Presentation on theme: "PREVENTING CERVICAL CANCER"— Presentation transcript:
1PREVENTING CERVICAL CANCER BRYANSTON COUNTRY CLUBDr Peter C Koll4th September 2010
2CERVICAL CANCER Cervical cancer should not happen Medical breakthroughs have occuredAll we need to do is :To create the awarenessTo find the resourcesTo stimulate the political will
3Global mortality per annum Worldwide, every 2 minutes a woman dies of cervical cancer1The highest burden of disease (up to 80%) occurs in less developed regions1 where there is a lack of effective screening programmesThis demonstrates a clear medical need for new cervical cancer interventionsEurope60,000 new cases30,000 deathsNorth America14,500 new cases6,000 deathsAsia266,000 new cases143,000 deathsLatin America72,000 new cases33,000 deathsGlobal mortality per annumAfrica generates almost 80,000 new cases of cervical cancer per year.Africa and Central and South America are regions with the highest incidences of cervical cancer, with substantial variations seen regionally. North Africa and the Middle East are regions of low to intermediate risk, according to GLOBOCAN data.GLOBOCAN is a compendium of data taken from cancer and mortality registries and pathology departments from all over the world. Strict methodology is applied across all regions. In countries where official statistics are affected by poor diagnostic capabilities and registration, GLOBOCAN generates estimated data based on those of neighbouring countries. The data shown here are the best estimates available, although they may not truly reflect the incidences seen by specialists in some countries and should be seen as the lower limit.ReferenceFerlay J, et al. GLOBOCAN 2002 Cancer Incidence, Mortality and Prevalence Worldwide. IARC CancerBase; Lyon, 2004.Africa79,000 new cases62,000 deaths< 7.9< 23.8< 14.0< 55.6< 3.9Cervical cancer mortality rates worldwide Cases per 100,000 women per year1. Ferlay J, et al. GLOBOCAN 2002 Cancer Incidence, Mortality and Prevalence Worldwide. IARC CancerBase; Lyon, 2004.
4The most frequent cancers in women: incidence and mortality Global dataIncidenceMortalityBreast13.237.4BreastCervix10.316.2LungColon/Rectum9.014.6CervixLung7.912.1StomachThe most frequent cancers in women: incidence and mortalityCervical cancer is the second most common cancer among women worldwide after breast cancer, although mortality rates are lower than for lung cancer.ReferenceFerlay J, et al. GLOBOCAN 2002 Cancer Incidence, Mortality and Prevalence Worldwide. IARC CancerBase; Lyon, 2004.7.6Stomach10.3Colon/RectumOvary5.76.6LiverCorpus4.06.5Ovary5101520253035402468101214Age-standardized rate per 100,000Age-standardized rate per 100,000Ferlay J, et al. GLOBOCAN 2002 Cancer Incidence, Mortality and Prevalence Worldwide. IARC CancerBase; Lyon; 2004.
5The most frequent cancers in women: incidence and mortality AfricaIncidenceMortality29.3Cervix23.1Cervix23.4Breast16.2Breast6.2LiverLiver6.24.9Stomach4.6StomachKaposi’s sarcoma4.6Kaposi’s sarcoma4.3The most frequent cancers in women: incidence and mortalityIn Africa, cervical cancer is the most common cancer and the leading cause of death from cancer among women.This is in part because of a lack of availability and awareness of screening as well as access to treatment.ReferenceFerlay J, et al. GLOBOCAN 2002 Cancer Incidence, Mortality and Prevalence Worldwide. IARC CancerBase; Lyon, 2004.4.3Colon/RectumOvary3.7Colon/Rectum4.2Oesophagus3.25101520253035510152025Age-standardized rate per 100,000Age-standardized rate per 100,000Ferlay J, et al. GLOBOCAN 2002 Cancer Incidence, Mortality and Prevalence Worldwide. IARC CancerBase; Lyon; 2004.
