India’s population is approximately 1/6 th of the world burden but the disease burden in India is more than 25%( 1/4 th )
Key Point Incidence of cervical cancer cases in India is highest as compared to other cancers in women 15-44 yrs of age Reference 1) WHO/ICO Information Centre on HPV and Cervical Cancer (HPV Information Centre). Summary report on HPV and cervical cancer statistics in India. 2007. [Accessed on 18th March 2008. Available at www. who. int/ hpvcentre c WHO/ICO Information Centre on HPV and Cervical Cancer
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
2/WHO/p 34/¶7. 1/Janeway/ p. 40/ ¶ 2
Key Point Antibody response to GARDASIL is durable, as evidenced by data through 5 years postdose 1. Background Subjects from the GARDASIL and placebo arms of the original dose-ranging study were eligible to participate in an extension of the trial, which included scheduled visits for the collection of efficacy samples at months 54 and 60. In addition, subjects in the extension received an immune challenge at month 60 and provided serum samples for summarizing immunogenicity at month 60, and 1 week following month 60. 1 The purpose of the extension was to provide efficacy and immunogenicity follow-up through 5 years postdose 1 and to assess the impact of an immune challenge given 5 years following the first dose. Two hundred forty one subjects entered the extension phase, 222 of whom received an injection of GARDASIL at month 60. For subjects who received a primary series of GARDASIL in the base study, the month-60 vaccination was an immune challenge dose (102 subjects); for subjects who received placebo in the base study, the month-60 vaccination was their first dose of GARDASIL (119 subjects), to be followed by second and third doses at months 62 and 66, respectively. 1 GMTs and the corresponding 95% CIs for all time points through month 61 were calculated for subjects in the extension phase of protocol 007. In order to be eligible to be included in these summaries, subjects must have (1) received all 3 injections of their respective primary series of vaccine/placebo and a vaccination with GARDASIL at month 60, (2) had serology data within acceptable day ranges of 4 weeks following month 60, and (3) received no other HPV vaccine. 1 As shown in this slide, there is evidence of an anamnestic response to immune challenge. Represented here are immunogenicity results in subjects who were seronegative to the relevant HPV type at day 1 and PCR-negative to the relevant HPV type through month 60. 1 Anti-HPV responses were similar for HPV types 6, 11, and 18 through 5 years of follow-up in 16- to 23-year-old females in the same subset analysis. 1 GARDASIL is a registered trademark of Merck & Co., Inc., Whitehouse Station, NJ, USA. Reference 1. Data on file, MSD.
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. http://www.fda.gov/BiologicsBloodVaccines/Vaccines/ ApprovedProducts/ucm111283.htm. Accessed June 1, 2009. 1/FDA approval letter/p. 2/¶9; p. 3/¶1
V501-015-21 Interim Report 1 p91A
Key Point Vaccination with a 4-type vaccine (HPV 6, 11, 16, and 18) could dramatically reduce CIN 2/3 and cervical cancer, as well as other HPV-associated diseases (CIN 1 and genital warts). Background The estimated annual incidence of low- and high-grade dysplasia in the United States is 1.4 million and 330,000 cases, respectively. 1 An estimated 1 million new cases of genital warts occurs every year in the United States. 2 The American Cancer Society (ACS) estimates that in 2007, 11,150 women in the United States will develop cervical cancer. 3 HPV Types 16 and 18 cause about 70% of cervical cancer cases and high-grade dysplasia, 4 and approximately 25% of all low-grade cervical dysplasias. 5 It has been shown that HPV 6 and 11 also cause 90% of anogenital warts, 6 and about 10% of CIN 1. 5 The addition of Types 6 and 11 in HPV vaccine may provide a significant additional reduction in the burden of HPV-related diseases. References: 1. Schiffman M, Solomon D. Findings to date from the ASCUS-LSIL Triage Study (ALTS). Arch Pathol Lab Med . 