2013-1-9 病毒性肝硬化的治療方針-final.ppt...

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病毒性肝硬化的治療方針治療方針

台大醫院內科部陳健弘陳健弘

2013-1-9

病毒性肝硬化的治療方針

B型肝炎導致的肝硬化(HBV-LC)型肝炎導致的肝硬化( )C型肝炎導致的肝硬化(HCV-LC)

酒精性肝硬化脂肪肝導致的肝硬化脂肪肝導致的肝硬化……

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Fibrosis scoreFibrosis score by pathology

Fibrosis METAVIR Ishak

N 0 0

Histologic Scoring Systems for Fibrosis

None 0 0Portal fibrosis (some) 1 1Portal fibrosis (most) 1 2Bridging fibrosis (occasional) 2 3Bridging fibrosis (marked) 3 4Incomplete cirrhosis 4 5Cirrhosis 4 6

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Assessing Liver Fibrosis: Ishak Staging Scale

Ishak Stage: Ishak Stage:Appearance Categorical Description Categorical Assignment

No fibrosis (normal) 0

Fibrous expansion of some portal areas ± short fibrous septa

Fibrous expansion of most portal areas ± short fibrous septa

1

2

Fibrous expansion of most portal areas with occasional portal to portal 3(P-P) bridging

Fibrous expansion of portal areas withFibrous expansion of portal areas with marked bridging (P-P as well as portal 4to central [P-C])

Marked bridging (P-P and/orP-C), with occasional nodules 5(incomplete cirrhosis)

Cirrhosis, probable or definite 6

Standish R, et al. Gut. 2006;55:569-578.

評估肝硬化的嚴重度評估肝硬化的嚴重度

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分數 1 2 3白蛋白 ≧3 5 2 8 3 4 <2 8

Child-Pugh classification

白蛋白 ≧3.5 2.8-3.4 <2.8膽紅素 <2 2-3 >3凝血酶原延長時間

1-3 4-6 >6

腹水無輕度中度以上腹水無輕度中度以上

肝昏迷無輕度中度以上

A級(第一期) ：5-6, B級(第二期)：7-9, C級(第三期)：10-15

3.8 X loge(膽紅素[mg/dL]) 11.2 X loge(INR,凝血酶原時間) 9.6 X loge(creatinine [mg/dL],肌酸酐,腎功能)

MELD score

9.6 X loge(creatinine [mg/dL],肌酸酐,腎功能)6.4 X (肝硬化的原因: 0 酒精性, 1 其他)

HEPATOLOGY 2001;33:464-470

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CompensatedStage 1: no varices, no ascitesStage 2: varices no ascites

Baveno IV staging of liver cirrhosis

Stage 2: varices, no ascitesDecompensatedStage 3: ascites ± varicesStage 4: variceal bleeding ± ascites

Franchis R. JH 2005;43:167–176

In Baveno IV, a session was devoted to predictive models in portalhypertension, during which classification stages of cirrhosis wereproposed. Prospective validation of this classification is under way.JH 2010;53:762–768

肝硬化的病人，

還可以活多久？

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Two-year survival rates of LC

D’Amico G et al., JH 2006;44:217–231

1-year outcome probabilities in LC

D’Amico G et al., JH 2006;44:217–231

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B型肝炎導致的肝硬化(HBV-LC)

治療B型肝炎的藥物

長效型干擾素 (Pegasys)

干安能 (lamivudine Zeffix LAM)干安能 (lamivudine, Zeffix, LAM)

干適能 (adefovir, Hepsera, ADV)

貝樂克 (entecavir, Baraclude, ETV)

喜必福 (t lbi di S bi LdT)喜必福 (telbivudine, Sebivo, LdT)

惠立妥 (tenofovir, Viread, TDF)

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B型肝炎肝硬化的B型肝炎肝硬化的治療指引

健保對於B型肝炎健保對於B型肝炎肝硬化的治療規定

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全民健康保險加強慢性B、C型肝炎治療試辦計畫

HBsAg(+)

肝硬化病患(1) HBsAg (+)且血清HBV DNA≧2 000IU/mL(1) HBsAg (+)且血清HBV DNA≧2,000IU/mL

+(2) 肝組織切片（Metavir F4或Ishak F5以上)

or超音波診斷為肝硬化併食道或胃靜脈曲張

or超音波診斷為肝硬化併脾腫大超音波診斷為肝硬化併脾腫大

可長期使用Zeffix(100mg) / Sebivo(600mg)

