efficacité de la vaccination hpv traitement des condylomes · •hpv 31 - 45 - 52 et 51 ( hpv)...
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Efficacité de la vaccination HPV-
Traitement des condylomes
•J. Squifflet•Service de Gynécologie
•Cliniques Universitaires Saint Luc
ECU Mont Godinne, mars 2012
HPV seronegative seropositive
PCR - Naïve Exposition ancienne
PCR+ Infection présenteInfection
présente et /ou chronique
WOMEN > 15:WOMEN > 15: 2,013,133,0002,013,133,000
N CASES > 15:N CASES > 15: 469,723469,723
00 2020 4040 6060 8080 100100
1616 53.553.51818 17.217.2
4545 6.76.73131 2.92.93333 2.62.65252 2.32.35858 2.22.23535 1.41.45959 1.31.35656 1.21.25151 1.01.03939 0.70.76868 0.60.67373 0.50.58282 0.30.3
OtherOther 1.21.2XX 4.44.4
251,199251,19980,85980,85931,54931,54913,67813,67812,13412,13410,92910,92910,24210,2426,5706,570
20,76920,7695,6325,6321,3501,350
6,1376,1375,7695,7694,6414,6413,2113,2112,7142,7142,3392,339
53.5% 53.5% 70.7% 70.7% 77.4% 77.4% 80.3% 80.3% 82.9% 82.9% 85.2% 85.2% 87.4% 87.4% 88.8% 88.8%
All world regions combined
Seronégative etDNA négative
3 Doses
Endpoint group N nVaccine Efficacy (95% CI)
% LL UL P-value
CIN2+ irrespective of HPV type in the lesion
Vaccine 8694 28733.1 22.2 42.6 <0.0001
Control 8708 428
CIN3+ irrespective of HPV type in the lesion
Vaccine 8694 8645.6 28.8 58.7 <0.0001
Control 8708 158
Endpoint Cohort HPV HAVVaccine Efficacy (96.1% CI)
% LL UL P-value
CIN2+ irrespective of HPV type in the lesion
vaccine 8667 22430.4 16.4 42.1 <0.0001
control 8682 322
CIN3+ irrespective of HPV type in the lesion
vaccine 8667 7733.4 9.1 51.5 0.0058
control 8682 116
7
1 End-of-study:
2 Final analysis:
TVC cohort: Population irrespective of HPV DNA and cytological status at baseline; N = number of evaluable women in each group; n = number of evaluable women reporting at least one event in each group;
TVC Cohort
Results CIN2+ and CIN3+ Overall efficacy irrespective of HPV type in the lesion
End of study analyse
1 Paavonen et al (IPC - Montreal July 2010)2 Paavonen J et al. Lancet 2009; 374 (9686): 301 - 314
Efficacité sur CIN2+ et CIN3+associés aux types d’HPV vaccinaux et non vaccinaux
(TVC)
Lehtinen M, et al. Lancet Oncol Nov 2011.
Cervarix
Vaccin HAV
Endpoint group N nVaccine Efficacy (95% CI)
% LL UL P-value
CIN2+ irrespective of HPV type in the lesion
vaccine 5466 6164.9 52.7 74.2 <0.0001control 5452 172
CIN3+ irrespective of HPV type in the lesion
vaccine 5466 393.2 78.9 98.7 <0.0001control 5452 44
Endpoint Cohort HPV HAVVaccine Efficacy (96.1% CI)
% LL UL P-value
CIN2+ irrespective of HPV type in the lesion
vaccine 5449 3370.2 54.7 80.9 <0.0001
control 5436 110
CIN3+ irrespective of HPV type in the lesion
vaccine 5449 387.0 54.9 97.7 <0.0001
control 5436 23
10
1 End-of-study:
2 Final analysis:
TVC-naïve cohort: Population naïve to 14 oncogenic HPV types at baseline; N = number of evaluable women in each group; n = number of evaluable women reporting at least one event in each group;
TVC-naïve Cohort
Results CIN2+ and CIN3+ Overall efficacy irrespective of HPV type in the lesion
End of study analyse
1 Paavonen et al (IPC - Montreal July 2010)2 Paavonen J et al. Lancet 2009; 374 (9686): 301 - 314
Efficacité sur CIN2+ et CIN3+ associée aux types d’HPV vaccinaux et non vaccinaux
(TVC-naïve)
Lehtinen M, et al. Lancet Oncol, Nov 2011.
