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1 帶狀疱疹疫苗 Varicella Zoster Vaccine 1 報告者 : 吳岱穎醫師臺北市立聯合醫院仁愛院區家庭醫學科主治醫師家庭醫學專科醫師老年醫學專科醫師臺大流行病與預防醫學研究所博士

2 2 帶狀疱疹的疾病負擔

3 誰得過水痘? 幾乎所有超過 50 歲成人都暴露在罹患帶狀疱疹的風險中因為這個族群幾乎都得過水痘病毒在初次感染時會引發水痘帶狀疱疹 (Herpes zoster; HZ)( 俗稱皮蛇 ) 是 VZV( 水痘帶狀疱疹病毒 ) 再度活化的表現初次感染之後, 此病毒會潛伏在背根神經節或腦感覺神經節中, 直到再度活化引發帶狀疱疹 1. Opstelten et al. Herpes zoster and post herpetic neuralgia: incidence and risk indicators using a general practice research database. Family Practice. 19:5; CDC Immunization. Immunization: Shingles Vaccine. 3 Accessed 14 Feb National Institute of Aging. Age Page: Shingles. Accessed 14 Feb ShinglesInfo.com FAQ. Accessed May

4 與水痘帶狀皰疹病毒 (VZV) 之潛伏與再活化有關的宿主因子外來水痘暴露無症狀再活化? 帶狀皰疹疫苗接種 VZV 記憶 T 細胞感染水痘帶狀皰疹帶狀皰疹界限值年齡 4 Reprinted with permission from Arvin A. N Engl J Med. 2005;352: Copyright 2005 Massachusetts Medical Society. All rights reserved.

5 年齡 - 重要因素年齡是罹患帶狀疱疹最重要的一項因素超過 50 歲後, 免疫力會隨著年齡增長而降低, 罹患帶狀疱疹的風險及嚴重性會大幅增加, - 到了 85 歲, 約有 50% 的人會出現至少一次的帶狀疱疹隨著年齡增長, 罹患帶狀疱疹的風險越高過去 50 年來, 老年人的數量已增加一倍 ; 在接下來的 50 年, 老年人增加的數量將更多有越來越多的人將達到易罹患帶狀疱疹的年齡 1. CDC. MMWR. Prevention of Herpes Zoster: Recommendations of the Advisory Committee on Immunization Practices. 2008; 57: Shinglesinfo.com. FAQ. Accessed 28 May Schmader, K. Herpes Zoster in Older Adults. Aging and Infectious Diseases. CID. 2001: Oxman, M.N. A Vaccine to Prevent Herpes Zoster and Postherpetic Neuralgia in Older Adults. N Engl J Med :22, National Institute 5 of Aging. Age Page: Shingles. accessed 14 Feb Population Division, DESA, United Nations. World Population Ageing: Chapter II: WHO. Ageing and Life Course Accessed on 29 May 2013.

6 帶狀疱疹的發生率台灣 : JHI. et.al. Acta Derm Venereol :

7 實際上, 只有約一半 seropositive 的人記得有得過 : seropositivity : positive history of varicella :positive history of vaccination 7

8 帶狀皰疹的表現帶狀疱疹的特徵為延著皮節分佈的單側性疼痛性水泡性皮疹水泡性皮疹是帶狀疱疹最明顯的表徵但最常見的影響生活品質的症狀是疼痛疼痛症狀可能發生於 : 感染前驅期急性發疹期以及疱疹後期在急性發疹期間, 免疫功能正常的人高達 90% 會發生局部疼痛 8

