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

Epoetin Alfa Once Weekly Improves Anemia in HIV/Hepatitis C Virus-Coinfected Patients Treated With Interferon/Ribavirin: A Randomized Controlled Trial

Sulkowski, Mark S MD*; Dieterich, Douglas T MD†; Bini, Edmund J MD‡; Bräu, Norbert MD§; Alvarez, Daniel MD§; DeJesus, Edwin MD¶; Leitz, Gerhard J MD#; for the HIV/HCV Coinfection Study Group

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*Viral Hepatitis Center, Johns Hopkins University, Baltimore, MD †Mt. Sinai Medical Center, New York, NY, ‡Veterans' Administration, New York Harbor Healthcare System, New York, NY, §Bronx Veterans' Administration, Medical Center, Bronx, NY, §Drexel University College of Medicine, Philadelphia, PA, ¶IDC Research Initiative, Altamonte Springs, FL, #Ortho Biotech Clinical Affairs, LLC, Bridgewater, NJ

Supported by Ortho Biotech Clinical Affairs, LLC.Mark S. Sulkowski has received research grants and/or research support and is a member of the speakers' bureaus for Schering-Plough Corporation, Roche Laboratories, and Ortho Biotech Products, LP. Douglas T. Dieterich has received honoraria from and has served on the speakers' bureaus of Ortho Biotech Products, LP, GlaxoSmithKline, Gilead Sciences, Inc., Schering-Plough Corporation, and Roche Laboratories. Edmund J. Bini has received research funding from Ortho Biotech Products, LP. Norbert Bräu has received research grants from and has served on the advisory board for Ortho Biotech Products, LP. Daniel Alvarez is a member of the speakers' bureaus at Ortho Biotech Products, LP and GlaxoSmithKline; he also has received research support from GlaxoSmithKline and Ortho Biotech Products, LP. Edwin DeJesus has received grant and research support from Roche Laboratories, Inc.; he is also a consultant to and/or serves on the advisory boards of Boehringer Ingelheim Pharmaceuticals, Inc., Bristol-Myers Squibb Company, Gilead Sciences, Inc. (regional consultant), GlaxoSmithKline, Merck & Company, Inc. (national ID consultant), Ortho Biotech Products, LP, and Roche Laboratories, Inc. In addition, he is a member of the speakers' bureaus at Boehringer Ingelheim Pharmaceuticals, Inc. (visiting professor program), Bristol-Myers Squibb Company, Gilead Sciences, Inc., GlaxoSmithKline, Ortho Biotech Products, LP, and Roche Laboratories, Inc. Gerhard J. Leitz is an employee of Ortho Biotech Clinical Affairs, LLC and a stockholder of Johnson and Johnson.

To the Editor:

Guidelines for HIV/hepatitis C virus (HCV)-coinfected patients recommend HCV treatment with pegylated interferon-α (PEG-IFN) plus ribavirin (RBV).1 The adverse effects of IFN/RBV, particularly anemia, may be more common among HIV/HCV-coinfected than HCV-monoinfected patients2 and are often associated with decreased health-related quality of life (HRQOL)3 as well as with discontinuation or dose reduction of RBV.4 This study evaluated the effectiveness of once-weekly (QW) epoetin alfa (epoetin alfa) compared with standard of care (SOC) in correcting anemia, improving HRQOL, and minimizing RBV dose reductions in HIV/HCV-coinfected patients receiving IFN/RBV therapy.

This was a 16-week, open-label, randomized, parallel-group, multicenter study in anemic patients with HIV/HCV coinfection receiving IFN/RBV therapy for an anticipated period of ≥16 additional weeks. Key inclusion criteria included patient age of 18 to 75 years and hemoglobin (Hb) ≤12 g/dL or a ≥2-g/dL decrease in Hb after IFN/RBV initiation. Key exclusion criteria included a history of uncontrolled hypertension or seizure disorder, anemia attributable to another cause, and exposure to any epoetin within 3 months.

Patients were randomized (1:1 ratio) to receive up to 16 weeks of epoetin alfa (PROCRIT™; Ortho Biotech Products, LP, Bridgewater, NJ) at a dose of 40,000 U subcutaneously QW or SOC (no epoetin alfa). Epoetin alfa dosage was increased to 60,000 U QW after 4 weeks of therapy if Hb had not returned to pre-IFN/RBV levels. Epoetin alfa was discontinued after an additional 4 weeks at 60,000 U QW if Hb had not increased ≥1.0 g/dL from the nadir Hb value. If Hb exceeded 14 g/dL in women or 16 g/dL in men, epoetin alfa was withheld temporarily.

