亚太乙肝指南

APASL最新内容分享,主要内容,恩替卡韦治疗核苷初治病人疗效,APASL指南更新,3,*Grade I at least 1 well-designed, randomized, control trial Grade II well-designed cohort or case- controlled studies Grade III case series, case reports or flawed clinical trials Grade IV opinions of respected authorities, descriptive studies or reports of expert committees * Recommendation A: Strong; B: weak,亚太指南推荐建议（摘自侯金林教授新浪微博） 说明：APASL新指南各推荐所依赖的证据划分为 （至少有一项设计良好的 随机对照试验）； （设计良好的队列或病例对照研究）； （系列病例、病例报告或有缺陷的临床试验）； （以临床经验、描述性研究或专家会议报告为基础的相关权威 专家的观点）共4个级别。 这些推荐分为两种，A极力推荐和B一般推荐。,Grade of evidence/ recommendation,4,Recommendation 1 General management,Thorough evaluation and counselling are mandatory before considering drug therapy (IIA),Counselling includes: Infectivity/transmission, prevention, life style, importance of monitoring, benefit/risks and advantage/disadvantage of possible therapies,推荐建议1： 在进行抗病毒治疗前，必须对患者进行强制性彻底评估及咨询指导。 治疗适应症(IIA),5,Recommendation 2 Indication,Patients with HBV replication but persistently normal or minimally elevated ALT levels should not be treated, except in patients with advanced fibrosis or cirrhosis. They need adequate follow-up and HCC surveillance every 3-6 months (IA),推荐建议2： 对病毒复制但血清ALT水平持续正常或轻微升高的患者，不应进行抗病毒治疗，除非患者存在严重肝纤维化或肝硬化。这些患者需要接受密切的随访，并且每36个月进行HCC监测(IA)。,6,Recommendation 3 Assessment of fibrosis,Assessment of liver fibrosis is recommended in viremic patients with high normal or minimally raised ALT levels and older than 40 except patients with clinical evidence of cirrhosis (IIA). Biopsy to grade, stage and exclude other causes as a guide to the indication; assessment by non-invasive method(s) is an alternative,推荐建议3： 对存在病毒血症同时ALT在正常高值水平或轻微升高且年龄大于40岁的患者，推荐进行肝纤维化评估，除外已经有临床诊断肝硬化证据的患者。,7,Recommendation 4 When to start,推荐建议4：治疗的起点 慢性HBV感染者若ALT2ULN同时HBeAg阳性者HBV DNA20000 IU/ ml(105拷贝/ml)，HBeAg阴性者HBV DNA2000 IU/ ml(104拷贝/ml)，应考虑抗病毒治疗。出现严重肝纤维化或者肝硬化，无论ALT水平多高，均应考虑抗病毒治疗（A）。若即将发生或已出现明显的肝功能失代偿，应尽早开始抗病毒治疗。除外上述情况外，建议观察36个月以确保治疗的必要性（A）。重新治疗的适应症同上。,8,Recommendation 5 Which drug or strategy,Nuc-nave patients can be treated with IFNa (IB),Peg IFN (IA), ETV (IA), TDF (IA), ADV (IB), LdT (IB) or LAM (IB). Thymosin-a can also be used (IB). ETV or TDF is the preferred Nuc* Consider duration, cost, rapidity of action and adverse effects,推荐建议5：初治患者可采用常规干扰素，或PegIFN-2a， IA推荐 恩替卡韦，替诺福韦（未上市）； IB推荐 阿德福韦，替比夫定，拉米夫定。也可以选用胸腺素 。 恩替卡韦和替诺福韦在这种情况下也是优先推荐的选择,9,Recommendation 6 How to monitor during therapy,*ALT, HBeAg and/or HBV-DNA should be monitored, at least 3 month (IA). *Renal function should be monitored if TDF or ADV is used (IA) *Muscle weakness should be monitored especially if LdT is used (IIIA) *During IFN-based therapy, monitoring of blood cell counts and other adverse effects are mandatory (IA),推荐建议6： 在抗病毒治疗过程中，应至少每3个月监测1次ALT、HBeAg 或HBV DNA（A）。若使用替诺福韦或者阿德福韦，还应监测肾功能（A）。用替比夫定治疗时应监测肌力是否减弱(IIIA)。在应用干扰素治疗期间，必须强制性监测全血细胞计数和其他的药物不良反应（A）。