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JAIDS Journal of Acquired Immune Deficiency Syndromes:
Letters to the Editor

Epoetin Alfa for Treatment of Anemia in HIV-Infected Patients

Bellman, Paul MD

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St. Vincent's Hospital, New York, NY

To the Editor:

As a subscriber to the Journal of Acquired Immune Deficiency Syndromes and a physician with an HIV practice in New York City, I rely on your journal as an important source of clinical information. I count on your peer review, disclosure, and editorial policies to ensure that the articles are not biased by hidden concerns or agendas, particularly by the profit interests of pharmaceutic companies. I read with interest your lead article in the October 2004 issue,1 hoping to learn more and be updated about this condition and to apply that knowledge to treating my patients.

The article contained many references to the potential for erythropoietin (EPO) to have expanded off-label uses for the treatment of HIV-infected patients, such as preventing transmission, increased survival, reduced sensory neuropathy, improved cognitive-motor function,2 correcting hypogonadism,3 reducing retinal pathologic changes in patients with cytomegalovirus (CMV) retinitis,4 and improving sexual function.1 None of these speculations were supported by clinical data but rather by the discovery that endogenous EPO is a widely distributed pleiotropic hormone,5 suggesting new therapeutic applications. Some in vitro studies were referenced regarding these speculations.

I was surprised that this discovery did not also cue the authors to raise concern regarding the potential that the pleiotropic hormonal nature of EPO could lead to unexpected side effects. I was even more concerned when the only reference to side effects in the article was referenced to 19926 and said, “In clinical practice, epoetin alfa is well tolerated. Most adverse effects reported in clinical trials with HIV-infected patients are consistent with the disease process and not considered treatment related.”1

In fact there is an extensive literature in the field of kidney disease and cancer regarding the potential for EPO to increase morbidity and mortality in some patients. This has led to US Food and Drug Administration (FDA)-mandated warning letters for physicians not to exceed hemoglobin levels of 12 with EPO therapy because of the increased risk of thrombotic complications.7,8 This was not mentioned in the article, nor was it clarified that the studies showing no treatment-related side effects with EPO were done before the era of highly active antiretroviral therapy (HAART) in zidovudine (AZT)-treated patients with low hemoglobin levels, already with a high morbidity and mortality rate from their underlying disease process.

Unfortunately, with the success of today's HAART regimens has come the lipodystrophy metabolic syndrome that puts current patients at much higher risk than pre-HAART patients for thrombotic complications. No mention was made of research in the cited article showing that it is safe to exceed FDA-approved target hemoglobin levels in today's patient prescribed HAART, and I have been unable to find such research in my own review of the literature.

I would have expected this point to be raised in the cited article and perhaps even highlighted as an important area for further study, but it was not. Why not? I am not sure, but the following facts concern me, and I believe that they should be brought to the attention of your readership.

The lead author of this article in the October 2004 issue, Paul Volberding, is the Clinical Editor-in-Chief of the Journal of Acquired Immune Deficiency Syndromes itself as well as a member of the Advisory Board of Ortho Biotech Products, LP, the company that sells epoetin alfa in the United States to HIV-infected patients. In addition to receiving speaking fees from Ortho Biotech Products, Dr. Volberding is the Chair of something called the “Anemia in HIV Working Group.” This group was described by Dr. Volberding in an article he wrote for the journal Clinical Infectious Diseases in May 2004 as an “expert panel to assess new data and translate these into evidenced-based treatment guidelines”9 to help physicians better treat anemic HIV-infected patients.

In this article, which is referenced in the article in J Acquired Immune Defic Syndr 2004;37(2):1221-1227, he issues guidelines advising that treatment be initiated in HIV male patients with hemoglobin levels as high as 13. At a hemoglobin level of 15, it is advised to stop therapy, which is substantially above the FDA-approved stopping point of 12. He also advises initiating EPO for any HIV-infected patient with uncorrectable anemia.9 Adopting these recommendations would involve a lot of off-label use of EPO, which is currently FDA approved only for AZT-caused anemia and only until target hemoglobin levels of 12 are reached.10

The upward adjustment of the threshold, target, and maximal hemoglobin levels was noticed by John G. Bartlett, current Co-Chair of the Department of Health and Human Services (DHHS) Guidelines Panel, who commented on the Journal of Acquired Immune Deficiency Syndromes article in the on-line site, the Hopkins Report, that “the review and prior recommendations are possibly biased by the author affiliations with the company that produces EPO, not so much for the recommendations for its use, but for the relatively high HGB levels suggested (after HAART) for its use 12 G/DL in women and 14 G/DL in men.”7 He also noted that at the “high doses recommended the weekly cost of the medicine was double that of HAART.”11

