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

Autores
Bellusci, Carolina Paula; Rocco, Carlos Alberto; Aulicino, Paula; Mecikovsky, Debora; Curras, Verónica; Hegoburu, Soledad; Bramuglia, Guillermo Federico; Bologna, Rosa; Sen, Luisa; Mangano, Andrea María Mercedes
Año de publicación
2013
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
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
Materia
HAART
HIV-1 PEDIATRIC INFECTION
LOPINAVIR
SINGLE NUCLEOTIDE POLYMORPHISM
Nivel de accesibilidad
acceso abierto
Condiciones de uso
https://creativecommons.org/licenses/by-nc-nd/2.5/ar/
Repositorio
CONICET Digital (CONICET)
Institución
Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identificador
oai:ri.conicet.gov.ar:11336/23952
Acceder
id CONICETDig_9a84409be38ca4212ad7741bad72e3b1
oai_identifier_str oai:ri.conicet.gov.ar:11336/23952
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling Influence of MDR1 C1236T polymorphism on lopinavir plasma concentration and virological response in HIV-1-infected childrenBellusci, Carolina PaulaRocco, Carlos AlbertoAulicino, PaulaMecikovsky, DeboraCurras, VerónicaHegoburu, SoledadBramuglia, Guillermo FedericoBologna, RosaSen, LuisaMangano, Andrea María MercedesHAARTHIV-1 PEDIATRIC INFECTIONLOPINAVIRSINGLE NUCLEOTIDE POLYMORPHISMhttps://purl.org/becyt/ford/3.3https://purl.org/becyt/ford/3Background: 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; ArgentinaFil: 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; ArgentinaFil: 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; ArgentinaFil: Mecikovsky, Debora. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; ArgentinaFil: Curras, Verónica. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Farmacología. Cátedra de Farmacología; ArgentinaFil: Hegoburu, Soledad. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Farmacología. Cátedra de Farmacología; ArgentinaFil: Bramuglia, Guillermo Federico. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Farmacología. Cátedra de Farmacología; ArgentinaFil: Bologna, Rosa. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; ArgentinaFil: 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; ArgentinaFil: 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; ArgentinaElsevier Science2013-06info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/23952Bellusci, Carolina Paula; Rocco, Carlos Alberto; Aulicino, Paula; Mecikovsky, Debora; Curras, Verónica; et al.; Influence of MDR1 C1236T polymorphism on lopinavir plasma concentration and virological response in HIV-1-infected children; Elsevier Science; Gene; 522; 1; 6-2013; 96-1010378-1119CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/url/http://www.sciencedirect.com/science/article/pii/S0378111913002540info:eu-repo/semantics/altIdentifier/doi/10.1016/j.gene.2013.03.020info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-nd/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-09-29T10:09:21Zoai:ri.conicet.gov.ar:11336/23952instacron:CONICETInstitucionalhttp://ri.conicet.gov.ar/Organismo científico-tecnológicoNo correspondehttp://ri.conicet.gov.ar/oai/requestdasensio@conicet.gov.ar; lcarlino@conicet.gov.arArgentinaNo correspondeNo correspondeNo correspondeopendoar:34982025-09-29 10:09:21.92CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Influence of MDR1 C1236T polymorphism on lopinavir plasma concentration and virological response in HIV-1-infected children
title Influence of MDR1 C1236T polymorphism on lopinavir plasma concentration and virological response in HIV-1-infected children
spellingShingle Influence of MDR1 C1236T polymorphism on lopinavir plasma concentration and virological response in HIV-1-infected children
Bellusci, Carolina Paula
HAART
HIV-1 PEDIATRIC INFECTION
LOPINAVIR
SINGLE NUCLEOTIDE POLYMORPHISM
