20131222 TASL HBV pre-S deletion mutants and HCC outcomes

B型肝炎病毒表面前區剔除性突變
與抗病毒藥物，對於肝細胞癌患者
接受切除手術後，腫瘤復發之影響
蘇建維1,2,3 邱昱維4 蔡宜璇1 鄧睿敦1
周嘉揚2,5 洪宏緒1,6 霍德義3,7 吳肇卿1,4
1陽明大學醫學院

臨床醫學研究所
2陽明大學醫學院醫學系
3台北榮民總醫院內科部胃腸科
4台北榮民總醫院醫學研究部轉譯研究科
5台北榮民總醫院外科部一般外科
6振興醫院內科部胃腸肝膽科
7陽明大學醫學院藥理學研究所

Nomogram for risk of HCC

Yang HI, et al. J Clin Oncol 2010;28:2437-44

HBV genotype, precore and BCP mutants
and HCC
Incidence rate per 100,000 person-years
1149.2

1400
1200
955.5

1000

785.8

800

Genotype B
Genotype C

600
400
200
0

305.6

269.4

358.7

Precore wild
Precore Mutant
BCP wild
BCP mutant

Yang HI, et al. JNCI 2008;100:1134-43

The life cycle of HBV






Chan HLY, J Hepatol 2011;55:1121-1131

Immune epitopes and functional domains within
the HBV pre-S region

Su IJ, et al. J Gastroenterol Hepatol 2008
Kao JH Liver Int 2012

Su IJ, et al. J Gastroenterol Hepatol 2008

Prevalence of pre-S deletion

Chen BF, Kao JH, et al. Gastroenterology 2006;130:1153-68

Pre-S deletion and HCC

Chen CH, et al. Gastroenterology 2007;133:1466-74

Combined risk of developing HCC associated
with HBV mutants and HCV genotype

Hung CH, Chen CH, Lee CM, et al. Intervirology 2013;56:316-24

Schematic representation of factors that influence the
progression of HBV-related liver disease
Host Factors
Age> 40 years
Gender: Male> Female
Immune status

Environmental
factors
Alcohol

Smoking
Aflatoxin exposure
Concurrent
HCV, HDV, HIV infection

Viral Factors
Genotype: C> B; D>A
Viral load:> 104
copies/mL
Genome Mutations: preS deletion, T1762/A1764

Liaw YF, Factors influencing liver disease progression in chronic hepatitis B. Liver Int 2006; 26: 23-29

The role of HBV pre-S deletion
mutants in HCC patients after
curative therapies

GGH predicts prognosis of HCC patients after
resection surgery

Tsai HW, Su IJ, et al. Cancer 2011; 117:2951-60

GGH predict prognosis of HCC patients after
resection surgery


GGH predict prognosis of HCC patients after resection surgery


Small pre-S deletion predict poor prognosis after
resection for HCC
178 patients from non-tumor part of liver specimens

Yeh CT, et al. Hepatology 2010;52:1922-33

Small pre-S deletion predict poor prognosis after
resection surgery for HCC
Disease-free survival

Overall Survival

Yeh CT, et al. Hepatology 2010;52:1922-33

Lack of Association Between HBV
Pre-S Mutations and Recurrence After Surgical
Resection in HCC

All were genotype C
19 (29.7%) of the 64 patients had pre-S deletion

Heo NY, Lee HC, Park YK, et al. J Med Virol 2013; 85:589-96

Lack of association between HBV
pre-S mutations and recurrence after resection in HCC


Lack of association between HBV
pre-S mutations and recurrence after resection in HCC

Recurrence-free survival

Overall Survival


Pre-S deletion mutants are associated
with HCC development.
However, the prognostic value of pre-S
deletion mutants in HCC patients after
curative therapies is still unclear.

Hepatitis B Viral Load, Pre-S Deletion
Mutations and Anti-viral Therapy Predict
Post-operative Recurrence of
Hepatocellular Carcinoma

PLoS ONE 2013;8(6):e66457

Materials and Methods
• From 1989 to 2007, 333 patients with HBV-related HCC
who underwent resection surgery at Taipei Veterans
General Hospital were enrolled.
• A total of 62 patients received antiviral therapy for HBV
infection after resection, while the remaining 271
patients did not take antiviral therapy during the
follow-up period.
• All serum samples of enrolled patients were tested for
HBV DNA levels and genotype; and clonal analysis of
pre-S regions were performed in 216 patients.
• After a median follow-up of 45.9 months, 165 patients
died and 208 patients had HCC recurrence after
resection. The 5-year overall survival and recurrencefree survival rates were 55.4% and 35.3%, respectively.

