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To determine the long-term immunologic and virologic effects of highly active antiretroviral therapy (HAART) in children with AIDS.A prospective observational study.Two pediatric HIV clinics.Twenty-five protease-inhibitor naive HIV-infected children (aged 2-18 years) with advanced disease (CD4≤6%).HAART (one protease inhibitor and one or more nucleoside analogs). Diphtheria and tetanus immunization in six patients after 18 months of therapy.Changes in percentage of CD4 cells and plasma HIV-1 RNA levels; post-treatment assays of lymphoproliferative responses to recall antigens; CD4 cell memory phenotype.Median duration of follow-up was 18.8 months (range, 7.5-28 months). At baseline the CD4 cell percentage was 2% (range, 0-6%), this increased significantly to 16% (range, 3-48%) above baseline at 12 months (P=0.002). The mean maximum CD4 cell increase was 20.7% (range 4-48%) which corresponds to 657×106 cells/l (range, 30-2240×106 cells/l) above baseline. By contrast, the median viral load was not significantly lower at 12 months than at baseline (P=0.34), and only 25% of the patients had sustained undetectable viral load. Of the reconstituted CD4 cells 70% were naive, and none of the subjects had lymphoproliferative responses to tetanus and diphtheria although 40% did develop responses to Candida, an environmental antigen. A single immunization with diphtheria and tetanus toxoid produced lymphoproliferative responses to tetanus in three out of six patients.HAART was associated with sustained increases in CD4 cell counts, despite a high incidence of‚virologic failure‚. CD4 counts and the proportion of naive cells were higher than have been reported in adults, which may be a reflection of greater thymic activity in children. Memory cell clones for antigens encountered in the past which are not prevalent before therapy could not be expanded without additional antigenic exposure.