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、中华医学会传染病与寄生虫病学会艾滋病专业学组副组长、中华医学会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、世界临床药物等十余本
2、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 HIV,HIV相关肝病的治疗方法,Chronic hepatitis ALT/AST elevation慢性肝炎 ALT/AST升高,Vira
3、l hepatitis 病毒性肝炎Hepatitis B, hepatitis C (hepatitis A, D, E) 乙肝, 丙肝 (甲肝, 丁肝, 戊肝)Anti-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, fatty li
4、ver 线粒体毒性, 脂肪肝Idiosyncratic drug-induced liver injury (DILI) 特异的DILIToxins 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,Mitochondrial toxicity 线粒体毒性NRTIs esp D drugs NRTIs 特别是“D”类药物Upper abdo pain, anorexia, weakness 上腹痛, 厌食, 虚弱Amylase, CPK, lactate 淀粉酶 ,肌
5、酸磷酸激酶 ,乳酸 Direct toxicity直接毒性ABC/AZT: lactate/lipids 乳酸/脂质PIs (RTV200 mg/d)TPVHypersensitivity超敏NVP, ABC: Rash皮疹Immune reconstitution inflammatory syndrome 免疫重建炎性综合征,JL Martin et al. Antimicrob Agents Chemother. 1994;38:2743,NRTI inhibition of DNA Polg,FIAU 13,Drug Induced Liver Injury药物诱导的肝损伤,Hepat
6、otoxicity 肝毒性Grade 4（4级）10 x ulnGrade 3（3级） 5-10 x ulnGrade 2（2级） 2.5-5 x ulnGrade 1（1级） 1.25-2.5 x ulnHys 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FDA clinical concern FDA 临床指标ALT 3 x uln and Direct bili（直接胆红素） 1.5 x uln（正常上限）,Grade 1-2 hepatitis
7、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Early cirrhosis is silent 早期肝硬化是静息的,Criteria of Drug Induced Liver DisordersReport of an International Consensus Meeting药物导致肝脏疾病的标准一国际会议共识,Exclu
8、sion 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Assessment 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 Rechallenge 最终的再挑战,J Hepatol
9、ogy 1990; 11:272-276,DILI - cART,Events are poorly defined 缺乏明确定义Multiple drugs are involved 涉及多种药物Cholestasis is probably under-reported 胆汁淤积可能未能足够报道 Any antiretroviral drug can be involved 任何抗病毒药可能ACTG retrospective analysis of hepatotoxicity occurring in 21 trials (10,622 patients) 关于21个肝毒性试验的ACT
10、G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 NRTIsClinical features NRTIs引起乳酸中毒临床特征,Age年龄(y): 21-63Gender 性别Male 男性: 5 (14%)Female 女性: 30 (83%)Unknown 不确定: 1 (3%)Weight体重 (kg)37 to 114Duration of th
11、erapy 疗程(days)Lamivudine 拉米夫定: 7 to 570Stavudine 司他夫定: 150 to 450,Major 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%)Liver function abnormalities 肝功能异常AST: 12 to 534 ALT: 23 to 230 LDH: 480 to 5792 ALP: 58 to 622 Bilirubin 胆红素: 0.5 to 3.9,Boxwell DE, et
12、 al. 39th ICAAC. San Francisco, 1999. Abstract 1284.,NNRTIs,Apparent modest class effect of NNRTIs on abnormal liver enzyme levels NNRTIs明显的有引起肝酶水平轻度异常的作用Grade 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 Unique hepatic event associated with nevirap
13、ine 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 counts 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Efavirenz results in higher ALT and AST elevation compared to IDV 和茚地那韦
14、（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,Rate of serious clinical (symptomatic) hepatotoxicity, ALT and/or AST levels 5 times ULN is relatively 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 se
15、vere 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Patients 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 Kaletr
16、a 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脏毒性没有相关性Kaletra appears to be equally effective against HIV infection in HCV positive and negative patients 在HCV 阳性或阴性的患者中，克力芝的抗病毒效用相同No data for atazanavir and
