The nucleoside analogues are an important class of antiviral agents now commonly used in the therapy of human immunodeficiency virus (HIV) infection, hepatitis B virus (HBV), hepatitis C virus (HCV), cytomegalovirus (CMV), herpes simplex virus (HSV) and varicella-zoster (VZV) infection. The nucleoside analogues resemble naturally occurring nucleosides and act by causing termination of the nascent DNA chain. These agents are generally safe and well tolerated as they are used by the viral, but not human polymerases in DNA replication. Actually, nucleoside analogues are a large class of agents that include drugs for cancer (cytarabine, gemcitabine, mercaptopurine, azacytidine, cladribine, decitabine, fluorouracil, floxuridine, fludarabine, nelarabine), and rheumatologic diseases (azathioprine, allopurinol) and even bacterial infections (trimethoprim). This chapter will focus on the antiviral nucleoside and nucleotide analogues.
The nucleoside analogues used to treat HIV infection are often referred to as reverse transcriptase inhibitors (NRTIs). However, they have activity against both DNA dependent and RNA dependent DNA polymerases. They are believed to inhibit viral replication by several mechanisms, either by competitive inhibition of the viral polymerase or by DNA chain termination. Many of the antiviral nucleoside analogues are blocked at the 3’ hydroxyl group of the deoxyribonucleic acid, which results in failure of elongation of the nascent DNA molecule. Other antiviral nucleoside analogues are negative enantiomers (L-forms: lamivudine, emtricitabine, telbivudine) of the natural (D-form) nucleosides and interfere with replication, partially because of steric hindrance when they are taken up by the viral polymerase or added to the DNA molecule. Nucleoside analogues that are phosphorylated at the 5’ site are often referred to as nucleotide analogues, but this distinction is artificial as these agents (tenofovir, adefovir) are also nucleoside analogues. These features of the structure of nucleoside analogues are important because of the danger that they might be used by human polymerases and incorporated into RNA or DNA, which is the basis of the serious toxicities of the nucleoside analogues.
Nucleoside analogues can cause liver injury by several mechanisms. Most characteristic is a mitochondrial type of hepatic injury that is probably caused by the nucleoside analogue becoming incorporated into or blocking mitochondrial DNA synthesis by the mitochondrial gamma polymerase, leading to a depletion of mitochondria or decrease in their function. Mitochondrial injury can affect multiple tissues thereby causing myopathy, neuropathy, pancreatitis, bone marrow suppression and/or hepatic injury. The hepatic injury is characterized by accumulation of lactic acidosis, microvesicular steatosis and hepatic synthetic failure (LASH). Serum aminotransferase levels may be minimally elevated and jaundice arises late. The most dramatic example of hepatic mitochondrial injury occurred with the drug fialuridine (FIAU), a nucleoside analogue that was withdrawn after several fatalities due to hepatic failure, lactic acidosis and pancreatitis arising 2 to 3 months after initiation of therapy during phase 2 trials in humans. A similar, but rare and less dramatic and partially reversible hepatic mitochondrial injury has been linked to use of didanosine (dideoxyinosine: ddI), zalcitabine (dideoxycytine: ddC), stavudine (d4T) and less commonly to zidovudine (AZT).