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Human Immunodeficiency Virus...

PEDIATRICS Vol. 107 No. 1 January 2001, p. e4

ELECTRONIC ARTICLE:
A Randomized, Double-Blind Study of Triple Nucleoside Therapy of Abacavir, Lamivudine, and Zidovudine Versus Lamivudine and Zidovudine in Previously Treated Human Immunodeficiency Virus Type 1-Infected Children

Received May 24, 2000; accepted Aug 30, 2000.

Xavier Sáez-Llorens*, Robert P. Nelson JrDagger , Patricia Emmanuel§, Andrew Wizniaparallel , Charles Mitchell, Joseph A. Church#, John Sleasman**, Russell Van DykeDagger Dagger , Carol Gilbert Richardson§§, Amy Cutrell§§, William Spreen§§, Seth Hetherington§§, and the CNAA3006 Study Team

From * Hospital del Niño, Servicio de Infectologia, Panama City, Republic of Panama; Dagger  Department of Hematology and Oncology, Indiana University, Indianapolis, Indiana; § Pediatric Infectious Disease, University of South Florida College of Medicine, Tampa, Florida; parallel  Department of Pediatrics, Jacobi Medical Center, Bronx, New York;  Division of Pediatric Infectious Diseases, University of Miami School of Medicine, Miami, Florida; # Division of Clinical Allergy and Immunology, Childrens Hospital of Los Angeles, Los Angeles, California; ** Division of Infectious Disease and Immunology, University of Florida at Gainesville, Gainesville, Florida; Dagger Dagger  Department of Pediatrics, Tulane University School of Medicine, New Orleans, Louisiana; and §§ Glaxo Wellcome Inc, Research Triangle Park, North Carolina.

Objectives.  Abacavir (ABC) is a potent inhibitor of human immunodeficiency virus type 1 (HIV-1) reverse transcriptase. We compared the efficacy, safety, and tolerability of combination therapy with ABC, lamivudine (3TC), and zidovudine (ZDV) versus 3TC and ZDV in antiretroviral experienced HIV-1-infected children over 48 weeks.

Methods.  Two hundred five HIV-1-infected children who had received previous antiretroviral therapy and had CD4+ cell counts >= 100 cells/mm3 were stratified by age and by previous treatment. Participants were randomly assigned to receive ABC (8 mg/kg twice daily [BID]) plus 3TC (4 mg/kg BID) and ZDV (180 mg/m2 BID; ABC/3TC/ZDV group) or ABC placebo plus 3TC (4 mg/kg BID) and ZDV (180 mg/m2; 3TC/ZDV group). Participants who met a protocol-defined switch criteria (plasma HIV-1 RNA >0.5 log10 copies/mL above baseline at week 8 or >10 000 copies/mL after week 16) had the option to switch to open-label ABC plus any antiretroviral combination or continue randomized therapy or withdraw from the study.

Results.  The Kaplan-Meier estimates (95% confidence interval) of the proportion of participants who maintained HIV-1 RNA levels <= 10 000 copies/mL for 48 weeks or more was significantly better in the ABC/3TC/ZDV group compared with the 3TC/ZDV group: 33% (23%-42%) versus 21% (13%-29%). At week 48, the proportions of participants with HIV-1 RNA <= 10 000 copies/mL were 36% versus 26% for the ABC/3TC/ZDV and 3TC/ZDV groups, respectively, by intent-to-treat analysis. For the subgroup of participants with baseline HIV-1 RNA >10 000 copies/mL, a significantly higher proportion of participants in the ABC/3TC/ZDV group had HIV-1 RNA <= 10 000 copies/mL compared with the 3TC/ZDV group (29% vs 12%) but no difference was observed in the subgroup of participants with baseline HIV-1 RNA <= 10 000 copies/mL (78% vs 72%). The median changes from baseline in CD4+ cell counts were greater in the ABC/3TC/ZDV group than in the 3TC/ZDV group. Few participants (3%) experienced abacavir-related hypersensitivity reaction.

Conclusions.  ABC, in combination with 3TC and ZDV, provides additional antiretroviral activity over 48 weeks, compared with combination therapy with 3TC and ZDV in antiretroviral experienced HIV-1-infected children. ABC was safe and generally well-tolerated and should be considered an active component of combination antiretroviral therapy in this pediatric population.  Key words:  human immunodeficiency virus type 1, abacavir, lamivudine, zidovudine, viral ribonucleic acid, CD4, antiretroviral therapy, pediatric.