17、 fosamprenavir and more data are needed in this patient population 没有关于阿扎那韦和福沙那韦（fosamprenavir）的数据；需要更多的患者样本量和数据PI based regimens are associated with significantly reduced fibrosis progression基于PI的治疗方案 与显著降低纤维化进程相关,48 yo man with new ascites新发腹水的48 岁男性,HIV pos on 3TC-AZT-Kaletra HIV阳性，药物治疗CD4 428 (2
18、2%), HIV 500假如CD4500，如何处理HBeAg+ HBV DNA 9 log IU/mL ALT 20HBeAg+ HBV DNA 6 log IU/mL, ALT 120HBeAg- HBV DNA 2 log IU/mL, ALT 20How to manage if CD4=200假如CD4=200，如何处理HBeAg+ HBV DNA 9 log IU/mL ALT 20HBeAg+ HBV DNA 6 log IU/mL, ALT 120HBeAg- HBV DNA 2 log IU/mL, ALT 20,Co-Infections happenShared route
19、s of infection（共感染发生时具有相似的感染途径）,Hepatitis B and HIV,1992 routine vaccination recommended （1992年推荐作常规计划免疫）2002 part of National Immunization Program （2002年作为国家计划免疫的项目的一部分）,FQ Cui et al. MMWR May 17, 2007,HBV-HIV,Birth,1-6 months,7-12 months,1-4 years,Older Children,Chronic infection慢性感染,Symptoms,%,症状
20、,Immunization of children born to HBsAg+ mothers（HBsAg阳性母亲所生的小孩的免疫）,HBV infection from age 1-10,14.3%,6.5%,972,805,7.6%,JS Wu et al. J Infect Dis 1999;179:1319,Case 1 HBV(案例1-HBV),man (MSM)（MSM）Age 12: HBV vaccine (12岁：HBV疫苗免疫)Age 24: HIV positive（24岁：HIV阳性，抗-HBs阳性52 mIU/mL ）Anti-HBs positive (52 mI
21、U/mL)Age 26: ALT abnormal for first time （26岁：ALT第一次异常）HIV: CD4 420 cells/mL, no treatment（HIV：CD4420个，没有治疗）Dx Acute HBV infection Chronic infection（急性HBV感染转化成慢性感染）HBeAg positive, viral load 9.08E9 IU/mL（e抗原阳性，病毒载量9.08E9 IU/ml）Rx 3TC-TDF-LPV/rHBsAg anti-HBs after 1 year HBeAg阳性 一年后抗-HBs阳性,Screening
22、tests for HBVSurface and Core(筛查实验检测表面和核心蛋白),Evaluating the person at risk（评估风险）,HBsAg anti-HBs, anti-HBc,Screen for HBV (HBV筛查),HBsAg-POS Infected（表面抗原阳性，属感染）,HBsAg-NEG Not-Infected（表面抗原阴性，未感染）,Anti-HBc POS Prior infection（抗-HBc阳性，既往感染）,Anti-HBc NEG, Anti-HBs NEG No infection, vaccinate（抗-HBc阴性，抗-H
23、Bs阴性，未感染需要免疫）,1a. Need for vaccine需要免疫,Other tests for HBVe antigen and viral load（HBV“e”抗原和病毒载量的检测）,HBV Viral load in log scale（用log表示HBV载量）,1 IU 5 copies/mL （1-5 拷贝/ml）Error of the test 0.5 log3 fold variations!My viral load tripled = within the error of the testVL 8-9 log IU/mL （载量大于8-9 log IU/ml
24、）Higher risk of HBV drug treatment failure （HBV药物治疗失败可能性高）Risk of neonatal infection （围产期感染的可能）,1 100 1E010 101 1E1 100 102 1E21,000 103 1E310,000 104 1E4100,000 105 1E51,000,000 106 1E610,000,000 107 1E7100,000,000 108 1E81,000,000,000 109 1E9,ImmuneTolerant（免疫耐受阶段，正常或者轻型肝炎）,ImmuneDamage（免疫损害，慢性肝炎）
25、,Immune control:Inactive carrier（免疫控制，静止的或进展性纤维化）,Ongoing immune damageHBeAg-negative CHB,HBV DNA,ALT,HBeAg,Anti-HBe,Normal or minimal hepatitis,Chronic hepatitis,Inactive fibrosisOr progressive fibrosis,Liver fibrosis assessment（肝纤维化的评估）,Fibrotest（纤维化检查）GGTBilirubin（胆红素）Haptoglobin（珠蛋白）a2-macroglob
26、ulin（a2-巨球蛋白）Apo-Lipoprotein A1AST to platelet ratio index (APRI) ASTPlatelet count（血小板计数）,What is the severityDoes the patient have cirrhosis?（病人有肝硬化吗，严重性是什么）,Cirrhosis,Symptoms,Imaging, Biopsy,HBV and HIV are similar,Treating the HBV patient（HBV病人的治疗）,WHO: ALL are candidates for treatment（所有的都应该治疗
27、）WHEN: is the most important question（何时开始治疗，是一个很重要的问题）,Disease Risk（疾病的风险）Liver failure（肝衰竭）Liver cirrhosis（肝硬化）Advanced liver fibrosis（进展性的肝纤维化）High activity（高活性）,Treatment Risk（治疗的风险）Failure from resistance, drug fatigue（耐药性产生）,When to treat HBV in HIV?（HIV感染者什么时候开始治疗HBV）,Treat YES!(需要治疗),Cirrhos
