EVALUATING EPOETIN ALFA 40,000 U SUBCUTANEOUSLYEVERY 2 WEEKS TO MAINTAIN HEMOGLOBIN LEVELS INANEMIC HIV-INFECTED PATIENTSAM Levine,1 GJ Leitz,2 and the Community HIV Anemia Management Protocol Sites 2 (CHAMPS 2) Study Group1University of Southern California, Keck School of Medicine, Los Angeles, CA; 2Ortho Biotech Products, L.P.,Bridgewater, NJ

Alexandra M. Levine, MDUSC/Norris Comprehensive Cancer

Center and Hospital1441 Eastlake Avenue, MS 34Los Angeles, CA 90033-0804

Telephone: 323-865-3913Fax: 323-865-0060

E-Mail: hornor@usc.edu

Gerhard Leitz, MD, PhDOrtho Biotech Products, L.P.

430 Route 22 East, P.O. Box 6914Bridgewater, NJ 08807-0914

Telephone: 908-541-4245Fax: 908-541-4295

E-Mail: gleitz@obius.jnj.com

ABSTRACT

Background: Previous studies have shown that initial dosing of epoetin alfa 40,000 U subcutaneously (SC) once weekly (QW) is safeand effective at increasing hemoglobin (Hb) levels and improving quality of life (QOL) in anemic, HIV-infected patients (pts). However, in a population already burdened with complex medication regimens, the efficacy, safety, and convenience of epoetin alfa 40,000 U SCevery 2 weeks (Q2W) to maintain Hb needs further exploration.

Methods: In a 24-week, multicenter, open-label study, HIV-infected pts with Hb ≤12 g/dL were administered epoetin alfa 40,000 U SCQW until target Hb (≥13 g/dL) was achieved. Patients were then switched to a maintenance phase during which epoetin alfa was givenat a dosage of 40,000 U SC Q2W. If, during Q2W dosing, Hb measured ≤11 g/dL, pts were switched back to QW dosing; if Hb was≥14 g/dL, dosing was temporarily withheld until Hb reached <14 g/dL, when previous maintenance dose resumed.

Results: At the time of this preliminary analysis, 63 pts were enrolled. Baseline characteristics are: median age 43 y (range, 25-74 y);57% men; 62% on HAART; median CD4+, 233 cells/µL (range, 3-1308); median HIV-RNA, 770 copies/mL (range, 49-533,000); medianHb, 11.2 g/dL (range, 7.2-12.8 g/dL). Fifty pts entered maintenance phase, having reached target Hb (≥13 g/dL) in a median of 3.1 wk(range, 1-7 wk). During maintenance, median dosing interval of epoetin alfa 40,000 U SC was Q2.1 wk (range, 1.1-9.5 wk). Target Hb(≥13 g/dL) was maintained in 6 pts with QW dosing, 25 (50%) with Q2W, 10 (20%) with Q3W, 4 (8%) with Q4W, and 2 (4%) with >Q4W.In 3 pts with only a few days in maintenance, dosing interval was not assessed. Median weekly dose of epoetin alfa was 18,667 U(range, 4211-37,333 U).

Conclusions: These preliminary data suggest that the majority of anemic, HIV-infected pts in this study can maintain a target Hb levelof ≥13 g/dL with the more convenient Q2W or Q3W dosing regimens.

Poster # H-1919As presented at the

Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC)Chicago, Illinois

September 14-17, 2003

This study was supported by Ortho Biotech Products, L.P.

