Complex impacts of genotype, child weight on efavirenz with anti-TB therapy
CYP2B6 genotype was a stronger predictor of efavirenz concentrations than rifampicin-based anti-TB therapy in South African children, according to results of a three-way comparison. The researchers believe their findings do not support higher efavirenz doses in children taking rifampicin.
Efavirenz-based antiretroviral therapy is recommended for
adults and children in many parts of the world, and it is
preferred for children over 3 with tuberculosis. But
rifampicin, a centerpiece of anti-TB regimens, induces the
CYP2B6 metabolizing enzyme, and greater CYP2B6 activity lowers
concentrations of efavirenz. Higher than standard doses of
efavirenz are recommended for adults weighing more than 50 kg.
But there is little information to guide efavirenz dosing in
children taking anti-TB therapy.
To address these issues, researchers compared efavirenz
concentrations in 40 children taking an efavirenz regimen with
a rifampicin-containing anti-TB combination, in the same 40
children after they stopped rifampicin, and in a control group
of efavirenz-treated children without TB.
The investigators examined potential associations between
anti-TB therapy and CYP2B6 genotype (516G→T, 983T→C,
and 15582C→T), weight, and time after dosing. Based on
CYP2B6 genotype, they divided children into extensive,
intermediate, and slow metabolizers of efavirenz.
Compared with extensive metabolizers, intermediate
metabolizers had 1.42-fold higher efavirenz concentrations
(95% confidence interval [CI] 0.94 to 2.15), while
concentrations in slow metabolizers were 2.85-fold higher (95%
CI 1.80 to 4.52).
Taking rifampicin-based anti-TB therapy with efavirenz boosted
efavirenz concentrations 1.49-fold (95% CI 1.10 to 2.01) in
children with slow-metabolizer genotypes but did not affect
efavirenz levels in intermediate or extensive metabolizers.
After statistical adjustment for efavirenz dose per kilogram
weight, each kilogram was associated with a 2.8% lower
efavirenz concentration (95% CI 0.9% to 4.7%). Although
children in the lowest weight group (10 to 13.9 kg) received a
higher mg/kg dose of efavirenz, a higher proportion of
low-weight children than larger children had efavirenz
concentrations less than 1.0 mg/L.
“Antituberculosis treatment was not associated with
reduced efavirenz concentrations in children,” the
researchers conclude, and that finding “does not support
increased efavirenz doses” for children taking anti-TB
therapy.
“Children with [a] slow metabolizer genotype have
increased efavirenz concentrations during antituberculosis
treatment,” the researchers note, probably because of
“isoniazid inhibiting enzymes involved in accessory
metabolic pathways for efavirenz.”
Source:
Helen M. McIlleron, Michael Schomaker, Yuan Ren, Phumla
Sinxadi, James J.C. Nuttall, Hermien Gous, Harry Moultrie,
Brian Eley, Concepta Merry, Peter Smith, David W. Haas, Gary
Maartens. Effects of rifampin-based antituberculosis therapy
on plasma efavirenz concentrations in children vary by CYP2B6
genotype. AIDS. 2013; 27: 1933-1940.
For the study abstract
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Source:
IAS