28、is（肝硬化）Platelets 3 log IU/mLSevere hepatitis（严重的肝炎）ALT/AST very high(转氨酶很高)INR or Bili（胆红素升高）Liver biopsy（肝活检中发现中度纤维化）More than minimal fibrosis,Treat unclear?（是否治疗不确定）,Immune tolerant?（免疫耐受？）ALT & liver normal（肝转氨酶正常）HBV DNA 9 log IU/mL（HBV DNA9 log IU/ml）Inactive(非活化状态)HBV DNA 2-3 log IU/mL（HBV DN
29、A 2-3 log IU/ml）,Treatment options for HBV（HBV治疗的选择药物）,Choice of treatment治疗的选择,Treat HBV and HIV3TC/FTC-TDF + HIV agentTreat HBV but NOT HIVInterferons?Telbivudine? Worry about HIV at 3TCAdefovir? Worry about HIV at TDFEntecavir NO Treat HIV but NOT HBV?Avoid 3TC-FTC-TDF?,Monitoring（监测）,Not on trea
30、tment（未治疗）Changes in status that require treatment（状况发生变化需要治疗）Hepatoma screening if risk is high（危险度很高时作肝癌筛查）On treatment（治疗）Continued virological suppression 200 IU/mL（持续的病毒载量被控制在200 IU/ml）Changes in renal function to eGFR 50（肾功能改变，肾小球滤过率50）Hepatoma screening if risk is high（危险度很高时作肝癌筛查）Stop treatm
31、ent(停止治疗)HBeAg anti-HBe seroconversion（e抗原阳性抗-HBe阳性）HBsAg+ HBsAg- （表面抗原阳性表面抗原阴性）,Co-Infections happenShared routes of infection共感染发生具有相似途径,Treatment of HCV in HIV（HIV感染中HCV的治疗）,Two steps to evaluate for HCV（HCV评估的2个步骤）,Anti-HCV, ALT, AST（抗体及转氨酶）,1. Screen for HCV（HCV筛查）,Anti-HCV NEG Not infected（抗体阴
32、性，未感染）,Check HCV PCRViral load and Genotype （PCR,病毒载量和基因分型）,2b. Assess severity（严重程度评估）,CBC, INR, Alb, Bili, Ultrasound完全血液计数 、凝血功能的国际标准比率、血清白蛋白 、胆红素、超声,Plts 35Alcohol 50g/dCD4 65 years old?（65岁？）Alcohol use（饮酒）,Hepatitis CTo treat or not to treat?（丙肝是治疗还是不治疗）,Benefits of treatment（治疗的好处）Cure of vir
33、al infection（病毒感染的治疗）Eliminate infectious source to others（降低作为传染源的危险）Stop complications cryoglobulinemia（降低并发症冷球蛋白血症）Stop/Reverse fibrosis progression（阻止或者逆转纤维化）Reduce risk of hepatocellular carcinoma（降低肝细胞肿瘤的危险）Prevent need for liver transplantPrevent infection of transplant graft（防止对移植来的肝脏的感染）,Ge
34、notype 1 SVR,Definition of treatment responses（治疗反应的定义）,50 IU/mL,600 IU/mL,RVR,EVC,PVR,SVR,Relapse,Non-Responder,Treatment of HCV G1,50 IU/mL,Week 4 PCR (RVR),NRTIs: Inhibition of DNA Polg DNA(多聚酶抑制剂）,Martin JL, et al. Antimicrob Agents Chemother. 1994;38:2743,Reference: FIAU 13.0,FatiguePancreatiti
35、sLactic Acidosis,Relative Potency of Inhibition*,*1/Ki/KM.,Fitted Probability,Platelet Count (x109/L),Mauss S, et al. AIDS. 2004;18:F21,Fitted Probability 24-Week Decompensation (24周失代偿概率）,How much anemia to expect（会发生多少贫血？）,Soza et al, Hepatology 2002;36:1273,Cell count (cells/mL),0,1000,2000,3000,
36、2500,1500,3500,500,No dose-reduction for WBC,Leukopenia on treatmentN=119（治疗中白细胞减少）,Neutropenia（中性粒细胞减少）,Neutropenia in oncology（在肿瘤发生后中性粒细胞减少）Preventing infection（预防感染发生）Prophylactic quinolones （预防性给予喹诺酮）G-CSF（巨系集落刺激因子）Other reasons for immune compromise（免疫系统缺陷的原因）Mucosal breaks “mucositis” （黏膜病）Ne
37、utropenia not greatly associated with infection（中性粒减少不只是与感染有关）Cyclical neutropenia（周期性的中性粒减少）Drug-induced（药物导致的）Clozapine, Olanzapine, Sertraline, Mirtazapine, InfliximabPegylated Interferon + Ribavirin,A Juarez-Navarro et al. Meth 27:317,Who should be treated?（那些人应该治疗）,Everyone with HCV-HIV should be evaluated for treatment（应评估所有HIV-HCV混合感染者是否应治疗）Current practice 10% treated（目前只有不到10%的参加治疗）Real life versus fear from lack of data?（真实的生活 VS 因数据缺乏的担心）Treat if HCV is the biggest risk of morbidity and mortality（如果HCV是发病和死亡的最大危险因素，就应该治疗）,