CHAMPS 2 INVESTIGATORS LISTManju Agrawal, MD, Pomona, CA; Timothy Babinchak, MD, Philadelphia, PA; Daniel Barbaro, MD, Fort Worth, TX; Ben Barnett, MD, Houston, TX; Paul Benson, DO, Berkley, MI; Jack D. Bissett, MD, Austin, TX; Bonnie Bock, MD, Newport Beach, CA; Wayne Bockmon, MD, Houston, TX; Hector Bonilla, MD, Akron, OH; Philip Brachman, MD, Atlanta, GA; David Brand, MD, Dallas, TX; Indira Brar, MD, Detroit, MI; Lawrence Brown, MD,Brooklyn, NY; Larry Bush, MD, FACP, Atlantis, FL; Lysette Cardona, MD, Weston, FL; Felix F. Carpio-Cedraro, MD, MPH, Los Angeles, CA; William Causey, MD, Jackson, MS; Paul Cimoch, MD, FACP, Fountain Valley, CA;Jeffrey Coco, MD, New Orleans, LA; Amy Colson, MD, MPH, Boston, MA; Marcus Conant, MD, San Francisco, CA; Patrick Daly, MD, Dallas, TX; Edwin DeJesus, MD, Altamonte Springs, FL; Lael Duncan, MD, Tacoma, WA;Victor Fainstein, MD, Houston, TX; Franco Felizarta, MD, Bakersfield, CA; Margaret Fischl, MD, Miami, FL; Joel E. Gallant, MD, MPH, Baltimore, MD; Jeffrey Galpin, MD, Tarzana, CA; Joseph Gathe, Jr., MD, Houston, TX;Eliot W. Godofsky, MD, Bradenton, FL; Kenneth Greenberg, DO, PharmD, Denver, CO; Howard Grossman, MD, New York, NY; David Henry, MD, Philadelphia, PA; Jose N. Hernandez, DO, Miami Beach, FL; Harold Horowitz, MD, Valhalla, NY; Ricky Hsu, MD, New York, NY; David Johnson, MD, St. Petersburg, FL; David Kaufman, MD, New York, NY; Harold Kessler, MD, Chicago, IL; Daniel Kluger, MD, Newport News, VA; KatherineKnapp, MD, Memphis, TN; Michael Kolber, MD, Miami, FL; Anthony LaMarca, MD, Ft. Lauderdale, FL; Marah Lee, MD, Oakland Park, FL; Arnold Lentnek, MD, Marietta, GA; Cyril Llamoso, MD, Milwaukee, WI; DavidMayorga, MD, Ft. Lauderdale, FL; Patrick McLeroth, MD, Baltimore, MD; John B. Montana, MD, New York, NY; Jose Moreno, MD, Miami, FL; Anne B. Morris, MD, Springfield, MA; Karam Mounzer, MD, Philadelphia, PA; IramNadeem, MD, Milwaukee, WI; Jeffrey Nadler, MD, Tampa, FL; Ronald G. Nahass, MD, FACP, Hillsborough, NJ; Stephen O’Brien, MD, Berkeley, CA; David Parks, MD, St. Louis, MO; Gerald Pierone, MD, Vero Beach, FL;Steven Pounders, MD, Dallas, TX; David J. Prelutsky, MD, St. Louis, MO; Arnaldo Quinones, MD, Ft. Lauderdale, FL; Karen Raben, MD, South Miami, FL; Bruce Rashbaum, MD, Washington, DC; Kristin Razzeca, MD,Sunnyvale, CA; James P. Ryan, MD, Orlando, FL; Michael S. Saag, MD, Birmingham, AL; Patricia Salvato, MD, Houston, TX; Michael Sands, MD, Jacksonville, FL; Steven Santiago, MD, Miami, FL; Guillermo Santos, MD,New York, NY; Kunthavi Sathasivam, MD, Washington, DC; Stefan Schneider, MD, Long Beach, CA; Robert C. Scott, MD, Oakland, CA; Michael Sension, MD, Ft. Lauderdale, FL; Victoria Sharp, MD, New York, NY; JihadSlim, MD, Newark, NJ; Louis Sloan, MD, Dallas, TX; Cheryl Smith, MD, New York, NY; Steven Sotman, MD, Fort Worth, TX; Roy Steigbigel, MD, Stony Brook, NY; Corklin Steinhart, MD, PhD, Miami, FL; Michelle Till, MD,Chicago, IL; Scott Ubillos, MD, Tampa, FL; Mary Van den Berg-Wolf, MD, Philadelphia, PA; Vilma Vega, MD, Sarasota, FL; Arthur Williams, MD, Philadelphia, PA; Sally Williams, MD, Vancouver, WA; Mallory Witt, MD,Torrance, CA; Michael Wohlfeiler, MD, Miami Beach, FL; Peter R. Wolfe, MD, Beverly Hills, CA; David Wright, MD, Austin, TX.

REFERENCES1. Mocroft A, Kirk O, Barton SE, et al. Anaemia is an independent predictive marker for clinical prognosis in HIV-infected patients from across Europe. AIDS 1999;13:943-950. 2. Servais J, Nkoghe D, Schmit J-C, et al.HIV-associated hematologic disorders are correlated with plasma viral load and improve under highly active antiretroviral therapy. J Acquir Immune Defic Syndr 2001;28:221-225. 3. Semba RD, Shah N, Klein RS, et al.Prevalence and cumulative incidence of and risk factors for anemia in a multicenter cohort study of human immunodeficiency virus-infected and -uninfected women. Clin Infect Dis 2002;34:260-266. 4. Moore RD, Keruly JC, Chaisson RE. Anemia and survival in HIV infection. J Acquir Immune Defic Syndr 1998;19:29-33. 5. Sullivan PS, Hanson DL, Chu SY, et al. Epidemiology of anemia in human immunodeficiency virus (HIV)-infected persons: results from the Multistate Adult and Adolescent Spectrum of HIV Disease Surveillance Project. Blood 1998;91:301-308. 6. Saag MS, Levine AM, Leitz GJ, Bowers PJ. Once-weekly epoetin alfaincreases hemoglobin and improves quality of life in anemic HIV-positive patients. Proceedings of the 39th Annual Meeting of the Infectious Diseases Society of America, San Francisco, CA, October 25-28, 2001:160.Abstract 708. 7. Grossman H, Goon B, Bowers P, Leitz G, and the 010 Study Group. Once-weekly epoetin alfa dosing is as effective as three-times-weekly dosing in increasing hemoglobin levels and is associated withimproved quality of life in anemic, HIV-infected patients. J Acquir Immune Defic Syndr (in press). 8. Cinti SK. Adherence to antiretrovirals in HIV disease. AIDS Reader 2000;10:709-717. 9. Patton J, Kuzur M, LiggettW, Miranda F, Varsos H, Porter L. Epoetin alfa 60,000 u once weekly followed by 120,000 u every three weeks maintains hemoglobin levels in anemic cancer patients receiving chemotherapy: final report. Proc Am SocClin Oncol 2003;22:754. Abstract 3033. 10. Farrell FX, Jolliffe LK. Administration of epoetin alfa every two weeks is able to sustain target hemoglobin in a nonhuman primate alternate dosing model. Blood 2001;98(11 Pt 1):297a. Abstract 1253.

