Background:  MDR-1 gene C3434T polymorphism has been associated with different in vitro expression of the p-glycoprotein on cell membranes and different circulating levels of ART drugs. We investigated whether these polymorphisms could be associated with a different risk of developing morphologic and metabolic alterations on HAART.

Methods:  Genomic DNA samples from HIV⁺ patients on HAART actively followed at the UCSC Rome were analyzed for MDR-1 3435 polymorphisms by polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP) analyses. Patients’ data were collected from clinical records beginning from initiation of HAART. Lipodystrophy, lipodystrophy in any trunk fat accumulation, and lipoatrophy were detected by objective examination. Time-to-event analyses for the 3, and NCEP-ATPIII definitions of high total cholesterol (TC), triglycerides (TG), LDL, non-HDL low-HDL cholesterol were performed using Kaplan-Meier method and Cox’s models.

Results:  We analyzed 180 patients, of whom 69% were male, 46% heterosexual, and 23% hepatitis C virus (HCV)⁺. At HAART initiation, median age was 38 years, CD4 157, and viral load 10,000; 82% started a protease inhibitor (PI)-based and 17% a non-nucleoside reverse transcriptase inhibitor (NNRTI)-based regimen, 45% with stavudine (d4T). During follow-up, high TC (³240 mg/dL), high non-HDL (³190 mg/dL), and high TG (³500 mg/dL) were reached by 43%, 11%, and 25%, respectively. In 154 patients evaluable for the morphologic outcomes, during a median follow-up of 50 months, 50% developed lipodystrophy, 29% lipodystrophy in any trunk fat accumulation, and 36% lipoatrophy. Alleles presented were:  3435 TT (26%), CC (17%), and CT (55%). Hazard of developing lipodystrophy in any trunk fat accumulation was significantly lower in patients with the TT genotype (HR compared to other genotypes 0.30; 95%CI 0.11 to 0.85, HR compared to CC 0.15, 0.03 to 0.65) and higher in women (HR 2.62, 1.45 to 4.73). TT genotype was independently predictive of lipodystrophy in any trunk fat accumulation after adjusting for gender and treatment type (HR 0.32, 0.11 to 0.89). Predictors of high TC were the CT genotype (HR 1.58, 1.02 to 2.45) and HCV⁺ status (HR 0.54, 0.27 to 1.06). After adjusting for HCV and treatment type, CT genotype remained predictive of high TC (HR 2.23, 1.30 to 3.82). The TT genotype predicted high non-HDL cholesterol levels (HR 3.41, 1.48 to 7.89).

Conclusions:  The TT homozygous genotype at position 3435 of MDR-1, which is related with higher expression of p-glycoprotein, was associated with a reduced risk of developing trunk fat accumulation, but a higher risk of high non-HDL cholesterol levels, while the heterozygous genotype was associated to high TC. Knowledge on the effect of genetic determinants on long-term HAART side effects might be useful for individualized treatment decisions.