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HPV Vaccine: - More than Cervical Cancer Prevention -

HPV Vaccine: - More than Cervical Cancer Prevention -. Tam Kar Fai Department of Obstetrics and Gynaecology University of Hong Kong. Diphtheria antitoxin discovered. Measles (live)*. Mumps*. Measles (live attenuated virus)*. Measles, mumps, rubella (MMR)*.

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HPV Vaccine: - More than Cervical Cancer Prevention -

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  1. HPV Vaccine:- More than Cervical Cancer Prevention - Tam Kar Fai Department of Obstetrics and Gynaecology University of Hong Kong

  2. Diphtheria antitoxin discovered Measles (live)* Mumps* Measles (live attenuated virus)* Measles, mumps, rubella (MMR)* Pneumococcal (14-valent polysaccharide)* 1963 1967 1968 1971 1977 1978 1981 1983 1986 1989 1995 1996 1996 1895 Haemophilusinfluenzae type b (liquid)* Hepatitis A (inactivated)* Varicella (chicken pox) virus* Haemophilusinfluenzae type b (conjugated)* Hepatitis B (recombinant)* Pneumococcal (23-valent polysaccharide)* Hepatitis B (plasma derived)* Measles, mumps, rubella virus vaccine live (new rubella strain: RA 27/3)* Quadrivalent HPV Vaccine(4 in 1HPV vaccine) Human Papillomavirus* Zoster (live)* Rotavirus* 1996 2005 2006 2006 2006 The First Cancer Vaccine of the World Measles, mumps, rubella, varicella* Haemophilusinfluenzae type b / Hepatitis B*

  3. Cervical Cancer Is Essentially Caused by Oncogenic HPV(致癌性的HPV種類引致的子宮頸癌) • HPV is a main cause (主因)of cervical cancer • Analysis of 932 specimens from women in 22 countries indicated prevalence of HPV DNA in cervical cancers worldwide = 99.7%. (致病相關率 99.7%) 1. Muñoz N, Bosch FX, de Sanjosé, et al. N Engl J Med. 2003;348:518–527. 2. Walboomers JM, Jacobs MV, Manos MM, et al. J Pathol. 1999;189:12–19.

  4. Importance of Cervical Cancer Effortto reduce cervical cancerbegan 50 years ago Various evidences suggested cervical screening led to a reduction in incidence up to 75% Second most common cancer among females worldwide1 1.WHO 2003

  5. Cervical Cancer in Hong Kong1 5thmost common cancer 9thleading cause of cancer death Cervical Screening Programin HK since March 2004 450 new cases per year 120 deaths per year 1.Hong Kong Cancer Registry, 2005

  6. GARDASIL加衛苗™MSD’s Quadrivalent HPV L1 VLP Vaccine1 • Quadrivalent HPV L1 VLP vaccine • (Types 6, 11, 16, 18) • VLPs manufactured in: • Yeast • Recombinant VLPs (empty shell protein L1) • Do not contain Virus DNA (not infectious) • Amorphous Aluminum Hydroxyphosphate Sulfate Adjuvant (225 μg per dose) • No Mercury preservative (thimerosal) • Storage: 2 to 8 OC GARDASIL is a trademark of Merck & Co., Inc., Whitehouse Station, NJ, USA. *VLP = Virus-like particle. 1. Villa LL, Costa RL, Petta CA, et al. Lancet Oncol.2005;6:271–278.

  7. GARDASIL • Prophylactic vaccine

  8. Approved in 86 Countries/Territories Europe (EU):Austria, Belgium, Bulgaria, Cyprus, Czech Republic, Denmark, Estonia, Finland, France, Germany, Greece, Hungary, Ireland, Italy, Latvia, Lithuania, Luxembourg, Malta, The Netherlands, Poland, Portugal, Romania, Slovakia, Slovenia, Spain, Sweden, UK Europe (non-EU): Bosnia, Croatia, Iceland, Liechtenstein, Norway, Russia,Serbia, Switzerland, Turkey North America: Canada, Mexico, USA 36 3 Caribbean: Aruba, Bahamas, Bermuda, Barbados, Cayman Island, Curacao, Dominican Republic, Jamaica, Puerto Rico,Trinidad, Tobago 11 Middle East and Africa: Central African Republic, Chad, Congo Kinshasa, Guinea Equatorial,Gabon, Ethiopia, Israel,Jordan, Kenya, Mauritania,Mauritius, Morocco, Togo, United Arab Emirates Asia Pacific:Australia, Hong Kong, Indonesia , Macau, Malaysia, New Zealand, Philippines, Taiwan, Thailand , Singapore, Korea 14 Central America: Costa Rica, El Salvador, Honduras, Guatemala, Nicaragua 11 5 South America: Argentina, Brazil, Chile, Colombia, Ecuador, Peru 6 As of 17 May 07 as of 2 October 07

