Influence of MDR1 C1236T polymorphism on lopinavir plasma concentration and virological response in HIV-1-infected children |
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Authors: | Carolina P Bellusci Carlos Rocco Paula Aulicino Debora Mecikovsky Verónica Curras Soledad Hegoburu Guillermo F Bramuglia Rosa Bologna Luisa Sen Andrea Mangano |
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Institution: | 1. Laboratorio de Biología Celular y Retrovirus - Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Hospital de Pediatría “Juan P. Garrahan”, Buenos Aires, Argentina;2. Servicio de Epidemiología e Infectología, Hospital de Pediatría “Juan P. Garrahan”, Buenos Aires, Argentina;3. Cátedra de Farmacología, Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires, Buenos Aires, Argentina |
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Abstract: | BackgroundVariability 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.MethodsGenotypes 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 2 h 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.ResultsMDR1 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 = 3.04 μg/ml and 6.50 μg/ml, respectively; p = 0.016). Children heterozygotes 1236CT also had a lower decrease of viral load after 36 weeks of LPV/r exposure compared with homozygotes 1236CC (median viral load changes = − 0.50 log10 copies/ml and − 2.08 log10 copies/ml, respectively; p = 0.047). No effect on the immunological response was observed for polymorphisms of MDR1 or PXR.ConclusionsOur 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. |
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