1 dr mario sideri

HPV NATURAL HISTORY AND HPV

TESTING

Mario SideriUnità Ginecologia Preventiva

Istituto Europeo di Oncologia, Milano

Italian HPV Study Group (IHSG)

What’s new?

In the last 30 years the causal association

between HPV infection and cervical cancer

has been demonstrated

papillomavirus

The Nobel Prize in Physiology or Medicine 2008

Harald Zur Hausen for his discovery of human

Papilloma viruses causing cervical cancer

Vaccination Population at

risk (screening)

Detection & Intervention

(pre-cancer elimination)

OLD STRATEGYNEW STRATEGY

Papillomavirus is known from decades.

However only in the recent years we have

recognized the wide diffusion and the benign

meaning of HPV infection

What is HPV?

Human Papillomavirus

Papillomavirus are species specific viruses

HPV are very common viruses and are present in almost all the species of mammalians and birds

More than 100 HPV types have beendescribed in humans

Human PV infect the skin and mucousmembranes where they can cause typicalbenign proliferations as warts and papillomas

Papillomavirus

De Villiers et al., Virology (2004)

HPV infection causes in some instances microproliferations not visiblewith the naked eye

HPV tends to prersist for long periodsof time, often as latent infection

Some HPV associated lesions can evolve into malignant neoplasia

Papillomavirus

De Villiers et al., Virology (2004)

HPV Infection

Langerhans

cells

Dendritic

cellsDermis

Micro-wound

Epidermis

Draining lymphatics

Basementmembrane

CD 16

90% of young women acquires the virus with the beginning of sexual intercourses

Most of them become negative after 6-18 months of transient infection

Only about 10% of young women become persistently infected with HPV for a longer period of time

HPV natural history

less than 30% of persitently infected women develops a CIN lesion

the vast majority of CIN clears spontaneously

some CIN persist, but even most of persistent CIN3 will never become cancer

HPV natural history

In this way, the almost ubiquitary HPV

infection, very rarely ends up into cervical

cancer.

Conversely, the association of HPV

infection with cervical cancer offers unique

opportunities of cancer prevention

HPV and Cervical Cancer

553 college students (mean age 19)

HPV test and pap smear every 4 months for 5 years

mean follow up 41.2 months

HPV natural history:Seattle Study

Winer et al., Am J Epidemiol (2003)

19.7% was HPV DNA positive at enrollment

During two years follow up 39% of women negative at enrollment became HPV DNA positive

High risk HPV were found more frequently, types 16,18,51,56,33,35,39


HPV natural history:Seattle Study

60 adolescents (14-17) were followed for a mean time of 26 months

Every three months were evaluated for HPV infection

In addition a weekly self sampling for HPV was performed for a time lenght up to 15 weeks

Brown et al., J Infect Dis (2005)

HPV natural history:Adolescent study

Timing HPV overall HPV oncogenic

Enrollment 28% 22%

Last visit 40% 37%

At least once* 82% 77%


* At least two positive samples


Only 3 girls were always negative to vaginal HPV testing

All referred to be virgins



HPV detectability rarely persist for more than 24 months

in more than 90% of the cases HPV becomes undetectable within 24 months

HPVNatural history

Detectable HPV

Author Age 6 12 24

__________________________________

Woodman 20 24 4 <1

Mosicki 20 50 30 10

Ho 20 30 9

% persistent HPV infection in months

persistent HPV infection may cause the development of invasive cervical cancer in 10 to 15 years

many known and unknown co-factors are responsible for cancer develpoment

HPVNatural history

20.817 women with neagtive cytology at baseline

HPV test at enrollement

Follow up for 10 years; endpoint CIN2-3 development

Natural history of HPV oncogenesisPortland study

Kahn et al., JNCI (2005)

0%

5%

10%

15%

20%

25%

0,0 4,5 15,0 27,0 39,0 51,0 63,0 75,0 87,0 99,0 111,0 119,5

Follow-Up Time (months)

Cu

mu

lati

ve I

ncid

en

ce R

ate

of

≥C

IN3 HPV16

+

HPV18

+

HPV

+

HPV+/

HPV16-

/18-HPV

-

Kahn et al., JNCI (2005)

CIN3 develpoment during follow up in relation to HPV status

ALL

HPV 16

Rodriguez et al., Proceedings of 24th International HPV Conference and Clinical Workshop, China 2007. Abstract

section

HPV persistent infection can cause the development of invasive cervical cancer in 10 to 15 years

many co-factors are involved in the process of cancer development

Natural history of HPV infection

Few studies addressed

in longitudinal studies

HPV status in sex

couples

HPV: what we know in sex couples?

