感谢制作者：Prof Eugene R. Schiff 本幻灯片制作用于帮助教育慢性乙肝方面的医疗保健专业人员，包括疾病特性和临床处理。此幻灯片中的信息作报告之用，不能代替个体从业者的诊断。 This slide kit is designed to be used to help educate healthcare professionals about chronic hepatitis B, including disease characteristics and clinical management. The information in this slide kit is meant to inform, not replace, individual practitioner judgment. Please see accompanying complete Prescribing Information. 本幻灯片制作用于帮助教育慢性乙肝方面的医疗保健专业人员，包括疾病特性和临床处理。此幻灯片中的信息作报告之用，不能代替个体从业者的诊断。 This slide kit is designed to be used to help educate healthcare professionals about chronic hepatitis B, including disease characteristics and clinical management. The information in this slide kit is meant to inform, not replace, individual practitioner judgment. Please see accompanying complete Prescribing Information.

慢性乙肝的评估与治疗 Prof Eugene R. Schiff, M.D. University of Miami, Florida, USA 美国佛罗里达州迈阿密大学

1、慢性乙肝 – 临床特点 潜伏期: 平均 60–90 天 范围 45–180 天 潜伏期: 平均 60–90 天 范围 45–180 天 临床发病期 (黄疸): <5 岁, <10% >5 岁, 30%–50% 急性病例死亡率: 0.5%–1% 慢性感染: <5 岁, 30%–90% >5 岁, 2%–10% 慢性肝病引起的过早死亡: 15%–25% 29

2、慢乙肝的自然病程 年龄 病期 免疫耐受 免疫清除 晚期 / 残余 再活动 前-C 区变异 HBV-DNA HBeAg(+) HBsAg 清除 肝硬化 HCC ALT/分级 HBeAg 细胞核 细胞浆 (++ ~) (-) (+++) 细胞膜 (++ ~) HBsAg/前S 细胞膜 细胞浆(++ ~) 细胞浆 (+++) HLA-1 (-) (++) (++) 20 年龄 40 60

3、慢性乙肝的自然史 轻度 (无症状性) 至严重慢性肝病的病程范围 纤维化及随后发生的肝硬化 肝衰竭 肝细胞肝癌 死亡 Natural History of Chronic Hepatitis B 慢性乙肝的自然史 The clinical course of chronic infection with HBV is variable, ranging from mild, asymptomatic infection to severe chronic liver disease. The more serious sequelae of HBV infection include: 慢性HBV感染的临床过程是可变的，包括范围从温和的、无症状的感染到严重的慢性肝病。更严重的HBV感染后遗症包括： • Fibrosis and subsequent cirrhosis 纤维化及随后发生的肝硬化 • Liver failure 肝衰竭 • Hepatocellular carcinoma (HCC) 肝细胞肝癌 • Mortality 死亡 Dusheiko G, Hoofnagle JH. Hepatitis B. In: McIntyre N, Benhamou J-P, Bircher J, Mizzetto M, Rodes J, eds. Oxford Textbook of Clinical Hepatology. 1st ed. New York, NY: Oxford University Press, Inc.; 1991:571-592. Please see accompanying complete Prescribing Information.

Adapted from Feitelson, Lab Invest 1994 4、慢性乙肝感染的自然史 代偿性肝硬化 痊愈 病情稳定 急性感染 慢性肝炎 肝硬化 肝癌 死亡 Key message Progression of hepatitis B is variable. Acute hepatitis B is usually self limiting and benign, but may progress to chronic hepatitis B in a proportion of patients. Chronic hepatitis B may lead to more serious conditions including cirrhosis, liver failure and hepatocellular carcinoma. Points of explanation In the liver, acute infection (short term infection) with hepatitis B causes the body to mount an immune response to eliminate the virus. The immune system attempts to eradicate the virus by destroying HBV infected liver cells. In some patients the immune response succeeds and the patient makes a complete recovery (resolution). However in other HBV-infected people, the immune response to the infection is insufficient to eliminate the virus for many months / years or not at all; slowly destroying more and more infected liver cells as the virus spreads (long-term infection). This slow persistent destruction of liver cells by the immune system can lead to fibrosis, cirrhosis and even hepatocellular carcinoma. Patients infected with HBV whose immune systems cannot eliminate the virus are referred to as chronic HBV carriers. Chronic HBV carriers can pass the virus to others. Hepatitis B surface antigen (HBsAg) is the first serological marker to appear in the serum and is present in high levels during acute and chronic infection. Persistence of HBsAg for more than 6 months defines a chronic infection. References Feitelson MA. Biology of disease: biology of hepatitis B virus mutants. Lab Invest 1994; 71: 324-349. 慢性携带者 病情进展 失代偿性肝硬化 (死亡) 30–50 年 Adapted from Feitelson, Lab Invest 1994

