Long-term outcomes for infants starting lopinavir/ritonavir at less than 6 months

World Health Organisation (WHO) and national guidelines recommend universal treatment with antiretrovirals for all HIV-infected infants.

Guidelines also recommend using protease inhibitor-based treatment for children exposed to single dose nevirapine through PMTCT.

Initiation of therapy is recommended as soon as possible but there are limited data to guide treatment of very young infants.

Ellen Chadwick and colleagues from IMPAACT P1030 showed data in AIDS, published ahead of print in February 2011, from a study designed to look at the pharmacokinetics (PK) and safety of the liquid formulation of lopinavir/ritonavir (LPV/r) in HIV-infected infants starting treatment between 2 weeks and 6 months of age.

This was a prospective, open label, phase I/II study of 31 children from 17 centres in the US and Brazil treated with a high dose (300mg LPV/75mg RTV/m2 twice daily). Children were enrolled into two age groups: 14 days to 6 weeks and 6 weeks to <6 months. Children were followed until 48 weeks after the last child was enrolled.

The median duration of follow up was 123 (range 4-252) weeks. Ten (32%) children permanently discontinued the study including four before 12 months of age. Two discontinued after viral rebound to >50,000 copies/mL (weeks 43 and 176); three after parents refusal to attend study visits and/or give medication (weeks 2,42 and 145), three had non-treatment related conditions (CMV resulting in death at week 8; failure to thrive due to severe food allergy at week 70 and severe iron-deficiency anaemia at week 120) and two because their research sites closed (weeks 73 and 120).

Intensive PK sampling was performed at in 26 children at 12 months of age, pre-dose and 2, 4, 8 and 12 hours after an observed dose. Of these, 20 children had evaluable results.

The investigators found, the median AUC of the two groups was comparable at 12 months of age (99.1 ug h/mL [IQR 82.4-124.5] vs 112 ug h/mL [IQR 95.0-148.8], p=0.93). They also found a significant positive correlation of LPV trough concentration and age, p<0.0001.

By ITT analysis, at week 48, 22/31 (71%) children had a viral load <400 copies/mL; 6/10 in group 1 and 16/21 in group 2. Of these 11/15 (73%) on study treatment at 48 weeks had a viral load <50 copies/mL. Overall 29/31 (94%) children achieved a viral load <400 copies/mL while on study treatment and 19/29 (66%) children remained undetectable until the end of the study at a median of 123 (range 42-252) weeks. The children who sustained viral suppression had a higher percentage of predose time points at which concentrations exceeded the LPV target of 1 ug/ML (92 vs 71%), p=0.002.

The median baseline CD4 percentage was 35% (range 11-59%). There was a median increase of 4% (95% CI – 4 to 13%), p=0.12, among the 24 children with data available at 48 weeks and 23 (96%) had CD4 percentage >25%. Among the 19 children with follow up through 96 weeks there was a median increase of 8% (95% CI -2 to 13%), p=0.15.

The investigators noted that low LPV levels occurred at two weeks of therapy, with the lowest in infants <6 weeks of age. In this very young age group the median AUC was approximately half that seen in the older children >6 months of age. But these values were comparable between the two groups by 12 months of age and comparable to adults. They also noted that the LPV dose of 300mg/m2 is higher than the currently recommended dose for children >6 months of age.

Chadwick EG et al. Long-term outcomes for HIV-infected infants less than 6 months of age at initiation of lopinavir/ritonavir combination antiretroviral therapy. AIDS, 25(6):767-776 (13 March 2011).
http://journals.lww.com/aidsonline/toc/2011/03130