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Prophylactic HPV vaccines to
prevent cervical cancer
—but what else?
Aimee R. Kreimer, Ph.D.
[email protected]
National Cancer Institute
March 20, 2010
American Medical Writers Association
Mid-Atlantic Chapter
(AMWA-MAC)
Cervical Cancer History
• 1842: Italian investigator D. Rigoni-Stern reported that
prostitutes had an unusually high rate of cervical cancer, while
nuns had virtually no cases of the disease (vice versa for breast
cancer).
• 1940’s: Papanicolaou develops his cytology test (Pap smear);
cervical cancer rates decline by >75% in U.S. over the next ~50
years
• 1960’s-1980’s: Infectious agents implicated---HSV2
Cervical Cancer History
• 1974: Zur Hausen identifies human papillomavirus (HPV) DNA
in cervical cancer tissue
• Late 1980s: Epidemiologic studies show association of HPV
and cervical cancer; PCR assays developed
• Mid to Late 1990’s: ≥95% cervical CA’s have HPV DNA
• 2003: FDA approval of HPV DNA Test for CxCA Screening
• 2003-5: Vaccines based on Capsid Proteins Protect Against
HPV infection and CIN
Summary of Today’s Talk
•
•
•
•
•
Global Epidemiology of cervical cancer
Etiology/biology
Anatomy/physiology
2° prevention through screening
1° prevention through prophylactic
vaccination
– Details of the HPV vaccine
Cervical Cancer
epidemiology
• Worldwide ~500,000 new cases per year
– 3rd most common cancer in women
• Worldwide ~250,000 deaths per year
– ~1/10th of all female cancer deaths
• Incidence and survival rates vary by race
and geographical region
Age-standardized incidence and mortality
rates of cervical cancer, 2002
Mortality rate
per 100,000
women
4.0
11.2
Incidence rate
per 100,000
women
10.3
19.1
0
5
10
15
20
Developed Countries
Less Developed Countries
GLOBOCAN 2002
25
Cervical Neoplasia
risk factors
The Primary Risk Factor for Cervical Cancer:
Human Papillomavirus (HPV)
Cervical Neoplasia
risk factors
• Risk factors for HPV acquisition
– lifetime # of sexual partners
– sexual practices of male partner
• Co-factors for progression
–
–
–
–
immunosuppression
other infectious agents (HSV-2, chlamydia)
Parity, oral contraceptives
smoking? dietary factors? genetics?
HPV
• Small DNA virus (~8000bp)
• More than 100 types
identified based on the
genetic sequence of the
outer capsid protein L1
HPV epidemiology
• Most common viral sexually transmitted infection
– MEN: oral cavity, penis, scrotum, urethra, anus
– WOMEN: oral cavity, cervix, vagina, vulva, anus
• Manifestation of infection depends on the site of
infection and the genotype of HPV
– Carcinogenic  neoplasia and cancer of cervix,
oropharynx, and anus; less likely to cause cancer
at other sites, ex: HPV16 and 18
– Non-carcinogenic anogenital warts, ex: HPV6
and 11
Infection From Time of First
Sexual Intercourse
Study of female college students (N=603)
1
Cumulative Incidence of
HPV Infection
0.8
0.6
0.4
0.2
0
0
4
8
12 16 20 24 28 32 36 40 44 48 52 56
Months Since First Intercourse
From Winer RL, Lee S-K, Hughes JP, Adam DE, Kiviat NB, Koutsky LA. Genital human papillomavirus infection:
incidence and risk factors in a cohort of female university students. Am J Epidemiol. 2003;157:218–226. Reprinted
with the permission of Oxford University Press.
Secondary Prevention:
Interrupting disease progression
In the right settings,
cervical cancer can be prevented
with a moderately sensitive test
• Forgiving disease: long pre-clinical
detectable phase
• Almost all precancer can be treated when
detected early
• With regular screening, an insensitive test
will detect all but the most rapidly
developing cases!
The Natural History of Disease
Outcome
Biologic Disease
Symptoms
Onset of detectable by
Disease screening
Preclinical phase
Detectable
preclinical
phase
Usual time
of
Diagnosis
Screening for cervical cancer
Screening for precursor lesions and HPV infections
Frequent pap smear cytology
HPV DNA testing (age 30+)
Treatment of precursor lesions by excisional therapy is
> 95% effective
If Pap Smears successfully prevented cervical
cancer in the mainstream U.S., why not use simply
use them to screen everyone else?
A. Three-visit cycle: 1. Cytology; 2. Colposcopy; 3. Treatment
B. Cytology is an insensitive test (negative test = poor
reassurance); repeat iterations (e.g., regular or annual Pap
smears) are necessary.
C. Cytology is a poorly reproducible (subjective) test and difficult to
maintain performance
D. Colposcopy is not as good as you think it is.
E. Bottom Line: U.S. program costs billions of $ annually
F. Tests with better test characteristics, less visits per cycle,
fewer cycles per lifetime
Incremental Etiologic Contributions of HPV types
120
% of Cancers
100
80
60
40
20
0
16
18
45
31
X
33
52
58
35
59
56
Cumulative Incidence of Cervical Precancer or
Cancer (≥CIN3) after a Single Oncogenic HPV Test
25%
Cumulative Incidence Rate of ≥CIN3
HPV+
HPV-
30 Years and Older, Cytologically Normal Women
20%
15%
10%
5%
0%
0.0
4.5
15.0
27.0
39.0
51.0
63.0
75.0
87.0
99.0
111.0
119.5
Follow-Up Time (Months)
Portland
Sherman et al., JNCI, 2003
HPV Test as Screening
Cumulative Incidence Rate of ≥CIN3
25%
HPV16+
20%
HPV18+
15%
10%
5%
HPV+
HPV+/
HPV16-/18-
0%
0.0
4.5
15.0
27.0
39.0
51.0
63.0
75.0
Follow-Up Time (months)
Portland
87.0
99.0
111.0 119.5
HPV-
Khan et al., JNCI, 2005
HPV testing
•
•
•
•
Sensitive - 98%
But not specific so high false+ rates •
Useful for equivocal Pap results
•
Useful for certain ages
Useful if can find persistent infection
Useful for infrequent screening!
