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Impact of Mandatory and/or Universal Immunization for HPV on the Epidemiology
of Cervical Cancer
Melinda Aldrich, ModeratorEduardo Franco, McGill University
Patricia Buffler, University of California, Berkeley
Annual Meeting of the American College of EpidemiologyInternational Epidemiological Association
September 17, 2007
How long does the protection last?
Is the vaccine protective in women with prior exposure to HPV?
Will cross-type protection last?
Will other types replace HPV 16 and 18?
Should men be vaccinated to protect women from cervical cancer?
Which groups should be prioritized to receive vaccination?
Is screening going to change after HPV vaccination?
Frequently asked questions concerning the implementation of HPV vaccination
Expected impact of HPV vaccines on current cervical cancer screening practices
Eduardo L. FrancoProfessor, Departments of Epidemiology and Oncology
Director, Division of Cancer EpidemiologyMcGill University, Montreal, Canada
American College of Epidemiology
25th Annual Meeting, Ft. Lauderdale
September 15-18, 2007
Roundtable on HPV vaccination and cervical cancer
Co-sponsored by the International Epidemiological Association
Points to cover: Evidence in favour of HPV vaccination: basic facts
Is screening needed after vaccination?
Expected effects of vaccination on the burden of precancerous lesions and cervical cancer: A plea for universal vaccination
Loss of cytology screening performance due to reduction in lesion prevalence: quantitative and qualitative effects
Advantages of HPV testing as primary screening test followed by cytologic triage
Incidence of Invasive Cervical Cancer
Age-standardized (world population 1960) rates per 100,000 women per year
Source: GLOBOCAN 2002 (Ferlay et al., 2004)
Relative risks for associations between HPV and cervical cancer in case-control
studies of first generation
NAH: non-amplified DNA hybridizationPCR: polymerase chain reaction
Cancer prevention target Population attributable risk
HPV infection and cervical cancer
> 95%
Smoking and lung cancer 75%-85%
Chronic HBV infection and liver carcinoma
10%-30% (low risk areas)50%-90% (high risk areas)
Alcohol drinking and oral cancer
25%-70%
Hormone replacement therapy and endometrial cancer
15%-50%
Environmental tobacco smoke and lung cancer
15%-20%
Proportion of a given cancer that is preventable by elimination of the exposure to the causal agent
Species A9: HPV 16 and
related
Species A7: HPV 18 and related
De Villiers et al., Virology 2004
Species A10: HPVs 6, 11 and related
(mucosal and cutaneous PVs of humans and primates)
(cutaneous PVs of humans)
(cutaneous PVs of humans)
0 20 40 60 80 100
HPV 16 53.5
HPV 18 17.2
HPV 45 6.7
HPV 31 2.9
HPV 33 2.6
HPV 52 2.3
HPV 58 2.2
HPV 35 1.4
HPV 59 1.3
HPV 56 1.2
HPV 51 1.0
HPV 39 0.7
HPV 68 0.6
HPV 73 0.5
HPV 82 0.3
Bivalent: 70.7
Trivalent: 77.4
Tetravalent: 80.3
Pentavalent: 82.9
Hexavalent: 85.2
Heptavalent: 87.4
Octavalent: 88.8
Monovalent: 53.5
Decavalent: 91.3
Nonavalent: 90.1
Vaccine Composition %
Adapted from: Munoz et al., IJC 2004
Phase IIb Efficacy Results
EndpointsEndpointsGSK's Vaccine
(5.5 yr Follow UpGall et al AACR Apr 2007)
Merck's Vaccine(5 yr Follow Up
