1. HPV Vaccine – Does it Prevent Cervical Cancer?

2. What is HPV?
HPV related diseases
Prevention

3. What is Human Papillomavirus (HPV)?
Cervical Cancer is caused by certain types of virus known as Human Papillomavirus.
~ Oncogenic
~ Non-oncogenic

4. Human Papillomavirus (HPV)

5. Vaginal & Vulvar Lesions/Cancer
Types of HPV
>100 Types
30-40 types
Anogenital area
15-20 types
High risk
10-15 types
Low risk
The cause of cervical cancer is a sexually transmitted virus, called human papillomavirus. There are many HPV types and only some cause cancer. HPV infections (even high-risk types) usually go away without treatment. Low-risk HPV types can cause genital warts. The high-risk types cause most abnormal pap smears, precancer and cancer of the cervix, vagina, and vulva.
HPV 6, 11 cause
90% of genital warts
HPV 16, 18 cause
70% of
cervical cancer
HPV 16, 18 can cause:
85% of anal cancers2
40% of penile cancers2
35% of throat cancers2
25% of mouth cancers2
HPV 6, 11, 16, 18 can cause
Vaginal & Vulvar Lesions/Cancer
1. Centers for Disease Control and Prevention. Genital HPV infection fact sheet. 2. Centers for Disease Control and Prevention. HPV-Associated Cancers 5

6. How does HPV get transmitted?
Sexual contact
Sexual intercourse
Genital–genital, manual–genital, oral–genital
Genital HPV infection in virgins is rare, but may result from nonpenetrative sexual contact.
Condom use may help reduce the risk, but not fully protective.
Nonsexual routes
Mother to newborn (vertical transmission)
Fomites (e.g., undergarments, surgical gloves, biopsy forceps)
Hypothesized but not well documented; would be rare
Most infected individuals are unaware that they are infected and may unknowingly spread the virus. 6

7. How common is HPV?
Most men and women who have had sex have been exposed to HPV
Lifetime risk according to the US Centers for Disease Control for sexually active men and women is at least 50%.
This is a very common virus.
Studies demonstrate that most sexually active women have had HPV at some time. In fact, HPV infection is so common in women ages 18-29, that current recommendations for screening advice against testing women in this age group. 7

8. Risk Factors of HPV Infection
Women
Young age (peak age group 20–24 years of age)
Lifetime number of sex partners
Early age of first sexual intercourse
Male partner sexual behavior
Smoking (↓immunity)
Oral contraceptive use (sexual behavior)
Uncircumcised male partners
Men
Young age (peak age group 25–29 years of age)
Lifetime number of sex partners
Being uncircumcised
Sexual partner with CIN
Key Point
Though less documented, risk factors for HPV infection in males seem similar to those in females.
Background
A number of factors directly or indirectly related to sexual behavior have been associated with increased risk for HPV infection in both men and women. Those consistently relating to infection in women are young age, intercourse at an early age, and sexual behavior, particularly with a higher number of partners.1,2 The sexual behavior of male partners,2 smoking,3 oral contraceptive use,3 and lack of circumcision of male partners4 also appear to increase risk. Risk factors for HPV infection among men are similar to those in women and include young age, number of sex partners, and being uncircumcised.5 HPV infections and HPV-associated penile lesions are frequently found in male sexual partners of women with CIN.6
References
1. Burk RD, Ho GY, Beardsley L, Lempa M, Peters M, Bierman R. Sexual behavior and partner characteristics are the predominant risk factors for genital human papillomavirus infection in young women. J Infect Dis. 1996;174:679–689.
2. Murthy NS, Mathew A. Risk factors for pre-cancerous lesions of the cervix. Eur J Cancer Prev. 2000;9:5–14.
3. Winer RL, Lee S-K, Hughes JP, Adam DE, Kiviat NB, Koutsky LA. Genital human papillomavirus infection: Incidence and risk factors in a cohort of female university students. Am J Epidemiol. 2003;157:218–226.
4. Schiffman M, Castle PE. Human papillomavirus: Epidemiology and public health. Arch Pathol Lab Med. 2003;127:930–934.
5. Svare EI, Kjaer SK, Worm AM, Osterlind A, Meijer CJ, van den Brule AJ. Risk factors for genital HPV DNA in men resemble those found in women: A study of male attendees at a Danish STD clinic. Sex Transm Infect. 2002;78:215–218.
6. Bleeker MC, Hogewoning CJ, Voorhorst FJ, van den Brule AJ, Berkhof J, Hesselink AT, Lettink M, Starink TM, Stoof TJ, Snijders PJ, Meijer CJ. HPV-associated flat penile lesions in men of a non-STD hospital population: less frequent and smaller in size than in male sexual partners of women with CIN. Int J Cancer. 2005;113:36-41. 8