2003;127:946 – 949. 2. Fleischer AB, Parrish CA, Glenn R, Feldman SR. Condylomata acuminata (genital warts): Patient demographics and treating physicians. Sex Transm Dis. 2001;28:643–647. 3. American Cancer Society. Cancer Facts and Figures 2007 . Atlanta, Ga: American Cancer Society; 2007:4. 4. Mu ñ oz 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. 5. Clifford GM, Rana RK, Franceschi S, Smith JS, Gough G, Pimente JM. Human papillomavirus genotype distribution in low-grade cervical lesions: Comparison by geographic region and with cervical cancer. Cancer Epidemiol Biomarkers Prev. 2005;14:1157–1164. 6. Gissmann L, Wolnik L, Ikenberg H, Koldovsky U, Schnűrch 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. 3/ACS/p. 4/ Table 1/Schiffman/ p. 946/ col 2/¶ 2 2/Fleischer/p. 643/col 2/¶ 2 5/Clifford/p.1159/ Table 2/calculation 4/Munoz/p.522/ col 2/¶ 2 6/Gissmann/ p. 561/Table 2 1/ACS/p. 4/ Table 2/Schiffman/ p. 946/col 2/¶ 2 3/Fleischer/p. 643/col 2/¶ 2 5/Clifford/p.1159/ col 1/¶ 3; col 2/¶3 4/Munoz/p.522/ col 2/¶ 2 5/Clifford/p.1159/ col 1/¶ 3; col 2/¶3 Table 2/calculation 6/Gissmann/ p. 561/Table 2
We want to make it available everywhere Approval vs. Launch * Note: Due to importation, distribution and other regulatory requirements as well as price negotiations, a licensed vaccine may not be marketed in a given country. Registration pending in 26 additional GAVI-eligible countries + WHO pre-qualification submitted Potential Q: which GAVI countries have access to GARDASIL? Indonesia, Kenya and Nicaragua
Gardasil - Do we need Cervical Cancer Vaccine in India?
Latest Update onHPV Disease & its prevention Dr Gaurav Gupta, (Ex PGI, GMCH) Practising Pediatrician, Charak Clinics, Mohali Member AAP, IAP.
Conflict of Interest• Received grants from various vaccine manufacturers including – Sanofi Pasteur – GSK * – Abbott – Wyeth – MSD * etc.
Scope• Global & Indian Disease burden• Need for HPV vaccine• Right age to give the HPV vaccine• Immune memory and HPV vaccine• Overview of clinical trials• Worldwide & Indian guidelines for HPV vaccine use
Cervical Cancer in India > 200 women die every day Cervical Cancer : 8 women die every hour India Every 7 minutes a women dies This ‘Cause’ need to be taken up by multiple stake holders.
CERVICAL CANCER• Estimated new cases and deaths from cervical (uterine cervix) cancer in the United States in 2009: – New Cases: 11,270 – Deaths: 4,070• India – New Cases: 1,32,000 – Deaths: 74,000
Cervical Cancer – Disease Burden Incidence Mortality India ~1,32,000 India ~ 74,000 World ~ 4,93,000 World ~ 2,73,000 India ~27% India - 27% India ~27% Rest of World - 73% Rest of World - 73% Rest of World - 73% India ~27% of new India ~27% of deathsCervical Cancer cases in world due to Cervical Cancer in world Bhatla N et al; Vaccine 2008; 26 2811-17 6
Incidence ( Women of all ages) – Cervical Cancer vs other Cancers2. X. Castellsagué, S. de Sanjose, T. Aguado, K. S. Louie, L. Bruni, J.Muñoz, M. Diaz, K. Irwin, M. Gacic, O. Beauvais, G. Albero, E. Ferrer, S. Byrne, F. X. Bosch. HPV andCervical Cancer in the World. 2009 Report. WHO/ICO Information Centre on HPV and Cervical Cancer (HPV Information Centre). Available at: www.who.int/hpvcentre 7
Years of Life Lost to Cervical Cancer* Cervical Breast (Female) Ovarian 18 19 26 0 5 10 15 20 25 3026 Average years of life lost in women with Cervical Cancer *In women in the United States (2003) 8 1. Ries LAG, Harkins D, Krapcho M, et al. (eds). SEER Cancer Statistics Review, 1975–2003, National Cancer Institute. Bethesda, MD; 2006.
HPV causes more than cervical cancer Cervical ~100% Cancer1,3 Penile 45% Cancer3 Vulvar ~40% Cancer1 Head & 12-70% Neck 60-90% Vaginal Cancer3 Cancer1 ~100% Genital Anal Warts1,3 Cancer1-3 80+% Percentages represent cases atrributable to HPV infectionBraaten 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.