Villa LL Br J Ca 2006)
Incident Infection HPV 16/18
98%(95% CI: 89-100)P/V: 43/1 events
(N=692, ATP)
Not Study Aim
Persistent InfectionAll vaccine related types
100%(95% CI: 72-100)P/V: 14/0 events
(N=775, ATP)
96%(95% CI: 83-100)P/V: 45/2 events
(N=468, PP)
CIN 2/3HPV 16/18
100%(95% CI: 33-100)P/V: 7/0 events(N=692, ATP)
100%(95% CI: 16-100)P/V: 6/0 events
(N=468, PP)
External Genital WartsHPV 6/11
Not Study Aim100%
(95% CI: <0-100)P/V: 3/0 events
(N=468, PP)
GSK’s Vaccine(15 mo Follow Up
Paavonen Lancet 2007)N=18,644
Merck’s Vaccine(3 yr Follow Up
Koutsky et al NEJM 2007N=12,167
Garland et al NEJM 2007 N=5,455)
Persistent HPV 16/18 Infection6 month
12 month
80% (97.9% CI: 70-87)
76% (97.9 % CI: 48-90)
Not Study Aim
Efficacy in preventing specific vaccine type associated
CIN 2/3+CIN 2/3+
90% (97.9 % CI: 53-99)
P/V: 21/2 events, TVC
100% (97.9 % CI: 74-100)
P/V: 20/0 events, PPR
95%(95% CI: 85-99)
P/V: 62/3 events, USP
98%(95% CI: 86-100)
P/V: 42/1 events, PPSP
Efficacy in preventing vaccine specific type associated
Condyloma, VIN, VaINNot Study Aim
95%(95% CI: 87-99)
P/V: 81/4 events, USP
• After receiving the first dose
• Women: negative for vaccine specific HPV types at day 0
Phase III Efficacy Results
GSK studies 001 & 007Sustained seropositivity andHigh antibody levels up to 4.5 years
0%17%
0% 0%12%11%12%10%10%6%
100%100%
100%99%99%99.7%
100%
100%
1
10
100
1000
10000
month 0 month 7 month 12month 18[M25-M32][M33-M38][M39-M44][M45-M50][M51-M53]
Vaccine HPV-16 IgGPlacebo IgG
% seropositive
log (ELU/ml)
Follow-up time (months)HPV-001 HPV-007
NaturalInfection
HPV-16
17 fold higher
High Correlation Between CVS and Serum Antibodies According to Age Group for GSK Vaccine
Log ratio (anti-HPV-16/total IgG) in serum
Lo
g r
atio
(a
nti
-HP
V-1
6/t
ota
l Ig
G)
in C
VS
Age groups
Anti-HPV-16
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
1.1
1.2
1.3
0.4 0.5 0.6 0.7 0.8 0.9 1.0 1.1 1.2
15-25 years
26-45 years
46-55 years
Presentation TF Schwarz, ACOG 2007
Impact on HPV 16/18-Related CERVICAL CANCER INCIDENCE with 16/18 Vaccine and Vaccine Lifetime
Coverage Starting at Age 12 Years
Elbasha EH, Dasbach EJ, Insinga RP. Emerg Infect Dis. 2007 Jan;13(1):28-41.
0
1
2
3
4
5
0 10 20 30 40
Years Since Vaccination
Inci
den
ce
per
100
,000
No Vaccination
12-yo females
12-26 year old females
0
20
40
60
80
100
0 10 20 30 40
Impact on HPV 16/18-Related CIN 2/3 INCIDENCE with 16/18 Vaccine and Vaccine Lifetime Coverage
Starting at Age 12 Years
Years Since Vaccination
Inci
den
ce
per
100
,000
Elbasha EH, Dasbach EJ, Insinga RP. Emerg Infect Dis. 2007 Jan;13(1):28-41.
No Vaccination
12-yo females
12-26 year old females
Applied to 70% of the eligible female population is shown. The range represents the minimum and maximum reductions achieved for each strategy using 50 good-fitting parameter sets, and the bold line represents the mean reduction achieved.
Public health benefits of different cervical cancer prevention strategies for Brazil (Goldie et al., Vaccine 2007)
Risk Factor
Cancer Precursor
Invasive Cancer
Death
Primary Prevention
Sexual Behaviour
HPV Infection and CIN
Incidence Rate
Mortality Rate
Secondary Prevention
Tertiary Prevention
Franco et al., Vaccine, 2006
Is screening needed after vaccination?
• Yes!!!
