Damm e al. Cos E Resou Alloc (2017) 15:18
DOI 10.1186/s12962-017-0080-9
RESEARCH
Cos -e ec i eness o human
papilloma i us accina ion inGe many
Oli e Damm1* , Johannes Ho n2, Ra ael T. Mikolajczyk2,3,4, Mi jam E. E. K e zschma 5,6, And eas M. Kau mann7,
Y onne Dele é8, Be nha d Ul sch9, Ole Wichmann9, Alexande K äme 10 and Wol gang G eine 1
Abs ac
Backg ound: The aim o his s udy was o assess he cos -e ec i eness o human papilloma i us (HPV) accina ion
in addi ion o he cu en ce ical cance sc eening p og amme in Ge many using a dynamic ansmission model.
Me hods: Based on a ma hema ical model simula ing he ansmission dynamics and he na u al his o y o HPV
in ec ion and associa ed diseases (ce ical in aepi helial neoplasia, ce ical cance , and geni al wa s), we es ima ed
he epidemiological and economic consequences o HPV accina ion wi h bo h he quad i alen and bi alen ac-
cines. In ou base case analysis, we assessed he cos -e ec i eness o accina ing 12-yea -old gi ls wi h a 3-dose
schedule. In sensi i i y analysis, we also e alua ed he use o a 2-dose schedule and assessed he impac o accina -
ing boys.
Resul s: F om a heal h ca e paye pe spec i e, inc emen al cos -e ec i eness a ios (ICERs) o a 3-dose schedule
we e €34,249 pe quali y-adjus ed li e yea (QALY) o he bi alen and €14,711 pe QALY o he quad i alen accine.
Inclusion o indi ec cos s dec eased ICERs by up o 40%. When adop ing a heal h ca e paye pe spec i e, ICERs o a
2-dose app oach dec eased o €19,450 pe QALY o he bi alen and o €3645 pe QALY o he quad i alen accine.
F om a socie al pe spec i e, a 2-dose app oach using he quad i alen accine was a cos -sa ing s a egy while using
he bi alen accine esul ed in an ICER o €13,248 pe QALY. I espec i e o he pe spec i e adop ed, addi ional ac-
cina ion o boys esul ed in ICERs exceeding €50,000 pe QALY, excep o scena ios wi h low co e age (20%) in gi ls.
Conclusions: Ou model esul s sugges ha ou ine HPV accina ion o 12-yea -old gi ls wi h h ee doses is likely
o be cos -e ec i e in Ge many. Due o he addi ional impac on geni al wa s, he quad i alen accine appea ed o
be mo e cos -e ec i e han he bi alen accine. A 2-dose schedule o he quad i alen accine migh e en lead o
cos sa ings when adop ing a socie al pe spec i e. The cos -e ec i eness o addi ional accina ion o boys was highly
dependen on he co e age in gi ls.
Keywo ds: HPV, Vaccina ion, Economic e alua ion, Cos -e ec i eness, Dynamic ansmission model, Ge many
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Backg ound
Pe sis en in ec ion wi h high- isk (oncogenic) ypes o
human papilloma i us (HPV) is he main cause o ce i-
cal cance and i s p ecu so s [1]. In ec ion wi h high- isk
HPV ypes can also cause o he ypes o anogeni al can-
ce (i.e. aginal, ul a , anal, and penile cance ) and o o-
pha yngeal cance [2, 3], whe eas in ec ion wi h low- isk
(non-oncogenic) HPV ypes is p ima ily associa ed wi h
geni al wa s [4].
