Background: The multidrug-resistance transporter gene (MDR1) encoding for P-glycoprotein and genes encoding for isoenzymes of cytochrome P450 (CYP) have an important role in transport and metabolism of many drugs including antiretrovirals. This research examined the impact of allelic variants of MDR1 and CYP genes on nelfinavir (NFV) and efavirenz (EFV) concentrations in plasma and the virologic and immunologic response to therapy in children.

Methods: Seventy-one (71) HIV-1 infected children from PACTG 382 receiving EFV, NFV, and 1 or 2 NRTIs had DNA from PBMC genotyped for MDR1 and P450 CYP3A5*3, CYP3A4-V and CYP3A5*6 polymorphisms by real-time PCR. Plasma drug concentrations, CD4⁺ lymphocyte counts and HIV-1 RNA were also measured.

Results: The MDR-3435-T allelic frequency was 0.5 in Whites (n = 8) and 0.45 in Hispanics (n = 16) compared to 0.26 in Blacks (n = 46) (p = 0.02). Plasma HIV-1 RNA was undetectable by week 8 in 91% (29/32) of children with C/T genotype compared to 59% (17/29) of children with C/C genotype (p = 0.004). Children with C/T genotypes had higher 8 hr post dose concentration (PDC) (2.8 mg/L, n = 32) for NFV compared to those with C/C genotype (1.4 mg/L, n = 30) (p = 0.02). Children with C/T genotypes also had higher AUC (21.8 mg/Lh, n = 30) compared to those with C/C genotypes (16.2 mg/Lh, n = 27) (p = 0.09). The oral clearance rate (L/h/kg) of NFV in children with the C/T genotype was lower than those with the C/C genotype (p = 0.04). Findings for the 7 subjects with the T/T mutation were somewhat inconsistent with respect to the agreement with those of the C/C vs C/T groups. No significant PK associations were observed for EFV response with MDR polymorphisms. The MDR1-C/T genotype was associated with CYP3A5*3 (p = 0.017) and CYP3A4-V (p = 0.014) polymorphisms, but not with the CYP3A5*6 (p = 0.98) polymorphism. However, CYP450 polymorphisms did not significantly affect the PK of NFV or EFV. No associations were observed in CD4⁺ recovery with MDR1 or CYP polymorphisms; however, because treatment dosages were guided by PK data, the ability to find differences in CD4⁺ recovery was limited.

Conclusions: HIV-1 infected children with the MDR-3435 C/C genotype had slower virologic responses to HAART consisting of 1-2 NRTI, EFV, and NFV at week 8 with lower plasma concentrations and higher clearance rates for NFV compared to the C/T group. These findings suggest that P-glycoprotein has an important role in the PK and virologic response to antiretroviral combinations containing NFV.