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1 HPV 感染與 HPV 疫苗衛生署疾病管制局中區傳染病防治醫療網王任賢指揮官

3 人類乳突病毒 (Human Papilloma Virus) - HPV 無外膜雙股 DNA 病毒 1 已找到超過 200 種型別 2, 其中超過 80 種型別已完成分類 1. Howley PM, Lowy DR. In: Knipe DM, Howley PM, eds. Philadelphia, Pa: Lippincott-Raven; 2001: Schiffman M, Castle PE. Arch Pathol Lab Med. 2003;127:

4 Normal Epidermis

HPV Replication & Transcription in the Epidermis Infects basal cells of dermal layer (low level of transcription & replication) DNA amplification

5 HPV Replication & Transcription in the Epidermis Infects basal cells of dermal layer (low level of transcription & replication) DNA amplification and capsid proteins made in the upper spinous layer Transcription increases in the spinous layer Squames released at surface to release viral particles

6 HPV Transmission Skin to Skin Contact

7 HPV Types Two major phylogenetic branches, differing affinities for site of infection Cutaneous: Keratinized squamous epithelium (genital & nongenital) Mucosal: Non-keratinized squamous epithelium (genital & nongenital)

8 Common & Plantar Warts

9 Common warts with thrombosed vessels (black dots). (From Medical Microbiology, 4 th ed., Murray, Rosenthal, Kobayashi & Pfaller, Mosby Inc., 2002, Fig

10 Nongenital Mucosal Laryngeal papilloma Conjunctival papillomas

11 Genital Warts

12 HPV Mucosal Types & Variants More than 30 types found in anogenital tract Low risk types: rarely found in cancers, HPV 6 & 11 are the most common types High risk types: frequently found in cancers, HPV 16 & 18 are the most common types High risk types most prevalent in population, regardless of disease status Variants best characterized for HPV 16 E6/E7 polymorphisms could modify oncogenicity Cross-reactive in ELISA assays

13 Three Forms of HPV Infection Residential Usually minimally six weeks from exposure Can persist undetected for decades Can be LR or HR type Can be prevented with vaccination Episomal Virally active HPV located in the cell nucleus Separate from the human DNA Can be LR or HR type Can cause abnormal Pap tests Can be seen colposcopically Can be prevented with vaccination Integrated HPV DNA circle has opened and joined the human DNA Only HR types Causes abnormal Pap tests Seen colposcopically: must be treated to prevent cancer Can be prevented with vaccination

14 HPV Genome: Episome URR E6 trans formation P97 E7 L2 caps id prote ins L1 late cytoplas mic prote in E4 E1 e pis ome re plication E5 trans formation E2 trans criptional re gulator

15 Residential

16 Episomal vs. Integration Episomal HPV 16 Releasing infectious particles into the cervical and vaginal secretions Integrated HPV 16 Basal Stem Cell HPV Infection CIN 2/3

17 Duration of HPV Infection HPV Types Months, median (95% CI) Franco (1999) Oncogenic Oncogenic 8.1 ( ) Woodman (2001) HPV ( ) HPV ( )

18 EPIDEMIOLOGY OF HPV INFECTION LUDWIG/MCGILL COHORT STUDY Prevalence HPV 13.8 % Non-oncogenic: 5 months Oncogenic: 8 months 38.9% HPV (+) by 18 months Franco, et al. JID 1999;

19 生殖器相關的人類乳突病毒之分類 (Human Papilloma Virus) - HPV 生殖器相關的乳突病毒約有 30~40 種 1,2, 可分成高危險型 ( 致癌型 ) : 共 15~20 種為 1,2, 其中 HPV 第型為主要造成子宮頸癌的型別 3 低危險型 ( 非致癌型 ) :HPV 第 6 11 型是引起 >90% 的尖頭濕疣 ( 菜花 ) 型別 2,4 子宮頸癌與菜花都是 HPV 病毒所引起之傳染病, 均可由疫苗注射而得到防治 1. Schiffman M, Castle PE. Arch Pathol Lab Med. 2003;127: Wiley DJ, Douglas J, Beutner K, et al. Clin Infect Dis. 2002;35(suppl 2):S210 S Muñoz N, Bosch FX, Castellsagué X, et al. Int J Cancer. 2004;111: Jansen KU, Shaw AR. Annu Rev Med. 2004;55:

