HIV-positive children in UK and Ireland often given too low doses of antiretrovirals

A significant proportion of HIV-positive children in the United Kingdom and Ireland have been treated with suboptimal doses of antiretroviral drugs, according to a study published in the May 19^th edition of the British Medical Journal.

Investigators established that children received subtherapeutic doses of antiretroviral drugs between 6 and 62% of the time, although the exact amount of time depended on which drugs they were taking. The investigators blame the lack of paediatric formulations of anti-HIV drugs and a failure to adjust drug doses with growth for the low dosing.

Suboptimal drug levels can lead to the emergence of drug-resistant HIV which is a particular problem in HIV-positive children. Although regulatory changes are being introduced in the United Kingdom, European Union and United States to improve prescribing in children, there are few studies looking at the scale, nature or obstacles to optimal prescribing in children.

Investigators from the United Kingdom and Irish Collaborative HIV Paediatric Study (CHIPS) looked at prescribing to children aged between two and twelve years who received antiretroviral therapy between 1997 and early 2005. The daily-prescribed dose was compared with the dose recommended by the 2004 European HIV paediatric treatment guidelines (PENTA).

A total of 598 children were eligible for inclusion in the study, with 8,907 weights and 36,660 dose changes available for analysis.

Doses relative to weight or body surface area - the two methods used to determine paediatric doses of drugs - varied widely between individual drugs and classes of antiretrovirals. The investigators observed that between 6 and 62% of the time children taking antiretrovirals were taking less than 90% of the appropriate dose of antiretrovirals. Protease inhibitors and non-nucleoside reverse transcriptase inhibitors (NNRTIs) were the classes of antiretrovirals most likely to be underdosed.

Three specific patterns of underdosing were observed by the investigators:

• Underdosing after changes in dosing recommendations after licensing. This was a particular issue with the protease inhibitor nelfinavir (Viracept) between 1997 and 1999 when 62% of the time involved subtherapeutic doses.
• Doses of antiretrovirals with alternative dosing strategies. The NNRTI nevirapine (Viramune) was licensed on studies using surface area doses, but in children aged eight and over doses can be extrapolated from weight. Doses calculated on surface area meant that 63% of the time children took an adequate amount of the drug, but this fell to 48% when doses extrapolated from weight were used.
• Dose prescribing by weight bands. Although efavirenz (Sustiva) was underdosed less than nevirapine at 17% of the time, the manufacturer’s guidelines recommending dosing by weight bands did produce a tendency to underdosing when a child’s weight approached the top of each weight band.

“We found considerable underdosing of antiretrovirals in the United Kingdom and Ireland based on current best practice. Some antiretrovirals were dosed suboptimally because of inadequate pharmacokinetic licensing; other underdosing seems attributable to confusing and inconsistent dosage strategies or failure to respond to growth, especially at extremes of weight bands”, comment the investigators.

Limitations with paediatric formulations caused about a third of underdosing, suggest the investigators, who also emphasise the need to regularly adjust doses of drugs as children grow.

The investigators make a plea for drug studies to include children so that suitable formulations and doses can be determined. They highlight a new United Kingdom Department of Health initiative, the Medicines for Children Research network (http://www.liv.ac.uk/mcrn), which aims to develop closer links between pharmaceuticals, regulators, paediatricians, and the families of children taking medications.