Opportunities and challenges for human papillomavirus vaccination in cancer prevention Johannes A Bogaards, PhD National Institute for Public Health and the Environment, The Netherlands VU University Medical Centre, Amsterdam, The Netherlands
Disclosure belangen spreker (potentiële) belangenverstrengeling Voor bijeenkomst mogelijk relevante relaties met bedrijven Sponsoring of onderzoeksgeld Honorarium of andere (financiële) vergoeding Aandeelhouder Andere relatie, namelijk Geen Niet van toepassing
About me Hans Bogaards MSc theoretical biology & bioinformatics (UU) PhD clinical epidemiology & biostatistics (UvA) HPV co-workers Dr. Hester de Melker (RIVM EPI) Prof.dr. Hans Berkhof (VU E&B) 3
Outline 1. HPV introduction 2. 3. 4.
Human papillomavirus (HPV) Papillomaviridae: small skin viruses ~8 kbp ds DNA circular genome Cutaneous vs mucosal tropism Virus host-species phylogeny High diversity in mammalian hosts >200 HPV genotypes identified alpha-genus oncogenic in humans up to 15 HPV types high-risk transmitted through sexual contact Bravo et al. (2010), Trends in Microbiology 5
de Villiers (2013), Virology 6
HPV infectious life cycle is intimately linked to epithelial differentiation Graham (2017), Clinical Science 7
HPV replication cycle: infectious virion producing pathway in nondividing cells and the clonal transforming pathway in dividing cells Depuydt et al. (2016), Facts Views Vis Obgyn 8
Graham (2017), Clinical Science 9
The natural history of cervical HPV progression to cancer Woodman et al. (2007), Nat Rev Cancer 10
Natural immune control of HPV infection: the action of neutralizing antibodies (nabs) vs. long-term protection via cell-mediated immunity Roden & Stern (2018), Nat Rev Cancer 11
The process of virus uptake into epithelial cells occurs over several hours and offers a time window for the action of vaccine induced nabs Roden & Stern (2018), Nat Rev Cancer 12
EV: epidermodysplasia verruciformis Abul Bajandar, Bangladesh (source: Wikipedia) 13
Some HPV types can cause cancer >80% exposed to oncogenic HPV in life HPV causes almost 5% of all cancer cases 650 thousand of 14 million cases (2012) HPV causes almost all cervical cancers 4th most frequent cancer in women low-risk types harmless (anogenital) warts (laryngeal) papillomatosis cancer in immunosuppressed or EV patients Plummer et al. (2016), Lancet Glob Health 14
Site HPV-associated diseases HPV types Skin Sites of HPV infection and associated diseases Common warts, benign lesions # possible link to HPV-induced carcinogenesis 1,2,3,4,7,10,26,27,28,29,41,48,50,57,60,63,65, 75,76,77,88,95 EV warts 5,8,9,12,14,15,17,19,20,21,22,23,24,25,36,37, 38,46,47,49,75,76,80,92,93,96 Larynx Laryngeal papillomatosis 6,11 (predominantly) Oral cavity Focal epithelial hyperplasia 13,32 Oropharynx, Head and neck cancers 16 (predominantly) larynx #, oral cavity # Anogenital tract Anogenital warts 6,11 (predominantly) LSIL 40,42,43,44,53,54,61,72,73,81 LSIL, HSIL, carcinomas 16,18,31,33,35,39,45,51,52,53,56,58,66,68,73 15
HPV-related cancers in men and women Cancer site HPV-attributable risk Lifetime risk per 100,000 (wo)men 10-year survival probability Cervix ~100% 706 60% Vagina ~70% 59 34% * Vulva ~20% 439 66% Anus ~90% 114 (women) 87 (men # ) Oropharynx 30-60% 196 (women) 396 (men # ) 55% 51% 34% * 28% * Penis 25-50% 199 69% * # elevated risk amongst men who have seks with men (MSM) * improved survival probability for HPV-positive tumors source: cijfersoverkanker.nl 16
Disease burden of HPV infection in the Netherlands, 2011-2014: approximately 60% due to cervical disease, 25% in males Females Females excl. cervix Males Infectious disease HPV (2011-2014) 13,795 Pneumococcal disease* 9,444 Influenza* 8,670 HIV* 6,987 HPV excl. cervix 5,627 Legionellosis* 4,283 Toxoplasmosis* 3,593 Chlamydia* 3,551 HPV excl. females 3,345 Est. average annual burden * est. average annual burden 2007 2011 McDonald et al. (2017), Cancer Causes Control van Lier et al. (2016), PLoS One 17
Trends in HPV-related disease burden in the Netherlands, 1989-2014: the gap between females and males is diminishing Females Projected Females excl. cervix Males McDonald et al. (2017), Cancer Causes Control 18
Secondary prevention: detecting early disease to slow its progress Restructured HPV-based screening program 19
