Could antiviral therapy reduce the incidence of HCC in patients with

chronic hepatitis B?

Hong You Beijing Friendship Hospital

2

Main Content

Natural progression history of hepatitis B disease and epidemiology and risk factors of HCC

Effective long-term treatment of nucleoside (nucleotide) drugs could reduce the development and recurrence risk of HBV-related liver cancer

Antiviral therapy with nucleoside (nucleotide) drugs could significantly reduce , but can't completely eliminate the risk of HCC

Part 1

Part 2

Effective long-term antiviral therapy can reduce the incidence of HCC in patients with chronic hepatitis B Effective antiviral therapy can reduce the incidence of HCC recurrence in patients with HBV-related HCC

Part 3

3

Natural history of hepatitis B disease progression

Acute HBV infection

Chronic HBV infection

Liver cirrhosis

Chronic liver failure HCC

Chronic Hepatitis B 5-year incidence: 8%~20%4 Annual incidence

3%~6%1

Liver transplant

350 million patients with chronic hepatitis B infection globally 1

30% of liver cirrhosis and 53% of HCC are associated with chronic HBV infection 2

21,000 cases of liver transplant each year3

1. Chinese Society of Hepatology, Chinese Society of Infectious Diseases, Chinese Medical Association. The Guideline of Prevention and Treatment for Chronic Hepatitis B (2010 Version) Chinese Journal of Hepatology 2011; 5: 13-2 4

2. Ashley Brown et al. Expert Rev Gastroenterol Hepatol. 2012 Apr;6(2):187-98. 3 Shi Y B W ld H lth O 2007 955 962

4

Epidemiology of HBV-related HCC

5-year cumulative incidence of HCC in patients with chronic HBV infection 5

Inactive carriers

CHB without cirrhosis

CHB with compensated cirrhosis

East Asia 1% 3% 17%

Europe 0.1% 1% 10% 1.Tan YJ, et al. World J Gastroenterol 2011;17:4853-4857. 2. European Association For The Study Of The Liver. Hepatol 2012;57:167-185. 3. Ngyuen VT, et al. J Viral Hepat 2009;16:453-463. 4. Wong CH, et al. Biomedical Imaging Intervention Journal 2006;2:e7. 5. Fattovich G, et al J Hepatol 2008;48:335-352

HCC is the fifth most common cancer, the third most common cause of death worldwide1,2

Approximately 50% of the global HCC cases is associated with HBV infection.3 In HBV-epidemic regions (Southeast Asia, Sub-Saharan Africa), as high as 70–80% of HCC cases is associated with HBV infection3,4

Approximately 25% of untreated CHB patients will experience HCC 1

There is a higher incidence of HBV-related HCC in cirrhotic patients 5

5

Risk factors for HBV-related HCC

Lok AS,et al.J Gastroenterol Hepatol 2011;26:221-7

Risk factors for HBV-related HCC

Viral factors Host factors Environmental factors

Continuous HBeAg positive Elderly Alcoholic

Continuous high load of HBV DNA

Male Aflatoxin

Mutation of HBV core promoter

Asian Smoking

HBV genotype C Liver cirrhosis

Continuous high ALT level

Co-infection of HDV and HCV

Family history of HCC

Diabetes mellitus Resistance can lead to an increased risk of HCC Antiviral therapy with nucleoside (nucleotide) drugs could significantly reduce, but can’t

completely eliminate the risk of HCC (especially in patients with liver cirrhosis )

6

Main Content

Natural progression history of hepatitis B disease and epidemiology and risk factors of HCC

Effective long-term treatment of nucleoside (nucleotide) drugs could reduce

the development and recurrence risk of HBV-related liver cancer

Antiviral therapy with nucleoside (nucleotide) drugs could significantly reduce, but can't completely eliminate the risk of HCC

Part 1

Part 2

Effective long-term antiviral therapy can reduce the incidence of HCC in patients with chronic hepatitis B Effective antiviral therapy can reduce the incidence of HCC recurrence in patients with HBV-related HCC