9. GENITAL WARTS HPV 6, 11 cause 90% of genital warts
Cauliflower-like lesions
Often found on the vulva, perineum, perianal area, vagina, cervix, penis and scrotum
HPV 6, 11 cause 90% of genital warts
Male perineum area 9

10. CERVICAL CANCER Progression from CIN to Cancer
Abnormal cell growth in the cervix
2nd most common cause of cancer death among women
HPV 16, 18 cause 70% of cervical cancer
Progression from CIN to Cancer
Where Pap tests are not available for screening, cervical cancer is the number one cancer killer of women. Cervical cancer typically affects women at younger ages than other gynecologic cancers. That’s why we urge all reproductive-age women to educate themselves and to participate in screening.
The Pap test has reduced the risk of cancer by early detection of cells destined to become cancer.
Normal
CIN 1
CIN 2
CIN 3/AIS
Invasive Cancer 10

11. Disease Progression
Time after HPV infection
3 to 6 months
4 to 5 Years
9 to 15 Years
Persistent Infection
Initial HPV Infection
CIN 2/3 or AIS
Cervical Cancer
CIN 1 +
co-factors
(viral, host, environmental)
“Cleared” HPV Infection
CIN=Cervical Intraepithelial Neoplasia
AIS=Adenocarcinoma in situ
The HPV detected today could have been acquired years ago
Many women diagnosed with cervical cancer were likely exposed to HPV during their teens and 20s

12. Cervical Cancer Incidence By Age, Peninsular Malaysia (Per 100,000)
0-9
10-19
20-29
30-39
40-49
50-59
60-69
70+
Age Group
0.0
71.6
Age specific cancer incidence per 100,000 population
Cervical cancer incidence rate
peak at ages years and
declined thereafter
increase with age after 30
Figure 4: Cervix Uteri Age specific Cancer Incidence per 100,000 population, Peninsular Malaysia 2003
Source: 2nd Report of National Cancer Registry Malaysia 2003 (Fig 1.2.3(b))

13. Incidence of Cervical Cancer in Malaysia
Cervical cancer is the 2nd most common cancer affecting Malaysian women of reproductive age below 49 years1
1. Malaysia Cancer Statistics - Data and Figure, Peninsular Malaysia, 2006 13

14. Cervical Cancer Incidence and Mortality Estimates by Region
2002 estimated cervical cancer incidence and mortality by region1:
14,
United States/ Canada
59,929 29,814
Europe
61,132 31,314
Eastern Asia
157,759 86,708
Southcentral Asia
17,
Central America
42,538 22,594
Southeast Asia
Key Point
Worldwide cervical cancer rates are high, particularly in developing countries,
and are still unacceptable in developed countries.
Background
According to data obtained from GLOBOCAN 2002, 82% of new cervical cancer cases occur in developing countries.1 As stated by WHO, without screening programs (ie, routine pap smears), “cervical cancer is detected too late and leads to death in almost all cases.”2 However, even in Europe, the United States, or Canada, where most women have access to routine screening, approximately 35,000 women die each year.1
References
Ferlay J, Bray F, Pisani P, Parkin DM. GLOBOCAN 2002: Cancer incidence, mortality and prevalence worldwide, version 2.0. IARC CancerBase No. 5. Lyon, France: IARC Press; 2004.
World Health Organization. State of the art of new vaccines research and development: Initiative for vaccine research. Geneva, Switzerland: World Health Organization; 2003: 1–74.
78,896 61,670
Africa
48,328 21,402
South America 1,
Australia/
New Zealand
1. Ferlay J, Bray F, Pisani P, Parkin DM. Lyon, France: IARC Press; 2004.

15. VaIN 3 and Vulvar Carcinoma Arising in VIN 3
VAGINAL LESIONS (VaIN*)
VaIN 3 and Vulvar Carcinoma Arising in VIN 3
VaIN 3
Photo courtesy of Dr. J. Monsonego
Photo courtesy of Dr. R.W. Jones
Commonly involves the upper third of the vagina and is often multifocal
Average age of women: 35–50 years
No symptoms and difficult to diagnose
Spontaneously clear, but potential to progress to invasive vaginal cancer
*VaIN=Vaginal Intraepithelial Neoplasia
CIN=Cervical Intraepithelial Neoplasia
VIN=Vulvar Intraepithelial Neoplasia 15

16. VULVAR LESION (VIN*)
*VIN=Vulvar Intraepithelial Neoplasia
HPV 16 appears to be the dominant HPV type associated with high-grade VIN
Estimated 42%–65% of VIN 1 cases are associated with HPV types 6 and 11
Most common symptoms include pruritus, pain, soreness, swelling and persistant ulcers. 16

