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Dr Kanika Gupta
Gynae-Oncologist
Cervical cancer worldwide
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.
2. Kitchener HC, et al. Vaccine 2006; 24(Suppl 3):S63–S70.
100% of cervical cancers are caused
by HPV
Global total HPV-attributable cancers in 2002
Attributable Attributable to HPV
to HPV % all 16/18
HPV
Total cancer
Site % Cases % Cases
cancers
Cervix 492,800 100 492,800 93.5 70+ 344,900
Vulva, vagina 40,000 40* 16,000 3 80 12,800
Anus 15,900 90* 14,300 2.7 92 13,100
Oropharynx 9,600 12* 1,100 0.2 91 1,000
Mouth 98,400 3* 2,900 0.5 97 2,800
Total 527,100 374,600
HPV16 61.6 HPV16 46.8 HPV16 66.6 HPV16 63.9 HPV16 60.1 HPV16 64.8
HPV18 8.2 HPV18 18.9 HPV18 7.2 HPV18 6.7 HPV18 7.5 HPV18 14.1
HPV45 5.5 HPV45 10.8 HPV58 4.7 HPV33 5.7 HPV45 6.0 HPV45 5.5
HPV31 4.5 HPV35 5.3 HPV33 4.5 HPV45 4.7 HPV31 5.8 HPV33 3.1
HPV33 4.3 HPV52 4.4 HPV52 3.1 HPV31 4.0 HPV33 3.7 HPV35 2.3
HPV16 47.8 HPV18 47.6 HPV18 46.0 HPV16 53.2 HPV16 48.8 HPV16 37.5
HPV18 29.0 HPV16 36.9 HPV16 32.4 HPV18 27.4 HPV18 23.5 HPV18 34.7
HPV45 12.3 HPV45 9.5 HPV45 10.1 HPV45 11.8 HPV45 13.5 HPV45 16.7
HPV31 1.2 HPV35 2.4 HPV59 5.4 HPV33 1.2 HPV31 2.4 HPV11 4.6
HPV33 1.1 HPV51 2.4 HPV66 3.4 HPV35 1.2 HPV39 1.7 HPV54 3.2
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.
HPV Lifecycle in the Cervix
Shedding of virus-
laden epithelial cells
Basement membrane
Normal Infected
epithelium epithelium Frazer IH. Nat Rev Immunol 2004; 4:46–54.
Progression of Cervical Disease
Progression*
Months Years
Time
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.
HPV infections continue to occur in women
over 25 years of age
• The risk starts from sexual debut1 and continues throughout
life2
• Incident infection of oncogenic types is estimated to be 5.3%
(range: 5–10%) in women 25–55 years of age3
• Although new infections decrease with age, risk of
persistence increases with age4
• Immune function declines with age resulting in decreased
capacity to respond to both new and previously encountered
infections5
Sexual contact
Proper condom use may help reduce the risk, but is not fully
protective against infection.
Nonsexual routes
1. Schiffman M. Lancet 2007; 370:890–907; 2. Walboomers JMM et al. J Pathol 1999; 189:12–19;
3. Stanley M. Vaccine 2006; 24(Suppl 3):S106–113; 4. Dunne EF, et al. JAMA 2007; 297:813–819.
Natural HPV infection induces a weak immune response1-4
Uses the natural life cycle of epithelial cells to release new viruses 1-4
No
Does not cause cellinflammation,
death1-4 no danger signals
Local infection1-4
No viremia
Infects the epithelium through micro abrasions 1-4
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
Neutralizing antibodies prevent HPV infection
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.
What makes a good cervical cancer
vaccine?
