Effects of CYP2B6 G516T polymorphisms on plasma efavirenz and nevirapine levels when co-administered with rifampicin in HIV/TB co-infected Thai adults.
BACKGROUND: Cytochrome P450 2B6 (CYP2B6) metabolizes efavirenz and nevirapine, the major core antiretroviral drugs for HIV in Thailand. Rifampicin, a critical component of tuberculosis (TB) therapy is a potent inducer of CYP enzyme activity. Polymorphisms of CYP2B6 and CYP3A4 are associated with...
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Main Authors: | , , , , , , , , , , , , |
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Format: | Article |
Language: | English |
Published: |
2013
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Online Access: | https://repository.li.mahidol.ac.th/handle/123456789/726 |
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Institution: | Mahidol University |
Language: | English |
Summary: | BACKGROUND: Cytochrome P450 2B6 (CYP2B6) metabolizes efavirenz and nevirapine,
the major core antiretroviral drugs for HIV in Thailand. Rifampicin, a critical
component of tuberculosis (TB) therapy is a potent inducer of CYP enzyme
activity. Polymorphisms of CYP2B6 and CYP3A4 are associated with altered activity
of hepatic enzyme in the liver and pharmacokinetics resulting in treatment
efficacy. This study aimed to investigate whether CYP2B6 or CYP3A4 polymorphisms
had effects on plasma efavirenz and nevirapine concentrations when
co-administered with rifampicin in HIV/TB co-infected Thai adults.
RESULTS: We studied 124 rifampicin recipients with concurrent HIV-1/TB
coinfection, receiving efavirenz (600 mg/day) (n = 65) or nevirapine (400 mg/day)
(n = 59) based antiretroviral therapy (ART). The frequencies of GG, GT and TT
genotypes of CYP2B6-G516T were 38.46%, 47.69% and 13.85% in efavirenz group and
44.07%, 52.54% and 3.39% in nevirapine group, respectively. The mean 12-hour
post-dose plasma efavirenz concentration in patients with TT genotype at weeks 6
and 12 of ART and 1 month after rifampicin discontinuation (10.97 +/- 2.32, 13.62
+/- 4.21 and 8.48 +/- 1.30 mg/L, respectively) were significantly higher than
those with GT (3.43 +/- 0.29, 3.35 +/- 0.27 and 3.21 +/- 0.22 mg/L, respectively)
(p < 0.0001) or GG genotypes (2.88 +/- 0.33, 2.45 +/- 0.26 and 2.08 +/- 0.16
mg/L, respectively) (p < 0.0001). Likewise, the mean 12-hour post-dose plasma
nevirapine concentration in patients carrying TT genotype at weeks 6 and 12 of
ART and 1 month after rifampicin discontinuation (14.09 +/- 9.49, 7.94 +/- 2.76
and 9.44 +/- 0.17 mg/L, respectively) tended to be higher than those carrying GT
(5.65 +/- 0.54, 5.58 +/- 0.48 and 7.03 +/- 0.64 mg/L, respectively) or GG
genotypes (5.42 +/- 0.48, 5.34 +/- 0.50 and 6.43 +/- 0.64 mg/L, respectively) (p
= 0.003, p = 0.409 and p = 0.448, respectively). Compared with the effects of
CYP2B6-516TT genotype, we could observe only small effects of rifampicin on
plasma efavirenz and nevirapine levels. After 12 weeks of both drug regimens,
there was a trend towards higher percentage of patients with CYP2B6-TT genotype
who achieved HIV-1 RNA levels <50 copies/mL compared to those with GT or GG
genotypes. This is the first report to demonstrate the effects of CYP2B6 G516T
polymorphisms on plasma efavirenz and nevirapine concentrations when
co-administered with rifampicin in HIV/TB co-infected Thai adults.
CONCLUSIONS: CYP2B6-TT genotype had impact on plasma efavirenz and nevirapine
concentrations, while rifampicin co-administration had only small effects. |
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