NNRTI and Liver Damage: Evidence of Their Association and the Mechanisms Involved

Abstract

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.

Keywords: DILI; HIV; antiretroviral drugs; cART; hepatotoxicity; liver.

Figure 1

Factors that promote chronic liver disease in the HIV-infected population. These factors can be associated with HIV infection (direct effect of the virus on the liver that has been shown to produce metabolic alterations, increased microbial translocation, hepatocyte injury and pro-fibrogenic and pro-inflammatory effects on non-parenchymal cells) and with cART (ability of each ARV drug to induce hepatotoxicity and metabolic alterations). Furthermore, patients present specific risk factors (variations arising from patient’s sex, ethnicity and age, and other pathophysiological aspects such as alcohol consumption, obesity, viral hepatitis infection, genetic predisposition, hyperuricemia, and gut microbiome composition).

Figure 2

Available anti-HIV drug families and their mechanisms of action. Antiretroviral drugs include entry inhibitors, fusion inhibitors, nucleoside/nucleotide analogue reverse transcriptase inhibitors (N(t)RTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs), integrase inhibitors (INSTIs), and protease inhibitors (PIs). Entry inhibitors and fusion inhibitors prevent HIV from entering target cells by inhibiting its binding or its fusion, respectively. The exact mechanism involved varies depending on which receptor or complex formation is blocked: inhibition of CCR5 interaction with viral gp120 protein (CCR5 antagonists), blocking of viral gp120 (attachment inhibitors), or inhibition of the conformational changes of CD4/gp120 complex, which allow the binding to co-receptors (CCR5 or CCR4) (post-attachment inhibitors). N(t)RTIs, which can be either nucleoside or nucleotide analogues, function by inhibiting the synthesis of DNA by reverse transcriptase, the viral enzyme that copies viral RNA into DNA in newly infected cells, acting as false nucleotides. NNRTIs also inhibit the synthesis of viral DNA, but by binding to and inhibiting the reverse transcriptase in a non-competitive way. INSTIs inhibit the viral integrase, thus impeding the incorporation of reverse-transcribed HIV DNA into host cell DNA. Finally, PIs bind to the active site of the viral protease enzyme, preventing the processing of immature viral proteins into their functional conformations and the generation of new viral particles.

Figure 3

Mechanisms of NNRTI-induced liver toxicity suggested by in vitro and in vivo studies for (a) Nevirapine (NVP) and (b) Efavirenz (EFV). NVP leads to the release of danger-associated molecular pattern molecules (DAMPs) by hepatocytes, and to the formation of hepatocytic inclusions composed of lipid droplets surrounded by smooth endoplasmatic reticulum cisternae (LSER), which are deposited in sinusoids. These two events presumably contribute to triggering the immune response. NVP is also proposed to induce mitochondrial dysfunction and to increase bile acid synthesis, while at supra-therapeutic concentrations, this drug induces hepatocyte apoptosis. EFV inhibits complex I of the electron transport chain, which diminishes oxygen consumption and mitochondrial membrane potential, and increases reactive oxygen species (ROS) production, resulting in mitochondrial dysfunction. Moreover, this drug produces ER stress, since it activates inositol-requiring 1α (IRE1α) and, consequently, IRE1α-catalyzed splicing of X-box binding protein 1(XBP1) mRNA. EFV-induced mitochondrial dysfunction and ER stress are thought to be interconnected, to alter autophagic flux and to promote lipid accumulation inside hepatocytes. c-Jun N-terminal kinase (JNK) pathway is also activated in response to EFV, possibly related to alterations in mitochondrial and ER function. In addition, EFV also inhibits bile acid transport. All these events have been shown to promote hepatocyte death.