Part 3

7

Sustained viral suppression may delay disease progression

0

5

10

15

20

25

0 6 12 18 24 30 36

The

pro

port

ion

of p

atie

nts w

ith

dise

ase

prog

ress

ion

Time to disease progression (months)

p = 0.001

21%

9%

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

Placebo

Lamivudine

Liaw YF, et al. N Engl J Med. 2004;351:1521-1531

Disease progression: liver decompensation, HCC, or death

8

117 matched patients

Kumada’s study: effects of treatment with nucleoside (nucleotide) drugs

(NUC) on incidence of HCC A retrospective single-center cohort study in Ogaki Hospital , Japan 785 CHB patients (enrolled into HCC monitoring project 1998–2008) The primary outcome: HCC incidence Follow-up period: until the development of HCC or December, 2011

Kumada, T. et al. J Hepatol, 2012, doi: http://dx.doi.org/10.1016/j.jhep.2012.10.025

Non-NUC traetment† 637 patients were followed

117 matched patients

NUC treatment 148 patients received treatment

(NUC treatment >1 year before NUC detection)

Propensity score match*

LVD

LVD+ADV 61%

ETV 24%

15%

* Propensity score match includes age, gender, HBV DNA, HBeAg status, platelet counting and ALT.

†NUC is not approved in Japan, or refused by patients。

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Kumada’s study: NUC treatment reduces the incidence of HCC

Kumada, T. et al. J Hepatol, 2012, doi: http://dx.doi.org/10.1016/j.jhep.2012.10.025

Cox proportional hazard model: HR 0.28 (95% CI 0.13–0.62) P=0.002

NUC treatment 117 117 115 108 96 77 56 32 16 10 7 Non-NUC treatment 117 117 115 111 106 100 85 73 67 54 47

Pts. at risk

NUC treatment*

0 1 2 3 4 5 6 7 8 9 10

0

20

40

60

80

100

The

cum

ulat

ive

inci

denc

e of

HC

C (%

)

Year

2.7% 3.3% 3.3%

11.3%

26.0%

40.0% Non-NUC treatment

NAs antiviral therapy including ETV could achieve the benefit of HCC risk reduction

10

Long-term ETV treatment can reduce the incidence rate of HCC in patients with chronic hepatitis B

A retrospective study in Japan involving 2107 patients with chronic hepatitis B (at least 6 months of HBsAg positive) analyzed the data from the 5-year follow-up period.

- ETV group: 2004-2010. Treatment-naive patients with chronic hepatitis B treated with 0.5mg ETV n=472, after propensity score match n=316 - Control group: 1973-1999, Chronic hepatitis B patients without NA treatment n=1143, after propensity score match n=316 - LAM group: 1995-2007 Chronic hepatitis B patients treated by LAM and matched with ETV group n=492，after

propensity score match n=182

Tetsuya Hosaka, et al. Hepatology. 2012 Dec 5. doi: 10.1002/hep.26180.

Complete cohort PS matched cohort*

ETV (N=472)

Control (N=1143) P ETV

(N=316) Control (N=316) P

Age (mean, years) 47 39 <0.001 46 46 0.907

Gender (n) 315 720 0.171 210 210 1.000

Cirrhosis (n/%) 116 (25) 195 (17) 0.001 79 (25) 85 (29) 0.324

HBV genotype (n/%) A B C D Other / deletion

– 12 (3) 66 (14) 344 (73)

0 (0) 50 (11)

– 41 (4)

188 (16) 791 (69)

1 (1) 122 (10)

<0.001 – – – – –

– 8 (3)

49 (16) 225 (71)

0 34 (11)

– 9 (3)

50 (16) 226 (72)

0 31 (10)

0.843 – – – – –

HBeAg(+) 219 (46) 398 (35) <0.001 135 (43) 133 (42) 0.936

HBV DNA (log10 copies/mL) 6.7 5.8 <0.001 6.3 6.6 0.795

ALT (IU/L) 70 33 <0.001 61 60 0.110 *Differences in baseline characteristics is eliminated by propensity score match of age, gender, presence of cirrhosis, HBeAg status, HBV DNA, AST,

ALT, γGTP, bilirubin, albumin, and platelet count.

