台灣地區6歲幼童HBsAg 抗原陽性率

Hepatitis B vaccination program in Taiwan 2009/6/4 衛生署疾病管制局防疫醫師蘇韋如 1

Outline Disease description Policy and vaccine administration Follow-up studies (Efficacy/ Effectiveness) Safety issues 2

Where is HBV a problem, globally? The world can be divided into three areas where the prevalence of chronic HBV infection is: high (>8%), intermediate (2-8%), and low (<2%) 3

http://www.who.int/csr/disease/hepatitis/whocdscsrlyo20022/en/index1.html 4

慢性 B 型肝炎流行狀況全球約有 20 億的人感染 B 型肝炎 5

Geographic distribution of HBV genotypes and serotypes 6

Clinical features Fever, jaundice, malaise, anorexia, nausea and vomiting, abdominal pain (RUQ), myalgia,, dark-coloured urine and light- coloured stools Incubation periods for AHB: 45~160 days (average 120 days) Period of communicability: several weeks before the onset of acute illness to the end of illness In approximately 30 to 50% of adults, infection causes symptomatic acute hepatitis 8

Asymptomatic chronic infection: : Infants, young children (< 10yrs), and immunosupressed adults Among adults with normal immunse status, 94-98% 98% recovered from newly acquired HBV infections Chronically infected carriers of HBV, long- term presence (longer than 6 months) of circulating HBsAg Persons with CHB often detected in screening programs, e.g. blood donors, pregnant women etc. 9

Following acute infection, up to 90% of infected neonates remain persistently infected The Australian Immunization Handbook, 9 th ed 10

不同年齡層感染後慢性帶原比例出生時感染者,90%, 發展為慢性帶原 1-5 歲感染者,20, 20-50% 發展為慢性帶原幼年或成年感染者, 僅 1-10% 10% 發展為慢性帶原出生時即阻斷 B 型肝炎病毒感染, 成為疾病防治最重要的一環 11

The Transmission Route of HBV Mother to Baby (vertical transmission) Transfusion (blood, blood products) Fluids (blood, semen) Hepatitis B Virus Contaminated Syringes and needles Organs and tissue transplantation 12

Clinical and Laboratory Finding in HBV Infected Course Icterus ALT HBeAg HBsAg IgM-anti-HBc Anti-HBe IgG-anti-HBc // // 0 4 8 12 16 20 24 28 32 36 52 100 // // Anti-HBs // // Exposure weeks 13 ( 哈里遜內科學,1991)

B 型肝炎之血清學變化 ( 慢性帶原者 ) Resource:Principles and Practice of Pediatric Infectious Diseases, 2nd ed 14

Policy Birth dose: 72 hrs after birth (3-5 d/o) In 2005, 48 hrs after birth (2-5 d/o) HBIG was administrated for infants born to HBeAg(+) mothers (within 24hrs of birth) During 1984-1992, 1992, 4 doses of plasma- derived HBV vaccine were given at 0, 1, 2, 12 m/o. After 1992, 3 doses of recombinant HBV vaccine were given at 0, 1, 6 m/o. Catch-up programs 15

台灣地區 B 型肝炎疫苗預防接種計畫之時程及族群 * 民國七十六年七月至民國七十九年九月 : 學齡前孩童之 B 型肝炎預防注射為志願自費性質 ** 民國七十九年十月以後 : 國小一年級及學齡前之孩童,B 型肝炎疫苗補接種為免費性質民國八十年七月以後, 所有入小學新生皆須查預防接種黃卡紀錄 ; 若未接種或未完成接種者, 皆須接種 B 型肝炎疫苗 16

VPD Surveillance Manual, 4th ed., 2008 17

Engerix-B 在台灣小孩與大人ㄧ律使用 20μg VPD Surveillance Manual, 4th ed., 2008 18

VPD Surveillance Manual, 4th ed., 2008 19

孕婦 B 型肝炎篩檢及 B 肝疫苗接種流程圖孕婦 HBsAg 及及 HBeAg 篩檢低傳染性 e 抗原陰性 HBeAg(-) RPHA<1:2560 高傳染性 e 抗原陽性 HBeAg(+) 或 RPHA>=1:2560 新生兒接受 3 劑 B 型肝炎疫苗 ( 滿 2-5 天,1,6 月 ) 新生兒出生 24 小時內儘速接受 1 劑 B 型肝炎免疫球蛋白及 3 劑 B 型肝炎疫苗 ( 滿 2-5 天,1,6 月 ) 21

