By Liz Highleyman

Darunavir (Prezista)

New antiretroviral drug are tested and approved based on safety and effectiveness in adults. While physicians may prescribe adult medications "off label" to children and adolescents, it is important that these agents also be evaluated in pediatric patients.

At the 48th International Conference on Antimicrobial Agents and Chemotherapy (ICAAC) this week in Washington, DC, researchers presented results from the DELPHI (TMC114-C212) trial looking at the safety and efficacy of ritonavir-boosted darunavir (Prezista) in treatment-experienced pediatric patients with multiple drug resistance mutations.

In this open-label Phase II study, 80 children and adolescents in the U.S., South America, and Europe aged 6-17 years (median 14 years) received darunavir/ritonavir plus an optimized background regimen for at least 48 weeks. Most were infected via mother-to-child transmission, nearly three-quarters (71%) were male, the mean baseline viral load was 4.64 log10 copies/mL, the median CD4 count was 330 cells/mm3, and the median CD4 percentage was 17%.

Participants had previously used a median of 9 antiretroviral drugs and almost all (96%) had used a protease inhibitor (PI). The patients had a median of 3 primary PI resistance mutations, 11 PI resistance-associated mutations, 2 NNRTI resistance mutations, and 4 NRTI resistance mutations

Darunavir/ritonavir was dosed according to body weight:

• 20-29 kg: 375/50 mg twice-daily (BID) (n = 20);
• 30-39 kg: 450/60 mg BID (n = 24);
• > 40 kg: 600/100 mg BID (n = 36).

Pharmacokinetics (PK), safety, and efficacy were assessed throughout the follow-up period.

Results

• Target darunavir PK exposures for treatment-experienced adults were achieved across all pediatric age groups and weight bands, confirming appropriate dose selection.

• At week 48, 65% of patients achieved at least a 1.0 log10 (10-fold) reduction in HIV RNA from baseline (time to loss of virological response, or TLOVR, analysis).

• 48% achieved viral load < 50 copies/mL (TLOVR).

• 59% achieved viral load < 400 copies/mL (TLOVR).

• 59% of patients with no baseline darunavir resistance mutations achieved < 50 copies/mL, compared with 47% of patients with 1-2 such mutations, and 0% of those with 3 or more mutations.

• The mean CD4 cell increase was 147 cells/mm3.

• Body weight scores improved significantly while on darunavir/ritonavir.

• 74 patients (93%) reported at least 1 adverse event (AE).

• The most common treatment-emergent AEs (occurring in at least 15% of patients) were pyrexia (fever), cough, upper respiratory tract infections, and diarrhea.

• Most AEs were mild to moderate (grade 1-2).

• 21 patients (26%) experienced grade 3-4 AEs.

• Most of these occurred as single events in individual patients and were considered unrelated to darunavir/ritonavir.

• 6 patients (8%) experienced grade 2-4 AEs at least possibly related to darunavir/ritonavir.

• 11 patients (14%) experienced serious AEs, but no deaths were reported.

• 1 patient (1%) permanently discontinued therapy due to grade 3 anxiety considered unrelated to darunavir/ritonavir.

Based on these results, the DELPHI investigators concluded that "Darunavir/ritonavir was beneficial in this treatment-experienced, pediatric population based on the favorable tolerability, PK profiles, and virologic response rates at week 48."

Paris, France; Buenos Aires, Argentina; Constantza, Romania; Memphis,TN; Barcelona, Spain; Tibotec, Belgium and PA.

10/31/08

Reference
S Blanche, R Bologna, P Cahn, and others. 48-Week Safety and Efficacy of Darunavir/Ritonavir (DRV/R) in Treatment-Experienced Children and Adolescents in DELPHI. 48th International Conference on Antimicrobial Agents and Chemotherapy (ICAAC 2008). Washington, DC. October 25-28, 2008. Abstract H-894.