– Vaccines protect mostly against HPVs 16 and 18 which cause at most 75% of all cervical cancers
– Vaccination is for pre-exposure prophylaxis; most women will continue to rely on screening
Adoption of HPV vaccination: Which approach to use,
opportunistic or universal?• What must not happen:
– To adopt only opportunistic vaccination and maintain cervical cancer screening based on frequent cytology, which benefit only women with health care access
• If this happens:– Resources will be wasted and there may be no
further reductions in morbidity and mortality from cervical cancer
– Lack of equitable access to prevention
Expected short-term outcomesSettings with organized or opportunistic Pap
screening:
• Reductions of case loads of ASC, LSIL, and HSIL to be triaged or managed; reductions of colposcopy referrals
• Plausible estimates: 40% for those vaccinated against 16/18 and 50% for those protected against 6/11/16/18
Franco et al., Vaccine, 2006
Expected short-term outcomes
• Reductions in case loads a function primarily of two factors:
– Uptake of HPV vaccination by successive cohorts of adolescents and young women
– Time it will take for protected women to reach screening age
• Impact on case loads initially minimal for women vaccinated between the ages of 11 and 18 years
Franco et al., Vaccine, 2006
Expected long-term outcomesSettings with organized or opportunistic Pap
screening:
• Reduction of cervical cancer burden unlikely to be observed for at least a decade because of the latency for averted HSILs to progress to invasive lesions
• Potential problems with opposite effects:
– 1) Lack of equitable access to benefit: High vaccine uptake may happen among women who will eventually be compliant with screening recommendations
– 2) Non-compliance with screening because of perception that vaccine is fully protective
Franco et al., Vaccine, 2006
Expected long-term outcomesLack of equitable access to benefit:
• Like mothers, like daughters…
– Young women who are vaccinated are likely to comply with screening later in life
– Initial enthusiasm with reduction in cervical abnormalities; however, because of their high compliance with screening these women would not be likely to develop cervical cancer
– Non-vaccinated women less likely to be screened their lesions will progress undetected cytology surveillance oblivious to their occurrence until cancer is diagnosed
Franco et al., Vaccine, 2006
Loss of screening performance due to vaccination
• As successive cohorts of women are vaccinated:
– Reduction in prevalence of cytological abnormalities
– End result: decrease in positive predictive value of cytology
– Increase in false positive rates will lead to non-rigorous diagnostic work-up
– Impact on cytotechnician training and quality assurance
0.00
0.10
0.20
0.30
0.40
0.50
0.60
0.70
0.80
0.90
1.00
0 0.1 0.2 0.3 0.4 0.5
PPV
NPV
Pre
dic
tiv
e V
alu
e
Prevalence
Assumptions: constant 51% sensitivity and 98% specificity (as per Nanda et al., 2000)
Franco et al., Vaccine 2006
Lesion No lesion
Test + 51 18
Test - 49 882
Total 100 900
Lesion No lesion
Test + 51 198
Test - 49 9702
Total 100 9900
Possible qualitative changes in Pap cytology performance
• Sensitivity will be negatively affected:
– Today’s typical case load: approximately 10% of all smears contain abnormalities that are serious enough to merit slide review
– Reduction in lesion prevalence fatigue will set in given expectation that abnormalities will be rare smears may not be read as thoroughly more false negatives
– End result: further decline in the PPV of cytology
– (some of the lowest estimates of Pap sensitivity are in frequently screened, low risk populations of developed countries)
Franco et al., Vaccine 2006
Possible qualitative changes in Pap cytology performance
• But specificity may suffer as well…
– Decrease in signal-to-noise ratio of cytology due to rarity of squamous abnormalities and koilocytotic atypias (the signal) inflammatory changes or reactive atypias (the noise) may be overcalled
– Could be aggravated by cytotechnician’s fear that relevant abnormalities will be missed
– Heightened awareness of the potential for false-negative diagnoses may lead to more false-positive reports loss in specificity
– End result: further decline in the PPV of cytology
Franco et al., Vaccine 2006
Sensitivity
Po
siti
ve
Pre
dic
tiv
e V
alu
e
0.0
0.2
0.4
0.6
0.8
1.0
0.0 0.2 0.4 0.6 0.8 1.0
0.0
0.2
0.4
0.6
0.8
1.0
0.0 0.2 0.4 0.6 0.8 1.0
0.0
0.2
0.4
0.6
0.8
1.0
0.0 0.2 0.4 0.6 0.8 1.0
0.0
0.2
0.4
0.6
0.8
1.0
0.0 0.2 0.4 0.6 0.8 1.0
0.0
0.2
0.4
0.6
0.8
1.0
0.0 0.2 0.4 0.6 0.8 1.0
0.0
0.2
0.4
0.6
0.8
1.0
0.0 0.2 0.4 0.6 0.8 1.0
Prev=50%
Prev=20%
Prev=10%
Prev=5%
Prev=1%
Prev=0.5%
Specificity: red: 95%, blue: 85%, and green: 75%
Graphs represent decreasing hypothetical situations of lesion prevalence: Africa and Latin America: 10%-20%, Western countries: 5%-10%, Triage: 50%
Joint effects of changes in sensitivity, specificity, and lesion prevalence on the PPV of a screening test
Franco et al., Vaccine, 2006