title_short Influence of MDR1 C1236T polymorphism on lopinavir plasma concentration and virological response in HIV-1-infected children
title_full Influence of MDR1 C1236T polymorphism on lopinavir plasma concentration and virological response in HIV-1-infected children
title_fullStr Influence of MDR1 C1236T polymorphism on lopinavir plasma concentration and virological response in HIV-1-infected children
title_full_unstemmed Influence of MDR1 C1236T polymorphism on lopinavir plasma concentration and virological response in HIV-1-infected children
title_sort Influence of MDR1 C1236T polymorphism on lopinavir plasma concentration and virological response in HIV-1-infected children
dc.creator.none.fl_str_mv Bellusci, Carolina Paula
Rocco, Carlos Alberto
Aulicino, Paula
Mecikovsky, Debora
Curras, Verónica
Hegoburu, Soledad
Bramuglia, Guillermo Federico
Bologna, Rosa
Sen, Luisa
Mangano, Andrea María Mercedes
author Bellusci, Carolina Paula
author_facet Bellusci, Carolina Paula
Rocco, Carlos Alberto
Aulicino, Paula
Mecikovsky, Debora
Curras, Verónica
Hegoburu, Soledad
Bramuglia, Guillermo Federico
Bologna, Rosa
Sen, Luisa
Mangano, Andrea María Mercedes
author_role author
author2 Rocco, Carlos Alberto
Aulicino, Paula
Mecikovsky, Debora
Curras, Verónica
Hegoburu, Soledad
Bramuglia, Guillermo Federico
Bologna, Rosa
Sen, Luisa
Mangano, Andrea María Mercedes
author2_role author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv HAART
HIV-1 PEDIATRIC INFECTION
LOPINAVIR
SINGLE NUCLEOTIDE POLYMORPHISM
topic HAART
HIV-1 PEDIATRIC INFECTION
LOPINAVIR
SINGLE NUCLEOTIDE POLYMORPHISM
purl_subject.fl_str_mv https://purl.org/becyt/ford/3.3
https://purl.org/becyt/ford/3
dc.description.none.fl_txt_mv 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
description 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.
publishDate 2013
dc.date.none.fl_str_mv 2013-06
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
http://purl.org/coar/resource_type/c_6501
info:ar-repo/semantics/articulo
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/11336/23952
Bellusci, Carolina Paula; Rocco, Carlos Alberto; Aulicino, Paula; Mecikovsky, Debora; Curras, Verónica; et al.; Influence of MDR1 C1236T polymorphism on lopinavir plasma concentration and virological response in HIV-1-infected children; Elsevier Science; Gene; 522; 1; 6-2013; 96-101
0378-1119
CONICET Digital
CONICET
url http://hdl.handle.net/11336/23952
identifier_str_mv Bellusci, Carolina Paula; Rocco, Carlos Alberto; Aulicino, Paula; Mecikovsky, Debora; Curras, Verónica; et al.; Influence of MDR1 C1236T polymorphism on lopinavir plasma concentration and virological response in HIV-1-infected children; Elsevier Science; Gene; 522; 1; 6-2013; 96-101
0378-1119
CONICET Digital
CONICET
dc.language.none.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/url/http://www.sciencedirect.com/science/article/pii/S0378111913002540
info:eu-repo/semantics/altIdentifier/doi/10.1016/j.gene.2013.03.020
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
https://creativecommons.org/licenses/by-nc-nd/2.5/ar/
eu_rights_str_mv openAccess
rights_invalid_str_mv https://creativecommons.org/licenses/by-nc-nd/2.5/ar/
dc.format.none.fl_str_mv application/pdf
application/pdf
application/pdf
dc.publisher.none.fl_str_mv Elsevier Science
publisher.none.fl_str_mv Elsevier Science
dc.source.none.fl_str_mv reponame:CONICET Digital (CONICET)
instname:Consejo Nacional de Investigaciones Científicas y Técnicas
reponame_str CONICET Digital (CONICET)
collection CONICET Digital (CONICET)
instname_str Consejo Nacional de Investigaciones Científicas y Técnicas
repository.name.fl_str_mv CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicas
repository.mail.fl_str_mv dasensio@conicet.gov.ar; lcarlino@conicet.gov.ar
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score 13.260194

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