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慢性乙型肝炎
抗病毒治疗策略
慢性乙型肝炎
抗病毒治疗策略 刘 克 洲
浙江大学医学院附属一院慢性乙型肝炎的治疗目标慢性乙型肝炎的治疗目标APASL
基本治疗目标(the primary goal)
清除或永久抑制乙肝病毒复制。从而减轻致病性和传染性,终止或减轻肝脏炎症和坏死
短期治疗目标(the short-term goal)
减轻肝炎活动性,预防肝纤维化和/或肝功能失代偿,确保HBV DNA持续阴转和ALT复常
长期治疗目标(the long-term goal)
防止肝炎复发及所导致的肝功能失代偿,防止进展为肝硬化和肝癌,最终延长生存期Asian-Pacific consensus update. J Gastroenterol and Hepatol (2003)18,239–245关键问
(1) 关键问题(1) 第一线抗病毒治疗用什么药?
HBeAg+ 病人
HBeAg- 病人
治疗反应的预测目标?
联合治疗的作用?
关键问题(2) 关键问题(2) 如何延迟耐药发生?
如何监测病人耐药?
如何处理病人耐药?
第一部分: HBeAg+慢乙肝第一部分: HBeAg+慢乙肝
HBeAg+慢乙肝的自然史
HBeAg+ 病人治疗有效的标志?
HBeAg+ 病人治疗最终目标?
HBeAg+ 病人第一线抗病毒治疗药物?
HBeAg+ 病人的联合治疗
nullStages of Chronic HBV InfectionAdapted from Fattovich. Sem Liver Dis 2003HBeAg+ 病人治疗有效的标志?HBeAg+ 病人治疗有效的标志?HBeAg血清转换
是HBeAg+ 病人治疗有效的标志
HBeAg血清转换与以下指标有关
HBVDNA 水平下降
ALT复常
疾病进展危险因素降低HBeAg+ 病人治疗最终目标HBeAg+ 病人治疗最终目标HBeAg+ 病人治疗最终目标是
HBsAg消失/血清转换(很少或迟发出现)
cccDNA根除的非现实性和非必要性?HBeAg+ 病人第一线抗病毒治疗药物 (ALT> 2ULN)HBeAg+ 病人第一线抗病毒治疗药物 (ALT> 2ULN)APASL2005
ALT 2-5ULN 干扰素,拉米夫定或阿德福韦
ALT > 5ULN 拉米夫定或阿德福韦
EASL2003
最初治疗考虑干扰素,若干扰素不适用或疗效不佳,用拉米夫定或阿德福韦
AASLD2004
拉米夫定或阿德福韦或干扰素
Off-therapy HBeAg Response with Conventional IFN for HBeAg-positive CHBOff-therapy HBeAg Response with Conventional IFN for HBeAg-positive CHB1. Di Bisceglie et al. Am J Gastroenterol 1993; 2. Fattovich et al. J Hepatol 1989;
3. Yalcin et al. Clin Infect Dis 2003; 4. Thomas et al. J Viral Hepat 1994; 5. Cooksley et al. J Viral Hepat 2003;6. Lok et al. Lancet 1988; 7. Lok et al. Gastroenterology 1992; 8. Yuen et al. Hepatology 2001* Intent-to-treat analysesMeta-analysis of Results of Conventional IFN TherapyMeta-analysis of Results of Conventional IFN Therapy1.81217337.837010203040HBsAgseroconversionHBeAglossHBV DNA<106 cp/mLIFN-treated Untreated controlsMainly patients infected with HBV genotype A% of patientsWong et al. Annals Int Med 1993HBeAg Seroconversion 24 Weeks After the End of Treatment (Week 72) HBeAg Seroconversion 24 Weeks After the End of Treatment (Week 72) 32%19%Patients with
HBeAg seroconversion (%) PEGASYS
+ placeboPEGASYS
+ lamivudinelamivudine27%n=271n=271n=272P=0.232 (OR = 0.8)P=0.023 (OR = 1.6)P<0.001 (OR = 2.0)Lau et al. AASLD 2004 HBeAg Seroconversion Rates Over TimeHBeAg Seroconversion Rates Over TimeOn-treatmentFollow-upStudy weekHBeAg Seroconversion (%)27%24%20%32%27%19%PEGASYS + placebolamivudinePEGASYS
+ lamivudineP=0.023P<0.001Lau et al. AASLD 2004 null52 weeks
end of therapy010203040 50PEG-IFN -2bPEG-IFN -2b + Lam %HBeAg loss (HBeAg消失)29%44%P=0.0178 weeks
end of follow-up36%35%P=0.91Janssen et al. Lancet 2005(n=136)(n=130)(n=136)(n=130)Pegylated IFN 治疗反应预示因素 Pegylated IFN 治疗反应预示因素 低病毒负荷