Dans le groupe vaccin seulement 1 CIN2+ associé
à HPV 16/18
Dans le groupe vaccin seulement 1 CIN2+ associé
à HPV 16/18
• Absolute risk of CIN2+ in women with a normal baseline Pap in relation to concurrent HR HPV status
Risk of progression to CIN2+ is higher in older vs younger HPV+ women
Younger women (22–32 years old) Older women (40–50 years old)
Adapted from Kjaer S, et al. Cancer Res 2006; 66:10630–10636.
HPV +veHPV –ve
HPV +veHPV –ve
Abs
olut
e ris
k of
≥ m
oder
ate
dysp
lasi
a, %
Years of follow-up
0
5
10
15
20
25
30
35
1 2 3 4 5 6 7 8 9 10 11
EFFETS COLLATERAUX….
Gardasil® remains efficacious in women who have undergone definitive surgical therapy and have thereafter developed CIN 1 or worse or external genital lesions and have had recurrence
Joura E. et al. Abstract presented at ESGO, Belgrade Oct. 2009
Average follow-up post-therapy: 1.5-1.9 years, Women aged 16-26 years, from protocol 013 and protocol 015
Definitive therapy for cervical disease
(Future I – II studies)
Endpoint Efficacy (%) 95% CI
CIN 1 or worse due to HPV 6,11,16,18 74 (<0, 97)
CIN 1 or worse due to any HPV type 47 (17-66)
Treatment for GW, VIN or VaIN
(Future I study)
Endpoint Efficacy (%) 95% CI
VaIN1-3, VIN1-3, GWdue to HPV 6/11/16/18 79 (53-92)
VaIN1-3, VIN1-3, GWdue to any HPV type 44 (14,64)
GARDASIL® Efficacy in women aged 16-26 years after definitive therapy (Future I & II) – ITT analysis with case counting after definitive surgery
Efficacy and safety of the bivalent HPV vaccine in women 15–25 years old
HPV 16/18 DNA status /serostatus
HPV 16/18 Endpoint
Vaccinecases (N)
Controlcases (N)
Efficacy*%
96.1% CI
DNA-/sero-
74%1
6-month PI 32 (7,177) 497 (7,122) 93.81,2 91.0–95.912-month PI 21 (7,035) 233 (6,984) 91.21,2 85.9–94.8CIN2+ 4 (7,344) 56 (7,312) 92.91,2 79.9–98.3CIN2+ TAA 1 (7,344) 53 (7,312) 98.11,2 88.4–100.0
DNA-/sero+
13.5% or 10%1
6-month PI 9 (1,462) 47 (1,496) 80.62 58.6–92.012-month PI 2 (1,427) 24 (1,461) 91.52 64.0–99.2CIN2+ 2 (1,510) 6 (1,547) 65.82 -105.7–97.1CIN2+ TAA 0 (1,510) 5 (1,547) 100.02 -22.9–100.0* PATRICIA trial; ATP cohort for efficacy (ATP-E). PI = Persistent infection; TAA = HPV type-assignment algorithm.
• The bivalent HPV vaccine has been shown to have a clinically acceptable safety profile in women regardless of their HPV DNA status or serostatus3
1. Paavonen J, et al. Lancet 2009; 374:301–314. 2. FDA. Cervarix®. Vaccines and Related Biological Products Advisory Committee (VRBPAC) Briefing Document. Available at: http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/BloodVaccinesanOtherBiologics/
VaccinesandRelatedBiologicalProductsAdvisoryCommittee/UCM181371.pdf. Accessed November 25, 2009. 3. Cervarix®. Europe SPC. December 2009.Cervical cancer vaccination should be in accordance with the approved Summary of Product Characteristics and with local official recommendations
.
