Pharmacokinetics and 48-week safety and efficacy of raltegravir for oral suspension in human immunodeficiency virus type-1-infected children 4 weeks to 2 years of age

Background. IMPAACT P1066 is a Phase I/II open-label multicenter trial to evaluate safety, tolerability, pharmacokinetics (PK), and efficacy of multiple raltegravir (RAL) formulations in human immunodeficiency virus (HIV)-infected youth. Methods. Dose selection of the oral suspension formulation for each cohort (IV: 6 months to < 2 years and V: 4 weeks to < 6 months) was based on review of short-term safety (4 weeks) and intensive PK evaluation. Safety data through Weeks 24 and 48 and Grade ≥ 3 or serious adverse events (AEs) were assessed. The primary virologic endpoint was achieving HIV RNA < 400 copies/mL or ≥ 1 log₁₀ reduction from baseline at Week 24 (Success). For Cohort IV, optimized background therapy (OBT) could have been initiated with RAL either at study entry or after intensive PK sampling was completed at Day 5-12. An OBT was started when RAL was initiated for Cohort V subjects because they were not permitted to have received direct antiretroviral therapy before enrollment. Results. Total accrual was 27 subjects in these 2 cohorts, including 1 subject who was enrolled but never started study drug (excluded from the analyses). The targeted PK parameters (area under the curve [AUC]_0-12hr and C_12hr) were achieved for each cohort allowing for dose selection. Through Week 48, there were 10 subjects with Grade 3+ AEs. Two were judged related to study drug. There was 1 discontinuation due to an AE of skin rash, 1 event of immune reconstitution syndrome, and no drug-related deaths. At Week 48, for Cohorts IV and V, 87.5% of subjects achieved virologic success and 45.5%had HIV RNA < 50 copies/mL. At Week 48, gains in CD4 cells of 527.6 cells/mm³ and 7.3% were observed. Conclusions. A total of 6 mg/kg per dose twice daily of RAL for oral suspensionwas well tolerated and showed favorable virologic and immunologic responses.