高ALT水平
基因型ADC
以前未用过干扰素
nullALT升高者贺普丁®治疗5年HBeAg血清转换率 Guan et al, J Gastro Hepatol 2001 (Abstr)27375456633842656977025507510012345疗程 (年)病人(%)ALT >1xULN (n=41)ALT >2xULN (n=26)血清转换 = HBeAg阴性+HBeAb阳性HBeAg 应答的持久性
在不同病人群中的HBeAg血清转换率HBeAg 应答的持久性
在不同病人群中的HBeAg血清转换率* HBeAg loss837787*67020406080100病人比例 (%)20/2330/3930/36189/283中位随访
(范围) 月:拉米夫定(亚洲人)(Leung et al 2001)拉米夫定(白种人)(Willems et al 2001)干扰素(Korenman et al 1991)自发 (Hsu et al 2002)19.6 (6–36)36.6 (5–46)51.6 (36–84)103.2 (12–221)nullLamivudine Maintenance Therapy in Patients with CirrhosisDisease progressionHCCIncreased
Child-Pugh score% of patients% of patients% of patientsPlacebo
n=215Lamivudine
n=436Liaw et al. N Eng J Med 2004Years123However, response compromised by development of resistancenullWild type (n=221)YMDD mutants (n=209) (49%)Time after randomisation (months)0510152025061218243036Time to Disease Progression
According to YMDD Mutant StatusPatients with disease progression (%)Placebo (n=215)5%13%21%Liaw et al. N Eng J Med 2004贺维力治疗HBeAg阳性CHB:
长期疗效总结贺维力治疗HBeAg阳性CHB:
长期疗效总结Marcellin P et al. 2004 AASLD; Abstract 1135ALT 复常HBV DNA < 3 log copies/mlHBeAg阴转HBeAg 血清转换(PCR
< 1000 copies/mL)3年治疗停止贺维力®治疗后
HBeAg血清转换(HBeAg-/HBeAb+)的持久性*停止贺维力®治疗后
HBeAg血清转换(HBeAg-/HBeAb+)的持久性*HBeAg-/HBeAb+
n=60HBeAg+/HBeAb-
n=4†
HBeAg-/HBeAb-
n=2† 91%3%6%0102030405060708090100Chang et al J Hepatol (abst); 2004* 停止贺维力®治疗的时间中位数:55 周 (范围:5-114周)
† 未持续血清转换的所有患者(n=6) 均为C基因型发生YMDD变异的患者在LAM基础上加
贺维力®或转为单用贺维力®
HBV DNA数据发生YMDD变异的患者在LAM基础上加
贺维力®或转为单用贺维力®
HBV DNA数据 Peters MG et al, Gastroenterology 2004;126: 91-101* 与拉米夫定比较p<0.001 贺维力® +LAM* (n=20)
贺维力® (n= 19)*
LAM (n=19)疗程(周)081624324048HBV DNA改变
(log10 copies/mL)0.0- 3.6- 4.0Entecavir in the Treatment of Patients
With HBeAg-positive CHBChang et al. AASLD 2004Entecavir in the Treatment of Patients
With HBeAg-positive CHB*<400 cp/mLEntecavir vs Lamivudine in the Treatment of Patients with HBeAg-positive CHBEntecavir vs Lamivudine in the Treatment of Patients with HBeAg-positive CHBChang et al. AASLD 20045021%18%010203040n=354n=355P=NSHBeAg seroconversion (%) 10-6.98 log10-5.46 log10-8-7-6-5-4-3-2-10012243648Week***HBV DNA by PCR (log copies/mL)10-6.98 log10-5.46 log10-8-7-6-5-4-3-2-10012243648Week*** * P<0.0001 for each comparison on-treatmentHBV DNA suppression阿德福韦相关突变在HBV多聚酶序列中的位置阿德福韦相关突变在HBV多聚酶序列中的位置末端蛋白间隔区逆转录酶RNase HFGACDEB1344YMDD
M204V or IA181VN236T拉米夫定耐药
突变V173L
L180M与HBsAg 读码区重叠阿德福韦相关sL173FHBV 交叉耐药(体外)HBV 交叉耐药(体外)LAM
ETV
LdT
FTC
ADVV173L L180M A181V A184G S202I M204I M204V N236T M250VYMDD突变株的选择可能会影响将来的治疗选择AASLD,2004第二部分: HBeAg-慢乙肝
第二部分: HBeAg-慢乙肝
HBeAg-慢乙肝定义
HBeAg-慢乙肝的自然史
HBeAg-病人治疗有效的标志?
