HIV-positive children in the United Kingdom and Ireland have been receiving inadequate doses of their anti-HIV drugs for almost half of their time on therapy, according to a study presented last week at the Eleventh Annual Conference of the British HIV Association with the British Association for Sexual Health and HIV in Dublin. “Largely unwittingly, we have greatly underdosed HIV-infected children on antiretroviral therapy over the past seven years,” the researchers conclude. This is due to a variety of factors including complex dosing guidelines based on insufficient clinical evidence, practical difficulties surrounding the adjustment of children’s doses as they grow, and limitations of current paediatric formulations, they argue.
Ensuring children receive the correct dose of antiretroviral drugs is important, in order to avoid the risks of resistance and treatment failure. However, this is made complicated by changes in drug levels produced in the body as children get older, as well as by complex and varied dosing calculations for different drugs. The appropriate doses must be calculated according to the child’s weight or body surface area, or according to predefined weight bands.
To investigate the extent of underdosing, investigators from the Collaborative HIV Paediatric Study (CHIPS) evaluated dosing of antiretroviral drugs in children aged between two and twelve years from 1997 to 2005. This cohort included 757 (78%) of the HIV-1-infected children in the United Kingdom and Ireland, 73% of whom where taking antiretrovirals. Underdosing was defined as receipt of less than 90% of the current recommended dose in the 2004 Paediatric European Network for the Treatment of AIDS (PENTA) guidelines.
The investigators found that children were underdosed for 41% of their time on antiretroviral therapy, with the most commonly underdosed drugs being efavirenz (Sustiva) and nelfinavir (Viracept).
Newer drugs such as ritonavir-boosted lopinavir (Kaletra) were underdosed least.
The investigators found that efavirenz, when dosed according to the weight band, is often given to children towards the top of each band at too low a dose. This may be due to a rounding down of body weights, a failure of doses to be increased in line with the child’s weight, or a lack of adequate pharmacy checks.
Other causes of underdosing included rounding down of calculated doses and failure to adhere strictly to the drugs' dosing instructions.
“Largely unwittingly, we have greatly underdosed HIV-infected children on antiretroviral therapy over the past seven years,” conclude the researchers. “Reasons for underdosing included failure to increase doses with growth; limitations of drug formulations; rounding-down calculated doses; and, for certain drugs, dosing using weight-bands or mg/kg for dose calculations, rather than as recommended in prescription guidelines.”
However, Esse Menson, presenting, acknowledged that these ‘system failures’ were being addressed.
The extent of underdosing remained constant across the study period for most drugs, particularly the nucleoside analogues. However, the investigators found that underdosing of nelfinavir fell from 62% between 1997 and 1999 to 21% between 2003 and 2005. A similar trend was seen for nevirapine (Viramune), falling from 38% to 16% over the same period. This may be due to changes in prescription guidelines for these drugs.
The presenter concluded by stressing the need for more evidence from clinical studies to guide dosing recommendations for children, such as dose adjustments according to age.
Menson EN et al. Extent of underdosage of antiretroviral therapy in HIV-infected children. Eleventh Annual Conference of the British HIV Association with the British Association for Sexual Health and HIV, Dublin, abstract O36, 2005.