11Limitations of PAP smear - Only prevents 70% of cancers- May miss adenocarcinomaAdenocarcinoma: may beinaccessible to the cervicalsmear brushSquamous cell carcinomaAdenocarcinomaEndometriumMyometriumUterine cavityAdenocarcinomaCervixSquamous cell carcinoma:usually accessible to the cervical smear brushSquamous cell carcinoma
12Limitations of PAP smear - Only prevents 70% of cancers- May miss adenocarcinomaLogisticsCostTreatmentRecall
13HISTORY OF Ca Cx PREVENTION George Papanicolaou first described the PAP test years agoHarald zur Hausen linked HPV to Ca CxHPV vaccines,the first vaccines specifically developedto prevent a cancer- IARC identified HPV DNA in 99.8% of cervical cancer specimens from 25 countries- Late 1990’s Carcinogenic subtypes of HPV identified- HPV VACCINES
14HPV >100 types identified2 ~30–40 anogenital2,3 ~15–20 oncogenic*,2,3HPV 16 and HPV 18 types account for the majority of worldwide cervical cancers.4Nononcogenic** typesHPV 6 and 11 are most often associated with external anogenital warts.3These two types are responsible for >90% of genital warts.5Nonenveloped double-stranded DNA virus1Key PointThere are many different types of human papillomavirus (HPV); globally, of the ~15–20 oncogenic types, HPV 16 and HPV 18 account for more than 10% of cervical cancers.BackgroundPapillomaviruses, such as HPV, are nonenveloped, double-stranded DNA viruses.1 More than 100 HPV types have been detected,2 with >80 types sequenced and classified.3 Approximately 30 to 40 types of HPV are anogenital, of which ~15 to 20 types are oncogenic.2,3 In an international meta-analysis, HPV types 16 and 18 were found to be oncogenic and accounted for more than 70% of all cervical cancers4—the next five most prevalent types (31, 33, 45, 52, 58) account for an additional 17% of cases.4 Other oncogenic HPV types include 35, 39, 51, and 56.4 HPV types 6 and 11 are nononcogenic and are associated with external anogenital warts.3References1. Howley PM, Lowy DR. Papillomaviruses and their replication. In: Knipe DM, Howley PM, eds. Fields Virology. 4th ed. Philadelphia, Pa: Lippincott-Raven; 2001:2197–2229.2. Schiffman M, Castle PE. Human papillomavirus: Epidemiology and public health. Arch Pathol Lab Med. 2003;127:930–934.3. Wiley DJ, Douglas J, Beutner K, et al. External genital warts: Diagnosis, treatment, and prevention. Clin Infect Dis. 2002;35(suppl 2):S210–S224.4. Muñoz N, Bosch FX, de Sanjosé S, et al. Epidemiologic classification of human papillomavirus types associated with cervical cancer. N Engl J Med. 2003;348:518–527.*High risk; ** Low risk1. Howley PM, Lowy DR. In: Knipe DM, Howley PM, eds. Philadelphia, Pa: Lippincott-Raven; 2001:2197– Schiffman M, Castle PE. Arch Pathol Lab Med. 2003;127:930– Wiley DJ, Douglas J, Beutner K, et al. Clin Infect Dis. 2002;35(suppl 2):S210–S Muñoz N, Bosch FX, Castellsagué X, et al. Int J Cancer. 2004;111:278– Jansen KU, Shaw AR. Annu Rev Med. 2004;55:319–331.2
15HPV Infection and Life Cycle Shedding of Virus-Laden Epithelial CellsCervical SurfaceMatureSquamousLayerViral Assembly(L1 and L2)SquamousLayerViral DNA Replication(E6 and E7)....ParabasalCellsEpisomal Viral DNAin Cell Nucleus(E1 and E2, E6 and E7)...Basal (Stem)CellsInfection of Basal Cells (E1 and E2)Basement MembraneNormalEpitheliumInfectedEpitheliumAdapted from Frazer IH. Nature Rev Immunol. 2004;4:46–54.
16Why are antibody responses so poor in natural HPV infections? No viraemiaHPV does not kill keratinocytesno inflammationno pro-inflammatory cytokinespoor activation of epithelial antigen presenting cellsFree virus particles are shed from mucosal surfaces with poor exposure to antigen presenting cell (APC)
17What are the consequences of this? Natural infection dose not necessarily confer protection against future disease.Women remain at risk of persistent HPV infection, throughout their lives .Persistent HPV infection is the cause of Cervical Cancer
18HPV Types in Cervical Cancer Worldwide HPV genotype1653.553.5 %VaccineHPV type1817.270.7 %456.777.4 %312.980.3 %332.6522.3582.2351.4591.3561.2511.0390.7680.6730.5820.3OtherX4.4102030405060708090100Cancer cases attributed to the most frequent HPV genotypes (%)Munoz N et al. Int J Cancer 2004;111:278–85.
19Worldwide Prevalence of HPV Types in Cervical Cancer*,1 69.714.6HPV Type1652.525.7184567.61731North America/Europe335712.652Key PointMost cases of invasive cervical cancer are associated with HPV 16 or 18, but approximately one quarter to one third of all cases are associated with other HPV types, the distribution of which varies by region.BackgroundIn a pooled analysis from an international survey of HPV types in cervical cancer and from a multicenter, case-control study (N = 3607), both co-coordinated by the International Agency for Research on Cancer (IARC) and with HPV DNA detection and polymerase chain reaction (PCR) done centrally, Muñoz and colleagues investigated geographic variations in the contribution made by different HPV types to invasive cervical cancer.1HPV DNA was detected in 96% of specimens from women with incident, histologically confirmed cervical cancer. Thirty different HPV types were identified. The 15 most common types (in descending order of frequency) were 16, 18, 45, 31, 33, 52, 58, 35, 59, 56, 39, 51, 73, 68, and 66.1Reference1. Muñoz N, Bosch FX, Castellsagué X, et al. Against which human papillomavirus types shall we vaccinate and screen? The international perspective. Int J Cancer. 2004;111:278–285.South Asia58OthersNorthern AfricaCentral/South America*A pooled analysis and multicenter case control study (N = 3607).1. Muñoz N, Bosch FX, Castellsagué X, et al. Int J Cancer. 2004;111:278–285.
