with symptomatic therapy-naive HIV-1 infection. Ross E. ... For patients concurrently randomized to all 3 treatment arms, both ZDV/3TC and ZDV/ddI recip-.
A
A randomized study of combined zidovudine-
lamivudine versus didanosine monotherapy in children with symptomatic therapy-naive HIV-1 infection
Ross E. McKinney, Jr, MD, George M. Johnson, MD, Kenneth Stanley, PhD, Florence H. Yong, MS, Amy Keller, Karen J. O’Donnell, PhD, Pim Brouwers, PhD, Wendy G. Mitchell, MD, Ram Yogev, MD, Diane W. Wara, MD, Andrew Wiznia, MD, Lynne Mofenson, MD, James McNamara, MD, Stephen A. Spector, MD, and the Pediatric AIDS Clinical Trials Group Protocol 300 Study Team Objective: The Pediatric AIDS Clinical Trials Group (PACTG) Protocol 300 assessed the clinical efficacy and safety of combination zidovudine/lamivudine (ZDV/3TC) compared with either didanosine (ddI) alone or combination ZDV/ddI. Study design: Children with symptomatic human immunodeficiency virus (HIV) infection, 6 weeks through 15 years of age, were stratified according to age and randomly assigned to receive ddI, ZDV/3TC, or ZDV/ddI. The primary endpoint was time to first progression of HIV disease or death. Enrollment in the ZDV/ddI arm stopped after 11 months on the basis of results of PACTG Protocol 152, but blinded follow-up continued. Results: For the 471 children who could be evaluated, the median age was 2.7 years, median CD4 cell count was 699 cells/mm3, and median log10 HIV RNA was 5.1/mL. Median follow-up was 9.4 months. Patients receiving ZDV/3TC had a lower risk of HIV disease progression or death than those receiving ddI alone (15 vs 38 failures, P = .0006) and a lower risk of death (3 vs 15 deaths, P = .0039). Weight and height growth rates, CD4+ cell counts, and RNA concentrations showed results favoring ZDV/3TC. For patients concurrently randomized to all 3 treatment arms, both ZDV/3TC and ZDV/ddI recipients had lower risk of HIV disease progression than those who received ddI alone (P = .0026 and P = .0045).
Conclusions: Combination therapy with either ZDV/3TC or ZDV/ddI was superior, as determined by clinical and laboratory measures, to monotherapy with ddI. (J Pediatr 1998;133:500-8)
Pediatric AIDS Clinical Trials Group Protocol 300 was designed to compare the clinical efficacy of combined zidovudine and lamivudine against the better of
didanosine monotherapy or combination ZDV/ddI, as determined by PACTG 152.1 Combination nucleoside antiviral regimens with 3TC have demonstrated
From the Department of Pediatrics and Psychiatry, Duke University Medical Center, Durham, North Carolina; Department of Pediatrics, Medical University of South Carolina, Charleston; Department of Biostatistics, Harvard School of Public Health, Boston, Massachusetts; Glaxo Wellcome, Inc, Research Triangle Park, North Carolina; Intramural Research Program, National Cancer Institute, Bethesda, Maryland; Children’s Hospital of Los Angeles, Los Angeles, California; Department of Pediatrics, Children’s Memorial Hospital, Chicago, Illinois; Department of Pediatrics, University of California, San Francisco; Department of Pediatrics, Bronx Lebanon Hospital Center, Bronx, New York; Pediatric, Adolescent, and Maternal AIDS Branch, National Institute of Child Health and Human Development, Bethesda, Maryland; Pediatric Medicine Branch, Division of AIDS, National Institute of Allergy and Infectious Diseases, Bethesda, Maryland; and the Department of Pediatrics, University of California, San Diego. Financial assistance: Sites were funded through the Pediatric AIDS Clinical Trials Group of the National Institute of Allergy and Infectious Diseases, the Pediatric/Perinatal HIV Clinical Trials Network of the National Institute of Child Health and Human Development, and by Glaxo-Wellcome, Inc. Funding for the RNA testing was provided by Glaxo-Wellcome. Didanosine was provided by Bristol Myers Squibb, and zidovudine and 3TC by Glaxo-Wellcome.