20 HPV 引起的女性疾病尖頭濕疣 ( 菜花 ) 子宮頸上皮細胞輕度病變復發性呼吸道乳突瘤子宮頸癌肛門癌陰道癌會陰癌 20

21 HPV 引起的男性疾病 HPV 隱性感染 1 尖頭濕疣 1 ( 菜花 ) 陰莖癌前病變 (PIN) 1 肛門癌前病變(AIN) 2 陰莖癌 1 肛門癌 3 頭頸部癌 4 復發性呼吸道乳突瘤 5 1.Gross G, Pfister H. Med Microbiol Immunol (Berl). 2004;193: Lillo FB. New Microbiol. 2005;28: Frisch M, Glimelius B, van den Brule AJC, et al. N Engl J Med. 1997;337: Gillison ML, et al. J Natl Cancer Inst. 2000;92: Derkay CS. Laryngoscope. 2001;111:

22 HPV Infection and Cervical Cancer Carcinogenic by epidemiologic definition HPV type % Odds Ratio 16 59% % % % ,35,51,52,58,

23 尖頭濕疣全球盛行 : 中國大陸感染 HPV 6 11 型人數 ( 無論男女 ) 遠超出其他 HPV 型別 Male (N=395) Female (N=478) HPV types No. % No. % Wang H, Qiao YL. Int J STD AIDS. 19(10):680-4, 2008

24 尖頭濕疣全球盛行 : 香港 1 感染 HPV 6 11 型佔高達 89.3% 1. Paul K.S. Chan and etc., Journal of Clinical Virology (2008) P

25 尖頭濕疣 - 國內性病排行榜第 1 名國人罹患淋病等性病的盛行率是十萬分之兩千四百人, 其中菜花佔 1,871 人, 佔性病人口 75% ( 是第 2 名淋病的 4 倍 ) 且國人罹患尖頭濕疣的盛行率飆升, 男性是十年前的 8 倍, 女性則高達 11 倍, 成長速度令人憂心! 25

26 HPV 病毒是唯一一個可以不經性行為傳播之性病病原菌

27 UW Students A UW study found that more than 60% of college women became infected over 5 years. SOURCE: GRAPH ADAPTED FROM R. L. WINER ET AL., AMERICAN JOURNAL OF EPIDEMIOLOGY 157, 218 (2003)

28 HPV 很容易在醫療環境中發現 28 S Strauss et. el, Contamination of environmental surfaces by genital human papillomavirus, Sex Transm Inf 2002; 78;

29 公共場所中隨處可找到 HPV 病毒 HPV 病毒可能經由觸摸被帶走, 因此醫療院所中的菜花危機, 便有可能就潛藏在我們生活週遭的公共場所中廁所門把水龍頭馬桶沖水按鈕把手病房床單病床遙控器民眾務必養成良好衛生習慣, 常洗手, 避免用不潔的手接觸身體黏膜處 ( 如 : 眼耳鼻生殖器官等 )! 29

30 尖頭濕疣傳染途徑性接觸傳染非性接觸性交或非侵入性性交生殖器 - 生殖器手生殖器口生殖器使用保險套能幫助降低風險, 但無法完全保護隔離 HPV 感染自體其他部位感染 / 接觸式感染產婦傳染新生兒 ( 垂直感染 ) 污染物 ( 例如 : 不潔內衣褲, 手術用具與手套 ) 衛生不潔的公共場合非自願性傳染 : 由於潛伏期長, 加上感染初期病徵不清楚, 病患可能在不知情的狀況下持續傳染給他人! 30

