The The role of polymorphism of the CYP3A4 gene in biotransformation of drugs in childrenwith antiretroviral therapy

Abstract

Background. The enzyme CYP3A4 is critically important for the metabolism of lopinavir and ritonavir, a combined first-line antiretroviral therapy drug in children. Polymorphisms of the CYP3A4 gene determine changes in the expression and functional activity of the CYP3A4 enzyme, which leads to variability in the pharmacokinetics of lopinavir and ritonavir and, as a result, to differences in the virological response.

The aim of the study was to evaluate lopinavir/ritonavir concentrations and the contribution of CYP3A4 gene polymorphism to lopinavir/ritonavir concentration variability in children with different virological efficacy on the background of antiretroviral therapy.

The methods. At the first stage of the study, 184 participants aged 1-18 years with perinatal HIV infection receiving antiretroviral therapy were included. All study participants underwent a single measurement of lopinavir and ritonavir concentrations using HPLC-MS. At the second stage of the study, 48 patients were selected from the total cohort, who, according to the results of double measurement of viral load, were divided into two groups: group 1 - 32 patients with undetectable viral load <50 kop/ml; group 2 - 16 patients with a viral load >50 kop/ml, for whom the region 21589–22545 of the CYP3A4 gene was studied using the Sanger sequencing method.

Results. The median concentrations of lopinavir and ritonavir were significantly higher in the group of children with virological efficacy than without it - 5041.9 ng/ml and 3002.5 ng/ml (p=0.001), 314 ng/ml and 103.24 ng/ml (p=0.004), respectively. Three polymorphisms of the CYP3A4 gene were identified in patients with HIV infection: rs4646437, rs71581995, rs2485880681. No statistically significant association was found between the carriage of a certain genotype of the identified CYP3A4 gene polymorphisms with virological efficacy in univariate and multiple logistic regression adjusted for age and gender.

Conclusion. Polymorphisms rs4646437, rs71581995, rs2485880681 of the CYP3A4 gene are not associated with virological efficacy in children with HIV infection receiving protease inhibitor therapy.