Silvia Franceschi Infections and Cancer Epidemiology Group International Agency for Research on Cancer Lyon, France

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1 From epidemiology to cancerpreventing vaccines: the example of HPV Silvia Franceschi Infections and Cancer Epidemiology Group International Agency for Research on Cancer Lyon, France Milan, 19 March 2007

2 Infection-attributable cancers in 2002 Developed countries Developing countries 7.7% of all cancers 26.3% of all cancers HIV/HHV-8: 0.3% EBV: 0.3% HBV & HCV: 1% H.pylori: 3.9% HPV: 2.2% HIV/HHV-8: 1.6% Other: 0.2% H.pylori: 7% EBV: 1.6% HBV & HCV: 8.2% HPV: 7.7% From Parkin, 2006

3 Phylogenetic tree of HPV genotypes

4 IARC Multi-centre HPV Prevalence Surveys Mexico Colombia Poland The Netherlands Ital Georgia Mongolia Spain y Iran China Korea Shanxi Algeria Nepal Shenyang Pakistan Shenzhen Nigeria India Hanoi Uganda Lampang Ho Chi Minh Guinea Kenya Songkla Chile Argentina South Africa completed ongoing in planning

5 Prevalence of cervical HPV DNA in sexually active women IARC Multi-centre HPV Prevalence Survey, Mongolia Nigeria China, Shenzhen Argentina India China, Shenyang Colombia China, Shanxi Chile Mexico Korea Vietnam, Ho Chi Minh Italy, Turin Thailand, Lampang Netherlands Thailand, Songkla Spain Vietnam, Hanoi

6 60 40 % % % most common HPV types in 14,097 cases of invasive cervical cancer by region 70% All cases (n=14,097) HPV type Asia (n=5,652) 40 67% % 74% HPV type 76% North America (n=1,311) HPV type % % % Africa (n=1,373) HPV type Europe (n=4,334) HPV type 65% South and Central America (n=1,427) HPV type

7 Preventive vaccines against HPV Which vaccines?

8 HPV 16

9 VLP IARC-FIS 2002

10 Location of main stages in HPV life cycle

11 Product profile of prophylactic HPV vaccine Cervarix, GSK Gardasil, Merck 16/18 High Risk HPV types Pure Cervical Cancer Vaccine Women only (10-55 yrs) 3 i.m. injections, 20 microg VLP Innovative AS04 adjuvant (MPL+Aluminium) 16/18 high risk plus 6/11 low risk HPV types. Cervical cancer&genital warts Women and Men (9-45 yrs). 3 i.m. injections, 40 microg for HPV 11/16 Conventional aluminium

12 Conditions associated with HPV types 16, 18, 6, 11 HPV 16, 18 Estimated attributable % Cervical cancer 70 % High grade cervical abnormalities 50 % Low grade cervical abnormalities 30 % Anal cancer ~70 % Vulva / Vagina / Penile ~40 % Head and neck cancers ~3-12 % HPV 6, 11 Low grade cervical abnormalities 10 % Genital warts 90 % Recurrent respiratory papillomatosis (RRP) 90 % Clifford, BJ Ca 2003; Munoz Int J Cancer 2004; Brown J Clin Micro 1993; Carter Cancer Res 2001; Clifford Cancer Epi Biomarkers Prev 2005; Gissman Proc Natl Acad Science 1983; Kreimer Cancer Epidemiol Biomarkers Prev 2005

13 Preventive vaccines against HPV Which vaccines? Do they protect against cervical cancer?

14 Combined PhaseII/III Efficacy studies of HPV6/11/16/18 vaccine Mean follow up (since day 30 after 1 st dose): 25 months By protocol Endpoint Vaccine (N=9,342) Placebo (N=9,400) Efficacy 95% Confidence Interval HPV 16/18-related CIN 2/3 or % 93%,100% HPV 16-related CIN 2/3 or % 92%,100% HPV 18-related CIN 2/3 or % 77%,100% HPV 16/18-related CIN % 89%,100% HPV 16/18-related CIN3/AIS * % 93%,100% Women are counted once per line. A woman can in more than 1 line. *CIN 3/AIS = Cervical Cancer Stage 0 FIGO

15 Safety conclusions GARDASIL is generally well tolerated in 9- to 26-year-old subjects GARDASIL is associated with: an increase in injection-site AE, compared with placebo higher incidence of low-grade fevers, compared with placebo Individuals 9 to 26 years of age who receive GARDASIL rarely discontinue vaccination due to an AE GARDASIL is generally well tolerated in 9- to 26-year-old subjects who are positive to >1 vaccine HPV type Overall pregnancy outcomes (950 women) are comparable between subjects who receive GARDASIL or placebo Further pharmacovigilance monitoring is planned From Eliav Barr

16 Preventive vaccines against HPV Which vaccines? Do they protect against cervical cancer? Duration of efficacy in women without evidence of current or previous infection with vaccine HPV types?

