Latest update on cervical cancer & hpv vaccine 2013


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  • 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, t he 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 .
  • Message: Of all the HPV types that have been identified, only 4 account for approximately 80% of all cervical cancer cases. Transmission of HPV occurs by skin-to-skin contact HPVs infect the skin and mucous membranes, causing - Benign skin warts (papilloma) - Genital warts ( condyloma acuminata) - Precancerous cervical dyskaryoses - Cervical cancer – caused by “high risk” types of HPV Condoms reduce the risk of transmission, but do not prevent it Types HPV16 and HPV45 are closely related; Types HPV18 and 31 are closely related
  • Key Points The comparative table between Quadrivalent and bivalent HPV vaccine highlights the differences in the efficacy and the spectrum of HPV diseases which can be prevented due to each vaccine. T here is substantial efficacy against either HPV 16 or 18-related CIN2/3 or AIS in the Quadrivalent HPV vaccine recipients. 1, 2 There is substantial efficacy against HPV 16-related CIN2/3 or AIS in the Bivalent HPV vaccine recipients; the efficacy against HPV 18-related CIN2/3 or AIS is not significant (≈ 83%; 97.9% CI: -79 to 100). 3 There is substantial efficacy against HPV 6/11/16/18-related CIN 1-3 or AIS in the Quadrivalent HPV vaccine recipients . 1,2 There is substantial efficacy against either HPV 16 or 18-related VIN2/3 or VaIN 2/3 in the Quadrivalent HPV vaccine recipients. 1,2 There is substantial efficacy against HPV 6/11/16/18-related external genital lesions (genital warts, VIN, VaIN, vulvar and vaginal cancer) in the Quadrivalent HPV vaccine recipients. 1,2 There is substantial efficacy against HPV 6/11-related genital warts in the Quadrivalent HPV vaccine recipients. 1,2 References 1. Garland SM, Hernandez-Avila M, Wheeler CM, et al. Quadrivalent HPV 6/11/16/18 vaccine: prevention of cervical, vulvar and vaginal disease. New Engl J Med . 2007;356: 1928–1943. 2. The FUTURE II Study Group. Quadrivalent HPV vaccine: prevention of high grade cervical intraepithelial neoplasia. New Engl J Med . 2007;356:1915–1927. 2. Paavonen J, Jenkins D, Bosch FX et al. Lancet. 2007;369:2161  2170.
  • Key Point Nordic European countries have organized mass cervical cancer screening programs. Since data collected from screening programs can be used in research, enrolling patients from these regions in phase III studies provides an opportunity for evaluating the duration effectiveness of GARDASIL™ [Quadrivalent Human Papillomavirus (Types 6, 11, 16, 18) Recombinant Vaccine]. Background Merck is committed to working with the cancer registries in Sweden, Norway, Iceland, and Denmark to assess long-term outcomes following administration of GARDASIL. Approximately 5500 subjects enrolled in protocol 015 will be followed for a total of 14 years. 1 A major goal of this study is to assess the long-term effectiveness of GARDASIL against HPV 6/11/16/18-related cervical intraepithelial neoplasia (CIN) 2/3, adenocarcinoma in situ (AIS) and cervical cancer, vulvar intraepithelial neoplasia (VIN) 2/3 and vulvar cancer, and vaginal intraepithelial neoplasia (VaIN) 2/3 and vaginal cancer. 1 1. Approval Letter – Human Papillomavirus Quadrivalent (Types 6, 11, 16, 18) Vaccine, Recombinant. June 8, 2006. ApprovedProducts/ucm111283.htm. Accessed June 1, 2009. 1/FDA approval letter/p. 2/¶9; p. 3/¶1