Baraclude(0.5mg) / Viread (300mg)

亞太肝病醫學會( S )對於(APASL)對於

B型肝炎肝硬化的治療指引治療指引

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Recommendation 4 When to start

Chronic HBV-infected patients with ALT ≧2 times ULN, andHBV DNA ≧ 2.0 x 104 IU/mL if HBeAg positive and ≧2.0 x

ti t ith103 IU/mL if HBeAg-negative as well as patients withadvanced fibrosis or cirrhosis with anyALT level should be considered for treatment (IA).

Treatment should be started as early as possible in case ofimpending or overt hepatic decompensation (IA)

2012 APASL guideline

impending or overt hepatic decompensation (IA).

Otherwise, 3–6 months’ observation is recommended toensure the need of therapy (IIA).

Indications are similar for retreatment.

ETV or TDF is the choice for patients with

Recommendation 13Patients with decompensated liver diseases

pimpending/ obvious hepatic decompensation(IA). LdT, LAM or ADV can also be used in Nuc-naïve patients (IB)

Renal function and lactic acidosis should bemonitored, especially in those with MELD score> 20 (IIIA)

• Start treatment as early as possible • IFN is usually contraindicated


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Liver cirrhosis

DecompensatedCompensatedConventional

supportive treatment

HBV-DNA<2x103 IU/ml

ALT ≥ 5x ULN

HBV-DNA≥2x103 IU/ml Antiviral therapyConsider transplant

ALT, HBeAg or HBV-DNA/3months

ETVTDF

treatment

Yes No

IFN basedETVTDF

ETVTDFHCC surveillance

AFP and ultrasonography/3-6months


歐洲肝病醫學會( S )對於(EASL)對於

B型肝炎肝硬化的治療指引治療指引

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PEG-IFN may increase the risk ofbacteraemic infection and hepaticd ti i ti t ith d d

Peg-IFN for liver cirrhosis

decompensation in patients with advancedcirrhosis. However, PEG-IFN in regimenssimilar to those used in CHB can be usedfor the treatment of well compensatedcirrhosis (A1).

2012 EASL guideline

Among NAs, monotherapies with tenofovir

NA (nucleoside/nucleotide analog)for liver cirrhosis

g , por entecavir are preferred because of theirpotency and minimal risk of resistance(A1). Lamivudine should not be used insuch patients.

2012 EASL guideline

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Prolonged and adequate suppression of HBVDNA can stabilize patients and prevent theprogression to decompensated liver disease

NA for liver cirrhosis

(A1).

Regression of fibrosis and even reversal ofcirrhosis have been reported in patients withprolonged suppression of viral replication.

Long-term monitoring for HCC is mandatorydespite virological remission under NA(s), sincethere is still a risk of developing HCC (B1).

2012 EASL guideline

NA therapy should usually be continuedindefinitely in cirrhotic patients. After at least12 months of consolidation therapy, treatment

NA for liver cirrhosis

py,might be stopped in HBeAg-positive patientsif they achieve confirmed anti-HBeseroconversion or ideally HBsAg loss andanti-HBs seroconversion and in HBeAg-negative patients if they achieve confirmedg p yHBsAg loss and anti-HBs seroconversion(B1).

2012 EASL guideline

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Patients with decompensated cirrhosisshould be treated in specialised liver units,as the application of antiviral therapy iscomplex, and these patients may becandidates for liver transplantation.Antiviral treatment is indicated irrespectiveof HBV DNA level in order to preventreactivationreactivation.

2012 EASL guideline

(PEG-)IFN is contraindicated in this setting.Entecavir or tenofovir should be used (A1).

–The licensed entecavir dose for patients with decompensated cirrhosis is 1 mg (instead of 0.5 mg for patients with compensated liver disease) once daily.

Drug choice for decompensated cirrhosis

compensated liver disease) once daily.

Lactic acidosis has been reported to develop insome NA, particularly entecavir, treated patientswith advanced decompensated cirrhosis (MELDscore >20). Clinical and laboratory parametersshould be closely monitored in this setting (A1).

The dose of all NAs needs to be adjusted inpatients with low creatinine clearance (<50ml/min) (A1). 2012 EASL guideline

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治療B型肝炎肝硬化治療B型肝炎肝硬化有什麼好處?

