LA PREVENZIONE NELLE GIOVANI - atti.ageo-federazione.itatti.ageo-federazione.it/2016-10-01/Mariani...

LA PREVENZIONE

NELLE GIOVANILuciano MarianiHPV-UNITGinecologia OncologicaIstituto Nazionale Tumori Regina Elena, Roma

Italian HPV Study Group (IHSG)

Congresso Nazionale AGEOFirenze, 29 Settembre 2016

DISCLOSURE

I declare to have worked and received royalties for

scientific discussions, studies and research from

Sanofi Pasteur-MSD, GSK, Qiagen, Roche Lab,

MTM Lab.

I have no conflict of interest with my presentation,

and the opinions expressed here are purely

personal and not of any other third parties.

OVERVIEW

AFTER 10 YRS

NONAVALENT

LA PIÙ DIFFUSA MALATTIA

A TRASMISSIONE SESSUALE

IL PIÙ IMPORTANTE VIRUS ONCOGENO

PER LA SPECIE UMANA

• The most successful family of vertebrate viruses, with over240 types classified in 37 genera.

(Bernard, 2010; de Villiers, 2004; Van Doorslaer, 2013)

• One of the most important human carcinogen ever identified(Int Agency for Reserach on Cancer - US National Toxicology Program)

CANCERS RELATED TO INFECTIOUS

2/12.7 (16.1%) million new cancer cases worldwide

attributable to HPV: less developed regions: 490.000 (30.2%)

more developed regions:120.000 (29.2%)

Total: 610.000 (30.0%)

incidence

(100.000)

%

HPV

%

HPV 16-18

% other

genotypes

cervix 10 (35) 100 70 30

vagina 0.3-0.7 65-90 88 20

vulva 0.5-1.5 40 91 <10

anus 1-2 85 93 <10

penis <1 47 74 25

oropharynx 2 70 80 20

Mod. Olsen et al., BMC Public Health, 2012

Rate of population covered by Population-Based Cancer Registries

Source: Curado, MP. Cancer Incidence in Five Continents. Volume IX. Lyon, France: International Agency for Research on Cancer; 2008

• 1991-92 Frazer I, Kirnbauer R L1 capsid protein self-assembled into avirus-like particle (VLP)

• 1998 L.Koutsky landmark trial on efficacy of monovalent HPV-16vaccine (proof of principle that HPV oncogenic infections and relatedcancer/precursors may be preventable)

• 2002 phase-3 trial with 4vHPV vaccine (VLPs of HPV 6, 11, 16, 18)licensed by FDA in 2006

• 2004 phase-3 trial with 2vHPV vaccine (VLPs of 16, 18) licensed by FDAin 2007

• 2007National organized programs of HPV vaccines

TIMELINE OF HPV VACCINES

OVERVIEW

BIVALENTE

Dall’età di 9 anni:

prevenzione nella donna

di cancro e precancerosi

del collo dell’utero e vulva-

vagina.

In entrambi i sessi per la

prevenzione delle lesioni

preneoplastiche e invasive

dell’ano.

QUADRIVALENTE

Dall’età di 9 anni:

prevenzione nella donna di

cancro e precancerosi del

collo dell’utero e vulva-

vagina.

In entrambi i sessi per la

prevenzione delle lesioni

preneoplastiche e invasive

dell’ano e condilomi genitali

NONAVALENTE

10/12/2014

Approvation by FDA

27/03/2015

Positive opinion of the

Committee for Medicinal

Products for Human Use

(CHMP) of EMA

THE HPV VACCINES ARE EVEN BETTER THAN WE HOPED

Vaccini a disposizione


Reduced overall

preventive costs

Fewer screening

rounds with HPV-

based test will be

required.

Interruption of the

HPV transmission

Vaccination creates

herd-protection effect

by reducing the

fraction of susceptible

individuals.

Wide benefit

Potentially protective

against all forms of

HPV-induced cancer-

precursor lesions and

invasive cancers,

and not only against

cervical cancer.

