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Pegylated interferon alpha2a is more effective in some hepatitis C patients with specific genotypes than the alpha2b form of the drug, an Italian researcher said here.

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Pegylated interferon plus ribavirin is the standard of care for HCV, but the two versions of the interferon have substantial differences, noted Maria Grazia Rumi, M.D., of Maggiore Hospital at the University of Milan.

The differences are in size, structure of the molecules, pharmacokinetics, and biologic activity, and it had not been known whether they have the same efficacy and safety profiles, she told the American Association for the Study of Liver Diseases meeting.

To find out, she and colleagues conducted the randomized open-label Milan Safety Tolerability (MIST) study from September 2003 through March 2007. They randomized 212 patients to the alpha2a form and 219 to the alpha2b form. They were stratified by genotype, and got fixed doses of ribavirin and alpha2a interferon, but weight-based doses of the alpha2b form for 48 weeks.

The efficacy endpoint was sustained virological response six months after the end of treatment, she said.

There were no significant differences in hematological disorders or common adverse events between the two arms of the study, Dr. Rumi said.

On the other hand, the alpha2a form showed a clear advantage in efficacy:

• Six months after treatment ended, 66% of patients getting the apha2a form had a sustained virological response, compared with 54% for alpha2b, which was significant at P=0.02.

• At end of treatment, 78% of the alpha2a patients had responded, compared with 67% of the others, which was significant at P=0.009.

• And 80% of the alpha2a patients had an early virological response, compared with 69%, which was significant at P=0.01.

• There was no difference in rapid virological response.

• No serious adverse events (AEs) were reported and there were no discontinuations due to AEs.


"These high response rates in a difficult-to-treat patient population suggest that combination therapy featuring R7128 deserves further exploration in both treatment-naive and non-responsive genotype 2/3 patients with HCV," they concluded.

Race/ethnicity and Weight

In a related study, investigators performed a sub-analysis of 2 cohorts (n = 25 each) of genotype 1 patients in the same study, looking at differences in response according to race/ethnicity and weight. Cohort 1 received 500 mg twice-daily R7128 or placebo while Cohort 2 received 1500 mg twice-daily R7128 or placebo, all with plus pegylated interferon/ribavirin.

Among the 50 subjects randomized into these 2 cohorts, 48% were white, 24% were Latino, 16% were African-American, and 8% were classified as "other." 54% of whites, 33% of Latinos, 38% of African-Americans, and 75% of "other" patients weighed > 85 kg. Proportions with body mass index (BMI) > 30 were 15%, 42%, 25%, and 25%, respectively.

When the researchers broke out the genotypes separately, they found significant benefits of the alpha2a form for patients with genotypes one and two, but not for three and four, she said.

The bottom line, Dr. Rumi said, is that at her institution, patients with genotypes one and two are now treated only with the alpha2a form of the interferon.

The researchers are planning larger trials to see whether they can improve outcomes for patients with the other two genotypes, she said.

U.S. clinical trials have consistently shown the drugs to be equivalent and Dr. Rumi's results may be partly explained by differences in study populations, according to Tarek Hassanein, M.D., of the University of California at San Diego, who was not involved in the study but moderated the session at which it was presented.

He noted that the average body weight of volunteers in the study was about 70 kg and their average body mass index was about 26.

"This is not what we see in the U.S., where the weight (in clinical trials) was 80 to 85 kg and the BMI was about 30," he said. "These are totally different types of populations."

He added that about the midpoint of the study, clinicians began widely using weight-based dosing to administer ribavirin. He said he would be interested to see whether the results changed before and after that point.

Co-moderator Reem Ghalib, M.D., of Methodist Health System in Dallas, said it may be too early to throw out the alpha2b form of the compound.

"We really need to see the final paper before making any conclusions," she said.

Dr. Ghalib noted that "all the clinical trials in this country have shown them to be equivalent" and in her clinical practice she makes no distinction -- "not yet."
 

Primary source: Hepatology
Source reference:
Rumi M, et al "Randomized study comparing Peginterferon-alfa2a plus Ribavirin and Peginterferon-alfa2b plus Ribavirin in nave patients with chronic hepatitis C: final results of the Milan Safety Tolerability (MIST) study" Hepatology 2008; 48(4): Abstract 212.

 


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