both laboratory and clinical benefits in adult clinical trials.2,3 Three-drug antiretroviral regimens containing 2 nucleoside analog reverse-transcriptase inhibitors and a protease inhibitor are now recommended for initial treatment of children and adults with human immuAIDS CDC CNS ddI HIV-1 PACTG PCR 3TC ZDV
Acquired immunodeficiency syndrome Centers for Disease Control and Prevention Central nervous system Didanosine Human immunodeficiency virus, type 1 Pediatric AIDS Clinical Trials Group Polymerase chain reaction Lamivudine Zidovudine
Submitted for publication Feb 20, 1998; revision received July 16, 1998; accepted Aug 12, 1998. Reprint requests: Ross McKinney, Jr, MD, Box 3461, Duke University Medical Center, Durham, NC 27710. Copyright © 1998 by Mosby, Inc. 0022-3476/98/$5.00 + 0 9/21/93783
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nodeficiency virus infection.4,5 It is nevertheless important to identify nucleoside regimens useful for initial therapy of
THE JOURNAL OF PEDIATRICS VOLUME 133, NUMBER 4 HIV-infected children, either as the nucleoside backbone for combination therapy with a protease inhibitor or as a dual nucleoside combination when a protease inhibitor cannot be used. Several pediatric and adult clinical trials have demonstrated the superiority of combination nucleoside therapies over ZDV monotherapy.1,3,6 Although theoretic models have supported the general use of combination antiretroviral regimens, several large clinical trials have not shown superiority of nucleoside combinations relative to monotherapy with ddI.1,6,7 In PACTG 152, the lack of added benefit from ZDV/ddI over ddI monotherapy made it difficult to uniformly recommend ZDV/ddI for children with symptomatic therapy-naive HIV infection. Although the combination of ZDV/3TC has shown promise in adults, data regarding its relative clinical efficacy in children are important in order to optimize pediatric antiretroviral treatment.
METHODS Study Design PACTG 300 was a multicenter, randomized, double-blind clinical trial to compare the efficacy of ZDV/3TC against the better of ddI monotherapy or ZDV/ ddI in previously untreated children. Selection of which ddI-containing regimen would be used for primary comparison with ZDV/3TC was to be determined by PACTG 152, which had not concluded at the time PACTG 300 began enrolling patients. In February 1996, results of PACTG 152 indicated that disease progression was similar in children receiving ddI or ZDV/ddI.1 There was a significantly greater rate of hematologic toxicity in the ZDV/ddI arm. Therefore randomization to the ZDV/ddI combination arm of PACTG 300 was terminated on May 16, 1996. Patients already entered into the ZDV/ddI arm remained blinded to their assigned therapy and continued to receive it until study closure. The primary endpoint for the study was time to first evidence of clinical progression of HIV disease. The definition of “clinical progression” included: (1) death; (2) new Centers for Disease Con-
MCKINNEY ET AL
trol Clinical Category C diagnosis; (3) central nervous system disease progression; (4) weight growth failure, defined as 3 consecutive months with less than the 3rd percentile for age- and genderspecific 6-month weight growth velocity on incremental growth curves,8 without an obvious alternative explanation (eg, a diet in an obese child). Because participants could not have 3 measurements of 6-month growth velocities, the study chair reviewed patients who had inadequate weight growth at the 24-week or 28-week study visits. Medication dosages were: ZDV, 160 mg/m2 per dose 3 times daily (maximum, 200 mg/dose); 3TC, 4 mg/kg per dose every 12 hours (maximum, 150 mg/dose); ddI monotherapy, 120 mg/m2 per dose every 12 hours (maximum, 200 mg/dose); and ddI in combination, 90 mg/m2 per dose every 12 hours (maximum, 150 mg/dose). An Institution Review Board–approved informed consent document was signed by all patients or their parents.
Study Population The study population consisted of children with symptomatic HIV infection, aged 42 days to 15 years, who had received ≤56 days of prior antiretroviral therapy. Patients were stratified by age,
