Population impact of HPV vaccination and effect on cervical cancer screening Karen Canfell Director, Cancer Research Division Viruses in May, April 30 2915

Declarations •

• •

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I am co-PI of an investigator-initiated trial of primary HPV screening in Australia (‘Compass’) conducted by the Victorian Cytology Service, which has received a funding contribution from Roche Molecular Systems and Ventana Inc., USA. The Renewal evaluation was funded by the Medical Services Advisory Committee, Department of Health Australia. The model platform used for the Renewal evaluation was developed with grants from the National Health and Medical Research Council Australia and funding from a number of other non-commercial agencies including Cancer Council NSW, Australia. I receive salary support (Career Development Fellowship) from NHMRC

Human papillomavirus (HPV) HPV is a common sexually transmitted virus, which can cause: • • • • • • •

Cervical cancer Vulvar cancer Vaginal cancer Anal cancer Penile cancer Oropharyngeal cancers Anogenital warts

There are over 100 types: • 15 anogenital types are ‘oncogenic’ • Virtually all cervical cancers caused by HPV, ~70-80% by HPV types 16/18 • HPV6/11 implicated in ~90% anogenital warts

“HPV 16 is a uniquely powerful human carcinogen” “HPV18,45,31,33,35,52,58 are the next most commonly identified in cancer, and a further 7 types have smaller and uncertain contributions to cancer (HPV51,56,39,59,68,73,66)”

Mark Schiffman, Infect Agents Cancer 2011

HPV to cervical cancer Persistence & Progression

Regression

Treated via cervical excisional procedure

High grade squamous epithelial abnormality (HSIL or CIN2/3)

Invasion in small proportion of women

Cervical cancer

Secondary prevention via screening with cytology Secondary prevention via HPV screening

Primary prevention via HPV vaccination

Adapted from Schiffman and Castle, NEJM 2005

Cervical screening

Cervical screening technology options • Cytology – (1st gen) Conventional cytology (‘Pap smear’) – (2nd gen) Manually-read liquid-based cytology (LBC) – (‘3rd gen’) Image-read LBC

• HPV DNA testing – (1st gen) For pooled oncogenic types – (2nd gen) With partial genotyping for HPV16/18 vs. other oncogenic types

Cervical screening in Australia • •

National Cervical Screening Program implemented 1991 Current recommendation: o 2-yearly conventional cytology in sexually active women 18-20 to 69 years1

•

Participation:2  2-yearly 58%  5-yearly 83%2

 Costs:3  A$195M in 2010; $215M in 2015  A$23 per adult woman in 2010 Participation by age, 2012 1NHMRC

Australia, Guidelines for Cervical Screening 2005. Institute of Health and Welfare 2014, Data for 2011-2012. 2Lew et al. BMC HS 2010 2Australian

Impact of the Program

Introduction of the National Cervical Screening Program

Invasive cervical cancer cases per 100,000

16 14 12 10

Adenocarcin oma proportion: 11.4% in 1982 26.0% in 2008.

Opportunistic screening

8 6 4 2

Organised screening: substantial decline in incidence (and mortality)

0

Australian Institute of Health and Welfare 2012, Australian Cancer Incidence and Mortality Books.

Organised screening: Plateau phase

Primary HPV screening: Longitudinal results for screen-negative women

Low risk

Copyright ©2008 BMJ Publishing Group Ltd.

Dillner, J. et al. Joint European Cohort Analysis. BMJ 2008;337:a1754

Primary HPV screening: Longitudinal results for screen-positive women HPV 16 +ve at baseline “Higher risk” Else HPV 18 +ve

“Intermediate risk” Else HPV other +ve

Oncogenic HPV -ve “Low risk”

Cumulative CIN3+ in 20,514 women (median age 34 years)

Khan MJ, Castle PE, et al. JNCI 2005

Primary HPV screening: Pooled data on invasive cervical cancer outcomes from four European trials - 176,000 women Cytology

Cytology

HPV

HPV

Effectiveness

Safety

“[At longer intervals] HPV-based screening provides 60—70% greater protection against invasive cervical carcinomas compared with cytology” Ronco et al, Lancet 2014

HPV vaccination

HPV vaccination • Prophylactic HPV vaccination is highly effective for HPV-naïve females and males prior to HPV exposure • Protects younger cohorts against persistent HPV 16,18 infection and associated disease • Three vaccine types: 1. Cervarix (GSK) bivalent (2v) vaccine: HPV 16,18 2. Gardasil (Merck/CSL) quadrivalent (4v) vaccine: +HPV 6,11 (warts) 3. Gardasil9 (Merck/CSL) includes the HPV types in the quadrivalent vaccine and 5 additional oncogenic types (31, 33, 45, 52, and 58 •

Second generation vaccine recently approved by FDA, under evaluation in Australia

Included HPV types in vaccines Wart viruses

“First tier” in cancer

“Second tier” in cancer

Responsible for 90% of anogenital warts

6

Responsible for 7080% of cervical cancers and ~90+% of other HPV cancers

16

Responsible for additional 10-20% of cervical cancers

31

Included in 4v vaccine

11 Included in 2v vaccine

18 Included in 9v vaccine

33

45 52 58

“Smaller and uncertain contributions”

Responsible for 51,56,39,59,68,73, ~10-11% of cervical 66 cancers

Not vaccine-included

Vaccine impact on screening

Female vaccination uptake: Australia • Female vaccination implemented in Australia from 2007, catch-up12-26 years until 2009 • Male vaccination implemented from 2013, catch-up 12-15 years until 2014. • Recommended 3 doses delivered at 0,2,6 months.

Suggests undernotification with actual uptake ~50%

Data extracted from the National HPV Vaccination Register as at Sept 2011 (excludes consumers who have opted off) Slide Acknowledgement: A/Prof. Marion Saville

SELF-REPORTED UPTAKE: AGES 18-26 YEARS Brotherton, Liu, Donovan, Kaldor and Saville, Vaccine 2013

Fall in HPV prevalence Modelled Predicted 70-79% decrease in 18-24 year olds from 2006 to end-2010

Adapted from: Smith MA, et al. Int J Cancer 2008. Also see: Smith and Canfell, BMC Res Notes 2014.

Observed Observed 77% decrease in 18-24 year olds from 2005-7 to 2010-2011

Tabrizi S/Brotherton J et al. JID 2012.

Further impact of male vaccination • From 2013, males aged 12-13 vaccinated at school – 2-year catch-up to Year 9.

• Via herd immunity, will provide incremental benefits to females • (But issues with cost-effectiveness in many other countries) Predicted reduction in HPV incidence in females in Australia, with female-only vaccination (Strategy 1) vs. both-sex vaccination (Strategy 2)

Smith M et al, International Journal of Cancer 2008

Fall in cervical high grade precancerous abnormalities (CIN2/3) Observed

From 2004-6 to 2012: • For women