Extended 72-week Treatment with Pegylated Interferon plus Ribavirin Did Not Improve Outcomes among Slow Responder Hepatitis C Patients

By Liz Highleyman

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About half of chronic hepatitis C patients treated with pegylated interferon plus ribavirin do not achieve a cure, or sustained virological response (SVR). In an attempt to improve outcomes, researchers have explored longer treatment duration for selected patients at risk for suboptimal response. But extending therapy to 72 weeks did not increase the response rate for slow responders, according to a study presented at the 44th Annual Meeting of the European Association for the Study of the Liver (EASL 2009) last month in Copenhagen.

The usual course of pegylated interferon (PegIntron or Pegasys) plus ribavirin is 48 weeks for people with hepatitis C virus (HCV) genotypes 1 or 4 and 24 weeks for those with easier-to-treat genotypes 2 or 3 (though many experts recommend 48 for HIV positive people regardless of genotype).

In the SUCCESS trial (Study to Assess Treatment With PegIntron And Rebetol in Naive Patients with Genotype 1 Chronic Hepatitis C and Slow Virological Response) -- sponsored by PegIntron manufacturer Schering-Plough -- an international research team evaluated the effect of extending treatment duration to 72 weeks for genotype 1 patients defined as slow responders.

More than 1400 participants enrolled in this prospective study were treated with 1.5 mcg/kg/week pegylated interferon alfa-2b (PegIntron) plus 800-1400 mg/day weight-adjusted ribavirin. More than half (61%) were men, the mean age was about 43 years, and more than 95% were white. At baseline, about 80% had HCV RNA > 800,000 IU/mL.

Slow response was defined as achieving at least a 2 log drop but still having detectable HCV RNA at week 12 of treatment, but undetectable HCV RNA at week 24. At week 36, slow responders were randomly assigned to continue treatment until they reached a total of either 48 weeks (n = 86) or 72 weeks (n = 73). Complete early virological responders with undetectable HCV RNA at week 12 received treatment for 48 weeks (n = 816). People with less than a 2 log drop in HCV RNA at week 12 stopped therapy, since this is a strong predictor of failure to achieve sustained response.

Results

816 patients (57%) achieved undetectable HCV RNA at week 12 of treatment.

At week 24, 159 patients (11%) were identified as slow responders.

Slow responders had similar response rates whether treated for 48 or 72 weeks, which were significantly lower than the rate for complete early virological responders.

In an intent-to-treat analysis, SVR rates were as follows:

43.0% for slow responders treated for 48 weeks;

47.9% for slow responders treated for 72 weeks;

79.5% for complete early responders treated for 48 weeks.

Relapse rates for the slow responders were 47.1% in the 48-week group and 32.7% in the 72-week group.

Among slow responders who achieved good adherence -- at least 80% of prescribed pegylated interferon and ribavirin doses for at least 80% of the planned treatment duration -- SVR rates were 44.3% in the 48-week group and 57.1% in the 72-week group.

Despite different treatment durations, the frequency of adverse events -- including anemia and depression -- were similar in both slow responder groups.

7.0% of participants in the 48-week arm and 8.2% in the 72-week arm experienced serious adverse events.

The rate of premature treatment discontinuation, however, was higher in the 72-week group than in the 48-week group (23.3% vs 9.3%).

"This, the largest prospective study among genotype 1 slow responders, demonstrated no statistically significant difference between 48 and 72 weeks of treatment," the investigators concluded.

However, they continued, "in these true slow responders, extending [pegylated interferon alfa-2b plus weight-adjusted ribavirin] treatment is associated with better SVR and a similar incidence of adverse events."
"These results are in line with those observed in other [weight-adjusted dose] ribavirin trials in slow responders" they added.

The failure to increase response rates by extending the duration of interferon-based therapy underscores the need for new therapies that work by different mechanisms, such as the various directly targeted "STAT-C" agents -- mostly HCV protease and polymerase inhibitors -- now in development.

Vall d'Hebron Hospital General, Barcelona, Spain; Sourasky Medical Center, Tel Aviv, Israel; Municipal Center of Prophylactic AIDS and Other Infections, St. Petersburg Municipal Center, St. Petersburg, Russia; Clinical Infection Hospital, Moscow, Russia; Hospital of Infectious Diseases, Warsaw, Poland; Medizinische Klinik I, Klinikum der J. W. Goethe Universität Frankfur, Frankfurt, Germany; Vilnius University Hospital of Tuberculosis and Infection Diseases, Vilnius, Lithuania; Schering-Plough Corporation, Kenilworth, NJ.

5/08/09

Reference
M Buti, Y Lurie, NG Zakharova, and others. Extended treatment duration in chronic hepatitis C genotype 1-infected slow responders: final results of the SUCCESS study. 44th Annual Meeting of the European Association for the Study of the Liver (EASL 2009). Copenhagen, Denmark. April 22-26, 2009.

Other Source
Schering-Plough. Schering-Plough Highlights Hepatitis C Clinical Data Presentations at the European Association for the Study of the Liver (EASL) Annual Meeting. Press release. April 27, 2009.

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