Due to the improved effectiveness and safety of combined antiretroviral therapy, human immunodeficiency virus (HIV) infection has become a manageable, chronic condition rather than a mortal disease. However, HIV patients are at increased risk of experiencing non-AIDS-defining illnesses, with liver-related injury standing out as one of the leading causes of death among these patients. In addition to more HIV-specific processes, such as antiretroviral drug-related toxicity and direct injury to the liver by the virus itself, its pathogenesis is related to conditions that are also common in the general population, such as alcoholic and non-alcoholic fatty liver disease, viral hepatitis, and ageing. Non-nucleoside reverse transcriptase inhibitors (NNRTIs) are essential components of combined anti-HIV treatment due to their unique antiviral activity, high specificity, and acceptable toxicity. While first-generation NNRTIs (nevirapine and efavirenz) have been related largely to liver toxicity, those belonging to the second generation (etravirine, rilpivirine and doravirine) seem to be generally safe for the liver. Indeed, there is preclinical evidence of rilpivirine being hepatoprotective in different models of liver injury, independently of the presence of HIV. The present study aims to review the mechanisms by which currently available anti-HIV drugs belonging to the NNRTI family may participate in the development of liver disease.

As the main extracellular matrix-producing cells, activated hepatic stellate cells (HSC) are fundamental mediators of liver fibrosis (LF), and understanding their activation/inactivation mechanisms is paramount to the search for novel therapeutics. The antiretroviral drug Rilpivirine (RPV) has demonstrated a hepatoprotective effect in several animal models of chronic liver injury that is related to its antifibrogenic and apoptotic action in HSC. In the present study, we evaluated whether autophagy is implicated in the hepatoprotective action of RPV, as autophagy plays an important role in HSC transdifferentiation. We employed two standard mouse models of chronic liver injury - fatty liver disease and carbon tetrachloride (CCl4)-induced hepatotoxicity -and cultured HSC activated with the profibrotic cytokine TGF-β. RPV enhanced autophagy in the whole liver of both mouse models and in activated HSC, evident in the protein expression of autophagy markers, increased autophagosome content and lysosomal mass. Moreover, increased autophagic flux was observed in RPV-exposed HSC as revealed by tandem fluorescence-tagged LC3 and p62 and analysis of LC3-II accumulation in cells exposed to the lysosomal inhibitor chloroquine. Importantly, autophagy was involved in the cytotoxic effect of RPV on HSC, though in a differential manner. Pharmacological inhibition of autophagy by 3-methyladenine (3-MA) did not affect the diminishing effect of RPV on viability, while treatment with wortmannin or depletion of specific autophagy proteins (ATG5, Beclin-1 and SQSTM1/p62) rescued the detrimental effect of high concentrations of RPV on the viability of activated HSC. Finally, we also provide evidence that RPV compromises the viability of TGF-β-induced HSC independently of its antifibrogenic effect, observed as reduced collagen 1A1 synthesis, and that this effect does not include RPV´s modulation of autophagy. In summary, as a contributor to the mechanisms involved in the hepatoprotective action of RPV, autophagy may be a good candidate to explore when developing novel therapeutics for LF.

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