Characterization of HBV related HCC patients between
genotype B and genotype C
All patients

B

C

(n= 333)

(n=174)

P

(n=139)

Patient Demographics (continuous variables are expressed as median; 25 and 75 percentiles)
Age (years)
Sex (M/F) (%)
HCC family history

56; 47-67

56; 44-68.3

57; 48-64

271/42 (86.6%/13.4%) 153/21 (87.9%/12.1%) 118/21 (84.9%/15.1%)

0.692
0.537

71/235

32/126

36/93

(23.2%/76.8%)

(20.3%/79.7%)

(27.9%/72.1%)

Albumin (g/dL)

4.0; 3.8-4.3

4.1; 3.9-4.4

3.9; 3.7-4.2

<0.001

Total bilirubin (mg/dL)

0.9; 0.7-1.2

0.8; 0.7-1.1

0.9; 0.7-1.2

0.715

42; 28-66

40; 26-61.5

46; 31.8-73.3

0.017

10.0; 6.0-16.0

10.0; 6.0-15.0

12; 7-17.5

0.024

162000; 120500-

167500; 132500-

143000; 104000-

0.023

212500

215750

200000

1.01; 0.95-1.07

1.00; 0.95-1.05

1.02; 0.96-1.13

(yes/no) (%)

ALT (U/L)

ICG-15R (%)
Platelet (/mm3)
PT INR

0.168

0.011

Characterization of HBV related HCC patients
between genotype B and genotype C
All patients

B

C

(n= 333)

(n=174)

P

(n=139)

Tumor factors (continuous variables are expressed as median; 25 and 75 percentiles)
Tumor size (cm)

4.0; 2.5-6.8

4.1; 2.5-6.7

3.5; 2.5-6.3

0.975

Multinodularity (%)

141/191 (42.3%/57.7%)

74/100 (42.5%/57.5%)

60/79 (43.2%/56.8%)

1.000

Macroscopic venous invasion (%)

61/271 (18.4%/81.6%)

36/138(20.7%/79.3%)

20/118(14.5%/85.5%)

0.205

45.5; 7.4-974.5

31.3; 7.0-996.5

51.1; 8.2-714.8

0.146

Cirrhosis (yes/no) (%)

143/180 (44.3%/55.7%)

58/108 (34.9%/65.1%)

76/61 (55.5%/44.5%)

0.001

Edmondson grading (I-II/III-IV)(%)

214/108 (66.5%/33.5%)

117/50 (70.1%/29.9%)

87/49 (64.0%/36.0%)

0.317

Microscopic venous invasion (%)

221/111 (66.6%/33.4%)

117/57 (67.2%/32.8%)

92/46 (66.7%/33.3%)

1.000

AFP (ng/ml)
Histo-pathological findings

Characterization of HBV related HCC patients
between genotype B and genotype C
All patients

B

C

P

(n= 333)

(n=174)

(n=139)

3.90 x 105;

3.21 x 105;

1.76 x 105;

25 and 75 percentiles)

1.73 x 104-7.64 x 106

2.24 x 104-4.17 x 106

2.45 x 104-1.39 x 106

HBsAg (IU/mL) (median; 25

830.0; 287.5-1830.0

935.0; 400.5-1781.3

897.0; 200.8-1959.4

0.241

194/102 (65.5%/34.5%)

119/46 (72.1%/27.9%)

74/55 (57.4%/42.6%)

0.012

209/86 (70.8%/29.2%)

96/69 (58.2%/41.8%)

112/16 (87.5%/12.5%)

<0.001

Pre-S deletion (yes/no) (%)

73/85 (46.2%/53.8%)

33/62 (34.7%/65.3%)

40/22 (64.5%/35.5%)

<0.001

Antiviral therapy (Y/N) (%)

40/293 (12.0%/88.0%)

26/148 (14.9%/85.1%)

10/129 (7.2%/92.8%)

0.067

Viral factors
HBVDNA(copies/mL) (median;

0.390

and 75 percentiles)
Pre-core mutation (G1896A)
(Y/N) (%)
BCP (A1762T, G1764A)
mutation (Y/N) (%)

