Our data indicate that the EPO prescription practices in diverse US HIV care settings from 1996-2006 were inconsistent with 2007 and 2011 FDA recommendations for duration of ESA therapy; thus, HIV care providers should consider that their earlier EPO prescribing practices may require change in light of FDA black box warnings and recent recommendations about ESAs. According to our data, from 9% to 71% of anemic, HIV-infected patients who received EPO in the several years before the new warnings were issued were treated to hemoglobin concentrations above the currently recommended thresholds. While these patterns of prescription were not inappropriate at the time of our observations, they indicate the need for changes from earlier prescribing practices. To our knowledge, these data are the first detailed published data on EPO prescription practices for anemic patients with HIV infection.
Recommendations on practice strategies and treatment guidelines for use of EPO in patients with anemia and HIV infection were not definitive during the period covered by our report. The label indication for Procrit® in HIV-infected patients was and still is for AZT-related anemia, but research reports [13
] and clinical HIV treatment guidelines [14
] have broadly recommended consideration of EPO therapy for anemia without identified cause, even when patients are not prescribed AZT. Most anemia in HIV-infected persons in the United States is probably attributable to the anemia of HIV infection (anemia of chronic disease) [4
], especially as prescriptions of AZT have decreased in recent years.
Previous recommendations for EPO treatment of anemia have been motivated by a large number of published reports describing the association of anemia and shorter survival (reviewed in 2002 [15
]), and by information about quality of life and its relationship to anemia [16
]. In 2000, an expert panel concluded that the target hemoglobin for EPO therapy was 12 g/dL for men and 11 g/dL for women [17
], but that EPO treatment should be discontinued only if hemoglobin concentration rose to > 13 g/dL during EPO therapy [14
]. Thus, for the many patients in our analysis who were treated to hemoglobin concentrations up to 13 g/dL, the EPO prescription practice may have been within recommended practice standards as documented by published treatment recommendations and published expert opinion.
Several new pieces of information have led to a reconsideration of EPO prescription practices, both from the regulatory point of view and based on meta-analytic data about survival and erythropoietin treatment. In 2006, trials of EPO in patients with chronic kidney disease [18
] demonstrated no improvement of cardiovascular outcomes, and, in one trial, a higher risk for a composite negative study endpoint (e.g., death or cardiac event). In 2007, preliminary data from an unpublished randomized trial of an ESA in spinal surgery patients found a higher incidence of deep venous thrombosis among EPO-treated patients [20
], and several studies reported to FDA have suggested that ESA prescription may be associated with progression of certain cancers, including breast cancer, cervical cancer, and head and neck tumors [20
]. Further, a 2007 meta-analysis of data on anemia, survival, and EPO therapy for patients with HIV suggested that treatment with EPO did not improve survival [22
]. We did not assess in our analysis endpoints, such as thrombotic events or cancer progression, that are potentially EPO-related, and to the best of our knowledge, there are not data directly demonstrating increased risk for these events associated with EPO prescription in HIV-infected patients.
In other disease conditions, there has been evidence of more aggressive treatment of anemia with ESA in the past 15 years. In a cohort of renal dialysis patients with anemia followed through the United States Renal Data System (USRDS), in 2005 57% of patients were treated with an ESA to hemoglobin concentrations > 13 g/dL; from 1994-2005, mean weekly ESA dose in incident dialysis patients doubled, and the mean monthly hemoglobin concentrations of all patients in care increased by nearly 20% [23
]. The increased use of ESA therapy for anemia in renal dialysis patients even caught the attention of the popular press; the New York Times reported that mean dosages of EPO prescribed in the United States were much higher than prescribed doses in other countries, characterizing the US prescribing practices as aggressive [24
]. We found that, among patients in our cohorts, the prevalence of EPO prescription was as high as among patients in the USRDS report, and that increases in EPO prescription were mostly observed among patients with moderate or severe anemia. The proportions of anemic HOPS patients treated to hemoglobin concentrations > 12 g/dL from 2003-2006 ranged from 53-71%, similar to the USRDS findings of “overshoot”, suggesting that prescription patterns in the two groups may be similar.
There were consistent differences between HOPS and ASD patients in our outcomes of EPO prescription, and hemoglobin concentrations at treatment initiation and discontinuation. Generally, patients in the ASD cohort were prescribed less EPO, were prescribed EPO at more advanced stages of anemia, and were treated with EPO to lower ending hemoglobin concentrations. Although both ASD and HOPS include a variety of public and private treatment facilities, the facilities included in the ASD cohort are more inclusive of public treatment facilities than are the HOPS treatment settings, and it is likely that some of the differences in EPO prescription between the two cohorts reflect differences in insurance status between patients in the two cohorts. Because the ASD cohort did not collect complete information about insurance status, we could not address this possibility directly.
Our analysis is subject to several limitations. First, despite the large number of diverse clinical settings included in the ASD and HOPS cohorts, the facilities and their patients are not representative of all patients in care for HIV infection in the United States. Also, because our studies were observational, we did not specify when hemoglobin measurements were taken, and the times from the hemoglobin measurements to initiation or discontinuation of EPO prescription were variable. In the ASD cohort, EPO prescription was documented only as occurring within a 6-month interval and in some cases only one hemoglobin measurement may have been recorded per 6 month interval in ASD; this led to less analytic precision than in the HOPS analysis, for which precise dates and length of prescription were abstracted. It is possible that other underlying indications for EPO therapy, such as chronic renal disease, may have increased in the ASD and HOPS patient populations over time, and we did not account for this in our analysis. Also, our datasets did not have additional data, such as MCV, serum EPO concentrations, and other measurements of iron that would have allowed us to classify the likely causes of anemia, so we could not stratify our analysis by etiology of anemia. We also did not analyze data on sequelae or patient well-being as it related to ESA dosing. Finally, our analyses did not span the period in 2006-2007 when the original FDA black box warnings were issued, so we cannot evaluate whether prescription patterns have changed since that time.
Our study documents that from 1996-2006, HIV care providers treated anemia, especially moderate and severe anemia, aggressively with EPO. These changes occurred during a period of time when multiple lines of evidence suggested that managing anemia more aggressively bore clinical consideration, and during which anemic patients (not necessarily HIV-infected) in renal dialysis were treated for anemia with increasing aggressiveness. However, these data taken together with our current understanding of the risks associated with treatment of anemia to hemoglobin concentrations > 11 g/dL in other populations suggest that the EPO prescription patterns of HIV care providers should be substantially more conservative than they were in our historical analysis. Future analyses of observational clinical databases (either cohort or representative cross sectional surveys [25
]) may be helpful in documenting changes in EPO prescription practices following the FDA warnings in 2006 and 2007, and the revised FDA recommendations for dosing in 2011.