1. PREVENTING CERVICAL CANCER
BRYANSTON COUNTRY CLUB
Dr Peter C Koll
4th September 2010

2. CERVICAL CANCER Cervical cancer should not happen
Medical breakthroughs have occured
All we need to do is :
To create the awareness
To find the resources
To stimulate the political will

3. Global mortality per annum
Worldwide, every 2 minutes a woman dies of cervical cancer1
The highest burden of disease (up to 80%) occurs in less developed regions1 where there is a lack of effective screening programmes
This demonstrates a clear medical need for new cervical cancer interventions
Europe
60,000 new cases
30,000 deaths
North America
14,500 new cases
6,000 deaths
Asia
266,000 new cases
143,000 deaths
Latin America
72,000 new cases
33,000 deaths
Global mortality per annum
Africa 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.
Reference
Ferlay J, et al. GLOBOCAN 2002 Cancer Incidence, Mortality and Prevalence Worldwide. IARC CancerBase; Lyon, 2004.
Africa
79,000 new cases
62,000 deaths
< 7.9
< 23.8
< 14.0
< 55.6
< 3.9
Cervical cancer mortality rates worldwide Cases per 100,000 women per year
1. Ferlay J, et al. GLOBOCAN 2002 Cancer Incidence, Mortality and Prevalence Worldwide. IARC CancerBase; Lyon, 2004.

4. The most frequent cancers in women: incidence and mortality
Global data
Incidence
Mortality
Breast
13.2
37.4
Breast
Cervix
10.3
16.2
Lung
Colon/
Rectum
9.0
14.6
Cervix
Lung
7.9
12.1
Stomach
The most frequent cancers in women: incidence and mortality
Cervical cancer is the second most common cancer among women worldwide after breast cancer, although mortality rates are lower than for lung cancer.
Reference
Ferlay J, et al. GLOBOCAN 2002 Cancer Incidence, Mortality and Prevalence Worldwide. IARC CancerBase; Lyon, 2004.
7.6
Stomach
10.3
Colon/
Rectum
Ovary
5.7
6.6
Liver
Corpus
4.0
6.5
Ovary 5 10 15 20 25 30 35 40 2 4 6 8 10 12 14
Age-standardized rate per 100,000
Age-standardized rate per 100,000
Ferlay J, et al. GLOBOCAN 2002 Cancer Incidence, Mortality and Prevalence Worldwide. IARC CancerBase; Lyon; 2004.

5. The most frequent cancers in women: incidence and mortality
Africa
Incidence
Mortality
29.3
Cervix
23.1
Cervix
23.4
Breast
16.2
Breast
6.2
Liver
Liver
6.2
4.9
Stomach
4.6
Stomach
Kaposi’s sarcoma
4.6
Kaposi’s sarcoma
4.3
The most frequent cancers in women: incidence and mortality
In 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.
Reference
Ferlay J, et al. GLOBOCAN 2002 Cancer Incidence, Mortality and Prevalence Worldwide. IARC CancerBase; Lyon, 2004.
4.3
Colon/
Rectum
Ovary
3.7
Colon/
Rectum
4.2
Oesophagus
3.2 5 10 15 20 25 30 35 5 10 15 20 25
Age-standardized rate per 100,000
Age-standardized rate per 100,000
Ferlay J, et al. GLOBOCAN 2002 Cancer Incidence, Mortality and Prevalence Worldwide. IARC CancerBase; Lyon; 2004.

6. The transformation zone
ANATOMY
The transformation zone
Columnar epithelium
The transformation zone
(squamous metaplasia)
Squamous epithelium

7. Pre-Cancerous lesions

8. Cervical cancer

9. HISTORY OF Ca Cx PREVENTION
George Papanicolaou first described the PAP test years ago

11. Limitations of PAP smear
- Only prevents 70% of cancers
- May miss adenocarcinoma
Adenocarcinoma: may be
inaccessible to the cervical
smear brush
Squamous cell carcinoma
Adenocarcinoma
Endometrium
Myometrium
Uterine cavity
Adenocarcinoma
Cervix
Squamous cell carcinoma:
usually accessible to the cervical smear brush
Squamous cell carcinoma

12. Limitations of PAP smear
- Only prevents 70% of cancers
- May miss adenocarcinoma
Logistics
Cost
Treatment
Recall

13. HISTORY OF Ca Cx PREVENTION
George Papanicolaou first described the PAP test years ago
Harald zur Hausen linked HPV to Ca Cx
HPV vaccines,
the first vaccines specifically developed
to 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

