Recombinant erythropoietins have been proven valuable in the treatment of patients with anemia caused by chronic kidney failure and certain types of cancer chemotherapy. These erythropoiesis-stimulating agents have also been proven beneficial in patients with human immunodeficiency virus infection whose anemia is caused by zidovudine, and in reducing the number of transfusions in patients scheduled for certain major surgeries. Granulocyte colony-stimulating factor (G-CSF) and granulocyte-macrophage colony-stimulating factor (GM-CSF) are indicated for neutropenia in patients with certain malignancies receiving chemotherapy, patients undergoing bone marrow transplantation, patients undergoing peripheral blood progenitor cell collection, and patients with severe chronic neutropenia.
Recently, Thévenot et al.1 reported that in France 46% of practitioners use erythropoietins and 31% use G-CSF in patients with chronic hepatitis C who develop anemia or neutropenia while being treated with an interferon and ribavirin. Although precise data are not available for the United States, the numbers are likely to be similar. In fact, the American Association for the Study of Liver Disease (AASLD) 2004 practice guidelines for the treatment of hepatitis C state that growth factors can be used for treatment-associated anemia (epoetin) and leukopenia (G-CSF, GM-CSF) and may limit the need for antiviral dose reductions in patients with decompensated cirrhosis.2 However, use of erythropoiesis-stimulating agents, and G-CSF and CM-CSF, have never been shown to improve the chances of achieving a sustained virological response in patients with chronic hepatitis C who develop anemia or neutropenia during treatment. The AASLD even acknowledges that its guideline is supported only by “Grade III” evidence, which is merely an opinion of “respected authorities” or descriptive epidemiology.2
On March 9, 2007, based on data obtained in large clinical trials, the U.S. Food and Drug Administration (FDA) issued a Public Safety Advisory on the potential dangers of erythropoiesis-stimulating agents.3 A “black box” warning was also added to the labels of these drugs noting serious cardiovascular and arterial and venous thromboembolic events as well as other adverse events. On May 14, 2007, based on the FDA's advisory, the U.S. Centers for Medicare and Medicaid Services announced its proposed decision to limit coverage of erythropoiesis-stimulating agent treatment for beneficiaries with certain cancers and related neoplastic conditions.4
In light of the new safety concerns and the FDA's recent action, the “off-label” use by hepatologists of erythropoiesis-stimulating agents, as well as G-CSF and GM-CSF, in patients being treated for hepatitis C should be re-evaluated. The AASLD should take a lead role by re-evaluating its own practice guidelines. Based on the lack of efficacy and clear-cut safety data in patients being treated for hepatitis C, the only prudent recommendation at this time may be to use these agents only in approved clinical trials, ideally those with a meaningful endpoint, such as the chance of achieving a sustained virological response.