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IAS 2013: Darunavir/Ritonavir Is Safe and Effective for Younger Children with HIV


Over 80% of treatment-experienced children with HIV aged 3 to 6 years who received ritonavir-boosted darunavir (Prezista) with an optimized background regimen achieved virological suppression by 48 weeks, with a favorable safety profile, according to a report at the 7th International AIDS Society Conference on HIV Pathogenesis, Treatment and Prevention (IAS 2013) this month in Kuala Lumpur.

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Darunavir/ritonavir is approved for children and adolescents with HIV aged 3 up to 18 years, either for weight-based dosing of darunavir oral suspension with liquid ritonavir, or for weight-based dosing of darunavir tablets with ritonavir capsules or tablets. Dosing is adjusted to twice-daily if 1 or more primary darunavir-associated resistance mutations are present.

Avy Violari, reporting on behalf of the ARIEL trial, presented a 48-week update of the initial 24-week analysis, which was presented as a poster at the 2011 Conference on Retroviruses and Opportunistic Infections.

At week 24, 57% of children age 3 to 6 years taking darunavir/ritonavir had viral loads under 50 copies/mL, with a safety profile comparable to adults taking the drug. These results compare to a 75% virological success rate among 6- to 12-year-olds and 39% among those aged 12 to 18 years. This led to the approval of darunavir/ritonavir for treatment-experienced children aged 3 to 6 weighing at least 10 kg.

The trial enrolled children age 3 to 6 years and weighing 10 to 20 kg from 10 sites in Argentina, Brazil, India, Kenya, and South Africa. They were on failing current antiretroviral regimens (viral load over 1000 copies/mL), had fewer than 3 darunavir resistance-associated mutations at screening, and had been on antiretroviral therapy for at least 12 weeks.

Participants were given darunavir oral suspension (100 mg/mL) initially dosed at 20 mg/kg plus 3 mg/kg ritonavir twice-daily with an investigator-selected optimized background regimen containing 2 or more active nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs).  

After a pharmacokinetic analysis at week 2 and following Data Safety Monitoring Board recommendations, the dose used in this study was increased to 25 mg/kg darunavir combined with 3 mg/kg ritonavir for children under 15 kg, given twice-daily. Children weighing from 15 to 20 kg received 375/50 mg/kg darunavir/ritonavir twice-daily.

This analysis comprised 21 children, of whom just under half were male, with a median age of 4.4 years at screening, a baseline mean viral load of 4.34 log copies/mL, a median CD4 cell count of 927 cells/mm3, and a median CD4 percentage of 27.7%.

Previously used antiretrovirals included lopinavir/ritonavir (76%), lamivudine (100%), stavudine (57%), and nevirapine (48%). 80% of children did not have any significant protease inhibitor resistance-associated mutations. 50% had non-nucleoside reverse transcriptase (NNRTI) resistance mutations. The majority (70%-80%) had NRTI resistance, predominantly the lamivudine-associated M184V mutation.

90% of children had 2 NRTIs in their optimized background regimen, while 10% had 3. These included: 62% lamivudine, 62% zidovudine, 38% abacavir, 38% stavudine, 5% didanosine, and 5% tenofovir.

The safety profile was favorable. The most common adverse events were upper respiratory tract infections, diarrhea, tinea capitis, and cough. 2 children had grade 4 adverse events, stenosing tenosynovitis and asthmatic crisis; while serious they were not treatment-related.

While almost all children (95%) experienced at least 1 grade 1 (mild) or higher adverse event, only 1 child (5%) had a grade 1 event possibly related to darunavir. Only 1 child stopped treatment (at week 24) because of grade 2 vomiting believed to be due to ritonavir.

With the exception of 1 grade 3 laboratory abnormality (neutropenia), present at baseline and not considered treatment-related, all others were grade 1. There were no lipid abnormalities above grade 1.

At baseline, mean age-adjusted Z-scores for child growth were below normal population values. At week 48, the mean increases from baseline were 5 cm in height, 1.7 kg in weight, and 0.1 kg/min body mass index.

By week 48, virological response (HIV RNA under 50 copies/mL) was high, increasing from 57% at week 24 to 81%. By week 48, over 90% had a 1 log or more drop in viral load. The mean increase in CD4 cell count at week 48 was 187 cells/mm3, up from a mean increase of 109 at week 24.

While it took longer for a significant proportion of children to reach viral suppression below 50 copies/mL, Violari noted that it is important to recognize that when using viral suppression below 400 copies/mL as a cut off, over 80% of the participants had a good response at 24 weeks.

The 2 children with baseline darunavir resistance-associated mutations (L76V and L33F/L+L76V) had viral load under 50 copies/mL at weeks 24 and 48.

Of the 3 children (14%) with virological failure, 2 never suppressed viral load and 1 experienced viral rebound. Of these, neither of the 2 children with paired baseline/endpoint genotypes developed protease inhibitor or NRTI resistance-associated mutations.

Violari concluded that treatment-experienced children 3 to 6 years of age receiving darunavir/ritonavir with an optimized background regimen had a high rate of virological response and favorable safety profile at 48 weeks. No development of resistance was seen in those experiencing virological failure.



A Violari, R Bologna, N Kumarasamy, 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 International AIDS Society Conference on HIV Pathogenesis, Treatment and Prevention. Kuala Lumpur, June 30-July 3, 2013. Abstract MOAB0102.