Background:  PACTG P1021 is an ongoing phase I/II study of a once-daily regimen of emtricitabine (FTC), didanosine (ddI), and efavirenz (EFV) in anti-retroviral therapy naïve, HIV-infected children 3 to 21 years old (a cohort of 90 days to 3 years old is planned). These results update a prior report based on a scheduled interim analysis with data through June 9, 2003.  The study goals are to establish safety, preliminary efficacy, and pharmacokinetics of the combination in a pediatric population. <

b>Methods: We enrolled 37 children stratified for age; patients remaining on treatment were followed for at least 24 weeks. The median time on study treatment was 54 weeks (range 2 days to 90 weeks). Median age was 10.5 yrs (21 were <12 yreas; 16 were 13 to 21 years old);  46% were female and 23 children were black non-Hispanic, 9 Hispanic, and 5 white non-Hispanic with median CD4 310 cells/µL and HIV RNA 47,775 copies/mL. Most were clinically well: 3 CDC Category N, 22 CDC A, 7 CDC B, 5 CDC C. Intensive pharmacokinetic studies were done at week 2 to evaluate dose regimens for achieving a target AUC.

Results: Of the total, 7 patients permanently discontinued therapy (2 viral failure, 1 voluntary withdrawal, 2 grade 2 or 3 rash, and 2 left care at the study sites). On study medications, there were 5 grade 3 or 4 lab abnormalities that spontaneously resolved, 3 evaluated as possibly drug related. Viral results (intent to treat, discont. = failure) at week 24 (n = 37): 81% <400 copies/mL, 78% <50 copies/mL; in children 3 to 12 years old (n = 21), 86% <400 copies/mL, 81% <50 copies/mL.  For CD4 at week 24 (n = 33), median change is +254 cells/µL and CD4 % is +12% with CD4 in all patients above baseline. FTC and ddI AUC have met protocol-defined AUC targets.  EFV AUC (mg/L*h; 0 to 24 hours) required an increased dose for younger patients receiving solution at an initial interim analysis. Median (range) EFV AUC were lower in children <12 years old (40.3; 11.6 to 55.1) than those >12 years (61; 28.7 to 130.6). Moreover, median (range) AUC was lower for solution (30.8; 11.6 to 52.9) than capsules (46.5; 35.2 to 55) for children <12 years. 

Conclusions:  Based on this planned interim analysis, an easily administered once-a-day combination of FTC/ddI/EFV in children 3 to 21 years of age remains highly effective and well tolerated by children with longer followup. EFV dose requirements in younger children require further evaluation to accommodate formulation and/or age related pharmacokinetic differences.

Keywords: emtricitabine; efavirenz; didanosine