14. HPV >100 types identified2 ~30–40 anogenital2,3
~15–20 oncogenic*,2,3
HPV 16 and HPV 18 types account for the majority of worldwide cervical cancers.4
Nononcogenic** types
HPV 6 and 11 are most often associated with external anogenital warts.3
These two types are responsible for >90% of genital warts.5
Nonenveloped double-stranded DNA virus1
Key Point
There 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.
Background
Papillomaviruses, 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.3
References
1. 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 risk
1. 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

15. HPV Infection and Life Cycle
Shedding of Virus-
Laden Epithelial Cells
Cervical Surface
Mature
Squamous
Layer
Viral Assembly
(L1 and L2)         
Squamous
Layer  
Viral DNA Replication
(E6 and E7)   .    .  . .
Parabasal
Cells
Episomal Viral DNA
in Cell Nucleus
(E1 and E2, E6 and E7)     .  . .
Basal (Stem)
Cells
Infection of Basal Cells (E1 and E2)
Basement Membrane
Normal
Epithelium
Infected
Epithelium
Adapted from Frazer IH. Nature Rev Immunol. 2004;4:46–54.

16. Why are antibody responses so poor in natural HPV infections?
No viraemia
HPV does not kill keratinocytes
no inflammation
no pro-inflammatory cytokines
poor activation of epithelial antigen presenting cells
Free virus particles are shed from mucosal surfaces with poor exposure to antigen presenting cell (APC)

17. What 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

18. HPV Types in Cervical Cancer Worldwide
HPV genotype 16
53.5
53.5 %
Vaccine
HPV type 18
17.2
70.7 % 45
6.7
77.4 % 31
2.9
80.3 % 33
2.6 52
2.3 58
2.2 35
1.4 59
1.3 56
1.2 51
1.0 39
0.7 68
0.6 73
0.5 82
0.3
Other X
4.4 10 20 30 40 50 60 70 80 90
100
Cancer cases attributed to the most frequent HPV genotypes (%)
Munoz N et al. Int J Cancer 2004;111:278–85.

19. Worldwide Prevalence of HPV Types in Cervical Cancer*,1
69.7
14.6
HPV Type 16
52.5
25.7 18 45
67.6 17 31
North America/
Europe 33 57
12.6 52
Key Point
Most 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.
Background
In 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.1
HPV 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 66.1
Reference
1. 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 Asia 58
Others
Northern Africa
Central/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.

20. Prevalence of the 10 most common oncogenic HPV types worldwide
In 2855 HPV Positive Cervical Cancer Cases & Rank By Region
Europe & North America
Sub-Saharan Africa
Northern Africa
Central-South America
South Asia
HPV type %
HPV type %
HPV type %
HPV type %
HPV type %
69.7
52.5
57.0
67.6
47.7
HPV 16
14.6
HPV 18
25.7
12.6
17.0
19.1
6.8
HPV 45
9.0
7.9
5.6
15.0
2.3
HPV 31
3.4
4.5
7.4
1.1
HPV 52
3.6
3.1
2.2
HPV 33
4.2
4.0
3.2
2.2
HPV 56
2.7
3.0
HPV 58
3.2
1.1
HPV 35
3.1
1.9
2.0
HPV 59
Adapted 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 Carcinomas
diagnosed died
-Anal
-Vulvo/vaginal
-Penile
-Oral
-Nasopharangeal
-Abnormal PAP smear
-Repeat visits
-Colpomicroscopy
-Biopsy
-Laser/Cone/LEEP/LLETZ
-Financial
-Emotional
-Physical
Morbidity

22. The most common STD
50% young females aquire it within 3 yrs of sexual debut
Cumulative detection is 59-82%
Majority transient in young women – only 10-20% persist for 24 mts
Peak at 20 sharp decline by 30
If present after 30 – more likely to be persistent
ONLY PERSISTENT HIGH RISK HPV CONSTITUTES RISK FOR CIN2 OR 3

23. Estimated World Burden of HPV-Related Diagnoses Focus on Cervical Disease and Genital Warts
1/WHO/p 5/ ¶1
Cervical Cancer: 0.5 million cases/year1
High-grade precancerous lesions: 10 million2
2/WHO/ p. 6/¶2
Low-grade cervical lesions: 30 million2
3/WHO/ p. 1/¶2
Genital warts: 30 million3
1/WHO/ p. 5/¶1
Attributable to oncogenic HPV types
Attributable to nononcogenic HPV types
Key Points
HPV 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.
Background
According 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.3
The 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.2
HPV 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.4
Nononcogenic 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.6
References
1. 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/¶1
HPV infection: 660 million1
2/WHO/ p. 6/¶2
3/WHO/ p. 1/¶2
2/WHO/ p. 6/¶2
1. 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. 2
5/Wiley/p. S210/col 1/¶1/col 2/¶1.
6/Gissmann/p. 561/Table 2.

