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1、 Dr. Hongzhou Lu (卢洪洲 教授) 上海市（复旦大学附属 ）公共卫生临床中心 副主任教授、主任医师、留美博士后，博士生导师 。上海市/复旦大学附属公共卫生中心副主任兼任 中心感染科主任。卫生部艾滋病专家咨询委员会 委员、传染病与寄生虫病学会艾滋病 专业学组副组长、热带病与寄生虫病 学会常委、中国中西医结合学会灾害医学专业委 员会常委、美国感染病与艾滋病学会会员。主要 研究方向：感染性疾病的诊治与发病机制研究。 中国真菌学杂志副主编、世界感染杂志 副总编辑；担任中华传染病杂志、中华 临床感染病杂志、临床内科杂志、诊断 学理论与实践、热带病与寄生虫学、微 生物与感染、世界临床药物等
2、十余本杂志 编委；兼任The Lancet、Journal of Clinical Microbiology、Applied and Environmental Microbiology、Mycoses英 文期刊审稿人。国内外发表各种论文136篇，参编 大型专业参考书27部。缺照片艾滋病合并乙肝/丙肝感染HIV and co-infection with hepatitis B and C卢 洪 洲 Approach to liver disease in HIVHIV相关肝病的治疗方法Chronic hepatitis ALT/AST elevation 慢性肝炎 ALT/AST升高nVir
3、al hepatitis 病毒性肝炎 Hepatitis B, hepatitis C (hepatitis A, D, E)乙肝, 丙肝 (甲肝, 丁肝, 戊肝)nAnti-retroviral therapy 抗反转录病毒治疗 IRIS (immune reconstitution inflammatory syndrome)IRIS (免疫重建炎性综合征) Loss of control of HBV 对乙肝失去控制 Resistance, stopping medication 耐药, 停止药物 Drug toxicity 药物毒性 Mitochondrial toxicity, fa
4、tty liver 线粒体毒性, 脂肪肝 Idiosyncratic drug-induced liver injury (DILI) 特异的DILInToxins 毒性因素 Alcohol, herbals, other medications 酒精, 草药, 其它因素Hepatotoxicity of ART 抗反转录病毒治疗所致肝脏毒性nMitochondrial toxicity线粒体毒性 NRTIs esp D drugsNRTIs 特别是“D”类药物 Upper abdo pain, anorexia, weakness 上腹痛, 厌食, 虚弱 Amylase, CPK, lact
5、ate淀粉酶 ,肌酸磷酸激酶 ,乳酸 nDirect toxicity直接毒性 ABC/AZT: lactate/lipids 乳酸/脂质 PIs (RTV200 mg/d) TPVnHypersensitivity超敏 NVP, ABC: Rash皮疹nImmune reconstitution inflammatory syndrome免疫重建炎性综合征JL Martin et al. Antimicrob Agents Chemother. 1994;38:2743NRTI inhibition of DNA PolgFIAU 13Drug Induced Liver Injury 药物
6、诱导的肝损伤nHepatotoxicity 肝毒性 Grade 4（4级）10 x uln Grade 3（3级） 5-10 x uln Grade 2（2级） 2.5-5 x uln Grade 1（1级） 1.25-2.5 x ulnnHys Law Hys法则 10-50% with hepatocellular jaundice will die of liver failure 10-50% 有肝细胞性黄疸者 将死于肝 衰竭nFDA clinical concernFDA 临床指标 ALT 3 x uln and Direct bili（直接胆红素） 1.5 x uln（正常上限）n
7、Grade 1-2 hepatitis 1-2 级 肝炎 Progressive fibrosis over years associated with HBV, HCV, Fatty Liver多年HBV, HCV及脂肪 肝相关的进行性纤维化 Concern about long term mitochondrial injury与长期的线粒体损伤有关nEarly cirrhosis is silent早期肝硬化是静息的Criteria of Drug Induced Liver Disorders Report of an International Consensus Meeting 药
8、物导致肝脏疾病的标准 一国际会议共识nExclusion of non drug related causes of Liver Injury排除非药物相关引起肝损伤的因素 Alcohol (AST/ALT2) 酒精 Viral Hepatitis (IgM anti-HAV, HBsAg, Anti-HCV) 病毒性肝炎 Others: Non-prescription medications 其它：非处方药物nAssessment of casualty by : 对疾病状况评估 Time of onset 发病时间 Course of the reaction 变化过程 Eventual