High and sustained antibodies above natural infection for at least 8.4 years for both HPV 16 and 18 1-2
Months after 1st
vaccination
Months after 1st
vaccination
HPV
-16
GM
T (E
L.U
/mL)
HPV
-18
GM
T (E
L.U
/mL)
1
10
100
1000
10000
M0 M7 M18 M33-M38
M39-M44
M45-M50
M51-M56
M57-M62
M63-M68
M69-M74
M75-M76
M77-M82
M83-M88
M89-M94
M95-M101
1
10
100
1000
10000
M0 M7 M18 M33-M38
M39-M44
M45-M50
M51-M56
M57-M62
M63-M68
M69-M74
M75-M76
M77-M82
M83-M88
M89-M94
M95-M101
11-fold higher than
natural infection
10-fold higher than
natural infection
HPV-001 HPV-007 HPV-023
Months after 1st
vaccination
Months after 1st
vaccination
HPV
-16
GM
T (E
L.U
/mL)
HPV
-18
GM
T (E
L.U
/mL)
1
10
100
1000
10000
M0 M7 M18 M33-M38
M39-M44
M45-M50
M51-M56
M57-M62
M63-M68
M69-M74
M75-M76
M77-M82
M83-M88
M89-M94
M95-M101
1
10
100
1000
10000
M0 M7 M18 M33-M38
M39-M44
M45-M50
M51-M56
M57-M62
M63-M68
M69-M74
M75-M76
M77-M82
M83-M88
M89-M94
M95-M101
11-fold higher than
natural infection
10-fold higher than
natural infection
HPV-001 HPV-007 HPV-023
HPV 16
HPV 18
1. Rotelli-Martins CM, et al. ESPID 2010; Abstract. 2. Data on File: GSKBio_WWMA_DoF053_1_2010.
Gardasil Cervarix
HPV 16 – 18 – 6 – 11 HPV 16 – 18Cross protection•HPV 31 ( CIN II +)
Cross protection•HPV 31 - 45 - 52 et 51 ( HPV)•HPV 31-33-45- ( CIN II +)
Protection•VaIN – VIN Related HPV•AIN MSM, EGL males
Preliminary data: VIN /VaIN
Long term follow-up•9.5 years
HPV 16 monovalent
Long term follow-up•9.4 years
HPV 16 - 18Immunology – immune response
Antibodies
Coût efficacité
• Efficacité• Durée d’éfficacité• Effets secondaires
• Quelles patient(e)s? Coût du vaccin, coût des soins de santé, nombre de cancer du col de l’utérus dans le pays, autres cancers HPV « dépendant », hommes?
QALYQuality-Adjusted Life Year
Account for quality and lenght of life
• One year in perfect health = 1 QALY• Death = 0 QALY• One year of live in less than perfect health is
given a value between = 0 and 1 QALY
Cost per QALY gained by vaccines in the US• D T P < 0 (cost saving)• Hib < 0 (cost saving)• MMR < 0 (cost saving)• Polio < 0 (cost saving)• Varicella < 0 (cost saving)• Influenza 10.000 $• HAV ~ 10.000 – 30.000 $• HPV target: 12 year old girls : 3000 to 45.000 $• HAV and HBV target: college freshmen: < 0 – 10.000 $
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• Nombre cancer col : efficience du dépistage• Effets collatéraux :
– Condylomes– Protection croisée– Cancers HPV dépendants (vulve, vagin, anus,ORL,…)
• Vaccination garçons :– Couverture filles– Certains groupes
• Booster• Efficacité du vaccin• Compliance vaccin - dépistage
Cost effective• Ratio of Euro per quality-adjusted life year (QUALY)• Netherlands:
– Ratio of 53.500 € per QALY (118 €/injection)– Ratio of 20.000 € (40 €/injection)
• If booster (33 €/injection)• If 4 boosters (16 €/injection)
Threshold: 20.000 € per QALY1.6/100.000 women year
HPV vaccination is not cost effective
Vaccination HPV :coût- efficacité
• Vaccins efficaces, suivi à long terme (rappel, effets secondaires, effets collatéraux, …)
• Coûts à réduire• Améliorer la couverture• (Ré)organisation du dépistage
• Les Naïves les premières……
Resolution of prevalent HPV infections by viral type at entry in women with ASCUS
Plummer M, et al. J Infect Dis 2007; 195:1582–1589.
Observed duration of infection (months)
Prop
ortio
n of
per
sist
ent i
nfec
tions
HPV types16525162318918535661average
0 6 12 18 24
1.0
0.8
0.6
0.4
0.2
ASCUS = atypical squamous cells of undetermined significance.
Most infections resolve within 12 months
Traitements des condylomes: « clearance » et « récidives »
Ting et al , 2004