20Prevalence of the 10 most common oncogenic HPV types worldwide In 2855 HPV Positive Cervical Cancer Cases & Rank By RegionEurope & North AmericaSub-Saharan AfricaNorthern AfricaCentral-South AmericaSouth AsiaHPV type%HPV type%HPV type%HPV type%HPV type%69.752.557.067.647.7HPV 1614.6HPV 1825.712.617.019.16.8HPV 459.07.95.615.02.3HPV 3126.96.36.199.1HPV 5188.8.131.52HPV 334.24.03.22.2HPV 562.73.0HPV 583.21.1HPV 3184.108.40.206HPV 59Adapted from Munoz N et al Int J Cancer 2004;111:
21- Carcinoma of the cervix -Laser/Cone/LEEP/LLETZ Global burden of HPV- Carcinoma of the cervix- Other HPV Carcinomasdiagnosed died-Anal-Vulvo/vaginal-Penile-Oral-Nasopharangeal-Abnormal PAP smear-Repeat visits-Colpomicroscopy-Biopsy-Laser/Cone/LEEP/LLETZ-Financial-Emotional-PhysicalMorbidity
22The most common STD50% young females aquire it within 3 yrs of sexual debutCumulative detection is 59-82%Majority transient in young women – only 10-20% persist for 24 mtsPeak at 20 sharp decline by 30If present after 30 – more likely to be persistentONLY PERSISTENT HIGH RISK HPV CONSTITUTES RISK FOR CIN2 OR 3
23Estimated World Burden of HPV-Related Diagnoses Focus on Cervical Disease and Genital Warts 1/WHO/p 5/¶1Cervical Cancer: 0.5 million cases/year1High-grade precancerous lesions: 10 million22/WHO/ p. 6/¶2Low-grade cervical lesions: 30 million23/WHO/ p. 1/¶2Genital warts: 30 million31/WHO/ p. 5/¶1Attributable to oncogenic HPV typesAttributable to nononcogenic HPV typesKey PointsHPV infection is very common, but, in the majority of cases, has no clinical significance. Of all HPV-related conditions, cervical cancer is the most serious manifestation of the virus. However, most HPV-related morbidity is associated with cervical dysplasia or genital warts.Cervical dysplasia is caused by both oncogenic and non-oncogenic types, and genital warts by non-oncogenic types.BackgroundAccording to estimates from the World Health Organization (WHO), worldwide annual incidence of HPV infection is 660 million1 with low- and high-grade dysplasia being 30 million, and 10 million cases, respectively.2 The WHO estimates that 30 million cases of genital warts occur every year.3The largest number of cases of cervical HPV infection have no detectable cytologic abnormalities, and many of these are self-limited. However, an important subset will subsequently become associated with disease.2HPV infection with oncogenic types, notably types 16 and 18, is associated with both low-grade and high-grade cervical lesions. HPV infection with these types can lead to cervical cancer.4Nononcogenic HPV types, notably types 6 and 11, are associated with low-grade cervical lesions and with anogenital warts.4,5 In a study by Gissmann and colleagues (N=63), HPV 6 and 11 DNA was detected in >90% of anogenital warts.6References1. World Health Organization. Report of the Consultation on Human Papillomavirus Vaccines. Geneva, Switzerland: World Health Organization; 2005:1–38.2. World Health Organization. The current status of development of prophylactic vaccines against human papillomavirus infection. Report of a technical meeting, 16–18 February Geneva, Switzerland: World Health Organization; 1999:1–22.3. World Health Organization. Sexually transmitted infections increasing–250 million new infections annually. WHO Office of Information. WHO Features. 1990;152:1–6.4. Burd EM. Human papillomavirus and cervical cancer. Clin Microbiol Rev. 2003;16:1–17.5. Wiley DJ, Douglas J, Beutner K, et al. External genital warts: diagnosis, treatment, and prevention. Clin Infect Dis. 2002;35(suppl 2):S210–S224.6. Gissmann L, Wolnik L, Ikenberg H, Koldovsky U, Schnurch HG, zur Hausen H. Human papillomavirus types 6 and 11 DNA sequences in genital and laryngeal papillomas and in some cervical cancers. Proc Natl Acad Sci USA. 1983;80:560–563.1/WHO/p 5/¶1HPV infection: 660 million12/WHO/ p. 6/¶23/WHO/ p. 1/¶22/WHO/ p. 6/¶21. World Health Organization, Geneva, Switzerland: World Health Organization; 2005:1– World Health Organization. Geneva, Switzerland: World Health Organization; 1999:1– World Health Organization. WHO Office of Information. WHO Features. 1990;152:1–6.4/Burd/p. 2/ Table 1.25/Wiley/p. S210/col 1/¶1/col 2/¶1.6/Gissmann/p. 561/Table 2.
