Background:  Antiretroviral drugs used in the treatment of HIV-1 inhibit the replication of mitochondrial DNA (mtDNA) may contribute to severe mitochondrial toxicity including lipodystrophy, through the inhibition of polymerase gamma (POLG). Polymorphisms of POLG could explain the variability of mitochondrial toxicity in HIV-1-infected patients. We explored the relationships between selected polymorphisms of POLG and lipodystrophy related to anti-retroviral therapy.

Methods:  We studied polymorphic changes at 3 highly conserved amino acid residues (R₁₁₄₂, E₁₁₄₃, and R₁₁₄₆) and the CAG repeats of POLG in a case-control study including HIV-1-treated patients with lipodystrophy (n = 69) and 2 controls (without lipodystrophy) per case matched by age, race and sex (n=138). Treatments (types + duration) and biological data (31 parameters including lactatemia, glycemia, mtDNA, aspartate aminotransferase [AST]) were recorded. Matched univariate odd ratio (OR) with 95% confidence interval (CI) was calculated by conditional logistic regression and the relative risk (RR) determinates. A MANOVA test was performed (a = 5%) to determine which parameters that were checked in the study were linked to the development of the lipodystrophy. We used Wilks’ lambda distribution, probability distribution, to test multivariate hypothesis.

Results:  Compared with matched controls, case patients had higher levels of triglycerides and alkaline phosphatase and a longer history of HIV-1 infection and treatment. Only polymorphism in E₁₁₄₃ was significantly more frequent in case patients with lipodystrophy (15% vs 3.6%, OR 4.5, 95%CI 1.32 to 17.44; p = 0.008, RR = 4), and this was associated with a significant decrease of mtDNA in peripheral blood mononuclear cells (PBMC). In addition, among 31 parameters tested, MANOVA test showed that the lipodystrophy syndrome has a strong link with E₁₁₄₃ polymorphisms (p = 0.043). The HIV-1-infected patients with lipodystrophy had also received significantly more protease inhibitors.

Conclusions:  We confirm the role of several traditional risk factors already reported in the development of lipodystrophy. Patients harbouring changes of E₁₁₄₃ of the catalytic site of POLG exhibit a 4-fold increased risk to develop lipodystrophy than HIV-1-treated patients who do not have changes in E₁₁₄₃, and this could be due to decreased content of mtDNA in PBMC in these patients. Therefore, the toxicity of HAART leading to lipodystrophy in some HIV-1-infected patients could be explained in part by the occurrence of POLG polymorphisms.