EVALUATING EPOETIN ALFA 40,000 U SUBCUTANEOUSLY EVERY 2 WEEKS TO MAINTAIN HEMOGLOBIN LEVELS IN ANEMIC HIV-INFECTED PATIENTSAM Levine,1 GJ Leitz,2 and the Community HIV Anemia Management Protocol Sites 2 (CHAMPS 2) Study Group1University of Southern California, Keck School of Medicine, Los Angeles, CA; 2Ortho Biotech Products, L.P., Bridgewater, NJ

ABSTRACT

Background: Previous studies have shown that initial dosing ofepoetin alfa 40,000 U subcutaneously (SC) once weekly (QW) issafe and effective at increasing hemoglobin (Hb) levels andimproving quality of life (QOL) in anemic, HIV-infected patients(pts). However, in a population already burdened with complexmedication regimens, the efficacy, safety, and convenience ofepoetin alfa 40,000 U SC every 2 weeks (Q2W) to maintain Hbneeds further exploration.

Methods: In a 24-week, multicenter, open-label study, HIV-infected pts with Hb ≤12 g/dL were administered epoetin alfa40,000 U SC QW until target Hb (≥13 g/dL) was achieved.Patients were then switched to a maintenance phase duringwhich epoetin alfa was given at a dosage of 40,000 U SC Q2W.If, during Q2W dosing, Hb measured ≤11 g/dL, pts wereswitched back to QW dosing; if Hb was ≥14 g/dL, dosing wastemporarily withheld until Hb reached <14 g/dL, when previ-ous maintenance dose resumed.

Results: At the time of this preliminary analysis, 63 pts wereenrolled. Baseline characteristics are: median age 43 y (range,25-74 y); 57% men; 62% on HAART; median CD4+, 233 cells/µL(range, 3-1308); median HIV-RNA, 770 copies/mL (range, 49-533,000); median Hb, 11.2 g/dL (range, 7.2-12.8 g/dL). Fifty ptsentered maintenance phase, having reached target Hb (≥13g/dL) in a median of 3.1 wk (range, 1-7 wk). During maintenance,median dosing interval of epoetin alfa 40,000 U SC was Q2.1 wk(range, 1.1-9.5 wk). Target Hb (≥13 g/dL) was maintained in 6pts with QW dosing, 25 (50%) with Q2W, 10 (20%) with Q3W, 4(8%) with Q4W, and 2 (4%) with >Q4W. In 3 pts with only a fewdays in maintenance, dosing interval was not assessed.Median weekly dose of epoetin alfa was 18,667 U (range, 4211-37,333 U).

Conclusions: These preliminary data suggest that the majorityof anemic, HIV-infected pts in this study can maintain a target Hblevel of ≥13 g/dL with the more convenient Q2W or Q3W dosingregimens.

INTRODUCTIONAnemia remains the most common hematologic abnormality inhuman immunodeficiency virus (HIV)-infected patients, even inthe era of highly active antiretroviral therapy (HAART).1-3 Thesymptoms commonly caused by anemia, such as weakness,fatigue, and shortness of breath, have adverse effects on qualityof life. In addition, anemia has been independently associatedwith decreased survival in HIV-positive patients.1,4,5

Recent studies show that once-weekly (QW) administration ofepoetin alfa 40,000 U is effective in improving anemia and qualityof life in HIV-infected patients receiving stable antiretroviral ther-apy.6,7 Given the challenges of treatment adherence with complexmedication regimens in this patient population,8 it is anticipatedthat less frequent dosing of epoetin alfa in maintenance afterachieving a target Hb level with QW dosing would be more con-venient for patients, and improve patient compliance. Anecdotalreports from clinicians suggest that dosing every 2 weeks(Q2W) may be effective. Alternate dosing regimens are beingstudied in anemic patients with cancer.9 In addition, in a studyin cynomolgous monkeys, target Hb levels were achieved morerapidly with a QW dosing regimen, compared with a larger dosegiven less frequently, and epoetin alfa was effective at maintain-ing target Hb levels with an every 2- or 3-week dosing schedulewhen initiated at higher Hb levels.10

STUDY OBJECTIVES

The present study sought to evaluate the efficacy and safety ofQ2W dosing of epoetin alfa in maintaining Hb levels of approxi-mately 13 g/dL in anemic HIV-infected patients.

METHODS

Inclusion Criteria• HIV-infected men or women 18 to 75 years of age

• Currently on stable antiretroviral regimen for at least 4 weeksprior to enrollment

• Hemoglobin ≤12 g/dL

Exclusion Criteria• Acute, symptomatic opportunistic infection or other acute AIDS-

defining illness within 6 months of screening

• History of primary hematologic disease

• Anemia attributable to factors such as iron, B12, or folate defi-ciency, hemolysis, or gastrointestinal bleeding

• Hepatitis C virus coinfection unless treatment with ribavirin/inter-feron was completed at least 12 weeks prior to study entry

• Ferritin level <40 ng/mL

• Pregnancy or lactation

Study DesignPhase IV, open-label, nonrandomized, multicenter study (Figure 1).