24. HPV Infection and Risk of Invasive Cervical Cancer in Selected Countries*,1
% HPV Prevalence cases/contro
97.0/17.3
96.9/33.3
97.1/21.6
98.1/19.8
96.4/9.2
96.5/15.7
95.3/17.7
82.4/5.9
78.4/17.5
96.6/15.6
Brazil
Mali
Morocco
Paraguay
Philippines
Thailand
Peru
Spain
Colombia
Overall
Key Point
Data 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.
Background
In 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.1
HPV 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/controls
Brazil 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)
Reference
1. 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.
0.1 10
100
1000
10,000
Odds Ratio (95% CI**)
*Assays used varied by site. **CI = confidence interval
1. Muñoz N, Bosch FX, de Sanjosé S, et al. N Engl J Med. 2003;348:518–527. 7

25. Human papillomavirus structure
HPV is a relatively small virus containing double-stranded DNA within a spherical shell (capsid)1
The capsid is composed of two proteins, the ‘late’ or structural proteins L1 and L21
Circular DNA
55 nm
L1 protein pentamer
L2 supporting protein
1. Burd EM. Clin Microbiol Rev 2003; 16:1–17.

27. Virus Like Particle (VLP)
VLP Looks exactly like the virus but contains no viral DNA
Thus elicits strong immune response without any risk of infection
L1 protein pentamer

28. Active protection via vaccination is mediated by neutralizing antibodies at the cervix
HPV
Neutralizing antibodies
Cervical canal
Cervical
epithelium
Blood vessel
Epithelial tear
Neutralizing antibodies are critical for inhibition of early infection before viral entry into cells.1
Immunization 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.2
Findings 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.3
It has been shown that a higher magnitude of antibodies in the serum correlates with higher antibody levels in cervicovaginal secretions (CVS).4
References
1. 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 membrane
1. 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).

29. GARDASIL™ (20/40/40/20 μg) Neutralizing Anti-HPV Immunogenicity
In a double-blind, placebo-controlled, dose-ranging study of
quadrivalent HPV (types 6, 11, 16, 18) L1 VLP vaccine.
Per-Protocol Subjects
(GARDASIL)
1000
1000
HPV 6
HPV 11
100
100 10 10 * * * * * * 1 1 7 12 18 24 30 36 54 60 7 12 18 24 30 36 54 60
GMT with 95% CI
mMU/mL (Log Scale)
10,000
Key Point
Vaccine-induced anti-HPV 6, 11, 16, and 18 GMTs peaked at month 7 and gradually decreased to reach a plateau at month 24.
Background
All 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 60.2
Note 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.3
GARDASIL is a trademark of Merck & Co., Inc., Whitehouse Station, NJ, USA.
References
1. 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.
1000
HPV 16
HPV 18
1000
100
100 10 10 * * * * * * 1 7 12 18 24 30 36 54 60 7 12 18 24 30 36 54 60
Time Since Vaccination (Months)
* vaccination
GARDASIL is a trademark of Merck & Co., Inc., Whitehouse Station, NJ, USA.
Adapted from Olsson S-E et al. Vaccine. 2007;25:4931–4939. 10

30. CERVARIX

31. GARDASIL™ [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 Lesions1,2
Per-protocol efficacy population, women 16–26 years of age followed up through 3–4 years
1/Haupt/slide 3/bullet 1; slide 5/Table
2/DOF End of study ISE/p.57/Table 14. (“n” numbers)
250
227
GARDASIL
Placebo
193
200
99% Efficacy (97, 100)
99% Efficacy (96, 100)
150
Related Cases
100% Efficacy (86,100)
100% Efficacy (83,100)
100
Key Point
The 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.
Background
Overall 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).1
Reduction 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.1
Reduction 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.1
Reduction 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.1
1. Haupt RM. Advisory Committee on Immunization Practices. February 27, mtg-slides-feb08/14-3-hpv.pdf. Accessed March 30, 2009. 50 28 23 2 2
HPV 6/11/16/ 18-Related EGL
Genital Warts
VIN 1, VaIN 1
VIN 2/3, VaIN 2/3
n=7900
n=7902
n=7900
n=7902
n=7900
n=7902
n=7900
n=7902
1/Haupt/slide 3/bullet 1; slide 5/Table
EGL = external genital lesion; VaIN = vaginal intraepithelial neoplasia; VIN = vulvar intraepithelial neoplasia. 1. Haupt RM. ACIP. February 27, Accessed July 11, Data on file, MSD ______.

