Eltrombopag for Thrombocytopenia in Cirrhotic Patients with HCV

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Summary and Comment

Eltrombopag for Thrombocytopenia in Cirrhotic Patients with HCV

A thrombopoietin agonist raises platelet counts in HCV-positive patients who are undergoing antiviral therapy.

Cirrhotic patients who are infected with hepatitis C virus (HCV) often experience thrombocytopenia as a result of the combination of portal hypertension–induced splenomegaly, decreased thrombopoietin production, and virus-mediated bone-marrow suppression. Thrombocytopenia can worsen during interferon-based therapy because of the bone marrow–suppressive effects of interferon. No effective platelet growth factor therapy is available to treat such thrombocytopenia episodes, so interferon therapy in cirrhotic HCV patients is problematic. In a new study, researchers evaluated the efficacy and safety of eltrombopag (a small, nonpeptide, oral platelet growth factor that acts as a thrombopoietin-receptor agonist) in HCV-positive cirrhotic patients with substantial thrombocytopenia.

In this industry-sponsored, multinational, double-blind, randomized phase II trial, researchers investigated the ability of eltrombopag to increase platelet counts and allow initiation of pegylated interferon- ${alpha}$ (peginterferon) and ribavirin therapy in cirrhotic HCV-positive patients with baseline platelet counts between 20,000 and 70,000 cells/mm³. Four groups of patients received daily eltrombopag (30 mg, 50 mg, or 75 mg) or placebo for 4 weeks. Then, in patients whose platelet counts rose to prespecified levels ( $≥$ 70,000 cells/mm³ for interferon alfa-2a and $≥$ 100,000 cells/mm³ for interferon alfa-2b, based on FDA labeling), peginterferon plus ribavirin was initiated, in addition to study medication, for 12 weeks. The primary endpoint analyzed was increase in platelet count from baseline to $≥$ 100,000 cells/mm³. Researchers planned to enroll 160 patients; however, during the second interim analysis, a prespecified difference in eltrombopag versus placebo was attained, and the study was stopped after 74 patients were enrolled.

At week 4, platelet counts of $≥$ 100,000 cells/mm³ were achieved by 95% of evaluable patients (21 of 22) in the 75-mg group, 79% (15 of 19) in the 50-mg group, 75% (9 of 12) in the 30-mg group, and 0% (0 of 18) in the placebo group (each treatment group vs. placebo, P<0.001). Peginterferon therapy (with either interferon) was initiated in 49 patients. Although platelet counts dropped during peginterferon therapy, they remained consistently above baseline and allowed for completion of 12 weeks of peginterferon therapy in 65%, 53%, and 36% of patients who received 75 mg, 50 mg, and 30 mg of eltrombopag (vs. 6% in the placebo group). Headache was the most common adverse event reported within the first 4 weeks in all groups; thereafter, adverse events were no different from those expected with peginterferon therapy alone.

Comment: This trial suggests that eltrombopag, especially at a daily dose of 75 mg, is effective in raising platelet counts in cirrhotic HCV-positive patients, and it seems to be safe. Although platelet counts dropped after initiation of peginterferon therapy, despite continuation of eltrombopag, most patients were able to complete 12 weeks of antiviral treatment. A phase III trial that will continue to define eltrombopag’s efficacy and safety in this patient group has just begun.

— Atif Zaman, MD, MPH

Published in Journal Watch Gastroenterology November 28, 2007