Fung James, Seto Wai-Kay, Lai Ching-Lung, Yuen Man-Fung
Department of Medicine, The University of Hong Kong, Hong Kong; State Key Laboratory for Liver Research, The University of Hong Kong, Hong Kong.
J Gastroenterol Hepatol. 2014 Mar;29(3):428-34. doi: 10.1111/jgh.12499.
Oral nucleoside/nucleotide analogues (NAs) are the mainstay of therapy for patients with chronic hepatitis B and are generally well tolerated. Despite this, the safety profile of NAs is of paramount importance since the majority of patients will require long-term treatment. All NAs can potentially affect human DNA polymerase with decrease in mitochondrial DNA, leading to manifestations of mitochondrial toxicity. As a class effect, therefore, NAs can potentially cause extrahepatic conditions, such as myopathy, nephropathy, neuropathy, and lactic acidosis. Indeed, effects on muscles, including myopathy and creatine kinase elevations, have been described with clevudine and telbivudine use. Both adefovir and tenofovir are associated with dose-dependent nephropathy, predominantly affecting the proximal renal tubules. Neuropathy appears to be rare, and most commonly reported in patients receiving combination therapy with telbivudine and interferon. Increased risk of lactic acidosis has also been described for those with impaired liver and renal function taking entecavir. Loss of bone mineral density and hypophosphatemia have been described with the use of NAs, although the overwhelming studies have been with human immunodeficiency virus-infected patients. However, not all extrahepatic effects are detrimental. Recent evidence has suggested a potential renal beneficial effect with the use of telbivudine. The effect of NAs on pregnancy appears to be minimal for all NAs, with telbivudine and tenofovir having a more favorable category B rating. Ongoing pharmacovigilance is essential to identify new and monitor existing extrahepatic effects associated with NA use.
口服核苷/核苷酸类似物（NAs）是慢性乙型肝炎患者治疗的主要药物，一般耐受性良好。尽管如此，NAs的安全性至关重要，因为大多数患者需要长期治疗。所有NAs都可能影响人类DNA聚合酶，导致线粒体DNA减少，从而引发线粒体毒性表现。因此，作为一类药物效应，NAs可能会引发肝外病症，如肌病、肾病、神经病变和乳酸性酸中毒。事实上，使用替比夫定和替诺福韦时已出现对肌肉的影响，包括肌病和肌酸激酶升高。阿德福韦和替诺福韦都与剂量依赖性肾病有关，主要影响近端肾小管。神经病变似乎较为罕见，最常见于接受替比夫定和干扰素联合治疗的患者。服用恩替卡韦的肝肾功能受损患者也有乳酸性酸中毒风险增加的报道。使用NAs时已出现骨矿物质密度降低和低磷血症的情况，不过绝大多数研究针对的是感染人类免疫缺陷病毒的患者。然而，并非所有肝外效应都是有害的。最近的证据表明，使用替比夫定可能对肾脏有有益作用。所有NAs对妊娠的影响似乎都很小，替比夫定和替诺福韦的B级分类更为有利。持续的药物警戒对于识别与使用NAs相关的新的肝外效应并监测现有效应至关重要。
