Response to antiretroviral treatment in HIV-1-infected individuals with allelic variants of the multidrug resistance transporter 1: a pharmacogenetics study

Lancet. 2002 Jan 5;359(9300):30-6. doi: 10.1016/S0140-6736(02)07276-8.

Abstract

Background: HIV-1-infected patients vary considerably by their response to antiretroviral treatment, drug concentrations in plasma, toxic events, and rate of immune recovery. This variability could have a genetic basis. We did a pharmacogenetics study to analyse the association between response to antiretroviral treatment and allelic variants of several genes.

Methods: In 123 patients, we did PCR analyses of the gene for the multidrug-resistance transporter (MDR1), which codes for P-glycoprotein, of genes coding for isoenzymes of cytochrome P450, CYP3A4, CYP3A5, CYP2D6, and CYP2C19, and of the gene for the chemokine receptor CCR5. We measured concentrations in plasma of the antiretroviral agents efavirenz and nelfinavir by high-performance liquid-chromatography, and measured levels of P-glycoprotein expression, CD4-cell count, and HIV-1 viraemia.

Findings: Median drug concentrations in patients with the MDR1 3435 TT, CT, and CC genotypes were at the 30th, 50th, and 75th percentiles, respectively (p=0.0001). In patients with CYP2D6 extensive-metaboliser or poor-metaboliser alleles, median drug concentrations were at percentiles 45 and 62.5, respectively (p=0.04). Patients with the MDR1 TT genotype 6 months after starting treatment had a greater rise in CD4-cell count (257 cells/microL) than patients with the CT (165 cells/microL) and CC (121 cells/microL) genotype (p=0.0048), and the best recovery of naïve CD4-cells.

Interpretation: The polymorphism MDR1 3435 C/T predicts immune recovery after initiation of antiretroviral treatment. This finding suggests that P-glycoprotein has an important role in admittance of antiretroviral drugs to restricted compartments in vivo.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / drug effects
  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / physiology*
  • Alleles
  • Anti-HIV Agents / blood
  • Anti-HIV Agents / therapeutic use*
  • Benzoxazines
  • Chromatography, High Pressure Liquid
  • Cytochrome P-450 Enzyme System / drug effects
  • Cytochrome P-450 Enzyme System / genetics*
  • Female
  • Genes, MDR / drug effects
  • Genes, MDR / genetics*
  • Genotype
  • HIV Infections / drug therapy*
  • HIV Protease Inhibitors / blood
  • HIV Protease Inhibitors / therapeutic use*
  • HIV-1*
  • Humans
  • Logistic Models
  • Male
  • Nelfinavir / blood
  • Nelfinavir / therapeutic use*
  • Oxazines / blood
  • Oxazines / therapeutic use*
  • Pharmacogenetics
  • Polymerase Chain Reaction
  • Prospective Studies
  • Treatment Outcome

Substances

  • ATP Binding Cassette Transporter, Subfamily B, Member 1
  • Anti-HIV Agents
  • Benzoxazines
  • HIV Protease Inhibitors
  • Oxazines
  • Cytochrome P-450 Enzyme System
  • Nelfinavir
  • efavirenz