  • 1/Data on file/ VRBPAC/p. 64/ Figure 11 Key Point Females from the Nordic region enrolled in phase III efficacy studies will be followed for at least 10 years through the Nordic registries. This will provide a forward view on the long-term safety and duration of efficacy of the vaccine several years ahead of follow-up of the first postlaunch vaccinees. Background Females from the Nordic region enrolled in protocol 015 (FUTURE II) will comprise a sentinel cohort to monitor the duration of efficacy of GARDASIL™ [Quadrivalent Human Papillomavirus (Types 6, 11, 16, 18) Recombinant Vaccine]. At completion of the study, the Nordic cohort will be followed through the cancer screening registries. All cases of cervical intraepithelial neoplasia (CIN) 2/3 and cancer will be detected, and biopsy specimens will undergo HPV analysis. 1 At any given time, this will be at least 3 years ahead of the first subject who will have received GARDASIL postlicensure with respect to efficacy follow-up. 1 1. Data on file, MSD___________. 1/Data on file/ VRBPAC/p. 63/¶3; p. 64/¶1
  • V501-015-21 Interim Report 1 p91A
  • Latest update on cervical cancer & hpv vaccine 2013

    1. 1. Latest Update on CERVICAL CANCER & HPV- Vaccine Dr. Sharda Jain Director :- Sec General : Delhi Gynae ForumLatest Update 2013
    2. 2. Cervical Cancer • Second most frequent cancer among women  worldwide • Most common cancer among women in developing countries • Most frequent cause of death from  cancer in women from developing countries 2nd 15.3 7.8 GLOBOCAN 2008
    3. 3. • 500,000 women diagnosed per year1 • 270,000 deaths per year1 – >1 million new cases of cervical cancer each year, • 1 out of 4 women who die due to Cervical Cancer in the world is an Indian3 1. Ferlay J, et al. GLOBOCAN 2002 Cancer Incidence, Mortality and Prevalence Worldwide. IARC CancerBase; Lyon, 2004; 2. Parkin DM, et al. Eur J Cancer 2001; 37(Suppl 8):S4-S66. 3. GLOBOCAN 2008
    4. 4. • Every year 134000 Indian women are diagnosed with Cervical cancer and around 72000 die from the disease • Cervical cancer ranks No. 1 among cancers in Indian women, that’s even more than Breast Cancer GLOBOCAN 2008 Cancer Incidence, Mortality andPrevalence India
    5. 5. Age-standardised incidence and mortality rates: Indian women GLOBOCAN 2008
    6. 6. > 200 women die every day Every 7 minutes a women dies 8 women die every hour Cervical Cancer : India This ‘Cause’ need to be taken up by multiple stake holders. Cervical Cancer in India
    7. 7. Economic burden • With 1,32,000 cases and 75- 80% in advanced stage, bimodality treatment, the cost will be huge • With only forty percent surviving, tremendous cost involved • Human loss, human manpower, hospital resources added to the cost. • According to the National Commission on Macroeconomics of Health report (2005), the per unit cost of providing secondary care for cervical cancer at the level of district hospitals is 10,016.04 INR, higher than that of all other chronic conditions with the exception of cardiovascular diseases. • Due to the high number of cervical cancer cases in the population, it has the highest total cost of secondary care (100,000 INR per 100,000 population) relative to all other cancers. “Report of the National Commission on Macroeconomics and Health”, NCMH, Ministry of H &FW, Government of India, August 2005.
    8. 8. The Nobel Prize in Physiology or Medicine 2008 Herold Zur Hausen HPV is the necessary or the key cause of cervical cancer Cervical cancer does not and will not develop in the absence of the persistent presence of HPV DNA.
    9. 9. Converted this extra-ordinary discovery into UTILIZABLE INVENTION BY Producing HPV Vaccine Awarded “Australian of the year” award in 2006 Ian Frazer – An Australian Scientist
    10. 10. HPV causes more than cervical cancer 80+% ~40% ~100% 60-90% ~100% Percentages represent cases atrributable to HPV infection Cervical Cancer1,3 Vulvar Cancer1 Vaginal Cancer1 Anal Cancer1-3 Genital Warts1,3 12-70% Head & Neck Cancer3 45% Penile Cancer3 Braaten KP et al. Rev Obstet Gynecol. 2008;1:2–10. Hoots BE et al. Int J Cancer. 2009;124:2375–2383. IARC. IARC monographs on the evaluation of carcinogenic risks to humans. Human papillomaviruses. Vol 90. Lyon, France: IARC, 2007.