HCC tumorigenesis
Tumor
factor

Liver
functional
reserve

Hepatic
fibrosis

Viral
factors

Univariate analysis of factors associated with overall
survival after resection for hepatocellular carcinoma.
(all patients)
Variable

Number

Median survival months (95% CI) Hazard ratio (95% CI)

P

Age > 60 /  60 y/o

131/201

50.6(41.0-60.2)/115.1(78.9-151.3)

1.743 (1.283-2.367)

<0.001

Sex Female/Male

45/287

128.3(25.7-230.9)/70.4(53.7-87.1)

0.690(0.422-1.126)

0.137

Albumin  4 / > 4 g/dL

165/163

46.1(36.0-56.2)/125.9(80.4-171.4)

1.843(1.345-2.526)

<0.001

Bilirubin > 1.6 /  1.6 mg/dL

20/312

81.9(46.3-117.5)/71.2(48.0-94.4)

0.855(0.450-1.623)

0.631

ALT >40 /  40 U/L

178/154

70.4(52.0-88.8)/79.7(42.8-116.6)

1.087(0.799-1.479)

0.594

ALK-P >100 /  100 U/L

132/199

41.2(26.1-56.3)/100.9(73.1-128.7)

1.892(1.392-2.571)

<0.001

GGT >60 /  60 U/L

131/197

46.7(35.1-58.3)/113.5(92.6-134.4)

1.843(1.356-2.506)

<0.001

Platelet  105 / > 105 /mm3

51/262

60.3(34.9-85.7)/74.2(45.5-102.9)

1.149(0.776-1.702)

0.488

ICG-15R > 10% /  10%

160/170

52.3(34.2-70.4)/120.9(80.1-161.7)

1.707(1.250-2.330)

0.001

MELD ≧8/<8

136/190

57.5(37.4-77.6)/94.5(67.4-121.6)

1.405(1.032-1.914)

0.013

(all patients)
Variable

Antiviral therapy (N/Y)

209/85
62/271

(0.821-1.529)

75.1(55.8-94.4)/

0.980
(0.715-1.344)

79.7(45.1-114.3)/

1.142
(0.803-1.624)

94.5(61.6-127.4)/

0.752
(0.544-1.040)

71.2(56.8-85.6)/

1.040

70.9(0-165.9)

A1762T/G1764A mutation Y/N

193/102

1.120

54.5(33.7-75.3)

Precore mutation Y/N

121/157

72.8(52.2-93.4)/

100.0(64.0-136.0)

HBsAg > 1000 / 1000 IU/mL

136/184

(95% CI)

70.4(29.6-111.2)

HBV DNA >106 / 106 cp/ml

Hazard ratio

69.9(23.6-116.2)

138/174

Median survival months
(95% CI)

HBV genotype C/B

Number

(0.722-1.499)

54.5(40.0-69.0)/

5.938

NA

(2.915-12.094)

P

0.475
0.901
0.459
0.085

0.833
<0.001

(all patients)
Variable

Number

Median survival months (95% CI) Hazard ratio (95% CI)

P

Tumor size > 5cm /  5cm

122/210

37.5(22.6-52.4)/100.0(68.0-132.0)

2.001 (1.472-2.721) <0.001

Multinodularity Y/N

141/191

45.7(33.6-57.8)/119.8(97.9-141.7)

2.182 (1.603-2.972) <0.001

Macroscopic venous invasion

61/271

16.8(0-36.5)/94.5(67.3-121.7)

2.809 (1.976-3.984) <0.001

Cut margin  1cm/ >1cm

223/108

60.3(45.9-74.7)/113.5(89.3-137.7)

1.520 (1.079-2.141)

0.017

AFP >20 /  20 ng/ml

192/136

69.7(48.1-91.3)/81.9(48.4-115.4)

1.308 (0.951-1.799)

0.099

Microscopic venous invasion

221/110

Y/N

52.3(40.6-64.0)/119.8(103.7-135.9) 2.203 (1.527-3.185) <0.001

Y/N
Cirrhosis on non-tumor part Y/N 143/179

54.2(40.9-67.5)/122.5(82.9-162.1)

1.706 (1.248-2.331)

0.001

Edmondson stage III or IV/ I or II 214/108

79.9(54.0-105.8)/64.0(38.3-89.7)

