CYP2C19 Genetic Variants Affect Nelfinavir Pharmacokinetics and Virologic Response in HIV-1–Infected Children Receiving Highly Active Antiretroviral Therapy

Division of Infectious Diseases, Department of Pediatrics, University of California, San Diego, La Jolla, CA, USA.
JAIDS Journal of Acquired Immune Deficiency Syndromes (Impact Factor: 4.56). 11/2009; 54(3):285-9. DOI: 10.1097/QAI.0b013e3181bf648a
Source: PubMed


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.
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.
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.
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.

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    • "CYP2C19 genotype can influence the bioavailability of nelfinavir, with lower oral clearance with the *2 allele.99 Saitoh et al99 examined the effect of CYP2C19 genotype on antiviral response to nelfinavir in 152 children taking highly active antiretroviral therapy. At 24 weeks, presence of the CYP2C19*2 allele was associated with a greater likelihood of achieving plasma HIV RNA < 400 copies/mL; 46%, 69%, and 63% of patients with the *1/*1, *1/*2, and *2/*2 genotypes, respectively, achieved concentrations <400 copies/mL. "
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