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HPV: infection, conséquence
et prévention
Bruxelles, janvier 2014
J. Squifflet
Service de Gynécologie
Cliniques Universitaires Saint Luc
[email protected]
• HPV-6, -11 :
• HPV Non oncogène
• HPV-16, -18, -31, -33,
-45, ...
• HPV Oncogène
Epidemiologie HPV
• Réservoir : humain
• Transmission : contact direct des muqueuses, auto-inoculation
entre différents sites génitaux.
• Fréquent chez les jeunes, femmes et hommes
• 80% de la population sera infectée par un HPV
Anogenital HPV transmission among 38 heterosexual couples over an average follow up of 7.5 months2
Number of transmission
events
Male-to-female
14
Female-to-male
39
Male self-inoculation
21
Female self-inoculation
4
Hernandez BY, et al. Emerg Infect Dis 2008; 14:888–894
HPV
PCR -
PCR+
seronegative
seropositive
Naïve
Exposition
ancienne
Infection présente
Infection
présente et /ou
chronique
HPV lifecycle and immune evasion
Cervical
canal
HPV has many immune
evasion mechanisms:1
• Viral lifecycle occurs entirely
within epithelium
• No viraemia
Cervical
epithelium
• No cell death
• No inflammation
• Local immunosuppression
caused by viral proteins
• HPV ‘stealth’ and immune evasive mechanisms enable infection to
persist1
• Persistent infection is a prerequisite, but may not be sufficient alone
for progression to cervical cancer2
1. Stanley M, et al. Vaccine 2006; 24S1:S1/16–S1/22;
2. Trottier H & Franco EL. Am J Manag Care 2006; 12:S462–S472.
Replication of papillomaviruses within
the epithelium
Virus assembly/
virus release
L1
Granular
L2
Virus
release
E4
Cornified
Basal
p97 p670
Cutaneous
Viral DNA
E6, E7
Suprabasal
E1, E2, E4, E5
Genome
amplification
Genome
maintenance/
cell proliferation
Genome
maintenance
p670
Mucosal
Doorbar J. Clin Sci (Lond) 2006; 110:525–541.
HPV gene expression in persistence
and disease progression
E7
Viral DNA
E4
L1
HPV
E4
CIN2
CIN3
E7
Viral DNA
Viral DNA
E7
E7
E4
L1
CIN1
Cervical cancer
Doorbar J. Clin Sci (Lond) 2006; 110:525–541.
Neutralizing antibodies prevent
HPV infection
• Neutralizing antibodies
are a type of antibody that
can ‘neutralize’ viral
infections
• Neutralizing antibodies
bind to HPV’s outer shell
(capsid) and prevent
infection of host cells1
HPV infects target cells in the basal
layer of the cervical epithelium
Infection
Basal cell layer
of cervical epithelium
Neutralizing antibodies prevent HPV
from infecting basal epithelial cells
No infection
X
1. Stanley M, et al. Vaccine 2006; 24(Suppl 3):S106–S113.
Cumulative risk of new HPV infection by
age group
Age at
baseline (Years)
Cumulative risk of HPV
infection, %
50
15–19
40
20–24
25–29
30
30–44
20
45+
10
0
0
1
2
3
4
5
Years
Cohort study, Bogota, Colombia, N = 1,610
Bosch FX, et al. Vaccine 2008; 26S:K1–K16.
Persistent HPV infection increases
with age: Guanacaste cohort
Infections at follow-up
due to persistence, %
60
Oncogenic
Non-oncogenic
50
40
30
20
10
0
< 25
25–34
35–44
45–54
55–64
≥ 65
Age group, years
Percentage of infections apparent at follow-up (5–7 years)
that had persisted since enrolment.
Castle PE, et al. J Infect Dis 2005; 191:1808–1816.
Risk of progression to CIN2+ is higher
in older vs younger HPV+ women
• Absolute risk of CIN2+ in women with a normal baseline
Pap in relation to concurrent HR HPV status
Absolute risk of
≥ moderate dysplasia, %
Younger women (22–32 years old)
HPV +ve
HPV –ve
Older women (40–50 years old)
HPV +ve
HPV –ve
35
30
25
20
15
10
5
0
1
2
3
4
5
6
7
Years of follow-up
8
9
10
11
Adapted from Kjaer S, et al. Cancer Res 2006; 66:10630–10636.
