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-old youth receiving the adult formulation and  in 6- to 12-year-old youths receiving a chewable tablet. Here we report initial pharmacokinetics, efficacy, and all safety data as of October 1, 2010 from Cohort III, 2- to 5-year-old subjects receiving the RAL chewable tablet,

Methods:  We enrolled 12 HIV⁺ 2- to 5-year-old children in a dose-finding study with intensive pharmacokinetic and safety and virologic response. Entry criteria included HIV RNA >1000 copies/mL, prior ARV experience but naïve to integrase inhibitors. A RAL chewable tablet 6 mg/kg twice daily was added to the existing ARV regimen, intensive pharmacokinetic samples drawn between day 5 and 12, then ARV were optimized. Summary pharmacokinetic parameters were evaluated and a dose was selected for continued study using an area-under-the-curve (AUC 12 h) targeted design (target range of 14 to 25 mM*h) based on available pharmacokinetic data with a C_12h target to exceed the protein-adjusted IC₉₅ of RAL against wild type virus (31 nM). Pharmacokinetic parameters were compared to existing data from 6- to 18-year-old children receiving the adult formulation and 6- to 11-year-old children receiving RAL chewable tablet. Virologic success was defined as vRNA <400 copies/mL or 1 log drop from baseline.

Results:  Of the 12 children, 67% were female, 75% black, 3 years old (±1); log₁₀ RNA, 4.14 copies/mL (0.89); CD4%, 33% (17%); CD4 count, 1505 cells (1568); weight, 14.3 kg (2.4), dose, 6.24 mg/kg (0.67); AUC_12h, 21 mM*h (13); C_max, 11.7 mM (6.6); and C_12h, 89 nM (49), compared to the 6- to 11-year-olds dosed at 6 mg/kg, mean AUC_12h, C_max, C_12h and weight; 24 mM*h, 12 mM, 171 nM, and 24 kg, respectively. There were 5 patients with 7 grade ≥3 adverse events (5 low ANC); none were related to the study drug. No treatment was discontinued. Virologic success was noted in 75% (95%CI 43 to 95%) of 12 subjects at week 12 and 60% (26 to 88%) of 10 subjects who reached week 24. There was a net gain (95%CI) in percentage of CD4 cells of 3 (1 to 9) points at week 12 and 7 (1 to 18) at week 24.

Conclusions:  Using weight-based dosing of RAL chewable tablet at 6 mg/kg twice daily, in 2- to 5-year old children, pharmacokinetic data were similar to those observed in 6- to 11-year-old children. A RAL chewable tablet dose of 6 mg/kg (maximum 300 mg) twice daily was chosen for continued study in this age group. In these subjects, RAL chewable tablet appeared to be generally safe and well tolerated. Partial efficacy data through week 24 were favorable.