….In our current study, less than half of the couples exhibited perfect HPV-type specific concordance. More than one third of couples had complete discordance…..

Multivariate regression analysis.

Reporting a new sex partner or the same sex partner or no sex partner was not significantly associated with the risk of infection reappearance.

HPV Clearance

HPV re-infection(redection)

HPV infection is very common and is

not a disease

pre-cancer is a rare event

cancer is an exceptional event

HPV: what we now know

HPV infection is very rarelyassociated to cancer

development

However HPV is necessary for cancer develpoment

HPV and Cervical Cancer

Cervical cancer screening

• Pap smear as primary screening test

• Identification of CIN3

• Elimination of CIN3 through excisional

conservative surgery

The historical strategy

Screening aim

To identify and eliminate this lesion

Vaccination Population at

risk (screening)

Detection & Intervention

(pre-cancer elimination)

USUAL STRATEGYNEW STRATEGY


• Testing the population for the

causative agent of cervical cancer

• Testing aimed to identifcation of CIN3

• Testing not aimed to detect infection

HPV TESTING


PROOF of PRINCIPLE

HPV TESTING

CERVICAL CANCER SCREENING IN INDIAN = 131.476

Four arms randomized study:

•Control

•VIA

•Pap smear

•HPV test

HPV test

Pap smear

VIA

Control


known limitations of

cytology screening

PAP SMEAR

30

40

50

60

70

80

90

100

1971 1973 1975 1977 1979 1981 1983 1985 1987 1989 1991 1993 1995 1997 1999 2001

8

9

10

11

12

13

14

15

16

17

18

Inc

ide

nc

e/1

00

00

0S

cre

en

ing

Co

ve

rag

e (

%)


Start of organised screening

Never pap smear 162 62%

Pos. pap & adequate

follow-up29 11%

False negative pap 37 14%

Previous abnormal

smear*34 13%

TOTAL 262 100%

Screening “failures”

italian data

Amadori A. Int J Gynecol Cancer 1998262 invasive cancer cases, TR Romagna and Toscana (1986-93).

* Repeat smear not done, colposcopy not done, colposcopy done late, negative colposcopies, negative biopsies, CIN3 diagnosed with no further action.

Cause, n (%)Kaiser

study1

Swedish

study2

No recent screen 464 (56%) 789 (64%)

Cytology detection

failure263 (32%) 300 (24%)

Failure of follow-up of

abnormal cytology106 (13%) 91 (7%)

Screening history of women with invasive cervical carcinoma

1. Leyden WA, et al. J Natl Cancer Inst 2005; 97:675683; 2. Andrae B, et al. J Natl Cancer Inst 2008; 100:622629.

Results of the NTCC study

(Nuove Tecnologie per lo Screening

del Cancro Cervicale)

Setting: population based screening programme

Prospective randomized study on new screening test

Accrual phase: March 2002 to December 2004

94,370 women aged 25–60 years were randomized

Arm A 47,001 = conventional cytology

Arm B 47,369 = HPV testing (HC2)

Two screening rounds were completed (6 years)

METHODS

Women were divided into two different age

groups:

• 25 to 34

• 35 to 60

METHODS

The primary endpoint was the detection of

grade 2 and 3 CIN, and of invasive cervical

cancers during the first and second screening

rounds.

Analysis was done by intention to screen.