台灣地區孕婦 B 型肝炎篩檢率 (1990-2007) Period Screening rate(%) 1992-1993 1993-1994 1994-1995 1995-1996 1996-1997 1997-1998 1998-1999 1999-2000* 2000 2001 2001-2002 2002 2002-2003 2003 2003-2004 2004 2004-2005 2005 2005-2006 2006 2006-2007 2007 資料來源 :B 肝資訊 PHIS 及 NIIS 等系統 78.8 78.3 78.4 78.6 81.4 80.9 84.8 86.2 85.0 87.0 88.8 86.0 88.0 88.3 86.3 22

台灣地區孕婦篩檢情況 (1988-2007) period HBsAg (+) HBeAg (+) (7/1-6/30) No of Screened No. % No. % 77~78 年 205,882 36,256 17.6 15,866 7.7 78~79 年 231,347 39,678 17.2 15,633 6.8 79~80 年 242,200 42,395 17.5 14,208 5.9 80~81 年 247,614 42,698 17.2 14,756 6.0 81~82 年 254,671 43,841 17.2 15,155 6.0 82~83 年 254,511 43,601 17.1 14,319 5.6 83~84 年 258,807 42,628 16.5 13,597 5.3 84~85 年 255,349 44,628 17.5 13,135 5.1 85~86 年 264,914 44,042 16.6 13,384 5.1 86~87 年 247,332 39,374 15.9 11,186 4.5 87~88 年 233,947 34,053 14.6 10,657 4.6 88~89 年 * 387,739 53,645 13.8 15,150 3.9 90 年 ** 221,319 29,256 13.2 8,751 4.0 91 年 ** 184,143 22,188 12.0 6,458 3.5 92 年 ** 185,305 21,593 11.7 6,402 3.5 93 年 ** 182,112 20,533 11.3 5,590 3.1 94 年 ** 177,118 19,743 11.1 5,405 3.1 95 年 ** 182,321 19,995 11.0 5,297 2.9 96 年 ** 157,550 17,099 10.9 4,298 2.7 Total 4,374,181 657,246 15.0 209,247 23 4.8 *7/1/88-12/31/89(1.5year) **1/1/90-12/31/96

HBV Vaccine administration Coverage of birth dose (1st dose) given within 30 d/o is 94%. HBV-2 2 coverage: 97.7% HBV-3 3 coverage: 95.6% 24

幼兒 B 型肝炎預防注射完成率 98.5 98.3 98 97.6 97.7 97.5 97.1 97.1 97 97.1 97 96.5 96 95.5 95.1 95.1 95.4 95.1 95.7 B 型肝炎第 2 劑 B 型肝炎第 3 劑 95 94.5 94 93.5 91 92 93 94 95 96

國小新生 B 型肝炎預防注射完成率 100 99 99.5 99.1 99.6 99.2 99.6 99.3 99.6 99.2 99.6 99.4 98 97 第二劑完成率 96 第三劑完成率 95 92 93 94 95 96 入學年度

Follow-up studies 1. HBsAg positive rate and anti-hbs titers 2. Prevention of Acute Hepatitis B, Fulminant Hepatitis B, and Hepatocellular Carcinoma 27

1. HBsAg positive rate and anti-hbs titers 30

台灣地區 6 歲幼童 HBsAg 抗原陽性率 1986 年開始全面接種疫苗 (%) 12 10 8 6 4 2 0 10.5 6.3 1.7 0.8 1989 1991 1993 2007 DOH investigated Year Studied 31

Age-specific Prevalence of HBsAg among Children in Taipei City 1984,1989 and 1994 12 Positivity Rate of HBsAg,% 10 8 6 4 2 1984 1989 1994 0 <1 1-2 3-4 5-6 7-8 9-10 11-12 Age(yrs) 32 (Chen et al. JAMA,1996,1276:906-908)

全民 B 型肝炎預防注射兒童 B 型肝炎標記之七年縱向追蹤研究追蹤 7 年中 7-14 歲兒童其 HBsAg 陽性率及 anti-hbs 保護率年齡總數 anti-hbs(s/n>10) anti-hbs(%) HBsAg(%) 7 1337 782 58 0.7 8 1228 757 61 0.6 9 1134 590 10 歲以後 52 0.6 開始較明 10 1062 492 46 0.6 顯下降 11 1025 427 42 0.7 12 1016 341 33 0.8 13 888 253 27 0.9 14 789 205 25 1 帶原率未明顯增加 MH Chang et al. JID 2003;187 Mei-Hwei etal., JID 2003:187 33

