Weight-based Ribavirin Is Superior to the Standard Fixed Dose in Combination wit

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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 son 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

and -Huy Han of the Greater Los Angeles Veterans

Healthcare Administration Hospital and the 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.

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, " 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, " 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