9 帶狀疱疹的症狀起初的徵兆並不明顯, 症狀往往是發癢疼痛及刺痛幾天之後會出現水泡紅疹, 通常會出現在身體或臉部的單側紅疹的出現通常伴隨 : - 焦慮 - 類流感症狀 - 從輕微到嚴重的疼痛, 包含 : 發癢灼熱感或刺痛抽痛 96% 罹患帶狀疱疹的人會感到疼痛 45% 每天都感到疼痛 42% 形容此疼痛感為可怕的或難忍受的 Phototake. Reprinted with permission. 1. Goh, CL. A retrospective study of the clinical presentation and outcome of herpes zoster in a tertiary dermatology outpatient referral clinic. International Journal of Dermatology. 1997, 36, Schmader, K. Herpes Zoster in Older Adults. Aging and Infectious 9 Diseases. CID. 2001: Oxman MN. Clinical manifestations of herpes zoster. In: Arvin AM, Gershon AA, eds. Varicella-Zoster Virus Virology and Clinical Management. 2000; Cambridge Press: pp Stankus et al. Management of Herpes Zoster (Shingles) and Postherpetic Neuralgia. Am Fam Physician. April 15;61(8): Katz, J. Acute Pain in Herpes Zoster and Its Impact on Health-Related Quality of Life. Clinical Infectious Diseases :342-8

10 帶狀疱疹的併發症 4 位病人當中就有 1 位會得到 1 種或多種併發症對某些人來說, 帶狀疱疹會導致長期的神經疼痛, 稱為帶狀疱疹後神經痛 (Postherpetic Neuralgia, PHN) 其它的併發症包含 : 帶狀疱疹病毒眼症 (Zoster opthalmicus) 罹患帶狀疱疹的病人有 10-25% 會發生在這些人當中,50-72% 的病人會得到嚴重的眼疾及視力退化皮膚細菌感染肌肉無力留下疤痕聽力損失 1. Lang et al. Stop Shingles in its tracks. Journal Fam Pract. Oct ;10: Yawn BP et al. Mayo Clin Proc. 2007;82: CDC Harpaz, R. Prevention of Herpes Zoster. Recommendations of the ACIP. MMWR. 2008: 57: Oxman MN. Clinical 10 manifestations of herpes zoster. In: Arvin AM, Gershon AA, eds. Varicella-Zoster Virus Virology and Clinical Management. 2000; Cambridge Press: pp Pavan-Langston, D. Ophthalmic zoster: Varicella-zoster virus. Virology and Clinical Management National Institute of Aging. Age Page: Shingles. Accessed 14 Feb US National Library of Medicine. PubMed Health. Shingles. Accessed May Available at:

11 Geniculate Ganglion: Ramsay Hunt syndrome type II acute facial nerve paralysis pain in the ear, taste loss in the front two-thirds of the tongue, dry mouth and eyes, and eruption of a erythematous vesicular rash in the ear canal, the tongue, and/or hard palate.

12 帶狀疱疹引起疼痛的程度及持續性與年齡層的的關聯性 Patients reporting pain (%) Age (years) >1 yr 6-12 mo 1-6 mo <1 mo Kost R et al. N Engl J Med. 1996; 355:32-42.

13 帶狀疱疹及帶狀疱疹後神經痛 (PHN) 對健康的衝擊生理層面疲勞缺乏食慾體重減輕行動力下降體能活動不足失眠社會層面退縮孤立社交聚會次數減少喪失獨立性社會角色的改變心理層面憂鬱焦慮情緒壓力注意力無法集中恐懼感功能層面穿著洗澡飲食行動旅行烹飪家務購物 Johnson, R. The impact of herpes zoster and post- herpetic neuralgia on quality of life. BMC Medicine : Katz, J. Acute Pain in Herpes Zoster and Its Impact on Health-Related Quality of Life. Clinical Infectious Diseases :342-8

14 帶狀疱疹的治療 Spinal cord Dorsal root ganglion VZV moves along the sensory nerve to the dorsal root ganglion Chickenpox (VZV) rash Skin VZV establishes latency in the dorsal root ganglion 14

15 帶狀疱疹治療的困難帶狀疱疹的治療 : 全方位複雜昂貴效果? Antivirals Non-narcotic analgesics Topical agents Herpes Zoster PHN Corticosteroids Narcotic analgesics Anticonvulsants for pain management 1. Gnann JW et al. N Engl J Med. 2002;347: Johnson, R. The impact of herpes zoster and post- herpetic neuralgia on quality of life. BMC Medicine :37 3. Goh, CL. A retrospective study of the clinical presentation and outcome of herpes zoster in a tertiary dermatology outpatient referral clinic. International Journal of Dermatology. 1997, 36, Watson, CP. The prognosis with postherpetic neuralgia (2) CDC. Prevention of Herpes Zoster: Recommendations of the ACIP. MMWR. 2008: 57: 1-30.

