제작 : 대한부인종양학회 / 발행처 : ( 재 ) 건강한여성재단
9 가자궁경부암예방백신의 Frequently Asked Questions List of Frequently Asked Questions Question 1. 9 가자궁경부암예방백신은어느질환에효과가있나요? Question 2. 9 가자궁경부암예방백신의접종연령은어떻게되나요? Question 3. 9 가자궁경부암예방백신의접종일정은어떻게되나요? Question 4. 9 가자궁경부암예방백신은중년여성에서접종이가능한가요? Question 5. 9 가자궁경부암예방백신은안전한가요? Question 6. 다른자궁경부암예방백신 (2가/4가) 을접종중인여성에게 9가자궁경부암예방백신의교차접종은가능한가요? Question 7. 이미다른자궁경부암예방백신 (2가/4가) 을접종완료한여성에게 9가자궁경부암예방백신을추가로접종할수있나요? 1
Question 1. 9 가자궁경부암예방백신은어느질환에효과가있나요? 9가자궁경부암예방백신은다음의질환을예방하는데효과가있습니다. 인유두종바이러스 16, 18, 31, 33, 45, 52 및 58형에의한자궁경부암, 외음부암, 질암, 항문암 인유두종바이러스 6, 11형에의한생식기사마귀 ( 첨형콘딜로마 ) 인유두종바이러스 (HPV) 6, 11, 16, 18, 31, 33, 45, 52 및 58형에의한지속적감염및다음의전암성또는이형성병변의예방 : - 자궁경부상피내선암 (Adenocarcinoma in situ, AIS) - 자궁경부상피내종양 (Cervical intraepithelial neoplasia, CIN) 1기, 2기및 3기 - 외음부상피내종양 (Vulvar intraepithelial neoplasia, VIN) 2기및 3기 - 질상피내종양 (Vaginal intraepithelial neoplasia, VaIN) 2기및 3기 - 항문상피내종양 (Anal intraepithelial neoplasia, AIN) 1기, 2기및 3기 Question 2. 9 가자궁경부암예방백신의접종연령은어떻게되나요? 9가자궁경부암예방백신임상시험결과에근거하여 9 26세여성및 9 15세남성에게접종할수있습니다. Question 3. 9 가자궁경부암예방백신의접종일정은어떻게되나요? 9가자궁경부암예방백신은 0, 2, 6개월접종을기본으로, 2차접종은 1차접종후 1 2 개월내에시행할수있으며, 2차접종과 3차접종의최소간격은 3개월로, 1차접종과 3차접종의최소간격은 6개월입니다. 2회접종스케쥴에대해서는현재까지발표된연구결과가없습니다. Question 4. 9 가자궁경부암예방백신은중년여성에서접종이가능한가요? 중년여성에서는현재까지발표된연구결과가없습니다. 중년여성 (27-45세) 에서는개인별위험도에대한임상적판단과접종대상자의상황을고려하여 9가자궁경부암예방백신의접종여부를결정해야합니다. 참고로, 유럽연합에서는 9가자궁경부암예방백신을 9세이상의남성및여성에게접종할수있다고하였으며, 캐나다에서는 9 45세여성및 9 26세남성에게접종할수있다고권고하였습니다. 2
Question 5. 9 가자궁경부암예방백신은안전한가요? 2가 /4가자궁경부암예방백신은 2014년세계보건기구의공식견해, 미국질병통제국의 2015년공식견해, 유럽식약처의 2015년공식견해및대한부인종양학회공식견해등에서안전하다고확인되었습니다. 9가자궁경부암예방백신은위약에비해서는통증, 부종및발적이유의하게많았으나기존 4가자궁경부암예방백신에비해서는유의한차이가없습니다. 따라서 9가자궁경부암예방백신은안전하다고할수있습니다. 또한, 임신부는 9가자궁경부암예방백신접종을권유하지않으며수유부는접종할수있습니다. Question 6. 다른자궁경부암예방백신 (2가/4가) 을접종중인여성에게 9가자궁경부암예방백신의교차접종은가능한가요? 기존 2가 /4가자궁경부암예방백신으로예방접종을시작하여, 9가자궁경부암예방백신으로접종을완료한경우에대한결과를분석한임상시험은없습니다. 참고로, 미국예방접종관리위원회에서는다른자궁경부암예방백신으로접종을시작하여접종지속또는완료를위해 9가자궁경부암예방백신이사용될수있다고하였습니다. Question 7. 이미다른자궁경부암예방백신 (2가/4가) 을접종완료한여성에게 9가자궁경부암예방백신을추가로접종할수있나요? 4가자궁경부암예방백신을접종완료한여성에게 1년이경과한이후 9가자궁경부암예방백신을접종하는것은추가된 5가지인유두종바이러스종류에대해면역원성이있음이입증되었습니다. 이경우국소주사부위의통증, 부종및발적이위약보다많았으나전신적이상반응은유의한차이가없었습니다. 따라서, 4가자궁경부암예방백신을접종완료한여성에게 9가자궁경부암예방백신을접종하는것은추가적인자궁경부병변을예방할수있겠습니다. 하지만, 2가자궁경부암예방백신을접종완료한여성에게 9가자궁경부암예방백신을접종한연구는아직까지없습니다. 3
Supplements 제작일정 1. 1차회의 : 2016.08.29. 온라인회의 - Question 선정및담당위원선정 1차선정한 Question 12개중회의를거쳐서 8개로수정함. 검색한근거문헌 (27개의논문및다른국가의 9가자궁경부암예방백신설명서 ) 을전체위원에게회람 2. 2차회의 : 2016.10.06. 대한산부인과학회사무국내회의실 - 참석자 : 이재관위원장, 성석주교수, 신진우교수, 주웅교수, 김성훈교수, 민경진간사 - 1차작성한 FAQ 내용검토및확정 - Question 종류를 7개로수정, 내용정리 4