Finally, there is an additional point that I believe should have been brought to the readers' attention in the Journal of Acquired Immune Deficiency Syndromes and Clinical Infectious Diseases articles. According to Gerhard Leitz, an employee of Ortho Biotech Products and coauthor of the Journal of Acquired Immune Deficiency Syndromes article, Ortho Biotech Products selected Dr. Volberding to chair the “Anemia in HIV Working Group” and Dr. Volberding then selected the rest of the panel members (G. Leitz, P. C. Bellman, personal conversation, approximately January 15, 2005). I do not believe that the disclosure statement accompanying his Journal of Acquired Immune Deficiency Syndromes article, which states that Dr. Volberding is “on the speaker's bureau and advisory board of Ortho Biotech” reflected this relationship.1 It was also absent from the Clinical Infectious Diseases article.

Just today, as I was preparing this letter, I received in the mail a special CME monograph entitled The Impact of Viral Load and Hemoglobin on Survival in Patients with HIV, which was sponsored by the University of Alabama School of Medicine, Division of Continuing Medical Education, and supported through an education grant from Ortho Biotech Products, LP.12 Faculty members included Paul Volberding. Again, bold conclusions are drawn in this monograph in my opinion without supporting clinical data, including consideration of treatment “in HIV-infected men with hemoglobin levels <12 g/dL.” Here, it is suggested, “Successful treatment of anemia probably contributes to avoiding end-organ damage such as myocardial infarction and stroke.” In this monograph, again, no mention is made of the possible toxicities of EPO that have been found in kidney and cancer patients, such as stroke and heart attack.

I refer you and my fellow readers to a recent book by Jerome Kassirer, the former editor of the New England Journal of Medicine, entitled “On the Take,”13 which addresses the concerns of how undue influence by pharmaceutic companies, particularly through the formation of such “expert panels,” can adversely affect the quality of patient care and clinical research. I hope your journal can demonstrate its commitment to the highest standards of editorship and reporting and address the concerns raised in this letter.

Paul Bellman, MD

St. Vincent's Hospital New York, NY

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REFERENCES

1. Henry DH, Leitz G, Volberding PA. Epoetin alfa for treatment of anemia in HIV-infected patients: past, present, and future. J Acquired Immune Defic Syndr. 2004;37:1221-1227.

2. Ruscher K, Freyer D, Karsch M, et al. Erythropoietin is a paracrine mediator of ischemic tolerance in the brain: evidence from an in vitro model. J Neurosci. 2002;22:10291-10301.

3. Wu SC, Lin SL, Jeng FR. Influence of erythropoietin treatment on gonadotropic hormone levels and sexual function in male uremic patients. Scand J Urol Nephrol. 2001;35:136-140.

4. Grimm C, Wenzel A, Groszer M, et al. HIF-1-induced erythropoietin in the hypoxic retina protects against light-induced retinal degeneration. Nat Med. 2002;8:718-724.

5. Sasaki R, Masuda S, Nagao M. Pleiotropic functions and tissue-specific expression of erythropoietin. News Physiol Sci. 2001;16:110-113.

6. Henry DH, Beall GN, Benson CA, et al. Recombinant human erythropoietin in the treatment of anemia associated with human immunodeficiency virus (HIV) infection and zidovudine therapy. Ann Intern Med. 1992;117:739-748.

7. Kamin M. Dear health care professional warning letter. Bridgewater, NJ: Ortho Biotech Clinical Affairs, Ortho Biotech LLC. August 13, 2004.

8. Heavey S. Amgen warns of higher doses of anemia drugs. Medical and Science News (Reuter's Health). 2005;16:3-4.

9. Volberding PA, Levine AM, Dieterich D,et al. Anemia in HIV infection: clinical impact and evidence-based management strategies. Clin Infect Dis. 2004;38:1454-1463.

10. Ortho Biotech product information. In: Physician's Desk Reference 2005. 2472-2479.

11. Bartlett JG. 2004 Literature Review Archives. December 2, 2004.

12. Volberding PA, et al. The Impact of Viral Load and Hemoglobin on Survival in Patients with HIV. Special CME monograph. 2005.

13. Kassirer J. On The Take: How Medicine's Complicity with Big Business Can Endanger Your Health. Oxford University Press; 2004.

© 2005 Lippincott Williams & Wilkins, Inc.

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