The Efficacy of of Antiviral Therapy on the Regression of...
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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
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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.)
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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.)
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WHO: GLOBAL HEPATITIS REPORT, 2017
3.5%
6.1%
3.3%
6.2%
2.0%1.6%
0.7%
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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
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Etiology of the 8080 liver cirrhosis patients
in southern China
Others 944 ( 0.12 ) …….. ………
n (%)
Wang X, et al. World J Gastroenterol 2014
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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
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HBV level is the major driver for disease progression
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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.
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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
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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.
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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.
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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
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Progression and regression of liver fibrosis
Regression
Fibrogenesis
Fibrolysis
Progression
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15
Lee YA, et al. Gut 2015;64:830–41.
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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
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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
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Antiviral therapy improved liver fibrosis
In HBeAg-negative CHB patients
Papachrysos N, et al. Ann Gastroenterol, 2015; 28: 374-8.
HAI score METAVIR score
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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
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Telbivudine Treatment Improves Necroinflammation
and Fibrosis in CHB
Hou JL, et al. Adv Ther. 2015; 32 :727-41
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Telbivudine Treatment Results in Resolution of Liver
Inflammation and Fibrosis in CHB
Hou JL, et al. Adv Ther. 2015; 32:727-41
Inflammation Cirrhosis
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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
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Histological changes in cirrhotic CHB patients
treated with TDF for 5 years
Buti M, et al. Hepatol Int, 2015; 9 : 243-50
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Histological outcomes in cirrhotic CHB
patients treated with TDF for 240 wks
Tsai NC, et al. Dig Dis Sci 2015; 60: 260-8
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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)
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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)
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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
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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
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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
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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
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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
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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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