Chronic HBV Infection and HCC in China

Jidong Jia, MD, PhDLiver Research Center

Beijing Friendship HospitalCapital Medical University

March 15, 2008, Hangzhou

Outlines

• HBV Infection and HCC• HBV viral load and HCC• HBV vaccine prevent HCC• Antiviral therapy to prevent HCC

Geographic Distribution of Chronic HBV Infection

HBsAg Prevalence≥8% - High 2-7% - Intermediate <2% - Low

CDC

HBsAg Prevalence in China(1992)

Jiangxi

Shaxi

Chongqing

Heilongjiang

Jilin

LiaoningInner M

ongolia

Beijing

TianjinHebei

Shandong

Jiangsu Shanghai

Zhejiang

TaiwanFujian

Guangdong

Hainan

GuaangxiYunnan

Guizhou

Sichuan

Tibet

Xinjiang

Qinghai

Gansu

Ningxia

Shanxi Henan

Hubei

Hunan

Anhui

HBsAg Prevalence

4~6%

7~8%

≥ 9%

National Survey of Serum Epidemiology of Viral Hepatitis in China. (part 1)（1992～1995),Science &Technology Literature Press, 1997

9.75%

Natural History of Chronic HBV Infection

AcuteInfection

Chronic CarrierChronic Carrier

ResolutionResolution

30 - 50 Years

ChronicHepatitis

StabilisationStabilisation

ProgressionProgression

Cirrhosis

CompensatedCompensatedCirrhosisCirrhosis

HCC Death

Adapted from Feitelson, Lab Invest 1994

DecompensatedDecompensatedCirrhosisCirrhosis((DeathDeath))

胃癌肝癌肺癌食管癌结直肠癌白血病子宫颈癌乳癌鼻咽癌膀胱其它

Chin J Oncol 1997

Stomach

LiverLungs

Esoph

Others

Colon-rect

LeukemiaUreters

HCC: No 2 Cause of Malignancy-deaths in China

Mortality Rate of HCC in 2006(deaths/100 000)

Small-medium cities24.50 54.54

Major cities 20.65 30.43

• All ages • >50 yrs

Year Book on Health Statistics:2007

wwww.moh.gov.cn/open/statistics/year2007/p270.htm

Chronic HBV infection and HCCChronic HBV infection and HCCin Taiwan, Chinain Taiwan, China

HBsAgHBsAg HBeAgHBeAg ALTALT Relative RiskRelative Risk---- ---- normnorm 11 (23/71,105 person(23/71,105 person--yr)yr)

---- ---- ↑↑ 5.45.4++ ---- Norm Norm 10.310.3++ ---- ↑↑ 29.329.3++ ++ Norm Norm 61.361.3++ ++ ↑↑ 109109

Yang et al NEJM, 2002; 347:168-74

Incidence of HCC among Different HBV Status

Study Sample F/U (yr) incidence (%)HBVHBV carriercarrierBeasley 1981 3032 3.3 0.27Beasley 1988 3414 8.9 0.47CHBCHBBeasley 1981 390 3.3 0.62Beasley 1988 407 8.9 0.77Liaw 1986 432 2.2 0.83*Lo 1982 52 3.8 1.0Cirrhosis Cirrhosis Beasley 1988 40 8.9 2.2Liaw 1989 76 2.9 2.8Chen 1994 657 5.0 3.5 Lo 1982 24 3.8 4.4

HBV DNA Level and Disease Progression including Occurrence of HCC

0

2

4

6

8

10

12

14

0 1 2 3 4 5 6 7 8 9 10 11 12 13Year of follow-up

Cum

ulat

ive

inci

denc

e of

HC

C %

>10>1066cpmcpm

101055--101066cpm cpm

101044--101055cpm cpm 300300--101044cpm cpm < 300cpm < 300cpm

REVEAL: Higher viral loads are associated with increased rate of HCC

1515%%

1.3%1.3%

RR=11RR=11

Chen CJ, et al. JAMA. 2006;295:65-73.