Resolution of prevalent HPV infections by
viral type at entry in women with ASCUS
Proportion of persistent infections
1.0
HPV types
16
52
51
62
31
89
18
53
56
61
average
0.8
0.6
0.4
Most infections
resolve within 12
months
0.2
0
6
12
18
24
Observed duration of infection (months)
ASCUS = atypical squamous cells of undetermined significance.
Plummer M, et al. J Infect Dis 2007; 195:1582–1589.
One in five HPV-16 pos women aged ≥30 will
develop a CINII+ lesion over a 10-year period
HPV 16+
HPV 18+
Non HPV 16/18
oncogenic HPV+
Oncogenic HPV-
Khan MJ et al. J Natl Cancer Inst 2005;97:1072–9.
HPV infection-attributable cancer in males
and females (2002)
Developed countries
Site
Developing countries
Attrib to
HPV, %
Total
cancers
Attrib to
HPV
All
cancer,
%
Total
cancers
Attrib to
HPV
All
cancer,
%
100
83,400
83,400
1.70
409,400
409,400
7.00
Penis
40
5,200
2,100
0.04
21,100
8,400
0.10
Vulva/
vagina
40
18,300
7,300
0.20
21,700
8,700
0.20
Anus
90
14,500
13,100
0.30
15,900
14,300
0.20
3
91,100
2,700
0.10
183,000
5,500
0.10
12
24,400
2,900
0.10
27,700
3,300
0.10
5,016,100
111,500
2.22
5,827,500
449,600
7.72
Cervix
Mouth
Orophar.
All sites
Parkin, DM. Int J Cancer 2006; 118:3030–3044.
<1%
Cancer col
40 ans
Dysplasie haut grade
30 ans
Dysplasie bas grade
< 3 -5 %
+/- 15 %
20 ans
Infection HPV
+/- 80 %
Population
Le cancer du col de l’utérus est une conséquence rare d’une infection fréquente
All world regions combined
WOMEN > 15: 2,013,133,000
N CASES > 15:
16
18
53.5
53.5%
70.7%
77.4%
80.3%
82.9%
85.2%
87.4%
88.8%
17.2
45
31
6.7
2.9
33
52
2.6
2.3
58
35
2.2
1.4
59
56
51
39
68
73
82
Other
X
60
80
31,549
13,678
12,134
10,929
10,242
6,570
5,769
1.0
4,641
0.7
3,211
0.6
2,714
0.5
2,339
0.3
1,350
5,632
4.4
40
80,859
1.2
1.2
20
251,199
6,137
1.3
0
469,723
100
20,769
Worldwide type-specific HPV prevalence across the
spectrum of HPV-related cervical diagnoses
HPV 16-18-45 lesions are more likely to progress to invasive cervical cancer
(ICC) than other oncogenic types
HSIL = high-grade squamous intraepithelial lesion; SCC = squamous cell
carcinoma; ADC = adenocarcinoma.
Multiple infections counted several times.
Type
Normal
HSIL
SCC
ADC
16
2.6
45.3
55.2
48.4
18
0.9
6.9
12.8
36.3
45
0.4
2.3
4.6
5.8
31
0.6
8.6
3.8
0.7
33
0.5
7.3
3.7
2.0
52
0.9
5.1
2.9
0
58
0.9
7.0
2.8
0.7
Other
6.8
23.9
7.6
7.7
Bosch FX, et al. Vaccine 2008; 26S:K1–K16.
The most common HPV types according
to grade of cervical lesion
LSIL/CIN1
HSIL/CIN2/3
20%
62%
Invasive cervical cancer
20%
6%
37%
45%
12%
61%
10%
11%
HPV 16
9%
HPV 18
7%
HPV 45/31
Other
Adapted from: http://www.who.int/hpvcentre/statistics; de Sanjose S et al. Presentation; 24th International Papilloma
Conference, Beijing 2007.
HPV persistent infection – precursor of CC
Incident
infection
Persistent
infection
6M
Persistent
infection
12M
M0
M6
M12
M18
M24
58
-
58
-
+58
33
-
-
+
+
16
-
16
-
CIN 3
5845
+
16
M30
M36
-
+
-
-
+
+
-
+
+
-
-
45
18
45
31
18
• HPV infection = presence of HPV DNA
• Depending on duration of the infection (with the same type!) we speak of 6M - 12M persistent
infection
Prevalence of multiple HPV infections in
women undergoing colposcopy (n = 1,323)
Proportion of women with multiple
HPV infections (%)
Prevalence of multiple infections according to CIN severity
100
81
80
63
60
44
40
20
14
0
Normal
CIN1
CIN2+
All women
(n = 334)
(n = 320)
(n = 265)
(n = 1,323)
Dal Bello B, et al. J Med Virology 2009; 81:703–712.