HBeAg-病人治疗最终目标?
HBeAg-病人第一线抗病毒治疗药物?
HBeAg+ 病人的联合治疗
HBeAg-慢乙肝定义HBeAg-慢乙肝定义HBsAg +
HBeAg-(常有抗-HBe)
HBVDNA104-105 拷贝/ml 或非PCR检测呈阳性(持续性或间歇性)
ALT水平升高(持续性或间歇性)
慢乙肝组织学改变
HBeAg-慢乙肝的自然史HBeAg-慢乙肝的自然史在欧洲60%-90%
慢乙肝自然史后阶段
特征
ALT和HBVDNA 波动
自发性持续缓解差异大
快速进展为肝硬化 每年8-10%HBeAg-慢乙肝病毒基因异质性 HBeAg-慢乙肝病毒基因异质性 前C区终28 (1896位点突变)
核心区启动子TA(1762/1766)突变
起始密码子突变
野生型HBV
病毒血症时出现野毒株变化和波动
A- F基因型地理分布不同
HBeAg阴性乙肝的临床特点HBeAg阴性乙肝的临床特点F. Bonino, M.R. Brunetto Journal of Hepatology 39 (2003) S160–S163HBeAg阴性乙肝的典型病例HBeAg阴性乙肝的典型病例HBeAg-慢乙肝治疗目标 HBeAg-慢乙肝治疗目标 防止进展为肝硬化及其并发症 肝衰竭 HCC 肝病相关性死亡
持续抑制HBV复制 HBVDNA 104 拷贝/ml和持续ALT正常
HBeAg-病人治疗最终目标?HBeAg-病人治疗最终目标?HBsAg清除和抗-HBs血清转换Current Treatment Guidelines
for HBeAg-negative CHBCurrent Treatment Guidelines
for HBeAg-negative CHB1. EASL Consensus Statement. J Hepatol 2003 (EASL Guidelines); 2. Liaw et al. J Gastroenterol Hepatol 2003 (APASL Guidelines); 3. Lok, McMahon. Hepatology 2004 (AASLD Guidelines)Long-term therapy required (≥12 months) and optimal duration of therapy is unknown1–3
First Line Therapy:
EASL = IFN 1
APASL = IFN or lamivudine 2*
AASLD = IFN, lamivudine or adefovir 3**
End point of treatment:
Sustained ALT normalisation + undetectable HBV DNA by PCR 3** IFN or adefovir are preferred due to need for long-term treatment* IFN has better sustained response than lamivudineIFN Therapy for
HBeAg-negative CHB4.5–13%HBsAg loss (EOF)2,4,527%Long-term (72 m post-Rx)56–33%Sustained response (EOF)1,2,428–69%Undetectable HBV DNA and ALT normalisation (EOT)1–41. Lampertico et al. Hepatology 1997; 2. Oliveri et al. Am J Gastroenterol 1999; 3. Brunetto et al. J Hepatol 2002; 4. Manesis, Hadziyannis. Gastroenterology 2001; 5. Papatheodoridis et al. J Hepatol 2001Treatment duration: 4–24 months
Dose range: 6–10 MIU tiwIFN Therapy for
HBeAg-negative CHBConventional IFN: Combined Response
6 Months After the End of TreatmentConventional IFN: Combined Response
6 Months After the End of TreatmentPatients with
combined response (%) 22%Lampertico‡
Treatment for 24 months*HBV DNA = ‡ <~300,000 cp/mL;
¶ <20,000 cp/mL33%Combined ALT normalisation and HBV DNA suppression*Various small studies§
