Latest Update

on

HPV 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

> 200 women die every day

Every 7 minutes a women dies

8 women die every hourCervical Cancer :

India

This ‘Cause’ need to be taken up by multiple stake holders.

Cervical Cancer in India

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

India ~1,32,000 World ~ 4,93,000

India ~27% of new Cervical Cancer cases in world

India ~ 74,000World ~ 2,73,000

India ~27%

Rest of World - 73%

India ~27% of deaths due to Cervical Cancer in world

Rest of World - 73%

India - 27%

Cervical Cancer – Disease Burden

Incidence Mortality

India ~27%

Rest of World - 73%

Bhatla N et al; Vaccine 2008; 26 2811-17

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

8

0 5 10 15 20 25 30

Cervical Breast (Female) Ovarian

Years of Life Lost to Cervical Cancer*

*In women in the United States (2003)1. Ries LAG, Harkins D, Krapcho M, et al. (eds). SEER Cancer Statistics Review, 1975–2003, National Cancer Institute. Bethesda, MD; 2006.

26

19

18

26 Average years of life lost in women with Cervical Cancer

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.

10 *Ray K et al, Indian J Med Res 2006; 124: 559-568

18%

6%

11% 10.5%

0

2

4

6

8

10

12

14

16

18

20

1990-93 1994-97 1998-01 2002-04

Study Period

Per

cen

tag

eGenital Warts – Disease Burden: India*

Increasing trend of Genital warts in India

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.

• 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 as jokes and fancies, then as blasphemies and treason, 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 regular PAP smear tests

Harald zur Hausen

Born March 11, 1936 (age 74)Germany

Nationality German

Known for Discovery that HPV can causecervical cancer

Notable awards 2008 

Nobel Prize in Physiology or Medicine

The NEED for vaccination against

Cervical cancer

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

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

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

Immune memory & HPV vaccine

[Quadrivalent Human Papillomavirus (Types 6, 11, 16, 18) Recombinant Vaccine]

25

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

1. Janeway C et al. New York, NY: Garland Science Publishing; 2005.

2. 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.

[Quadrivalent Human Papillomavirus (Types 6, 11, 16, 18) Recombinant Vaccine]

26

Immune Memory at Month 60

HPV 16 responses* in 16- 23 yr females after 5 years of follow-up

*In subjects naïve to the relevant HPV type from day 1 through month 601. Olsson S-E et al. Vaccine. 2007;25:4931–4939.

10,000

1,000

100

10

0 2 3 7 12 18 24 30 36 5460 61

60+1week

GARDASIL

n = 78

Placebo (Sero (-) and PCR (-))n = 70

An

ti-H

PV

Res

po

nse

(GM

T le

vels

wit

h 9

5% C

I[l

og

10 s

cale

])

Vaccination on Day 0, at 2 and 6 monthsImmune challenge at 60 months

Months

6

↴

• Similar results seen with HPV 18, 6, and 11

Immune challenge

Immune memory

[Quadrivalent Human Papillomavirus (Types 6, 11, 16, 18) Recombinant Vaccine]

Clinical Trials Overview

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 StudiesFUTURE = Females United To Unilaterally Reduce Ecto/endo cervical diseases

Adolescent Study (’04-06) (N=4800) 9-15 yrs both sexes – 3 year extensionMale Efficacy Studies

GARDASILConclusions (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 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

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.

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

Worldwide Guidelines

35

3

North America:

USACanada Mexico

8

South America:

Brazil BoliviaArgentina

UruguayPeru

EcuadorColombia Chile

30

Middle East & Africa:

Gabon Congo KinshasaIsrael C.A.R.Morocco MauritiusKenya KuwaitMauritania UAE Guinea Eq. EthiopiaUganda TogoMalawi Congo BrazzavilleJordan EgyptCote d’Ivoire Burkina FasoChad BahrainSaudi Arabia BotswanaSouth Africa CameroonPakistan

13

Asia Pacific:

Australia Indonesia KoreaTaiwanHong KongSingaporeNew ZealandMacauMalaysiaPhilippinesThailandIndiaVietnam

38

Europe:

Germany Cyprus Ireland France Czech Republic LatviaUK Denmark LithuaniaSpain Estonia

LuxembourgItaly Finland MaltaAustria Greece

NetherlandsBelgium Hungary NorwayBulgaria Iceland PolandPortugal Romania SlovakiaSlovenia Sweden SerbiaMontenegro Switzerland

LiechtensteinBosnia Russia BelarusCroatia Turkey

Caribbean & Central America:

Costa Rica TrinidadPuerto Rico El SalvadorGuatemala HondurasCuraçao NicaraguaBermuda PanamaBahamas Cayman IslandsBarbados ArubaJamaica Dominican

Republic

16

Gardasil / Silgard Approvals

GARDASIL approved in 108 countries (includes 22 GAVI-eligible)

[Quadrivalent Human Papillomavirus (Types 6, 11, 16, 18) Recombinant Vaccine]

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 - 2011

Consider giving HPV4 to MALES

age 9 through 26yrs to reduce their

likelihood of acquiring genital

warts.

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).“

• 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

• 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

FOGSI & IAP Recommendations– Vaccine Schedule

www.fogsi.org/hpv vaccine

• 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:Women With Previous CIN & sexually

active women

–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

• 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

FOGSI Recommendations:Vaccination & SCREENING

•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.

Vaccination against HPV is safe & effective

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)

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.

• 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!

Value of Vaccination Today

Thank You