16 臺灣帶狀疱疹藥物治療狀況 2000~2006 Jih JS et al., Acta Derm Venereol Nov;89(6):

17 Provided by Dr. Chou NCKUH

18 Provided by Dr. Chou NCKUH

19 Provided by Dr. Chou NCKUH

20 伏帶疹活性帶狀疱疹疫苗 ZOSTAVAX 20

21 帶狀疱疹疫苗的重要研究兩項重要研究評估帶狀疱疹疫苗的功效安全性預防性及減輕疼痛的效果 : 2005 帶狀疱疹預防研究 (SPS) 38,546 位 60 歲以上 (19,270 ZOSTAVAX vs. 19,276 安慰劑 ) 的男性及女性, 無帶狀疱疹病史子研究 : 免疫製劑 (1,395); 藥物不良反應 (AEMS) (6,616) 2012 效果及安全性測試 (ZEST) 22,439 位曾得過水痘但無帶狀疱疹病史的男性及女性年齡介於 50 至 59 歲之間 (11,211 ZOSTAVAX vs. 11,228 安慰劑 ) Merck & Co. World Product Circular ZOSTAVAX. WPC-V211-ZST-R-I :1-24

22 Shingles Prevention Study (SPS) Subject Randomization Subjects Enrolled 38,546 (22 sites in US) Adverse Event Substudy 6616 CMI Substudy 1395 Age 60 to 69 years 20,747 Age 70 years 17,799 ZOSTAVAX 10,378 Placebo 10,369 ZOSTAVAX 8892 Placebo 8907 Oxman MN, Levin MJ, Johnson GR, et al. N Engl J Med. 2005;352: CMI=Cell Mediated Immunity. 22

23 SPS: Baseline Study Subjects Characteristics (1) 23 Oxman MN et al. N Engl J Med. 2005;352:

24 SPS: Overall Efficacy of ZOSTAVAX on Zoster Incidence Compared With Placebo Overall, ZOSTAVAX significantly reduced the risk of herpes zoster in subjects 60 years of age and older. OVERALL LOWER INCIDENCE OF ZOSTER Number of Zoster Cases 51% (95% CI: 44 58) Placebo (n=19,247) ZOSTAVAX (n=19,254) Oxman MN et al. N Engl J Med. 2005;352: CI = confidence interval; SPS = Shingles Prevention Study. 24

25 SPS: Efficacy of ZOSTAVAX on Zoster Incidence Compared With Placebo by Age Group (Years) Vaccine efficacy for the prevention of herpes zoster was highest in those subjects 60 to 69 years of age and declined with increasing age. Number of Zoster Cases 64% in subjects yrs (95% CI: 56 71) Number of Zoster Cases 41% in subjects yrs (95% CI: 28 52) Number of Zoster Cases 18% in subjects 80 yrs (95% CI: 29 48; NS) Placebo ZOSTAVAX (n=10,356) (n=10,370) Placebo ZOSTAVAX (n=7,559) (n=7,621) Placebo ZOSTAVAX (n=1,332) (n=1,263) 25 Harpaz R et al. MMWR Recomm Rep. 2008;57(RR-5):1 30 CI = confidence interval; SPS = Shingles Prevention Study.

26 帶狀疱疹預防研究 : 減少發生帶狀疱疹後神經痛的效果帶狀疱疹後神經痛 : 假如將疼痛程度分為 10 個等級, 帶狀疱疹引起的疼痛程度不小於等級 3, 同時疼痛感自水泡紅疹出現後至少持續 90 天 % of HZ Cases With PHN Number of PHN Cases Number of HZ Cases VE a 67% (95% CI: 48 79) 12.5 Placebo (n=19,247) ZOSTAVAX (n=19,254) ZOSTAVAX 效果的測試結果並不依不同年齡而有明顯差異研究顯示 ZOSTAVAX 能提升水痘 - 帶狀疱疹的特定免疫力, 藉以達到預防帶狀疱疹及併發症的功效 1. Oxman, M.N. A Vaccine to Prevent Herpes Zoster and Postherpetic Neuralgia in Older Adults. N Engl J Med :22, Merck & Co. World Product Circular ZOSTAVAX. WPC-V211-ZST-R-I :1-24