17 Vaccine efficacy for persistent infection up to 4.5 years (intention-to-treat) Placebo Vaccine women Event women Efficacy rate % (95%CI) HPV ( ) HPV ( ) HPV 16/ ( ) Harper et al, 2006

18 Vaccine efficacy for incident infection up to 4.5 years (intention-to-treat) Placebo Vaccine women Event women Efficacy rate % (95%CI) HPV ( ) HPV ( ) Harper et al, 2006

19 Preventive vaccines against HPV Which vaccines? Do they protect against cervical cancer? Duration of efficacy in women without evidence of current or previous infection with vaccine HPV types. Efficacy in women with evidence of current or previous infection with vaccine HPV types?

20 Efficacy of HPV vaccine from 4 trials against HPV16/18-related CIN2+ CIN2+ / Women Vaccine Placebo Efficacy By protocol 0 / / % (93%-100%) By intention to treat 122 / / % (23%-52%) Among women already exposed to HPV16/ / / % (non-significant) IARC-ICE

21 Preventive vaccines against HPV Which vaccines? Do they protect against cervical cancer? Duration of efficacy in women without evidence of current or previous infection with vaccine HPV types. Efficacy in women with evidence of current or previous infection with vaccine HPV types. Will screening benefit from preventive HPV vaccines?

22 Fraction of cervical lesions prevented by HPV 16/18 vaccine in Europe and approximate number prevented per year in Italy (assuming no protection against other types) EUROPE ITALY Cancer 73% HSIL 57% LSIL 24% ASCUS 19% Cancer : 2,500 HSIL : 8,400 LSIL : 11,300 ASCUS : 17,500 Clifford et al, in press

23 Which vaccines. Vaccines against HPV Consequences on diseases. Consequence on the behaviour of the women or the virus.

24 Main reason for not having sex among adolescents who have never had sex: NSFG % Males Females Against religion/ morals Don t want to get (a female) pregnant Haven t found right person Don t want STD In a relationship, waiting for right time Other Abma et al, 2004; Vital and Health Statistics, Series 23, No 24. From Nicole Liddon

25 Impact of vaccine on sexual behaviour Adolescent sexual behaviour indicates an opportunity during early adolescence for HPV vaccine delivery Unlikely sexual behavioural disinhibition will result from HPV vaccine: Multiple other factors associated with adolescent sexual risk Fear of STD not apparent major motivation for abstinence No evidence of behavioral disinhibition in other similar fields From Nicole Liddon

26 Changes in the virus HPV type replacement can occur only if there is: a) partial competition of different types during natural history and b) the vaccine does not protect against types naturally competed against. In reality, a) anti-hpv ab+ women have strong risk to be also positive for ab against other types, and b) large studies of multiple-type infections did not find types that do not go together. Cross-protection stronger with vaccine than natural infection. Viral escape mutants can occur if a virus has high mutation rate (HIV, HCV). However, HPV mutation rate is very low (approx 2% since human origin) and HPV 16 strains and variants all over the world are a single serotype.

27 Preventive vaccines against HPV Which vaccines? Do they protect against cervical cancer? Duration of efficacy in women without evidence of current or previous infection with vaccine HPV types. Efficacy in women with evidence of current or previous infection with vaccine HPV types. Will screening benefit from preventive HPV vaccines? Any consequence on the behaviour of the women or the virus? What next?

28 June, 2006: US Food and Drug Administration approves HPV 6/11/16/18 Vaccine. The 3-shot, $ 360 series available by July 2006 in the US and few other countries. September, 2006: the European Medicines Agency approves the same vaccine. Quadrivalent vaccine already licensed in 50 countries. Efficacy trials in older women and males still on-going.

29 Challenges to introduction, especially in developing countries 1. Accurate and accessible information on HPV generally not available 2. Socio-cultural barriers to HPV vaccine unclear 3. Health delivery strategies/systems for reaching adolescent girls limited 4. Vaccine affordability and financing not yet known 5. Demand for/uptake of vaccine not yet known, so supply is hard to predict 6. Interaction with screening programs not yet clear 7. Competition with other new vaccines and health needs Longer-term efficiency trials are still necessary

Epidemiologia dell HPV e cancro della cervice nel mondo. Silvia Franceschi

Epidemiologia dell HPV e cancro della cervice nel mondo Silvia Franceschi Infezione da HPV: dalla diagnosi precoce alla prevenzione primaria. Roma, 27 Giugno 2012 Cancer incidence 2008 attributable to