国家食品药品监督管理局关于乙肝抗病毒药不良反应的《通报》引发患者忧虑——

　　专家：随意停换乙肝治疗药物，比不良反应更危险

　　7月22日，国家食品药品监督管理局发布了《药品不良反应信息通报（第30期）——警惕治疗乙型肝炎的核苷类抗病毒药替比夫定和拉米夫定的横纹肌溶解症》（下简称《通报》）。《通报》一经发布，立即引起轩然大波。因为我国有大约2000～3000万慢性乙肝患者，估计至少有500万人可能正在服用核苷类药物治疗。连日来，很多患者因担心核苷类抗病毒药品的不良反应而要求医生停药或者换药。

　　针对患者们的疑问和困惑，日前在一个关于乙肝治疗的媒体活动上，来自北京地坛医院感染科的蔡晧东教授就临床常用的四种乙肝治疗药物的特点和安全性分别作出了解读。

　　文/记者黎蘅

　　医学指导/北京药品不良反应监测中心上市后药品安全性监测与再评价特聘专家、北京地坛医院感染科主任蔡皓东教授

　　拉米夫定：

　　不良反应多数发生于艾滋病治疗

　　拉米夫定是一种既能治疗艾滋病，又能治疗乙肝的药物。“但治疗乙型肝炎和艾滋病使用的剂量是不一样的，治疗乙肝的用量每天只要100毫克，而治疗艾滋病每天需要服用300毫克，是治疗乙肝的3倍。”蔡皓东指出，尤其需要说明的是，拉米夫定治疗艾滋病时绝对不是单药治疗，它需要和齐多夫定等至少三种药物联合应用。

　　“检索不良反应的医学文献发现，药监局《通报》中所说的不良反应绝大多数发生在治疗艾滋病的过程中，而且肌病及横纹肌溶解症多数与齐多夫定相关。”蔡皓东说，国内外医学文献，在治疗乙肝过程中只有3例发生肌病和横纹肌溶解症与3例肾损害的报道，均发生在肝肾移植术后的病人中，这些病人一般还同时服用抗排异药，而抗排异药中的他克莫司也有引起横纹肌溶解症和肾损害的报告。至于临床上单用拉米夫定治疗的乙肝病人，到目前为止还没有一例确诊为肌病的文献报道。

　　据了解，拉米夫定于1998年被批准用于治疗慢性乙肝，1999年在我国上市，已经应用了10年之久。目前，我国至少有200万人服用拉米夫定治疗乙肝，而全球使用拉米夫定治疗的患者就更多了。“上市了这么长的时间，又有这么多的患者应用，只有这么少的不良反应报道，可见拉米夫定长期治疗是非常安全的，不良反应极为罕见。所以，服用拉米夫定的乙肝患者不必过分担心。”

　　阿德福韦酯：

　　肾损害发生率取决于使用剂量

　　蔡皓东告诉记者，阿德福韦酯是2002年被批准用于治疗慢性乙肝的，主要的不良反应是有潜在的肾损害风险。“在临床试验中，医生发现阿德福韦酯的肾损害与剂量有关，如果每天使用30毫克治疗，一年有8%的患者发生肾损害，但剂量减少到每天10毫克，治疗一年肾损害的发生率为0，治疗五年肾损害的发生率是3%～8%。”蔡皓东说，因此，阿德福韦酯目前被批准用于治疗慢性乙型肝炎的剂量是每天10毫克。

　　另外，截至目前，全球只有1例肾移植患者在服用阿德福韦酯后发生了急性肾小管坏死，说明阿德福韦酯的肾毒性是很轻的。只要服药的患者注意检查肾功能和血磷都可以及时发现，不会造成严重后果。而到目前为止，国内外文献中还没有检索到它引起肌病和横纹肌溶解症的报道。

　　恩替卡韦：

　　动物试验显示肿瘤发生率增加

　　恩替卡韦是2005年被批准用于治疗慢性乙肝的。我国和国外几乎同时上市。恩替卡韦的说明书中提到，它在动物试验中发现了一些动物肿瘤的发生率增加，许多患者对此也很紧张，希望医生给自己使用别的药物。

　　“其实，动物试验所用的剂量常常是人类最高推荐剂量(1.0mg/每天)的几倍甚至几十倍。参加恩替卡韦上市前临床试验的患者目前服用恩替卡韦已经有7～8年了，还未发现肿瘤发生增加的情况。”蔡皓东说，检索国内外文献，德国一位作者发现晚期肝硬化且肝肾功能都非常差的肝病患者在使用恩替卡韦后，有5例发生乳酸酸中毒，但没有引起肌病和横纹肌溶解症的报道。