24HPV Infection and Risk of Invasive Cervical Cancer in Selected Countries*,1 % HPV Prevalence cases/contro97.0/17.396.9/33.397.1/21.698.1/19.896.4/9.296.5/15.795.3/17.782.4/5.978.4/17.596.6/15.6BrazilMaliMoroccoParaguayPhilippinesThailandPeruSpainColombiaOverallKey PointData from a pooled analysis of International Agency for Research on Cancer (IARC) studies show that HPV is strongly associated with cervical cancer, whatever the incidence of cervical cancer.BackgroundIn a pooled analysis of 11 case-controlled studies from 9 countries, Muñoz and colleagues1 evaluated the risk associated with HPV by country and by HPV type. The analysis included 1,918 women with histologically confirmed squamous-cell cervical cancer and 1,928 controls. Cervical cells were collected for detection of HPV DNA and typing in a central laboratory by PCR-based assays.1HPV DNA was detected in 1,739 of the women with cervical cancer (90.7%) and 259 of the controls (13.4%). The pooled odds ratio for invasive cervical cancer associated with the presence of any HPV was (95% CI, 113–220.6). The association between HPV and invasive cervical cancer was clear in each of the 9 countries, with odds ratios ranging from 17.7 (95% CI, 9.1–34.3) in Colombia to (95% CI, 139.7–548.3) in the Philippines.The number of cases versus controls, HPV prevalence, and the respective odds ratios and 95% CIs from each country were:Country n % HPV Prevalence Odds Ratio (95% CI)cases/controls cases/controlsBrazil 169/ / (65.5–478.3)Mali 65/ / (10.6–1119.0)Morocco 175/ / (42.3–305.3)Paraguay 106/ / (46.4–932.8)Philippines 331/ / (139.7–548.3)Thailand 339/ / (82.0–325.9)Peru 171/ / (48.6–276.4)Spain 159/ / (32.9–174.2)Colombia 111/ / (9.1–34.3)Overall 1356/ / (113.4–220.6)Reference1. Muñoz N, Bosch FX, de Sanjosé S, et al. Epidemiologic classification of human papillomavirus types associated with cervical cancer. N Engl J Med. 2003;348:518–527.0.110100100010,000Odds Ratio (95% CI**)*Assays used varied by site. **CI = confidence interval1. Muñoz N, Bosch FX, de Sanjosé S, et al. N Engl J Med. 2003;348:518–527.7
25Human papillomavirus structure HPV is a relatively small virus containing double-stranded DNA within a spherical shell (capsid)1The capsid is composed of two proteins, the ‘late’ or structural proteins L1 and L21Circular DNA55 nmL1 protein pentamerL2 supporting protein1. Burd EM. Clin Microbiol Rev 2003; 16:1–17.
27Virus Like Particle (VLP) VLP Looks exactly like the virus but contains no viral DNAThus elicits strong immune response without any risk of infectionL1 protein pentamer
28Active protection via vaccination is mediated by neutralizing antibodies at the cervix HPVNeutralizing antibodiesCervical canalCervicalepitheliumBlood vesselEpithelial tearNeutralizing antibodies are critical for inhibition of early infection before viral entry into cells.1Immunization against HPV will increase serum levels of HPV-specific antibodies; however, anti-HPV antibodies must be present within the genital tract, at the site of infection, for immunization to be protective.2Findings by Nardelli-Haefliger and colleagues suggest that higher levels of serum IgG, induced by prophylactic vaccination, have the potential to diffuse across the cervical epithelium at a concentration that is sufficient for neutralization of the virus.3It has been shown that a higher magnitude of antibodies in the serum correlates with higher antibody levels in cervicovaginal secretions (CVS).4References1. Stanley M. Vaccine 2006; 24:S16–22.2. Giannini S, et al. Vaccine 2006; 24:5937–5949.3. Nardelli-Haefliger D, et al. J Natl Cancer Inst 2003; 95:1128–1137.4. Poncelet S, et al. IPC 2007 (poster).Basement membrane1. Stanley M. Vaccine 2006; 24:S16–S22;2. Giannini S, et al. Vaccine 2006; 24:5937–5949;3. Nardelli-Haefliger D, et al. J Natl Cancer Inst 2003; 95:1128–1137;4. Poncelet S, et al. IPC 2007(poster).