NAs improve Child-Pugh scores

in HBV-LC

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Improved CTP and MELD Scores in Decompensated CHB Patients Treated With ETV

12 20

ge in

CTP

Sco

re T

hrou

gh

12 M

os

8

6

4

P < .001

10

12

hang

e in

MEL

D S

core

Thro

ugh

12 M

os 16

12

10

P < .00118

20

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Shim JH, et al. J Hepatol. 2010;52:176-182.

Cha

ng 4

28.1 ± 1.7 6.6 ± 2.4

At 12 Mos

At Pretreatment

Ch

211.1 ± 3.8 8.8 ± 2.3

At 12 Mos

At Pretreatment

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ParameterWk 24 Wk 48

ETV-048: Improvement in MELD/CTP Scores

ParameterETV ADV ETV ADV

Mean MELD score change from BL (SE) -2.0 (0.45) -0.9 (0.46) -2.6 (0.62) -1.7 (0.50)

CTP score improvement or no worsening,* n/N (%)

66/100 (66)

65/91 (71) 61/100 (61) 61/91

(67)CTP score ≥ 2 point reduction,* n/N (%)

32/100 (32)

22/91 (24) 35/100 (35) 25/91

(27)

Liaw YF, et al. Hepatology. 2011;54:91-100.

CTP class improvement,†n/N (%)

25/93 (27)

22/81 (27)

35/93 (38)

29/81 (36)

*Noncompleter = failure.†CTP class C/B to A only.

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t ti t dretrospective studyfrom 2005HBV-associated cirrhosis18 centers in Turkey227 patients

Changes in CTP scores

KÖKLÜ S et al., CGH 2013;11:88–94

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NAs decrease fibrosis in HBV-LC

Chang TT et al., HEPATOLOGY 2010;52:886-893

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Knodell

ETV-long term treatmentDistribution of Knodell necroinflammatory scores at baseline, Year 1 and Years 3–7

0–34–67–910–14

MissingPatie

nts

(n)

20

30

40

50Knodell

Necroinflammatory Score

n=57

0

10

Baseline Week 48 Long-term** Median time of long-term biopsy: 280 weeks (range: 144–316 weeks).

100% of patients achieved HBV DNA <300 copies/mL in the long-term cohort


Ishak

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ETV Long term treatmentDistribution of Ishak fibrosis

scores at baseline, Year 1 and Years 3–7

Ishak fibrosis score

123456

Patie

nts

(n)

20

30

40

50

1

Missing0

n=57

10

Baseline Week 48 Long-term*0

* Median time of long-term biopsy: 280 weeks (range: 144–316 weeks).


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Liver biopsy after long-term ETV treatment


Marcellin P et al., Lancet 2013 in press

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Improvement of hepatic fibrosis after 5-year TDF

N=384Baseline cirrhosis: N=96

Marcellin P et al., Lancet in press

Improvement of hepatic fibrosis after 5-year TDF


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Impact of TDF on Liver Fibrosis at Year 5 for Subjects With Cirrhosis at Baseline

N=96

N=1N=24 N=1


N=15

N=41

N=14

NAs decrease decompensation rate

in HBV-LC

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NAs decrease decompensation rate in HBV-LC

Kim et al. JGH 2012;27:1589–1595

NAs improve survival in HBV-LC

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NA increases survival rate in HBV-LC

NANA

Historical control

Kim et al. JGH 2012;27:1589–1595

NA increases survival rate in HBV-LC

Kim et al. JGH 2012;27:1589–1595

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NAs decrease HCC incidence

in HBV-LC ?

Time to diagnosis of HCCDB treatment and off-treatment follow-up

Percentage with diagnosis

Placebo

P=0.047

10%

Placebo (n=215) Lamivudine (n=436)

Time to diagnosis (months)

Lamivudine

Excluding 5 cases in yr1: HR=0.47; P=0.052

5%

Liaw YF, et al. N Engl J Med 2004;351:1521-31

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NAs decrease HCC incidence in HBV-LC ?