尖頭濕疣病徵男性多長在陰莖冠狀溝龜頭包皮陰囊女性多長在陰唇陰道壁和子宮頸, 也可能長在肛門周圍直腸口腔聲帶感染菜花的患部表面成乳頭狀突起, 但漸漸增生成簇傳染力 :75%; 復發率 :4 分之 1

31 尖頭濕疣病徵男性多長在陰莖冠狀溝龜頭包皮陰囊女性多長在陰唇陰道壁和子宮頸, 也可能長在肛門周圍直腸口腔聲帶感染菜花的患部表面成乳頭狀突起, 但漸漸增生成簇傳染力 :75%; 復發率 :4 分之 Soper DE. In: Berek JS, ed. Novak s Gynecology. 13th ed. Lippincott Williams & Wilkins, 2002:

32 案例 : 性接觸傳染 Anthony Wisdom, 1989: A color atlas of sexually transmitted diseases. Year Book Medical Publishers, Chicago, 296pp. 32

33 案例 : 非性接觸傳染照片出處 :2009/10/25 蘋果日報健康版照片出處 :2009/11/07 聯合報健康版 33

34 防堵尖頭濕疣困難重重傳染力高 : 一但感染 HPV, 傳染給他人機會為 75% 復發率高 : 無法以藥物根治, 復發率為 4 分之 1 治療痛苦指數高 : 需反覆電燒或化學燒灼女性罹癌機率高 : 高風險型與低風險型傳染途徑一樣, 也常合併出現, 伴侶未來罹患子宮頸癌機率提高, 若為產婦, 恐傳染腹中胎兒, 影響孩子的健康潛伏藏匿性高 : 潛伏期長達 3 週至 8 個月之久, 甚至有 1 年未接觸異性才發病男女應積極防衛, 嚴格管制感染來源 34

35 TCA EF CRYO ALEX FERENCZY, MD Traditional provider administered LASER 35

36 Home therapies 0.5% PODOPHYLLOTOXIN All have adverse events: burning to scarring 36 ALEX FERENCZY, MD

37 HPV Vaccination

38 Vaccines on the Horizon SOURCE: Merck and GSK. Science Magazine, Vol. 308, Issue 5722, pages , 29 April 2005

39 Randomized Controlled Trials Phase II - HPV Vaccines Reference Quadrivalent Vaccine 1 Bivalent Vaccine 2 Villa LL et al., Lancet Oncology Online, April 7, 2005 Harper DM et al., Lancet 364: , November 2004 Vaccine Type Quadrivalent HPV-6/11/16/ 18 VLP, L1 capsid component Bivalent HPV-16 and HPV-18 VLP, L1 capsid component Manufacturing Yeast Insect Cells (Baculovirus) Concentration 20 µg HPV 6 40 µg HPV µg HPV µg HPV 18 Adjuvant 225 µg Aluminum Hydroxyphosphate Sulfate 20 µg HPV µg HPV µg Aluminum Hydroxide with 50 µg 3-deacylated monophosphoryl lipid A (AS04) 1 Villa LL, et al. Lancet Oncol. 2005;6: Harper DM, et al. Lancet. 2004;364:

40 Quadrivalent Vaccine 1 Bivalent Vaccine 2 Dose and Administration 0.5 ml, intramuscular 0.5 ml, intramuscular Schedule 0, 2, 6 months 0, 1, 6 months Trial Size 277 vaccinees, 275 placebo 560 vaccinees, 553 placebo Site US, Brazil, Europe US, Canada, Brazil Age Range of Women years years Key Eligibility Requirements No history of cervical lesions, few sexual partners No history of cervical lesions, few sexual partners Duration Up to 35 months Up to 27 months Primary Endpoint Persistent Type-Specific HPV Persistent Type-Specific HPV 1 Villa LL, et al. Lancet Oncol. 2005;6: Harper DM, et al. Lancet. 2004;364:

