Background:  TMC114-C212 is an ongoing 48-week, open-label, 2-part phase II study to support dosing recommendations of darunavir co-administered with low-dose ritonavir (DRV/r) and to evaluate pharmacokinetics, safety, tolerability, and efficacy in HIV-1-infected treatment-experienced children and adolescent patients aged 6 to 17 years. In part I, patients were randomized to 2 DRV/r dose groups; all patients received the recommended dose per body weight in part II. Primary 24-week safety and efficacy results of part II are presented.

Methods:  Patients were administered doses of DRV/r by body weight for at least 24 weeks:  20 to <30 kg, 375/50 mg twice a day (20 patients); 30 to <40 kg, 450/60 mg twice a day (24 patients); ≥40 kg, 600/100 mg twice a day (36 patients). Assessments for pharmacokinetics, safety, and efficacy parameters (HIV-1 RNA, CD4 percentage, and CD4 cell counts) were performed throughout the study.

Results:  A total of 80 children and adolescents (71% male; median age of 14 years [range 6 to 17]) received DRV/r; mean baseline HIV-1 RNA was 4.64 log₁₀ copies/mL, median baseline CD4 count was 330 cells/mm³, and CD4 percentage was 17% (31% had CD4 <200 cell/mm³). Median number of antiretrovirals (ARV) previously used was 9. Median baseline of 3 International AIDS Society (IAS) -USA primary protease inhibitor (PI) mutations, 11 PI resistance-associated mutations (RAM; 65% had ≥10 PI RAM) and 1 NNRTI and 4 NRTI RAM. The target DRV pharmacokinetic exposures for treatment-experienced adults were achieved across all age groups and weight bands confirming appropriate dose selection in this pediatric population; 71 patients (89%) reported 1 adverse event. The most common treatment-emergent adverse events (>10% of patients) were upper respiratory tract infection, cough, pyrexia, vomiting, diarrhea, and lymphadenopathy. Most adverse events were grade 1 or 2 in severity. Grade 3 or 4 adverse events were reported in 18 patients (23%); the majority occurred as single events in individual patients and was considered unrelated to DRV/r. Serious adverse events, all single events, were reported in 9 patients (11%); no deaths were reported during treatment. One patient permanently discontinued treatment due to grade 3 anxiety considered to be unrelated to DRV/r by the investigator. At week 24, 74% of patients had a reduction of ≥1.0 log₁₀ HIV-1 RNA from baseline (confirmed virologic response). HIV-1 RNA <400 copies/mL and <50 copies/mL were achieved by 64% and 50% of patients, respectively. At this time, the mean change in CD4 cell count from baseline was 117 cells/mm³.

Conclusions:  DRV/r was an effective treatment in treatment-experienced HIV-1-infected pediatric patients (6 to 17 years) due to the favorable tolerability and pharmacokinetics profiles, and virologic response rates at Week 24.