Week 24 results from a study of darunavir (Prezista) in a treatment experienced, HIV-infected pediatric population have shown the drug to be virologically effective and generally well tolerated, with a pharmacokinetic profile comparable to that in treatment-experienced adults.
The late-breaker results were presented to the Fifteenth Conference on Retroviruses and Opportunistic Infections in Boston on Tuesday by Sabrina Spinoza-Guzman of Tibotec on behalf of a multinational study group.
TMC114-C212 is an ongoing open-label study of ritonavir-boosted darunavir (DRV/r) in antiretroviral-experienced children and adolescents, otherwise known as the DELPHI (Darunavir EvaLuation in Pediatric HIV-1-Infected treatment-experienced patients) trial. In part I, patients were randomised to one of two DRV/r dose groups. In part II, presented here, all patients received the recommended dose per body weight, as described below. Safety, tolerability, and efficacy data from week 24 of this 48-week study were presented at the Tuesday oral session.
All 80 study participants were aged 6 to 17 years, and had been on HAART for at least 12 weeks. All received an optimised background regimen of at least two antiretroviral agents. In addition, DRV/r dosages were assigned based on body weight. Twenty patients weighing from 20 to <30 kg received 375/50mg (darunavir/ritonavir) twice daily.
Twenty-four patients weighing from 30 to <40 kg received 450/60mg twice daily, and thirty-six patients weighing ≥40 kg received 600/100mg twice daily.
Median age at baseline was 14 years. Fifty-seven participants (71%) were male. At baseline, mean HIV viral load was 4.64 log10 copies/mL, median CD4 count was 330 cells/mm3 (range, 6 to 1505), and CD4 percentage was 17% (range, 0.7 to 47). CD4 counts were <200 cell/mm3 in 31% of the participants. Participants were heavily treatment-experienced, with a median of nine ARVs having previously been used (range, 3 to 19), and a median baseline of 4 NRTI resistance-associated mutations (RAMs), 1 NNRTI RAM, 11 PI RAMs (65% had ≥10 PI RAMs), and 3 primary protease inhibitor (PI) mutations as defined by the International AIDS Society-USA (IAS-USA).
At week 24, viral load had decreased to below 50 copies/ml in 50% of the study participants, and below 400 copies/mL in 64%. A reduction of at least 1 log10 in viral load was achieved by 74%. The mean increase in CD4 cell count from baseline was 117 cells/mm3.
At least one adverse event (AE) was reported by 71 participants (89%). The most common, occurring in over 10% of participants, were upper respiratory tract infection, cough, pyrexia, vomiting, diarrhea, and lymphadenopathy. Most AEs were grade 1 or 2 in severity; grade 3 or 4 adverse events were reported in 18 patients (23%). Serious adverse events were reported by 9 (11%) of the participants and were all single events. There were no deaths during the 24-week period and only one participant withdrew from the study due to an AE (grade 3 anxiety that the investigator considered to be unrelated to the study drug).
Targeted darunavir pharmacokinetic exposures for treatment-experienced adults were reached in all weight bands and age groups. 24-hour AUC and trough concentrations (C0h) were very close to those found in adults in the POWER1 and 2 studies; trough concentrations (mean, 3888 ng/ml, range 1836 – 7821) were well above the corrected EC50 value of 550 ng/ml in all children.
The investigators concluded that ritonavir-boosted darunavir showed good virologic response rates, positive clinical outcomes, favourable safety and tolerability, and comparable exposure to adults in this group of treatment-experienced children and adolescents at week 24.