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Good 48-Week Response to Darunavir in Children With Antiretroviral Experience
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7th IAS Conference on HIV Pathogenesis, Treatment and Prevention, June 30-July 3, 2013, Kuala Lumpur
Mark Mascolini
Four in 5 children taking a failing antiretroviral regimen responded virologically to a darunavir/ritonavir combination for 48 weeks, according to results of the noncomparative ARIEL trial [1]. Only 3 children had virologic failure and only 1 dropped out because of adverse events in this 21-child analysis.
Week-24 results of ARIEL led to approval of darunavir/ritonavir for antiretroviral-experienced children from 3 to 6 years old and weighing 10 to under 20 kg. At the 7th IAS Conference, researchers presented 48-week results of this phase 2, open-label, 5-country trial. All study participants had a viral load above 1000 copies, had taken antiretroviral therapy for at least 12 weeks, and had fewer than three darunavir-associated resistance mutations.
After 2 weeks of treatment and Data and Safety Monitoring Board advice, the ARIEL team settled on darunavir/ritonavir doses of 25/3 mg/kg twice daily for children 10 to under 15 kg and 375/50 mg/kg twice daily for those weighing 15 to under 20 kg. All children took darunavir/ritonavir oral suspension plus an investigator-selected background regimen of two or three nucleosides.
Of the 21 study participants, 11 were girls, 12 black or African American, 6 white, 1 Asian, and 2 mixed race. Median age stood at 4.4 years and ranged from 3 to 6. Baseline viral load averaged about 22,000 copies, and baseline median CD4 count was 927. Median number of primary protease inhibitor mutations was 0, darunavir mutations 0, and secondary protease inhibitor mutations 4. Median fold change in 50% effective concentration for darunavir was 0.55 and ranged from 0.2 to 2.3.
Sixteen children had taken lopinavir/ritonavir and 10 had taken nevirapine. Nineteen children took two nucleosides in their background regimen and 2 took three, usually lamivudine (62%), zidovudine (62%), abacavir (38%), or stavudine (38%).
After an average 47.9 weeks of treatment, only 1 child had an adverse event at least possibly related to darunavir (QT prolongation on ECG), and only 1 child discontinued therapy (because of grade 2 vomiting probably related to ritonavir). Two children had grade 3 or 4 adverse events (both considered unrelated to treatment). No child had a clinically relevant lab value change from baseline. All lab abnormalities were grade 1 or 2 except for grade 3 neutropenia in 1 child, which was present at baseline and not considered related to treatment.
A week-48 time-to-loss-of-virologic-response analysis determined that 81% of children had a viral load below 50 copies and 85.7% had a sub-400-copy viral load. By the FDA snapshot analysis, 71.4% had a week-48 viral load below 50 copies. Almost all children (90.5%) had at least a 10-fold drop in viral load by week 48. CD4 percent rose an average 4% from baseline to week 48.
Two children had darunavir-related resistance mutations when the study began, L33F/L plus L76V in 1 and L76V in 1. Both had a viral load below 50 copies at weeks 24 and 48. Among the 3 children (14%) with virologic failure at week 48, 2 never reached an undetectable viral load and 1 had a viral load rebound. Two children with virologic failure had baseline and endpoint genotypes, and no protease inhibitor or nucleoside mutations emerged in either. Both remained susceptible to darunavir and to nucleosides in the background regimen.
Reference
1. Violari A, Bologna R, Kumarasamy N, et al. Safety and efficacy of darunavir/ritonavir in treatment-experienced pediatric patients aged 3 to < 6 Years: week 48 analysis of the ARIEL trial. 7th IAS Conference on HIV Pathogenesis, Treatment and Prevention, June 30-July 3, 2013, Kuala Lumpur. Abstract MOAB0102.
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