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

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.

[1]  H. Macdonald,et al.  Developmentally regulated expression of P‐glycoprotein (multidrug resistance) activity in mouse thymocytes , 1995, European journal of immunology.

[2]  M. Liscovitch,et al.  Changes in lipid and protein constituents of rafts and caveolae in multidrug resistant cancer cells and their functional consequences , 2000, Glycoconjugate Journal.

[3]  I. Roninson,et al.  Expression and activity of P-glycoprotein, a multidrug efflux pump, in human hematopoietic stem cells , 1991, Cell.

[4]  A. Schinkel,et al.  Significance of P-glycoprotein for the pharmacology and clinical use of HIV protease inhibitors , 2000, AIDS.

[5]  I. Pastan,et al.  Effect of ABC transporters on HIV‐1 infection: inhibition of virus production by the MDR1 transporter , 2000, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[6]  J. Kigawa,et al.  Expression of P-glycoprotein in human placenta: relation to genetic polymorphism of the multidrug resistance (MDR)-1 gene. , 2001, The Journal of pharmacology and experimental therapeutics.

[7]  M. Battegay,et al.  Clinical progression, survival, and immune recovery during antiretroviral therapy in patients with HIV-1 and hepatitis C virus coinfection: the Swiss HIV Cohort Study , 2000, The Lancet.

[8]  G. Plosker,et al.  Nelfinavir , 2000, Drugs.

[9]  U. Meyer,et al.  Genotyping of poor metabolisers of debrisoquine by allele-specific PCR amplification , 1990, The Lancet.

[10]  D. Meijer,et al.  Hepatobiliary and intestinal clearance of amphiphilic cationic drugs in mice in which both mdr1a and mdr1b genes have been disrupted , 1998, British journal of pharmacology.

[11]  Alan S. Perelson,et al.  The decay of the latent reservoir of replication-competent HIV-1 is inversely correlated with the extent of residual viral replication during prolonged anti-retroviral therapy , 2000, Nature Medicine.

[12]  U. Brinkmann,et al.  Functional polymorphisms of the human multidrug-resistance gene: multiple sequence variations and correlation of one allele with P-glycoprotein expression and activity in vivo. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[13]  U. Brinkmann,et al.  Frequency of C3435T polymorphism of MDR1 gene in African people , 2001, The Lancet.

[14]  G R Wilkinson,et al.  The major genetic defect responsible for the polymorphism of S-mephenytoin metabolism in humans. , 1994, The Journal of biological chemistry.

[15]  D. Dormont,et al.  Significance of P-glycoprotein for the pharmacology and clinical use of HIV protease inhibitors. , 2000, AIDS.

[16]  Li,et al.  Transport, metabolism and elimination mechanisms of anti-HIV agents. , 1999, Advanced drug delivery reviews.

[17]  Ann Daly,et al.  Sequence diversity in CYP3A promoters and characterization of the genetic basis of polymorphic CYP3A5 expression , 2001, Nature Genetics.

[18]  D. Middlemas,et al.  Human Immunodeficiency Virus Protease Inhibitors Serve as Substrates for Multidrug Transporter Proteins MDR1 and MRP1 but Retain Antiviral Efficacy in Cell Lines Expressing These Transporters , 1998, Antimicrobial Agents and Chemotherapy.

[19]  M. Relling,et al.  Altered expression of hepatic cytochromes P-450 in mice deficient in one or more mdr1 genes. , 2000, Molecular pharmacology.

[20]  M. Relling,et al.  P-glycoprotein: a major determinant of rifampicin-inducible expression of cytochrome P4503A in mice and humans. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[21]  D. Roden,et al.  The drug transporter P-glycoprotein limits oral absorption and brain entry of HIV-1 protease inhibitors. , 1998, The Journal of clinical investigation.

[22]  M. Fromm,et al.  The C3435T mutation in the human MDR1 gene is associated with altered efflux of the P-glycoprotein substrate rhodamine 123 from CD56+ natural killer cells. , 2001, Pharmacogenetics.

[23]  C. Cass,et al.  Multidrug transporter p‐glycoprotein 170 as a differentiation antigen on normal human lymphocytes and thymocytes: Modulation with differentiation stage and during aging , 1995, American journal of hematology.

[24]  G R Wilkinson,et al.  Pharmacological inhibition of P-glycoprotein transport enhances the distribution of HIV-1 protease inhibitors into brain and testes. , 2000, Drug metabolism and disposition: the biological fate of chemicals.

[25]  J. Drewe,et al.  Interactions of HIV protease inhibitors with ATP-dependent drug export proteins. , 1999, Molecular pharmacology.

[26]  H. McLeod,et al.  MDR1 pharmacogenetics: frequency of the C3435T mutation in exon 26 is significantly influenced by ethnicity. , 2001, Pharmacogenetics.

[27]  J. Margolick,et al.  Immunologic and virologic response to highly active antiretroviral therapy in the Multicenter AIDS Cohort Study , 2001, AIDS.

[28]  G. Elizondo,et al.  CYP3A4 allelic variants with amino acid substitutions in exons 7 and 12: Evidence for an allelic variant with altered catalytic activity , 2000, Clinical pharmacology and therapeutics.

[29]  A. Telenti,et al.  Simultaneous determination of the HIV protease inhibitors indinavir, amprenavir, saquinavir, ritonavir, nelfinavir and the non-nucleoside reverse transcriptase inhibitor efavirenz by high-performance liquid chromatography after solid-phase extraction. , 2000, Journal of chromatography. B, Biomedical sciences and applications.

[30]  S. Khoo,et al.  Differences in the intracellular accumulation of HIV protease inhibitors in vitro and the effect of active transport , 2001, AIDS.

[31]  J. A. Carrillo,et al.  Analysis of midazolam and metabolites in plasma by high-performance liquid chromatography: probe of CYP3A. , 1998, Therapeutic drug monitoring.

[32]  R. Kim,et al.  Identification of functionally variant MDR1 alleles among European Americans and African Americans , 2001, Clinical pharmacology and therapeutics.

[33]  M. Ingelman-Sundberg,et al.  PCR-based genotyping for duplicated and deleted CYP2D6 genes. , 1996, Pharmacogenetics.

[34]  J. Polli,et al.  Induction of P-glycoprotein and cytochrome P450 3A by HIV protease inhibitors. , 2001, Drug metabolism and disposition: the biological fate of chemicals.

[35]  P. Borst,et al.  Absence of the mdr1a P-Glycoprotein in mice affects tissue distribution and pharmacokinetics of dexamethasone, digoxin, and cyclosporin A. , 1995, The Journal of clinical investigation.