27 27 ZEST Study 研究結果

28 SPS Safety Profile for ZOSTAVAX in Patients 60 Years 1 The Adverse Event Monitoring Substudy (AEMS) (n=6,616) Vaccination report cards (VRCs) Vaccine-Related Injection-site and Systemic Reactions in 1% of Adults Who Received ZOSTAVAX or Placebo (Days 0-42) Adverse Reaction Erythema Solicited (%) Unsolicited (%) Pain/ Tenderness Swelling Hematoma Pruritus Warmth Headache (Systemic) ZOSTAVAX (n=3,345) Placebo (n=3,271) Most of these adverse events (AEs) were reported as mild in intensity Overall incidence of vaccine-related injection site AEs was significantly greater with ZOSTAVAX vs. placebo (48% vs. 17%), respectively Types of events reported in larger study cohort were generally similar to AEMS 28 Oxman MN et al. N Engl J Med. 2005;352:

29 帶狀疱疹預防研究 (SPS) 帶狀疱疹預防研究 (SPS) 與施打安慰劑相比,ZOSTAVAX 明顯地減少罹患帶狀疱疹風險達 51% ZOSTAVAX 在預防帶狀疱疹的效果上, 對歲間的老年人是最顯著的減少罹患風險達 64% 與施打安慰劑相比,ZOSTAVAX 降低帶狀疱疹後神經痛的整體發生率, 達到 67% Merck & Co. World Product Circular ZOSTAVAX. WPC-V211-ZST-R-I : Oxman et al. N Engl J Med. 2005;352:

30 ZEST Baseline Characteristics Characteristic Sex, n (%) Male Female Age, years Mean ± SD Range Race, n (%) White Black Asian Other a ZOSTAVAX (N=11,211) 4298 (38.3) 6913 (61.7) 54.9 ± to 59 10,588 (94.4) 468 (4.2) 80 (0.7) 75 (0.7) Placebo (N=11,228) 4256 (37.9) 6972 (62.1) 54.8 ± to 59 10,601 (94.4) 476 (4.2) 68 (0.6) 83 (0.7) N=Number of subjects randomized n=number of subjects contributing to each category SD = standard deviation; ZEST = ZOSTAVAX Efficacy and Safety Trial. a Other includes American Indian or Alaska Native, Multiracial, Native Hawaiian, or Other Pacific Islander. Schmader KE et al., Clin Infect Dis, 2012;54:

31 ZEST Primary Objective Results: Incidence of Confirmed Herpes Zoster (HZ) Cases in ITT Population Efficacy of ZOSTAVAX on Incidence of HZ in Subjects 50 to 59 Years of Age n m ZOSTAVAX (N=11,211) Total Follow-Up Time (Person-Years) Estimated Incidence Rate of HZ (Per 1000 Person-Years) n m Placebo (N=11,228) Total Follow-Up Time (Person-Years) Estimated Incidence Rate of HZ (Per 1000 Person- Years) 30 11,211 15, ,228 15, Vaccine Efficiency With Respect to HZ Point Estimate (95% CI) 69.8% ( ) p-value for testing the vaccine efficacy for HZ being less than 25% is < N=Number of subjects randomized. n=number of confirmed HZ cases. m=number of subjects in the intent-to-treat (ITT) population. CI = confidence interval; ZEST = ZOSTAVAX Efficacy and Safety Trial. Schmader KE et al. Efficacy, Safety, and Tolerability of Herpes Zoster Vaccine in Persons Aged Years, Clin Infect Dis, 2012;54:

