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1 B 型肝炎治療的臨床實務劉俊人台大醫學院臨床醫學研究所台大醫院內科部暨肝炎研究中心 Features of CHB In Asia 75% in Asia Chronic hepatitis B virus infection: > 35 million chronic carriers globally Perinatally acquired HBV infection Prolonged immune tolerance phase Current guidelines recommend treatment initiation in patients with specified viral load and ALT >2 x ULN, or with moderate/severe hepatitis on biopsy 1

2 國人每年因肝病而死亡者肝癌 : 約七千人肝硬化 : 約四千人肝炎及其他 : 約一千人合計 : 一萬二千人急性 HBV 感染新生兒或嬰兒不明顯症狀復原 ( < 1%) 3-% 慢性肝炎 2%/yr 肝硬化 3-1%/yr 慢性感染 ( > 9%).8%/yr 肝癌 6-7% 不活動帶原者不活動帶原者.1%/yr 2

3 肝病三部曲慢性肝炎肝硬化肝細胞癌肝臟纖維化正常 No fibrosis 第一級 Portal fibrosis Few septa 第二級第三級 Numerous septa Cirrhosis 第四級 Downloaded from Clinical Care Options 3

4 肝病三部曲 - 肝細胞癌肝發炎肝纖維化及再生會伴隨肝細胞變性慢性肝炎肝硬化肝細胞癌染色體變異肝細胞變性分化良好肝癌分化不良肝癌葉等,Gastroenterology 1 慢性 B 型肝炎之致病機轉病毒蛋白質 ( 抗原 ) 造成肝發炎壞死修復過程形成肝纖維化感染時間越久, 病程進展越嚴重病毒濃度 ( 蛋白質抗原 ) 越高, 惡化機會越大 4

5 慢性 B 型肝炎之治療目標清除 / 壓抑病毒 * 減少致病原 * 減少傳染性減少肝發炎壞死 * 肝炎緩解 * 預防肝衰竭遏止病程進展 * 減少急性發作, 肝硬化和肝細胞癌改善存活率慢性 B 型肝炎之進展與介入性治療 HBeAg 陽性 3-1%/yr 肝細胞癌慢性肝炎 2%/yr 肝硬化死亡或肝移植 HBeAg 陰性 4-5%/yr 肝代償失調 5

6 慢性 B 型肝炎之進展與介入性治療干安能 / 干適能 / 貝樂克 / 喜必福 / 長效型干擾素輔助治療 HBeAg 陽性 3-1%/yr 肝細胞癌慢性肝炎 2%/yr 肝硬化死亡或肝移植 HBeAg 陰性 4-5%/yr 肝代償失調干安能 / 干適能 / 貝樂克 / 喜必福 / 長效型干擾素干安能 / 干適能 / 貝樂克 / 喜必福如何知道自己有無肝病肝功能檢查 B 型肝炎檢驗 C 型肝炎檢驗甲種胎兒蛋白檢查腹部超音波檢查 6

7 臨床上需積極接受治療者 HBe 抗原陽性之慢性 B 型肝炎 :ALT > 2 倍正常值上限, 且 HBV DNA >, IU/mL ( 或 1, copies/ml) HBe 抗原陰性之慢性 B 型肝炎 :ALT > 2 倍正常值上限, 且 HBV DNA > 2, IU/mL ( 或 1, copies/ml) 肝硬化 :HBV DNA > 2, IU/mL ( 或 1, copies/ml) 肝臟移植前後接受化學藥物治療之癌症 B 型肝炎帶原者慢性 B 型肝炎之治療藥物傳統型干擾素長效型干擾素佩格西施 (Pegasys) 干安能 (lamivudine) 干適能 (adefovir dipivoxil) 貝樂克 (entecavir) 喜必福 (telbivudine) 惠立妥 (Tenofovir) 7

