Using a nevirapine-containing fixed dose combination in the CHAPAS trial
Polly Clayden, HIV i-Base
Paediatric fixed dose combination (FDC) tablets provide simpler alternatives to liquids for children.
Cipla have produced scored, dispersible tablets of d4T/3TC/ NVP (baby and junior Triomune) with the correct dose ratios for children.
A sub-study of the CHAPAS trial (Children with HIV in Africa Pharmocokinetics and Adherence of Simple Antiretroviral Regimens), in Zambia, evaluated the need for dose escalation of NVP. This strategy is currently recommended but requires dosing with separate tablets, making initial treatment more complex.
Children were randomised to start antiretroviral therapy with full-dose NVP (Triomune am/pm) vs dose escalation, using an initial 14 days of half-dose NVP (Triomune am; Lamivir-S (combined d4T/3TC) pm) followed by full dose. Children were dosed in accordance with WHO weight band tables. The primary endpoint was clinical/laboratory grade 3/4 adverse events (AEs) related to NVP.
In this comparison, 211 children aged 2 – 9 years with a median CD4 percentage of 13% were followed for a median of 92 weeks. Severe stunting, wasting and immunosuppression were common in the children. Seventeen children were lost to follow-up.
The investigators reported 31(18 per 100 person-years) vs 29 (16.5 per 100 person-years) grade 3/4 AEs definitely/probably or uncertainly NVP-related in children receiving full-dose vs dose-escalation (incidence rate ratio (IRR) 1.09 (95% CI 0.63 – 1.87), p=0.74).
Twelve (11%) full-dose vs 2 (2%) dose escalation children had grade 2 disseminated skin rash and 1 receiving full dose had grade 1 rash. Two children (one from each arm) substituted with EFV; 3 continued full-dose NVP; 9 (8 full dose and 1 dose escalation) stopped NVP and restarted with successful dose escalation; and 1 full dose stopped, started a lower NVP dose, had another rash and substituted EFV.
Overall 90% of children who started with full-dose NVP continued uninterrupted in this study. As dose escalation requires provision of separate drug formulations, the evaluation of policy implications for dose escalation of NVP in fixed-dose combination HAART is ongoing.
The CHAPAS trial also investigated the pharmacokinetics of NVP in children treated with Triomune Baby/Junior and rifampicinbased tuberculosis treatment. 
EFV-based regimens are currently recommended for concomitant use with rifampicin, but EFV is not currently indicated for children below 3 years of age. Earlier CHAPAS data suggest that the higher dose ratio of NVP to NRTI in Triomune Baby/Junior may compensate for the dose reduction induced by rifampicin.
Pharmacokinetic sampling was performed in 22 children after 4 weeks of concurrent NVP and rifampicin-containing regimens. Rifampicin was dosed at 10 – 20 mg/kg per day. Samples were pre-dose (C0) and 1, 2 and 6 hours post-dose, and nevirapine plasma concentrations were determined using LC-MS/MS. NVP pharmacokinetics in children without TB treatment (n=16) were compared in multivariate linear regression analysis. The median age of the 21 children analysed was 1.55 (range 0.66 – 3.18) years, and 10 were girls.
The investigators found that only 11 (52%) of the children receiving TB treatment reached sufficient NVP trough levels (C0 <3.0 mg/L). Multvariate analysis revealed a 41% (95% CI 24 – 55%) reduction in nevirapine AUC with concomitant rifampicin. They noted a 3.4% increase in AUC for each 10 mg/m2 increase in NVP dose/m2.
They recommend caution with this approach in young children until more efficacy and safety data are available. They suggest that an increased NVP dose is likely to be necessary and requires further evaluation.
This article first appeared in issue 36 of the Journal of HIV Medicine, the journal of the Southern African Clinicians Society.
Unless otherwise stated, all references are to the programme and abstracts of the 5th IAS Conference on HIV Pathogenesis, Treatment and Prevention, 19 – 22 July 2009, Cape Town.
17. Kabamba D et al. Strategies for nevirapine initiation in HIV-infected children taking paediatric fixed-dose combination baby pills in Zambia: a randomised controlled trial. Abstract MOPEB090.
18. Oudijk JM et al. Pharmacokinetics of nevirapine in young children during combined ART and rifampicin-containing antituberculosis treatment. Abstract LBPEB10.