• Antigens (virus-like particles) that closely mimic the virus
structure
• Generation of neutralizing antibodies – the major basis
of protection
• High levels of antibodies in the serum that can transude
to the site of infection resulting in:
– An immune response that improves on natural immunity, as natural
immunity does not guarantee protection
– The greatest possible protection against cervical cancer-causing
HPV types
– Durable protection afforded by sustained protective immune
responses
Development of virus-like particles as HPV
vaccine antigens
CervarixTM
+ Aluminium
salt
(Al(OH)3)
+ MPL
Immunostimulant
AS04-containing vaccine
Antigens Adjuvant
AAHS-containing vaccine
HPV Vaccines: Cross-protective
Efficacy
Papillomavirus phylogenetic tree
40 39 70 59
7 32
44 55 42
PCV1 18 27
13 45 61 2a
11 57
6
73 3
34 28
10
RhPV1 29
58
33 51
52 26 30
16
35 53
56
31 66
15
15
10 10
5 5
0 0
20–24 25–29 30–34 35–39 40–44 45–49 50–54 55–59 60–64
* Two different cohorts (cross-sectional study) followed during the same time span to measure the rate of high-risk HPV infection in one and the rate of cervical cancer in the other.
1. Adapted from Bosch FX, Lorincz A, Muñoz N, Meijer CJLM, Shah KV. J Clin Pathol. 2002;55:244–265, with permission from the BMJ Publishing Group.
Median age (in years) sexual debut and gender
At the national level median age at sexual debut was 18 years in both rural and urban areas.
National Behavioural Surveillance Survey (BSS) 2006, NACO
What to do if patient is between 26-45 years
of age ?
• Present recommendation in India is from 9-26 years
• Some countries recommend up to age of 45 years
• Chance of patients getting all 4 strains is one in a
thousand , so some benefit is likely for all patients.
• It may protect against further re-infections if the
infection is cleared of naturally
• Some cross protection to other strains may also be
there.
• To be decided on a case to case basis after discussion
with patients
WHO position on HPV vaccines
WHO position paper, WEEKLY EPIDEMIOLOGICAL RECORD, NO. 15, 10 APRIL 2009
Recommendations of the Indian Academy of Pediatrics
Committee on Immunisation (IAPCOI)
http://www.iapcoi.com/hpv.htm
Recommendations of the Indian Academy of Pediatrics
Committee on Immunisation (IAPCOI)
• The recommended age for initiation of vaccination is 10-
12 years.
• HPV vaccines can be given simultaneously with other
vaccines such as hepatitis B and Tdap.
• As a precaution against syncope following any vaccine in
adolescents, the vaccinee should be counseled prior to
vaccination, vaccine be administered in a sitting/lying
down position and the patient observed for 15 minutes
post vaccination.
http://www.iapcoi.com/hpv.htm
The Association of Physicians of India (API)
Guidelines
• The bivalent vaccine has been approved for use in females aged
10 to 45 years
• The Quadrivalent vaccine has been approved for use in females
aged 9 to 26 years
• Vaccination is not recommended in males, at present
• The HPV vaccine is not therapeutic. It does not treat existing HPV
infection or cervical intraepithelial neoplasia
• Women who have been vaccinated with the HPV vaccine should
continue with the cervical cancer screening
• For the quadrivalent vaccine three doses at 0, 2 and 6 months
• For bivalent vaccine three doses at 0,1 and 6 months
• At present there are no data to support the use of boosters.
FOGSI Oncology Committee, www.fogsi.org, HPV vaccine
FOGSI Recommendations for Vaccination against HPV
Infection For the prevention of Cervical Cancer (ii)
1. Schiffman M. Lancet 2007; 370:890–907; 2. Walboomers JMM et al. J Pathol 1999; 189:12–19;
3. Stanley M. Vaccine 2006; 24(Suppl 3):S106–113; 4. Dunne EF, et al. JAMA 2007; 297:813–819.
Prevention of cervical cancer – secondary
prevention
• Cervical cancer screening has greatly reduced morbidity and
mortality, but has limitations
– It does not prevent infection or development of precursors
of cervical cancer1
– Lesions which progress quickly may not be detected in
time2
– Early stages of adenocarcinoma are difficult to detect3
– Cervical cancer screening is not widely available in all
countries4