17. HPV-Related Disease in Males
B&W image is from laryngeal cancer from: other images are from earlier slide kits.
1/Lillo/p111/ abstract
2/Gross/p35/ col2/¶1
1/Lillo/p111/ abstract 2/Gross/p40/ col2/¶2
Genital warts
Penile intraepithelial neoplasia (PIN) and carcinoma
Anal intraepithelial neoplasia (AIN) and carcinoma
Some oropharyngeal cancers (tongue, tonsillar, throat and soft palate)
1/Lillo/p111/ abstract
3/Frisch/p1350/abstract; p 1356/Tab 5; p 1458/col 1/¶1
1/Lillo/p111/ abstract
4/Gillison/ p709/abstract; p712/Tab 1
1/Lillo/ abstract
2/Gross/p35/ col1/¶1
Key Point
The disease burden related to HPV infection in males is substantial and includes penile cancer, anal cancer, some oropharyngeal cancers, and genital warts.
Background
Considerable laboratory and epidemiologic evidence demonstrates that HPV is a major cause of clinical disease in men as well as women.1,2 Consequences of HPV infection in men include genital warts, penile intraepithelial neoplasia (PIN) and carcinoma, anal intraepithelial neoplasia (AIN) and carcinoma, and a subset of oropharyngeal cancers.
High-risk types of HPV (primarily HPV 16 and HPV 18) are present in the majority of anal cancers and in a significant fraction of penile cancers.2,3 High-risk HPV (usually HPV 16) has also been found in some oropharyngeal cancers.4
HPV 6 and HPV 11, are known to cause >90% of all cases of genital warts.5
2/Gross/p 40/ col 2/¶2 3/Frisch/p 1356/Tab 5
4/Gillison/p 711/col 2/¶2.
5/Gissmann/p561/Tab 2
HPV = human papillomavirus.
References
Lillo FB. Human papillomavirus infection and its role in the genesis of dysplastic and neoplastic lesions of the squamous epithelia. New Microbiol. 2005;28:111–118.
Gross G, Pfister H. Role of human papillomavirus in penile cancer, penile intraepithelial squamous cell neoplasias and in genital warts. Med Microbiol Immunol. 2004;193:35–44.
Frisch M, Glimelius B, van den Brule AJC, et al. Sexually transmitted infection as a cause of anal cancer. N Engl J Med. 1997;337:1350–1358.
Gillison ML, Koch WM, Capone RB, et al. Evidence for a causal association between human papillomavirus and a subset of head and neck cancers. J Natl Cancer Inst. 2000;92:709–720.
Gissmann L, Wolnik L, Ikenberg H, Koldovsky U, Schnürch 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 U S A. 1983;80:560–563.

18. HPV Disease Prevention
Primary*
*Applicable for males & females
Secondary*
*Applicable for females only
Prevention of any factors that could lead to disease in healthy individuals
Prevention by halting the progression of the infection/disease
Modifying lifestyle risks
ie. tobacco, keep healthy, sexual intercourse >20yrs, condoms
Vaccination
Pap Smear

19. HPV Prophylactic Vaccination:
A shift from secondary to
primary prevention 19

20. 2 Types of HPV Vaccines
Quadrivalent HPV Vaccine which protects against HPV types 6, 11, 16, 18
Bivalent HPV Vaccine which protects against HPV 16, 18 only
Key Point
GARDASIL™ is Merck’s quadrivalent HPV L1 virus-like particle (VLP) vaccine. It is produced in recombinant yeast and adsorbed on a proprietary aluminum adjuvant.
Background
GARDASIL is a non-infectious recombinant, quadrivalent vaccine, prepared from the highly purified VLPs of the recombinant major capsid (L1) protein of HPV types 6, 11, 16, and 18. The L1 proteins are produced by separate fermentations in recombinant Saccharomyces cerevisiae and self-assembled into VLPs.1
The VLPs for each type are purified and adsorbed on aluminum-containing adjuvant (amorphous aluminum hydroxyphosphate sulfate). The quadrivalent HPV VLP vaccine is a sterile liquid suspension that is prepared by combining the adsorbed VLPs of each HPV type and additional amounts of the aluminum-containing adjuvant and the final purification buffer.1
GARDASIL is a sterile preparation for intramuscular administration. Each 0.5-mL dose contains approximately 20 µg of HPV 6 L1 protein, 40 µg of HPV 11 L1 protein, 40 µg of HPV 16 L1 protein, and 20 µg of HPV 18 L1 protein. Each 0.5-mL dose of the vaccine contains approximately 225 µg of aluminum (as amorphous aluminum hydroxyphosphate sulfate adjuvant).1
GARDASIL should be administered intramuscularly as 3 separate 0.5-mL doses at day 1, month 2, and month 6.1
GARDASIL is a trademark of Merck & Co., Inc., Whitehouse Station, NJ, USA.
Reference
1. GARDASIL Prescribing Information. Merck & Co., Inc., Whitehouse Station, NJ, USA. .

