HPV Vaccination Gudrun Neumann Department of Obstetrics and Gynaecology
Cervixcancer - forebyggelse HPV-vaccination til hvem? Ole Mogensen Gynækologisk-Obstetrisk afd. Odense Universitetshospital
Cervixcancer 350-400 nydiagnosticerede pr. år
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Cervixcancer 350-400 nydiagnosticerede pr. år 70% skyldes infektion med HPV 16/18 Kan forebygges med Vaccination Screening
HPV infection Oral communication 10-03-2014 Variable period ~2 years High grade dysplasia CIN 3 High grade dysplasia CIN 2/3 Low grade dysplasia CIN 1 Transient infection Variable can occur in <1 year Invasive cervical Cancer 10-15 years normal cytology 6
HPV Infection and Cancer Females Males Both sexes All types 16/18 All types 16/18 All types 16/18 Pct. 10.4 7.4 0.6 0.5 5.2 3.7 Numbers 527,200 374,700 33,900 28,100 561,100 402,900 7 HPV infection contributes substantially to the development of cancer especially in females 10-03-2014
Global Burden of Cervical Cancer Second biggest course of female cancer mortality New cases per year 510.000 80% in developing countries Mortality worldwide 288.000 (56%) 8 Figures from WHO 10-03-2014
Human Papilloma Virus (HPV) Nonenveloped double-stranded DNA virus 1 >100 types 30 40 anogenital 15 20 oncogene types 16, 18, 31, 33, 35, 39, 45, 51, 52, 58 Low malignant potential 6, 11, 40, 42, 43, 44, 54 HPV 6 and 11 causes condylomas
Beyond Cervical Cancer Cancer type HPV prevalence (%) HPV 16/18 (%) Possible preventable by vaccination (%) Vulvar 40 90 36 Vaginal 70 88 62 Anal 84 93 78 Penile 48 86 41 Head and neck 26 85-95 20 Cervical cancer Vulvar, vaginal, anal cancers Penile Head and neck Smith et al. Int J Cancer 2007 De Vuystet al. Int J Cancer 2009 Backes et al. Cancer causes and control 2009 Kreimer et al. Cancer Epidemiol, Biomarkers and Prev 2005
Incidence of HPV positive tonsil cancer HPV positive HPV negative Estimated age standardized incidence rate of HPV-positive and HPV negative tonsil SCC cases per 100,000 person-years in the County of Stockholm between 1970 and 2006 Näsman et al, Int J Cancer 2009
HPV Vaccines Facts from Phase III Randomized Trials Quadrivalent Bivalent Prophylactic efficacy HPV 16/18 CIN 2/3 100% 98% AIS 100% Not reported VIN3/VaIN3 100% Not reported HPV 6/11 99% --- Persistent antibody 9.5 years 7.3 years Both vaccines Well tolerated No therapeutic effect Modified after Stanley, M. Gynecol Oncol 118, April 2010 12 10-03-2014
Population based study <15 years of age when vaccinated 3-dose coverage 71-79% Low prevalence of HPV Significant decrease in high grade abonormalities Brotherton et al. The Lancet 2011; vol. 377, June 18
Vaccination of Women aged 16-26 Effect of vaccination Naivety for: HPV 6/11/16/18 85 % HPV 6 96 % HPV 11 99 % HPV 16 91 % HPV 18 96 % Brown et al. JID 2009:199 10-03-2014 14
HPV Vaccination in Women aged 16-26 Recommended Protection against: cervical cancer: 64% cervical dysplasia: 50% condyloma: 90% Follow the screening program
Case 37 year old woman Divorced recently Sister had CIN II in the age of 25 years Vaccination? 17 10-03-2014
HPV Vaccination of Women aged 26-45 The serological response is independent of age 10 times higher than the natural response One randomised investigation (Munoz et al, Lancet June 2009) HPV vaccine = 1911, placebo = 1908 Data after 2.2 years: 83% protection against HPV 16/18 related ano-genital lesions Data after 3.8 years: 95.7% protection
