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
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
THE HPV VACCINES ARE EVEN BETTER THAN WE HOPED
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
THE HPV VACCINES ARE EVEN BETTER THAN WE HOPED
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
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
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 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)
LESSON FROM THE HPV VACCINES
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)
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)
Real-world results:
LESSON FROM THE HPV VACCINES
SPERIMENTAZIONE
PRE-
REGISTRAZIONE
Valutazione
dell’efficacia
(efficacy)
PROGRAMMA
ORGANIZZATO DI
VACCINAZIONE
Valutazione del
beneficio
(effectiveness)
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 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)
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)
LESSON FROM THE HPV VACCINES
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)
DECLINE OF HPV PREVALENCE
-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%
DECLINE OF HPV PREVALENCE
Mesher D, et al. BMJ Open 2016
ENGLAND
2-HPV vaccine from 2008; females 16-24 yrs; coverage 80%; period 2008 vs 2010-13
DECLINE OF HPV PREVALENCE
-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?
DECLINE OF HPV PREVALENCE
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%
DECLINE OF HIGH-GRADE CIN
SWEDEN
(nationwide Swedish analysis on 4-HPV vaccination after 8 yrs)
(Herweijer E, 2016)
DECLINE OF HIGH-GRADE CIN
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)
DECLINE OF HIGH-GRADE CIN
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