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]
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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]
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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