29GARDASIL™ (20/40/40/20 μg) Neutralizing Anti-HPV Immunogenicity In a double-blind, placebo-controlled, dose-ranging study ofquadrivalent HPV (types 6, 11, 16, 18) L1 VLP vaccine.Per-Protocol Subjects(GARDASIL)10001000HPV 6HPV 111001001010******11712182430365460712182430365460GMT with 95% CImMU/mL (Log Scale)10,000Key PointVaccine-induced anti-HPV 6, 11, 16, and 18 GMTs peaked at month 7 and gradually decreased to reach a plateau at month 24.BackgroundAll women randomized to GARDASIL™ in the per-protocol immunogenicity (PPI) population developed detectable neutralizing antibodies to HPV 6, 11, 16, and 18 at completion of the vaccine regimen (ie, month 7). Vaccine-induced neutralizing anti-HPV GMTs were substantially higher in women receiving GARDASIL than in those given placebo whose anti-HPV 6, 11, 16, or 18 antibodies and absence of corresponding HPV DNA at baseline hinted to a previous history of cleared HPV infection (not shown).1,2 Although mean antibody titers in the vaccine arm started to decline after month 7, they remained at comparable levels from month 24 through month 60.2Note that direct comparisons of the relative immunogenicity of the four VLP components cannot be made from the absolute titers, as the titers for each of the reference sera for the individual assays were not identical.3GARDASIL is a trademark of Merck & Co., Inc., Whitehouse Station, NJ, USA.References1. Villa L, Costa R, Petta R et al. High sustained efficacy of a prophylactic quadrivalent human papillomavirus types 6/11/16/18 L1 virus-like particle vaccine through 5 years of follow up. Br J Cancer. 2006;95:1459–1466.2. Olsson S-E, Villa LL, Costa RLR, et al. Induction of immune memory following administration of a prophylactic quadrivalent human papillomavirus (HPV) types 6/11/16/18 l1 virus-like particle (VLP) vaccine. Vaccine. 2007;25:4931–4939.3. Villa LL, Ault KA, Giuliano AR, et al. Immunologic responses following administration of a vaccine targeting human papillomavirus types 6, 11, 16, and 18. Vaccine. 2006;24(27–28): 5571–5583.1000HPV 16HPV 1810001001001010******1712182430365460712182430365460Time Since Vaccination (Months)* vaccinationGARDASIL is a trademark of Merck & Co., Inc., Whitehouse Station, NJ, USA.Adapted from Olsson S-E et al. Vaccine. 2007;25:4931–4939.10
31GARDASIL™ [Quadrivalent Human Papillomavirus (Types 6, 11, 16, 18) Recombinant Vaccine] GARDASIL: FUTURE I-II End-of-Study Results Efficacy Against HPV 6/11/16/18-Related External Genital Lesions1,2Per-protocol efficacy population, women 16–26 years of age followed up through 3–4 years1/Haupt/slide 3/bullet 1; slide 5/Table2/DOF End of study ISE/p.57/Table 14. (“n” numbers)250227GARDASILPlacebo19320099% Efficacy (97, 100)99% Efficacy (96, 100)150Related Cases100% Efficacy (86,100)100% Efficacy (83,100)100Key PointThe efficacy of GARDASIL™ [Quadrivalent Human Papillomavirus (Types 6, 11, 16, 18) Recombinant Vaccine] against HPV 6/11/16/18-related external genital lesions remained high in women 16–26 years of age (FUTURE I-II trials) followed up through 3–4 years.BackgroundOverall reduction of HPV 6/11/16/18-related external genital lesions (EGLs) was 99% (95% CI: 97, 100) for the subjects receiving GARDASIL (n=7900) vs placebo (n=7902) with only 2 related cases in the subjects receiving GARDASIL and 227 related cases in the placebo group (per-protocol efficacy population).1Reduction of HPV 6/11/16/18-related genital warts was 99% (95% CI: 96, 100) for the subjects receiving GARDASIL vs placebo with only 2 related cases in the subjects receiving GARDASIL and 193 related cases in the placebo group.1Reduction of HPV 6/11/16/18-related vulvar intraepithelial neoplasia (VIN) 1, vaginal intraepithelial neoplasia (VaIN) 1 was 100% (95% CI: 86, 100) for the subjects receiving GARDASIL vs placebo with no related cases in the subjects receiving GARDASIL and 28 related cases in the placebo group.1Reduction of HPV 6/11/16/18-related VIN 2/3, VaIN 2/3 was 100% (95% CI: 83, 100) for the subjects receiving GARDASIL vs placebo with no related cases in the subjects receiving GARDASIL and 23 related cases in the placebo group.11. Haupt RM. Advisory Committee on Immunization Practices. February 27, mtg-slides-feb08/14-3-hpv.pdf. Accessed March 30, 2009.50282322HPV 6/11/16/ 18-Related EGLGenital WartsVIN 1, VaIN 1VIN 2/3, VaIN 2/3n=7900n=7902n=7900n=7902n=7900n=7902n=7900n=79021/Haupt/slide 3/bullet 1; slide 5/TableEGL = external genital lesion; VaIN = vaginal intraepithelial neoplasia; VIN = vulvar intraepithelial neoplasia. 1. Haupt RM. ACIP. February 27, Accessed July 11, Data on file, MSD ______.