　　替比夫定：

　　使用期间要注意定期监测

　　替比夫定于2006年被批准用于治疗慢性乙肝，2007年在我国上市。研究显示，替比夫定确实有引起肌病的可能性，在临床研究中，肌病的发生率为0.3%～4%。“替比夫定上市后，我国确实发生了少数横纹肌溶解症的病例，甚至有死亡的病例。另外，替比夫定与干扰素联合应用还有增加周围神经病发生的风险。”蔡皓东指出，因此，患者在服用替比夫定期间要注意监测肌酸激酶(CK)，不要与干扰素联合用药，也不要与可能引起肌病的其他药物(如他汀类的降血脂药)联合应用。另外，使用替比夫定的患者应定期到医院检查。

　　特别提醒：

　　随意停换药会加重肝病

　　蔡皓东认为，总体来看，目前四种慢性乙肝临床治疗中常用的核苷类似物，其安全性和有效性都是肯定的，少数不良反应只要定期到医院监测，就能避免造成不良后果。而慢性乙肝的抗病毒治疗已被全球公认为有效而且必要的手段。“因此，乙肝患者千万不能盲目停药，否则很可能导致肝病加重。”蔡皓东提醒说，此外也不要随便换药，因为有可能增加病毒耐药的机会，以后治疗起来会变得更困难。“实际上，停药或随意换药所带来的后果，可能比不良反应发生的风险要大得多。”

　　名词解释：

　　横纹肌溶解症

　　横纹肌溶解症基本定义为因肌细胞产生毒性物质而导致肾损害的一种疾病，俗称肌肉溶解。许多药物可引起横纹肌（骨骼肌）损害，轻者表现为肌肉疼痛和乏力，重者出现横纹肌溶解症、急性肾功能衰竭，甚至危及生命。

• 艾滋病早期治疗是康复与延长30～60年生命的保
• 艾滋病免疫重建的重要意义是挽救生命的根本
• 从食品植物研究开发的治疗艾滋病新药三合皂甙
• 康生丹颗粒免疫实验提示符合艾滋病、肿瘤等应
• 鸡尾酒疗法并非万能，抗药性与毒副作用导致联合疗法与中药疗法应用的迫切性
• 康生丹配合西药治疗AIDS总结
• 三合皂甙，康生丹片
• 中药康生丹治愈艾滋病中医论析

• 艾滋病成为第一大死因病种[刘君]的对策与思考

• Hepatitis B antiviral drugs in the end is safe to?
  Ocean News Time: 2010-08-11 Source: Guangzhou Daily on: Li Heng
  (Gettyimages for map)
  State Food and Drug Administration on antiviral drug side effects of hepatitis B "informed" patients caused concerns -
  
  Expert: random stop for hepatitis B therapy, adverse reactions are more dangerous than
  
  July 22, the State Food and Drug Administration issued the "Adverse Drug Reaction Information Bulletin (No. 30) - alert antiviral treatment of hepatitis B nucleoside telbivudine and lamivudine rhabdomyolysis disease "(hereinafter referred to as" notification "). "Alert" upon release, immediately caused a great uproar. Since 2000 China has approximately 30 million chronic hepatitis B patients, it is estimated that at least 500 million people may be taking nucleoside drugs. In recent days, many patients with nucleoside anti-viral drugs for fear of adverse reactions and the doctors discontinued or dressing.
  
  For patients with their questions and confusion, a few days ago at a media event on hepatitis B treatment, the infection from the Beijing Ditan Hospital, Division of Professor Cai Haodong four common on the clinical characteristics of hepatitis B therapy and safety of interpretation were made.
  
  Text / reporter Li Heng
  
  Medical guide / Beijing ADR Monitoring Centre to monitor post-marketing drug safety and re-evaluation of specially appointed experts, Beijing Ditan Hospital, Professor Cai Haodong, director of infection
  
  Lamivudine:
  
  Most adverse events occurred in HIV treatment
  
  Lamivudine is a treat not only AIDS, but also the treatment of hepatitis B drug. "But the treatment of hepatitis B and AIDS is not the same dose used in the treatment of hepatitis B as long as the amount of 100 mg per day, while the treatment of AIDS need to take 300 mg per day, is the treatment of hepatitis B 3 times." Caihao Dong pointed out that, in particular, need to explain that lamivudine therapy of AIDS is absolutely not a single drug treatment, it needs to, and at least three of zidovudine and other drugs combined.
  