Treatment for 2–24 months§Average combined response rate from 11 small studies reported in Manesis and Hadziyannis, Gastroenterology 2001 (duration of treatment 2–24 months) nullPatients (%) n=177n=179n=18143%29%44%P=0.849P=0.003P=0.007PEGASYS
+ placeboPEGASYS
+ lamivudinelamivudine* HBV DNA response defined as <20,000 cp/mLHBeAg-negative CHB:
Co-primary Endpoint HBV DNA Response* 24 Weeks After End of Treatment (Week 72)
Marcellin et al. N Eng J Med 2004null19%20%7%Patients (%) PEGASYS
+ placeboPEGASYS
+ lamivudinelamivudinen=177n=179n=181P=0.909P<0.001P<0.001HBeAg-negative CHB:
HBV DNA <400 Copies/mL24 Weeks After End of Treatment (Week 72)
Marcellin et al. N Eng J Med 2004HBeAg-negative CHB:
Mean HBV DNA Levels Over Time HBeAg-negative CHB:
Mean HBV DNA Levels Over Time Study weekOn-treatmentFollow-upMean HBV DNA (log10 cp/mL)234567061218243036424854606672– 4.1*– 5.0*– 4.2*– 1.6*– 2.4*– 2.3** Change in HBV DNA from baseline Marcellin et al. N Eng J Med 2004null36%38%23%Patients (%) PEGASYS
+ placeboPEGASYS
+ lamivudinelamivudinen=177n=179n=181*Combined response defined as ALT normalisation and HBV DNA <20,000 cp/mLHBeAg-negative CHB: Combined Response* 24 Weeks After End of Treatment (Week 72)
Marcellin et al. N Eng J Med 2004HBV基因型对IFN治疗反应的影响 HBV基因型对IFN治疗反应的影响 HBV基因型可影响IFN 和PegIFN治疗的病人持续的病毒学反应,包括HBeAg+/- 病人
SVR以基因型A 和B 最高,D最低
南欧HBeAg-病人基因型D呈高度流行 HBeAg-慢乙肝病人干扰素治疗局限性 HBeAg-慢乙肝病人干扰素治疗局限性 长期干扰素治疗与病人耐受性和安全性有关
25%病人由于副作用而中止治疗
20%病人剂量减量
IFN在进展性肝病中的不宜应用
即使长期治疗仍有2/3病人不能达到持续反应
应用pegIFN长期结果仍有争论
Proportion of HBeAg-ve patients with normal ALT and negative HBV DNAProportion of HBeAg-ve patients with normal ALT and negative HBV DNATotal: N= 74 67 69 73 66 66 67 68 61 47 21 1467%51%34%29%Esteban et al, AASLD 2001: Abstract 1097YMDD mutants: 39% 54% 57%Histological Response in HBeAg(-) CHB
with lamivudine therapyHistological Response in HBeAg(-) CHB
with lamivudine therapyEsteban et al, AASLD 2001: Abstract 1097Fibrosis Stage贺维力治疗HBeAg阴性CHB :
总Knodell评分自基线的改变
(96周肝活检病例)贺维力治疗HBeAg阴性CHB :
总Knodell评分自基线的改变