Epidemiology of HPV infection in South Korea Prevalence and Distribution of Human Papillomavirus Infection in General population of Korean Women [1] 1 Method: by restriction fragment mass polymorphism (RFMP) test 2 Total specimen: a total of 60,775 specimens taken from liquid-based cytology 3 Age: 18-79 years old, median - 44 4 Overall HPV positive rate of total patients: 34.2%. A. Single type infections: 87.7% B. Multiple HPV infections: 12.3% C. HPV Genotype: HPV-16 in 2,307 (26.0%), HPV-52 in 2,269 (25.5%), HPV-58 in 1,090 (12.3%), HPV-18 in 633 (7.1%), HPV-56 in 436 (4.9%) Human Papillomavirus Type Distribution in Invasive Cervical Cancer and High-Grade Cervical Intraepithelial Neoplasia Across 5 Countries in Asia [2] 1. Independent, prospective, multicenter, hospital-based cross-sectional studies 2. 5 Asia countries: Malaysia, Vietnam, Singapore, South Korea, and the Philippines 3. Age: 21 years old (Mean- 47.68 in Invasive cervical Cancer, 40.14 in CIN2/3) 4. Overall HPV genotypes in cervical cancer and CIN2/3 A. Invasive cervical cancer i. HPV-16: 61.3%, HPV-18: 12.9%, HPV-33: 6.5%, HPV-52: 5.4%, HPV-31: 3.2% B. Squamous cell carcinoma i. HPV-16: 60.3%, HPV-18: 9.0%, HPV-33: 7.7%, HPV-52: 6.4%, HPV-31: 3.8%, HPV-35: 2.6%, HPV-58: 2.6% C. Adenocarcinoma i. HPV-16: 66.7%, HPV-18: 33.3%, HP-53: 6.7% D. CIN2/3 and Adenocarcinoma in situ i. HPV-16: 39%, HPV-52: 17%, HPV-58: 16%, HPV-31: 12%, HPV-51: 12%, HPV-33: 10%, HPV-18: 4%, HPV-35: 4% 5
Human Papillomavirus Type Distribution [3] 1. 968 healthy women in single hospital of South Korea 2. Age: 48.3 ± 11.7 years old 3. Overall HPV infection: 33.7% A. Single infection: 225 B. Multiple infection: 101 C. The most frequently occurring HR HPV types i. HPV-53 (6.5%), HPV-52 (6.1%), HPV-58 (4.8%), HPV-16 (4.5%), HPV-68 (4.2%). Summary of Clinical trial about 9-valent HPV vaccine 3 Phase II studies to select the formulation of a 9vHPV Vaccine [4] 1. Study 1 A. Double-blind, randomized, Phase II immunogenicity and safety study i. To evaluate the immunogenicity of one of 3 doses of an 8vHPV type 6/11/16/18/31/45/52/58 vaccine that contained the original qhpv types plus additional VLPs of the HPV types 31/45/52/58 in varied protein concentrations. B. Participants i. Number: 680 women (qhpv: 168, low-dose 8vHPV: 172, mid-dose 8vHPV: 168, high-dose 8vHPV: 172) ii. Age: 16 23 years old 2. Study 2 A. Phase II portion of a double-blind dose ranging, immunogenicity, safety, and efficacy Phase II/III study i. To evaluate the immunogenicity of one of 3 dose formulations of a 9vHPV type 6/11/16/18/31/33/45/52/58 vaccine B. Participants i. Number: 1,242 women (qhpv: 310, low-dose 9vHPV: 315, mid-dose 9vHPV: 307, high-dose 9vHPV: 310) ii. Age: 16 26 years old 3. Study 3 A. Duble-blind, randomized, Phase II immunogenicity and safety study i. To compare the immunogenicity of qhpv vaccine given alone or concomitantly with a 5vHPV type 31/33/45/52/58 vaccine B. Participants i. Number: 623 women (qhpv+placebo: 313, qhpv+5vhpv: 310) ii. Age: 16 26 years old 6
4. Vaccine dose 5. Primary endpoint A. HPV 6/11/16/18: noninferior immunogenicity at month 7 vs. qhpv vaccine B. HPV 31/33/45/52/58: immunogenicity at month 7 6. Immunogenicity of the 9vHPV vaccine A. Study 1/GMT ratio 8vHPV vs. qhpv (HPV 6/11/16/18) B. Study 2/GMT ratio 9vHPV vs qhpv (HPV 6/11/16/18) interim analysis 7