Haimen study: HCC Mortality by HBV Viral Load at Baseline

1.00

0.96

0.92

0.88

0.84

0.800 1 2 3 4 5 6 7 8 9 10 11 12

Surv

ival

Dis

trib

utio

n Fu

nctio

n

Survival Time (Years)

HBV DNA High (+)>105 copies/mL

RR=9.9 (3.2–31.0)

HBV DNA Low (+)1.6x103– <105 copies/mL

RR=1.8 (0.5–5.8)

HBV DNA (-)<1.6x103

copies /mL

Chen G, et al Am J Gastroenterol 2006;101:1797–1803

Haimen study: Chronic Liver Disease Mortality by HBV Viral Load at Baseline

1.00

0.96

0.92

0.88

0.84

0.800 1 2 3 4 5 6 7 8 9 10 11 12

Surv

ival

Dis

trib

utio

n Fu

nctio

n

Survival Time (Years)

HBV DNA Low (+)1.6x103– <105 copies/mLRR=1.5 (0.2–11.8)

HBV DNA (-) <1.6x103 c/mL

HBV DNA High (+)>105 copies/mL

RR=13.4 (1.9–97.1)

Chen G, et al Am J Gastroenterol 2006;101:1797–1803

Routine HBV Vaccination in the World，2002Yes No

Prevent HCC by HBV Vaccination

Routine infant HBV vaccination

recommended, but families must pay for the vaccine & service

1st Jan 1992 1st Jan 2002

HBV vaccine integrated into EPI, but families must

pay for the service (~1 US$)

1st Jun 2005

HBV vaccine fully integrated into EPI for free

Universal Hepatitis B Vaccinationin Newborns in China

Jiangxi

Shaxi

Chongqing

Heilongjiang

Jilin

LiaoningInner

Mongolia

BeijingTianjinHebei

Shandong

Jiangsu Shanghai

Zhejiang

TaiwanFujian

Guangdong

Hainan

GuaangxiYunnanGuizhou

Sichuan

Tibet

Xinjiang

Qinghai

Gansu

Ningxia

ShanxiHenan

Hubei

Hunan

Anhui

Jiangxi

Shaxi

Chongqing

Heilongjiang

Jilin

LiaoningInner

Mongolia

BeijingTianjinHebei

Shandong

Jiangsu Shanghai

Zhejiang

TaiwanFujian

Guangdong

Hainan

GuaangxiYunnanGuizhou

Sichuan

Tibet

Xinjiang

Qinghai

Gansu

Ningxia

ShanxiHenan

Hubei

Hunan

Anhui

Geographic Distribution of HBsAg Prevalence in China

HBsAg Prevalence

≥ 9%

4~6%

7~8%

National Survey for HBV Prevalence, 2004

National Survey for HBV Prevalence, 1992~1995

19952004

HBsAg + (%)

9.79.0

Year

1~ 2~ 3~ 4~ 5~ 6~ 10~ 15~ 20~300

2

4

6

8

10

12

HB

sAg

Prev

alen

ce (%

)

Years of Age

2004

1992~1995

2.23.6

4.5

8.5

10.2 10.5

2.2 2.4

4.8

7.1

9.29.7

12.011.7 11.212.7

11.510.5

13

Age Distribution of HBsAg Prevalence in 1992~1995 & 2004National Surveys for HBV Prevalence, 1992~1995 & 2004

Mortality of Liver Cancer of Different Age Groups in Longan County, Guangxi Zhuang Autonomous

Region

Age (Yrs)

10~

20~

30~

40~

50~

≥60

Population

1969-1988

No. HCC(1/100,000)

No. HCC(1/100,000)

Population

Times of Decline

1996-2001

1585 365

836 197

615 279

530 998

388 921

456 126

484 390

415 159

261 755

194 943

159 779

190 543

2( 0.4)

53(12.8)

154(58.8)

162(83.1)

145(90.8)

118(61.9)

91( 5.7)

438( 52.4)

