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EASL 2012: Ribavirin Dose Reduction Is Effective for Managing Anemia in Patients Using Boceprevir or Telaprevir

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Reducing the dose of ribavirin and adding erythropoietin are both good options for managing anemia in hepatitis C patients treated with boceprevir (Victrelis) triple therapy, according to study findings presented at the 47th International Liver Congress (EASL 2012) this week in Barcelona. A related study found that ribavirin reduction also did not impair cure rates with telaprevir (Incivek).

Approval of the first direct-acting antiviral agents has brought about a new era in chronic hepatitis C treatment. While many people look forward to interferon-free regimens, others need treatment now and can benefit from the first-generation HCV protease inhibitors -- boceprevir or telaprevir -- added to pegylated interferon plus ribavirin.

Triple therapy raises the likelihood of a cure and offers the potential for shorter treatment, but it also increases side effects such as anemia (low red blood cell or hemoglobin levels). Various approaches are used to manage anemia including reducing the dose of ribavirin, adding erythropoietin (EPO; brand names Epogen and Procrit) to stimulate red blood cell production, and blood transfusion. Ribavirin dose reduction is risky for patients on interferon dual therapy since it helps lessen the likelihood of post-treatment relapse.

Boceprevir

Fred Poordad from Cedars-Sinai Medical Center and colleagues compared ribavirin dose reduction and EPO as anemia management strategies for patients receiving boceprevir with pegylated interferon and ribavirin. Anemia is a notable side effect of boceprevir, which raises concerns for combination therapy because ribavirin can also cause anemia.

The study included 687 treatment-naive patients with HCV genotype 1 enrolled in a multinational, open-label trial. About two-thirds were women, 77% were white, and the mean age was 49 years.

Participants received pegylated interferon alfa-2b (PegIntron) plus 600-1400 mg/day weight-adjusted ribavirin for a lead-in period of 4 weeks, then added 800 mg boceprevir 3-times-daily for 24 or 44 weeks, depending on HCV RNA levels at week 8.

Baseline hemoglobin levels were 12-15 g/dL for women or 13-15 g/dL for men. Participants who developed anemia -- defined as hemoglobin < 10 g/dL -- or were expected to soon reach that level were randomly assigned to reduce their ribavirin dose by 200-400 mg/day or add 40,000 units/week subcutaneous injections of EPO. If hemoglobin fell to 8.5 g/dL, secondary methods of anemia management could be added. If it dropped to 7.5 g/dL, treatment was discontinued.

The primary endpoint was sustained virological response (SVR), or continued undetectable HCV viral load after completion of treatment.

Results

  • A total of 500 patients (about 73%) developed anemia during treatment.
  • SVR rates were comparable for patients randomized to ribavirin dose reduction and those taking EPO, at 71% for both groups.
  • 10% of patients in both groups relapsed after treatment.
  • In a multivariate analysis, ribavirin dose reduction vs EPO was not a significant predictor of treatment success.
  • Serious adverse events occurred with similar frequency in both arms, 16% with ribavirin dose reduction and 13% with EPO.
  • Discontinuation rates due to any adverse event were also similar, 11% and 13% respectively.
  • 2.0% and 2.4%, respectively, stopped treatment due to anemia.

"Early ribavirin dose reduction did not negatively impact SVR compared with early EPO use," the investigators concluded. "These data support ribavirin dose reduction for primary anemia management."

Telaprevir

A related retrospective analysis by Mark Sulkowski from Johns Hopkins School of Medicine and colleagues looked at outcomes among patients who developed anemia in pivotal trials of telaprevir.

The Phase 3 ADVANCE and ILLUMINATE trials evaluated telaprevir triple therapy in treatment-naive genotype 1 chronic hepatitis C patients, while REALIZE looked at prior non-responders and relapsers. Control arms i all studies received pegylated interferon/ribavirin alone.

Telaprevir is not as likely as boceprevir to cause anemia -- its notable side effect is skin rash -- but anemia rates among people on telaprevir triple therapy were higher than those for patients taking pegylated interferon/ribavirin dual therapy.

Results

  • Among treatment-naive patients, half of those taking telaprevir triple therapy had a ribavirin dose reduction compared with 18% of those on pegylated interferon/ribavirin alone.
  • 45% and 11%, respectively, received < 600 mg/day of ribavirin while on triple therapy.
  • Ribavirin dose reduction did not negatively affect the likelihood of treatment success, with the following SVR rates:
    • 79% with telaprevir triple therapy and 46% with pegylated interferon/ribavirin among patients who never reduced their ribavirin dose;
    • 75% and 54%, respectively, among those who used 800-1000 mg/day ribavirin;
    • 74% and 42%, respectively, among those who used < 600 mg ribavirin.
  • Turning to the more challenging treatment-experienced group, 39% of prior relapsers, 31% of prior partial responders, and 18% of prior null responders taking triple therapy reduced their ribavirin dose, compared with 19%, 26%, and 19%, respectively, taking pegylated interferon/ribavirin alone.
  • Again, ribavirin dose reduction did not have a detrimental affect on SVR rates:
    • Prior relapsers:
      • 82% with triple therapy and 20% with pegylated interferon/ribavirin among patients who never reduced their ribavirin dose;
      • 84% and 29%, respectively, among those who used 800-1000 mg/day ribavirin;
      • 90% and 33%, respectively, among those who used < 600 mg ribavirin.
    • Prior partial responders:
      • 62% and 20%, respectively, among people who never reduced their ribavirin dose;
      • 50% and 0%, respectively, among those who used 800-1000 mg/day ribavirin;
      • 62% and 0%, respectively, among those who used < 600 mg ribavirin.
    • Prior null responders:
      • 31% and 3%, respectively, among people who never reduced their ribavirin dose;
      • 50% and 0%, respectively, among those who used 800-1000 mg/day ribavirin;
      • 22% and 25%, respectively, among those who used < 600 mg ribavirin.

"In treatment-naive and previously treated patients who received telaprevir combination treatment, ribavirin dose reduction was more frequent than in the control group," the researchers concluded. "Ribavirin dose reduction, including dose reduction to < 600 mg/day, had no substantial effect on SVR rates in patients treated with telaprevir combination treatment."

Taken together, these studies indicate that the extra potency of HCV protease inhibitors helps overcome the tendency to relapse among patients who take inadequate ribavirin in dual therapy with pegylated interferon.

In his summary of research highlights on the final day of the conference, Jean-Michel Pawlotsky from the University of Paris said these findings "validate the use of ribavirin dose reduction" rather than adding the expense of EPO to an already costly regimen.

5/8/12

References

FF Poordad, EJ Lawitz, KR Reddy, et al. A Randomized Trial Comparing Ribavirin Dose Reduction versus Erythropoietin for Anemia Management in Previously Untreated Patients with Chronic Hepatitis C Receiving Boceprevir plus Pginterferon/Riba. 47th International Liver Congress (EASL 2012). Barcelona, April 18-22, 2012. Abstract 1419.

M Sulkowski, S Roberts, N Afdhal, et al. Ribavirin Dose Modification in Treatment-naive and Previously Treated Patients who Received Telaprevir Combination Treatment: No Impact on Sustained Virologic Response in Phase 3 Studies. 47th International Liver Congress (EASL 2012). Barcelona, April 18-22, 2012. Abstract 1162.

Other Source

Merck. Merck Reports Phase III Study Results Evaluating Anemia Management Strategies Used With Victrelis (boceprevir) Combination Therapy. Press release. April 19, 2012.