11

Long- term ETV treatment can reduce the incidence rate of HCC in patients with chronic hepatitis B

Compared with the control group, ETV treatment can reduce the 5-year risk of HCC by more than 60%

In cirrhotic patients, cumulative incidence of HCC was significantly lower in ETV h h i LAM

Control (n=316)

ETV (n=316)

Log-rank test: P < 0.001

Treatment period (Years)

The

cum

ulat

ive

inci

denc

e of

HC

C

(%)

0 1 3 5 7

0

10

20

30

40

50

4.0% 7.2%

10.0%

13.7%

3.7% 2.5% 1.2% 0.7%

316 316 316 277 246 223 200 187 17

0

2 2 44 101 185 264 316

Pts. at risk

ETV Control

50

40

30

20

10

0

0 1 3 5

Pts. at risk Treatment period (Years)

ETV 79 79 72 53 35 17

LAM 49 49 41 35 32 29

Control 85 85 76 65 54 47

ETV

LAM

Control

11.4%

20.9%

28.5%

38.9%

4.8%

12.2%

19.7% 22.2%

2.6% 4.3% 7.0% 7.0%

The

cum

ulat

ive

inci

denc

e of

HC

C

prog

ress

ion

(%)

Figure 2. The cumulative incidence rate of HCC in patients with liver cirrhosis

Figure 1. The cumulative incidence rate of HCC

ETV vs control (P < 0.001) ETV vs LAM (P < 0.043)

12

In HCC patients at high risk, the largest decrease of the incidence of HCC has occured in patients receiving ETV

treatment

*Log-rank test 1. Hosaka T, et al. Hepatology, 2012 Dec 5. doi: 10.1002/hep.26180. [Epub ahead of print]. 2. Yang HI, et al. Lancet Oncol 2011; 12:568-574. 3. Yuen MF, et al. J Hepatol 2009; 50:80-88. 4. Wong VWS, et al. J Clin Oncol 2010; 28:1660-1665.

5-year cumulative incidence rate of HCC(%)1

Risk Score Risk n ETV Control P* Yang HI 20112 Low

High 1272 342

1.1 8.3

2.4 23.9

0.313 0.006

Yuen MF 20093 Low High

1110 505

0.7 7.2

0.5 21.0

0.914 0.002

Wong VWS 20104 Low Middle High

1054 339 222

0.5 4.3 8.0

1.5 10.6 33.3

0.246 0.062

<0.001

Control

ETV

50

40 30

20 10

0 0 1 3 5

P = 0.062

1.0% 2.7%

6.9% 10.6%

Pts. at risk 146 ETV 193 Control

146 193

139 181

103 173

67 162

42 148

0% 0% 1.7% 4.3%

F 50

40

30

20

10

0 0 1 3 5

ETV

Control

P < 0.001

10.1%

19.0%

24.3%

33.3%

8.0% 8.0% 8.0% 4.5%

111 111 111 104 84 77 71

47 67 88 107 111

Pts. at risk

ETV Control

G

Year

Year

The

cum

ulat

ive

inci

denc

e of

HC

C (%

)

The

cum

ulat

ive

inci

denc

e of

HC

C (%

)

The

cum

ulat

ive

inci

denc

e of

HC

C (%

)

Year

Control ETV

50

40

30

20 10

0 0 1 3 5

P = 0.246

0.6% 0.6% 1.5% 1.5% The number of patients at risk

215 ETV 839 Control

215 839

200 789

140 734

99 696

52 658

0.2% 0.4% 0.5% 0.5%

E

13

Real-Life Study in Taiwan: C-TEAM interim report: ETV long-term treatment—— a significant reduction of disease

progression (HCC) risk in patients with cirrhosis

Su TH, et al. 64th AASLD meeting, Nov 1-5, Washington DC, USA. Poster 189.

• A multi-center study in Taiwan, 666 patients with cirrhosis receiving ETV monotherapy; 621 patients without treatment as the control group. In ETV group, the mean time of follow-up period was 2.7 years; in control group, the mean time of follow-up period was 9.1 years.

