CYP2C19 genetic variants affect nelfinavir pharmacokinetics and virologic response in HIV-1-infected children receiving highly active antiretroviral therapy.
BACKGROUND
The objective of this research was to identify the impact of genetic variants of P-glycoprotein (ABCB1) and cytochrome P450 (CYP) on nelfinavir pharmacokinetics and response to highly active antiretroviral therapy (HAART) in HIV-1-infected children.


METHODS
HIV-1-infected children (n = 152) from Pediatric AIDS Clinical Trial Group 366 or 377 receiving nelfinavir as a component of HAART were evaluated. Genomic DNA was assayed for ABCB1 and CYP genetic variants using real-time polymerase chain reaction Nelfinavir oral clearance (CL/F), M8 to nelfinavir ratios, CD4 T cells, and HIV-1-RNA were measured during HAART.


RESULTS
Nelfinavir CL/F and M8 to nelfinavir ratios were significantly associated with the CYP2C19-G681A genotypes (P < 0.001). Furthermore, the CYP2C19-G681A genotype was related to virologic responses at week 24 (P = 0.01). A multivariate analysis demonstrated that age (P = 0.03), concomitant protease inhibitor use (P < 0.001), and the CYP2C19-G681A genotype (P < 0.001) remained significant covariates associated with nelfinavir CL/F.


CONCLUSIONS
CYP2C19 genotypes altered nelfinavir pharmacokinetics and the virologic response to HAART in HIV-1-infected children. These findings suggest that CYP2C19 genotypes are important determinants of nelfinavir pharmacokinetics and virologic response in HIV-1-infected children.
Saitoh
Akihiko
A
Division of Infectious Diseases, Department of Pediatrics, University of California, San Diego, La Jolla, CA, USA. saitoh-aki@ncchd.go.jp
Capparelli
Edmund
E
Aweeka
Francesca
F
Sarles
Elizabeth
E
Singh
Kumud K
KK
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 / Q000378:metabolism; D019380:Anti-HIV Agents / Q000493:pharmacokinetics* / Q000627:therapeutic use; D023241:Antiretroviral Therapy, Highly Active; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics* / Q000378:metabolism; D065731:Cytochrome P-450 CYP2C19; D005786:Gene Expression Regulation / Q000502:physiology; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D005838:Genotype; D015658:HIV Infections / Q000188:drug therapy / Q000235:genetics*; D015497:HIV-1 / Q000187:drug effects / Q000235:genetics; D006801:Humans; D019888:Nelfinavir / Q000493:pharmacokinetics* / Q000627:therapeutic use; D012367:RNA, Viral / Q000097:blood; D012189:Retrospective Studies; D016896:Treatment Outcome
C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D019380:Anti-HIV Agents; D012367:RNA, Viral; D001189:Aryl Hydrocarbon Hydroxylases; C045793:CYP2C19 protein, human; D065731:Cytochrome P-450 CYP2C19; D019888:Nelfinavir