Quantitative and qualitative penalties on the PPV of cytology
• In consequence:
– Cytology laboratories will tend to err on the side of conservatism to decrease risk of malpractice suits
– Safequard: to maintain unnecessarily frequent screening visits as policy to provide protection against false-negatives
• Conclusion: costly and ineffective way of combining screening to vaccination
Age standardized incidence of invasive cervical cancer and coverage of screening, England, 1971 95
(Quinn et al., BMJ 1999; 318: 904 8)
Population World Standard; Sources: System of Information on Mortality - SIM/DATASUS/MS; Foundation IBGE; Division of Epidemiologia and Vigilância - CONPREV/INCA/MS
Crude rate
Age-standardized rate
6.00
5.00
4.00
3.00
2.00
1.00
0.00
1979
1980
198
1982
1983
1984
1985
1986
1987
1988
1989
1990
1991
1992
1993
1994
1995
1996
1997
1998
1999
Year
Rat
e
Cervical Cancer Mortality Rates, Crude and Adjusted for Age, per 100,000 Women in Brazil (1979-99)
Women who have sex with HPV-infected men
HR-HPV infection
(within weeks to months some will develop)
Persistent HR-HPV infection
(within months some will develop)
HG cervical lesions
(within months to years some will develop)
Cervical cancer
(within months to years some will develop)
Detected with
moderate sensitivity
Detected with low
sensitivity
Pap Cytology
Detected with high sensitivity
Detected with high sensitivity
HPV Testing
Perceived as cause
of low specificity
CCCaST Study: First Screening Round Results*
* 10,171 women in Montreal and St. John’s, aged 30-69 years, randomized to Pap or HPV as primary screening method; estimates corrected for verification bias (Mayrand et al., NEJM in press)
Indices Screening test Estimate (95%CI)
SensitivityPap 55.4 (33.6-77.2)
HPV 94.6 (84.2-100)
SpecificityPap 96.8 (96.3-97.3)
HPV 94.1 (93.4-94.8)
PPVPap 4.1 (2.4-6.8)
HPV 7.8 (5.4-11.3)
NPVPap 97.6 (96.1-98.6)
HPV 99.8 (98.8-100)
Why is HPV testing an attractive option for cervical cancer screening?
• More sensitive than the Pap test
• More “upstream” in the carcinogenic process, thus enabling a longer safety margin for screening intervals
• Can be automated, centralized, and be quality-checked for large specimen throughput
• May be more cost-effective than cytology if deployed for high volume testing, such as in primary screening
• A more logical choice for screening women vaccinated against HPV infection
Need for assessing the basis of screening programs following vaccination
• Pap cytology will not be the same if left as primary test
• Solution: HPV testing as primary screening test followed by cytologic triage:– HPV testing more “upstream” than cytology longer latency
safety window
– HPV testing more sensitive and not prone to the vagaries of a test based on subjective interpretation
– HPV testing less likely to vary in sensitivity and specificity as a function of decreasing prevalence in infections and lesions
– Cytology will perform better in the artificially high lesion prevalence when triaging HPV+ women
Franco et al., Vaccine, 2006
Other benefits from the HPV-Pap screening algorithm
• Dividend: A surveillance system integrated with vaccination registries to monitor vaccine efficacy, duration of protection, and cross-protection
• Rational approach to assuage concerns that frequency of screening must not be changed to avoid missing lesions caused by other oncogenic HPV types
• Improved detection of glandular lesions
• Potential for using self-collected cervical samples
• Cytology too important to be used as screening test; it should be reserved for diagnostic triage
Franco et al., Vaccine 2006
The case for synergy in prevention modalities
1. Screening will have to continue in the HPV vaccination era
2. Opportunistic (as opposed to universal) vaccination will create (further) inequity in access to benefit
3. Cytology screening performance will degrade following vaccination
4. HPV infection surveillance will be needed post-vaccination
5. Proposal: reformulate screening as an integrated approach complementing vaccination
Policy and Ethical Aspects of Universal HPV Vaccination
• People generally know very little about HPV and vaccination.
• When given information, most (approximately 75%) support a vaccine that prevents cancer (provided it is effective and safe).
• Advisory Council on Immunization Practices in the US recommends HPV vaccination for various groups, including women up to 26 years old. (Texas first state to make HPV vaccination in girls legally compulsory for students entering sixth grade; other states considering such legislation. Legislation subsequently rescinded in Texas.)
Policy and Ethical Aspects of Universal HPV Vaccination
• HPV vaccination not the technological “silver bullet”. • “Decisions about HPV vaccine will be made in the
context of organised opposition to childhood vaccines, allegations that vaccine risks are downplayed, mistrust towards physicians and drug manufacturers, disagreements over childrearing and sexuality, and inaccurate information on the internet.”