Kim et al. JGH 2012;27:1589–1595

C型肝炎導致的肝硬化(HCV-LC)

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治療C型肝炎唯一有效的藥︰干擾素 + ribavirin

各式各樣的保肝片，都沒有實質療效。

Peg-Intron Pegasys

Rebetol Robetrol

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C型肝炎肝硬化的C型肝炎肝硬化的治療指引

健保對於C型肝炎健保對於C型肝炎肝硬化的治療規定

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ALT異常ALT異常Anti-HCV陽性HCV RNA陽性C 陽性

1.干擾素與Ribarvirn併用2.限ALT異常且Anti-HCV 與 HCV RNA均為陽性者或經由肝組織切片，證實纖維化 ≥F1及肝炎變化，且無肝功能代償不全


復發

無RVR但有EVR(早期病毒反應)

給付治療48週

有RVR(快速病毒反應)給付治療不超過24週

治療至12週未到達EVR者,應終止治療，治療期間不超過16週

復發定義：治療完成時血中偵測不到病毒發

附註:血友病患及類血友病患經照會消化系專科醫師同意後，得不做切片

治療完成時，血中偵測不到病毒，停藥後血中病毒又再次偵測到

第一次治療24週後復發者，可給予第二次治療，不超過48週

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亞太肝病醫學會( S )對於(APASL)對於

C型肝炎肝硬化的治療指引治療指引

10. Patients with compensatedcirrhosis but not decompensated

Treatment of HCV infection-chronic HCV infection

cirrhosis, but not decompensatedcirrhosis, can be considered fortreatment (I).

Hepatol Int 2012 6:409–435

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歐洲肝病醫學會( S )對於(EASL)對於

C型肝炎肝硬化的治療指引治療指引

(1) All treatment-naïve patients with compensateddisease due to HCV should be considered for

4.6. Indications for treatment: who should be treated?

therapy (A2).(2) Treatment should be initiated promptly in

patients with advanced fibrosis (METAVIRscore F3–F4), and strongly considered inpatients with moderate fibrosis (METAVIR

F2) (B2)score F2) (B2).(3) In patients with less severe disease, indication

for therapy is individual (C2).

2011 EASL guideline

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治療C型肝炎肝硬化治療C型肝炎肝硬化有什麼好處?

IFN treatment regress HCV-related

fibrosis

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Comparison of Liver Fibrosis Stage in patients of CHC reaching SVR

Maylin S. et al., GASTROENTEROLOGY 2008;135:821–829

Fibrosis improved in 56%, stable in 32%, Deteriorated in 12%Regression of cirrhosis in 9/14 patients

Cirrhosis Regression after IFN

D’Ambrosio & Aghemo. Hepat Mon 2012;12:361-368

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Post-SVR Cirrhosis Regression Rates According to the METAVIR Score

D’Ambrosio & Aghemo. Hepat Mon 2012;12:361-368

Histologic benefits may be observed even in the absence of an SVR

Metavir

Pockros PJ. et al., HEPATOLOGY 2010;52:1193-1200

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IFN treatment decreases mortalityin patients with CHC

Design, Setting, and Patients An international, multicenter, long-term follow-up study from 5 large tertiary care hospitals in Europe and Canada of 530 patients with chronic HCV infection who started an interferon-based treatment regimen between 1990 and 2003, following histological proof of advanced hepatic fibrosis or cirrhosis (Ishak score 4-6). Complete follow-up ranged between January 2010 and October 2011.up ranged between January 2010 and October 2011.(The Ishak fibrosis score was 4 in 143 patients (27%),5 in 101 patients (19%), and 6 in 286 patients (54%).)

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SVR and all-cause mortality

Van der Meer AJ et al., JAMA 2012-;308:2584-2593

SVR and Liver-related mortality


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SVR and Liver failure


IFN decreases HCC incidence

in CHC

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HCC in HCV-related liver cirrhosis (SVR vs no SVR

Singal et al. CGH 2010;8:192–199

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HCC in HCV-related liver cirrhosis (treated vs untreated)

Singal et al. CGH 2010;8:192–199

Cumulative incidence of HCC in HALT-C Trial

Lok AS et al., GASTROENTEROLOGY 2011;140:840–849

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SVR and HCC


逆轉肝硬化

Mission impossible?

T C i 都完成了耶!Tom Cruise都完成了耶!

Mission possible

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結論病毒性肝硬化是可逆的治療病毒性肝硬化可延長病人的存活治療病毒性肝硬化可降低肝癌的發生率需要積極治療與移植中心合作

您與您的病人，可以雙贏

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2013-1-9 病毒性肝硬化的治療方針-final.ppt...

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