Genital Warts – Disease Burden: India* Increasing trend of Genital warts in India 20 18% 18 16 14Percentage 12 11% 10.5% 10 8 6% 6 4 2 0 1990-93 1994-97 1998-01 2002-04 Study Period *Ray K et al, Indian J Med Res 2006; 124: 559-568 10
100 HPV Types Have Been Identified1 30 HPV Types are Transmitted by Genital skin to skin Contact 15 HPV Types are OncogenicIn India 4 HPV Types: HPV 16, 18, 31 and 45 are responsible for >90% Squamous Cell Carcinoma2 >95% Adenocarcinoma2 unoz N et al. N Engl J Med 2003; 348(6):518-527
• 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;
New opinions often appear first asjokes and fancies, then as blasphemies andtreason, then as questions open to discussion,and finally as established truths »George Bernard Shaw
PREVENTION OF HPV • Primary Prevention: Vaccination • Secondary Prevention: Screening Program including Harald zur Hausen regular PAP smear tests Born March 11, 1936 (age 74) Germany Nationality German Known for Discovery that HPV can cause cervical cancer Notable awards 2008 Nobel Prize in Physiology or M
The NEED forvaccination against Cervical cancer
Natural HPV infection induces a weak immune response1-4 No inflammation, no danger signals Local immunosuppression No viremia 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
Vaccination induces higherantibodies 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 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.
[Quadrivalent Human Papillomavirus (Types 6, 11, 16, 18) Recombinant Vaccine] Immune Memory: A Hallmark of Long Term Vaccine Protection • Definition1 – The ability to mount a specific and more rapid immune response upon a subsequent encounter with the antigen • World Health Organization (WHO) guidance on measurement2 – Induction of immune memory should be assessed by means of evaluating immune responses to additional doses of vaccine administered at planned intervals following completion of the primary series• Janeway C et al. New York, NY: Garland Science Publishing; 2005.• World Health Organization Expert Committee on Biological Standardization. Guidelines to Assure the Quality, Safety, and Efficacy of Recombinant Human Papillomavirus Virus-Like Particle Vaccines. Geneva, Switzerland: World Health Organization; 2006. 25
[Quadrivalent Human Papillomavirus (Types 6, 11, 16, 18) Recombinant Vaccine] Immune Memory at Month 60 HPV 16 responses* in 16- 23 yr females after 5 years of follow-up Immune memory 10,000(GMT levels with 95% CI Anti-HPV Response 1,000 [log10 scale]) 100 GARDASIL® n = 78 10 Placebo (Sero (-) and PCR (-)) n = 70 ↴ 0 2 3 6 7 12 18 24 30 36 54 60 61 Months 60+1 week Vaccination on Day 0, at 2 and 6 months Immune Immune challenge at 60 months challenge • Similar results seen with HPV 18, 6, and 11 *In subjects naïve to the relevant HPV type from day 1 through month 60 1. Olsson S-E et al. Vaccine. 2007;25:4931–4939. 26
Vaccine – Quadrivalent FUTURE Trials.On the basis of causality established by monovalent vaccine, Phase 3 trials with Quadrivalentvaccine started named as FUTURE StudiesFUTURE = Females United To Unilaterally Reduce Ecto/endo cervical diseases 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%Adolescent Study (’04-06) (N=4800) 9-15 yrs both sexes – 3 year extensionMale Efficacy Studies
GARDASIL Conclusions (FUTURE Trials)• GARDASIL yields the greatest benefit in adolescent girls prior to exposure to HPV• 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
GARDASIL® : Nordic Cancer Registry ExtensionEvaluation of Long-Term Efficacy of Vaccination • Nordic European countries have organized mass screening programs. – Compulsory reporting of Paps, biopsies, Denmark CIN/cancer • By enrolling phase III studies in the region, we can evaluate: Norway – Duration of effectiveness – Data for use in assessing interaction of vaccination with cervical screening Iceland programs – Long-term safety Sweden
Conclusions – Nordic Study• No breakthrough cases of HPV 16/18 related CIN 2 or worse.• GARDASIL shows a trend of continued protection up to 7 years at least.• GARDASIL continues to be safe and well tolerated up to 6 years & more.