1.369 (0.997-1.879)

0.052

Overall survival: antiviral therapy

P < 0.001

The impact of anti-viral therapy on overall
survival stratified by BCLC stage

Multivariate analysis of factors associated with overall
survival after resection for HCC (all patients)
Variable

Hazard ratio

Standard error

P

(95% confidence interval)
ICG-15R > 10%

1.574(1.122-2.208)

0.173

0.009

ALK-P >100 U/L

1.762(1.267-2.450)

0.168

0.001

Macroscopic venous

2.326(1.580-3.425)

0.197

<0.001

1.848(1.225-2.786)

0.209

0.003

8.275(2.631-26.023)

0.585

<0.001

invasion
Microscopic venous
invasion
Without antiviral
therapy

The impact of anti-viral therapy on recurrence
stratified by viral factors
HBV DNA levels

P< 0.001

P=0.038

stratified by viral factors
Serum HBsAg levels

The effect of anti-viral therapy in decreasing
recurrence is irrespective of viral load

P= 0.001

P= 0.037

stratified by BCLC stage

Impact of antiviral therapy on prognosis of
HBV-related HCC after resection

AJCC stage I and II

The effect of anti-viral therapy in improving
overall survival is more apparent in early stage HCC
AJCC stage III

Overall survival
Chan ACY, et al. Arch Surg 2011;146:675-81

Disease-free survival

Multivariate analysis of factors associated with
recurrence after resection for HCC (all patients)
Variable

Hazard ratio

Standard error

P

(95% confidence interval)
GGT >60 U/L

1.628 (1.210-2.190)

0.151

0.001

ICG-15 > 10%

1.386 (1.036-1.854)

0.148

0.028

Without antiviral therapy

2.296 (1.451-3.632)

0.234

<0.001


2.375(1.650-3.425)

0.186

<0.001


1.499(1.080-2.083)

0.167

0.016

Strategy for Preventing HBV-HCC
Primary
prevention

• HBV vaccination

Secondary
prevention

• Adequate antiviral therapy
• Close surveillance
(sonography and AFP)

Tertiary
Prevention

• Adjuvant anti-tumor
therapy (such as target
therapy) for reducing
early recurrence
• Antiviral therapy for
improving liver
functional reserve and
reducing late recurrence

Summary
• Anti-viral therapy could improve the post-operative
prognosis both in terms of overall survival and
recurrence in patients with early stage HCC, but the
effect was less significant in those with BCLC stage C.
• As anti-viral therapy might confound the impact of
viral factors, to eliminate this bias, 62 patients who
received anti-viral therapy after resection surgery
were excluded and the remaining 271 patients were
further analyzed for prognostic factors.

survival and recurrence after resection for HCC (without
antiviral therapy)
Variable

HR (95% CI)

Standard error

P

ICG-15 > 10%

1.618 (1.142-2.292)

0.178

0.007

ALK-P >100 U/L

1.441 (1.035-2.006)

0.169

0.031

Tumor size > 5 cm

1.602 (1.127-2.276)

0.179

0.009

Overall survival

Ongoing viral replication

2.155 (1.462-3.174)
0.198
<0.001
is a crucial predictor of post-operative HCC
Microscopic venous anti-viral therapy can reduce recurrence and improve
1.842 (1.209-2.801)
0.214
0.004
recurrence, invasion
Cirrhosis on non-tumor part
1.486 (1.043-2.116)
0.180
0.028
prognosis.
Recurrence
HBV DNA >106 copies/mL

1.428 (1.047-1.947)

0.158

0.024

GGT >60 U/L

1.700 (1.239-2.331)

0.194

0.001


2.387 (1.634-3.497)

0.180

<0.001


1.594 (1.121-2.273)

0.195

0.010

Characterization of HBV related HCC patients with and
without pre-S deletion (n=216)
Without Pre-S deletion With Pre-S deletion
(n=143)
(n=73) 15: pre-S1

43: pre-S2
15: pre-S1+ pre-S2

Patient Demographics
Age (years)

P

58; 46-69

54; 46-64

0.500

Sex (male/female) (%)

123/20 (86/0%/14.0%)

65/8 (89.0%/11.0%)

0.680

HCC family history (yes/no)
(%)
Albumin (g/dL)

28/100 (21.9%/78.1%)

20/47 (29.9%/70.1%)