(Bernard Lo, BMJ. May 13, 2006.)
Policy and Ethical Aspects of Universal HPV Vaccination
• Opposition of bio-ethicists to compulsory vaccination programs in general.
• Tension between the utilitarian philosophy of public health versus emphasis on cardinal principles of beneficence, non-maleficence, justice and autonomy.
• Ethical aspects of mandatory vaccination programs for sexually transmitted infections more pronounced than for casually transmitted infections. (Not a clear mandate for universal protection with a sexually transmitted disease.)
Policy and Ethical Aspects of Universal HPV Vaccination
• Utilitarianism looks at the rightness or wrongness of a decision based on its consequences.
• Utilitarian ethics supports universal vaccination at age 11-12 years, but as a theory it is problematic as the main basis for the HPV public policy decision. (Likelihood of some injustice against innocent persons, may compromise personal integrity, may trample individual liberty and conscience, and may be used to justify harm to minorities in order to satisfy the preference of the majority.)
Policy and Ethical Aspects of Universal HPV Vaccination
• Beneficence (“doing good”) is straightforward as HPV vaccination reduces cervical cancer.
• Theoretical harms are proposed under non-maleficence category, e.g. decreases in safer sex practices and inappropriate decreased use of cytological screening due to confusion.
Policy and Ethical Aspects of Universal HPV Vaccination
• Concept of justice requires equitable treatment and that the vaccine should be available to all who need it. (There are currently a large number of uninsured children and adults and insurance programs for children and adults without vaccine coverage.)
• Concept of justice also implies that those at risk for the disease itself are those that incur the risks of the vaccine.
Policy and Ethical Aspects of Universal HPV Vaccination
• Inequities existing in access to current cervical cancer screening will affect access to HPV vaccination as well.
• Opportunistic vaccination efforts (as opposed to universal or mandatory access) will exacerbate these inequities.
Policy and Ethical Aspects of Universal HPV Vaccination
• Principle of autonomy indicates that persons should make their own choices and decisions reflecting the concept of inherent worth of the individual.
• In summary, HPV vaccination would clearly be recommended due to beneficence, but not required for school entry due to autonomy, justice and hypothetical non-maleficence concerns.
Policy and Ethical Aspects of Universal HPV Vaccination
• Concern that proposals for universal vaccination may be premature.
• Impact of HPV vaccination on the natural history of HPV infection, i.e. the chickenpox analogy.
Policy and Ethical Aspects of Universal HPV Vaccination
• Lack of clarity regarding goals of HPV vaccination programs – Is the goal prevention of cervical cancer or prevention of HPV infection?
• If the goal is to reduce HPV infection, should boys be vaccinated as well as girls, i.e. “herd immunity”?
Policy and Ethical Aspects of Universal HPV Vaccination
• Concern that HPV vaccination programs will promote sexual promiscuity and/or undermine abstinence-based programs.
• Parental versus child/adolescent consent with respect to prevention of diseases related to adolescent’s sexuality and reproductive health. (For adolescents under age 18, vaccinations generally require informed consent from both parents and the adolescent.)
Policy and Ethical Aspects of Universal HPV Vaccination
• Questions about adequate justification for universal or mandatory vaccine, i.e., Is there an epidemic that needs to be addressed? Lack of understanding about the importance of prevention.
• Need to address existing perception of HPV infection as benign. (Analogy with HBV vaccination is useful, but may not be perfect because of differences in transmission of HBV.)
Policy and Ethical Aspects of Universal HPV Vaccination
• Growing societal concerns about the safety of vaccines.
• Increasing number of parents/children who are opting out of mandatory vaccination programs for reasons other than religious beliefs, and the impact of reduced vaccination levels on population immunity.
• Concern about increase in number of vaccinations now required and potential impact on compliance with existing vaccination programs.
Policy and Ethical Aspects of Universal HPV Vaccination
• Concerns about influence of commercial interests on the promotion of HPV vaccination.
• Concerns about the effectiveness of the available vaccines (What will happen in actual practice?).
• Uncertainties about the impact of HPV vaccination on the natural history of HPV.
Policy and Ethical Aspects: Conclusions
• Only certain way to determine long term effects of HPV vaccination will be to follow vaccinated adolescents and women for several decades.
• Implies a commitment to long term surveillance.
Policy and Ethical Aspects: Conclusions
• Societal concerns emphasize the need for transparent policies that acknowledge disagreements and uncertainties regarding HPV vaccination.
• And policies that will build trust and support for HPV vaccine in the context of all programs to promote adolescent health.