,10,Recommendation 7 How to monitor after the end of therapy,ALT and HBV markers (including HBV DNA) should be monitored monthly for the first 3 mo and then every 3 mo in the 1st year. If uneventful, monitor every 3 mo (for cirrhotics) to 6 mo (IIA) For non-responders, further monitoring is required to recognize a delayed response and to plan retreatment when indicated (IIA),推荐建议7： 在抗病毒治疗结束后，头3个月内应当每月监测ALT和HBV DNA以发现早期复发，以后每三个月监测一次。若无症状出现，以后每3个月（对于肝硬化患者）到6个月（对于已产生应答的患者）监测1次（A）。 对于无应答的患者，应进一步监测HBV标志物，以便识别延迟应答和在有指征时重新治疗（A）。,11,Recommendation 8 Finite duration of therapy,IFNa:4-6 months for HBeAg (+) patients and at least a year for HBeAg(-) patients (IA) Peg IFN: 12 mo (IA) Thymosin a1: 6 mo for HBeAg (+) patients (IA) and HBeAg (-) patients (IIB) * 6-12 mo post-therapy observation,推荐建议8： 对于常规干扰素，目前推荐的疗程为HBeAg阳性患者46个月（A），HBeAg阴性患者至少1年（A）。对于PegIFN，推荐的疗程为12个月（A）。对于胸腺素1，推荐的疗程为HBeAg阳性患者（A）和HBeAg阴性患者（B）均为6个月。,12,Recommendation 9 When to stop oral antiviral agent(s), HBeAg (+) patients: HBeAg seroconversion with undetectable HBV DNA maintained 12 mo (IIA) HBeAg (-) patients: HBV-DNA undetectable on 3 separate occasions 6 mo apart (IIA) For primary treatment failure (mo 3) or suboptimal response (mo 6), stop and switch to a more potent Nuc or add-on a Nuc without cross resistance if LAM, LdT or ADV was used (IIIA),推荐建议9： 对于口服抗病毒药物，在HBeAg阳性患者，当证实至少持续12个月出现HBeAg血清学转换伴HBV DNA检测不出，可考虑停药（A）。在HBeAg阴性患者，如果HBsAg仍然阳性尚不清楚需要持续治疗多长时间，但在治疗至少持续2年并间隔至少6个月的3个不同时间点检测不出HBV DNA (IIA)，可以考虑终止治疗。对于依从性好的初治患者在开始治疗3个月时出现原发治疗失败或者在第6个月时病毒控制不理想的，如果已用拉米夫定，替比夫定或者阿德福韦治疗，可以改用更强的或加用没有交叉耐药的药物治疗(IIIA)。,13,Recommendation 10 Female patients in the child-bearing age,1. Nonpregnant women require treatment: IFN/Peg IFN is preferred; discouraged pregnancy during therapy (IA) Pregnant women require treatment: LdT or TDF* (IIA) 2. Pregnant women with HBV DNA 2x106 IU/mL can be treated with LdT in the 3rd trimester to prevent transmission (IIA). TDF is an alternative (IIIA) * Category B drug(s): No risk in animal, unknown in human,推荐10-1： 对于育龄妇女，尚未怀孕者优先考虑选用基于干扰素的治疗(IA)，在干扰素治疗期间不宜怀孕。怀孕需要治疗的可以用妊娠B级口服药治疗(IIA)。推荐10-2： 为了防止母婴传播，对于HBV DNA2x106 IU/mL的妊娠妇女在妊娠晚期可以用替比夫定(IIA)治疗，替诺福韦也可作为选择之一(IIIA)。,14,Recommendation 13 Patients with decompensated liver diseases,ETV or TDF is the choice for patients with impending/ obvious hepatic decompensation (IA). LdT, LAM or ADV can also be used in Nuc-nave patients (IB) Renal function and lactic acidosis should be monitored, especially in those with MELD score 20 (IIIA) Start treatment as early as possible IFN is usually contraindicated,推荐建议13： 对于存在明显或即将发生肝功能失代偿、且初治的患者，选用恩替卡韦或者替诺福韦(IA)。但对于初始用口服抗病毒药的患者也可选用替比夫定、拉米夫定治疗或者阿德福韦(IB)。对于这类人群必须监测肾功能和乳酸，尤其是MELD平分高于20的患者(IIIA)。