Gudrun Neumann
Department of Obstetrics and Gynaecology
HPV Vaccination
Cervixcancer - forebyggelseHPV-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
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HPV
infection
Transient
infection
High grade
dysplasia
CIN 2/3
Invasive
cervical
Cancer
Low grade
dysplasia
CIN 1
Oral communication
High grade
dysplasia
CIN 3
normal
cytology
Variable can
occur in <1 year
10-15 years
Variable period
~2 years
HPV Infection and Cancer
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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
HPV infection contributes substantially
to the development of cancer – especially in females
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%)
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Figures from WHO
Human Papilloma Virus (HPV)
• >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
Nonenveloped double-stranded DNA virus1
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
Kreimer et al. Cancer Epidemiol, Biomarkers and Prev 2005Head and neck
Backes et al. Cancer causes and control 2009Penile
De Vuyst et al. Int J Cancer 2009Vulvar, vaginal, anal cancers
Smith et al. Int J Cancer 2007Cervical cancer
Kreimer et al. Cancer Epidemiol, Biomarkers and Prev 2005Head and neck
Backes et al. Cancer causes and control 2009Penile
De Vuyst et al. Int J Cancer 2009Vulvar, vaginal, anal cancers
Smith et al. Int J Cancer 2007Cervical cancer
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 2006Näsman et al, Int J Cancer 2009
HPV VaccinesFacts 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 effectModified after Stanley, M. Gynecol Oncol 118, April 2010
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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
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HPV Vaccination in Women aged 16-26
• Recommended
• Protection against:
– cervical cancer: 64%
– cervical dysplasia: 50%
– condyloma: 90%
• Follow the screening program
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Case
37 year old woman
Divorced recently
Sister had CIN II in the age of 25 years
Vaccination?
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
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26-45 years of age – how much disease is prevented?
The prevalence of HPV
decreases with age
Kjær, SK et al. Int J Cancer 2008
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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
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Case
• 24 year old woman, follow-up 8 weeks after a LEEP
• Histology: CIN III, free margins
– Vaccination?
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
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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
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HPV after Conisation
HPV 16/18
• Persistens (6 months after conisation) 12-22 %
• Reinfection 7-12 %
Kreimer et al. Cancer Epidemiol Biomarkers Prev 2007
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<0.001Kang et al. Gynecol Oncol 2013
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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
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Boys?
• Condyloma
• Cancer
– Anal
– Penis
– Tonsil
HPV
positiveHPV
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
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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)
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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
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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
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• 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
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Hvorfor vaccinere alle piger?
• Ingen terapeutisk effekt
• Høj immunogenicitet (>99 %) efter 3 doser vaccine
• Flokimmunitet ogsåfor heterosexuelle mænd
9-14 årige – bridging studie
• 2 doser vaccine i stedet for 3 doser
• Samfundsøkonomisk interesse
• Bedre accepteret
• Bedre compliance
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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
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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 ikke-onkogene 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 6,11,16,18,31,33,45,52,58
• Competitiv Luminex Immunoassay cLIA
• Serum opsamles før den første dosis vaccine
Safety
• Serious adverse experience
• Graviditet og amning46
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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 ?
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