An MDR1-3435 variant is associated with higher plasma nelfinavir levels and more rapid virologic response in HIV-1 infected children

Akihiko Saitoh, Kumud K. Singh, Christine A. Powell, Terrence Fenton, Courtney V. Fletcher, Richard Brundage, Stuart Starr, Stephen A. Spector

Research output: Contribution to journalArticle

101 Citations (Scopus)

Abstract

Objective: The multidrug-resistance transporter gene (MDR1) encoding for P-glycoprotein (P-gp) and genes encoding for isoenzymes of cytochrome P450 (CYP) have an important role in transport and metabolism of antiretroviral agents. This research examined the impact of single nucleotide polymorphisms (SNP) of MDR1 and CYP genes on nelfinavir and efavirenz pharmacokinetics and the response to highly active antiretroviral therapy (HAART) in HIV-1 infected children. Methods: Seventy-one HIV-1-infected children from PACTG 382 receiving nelfinavir, efavirenz and one or two nucleoside reverse transcriptase inhibitors had genomic DNA from PBMC evaluated for MDR1 and CYP SNP by real-time PCR. Plasma drug concentrations, CD4 lymphocyte counts and HIV-1 RNA were measured during HAART. Results: The frequencies of C/C, C/T and T/T genotypes in the MDR1-3435-C→T polymorphisms were 44% (n = 31), 46% (n = 33) and 10% (n = 7), respectively. Ninety-one percent of children with the C/T genotype reached plasma HIV-1 RNA < 400 copies/ml by week 8 compared to 59% of children with the C/C genotype (P = 0.01). Children with the C/T genotypes had higher 8 h postdose concentration (P = 0.02) and lower clearance rate (P = 0.04) for nelfinavir compared to those with the C/C genotype. The seven children with the T/T genotype had nelfinavir pharmacokinetics and virologic response similar to those with the C/C genotype. No compensatory polymorphisms were observed between MDR1 and CYP genotypes. Conclusions: HIV-1 infected children with the MDR1-3435-C/T genotype had more rapid virologic responses to HAART at week 8 with higher plasma nelfinavir concentrations compared to those with the C/C genotype. These findings suggest that P-gp may play an important role in the pharmacokinetics and virologic response to HAART containing nelfinavir.

Original languageEnglish (US)
Pages (from-to)371-380
Number of pages10
JournalAIDS
Volume19
Issue number4
DOIs
StatePublished - Mar 4 2005

Fingerprint

Nelfinavir
HIV-1
Genotype
efavirenz
Highly Active Antiretroviral Therapy
Cytochrome P-450 Enzyme System
Pharmacokinetics
P-Glycoprotein
Single Nucleotide Polymorphism
RNA
Anti-Retroviral Agents
MDR Genes
Reverse Transcriptase Inhibitors
CD4 Lymphocyte Count
Nucleosides
Isoenzymes
Genes
Real-Time Polymerase Chain Reaction

Keywords

  • Children
  • Cytochrome P450
  • HIV-1
  • MDR1
  • Nelfinavir
  • P-glycoprotein
  • Single nucleotide polymorphisms (SNPs)

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology
  • Infectious Diseases

Cite this

An MDR1-3435 variant is associated with higher plasma nelfinavir levels and more rapid virologic response in HIV-1 infected children. / Saitoh, Akihiko; Singh, Kumud K.; Powell, Christine A.; Fenton, Terrence; Fletcher, Courtney V.; Brundage, Richard; Starr, Stuart; Spector, Stephen A.

In: AIDS, Vol. 19, No. 4, 04.03.2005, p. 371-380.

Research output: Contribution to journalArticle

Saitoh, Akihiko ; Singh, Kumud K. ; Powell, Christine A. ; Fenton, Terrence ; Fletcher, Courtney V. ; Brundage, Richard ; Starr, Stuart ; Spector, Stephen A. / An MDR1-3435 variant is associated with higher plasma nelfinavir levels and more rapid virologic response in HIV-1 infected children. In: AIDS. 2005 ; Vol. 19, No. 4. pp. 371-380.
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AU - Saitoh, Akihiko

AU - Singh, Kumud K.

AU - Powell, Christine A.

AU - Fenton, Terrence

AU - Fletcher, Courtney V.

AU - Brundage, Richard

AU - Starr, Stuart

AU - Spector, Stephen A.

PY - 2005/3/4

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N2 - Objective: The multidrug-resistance transporter gene (MDR1) encoding for P-glycoprotein (P-gp) and genes encoding for isoenzymes of cytochrome P450 (CYP) have an important role in transport and metabolism of antiretroviral agents. This research examined the impact of single nucleotide polymorphisms (SNP) of MDR1 and CYP genes on nelfinavir and efavirenz pharmacokinetics and the response to highly active antiretroviral therapy (HAART) in HIV-1 infected children. Methods: Seventy-one HIV-1-infected children from PACTG 382 receiving nelfinavir, efavirenz and one or two nucleoside reverse transcriptase inhibitors had genomic DNA from PBMC evaluated for MDR1 and CYP SNP by real-time PCR. Plasma drug concentrations, CD4 lymphocyte counts and HIV-1 RNA were measured during HAART. Results: The frequencies of C/C, C/T and T/T genotypes in the MDR1-3435-C→T polymorphisms were 44% (n = 31), 46% (n = 33) and 10% (n = 7), respectively. Ninety-one percent of children with the C/T genotype reached plasma HIV-1 RNA < 400 copies/ml by week 8 compared to 59% of children with the C/C genotype (P = 0.01). Children with the C/T genotypes had higher 8 h postdose concentration (P = 0.02) and lower clearance rate (P = 0.04) for nelfinavir compared to those with the C/C genotype. The seven children with the T/T genotype had nelfinavir pharmacokinetics and virologic response similar to those with the C/C genotype. No compensatory polymorphisms were observed between MDR1 and CYP genotypes. Conclusions: HIV-1 infected children with the MDR1-3435-C/T genotype had more rapid virologic responses to HAART at week 8 with higher plasma nelfinavir concentrations compared to those with the C/C genotype. These findings suggest that P-gp may play an important role in the pharmacokinetics and virologic response to HAART containing nelfinavir.

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