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

• Published in: The Lancet (British edition) Vol. 359; no. 9300; pp. 30 - 36
• Main Authors: Fellay, Jacques, Marzolini, Catia, Meaden, Emma R, Back, David J, Buclin, Thierry, Chave, Jean-Philippe, Decosterd, Laurent A, Furrer, Hansjakob, Opravil, Milos, Pantaleo, Giuseppe, Retelska, Dorota, Ruiz, Lidia, Schinkel, Alfred H, Vernazza, Pietro, Eap, Chin B, Telenti, Amalio
• Format: Journal Article
• Language: English
• Published: London Elsevier Ltd 05.01.2002; Lancet; Elsevier Limited
• Subjects: Alleles; Anti-HIV Agents - blood; Anti-HIV Agents - therapeutic use; Antibiotics. Antiinfectious agents. Antiparasitic agents; Antiretroviral agents; Antiretroviral drugs; Antiviral agents; ATP-Binding Cassette, Sub-Family B, Member 1 - drug effects; ATP-Binding Cassette, Sub-Family B, Member 1 - physiology; Benzoxazines; Biocompatibility; Biological and medical sciences; CCR5 protein; CD4 antigen; Chromatography, High Pressure Liquid; CYP2D6 protein; Cytochrome P-450 Enzyme System - drug effects; Cytochrome P-450 Enzyme System - genetics; Cytochrome P450; Drug resistance; Drug therapy; Efavirenz; Electrical impedance; Female; Gene amplification; Gene polymorphism; Genes; Genes, MDR - drug effects; Genes, MDR - genetics; Genotype; Genotypes; Glycoproteins; HIV; HIV Infections - drug therapy; HIV Protease Inhibitors - blood; HIV Protease Inhibitors - therapeutic use; HIV-1; Human immunodeficiency virus; Humans; Immunology; Immunosuppressive agents; Isoenzymes; Logistic Models; Male; MDR1 protein; Medical research; Medical sciences; Multidrug resistance; Multidrug resistant organisms; Mutation; Nelfinavir; Nelfinavir - blood; Nelfinavir - therapeutic use; Oxazines - blood; Oxazines - therapeutic use; P-Glycoprotein; Patients; Pharmacogenetics; Pharmacology; Pharmacology. Drug treatments; Polymerase Chain Reaction; Polymorphism; Prospective Studies; Proteins; Recovery; Treatment Outcome; Viremia; United Kingdom > UK; United States > US; Human; Pharmacogenetics; Treatment resistance; Multiple; HIV-1 virus; P Glycoprotein; Retroviridae; Lentivirus; Blood plasma; Result; Infection; Virus; Allele; Chemotherapy; Treatment; Gene; Viral disease; Genetics; Antiviral; Human immunodeficiency virus; Quantitative analysis; Polymorphism
• ISSN: 0140-6736; 1474-547X
• DOI: 10.1016/S0140-6736(02)07276-8

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. 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. 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/μL) than patients with the CT (165 cells/μL) and CC (121cells/μL) genotype (p=0·0048), and the best recovery of naive CD4-cells. 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.