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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