8 慢性 B 型肝炎之治療指標短中期指標清除 / 壓抑病毒 e 抗原消失 e 抗體出現 s 抗原消失減少肝發炎壞死長期指標遏止病程進展減少肝硬化和肝細胞癌改善存活率治療 1 年後病毒量下降之比率 *Collation of currently available data not head-to-head comparison 8 e 抗原陽性 B 肝 1 e 抗原陰性 B 肝 HBV DNA undetectable (% patients) 貝樂克喜必福干安能干適能珮格西施 *Undetectable <3 copies/ml #Undetectable < copies/ml LaiCL,etal. Hepatology 5;42(Suppl1):748A (abstractlb1);lau G, et al. NEJM 5; 352: ; Chang T-T, et al. NEJM 6; 354:1 11; Lai CL, et al. NEJM 6; 354:111 1; Marcellin P, et al. NEJM 3;348:88 816; Marcellin P, et al. NEJM 4;348: ; Hadziyannis SJ, et al. NEJM 3;348:8 87 8

9 治療一年後之 HBe 抗原轉換率 HBe 抗原轉換 = HBe 抗原轉陰和 HBe 抗體轉陽 *Not head-to-head comparison HBe eag seroconversion (% patients) 貝樂克喜必福干安能干適能珮格西施 Lai CL, et al. Hepatology 5; 42:748A (AASLD abstract LB1). Lau G, et al. NEJM 5; 352: Chang T-T, et al. NEJM 6; 354:1 11. Marcellin P, et al. NEJM 3;348: 治療 1 年後 ALT 正常之比率 1 e 抗原陽性 B 肝 1 e 抗原陰性 B 肝 ALT normalisation (% patients) 貝樂克喜必福干安能 38 干適能珮格西施 Lai CL, et al. Hepatology 5; 42(Suppl 1):748A (abstract LB1); Lau G, et al. NEJM 5; 352: ; Chang T-T, et al. NEJM 6; 354:1 11; Lai CL, et al. NEJM 6; 354:111 1; Marcellin P, et al. NEJM 3;348:88 816; Marcellin P, et al. NEJM 4;348: ; Hadziyannis SJ, et al. NEJM 3;348:8 87; 9

10 Patients (%) Increasing rates of HBeAg seroconversion after EOT with Peg-IFN therapy 27% 32% 43% 48% EOT 24 wks after EOT 36 wks 48 wks Lau, Piratvisuth et al. AASLD 6 3-yr ETV in HBeAg-neg CHB Treatment cohort: Virological response ETV-27 ETV-91 Propo ortion of patients (%) HBV DNA <3 copies/ml % Off-treatment >6 days 4% 59% 83% 93% 94% 91% 95% EOD Baseline Wk 12 Wk 24 Wk 48 Wk 72 Wk 96 Wk 144 n= 93/99 4/99 56/95 79/95 84/9 72/77 67/74 54/57 EOD= end-of-dosing 1 patients who remained on treatment at the Week 144 of ETV-91 visit had missing PCR samples D. Shouval et al, AASLD 8 1

11 5-yr ETV for HBeAg-positive CHB Virological response ETV-22 HBeAg(+) Baraclude Long-term Cohort (ETV-22 ETV-91) Prop portion of patients (%) HBV DNA <3 copies/ml Year 1 67% Year 1 Year 2 Year 3 89% Year 4 91% 83% 55% Year 5 94% n = 236/354 8/ /1 116/131 98/18 88/94 * Different dosing regimen for naïve patients in the 91 study Five patients who remained on treatment at the Year 5 visit had missing PCR values (NC=M). Han S, et al. 59 th AASLD, October 31-November 4,8, San Francisco, USA. Poster year TDF in HBeAg-negative patients with CHB: HBV-DNA < cp/ml On-Treatment Analysis (Observed; missing=excluded/addition of FTC = included) 99% 99% 8 oportion of Subjects (%) Pro TDF-TDF ADV-TDF Weeks on Study Marcellin et..al; AASLD 11 Gilead on-file 11

12 1 5-year TDF in HBeAg-positive patients with CHB: HBV-DNA < cp/ml On-Treatment Analysis (Observed; missing=excluded/addition of FTC = included) 1% % Proportion of Subjects (%) PTDF-TDF 3 ADV-TDF Marcellin et.al; AASLD 11 Gilead on-file Weeks on Study 5-year TDF in HBeAg-positive patients with CHB: HBeAg Loss and Seroconversion 1 5 HBeAg Loss 45 HBeAg Seroconversion 35 % Patients Study Week 1 On treatment analysis, Missing = Excluded / Addition of FTC included Marcellin et.al; AASLD 11 Gilead on-file 12