  9. HPV Vaccine: National Immunization Program 15 countries Eleven European countries (Germany, France, Italy, Belgium, Austria, Norway, Sweden, Greece, Denmark, Luxemburg and Switzerland), as well as the United States, Canada, Australia and UK have already reviewed the positive public health impact and recommended the quadrivalent HPV vaccine for universal human papillomavirus vaccination with accelerated reviews.

  10. GARDASIL • The only vaccine registered in Hong Kong in the moment • Indication: 9 – 26 year old females

  11. Dosage & Administration • 3 doses within 6 months • (0, 2, 6 months) • 0.5 mL volume IM injection • Package: • Prefilled syringe • Shake well before use • Injection Site: • Upper arm (Deltoid region) • Thigh (higher anterolateral area)

  12. Natural History of HPV Infection:Surrogate Markers for Cervical Cancer 0 to 5 Years Up to 20 Years CIN 3 CIN 2 Sq. Cell Carcinoma InitialHPV Infection PersistentInfection AIS Adeno- Carcinoma CIN 1 Cleared HPV Infection

  13. Basis for Licensure/Cancer Efficacy:Demonstrate Prevention of HPV 16/18-CIN 2/3 + AIS Natural History of HPV Infection:Surrogate Markers for Cervical Cancer 0 to 5 Years Up to 20 Years CIN 3 CIN 2 Sq. Cell Carcinoma InitialHPV Infection PersistentInfection AIS Adeno- Carcinoma CIN 1 Cleared HPV Infection

  14. Clinical Program Combined Efficacy Analysis Ph II–P005 (N=2392)1Proof of Principle 16- to 23-year-old women • ~33,000 subjects enrolled • Multinational Ph II–P007 (N=1158)2Dose-ranging 16- to 23-year-old women Yr 5 Immune MemoryEvaluation Ph III–FUTURE I CIN/EGL (N=5455)316- to 24-year-old women Ph III–FUTURE II CIN 2/3 (N=12,167)415- to 26-year-old women Duration of Efficacy Registry StudyNordic Region Norwegian HPV Surveillance and Disease Burden/Population Effectiveness Study Ph III–P016, P018 (N=4836) Safety/Immunogenicity 9- to 15-year-old boys and girls5,6 Efficacy in women up to 45 years old6 Efficacy in 16- to 26-year-old men6 Jan2003 Jan2004 Jan2005 Jan2006 Jan2007 Jan2008 Jan2009 Jan2010 EGL = external genital lesions. 1. Koutsky LA, Ault KA, Wheeler CM et al. N Engl J Med. 2002;347:1645–1651. 2. Villa LL, Costa RLR, Petta CA, et al. Lancet Oncol. 2005;6:271–278. 3. Garland SM, Hernandez-Avila M, Wheeler CM, et al. Submitted. 2006 4. FUTURE II study group. Submitted. 2006. 5. Block SL, Nolan T, Sattler C, et al. Submitted. 2006. 6. Data on file, MSD.

  15. HPV 6/11/16/18-Related High Grade Disease (Cervix, Vulva, Vagina, Genital Warts) Per-Protocol Efficacy Population - Protocols 007, 013, 015 (n=18780) PP = received 3 vaccinations within 1 year; no major protocol violations; HPV 16/18 sero(-) at day 1 and HPV 16/18 DNA(-) day 1 to month 7; cases counted starting after month 7. CIN = cervical intraepithelial neoplasia; AIS = adenocarcinoma in situ. Eliav Barr’s Presentation to ACIP (CDC) FEB 2007 Average follow up for 3 years

  16. HPV disease burden: More than Cancer Prevention Cervical cancer: 0.500 million in 2002 1 HPV 16, 18 and others High-grade precancerous lesions: 10 million 2 Very high global burden of HPV-related diseases Low-grade cervical lesions: 30 million 2 Genital warts: 30 million 3 Attributable to oncogenic HPV types HPV 6, 11 and others Attributable to non-oncogenic HPV types HPV infectionwithout detectable abnormalities: 300 million 2 1.Parkin et al. 2005 2.WHO 1999 3.WHO 1990