32. GARDASIL™: Durable Protection Through Five Years
PPE population; subjects were naïve to HPV types 6, 11, 16, and/or 18
HPV 6, 11, 16, or 18-related
GARDASIL
Placebo N
Cases
Efficacy
95% CI
Persistent
Infection
235 2*
233 45
96%
(83, 100)
Disease 6
100%
(12, 100)
CIN 1, 2, or 3 3
(<0, 100)
Vulvar/vaginal neoplasias or genital warts
Key Point
Long-term efficacy of GARDASIL™ against vaccine type-related HPV disease remains at 100% five years after vaccination.
Background
High 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.1
Subjects vaccinated with GARDASIL did not present with any breakthrough cases of infection or disease during the extended follow-up period.1
GARDASIL is a trademark of Merck & Co., Inc., Whitehouse Station, NJ, USA.
Reference
1. 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 the
five-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

33. Up to 5.5 years Substantial Protection against HPV-16/18 infections and CIN outcomes
Endpoints*
HPV Vaccine
Control
Vaccine Efficacy n n %
95% CI
6 Month Persistence 29
100
12 Month Persistence 14
100
CIN1+ 11
100
CIN2+ 7
100
*Combined analysis initial efficacy study and extended follow-up
ATP analysis for virologic endpoints; ITT analysis for cytologic and CIN endpoints
Presentation Gall S, AACR, Los Angeles, April 14-18, 2007

34. Disease Cross-Protection Analysis: Efficacy Against CIN 2/3 or AIS in the Generally HPV-Naïve Population
CIN 2/3 or AIS*
# of cases GARDASIL
n=4616
# of cases Placebo
n=4675
Efficacy
95% CI
HPV 31/45 8 21
62%
10, 85
HPV
31/33/45/52/58 27 48
43%
7, 66
31/33/35/39/45/51/52/56/58/59 38 62
38%
6, 60
Brown/Table 6
Key Points
In 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.
Background
The 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).
Reference
Brown 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 6
Cross-Protection Special Report, Sec , P 225, last para; Sec 5.3, P 238, 2 para; Table 4-53
Brown D; for the FUTURE Study Group. Poster presented at ICAAC; September 17-20, 2007; Chicago, IL.

35. Cross 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 18
Vaccine 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 endpoint
Global incidence
The 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.
Reference
Ferlay J, et al. GLOBOCAN 2002 Cancer Incidence, Mortality and Prevalence Worldwide. IARC CancerBase; Lyon, 2004.

36. SAFETY
No clinically meaningful differences between study groups with respect to:
Medically significant conditions
Serious Adverse Events
New onset chronic disease and new onset autoimmune diseases
Pregnancy outcomes

37. WHICH ONE ? Both safe Both very effective
Both equally effective in preventing Ca Cx
Only two undisputed facts:
1) Gardasil protects against 6 and 11
2) Cervarix is cheaper

38. The Gardasil argument
Proven protection against vulval and vaginal carcinoma
Protection against 6 and 11

39. GARDASIL
HPV 6 & 11
HPV Types 6 and 11 responsible for >90% of anogenital warts1
Estimated lifetime risk of developing genital warts ~10%2,3
External genital warts are very contagious.
Infectivity >75%

40. RRP 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.2
Papillomas are stratified squamous epithelial masses that can obstruct the airway if not removed.3
Although histologically benign, RRP causes significant morbidity and mortality due to recurrent nature.3
Could require surgery under general anesthesia as frequently as every few weeks
Possible causative role of RRP in head and neck cancers3-5
RRP is rare.6
Key Point
RRP is a nonmalignant lesion of the larynx and trachea caused by HPV Types 6 and 11.
Background
The 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).1
RRP 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.2
Although 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.2,3
References
1. 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.

41. The Cervarix argument Higher antibody levels
Higher number of memory b cells
Higher antibody levels in cervical mucous
Better cross protection data

42. HPV-16 and 18 Neutralising antibody responses: Geometric Mean Titers
Cervarix®
Gardasi™
GMT (ED50)
31715
8682
1886
13732
3.7 -fold
7.3 -fold
p<0.0001
1:GSKBio_WWMA_DoF018_3_2009
TVC* = at least 1 dose received

43. Memory B cells
The 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).

44. Mucosal 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 16
33.3% vs 8.8% for HPV 18

45. Thus, we have two teams of international immunoligical heavyweights sending us different messages !
RESULT

47. REMEMBER Both safe Both very effective
Both equally effective in preventing Ca Cx
Only two undisputed facts:
1) Gardasil protects against 6 and 11
2) Cervarix is cheaper