• During the 2.7 years of follow-up, 2.4% of patients in ETV group developed HCC; while it was 5.2% in control group (P=0.009)

• 2.7 years of ETV monotherapy reduced the risk of HCC by 59% in patients with cirrhosis

14

Main Content

Natural progression history of hepatitis B disease and epidemiology and risk factors of HCC

Effective long-term treatment of nucleoside (nucleotide) drugs could reduce the development and recurrence risk of HBV-related

liver cancer

The impact of resistance on incidence of HBV-related HCC

Part 1

Part 2 Effective long-term antiviral therapy can reduce the incidence of

HCC in patients with chronic hepatitis B Effective antiviral therapy can reduce the incidence of HCC recurrence in patients with HBV-related HCC

Part 3

15

Wu’s study: the impact of nucleoside (nucleotide) drugs on the recurrence of HCC

A prospective, national cohort study (2003-2010) in Taiwan *

All newly diagnosed HCC patients who underwent liver resection

The primary outcome: HCC recurrence > 3 months after resection +/- NUC treatment

Wu, CY, et al. JAMA, 2012 Nov 14;308(18):1906-14. |

NUC treatment (duration ≥90 days) N=518

NUC combination treatment

Effective hepatic resection for patients with newly diagnosis of HBV related HCC †

N= 4569

Non-NUC treatment N=4051

NUC combination treatment: combination treatment with nucleoside (nucleotide).

*Data from the Taiwan’s National Health Insurance (NHI) Research Database

(representing >99% of Taiwan total population). †Those who had accepted antiviral therapy for more

than 3 months before surgery were excluded.

LdT

16

Nucleoside (nucleotide) drugs reduced the recurrence risk of HCC

*In multivariate group, due to the high incidence of liver cirrhosis in the treatment cohort, the difference of absolute recurrence rate is less than that of HR recurrence (0.67; see the next slide)

Wu, CY, et al. JAMA, 2012 Nov 14;308(18):1906-14.

Follow up (years)

0 1 2 3 4 5 6 0

10

20

30

40

50

60 Th

e cu

mul

ativ

e in

cide

nce

rate

of H

CC

(%

)

Recurrence of HCC

Untreated

Treated (56% ETV

monotherapy)

P<0.001 45.6%*

54.6%*

4051 518 246 124 68 40 19 9

205 411 667 1080 1685 2697 Pts. at risk

Untreated Treated

17

Treatment with nucleoside (nucleotide) drugs reduced the risk of death

Wu, CY, et al. JAMA, 2012 Nov 14;308(18):1906-14.

Pts. at risk Untreated Treated

Cum

ulat

ive

over

all

mor

talit

y (%

)

Follow up (years)

0 1 2 3 4 5 6 0

10

20

30

40

50

60

Untreated

Treated

P=0.002

Overall mortality rate

29.0%

42.4%

4051 518 289 162 96 61 32 11

368 734 1177 1763 2506 3428

Conclusion: Patients with HCC who underwent liver resection and received NUC treatment (56% received ETV monotherapy) had significantly reduced recurrence rate of HCC and improved overall survival rate. Considering the baseline viral load, NUC treatment may have greater impact on the risk of HCC recurrence.

18

Lee's study: effects of ETV treatment on recurrence of HCC

A prospective, single-center cohort study (2007̶ 2011) in Korea

Objective: to investigate whether ETV will increase the risk of HCC recurrence

Lee D, et al. AASLD 2012; abstract 367.

Patients HBV-related cirrhosis, Child-Pugh level A Newly diagnosed HCC, Phase I Who accepted radiofrequency ablation (RFA) treatment

NUC monotherapy starts between 3 months before and after RFA

treatment

ETV N=29

Non-NUC treatment

N=58

Other NUCs N=19

19

In patients treated by ETV, HCC recurrence rate is lower than in those without NUC therapy

Lee D, et al. AASLD 2012; abstract 367.

Follow up (months) 12 24 36 48

0.0

0.2

0.4

0.6

0.8

1.0 H

CC

recu

rren

ce ra

te (%

)

Non-NUC treatment ETV Other NUCs

0

Pts. at risk

58 29 19

Treatment-naive ETV Other NUCs

31 21 12

1211 5

4 4 1

0 0 0

Multivariate analysis The risk of HCC recurrence ETV vs Non-NUC treatment: OR 0.454 P=0.015

ETV treatment after RFA could reduce the recurrence risk of HCC in patients with HCC; improve disease-free survival; and provide more potent anti-viral suppression compared with non-NUC treatment.