9、 Rechallenge 最终的再挑战J Hepatology 1990; 11:272-276J Hepatology 1990; 11:272-276DILI - cARTnEvents are poorly defined缺乏明确定义nMultiple drugs are involved 涉及多种药物nCholestasis is probably under-reported 胆汁淤积可能未能足够报道 nAny antiretroviral drug can be involved任何抗病毒药可能 ACTG retrospective analysis of hepatotoxici
10、ty occurring in 21 trials (10,622 patients)关于21个肝毒性试验的ACTG回顾性分析 (10,622例患者) NRTI: 6.3% NNRTI: 8.2% PI: 6.2% Liver-related death rate: 0.4% (3.0% of all deaths)肝脏相关的死亡率: 0.4% (总死亡率3.0% )Lactic acidosis with NRTIs Clinical features NRTIs 引起乳酸中毒临床特征nAge年龄(y): 21-63nGender 性别 Male 男性: 5 (14%) Female 女性:
11、 30 (83%) Unknown 不确定: 1 (3%)nWeight体重 (kg) 37 to 114nDuration of therapy 疗程 (days) Lamivudine 拉米夫定: 7 to 570 Stavudine 司他夫定: 150 to 450nMajor concomitant diagnoses 主要伴随诊断 Hepatic steatosis 肝脂肪变 性: 25/36 (69%) Pancreatitis 胰腺炎: 8/36 (22%)nLiver function abnormalities 肝功能异常 AST: 12 to 534 ALT: 23 to
12、230 LDH: 480 to 5792 ALP: 58 to 622 Bilirubin 胆红素: 0.5 to 3.9Boxwell DE, et al. 39th ICAAC. San Francisco, 1999. Abstract 1284. Boxwell DE, et al. 39th ICAAC. San Francisco, 1999. Abstract 1284. NNRTIsnApparent modest class effect of NNRTIs on abnormal liver enzyme levelsNNRTIs明显的有引起肝酶水平轻度异常的作用nGrad
13、e 3-4 hepatitis 3-4级肝炎 May be significantly higher in patients with HBV and/or HCV在乙肝或丙肝患者中可能明显升高n Unique hepatic event associated with nevirapine奈伟拉平相关的独特的肝脏事件 Hypersensitivity fatal hepatic necrosis 超敏引起的致命的肝坏死 Risk is greatest in women with CD4 cell counts 250 cell/mm3 and in men with CD4 cell co
14、unts 400 cell/mm3最大风险发生于 CD4 计数 250 cell/mm3 的女性和 CD4 计数 400 cell/mm3的男性nEfavirenz results in higher ALT and AST elevation compared to IDV和茚地那韦（IDV）相比，依菲韦仑更易引起 ALT和 AST 升高PIs and Hepatic Safety PIs与肝脏安全nRate of serious clinical (symptomatic) hepatotoxicity, ALT and/or AST levels 5 times ULN is relat
15、ively low 严重的临床 (出现症状) 肝毒性发生率, 出现ALT 和/或者AST 水平5 倍正常上限的情况较低 Boosting doses of ritonavir not associated with significantly higher incidence of severe hepatotoxicity versus other PIs和其它PIs比较，增加利托那韦（ritonavir）剂量与显著的肝脏毒性发生无关nPatients coinfected with HBV and/or HCV 患者同时合并 HBV和/或者HCV感染 Greater risk of hepatotoxicity 显著增加肝脏毒性风险 Kaletra appears at least as safe as nelfinavir but with better efficacy. ALT and AST elevation tend to be lower with Kaletra 克力芝（Kaletra） 显示出和那非那韦（nelfinavir）一样安全，但是有更好的疗效 。使用克力芝，ALT和AST 水平升高相对较低 。 No association between Kaletra levels and hepatotoxicity 克力芝使用剂量与肝
