Reduction of nevirapine-driven HIV mutations by carbamazepine is modulated by CYP3A activity.
J Antimicrob Chemother
; 69(7): 1933-7, 2014 Jul.
Article
em En
| MEDLINE
| ID: mdl-24695353
ABSTRACT
OBJECTIVES:
The reduction in mother-to-child transmission of HIV-1 by single-dose nevirapine given at birth onset is achieved at the expense of de novo HIV-1 resistance mutations. In the VITA1 study, single-dose carbamazepine accelerated nevirapine elimination, but the accompanying trend towards fewer de novo HIV-1 mutations was statistically non-significant.METHODS:
We investigated if the effect of carbamazepine was confounded by the individual variability in nevirapine metabolism and transport.RESULTS:
Nine of 34 (26%) single-dose nevirapine-treated women had one or more nevirapine-associated resistance mutations, compared with 3 of 34 (9%) in the single-dose nevirapine/carbamazepine arm. The genetic polymorphisms in CYP2B6 and MRP7 affected neither nevirapine kinetics nor the development of HIV-1 resistance. In contrast, the reduction in HIV-1 mutations by single-dose carbamazepine reached statistical significance at Pâ=â0.04 with an OR of 0.1 (95% CI 0.01-0.90) upon consideration of CYP3A activity, defined as the ratio of 4ß-hydroxycholesterol to cholesterol, and it was more likely in women with higher CYP3A activity. These findings were in agreement with CYP3A induction in carbamazepine-treated patients. Likewise, carbamazepine induced CYP3A4, but not CYP2B6, in vitro when combined with nevirapine.CONCLUSIONS:
The induction of nevirapine elimination reduces HIV-1 resistance mutations, but this effect is modulated by individual CYP3A activity. The study suggests that CYP3A4 activity could be monitored using an endogenous marker and, if needed, boosted to improve clinical endpoints.Palavras-chave
Texto completo:
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Base de dados:
MEDLINE
Assunto principal:
Carbamazepina
/
HIV-1
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Fármacos Anti-HIV
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Nevirapina
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Mutação de Sentido Incorreto
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Farmacorresistência Viral
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Indutores do Citocromo P-450 CYP3A
Limite:
Female
/
Humans
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Pregnancy
Idioma:
En
Ano de publicação:
2014
Tipo de documento:
Article