HPV Vaccine – Does it Prevent Cervical Cancer?

What is HPV? HPV related diseases Prevention

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

Human Papillomavirus (HPV)

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

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

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

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

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

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

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

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 60-69 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))

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

Cervical Cancer Incidence and Mortality Estimates by Region 2002 estimated cervical cancer incidence and mortality by region1: 14,670 5796 United States/ Canada 59,929 29,814 Europe 61,132 31,314 Eastern Asia 157,759 86,708 Southcentral Asia 17,165 8124 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 1,063 330 Australia/ New Zealand 1. Ferlay J, Bray F, Pisani P, Parkin DM. Lyon, France: IARC Press; 2004.

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

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

HPV-Related Disease in Males B&W image is from http://www.scielo.br/scielo.php?script=sci_arttext&pid=S1516-31802007000500009&lng=pt&nrm=iso; laryngeal cancer from: http://www.aafp.org/afp/980600ap/rosen.html; 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.

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

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

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. .

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

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

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

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

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

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

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

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

AUSTRALIA: National Immunization Program April 2007: - target group  ongoing target group of 12 - 18 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 11-12 year olds, and 13-26 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

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

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

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!

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