Screening relies on accurate diagnosis and treatment of neoplasia NORMAL CERVIX clearance infection high-risk HPV INFECTION regression progression PRE-CANCER LESIONS CIN1 CIN2+ invasion CERVICAL CANCER progression FIGO1 FIGO2+ death 14 high-risk HPV types Detection and treatment on basis of cytological screening Death from Cervical cancer Bogaards et al (2011), Epidemiology Screening aims to detect cervical intraepithelial neoplasia (CIN) traditionally done by Pap(anicolaou) test New national HPV-based screening program since 2016 Roche cobas as the first-line screening test HPV-test vs. cytology: sensitivity vs. specificity 20
Molecular events leading to HPV-induced (high-grade) neoplasia, i.e. the abnormal proliferation of benign or malignant cells # Wilting & Steenbergen (2016), Papillomavirus Res # Vink et al. (2013), Am J Epidemiol 21
Primary prevention: preventing exposures to causative hazards HPV-VLP vaccines available since 2006 >95% efficacy if given before sexual debut Three vaccines; all target HPV16 and -18 associated with majority of (cervical) cancers bi- (Cervarix), quadri- (Gardasil) and nonavalent Nowadays, all vaccines are licensed in a reduced two-dose schedule (initially three) Strong cross-protection reported for Cervarix correlates w/ phylogenetic distance to HPV16, -18 A VLP (virus-like particle) looks exactly like the virus but contains no viral DNA 22
Primary prevention breaks the chain of transmission The Brookings Institution 23
Factors affecting heterosexual transmission dynamics of mucosal HPV infection: sex-specific reproduction numbers Veldhuijzen et al. (2010), Lancet Infect Dis 24
Primary vs. secondary HPV-related cancer prevention Cascade effect primary prevention very effective not necessarily efficient Number needed to treat blanket vs. targeted immunization population- vs. risk-based screening Sparsity and proximity: economically desirable limits eventual side-effects Bogaards et al. (2015), BMJ 25
Secondary prevention in the Netherlands; something does not compute Trends in cervical cancer incidence vs. participation in cervical screening program source: cijfersoverkanker.nl source: LEBA 2015 26
A decade since the first national introduction of HPV vaccination in Australia, we have seen vaccine introductions in over 50 countries Donken et al. (2016), Hum Vaccin Immunother 27
Uptake (%) among vaccineeligible girls in the Netherlands HPV introduction but vaccine acceptability has been disappointing in many countries Qendri et al. (in press), Expert Rev Vaccines 28
The case for sex-neutral vaccination http://nos.nl/artikel/2035424-geef-prikbaarmoederhalskanker-ook-aan-jongens.html Various lines of reasoning herd immunity to females direct benefit for males snowball effect equity (ethics) Recommended in more and more countries Norway, Sweden, Germany, Austria, Switzerland, Italy Until recently, UK adhered to girls-only program with selective immunization of MSM 29
Who will benefit from expanding HPV vaccination programs to boys? Qendri et al. (submitted) 30
Increasing vaccine uptake among girls is more efficient than to start vaccinating boys along with girls Effect on reproduction number HPV cancer burden reduction (%) Bogaards et al. (2011), PLoS Med Qendri et al. (2017), J Infect Dis 31
but sex-neutral vaccination would be cost-effective in the Netherlands (at anticipated vaccine tender prices; irrespective uptake among girls) ICER of extending eligibility to boys (40% boys-60% girls): 9000 euro/ly ICER of extending eligibility to boys (40% boys-90% girls): 36000 euro/ly (under 3% annual discounting of future costs and benefits) Qendri et al. (2017), J Infect Dis 32
Take home messages HPV is a skin virus that causes a very high disease burden Cervical cancer is (and remains) the predominant source of HPV-related burden Even so, the burden in males is considerable by any standard HPV vaccination complements longstanding cervical cancer screening Integrated approach is urgently needed to curb rising cervical cancer incidence Vaccination of girls is projected to be very cost-effective But vaccine acceptability among girls has been disappointingly low (so far) Sex-neutral vaccination will be cost-effective at tendered prices Vaccinating boys w/girls is modestly less efficient than increasing uptake among girls Public confidence decisive for the long-term impact of HPV vaccination program 33
The optimist says the glass is half full. The pessimist says the glass is half empty. The project manager says the glass is twice as big as it needs to be.