Pap testing
HPV testing
Current Recommendations in US
Women 30 Years and Older
Cytology
Negative
Oncogenic HPV Testing
Oncogenic
HPV-
Oncogenic
HPV+
Repeat
Tests in
3 Years
Repeat
Tests in
6--12 Months
Concerns about Screening Using
HPV Tests
• Will the tests include the right types and
proper thresholds for positivity?
• Will screening be used incorrectly, e.g.,
among young women?
• Will the companies act and price fairly?
• Will the “winner” be the best test?
• How can “home-brew” assays be qualitycontrolled or discouraged?
Primary Prevention:
Prophylactic vaccination
Current Prophylactic Vaccines are Based on
Purified Papillomavirus-Like Particles (VLPs)
• Empty viral capsid composed of the
L1 major virion protein
• Non-infectious and non-oncogenic
(Subunit vaccine)
HPV VLP Vaccines
Manufacturer
Merck
GlaxoSmithKline
Trade name
Gardasil®
Cervarix™
HPV types
6,11,16,18
16,18
Theoretic
coverage
70% of CxCa
90% GW
70% of CxCa
Adjuvant
Alum
ASO4
(Alum+MPL)
0, 2, 6 months
0, 1, 6 months
Dosing Schedule
Phase III Trials--Main Results
•Design: double blind, placebo controlled trials of
>10,000 women
•Main Finding: protection against cervical
precancer caused by HPV16/18 among women
naïve to these types during the vaccination
period: VE ~100%
•Tolerability: slightly more injection site pain than
control vaccine
•Immunogenicity: 99.5% seroconversion with
titers 10-50 fold higher than natural infection
•Safety: no evidence of elevated adverse events
among vaccinees
How durable is protection?
Serum HPV16 antibody titers postvaccination plateau at levels
higher than in natural infection
Vaccinees
Naturally
infected
Uninfected
From Mao et al, Obstet Gynecol 107:18-27, 2006
Can the vaccine be used to treat
existing infections and/or
disease?
Vaccine efficacy among women
already infected with HPV16 or 18
• Vaccine efficacy against viral clearance:
2.5% (95% CI -9.8 to 13.5%)
• HPV vaccination does not accelerate viral
clearance among those infections
• No evidence of a therapeutic effect of this
vaccine
Hildesheim et al. JAMA 2007; 298(7):743-53
Does the vaccine protect against
other HPV types?
(cross-protection)
Efficacy Against 12 month persistent HPV infection
Other High Risk HPV Types
GSK HPV16/18 Vaccine
ITT Analysis; ca. >700 per arm: 3.5 yr follow-up*
HPV Type
# Vaccine
# Placebo
Efficacy
(95%CI)
45
10
27
63 (18-85)
31
21
102
79 (66-88)
33
31
50
52
150
143
5 (-34-18)
58
64
56
-15 (-71-23)
31
35
16
33 58 52
X X
34
18 45 39 68
38 (18-85)
26 51
30 53 56 66
High-risk
HPV types
*Paavonen et al,
Lancet 2009
Does the vaccine protect against
HPV infections at other anatomic
sites?
Burden of HPV in all cancers
Site
Attributable
to HPV
(%)
Of which,
HPV16/18
(%)
Total Cancers
Attributable
to HPV
% of all
cancers
Cervix
100
70
492,800
492,800
4.54
Penis
40
63
26,300
10,500
0.1
Vulva, vagina
40
80
40,000
16,000
0.15
Anus
90
92
30,400
27,300
0.25
Mouth
3
95
274,300
8200
0.08
Oropharynx
12
89
52,100
6200
0.06
10,862,500
561,100
5.17
All sites
Adapted from Parkin and Bray, Vaccine 2006
Protection against other cancers
• Vaginal/vulvar- 100% VE
• Anal- studies on-going
• Penile- high protection against penile
precancer
• Oral- no data yet
Important considerations
• ~ $375 for the 3 dose series in the USA
• Requires a cold chain and 3 visits
• It doesn’t protect women with past infection
• Still have to screen for other carcinogenic types
(~30% of cancer)
How do we integrate HPV
vaccination into current screening
programs?
(goal: maximize impact in a costeffective manner)
Summary of Vaccine Findings in
Young Women
• High level prevention of precancerous cervical
lesions when administered to females without
infection by vaccine-type HPVs
– Not therapeutic
• Generally safe and well-tolerated
– Cannot cause infection or cancer (b/c only contains 1
protein from each targeted type)
• High antibody titers sustained for ~8 years
• Additional results
– High efficacy for prevention of HPV-related
vaginal/extra-genital lesions
Summary of questions that still
need addressed
• How long is the duration of protection (past
10 yrs)?
• Will the vaccine protect against infections
and disease at other anatomic sites?
• Will the vaccine work in special populations
(i.e.: HIV-positive)?
• How should the vaccine be integrated into
existing screening programs?
• How should the vaccine be introduced in
countries without screening programs?