807(131.2)

758(142.8)

469(120.6)

265( 58.1)

14.3

4.1

2.2

1.7

1.3

0.9

Li RC, et al. Chin J Hepatol 2004; 12

Mor

talit

y of

HC

C (p

er 1

00,0

00 )

1

0

2

3

4

5

6

5.7

2.6

0.0

P < 0.01

1969~1985 1986~1992 1993~1996

Li RC, Yang JY, Gong J, et al. Proceedings of the Ninth National Symposium on Viral Hepatitis, 1998, Hangzhou, 79-82

Before Vaccination After Vaccination

Mortality Rates of HCC in Children Aged 10~19 Years in Longan County, Guangxi Zhuang Autonomous Region

before and after HBV Vaccination

0

0.2

0.4

0.6

0.8

1.0

1981~1986 1986~1990 1990~1996

0.7 0.57

0.36

Chang MH, et al. N Engl J Med 1997

Changes in Incidence Rates of HCC among Children 6~14 years of age in

Taiwan

Inci

denc

e (/1

0,00

0)

Hepatitis B ImmunizationDecreases HCC In Singapore

Age-standardised incidence rate ofliver cancer in males, 1968-1997

28.8 27.6 27.8

22.919.0 18.9

0

10

20

30

40

50

1968-72 1973-77 1978-82 1983-87 1988-92 1993-97

Year

Inci

denc

e ra

te p

er 1

00,0

00

Lyn James，Deputy Director (Communicable Diseases)Epidemiology & Disease Control Division, Ministry of Health,Singapore

Antiviral Therapy to Reduce the Incidence of HCC

InterferonsInterferons Reduce HCC Incidence Reduce HCC Incidence in Cirrhotic Patientsin Cirrhotic Patients

IFNIFN

5185183434404049499494

ContrContr

162162282850509797219219

IFNIFN

001.41.41.41.4

1.51.5

ContrContr

6.26.23.63.61.71.7

3.33.3

RRRR

0.030.030.40.40.960.960.980.980.450.45

SigaporeSigaporeItalyItalyEuropeEuropeItalyItalyJapanJapan

Case NCase N HCC Incidence HCC Incidence

Oon CJ, et al. Cancer Chemother Pharmacol, 1992,31(Suppl 1):S137-S142 Mazzella G, et al. J Hepatol, 1996,24:141-147Fattovich G, et al. Hepatology, 1997,26:1338-1342International Interferon-alfa Hepatocellular Carcinoma Study Group. Lancet, 1998,351:1535-1539Ikeda K, et al. Cancer, 1998,82:827-835

24

HC

Cdi

agno

sis

Diagnostic time（m）

Lam

Placebo

P=0.047

Excluding the 5 cases of 1 sr yr, HR=0.47; P=0.052

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

Lam Reduces HCC IncidenceLam Reduces HCC Incidence

5%

10%

25

Wild type (n=221)YMDD variant (n=209) (49%)

Time after randomizaiton (m)

0

5

10

15

20

25

0 6 12 18 24 30 36

Dis

ease

pro

gres

sion

% Placebo (n=215)

YMDD variant

Wild

Placebo

5%

13%

21%

Liaw et al, NEJM 2004

Lam Prevents Disease Progression Lam Prevents Disease Progression

26

Antiviral Agents for HBV in ChinaAntiviral Agents for HBV in China

InterferonsConventional IFN alphaPEG-IFN alpha

Nucleos(t)ide analogsLamivudineAdefovir dipivoxilEntecavirTelbivudine

Guideline on the Prevention and Treatment of CHB

Chinese Society of HepatologyChinese Society of Infectious Diseases

Dec 10, 2005

The Great Hall of People

中华医学会肝病学分会中华医学会肝病学分会 中华医学会感染病学分会中华医学会感染病学分会

China Chronic Hepatitis B Education Program(CCHEP)

Acknowledgement

Special thanks to Prof Zhuang Hui at PU

for give me some excellent slides

in this talk!