  "Adverse medical literature search found that FDA" Bulletin "says the vast majority in adverse reactions during treatment of AIDS, but most of myopathy and rhabdomyolysis associated with zidovudine." Caihao Dong said domestic and foreign medical literature, the process in the treatment of hepatitis B occurred in only three cases of myopathy and rhabdomyolysis and kidney damage in 3 cases reported occurred in patients after liver transplantation, these patients usually take anti-rejection while also drugs, and anti-rejection drug tacrolimus in there cause rhabdomyolysis and kidney damage were reported. As for the clinical treatment of hepatitis B using lamivudine patients, so far not one case diagnosed as myopathy reported in the literature.
  
  It is understood that lamivudine was approved in 1998 for the treatment of chronic hepatitis B, listed in 1999 in China, has been used for 10 years. At present, there are at least 200 million people lamivudine treatment of hepatitis B, while the global use of lamivudine in the treatment of patients with even more numerous. "Listed for so long, there were so many applications, only a small number of adverse reactions reported, showing that long-term lamivudine therapy is very safe, adverse reactions are extremely rare. Therefore, hepatitis B lamivudine Patients need not worry too much about. "
  
  Adefovir dipivoxil:
  
  The incidence of renal damage depends on dose
  
  Caihao Dong told reporters, adefovir dipivoxil was approved in 2002 for the treatment of chronic hepatitis B, the main adverse reactions are potentially the risk of kidney damage. "In clinical trials, doctors found that adefovir dipivoxil dose-related renal damage, using 30 mg a day, year, 8% patients with renal impairment, but the dose reduced to 10 mg per day, treatment of a Renal injury was 0, the treatment five years the incidence of renal damage is 3% to 8%. "Caihao Dong said, therefore, adefovir dipivoxil is currently approved for the treatment of chronic hepatitis B is a daily dose 10 mg.
  
  In addition, as of now, the world's only one case of renal transplant patients taking adefovir after the occurrence of acute tubular necrosis, renal toxicity that 明阿德福韦 ester is very light. As long as the medication of patients pay attention to check renal function and serum phosphorus can be found in time, will not lead to serious consequences. So far, domestic and foreign literature not retrieve it cause myopathy and rhabdomyolysis were reported.
  
  Entecavir:
  
  Animal trials have shown an increased incidence of tumors
  
  Entecavir was approved in 2005 for the treatment of chronic hepatitis B. Almost simultaneously in China and overseas market. Entecavir is mentioned in the description, it is found in animal tests some animals to increase the incidence of cancer, many patients have to be nervous, want doctors to their own use other drugs.
  
  "In fact, the dose used in animal testing is often the maximum recommended human dose (1.0mg / day) for several times or even dozens of times. Entecavir listed to participate in clinical trials before the patient is currently taking entecavir has been 7 to 8 years, yet increase in tumor occurrence. "Caihao Dong said, searching review of literature, a German author found that liver and kidney functions with advanced cirrhosis and liver disease are very poor in the use of entecavir after 5 patients had lactic acidosis, but did not cause myopathy and rhabdomyolysis were reported.
  
  Telbivudine:
  
  Should pay attention to regular monitoring of the use period
  
  Telbivudine was approved in 2006 for the treatment of chronic hepatitis B, listed in 2007 in China. Studies have shown that telbivudine is indeed possible to cause a myopathy, in clinical studies, the incidence of myopathy was 0.3% to 4%. "After listing telbivudine, China indeed had a small number of rhabdomyolysis cases, even death. In addition, telbivudine in combination with interferon also increases peripheral neuropathy occurred in risk." Caihao Dong pointed out that, so patients taking telbivudine should pay attention during the monitoring of creatine kinase (CK), not in combination with interferon, nor may cause myopathy with other drugs (such as the lipid-lowering drugs statins) in combination. In addition, the use of telbivudine patients to the hospital regularly.
  
  Special Reminder:
  
  Random stop dressing will increase liver
  
  Cai Haodong that the whole, the clinical treatment of chronic hepatitis B at present four types of commonly used nucleoside analogues, its safety and efficacy are positive, a small number of adverse reactions to the hospital as long as the periodic monitoring, can avoid adverse consequences. The anti-viral treatment of chronic hepatitis B has been recognized as an effective global and necessary means. "Therefore, patients with hepatitis B must not blind withdrawal, or is likely to lead to increased liver disease." Cai Haodong reminded that, in addition to casual dressing should not, because there may increase the chance of viral resistance, treatment of up and make it more difficult later. "In fact, withdrawal, or the consequences of casual dressing, than the risk of adverse events is much greater."
  
  Glossary:
  
  Rhabdomyolysis
  
  Basic definition of rhabdomyolysis as a result of muscle cells to produce toxic substances as a result of renal disease, commonly known as muscle dissolved. Many drugs can cause rhabdomyolysis (skeletal muscle) damage, who showed mild muscle pain and fatigue, severe cases, rhabdomyolysis occurred, acute renal failure, even life-threatening.