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Alternating and Intermittent Regimens of Zidovudine and Dideoxycytidine in Patients with AIDS or AIDS-Related Complex

Gail Skowron, MD; Samuel A. Bozzette, MD; Lynette Lim, PhD; Carla B. Pettinelli, MD, PhD; Herbert H. Schaumburg, MD; Joseph Arezzo, PhD; Margaret A. Fischl, MD; William G. Powderly, MD; David J. Gocke, MD; Douglas D. Richman, MD; John C. Pottage, MD; Diana Antoniskis, MD; George F. McKinley, MD; Newton E. Hyslop, MD; Graham Ray, BSN; Gary Simon, MD, PhD; Nancy Reed, MSN, CANP; Marsha L. LoFaro, MA; Raj B. Uttamchandani, MD; Lawrence D. Gelb, MD; Steven J. Sperber, MD; Robert L. Murphy, MD; John M. Leedom, MD; Michael H. Grieco, MD; James Zachary, MD; Martin S. Hirsch, MD; Stephen A. Spector, MD; Joseph Bigley, MS; Whaijen Soo, MD, PhD; and Thomas C. Merigan, MD
[+] Article and Author Information

Requests for Reprints: Gail Skowron, MD, Division of Infectious Diseases, Roger Williams Hospital, 825 Chalkstone Avenue, Providence, RI 02908. Acknowledgments: The authors thank the patients who participated in this study; Dennis Dixon, PhD, and Susan Ellenberg, PhD, for their review of the manuscript; Lori Brashears, RN, Janet Austen Herman, MBA, Elizabeth Hawkins, AA, Mary Culnane, MS, Bernard Landry, MPH, and Pamela Clax, DPM, in the AIDS Clinical Trials Group Operations Office for administrative support; and Susan Auclair, Bill Jesdale, and Lucile Lopez for assistance with manuscript preparation. Grant Support: In part by the AIDS Clinical Trials Group of the National Institute of Allergy and Infectious Diseases.


Copyright ©2004 by the American College of Physicians


Ann Intern Med. 1993;118(5):321-330. doi:10.7326/0003-4819-118-5-199303010-00001
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Objective: To determine whether alternating regimens consisting of zidovudine and 2′,3′-dideoxycytidine (ddC) reduce the toxicity and maintain or increase the antiretroviral effect associated with each drug alone.

Design: An unblinded, randomized (phase II) clinical trial in which seven treatment regimens were compared.

Setting: Outpatient clinics of 12 AIDS Clinical Trials Units.

Patients: One hundred thirty-one patients with the acquired immunodeficiency syndrome (AIDS) or AIDS-related complex and serum p24 antigenemia (≥ 70 pg/mL).

Intervention: Treatments included weekly or monthly alternating zidovudine (200 mg every 4 hours) and ddC (0.01 or 0.03 mg/kg body weight every 4 hours); weekly intermittent zidovudine, 200 mg every 4 hours, or ddC, 0.03 mg/kg every 4 hours; and continuous zidovudine.

Measurements: Toxicity, CD4 cell counts, serum p24 antigen levels, and clinical end points. Data were analyzed for the first 48 weeks of therapy (median follow-up, 40 weeks).

Results: Hematologic toxicity was significantly less frequent in patients who received zidovudine therapy every other week (11% to 15%) or every other month (11% to 14%) than in those who received continuous zidovudine therapy (33%) (P < 0.02). Weekly alternating therapy with zidovudine and ddC, 0.03 mg/kg, or intermittent therapy with ddC, 0.03 mg/kg, produced high rates of peripheral neuropathy (41% and 50%, respectively). Neuropathy occurred in 10% to 21% of patients in the other three alternating-therapy limbs and in 17% of patients receiving zidovudine alone (intermittently or continuously). Initial increases in CD4 cell counts were sustained in three alternating-therapy limbs, but counts returned to baseline by week 28 in the remaining limbs. The median weight gain at week 48 was significantly greater in patients treated with alternating regimens (0.9 to 3.8 kg) compared with those treated with continuous zidovudine therapy ( −0.7 kg) (P = 0.008). Patients treated with alternating regimens and those treated with continuous zidovudine had similarly sustained decreases in p24 antigen levels.

Conclusions: These findings suggest that alternating therapy with zidovudine and ddC reduces the toxicity associated with each drug alone while maintaining strong antiretroviral activity.

Figures

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Figure 1.
The seven treatment regimens.

ddC = 2′,3′-dideoxycytidine.

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Figure 2.
Median change in CD4 cell count from baseline.Top.Middle.Bottom.Figure 1

Alternating regimens (limbs A, B, C, and D) compared with continuous zidovudine (limb G). Intermittent regimens (limbs E and F) compared with continuous zidovudine (limb G). Imputed combined alternating regimens (indicated by X) compared with continuous zidovudine (limb G); missing values for patients not completing 48 weeks of study were imputed using the average of the last two CD4 counts on therapy. The curve labeled X represents combined values for alternating-therapy limbs A, B, C, and D. The baseline CD4 cell count was calculated as the mean of two pretreatment values. The number of participants on therapy in each limb at each time point is indicated along the abscissa. The standard errors of the mean change in CD4 cell count from baseline to weeks 8 and 24 were as follows: limb A, 16.7 and 33.7; limb B, 25.4 and 37.8; limb C, 19.1 and 33.9; limb D, 18.6 and 27.8; limb E, 21.7 and 10.9; limb F, 22.3 and 43.8, and limb G, 228.3 and 20.3. For a detailed description of the regimens, see .

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Figure 3.
The median percent change in serum p24 antigen from baseline.Top.Middle.Bottom.Figure 1

Alternating regimens (limbs A, B, C, and D) compared with continuous zidovudine (limb G). Intermittent regimens (limbs E and F) compared with continuous zidovudine (limb G). Combined alternating regimens (indicated by X) compared with continuous zidovudine (limb G). The curve labeled X represents combined values for alternating-therapy limbs A, B, C, and D. Baseline serum p24 antigen values were calculated as the mean of two pretreatment values. The number of participants on therapy in each limb at each time point is indicated along the abscissa. Antigen testing was done in batch at the conclusion of the study. The standard errors of the mean percent changes in p24 antigen level from baseline to weeks 8 and 24 were as follows: limb A, 32.3 and 5.3; limb B, 12.8 and 22.4; limb C, 4.6 and 11.7; limb D, 21.4 and 12.3; limb E, 21.2 and 20.6; limb F, 41.0 and 11.9; and limb G, 5.4 and 8.3. One patient in limb D was excluded from this calculation. For a detailed description of the regimens, see .

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