OVERVIEW

Preventive advantages over screening


OPPORT. PROPHYLAXIS

Women/males up to 45+

Infants (?)

ADJUVANT THERAPY

Post-conization

Post-therapy for GWs

RRP (?)

During pregnancy (?)

HIGH-RISK GROUPS

HIV – MSM

Transplant

Immunosuppressed

Migrants/marginal

Abused

Possible future indications

OVERVIEW

Global Progress in HPV

vaccine introduction

Cervical Cancer Action

(August 2015)Licensure in 129 countries, (64

countries having HPV vaccines

in their national programs)

Countries that have not yet

introduced the vaccine are

those that can gain the

most in terms of health

benefits.(Jit M, 2014; Bruni L 2016)

COVERAGE RATE OF HPV VACCINESVaccination coverage is a

key-indicator of programme

performance, and critical to

monitor the potential impact

of HPV vaccines.(Bruni L, 2016)threshold for optimum

cost-effectiveness

Clinical impact of ≥50%:

-68% HPV 16/18 infections

-61% ano-genital warts(M Drolet, 2015)

1997 1998 1999

2000 2001 2002

ITALY: OVERVIEW OF VACCINE OFFER

Bivalent

Quadrivalent

Both vaccines

Bivalent for F and Quadrivalent for M

HPV VACCINE TYPE* DISPENSED BY REGION

* the assignment of the vaccine

is through a periodical regional

tender by cost (from every 6

months to 2 years)

ITALY: TARGET POPULATIONS

Male (12 yrs)

FEMALE POPULATION

(active call, free-of-charge)

1 cohort (12 yrs)

2 cohorts (11-15/16/17 yrs)

4 cohorts (11-15-18-25 yrs)

GENDER-NEUTRAL VACCINATION

(active call, free-of-charge)

MOVING TO UNIVERSAL HPV VACCINATION IN ITALY

The perception of the italian public opinion (and physicians

as well) was that HPV-infection and related diseases were

exclusively, or mainly, confined to female population.

• Reduced health care funding for the vaccination campaign

from 53 million/yr to 34 million/yr (coverage 70%, lower price,

added cohort closed, 2 vs 3 dose)

• Calendar for life

• Universal HPV vaccination (PNPV)

MOVING TO UNIVERSAL HPV VACCINATION IN ITALY

“La sanità pubblica oggi si pone come obiettivo

l’immunizzazione di adolescenti di entrambi i sessi verso il

più alto numero di ceppi HPV per la prevenzione di tutte le

patologie HPV-correlate direttamente prevenibili con la

vaccinazione.

E raccomandata la vaccinazione con offerta attiva e gratuita

delle donne di 25 anni di eta con vaccino anti-HPV, anche

utilizzando l’occasione opportuna della chiamata al primo

screening.”

(Piano Nazionale Prevenzione Vaccini 2016-18)

OVERVIEW

AFTER 10 YRS

NONAVALENT

Safe: -over 200 million doses (Vichnin M, Bonanni P 2015)

-no safety concern: GAVCVS (WHO) last assessment reviewed in december 2015:

autoimmune, neurologic, thromboembolic diseases

(Scheller 2015; Grimaldi-Bensauda 2014; Arnheim-Dalstrom 2013)

even if inadvertentlyadministered in pregnancy (Moro 2015; Gross 2014)

LESSON FROM THE HPV VACCINES







Reviews of pre- and post-licensure data provide no evidence

that these syndromes are associated with HPV vaccination.