32GARDASIL™: Durable Protection Through Five Years PPE population; subjects were naïve to HPV types 6, 11, 16, and/or 18HPV 6, 11, 16, or 18-relatedGARDASILPlaceboNCasesEfficacy95% CIPersistentInfection2352*2334596%(83, 100)Disease6100%(12, 100)CIN 1, 2, or 33(<0, 100)Vulvar/vaginal neoplasias or genital wartsKey PointLong-term efficacy of GARDASIL™ against vaccine type-related HPV disease remains at 100% five years after vaccination.BackgroundHigh sustained efficacy against persistent infection and disease was observed through five years postenrollment.1 During the extension phase, all new cases of HPV were found in the placebo cohort. Through five years in the per-protocol population, there were no cases of HPV 6-, 11-, 16-, or 18-related CIN or external anogenital or vaginal lesions in vaccine recipients.1Subjects vaccinated with GARDASIL did not present with any breakthrough cases of infection or disease during the extended follow-up period.1GARDASIL is a trademark of Merck & Co., Inc., Whitehouse Station, NJ, USA.Reference1. Villa L, Costa R, Petta R, et al. High sustained efficacy of a prophylactic quadrivalent human papillomavirus types 6/11/16/18 L1 virus-like particle vaccine through 5 years of follow up. Br J Cancer. 2006;95:1459–1466.A total of 241 subjects were entered into the five-year extension phase of protocol 007.*One case of confirmed persistent infection: HPV 18 DNA detected at months 12 and 18 only (not a case in thefive-year extension).*One case of HPV 16 DNA detected at the last visit (month 36); not a subject in the five-year extension phase.GARDASIL is a trademark of Merck & Co., Inc., Whitehouse Station, NJ, USA.Villa LL, Costa R, Petta R, et al. Br J Cancer. 2006;95:1459–1466.15
33Up to 5.5 years Substantial Protection against HPV-16/18 infections and CIN outcomes Endpoints*HPV VaccineControlVaccine Efficacynn%95% CI6 Month Persistence2910012 Month Persistence14100CIN1+11100CIN2+7100*Combined analysis initial efficacy study and extended follow-upATP analysis for virologic endpoints; ITT analysis for cytologic and CIN endpointsPresentation Gall S, AACR, Los Angeles, April 14-18, 2007
34Disease Cross-Protection Analysis: Efficacy Against CIN 2/3 or AIS in the Generally HPV-Naïve PopulationCIN 2/3 or AIS*# of cases GARDASILn=4616# of cases Placebon=4675Efficacy95% CIHPV 31/4582162%10, 85HPV31/33/45/52/58274843%7, 6631/33/35/39/45/51/52/56/58/59386238%6, 60Brown/Table 6Key PointsIn the generally HPV-naïve population, GARDASIL was effective at reducing the incidence of CIN 2/3 or AIS caused by non-vaccine HPV types, up to 62% for the composite endpoint of HPV 31/45. However, when the components were analyzed individually, no efficacy was seen against HPV 45.BackgroundThe incidence of CIN 2/3 or AIS caused by vaccine-related types was analyzed in the generally HPV-naïve population (naïve to all 14 HPV types tested at Day 1). Composite endpoints of disease caused by multiple HPV types (types 31/45, 31/33/45/62/56, and 31/33/35/39/45/51/52/56/58/59) were used for the primary endpoints.The study was not powered to evaluate the efficacy of individual types for cross-protection, but an analysis of individual components indicated that the effects were variable, and there was no evidence of efficacy with respect to disease caused by HPV 45 (Species A7) or 35 (Species A9).ReferenceBrown D; for the FUTURE Study Group. HPV type 6/11/16/18 vaccine: first analysis of cross-protection against persistent infection, cervical intraepithelial neoplasia (CIN), and adenocarcinoma in situ (AIS) caused by oncogenic HPV types in addition to 16/18. Poster presented at: 47th Annual Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC); September 17-20, 2007; Chicago, IL.* Composite endpoints were analyzed (primary endpoints). In analyses for the individual components of the endpoints, efficacy was variable, and there was no evidence of efficacy with respect to HPV 35 and 45-related disease.Brown/Table 6Cross-Protection Special Report, Sec , P 225, last para; Sec 5.3, P 238, 2 para; Table 4-53Brown D; for the FUTURE Study Group. Poster presented at ICAAC; September 17-20, 2007; Chicago, IL.
