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).
核苷类似物是一类重要的抗病毒药物，目前常用于治疗人类免疫缺陷病毒（HIV）感染、乙型肝炎病毒（HBV）、丙型肝炎病毒（HCV）、巨细胞病毒（CMV）、单纯疱疹病毒（HSV）和水痘 - 带状疱疹病毒（VZV）感染。核苷类似物类似于天然存在的核苷，其作用机制是导致新生DNA链的终止。这些药物通常是安全的，耐受性良好，因为它们在DNA复制过程中被病毒而非人类聚合酶所利用。实际上，核苷类似物是一大类药物，包括用于癌症治疗的药物（阿糖胞苷、吉西他滨、巯嘌呤、阿扎胞苷、克拉屈滨、地西他滨、氟尿嘧啶、氟尿苷、氟达拉滨、奈拉滨）、风湿性疾病（硫唑嘌呤、别嘌醇）甚至细菌感染（甲氧苄啶）。本章将重点讨论抗病毒核苷和核苷酸类似物。用于治疗HIV感染的核苷类似物通常被称为逆转录酶抑制剂（NRTIs）。然而，它们对依赖DNA的和依赖RNA的DNA聚合酶均有活性。据信它们通过多种机制抑制病毒复制，要么通过竞争性抑制病毒聚合酶，要么通过DNA链终止。许多抗病毒核苷类似物在脱氧核糖核酸的3'羟基处被阻断，这导致新生DNA分子的延伸失败。其他抗病毒核苷类似物是天然（D型）核苷的阴性对映体（L型：拉米夫定、恩曲他滨、替比夫定），并干扰复制，部分原因是当它们被病毒聚合酶摄取或添加到DNA分子中时存在空间位阻。在5'位点磷酸化的核苷类似物通常被称为核苷酸类似物，但这种区分是人为的，因为这些药物（替诺福韦、阿德福韦）也是核苷类似物。核苷类似物的这些结构特征很重要，因为它们可能被人类聚合酶利用并掺入RNA或DNA的风险，这是核苷类似物产生严重毒性的基础。核苷类似物可通过多种机制导致肝损伤。最典型的是线粒体类型的肝损伤，这可能是由于核苷类似物被线粒体γ聚合酶掺入或阻断线粒体DNA合成，导致线粒体耗竭或其功能下降。线粒体损伤可影响多个组织，从而导致肌病、神经病变、胰腺炎、骨髓抑制和/或肝损伤。肝损伤的特征是乳酸酸中毒、微泡性脂肪变性和肝合成功能衰竭（LASH）。血清氨基转移酶水平可能仅轻微升高，黄疸出现较晚。肝线粒体损伤最显著的例子发生在药物菲夫利定（FIAU）上，这是一种核苷类似物，在2期人体试验开始治疗2至3个月后，因肝功能衰竭、乳酸酸中毒和胰腺炎导致数人死亡后被撤市。一种类似但罕见、不太显著且部分可逆的肝线粒体损伤与使用去羟肌苷（双脱氧肌苷：ddI）、扎西他滨（双脱氧胞苷：ddC）、司他夫定（d4T）有关，较少与齐多夫定（AZT）有关。
