Influence of polymorphisms within the CX3CR1 and MDR-1 genes on initial antiretroviral therapy response

Objective: Single nucleotide polymorphisms (SNP) in the genes encoding the human CX(3)CR1 chemokine receptor and the P-glycoprotein multidrug transporter have been associated with accelerated disease progression in untreated individuals and implicated in therapeutic response, respectively. This retrospective study assessed the influence of SNP in the CX(3)CR1 and MDR-1 genes on initial virological and immunological response in 461 HIV-infected, anti retroviral-naive individuals initiating antiretroviral therapy in British Columbia, Canada. Methods: CX(3)CR1 and MDR-1 SNP were determined by PCR amplification of human DNA from plasma, followed by DNA sequencing. Time to virological success [time to HIV plasma viral load (pVL)less than or equal to500 copies/ml], virological failure (subsequent time to the second of two consecutive pVLgreater than or equal to500) and immunological failure (time to the second consecutive CD4 cell count below baseline) were analyzed by Kaplan-Meier methods. Results: Frequencies of CX(3)CR1 amino acid haplotypes were 249V 280T (0.75), 2491 280M (0.15), and 2491 280T (0.1). Frequencies of MDR-1 nucleotide polymorphisms were 3435C (0.47) and 3435T (0.53). There was no effect detected for SNP in CX(3)CR1 or MDR-1 on time to virological success, nor of CX(3)CR1 and MDR-1 SNP on time to virological and immunological failure, respectively (P>0.1). There was a trend to earlier virological failure in the MDR-1 3435C/C genotype group (P=0.07), and a statistically significant trend to earlier immunological failure in individuals with the CX(3)CR1 2491 polymorphism (P=0.02). These remained significant after correcting for baseline age, sex, pVL, CD4 cell count, type of therapy, and adherence (P<0.05). Conclusion: Polymorphisms in MDR-1 and CX(3)CR1 may be associated with accelerated virological and immunological therapy failure, respectively. (C) 2003 Lippincott Williams & Wilkins.