title: Influence of MDR1 C1236T polymorphism on lopinavir plasma concentration and virological response in HIV-1-infected children.
abstract: 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 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.
  
  
  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 log 10 copies/ml and -2.08 log 10 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.
authors.affiliation: Laboratorio de Biología Celular y Retrovirus - Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Hospital de Pediatría "Juan P. Garrahan", Buenos Aires, Argentina.
authors.forename: Carolina P
authors.initials: CP
authors.lastname: Bellusci
authors.forename: Carlos
authors.initials: C
authors.lastname: Rocco
authors.forename: Paula
authors.initials: P
authors.lastname: Aulicino
authors.forename: Debora
authors.initials: D
authors.lastname: Mecikovsky
authors.forename: Verónica
authors.initials: V
authors.lastname: Curras
authors.forename: Soledad
authors.initials: S
authors.lastname: Hegoburu
authors.forename: Guillermo F
authors.initials: GF
authors.lastname: Bramuglia
authors.forename: Rosa
authors.initials: R
authors.lastname: Bologna
authors.forename: Luisa
authors.initials: L
authors.lastname: Sen
authors.forename: Andrea
authors.initials: A
authors.lastname: Mangano
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics*; D000293:Adolescent; D000328:Adult; D023241:Antiretroviral Therapy, Highly Active / Q000379:methods; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism; D002648:Child; D002675:Child, Preschool; D005260:Female; D005787:Gene Frequency; D005838:Genotype; D015658:HIV Infections / Q000097:blood / Q000188:drug therapy* / Q000235:genetics* / Q000821:virology; D017320:HIV Protease Inhibitors / Q000097:blood* / Q000627:therapeutic use; D015497:HIV-1 / Q000187:drug effects*; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D007223:Infant; D061466:Lopinavir / Q000097:blood* / Q000627:therapeutic use; D008297:Male; D020641:Polymorphism, Single Nucleotide; D000077297:Pregnane X Receptor; D011987:Receptors, Steroid / Q000235:genetics; D055815:Young Adult
chemical_list: C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D017320:HIV Protease Inhibitors; D000077297:Pregnane X Receptor; D011987:Receptors, Steroid; D061466:Lopinavir