26-45 years of age how much disease is prevented? The prevalence of HPV decreases with age 19 Kjær, SK et al. Int J Cancer 2008 10-03-2014
HPV Vaccination in Women aged 26-45 Efficacy against ano-genital disease: 83% (95.7%) Risk of HPV infection decreases by age Very low risk of infection: HPV 6/11 above 30 years HPV 16/18 above 40 years The effect of HPV vaccination in the population is smaller than among women aged 16-26 Individual advice dependent on the woman s age, her wish for protection and the number of (new) sexual partners 20 10-03-2014
Case 24 year old woman, follow-up 8 weeks after a LEEP Histology: CIN III, free margins Vaccination? 21 10-03-2014
Aprox. 6000 conisations in DK per year
Conisation and Pregnancy Risk of preterm delivery (<37 weeks of gestation) increases 2-3 fold after one conisation 1/9 women Positive association between preterm delivery and Number of conisations 10-fold after two conisations -1/3 women (small number of patients) Conus height Risk of perinatal death increases up to 2.8 fold 23 1. Ørtoft et al. BJOG 2009 2. Noehr et al. Am J Obstet Gynecol 2009 3. Sjöborg et al. Acta Obstet Gynecol Scand 2007 4. Jakobsson et al. Obstet Gynecol 2007 10-03-2014
HPV after Conisation HPV 16/18 Persistens (6 months after conisation) 12-22 % Reinfection 7-12 % 24 Kreimer et al. Cancer Epidemiol Biomarkers Prev 2007 10-03-2014
Recurrent disease after LEEP and +/- vaccination Infections with HPV 16 and/or 18 5 patients (2.5%) in the vaccination group (n=197) 18 patients (8.5%) in the non-vaccination group (n=211) P<0.001 Kang et al. Gynecol Oncol 2013 25 10. marts 2014
Amount of prevented disease? Need for re-conisation: Birth cohort study: 5% (37/721) Ørtoft et al. BJOG 2009 When to vaccinate? Not possible to give evidence based recommandations Randomized, controlled trial necessary 26 10-03-2014
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Boys? Condyloma Cancer Anal Penis Tonsil HPV positive HPV negative
Boys? Condyloma Cancer Anal Penis Tonsil Sperm quality, abortions?
Boys? Condyloma Cancer Anal Penis Tonsil Sperm quality, abortions? MSM
Bottom Line The HPV vaccines - if delivered to girls, women (and men) with no evidence of infection with the HPV types in the vaccine at the time of immunization will prevent disease caused by those HPV types (Stanley, M. Gynecol Oncol 118, April 2010) The effect is long lasting No serious side effects 31 10-03-2014
Bottom Line HPV vaccination has the potential to prevent 7.4% of all female cancers (70% of cervical cancers) 0.5% of all male cancers (anal, head & neck(?)) More than 50% of cervical dysplasia 90% of all condylomas (Gardasil, female & male) 32 10-03-2014
Bottom Line Vaccination is recommended to Girls/women up to 26 years of age regardles of sexual activity Women >26 years of age: Individual advice based on age, wish for protection and number of (new) sexual partners Pending questions Vaccination after conisation Boys/males 33 10-03-2014
HPV-vaccination Fase III Clinical Trial to Study Tolerability and Immunogenicity of 3-dose regimen of V503 (multivalent HPV) L1 Virus-Like Particle Ni-valente HPV-vaccine; undertyper 6, 11, 16, 18, 31, 33, 45, 52, 58
Baggrund I 2006 blev den tetravalente HPV-vaccine Gardacil godkendt til forebyggelse af CC, dysplasi i cervix, vulva, vagina. HPV 6, 11, 16 og 18 Siden 2009 en del af børne-vaccinationsprogrammet Tilbydes piger fra 12 år og afsluttes inden de er 15 år Cath-up programmer. Tilslutning på 80 %