32 ZEST Exploratory Objective Results: Severity-by-Duration Scores of Herpes Zoster (HZ) Pain in ITT Population n m ZOSTAVAX (N=11,211) Total Follow-Up Time (Person- Years) Mean Severityby-Duration Scores HZ Pain n m Placebo (N=11,228) Total Follow-Up Time (Person- Years) Mean Severityby-Duration Scores HZ Pain 30 11,211 15, ,228 15, Relative Reduction in Mean HZ Pain Severity-by- Duration Score [ZOSTAVAX Placebo] Point Estimate (95% CI) 73.0% ( ) N=Number of subjects randomized. n=number of confirmed HZ cases. m=number of subjects in the intent-to-treat (ITT) population. CI = confidence interval; ZEST = ZOSTAVAX Efficacy and Safety Trial. Schmader KE et al. Efficacy, Clin Infect Dis, 2012;54:

33 效果及安全性測試 (ZEST) ZOSTAVAX 效果及安全性測試的結果顯示, ZOSTAVAX 能降低歲間男女性帶狀疱疹的發生率與施打安慰劑相比,ZOSTAVAX 有效降低帶狀疱疹發生率達 (69.8%) (30 個案例 vs. 99 個案例 ) 普遍來說, 病患對 ZOSTAVAX 的耐受度佳 Merck & Co. World Product Circular ZOSTAVAX. WPC-V211-ZST-R-I :1-24

34 ZOSTAVAX 能有效降低 50 歲含以上成人帶狀疱疹的發生率 ; 亦全面減少 60 歲含以上成人帶狀疱疹後神經痛的發生率 Overall Incidence of Herpes Zoster (HZ) In patients y.o. Overall Incidence of Herpes Zoster (HZ) In patients > 60 y.o. Overall Incidence of Postherpetic Neuralgia (PHN) In patients > 60 y.o. Number of HZ Cases 70% Reduction (95% CI:54-80) Number of HZ Cases 51% Reduction Number of PHN Cases 67% Reduction (95%CI: 44-58) (95%CI: 48-79) Placebo (n=11,228) ZOSTAVAX (n=11,211) Placebo (n=19,247) ZOSTAVAX (n=19,254) Placebo (n=19,247) ZOSTAVAX (n=19,254) 普遍來說, 病患對 ZOSTAVAX 的耐受度佳嚴重的藥物不良反應發生率與施打安慰劑相比有明顯差異最常見的藥物不良反應為注射部位過敏反應 ZOSTAVAX 證實能有效降低帶狀皰疹的發生率及減少帶狀疱疹後神經痛的發生 34 * ZOSTAVAX 的使用指示不包含預防帶狀疱疹後神經痛 1. Schmader, K. Efficacy, Safety, and Tolerability of Herpes Zoster Vaccine in Persons Aged Years. CID p Oxman, M.N. A Vaccine to Prevent Herpes Zoster and Postherpetic Neuralgia in Older Adults. N Engl J Med :22, Merck & Co. World Product Circular ZOSTAVAX. WPC-V211-ZST-R-I :1-24

35 疫苗可以預防 PHN Chen N et al,. Cochrane Database Syst Rev Mar 16;(3):CD007795

38 ACIP Recommendations for the Use of ZOSTAVAX According to the CDC s Advisory Committee on Immunization Practices (ACIP), zoster vaccine should be offered to appropriate patients 60 years of age and older at the first clinical encounter ACIP-recommended strategies to promote zoster vaccination include: linking delivery of zoster vaccine to delivery of other preventivehealth interventions. Residents of nursing homes and other long-term care facilities who are at least aged 60 years and without contraindications should be included in routine zoster vaccination activities. ACIP = Advisory Committee on Immunization Practices; CDC = Centers for Disease Control and Prevention. Harpaz R et al. MMWR Recomm Rep. 2008;57(RR-5):

39 疫苗資訊 - 台灣適應症 ZOSTAVAX 適用於 : 預防歲之成人帶狀疱疹 ( 皮蛇 ) ZOSTAVAX 可與去活性流感疫苗同時接種 39

40 禁忌症曾對此疫苗的任何成分 ( 包括明膠 ) 產生過敏反應曾對 Neomycin ( 每劑泡製後的疫苗含有微量的 Neomycin) 產生過敏 / 類過敏反應 Neomycin 過敏常會出現接觸性皮膚炎的表徵不過, 因使用 Neomycin 而發生接觸性皮膚炎的病史並非接種活性病毒疫苗的禁忌原發性或後天性的免疫不全狀態免疫抑制治療 ( 包括高劑量的皮質類固醇 ) 未經治療的活動性結核病懷孕發燒 >38.5 C (>101.3 F) 的情況下, 應考慮延後接種疫苗 40