Patient Monitoring• Complete blood count (including Hb) at baseline (BL), Weeks

1–4, and every 2 weeks thereafter or upon early withdrawal

• Adverse events monitored throughout the study and collectedat each study visit

Obtain baseline Hb (≤12 g/dL); initiate epoetin alfa 40,000 U SC QW

for 4 weeks (baseline, Study Day 1)

If Hb ≥13 g/dL Titrate epoetin alfa dose up to 60,000 U SC QW for 4 additional weeks

If Hb ≥13 g/dL

Continue maintenance dose ofepoetin alfa 40,000 U SC Q2W;total treatment duration not to

exceed 24 weeks from Study Day 1

If Hb ≥14 g/dL If Hb ≤11 g/dL

Withholdepoetin alfa

until Hb <14 g/dL

If Hb ≥14 g/dL If Hb ≤11 g/dL

If Hb increase <1 g/dL

Return following week, convert to maintenance dose of epoetin alfa 40,000 U SC Q2W; total treatment duration not to

exceed 24 weeks from Study Day 1

Switch backto epoetin alfa

dose of40,000 U SC QW

Discontinueepoetin

alfa therapy

Return following week, convertto maintenance dose of epoetin alfa 60,000 U SC Q2W; total treatment duration not to exceed 24 weeks

from Study Day 1

Continue maintenance dose ofepoetin alfa 60,000 U SC Q2W;total treatment duration not to

exceed 24 weeks from Study Day 1

Temporarily withhold epoetin alfa

until Hb <14 g/dL

Switch backto epoetin alfa

dose of60,000 U SC QW

If Hb increase <1 g/dL

If Hb increase ≥1 g/dL and Hb <13 g/dL

Continue epoetin alfa 60,000 U QW

If Hb increase ≥1 g/dL and Hb <13 g/dL

Continue epoetin alfa 40,000 U QW

FIGURE 1. Study design. RESULTS

Patient DemographicsBL characteristics were: Median age = 43 years (range: 23-74 years); Ethnicity: 53% black, 34% white, 8% Hispanic, 5%other; 62% on HAART; Median CD4+ count = 199 cells/µL (range:2-1,308 cells/µL); Median HIV-RNA = 1,240 copies/mL (range:31-533,000 copies/mL); and Median Hb level = 11.0 g/dL(range: 7.2-12.8 g/dL).

RESULTS (cont’d)METHODS (cont’d)

Statistical Analysis and Definitions• Descriptive statistics for BL characteristics, Hb changes,

and epoetin alfa dosing information are summarized

• Day 1 of the maintenance phase (MP) is defined as the firstday that a patient reaches target Hb (≥13 g/dL)

• For Hb analysis in MP, patients had to have target Hb (≥13 g/dL) value plus ≥1 subsequent Hb measurement

• To calculate average epoetin alfa dosing during MP, patientshad to have target Hb value plus ≥1 subsequent Hb measure-ment and ≥1 epoetin alfa dose

• Mean dosing interval in MP (in weeks)* = Number of weeks inMP / Number of doses during MP

• Definitions of categories of calculated dosing intervals:– QW = Dosing interval of ≤10 days (target day of 7) – Q2W = Dosing interval of >10 and ≤17 days (target day of 14) – Q3W = Dosing interval of >17 and ≤24 days (target day of 21) – Q4W = Dosing interval of >24 and ≤31 days (target day of 28) – >Q4W = Dosing interval of >31 days

• Calculated weekly dose = Total dose amount during MP / Numberof weeks in MP

*Depending on Hb response and length of time in MP, mean maintenancedosing interval could vary from Q2W. (See Figure 1)

CONCLUSIONS• In this preliminary analysis of 120 patients, 87% had Hb increases of ≥1 g/dL; 77% achieved target Hb ≥13 g/dL with

epoetin alfa 40,000 U QW• Once patients reached target Hb, 83% were able to maintain Hb levels at ≈13 g/dL, using epoetin alfa once every

2 weeks to once every 4+ weeks• The calculated median dosing interval for efficacious epoetin alfa maintenance was on average 40,000 U every

2.7 weeks• The longer dosing intervals of epoetin alfa in maintenance provide greater patient and provider ease, while potentially

increasing compliance• Epoetin alfa was well tolerated

TABLE 1. Disposition of Evaluated Patients

Total number of patients evaluated 120

Patients transfused 1

Initiation phase 119

Number of patients withdrawn* 7

Number of patients not yet achieving target Hb 18

Maintenance phase (Hb ≥13 g/dL) 94Number of patients who have reached MP but 8have no subsequent assessment available

Patients in MP who received epoetin alfa 86

*The reasons for withdrawals are as follows: lost to follow-up(n = 2), patient request (n = 2), adverse events unrelated toepoetin alfa (n = 2), and noncompliance (n = 1).

FIGURE 2. Initiation phase plus maintenance phase.

RESULTS (cont’d)

Safety• A total of 227 adverse events were reported; most were

mild to moderate in severity and not related to epoetin alfa– Only 1 adverse event (mild muscle spasms in lower

back) was considered possibly related to epoetin alfa

• 13 patients experienced serious adverse events, including1 death—none were related to epoetin alfa– 74 year old admitted to hospital with fractured hip requiring

surgery; expired probably due to pulmonary embolism

10

11

12

13

14

StudyBaseline

2 4 8 12

Time (Weeks)

n =

Med

ian

Hb (g

/dL)

16

104 102119

6 10 14 18 20 22 24

95 91 53 60 36 60 32 52 27 39 23 35 21 29 15 20 12 17 10 17 9 20

11

12

13

14

15

MP Baseline 2 4 8 12

Time (Weeks)

n =

Med

ian

Hb (g

/dL)

16

68 3486

6 10 14 18 20 22 24

53 14 50 15 43 12 39 9 35 10 26 6 21 5 16 4 13 5 2

Calculated median dosing inteval = 2.7 weeks

14 4

Maintenance phase• 79% (94/119) of patients reached target Hb level (≥13 g/dL)

– 77% (92/119) with epoetin alfa 40,000 U QW– 2% (2/119) after epoetin alfa dose escalation to 60,000 U QW

• 85% (73/86) of patients maintained target Hb level (≈13 g/dL). Median Hb values are displayed in Figure 3.