Results CIN2+
Case description CIN2+ case in the vaccine group (ATP-E cohort)
M0
M6
M12
M18
M24
M30
M36
M42
M48
52
52
52
52
52
52
52
18
52
18
NA
59
59
54
45
68
PCR
06
Cytology
ASC-US
Normal
Normal
Normal
Biopsy
Normal
NA
ASC-US
ASC-US
LSIL
CIN2
52
18
NA: not assessed
ASCUS: atypical squamous cells of unknown significance
LSIL: Low grade squamous intraepithelial lesion
Adapted from Paavonen J et al. Lancet 2009; 374 (9686): 301 - 314
Information on TVC naïve cohorts
Note: Bivalent HPV vaccine and quadrivalent HPV vaccine data from separate trials are not directly comparable due to differences in HPV/antibody detection
assays as well as the cohort differences summarized above.
GSK
Merck
Dose administered
≥1
≥1
Protocol violations
Included
Included
After day 1
After day 1 (Brown et al 2009)
After day 30 (EMEA 2008)
Serostatus VT at
baseline
Negative for 16/18
Negative for 6/11/16/18
DNA VT status at
baseline
Negative for 16/18
Negative for 6/11/16/18
DNA NVT status at
baseline
Negative for 12 types (66/68)*
Negative for 10 types
Cytology at baseline
Normal
Normal
0–6
0–4
15–25
16–26
Case counting
Number of sexual
partners
Age range
* HPV 68 detected in 0.6% of cervical cancers; HPV 66 < 0.3% of cervical cancers (Muñoz N et
al. Int J of Cancer 2004; 111:278–285).
VT = vaccine HPV type; NVT = non-vaccine HPV type.
Brown DR, et al. J Infect Dis 2009; 199:926–935;
EMEA. Assessment Report for Gardasil. 30 May 2008;
Paavonen J, et al. Lancet 2009; 374:301–314.
Baseline data from a Phase III HPV trial
18–25 years
Baseline
data
15–17 years
Baseline
data
No evidence of
previous exposure
to HPV 16 AND 18
sero- and DNA-
80.4%
70.7%
HPV 16 OR HPV 18
sero+/DNA-
9.0% or 6.6%
5.1% or 2.5%
< 1%
HPV 16 OR HPV 18
DNA+
HPV 16
AND 18
DNA+
PATRICIA trial; Total Vaccinated Cohort (N = 18,644)
16.2% or 12.4%
5.5% or 2.3%
< 1%
Apter D et al. EUROGIN. 2010. Monaco; Abstract.
•Antibody levels reported here are measured by different methods
•and in separate studies for CervarixTM and Gardasil® and therefore cannot be directly compared
Adapted from Olsson SE, et al. Vaccine 2007; 25:4931–4939; Villa LL, et al. Vaccine 2006; 24:5571–5583.
Schwarz TF, Hum Vaccin. 2010 Dec 1;6(12). [Epub ahead of print]
CVS neutralizing antibody positivity rates for HPV 16
and HPV 18 antibodies at Month 7 (HPV-010)
•
A greater proportion of women achieved cervicovaginal secretion (CVS)
neutralizing antibody positivity with the bivalent HPV vaccine than with
the quadrivalent HPV vaccine for both HPV 16 (81.3% versus 50.9%) and
HPV 18 (33.3% versus 8.8%)
Bivalent HPV vaccine
Quadrivalent HPV
vaccine
Antigen
Timing
N
n
Positivity, %
(95% CI)
N
n
Positivity, %
(95% CI)
HPV 16
Baseline
24
3
12.5 (2.7–32.4)
36
5
13.9 (4.7–29.5)
Month 7
48
39
81.3 (67.4–91.1)
57
29
50.9 (37.3–64.4)
Baseline
24
1
4.2 (0.1–21.1)
36
2
5.6 (0.7–18.7)
Month 7
48
16
33.3 (20.4–48.4)
57
5
8.8 (2.9–19.3)
HPV 18
ATP cohort.