The primary end point was to compare the mean change in Hb from baseline (ie, first dose of study drug in epoetin alfa group, day 1 in SOC group) to week 16 in the epoetin alfa group with that in the SOC group. Secondary end points were mean change in RBV dosage, HRQOL scores (measured by modified Short Form-12 [SF-12] Health Survey-Acute; Physical and Mental Health Components [PCS, MCS]),5 and transfusion. Patients were required to complete HRQOL assessments before each visit. Safety assessments included monitoring vital signs, adverse events, alanine aminotransferase (ALT) levels, CD4+ counts, and HIV and HCV viral loads.

Efficacy analyses were based on a modified intent-to-treat (MITT) population defined as all patients who had baseline Hb measured and had at least 1 follow-up Hb assessment and, for the epoetin alfa group, received at least 1 dose of epoetin alfa. Safety analysis considered all patients. Missing values were imputed for the efficacy analyses using the last-value-carried-forward technique. Changes in Hb and SF-12 PCS and MCS scores were analyzed within each treatment group using paired t tests and were compared between groups using an analysis of covariance (ANCOVA) model with treatment group as a factor and baseline values as a covariate. RBV dosage changes were assessed by on-treatment analysis and were analyzed using a Wilcoxon signed-rank test to compare between groups. A post hoc analysis of changes in Hb stratified by zidovudine (AZT) status was performed. The incidence of adverse events between groups was compared using the Fisher exact test.

Sixty-six patients were randomized (34 to epoetin alfa group and 32 to SOC group). Baseline characteristics were comparable between the 2 groups. Immediately after randomization (day 1/week 0), 14 patients (4 epoetin alfa and 10 SOC) dropped out of the study without baseline or follow-up assessments. Compared with SOC patients included in the MITT analysis, early SOC dropout patients had lower Hb levels at study entry (10.3 vs. 11.5 g/dL; P = 0.03). Thirty epoetin alfa patients and 22 SOC patients were included in the MITT analysis. Twenty (63%) SOC patients and 11 (32%) epoetin alfa patients dropped out during the 16-week study period. The median time between initiation of IFN/RBV and baseline was 50 days (range: 16-306 days) in the epoetin alfa group and 60 days (range: 22-171 days) in the SOC group.

Mean baseline Hb (±SE) was 11.1 ± 0.3 g/dL in the epoetin alfa group and 11.5 ± 0.3 g/dL in the SOC group (P = 0.33), and mean increases in Hb from baseline to week 16 were 2.6 ± 0.3 g/dL and 0.2 ± 0.3 g/dL, respectively (P < 0.001). No patient had epoetin alfa withheld because of reaching the upper limit of Hb. Patients receiving epoetin alfa and AZT had a greater mean increase in Hb from baseline to week 16 than those not receiving AZT (3.2 ± 0.4 g/dL [n = 13] vs. 2.1 ± 0.4 g/dL [n = 17]; Fig. 1). For SOC patients, the mean change in Hb was similar in AZT users and nonusers. No transfusions occurred.

Figure 1
Figure 1
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Mean RBV doses at initiation of IFN/RBV and at baseline, respectively, were 1047 and 973 mg/d in the epoetin alfa group and 1027 and 982 mg/d in the SOC group. At week 16, 67% of epoetin alfa patients and 45% of SOC patients were receiving RBV doses ≥10.6 mg/kg/d (P = 0.09).

The SF-12 PCS score (mean ± SE) increased significantly from baseline to week 16 in the epoetin alfa group (6.0 ± 1.8 points; P = 0.004), whereas the mean increase in the SOC group was not significant (2.2 ± 1.2 points; P = 0.09). The mean increase in the SF-12 MCS scale score was 2.3 ± 2.0 points in the epoetin alfa group and 0.1 ± 1.5 points in the SOC group (P = nonsignificant vs. baseline for both groups). There were no significant differences between groups for mean change from baseline to week 16 in the SF-12 PCS or SF-12 MCS scale score.

Epoetin alfa was well tolerated, with most adverse events mild to moderate in severity. Patients treated with epoetin alfa had significantly less fatigue (n = 3 [10%]) compared with those in the SOC arm (n = 9 [38%]) (P = 0.02); there was no other significant difference between groups in the incidence of common adverse events. Four serious adverse events were reported: 1 in the epoetin alfa group (constipation, which was considered unrelated to epoetin alfa) and 3 in the SOC group (chest pain, myocardial infarction, and psychosis). There were no reports of thrombovascular events or antierythropoietin antibodies related to epoetin alfa.

