Hpv Franceschi

Vaccino contro l’HPV: la Lunga Marcia

Silvia Franceschi Infections and Cancer Epidemiology GroupInternational Agency for Research on Cancer

Lyon, France

Ist. Mario Negri, Milano, 14 Aprile, 2008

IARC-ICE 2007

Tumori attribuibili a infezione nel 2002

From Parkin, 2006

Paesi sviluppati Paesi in via di sviluppo

7.7% di tutti I tumori 26.3% di tutti I tumori

HPV: >4% dei tumori nelle donne HPV: >15% dei tumori nelle donne

Other: 0.2% H.pylori:

7%

HPV: 7.7%

HBV & HCV: 8.2%

EBV: 1.6%

HIV/HHV-8: 1.6%

HIV/HHV-8: 0.3% EBV: 0.3%

HBV & HCV: 1%

HPV: 2.2%

H.pylori: 3.9%

0 100 200 300 400 500 600 700

Breast

Colon\Rectum

Cervix

Stomach

Lung

Ovary

Corpus Uteri

Liver

Esophagus

Leukemia

NHL

Pancreas

Oral Cavity

Thyroid

Kidney

Can

cer

Sit

es

(Thousands)

DevelopedDeveloping

Incidenza dei tumori per tipo di Paese

Incidenza del cancro

alla cervice secondo

l’età

Fasi dello sviluppo del tumore alla cervice

HPV discovery have fostered:

• Introduction of highly efficacious prophylactic HPV vaccines

• Increase in the role of HPV testing in cervical cancer screening, i.e., in triage, treatment evaluation and as an alternative or supplement of cytology in primary screening

Albero filogenetico dei genotipi di HPV

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 56

HPV 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 di più diffusi tipi di HPV in 14.097 casi di tumore invasivo della cervice divisi in

regioni70%

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.

ChinaChina

LampangLampang

ArgentinaArgentina

IARC Multi-centre HPV Prevalence Surveys

HanoiHanoi

Ho ChiHo Chi MinhMinh

KoreaKorea

ColombiaColombia

NigeriaNigeria

SpainSpain

SongklaSongkla

ChileChile

ItalyItaly

ShenzhenShenzhenMexicoMexico

The NetherlandsThe Netherlands

IndiaIndia

completed ongoing

MongoliaMongolia

AlgeriaAlgeria

GuineaGuinea

UgandaUganda

PolandPoland

ShenyangShenyangShanxiShanxiNepalNepal

PakistanPakistan

IranIranGeorgiaGeorgia

Prevalence of cervical HPV DNA in sexually active women

IARC Multi-centre HPV Prevalence Survey, 1995-2002

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

999933534908

1940685834

1981671971

1340870918

101310243299

716908

1007

0 5 10 15 20 25 30 35

hpv 16 or 18

other high-risk type

low-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 55-59

Age group (years)

HP

V p

rev

ele

nc

e (

%)

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

India

0

5

10

15

20

25

30

35

40

<25 25-34 35-44 45-54 55+

Age group (years)

HP

V p

reva

len

ce (

%)

Nigeria

0

5

10

15

20

25

30

35

40

<25 25-34 35-44 45-54 55+

Age group (years)

HP

V p

reva

len

ce (

%)

IARC-ICE 2007

HPV 16

IARC-ICE 2007

VLP

IARC-FIS

2002

(Congresso Nazionale GISCI, Orvieto 3-4 (Congresso Nazionale GISCI, Orvieto 3-4 aprile 2008)aprile 2008)

• Seronegative and HPV-DNA negative at day 1;Seronegative and HPV-DNA negative at day 1;• Remained negative through 1 month after 3° Remained negative through 1 month after 3°

dose; dose; • 3 doses within 12 months;3 doses within 12 months;• No major protocol violationsNo major protocol violations


• Included even if they had infection or disease to Included even if they had infection or disease to HPV-16 and 18 (HPV-16 and 18 (9% to HPV-16; 4% to HPV-18; 1% both 9% to HPV-16; 4% to HPV-18; 1% both genotypes)genotypes)

• Included even if protocol violations were present.Included even if protocol violations were present.• Included even if results on cytologic examination at day Included even if results on cytologic examination at day

1 were abnormal (1 were abnormal (ASCUS and LSIL combined 12%).ASCUS and LSIL combined 12%).