  17. HPV-6/11 related diseases

  18. HPV and Anogenital Warts • HPV 6 and 11 responsible for >90% of anogenital warts1 • Clinically apparent in ~1% of sexually active US adult population2 • Estimated lifetime risk of developing genital warts ~10%3,4 Images top left and top right: Reprinted with permission from NZ DermNet (www.dermnetnz.org) 1. Jansen KU, Shaw AR. Annu Rev Med.2004;55:319–331. 2. Koutsky L. Am J Med. 1997;102:3–8. 3. Franco EL, Villa LL, Richardson H, Rohan TE, Ferenczy A. In: Franco EL, Monsonego J, eds. Oxford, UK: Blackwell Science; 1997:14–22. 4. Tortolero-Luna G. Hematol Oncol Clin North Am. 1999;13:245–257, x.

  19. In Hong Kong, between 3 – 4 thousand patients with genital warts attended the Social Hygiene Clinic every year in the past decade, which account for about 9% of all attendances

  20. Incubation period – 3 weeks to 8 months, majority around 2-3 months • Reported spontaneous complete clearance rate was low ~ 5% • No report on the rate of spontaneous regression in long term • Recurrence is common after treatment, 25% occurs within 3 months

  21. Treatment • Antiproliferative agents – podophlyllin • Destructive therapies – trichloroacetic acid, electrosurgery, laser, excision • Immunomodulators - Imiquimod

  22. HPV-6/11 related cervical neoplasia • HPV-6 and –11 are associated with LSIL • A meta-analysis of 55 studies – HPV-6 and -11 were present in 8.1% and 3.2% of HPV-positive LSIL • Causal relationship still not clear

  23. Recurrent Respiratory Papillomatosis(RRP) • A rare condition • Can occur anywhere in the respiratory tract, most commonly in the larynx • Hoarseness of voice and respiratory obstruction are the commonest presentations • Commonly recurrent after treatment • HPV-6 and -11 are the causative agents for almost all the RRP

  24. Juvenile onset RRP • Before age of 4 • Source of virus - most probably from the genital tract during birth • Condyloma during pregnancy increases the risk for more than 200 folds • Risk still < 1%

  25. Adult onset RRP • Peak at 21 - 30 • Adult onset RRP – result from sexual or non-sexual contact with an infected lesion

  26. Treatment • Surgical • In case of multiple recurrence, surgical excision is still the mainstay of the treatment • Use of other therapies – remain controversial

  27. GARDSIL is highly effective in the prevention of HPV-6 and -11 related genital warts in women • Cost-effectiveness of including GARDSIL as part of the immunization programme for the prevention of genital warts among different countries, public acceptability and efficacy in men have to be evaluated • Role of GARDSAIL in RRP has to be evaluated

  28. Vaginal and Vulval Intraepithelial Neoplasia

  29. Vaginal Intraepithelial Neoplasia (VaIN) • Main predisposing factor for VaIN is likely exposure to HPV.1 • VaIN is often found in conjunction with cervical intraepithelial neoplasia (CIN). • Average age of women with VaIN: 35–50 years2 • On average, older than those presenting with CIN • True incidence unknown, but lower than for CIN1 • Incidence expected to rise due to wider use of cytological screening and colposcopy, as well as increased awareness of disease2 • VaIN is often asymptomatic and difficult to diagnose.2 • While untreated VaIN can spontaneously regress, there is a potential for VaIN to progress to invasive vaginal cancer.2 1. Winter-Roach B, Monaghan JM, de Lopes A. Colposcopy of the vagina. In: Bosze P, Luesley D, eds. EAGC Course Book on Colposcopy. Budapest: Primed-X Press; 2004:120–123. 2. Dodge JA, Eltabbakh GH, Mount SL, et al. Gynecol Oncol. Nov 2001;83:363–369.

  30. Photo courtesy of Dr. J. Monsonego Photos courtesy of Dr. E.J. Mayeaux Vulval Intraepithelial Neoplasia (VIN) • Incidence of VIN is increasing in the United States and worldwide.1 • In the United States, the incidence has nearly doubled between 1973 and 1987 (1.1 to 2.1 per 100,000 woman year)2 • Mean age of women with VIN is decreasing2–4 • The peak incidence has shifted from women ≥50 to women aged >35 to 50. • Symptoms occur and may be present for a long time prior to diagnosis (median of 1 year)4 • The most common symptoms include pruritus (56%), vulval pain and soreness (29%), and vulval swelling (16%). 1. Joura EA. Curr Opin Obstet Gynecol. 2002;14:39–43. 2. Sturgeon SR, Brinton LA, Devesa SS, Kurman RJ. Am J Obstet Gynecol. 1992;166:1482–1485. 3. Jones RW, Rowan DM, Stewart AW. Obstet Gynecol. 2005;106:1319–1326. 4. Herod JJ, Shafi MI, Rollason TP, et al. Br J Obstet Gynaecol. May 1996;103:446–452.