9가 자궁경부암 예방백신 FAQ C. Study 2/GMT ratio 9vHPV-mid vs qhpv (HPV 6/11/16/18) final analysis D. Study 3/ GMT ratio qhpv+5vhpv vs qhpv+placebo (HPV 6/11/16/18) final analysis E. Anti-HPV31, 45, 52, 58 GMTs in study 1 F. Anti-HPV31,33,45,52,58 GMTs in study 2 8
G. Adverse events i. Study 1 ii. Study 2 iii. Study 3 A 9vHPV Vaccine against Infection and Intraepithelial Neoplasia in Women: Protocol 001 [5] 1. A randomized, international, double-blind, phase 2b 3 study 2. Participants A. Number: 14,215 women (9vHPV vaccine: 7,106 vs. qhpv vaccine: 7,109) B. Age: 16 26 years old (21.9 ± 2.5 vs. 21.8 ± 2.5) 9
C. Swab sample collected on day 1 and at months 7, 12, 18, 24, 30, 36, 42, 48, and 54 3. Vaccine dose A. 9vHPV vaccine: 20 g of HPV-6, 40 g of HPV-11, 40 g of HPV-16, and 20 g of HPV-18 virus-like particles (VLPs) + 225 g of adjuvant amorphous aluminum hydroxyphosphate sulfate (AAHS) B. qhpv vaccine: 30 g of HPV-6, 40 g of HPV-11, 60 g of HPV-16, 40 g of HPV-18, 20 g of HPV-31, 20 g of HPV-33, 20 g of HPV-45, 20 g of HPV-52, and 20 g of HPV-58 VLPs, and 500 g of AAHS 4. Primary endpoint A. HPV 6/11/16/18: noninferior immunogenicity at month 7 B. HPV 31/33/45/52/58: reduction of combined incidence of HPV-31/33/45/52/58-related high grade lesion 5. Efficacy and immunogenicity of the 9vHPV vaccine A. HPV 6/11/16/18 10
B. HPV 31/33/45/52/58 6. Adverse events A. Injection site adverse events B. Systemic adverse events Immunogenicity and Safety of a 9-Valent HPV Vaccine: Protocol 002 [6] 1. Immuno-bridging study between young women(16 26 years) and girls and boys(9 15 years) 2. Participants A. Number: 2,800 women (girls: 1,800 vs. boys: 600 vs. women: 400) 3. Primary endpoint A. anti-hpv 6, 11, 16, 18, 31, 33, 45, 52, 58 geometric mean titers (GMTs) at month 7 4. Immunogenicity 11
5. Adverse events A. Injection site adverse events B. Systemic adverse events Immunogenicity and Safety of a 9-Valent HPV Vaccine in men: Protocol 003 [7] 1. Immunogenicity and tolerability of 9vHPV vaccine in young men 16 26 years of age in comparison to young women 16 26 years of age 2. Participants A. Number: 2207 (1106 heterosexual men, 1101 women who had not yet received HPV vaccination) 3. Primary endpoint A. Non-inferiority of anti-hpv 6, 11, 16, 18, 31, 33, 45, 52, 58 geometric mean titers (GMTs) at month 7 compared with young women 16 26 years of age 12
4. Immunogenicity 5. GMT ratio (Heterosexual men/women) at month 7 6. Adverse events A. Injection site adverse events B. Systematic adverse events 13