5、慢性乙肝: 定义 HBsAg阳性史 ≧6月 病程多样化 肝内慢性坏死炎症性病变引起临床发病与死亡 病程进展与HBV持续高复制相关 Chronic Hepatitis B: Summary • Chronic infection with HBV is defined as the presence of HBsAg in the serum for 6 months. • The clinical course is variable. Patients are generally asymptomatic or have nonspecific signs and symptoms until the onset of hepatic insufficiency. • Some patients will develop chronic necroinflammatory liver disease, which may lead to liver failure due to advanced cirrhosis or hepatocellular carcinoma. HBV infection can cause considerable morbidity and mortality. • Disease progression is associated with persistently high HBV replication. Please see accompanying complete Prescribing Information.

6、慢性乙肝病程进展的预测因子 肝活检提示桥样坏死 HBeAg持续阳性 HBeAg阴性的前C区变异慢性乙肝患者 HBV DNA持续阳性及 ALT 水平升高

7、慢性乙肝预后改善的预测因子 HBeAg转阴 伴病毒复制水平降低 生存率改善 HBV DNA持续阳性提示前C区变异及持续慢性肝炎 ALT正常化提示生存时间延长 病期越短预示生存时间越长 对肝脏损害的组织学评估程度也是生存期的预测因子

8、对乙型肝炎严重程度的评估 轻度 仅 ALT 和/或 AST 升高 较严重 ALT 和/或 AST 与胆红素升高 严重, 将发生肝衰竭 白蛋白降低 凝血酶原时间延长

9、慢乙肝的治疗 治疗目标： 对病毒复制的抑制 肝坏死炎症病变的改善 降低乙肝相关性肝病长期结局 (肝硬化, 肝细胞肝癌) 的发生率 Management of Chronic Hepatitis B The goals of managing patients with chronic hepatitis B are: • Suppression of viral replication • Improvement in hepatic necroinflammatory disease • Reduction in the likelihood of long-term sequelae of HBV infection, such as cirrhosis and hepatocellular carcinoma Please see accompanying complete Prescribing Information.

10、乙型肝炎– 诊断指标 病毒指标 HBV DNA HBeAg HBsAg 肝脏损害的指标 ALT AST 胆红素 病毒抗体 抗-HBc 肝脏损害的严重程度 胆红素 白蛋白 凝血酶原时间

11、未接触过乙肝 无阳性病毒指标 对病毒无免疫学反应 HBsAg - 抗-HBc - HBeAg - 抗-HBs - HBV DNA -

12、HBV DNA检测的敏感性 106 105 104 103 102 试验 方法 定量范围 点杂交 快速试验 Abbott 液相杂交 试验 方法 定量范围 点杂交 快速试验 Abbott 液相杂交 Digene RNA-DNA杂交 Chiron 支链DNA Amplicor 定性 PCR Monitor 106 105 103 102 104 Key message: YMDD variant HBV is detected using tests based on the polymerase chain reaction (PCR) and may therefore be found in patients who are HBV DNA negative by the less sensitive solution hybridisation assays that are used routinely in clinical practice. Explanation: In routine clinical practice, serum HBV DNA is commonly assayed by solution hybridisation (e.g. Chiron assay). This type of test has a sensitivity that is usually sufficient for identifying patients with higher levels of viraemia associated with increased risk of disease progression. In contrast, tests based on the polymerase chain reaction (PCR) are approximately 1,000-fold more sensitive and can often detect HBV in serum even after HBeAg or HBsAg seroconversion. The clinical significance of viraemia detectable only by PCR is unknown. PCR methodology is used to test for the presence of YMDD variant HBV. It is therefore possible to detect the presence of YMDD variant HBV in the serum of a patient that tests negative for HBV DNA by less sensitive routine assays. Reference: Zeuzem S, Workshop on Management of hepatitis B: 2000, NIH Bethesda, US

13、血清 HBV DNA 检测值 预后 不管是否存在HBeAg阳性，均可确诊病毒血症 治疗选择 监测 对治疗的病毒学反应 疾病进程

14、急性乙肝 病毒学指标均阳性，但持续时间< 6 个月 HBsAg + HBeAg + HBV DNA + 对病毒存在部分免疫反应 Anti-HBc + Anti-HBs - Anti-HBe - 急性感染的证据 抗-HBc IgM +

15、急性乙肝痊愈的典型血清学过程 总 抗-HBc 滴度 抗-HBs HBsAg 抗-HBc IgM 接触乙肝病毒后的时间（周） HBeAg 症状 HBeAg 抗-HBe 总 抗-HBc 滴度 抗-HBc IgM 抗-HBs HBsAg 4 8 12 16 20 24 28 32 36 52 100 接触乙肝病毒后的时间（周） 30