41 ATP Group Quadrivalent Vaccine 1 Bivalent Vaccine 2 (cx/cxvag samples) Efficacy in Preventing Persistent Vaccine Specific HPV type Infections HPV 6 HPV 11 HPV 16 HPV 18 89% (95% CI: P/V: 47/6 events) 100% (95% CI: P: 13 events) NS (P: 3 events) 86% (95% CI: P/V: 21/3 events) 89% (95% CI: P/V: 9/1 events) 100% (95% CI: P: 16 events) Not a Study Aim Not a Study Aim 100% (95% CI: P: 13 events) 100% (95% CI: P: 4 events) 1 Villa LL, et al. Lancet Oncol. 2005;6: Harper DM, et al. Lancet. 2004;364:

42 ITT Group Quadrivalent Vaccine 1 Bivalent Vaccine 2 (cx/cxvag samples) Efficacy in Preventing type specific associated Cytologic Abnormalities Efficacy in Preventing Any type specific associated Lesions CIN Lesions External Genital Warts Not Reported 100% (95% CI: ) 10 placebo events 100% (95% CI: ) (7 events) 100% No CI (4 events) 94% (95% CI: 70-98) 100% (95% CI: ) 6 placebo events 100% (6 events) Not a Study Aim 1 Villa et al. Lancet Oncol. 2005;6: Harper et al. Lancet. 2004;364:

43 Quadrivalent Vaccine 1 Bivalent Vaccine 2 Acceptable rate of adverse events Yes Yes Serious Adverse Events No No Seroconversion 100% 100% Specific Titers compared to Natural Infection at Month 7 Specific Titers compared to Natural Infection at follow-up 10 times greater for HPV 6 10 times greater for HPV times greater for HPV times greater for HPV months 1.4 times greater for HPV 6 No greater for HPV times greater for HPV 16 6 times greater for HPV times greater for HPV times greater for HPV month 100 times greater for HPV times greater for HPV 18 1 Villa et al. Lancet Oncol. 2005;6: Harper et al. Lancet. 2004;364:

44 Efficacy of HPV Vaccines for HPV 16 or 18 (+) CIN 2,3 Per protocol analysis Quadrivalent Vaccine 1 P/V (n=5258/5301) 100% 95% CI: 76, 100 P/V: 21/0 P/V (n=5766/5736) 97% 95% CI: 83, 100 P/V: 36/1 Intention-to-treat Phase III Trial Skjeldestad FE, et al. IDSA. San Francisco, Abstract LB-8a.

45 Recommendations The Advisory Committee on Immunization Practices (ACIP) 1. Routine vaccination 2. Catch-up vaccination 3. Special situations 4. Precautions and contraindications CDC Policy

46 HPV Vaccine Recommendations (1) Routine Vaccination ACIP recommends that HPV vaccine be routine given for girls when they are 11~12 years old ACIP allows for vaccination of girls beginning at 9 years old. CDC Policy

47 HPV Vaccine Recommendations (2) Catch-up Vaccination ACIP recommends that HPV vaccine (GARDASIL) is indicated in females aged years for the prevention of CIN, cervical cancer, and infection caused by HPV 6, 11, 16 and 18. Immunization Catch-Up (ICU) CDC Policy

48 VFC ( Vaccines for Children ) The Vaccines for Children (VFC) Program automatically covers vaccines recommended by the Advisory Committee on Immunization Practices (ACIP) and approved by the Centers for Disease Control and Prevention (CDC).