  31. Vulval Intraepithelial Neoplasia (VIN) • No biological continuum between histological grades of VIN has been shown:1 • Rarely has progression from VIN 1 to VIN 3 been documented. • The annual progression rate of untreated VIN 3 to invasive cancer is at least 10%. • Surgically treated VIN have a high rate of recurrence, and in untreated women >30 years there is an appreciable invasive potential.2 • HPV 16 appears to be the dominant HPV type associated with high-grade VIN (up to 81% in VIN 3)3 • Majority of VIN 1 cases are associated with HPV types 6 and 113 • HPV 6, 11, 16, or 18 can be found in VIN 2 or 34 1. Jones RW. Eur J Gynaecol Oncol. 2001;22:393–402. 2. Jones RW, Rowan DM, Stewart AW. Obstet Gynecol. 2005;106:1319–1326. 3. Buscema J, Naghashfar Z, Sawada E, et al. Obstet Gynecol. 1988;71:601–606. 4. Koutsky L. Am J Med. 1997;102:3–8.

  32. VaIN and VIN are of concern because they are considered as precancerous lesions with about 40 - 50% associated with HPV infection • In UK, vulval cancer is 6 times and vaginal cancer 20 times less common than cervical cancer1 • No screening programme exists 1. Gonzalez Inchaurraga MA et al. HPV and carcinogenesis. Acta Dermatovenerol. 2002;1:1-8. 2. Parkins DM et al. International Agency for Research on Cancer, 2002;8.

  33. HPV 6/11/16/18-Related High Grade Disease (Cervix, Vulva, Vagina, Genital Warts) Per-Protocol Efficacy Population - Protocols 007, 013, 015 (n=18780) PP = received 3 vaccinations within 1 year; no major protocol violations; HPV 16/18 sero(-) at day 1 and HPV 16/18 DNA(-) day 1 to month 7; cases counted starting after month 7. CIN = cervical intraepithelial neoplasia; AIS = adenocarcinoma in situ. Eliav Barr’s Presentation to ACIP (CDC) FEB 2007 Average follow up for 3 years

  34. Updates on HPV Vaccines

  35. Safety • Duration of protection • Cross protection • Age

  36. Safety

  37. Safety • VACCINE ADVERSE EVENT REPORTING SYSTEM (VAERS)http://vaers.hhs.gov/info.htm - A passive reporting system which records any hearsays and Adverse Events (AEs) from any sources - CDC Will investigate the casual relationship of AEs and vaccines • Deaths – 11 cases from VAERS (9 from the FUTURE studies) • Guillain-Barre Syndrome – 13 cases

  38. Deaths • 11 deaths in recipients of GARDSIL among approximately 18.3 million doses of distribution (another 9 cases in FUTURE I & II) • Causal relationship between the events and the vaccination has not beenestablished • From the studies, number of death cases were not different between vaccine groups and placebo groups

  39. Cases in FUTURE I & II • 4 cases of traffic accident • 1 case of suicide • 1 case of drug overdose • 1 case of pneumonia and sepsis • 1 case of pulmonary embolism • 1 case of infective thrombosis

  40. Other cases • Several of these reports are hearsay and did not have first hand information and may be duplicates (one case was confirmed as false report and the subject is still alive). These cases generally were associated with underlying life threatening or chronic cardiovascular diseases • 1 died before vaccination • 1 due to pulmonary embolism • 1 died of influenza B viral infection with secondary staphylococcal infection • 1 had severe heart problems, died of myocarditis 6 days after vaccination of 3 vaccines including Gardasil

  41. Guillain-Barre Syndrome • 13 reports of GBS are within the numbers of reports that could be expected to occur by chance alonewith or without a vaccination • 6 of 13 reports also involved simultaneous injection of Menactra (meningococcal vaccine). Current studies are underway to evaluate the small increased risk of GBS, which might be associated with Menactra • Only 2 reports met the case definition of GBS, occurred within six weeks after vaccination, and had received Gardasil alone

  42. Summary: Safety of Gardasil • CDC and FDA were satisfied withthe safety data in the context of more than18 millions doses of Gardasil distributed. • Large scale clinical trials have also shown well tolerated safety profile. • Therefore, CDC and FDA continue to support the universal vaccination program of Gardasil. There are no changes of recommendations.