METHODS

Relative detection (HPV vs cytology) was:

• 2·00 for CIN2

• 2·08 for CIN3

• 2·03 for CIN2 and 3

RESULTS: first round, 35-60 yrs

Meaning:HPV test detects 2 times more CIN 2-3 than pap

In other words the pap smear is negative in 50% of

CIN2-3

Relative detection (HPV vs cytology) was:

• 2·00 for CIN2

• 2·08 for CIN3


RESULTS: first round, 35-60 yrs

Question:

Are these “new” CIN2-3 clinically relevant?

Go to the second round…

RESULTS: second round, 35-60 yrs

Meaning:

In the HPV group the CIN2-3 were identified

earlier than in the cytology arm

the relative detection (HPV vs cytology) was

• 0·54 for CIN2,

• 0·48 for CIN3


RESULTS: second round, 35-60 yrs

Question:

Which is the clincal value of the “anticipated”diagnosis?

the relative detection (HPV vs cytology) was

• 0·54 for CIN2,

• 0·48 for CIN3


RESULTS: 35-60 yrs

Question:

Which is the clincal value of the “anticipated”diagnosis?

It is safe to increase the intervals between two

screens.

But what about the invasive cancers?

First Round 6 8 0.61Second Round 0 7 0.016Total 6 15 0.052

HPV test pap smear P value

RESULTS: 35-60 yrs

Number of invasive cancers

Meaning:

Follow up of untreated CIN2-3 carries the risk

of cancer development



RESULTS: 35-60 yrs


Clinical consequences of the study:

Stop pap smear screening and switch to HPV

testing

Relative detection (HPV vs cytology) round one

• 2·00 for CIN2

• 2·08 for CIN3

• 2·03 for CIN2 and 3 together.

Relative detection (HPV vs cytology) at round two

• 0·54 for CIN2

• 0·48 for CIN3

• 0·51 for CIN2 and 3 together.

RESULTS: 35-60 yrs

HPV testing:

•Reassure more than 90% of negative women

(negative is negative; interval increase)

•Offer better protection against cancer

RESULTS: 25-34 yrs

What about the young women,

aged 25 to 34?

Same results or different situation?

RESULTS: 25-34 yrs The relative detection (HPV vs cytology) was:

Round 1

• 3·91 for CIN3 and AIS

Round two

• 0·20 for CIN3 and AIS.

Meaning:

Four times more CIN3 and AIS detected by

HPV testing

Five times less CIN3 and AIS in the subsequent

round (more evident effect in young women

than in older)



RESULTS: 25-34 yrs


Clinical consequences of the study:

Some considerations….

RESULTS: 25-34 yrs The relative detection (HPV vs cytology) was:

Round 1

• 3·91 for CIN3 and AIS

Round two

• 0·20 for CIN3 and AIS.

Considerations:

Double number of lesions in the whole period

(overdiagnosis-overtreatment)



RESULTS: 25-34 yrs


Clinical consequences of the data 25-34 yrs:

The increment in cancer detection is counter balanced by an

increase in diagnosis and treatment of clinically non relevant

(regressing?) CIN2-3



RESULTS: 25-60 yrs


The total figures of cancer reduction is still

impressive; this figure prompted GISCi to start

the long and difficult process to abandon pap

smear as primary screening test because it is

unethical to continue with pap smear screening

HPV TEST:

Which optimal use?

• HPV test has an high NPV

• HPV test is ideally suited to reassure the

negative HPV individuals and to increase

intervals between two subsequent screens

• at any age HPV negative test is reassuring

There are no scientific doubt that HPV test should be used as

primary screening test.

Implementation is still a problem where pap smear

screening system is in place

CONCLUSIONS

It is a Copernican revolution…Copernicus was placed under investigation…..

1940’ TECHNOLOGY

H:%5Cindex.html

H:%5CSwift%20poster.html

H:%5CSunbeam%20Rapier.html

THANK YOU FOR YOUR

ATTENTION!

Mario SideriUnità Ginecologia Preventiva

Istituto Europeo di Oncologia, Milano

Italian HPV Study Group (IHSG)

1 dr mario sideri

Science

Transcript of 1 dr mario sideri