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
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; 2001:2197 2229. 2. Schiffman M, Castle PE. Arch Pathol Lab Med. 2003;127:930 934. 3
Normal Epidermis
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
HPV Transmission Skin to Skin Contact
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)
Common & Plantar Warts
Common warts with thrombosed vessels (black dots). (From Medical Microbiology, 4 th ed., Murray, Rosenthal, Kobayashi & Pfaller, Mosby Inc., 2002, Fig. 49-4.
Nongenital Mucosal Laryngeal papilloma Conjunctival papillomas
Genital Warts
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
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
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
Residential
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
Duration of HPV Infection HPV Types Months, median (95% CI) Franco (1999) Oncogenic Oncogenic 8.1 (6.0-12.6) Woodman (2001) HPV 16 10.3 (6.8-17.3) HPV 18 7.8 (6.0 12.6)
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;180-1415-23.
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 16 18 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;127:930 934. 2. Wiley DJ, Douglas J, Beutner K, et al. Clin Infect Dis. 2002;35(suppl 2):S210 S224. 3. Muñoz N, Bosch FX, Castellsagué X, et al. Int J Cancer. 2004;111:278 285. 4. Jansen KU, Shaw AR. Annu Rev Med. 2004;55:319 331. 19
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
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;193:35 44. 2. Lillo FB. New Microbiol. 2005;28:111 118. 3. Frisch M, Glimelius B, van den Brule AJC, et al. N Engl J Med. 1997;337:1350 1358. 4. Gillison ML, et al. J Natl Cancer Inst. 2000;92:709 720. 5. Derkay CS. Laryngoscope. 2001;111:57 69. 21
HPV Infection and Cervical Cancer Carcinogenic by epidemiologic definition HPV type % Odds Ratio 16 59% 182 18 12% 231 45 4.8% 148 31 3.7% 71.5 33,35,51,52,58, 59 31-146 22
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. % 6 183 46.3 225 47.1 11 179 45.3 190 39.7 16 36 9.1 63 13.2 81 2 0.5 1 0.2 58 1 0.3 6 1.3 61 1 0.3 0 0.0 7 1 0.3 2 0.4 45 0 0.0 1 0.2 59 0 0.0 2 0.4 66 0 0.0 1 0.2 67 0 0.0 1 0.2 23 Wang H, Qiao YL. Int J STD AIDS. 19(10):680-4, 2008
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 1-4. 24
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
HPV 病毒是唯一一個可以不經性行為傳播之性病病原菌
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)
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; 135-138
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
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 1 1. Soper DE. In: Berek JS, ed. Novak s Gynecology. 13th ed. Lippincott Williams & Wilkins, 2002:453-470. 31
案例 : 性接觸傳染 Anthony Wisdom, 1989: A color atlas of sexually transmitted diseases. Year Book Medical Publishers, Chicago, 296pp. 32
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
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
TCA EF CRYO ALEX FERENCZY, MD Traditional provider administered LASER 35
Home therapies 0.5% PODOPHYLLOTOXIN All have adverse events: burning to scarring 36 ALEX FERENCZY, MD
HPV Vaccination
Vaccines on the Horizon SOURCE: Merck and GSK. Science Magazine, Vol. 308, Issue 5722, pages 618-621, 29 April 2005
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 364:1757-1765, 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 11 40 µg HPV 16 20 µg HPV 18 Adjuvant 225 µg Aluminum Hydroxyphosphate Sulfate 20 µg HPV 16 20 µg HPV 18 500 µg Aluminum Hydroxide with 50 µg 3-deacylated monophosphoryl lipid A (AS04) 1 Villa LL, et al. Lancet Oncol. 2005;6:271-278. 2 Harper DM, et al. Lancet. 2004;364:1757-1765.
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 16-23 years 15-25 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;6:271-278. 2 Harper DM, et al. Lancet. 2004;364:1757-1765.
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: 70-97 P/V: 47/6 events) 100% (95% CI: 68-100 P: 13 events) NS (P: 3 events) 86% (95% CI: 54-97 P/V: 21/3 events) 89% (95% CI: 21-100 P/V: 9/1 events) 100% (95% CI: 77-100 P: 16 events) Not a Study Aim Not a Study Aim 100% (95% CI: 72-100 P: 13 events) 100% (95% CI: 7-100 P: 4 events) 1 Villa LL, et al. Lancet Oncol. 2005;6:271-278. 2 Harper DM, et al. Lancet. 2004;364:1757-1765.
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: 56-100) 10 placebo events 100% (95% CI: 32-100) (7 events) 100% No CI (4 events) 94% (95% CI: 70-98) 100% (95% CI: 16-100) 6 placebo events 100% (6 events) Not a Study Aim 1 Villa et al. Lancet Oncol. 2005;6:271-278. 2 Harper et al. Lancet. 2004;364:1757-1765.
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 11 100 times greater for HPV 16 20 times greater for HPV 18 27 months 1.4 times greater for HPV 6 No greater for HPV 11 20 times greater for HPV 16 6 times greater for HPV 18 200 times greater for HPV 16 100 times greater for HPV 18 18 month 100 times greater for HPV 16 10 times greater for HPV 18 1 Villa et al. Lancet Oncol. 2005;6:271-278. 2 Harper et al. Lancet. 2004;364:1757-1765.
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, 2005. Abstract LB-8a.
Recommendations The Advisory Committee on Immunization Practices (ACIP) 1. Routine vaccination 2. Catch-up vaccination 3. Special situations 4. Precautions and contraindications CDC Policy
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
HPV Vaccine Recommendations (2) Catch-up Vaccination ACIP recommends that HPV vaccine (GARDASIL) is indicated in females aged 13-26 years for the prevention of CIN, cervical cancer, and infection caused by HPV 6, 11, 16 and 18. Immunization Catch-Up (ICU) CDC Policy
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).
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 11 40 µg HPV 16 20 µg HPV 18 225 µg Aluminum Hydroxyphosphate Sulfate 20 µg g HPV 16 20 µg g HPV 18 500 µg g Aluminum Hydroxide with (MPL) 50 µg g 3-deacylated monophosphoryl lipid A (AS04)
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
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
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%
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 020 2009.08 54
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 2007-2008 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
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
菜花 疫苗疫苗 子宮頸癌 摸蛤子兼洗褲
謝謝大家! 58