Underdosing of ARVs in children: results from CHIPS cohort
Polly Clayden, HIV i-Base
In an oral presentation, Esse Menson presented findings from the Collaborative HIV Paediatric Study (CHIPS), evaluating the extent to which HIV positive children have been under-dosed with antiretrovirals between 1997 and March 2005.
The CHIPS cohort includes 934 children from 23 centres in the UK and Ireland. 80% of all known HIV positive children are under follow up in this study, 73% of whom had received antiretroviral drugs. The children evaluated were aged between two and 12 years.
The authors defined underdosing as having received <90% of the current recommended minimum doses (CRD) in the Paediatric European Network for the Treatment of AIDS (PENTA) guidelines.
Children were underdosed for 42% of the time. Very high rates of underdosing of nelfinavir were reported when the drug was first available: 62% in the time period 1997 to 1999, falling to 21% in the period 2003 to 2005; nevirapine was under-dosed in 38% children in 1997 to 1999 and 16% in 2003 to 2005, and efavirenz was under-dosed in 17% of children in 2003-2005. Underdosing was also seen with the nucleoside analogues varied between 7% (with ddI) and 21% (with d4T).
Prevalence of under dosing was reduced over time – particularly with nevirapine and nelfinavir, as more data became available, and guidelines were updated. Underdosing was less frequent with lopinavir/ritonavir, 4% in the period 2003 to 2005 (the drug was not used in the earlier time periods).
Dr Menson also described potential confusions with inconsistencies of recommended dosing calculation strategy ie weight, body surface area or age bands. Efavirenz, when dosed according to weight band resulted in underdosing when the child reached the end of each weight band.
In a small sub-study, a case note review of 53 childrens records from one centre was performed. The authors reported that failure to increase dose as child grew and rounding down of doses, were given as the reasons for under dosing in 56% of the cases and formulation limitations and clinical indication/drug interaction in 33% and 5% cases respectively.
This clinic cited system failures in the early years of prescribing ART to children, eg children missing appointments, lack of pharmacy checks, and the time lag between prescription and administration of new dose as potential causes. These issues have since been addressed, perhaps contributing to the reduction in underdosing observed over time.
The authors concluded: Largely unwittingly we have greatly under-dosed HIV-infected children on ART over the past seven years.
Dr Menson suggested that these results may be the tip of the iceberg and there was much discussion after the talk that they could make a strong argument for therapeutic drug monitoring (TDM) in children.
For clinics that do not already use TDM routinely, PENTA 14, a randomised trial of differing levels of TDM compared with no TDM in children starting or switching to a new antiretroviral regimen is currently recruiting in the UK. Please visit the trials section of the PENTA website for more details.
Menson EN, Walker AS, Duong et al. Extent of under dosing of antiretroviral therapy in HIV-infected children. 11th BHIVA Conference, 20-23 April 2005, Dublin. Oral abstract O36.