versus flat-dose ribavirin (44.2% vs 40.5%; P = 0.008).

• SVR rates by intention-to-treat analysis were 34.0% and 28.9%, respectively, in patients with genotype 1 (P = 0.005).

• Corresponding SVR rates were 31.2% and 26.7%, respectively, in genotype 1 patients with a high baseline viral load (P = 0.056).

• Among patients with genotype 2 or 3, SVR rates were not significantly different depending on ribavirin dose (61.8% for weight-based and 59.5% for flat-dose), regardless of treatment duration.

• Among these patients, 48-week treatment was not superior to the standard 24-week course.

• Weight-based ribavirin was associated with larger reductions in hemoglobin levels.

• Other than hemoglobin reductions, safety profiles were similar across the ribavirin dose groups, including the 1400 mg/day group.

In conclusion, the study authors wrote, "Pegylated interferon alfa-2b plus weight-based ribavirin is more effective than flat-dose ribavirin, particularly in genotype 1 patients, providing equivalent efficacy across all weight groups."

They added that, "For genotype 2/3 patients, 24 weeks of treatment with flat-dose ribavirin is adequate; no evidence of additional benefit of extending treatment to 48 weeks was demonstrated."

Report 2: African Americans

Research has shown that individuals of African descent do not respond as well as Caucasians to interferon-based therapy for hepatitis C, though the reasons for this remain poorly understood.

Since black patients are harder to treat and thus particularly in need of improved treatment strategies, the WIN-R researchers conducted a sub-analysis of the 362 African American patients with HCV genotype 1 in the study. This was the largest number of black patients ever in a clinical trial of combination therapy for hepatitis C.

Of the 362 African American patients, 188 received flat-dose ribavirin and 174 received weight-based ribavirin (participants were not randomized separately for each racial group).

Results

• SVR rates were higher among patients in the weight-based compared with the fixed-dose ribavirin group (21.0% vs 10.0%; P = 0.0006).

• Relapse rates were lower in the weight-based group (22.0% vs 30.0%).

• Overall safety profiles and rates of drug discontinuation were similar in the 2 dosing groups.

• Weight-based dosing of ribavirin is more effective than flat dosing in combination with pegylated interferon alfa-2b in African American individuals with HCV genotype 1," the authors concluded.

However, they added, "Even with weight-based dosing, response rates in African American individuals are lower than reported in other ethnic groups."

Editorial

Jason Smith and Steven-Huy Han of the Greater Los Angeles Veterans Healthcare Administration Hospital and the David Geffen School of Medicine at the University of California at Los Angeles discussed the results of the 2 WIN-R reports in an accompanying editorial.

The editorial authors compared sustained response rates in WIN-R and past hepatitis C trials, noting that it is difficult to compare results due to differences in study design such as use of erythropoietin to manage anemia and "true" (800-1400 mg/day) versus standard (1000-1200 mg/day) weight-based dosing of ribavirin.

Smith and Han were particularly interested in the results of the subanalysis of black patients. "The most puzzling finding in this WIN-R African American sub-analysis is the independent finding that SVR increased as body weight increased in the 'true' weight-based dosing arm," they wrote. "This is counterintuitive given that the dosing protocol was designed to insure that patients in the true weight-based dosing arm receive equivalent amounts of ribavirin adjusted for weight." The study authors were unable to explain this finding, and further research is required.

"The WIN-R subanalysis of African American patients may not have the power to detect its statistical goal, but it does have the power to change the way we think about ribavirin dosing in African Americans, who will benefit from the awareness derived herein and its translation into more vigilant care of this difficult-to-treat population," Smith and Han continued.

Ultimately, they concluded, it is still unclear whether "true" weight-based dosing is superior to the currently approved standard weight-based dosing. Other possibilities being explored are use of therapeutic drug monitoring to ensure a desired plasma concentration of ribavirin, or adjusting doses based on kidney function (creatinine clearance), since ribavirin is excreted by the kidneys.

But while further studies are needed, "the results of WIN-R are compelling," Smith and Han wrote. "At least 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."

10/16/07

References

IM Jacobson, RS Brown, B Freilich, and others. Peginterferon alfa-2b and weight-based or flat-dose ribavirin in chronic hepatitis C patients: A randomized trial. Hepatology 46(4): 971-981. September 25, 2007 [Epub ahead of print].

IM Jacobson, RS Brown, J McCone, and others. Impact of weight-based ribavirin with peginterferon alfa-2b in African Americans with hepatitis C virus genotype 1. Hepatology 46(4):982-990. September 25, 2007 [Epub ahead of print].

J Smith and SH Han. "True" weight-based dosing versus "flat"dosing of ribavirin: Will the WIN-R please come forward? [Editorial]. Hepatology 46(4): 953-956. September 25, 2007 [Epub ahead of print].