An MDR1-3435 variant is associated with higher plasma nelfinavir levels and more rapid virologic response in HIV-1 infected children.
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.
Saitoh
Akihiko
A
Division of Infectious Diseases, Department of Pediatrics, University of California, San Diego, La Jolla, California 92093-0672, USA.
Singh
Kumud K
KK
Powell
Christine A
CA
Fenton
Terrence
T
Fletcher
Courtney V
CV
Brundage
Richard
R
Starr
Stuart
S
Spector
Stephen A
SA
D023241:Antiretroviral Therapy, Highly Active; D018791:CD4 Lymphocyte Count; D002648:Child; D002675:Child, Preschool; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics; D005260:Female; D019450:Genes, MDR / Q000235:genetics*; D005838:Genotype; D015658:HIV Infections / Q000097:blood* / Q000188:drug therapy / Q000235:genetics; D017320:HIV Protease Inhibitors / Q000097:blood* / Q000627:therapeutic use; D015497:HIV-1 / Q000302:isolation & purification*; D006801:Humans; D008297:Male; D019888:Nelfinavir / Q000097:blood* / Q000627:therapeutic use; D020641:Polymorphism, Single Nucleotide; D012367:RNA, Viral / Q000097:blood; D016896:Treatment Outcome
D017320:HIV Protease Inhibitors; D012367:RNA, Viral; D003577:Cytochrome P-450 Enzyme System; D019888:Nelfinavir