    11. 11. Attributable to HPV Site Total cancers % Cases Cervix 492,800 100 492,800 Vulva, vagina 40,000 40* 16,000 Anus 15,900 90* 14,300 Oropharyn x 9,600 12* 1,100 Mouth 98,400 3* 2,900 Total 527,100
    12. 12. In India 4 HPV Types: HPV 16, 18, 31 and 45 are responsible for >90%>90% Squamous Cell Carcinoma2 >95%>95% Adenocarcinoma2 100 HPV Types Have Been Identified1 30 HPV Types are Transmitted by Genital skin to skin Contact 15 HPV Types are Oncogenic 1.Munoz N et al. N Engl J Med 2003; 348(6):518-527 2. WHO/ICO Information Centre on HPV and Cervical Cancer (HPV Information Centre). Human Papillomavirus and Related Cancers in India. Summary Report 2010.
    13. 13. • HPV infections are very common and up to 80% of women will acquire an HPV infection in their lifetime5–7 • The risk of oncogenic HPV infection is high even after first intercourse and continues throughout a woman’s sexually active lifetime2–4 • Although new infections decrease with age, risk of their persistence increases with age8 • The cumulative risk of acquiring cervical HPV infection in women with only one sexual partner is 46% (3 years after first sexual encounter)1 1. Collins S, et al. Br J Obstet Gynaecol 2002; 109:96–98; 2. Schiffman M, et al. J Natl Cancer Inst 2003; 31:14–19; 3. Sellors JW, et al. CMAJ 2003; 168:421–425; 4. Dunne EF, et al. JAMA 2007; 297:813–819; 5. Brown DR, et al. J Infect Dis 2005; 191:182–192; 6. Koutsky L, et al. Am J Med 1997; 102:3–8; 7. Bosch FX, et al. J Natl Cancer Inst Monogr 2003; 31:3–13; 8. Castle PE, et al. J Infect Dis 2005; 19:1808–1816. 8. Castle PE, et al. J Infect Dis 2005;191:808–816;
    14. 14. The NEED for vaccination against Cervical cancer
    15. 15. 1.Stanley M. Vaccine 2006; 24: S106-13, 2.Tindle, Nat Rev Cancer 2002; 2, 59, 3.Stanley M. Vaccine 2006; 24: S16-22, 4. Stanley M. HPV Today 2007; 11: 1-16 No viremia Local immunosuppression No inflammation, no danger signals Natural HPV infection induces a weak immune response1-4
    16. 16. 1. Parr EL et al. J Virol 1997;71(11):8109-15, 2. Nardelli-Haefliger D et al. J Natl Cancer Inst 2003;95(15):1128-37, 3. Schiller JT et al. Nat Rev Microbiol 2004;2(4):343-7, 4. Poncelet et al. ESPID, Porto, Portugal 2007; Abstract 37, session ES2, 5. Stanley M. HPV Today 2007; 11: 1-16, 6. Einstein M, Cancer Immunol Immunother 2007; 57(4):443- 51. Vaccination induces higher antibodies in the blood and site of infection • Vaccine induces higher antibody levels in the blood which means higher antibody levels at the site of infection4 • These Antibodies neutralize the virus & prevent entry into cells5,6
    17. 17. 1. Induce high antibody levels at the basal epithelium of the cervix 2. Induce long lasting protection
    18. 18. Basic Characteristics of CERVARIX and GARDASIL
    19. 19. Quadrivalent vs Bivalent Vaccine Parameters Quadrivalent HPV Vaccine Bivalent HPV Vacine Time of follow-up 36 months (advanced) 15 months (interim) HPV types included 6, 11, 16, 18 16, 18 Efficacy HPV 16 or 18 CIN 2+ Proven Proven Efficacy HPV 16 CIN 2+ Proven Proven Efficacy HPV 18 CIN 2+ Proven Not yet provena Efficacy 16 or 18 CIN 2 Proven Proven Efficacy 16 or 18 CIN 3 Proven Not yet provena Therapeutic efficacy None None Efficacy on VIN 2/3 Proven Not yet reported Efficacy on VAIN 2/3 Proven Not yet reported Efficacy on genital warts Proven Not in target Safety at 6 years follow-up Safeb Safec Tolerability Acceptable Acceptable Cross protection (persistent HPV infection) 6 months 12 months Cross protection (lesions) Reported Not yet reported Duration of protectiond 5 – 6 years 5 – 6 years Immunogenicityn preadolescents Proven Proven Immunogenicity in older women Proven Proven Immune memory at 6 years Proven Not yet reported
    20. 20. Worldwide Guidelines
    21. 21. Organizations That Have Issued Guidelines for Quadrivalent HPV Vaccine • Advisory Committee on Immunization Practices (ACIP) • American College of Obstetricians & Gynecologists (ACOG) • American Cancer Society (ACS) • American Academy of Pediatrics (AAP) • American Academy of Family Physicians (AAFP) • American College Health Association (ACHA). • World Health Organization (WHO) - Consultation on HPV vaccines • Canada (National Advisory Committee on Immunization) • Australia and New Zealand HPV Project • High Council of Public Health - France • The International Union Against Cancer (IUCC) • Canadian Pediatric Society
    22. 22. ACIP & AAP - 2011 Consider giving HPV4 to MALES age 9 through 26yrs to reduce their likelihood of acquiring genital warts.
