Initiating nevirapine with fixed dose combination mini-pills in Zambia
Polly Clayden, HIV i-Base
The shortage of appropriate paediatric antiretroviral formulations has been a major barrier to scale up of treatment of children in resource-limited settings. The initiation of nevirapine is complicated by the recommendation to escalate the dose, requiring a regimen change two weeks after starting treatment.
The Children with HIV in Africa Pharmacokinetics and Adherence of Simplified Antiretroviral Regimens (CHAPAS) Trials, are investigating new antiretroviral formulations and strategies for children. This is a joint project of the University of Zambia and University Teaching Hospital Zambia, the Medical Research Council (UK), Radboud University Nijmegen, Netherlands and the University of Padova, Italy, began in 2005.  We have followed this project in HTB for some time.
CHAPAS-1 looked at treatment with Triomune Baby/Junior – fixed dose combination (FDC) scored, dispersible mini pills of stavudine (d4T), lamivudine (3TC) and nevirapine in the correct ratios for children, manufactured for the trial by Cipla. The doses of the tablets are: 6 and 12 mg d4T, 30 and 60 mg 3TC and 50 and 100 mg nevirapine in Triomune Baby and Junior respectively. Data from this trial contributed to the tentative approval by the FDA for these formulations, and to the WHO dosing recommendations by weight band for fixed dose combinations of these drugs, down to 3kg.
Nevirapine toxicity has been reported to be uncommon in children receiving full dose nevirapine at initiation, but there have been no randomised trials to evaluated the safety of this strategy. CHAPAS-1 compared the initiation of antiretroviral therapy (ART) with full dose nevirapine versus half dose nevirapine for the first two weeks of treatment.
An article, authored by Veronica Mulenga and colleagues and published in the November 1, 2010 issue of Clinical Infectious Diseases, showed findings from this trial.
Children aged 3 months to 14 years, indicated for treatment in accordance with WHO 2006 guidelines, were randomised 1:1 to receive either Triomune Baby or Junior twice daily for the first two weeks (full dose group, or Triomune Baby/Junior once daily plus once daily Lamivir-S, Baby or Junior – dual 3TC and d4T combination tablets (dose escalation group).
The primary end point was grade 3 or 4 adverse events (AEs) related to nevirapine.
A total of 211 children were randomised and included in the intent to treat analysis. Children in the two groups were similar. The median age at ART initiation was 5 years (IQR 2-9 years) and 35% were less than 3 years. The median CD4 percentage was 13% and 99% of children had WHO stage 3 or 4 disease. Severe wasting and/or stunting were common.
All children were seen by a nurse at 2 and 4 weeks from initiation and subsequently every 4 weeks. Children were weighed and measured, any adverse events or new WHO events were recorded and additional ART prescribed. They were also routinely seen by a doctor at weeks 2, 4, 8 and 12 and then every 12 weeks where they had a clinical examination and blood samples were obtained.
There were 60 (31 the full dose and 29 in the escalated groups), grade 3 or 4 AEs reported in 49 children (25 in the full dose and 24 in the dose escalated) that were considered definitely or probably related to nevirapine (n=8), or there was uncertainty as to their relation to nevirapine (n=52). This gave 18 vs 16.5 events per 100 child years in the full dose and dose escalated groups respectively; incidence rate ratio [IRR] 1.09 (95% CI 0.63-1.87), p=0.74.
All AEs were asymptomatic and the children continued treatment with nevirapine. Elevated aspartate aminotransferase (AST) or alanine aminotransferase (ALT) were the most common; 11 events in the full dose and 3 in the dose elevated groups), and elevated bilirubin levels (n=34).
There was no grade 3 or 4 rash, but 13 and 2 children had grade 1 (2 in the full dose group) or grade 2 (11 in the full dose and 2 in the dose elevated groups) rashes, p=0.003. One child in the full dose group developed a second grade 2 rash after reintroducing nevirapine at half dose. Rashes started at a median of 17 days (range 8-25 days) after initiation and lasted for a median of 9 days 9range 2-24 days).
Of the 15 children who developed rashes, 3 continued full dose nevirapine; 9 (8 full and 1 elevated dose) stopped nevirapine temporarily and then successfully dose escalated; 1 in whom the rash returned after changing from full dose to half dose, substituted efavirenz and 2 (1 full and 1 dose escalated) substituted efavirenz without retrying half dose nevirapine. All but 2 children in the full dose group were managed as outpatients.
In multivariate analysis, older age (per year increase), OR 1.35(95% CI, 1.10-1.64) p=0.003, and higher CD4 count for age (per unit increase), OR 1.51 (1.03-2.20) p=0.03 were associated with nevirapine rash. More rash occurred in the full dose group versus dose escalated, OR 9.79 (1.97-48.6), p=0.005.
Twenty-two children (10%) died (12 in the full dose and 10 in the dose escalated groups). More than half the deaths occurred within the first 3 months of ART, and were most frequently due to diarrheoa and pneumonia. Most children who died had advanced HIV disease and very low weight-for-age z-scores. No deaths were judged to be drug-related.
Children in both groups had similar increases in weight for age and height for age z-scores and CD4 counts or percentages (+17.3%) at 96 weeks.
The investigators concluded that rash occurred more frequently among children starting nevirapine at full dose but 88% had no clinical toxicity. Where possible they recommend using dual d4T/3TC paediatric tablets for dose escalation
If children are initiated on full dose Triomune, caregivers need to be aware of the timing of rash. For those in whom this occurs the options are to treat through under careful observation or to manage temporarily with half dose Triomune or efavirenz.
They noted that the elevated AST or ALT values were unconfirmed, transient and resolved spontaneously. They suggested that their results concur with that of the DART trial, which showed no difference in AEs requiring regimen modifications among adults receiving routine versus clinical biochemistry monitoring, including those receiving nevirapine. The results from both DART and CHAPAS-1 suggest that routine liver function tests are not necessary after nevirapine initiation in resource-limited settings.
- European and developing countries clinical trails partnership (EDCTP). Project at a glance: Custom made treatments for HIV-infected
- Mulenga V et al. Strategies for nevirapine initiation in HIV-infected children taking paediatric fixed-dose combination baby pills in Zambia: A
randomised controlled trial. Clin Infect Dis 2010: 51. 1 November 2010. http://www.journals.uchicago.edu/doi/abs/10.1086/656628?journalCode=cid