Presented in June 2012 at Adolescent Health Symposia at GMCH Sector 32, Chandigarh

1. Latest Update
on
HPV Disease & its prevention
Dr Gaurav Gupta, (Ex PGI, GMCH)
Practising Pediatrician,
Charak Clinics, Mohali
Member AAP, IAP.

2. Conflict of Interest
• Received grants from various vaccine
manufacturers including
– Sanofi Pasteur
– GSK *
– Abbott
– Wyeth
– MSD * etc.

3. 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

4. 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.

5. 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

6. 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 deaths
Cervical Cancer cases in world due to Cervical Cancer in world
Bhatla N et al; Vaccine 2008; 26 2811-17
6

7. Incidence ( Women of all ages) – Cervical Cancer vs
other Cancers
2. 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 and
Cervical 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

8. Years of Life Lost to Cervical Cancer*
Cervical Breast (Female) Ovarian
18
19
26
0 5 10 15 20 25 30
26 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.

9. 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 infection
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.

10. Genital Warts – Disease Burden: India*
Increasing trend of Genital warts in India
20
18%
18
16
14
Percentage
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

11. 100 HPV Types Have Been Identified1
30 HPV Types are Transmitted by Genital skin to skin Contact
15 HPV Types are Oncogenic
In 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

12. • 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;

13. New opinions often appear first as
jokes and fancies, then as blasphemies and
treason, then as questions open to discussion,
and finally as established truths
»George Bernard Shaw

14. 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

15. The NEED for
vaccination against
Cervical cancer

16. 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

17. 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
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.

18. Basic Characteristics of
CERVARIX and GARDASIL
Bivalent vaccine – HPV 2
– HPV 16, 18 L1 virus-like particles (VLPs)
– Adjuvant (ASO4)
– Insect cells infected with baculovirus
– 0, 1 & 6 months
Quadrivalent Vaccine – HPV 4
-- HPV 6, 11, 16, 18 L1
virus-like particles (VLPs)
-- Proprietary aluminum adjuvant
(AAHS)
-- Yeast with recombinant plasmid
-- 0, 2 & 6 months
18

24. [Quadrivalent Human Papillomavirus (Types 6, 11, 16, 18) Recombinant Vaccine]
Immune memory & HPV
vaccine

25. [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

26. [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

27. Clinical Trials
Overview

28. 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
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 extension
Male Efficacy Studies

29. 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

30. 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, 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

31. 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.

32. 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

33. Twenty years from now you will
be more disappointed by the
things that you didn't do than by
the ones you did do. Explore.
Dream. Discover.
Mark Twain

34. Worldwide
Guidelines

35. [Quadrivalent Human Papillomavirus (Types 6, 11, 16, 18) Recombinant Vaccine]
Gardasil / Silgard Approvals
Caribbean & Central America: Europe:
North America:
Germany Cyprus Ireland
Costa Rica Trinidad France Czech Republic Latvia
Puerto Rico El Salvador UK Denmark Lithuania
USA
Guatemala Honduras Spain Estonia Luxembourg
Canada
Curaçao Nicaragua Italy Finland Malta
Mexico
Bermuda Panama Austria Greece Netherlands
Bahamas Cayman Islands Belgium Hungary Norway
Barbados Aruba Bulgaria Iceland Poland
Jamaica Dominican Republic Portugal Romania Slovakia Asia Pacific:
Slovenia Sweden Serbia
38 Montenegro Switzerland Liechtenstein
Bosnia Russia Belarus Australia
South America:
3 Croatia Turkey Indonesia
Brazil Bolivia Korea
Argentina Uruguay Taiwan
Peru Ecuador 16 13 Hong Kong
Colombia Chile 30 Singapore
New Zealand
8 Macau
Middle East & Africa: Malaysia
Philippines
Gabon Congo Kinshasa Thailand
Israel C.A.R. India
Morocco Mauritius Vietnam
Kenya Kuwait
Mauritania UAE
Guinea Eq. Ethiopia
Uganda Togo
Malawi Congo Brazzaville
Jordan Egypt GARDASIL approved in 108 countries (includes 22 GAVI-eligible)
Cote d’Ivoire Burkina Faso
Chad Bahrain
Saudi Arabia Botswana
South Africa Cameroon
Pakistan 35

36. 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

37. ACIP & AAP - 2011
Consider giving HPV4 to MALES
age 9 through 26yrs to reduce their
likelihood of acquiring genital
warts.

38. 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).“

39. • 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

40. 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

41. 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)

42. 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

43. 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

44. 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.

45. 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

46. 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

47. 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.

48. 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!

49. Thank You