    23. 23. IAP & FOGSI • HPV vaccine should be given to females from 9-45 years of age for prevention of cervical cancer.
    24. 24. GARDASIL® indication as per DCGI GARDASIL® is indicated in females aged 9 through 45 years "for prevention of cervical, vulvar, and vaginal cancer, precancerous or dysplastic lesions, genital warts, and infections caused by Human Papillomavirus (HPV) Types 6, 11, 16 and 18 (which are included in the vaccine).“
    25. 25. Clinical Trials Overview
    26. 26. GARDASIL Conclusions (FUTURE Trials) • GARDASIL yields the greatest benefit in adolescent girls prior to exposure to HPV • However, women of all ages remain at risk for HPV- related infection and disease • Data demonstrate that women aged 24-45 benefit from vaccination with GARDASIL – GARDASIL showed a high level of efficacy against disease caused by HPV Types 6/11/16/18 in this age group – GARDASIL significantly reduced abnormal Pap tests caused by vaccine HPV types – Vaccination with GARDASIL may significantly impact the burden of cervical cancer and HPV-related diseases among women aged 24-45
    27. 27. A registry based long term follow up (LTFU) study of the Quadrivalent HPV vaccine in 4 Nordic Countries
    28. 28. Future I (2002-06) - Age group – 16 to 24 years (end point cervical, vulvar, vaginal, anal disease & warts) (n=5,455) Efficacy 100% Future II (2004-08) - Age group – 15 to 26 years (n=12,167) Extended as Nordic Study (end point cervical disease) Efficacy 100% Extended in Nordic region for 10 years Future III (2004-08) - Age group – 24 to 45 years - Adult Woman Efficacy Study (end point cervical, vulvar, vaginal diseases & warts) (n=3,819) Efficacy 91% Vaccine – Quadrivalent FUTURE Trials. On the basis of causality established by monovalent vaccine, Phase 3 trials with Quadrivalent vaccine started named as FUTURE Studies FUTURE = Females United To Unilaterally Reduce Ecto/endo cervical diseases Adolescent Study (’04-06) (N=4800) 9-15 yrs both sexes – 3 year extension Male Efficacy Studies
    29. 29. GARDASIL® : Nordic Cancer Registry Extension Evaluation of Long-Term Efficacy of Vaccination • Nordic European countries have organized mass screening programs. – Compulsory reporting of Paps, biopsies, CIN/cancer • By enrolling phase III studies in the region, we can evaluate: – Duration of effectiveness – Data for use in assessing interaction of vaccination with cervical screening programs – Long-term safety Denmark Norway Iceland Sweden
    30. 30. 2003 2004 2005 2006 2007 2008 20132010 2011 20122009 FUTURE II Study Registry-Based Follow-Up VaccinationVaccination Efficacy Reports 5 yr 7 yr 9 yr 4 yr 6 yr2 yr 2002 Launch in USLaunch in US 3.5 yr Evaluation of Long-Term Disease Protection: Follow-Up Through Registry Program
    31. 31. Conclusions – Nordic Study • Extensive monitoring of Gardasil is ongoing in Nordic countries as an extension of FUTURE 2 study. • No breakthrough cases of HPV 16/18 related CIN 2 or worse. • GARDASIL shows a trend of continued protection in women who were vaccinated up to 7 years previously. • GARDASIL continues to be generally safe and well tolerated up to 6 years following vaccination.