Coadministration of a 9vHPV Vaccine With Meningococcal and Tdap Vaccines: Protocol 005 [8] 1. A open-label, randomized, multicenter, comparative study with Menactra R and Adacel R 2. Participants A. Number: 1,241 girls and boys (Concominant: 621, nonconcominant: 620) i. stratified by gender (1:1 ratio) ii. randomly assigned to 1 of 2 vaccination groups (concomitant group [Group A] or nonconcomitant group [Group B]) in a 1:1 ratio iii. 1 dose of Menactra and 1 dose of Adacel were administered at either day 1 (concomitant group) or month 1 (nonconcomitant group) B. Age: 11 15 years old 3. Primary endpoint A. Geometric mean titers (GMTs) to HPV6/11/16/18/31/33/45/52/58 B. the percentages of subjects who seroconverted for each HPV type by 4 weeks after the third dose of 9vHPV vaccine 4. Immunogenicity 5. Adverse events Safety and immunogenicity of a 9vHPV vaccine in females 12-26 years of age who previously received the qhpv vaccine: Protocol 006 [9] 1. A randomized, double-blinded, safety/tolerability and immunogenicity study of the 9vHPV vaccine in females who were previously vaccinated with qhpv vaccine 2. Participants A. Number: 924 women (9vHPV vaccine: 618 vs. saline placebo: 306) B. Age: 12 26 years old (21.9 ± 2.5 vs. 21.8 ± 2.5) 3. Primary endpoint A. Injection site and systemic adverse events and Serious adverse events(saes), and death and 14
vaccine-related SAEs B. Anti-HPV 6, 11, 16, 18, 31, 33, 45, 52, 58 GMTs at day 1, month 2, and month 7 4. Adverse events A. Overview B. Injection site Adverse events C. Vaccine-related Systemic adverse events D. Immunogenicity results 15
E. Seropositivity results 9vHPV Vaccine concomitantly with DTP vaccines to healthy adolescents 11-15 years of age: Protocol 007 [10] 1. A open-label, randomized, multicenter study with Repevax R 2. Participants A. Number: 1,054 girls and boys (Concominant: 526, nonconcominant: 528) i. stratified by gender (1:1 ratio) ii. randomly assigned to 1 of 2 vaccination groups (concomitant group [Group A] or nonconcomitant group [Group B]) in a 1:1 ratio iii. 1 dose of Repevax was administered at either day 1 (concomitant group) or month 1 (nonconcomitant group) B. Age: 11 15 years old 3. Primary endpoint A. Geometric mean titers (GMTs) to HPV6/11/16/18/31/33/45/52/58 B. the percentages of subjects who seroconverted for each HPV type by 4 weeks after the third dose of 9vHPV vaccine 4. Immunogenicity 16
5. Adverse events Immunogenicity and Safety of a 9vHPV vaccine vs. Gardasil(R) in 9-15-Year-Old Girls: Protocol 009 [11] 1. Immuno-bridging study between 9vHPV vaccine and qhpv vaccine in girls (9 15 years) 2. Participants A. Number: 600 girls (9vHPV vaccine: 300 vs. qhpv vaccine: 300) B. Age: 9 15 years old 3. Primary endpoint A. anti-hpv 6, 11, 16, 18 geometric mean titers (GMTs) at month 7 4. Immunogenicity 5. Adverse events A. Injection site adverse events 17
B. Systemic adverse events 9vHPV vaccine recommendation in the other country Centers for Disease Control and Prevention Morbidity and Mortality Weekly Report of United State (CDC MMWR of U.S.)