13 慢性 B 型肝炎之治療指標短中期指標清除 / 壓抑病毒 e 抗原消失 e 抗體出現 s 抗原消失減少肝發炎壞死長期指標遏止病程進展減少肝硬化和肝細胞癌改善存活率 Short course of IFN therapy: Reduces cirrhosis in HBeAg-positive cases 11-year follow-up in Asian patients treated for weeks with IFN ) Cumulativ ve incidence of cirrhosis (%) 5 3 Untreated control P=.41 IFN Months Non-seroconverters in control group P=.31 vs. P=.23 vs. Non-seroconverters in IFN group Seroconverters in control group Seroconverters in IFN group Months Lin SM, et al. J Hepatol 7 13

14 Short course of IFN therapy: Reduces HCC 11-year follow-up in Asian patients treated for weeks with IFN tive incidence of HCC (%) Cumulat 7 6 Control: cirrhosis 5 Untreated control P= P=.11 IFN: cirrhosis --- Control: no cirrhosis IFN IFN: no cirrhosis Months Months Lin SM, et al. J Hepatol 7 Direct correlation between a decrease in viral load and improved histology following antiviral therapy 4 Median histolo ogical activity index improvement from baseline r 2 =.96 p< Median log 1 HBV DNA level decrease from baseline 2 Adapted from Mommeja-Marin H, et al. Hepatology 3;37:

15 Long-Term Efficacy: Improvements in Liver Histology with Long-Term ETV 6 Time Patients (n) 5 Ishak fibrosis score Missing Baseline Week 48 Long-term cohort* * Median time of long-term biopsy: 6 years (range: 3 7 years); all patients achieved undetectable HBV DNA (<3 copies/ml) at the time of long-term biopsy. Chang TT, et al. Hepatology 1;51:422 3 Severity 5-year TDF treatment in patients with CHB Fibrosis scores over time nts Per rcentage of Patie 1% 9% 8% 7% 6% 5% % 3% % 1% Baseline Year 1 Year 5 Ishak Fibrosis Score N=348 patients 344/348 patients had liver biopsy data available at all three time points Percentage of the population with cirrhosis (Ishak Score 5) progressively decreased from 28% at baseline to 8% at Year 5 Marcellin P et al, AASLD 11, poster #

5-year TDF treatment in patients with CHB: Changes of fibrosis in cirrhotics Chan nge from Baseline in

cirrhosis (Ishak fibrosis score 5) had paired BL and Year 5 biopsies 74% (n=71) of patients had

5; 25% (n=24) did not change Of 94 patients who did not add FTC, 73% had cirrhosis reversed; 26% showed

16 5-year TDF treatment in patients with CHB: Changes of fibrosis in cirrhotics Chan nge from Baseline in Fibros sis Score n = 15 n = 41 n = 14 n = 1 n = 24 n = 1 96 patients with cirrhosis (Ishak fibrosis score 5) had paired BL and Year 5 biopsies 74% (n=71) of patients had cirrhosis reversed (Ishak fibrosis score <5) at Year 5, and 73% (n= 7) had decreases of 2 points at Year 5; 25% (n=24) did not change Of 94 patients who did not add FTC, 73% had cirrhosis reversed; 26% showed no change Marcellin P et al, AASLD 11, poster # 台灣地區主要死因死亡人數 National Taiwan University Hospital 行政院衛生署 16

17 台灣地區歷年死亡率 ( 每 1 萬人口 ) IFN-α LAM ETV TBV TDF Vaccine 行政院衛生署 Incidence of HBV-related LC 3 Male Female National Health Insurance database Taiwan 17

Taichung Veterans General Hospital; 3 Division of gastroenterology, National Taiwan University Hospital; 3 Graduate institute of clinical

