Diagnosi di HPV: I dati mondiali ed europei

Convegno Nazionale GISCi , Orvieto 2008

Silvia Franceschi

International Agency for Research on Cancer150 cours Albert Thomas

69372 LyonFrance

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).

All cases (n=14,097)

0

20

40

60

16 18 33 45 31 58 52 35HPV type

%Africa (n=1,373)

0

20

40

60

16 18 33 45 35 31 58 52HPV type

%

Asia (n=5,652)

0

20

40

60

16 18 58 33 52 45 31 35HPV type

%Europe (n=4,334)

0

20

40

60

16 18 33 31 45 35 58 56HPV type

%

North America(n=1,311)

0

20

40

60

16 18 31 33 45 52 35 58HPV type

%South and CentralAmerica (n=1,427)

0

20

40

60

16 18 31 45 33 58 52 35HPV type

%

8 most common HPV types in 14,097 cases of invasive cervical cancer by region

70%

72%

67% 74%

76%65%

IARC Multi-centric HPV Prevalence Survey• Population-based samples of approx. 1000 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.

China

Lampang

Argentina

IARC Multi-centre HPV Prevalence Surveys

HanoiHo Chi Minh

Korea

ColombiaNigeria

Spain

Songkla

Chile

Italy

ShenzhenMexico

The Netherlands

India

completed ongoing

Mongolia

Algeria

Guinea Uganda

Poland

ShenyangShanxiNepal

Pakistan

IranGeorgia

Prevalence of cervical HPV DNA in sexually active women IARC Multi-centre HPV Prevalence Survey, 1995-2002

MongoliaNigeriaChina, ShenzhenArgentina IndiaChina, ShenyangPolandColombiaChina, ShanxiChileMexicoKoreaVietnam, Ho Chi Minh Italy, TurinThailand, LampangNetherlandsThailand, SongklaSpain Vietnam, Hanoi

999933534908

1940685834

1981671971

1340870918

101310243299716908

1007

0 5 10 15 20 25 30 35

hpv 16 or 18other high-risk typelow-risk type only

Age-specific high risk HPV prevalence in Manchester, 1988-93 and 2001-03

(Kitchener and Peto, 2006)

0

5

10

15

20

25

30

35

40

45

20-24 25-29 30-34 35-39 40-44 45-49 50-54 55-59Age group (years)

HPV

pre

vele

nce

(%)

Manchester, 1988-93 (MY0911 PCR)

ARTISTIC, 2001-03 (Hybrid Capture II)

HPV 16 0r 18 Other high-risk types

Prevalence of cervical HPV DNA by age and HPV typeIARC Multi-centre HPV Prevalence Survey

Low-risk types only

Prevalence of cervical HPV DNA by age and HPV typeHPV 16 0r 18 Other high-risk types Low-risk types only

05

10152025303540

<25 25-34 35-44 45-54 55+Age group (years)

Prev

alen

ce (%

)

Poland, Warsaw

05

10152025303540

<25 25-34 35-44 45-54 55+Age group (years)

Prev

alen

ce (%

)

Italy, Torino

Prevalence of cervical HPV DNA by age and HPV typeHPV 16 0r 18 Other high-risk types Low-risk types only

Married

05

10152025303540

<25 25-34 35-44 45-54 55+Age group (years)

Prev

alen

ce (%

)

Poland, Warsaw

05

10152025303540

<25 25-34 35-44 45-54 55+Age group (years)

Prev

alen

ce (%

)

Italy, Torino

Prevalence of cervical HPV DNA by age and HPV typeHPV 16 0r 18 Other high-risk types Low-risk types only

Single/separated/widowedMarried

05

10152025303540

<25 25-34 35-44 45-54 55+Age group (years)

Prev

alen

ce (%

)

Poland, Warsaw

05

10152025303540

<25 25-34 35-44 45-54 55+Age group (years)

Prev

alen

ce (%

)

Italy, Torino

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.

3

North America:

USA CanadaMexico

7

South America:

Brazil ArgentinaPeruColombiaChileEcuadorUruguay

18

Middle East & Africa:

Israel MoroccoUAEEgypt---------14 others

11 Asia Pacific:

AustraliaIndonesiaKoreaTaiwanHong KongSingapore--------------5 others

39

Europe:

Germany FranceUKSpainItaly---------34 others

Caribbean & Central America:

Costa RicaPuerto RicoGuatemalaBermuda--------------11 others

15

Gardasil/Silgard Approved in 93 Markets: Most Under Accelerated TimelinesIntelligence about approvals for GSK are not as timelyGlobal status of Merck Gardasil licensure, December 2007

Global status of GSK Cervarix® licensure, December 2007

Source: GSKbio, Belgium

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 2007.

• 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).

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.

Regional Group Purchasing

PATH demonstration projects on HPV vaccine, 2007–2011

Build on results of formative research to

design, implement, and evaluate cervical cancer

vaccine delivery to young girls.

source: WHO/EIP Burden of Disease Projections –http://www.who.int/healthinfo/statistics/bodprojections2030/en/index.html

Peru

Uganda

India Vietnam

Four project countries

Age-adjusted cervical cancer incidence rates

Ideal age group for vaccination

Girls aged 10–13 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 low-

resource 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.

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 testsfor secondary prevention

Characteristics

Comments

Number of visits required for screening and treatment

Conventional cytology

HPV DNA tests

Visual inspection tests

Sensitivity

Specificity(for high-grade lesions and invasive cancer)

47-62% 66-100% 78-98%

60-95% 62-96% 49-86%

VIA VILI

67-79%

73-91%

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

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

Source: Sankaranarayan et al. Int J Obstet Gynaecol, 2005.

Cluster Randomised Controlled Trial of VIA Screening,

Dindigul District, India

R. Sankaranarayanan et al. Effect of visual screening on cervical cancer incidenceand mortality in Tamil Nadu, India: a cluster-randomised trial Lancet, August 4, 2007

• 113 Village clusters• 80 252 eligible women aged 30-59 years

• Intervention: Single screening• Follow-up: 7 years

Hazard ratio (95% CI)*

Control group 1.0

Intervention group (VIA)Overall

Cervical cancer incidence 0.75 (0.59-0.95)Cervical cancer death 0.65 (0.47-0.89)

30-39 yearsCervical cancer incidence 0.62 (0.40-0.96)Cervical cancer death 0.34 (0.18-0.66)

40-49 yearsCervical cancer incidence 0.82 (0.55-1.24)Cervical cancer death 0.55 (0.31-1.00)

50-59 yearsCervical cancer incidence 0.76 (0.50-1.16)Cervical cancer death 0.99 (0.58-1.66)

* C.I.: Confidence interval

Overall and age-specific hazard ratio for incidence for all cervical cancers and for cervical cancer deaths

Comparison of VIA, cytology and HPV testing, CIN2+, 2005-2008

StudyPlace Sensitivity (%) Specificity (%)

N. VIA Cyto HPV VIA Cyto HPV

Sarian et al, 2005

Brazil10,138 50 58 83 90 99 86

De Vuyst et al,2005

Kenya653 73 83 94 78 90 69

Sangwa-Lugomaet al, 2006

Congo1,571 56 72 - 65 95 -

Pretorius et al, 2007

China8,497 46 88 97 92 81 80

Almonte et al, 2007

Peru5,435 55 70 77 77 84 89

Li et al,submitted

China2,562 35 87 90 89 85 86

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.

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