48. So, which one ? Short answer: -it doesn’t matter
If can’t make up mind:
-toss a coin
-Either way, you won’t be wrong
For goodness sake
VACCINATE

49. WHO AND WHEN

50. Cumulative Risk of Any HPV Infection by Age in Women*,150
Age at Baseline
15–19
N=1610 40
20–24
25–29
30–44 30
45+
Cumulative Risk of HPV Infection (%) 20
Key Point
The highest risk of HPV infection occurs in adolescents 15–19 years of age, but the risk of infection remains throughout life.
Background
In this study, a cohort of 1610 HPV-negative Colombian women 15–85 years of age with normal cytologic results at baseline was monitored every 6 months for an average of
4.1 years. Information on risk factors and cervical samples for cytologic testing and HPV DNA detection and typing were obtained at each visit.1
This slide shows the cumulative risk of acquiring an infection with any HPV type grouped according to age. For any HPV infection, the highest five-year cumulative risk (42.5%) was observed among women 15–19 years of age; incidence thereafter decreased monotonically with age, but the lowest level (in women 45 years of age and older) was still 12.4%.1
Reference
1. Muñoz N, Méndez F, Posso H, et al. Incidence, duration, and determinants of cervical human papillomavirus infection in a cohort of Colombian women with normal cytological results. J Infect Dis. 2004;190:2077–2087. 10 1 2 3 4 5
Years
*In a cohort of Colombian women
1. Adapted from Muñoz N, Méndez F, Posso H, et al. J Infect Dis. 2004;190:2077–2087. Reprinted with permission from The University of Chicago Press. Copyright © 2004 by the Infectious Diseases Society of America. All rights reserved. 8

51. WHO AND WHEN BUT THEREFORE Before sexual debut ?9-13
“screen yourselves-vaccinate your daughters”
BUT
20 years to see any impact
30-40 years to see benefit on Ca Cx
THEREFORE
May consider “catch up” vaccination for all sexually active women
We know its effective and safe in older women (10-55)
SUGGESTS SIGNIFICANT BENEFIT FOR ALL SEXUALLY ACTIVE WOMEN
We know very few carry both 16 and 18
We know most HPV infections are transient

52. WHO AND WHEN
In other words, vaccinating all sexually active women will probably :
Reduce Ca Cx
And consequently reduce the -
Reduce repeat visits and smears
Psychological
Reduce colposcopies
Physical
Reduce destructive cervical procedures and the obstetric complications associated with them
Financial
- Morbidity and mortality associated with them
Reduce hysterectomies for pre-invasive cervical lesions

53. WHO AND WHEN NOT only pre sexual debut NOT only up to 26
NOT only the promiscuous
Current PAP status irrelevant
Current HPV status irrelevant

54. WHO 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

55. PSYCOLOGICAL ASPECTS Parents don’t mind
Vaccination does not change sexual behavior (ie promiscuity)
Vaccination does not change sexual practice (ie safe sex)

56. Screening to prevent Ca Cx
PAP remains the mainstay of screening
Importance of PAP even after vaccination
What is the place of HPV testing?

57. SCREENING Potential use of HPV testing: 1) Primary screening
2) Triange of abn PAP
3) Test of cure

58. SCREENING 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 low
Logic for primary HPV screen

59. HPV TESTING - Problems HPV is common (80%) Only 10 to 20% persist
Only some of the persistent HPV lead to High-Gr Sil
Peak at 20 sharp decline by 30
Only persistent HPV is a problem but current tests only show presence

60. TRIANGE OF ABN PAP ASCUS 43% HPV Positive LSil 76% HPV Positive
Therefore only worthwhile in ASCUS
Low-Gr Sil needs Colposcopy
In ASCUS HC2 identifies 37% more CIN2 than repeat cytology

61. TEST OF CURE
Sweedish study looked at longterm incidence/mortality following treatment for CIN3
Showed lifelong increased risk of invasive Ca that accelerated with age.
We thus need better Risk stratification of these patients

62. TEST OF CURE 6 months post treatment HPV test showed 99% sensitivity
Cytology + HPV 100%
Good test of cure
Longer follow up needed

63. LIQUID BASED CYTOLOGY
No convincing evidence of better detection of High-Gr Sil
Two advantages:
1) Reflex HPV test if ASCUS found
2) Better in automated screening
What will it’s place be in future?

64. Take home message Vaccinate all women 10 to 50
Vaccinate boys on request
Continue screening after vaccination