結論 : 在青少年到達 15 歲以前, 不需要常態性的施打追加劑一施打疫苗後在各群之間 B 型肝炎病毒感染情形原 B 肝 marker 7 歲至 14 歲新 B 肝 marker 新的 HBsAg 新的 Anti-HBc 打疫苗群 HBsAg(+) Anti-HBc(+) 陽轉 No.(%) 陽轉, No.(%) Ia (n=267) booster 8 10 0(0%) 2(0.11%) Ib (n=200) 0 0 0(0%) 1(0.07%) II (n=683) 0 7 0(0%) 7(0.16%) total 8 17 0(0%) 10(0.13%) a 群 :7 歲時 B 型肝炎表面抗體 <10 miu/ml 的兒童, 在追蹤期間沒有施打任何追加劑 b 群 :7 歲時 B 型肝炎表面抗體 <10 miu/ml 並在 7 歲時施打追加劑 II 群 :7 歲時 B 型肝炎表面抗體 10 miu/ml 的兒童, 在追蹤期間沒有施打追加劑 MH Chang et al. JID 2003;187 34

Humoral and cellular immune respones to a HBV Vaccine booster 15-18 years after neonatal immunization Background. aimed to investigate long-term HB immunity in adolescents. Methods. 1. In 2004 2005, 6156 high school students (15 21 years old) who had been vaccinated with plasma-derived HBV vaccine as infants were recruited for HB seromarker screening. 2. The immune response to an HB vaccine booster was evaluated in 872 subjects who were seronegative. 3. HBV surface antibody (anti-hbs) titers and levels of HB surface antigen (HBsAg) specific interferon (IFN) or interleukin (IL) 5 secreting peripheral blood mononuclear cells (PBMCs; measured by enzyme-linked immunospot assay) were determined 4 weeks later. 35

6156 high school students were recruited for HBV serology checkup Birth cohort Age at study Number of subjects tested Number (%) of subjects positive for HBsAg Anti-HBc Anti-HBs Pre-1986 18-21 175 11 (6.3) 20 (11.4) 109 (62.2) Post-1986 15-18 18 5981 96 (1.6) 247 (4.1) 2215 (37.0) Total 15-21 6156 107 (1.7) 267 (4.3) 2324 (37.8) Chun-yi lu etal, JID,2008:197 36

A booster dose was given to 872 subjects with negative HBsAg,, anti-hbs HBs,, and anti-hbc Anti-HBs titer (miu/ml) Pre-booster No. (%) of subjects GMC Post-booster No. (%) of subjects GMC < 10 872 (100%) 0.75 255 (29.2%) 0.48 10-100 100 0 227 (26.0%) 38.0 >100 0 390 (44.7%) 426.6 GMC denotes geometric mean concentration. 29.2% 的人對 booster 沒有反應 Chun-yi Lu etal, JID,2008:197 37

Conclusion A notable proportion of fully vaccinated adolescents had lost immune memory conferred by a plasma-derived HB vaccine 15 18 years later. This decay of immune memory may raise concerns about the need for a booster vaccine for high-risk groups in the long run. 38

Two Decades of Universal Hepatitis B Vaccination in Taiwan: Impact and Implication for Future Strategies From Jan to Dec 2004, 18,779 subjects as follows: 17,637apparently healthy individuals youngerthan 20 years (born after 1984) 1142 individuals aged between 20 and 30 years. All of the subjects were recruited from schools, institutes,, or workplaces in Taipei City,, the same area in which the baselineand follow-up seroepidemiologic studies were conducted. Yen-Hsuan Ni etal.gastroenterology2007;132:1287-1293 39