[12] 1. Vaccination age A. Female and male: 9 26 years old (routine age: 11 12 years old) 2. Vaccination schedule A. 1 st dose: 0 months, 2 nd dose: 1 2 months after the first dose, 3 rd dose: 6 months after the first dose B. Not need to be restarted in the interrupted vaccine schedule C. 2 dose schedule: presently no data on efficacy not yet 3. Special population A. Men have sex with men and immunocompromised persons: recommended vaccination more than 26 years old 4. Precautions and Contraindications A. Contraindication i. A history of immediate hypersensitivity to any vaccine component ii. A history of immediate hypersensitivity to yeast B. Precautions i. Not recommended for use in pregnant women If a woman is found to be pregnant after initiating the vaccination series, the remainder of the 3-dose series should be delayed until completion of pregnancy. Pregnancy testing is not needed before vaccination. If a vaccine dose has been administered during pregnancy, no intervention is needed. An Advisory Committee Statement (ACS) National Advisory Committee on Immunization (NACI) of Canada [13,14] 1. Vaccination target A. Female and male: 9 26 years old B. Female aged over 26 years who have not been vaccinated previously or who have not completed the vaccination series 18
2. Vaccination schedule A. 1 st dose: 0 months, 2 nd dose: 1 2 months after the first dose, 3 rd dose: 6 months after the first dose, minimum interval between 1 st and 3 rd dose: 3 months B. Not need to be restarted in the interrupted vaccine schedule C. 2 dose schedule: presently no data on efficacy not yet, but a clinical trial is currently underway European public assessment report (EPAR) summary of European Medicines Agency [15] 1. Vaccination target A. Female and male: 9 14 years old by 2-dose or 3-dose schedule B. Female and male: 15 years old over by 3-dose schedule 2. Vaccination schedule A. 2-dose schedule i. 1 st dose: 0 months, 2 nd dose: 5 13 months after the first dose B. 3-dose schedule i. 1st dose: 0 months, 2nd dose: 1 2 months after 1 st dose, 3rd dose: 3 4 months after 2 nd dose ii. All doses should be given within a year 19
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19. Alemany L, Saunier M, Tinoco L, Quiros B, Alvarado-Cabrero I, Alejo M, et al. Large contribution of human papillomavirus in vaginal neoplastic lesions: a worldwide study in 597 samples. Eur J Cancer 2014;50:2846-54. 20. Alemany L, Saunier M, Alvarado-Cabrero I, Quiros B, Salmeron J, Shin HR, et al. Human papillomavirus DNA prevalence and type distribution in anal carcinomas worldwide. Int J Cancer 2015;136:98-107. 21. Moreira ED, Jr., Block SL, Ferris D, Giuliano AR, Iversen OE, Joura EA, et al. Safety Profile of the 9-Valent HPV Vaccine: A Combined Analysis of 7 Phase III Clinical Trials. Pediatrics 2016;138. 22. Iversen OE. Comparison of immunogenicity of 2-dose and 3-dose regimens of 9-valent HPV vaccine. EUROGIN 2016. Salzburg, Austria; 2016. 23. Centers for Disease Control and Prevention. Clinician Factsheets of Human Papillomavirus (HPV). Atlanta: Centers for Disease Control and Prevention [cited 2015 September 30]. Available from: http://www.cdc.gov/hpv/hcp/clinician-factsheet.html. 21