Impact of vaccination with Gardasil Genital warts CIN 1 CIN 2/3 Cervical Cancer 75,000,000 HPV 16, 18 -70% 65,000,000 HPV 6, 11 -50%Number of Cases 55,000,000 45,000,000 -25% 35,000,000 25,000,000 -10% 15,000,000 -90% 5,000,000 0 Cases Without After Vaccination After Vaccination Vaccination With HPV 16/18 With HPV 6/11/16/18 32
Twenty years from now you willbe more disappointed by thethings that you didnt do than bythe ones you did do. Explore.Dream. Discover. Mark Twain
[Quadrivalent Human Papillomavirus (Types 6, 11, 16, 18) Recombinant Vaccine] Gardasil / Silgard ApprovalsCaribbean & Central America: Europe: North America: Germany Cyprus IrelandCosta Rica Trinidad France Czech Republic LatviaPuerto Rico El Salvador UK Denmark Lithuania USAGuatemala Honduras Spain Estonia Luxembourg CanadaCuraçao Nicaragua Italy Finland Malta MexicoBermuda Panama Austria Greece NetherlandsBahamas Cayman Islands Belgium Hungary NorwayBarbados Aruba Bulgaria Iceland PolandJamaica Dominican Republic Portugal Romania Slovakia Asia Pacific: Slovenia Sweden Serbia 38 Montenegro Switzerland Liechtenstein Bosnia Russia Belarus AustraliaSouth America: 3 Croatia Turkey IndonesiaBrazil Bolivia KoreaArgentina Uruguay TaiwanPeru Ecuador 16 13 Hong KongColombia Chile 30 Singapore New Zealand 8 MacauMiddle East & Africa: Malaysia PhilippinesGabon Congo Kinshasa ThailandIsrael C.A.R. IndiaMorocco Mauritius VietnamKenya KuwaitMauritania UAEGuinea Eq. EthiopiaUganda TogoMalawi Congo BrazzavilleJordan Egypt GARDASIL approved in 108 countries (includes 22 GAVI-eligible)Cote d’Ivoire Burkina FasoChad BahrainSaudi Arabia BotswanaSouth Africa CameroonPakistan 35
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
ACIP & AAP - 2011Consider giving HPV4 to MALESage 9 through 26yrs to reduce theirlikelihood of acquiring genitalwarts.
GARDASIL® indication as per DCGIGARDASIL® is indicated in females aged9 through 45 years "for prevention ofcervical, vulvar, and vaginal cancer,precancerous or dysplastic lesions,genital warts, and infections causedby Human Papillomavirus (HPV) Types6, 11, 16 and 18 (which are included inthe vaccine).“
• HPV vaccine to be offered to all appropriate females who can afford the vaccine• Vaccine should be given preferably prior to sexual debut www.fogsi.org/hpv vaccine
FOGSI & IAP Recommendations– Vaccine Schedule• Age for initiation of vaccination is 10- 12 years. – Catch up vaccination is permitted up to the age of 45 years• 3 doses at 0, 2 and 6 months with quadrivalent vaccine• 3 doses 0, 1 and 6 months with bivalent vaccine• No need for Booster doses www.fogsi.org/hpv vaccine
FOGSI Recommendations: Women With Previous CIN & sexually active women• The vaccine can be given, 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: Pregnancy & Lactation– 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: Vaccination & SCREENING• Screening/ HPV test is NOT REQUIRED prior to vaccination• Vaccinated women should be screened after vaccination as per the standard guideline• Screen positive women may be vaccinated after counseling
Vaccination against HPV is safe & effective• The WHO’s (World Health Organisation)• Global advisory committee on vaccine safety (GACVS),• Food & drug administration (FDA) and• 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.
HPV Vaccine - Adverse Reactions • Local reactions commonest (pain, swelling) – 80-90 % • Fever -10-20 % • Syncope – Give vaccine in sitting / lying down position, and observe for 15 minutes after vaccination • No serious adverse reactions reported. No deaths associated worldwide
Alternate Dosing• Efficacy has been demonstrated in individuals who have received all 3 doses within a 1-year period.• If an alternate vaccination schedule is necessary: – The 2nd dose should be administered at least 1 month after the 1st dose – The 3rd dose should be administered at least 3 months after the 2nd dose. (0, 1 & 4 months – accelerated schedule) 46
Summary HPV is a necessary cause of cervical cancer – 99.7% Induction of neutralizing antibodies by vaccination is critical for early protection, memory T cell response for long term 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.
Value of Vaccination Today• 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 disease• 26 diseases are now vaccine preventable Let’s add Cervical Cancer to this list!