Diagnosi di HPV: I dati mondiali ed europei Convegno Nazionale GISCi, Orvieto Silvia Franceschi

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1 Diagnosi di HPV: I dati mondiali ed europei Convegno Nazionale GISCi, Orvieto 2008 Silvia Franceschi International Agency for Research on Cancer 150 cours Albert Thomas Lyon France

2 La mia presentazione di oggi: Frequenza dell HPV (soprattutto IARC HPV Surveys). La diffusione del vaccino HPV nel mondo. Nuovi sviluppi nello screening (VIA e Fast HPV test).

3 % most common HPV types in 14,097 cases of invasive cervical cancer by region 70% All cases (n=14,097) % % Africa (n=1,373) % % HPV type Asia (n=5,652) 40 67% 74% HPV type 76% North America (n=1,311) % % HPV type Europe (n=4,334) HPV type 65% South and Central America (n=1,427) HPV type HPV type

4 IARC Multi-centric HPV Prevalence Survey Population-based samples of approx women 100 women per 5-year age group Testing for at least 36 HPV types using GP5+/6+ PCR and antibodies against 6 HPV types.

5 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 Guinea Uganda Lampang Ho Chi Minh Songkla Chile Argentina completed ongoing

6 Prevalence of cervical HPV DNA in sexually active women IARC Multi-centre HPV Prevalence Survey, Mongolia Nigeria China, Shenzhen Argentina India China, Shenyang Poland Colombia China, Shanxi Chile Mexico Korea Vietnam, Ho Chi Minh Italy, Turin Thailand, Lampang Netherlands Thailand, Songkla Spain Vietnam, Hanoi hpv 16 or 18 other high-risk type low-risk type only

7 HPV prevelence (%) Age-specific high risk HPV prevalence in Manchester, and (Kitchener and Peto, 2006) Manchester, (MY0911 PCR) ARTISTIC, (Hybrid Capture II) Age group (years)

8 Prevalence of cervical HPV DNA by age and HPV type IARC Multi-centre HPV Prevalence Survey HPV 16 0r 18 Other high-risk types Low-risk types only

9 Prevalence of cervical HPV DNA by age and HPV type HPV 16 0r 18 Other high-risk types Low-risk types only Poland, Warsaw Italy, Torino Prevalence (%) < Age group (years) Prevalence (%) < Age group (years)

10 Prevalence of cervical HPV DNA by age and HPV type HPV 16 0r 18 Other high-risk types Low-risk types only Married Poland, Warsaw Italy, Torino Prevalence (%) < Age group (years) Prevalence (%) < Age group (years)

11 Prevalence of cervical HPV DNA by age and HPV type HPV 16 0r 18 Other high-risk types Low-risk types only Married Single/separated/widowed Poland, Warsaw Italy, Torino Prevalence (%) < Age group (years) Prevalence (%) < Age group (years)

12 HPV infection in HIV-positive women Chronic infection with HPV 16, 18 and a dozen of other HPV types is considered the necessary cause of cervical cancer. Certain factors (e.g., high parity, long-term OC use, smoking, and immunodeficiency) can modify the probability of progression of HPV infection into precancerous lesions and cancer. HPV infections in HIV+ women are more likely to occur and persist than in HIV- women. Increased RRs of cervical cancer and precancerous lesions are seen among HIV+ women and their magnitude depends from screening practices, background HPV risk and competing causes of death in different areas of the world.

13 Gardasil/Silgard Global status Approved of in Merck 93 Markets: Gardasil Most Under licensure, Accelerated Timelines December 2007 Intelligence about approvals for GSK are not as timely Europe: North America: USA Canada Mexico Germany France UK Spain Italy others Caribbean & Central America: Costa Rica Puerto Rico Guatemala Bermuda others 3 7 South America: Brazil Argentina Peru Colombia Chile Ecuador Uruguay Middle East & Africa: Israel Morocco UAE Egypt others 11 Asia Pacific: Australia Indonesia Korea Taiwan Hong Kong Singapore others

14 Global status of GSK Cervarix licensure, December 2007 Source: GSKbio, Belgium

15 Vaccine affordability and financing High-income (industrialized) countries can afford to introduce HPV vaccine in the public sector, and several countries launched vaccine introduction in Poorest (GAVI-eligible) countries will most likely have access to heavily subsidized vaccine from GAVI Alliance. Greatest difficulty now facing middle-income countries, that cannot afford current high prices and are not eligible for subsidized vaccine. Options under discussion: Local private philanthropic financing schemes. Tiered pricing for available vaccines, in accordance with capacity to pay, promised by current manufacturers. Eventual price decline as developing-country manufacturers enter the market (starting 2015).