Epidemiologi Kummulative risiko for HPV i sexuelt aktive kvinder er > 50 % Smitter ved sexuel kontakt 60 % smittes inden for 4-8 uger efter smitte HPV pådrages ofte lige efter sexuel debut Risiko for HPV-infektion er korreleret med antal sexual partnere
Future studier V 503-001 Future 9 16-26 årige kvinder V 503-003-00 16-26 årige mænd og kvinder V 503-001Future Kids V 503-001-00 2-dose regime af V503 til 9-14 årige drenge og pige
Future 9 16-26- år Ingen dysplasi Max. 4 sexual partnere Study Flow Chart: Obtain Informed Consent Consent for Future Biomedical Research Screening Number Patient ID Card Inclusion/Exclusion Criteria Medical History Gynecological History Medical History Medication and Non-study Vaccination Pregnancy test Serum For Anti HPV-Antibody Blood for Further Medical reserch Obj. Us Vital Signs STD undersøgelse Randomiserings nummer Vaccineret Vaccination Report Card; dagbog Adverse Experience, Clinical Follow up for Safety GU Svap Genitalia Externa Cyt skrab Palpation 39 10-03-2014
Ingen association mellem HPV incidens og alder hos mænd Større immunresponds hos kvinder Højere prævalens af anti-hpv antistoffer hos kvinder end hos mænd i alle aldre
Safety Dagbog ved 1. besøg, mdr. 2. og mdr. 6 Oral temperatur Injektionssted Adverse Experience Concomitant medicin, vaccination Graviditet og amning 41 10-03-2014
Hvorfor vaccinere alle piger? Ingen terapeutisk effekt Høj immunogenicitet (>99 %) efter 3 doser vaccine Flokimmunitet også for heterosexuelle mænd
9-14 årige bridging studie 2 doser vaccine i stedet for 3 doser Samfundsøkonomisk interesse Bedre accepteret Bedre compliance 43 10-03-2014
Immunogenicitet Serum undersøges for Anti-HPV: 6,11,16,18,31,45,52, 58 Competitive Luminex Immunoassay (clia) Further Biomedical Research Genetisk analyse DNA, Gen ekspression profiling RNA Proteom Formål: undersøge og identificere biomarkører i profylaktisk og terapeutisk øjemed 44 10-03-2014
Immunresponds ved HPV-vaccination Det naturlige immunrespons er forskelligt 18 % hos piger og 8 % hos drengene Prævalencen er ens hos begge køn, men drenge har højere incidens af HPV -> hurtigere clerance Kvinder clearer onkogene HPV-typer hurtigere end ikkeonkogene typer HPV typer cleares på 6 mdr. Dog ikke HPV 16; median clearingstid på 12 mdr for begge køn
Endpoint Immunogenicitet Serum samles til analyse for anti-hpv 6,11,16,18,31,33,45,52,5 8 Competitiv Luminex Immunoassay clia Serum opsamles før den første dosis vaccine Safety Serious adverse experience Graviditet og amning 46 10-03-2014
HPV-vaccination er sikker Hyppigste bivirkninger: Lokale reaktioner på indstiksstedet, hovedpine, smerter i ekstremiteter, kvalme og feber Danske myndigheder, EMA, FDA, WHO følger forekomsten af bivirkninger Globalt er der givet 170 mil. doser Gardacil I DK er mindst 350.000 kvinder vaccineret SST har modtaget 786 indberetninger om bivirkninger; heraf 129 klassificeret som alvorlige
HPV-vaccination er sikker Neurologiske symptomer, symptomer på påvirket immunsystem. Intet mønster SSI afkræfter sammenhæng mellem vaccine og bivirkninger. Undersøgelser har fulgt 1 million svenske og danske kvinder, hvor af 1/3 er vaccineret-uden at finde øget forekomst- Ingen ændring i Gardacils sikkerhedsprofil Udviklingen følges tæt Fordele er større end bivirkninger
Resultater Afventes... Studie er af høj kvalitet Mange delstudier Basis for anvendelse af HPV vaccine med bredere dækning To dosis program? 49 10-03-2014