Influence of MDR1 C1236T polymorphism on lopinavir plasma concentration and virological response in HIV-1-infected children
| Autor: | Soledad Hegoburu, Andrea Mangano, Carlos Rocco, Debora Mecikovsky, Paula C. Aulicino, Guillermo F. Bramuglia, Rosa Bologna, Luisa Sen, Verónica Curras, Carolina Paula Bellusci |
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| Rok vydání: | 2013 |
| Předmět: |
SINGLE NUCLEOTIDE POLYMORPHISM
Adult CD4-Positive T-Lymphocytes Male Heterozygote Receptors Steroid HAART CIENCIAS MÉDICAS Y DE LA SALUD ATP Binding Cassette Transporter Subfamily B Adolescent Genotype Ciencias de la Salud Single-nucleotide polymorphism HIV Infections Biology Polymorphism Single Nucleotide Lopinavir HIV-1 PEDIATRIC INFECTION Young Adult Gene Frequency Antiretroviral Therapy Highly Active Genetics medicine Humans ATP Binding Cassette Transporter Subfamily B Member 1 Allele Child Allele frequency Homozygote Pregnane X Receptor LOPINAVIR Infant Ética Médica Heterozygote advantage General Medicine HIV Protease Inhibitors Child Preschool Immunology HIV-1 Ritonavir Female Viral load medicine.drug |
| Zdroj: | Gene. 522(1) |
| ISSN: | 1879-0038 |
| Popis: | Background: 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. Methods: 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 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. Results: 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 = 3.04 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. Conclusions: 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. Fil: Bellusci, Carolina Paula. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan". Laboratorio de Biología Celular y Retrovirus; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: Rocco, Carlos Alberto. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan". Laboratorio de Biología Celular y Retrovirus; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: Aulicino, Paula. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan". Laboratorio de Biología Celular y Retrovirus; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: Mecikovsky, Debora. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; Argentina Fil: Curras, Verónica. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Farmacología. Cátedra de Farmacología; Argentina Fil: Hegoburu, Soledad. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Farmacología. Cátedra de Farmacología; Argentina Fil: Bramuglia, Guillermo Federico. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Farmacología. Cátedra de Farmacología; Argentina Fil: Bologna, Rosa. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; Argentina Fil: Sen, Luisa. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan". Laboratorio de Biología Celular y Retrovirus; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: Mangano, Andrea María Mercedes. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan". Laboratorio de Biología Celular y Retrovirus; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina |
| Databáze: | OpenAIRE |
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