,15,HBeAg-Positive,HBV DNA 20,000 IU/mL,HBV DNA 20,000 IU/mL,ALT Normal,Consider other strategies (including OLT),ALT Normal,ALT 1-2 ULN,Treatment if persistent (36 months) or has concerns for hepatic decompensation Interferon- based therapy or Nuc (ETV & TDF preferred),Treatment indicated If HBV-DNA 5 ULN,ALT 2-5 ULN,Monitor HBV DNA, HBeAg, ALT/1-3 months post-therapy,Non-response,Response,Patients at risk: HCC surveillance AFP and ultrasonograph/6 months,Liver biopsy or non-invasive fibrosis assessment if patient 40 years Treat if moderate or greater inflammation or fibrosis on biopsy,ETV or TDF preferred!,16, Liver biopsy or non-invasive fibrosis assessment if patient 40 years Treat if moderate or greater inflammation or fibrosis on biopsy, No treatment Monitor HBV DNA, HBeAg, ALT/13months, No treatment Monitor HBV DNA, HBeAg, ALT/ 3 months,ALT 1-2 ULN,ALT Normal,HBV DNA 20,000 IU/mL,17,HBeAg-Negative,HBV DNA 2 ULN,ALT 1-2 ULN,Monitor HBV DNA and ALT/1-3 months post-therapy,Non-response,Response,Patients at risk: HCC surveillance AFP and ultrasonograph/6 months, Liver biopsy or non-invasive liver fibrosis assessment if patient 40 years Treat if moderate or greater inflammation or fibrosis on biopsy,ETV or TDF preferred!,18, Liver biopsy or non-invasive liver fibrosis assessment if patient 40 years Treat if moderate or greater inflammation or fibrosis on biopsy, No treatment Monitor HBV DNA and ALT/ 13 months, No treatment Monitor HBV DNA and ALT/3 months,ALT 1-2 ULN,ALT Normal,HBV DNA 20,000 IU/mL,19,HCC surveillance AFP and ultrasonography /3-6months,HBV-DNA 2x103 IU/ml,HBV-DNA2x103 IU/ml,Decompensated,Compensated,Liver cirrhosis,ALT, HBeAg or HBV-DNA /3months,ETV TDF,ALT 5x ULN,Antiviral therapy Consider transplant,ETV TDF,IFN based ETV TDF,Conventional supportive treatment,Yes,No,主要内容,恩替卡韦治疗核苷初治病人疗效,APASL指南更新,应用恩替卡韦治疗台湾HBeAg阳性的慢性乙型肝炎初治患者,Chia-Yen Dai, Ming-Lun Yeh, Chun-Yi Huang, Nai-Jen Hou, Jee-Fu Huang, Zu-Yau Lin, Wan-Long Chuang高雄医科大学,初治患者(1),PP09-006,研究设计和人群,共150例在高雄医科大学接受恩替卡韦0.5mg/日治疗的患者纳入本研究（男性100例（66.7%），平均年龄43.412.3岁）所有患者均为初治，在接受恩替卡韦治疗前均为HBeAg和HBV DNA阳性，接受恩替卡韦治疗的疗程超过3个月,22,基线数据,150例HBeAg阳性初治患者入组,ETV治疗疗效随时间延长提高,基线ALT水平及HBV DNA水平是病毒学应答的显著相关因素,患者数,150,130,93,19,49,累积HBeAg 血清学转换率,基线年龄、ALT水平是HBeAg血清学转换的显著相关因素,月,HBeAg血清学转换累积发生率,结论,应用ETV治疗2年余，患者的病毒学应答率及HBeAg血清学转换率分别超过90%及30%年龄、基线时血清ALT水平和HBV DNA水平是病毒学应答及HBeAg血清学转换的显著相关因素,中国慢性乙型肝炎初治患者应用恩替卡韦连续治疗后病毒学抑制及耐药性情况的8年随访,J. Cheng, H. Cai,首都医科大学北京地坛医院,PP09-036,初治患者(2),研究设计,ALT： 谷丙转氨酶；CHB ： 慢性乙型肝炎；ETV ：恩替卡韦；HBeAg ：乙型肝炎e抗原； HBV ：乙型肝炎病毒；LVD ： 拉米夫定；PCR ：聚合酶链反应,核苷(酸)类药物初治HBeAg(+)/(-)CHB患者,ETV 0.5mg 每日1次,LVD 100mg 每日1次,ETV-023研究,96周,8年,ETV 1.0mg 每日1次,Rollover 研究,评估：HBV DNA下降情况达到以下终点的患者比例PCR检测HBV DNA最低可测值 (LLOD)HBeAg消失,治疗停止标准：HBeAg阴性抗-HBe阳性PCR检测HBV DNA最低可测值(LLOD)ALT复常至少24周,研究终点,疗效终点：HBV DNA水平（log10 拷贝/mL）HBV DNA低于最低检测下限的患者比例 （0-4年300拷贝/mL；4年后500拷贝/mL）基线时HBeAg阳性患者出现HBeAg消失及血清学转换的患者比例安全性终点：因不良事件（AE）终止治疗及严重不良事件（SAE）,研究结果,96周前失访（转院）n=1,3年时失访n=2,4年时符合停药标准*n=2,随机化治疗至96周ETV 0.5mgn=15,进入rollover研究n=14,接受ETV治疗达8年n=10,治疗人群,*停药后继续随访3年,患者基线特征,SD = 标准差,HBV DNA不可测患者比例,32,12,24,48,96,4,8,20.0%,53.3%,86.7%,92.9%,100.0%,80.0%,周,3/15,8/15,13/15,13/14,12/12,8/10,HBV