• Of the 73 patients who maintained target Hb, the following calculated dosing intervals were used:– 2 patients (2%) with QW dosing – 23 patients (27%) with Q2W dosing– 29 patients (34%) with Q3W dosing – 9 patients (10%) with Q4W dosing – 10 patients (12%) with >Q4W dosing

• For evaluable patients in the MP (n = 86):– Median time in the MP was 12.4 weeks (range: 1.1-24.1

weeks)– Median epoetin alfa dosing interval in the MP was 2.7

weeks (range: 1.1-12.3 weeks)– Median weekly epoetin alfa dose in the MP was 14,737 U

(range: 3,256-35,000 U)

Initiation phase• 87% of patients had a ≥1-g/dL increase in Hb by Week 8

• Hb level increased from a median BL value of 11.0 g/dL (range7.2-12.8 g/dL) to a median of 13.4 g/dL (range 13.0-17.7 g/dL)upon reaching target (≥13 g/dL) – Mean Hb change was 2.7 g/dL

– Median time to achieve target Hb level was 3.1 weeks (range:1.0-15.7 weeks)

• Change in median Hb level during the study is shown in Figure 2

FIGURE 3. Maintenance phase.

Hematologic Assessments

H-1919

EVALUATING EPOETIN ALFA 40,000 U SUBCUTANEOUSLY EVERY 2 WEEKS TO MAINTAIN HEMOGLOBIN LEVELS IN ANEMIC HIV-INFECTED PATIENTSAM Levine,1 GJ Leitz,2 and the Community HIV Anemia Management Protocol Sites 2 (CHAMPS 2) Study Group1University of Southern California, Keck School of Medicine, Los Angeles, CA; 2Ortho Biotech Products, L.P., Bridgewater, NJ

ABSTRACT

Background: Previous studies have shown that initial dosing ofepoetin alfa 40,000 U subcutaneously (SC) once weekly (QW) issafe and effective at increasing hemoglobin (Hb) levels andimproving quality of life (QOL) in anemic, HIV-infected patients(pts). However, in a population already burdened with complexmedication regimens, the efficacy, safety, and convenience ofepoetin alfa 40,000 U SC every 2 weeks (Q2W) to maintain Hbneeds further exploration.

Methods: In a 24-week, multicenter, open-label study, HIV-infected pts with Hb ≤12 g/dL were administered epoetin alfa40,000 U SC QW until target Hb (≥13 g/dL) was achieved.Patients were then switched to a maintenance phase duringwhich epoetin alfa was given at a dosage of 40,000 U SC Q2W.If, during Q2W dosing, Hb measured ≤11 g/dL, pts wereswitched back to QW dosing; if Hb was ≥14 g/dL, dosing wastemporarily withheld until Hb reached <14 g/dL, when previ-ous maintenance dose resumed.

Results: At the time of this preliminary analysis, 63 pts wereenrolled. Baseline characteristics are: median age 43 y (range,25-74 y); 57% men; 62% on HAART; median CD4+, 233 cells/µL(range, 3-1308); median HIV-RNA, 770 copies/mL (range, 49-533,000); median Hb, 11.2 g/dL (range, 7.2-12.8 g/dL). Fifty ptsentered maintenance phase, having reached target Hb (≥13g/dL) in a median of 3.1 wk (range, 1-7 wk). During maintenance,median dosing interval of epoetin alfa 40,000 U SC was Q2.1 wk(range, 1.1-9.5 wk). Target Hb (≥13 g/dL) was maintained in 6pts with QW dosing, 25 (50%) with Q2W, 10 (20%) with Q3W, 4(8%) with Q4W, and 2 (4%) with >Q4W. In 3 pts with only a fewdays in maintenance, dosing interval was not assessed.Median weekly dose of epoetin alfa was 18,667 U (range, 4211-37,333 U).

Conclusions: These preliminary data suggest that the majorityof anemic, HIV-infected pts in this study can maintain a target Hblevel of ≥13 g/dL with the more convenient Q2W or Q3W dosingregimens.

INTRODUCTIONAnemia remains the most common hematologic abnormality inhuman immunodeficiency virus (HIV)-infected patients, even inthe era of highly active antiretroviral therapy (HAART).1-3 Thesymptoms commonly caused by anemia, such as weakness,fatigue, and shortness of breath, have adverse effects on qualityof life. In addition, anemia has been independently associatedwith decreased survival in HIV-positive patients.1,4,5

Recent studies show that once-weekly (QW) administration ofepoetin alfa 40,000 U is effective in improving anemia and qualityof life in HIV-infected patients receiving stable antiretroviral ther-apy.6,7 Given the challenges of treatment adherence with complexmedication regimens in this patient population,8 it is anticipatedthat less frequent dosing of epoetin alfa in maintenance afterachieving a target Hb level with QW dosing would be more con-venient for patients, and improve patient compliance. Anecdotalreports from clinicians suggest that dosing every 2 weeks(Q2W) may be effective. Alternate dosing regimens are beingstudied in anemic patients with cancer.9 In addition, in a studyin cynomolgous monkeys, target Hb levels were achieved morerapidly with a QW dosing regimen, compared with a larger dosegiven less frequently, and epoetin alfa was effective at maintain-ing target Hb levels with an every 2- or 3-week dosing schedulewhen initiated at higher Hb levels.10

STUDY OBJECTIVES

The present study sought to evaluate the efficacy and safety ofQ2W dosing of epoetin alfa in maintaining Hb levels of approxi-mately 13 g/dL in anemic HIV-infected patients.

