Study suggests many children could have subtherapeutic levels of efavirenz

Many children could have subtherapeutic concentrations of efavirenz in their blood, according to a small South African study published in the June 1^st edition of the Journal of Acquired Immune Deficiency Syndromes. The investigators found that the majority of children with subtherapeutic concentrations of efavirenz had a detectable viral load, and are calling for larger studies to be designed as a matter of urgency to determine the optimum efavirenz dose for children.

The non-nucleoside reverse transcriptase inhibitor (NNRTI) efavirenz is recommended by the World Health Organization (WHO) as a preferred drug for the treatment of HIV-positive children aged three or over. Few studies have examined plasma concentrations of efavirenz in children, but those that have looked at this issue have found wide variations. High concentrations of the drug are associated with central nervous system side-effects and low levels of efavirenz in the blood can lead to the development of HIV that has resistance to efavirenz and the other licensed NNRTI, nevirapine. It is recommended that trough (or C_min) levels of efavirenz in children should be between 1mg/l and 4mg/ml..

Investigators in South Africa therefore measured trough levels of efavirenz in 15 children aged between two years three months and 15-years. All weighed over 10kg and were provided with the appropriate weight-related dose of efavirenz. None of the children had liver or kidney disease, problems absorbing food or medicines, or an active opportunistic infection. Efavirenz was taken in combination with two NRTIs as part of a stable, potent anti-HIV treatment regimen.

An adult was asked to record the time the child took their efavirenz in the evening, and at least twelve hours after the dose of efavirenz was taken, three blood samples were obtained to determine trough levels of the drug. Blood tests were also performed between 16 – 20 hours after dosing to determine the middosing interval concentration. Viral load testing was also performed. The adult was also asked to provide details of their child’s adherence to anti-HIV therapy.

The median duration of anti-HIV therapy was 71 weeks. All the children provided blood samples for three plasma concentrations of efavirenz to be determined. These concentrations ranged between 0.356mg/l and 8.98mg/l. Sampling time ranged between 13 and 24 hours after dosing.

Every child provided at least one blood sample between 16 and 20 hours after dosing. Median middosing interval plasma concentration of efavirenz in these samples was 1.58mg/l. Six children had a trough level of efavirenz below the recommended 1mg/l and four children had a middosing interval plasma concentration below 1mg/l.

Although the children who weighted more took lower doses of efavirenz per kilogramme of weight, they had higher tough concentrations of the drug (p = 0.045).

All the children were reported to be fully adherent and ten children had an undetectable viral load (below 50 copies/ml). The remaining five children had viral loads ranging between 250 – 16,000 copies/ml. Three children with a detectable viral load had trough levels of efavirenz below the recommended 1mg/l.

“We found that a substantial proportion (40%) of children receiving recommended efavirenz doses had estimated C_min levels lower than the recommended minimum therapeutic concentrations”, write the investigators.

Although there were not enough children in the study to say if subtherapeutic levels of efavirenz were significantly associated with a risk of treatment failure, the investigators note “virologic failure was observed in 3 (60%) of the 5 children who had low efavirenz levels compared with 21% of those who had efavirenz levels above 1mg/l.”

The investigators conclude, “because low efavirenz concentrations may result in the rapid emergence of NNRTI-resistant mutants and treatment failure, our findings raise concern that many children are underdosed using current treatment guidelines…pharmacokinetic studies, including the evaluation of safety and efficacy, are urgently needed in paediatric populations to define optimum dosing strategies.”