1首都医科大学附属北京友谊医院

Beijing Friendship Hospital, Capital Medical University

The Efficacy of of Antiviral Therapy on the Regression of Liver Fibrosis in CHB

Jidong Jia, MD, PhD

Global annual mortality from hepatitis, HIV, tuberculosis and malaria

2000–2015:

Source: Global Health Estimates 2015: deaths by cause, age, sex, by country and by region, 2000-2015. Geneva: WHO; 2016.)

Deaths from viral hepatitis, by virus and type of sequelae in

2015

Source: Global Health Estimates 2015: deaths by cause, age, sex, by country and by region, 2000-2015. Geneva: WHO; 2016.)

WHO: GLOBAL HEPATITIS REPORT, 2017

3.5%

6.1%

3.3%

6.2%

2.0%1.6%

0.7%

Age-standardised disability-adjusted life-year rates

attributable to HBV in 2013, by country

5

Per 100 000 per year

Stanaway JD, et al. Lancet 2016DALY=伤残调整寿命年

Etiology of the 8080 liver cirrhosis patients

in southern China

Others 944 ( 0.12 ) …….. ………

n (%)

Wang X, et al. World J Gastroenterol 2014

HCC

Chronic HBV infection

5%-10% Adults195% infants1

Cirrhosis

Chronic Hepatitis

HBeAg(+)：8%-17% in 5y 2

HBeAg (-)：13%-38% in 5y 2

3%-6% per y 1 ≈20% in 5y 2

Acute HBV infection

Decompensation

71. Chinese guidelines of chronic hepatitis B (2010). Chin Hepatol 2011;5:13-242. Vallet-Pichard A,et al. Expert Rev Anti Infect Ther. 2009 ;7:527-35.

Natural history of chronic HBV infection

HBV level is the major driver for disease progression

HBV promotes expression of TGF by Kupffer

9

N=6,P=0.001 N=6,P=0.001

对照 HBV4 Log

HBV6 Log

TG

F1 r

ela

tive e

xpre

ssio

n

Li H, et al. Dig Liver Dis. 2012.44:328-33.

HBV-C, X proteins promote mRNA levels

of PDGF/-R in HSCs (LX-2)

10Bai QX, et al. Int J Mol Med. 2012;30: 1443-50

HBV increases collagen I expression in LX-2 HSCs

1 1

2.2

1.3

0.6

3.2

1.51

0.8

0

0.5

1

1.5

2

2.5

3

3.5

12h 24h 48hCo

lla

ge

n

I m

RN

A e

xp

res

sio

n

by

re

al-

tim

e P

CR

(fo

lds

)

negative control

purified HBV

CHB human serum

Wu X, et al. Hepatol Res. 2012;42:911-21.

HBV Increase TGF-β mRNA Expression in LX-2 HSCs

1

1.8 1.9

0.7

2.1

3.4

110.9

0

0.5

1

1.5

2

2.5

3

3.5

4

12h 24h 48h

TG

F-β

1 m

RN

A e

xp

ressio

n b

y

real-

tim

e P

CR

(fo

lds) negative control

purified HBVCHB human serum

COL/GAPDH

Wu X, et al. Hepatol Res. 2012;42:911-21.

巨噬细胞

TGF-β1 PDGF

Proliferation

ECM synthesis

ECM degradation

提出了HBV 导致肝纤维化的双途径假说

HBV

TGF-β1,

PDGF

IL-1β

T 细胞

TLRs

Th1/Th2

Li H, et al. Dig Liver Dis. 2012. 44:328-33.

Bai QX, et al. Int J Mol Med. 2012; 30::1443-50

Liu X, et al. Chin Med J 2009; 122::1455-61

Wu X, et al. Hepatol Res. 2012; 42:911 -21

Li H, et al. BMJ Open Gastroenterol.2016;25;3:e000079.

Xu F, et al. Cell Biol Int. 2013; 37:284-91

星状细胞

肌成纤维细胞样细胞

HBV and liver fibrosis- a hypothesis

Progression and regression of liver fibrosis

Regression

Fibrogenesis

Fibrolysis

Progression

15

Lee YA, et al. Gut 2015;64:830–41.

Strategies for antifibrotic therapies in CHB

Effective causal treatment-antiviral therapy

Prevention of HSC Activation and/or proliferation

Inhibit fibrogenesis

Promote resolution of fibrosis

Apoptosis and inactivation of HSCs

Degradation of extracellular matrix

Reversal of Fibrosis: An Achievable Goal of

Hepatitis B Antiviral Therapy

Lok AS, et al. Nat Rev Gastroenterol Hepatol. 2013; 10:199-200.

Study Agents HBeAg Biopsy/NTreatment

period

Cases

achieved

decrease of

Ishak score

（%）

Ishak 5-6,

decrease ≥1

（%）

Dienstag et al.

2003LAM + 63/267 3 12/19 (63%) 8/11 (73%)

Rizzetto et al.

2005LAM - 48/76 3 8/18 (44%) 3/6 (50%)

Hadziyannis

et al.2006ADV - 46/125 4-5 29/46 (63%) 3/4 (75%)

Chang et al.

2010ETV +/- 57/679 5 50/57 (88%) 4/10 (40%)

Marcellin et al.

2012TDF +/- 348/641 5 176/348 (51%) 71/96 (74%)

Liaw YF. J Hepatol. 2013;59:880-1.17

Antiviral therapy improved liver fibrosis

In HBeAg-negative CHB patients

Papachrysos N, et al. Ann Gastroenterol, 2015; 28: 374-8.