METHODS

Inclusion Criteria• HIV-infected men or women 18 to 75 years of age

• Currently on stable antiretroviral regimen for at least 4 weeksprior to enrollment

• Hemoglobin ≤12 g/dL

Exclusion Criteria• Acute, symptomatic opportunistic infection or other acute AIDS-

defining illness within 6 months of screening

• History of primary hematologic disease

• Anemia attributable to factors such as iron, B12, or folate defi-ciency, hemolysis, or gastrointestinal bleeding

• Hepatitis C virus coinfection unless treatment with ribavirin/inter-feron was completed at least 12 weeks prior to study entry

• Ferritin level <40 ng/mL

• Pregnancy or lactation

Study DesignPhase IV, open-label, nonrandomized, multicenter study (Figure 1).

Patient Monitoring• Complete blood count (including Hb) at baseline (BL), Weeks

1–4, and every 2 weeks thereafter or upon early withdrawal

• Adverse events monitored throughout the study and collectedat each study visit

Obtain baseline Hb (≤12 g/dL); initiate epoetin alfa 40,000 U SC QW

for 4 weeks (baseline, Study Day 1)

If Hb ≥13 g/dL Titrate epoetin alfa dose up to 60,000 U SC QW for 4 additional weeks

If Hb ≥13 g/dL

Continue maintenance dose ofepoetin alfa 40,000 U SC Q2W;total treatment duration not to

exceed 24 weeks from Study Day 1

If Hb ≥14 g/dL If Hb ≤11 g/dL

Withholdepoetin alfa

until Hb <14 g/dL

If Hb ≥14 g/dL If Hb ≤11 g/dL

If Hb increase <1 g/dL

Return following week, convert to maintenance dose of epoetin alfa 40,000 U SC Q2W; total treatment duration not to

exceed 24 weeks from Study Day 1

Switch backto epoetin alfa

dose of40,000 U SC QW

Discontinueepoetin

alfa therapy

Return following week, convertto maintenance dose of epoetin alfa 60,000 U SC Q2W; total treatment duration not to exceed 24 weeks

from Study Day 1

Continue maintenance dose ofepoetin alfa 60,000 U SC Q2W;total treatment duration not to

exceed 24 weeks from Study Day 1

Temporarily withhold epoetin alfa

until Hb <14 g/dL

Switch backto epoetin alfa

dose of60,000 U SC QW

If Hb increase <1 g/dL

If Hb increase ≥1 g/dL and Hb <13 g/dL

Continue epoetin alfa 60,000 U QW

If Hb increase ≥1 g/dL and Hb <13 g/dL

Continue epoetin alfa 40,000 U QW

FIGURE 1. Study design. RESULTS

Patient DemographicsBL characteristics were: Median age = 43 years (range: 23-74 years); Ethnicity: 53% black, 34% white, 8% Hispanic, 5%other; 62% on HAART; Median CD4+ count = 199 cells/µL (range:2-1,308 cells/µL); Median HIV-RNA = 1,240 copies/mL (range:31-533,000 copies/mL); and Median Hb level = 11.0 g/dL(range: 7.2-12.8 g/dL).

RESULTS (cont’d)METHODS (cont’d)

Statistical Analysis and Definitions• Descriptive statistics for BL characteristics, Hb changes,

and epoetin alfa dosing information are summarized

• Day 1 of the maintenance phase (MP) is defined as the firstday that a patient reaches target Hb (≥13 g/dL)

• For Hb analysis in MP, patients had to have target Hb (≥13 g/dL) value plus ≥1 subsequent Hb measurement

• To calculate average epoetin alfa dosing during MP, patientshad to have target Hb value plus ≥1 subsequent Hb measure-ment and ≥1 epoetin alfa dose

• Mean dosing interval in MP (in weeks)* = Number of weeks inMP / Number of doses during MP

• Definitions of categories of calculated dosing intervals:– QW = Dosing interval of ≤10 days (target day of 7) – Q2W = Dosing interval of >10 and ≤17 days (target day of 14) – Q3W = Dosing interval of >17 and ≤24 days (target day of 21) – Q4W = Dosing interval of >24 and ≤31 days (target day of 28) – >Q4W = Dosing interval of >31 days

• Calculated weekly dose = Total dose amount during MP / Numberof weeks in MP

*Depending on Hb response and length of time in MP, mean maintenancedosing interval could vary from Q2W. (See Figure 1)

CONCLUSIONS• In this preliminary analysis of 120 patients, 87% had Hb increases of ≥1 g/dL; 77% achieved target Hb ≥13 g/dL with

epoetin alfa 40,000 U QW• Once patients reached target Hb, 83% were able to maintain Hb levels at ≈13 g/dL, using epoetin alfa once every

2 weeks to once every 4+ weeks• The calculated median dosing interval for efficacious epoetin alfa maintenance was on average 40,000 U every

2.7 weeks• The longer dosing intervals of epoetin alfa in maintenance provide greater patient and provider ease, while potentially

increasing compliance• Epoetin alfa was well tolerated

TABLE 1. Disposition of Evaluated Patients

Total number of patients evaluated 120

Patients transfused 1

Initiation phase 119

Number of patients withdrawn* 7

Number of patients not yet achieving target Hb 18

Maintenance phase (Hb ≥13 g/dL) 94Number of patients who have reached MP but 8have no subsequent assessment available

Patients in MP who received epoetin alfa 86

*The reasons for withdrawals are as follows: lost to follow-up(n = 2), patient request (n = 2), adverse events unrelated toepoetin alfa (n = 2), and noncompliance (n = 1).

