hpv franceschi
DESCRIPTION
hpv e vaccinoTRANSCRIPT
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
(Congresso Nazionale GISCI, Orvieto 3-4 (Congresso Nazionale GISCI, Orvieto 3-4 aprile 2008)aprile 2008)
• 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)
(Congresso Nazionale GISCI, Orvieto 3-4 (Congresso Nazionale GISCI, Orvieto 3-4 aprile 2008)aprile 2008)
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.
(Congresso Nazionale GISCI, Orvieto 3-4 (Congresso Nazionale GISCI, Orvieto 3-4 aprile 2008)aprile 2008)
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.
(Congresso Nazionale GISCI, Orvieto 3-4 (Congresso Nazionale GISCI, Orvieto 3-4 aprile 2008)aprile 2008)
(Congresso Nazionale GISCI, Orvieto 3-4 (Congresso Nazionale GISCI, Orvieto 3-4 aprile 2008)aprile 2008)
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).
(Congresso Nazionale GISCI, Orvieto 3-4 (Congresso Nazionale GISCI, Orvieto 3-4 aprile 2008)aprile 2008)
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
(Congresso Nazionale GISCI, Orvieto 3-4 (Congresso Nazionale GISCI, Orvieto 3-4 aprile 2008)aprile 2008)