Efavirenz in children: WHO dosing guidelines raise the risk of side-effects in Thai children

Taking efavirenz according to 2010 World Health Organization (WHO) guidelines ensures a higher proportion of children with HIV have drug levels in the blood above recommended therapeutic levels (1mg/L) compared to the US Food and Drug Administration (FDA) guidelines, but also results in a higher percentage with potentially toxic levels (above 4mg/L), according to a population pharmacokinetic (PK) model presented last week at the 7th International AIDS Society Conference (IAS 2013) in Kuala Lumpur.

This retrospective analysis looked at 623 blood samples from 190 Thai children with HIV. The children had a median age of 7.2 years (IQR 0.1-15.2), bodyweight of 16kg (IQR 5-42) and with efavirenz dose given according to FDA bodyweight band recommendations, 8% (16) had an efavirenz level below 1mg/L twelve hours after a dose (C₁₂) while 6% (12) had a level above 4mg/L. There were no adverse events reported among the children. 

Model simulations showed that the percentage of children with a drug concentration (C₂₄ – 24 hours after a dose) between 1mg/L and 4mg/L using FDA dosing guidelines was similar to 2010 WHO recommendations. While the percentage with sub-optimal levels was lower using WHO guidelines the percentage of children with levels above 4mg/L increased by 11%. 

Efavirenz, a non-nucleoside reverse transcriptase inhibitor (NNRTI) together with a backbone of two nucleoside reverse transcriptase inhibitors (NRTIs) is the preferred ART regimen for children with HIV aged three and over weighing over 10kg.

Relatively little is known about how well efavirenz is absorbed in children. Some studies have shown sub-optimal as well as toxic levels in children and a greater variability compared to adults.

Between 1 and 4mg/L is a suggested concentration target 12 hours after efavirenz dosing to ensure efficacy and minimise the risk of toxicities, the majority of which are central nervous system disorders.

Dr Cressey cited two studies, both evaluating efavirenz levels according to WHO 2006 guidelines in African children, which reported high proportions of children with sub-therapeutic levels of efavirenz in the blood. One reported 40% of children and a sub-study of the ARROW trial reported 38% of children having efavirenz levels under 1mg/dl at C₂₄.

A poster presentation at the19th International AIDS Conference evaluating the 2010 WHO guidelines using scored generic 600mg efavirenz tablets among Zambian and Ugandan children (a sub-study of the CHAPAS-3 trial) showed more variability than adult data but similar to previously reported paediatric values “demonstrating the challenges of fixed-dosing when the therapeutic range is narrow”.

However, in Thailand, a study evaluating dosing according to FDA guidelines reported a lower percentage (15%) of children with sub-therapeutic efavirenz levels twenty-four hours after a dose (C₂₄).

Efavirenz dosing guidelines in HIV-infected children

                       Body weight (kg)

The investigators, wanting to evaluate current FDA and WHO 2010 efavirenz dosing guidelines, developed a population pharmacokinetic model to describe efavirenz absorption over time in Thai children with HIV.

Of the 190 children, 40 had 24-hour pharmacokinetic sampling data available.

Bodyweight affected efavirenz clearance.

The estimated median area under the concentration-time curve (AUC _0-24) was 49 (IQR 8-296) h.mg/L. The area under the curve (AUC) is a measure used to estimate the concentrations of active drug available to suppress HIV. If the AUC falls too low virus levels will increase, leading to virologic rebound and virologic resistance.

Some studies have suggested AUC in children above 50 h.mg/L is associated with virological efficacy.

A predicted efavirenz C₁₂ was 2.3 (0.07 to 11.9) mg/L.

FDA compared to WHO 2010 dosing guidelines, across all bodyweight bands, consistently showed higher percentages of those with sub-therapeutic levels (under 1 mg/dL) at C_12: from 14<15 , 15<20, 25<32.5 and 35<40 kg were 16 and 8%, 14 and 11%, 16 and 12% and 15 and 8%, respectively.

Conversely WHO 2010 guidelines compared to FDA guidelines showed consistently higher numbers, across all bodyweight bands, of those with potentially toxic levels (above 4 mg/dl) at C₁₂ : from 14<15 , 15<20, 25<32.5 and 35<40 kg were 39 and 25%, 33 and 24%, 28 and 21% and 42 and 21%, respectively.

Genotyping for CYP2B6 polymorphisms was not done. An estimated 11% prevalence of CYP2B6 TT (associated with high EFV exposure) in this population may explain higher levels in this group.

While the model suggests drug concentrations may be appropriate, safety data on EFV in children are needed for those getting WHO 2010 weight-band dosing.