20

Main Content

Natural progression history of hepatitis B disease and epidemiology and risk factors of HCC

Effective long-term treatment of nucleoside (nucleotide) drugs could

reduce the development and recurrence risk of HBV-related liver cancer

Antiviral therapy with nucleoside (nucleotide) drugs could significantly reduce, but can't completely eliminate the risk of HCC

Part 1

Part 2

Effective long-term antiviral therapy can reduce the incidence of HCC in patients with chronic hepatitis B Effective antiviral therapy can reduce the incidence of HCC recurrence in patients with HBV-related HCC

Part 3

21

Resistance reduces the long-term benefit of antiviral therapy

Adapted from Liaw. Semin Liver Dis 2005; 25:40–47; Liaw et al. N Eng J Med 2004; 351:1521–1531

Wild-type（n = 221）

Time after random sampling (months)

0

5

10

15

20

25

0 6 12 18 24 30 36

Prop

ortio

n of

pat

ient

s with

di

seas

e pr

ogre

ssio

n（%）

Placebo（n = 215）

5%

21% M204I/V mutation（n = 209, 49%）

13%

22

Resistance may lead to progression of HCC in patients with HBV-related cirrhosis

A case-control study in Korea: 413 patients with HBV-related cirrhosis treated by lamivudine , 260 patients untreated

The median follow-up period is 4.7 years. 47.6% of patients treated by lamivudine experienced virologic breakthrough

Eun JR et al. J Hepatol; 53:118-25

The

inci

denc

e of

H

CC

(%)

Control group

Lamivudine resistance group

Sustained viral suppression group

Follow up (years)

P=0.144 (Control group vs Lamivudine resistance group) P=0.005 (Control group vs Sustained viral suppression group）

23

Kobashi's study: Drug resistance may lead to increased risk of HCC

A prospective study: 194 patients with CHB and 62 patients with liver cirrhosis were enrolled. Among them, 129 patients received ETV therapy and 127 patients received treatment with LVD.

Follow-up period last for 4.25 years, with a total of 60 patients developing LVD resistance

Kobashi H, et al. Hepatology Research 2011; 41:405-416.

LVDr 60 58 57 53 51 43 26 18 13 5 1 LVDs 67 66 62 61 57 51 37 24 18 9 1

LVDr

LVDs

Year

P=0.0352

The

inci

denc

e ra

te o

f HC

C (

%)

0 1 2 3 4 5 6 7 8 9 10

0.0

0.4

0.6

0.8

0.9

1.0

0.7

0.5

0.3

0.2

0.1 11.7%

20.3% 22.7%

42.0%

1.5% 3.2% 9.6%

26.5%

Number of patients at risk

24

Virological remission after salvage therapy could not reduce the risk of HCC in LAM-resistant patients

Papatheodoridis,GV,et al.J Hepatol 2010;53:348-56

The incidence of HCC after virologic response following salvage therapy in lamivudine resistant patients was analyzed by a meta-analysis: in the 104 patients without virological response, after 13 patients who developed HCC at the start of adefovir treatment being excluded, statistics data (8/91, 8.8% vs 19/320, 5.9%, p = 0.466) did not show any significant difference.

There was no difference in the incidence of HCC regardless the efficacy of salvage therapy.

982/852 320/91

P＜0.001

Column 1 Virological response Without virological response

Patient Without Nucleotide treatment Lamivudine-resistant

The

prop

ortio

n of

pat

ient

s w

ith H

CC

(%)

25

Despite antiviral therapy, the risk of HCC is still higher in CHB patients than in patients of immune

tolerance phase

Cho et al, Gut 2014, in press

26

Summary

Occurrence of HCC is associated with HBV infection. Hepatic cirrhosis, high

HBV DNA levels at baseline, sustained high viral load, high HBsAg levels are

independent risk factors of HCC.

For patients with chronic hepatitis B, sustained suppression of HBV

replication by nucleoside (nucleotide) drugs can reduce the risk of HCC,

especially for patients with hepatic cirrhosis.

For HCC patients after operation, antiviral treatment with nucleoside

(nucleotide) drugs can reduce or delay the recurrence of residual tumor in

liver tissue, and improve disease-free survival rate

Antiviral treatment with nucleoside (nucleotide) drugs could significantly

reduce , but can't completely eliminate the risk of HCC

27

Thank you!