Reduction of nevirapine-driven HIV mutations by carbamazepine is modulated by CYP3A activity.
OBJECTIVE
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 P = 0.04 with an OR of 0.1 (95% CI 0.01-0.90) upon consideration of CYP3A activity, defined as the ratio of 4β-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.
Department of Pharmacology, University Medical Centre of the Johannes Gutenberg University Mainz, Mainz, Germany.
Dorothea
D
Baranyai
Kilimanjaro Christian Medical College, Moshi, Tanzania.
Eva
E
Muro
Department of Pharmacology, University Medical Centre of the Johannes Gutenberg University Mainz, Mainz, Germany.
Ute
U
Gödtel-Armbrust
Institute of Clinical Pharmacology, University Medical Centre Göttingen, Göttingen, Germany.
Markus A
MA
Schirmer
Kilimanjaro Christian Medical College, Moshi, Tanzania.
Elton
E
Kisanga
Department of Laboratory Medicine, Division of Clinical Chemistry, Karolinska Institute, Karolinska University Hospital, Stockholm, Sweden.
Ulf
U
Diczfalusy
Department of Pharmacy, Radboud University Nijmegen Medical Centre, and Institute for Infection, Inflammation and Immunity (N4i), Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.
Quirine
Q
Fillekes
Department of Virology, University Medical Centre Utrecht, Utrecht, The Netherlands.
Rob
R
Schuurman
Department of Pharmacy, Radboud University Nijmegen Medical Centre, and Institute for Infection, Inflammation and Immunity (N4i), Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.
David
D
Burger
Department of Pharmacology, University Medical Centre of the Johannes Gutenberg University Mainz, Mainz, Germany wojnowski@uni-mainz.de.
Leszek
L
Wojnowski
D019380:Anti-HIV Agents / Q000008:administration & dosage* / Q000494:pharmacology; D002220:Carbamazepine / Q000008:administration & dosage* / Q000378:metabolism; D018890:Chemoprevention / Q000379:methods; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism; D065701:Cytochrome P-450 CYP3A Inducers / Q000008:administration & dosage* / Q000378:metabolism; D024882:Drug Resistance, Viral; D005260:Female; D015658:HIV Infections / Q000517:prevention & control; D015497:HIV-1 / Q000187:drug effects* / Q000235:genetics; D006801:Humans; D020125:Mutation, Missense / Q000187:drug effects*; D019829:Nevirapine / Q000008:administration & dosage* / Q000494:pharmacology; D011247:Pregnancy; D016896:Treatment Outcome
D019380:Anti-HIV Agents; D065701:Cytochrome P-450 CYP3A Inducers; D002220:Carbamazepine; D019829:Nevirapine; C104464:CYP3A protein, human; D051544:Cytochrome P-450 CYP3A
4β-hydroxycholesterol; induction; mother-to-child transmission