Clinical s udies ha e demons a ed high e icacy o p o-
phylac ic HPV accines in he p e en ion o HPV in ec-
ions, p emalignan anogeni al lesions (ce ical, aginal,
ul a , and anal lesions), and geni al wa s [5–7]. In Ge -
many, he e a e cu en ly h ee HPV accines a ailable
o p e en HPV in ec ion and ela ed diseases: a bi alen
accine (Ce a ix®), a quad i alen accine (Ga dasil®),
and a 9- alen accine (Ga dasil® 9). All h ee accines
p o ec agains he high- isk geno ypes 16 and 18, which
cause app oxima ely 70% o all ce ical cance cases
Open Access
Cos E ec i eness and
Resou ce Alloca ion
*Co espondence: oli e [email p o ec ed]
1 Depa men o Heal h Economics and Heal h Ca e Managemen ,
School o Public Heal h, Biele eld Uni e si y, Uni e si ä ss aße 25,
33615 Biele eld, Ge many
Full lis o au ho in o ma ion is a ailable a he end o he a icle
Page 2 o 19
Damm e al. Cos E Resou Alloc (2017) 15:18
[8]. The quad i alen accine is addi ionally di ec ed
agains he low- isk geno ypes 6 and 11, which accoun
o app oxima ely 90% o geni al wa s [9]. The ecen ly
app o ed 9- alen e sion o Ga dasil® p o ec s agains
he ou s ains o he quad i alen accine and i e addi-
ional high- isk s ains (31, 33, 45, 52, and 58). All a ail-
able accines a e licensed o use in emales and males.
In Ge many, ou ine HPV accina ion wi h wo doses
is cu en ly ecommended o emales aged 9–14yea s
[10, 11]. Howe e , h ee doses a e necessa y when ac-
cina ing adolescen gi ls aged 15–17 yea s (due o
delayed ini ia ion o se ies comple ion) o when he
in e al be ween he i s and he second dose alls below
6mon hs. Be o e Augus 2014, h ee HPV accine doses
we e ecommended o emales aged 12–17yea s. Bo h
ecommenda ions ha e p ima ily aimed a p e en ing
ce ical cance . Since 1971, a ce ical cance sc eening
p og amme is implemen ed in Ge many, which is cu -
en ly based on an annual Pap smea beginning a he age
o 20yea s.
No independen ly unded dynamic ansmission model
analysing he cos -e ec i eness o HPV accina ion in
he Ge man heal h ca e se ing, which can suppo he
na ional decision-making p ocess o he S anding Vacci-
na ion Commi ee (STIKO), has been published ye .
The pu pose o his s udy was h ee old: (a) o assess
he cos -e ec i eness o he bi alen and quad i a-
len accines in addi ion o he exis ing ce ical can-
ce sc eening p og amme in Ge many using a dynamic
ansmission model, (b) o quan i y he economic impac
o swi ching om a 3-dose o a 2-dose schedule, and (c)
o compa e ou esul s wi h indings o p e iously pub-
lished s udies on he cos -e ec i eness o HPV accina-
ion in Ge many.
Me hods
O e iew
We de eloped a ma hema ical model simula ing he
ansmission dynamics and he na u al his o y o HPV
in ec ion and associa ed diseases o e alua e he epi-
demiological and economic consequences o HPV ac-
cina ion in Ge many. The age-s uc u ed model akes
accoun o he occu ence o ce ical in aepi helial
neoplasia (CIN), ce ical cance , and geni al wa s. I
was calib a ed using Ge man cance s a is ics and o he
da a. In he base case analysis, which was conduc ed
om bo h a heal h ca e paye and a socie al pe spec i e,
HPV accina ion o 12yea old gi ls in conjunc ion wi h
he exis ing cy ological sc eening p og amme was com-
pa ed o sc eening alone. The ime ho izon was se o
100yea s a e he in oduc ion o HPV accina ion. Epi-
demiological and economic pa ame e es ima es we e
ob ained om published li e a u e and supplemen ed
by expe in e iews. The model was p og ammed using
he so wa e R. All cos calcula ions we e pe o med
using Mic oso Excel. De ails on he me hods and da a
sou ces used o cons uc he model a e desc ibed in he
ollowing sec ions. A mo e de ailed desc ip ion o he
unde lying epidemiological model and he co espond-
ing model pa ame e s ega ding he ansmission o
HPV, he na u al his o y o ce ical HPV in ec ion, and
he simula ed sc eening p og amme has been published
p e iously [12].
