Long‐Term Effects of Highly Active Antiretroviral Therapy on CD4+Cell Evolution among Children and Adolescents Infected with HIV: 5 Years and Counting

Abstract

Background. Lower percentages of CD4⁺ T lymphocytes are associated with adverse clinical outcomes among children and adolescents infected with human immunodeficiency virus (HIV). CD4⁺ lymphocyte percentage generally increases with receipt of highly active antiretroviral therapy (HAART), but long-term follow-up is required to assess whether these increases in CD4⁺ cell percentage are maintained and whether they lead to normal CD4⁺ cell percentages in children with severe immunosuppression. Methods. The study population included 1236 children and adolescents perinatally infected with HIV who were enrolled in a US-based multicenter prospective cohort study (Pediatric AIDS Clinical Trials Group 219/219C) and who were not receiving HAART at study initiation. We estimated the effects of HAART, HAART with protease inhibitors, and HAART with nonnucleoside reverse-transcriptase inhibitors on CD4⁺ cell percentage, using marginal structural models to account for confounding by severity. Results. Initiation of any type of HAART increased CD4⁺ cell percentage by 2.34% (95% confidence interval, 1.35%–3.33%) in the first year, relative to noninitiation of HAART. The substantial increases in CD4⁺ cell percentage observed after the first year of experience with these combination therapies were followed by relatively smaller increases that continued for 5 years after initiation. Although larger increases in CD4⁺ cell percentage were observed among children with a greater degree of immunosuppression at baseline, the mean CD4⁺ cell percentage after 5 years of HAART did not reach normal levels. Conclusions. Our study supports the initiation of HAART in children before severe immunosuppression occurs for long-term maintenance of normal CD4⁺ cell percentages. This beneficial result must be weighed against the evidence of potential adverse events associated with the prolonged use of such therapy.