0.292

4.1;3.9-4.4

4.0; 3.7-4.2

0.018

0.9; 0.7-1.2

0.9; 0.7-1.3

0.847

42; 27.5-65.6

49; 39-74

0.084

11; 6-16

10; 7-17

0.735

156000; 125000-199000

148000; 98000-209000

0.849

PT INR

1.01; 0.96-1.06

1.00; 0.94-1.12

0.571

MELD

7.7; 6.6-8.6

7.9; 6.9-9.3

0.796

Total bilirubin (mg/dL)
ALT (U/L)
ICG-15R (%)
Platelet (/mm3)

(n=143)
(n=73)

P

Tumor factors
Tumor size (cm)

3.4; 2.5-6.0

3.0; 2.1-6.0

0.191

Multi-nodularity/single tumor
(%)
(yes/no) (%)
AFP (ng/ml)

57/86 (39.9%/60.1%)

25/48 (34.2%/65.8%)

0.512

21/121 (14.8%/85.2%)

12/61 (16.4%/83.6%)

0.906

20.8; 6.7-752.3

50.6; 12.1-803.0

0.343

Cut margin ≤1/>1 cm (%)

101/42 (70.6%/29.4%)

45/27 (62.5%/37.5%)

0.294

Cirrhosis (yes/no) (%)

51/86 (37.2%/62.8%)

40/30 (57.1%/42.9%)

0.010

Edmondson grading (I-II/III-IV)
(%)
(yes/no) (%)
BCLC (A/B/C) (%)

47/91 (34.1%/65.9%)

18/53 (25.4%/74.6%)

0.258

93/49 (65.5%/34.5%)

47/26 (64.4%/35.6%)

0.992

84/40/14
(59.6%/28.4%/12.1%)

45/16/11
(62.5%/22.2%/15.3%)

0.566

(n=143)
(n=73)

P

Viral factors
HBVDNA(copies/mL)*

4.85 x 105;
3.67 x 104-1.08 x 107

1.61x 106;
9.95 x 104-1.51 x 107

0.055

HBsAg (IU/mL)*

896.3; 339.5-1732.4

1127.5; 405-2101

0.297

Genotype B/C (%)

98/44 (69.0%/31.0%)

33/40 (45.2%/54.8%)

0.001

Pre-core (G1896A) mutation
(yes/no) (%)*

88/42 (67.7%/32.3%)

40/28 (58.8%/41.2%)

0.279

BCP (A1762T, G1764A)
mutation (yes/no) (%)*

83/47 (63.8%/36.2%)

52/16 (76.5%/23.5%)

0.099

survival and recurrence after resection for HCC (without
antiviral therapy)
Variable

HR (95% CI)

Standard error

P

Age >60 years

2.035 (1.288-3.215)

0.233

0.002

Alk-P >100 U/L

2.288 (1.451-3.606)

0.232

<0.001


2.967 (1.730-5.102)

0.276

<0.001


1.825 (1.046-3.185)

0.284

0.034

G1896A mutation

0.598 (0.382-0.937)

0.229

0.025

Multi-nodularity

1.693 (1.115-2.571)

0.213

0.013


2.415 (1.418-4.098)

0.271

0.001

Cirrhosis

1.544 (1.047-2.279)

0.198

0.029

Edmondson stage III or IV

1.526 (1.029-2.263)

0.201

0.036

Pre-S deletion

1.564 (1.057-2.314)

0.200

0.025

Overall survival

Recurrence

Pre-S deletion and post-operative recurrence stratified
by serum HBVDNA and HBsAg levels

P=0.028

P=0.926

P=0.047

P=0.253

The impact of pre-S deletion mutants on
recurrence for patients receiving anti-viral therapy

hepatocarcinogenesis and tumor recurrence induced by pre-S deletion
mutants may be based on active HBV viral replication, the accumulation
of oxidative stress, and subsequent chromosomal instability
P=0.161

Conclusion
• On-going viral replication and the presence of
pre-S deletion mutants are both crucial
predictors of post-operative HCC recurrence.
• Hepatocarcinogenesis and tumor recurrence
induced by pre-S deletion mutants may be
based on active HBV viral replication, the
accumulation of oxidative stress, and
subsequent chromosomal instability
• Antiviral therapy may improve post-operative
outcomes, especially in early stage HCC.

20131222 TASL HBV pre-S deletion mutants and HCC outcomes

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