21. Quadrivalent HPV (HPV 6, 11, 16, 18) Vaccine
Protects Against
90% of Genital warts
caused by HPV 6 & 11
70% of Pre-cancers
& cervical cancer
caused by HPV 16 & 18
Vulvar & vaginal cancer
caused by
HPV 6, 11, 16 & 18

22. VACCINE GARDASIL Quadrivalent (HPV 6, 11, 16, 18) Bivalent
Vulva & Vagina Cancer
HPV 6, 11, 16, 18
Cervical Cancer
HPV 16 & 18
Genital Warts
HPV 6 & 11

23. The Right Vaccine for the Right Health Impact
GARDASIL [(Quadrivalent Human Papillomavirus (Types 6, 11, 16, 18) Recombinant Vaccines] has been demonstrated to prevent more cancers and diseases :
98%
of cases of cervical cancer related to HPV Types 16 and 18
96%
of cases of cervical precancerous lesions related to HPV Types 6, 11, 16 and 18
99%
of cases of genital warts related to HPV Types 6 and 11
100%
of cases of vaginal and vulvar cancer related to HPV Types 16 and 18

24. 91% 83% Adult women (24-45 years old)
HPV 6-, 11-, 16-, or 18-related persistent infection, genital warts, vulvar and vaginal lesions, CIN of any grade, AIS and cervical cancer
83%
HPV 16- or 18-related persistent infection, genital warts, vulvar and vaginal lesions, CIN of any grade, AIS and cervical cancer

25. Is Gardasil for boys/men?
Indicated in boys and men 9 to 26 years of age for the prevention of genital warts (condyloma acuminata) caused by HPV types 6 and 11.
Is efficacious in reducing the incidence of genital warts related to HPV types 6 and 11 in males relevant to the HPV type(s) 6, 11, 16 and 18

26. Males (18-26 years old)
90%
efficacious against HPV type 6, 11, 16, 18-related external genital lesions (EGL) – 91% were genital warts
89%
efficacious against HPV 6 and 11-related genital warts

27. Gardasil - Administration
0-, 2-, 6-month dosing regimen
Intramuscular administration
Each 0.5-mL injection volume
For women from age 9 to 26 years of age
For boys/men age 9 – 26 years old
Ideally given before first sexual contact, but females who have had sexual activity should still be vaccinated
Regular Pap smear screening still required after vaccination

28. HPV Vaccines – Global Funding
Tender with Gardasil (2012) - MALAYSIA
To date GARDASIL is available through public funding in 23 countries

29. AUSTRALIA: National Immunization Program April 2007: - target group
 ongoing target group of year old girls
- largely delivered in a school based program
 women aged up to 26 years
- delivered through general practice as a catch up for 2 years
In June 2006 the Food and Drug administration approved the use of the HPV vaccine for use in 9-26 year olds, and the Centers for Disease Control and Prevention recommended the vaccine be routinely administered in year olds, and year olds who had not received the vaccine, with 9-10 year olds being vaccinated at the discretion of the parent and provider
Aust school based uptake 80% 29

31. HPV vaccination can help prevent certain HPV-related cancers and most genital warts
WPC072010: p1B–D
WHO-CCCC: p20A; p21A
Adding HPV vaccination to Pap exams comprises a comprehensive approach to cervical cancer prevention1
Pap exams are essential, but alone may not be enough
In a retrospective study of 642 women diagnosed with cervical cancer in a large prepaid health plan between 1988 and 1994:
~28% of women diagnosed with cervical cancer had at least one normal Pap exam 6 to 36 months prior to diagnosis.
AND
PAP
EXAM
PATIENT
EDUCATION
HPV
VACCINATION
Sung: p2285A, B, C
Sung: p2285A 31 31

32. What have we learned so far?
Human Papillomavirus (HPV) can:
Affect males & females (at least 50% in a lifetime)
Cause cervical cancer, genital warts, vaginal & vulvar cancer
Be PREVENTED through:
Regular Pap smear screening
Vaccination
HPV vaccine can prevent:
genital warts in males & females
cervical cancer, vaginal & vulvar cancers in females 32

33. Protect Yourself. Protect Your Loved Ones. Now!
Cervical cancer & HPV diseases can be prevented. Don’t Wait until it is too late.
Protect Yourself. Protect Your Loved Ones. Now!

35. Dr. Christine Lee Department of O&G SGH
Thank You!
Dr. Christine Lee
Department of O&G
SGH