50 What are we vaccinated? Quadrivalent Vaccine 1 Bivalent Vaccine 2 Quadrivalent HPV Vaccine 6,11,16, 18 VLP, L1 capsid component Bivalent HPV 16 and 18 VLP, L1 capsid component 20 µg HPV 6 40 µg HPV µg HPV µg HPV µg Aluminum Hydroxyphosphate Sulfate 20 µg g HPV µg g HPV µg g Aluminum Hydroxide with (MPL) 50 µg g 3-deacylated monophosphoryl lipid A (AS04)

51 How to vaccinate? 應在上臂的三角肌區域, 或是在大腿較高的前外側區域給予肌內注射不可注入血管內不建議皮下和皮內使用在使用之前必須徹底搖勻, 以保持疫苗的懸浮性如果該產品有顆粒存在或變色, 請勿使用並將其丟棄

52 HPV Vaccine 冷藏在 2 到 8 不可冷凍避光儲存 GARDASIL 若自冷藏狀態中拿出, 應儘早使用若自冷藏狀態移出, 在 25 C 或以下之室溫, 則可保存至三天 No Drugs interaction : steroid, hormone, immunosuppressive drugs May vaccinate combined with other vaccination

53 Clinical Schedule Schedule: 0, 2, 6 months 0.5 CC 1. 在 1 年內完成全部三劑接種的人都具有保護效力 2. 第二劑量必須距接種首劑後 1 個月以上才能施打 3. 第三劑必須在第二劑施打至少 3 個月之後才能使用第三劑必須在一年內施打 Payment: Consultation fee?: 200~500 $NT dollars Self-pay profit?: 5%

54 四價 HPV 疫苗可有效防護尖頭濕疣四價 HPV 疫苗可以降低 90.4% 由 HPV 6/11/16/18 引起的生殖器外部病變尖頭濕疣單獨防護效果高達 89.4% 美國食品藥物管理局 (FDA) 現已核准男性施打四價 HPV 疫苗防護因 HPV 病毒 6 11 型所引起的尖頭濕疣 TUA Lecture: The Efficacy of Quadrivalent (Types 6/11/16/18) HPV Vaccine Against HPV-related Genital disease and Infection in Young Men - Protocol

55 核准男性施打 HPV 疫苗防護的國家目前全球有超過 40 個國家核准男性施打 HPV 疫苗, 包括澳洲墨西哥美國及其他歐盟國家 ( 如 : 義大利法國德國比利時西班牙奧地利等 ) 其中澳洲在年間提供男性公費施打 HPV 疫苗後, 尖頭濕疣罹患率大幅下降 50% 55

56 結論若罹患菜花, 感染另外一半的機率高達 75% 菜花復發率高, 超過 30% 的女性在四個月後再度復發 1 超過 90% 的菜花為 HPV 第 6 11 型所引起的, 由於與高風險病毒感染途徑相同, 一旦感染高風險 HPV 病毒, 未來罹患相關癌症的風險上升菜花傳染途徑並非只有性, 其實透過接觸也可能感染菜花, 應破除傳統社會觀念, 了解感染來源才可有效控管與防治! 而傳播者男性也應自我控管 1. Lacey CJN. J Clin Virol 2005;32(suppl):S82-S90. 56

57 菜花疫苗疫苗子宮頸癌摸蛤子兼洗褲

58 謝謝大家! 58

< 愛滋病毒感染與人類乳突病毒感染之相關問題. 上 > 毒在細胞核中複製病毒基因可分為三個區塊, 包括非轉錄的長調控區 (noncoding long control region;lcr, 約 1 Kb)

< 愛滋病毒感染與人類乳突病毒感染之相關問題. 上 > 毒在細胞核中複製病毒基因可分為三個區塊, 包括非轉錄的長調控區 (noncoding long control region;lcr, 約 1 Kb) 人類乳突病毒介紹張淑媛台大醫學院醫技系人類乳突病毒, 或稱人類乳頭狀瘤病毒 (Human papillomavirus,hpv ) 是一種無套膜 (un-enveloped) 具二十面體外殼 (capsid) 的雙股 DNA 病毒人類乳突病毒為乳突瘤病毒科成員之一, 能夠