Background:  The mechanism of lipid changes in patients receiving ART has not been delineated. A pharmacogenetic approach can be used to correlate genetic variants with lipid changes observed during treatment, thereby suggesting that the gene product may be part of a relevant pathway affected by a drug regimen. In the general population, apolipoprotein genotypes APOC3 3238C>G and APOA5 56C>G appear to be independent risk factors for increased triglycerides (TG). A recent report described increased TG changes in joint carriers of an APOE variant and APOC3 -482C>T, -455T>C, and 3238C>G variants treated with ritonavir (RTV)-containing regimens.

Methods:  Relationships of total cholesterol (TC) and TG with variants of APOE, APOC3, and APOA5 genes were assessed in a phase 3 randomized, double-blind clinical trial (n = 653) comparing the safety and efficacy of regimens containing stavudine (d4T), lamivudine (3TC), and either lopinavir/ritonavir (LPV/r) or nelfinavir (NFV) for the initial treatment of HIV infection. Baseline TC and TG, and maximum and average TC and TG changes from baseline within 48 weeks were analyzed by analysis of co-variance including factors for genotype, sex, race/ethnicity, smoking status and treatment arm; and age, body mass index, viral load, CD4 count, and baseline TC or TG levels as co-variates. Non-significant terms were sequentially dropped from the models.

Results:  Genotypes and on-study lipid data were available from 364 subjects. Baseline TC was not associated with any tested genotype. Baseline TG was associated with APOC3 3238C>G (p = 0.04) and APOA5 56C>G (p = 0.03) genotypes. Both maximum (p = 0.03) and average (p = 0.04) TC changes from baseline were inversely associated with APOE e4 genotype. Average TG change from baseline was associated with APOC3 3238C>G genotype (p = 0.03) but not with APOA5 56C>G genotype. No lipid parameters (baseline or changes) were associated with APOE e2, APOC3 -482C>T or APOC3 -455T>C genotypes. TG changes in LPV/r-treated subjects were not associated with joint APOE/APOC3 variant carrier status.

Conclusions:  The mean magnitudes of TC changes from baseline in different APOE genotypes (e3/e3 > e 3/e4 > e4/e4) are consistent with increased affinity of the ApoE e4 protein for the low density lipoprotein receptor. Patients with APOC3 3238GG genotype (~4% of the genotyped subjects) had higher co-variate-adjusted average TG changes from baseline. These relationships were not dependent on treatment arm.