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.


RESULTS
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.


CONCLUSIONS
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.
Fellay
Jacques
J
Division of Infectious Diseases, University Hospital of Lausanne, Lausanne, Switzerland.
Marzolini
Catia
C
Meaden
Emma R
ER
Back
David J
DJ
Buclin
Thierry
T
Chave
Jean Philippe
JP
Decosterd
Laurent A
LA
Furrer
Hansjakob
H
Opravil
Milos
M
Pantaleo
Giuseppe
G
Retelska
Dorota
D
Ruiz
Lidia
L
Schinkel
Alfred H
AH
Vernazza
Pietro
P
Eap
Chin B
CB
Telenti
Amalio
A
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000187:drug effects / Q000502:physiology*; D000480:Alkynes; D000483:Alleles; D019380:Anti-HIV Agents / Q000097:blood / Q000627:therapeutic use*; D048588:Benzoxazines; D002851:Chromatography, High Pressure Liquid; D003521:Cyclopropanes; D003577:Cytochrome P-450 Enzyme System / Q000187:drug effects / Q000235:genetics*; D005260:Female; D019450:Genes, MDR / Q000187:drug effects / Q000235:genetics*; D005838:Genotype; D015658:HIV Infections / Q000188:drug therapy*; D017320:HIV Protease Inhibitors / Q000097:blood / Q000627:therapeutic use*; D015497:HIV-1; D006801:Humans; D016015:Logistic Models; D008297:Male; D019888:Nelfinavir / Q000097:blood / Q000627:therapeutic use*; D010078:Oxazines / Q000097:blood / Q000627:therapeutic use*; D010597:Pharmacogenetics; D016133:Polymerase Chain Reaction; D011446:Prospective Studies; D016896:Treatment Outcome
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000480:Alkynes; D019380:Anti-HIV Agents; D048588:Benzoxazines; D003521:Cyclopropanes; D017320:HIV Protease Inhibitors; D010078:Oxazines; D003577:Cytochrome P-450 Enzyme System; D019888:Nelfinavir; C098320:efavirenz