CYP2B6 genetic variants are associated with nevirapine pharmacokinetics and clinical response in HIV-1-infected children.
BACKGROUND
Cytochrome P450 2B6 (CYP2B6)-G516T genotype is associated with altered activity of hepatic CYP2B6 and efavirenz pharmacokinetics, but the relationship between the CYP2B6-G516T genotype and nevirapine (NVP) pharmacokinetics in plasma and cerebrospinal fluid (CSF) is limited.


METHODS
In 126 children who received NVP and protease inhibitors from PACTG 366 and 377 cohorts, CYP2B6 and ATP-binding cassette, sub-family B, member 1 (ABCB1) gene polymorphisms were analyzed using real-time PCR. Plasma NVP pharmacokinetics and clinical data were collected and levels of NVP in CSF were evaluated in children with HIV-related neurologic diseases.


RESULTS
NVP oral clearance in children with the CYP2B6-516-T/T genotype (homozygous variant, n = 14) was 1.6 l/h per m2, which was significantly decreased compared to 2.3 l/h per m2 in those with the -G/G (wild type, n = 49, P = 0.002) and 2.1 l/h per m2 in those with the -G/T genotype (heterozygous variants, n = 63, P = 0.008). Furthermore, children with the -T/T genotype had a significant increase in CD4+ T-cell percentage (+9.0%) compared with those with the -G/G (+3.2%, P = 0.01) and -G/T genotype (+5.0%, P = 0.04) from baseline to week 12. The same trend continued at week 24. Although ABCB1-C3435T genotypes did not affect plasma NVP pharmacokinetics (P = 0.39), the NVP CSF: plasma ratios were significantly higher in children with the ABCB1-3435-C/T or -T/T genotypes (0.62, n = 9) in comparison with those with the ABCB1-3435-C/C genotype (0.43, n = 5) (P = 0.01).


CONCLUSIONS
The CYP2B6-G516T genotype alters NVP pharmacokinetics and the immunologic response to NVP-containing HAART regimens in children. These data suggest that the CYP2B6-G516T is an important genetic variant that alters the pharmacokinetics and response to HAART regimens containing NVP.
Saitoh
Akihiko
A
Division of Infectious Diseases, Department of Pediatrics, University of California, San Diego, La Jolla, California 92093-0672, USA. asaitoh@ucsd.edu
Sarles
Elizabeth
E
Capparelli
Edmund
E
Aweeka
Francesca
F
Kovacs
Andrea
A
Burchett
Sandra K
SK
Wiznia
Andrew
A
Nachman
Sharon
S
Fenton
Terence
T
Spector
Stephen A
SA
D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics; D000480:Alkynes; D023241:Antiretroviral Therapy, Highly Active; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics*; D048588:Benzoxazines / Q000627:therapeutic use; D018791:CD4 Lymphocyte Count; D002675:Child, Preschool; D003521:Cyclopropanes; D065702:Cytochrome P-450 CYP2B6; D005260:Female; D005787:Gene Frequency; D005838:Genotype; D015658:HIV Infections / Q000134:cerebrospinal fluid / Q000188:drug therapy / Q000235:genetics*; D017320:HIV Protease Inhibitors / Q000627:therapeutic use; D015497:HIV-1; D006801:Humans; D008297:Male; D015999:Multivariate Analysis; D019829:Nevirapine / Q000134:cerebrospinal fluid / Q000493:pharmacokinetics* / Q000627:therapeutic use; D010089:Oxidoreductases, N-Demethylating / Q000235:genetics*; D011110:Polymorphism, Genetic; D012189:Retrospective Studies; D018894:Reverse Transcriptase Inhibitors / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use; D016896:Treatment Outcome
C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000480:Alkynes; D048588:Benzoxazines; D003521:Cyclopropanes; D017320:HIV Protease Inhibitors; D018894:Reverse Transcriptase Inhibitors; D019829:Nevirapine; D001189:Aryl Hydrocarbon Hydroxylases; C585599:CYP2B6 protein, human; D065702:Cytochrome P-450 CYP2B6; D010089:Oxidoreductases, N-Demethylating; C098320:efavirenz