Influence of MDR1 C1236T polymorphism on lopinavir plasma concentration and virological response in HIV-1-infected children

• Published in: Gene 2013-06, Vol.522 (1), p.96-101
• Main Authors: Bellusci, Carolina P., Rocco, Carlos, Aulicino, Paula, Mecikovsky, Debora, Curras, Verónica, Hegoburu, Soledad, Bramuglia, Guillermo F., Bologna, Rosa, Sen, Luisa, Mangano, Andrea
• Format: Article
• Language: English
• Subjects: absorption; Adolescent; Adult; alleles; Antiretroviral Therapy, Highly Active - methods; ATP Binding Cassette Transporter, Sub-Family B; ATP-Binding Cassette, Sub-Family B, Member 1 - genetics; CD4-positive T-lymphocytes; CD4-Positive T-Lymphocytes - metabolism; Child; Child, Preschool; children; drugs; enterocytes; Female; Gene Frequency; Genotype; HAART; heterozygosity; Heterozygote; HIV Infections - blood; HIV Infections - drug therapy; HIV Infections - genetics; HIV Infections - virology; HIV Protease Inhibitors - blood; HIV Protease Inhibitors - therapeutic use; HIV-1 - drug effects; HIV-1 pediatric infection; homozygosity; Homozygote; Humans; immune response; Infant; Lopinavir; Lopinavir - blood; Lopinavir - therapeutic use; Male; MDR1; Polymorphism, Single Nucleotide; PXR; Receptors, Steroid - genetics; Single nucleotide polymorphism; therapeutics; viral load; Young Adult
• ISSN: 0378-1119; 1879-0038
• DOI: 10.1016/j.gene.2013.03.020

Variability in MDR1 and PXR has been associated with differences in drug plasma levels and response to antiretroviral therapy. We investigated whether polymorphisms in MDR1 (T-129C, C1236T and C3435T) and PXR (C63396T) affect lopinavir plasma concentration and the virological or immunological response to HAART in HIV-1-infected children. Genotypes were identified in 100 blood donors and 38 HIV-1-infected children. All children received HAART with lopinavir boosted with ritonavir (LPV/r) at the time of LPV plasma level quantification, before (Ctrough) and between 1 and 2h after (Cpost-dose) the administration of the next dose of drug. CD4+ T-cell counts and plasma viral load were analyzed before and after the initiation of LPV/r. MDR1 1236T, MDR1 3435T and PXR 63396T alleles showed a frequency of ~50% while the MDR1 -129C allele only reached 5%. Children heterozygotes 1236CT showed a significantly lower LPV Cpost-dose than homozygotes 1236TT (median Cpost-dose=3.04μg/ml and 6.50μg/ml, respectively; p=0.016). Children heterozygotes 1236CT also had a lower decrease of viral load after 36weeks of LPV/r exposure compared with homozygotes 1236CC (median viral load changes=−0.50log10 copies/ml and −2.08log10 copies/ml, respectively; p=0.047). No effect on the immunological response was observed for polymorphisms of MDR1 or PXR. Our results suggest that the MDR1 C1236T SNP significantly reduces LPV plasma concentration affecting the virological response to HAART. Heterozygotes 1236CT might have an altered level of P-gp expression/activity in enterocytes and CD4+ T lymphocytes that limits the absorption of LPV leading to an impaired virological suppression. •A pharmacogenetic study was performed in 38 HIV-1-infected children.•Children MDR1 1236CT showed lower LPV Cpost-dose than children MDR1 1236TT.•Children MDR1 1236CT had a lower decrease in plasma VL than children MDR1 1236CC.•The MDR1 C1236T SNP affects LPV plasma levels and the virological response.