16 HPV vaccine theoretical/optimal global timeline for GAVI-eligible countries Late 2008: WHO pre-qualifies HPV vaccine for UN procurement. WHO Strategic Advisory Group of Experts (SAGE) recommends global HPV vaccine use. GAVI/UNICEF/PAHO negotiate with manufacturers for HPV vaccine supply. Early 2009: WHO issues position paper on HPV vaccine. GAVI incorporates HPV vaccine in portfolio of subsidized vaccines. GAVI invites eligible countries to apply for vaccine. Mid 2010 : Vaccine delivered to first countries.

17 Regional Group Purchasing

18 PATH demonstration projects on HPV vaccine, Build on results of formative research to design, implement, and evaluate cervical cancer vaccine delivery to young girls.

19 Four project countries India Vietnam Uganda Peru Age-adjusted cervical cancer incidence rates source: WHO/EIP Burden of Disease Projections

20 Ideal age group for vaccination Girls aged years Before sexual debut and exposure to the virus that causes cervical cancer for highest impact. Age when girls are easier to reach efficiently. First priority given to single cohort in lowresource settings. Vaccinating older adolescents and young women ( catch-up ) less cost-effective and logistically more difficult; gives earlier result but with much lower net benefit.

21 Service delivery options School-based programs (all four countries). Comparing performance during and outside Child Health Days (Uganda). Comparing performance with and without community outreach for out-of-school girls (Peru, India). Comparing performance in school-based and health facility-based settings (Vietnam).

22 Characterictics of screening tests for secondary prevention Characteristics Conventional cytology HPV DNA tests Visual inspection tests VIA VILI Sensitivity 47-62% % 67-79% 78-98% Specificity (for high-grade lesions and invasive cancer) Comments Number of visits required for screening and treatment 60-95% 62-96% 49-86% Assessed over the last 50 years in a wide range of settings in developed and developing countries 2 or more visits Assessed over the last decade in many settings in developed and relatively few in developing countries 2 or more visits Assessed over the last decade in many settings in developing countries Source: Sankaranarayan et al. Int J Obstet Gynaecol, % Assessed by IARC over the last four years in India and 3 countries in Africa. Need further evaluation for reproducibility Can be used in single-visit or 'see and treat' approach where outpatient treatment is available 22

23 Cluster Randomised Controlled Trial of VIA Screening, Dindigul District, India 113 Village clusters eligible women aged years Intervention: Single screening Follow-up: 7 years R. Sankaranarayanan et al. Effect of visual screening on cervical cancer incidence and mortality in Tamil Nadu, India: a cluster-randomised trial Lancet, August 4, 2007

24 Overall and age-specific hazard ratio for incidence for all cervical cancers and for cervical cancer deaths Control group 1.0 Hazard ratio (95% CI)* Intervention group (VIA) Overall Cervical cancer incidence 0.75 ( ) Cervical cancer death 0.65 ( ) years Cervical cancer incidence 0.62 ( ) Cervical cancer death 0.34 ( ) years Cervical cancer incidence 0.82 ( ) Cervical cancer death 0.55 ( ) years Cervical cancer incidence 0.76 ( ) Cervical cancer death 0.99 ( ) * C.I.: Confidence interval

25 Comparison of VIA, cytology and HPV testing, CIN2+, Study Sarian et al, 2005 De Vuyst et al, 2005 Sangwa-Lugoma et al, 2006 Pretorius et al, 2007 Almonte et al, 2007 Li et al, submitted Place Sensitivity (%) Specificity (%) N. VIA Cyto HPV VIA Cyto HPV Brazil 10,138 Kenya 653 Congo 1,571 China 8,497 Peru 5,435 China 2,

26 VIA sensitivity overestimated Only a fraction of VIA-negative findings underwent colposcopy in some studies (verification bias). In others, all VIA-negative findings underwent colposcopy, but colposcopy was shown to be an alloyed gold standard due to the correlation between visual inspection methods. When random biopsies (Pretorius et al, 2007) were used, the sensitivity of VIA, but not cytology or HPV test, diminished substantially.

27 Fast, affordable, accurate, and acceptable HPV tests are on horizon PATH project - START (Screening Technologies to Advance Rapid Testing) - New developments: rapid HPV DNA, E 6 onco-protein tests, - R&D and commercialization of two different rapid tests for primary screening in low-resource settings. -Development catalyzed through public-private partnerships - Tests will be provided to the public health sector in middle and low-income countries at a preferential price for at least ten years