Prospects for a Prophylactic

HPV Vaccine and Future Implications

for Cervical Cancer ScreeningDr. Fuat Demirkıran

İ.Ü Cerrahpaşa Tıp Fak.Kadın Hast. ve Doğum ABD, Jinekolojik Onkoloji Bilim Dalı

Antalya ,2011

Prevalence of cervical cancer in the worldPrevalence of cervical cancer in the world

< 91.5< 91.5

< 15.4< 15.4

< 33.2< 33.2

< 9.7< 9.7

< 25.3< 25.3

*/100.000 */100.000 womenwomen

World population prospects for women >15 years.

case increase 50-55% case increase 6-23%

Secondary prevention

Primary prevention

Faz III Etkinlik Sonuçları

Cervarix(15 aylık takip

Paavonen Lancet 2007)N=18,644

Gardasil(3 yıllık takip

Koutsky et al. NEJM 2007N=12,167

Garland et al. NEJM 2007 N=5,455)

CIN 2/3+CIN 2/3+HPV 16/18’e bağlı

%90(%97.9 GA: 53-99)P/V: 21/2 olay, TVC

%100(%97.9 GA: 74-100)P/V: 20/0 olay, PPR

%95(%95 GA: 85-99)

P/V: 62/3 olay, USP

%98(%95 GA: 86-100)

P/V: 42/1 olay, PPSP

CIN 1+HPV 16’ya bağlı

HPV 18’e bağlı

%94(%97.9 GA: 54-100)P/V: 17/1 olay, PPR

%100(%97.9 GA: 34-100)P/V: 9/0 olay, PPR

%100((%95 GA: 93-100)P/V: 53/0 olay, USP

%95((%95 GA: 72-100)P/V: 22/1 olay, USP

• İlk doz sonrası

• Kadınlar: 0. günde aşıya özgü HPV tipleri için negatif

American Cancer Society (ACS) Recommendations for Human Papillomavirus (HPV) Vaccine Use to Prevent Cervical Cancer and Its Precursors 2007

CDC

March 2009

The Countries that are made reimbursement

Screening for cervical pathology should be go on after vaccination

Efficacy of HPV vaccines

Barriers to HPV vaccine and covarage rate

New HPV infection in advanced ages

Based on statistical analysis of HPV type distributions in populations, it appears unlikely that reducing the frequency of specific HPV types

in a population through vaccination would lead to an increase in the frequency of other HPV types

1. Munoz N. Against which human papillomavirus types shall we vaccinate and screen? The international perspective Int J Cancer 2004; 111: 278–85.

Cancer cases associated with most frequent HPV genotypes (%)

%53.5%70.7%77.4%80.3

53.5

2.3

2.2

1.4

1.3

1.2

1.0

0.7

0.6

0.5

0.3

1.2

4.4

2.6

17.2

6.7

2.9

0 10 20 30 40 50 60 70 80 90 100

X

Diğer

82

73

68

39

51

56

59

35

58

52

33

31451816

0 10 20 30 40 500 10 20 30 40 60500 10 20 30 40 70 80 90 10060500 10 20 30 40

X

82

73

68

39

51

56

59

35

58

52

33

31

45

18

16

Worldwide distribution of HPV types in cervical cancer

Efficacy Against HPV 6/11/16/18 Related CIN 2/3 or Worse and AIS (Protocols 005, 007, 013, and 015)

Gardasil Placebo

Day 1 Status

NNo.

casesIncidence N

No. of cases

IncidenceEfficacy95% CI

MITT-3 9831 122 0.7 9896 201 0.9 39.0%(23.3, 51.7%)

PCR (-)Sero (-)

9342 1 0.6 9400 81 0.4 98.8%(92.9, 100.0%)

PCR (-)Sero (+)

853 0 0.0 910 4 0.2100%(-63.6,

100.0%)

PCR (+)Sero (-)

661 42 3.2 626 57 4.6 31.2%(-4.5, 54.9%)

PCR (+)Sero (+)

473

79

[121]

*

9.1 499

69

[130]* 7.3 -25.8%(-76.4, 10.1%)

* Total number of cases in subjects who were sero+ and/or PCR+ at baseline for the relevant HPV type which was associated with disease.Source: Table 1-1, Additional efficacy analysis requested by CBER

In fact, in the total vaccinated cohort, efficacy against any CIN II/III irrespective of HPV type was

30.4% at 39 months after the first vaccination and is expected to increase with longer follow-up.

In fact, in the total vaccinated cohort, efficacy against any CIN II/III irrespective of HPV type was

30.4% at 39 months after the first vaccination and is expected to increase with longer follow-up.

Gynecologic Oncology 115 (2009) S15–S23

Worldwide female population and a speculative anticipation on the initial introduction of HPV vaccines.

Expanded Program of Immunization 1980–2005 DTP3 coverage by level of development

Covarage Rate

HPV Vaccination Coverage by dose number, age in years as at mid 2007 and place of vaccination,

as notified for the National HPV Vaccination Program catch up cohorts (Avustralia Women vaccinated between April 2007-December 2009)

Place of Vaccination School Program

School Catch Up

School Catch Up

GP/community GP/community

Age (in years as at mid 2007)

12-13 14-15 16-17 18-19 20-26

Population (as at mid 2007)

275,597 277,689 282,408 281,065 1,031,500

Total No of Doses Notified

649,310 652,014 624,410 433,856 1,278,678

Coverage rate as at

21 Mar 2011

Dose 1 83% 84% 81% 64% 52%

Dose 2 80% 79% 75% 53% 42%

Dose 3 73% 72% 66% 38% 30%

Prevalence of HPV infection, precancerous lesions and cervical cancer by age of women

at least 5%

35 %

in different regions of the world have shown that each year between approximately 5% and 15% of sexually active mid-adult women acquire a new infection with an oncogenic HPV

type

Age-specific incidence of oncogenic HPV infections in Ontario, Canada , Adapted from Sellors et al.