Neutralizing antibody positivity defined as a CVS dilution greater than or equal to the assay threshold of 40 ED50 for each antigen
with both vaccines.
N = number of subjects with available results in CVS.
n = number of subjects with antibody titres within the defined range for positivity.
Einstein MH, et al. Hum Vacc 2009; 5[Epub ahead of print].
Pseudovirion-based neutralization assay (PBNA)
measures all anti-HPV neutralizing antibodies against
HPV 16 or HPV 18
Serum
Pseudovirions
Vaccinee serum is
mixed with pseudovirions
Substrate
Mixed serum and pseudovirions
Human cells are incubated
with this mix
Expression of alkaline phosphatase
in the liquid
Substrate is added and reacts with the
enzyme and light emission is measured
wash
Non-HPV antibodies
Non-neutralizing anti-L1 VLP antibodies
Neutralising anti-L1 VLP antibodies
Head to head study
CERVARIX – GARDASIL
Immune response, neutrolising antibodies, memory B cells
Women 18-45 years
Neutralising
Antibodies
HPV 16
Cervarix
Gardasil
>2
Neutralising
Antibodies
HPV 18
Cervarix
Gardasil
>6
Memory B cells
HPV 16 - 18
Cervarix
Gardasil
> 2.7
Seronégative et
DNA négative
3 Doses
End of study analyse
Results CIN2+ and CIN3+
Overall efficacy irrespective of HPV type in the lesion
TVC Cohort
1 End-of-study:
Endpoint
group
N
Vaccine
8694
287
Control
8708
428
Vaccine
8694
86
Control
8708
158
Endpoint
Cohort
HPV
HAV
CIN2+ irrespective of HPV type in the
lesion
vaccine
8667
224
control
8682
322
vaccine
8667
77
control
8682
116
lesion
lesion
Vaccine Efficacy (95% CI)
n
%
LL
UL
P-value
33.1
22.2
42.6
<0.0001
45.6
28.8
58.7
<0.0001
2 Final analysis:
lesion
Vaccine Efficacy (96.1% CI)
%
LL
UL
P-value
30.4
16.4
42.1
<0.0001
33.4
9.1
51.5
0.0058
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;
1 Paavonen et al (IPC - Montreal July 2010)
2 Paavonen J et al. Lancet 2009; 374 (9686): 301 - 314
37
Efficacité sur CIN2+ et CIN3+
associés aux types d’HPV vaccinaux et non vaccinaux
(TVC)
Lehtinen M, et al. Lancet Oncol Nov 2011.
Vaccin HAV
Cervarix
Overall efficacy irrespective of HPV type in the lesion
TVC-naïve Cohort
1 End-of-study:
Endpoint
group
N
Vaccine Efficacy (95% CI)
n
lesion
vaccine
5466
61
control
5452
172
lesion
vaccine
5466
3
control
5452
44
Cohort
HPV
HAV
%
LL
UL
P-value
64.9
52.7
74.2
<0.0001
93.2
78.9
98.7
<0.0001
2 Final analysis:
Endpoint
lesion
lesion
vaccine
5449
33
control
5436
110
vaccine
5449
3
control
5436
23
Vaccine Efficacy (96.1% CI)
%
LL
UL
P-value
70.2
54.7
80.9
<0.0001
87.0
54.9
97.7
<0.0001
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;
1 Paavonen et al (IPC - Montreal July 2010)
2 Paavonen J et al. Lancet 2009; 374 (9686): 301 - 314
40
Efficacité sur CIN2+ et CIN3+
associée aux types d’HPV vaccinaux et non vaccinaux
(TVC-naïve)
Dans le groupe
vaccin seulement
1 CIN2+ associé
à HPV 16/18
Lehtinen M, et al. Lancet Oncol, Nov 2011.