Prophylactic Vaccine Efficacy: Merck & GSK

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

Koutsky, 2007(Merck)

Ault, 2007 (Merck) Garland, 2007(Merck)

Paavonen, 2007(Merck)

2007 Reports

Eff

icac

y vs

. C

IN2/

3 &

AIS

(H

PV

16/H

PV

18)

Per Protocol

Modified ITT

ITT

IARC-ICE 2007

Efficacy of quadrivalent vaccine against HPV 16/181

Per protocol By intention to treat, against

HPV-negative HPV 16/18 Any type

CIN2/3 or AIS 99% 44% 18% (93 to 100) (31 to 55) (7 to 29)

By lesion:

CIN 2 100% 50% 21% (93 to 100) (34 to 62) (7 to 33)

CIN 3 98% 39% 17% (89 to 100) (21 to 53) (-0.1 to 31)

AIS 100% 54% 57% (31 to 100) (-30 to 86) (-19 to 87)

1 Future II, Lancet, 2007

IARC-ICE 2007

Time to CIN2/3 or AIS in intention-to-treat population

HPV 16/18 Any HPV

* Of randomised women, 9841 vaccine and 9904 placebo recipients received at least one dose and had at least one follow-up visit after dose 1.

Future II, Lancet, 2007

Rate of HPV-16/18 Clearance by Trial Arm

Hildesheim et al., JAMA, 2007

0%

10%

20%

30%

40%

50%

60%

70%

6-Month 12-Month 6-Month 12-Month 6-Month 12-Month 6-Month 12-Month

HPV16 HPV18 HPV16&18 HPV16&18 (alldoses)

Baseline HPV16/18 Status

%C

lear

ance

VaccinePlacebo (Hep A)

N = HPV16: 181(V)/232(P); HPV18: 81(V)/81(C)


SEROCONVERSIONSEROCONVERSIONIMMUNOGENICITY IMMUNOGENICITY (GMT neutralizing (GMT neutralizing IgG)IgG)ANAMNESTIC IMMUNE-ANAMNESTIC IMMUNE-RESPONSE MEMORYRESPONSE MEMORY

(Sven-Eric Olsson, (Sven-Eric Olsson, Vaccine 2007)Vaccine 2007)

immunity following vaccination exceeds 5 years and appears to be sustained.


SEROCONVERSIONSEROCONVERSIONIMMUNOGENICITY IMMUNOGENICITY (GMT neutralizing (GMT neutralizing IgG)IgG)ANAMNESTIC IMMUNE-ANAMNESTIC IMMUNE-RESPONSE MEMORYRESPONSE MEMORY

(Sven-Eric Olsson, (Sven-Eric Olsson, Vaccine 2007)Vaccine 2007)

It is possible that re-infection will provide a means of naturally sustaining immunity in the absence of vaccineboosting.


HPVTypes Objectiv

e

QuadrivalentVaccine

Placebo

EfficacEfficacyy

95% CI

n cases n cases

31,45CIN2-3

AIS4616 8 4675 21 62%62% (10, 85)

31,33,4552,58

CIN2-3 AIS

4616 27 4675 48 43%43% (7,66)

31,33,3539,45,5152,56,58 59

CIN2-3 AIS

4616 38 4675 62 38%38% (6, 60)Presented at the 24Presented at the 24thth Int. Papillomavirus Conference and Clinical Int. Papillomavirus Conference and Clinical

Workshop, Workshop, Beijing, 3-9 November, 2007Beijing, 3-9 November, 2007

3

North America:

USA CanadaMexico

7

South America:

Brazil ArgentinaPeruColombiaChileEcuadorUruguay

18

Middle East & Africa:

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

11 Asia Pacific:

Australia Indonesia

KoreaTaiwanHong 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 Timelines Intelligence about approvals for GSK are not as timely

Global 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).


99 1100

1111

1122

1133

1144

1155

1166

1177

1188

1199

2200

2211

2222

2233

2244

2255

2266

Germania

Francia

Italia

Svizzera

Austria

Norvegia

Belgio

Lussemb.

Svezia

Danimarca

Spagna

Grecia

UK

Portogallo

Regional Group Purchasing

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.

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).

IARC-ICE 2007

The Promise of Global Cervical-Cancer Prevention

Schiffman and Castle, NEJM, 2005

Hpv Franceschi

Health & Medicine

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