41 副作用在臨床試驗中, 針對超過 60,000 名 50 歲 ( 含 ) 以上的成人評估過 ZOSTAVAX 的一般安全性 ZOSTAVAX 通常具有良好的耐受性紅斑疼痛腫脹搔癢血腫溫熱感硬結全身性症狀與投藥部位反應 : 頭痛 41

42 藥物交互作用 ZOSTAVAX 不可與任何其他藥物混用於同一支針筒中其他藥物必須使用不同的注射器施打於不同的身體部位目前尚未評估過將 ZOSTAVAX 和已知可有效對抗 VZV 之抗病毒藥物同時投予的結果 ZOSTAVAX 與 PNEUMOVAX 23 不應同時接種, 因為同時接種會導致 ZOSTAVAX 的免疫生成性降低不過, 若已確定病患先前未曾感染水痘 - 帶狀疱疹病毒, 則建議應施打兩劑水痘疫苗 ( 相隔至少 4 週 ) 42

43 每天使用乙醯水楊酸 (ASA) 的病患可以接種此疫苗嗎針對兒童用水痘疫苗 ( 與成人用水痘疫苗不同 ) 的使用指引提到 : 由於可能併發罕見的雷氏症候群 (Reye syndrome), 因此不得以乙醯水楊酸 (acetylsalicylic acid) 治療與疫苗接種相關的發燒兒童身上此一可能性並不存在於成年人中因此, 接受長期乙醯水楊酸治療的成年人如有適應症, 仍應接種疫苗

44 劑量與用法 44 僅供皮下注射使用, 最好是注入上臂 ( 以三角肌部位為佳 ) 切勿以靜脈注射的方式施打再次接種的必要性尚未確立 ZOSTAVAX 可與去活性流感疫苗同時施打, 但應使用不同的針筒自冰箱中取出後應立即進行泡製建議此疫苗在泡製後應立即施打, 以免效價減弱泡製後的疫苗若未在 30 分鐘內使用, 即應予以拋棄泡製後的疫苗切勿冷凍注射藥品在施打前都應目視檢查是否有外來異物或變色的現象 ZOSTAVAX 在泡製後會形成一種半透明至透明的灰白色至淡黃色液體 ZOSTAVAX 應冷藏貯存於 2 至 8 C (36 至 46 F) 或更低的溫度下, 直到準備泡製成注射液再取出稀釋液應另外貯存於室溫下 (20 至 25 C,68 至 77 F) 或冰箱中 (2 至 8 C,36 至 46 F)

47 TW 6000 嘩!! 比我想像中來的貴

48 自費疫苗 HPV vaccine: 3500 * 3 = Rotavirus vaccine: For public health: Cost-Effective Analysis For individual: Valueless

49 Take Home Message 伏帶疹活性帶狀疱疹疫苗 ZOSTAVAX 適應症 : 歲之成人, 施打一劑禁忌症 : 對新黴素 / 明膠過敏者懷孕發燒 HIV 患者免疫不全者效用 : 預防 5~7 成帶狀疱疹預防 7 成帶狀疱疹後神經痛 ~THANK YOU~ 副作用 : 極輕微, 局部副作用為主 50 注意事項 : 不要跟肺炎鏈球菌一起施打

50 THANK YOU! 給自己和家人一個健康禮物 ---- 自費打皮蛇疫苗!

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桃園縣藥師公會藥師持續教育訓練認識帶狀疱疹及預防方式台大醫院家庭醫學部主治醫師台大醫學院一般醫學科臨床助理教授蔡詩力帶狀皰疹的病原體 Varicella Zoster Virus, VZV ( 水痘病毒 ) 的入侵 3 初識 VZV -- 水痘流行季節在冬季及早春好發年齡 :60% 個案為 3-9 歲 90% 以上民眾在 15 歲以前曾經感染過水痘絕大部份病患都不會引起併發症併發症的高危險群