Impact of Mandatory and/or Universal Immunization for HPV on the Epidemiology of Cervical Cancer Melinda Aldrich, Moderator Eduardo Franco, McGill University Patricia Buffler, University of California, Berkeley Annual Meeting of the American College of Epidemiology International Epidemiological Association September 17, 2007
Frequently asked questions concerning the implementation of HPV vaccination • 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?
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 Expected impact of HPV vaccines on current cervical cancer screening practices Eduardo L. Franco Professor, Departments of Epidemiology and Oncology Director, Division of Cancer Epidemiology McGill University, Montreal, Canada
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 hybridization PCR: polymerase chain reaction
Proportion of a given cancer that is preventable by elimination of the exposure to the causal agent
(mucosal and cutaneous PVs of humans and primates) Species A10: HPVs 6, 11 and related Species A7: HPV 18 and related Species A9: HPV 16 and related (cutaneous PVs of humans) (cutaneous PVs of humans) De Villiers et al., Virology 2004
53.5 Vaccine Composition % HPV 16 17.2 HPV 18 Monovalent: 53.5 6.7 HPV 45 Bivalent: 70.7 2.9 HPV 31 Trivalent: 77.4 2.6 HPV 33 Tetravalent: 80.3 2.3 HPV 52 Pentavalent: 82.9 2.2 HPV 58 Hexavalent: 85.2 1.4 HPV 35 Heptavalent: 87.4 1.3 HPV 59 Octavalent: 88.8 HPV 56 1.2 Nonavalent: 90.1 1.0 HPV 51 Decavalent: 91.3 0.7 HPV 39 HPV 68 0.6 HPV 73 0.5 HPV 82 0.3 0 20 40 60 80 100 Adapted from: Munoz et al., IJC 2004
Phase III Efficacy Results • After receiving the first dose • Women: negative for vaccine specific HPV types at day 0
100% 100% 99% 99.7% 100% 100% 99% 100% 17% 12% 10% 12% 11% 10% 6% 0% 0% 0% GSK studies 001 & 007Sustained seropositivity andHigh antibody levels up to 4.5 years HPV-16 log (ELU/ml) 10000 % seropositive Vaccine HPV-16 IgG Placebo IgG 1000 17 fold higher 100 Natural Infection 10 1 month 0 month 7 month 12 month 18 [M25-M32] [M33-M38] [M39-M44] [M45-M50] [M51-M53] HPV-001 HPV-007 Follow-up time (months)
15-25 years 26-45 years 46-55 years High Correlation Between CVS and Serum Antibodies According to Age Group for GSK Vaccine 1.3 Anti-HPV-16 1.2 Age groups 1.1 1.0 0.9 Log ratio (anti-HPV-16/total IgG) in CVS 0.8 0.7 0.6 0.5 0.4 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 1.1 1.2 Log ratio (anti-HPV-16/total IgG) in serum 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 5 No Vaccination 12-yo females 4 12-26 year old females 3 Incidence per 100,000 2 1 0 0 10 20 30 40 Years Since Vaccination Elbasha EH, Dasbach EJ, Insinga RP. Emerg Infect Dis. 2007 Jan;13(1):28-41.
Impact on HPV 16/18-Related CIN 2/3 INCIDENCE with 16/18 Vaccine and Vaccine Lifetime Coverage Starting at Age 12 Years 100 80 No Vaccination 12-yo females 60 Incidence per 100,000 12-26 year old females 40 20 0 0 10 20 30 40 Years Since Vaccination Elbasha EH, Dasbach EJ, Insinga RP. Emerg Infect Dis. 2007 Jan;13(1):28-41.
Public health benefits of different cervical cancer prevention strategies for Brazil (Goldie et al., Vaccine 2007) 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.
Risk Factor Sexual Behaviour Primary Prevention HPV Infection and CIN Cancer Precursor Secondary Prevention Incidence Rate Invasive Cancer Tertiary Prevention Death Mortality Rate 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 outcomes Settings 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 outcomes Settings 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 outcomes Lack 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
Predictive Value Prevalence Assumptions: constant 51% sensitivity and 98% specificity (as per Nanda et al., 2000) Franco et al., Vaccine 2006
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
Prev=50% Prev=20% Prev=10% Positive Predictive Value Prev=5% Prev=1% Prev=0.5% Sensitivity Joint effects of changes in sensitivity, specificity, and lesion prevalence on the PPV of a screening test 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% 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, 197195 (Quinn et al., BMJ 1999; 318: 9048)
Crude rate Age-standardized rate Cervical Cancer Mortality Rates, Crude and Adjusted for Age, per 100,000 Women in Brazil (1979-99) 6.00 5.00 4.00 3.00 Rate 2.00 1.00 0.00 1983 1984 1985 1986 1987 1988 1989 1990 1991 1992 1993 1994 1995 1996 1997 1998 1999 1979 1980 198 1982 Year Population World Standard; Sources: System of Information on Mortality - SIM/DATASUS/MS; Foundation IBGE; Division of Epidemiologia and Vigilância - CONPREV/INCA/MS
Women who have sex with HPV-infected men Pap Cytology HPV Testing (within weeks to months some will develop) HR-HPV infection Perceived as cause of low specificity (within months some will develop) Detected with low sensitivity Detected with high sensitivity Persistent HR-HPV infection (within months to years some will develop) Detected with moderate sensitivity HG cervical lesions Detected with high sensitivity (within months to years some will develop) Cervical cancer
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)
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 • Screening will have to continue in the HPV vaccination era • Opportunistic (as opposed to universal) vaccination will create (further) inequity in access to benefit • Cytology screening performance will degrade following vaccination • HPV infection surveillance will be needed post-vaccination • 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.