Approximately 5–15% of sexually active midadult

women acquire a new infection with an oncogenic

HPV type each year and in approximately 1–

2% of these women, the responsible

oncogenic HPV types will be HPV-16 or

-18

Approximately 5–15% of sexually active midadult

women acquire a new infection with an oncogenic

HPV type each year and in approximately 1–

2% of these women, the responsible

oncogenic HPV types will be HPV-16 or

-18

Gynecologic Oncology 115 (2009) S15–S23

≥ CIN3

HPV18+

HPV16+

HC2+

HC2-

Cumulative incidence of cervical intraepithelial neoplasia grade 3 andcancer ( ≥ CIN3) over a 10-year period in 20 514 women according to oncogenichuman papillomavirus (HPV) status at enrollment. HPV status is defi nedhierarchically as: positive for HPV 16 ( closed circles ), else positive for HPV18( open circles ), else positive for the non-HPV16/18 oncogenic types in HybridCapture 2 ( closed triangles ), else oncogenic HPV negative ( open triangles

Cumulative incidence of cervical intraepithelial neoplasia grade 3and cancer ( ≥ CIN3) over a 10-year period in 12 976 women 30 years old andolder with negative cytology at enrollment, according to oncogenic humanpapillomavirus (HPV) status at enrollment. HPV status is defi ned hierarchicallyas: positive for HPV 16 ( closed circles ), else positive for HPV18 ( open circles ),else positive for the non-HPV16/18 oncogenic types in Hybrid Capture 2 (HC2)( closed triangles ), else oncogenic HPV negative ( open triangles ).

It is unclear whether new acquisition or reactivation of a

latent infection is responsible for the higher detection rates

observed in older women. It has been proposed that what

we call incident infections at higher ages may be due to new

infections as well as reactivation of latent persistent

infections

it is unclear whether a prophylactic

vaccine can

be efficacious in preventing reactivation

of latent infection.

Any suggested screening program….

Implementation of a prophylactic HPV vaccination

program

would have important implications for cervical cancer

screening.

During the initial period following the introduction

of a vaccine program, the population will include both

vaccinated women at low risk for cervical neoplasia

and

women who have not been vaccinated who will be at

greater

risk.

TEN MOST FREQUENT HPV TYPES AMONG HIGH GRADE CERVICAL LESIONS WORLDWIDE

WORLD DEVELOPING REGIONS DEVELOPED REGIONS

Data source: IARC Infection and Cancer Epidemiology Group. Clifford et al Br J Cancer 2003, Smith et al Int J Cancer 2007 Available at: HPV Information Centre. Human Papillomavirus and Related Cancers in World. Summary Report 2009. [Accessed: 27 May 2010]. Available at www. who. int/ hpvcentre

TEN MOST FREQUENT HPV TYPES AMONG LOW GRADE CERVICAL LESIONS WORLDWIDE

WORLD DEVELOPING REGIONS DEVELOPED REGIONS

Data source: IARC Infection and Cancer Epidemiology Group. Clifford et al CEBP 2005

Available at: HPV Information Centre. Human Papillomavirus and Related Cancers in World. Summary Report 2009. [Accessed: 27 May 2010]. Available at www. who. int/ hpvcentre

Vaccination of adolescents

reduction in rates of HPV infection

low-grade SIL

High-grade SIL- Cancer

With Vaccination program, over time

The SILs remaining in the population would be related increasingly to HPV types that are less likely to persist and to progress to cancer.

Consequently, there would be fewer SILs in the population, and the SILs remainingwould be more likely to spontaneously regress without treatment.

In general population, the lifetime risk for developing carcinoma

in women with low-grade SIL….….1%.

In vaccinated population,

this risk………….1/500-1000

Would LSIL require treatment ?

focus on the detection of high-grade SIL.

After post-vaccination program

Increase incidence of low risk lesions

following vaccination

Many problems related to screening

program after Broad-Spectrum Vaccination

Decrease the alertness of the cytology screeners,

decrease the positivepredictive value of cytological

screening.

Long term impact of vaccination

As time goes on, more women will receive the HPV

vaccine before the onset of sexual activity. This will

result in a fall in positive predictive value of the Pap

test.

Modifications to the screening Program.

a change in the age of commencement of

screening,

a change to the screening interval,

the addition of HPV DNA tests.

Cost-efective cancer prevention in

HPV-vaccinated population….

probably require targeted screening with HPV testing

a few times during entire lifetime

secondary screening with cytology

Combining vaccination with screening still will be the most

effective way to reduce the lifetime risk of cervical cancer in

next years.

.

Forward looking views on cervical cancer prevention strategies

Widespread implementation of an HPV

vaccine program is unlikely to occur until the

next century, and its impact would not be

fully appreciated for decades.

Dramatic changes in screening program of

cervical cancer has not been seen

reasonable

for next few decades.

Dramatic changes in screening program of

cervical cancer has not been seen

reasonable

for next few decades.

A clear message is that the vaccine is not a

substitute for screening tests

Modifications to the screening program will be necessary in the

long term.