In this randomized study, epoetin alfa effectively corrected anemia in HIV/HCV-coinfected patients treated with IFN/RBV, including those taking AZT. The magnitude of Hb increase (mean = 2.6 g/dL) in coinfected patients was similar to that previously observed in IFN/RBV-related anemia in patients with HCV monoinfection.6,7 In contrast to studies in patients with HCV alone, no effect of epoetin on RBV dose was observed.6,7 A significant number of SOC patients dropped out after randomization (10 patients) and before week 16 (20 patients), however, substantially limiting our ability to assess the secondary end point of RBV dose, because patients and investigators may have selectively discontinued study participation in those SOC patients with worse outcomes. Improvements in HRQOL scores were greater in patients receiving epoetin alfa, but the small sample size precluded definitive conclusions. Significantly fewer patients treated with epoetin alfa than SOC reported fatigue as an adverse event. In conclusion, epoetin alfa was effective in correcting anemia and was well tolerated in HIV/HCV-coinfected patients receiving IFN/RBV therapy compared with SOC. Larger, double-blind, placebo-controlled studies as well as studies evaluating alternative criteria for the use of epoetin alfa are warranted to further assess the effects of epoetin alfa on HRQOL, maintenance of RBV dose, and HCV response.

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ACKNOWLEDGMENTS

Coinvestigators include the following individuals: Philip Keiser, MD, University of Texas, Dallas, TX; David Bernstein, MD, North Shore University Hospital, Manhasset, NY; Christine Zurawski, MD, Office of Joel Rosenstock, MD, Atlanta, GA; Coleman Smith, MD, Minnesota Clinical Research Center, St. Paul, MN; Vilma Vega, MD, Infectious Diseases Associates, Sarasota, FL; Daniel Wolde-Rufael, MD, Chase Brexton Health Services, Baltimore, MD; Joseph Jemsek, MD, Jemsek Clinic, Huntersville, NC; Sangik Oh, MD, Beth Israel Deaconess Medical Center, Boston, MA; and Gerald Pierone, MD, Treasure Coast Infectious Disease Consultants, Vero Beach, FL.

The authors acknowledge the contributions of Kimberly Marino, Bann-Mo Day, Nicole Slacik, Kevin Smith, and Angela Klopfer of Ortho Biotech Clinical Affairs, LLC.

Mark S. Sulkowski, MD*

Douglas T. Dieterich, MD†

Edmund J. Bini, MD‡

Norbert Bräu, MD§

Daniel Alvarez, MD§

Edwin DeJesus, MD¶

Gerhard J. Leitz, MD# for the HIV/HCV Coinfection Study Group

*Viral Hepatitis Center, Johns Hopkins University, Baltimore, MD †Mt. Sinai Medical Center, New York, NY, ‡Veterans' Administration, New York Harbor Healthcare System, New York, NY, §Bronx Veterans' Administration, Medical Center, Bronx, NY, §Drexel University College of Medicine, Philadelphia, PA, ¶IDC Research Initiative, Altamonte Springs, FL, #Ortho Biotech Clinical Affairs, LLC, Bridgewater, NJ

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REFERENCES

1. National Institutes of Health. National Institutes of Health consensus development conference statement. Management of chronic hepatitis C: 2002. Available at: www.hivandhepatitis.com/2002conf/nih/rqxz8xsb.pdf. Accessed June 15, 2004.

2. Soriano V, Sulkowski M, Bergin C, et al. Care of patients with chronic hepatitis C and HIV co-infection: recommendations from the HIV-HCV International Panel. AIDS. 2002;16:813-828.

3. McHutchinson JG, Ware JE, Jr, Bayliss MS, et al, and the Hepatitis Interventional Therapy Group. The effects of interferon alpha-2b in combination with ribavirin on health related quality of life and work productivity. J Hepatol. 2001;34:140-147.

4. Bräu N, Rodriguez-Torres M, Prokupek D, et al, for the amfAR DCRI 010 Study Group. Treatment of chronic hepatitis C in HIV/HCV-coinfection with interferon α-2b+ full-course vs. 16-week delayed ribavirin. Hepatology. 2004;39:989-998.

5. Ware JE, Kosinski M, Turner-Bowker DM, et al. How to Score Version 2 of the SF-12 Health Survey (with a supplement documenting version 1). Lincoln, RI: Quality Metric Incorporated; 2002.

6. Dieterich DT, Wasserman R, Bräu N, et al. Once-weekly epoetin alfa improves anemia and facilitates maintenance of ribavirin dosing in hepatitis C virus-infected patients receiving ribavirin plus interferon alfa. Am J Gastroenterol. 2003;98:2491-2499.

7. Afdhal NH, Dieterich DT, Pockros PJ, et al, and the PROACTIVE Study Group. Epoetin alfa maintains ribavirin dose in HCV-infected patients: a prospective, double-blind, randomized controlled study. Gastroenterology. 2004;126:1302-1311.

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