Background:  Nelfinavir (NFV) is transported via P-glycoprotein and metabolized to active metabolite (M8) by cytochrome P450 (CYP) 2C19. We previously reported that genetic variants encoding for P-glycoprotein (ABCB1) were associated with NFV pharmacokinetics and virologic response in HIV-1-infected children (n = 71) receiving HAART. This study extended the number of subjects from different cohorts to investigate the association between genetic variants of CYP and ABCB1 on NFV pharmacokinetics and the response to HAART in HIV-1-infected children.

Methods:  We evaluated 152 HIV-1-infected children from Pediatric AIDS Clinical Trials Group (PACTG) 366 and 377 receiving NFV as a component of HAART. Concomitant antiretrovirals included NRTI alone (n = 23), ritonavir (RTV, n = 40), nevirapine (NVP, n = 60), and RTV + NVP (n = 29). Genomic DNA from peripheral blood mononuclear cells was tested for ABCB1 and CYP genetic variants by real-time polymerase chain reaction (RT-PCR). Intensive (70%) and sparse (30%) pharmacokinetics were used to calculate NFV and M8 levels. CD4⁺ T cell and HIV-1 RNA were measured during HAART.

Results:  The parameters associated with NFV oral clearance (CL/F) included age (p <0.001), RTV use (p = 0.001), CYP2C19-G681A (p = 0.001), and ABCB1-C3435T (p = 0.03) by univariate analyses. The NFV CL/F (L/h/kg) in children with the CYP2C19-681-G/G (wild type, 1.86, n = 102) was higher than for those with the G/A (heterozygous variant, 1.33, n = 42, p = 0.001) and A/A (homozygous variant, 1.29, n = 8, p = 0.02). In contrast, the ratio of M8 to NFV (M8:NFV) was higher in children with the CYP2C19-681-A/A than for those with the G/A (p = 0.003) and the G/G (p <0.001). Furthermore, the children with the CYP2C19-681-G/A or A/A achieving HIV-1 RNA <400 copies/mL (68%) was higher than those with the G/G (46%) at week 24 (p = 0.01). The immunologic recovery was not associated with the genotypes at weeks 12 or 24 (p >0.44). The allelic frequencies of the CYP2C19-681-A were higher in blacks (0.61) than whites (0.15), or Hispanics (0.12) (p <0.001). The multivariate analyses demonstrated that the CYP2C19-G681A, age, and RTV use were independently associated with NFV CL/F (p <0.001), but not ABCB1-C3435T (p = 0.13).

Conclusions:  This is the first study demonstrating the association between the CYP2C19 genotypes and NFV pharmacokinetics, and the virologic response to HAART in HIV-1-infected children. These findings suggest that CYP2C19 genetic variants play an important role in NFV pharmacokinetics and virologic response in HIV-1-infected children.