35Cross Protection 100% for HPV 31/45 against CIN2+ Cervarix® showed significant type-specific efficacy against pre-cancers (CIN 2+) associated with HPV types beyond 16 and 18Vaccine efficacy was:100% for HPV 31/45 against CIN2+68.2% for the 5 most frequent oncogenic types (31,33,45,52,58)68.4% for the 10 most frequent oncogenic types (31,33,35,39,45,51,52,56,58,59)Cervarix® showed vaccine efficacy of 77.7% for 14 oncogenic types, including HPV 16 and 18 measured as a composite endpointGlobal incidenceThe incidence of cervical cancer varies widely around the world, with the highest incidence in developing countries. Incidence rates exceeding > 30 cases per 100,000 population occur in Latin America and Sub-Saharan Africa with lower incidences observed in Western Europe, North America and Japan. The incidence rates for each country are available from the International Agency for Research on Cancer (IARC) database.The main reason for these variations in incidence is the availability of screening programmes in developed countries but not in poorer developing countries. Screening can detect the early signs of cervical cancer, allowing for prompt treatment to prevent the development of invasive and potentially fatal cervical cancer.It is important to understand that these figures are not necessarily accurate everywhere. They are sourced from World Health Organization and IARC data, which varies in quality depending on country. Data from Finland, for example, will be perfect because they have good records systems and all cancers are routinely reported. In India, by contrast, very few centres report into data sources and, in some areas of Africa, incidence figures are an estimate only because of the lack of availability of cancer registries or other reporting mechanisms. Likewise, the incidence in China is reported to be low but this may be because of under-reporting.ReferenceFerlay J, et al. GLOBOCAN 2002 Cancer Incidence, Mortality and Prevalence Worldwide. IARC CancerBase; Lyon, 2004.
36SAFETYNo clinically meaningful differences between study groups with respect to:Medically significant conditionsSerious Adverse EventsNew onset chronic disease and new onset autoimmune diseasesPregnancy outcomes
37WHICH ONE ? Both safe Both very effective Both equally effective in preventing Ca CxOnly two undisputed facts:1) Gardasil protects against 6 and 112) Cervarix is cheaper
38The Gardasil argumentProven protection against vulval and vaginal carcinomaProtection against 6 and 11
39GARDASILHPV 6 & 11HPV Types 6 and 11 responsible for >90% of anogenital warts1Estimated lifetime risk of developing genital warts ~10%2,3External genital warts are very contagious.Infectivity >75%
40RRP Age distribution is bimodal with peaks at1: 2 to 4 years of age (childhood-onset)20 to 40 years of age (adult-onset)HPV Types 6 and 11 cause ~100% of both juvenile and adult-onset RRP.2Papillomas are stratified squamous epithelial masses that can obstruct the airway if not removed.3Although histologically benign, RRP causes significant morbidity and mortality due to recurrent nature.3Could require surgery under general anesthesia as frequently as every few weeksPossible causative role of RRP in head and neck cancers3-5RRP is rare.6Key PointRRP is a nonmalignant lesion of the larynx and trachea caused by HPV Types 6 and 11.BackgroundThe age distribution of RRP is bimodal: the first peak in incidence occurs between 2 and 4 years of age (childhood-onset); the second occurs between ages 20 and 40 years (adult-onset).1RRP is a benign lesion of the larynx and trachea caused by HPV Types 6 and Most studies indicate that RRP in children occurs after exposure of a child’s upper aerodigestive tract to the cervix and vagina of a mother with genital HPV infection at birth.2Although lesions histologically and pathologically seem similar in children and adults, clinically, they behave very differently. In children, RRP may be life-threatening if the papillomas obstruct the airway and can be a devastating disease, occasionally necessitating up to 150 surgeries over a child’s lifetime. In contrast, adults with RRP usually only require a few surgical excisions to eliminate the disease.2,3References1. Derkay CS. Recurrent respiratory papillomatosis. Laryngoscope. 2001;111:57–69.2. McClay JE. Recurrent respiratory papillomatosis. Available at: Accessed January 26, 2005.3. Wiley DJ, Douglas J, Beutner K, et al. External genital warts: Diagnosis, treatment, and prevention. Clin Infect Dis. 2002;35(suppl 2):S210–S224.4. Lacey CJN, Lowndes CM, Shah KV. Chapter 4: Burden and management of non-cancerous HPV-related conditions: HPV-6/11 disease. Vaccine. 2006;24S3:S3/35–S3/41.GARDASIL™ is not indicated for RRP.1. Derkay CS. Laryngoscope. 2001;111:57– Lacey CJN, Lowndes CM, Shah KV. Vaccine. 2006;24S3:S3/35–S3/ Abramson AL, Nouri M, Mullooly V, Fisch G, Steinberg BM. J Med Virol. 2004;72:473– Steinberg BM, DiLorenzo TP. Cancer Metastasis Rev. 1996;15:91– Szentirmay Z, Pólus K, Tamás L, et al. Cancer and Metastasis Reviews. 2005;24:19– Derkay CS, Darrow DH. Ann Otol Rhinol Laryngol. 2006;115:1–11.