Policy decisions based on weak evidence, leading to lack of

use of safe and effective vaccines, can result in real harm





even if inadvertently administered in pregnancy (Moro 2015; Gross 2014)

Immunogenic:

-2 doses equivalent as 3 (Dobson 2013; Romanowski 2014)

-long-term Ab titers detected > 9 years after vaccines (Naud P 2014; Kjaer S 2015)







Immunogenic:



Real-world results:


SPERIMENTAZIONE

PRE-

REGISTRAZIONE

Valutazione

dell’efficacia

(efficacy)

PROGRAMMA

ORGANIZZATO DI

VACCINAZIONE

Valutazione del

beneficio

(effectiveness)





even if inadvertently administered in pregnancy (Moro 2015; Gross 2014)

Immunogenic:



Real-world results:

-decline of GW in females: up to 90% (H.Ali 2013; Mariani 2015; Drolet 2015)

-decline of GW heterosexual male: herd-immunity (Tabrizi 2014; Drolet 2015; Chow 2015)

-protection against EGL in males (A.Giuliano 2011)

-reduction of HPV prevalence: up to 60% (L.Markovitz 2013, 2016; Mesher D, 2016)

-reduction of pap-abnormalities: up to 60% (B.Baldur-Felskov 2014)

-reduction of CIN 2+: close to 50% (Niccolai 2013; Baldur-Felskov 2014; ; Pollock 2014;

Ogilvie 2015; Hariri 2015; Herweijer E, 2016)

-some protection (?) if administered after HPV-treatment (Joura 2012; Kang 2013)

-some degree of protection to non-vaccines genotypes due to the cross-immune reaction

(Malagon 2012)


HPV 6/11

(4vHPV)

HPV 6/11

HPV 16/18

(4vHPV)

(2vHPV)

?

DECLINE OF HPV PREVALENCE

Viral end points (detection of HPV types

directly targeted by the vaccines) are the

earliest indicators of the impact of an

effective program.

Virological end-points are attractive when

they represent valid surrogates for clinical

premalignant end-points (IARC, 2014)

The effectiveness of vaccination

in reducing HPV-related infection

and diseases depended on:

• vaccine coverage rate,

• age of birth of the cohort,

• implementation and duration of a

catch-up program,

• time between program initiation and

measurement of impact,

• length of follow-up time.

(S Garland, 2016)


-64%

-34%

USA

• 57% received at

least 1 dose

• no statistically

significant change

in prevalence of

other HPV types

(L.Markowitz 2016)

AUSTRALIA

• >70% coverage

• females 18-24 yrs

• 4HPV prevalence

decreased from

29% to 7% in

partially and 2% in

fully vaccinated

(S.Tabrizi 2014)

-93%


Mesher D, et al. BMJ Open 2016

ENGLAND

2-HPV vaccine from 2008; females 16-24 yrs; coverage 80%; period 2008 vs 2010-13


-77.1%

-74.3%

-85.8%

Mesher D, et al. BMJ Open 2016

1. no evidence of a reduction in the overall prevalence of HPV33 or of HPV452. increases in the other HR-HPV types: limitation of the study? replacement?


ENGLAND

2-HPV vaccine from 2008; females 16-24 yrs; coverage 80%; period 2008 vs 2010-13

AUSTRALIA

Fairley CK 2009

Donovan B 2011

Read TR 2011

Ali H 2013

Drolet M 2015-92.6%

-72.6%

heterosexual men diagnosed as having genital warts

-82%

DECLINE OF GENITAL WARTS

-51%

(S.Bollerup, 2016)

DENMARK

4HPV vaccine since 2008-2009

• Dramatic decline of GWs incidence in women;• a similar pattern was observed for men aged 12 to 29

years, indicating herd protection

DECLINE OF GENITAL WARTS

AUSTRALIA Oliphant J 2011Tabrizi S 2014

GERMANY Mikolajczyk R 2013

DENMARK Blomberg M 2012Bollerup S 2016

SWEDEN Leval A 2012

BELGIUM Dominiak-Felden G 2015

Systematic review and meta-analysis (Drolet M, 2015)

Boys/men herd-effect, with high female

vaccination coverage (≥50%)

DECLINE GENITAL WARTS AND HERD-IMMUNITY

ONTARIO Guerra F 2016YES NO

Boys/men herd-effect, with low female

vaccination coverage (<50%)

The risks for CIN2/3 and CIN3 were statistically significantly reduced by

up to -80% in fully vaccinated and -60% with only 1 dose.