Overall efficacy irrespective of HPV type in the lesion (TVC-naïve)
CIN2+
CIN3+
Irrespective of DNA in
the lesion
Irrespective of DNA in
the lesion
group
N
n
vaccine
5449
33
control
5436
110
vaccine
5449
3
control
5436
23
Vaccine
efficacy %
(96.1% CI)
p value
70.2
(54.7; 80.9)
< 0.0001
87.0
(54.9; 97.7)
< 0.0001
Estimated worldwide prevalence of HPV 16/18 in high-grade lesions (CIN 2/3): 52%1
N = number of evaluable women in each group;
n = number of evaluable women reporting at least one event in each group
Paavonen J et al. Lancet 2009; 374 (9686): 301 - 314
1. Bosch et al. Vaccine 2008, 26S:K1-K16
CIN2+ Results
Vaccine efficacy related to individual oncogenic non-vaccine HPV types
TVC naïve Cohort; Primary analysis
Final analysis1
HPV type
group
N
n
vaccine
5449
0
control
5436
20
vaccine
5449
5
control
5436
18
vaccine
5449
0
control
5436
5
HPV-high risk
oncogenic types
excluding HPV-16
and -18
vaccine
5449
21
control
5436
67
HPV-high risk
oncogenic types
vaccine
5449
22
control
5436
98
HPV-31
HPV-33
HPV-45
End-of-study analyis2
Efficacy%
96.1% CI
P value
100.0
(78.3; 100.0)
<0.0001
72.3
(19.1; 92.5)
0.0065
100.0
(-19.5; 100.0)
0.0310
68.8
(47.1; 82.4)
<0.0001
77.7
(63.5; 87.0)
<0.0001
N
n
5466
3
5452
28
5466
5
5452
28
5466
0
5452
8
5466
45
5452
102
5466
46
5452
151
Efficacy%
95% CI
P value
89.4
(65.5; 97.9)
<0.0001
82.3
(53.4; 94.7)
<0.0001
100.0
(41.7; 100.0)
0.0039
56.2
(37.2; 69.9)
<0.0001
69.8
(57.8; 78.8)
<0.0001
Subjects DNA negative at baseline for the corresponding type; N = number of evaluable women in each group; n = number of evaluable women reporting at least one event in each group
1 Skinner et al.oral presentation IPC2009 Sweden
2 Romanovski et al IPC - Montreal July 2010
Quadrivalent HPV vaccine: cross-protective efficacy
results of FUTURE I/II (Subjects naïve to 14
HPV types)
CIN 2–3 or
adenocarcinoma
in situ related to:
Quadrivalent HPV
vaccine (N = 4,616)
Cases
Placebo (N = 4,680)
Rate*
Cases
Rate*
Efficacy
95% CI
Non-vaccine A9 species
HPV 31
8
< 0.1
27
0.2
70.0
32.1– 88.2
HPV 33
12
0.1
16
0.1
24.0
–71.2–67.2
HPV 35
4
< 0.1
4
< 0.1
–1.5
–444.9–81.1
HPV 52
17
0.1
23
0.1
25.2
–46.4–62.5
HPV 58
16
0.1
20
0.1
18.9
–64.7–60.7
Non-vaccine A7 species
HPV 39
4
< 0.1
10
< 0.1
59.6
–40.2–90.7
HPV 45
3
< 0.1
2
< 0.1
–51.9
–1717.8–82.6
HPV 59
5
< 0.1
9
< 0.1
43.8
–86.9–85.2
Other non-vaccine types
HPV 51
16
0.1
15
0.1
–8.1
–134.7–50.0
HPV 56
12
0.1
16
0.1
24.1
–71.1–67.2
Prespecified analysis (negative for the four HPV vaccine types and 10 non-vaccine types on Day 1).
*Cases per 100 person-years at risk.
Adapted from Brown DR, et al. J Infect Dis. 2009; 199:926-35.
Estimate of coincident temporal association between
hypothetical HPV vaccination and medical conditions
• The likelihood of an external factor being considered as a
potential triggering/precipitating factor essentially results
from a temporal association
Hospitalisation/
condition
Adolescents
Rate per 100,000* at different
time points post-vaccination
Adults
Rate per 100,000* at different time
points post-vaccination
1 day
1 week
6 weeks
1 day
1 week
6 weeks
Thyroid disease
0.1
0.9
4.0
2.4
16.6
71.8
Systemic lupus
erythematosus
0.1
0.5
2.0
0.3
1.8
7.8
Multiple sclerosis/
optic neuritis
0.0
0.2
1.0
0.1
0.7
3.0
* Assumes putative placebo injections were administered at 0, 1 and 6 months, and corrected for vaccine
coverage to be 80% in adolescents and 40% in adults.
Siegrist C-A, et al. Pediatr Infect Dis J 2007; 26:979–984.