41The Cervarix argument Higher antibody levels Higher number of memory b cellsHigher antibody levels in cervical mucousBetter cross protection data
42HPV-16 and 18 Neutralising antibody responses: Geometric Mean Titers Cervarix®Gardasi™GMT (ED50)3171586821886137323.7 -fold7.3 -foldp<0.00011:GSKBio_WWMA_DoF018_3_2009TVC* = at least 1 dose received
43Memory B cellsThe frequency of antigen-specific memory B-cells in responders was significantly higher (2.7-fold) in the Cervarix® group than in the Gardasil™ group for both HPV 16 and HPV 18 (women aged 18–45 years, p<0.0001).
44Mucosal HPV antibody response in cervicovaginal secretion (CVS) Positivity rates for anti-HPV-16/18 neutralizing antibodies in CVS frequencies were higher for Cervarix®.81.3% vs 50.9% for HPV 1633.3% vs 8.8% for HPV 18
45Thus, we have two teams of international immunoligical heavyweights sending us different messages ! RESULT
51WHO AND WHEN BUT THEREFORE Before sexual debut ?9-13 “screen yourselves-vaccinate your daughters”BUT20 years to see any impact30-40 years to see benefit on Ca CxTHEREFOREMay consider “catch up” vaccination for all sexually active womenWe know its effective and safe in older women (10-55)SUGGESTS SIGNIFICANT BENEFIT FOR ALL SEXUALLY ACTIVE WOMENWe know very few carry both 16 and 18We know most HPV infections are transient
52WHO AND WHENIn other words, vaccinating all sexually active women will probably :Reduce Ca CxAnd consequently reduce the -Reduce repeat visits and smearsPsychologicalReduce colposcopiesPhysicalReduce destructive cervical procedures and the obstetric complications associated with themFinancial- Morbidity and mortality associated with themReduce hysterectomies for pre-invasive cervical lesions
53WHO AND WHEN NOT only pre sexual debut NOT only up to 26 NOT only the promiscuousCurrent PAP status irrelevantCurrent HPV status irrelevant
54WHO AND WHEN ? Males ? Prev abn PAP ? Current abn PAP - Controvercial? Prev abn PAP- Vaccinate? Current abn PAP- Vaccinate? Pre vaccination HPV test- Not necessary? Pregnancy- Postpone? Lactation- Benefit vs Risk? Boosters- Not needed to 7.3 years trials ongoing but look promising for long term
55PSYCOLOGICAL ASPECTS Parents don’t mind Vaccination does not change sexual behavior (ie promiscuity)Vaccination does not change sexual practice (ie safe sex)
56Screening to prevent Ca Cx PAP remains the mainstay of screeningImportance of PAP even after vaccinationWhat is the place of HPV testing?
57SCREENING Potential use of HPV testing: 1) Primary screening 2) Triange of abn PAP3) Test of cure
58SCREENING Sensitivity 53% Specificity 96% How good is HPV testing ? How good are PAPs ?(Pooled European and Canadian studies)Sensitivity 53%Specificity 96%How good is HPV testing ?Sensitivity almost 100%Specificity very lowLogic for primary HPV screen
59HPV TESTING - Problems HPV is common (80%) Only 10 to 20% persist Only some of the persistent HPV lead to High-Gr SilPeak at 20 sharp decline by 30Only persistent HPV is a problem but current tests only show presence
60TRIANGE OF ABN PAP ASCUS 43% HPV Positive LSil 76% HPV Positive Therefore only worthwhile in ASCUSLow-Gr Sil needs ColposcopyIn ASCUS HC2 identifies 37% more CIN2 than repeat cytology
61TEST OF CURESweedish study looked at longterm incidence/mortality following treatment for CIN3Showed lifelong increased risk of invasive Ca that accelerated with age.We thus need better Risk stratification of these patients
62TEST OF CURE 6 months post treatment HPV test showed 99% sensitivity Cytology + HPV 100%Good test of cureLonger follow up needed
63LIQUID BASED CYTOLOGYNo convincing evidence of better detection of High-Gr SilTwo advantages:1) Reflex HPV test if ASCUS found2) Better in automated screeningWhat will it’s place be in future?
64Take home message Vaccinate all women 10 to 50 Vaccinate boys on requestContinue screening after vaccination