Age, y No. Anti-HBs alone persons HBsAg (95% CI) (95% CI) <1 110 0.9 (0.7 1.1) 62.7 (61.9 63.6) 63.6) 1 2 235 0.4 (0.4 0.5) 0.5) 88.9 (88.7 89.2) 89.2) 3 4 709 0.4 (0.4 0.4) 0.4) 80.8 (80.7 80.9) 80.9) 5 6 993 0.5 (0.5 0.5) 0.5) 52.3 (52.1 52.4) 52.4) 7 8 651 0.6 (0.6 0.6) 0.6) 49.5 (49.3 49.6) 49.6) 9 10 681 0.3 (0.3 0.3) 0.3) 43.3 (43.2 43.5) 43.5) 11 12 12 1088 0.5 (0.5 0.5) 0.5) 41.7 (41.6 41.8) 41.8) 13 14 14 2767 0.6 (0.6 0.6) 0.6) 41.8 (41.8 41.9) 41.9) 15 17 17 6531 1.5 (1.5 1.5) 1.5) 34.9 (34.9 34.9) 34.9) 18 19 19 3872 2.1 (2.1 2.1) 2.1) 68.5 (68.5 68.5) 68.5) Total 17,637 1.2 48.4 20 21 21 346 6.7 (6.5 6.8) 6.8) 64.2 (63.9 64.4) 64.4) 22 23 23 256 10.2 (9.9 10.4) 60.9 (60.6 61.3) 61.3) 24 25 25 242 10.3 (10.0 10.6) 10.6) 51.7 (51.3 52.1) 52.1) 26 27 27 184 17.9 (17.5 18.3) 18.3) 41.8 (41.3 42.4) 42.4) 28 29 29 114 14.9 (14.3 15.5) 15.5) 31.6 (30.8 Yen-Hsuan Ni etal.gastroenterology2007;132:1287-1293 31.6 (30.8 32.4) 32.4) 40

Conclusion Universal HBV vaccination provides longterm protection up to 20 years, and a universal booster is not indicated for the primary HBV vaccinees before adulthood. Maternal transmission is the primary reason for vaccine failure and is the challenge that needs to be addressed in future vaccination programs. 41

2. Prevention of Acute Hepatitis B, Fulminant Hepatitis B, and Hepatocellular Carcinoma 42

台灣地區急性肝炎之分布比例 (2000-2007) 2007) acute hepatits D 1% acute hepatits C 22% acute hepatits E 2% acute hepatits A 29% acute hepatits A acute hepatits B acute hepatits C acute hepatits D acute hepatits E acute hepatits B 46% Data source:national Notifiable Disease Surveillance System (confirmed case) 43

急性 B 型肝炎報告確定病例及每十萬人口發生率 (2001-2007) 2007) 450 419 417 3.00 400 350 367 355 334 327 380 379 32321 2.60 2.20 300 250 200 150 100 1.58 1.85 1.45 1.67 275 264 1.80 245 1.41 202 1.40 1.08 1.00 0.88 0.60 報告病例確定病例每十萬人口發生率 ( 確定病率 ) 50 0.20 0 2001 2002 2003 2004 2005 2006 2007-0.20 Data source:national Notifiable Disease Surveillance System 44

急性 B 型肝炎確定病例之年齡分布 (2005-2007) 2007) Data source:national Notifiable Disease Surveillance System 45

Annual mortality from fulminant hepatitis in infant in Taiwan Year pop(0-1y) mortality from fulminant hepatitis No. (rate per 100,000) 1975 331,760 20(6.0) 1976 359,611 16(4.4) 1977 370,443 24(6.5) 1978 366,345 19(5.2) 1979 376,966 20(5.3) 1980 376,970 23(6.1) 1981 374,254 25(6.7) 1982 368,901 14(3.8) 1983 359,022 24(6.7) 1984 345,625 10(2.9) 1985 325,084 15(4.6) 46

Year pop(0-1y) mortality from fulminant hepatitis No. (rate per 100,000) 1986 302,342 6(2.0) 1987 289,687 5(1.7) 1988 300,777 6(2.0) 1989 304,541 9(3.0) 1990 309,435 13(4.2) 1991 315,568 2(0.6) 1992 307,460 9(2.9) 1993 306,815 4(1.3) 1994 299,810 1(0.3) 1995 297,261 2(0.7) 1996 303,000 1(0.3) 1997 305,622 3(1.0) 1998 281,091 1(0.4) J of pediatrics 2001 47

Since the institution of a program of mass hepatitis B vaccination in Taiwan, the mortality associated with fulminant hepatitis in infants has declined significantly 48

台灣地區不同出生世代六至九歲兒童肝細胞癌發生率出生日期年發生率 ( 十萬分之一 ) 1974/7-1984/6 0.52 1984/7-1986/6 0.13 資料來源 : Mei-Hwei Chang, et al. N Engl J Med 1997: 336:1855-9

HCC MH Chang et al. 50

Safety Data source: form VICP (vaccine injury compensation program) since 1987 During 1987-2008, 15/344 (4.4%) apply for HBV-related vaccine injury, 12/15 (80%) with compensation The reasons of compensation: most are time relationship, no causal relationship Death (n=7), severe local reaction (n=2), Steven-Jonson syndrome (n=1), vasculitis (n=1) etc. 52

Thank you! wei-ju@cdc.gov.tw Office: 02-23959825 23959825 ext 3663 53