Combination of Tenofovir and Emtricitabine with Efavirenz Does Not Moderate Inhibitory Effect of Efavirenz on Mitochondrial Function and Cholesterol Biosynthesis in Human T Lymphoblastoid Cell Line

Efavirenz (EFV), the most popular non-nucleoside reverse transcriptase inhibitor, has been associated with mitochondrial dysfunction in most in vitro studies. However, in real life the prevalence of EFV-induced mitochondrial toxicity is relatively low. We hypothesized that the agents given in combination with EFV might moderate the effect of EFV on mitochondrial function. To test this hypothesis, we cultured human T lymphoblastoid cell line (CEM cells) with EFV alone and in combination with emtricitabine (FTC) and tenofovir disoproxil fumarate (TDF) to investigate the effects on mitochondrial respiration and function and cholesterol biosynthesis. There was a statistically significant concentration- and time-dependent apoptosis, reduction in mitochondrial membrane potential (ΔΨ), and increase production of reactive oxygen species (ROS) in cells treated with either EVF alone or in combination with TDF/FTC. EFV treated cells compared to DMSO treated cells had significant reduction in oxygen consumption rate (OCR) contributed by mitochondrial respiration, ATP production-linked respiration, and spare respiratory capacity (SRC). Treatment with EFV resulted in a decrease in mitochondrial DNA content, and perturbation of more coding genes (n=13); among these were 11 genes associated with lipid or cholesterol biosynthesis. Our findings support the growing body of knowledge on the effects of EFV on mitochondrial respiration and function and cholesterol biosynthesis. Interestingly, combining TDF/FTC with EFV did not alter the effects of EFV on mitochondrial respiration and function and cholesterol biosynthesis. The gap between the prevalence of EFV-induced mitochondrial toxicity in vitro and in vivo studies may be explained by individual differences in the pharmacokinetic of EFV.