(96周肝活检病例)2年治疗贺维力治疗HBeAg阴性CHB : HBV DNA 阴转率和ALT复常率贺维力治疗HBeAg阴性CHB : HBV DNA 阴转率和ALT复常率HBsAg loss was observed in 4/125 (3.2%) of patients by Week 192
Kaplan Meier estimates77%010203040506070809010077%77%48周 96周192周63%0102030405060708090100患者(%)144周Hadzyannis et al J Hepatol 2005;42(suppl 2):17873%83%88%91%LLQ< 1,000 copies/mLHBV DNAALTResponses after Discontinuation of
Adefovir in HBeAg-negative CHBResponses after Discontinuation of
Adefovir in HBeAg-negative CHB* HBV DNA <1000 copies/mLHadziyannis. AASLD Oral 2003Patients (%)ALT normalisationWeeks32%8%HBV DNA response*Adefovir 10 mg qd31%5%0%10%20%30%40%50%60%70%80%90%100%0481224364860728496Entecavir in the Treatment of Patients
With HBeAg-negative CHBShouval et al. AASLD 2004*<400 cp/mLEntecavir in the Treatment of Patients
With HBeAg-negative CHB‡ HBV DNA <0.7 MEq/mL by bDNA and ALT <1.25 x ULNOn-treatment Response to Nucleos(t)ide Analogue Therapy for HBeAg-negative CHBOn-treatment Response to Nucleos(t)ide Analogue Therapy for HBeAg-negative CHB* Measured by PCR assays with varying lower limits of detection; N/A = not availableAASLD Guidelines Lok, McMahon. Hepatology 2004; Shouval et al. AASLD 2004HBeAg-病人联合治疗 HBeAg-病人联合治疗 核苷或核苷酸类似物+(peg)IFN 可增加抗病毒效果, 但没有提高SVR
核苷或核苷酸类似物联合应用 可增加抗病毒效果,长期效果仍需进一步评价
联合治疗可推迟耐药性发生
第三部分: 耐药问题 第三部分: 耐药问题 如何延迟耐药发生?
如何监测病人耐药?
如何处理病人耐药?
耐药的临床后果
耐药的临床后果
临床效果下降
HBeAg血清转换下降
组织学改善降低
疾病进展率增高
肝硬化病人病情严重加剧
肝移植病人移植失败或死亡
公共卫生潜在问题
耐药株的转移
HBsAg基因突变导致疫苗接种失败 如何延迟耐药发生 如何延迟耐药发生 选择耐药发生率低的药物
改善依从性和治疗间断
联合治疗效益需进一步评估
延迟耐药首选治疗
延迟耐药首选治疗方案 代偿性肝病
单一药物治疗 ADV-LAM-PEG-IFN
良好的治疗反应 PEG-IFN;
长期治疗选择ADV
肝硬化病人,失代偿肝病或肝移植病人
联合治疗 ADV+LAM 药物耐药监测 药物耐药监测 血清HBVDNA是最有使用价值的指标
应用敏感的PCR检测方法
在治疗期间用相同的检测方法检测
根据下列情况决定检测频率
疾病严重性
轻度肝病:每6个月
进展性肝病/肝硬化:每3个月
药物耐药谱
阿德福韦治疗可减少监测频率
药物耐药性诊断 药物耐药性诊断 治疗失败的界限
病毒复制反弹1.0log, 相对应的是抗病毒治疗
下降至最低点
排除非HBV相关的原因
坚持治疗
个体代谢因素
HBV突变株耐药测定
鉴定突变有助于指导进一步治疗(交叉耐药) 耐药处理(1)
--------如何选择一种新的药物
耐药处理(1)
--------如何选择一种新的药物
根据耐药特性
体外
型测定
组织培养中药物敏感型测定
根据临床效果特征
ADV:对LAM耐药株所有类型均有效
LAM:对N236T 突变株有效
ETV:对LAM-R突变株需要双倍剂量
ETV耐药发生率一年为7.4% 耐药处理(2)
----------联合治疗原则 耐药处理(2)
----------联合治疗原则 大多数病人需要长期治疗
LAM+pegIFN 最大限度抑制病毒 减少LAM耐药发生 不增加治疗后反应
核苷或核苷酸类似物联合
一些药物联合可提高抗病毒作用
可减少或延迟耐药性发生
需进一步评估