    32. 32. • Cervical cancer causes significant morbidity/ mortality • HPV vaccine to be offered to all appropriate females who can afford the vaccine • Vaccine should be given prior to sexual debut vaccine
    33. 33. • Age for initiation of vaccination is 10- 12 years. – Catch up vaccination is permitted up to the age of 45 years for both vaccine • 3 doses at 0, 2 and 6 months with quadrivalent vaccine • 3 doses 0, 1 and 6 months with bivalent vaccine vaccine
    34. 34. •At present there is no data to support use of boosters
    35. 35. • Sexually active women and women with previous abnormal cervical cytology can receive the HPV vaccine • Benefits may be limited to the protection against infection of HPV genotypes with which they have not been infected
    36. 36. • The vaccine can be given to patients with previous CIN, but the benefits may be limited to the protection against infection of HPV genotypes (and related CIN) with which they have not been infected • The HPV vaccine is not therapeutic. It does not treat existing HPV infection or cervical intraepithelial neoplasia (cervical pre-cancers) FOGSI Recommendations: Women With Previous CIN
    37. 37. –Not recommended for use in pregnancy –If patient becomes pregnant - Delay remaining doses till delivery –If vaccinated during pregnancy - No intervention (MTP) needed –Lactating women can receive the HPV vaccine (Gardasil) and still continue breastfeeding as it is a vaccine without live viral DNA FOGSI Recommendations: Pregnancy & Lactation
    38. 38. • Vaccinated women should be screened as per the standard guideline • Screen positive women may be vaccinated after counseling • Screening/ HPV test is NOT REQUIRED prior to vaccination FOGSI Recommendations: Vaccination & SCREENING
    39. 39. The WHO’s (World Health Organisation) Global advisory committee on vaccine safety (GACVS), the Vaccine adverse event reporting system (VAERS), the Food & drug administration (FDA) and the Centers for disease control & prevention (CDC) have all confirmed and declared that the HPV vaccination is safe & effective providing protection against HPV 16, 18, 6 & 11 associated cervical, vulvar & vaginal cancer, genital warts and other HPV-related genital diseases in females. Vaccination against HPV is safe & effective
    40. 40. • VACCINATION: One of greatest public health achievements in the world • With the exception of clean drinking water, vaccines are the most effective intervention in reducing and preventing the return of infectious disease1 • 26 diseases are now vaccine preventable2 Let’s add Cervical Cancer to this list! Value of Vaccination Today
    41. 41. Summary  HPV is a necessary cause of cervical cancer – 99.7%  Induction of neutralizing antibodies by vaccination is critical for protection  HPV 16 & 18 cause ~75%* of cervical cancer cases while HPV 6 & 11 cause ~90% genital warts  27% of the world burden of Cervical Cancer is seen in India.  Every 7 minutes a woman dies in India due to cervical cancer  Cervical Cancer is usually diagnosed in late stages in India.  Cervical cancer screening is recommended in women >30yrs  Vaccination between 9-45yrs can be an effective strategy to help reduce this huge disease burden.
    42. 42. Let’s Recap HPV Vaccination
    43. 43. Is cervical cancer common?
    44. 44. What is the best age to vaccinate?
    45. 45. Is there any benefit in vaccinating sexually active women?
    46. 46. Why do we need to vaccinate women in monogamous relationships?
    47. 47. Do we need to screen before vaccination?
    48. 48. Do we need to screen after vaccination?
    49. 49. Looking at the high cost of vaccination is it not better to screen?
    50. 50. What is expected of a good cervical cancer vaccine?
    51. 51. What are the key differences between the two vaccines?
    52. 52. Head- to-Head comparison between the two vaccines?
    53. 53. Efficacy & Duration of Protection?
    54. 54. Which are the global bodies that have recommended vaccination?
    55. 55. What about safety and adverse effects?
    56. 56. How should it be administered?
    57. 57. Thank You