FIGURE 2. Initiation phase plus maintenance phase.

RESULTS (cont’d)

Safety• A total of 227 adverse events were reported; most were

mild to moderate in severity and not related to epoetin alfa– Only 1 adverse event (mild muscle spasms in lower

back) was considered possibly related to epoetin alfa

• 13 patients experienced serious adverse events, including1 death—none were related to epoetin alfa– 74 year old admitted to hospital with fractured hip requiring

surgery; expired probably due to pulmonary embolism

10

11

12

13

14

StudyBaseline

2 4 8 12

Time (Weeks)

n =

Med

ian

Hb (g

/dL)

16

104 102119

6 10 14 18 20 22 24

95 91 53 60 36 60 32 52 27 39 23 35 21 29 15 20 12 17 10 17 9 20

11

12

13

14

15

MP Baseline 2 4 8 12

Time (Weeks)

n =

Med

ian

Hb (g

/dL)

16

68 3486

6 10 14 18 20 22 24

53 14 50 15 43 12 39 9 35 10 26 6 21 5 16 4 13 5 2

Calculated median dosing inteval = 2.7 weeks

14 4

Maintenance phase• 79% (94/119) of patients reached target Hb level (≥13 g/dL)

– 77% (92/119) with epoetin alfa 40,000 U QW– 2% (2/119) after epoetin alfa dose escalation to 60,000 U QW

• 85% (73/86) of patients maintained target Hb level (≈13 g/dL). Median Hb values are displayed in Figure 3.

• Of the 73 patients who maintained target Hb, the following calculated dosing intervals were used:– 2 patients (2%) with QW dosing – 23 patients (27%) with Q2W dosing– 29 patients (34%) with Q3W dosing – 9 patients (10%) with Q4W dosing – 10 patients (12%) with >Q4W dosing

• For evaluable patients in the MP (n = 86):– Median time in the MP was 12.4 weeks (range: 1.1-24.1

weeks)– Median epoetin alfa dosing interval in the MP was 2.7

weeks (range: 1.1-12.3 weeks)– Median weekly epoetin alfa dose in the MP was 14,737 U

(range: 3,256-35,000 U)

Initiation phase• 87% of patients had a ≥1-g/dL increase in Hb by Week 8

• Hb level increased from a median BL value of 11.0 g/dL (range7.2-12.8 g/dL) to a median of 13.4 g/dL (range 13.0-17.7 g/dL)upon reaching target (≥13 g/dL) – Mean Hb change was 2.7 g/dL

– Median time to achieve target Hb level was 3.1 weeks (range:1.0-15.7 weeks)

• Change in median Hb level during the study is shown in Figure 2

FIGURE 3. Maintenance phase.

Hematologic Assessments

H-1919

EVALUATING EPOETIN ALFA 40,000 U SUBCUTANEOUSLYEVERY 2 WEEKS TO MAINTAIN HEMOGLOBIN LEVELS INANEMIC HIV-INFECTED PATIENTSAM Levine,1 GJ Leitz,2 and the Community HIV Anemia Management Protocol Sites 2 (CHAMPS 2) Study Group1University of Southern California, Keck School of Medicine, Los Angeles, CA; 2Ortho Biotech Products, L.P.,Bridgewater, NJ

Alexandra M. Levine, MDUSC/Norris Comprehensive Cancer

Center and Hospital1441 Eastlake Avenue, MS 34Los Angeles, CA 90033-0804

Telephone: 323-865-3913Fax: 323-865-0060

E-Mail: hornor@usc.edu

Gerhard Leitz, MD, PhDOrtho Biotech Products, L.P.

430 Route 22 East, P.O. Box 6914Bridgewater, NJ 08807-0914

Telephone: 908-541-4245Fax: 908-541-4295

E-Mail: gleitz@obius.jnj.com

ABSTRACT

Background: Previous studies have shown that initial dosing of epoetin alfa 40,000 U subcutaneously (SC) once weekly (QW) is safeand effective at increasing hemoglobin (Hb) levels and improving quality of life (QOL) in anemic, HIV-infected patients (pts). However, in a population already burdened with complex medication regimens, the efficacy, safety, and convenience of epoetin alfa 40,000 U SCevery 2 weeks (Q2W) to maintain Hb needs further exploration.

Methods: In a 24-week, multicenter, open-label study, HIV-infected pts with Hb ≤12 g/dL were administered epoetin alfa 40,000 U SCQW until target Hb (≥13 g/dL) was achieved. Patients were then switched to a maintenance phase during which epoetin alfa was givenat a dosage of 40,000 U SC Q2W. If, during Q2W dosing, Hb measured ≤11 g/dL, pts were switched back to QW dosing; if Hb was≥14 g/dL, dosing was temporarily withheld until Hb reached <14 g/dL, when previous maintenance dose resumed.

Results: At the time of this preliminary analysis, 63 pts were enrolled. Baseline characteristics are: median age 43 y (range, 25-74 y);57% men; 62% on HAART; median CD4+, 233 cells/µL (range, 3-1308); median HIV-RNA, 770 copies/mL (range, 49-533,000); medianHb, 11.2 g/dL (range, 7.2-12.8 g/dL). Fifty pts entered maintenance phase, having reached target Hb (≥13 g/dL) in a median of 3.1 wk(range, 1-7 wk). During maintenance, median dosing interval of epoetin alfa 40,000 U SC was Q2.1 wk (range, 1.1-9.5 wk). Target Hb(≥13 g/dL) was maintained in 6 pts with QW dosing, 25 (50%) with Q2W, 10 (20%) with Q3W, 4 (8%) with Q4W, and 2 (4%) with >Q4W.In 3 pts with only a few days in maintenance, dosing interval was not assessed. Median weekly dose of epoetin alfa was 18,667 U(range, 4211-37,333 U).