DENMARK

4-HPV vaccine uptake 85% (≥ 1 dose) from 2006, period 2006-2012

birth cohorts

1989-99

(B.Baldur-Felskov 2014)

DECLINE OF HIGH-GRADE CIN

Trends in

high-grade

cervical

histologically

confirmed

abnormalities

(x1000)<20 yrs

from 10.9 to 5.0

(p<0.0001)

20-24 yrs

from 21.5 to 13.5

(p<0.0001)

AUSTRALIA

4-HPV vaccine uptake 80%, 4-HPV from 2007

Victorian Cervical Cytology Registry (2000-2013)

(J.Brotherton, 2015)

Over time in Australia, the median age of sexual debut has fallen and

the mean number of partners has risen, suggesting increasing rather

than decreasing HPV exposure in younger cohorts over time.

-37.2%

-54.1%


SWEDEN

(nationwide Swedish analysis on 4-HPV vaccination after 8 yrs)

(Herweijer E, 2016)


Follow-up: for a mean of 2.6

and 5.1 year (>236.000

vaccinated women).

Declines of CIN2+ and CIN3+

among fully vaccinated

females <17 years of age at

vaccination were 75% and

84%, respectively.

In contrast, among those

vaccinated between 20 and 29

years of age, declines in

CIN2+ and CIN3+ were 22%

and 25%, respectively.

Prevalence of CIN2+ HPV 16/18 related decreased from 53.6% to

28.4% (-47%; p<.001) after 4vHPV vaccine

USA

4-HPV vaccine uptake <60% (≥ 1 dose), 4-HPV from 2006, period 2008-2012

53.6

28.4

(S Hariri 2015)


OVERVIEW

AFTER 10 YRS

NONAVALENT

9vHPV vaccine

2vHPV vaccine

4vHPV vaccine

Direct multivalent approach

The potential of prevention

increases with the number of

genotypes.(X.Bosch, 2015)

ROLE OF MULTIVALENT DIRECT VACCINES

(AAHS 225μg)

(AAHS 500μg)

620μg

1140μg

4vHPV vaccine

9vHPV vaccine

1640μg

1820μg

630μg

1140μg

1660μg

1840μg

3120μg

3320μg

4520μg

5220μg

5820μg

AAHS =Amorphous aluminum hydroxyphosphate sulfate

9vHPV VACCINE: composition

7 HIGH-RISK HPV GENOTYPES

(mod. S.Hartwig 215)

Attribution to HPV of pre-neoplastic ano-genital lesions

Expected increase of protection from 4vHPV to 9vHPH vaccine

Total lesions

9vHPV VACCINE: estimated prevention

Due to the attribution

of the single genotype,

uterine cervix has

the highest potential

to benefit from 9v

HPV.

+75%

Attribution to HPV of invasive ano-genital cancers

Expected increase of protection from 4vHPV to 9vHPH vaccine

(Hartwig S 2015; Saraiya M 2015; Serrano B 2012 )

Cervix Vulva Vagina Anus Penis

9vHPV VACCINE: estimated prevention

Due to the attribution

of the single

genotype, uterine

cervix has the highest

potential to benefit

from 9v HPV.

(E.A. Joura et al, NEJM 2015)

Geometric Mean Titer (GMT) and Seroconversion for HPV Types 6, 11, 16,

and 18 in Noninferiority Analyses at Month 7 in the Per-Protocol Population

9vHPV VACCINE: GMT and seroconversion

9vHPV VACCINE: vaccine efficacy

(E.A. Joura et al, NEJM 2015)

Definitive therapy procedures

(LEEP, conization)

Nu

mb

er

of

ca

se

s

n=6014 n=6013

4vHPV

9vHPV

http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_Product_Information/human/00385

2/WC500189111.pdf

9vHPV VACCINE: vaccine efficacy

506

n=5882 n=5883

Pap-abnormalities

(≥ ASCUS HPV+)

VE: 90.2%(95% CI:

75.0, 96.8)

VE: 92.9%(95% CI:

90.2, 95.1)

Grazie

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