18 Chun-Ying Wu 1,2, Hsiu J. Ho 3, Yao-Chun Hsu 4, Ken N. Kuo 5,6, Ming-Shiang Wu 3, Jaw-Town Lin* 4,6 1 Faculty of medicine, National Yang Ming g University; 2 Division of gastroenterology, Taichung Veterans General Hospital; 3 Division of gastroenterology, National Taiwan University Hospital; 3 Graduate institute of clinical medicine, China Medical University; 4 Department of internal medicine, E Da Hospital & I Shou University 5 Taipei Medical University 6 School of Medicine, Fu Jen Catholic University HCC recurrence and overall survival NNT=12 NNT=8 18

19 選擇那一個藥? 打針或吃藥? Factors Affecting Selection of Antiviral Therapy Nucleos(t)ide Analogues Peginterferon Safety & tolerability Barrier to resistance & durability Efficacy (potency) Finite duration & durability Efficacy (potency) Safety & tolerability 19

20 IFNα 之作用機轉 Interferon -alfa 免疫調節 Antigen presenting cell Cytotoxic T cell T helper cell 抗病毒 B cell Natural killer cell 干擾素療法 : 摘要有效率 3-%, 復發率低 5-1% 較無效者 : 病毒量高,ALT 低無效者 : 免疫耐受期長期效果 : 減少肝硬化和肝癌副作用 : 常見, 但多可忍受可選擇合適患者來治療 Pegasys 18 mcg/wk, weeks IFN 5-1 mu, 3x/wk, 4-6 months

21 和干擾素療效有關之因素低 HBV 病毒濃度病毒基因型 B 高 ALT 值和高肝炎活性未使用免疫抑制劑成年期感染新近感染 e 抗原陽性, 無 D 型肝炎感染女性口服抗病毒療法 : 摘要對 HBe 抗原陽性和陰性患者均有效 HBe 抗原轉換率與治療前 ALT 值有關長期使用可能有抗藥性, 抗藥性和治療期間有關, 少數會發生急性發作甚至肝衰竭, 要小心新一代口服藥 ( 貝樂克和惠立妥 ) 抗藥性發生機會很低, 推薦使用只能抑制病毒, 無法根除 cccdna, 停藥後易復發目前建議長期治療以避免復發長期影響尚待觀察 21

22 干擾素和口服抗病毒劑治療之比較干擾素口服抗病毒劑優點療程固定價格較便宜無抗藥株副作用少反應較持久口服使用缺點副作用多需長期治療價格較高長期使用後有抗藥性皮下注射反應較不持久選擇打干擾素基因型 B 病毒量低 ALT 高無其他嚴重疾病希望療程固定者不希望發生抗藥性考量結婚懷孕打針或吃藥? 選擇吃口服藥藥效強度貝樂克惠立妥最強抗藥性機會貝樂克惠立妥最低藥費干安能最低安全性 : 腎臟骨頭考量懷孕 : 喜必福惠立妥 22

23 Treatment of CHB - Second Decision- Lamivudine NUC Tenofovir Adefovir Entecavir Telbivudine Cumulative Rates of Resistance in Nucleos(t)ide-Naive Patients Not head-to-head trials; different patient populations and trial designs Drug Generation Yr 1 Yr 2 Yr 3 Yr 4 Yr 5 Yr 6 1st LAM 24% 38% 49% 67% 7% 2nd 3rd ADV LdT ETV TDF % 3% 11% 18% 29% 4% 17%.2%.5% 1.2% 1.2% 1.2% 1.2% % % % % % % EASL. J Hepatol. 9;5: Tenny DJ, et al. EASL 9. Abstract. Marcellin P, et al. AASLD 9. Abstract 481. Heathcote E, et al. AASLD 9. Abstract

