Higher than currently recommended NVP dose shows greater efficacy in HIV-infected children

Polly Clayden, HIV i-Base

Nevirapine (NVP, Viramune)) has been available for paediatric use in the UK since August 1997 through a compassionate access scheme (running until March 1999).

Investigators from St Mary’s Family Clinic, Paddington and North Manchester General Hospital conducted a case note review of 74 children using NVP-containing combination therapy under this scheme at 96 weeks from initiation.

Nevirapine was dosed at the discretion of the paediatrician, according to the manufacturer’s guidelines – a starting dose of 120mg/m2 per day increasing to 300mg/m2 daily for children less than eight years and 240mg/m2 daily for children eight years and over if no rash occurred.

Children were categorised as “high” if dose greater than 300mg/m2, “recommended” 240-300mg/m2 and “low” less than 240mg/m2 per day (or the equivalent liquid formulation dose).

Seventy-four children, 36 boys and 38 girls, were enrolled in the study, with a median age of 5.2 years, viral load of 5.1 log copies/ml and CD4 percentage of 13.5%. Twenty-eight children were antiretroviral naïve, of the 46 pretreated children, 13 had previously received a PI containing regimen and all children were NNRTI naïve. All but four children received NVP as part of a new combination.

Overall, in intent to treat analysis 20 children (33%) had an undetectable viral load below 400 copies/ml at week 96.

In children using nevirapine and NRTI who received a high dose of NVP significantly more had an undetectable viral load at week 24 (p=0.012) and 96 (p=0.007) compared to those on recommended or low doses. Sixty per cent had undetectable viral loads at week 96, compared with 17% on recommended doses. Among a group of six children that were both drug naïve and receiving a high dose of NVP the proportion of patients with an undetectable viral load was 67% at week 12, 100% at week 24, 83% at weeks 48 and 96. This was statistically significantly higher than in other children receiving NVP and NRTI at weeks 24 (p=0.006), 48 (p=0.031) and 96 (p=0.007). The difference between children receiving once or twice day NVP was not statistically significant.

The investigators also reported that CD4 cell percentages increased significantly, with median values sustained above 25% by week 48 onwards. CD4 cell percentages were not significantly different between high, recommended and lower doses of NVP. But data were missing for five to 10 children from weeks 12 to 96 receiving higher doses of NVP.

Median z-scores for both weight and height increased significantly during 96 weeks of treatment. Adverse events included rash which occurred in 15/74 children (20%), of which four (5%) were severe (grade 3-4) and required cessation of treatment. There were no cases of Stevens-Johnson syndrome. There was no significant difference in adverse events between children who received the different doses.

The investigators note that this is one of the largest reported cohorts of children receiving NVP to date and with 96 weeks follow up also one of the longest paediatric studies.

They report: “Our data suggest that a higher dosage of nevirapine than currently recommended by the manufacturer is needed to achieve satisfactory virological response.” Adding: “A maximum tolerated dosage has never been established in children. Given the tolerability of the drug, the lack of dose-related toxicity, and the better virological response associated with the higher dose, we recommend that doses should be maintained well above 300mg/m2 per day.” And they conclude: “The search for well-tolerated regimens that fully suppress viral replication long-term in children continues, and nevirapine appears to be a valuable component of such combinations.”

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