Background:  Raltegravir (RAL) is an HIV-1 integrase inhibitor approved for use in adults. P1066 is an open-label study of RAL in treatment experienced HIV⁺ youth; acceptable pharmacokinetics, safety, and short-term efficacy have been described in 6- to 18-year-olds receiving the adult formulation and 2- to 11-year-olds receiving a chewable tablet formulation. We report intensive pharmacokinetics, available safety data, and 12-week efficacy from cohort IV, 6-month- to <2-year-old subjects receiving the RAL oral granule formulation.

Methods:  We enrolled 9 HIV⁺ 6 month-old to <2-year-old patients in a dose-finding study. Entry criteria included HIV RNA >1000 copies/mL, and either prior ARV experience or failure of PMTCT. Patients received weight-based RAL oral granule suspension at ~6 mg/kg, every 12 hours. Intensive pharmacokinetic samples were drawn between day 5 and 12, then ARV were optimized, when possible. Summary pharmacokinetic parameters were evaluated and a dose was selected for continued study using an area-under-the-curve (AUC_{12 hr}) targeted design (geometric mean [GM] target range of 14 to 25 µM*h) with C_12h target to exceed the RAL IC₉₅ (31 nM). Virologic success was defined as HIV RNA <400 copies/mL or ≥1 log drop from baseline.

Results:  Of the 9 patients (8 with pharmacokinetic data):  67% were male; 78% black; mean (SD) age, 13 months (6.3); log₁₀ RNA, 5.68 copies/mL (0.95); CD4%, 21% (9%); CD4 count, 1338 cells (822); weight, 8.3 kg (2.6), dose, 5.94 mg/kg (0.42). Cohort GM values:  AUC_12hr, 20 µM*h; C_max, 10.7 µM; and C_12h, 115 nM. Of the 9 patients, 3 had 12 grade ≥3 adverse events, none related to study drug.  Patient 1, 3 low ANC and 7 reports of elevated lipase with concurrent acute Epstein-Barr virus (EBV) infection; patient 2, dyspnea; and patient 3, low ANC. One child spit up (grade 1) after taking the study drug. No adverse events (to date) were reported after week 8, with no treatment discontinuation due to study drug. Virologic success was noted in 78% (95%CI 40% to 97%) of the 9 subjects at week 12. There was a median net gain in CD4% of 5 (–3 to 7) and CD4 cells of 687 (–297 to 1237) at week 12.

Conclusions:  Using weight-based dosing of RAL oral granules at ~6 mg/kg every 12 hours, in 6 month- to 2-year-old patients, pharmacokinetic values achieved study targets and were similar to those observed in 2- to 11-year-old patients. The 6 mg/kg every 12 hours dose was chosen for continued study in this age group. These data suggest that RAL oral granules are safe and well tolerated by young children. Preliminary efficacy data through week 12 are favorable.