The Potential of Combination Drug Therapy for Hepatitis B to Cause Mitochondrial Damage

Abstract

Even after extensive preclinical and clinical testing, 20% of new drugs will cause adverse drug reactions that will only become apparent after they are on the market. Adverse drug reactions commonly manifest in the liver because it is the primary site for drug metabolism. The leading cause of drug withdrawal is idiosyncratic drug induced liver injury. Genetic variation and hypersensitivity are long-recognised mechanisms explaining idiosyncratic drug induced liver injury. Mitochondrial toxicity is believed to be an additional mechanism that causes idiosyncratic drug induced liver injury. Mitochondria have a key role in energy production and maintenance of cellular homeostasis. It is also extremely difficult to determine the mechanism of mitochondrial toxicity due to multiple potential targets and their relationship. When one target of mitochondria is impaired it starts a vicious cycle that amplifies damage. Nucleoside reverse transcriptase inhibitors (NRTIs), used to treat viral infections such as human immunodeficiency virus (HIV) and hepatitis B virus, are known mitochondrial toxins. This has been extensively studied in HIV-positive patients because their most common cause of death is liver failure. It has been shown that using NRTIs in combination increases their mitochondrial toxicity. However, even though NRTI toxicity has been studied in HIV-positive patients, there is limited data for chronic hepatitis B patients. Idiosyncratic drug induced liver injury is often ignored as a potential cause of liver damage due to underlying hepatitis infection. The study of combination drugs used to treat other potential co-morbidities that are common with chronic hepatitis B patients has also not been studied. This present study examines the potential toxicity of cyclosporine, didanosine, lamivudine, and telbivudine in combination using three endpoints for mitochondrial toxicity: mitochondrial DNA, AMP/ADP/ATP, and glutathione levels.