Results
Safety outcomes (TVC)
N= women assessed; n= number of women reporting an event
Safety outcomes
Serious adverse event (SAE)
Vaccine-related SAE
Medically-significant condition
New-onset chronic disease
New onset autoimmune disease
Deaths
Vaccine
N = 9319
n
%
701
11
2960
251
78
9
8
<1
32
3
<1
<1
Control
N = 9325
n
%
699
6
3025
268
77
8
8
<1
32
3
<1
<1
No deaths were thought to be possibly related to vaccination in either group.
Medically significant conditions were defined as adverse events (prompting visits to the emergency department or to the
physician) that are not routine or related to common diseases, or serious adverse events that are not related to common
diseases.
EFFETS COLLATERAUX….
Reductions in numbers of colposcopy
referral and cervical excision procedure
Vaccine Control
TVC
Naive
Reduction %
P
colposcopy
354
476
26
0.0001
cervical
procedures
(leep-laser)
26
83
68
0.0001
colposcopy
1107
1235
10
0.0055
cervical
procedure
180
240
24
0.0035
TVC
PATRICIA, HPV008
Fairley, Malmö, 2009
GARDASIL® Efficacy in women aged 16-26 years after definitive
therapy (Future I & II) – ITT analysis with case counting after definitive
surgery
Definitive therapy
for cervical disease
(Future I – II studies)
Treatment for GW,
VIN or VaIN
(Future I study)
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)
Endpoint
Efficacy (%)
95% CI
79
(53-92)
44
(14,64)
VaIN1-3, VIN1-3, GW
due to HPV 6/11/16/18
VaIN1-3, VIN1-3, GW
due to any HPV type
Average follow-up post-therapy: 1.5-1.9 years, Women aged 16-26 years, from protocol 013 and protocol 015
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
HPV-16 GMT (EL.U/mL)
High and sustained antibodies above natural infection
for at least 8.4 years for both HPV 16 and 18 1-2
10000
HPV 16
1000
≥ 11-fold
higher
than
natural
infection
100
10
1
HPV-18 GMT (EL.U/mL)
M0
M7
M18
M33M38
M39M44
M45M50
M51M56
10000
M57M62
M63M68
M69M74
M75- M77M76 M82
M83M88
M89- M95M94 M101
Months after 1st
vaccination
HPV 18
1000
≥ 10-fold
higher
than
natural
infection
100
10
1
M0
M7
HPV-001
M18
M33M38
M39M44
M45M50
M51M56
M57M62
HPV-007
M63M68
M69M74
M75M76
M77M82
M83M88
M89- M95M94 M101
HPV-023
1. Rotelli-Martins CM, et al. ESPID 2010; Abstract. 2. Data on File: GSKBio_WWMA_DoF053_1_2010.
Months after 1st
vaccination
Gardasil
Cervarix
HPV 16 – 18 – 6 – 11
HPV 16 – 18
Cross 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 - 18
Immunology – 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?
QALY
Quality-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
•
•
•
•
•
•
•
•
•
DTP
< 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 $
3000 to 45.000 $
HPV target: 12 year old girls :
HAV and HBV target: college freshmen: < 0 – 10.000 $
• 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
Cervarix
• N=960
• 2 doses vs 3 doses
M 0,6
M 0,1,6
• Follow-up 4 years
• Compare:
– 2 doses
– 3 doses
9-14 years
15-25 years
2 doses
9-14 years
3 doses
15-25 years
Sero+ HPV16
3.3%
14.3%
Sero+ HPV18
6.7%
14.4%
•
•
•
All subjects were seropositive for HPV16 and 18
Months 7 → 48
Kinetics were comparable
•
•
HPV16
HPV18
44x higher than natural
24x higher than natural
B cells
→
CD4 cells
HPV16
HPV18
HPV31
HPV45
Cervarix
9-14
2 doses
0,6
5-7
15
3 doses
0,1,6
5-12
Traitements des condylomes: « clearance » et « récidives »
Ting et al , 2004
Traitements des dysplasies
Chirurgie:
LLETZ, electrochirurgie, laser CO2, bistouri froid/ electrique
Destruction tissulaire: cryotherapie, formaldéhyde, acide trichloracétique
Agent cytotoxique:
bleomycine, podophyllotoxine, podophylline, 5 FU
Antiviral:
cidofovir
Immunothérapies:
imiquimod, interferon, vaccins thérapeutiques
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……

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