HAI score METAVIR score

Long-term lamivudine treatment achieves regression of

advanced liver fibrosis/cirrhosis in CHB patients

Xu B, et al. J Gastroenterol Hepatol. 2015; 30: 372-8

Telbivudine Treatment Improves Necroinflammation

and Fibrosis in CHB

Hou JL, et al. Adv Ther. 2015; 32 :727-41

Telbivudine Treatment Results in Resolution of Liver

Inflammation and Fibrosis in CHB

Hou JL, et al. Adv Ther. 2015; 32:727-41

Inflammation Cirrhosis

Knodell score Ishak score

Improvement of Histology after TDF

Therapy for 5 Years

Marcellin P, et al. Lancet 2013: 468–475.

348/641 (54%) with biopsy samples at year 5

Histological changes in cirrhotic CHB patients

treated with TDF for 5 years

Buti M, et al. Hepatol Int, 2015; 9 : 243-50

Histological outcomes in cirrhotic CHB

patients treated with TDF for 240 wks

Tsai NC, et al. Dig Dis Sci 2015; 60: 260-8

Decrease of Necroinflammation and Fibrosis Stage after Long-term Entecavir Therapy

Chang TT, et al. Hepatology 2010; 52:886-93.

Knodell score Ishak score

25

(median: 5.6 yr, n=57)

ETV

52w 78 w 104 w26 w

ETV ETV

ETV

ETV ETV+Thy-a ETV

Biopsy

0 w

Biopsy

100 cases

200 cases

50 cases

100 cases

ETV+Peg-IFNa

Liver Biopsy: S4 (Early Cirrhosis)

2013 y 2014 y 2015 y

Regress Study - 1

Regress Study - 2

Liver Biopsy: S2/S3 (Liver Fibrosis)

Liver Fibrosis Regression Rate: Evaluated by Biopsy

Before and After Treatment

Beijing Friendship Hospital, CMU. “Optimized Treatment for Regression of HBV-related Liver Fibrosis or Cirrhosis”,

supported by National Science and Technology Major Project (2013ZX10002004)

TDF Recommended for HBV Therapy by Major Guidelines

AASLD3 2015 PEG-IFN, TDF or ETV are preferred.

China4 2015 ETV, TDF, PEG IFN are the preferred

2015ETV or TDF are the preferred NUCs for NUC-

naïve CHB patients.

EASL2 2017 ETV and TDF

2013 PEG-IFN /ETV/TDF first

2015 TDF, ETV

New Proposal on the Classification of Liver Fibrosis

Chronic liver

Disease

慢性肝病

CHB Fibrosis Cirrhosis

Progression

Regression

HEPATOLOGYOfficial Journal of American Association for the Study of Liver Diseases

Sun Y, et al. Hepatology. 2017; 65:1438–5028

29

HEPATOLOGYOfficial Journal of American Association for the Study of Liver Diseases

Kleiner. Hepatology 2017; 65:1432–1434

New Proposal on the Classification of Liver Fibrosis

Chronic liver

Disease

慢性肝病

CHB Fibrosis Cirrhosis

Progression

Regression

Post-treatment P-I-R Score versus Ishak Stage

to Evaluate Disease Progress or Reverse

Ishak

(pre-post)

Post-treatment P-I-R score

n=71

Progressive

n=8

Indeterminate

n=8

Regressive

n=55

Increase,

n=367% (2/3)

0 33% (1/3)

Stable,

n=35

Probably advancing

17% (6/35) 11% (4/35)

Probably reversing

72% (25/35)

Decrease,

n=33 0

Probably reversing

12% (4/33)88% (29/33)

Sun Y, et al. Hepatology. 2017; 65:1438–50

Improvement of Liver Fibrosis after Long-Term Antiviral Therapy Assessed by Fibroscanin CHB Patients With Advanced Fibrosis

• NA-naive CHB with Lx ≥F3, HBV DNA ≥2,000 IU/ml, &ALT<2 ×ULN

• LSM at baseline and annually for 5 years during antiviral therapy

• Five-year fibrosis improvement was defined as LS value <7.2 kPa(<F3) at year 5.

• LSM changes: from baseline to year 1, 2, 3, 4 and 5.

• 14.511.3 9.62 9.3 8.6 8.3 kPa

• Patients with baseline LSM<12.0 kPa had a greater probability of

experiencing significant fibrosis improvement than those with

baseline LSM ≥12.0 kPa (81.5% vs. 29.0%, P<0.001).

Chon YE, et al. Am J Gastroenterol. 2017

Summary

• HBV may cause liver fibrosis through direct and indirect

pathways

• Effective antiviral therapy is the currently available most

efficacious anti-fibrotic therapy for CHB

• Antiviral therapy combined with novel therapeutic

approaches may needed to treat advanced

fibrosis/cirrhosis.

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中国慢性肝病注册研究 (China Registry, CR)

CHB Fibrosis Cirrhosis

• 参加单位47家• 录入患者139,443例• 随访患者521,672人次

You H, et al. Sci Rep 2016

中国乙肝注册系统-CR-HepB 中国遗传代谢性肝病注册网-CR-GMLD

• 开展12种基因检测：

血色病、Wilson病、Gaucher病、糖原

累积症、PFIC、BRIC、Citrin缺乏症等

• 为肝移植提供基因诊断依据

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