Deciphering the Molecular Mechanisms of HAART‐Induced Hepatotoxicity

ABSTRACT Highly active antiretroviral therapy (HAART), consisting of three or more antiretroviral drugs, is recommended for patients with HIV infection. HAART effectively reduces HIV RNA levels, lowers the risk of opportunistic infections, and improves immune function and survival rates. However, it is also associated with an increased risk of liver injury in HIV‐infected individuals. This review aims to summarize the mechanisms underlying HAART‐induced liver injury. A comprehensive search was conducted in PubMed and EMBASE using keywords such as “Antiretroviral/ARV drugs and drug‐induced liver injury (DILI),” “HAART and DILI,” “Antiretroviral therapy and DILI,” and “HIV infection and DILI.” Relevant papers published before March 2024 were included. Experimental studies have demonstrated that zidovudine and efavirenz can cause structural alterations in mitochondria, impair the respiratory chain, generate free radicals, and deplete mitochondrial DNA, leading to oxidative and endoplasmic reticulum stress, as well as the accumulation of advanced glycation end products in liver tissue. Zidovudine disrupts lipid homeostasis by increasing fatty acid synthesis and reducing metabolism. Efavirenz and its metabolite, 8‐hydroxyefavirenz, induce hepatocellular death and activate proapoptotic markers through c‐Jun N‐terminal kinase signaling. Additionally, lamivudine has been shown to induce liver injury and oxidative stress in rats. Clinically, approximately 50% of HIV patients on HAART regimens containing non‐nucleoside reverse transcriptase inhibitors experience mild to moderate liver injury. HAART regimens that include efavirenz, lamivudine, and tenofovir impair glucose and lipid homeostasis in rats, highlighting the need for caution in HIV patients with fatty liver disease. Patients with viral hepatitis coinfection, those taking antitubercular drugs or cotrimoxazole, and those on nevirapine‐containing regimens are at particularly high risk. Regular monitoring of liver function is essential to prevent liver damage associated with HAART in HIV‐infected patients. While HAART significantly improves survival rates in HIV patients, it also poses a considerable risk of liver injury, necessitating careful monitoring and management.