A randomized study of combined zidovudine-lamivudine versus didanosine monotherapy in children with symptomatic therapy-naive HIV-1 infection☆,☆☆,★,★★

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Abstract

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)

Section snippets

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

Study Population

Patients were randomized beginning on July 12, 1995. As of April 4, 1997 (the date at which the data set was frozen), a total of 615 patients had been randomized, of whom 596 were included in this analysis. The other 19 were excluded because of recent study entry and no information regarding initiation of treatment (n = 13), nonreceipt of study drug because of parental refusal to participate (n = 5), or ineligibility because of exclusion criteria (n = 1). Overall, 236 subjects who could be

Discussion

PACTG Protocol 300 demonstrated a significant benefit to combination ZDV/3TC over ddI monotherapy by almost all measures. Although it was not part of the primary analysis, a comparable clinical benefit was seen with combination ZDV/ddI. The beneficial effects were most clearly demonstrable in the <3-year-old stratum, because 83% of the endpoints occurred in that cohort. Fifty-three percent of the enrollees were in the younger stratum. The rapid progression of HIV disease in the first years of

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    • Cited by (0)

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    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.

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    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.

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    Reprint requests: Ross McKinney, Jr, MD, Box 3461, Duke University Medical Center, Durham, NC 27710.

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    0022-3476/98/$5.00 + 0  9/21/93783

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