In clinical trials, the concentration of tenofovir diphosphate (TFV-DP) in peripheral mononuclear cells was 4 to 5-fold higher in individuals treated with tenofovir alafenamide (TAF) compared to individuals treated with tenofovir disoproxil fumarate (TDF). We hypothesized that the higher intracellular accumulation of TFV-DP could cause mitochondrial toxicity from either polymerase gamma (Pol-γ)-dependent or Pol-γ-independent mechanism(s). To test this hypothesis, we cultured human T lymphoblastoid cell line (CEM cells) for up to 12 days with TAF or TDF (multiplicities of Cmax) to investigate the effects on mitochondrial function and respiration, and cholesterol biosynthesis. Both TAF and TDF treatments had no significant effect on cell growth, mitochondrial potential (ΔΨ), production of reactive oxygen species (ROS), and mitochondrial respiratory parameters. TAF had no statistically significant effect on expression of Pol-γ mRNA, mitochondria DNA (mtDNA) content, expression of proteins of the electron transport chain (ETC), and key genes of cholesterol biosynthesis. TDF had significant reduction in mtDNA content at 8xCmax, and statistically significant reduction in mRNA expression of squalene epoxidase (SQLE). Our findings do not support our hypothesis that the higher intracellular accumulation of TFV-DP in cells treated with TAF could cause mitochondrial dysfunction. In conclusion, our findings add to the emerging data that TAF may have a low potential for causing mitochondrial toxicity in HIV-infected individuals on TAF-containing regimens.
Keywords: Antiretroviral toxicity; Cholesterol biosynthesis; Mitochondria function; Nucleoside reverse transcriptase inhibitors; Tenofovir alafenamide.
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