  43. Duration of Protection

  44. Sustained clinical efficacy and antibody titer for at least 5 years GMT (mMU/mL) GARDASIL 100% 10 000 GARDASIL 1 000 Neutralising antibodies (HPV type 16) Clinical efficacy* 100 10 Natural infection 0 7 12 18 18 24 30 36 54 60 5 years months 1st 2nd 3rd Dose * against infection, CIN (Cervical intraepithelial neoplasia) and genital warts due to HPV types 6,11,18; 5 yrs follow up (after dose 1) of a subset (241 women, vaccine & placebo) from a phase II efficacy study Villa L High Sust Eff Proph Quad HPV Vacc 5 Year Followup Br J Can 2006 95 1459

  45. Poliovirus Vaccine (Inactivated) 19551 • Recommended to give series of four doses at two, four, and 18 months, and a booster dose at 4 to 6 years1 • 18-year follow-up shows that vaccine remains effective.2 • The need for subsequent boosters has not been established.1 Hepatitis B Vaccine 1981 and 19861 • 15-year follow-up shows that vaccine remains effective.3,4 • To date, routine booster is not recommended.1 Hepatitis A Vaccine 19951 • 12-year persistence of antibodies and anamnestic response5 • To date, based on mathematical models, it is estimated that the protection could last 20+ years.1,5 Vaccines’ Long-Term Protection: 3 ExamplesAt licensing,vaccines are typically used broadly, despite that full knowledge of their duration of protection is unknown. 1. Mast E, Mahoney F, Kane M, Margolis H. Hepatitis B vaccine. In: Vaccine, 4th Ed. Plotkin SA, Orenstein WA editors. Elsevier Inc. USA publisher; 2004. 2. Bottiger M. Vaccine. 1990;8:443–445. 3. McMahon BJ, Bruden DL, Petersen KM, et al. Ann Intern Med. 2005;142:333–341. 4. Ni Y-H, Chang M-H, Huang L-M, et al. Ann Intern Med. 2001;135:796–800. 5. Van Herck K, Van Damme P, Lievens M, et al. J Med Virol. 2004;72:194–196.

  46. Hepatitis B Immune Response Level Through 5 Years Post-Vaccination1 • Protection against hepatitis B virus (HBV) is based on the presence of specific antibodies against anti-HBs antigen.2 • Anti-HBs levels disappear in 10-50% of vaccinees after a few years.2 • No booster has been recommended to date.3 6 12 24 36 48 60 Months After First Vaccine Dose 1. Wainwright RB, McMahon BJ, Bulkow LR, et al. JAMA. 1989;261:2362–2366. 2. Bauer T and Jilg W. Vaccine. 2006;24:572-577. 3. Mast E, Mahoney F, Kane M, Margolis H. Hepatitis B vaccine. In: Vaccine, 4th Ed. Plotkin SA, Orenstein WA editors. Elsevier Inc. USA publisher; 2004.

  47. Anti-HBs After Immune Challenge1 • Immune memory persists beyond the time at which anti-HBs levels may no longer be detectable. • Immune memory leads to a rapid anamnestic response after exposure to HBV, which prevents acute infection (and disease). • To demonstrate this, a typical anamnestic response is observed to immune challenge. In vivo anti-HBs response 105 104 Anti-HBs [IU/I] 103 102 101 100 0 10 28 Days Immune Challenge 1. Bauer T, Jilg W. Vaccine. 2006;24:572–577.

  48. Immune Memory Study of Gardasil Vaccine 25 (2007) 4931–4939

  49. Principle • Vaccines that induce long-term protection are usually characterized by the generation of immune memory • Gardasil have demonstrated high efficacy through 5 years of follow-up • Evaluated whether Gardasil is able to generate HPV type-specific immune memory

  50. Ph II–P007 Dose-Ranging 16- to 23-year-old women Neutralizing Antibodies Suggest an Anamnestic Response (Immune Memory) to GARDASIL™1* Challenge by vaccine The hallmark of long term protection HPV 11 HPV 6 HPV 18 HPV 16 *In subjects naïve to the relevant HPV type from Day 1 through Month 60. Sven-Eric Olsson Induction of immune memory of quadrivalent vaccine Vaccine 25 (2007) 4931–4939

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