Conclusions: These preliminary data suggest that the majority of anemic, HIV-infected pts in this study can maintain a target Hb levelof ≥13 g/dL with the more convenient Q2W or Q3W dosing regimens.

Poster # H-1919As presented at the

Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC)Chicago, Illinois

September 14-17, 2003

This study was supported by Ortho Biotech Products, L.P.

CHAMPS 2 INVESTIGATORS LISTManju Agrawal, MD, Pomona, CA; Timothy Babinchak, MD, Philadelphia, PA; Daniel Barbaro, MD, Fort Worth, TX; Ben Barnett, MD, Houston, TX; Paul Benson, DO, Berkley, MI; Jack D. Bissett, MD, Austin, TX; Bonnie Bock, MD, Newport Beach, CA; Wayne Bockmon, MD, Houston, TX; Hector Bonilla, MD, Akron, OH; Philip Brachman, MD, Atlanta, GA; David Brand, MD, Dallas, TX; Indira Brar, MD, Detroit, MI; Lawrence Brown, MD,Brooklyn, NY; Larry Bush, MD, FACP, Atlantis, FL; Lysette Cardona, MD, Weston, FL; Felix F. Carpio-Cedraro, MD, MPH, Los Angeles, CA; William Causey, MD, Jackson, MS; Paul Cimoch, MD, FACP, Fountain Valley, CA;Jeffrey Coco, MD, New Orleans, LA; Amy Colson, MD, MPH, Boston, MA; Marcus Conant, MD, San Francisco, CA; Patrick Daly, MD, Dallas, TX; Edwin DeJesus, MD, Altamonte Springs, FL; Lael Duncan, MD, Tacoma, WA;Victor Fainstein, MD, Houston, TX; Franco Felizarta, MD, Bakersfield, CA; Margaret Fischl, MD, Miami, FL; Joel E. Gallant, MD, MPH, Baltimore, MD; Jeffrey Galpin, MD, Tarzana, CA; Joseph Gathe, Jr., MD, Houston, TX;Eliot W. Godofsky, MD, Bradenton, FL; Kenneth Greenberg, DO, PharmD, Denver, CO; Howard Grossman, MD, New York, NY; David Henry, MD, Philadelphia, PA; Jose N. Hernandez, DO, Miami Beach, FL; Harold Horowitz, MD, Valhalla, NY; Ricky Hsu, MD, New York, NY; David Johnson, MD, St. Petersburg, FL; David Kaufman, MD, New York, NY; Harold Kessler, MD, Chicago, IL; Daniel Kluger, MD, Newport News, VA; KatherineKnapp, MD, Memphis, TN; Michael Kolber, MD, Miami, FL; Anthony LaMarca, MD, Ft. Lauderdale, FL; Marah Lee, MD, Oakland Park, FL; Arnold Lentnek, MD, Marietta, GA; Cyril Llamoso, MD, Milwaukee, WI; DavidMayorga, MD, Ft. Lauderdale, FL; Patrick McLeroth, MD, Baltimore, MD; John B. Montana, MD, New York, NY; Jose Moreno, MD, Miami, FL; Anne B. Morris, MD, Springfield, MA; Karam Mounzer, MD, Philadelphia, PA; IramNadeem, MD, Milwaukee, WI; Jeffrey Nadler, MD, Tampa, FL; Ronald G. Nahass, MD, FACP, Hillsborough, NJ; Stephen O’Brien, MD, Berkeley, CA; David Parks, MD, St. Louis, MO; Gerald Pierone, MD, Vero Beach, FL;Steven Pounders, MD, Dallas, TX; David J. Prelutsky, MD, St. Louis, MO; Arnaldo Quinones, MD, Ft. Lauderdale, FL; Karen Raben, MD, South Miami, FL; Bruce Rashbaum, MD, Washington, DC; Kristin Razzeca, MD,Sunnyvale, CA; James P. Ryan, MD, Orlando, FL; Michael S. Saag, MD, Birmingham, AL; Patricia Salvato, MD, Houston, TX; Michael Sands, MD, Jacksonville, FL; Steven Santiago, MD, Miami, FL; Guillermo Santos, MD,New York, NY; Kunthavi Sathasivam, MD, Washington, DC; Stefan Schneider, MD, Long Beach, CA; Robert C. Scott, MD, Oakland, CA; Michael Sension, MD, Ft. Lauderdale, FL; Victoria Sharp, MD, New York, NY; JihadSlim, MD, Newark, NJ; Louis Sloan, MD, Dallas, TX; Cheryl Smith, MD, New York, NY; Steven Sotman, MD, Fort Worth, TX; Roy Steigbigel, MD, Stony Brook, NY; Corklin Steinhart, MD, PhD, Miami, FL; Michelle Till, MD,Chicago, IL; Scott Ubillos, MD, Tampa, FL; Mary Van den Berg-Wolf, MD, Philadelphia, PA; Vilma Vega, MD, Sarasota, FL; Arthur Williams, MD, Philadelphia, PA; Sally Williams, MD, Vancouver, WA; Mallory Witt, MD,Torrance, CA; Michael Wohlfeiler, MD, Miami Beach, FL; Peter R. Wolfe, MD, Beverly Hills, CA; David Wright, MD, Austin, TX.

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