Background: Patients (pts) receiving Highly Active Antiretroviral Therapy (HAART) have differing responses to therapy that are attributed to variable adherence and individual differences in viral and host genetic factors. Host factors have not been well-characterized. The MDR1 gene encodes P-glycoprotein, a drug efflux protein which influences gastrointestinal uptake and intracellular concentrations of protease inhibitors in HIV-infected cells. A recent report suggested that CD4⁺ cell counts increased to a statistically significantly greater degree in pts with the variant allele (T) at the MDR1 C3435T locus when they were treated with nelfinavir or efavirenz. CYP2C19 and CYP3A have been reported to be the most important of the P450 enzymes in the metabolism of nelfinavir.

Methods: Genotypic analyses at four loci (MDR1 C3435T, MDR1 A61G, CYP2C19*2, and CYP3A5*3) were performed using DNA extracted from PBMCs of 142 pts enrolled in an open-label, randomized phase IIIb study comparing nelfinavir and efavirenz for treatment of HAART-naïve individuals. Consent for genomic testing was obtained after the study had been opened. Not all pts enrolled (n = 222) were available for consent because they had either completed or terminated the study. Allelic frequency was determined as a function of racial background (Caucasian, African-American or Hispanic) and was correlated with the change in CD4 cell count at 48 weeks.

Results: The ethnic distribution of pts with genotypes in this analysis was 41% Caucasian, 43% African-American and 16% Hispanic. The C and T alleles at the MDR1 C3435 locus were equally frequent in the Caucasian population, but the C or wild-type allele was most prevalent in the African-American population [62% homozygous (CC), 33% heterozygous (CT)]. The wild-type allele of CYP 3A5*3 was most prevalent in the African-American population (wt/wt 52%, wt/v 38%). The variant allele of CYP3A5*3 was more abundant in Caucasians (wt/v 12.5%, v/v 87.5). The homozygous variant genotypes for each of these loci were highly associated (p < 0.001). No significant ethnic differences were seen in alleleic frequencies for MDR1 A61G or CYP2C19*2. CD4 cell counts did not increase to a higher level in individuals with the homozygous variant genotype (TT) at the MDR1 C3435T locus in either the nelfinavir or the efavirenz treatment groups.

Conclusions: This analysis did not support the previous observation that the T allele at the MDR1 C3435T locus is associated with higher CD4 cell elevations during therapy with nelfinavir or efavirenz.