To the Editor:
In Paul Bellman's letter regarding our recent review article,1 he raises an important issue regarding the potential of epoetin alfa to induce thrombotic vascular events (TVEs) and to have an adverse impact on survival. This phenomenon was observed in several studies exploring the investigational use of recombinant human erythropoietin in cancer patients in whom hemoglobin (Hb) levels rose beyond the usual target of 12 g/dL. Epoetin alfa and beta products were both involved. The US Food and Drug Administration (FDA) held an Oncology Drug Advisory Committee (ODAC) meeting on May 4, 2004 to review this issue. Ortho Biotech Products, LP (OBP), along with the manufacturers of other erythropoietin products, worked closely with the FDA to ensure that the product labeling for all erythropoietin products included appropriate information regarding the benefits and risks for patients. Amgen and OBP, distributors of erythropoietin products in the United States, issued letters to health care professionals advising them of the important safety information regarding TVEs and survival.2,3 In addition, to ensure consistency with labeling for other products in the class, changes to Hb rate of rise and target levels were made to the epoetin alfa prescribing information.4 Mention of this issue was not included in our article because the ODAC discussion was ongoing while the manuscript was in press.
The dosage and administration of epoetin alfa in HIV-infected patients treated with zidovudine was not affected by the outcome of the ODAC meeting. The product label for HIV-infected patients recommends that treatment be discontinued if Hb exceeds 13 g/dL and resumed only after Hb drops to 12 g/dL. The dose should be reduced by 25% when treatment is resumed and then titrated to maintain the desired Hb level.
Dr. Bellman also points out that the dyslipidemia associated with the use of highly active antiretroviral therapy (HAART) could theoretically put HIV patients who are treated with epoetin alfa at greater risk of developing thrombotic complications; however, our review of the literature did not yield any such reports despite the widespread use of epoetin alfa in patients on HAART regimens.
Dr. Bellman further states that we have provided recommendations in our article to the effect that epoetin alfa therapy should be used to achieve Hb levels >12 g/dL. In fact, we made no such recommendations. Our intent was to review the medical literature and to report accurately the results of published trials that have furthered our understanding of anemia in the HIV population and the role of epoetin alfa therapy. Dr. Bellman may have misinterpreted the definitions of anemia used in epidemiologic studies as guidance for the management of patients in his practice. The reference that he cites describing the safety of epoetin alfa in HIV-infected patients refers to a report of 4 placebo-controlled trials. To our knowledge, this report represents the only published placebo-controlled trials of epoetin alfa in HIV patients. Subsequent trials of epoetin alfa examining different dosing strategies have confirmed that the adverse event profile of epoetin alfa is generally consistent with those described in the prescribing information.5,6
Dr. Bellman is correct in his observation that speculation regarding future uses of epoetin alfa in the HIV-infected population mentioned in our review was largely supported by data derived from animal models, and this is clearly delineated in the article. We reviewed these data to satisfy the basic science interests of the readers of the Journal of Acquired Immune Deficiency Syndromes and to suggest potential areas for future research.
The balance of Dr. Bellman's commentary refers to publications outside the scope of our review. He suggests that the authors have not provided adequate disclosure of their relationships with commercial interests. The authors disagree with Dr. Bellman's opinion and have disclosed any potential conflict. They, furthermore, were not involved in the selection of this article for publication. We can assure Dr. Bellman that our research interests and publications are driven by the desire to optimize the care of our HIV patients.
David H. Henry, MD*
Paul A. Volberding, MD†
Gerhard Leitz, MD, PhD‡
*Pennsylvania Hospital Philadelphia, PA †University of California, San Francisco San Francisco, CA ‡Ortho Biotech Clinical Affairs, LLC Bridgewater, NJ
1. Henry DH, Leitz G, Volberding PA. Epoetin alfa for treatment of anemia in HIV-infected patients: past, present, and future. J Acquir Immune Defic Syndr
2. Kamin M. Dear health care professional. Bridgewater, NJ: Ortho Biotech Clinical Affairs, Ortho Biotech LLC. August 13, 2004.
3. Baynes R. Dear health care professional. Amgen Inc, Thousand Oaks, CA. January 11, 2005.
4. Procrit prescribing information. Bridgewater, NJ: Ortho Biotech, LLC. 2004.
5. Grossman HA, Goon B, Bowers P, et al. for the 010 Study Group. Once-weekly epoetin alfa dosing is as effective as three times-weekly dosing in increasing hemoglobin levels and is associated with improved quality of life in HIV-infected patients. J Acquir Immune Defic Syndr
6. Saag MS, Bowers P, Leitz GJ, et al, for the Community HIV Anemia Management Protocol Sites (CHAMPS) Study Group. Once-weekly epoetin alfa improves quality of life and increases hemoglobin in anemic HIV+ patients. AIDS Res Hum Retroviruses