Lack of mitochondrial toxicity of darunavir, raltegravir and rilpivirine in neurons and hepatocytes: a comparison with efavirenz

J Antimicrob Chemother. 2014 Nov;69(11):2995-3000. doi: 10.1093/jac/dku262. Epub 2014 Jul 9.


Objectives: Growing evidence associates the non-nucleoside reverse transcriptase inhibitor efavirenz with several adverse events. Newer antiretrovirals, such as the integrase inhibitor raltegravir, the non-nucleoside reverse transcriptase inhibitor rilpivirine and the protease inhibitor darunavir, claim to have a better toxicological profile than efavirenz while producing similar levels of efficacy and virological suppression. The objective of this study was to determine the in vitro toxicological profile of these three new antiretrovirals by evaluating their effects on the mitochondrial and cellular parameters altered by efavirenz in hepatocytes and neurons.

Methods: Hep3B cells and primary rat neurons were treated with clinically relevant concentrations of efavirenz, darunavir, rilpivirine or raltegravir. Parameters of mitochondrial function, cytotoxicity and oxidative and endoplasmic reticulum stress were assessed using standard cell biology techniques.

Results: None of the new compounds altered the mitochondrial function of hepatic cells or neurons, while efavirenz decreased mitochondrial membrane potential and enhanced superoxide production in both cell types, effects that are known to significantly compromise the functioning of mitochondria, cell viability and, ultimately, cell number. Of the four drugs assayed, efavirenz was the only one to alter the protein expression of LC3-II, an indicator of autophagy, and CHOP, a marker of endoplasmic reticulum stress and the unfolded protein response.

Conclusions: Darunavir, rilpivirine and raltegravir do not induce toxic effects on Hep3B cells and primary rat neurons, which suggests a safer hepatic and neurological profile than that of efavirenz.

Keywords: CNS; HIV; adverse effects; hepatotoxicity; mitochondria.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alkynes
  • Animals
  • Anti-HIV Agents / toxicity
  • Benzoxazines / toxicity*
  • Cell Line, Tumor
  • Cells, Cultured
  • Cyclopropanes
  • Darunavir
  • Drug Resistance, Viral / drug effects
  • Hepatocytes / drug effects*
  • Hepatocytes / metabolism
  • Humans
  • Mitochondria / drug effects*
  • Mitochondria / metabolism
  • Neurons / drug effects
  • Neurons / metabolism
  • Nitriles / toxicity*
  • Pyrimidines / toxicity*
  • Pyrrolidinones / toxicity*
  • Raltegravir Potassium
  • Rats
  • Reverse Transcriptase Inhibitors / toxicity
  • Rilpivirine
  • Sulfonamides / toxicity*


  • Alkynes
  • Anti-HIV Agents
  • Benzoxazines
  • Cyclopropanes
  • Nitriles
  • Pyrimidines
  • Pyrrolidinones
  • Reverse Transcriptase Inhibitors
  • Sulfonamides
  • Raltegravir Potassium
  • Rilpivirine
  • efavirenz
  • Darunavir