CYP2C19 genetic variants affect nelfinavir pharmacokinetics and virologic response in HIV-1-infected children receiving highly active antiretroviral therapy.

Abstract

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.

• Authors: Akihiko Saitoh, Edmund Capparelli, Francesca Aweeka, Elizabeth Sarles, Kumud K Singh, Andrea Kovacs, Sandra K Burchett, Andrew Wiznia, Sharon Nachman, Terence Fenton, Stephen A Spector
• Journal: Journal of acquired immune deficiency syndromes (1999) (J Acquir Immune Defic Syndr) Vol. 54 Issue 3 Pg. 285-9 (Jul 2010) ISSN: 1944-7884 [Electronic] United States
• PMID: 19890215 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• ABCB1 protein, human
• ATP Binding Cassette Transporter, Subfamily B
• ATP Binding Cassette Transporter, Subfamily B, Member 1
• Anti-HIV Agents
• RNA, Viral
• Aryl Hydrocarbon Hydroxylases
• CYP2C19 protein, human
• Cytochrome P-450 CYP2C19
• Nelfinavir

Topics

• ATP Binding Cassette Transporter, Subfamily B
• ATP Binding Cassette Transporter, Subfamily B, Member 1 (genetics, metabolism)
• Anti-HIV Agents (pharmacokinetics, therapeutic use)
• Antiretroviral Therapy, Highly Active
• Aryl Hydrocarbon Hydroxylases (genetics, metabolism)
• Cytochrome P-450 CYP2C19
• Gene Expression Regulation (physiology)
• Gene Frequency
• Genetic Predisposition to Disease
• Genetic Variation
• Genotype
• HIV Infections (drug therapy, genetics)
• HIV-1 (drug effects, genetics)
• Humans
• Nelfinavir (pharmacokinetics, therapeutic use)
• RNA, Viral (blood)
• Retrospective Studies
• Treatment Outcome