Darunavir/ritonavir safe and effective for younger children

Over 80% of treatment-experienced children with HIV aged three to six years from ten sites in Argentina, Brazil, India, Kenya and South Africa receiving darunavir/ritonavir (DRV/r) with an optimised background regimen were virologically suppressed (viral loads under 50 copies/ml) by week 48, Avy Violari, reporting on behalf of the ARIEL trial, told participants at the 7th International AIDS Society Conference (IAS 2013) in Kuala Lumpur last week.

The safety profile was favourable. While almost all children (95%) experienced at least one grade 1 or above adverse event (AE), only one child (4.8%) had a grade 1 adverse event possibly related to darunavir.

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

Findings from the initial 24-week analysis were presented as a poster at the 18th Conference on Retroviruses and Opportunistic Infections (CROI) in 2011. Fifty-seven per cent had viral loads under 50 copies/ml at week 24 with a safety profile comparable to adults. These results compare to a 75% virologic success rate (under 50 copies/ml at 24 weeks) among 6-12 year olds and 39% among those aged 12 to 18 years. This led to the approval of DRV/r for treatment-experienced children aged three to six weighing at least 10kg.

The trial comprised children aged three to six years, weighing 10 to under 20kg who were failing their current antiretroviral regimens (viral load over 1000 copies/ml), had fewer than three DRV resistance-associated mutations (RAM) at screening and had been on ART for at least 12 weeks.

Participants were given darunavir oral suspension (100mg/ml) initially dosed at 20mg per kg plus 3mg of ritonavir per kg twice a day with an investigator-selected optimised background regimen (more than two active nucleoside reverse transcriptase inhibitors).  

After a pharmacokinetic analysis at week two and following Data Safety Monitoring Board recommendations, the dose used in this study was increased to darunavir 25mg per kg combined with 3mg ritonavir per kg for children under 15kg given twice daily. Children weighing from 15 to under 20kg received darunavir/ritonavir 375/50mg per kg 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 log₁₀ viral load of 4.34 copies/ml and median CD4 cell count of 927 cells/mm³ (IQR:209-2429) and median CD4 percentage of 27.7% (IQR: 15,6-51.1).

Eighty per cent of children did not have any significant protease inhibitor (PI) RAMs. Fifty per cent had non-nucleoside reverse transcriptase (NNRTI) mutations. The majority (70-80%) had nucleoside resistance, predominantly in the form of the lamivudine-associated M184V mutation.

Previously used antiretrovirals included lopinavir/r (76%), lamivudine (100%), stavudine (57%) and nevirapine (48%).  

Ninety per cent (19) of children had two nucleoside reverse transcriptase inhibitors (NRTIs) in the optimised background regimen (OBR), while 10% (2) had three. These included: 62% (13) lamivudine, 62% (13) zidovudine, 38% (8) abacavir, 38% (8) stavudine, 5% (1) didanosine and 5% (1) tenofovir disoproxil fumarate.

The most common AEs were upper respiratory tract infections, diarrhoea, tinea capitis and cough. Two children had grade 4 AEs, stenosing tenosynovitis and asthmatic crisis, while serious they were not treatment-related.

Only one child stopped treatment (at week 24) because of grade 2 vomiting believed to be due to ritonavir.

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

At baseline, mean age-adjusted z-scores for child growth were below normal population values. At week 48, the mean increase from baseline was 5cm in height, 1.7kg in weight and 0.1kg/m² in body mass index

By week 48, virologic response (under 50 copies/ml) was high increasing from 12 (57.1%) at week 24 to 17 (81%); the mean (standard error SE) increase in CD4 cell count at week 48 was 187 (76,7) cells/mm³ from a mean increase of 109 at week 24.

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

By week 48 over 90% had 1 log₁₀ or more drop in viral load.

Two children with baseline DRV RAMs (L33F/L+L76V [1] and L76V [1]) had viral load under 50 copies/ml at weeks 24 and 48.

Of the three children (14.3%) with virologic failure, two never suppressed viral load and one experienced viral rebound. Of these, neither of the two children with paired baseline/endpoint genotypes developed PI or NRTI RAMs.

Dr Violari concluded treatment-experienced children three to six years of age receiving darunavir/ritonavir with an OBR had a high rate of virologic response and favourable safety profile at 48 weeks. No development of resistance was seen in those experiencing virologic failure.