16、慢乙肝病毒复制的证据 病毒学指标均阳性，但持续时间> 6 个月 HBsAg + HBeAg + HBV DNA + 对病毒存在部分免疫反应 Anti-HBc + Anti-HBs - Anti-HBe - 无急性感染的证据 抗-HBc IgM -

17、慢性乙肝病毒感染病程的典型血清学表现 滴度 接触乙肝病毒后时间（年） 急性 慢 性 (6 个月) (年) HBeAg 抗-HBe 慢 性 (年) HBeAg 抗-HBe HBsAg 总 抗-HBc 滴度 抗-HBc IgM 4 8 12 16 20 24 28 32 36 52 接触乙肝病毒后时间（年） 31

18、如何监测? 治疗期间: ALT，HBeAg 和/或 HBV-DNA 每3个月一次

19、拉米夫定治疗期间ALT升高的可能原因 肝炎相关性 HBeAg 血清转换 疾病波动 治疗相关性 对治疗不顺应 出现HBV YMDD 变异株 伴发疾病 酗酒 HAV, HCV 感染 非酒精性脂肪肝（NASH） 其它药物性肝损

20、出现YMDD 变异株是否会导致血清 ALT 升高? HBV重新出现 (野生型或YMDD变异株 ) 可导致血清ALT升高，但一般为一过性或无症状 伴肝脏失代偿的血清ALT升高罕见

21、治疗3年中的血清ALT 升高 2 x 基线 ALT 22* 38 3 x 基线 ALT 14 24 定义 拉米夫定100 mg (n=58) n % 2 x 基线 ALT 22* 38 3 x 基线 ALT 14 24 2 x 基线 ALT 与 >500 ALT (U/L) 6 10  2 x 基线 ALT 与 >2 x ULN 胆红素水平 和  2 x基线胆红素水平 2 3 Key message During three years continuous lamivudine treatment, the incidence of ALT elevations associated with hepatic insufficiency is very low (3%). Points of explanation These data are based on the 58 patients who received 3 years of continuous lamivudine treatment (Liaw study). In that study, there is no 3 year placebo group for comparison. A total of 22 (38%) patients had ALT elevations 2 x baseline during 3 years of lamivudine treatment. However, in 10 of these patients the ALT elevation was just prior to HBeAg seroconversion (?true). ALT elevations associated with a bilirubin elevation occurred in only 2 (3%) patients during the whole 3 year period. References Leung NWY, Lai CL, Chang TT, et al. Three year lamivudine therapy in chronic HBV. J Hepatol 1999;30:59 (Abstract GS5/25). Leung NWY. Oral presentation: EASL 1999. * 4 个病例 HBeAg阴性, HBeAb阳性 和 DNA阴性 6 个病例HBeAg阴性, HBeAb阳性 和 DNA阳性 Leung et al., 1999

22、YMDD变异与临床失效患者的治疗选择 对110位欧洲医生的调查，维也纳，2001年3月 继续拉米夫定治疗 终止拉米夫定治疗 加其它抗病毒药物- 阿地弗韦, IFN 80 70 60 50 Explanation: At a recent meeting† of European physicians in Vienna, the delegates were asked how they would manage patients with YMDD variant HBV who developed loss of clinical efficacy to lamivudine. The management options included: continuing lamivudine treatment stopping lamivudine treatment adding another agent The majority of doctors (75%) were in favour of continuing treatment with lamivudine; 10% of the delegates said they would stop lamivudine treatment and 15% favoured the option of adding another agent. † European Symposium on the Management of Chronic Hepatitis B, Vienna, Austria, 9-11 March, 2001. % 40 30 20 10 继 续 终 止 加 药

23、在YMDD变异的乙肝病人中继续拉米夫定治疗的益处 仍可出现HBeAg血清转换 对野生型病毒持续抑制 在绝大多数患者中可获得血清ALT与HBV DNA 的改善 可获得组织学改善 不良反应无显著上升

24、总结 在乙肝高发区筛检乙肝感染病人非常重要，因为早期发现可以使病人在进展到晚期肝病前得到治疗 在治疗乙肝过程中了解血清参数HBV与ALT 升高的意义十分重要 乙肝将随着疫苗的普遍应用而被消灭 Outline of Presentation Reviews subjects of concern to healthcare professionals who manage patients with chronic hepatitis B, including: • HBV epidemiology • HBV virology and infection • Patient diagnosis and management • Results of clinical trials of EPIVIR-HBV®, also known as lamivudine - Initial trials evaluating the pharmacology of EPIVIR-HBV in humans - Several phase III controlled clinical trials conducted worldwide (North America, Europe, Asia, Rest of World) evaluating the efficacy and safety of EPIVIR-HBV • Conclusions about the use of EPIVIR-HBV to treat chronic HBV infection Please see accompanying complete Prescribing Information.