24 Respon nse at Wk (%) Selection of Entecavir vs Tenofovir in NUC-naïve Patients: Similar Antiviral Activity HBeAg seroconversion 2 3 HBsAg loss HBeAg Positive Entecavir Tenofovir < 1 HBsAg loss HBeAg Negative Log HBV DNA at Wk Entecavir Tenofovir HBeAg positive HBeAg negative Genotypic resistance, % NUC naive 1.2 (Yr 5) (Yr 3) Lamivudine experienced 51 (Yr 5) NR Pregnancy rating Class C Class B AEs None Renal toxicity; BMD Lok AS. Hepatology. 1;52: Efficacy of Entecavir vs. Tenofovir in the Setting of NUC Resistance: Efficacy differs Activity it According Entecavir Tenofovir to Resistance LAM/LdT resistance Decreased Active ETV resistance -- Active ADV resistance Active Decreased TDF resistance Active -- Lok AS. Hepatology. 1;52:

25 使用口服抗病毒藥物之建議治療終點 ( 停藥時機 ) e 抗原陽性慢性 B 型肝炎 e 抗原陰轉病毒量測不到鞏固療法一年 e 抗原陰性慢性 B 型肝炎連續一年病毒量測不到 ALT 正常 ( 歐美 : 表面抗原消失 ) 1. AASLD. Lok & McMahon. Hepatol 9 2. EASL. EASL Jury. J Hepatol APASL. Liaw, et al. Hepatology Int 12 全民健保慢性 B 型肝炎藥物治療建議流程 - 更新版 ( ) HBsAg (+) 6 個月 HBeAg (+) >3 個月 ALT 5x 2x ALT< 5x And 肝組織切片 HBcAg (+) 或 HBV DNA IU/mL 已發生肝代償不全 (PT 3 秒或 Bil 2mg/dl) HBeAg (-) >3 個月半年內 2 次以上 ALT 2x ( 每次間隔 3 個月 ), And 肝組織切片 HBcAg (+) 或 HBV DNA IU/mL 慢性 B 型肝炎病毒感染者, 接受器官移植後發作者可長期使用接受肝臟移植者, 可預防性使用癌症化學治療後發作 B 型肝炎者, 經消化系專科醫師同意後可長期使用癌症化學治療前預防 B 型肝炎發作者, 經消化系專科醫師同意後 LAM/ETV/LdT /TDF 12 to 36M IFN 4 to 6M Pegasys 6M LAM/ETV/LdT/TDF 12 to 36M LAM/ETV/LdT/TDF 12 to 36M IFN 4 to 6M Pegasys 12M LAM/ETV/LdT/TDF (Pre-C/T to 6m after end-of-c/t) 25

26 全民健康保險慢性 B 型肝炎藥物治療建議流程 (2) (1) 抗藥性 : 治療中病毒量與最低點相比增加 1 倍干安能加干適能合併使用 36 個月貝樂克 (1mg) 36 個月干擾素 12 個月 (2) 第二次治療第一次使用干擾素口服藥或干擾素第一次使用口服藥干擾素或口服藥 (3) 治療結束後追蹤過程中發生肝功能代償失調馬上使用口服藥修正版 (3) 肝硬化病患, 可長期使用 Lamivudine;Entecavir (.5mg);Telbivudine;Tenofovir 肝硬化條件為需同時符合下列二項條件 : ( 一 ) HBsAg (+) 且血清 HBV DNA 2, IU/mL 者 ( 二 ) 診斷標準 : 1 肝組織切片(Metavir F4 或 Ishak F5 以上, 血友病患及類血友病患經照會消化系專科醫師同意後, 得不作切片 ); 或 2 超音波診斷為肝硬化併食道或胃靜脈曲張, 或超音波診斷為肝硬化併脾腫大 26

27 結論及未來方向慢性 B 型肝炎之治療仍有努力的空間長效型干擾素之適當療程減少停藥後復發是當前研究之重點發展更有效的口服抗病毒藥物和免疫調節劑合併療法是未來努力的方向, 但最佳之處方尚待發掘依宿主病毒和肝病狀況訂做個人化療法謝謝大家聆聽 27

提案一報告人：賴貞橞

提案一報告人：賴貞橞全民健康保險藥品給付規定修正規定第 10 章抗微生物劑 Antimicrobial agents 修正後給付規定 10.7. 抗病毒劑 Antiviral drugs 10.7.3 Lamivudine( 限使用 Zeffix tablets 100mg);Entecavir ( 如 Baraclude 0.5mg); Telbivudine ( 如 Sebivo 600mg):(92/10/1