Model s uc u e
The basic model s uc u e combines an age-s uc u ed
de e minis ic compa men al model, which simula es he
sexual ansmission o HPV, wi h a model ha ep esen s
he na u al his o y o ce ical cance .
The ansmission dynamics a e desc ibed by a SIRS-
model whe e he popula ion is di ided in o suscep ible
indi iduals (S), in ec ious indi iduals (I), and eco e ed
(and he e o e immune) indi iduals (R). Ou model con-
side s six g oups o i al s ains: HPV 16, HPV 18, phy-
logene ically ela ed high- isk ypes wi h po en ial o
c oss-p o ec ion (HPV 31/33/35/39/45/51/52/56/58/59),
o he high- isk ypes wi hou po en ial o c oss-p o ec-
ion, HPV 6/11, and o he low- isk ypes. We neglec ed
any syne gis ic and an agonis ic in e ac ions be ween di -
e en HPV ypes as mul i-s ain in e ac ions a e subjec
o con o e sy.
To es ima e he long- e m consequences o HPV in ec-
ion, he ansmission model was complemen ed by a
module co e ing he ce ical ca cinogenesis. This pa o
he model includes ype-speci ic heal h s a es o ha ing
CIN o h ee g ades (CIN 1, CIN 2, o CIN 3), ha ing ca -
cinoma insi u (CIS), and ha ing in asi e ce ical cance
o di e en s ages acco ding o he In e na ional Fede a-
ion o Gynecology and Obs e ics (FIGO) classi ica ion
sys em. CIS and in asi e cance s a es we e u he sub-
di ided in o unde ec ed and de ec ed disease s a es. Fo
women who had unde gone hys e ec omy, only ansi-
ions be ween he suscep ible, in ec ed, and immune
( eco e ed) s a es we e pe mi ed. The e o e, wi h he
excep ion o sexual mixing and backg ound mo ali y,
hose women we e modelled iden ically o males who
we e only allowed o mo e be ween he suscep ible,
in ec ed, and immune s a es. The occu ence o geni-
al wa s in bo h gende s was modelled as an e en ha
was linked wi h inciden in ec ions wi h low- isk ypes,
bu only a p opo ion o hose newly in ec ed indi idu-
als we e assumed o de elop clinical symp oms o geni al
wa s and o seek medical ea men . A simpli ied low
diag am o he model s uc u e ep esen ing he na u al
his o y o HPV in ec ion and ce ical cance in women is
ou lined in Fig.1.
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Damm e al. Cos E Resou Alloc (2017) 15:18
Da a sou ces andmodel inpu s
Demog aphic, beha iou al, and ansmission pa ame e s
The model popula ion is based on a cons an numbe o
one million bi hs pe yea and he 2008 mo ali y a es
in Ge many de i ed om he Fede al S a is ical O ice.
Ou model ocusses on he e osexual ansmission o
HPV in ec ion only. We assumed he sexual debu o be
a he age o 12yea s and di ided he sexually ac i e pop-
ula ion in o en age g oups (12–13, 14–15, 16–17, 18–24,
25–34, 35–44, 45–54, 55–64, 65–74, and 75–100yea s)
and h ee sexual ac i i y-based isk g oups (low, mod-
e a e, and high ac i i y). The p opo ions o indi iduals
belonging o he di e en ac i i y classes we e 80, 15,
and 5% o he low, mode a e, and high ac i i y g oups,
espec i ely [13]. The mixing pa e ns be ween indi-
iduals o he di e en age and isk g oups we e de e -
mined by wo mixing pa ame e s. These pa ame e s o
he asso a i eness o mixing by age and by isk g oup
we e se o 0.4 and 0.3, espec i ely [14]. An asso a i e-
ness by age o 0.4 means ha 40% o new sexual pa ne s
a e p e e en ially chosen om he same age g oup while
he emaining sexual pa ne s a e chosen p opo ionally
om all age g oups depending on hei size. An asso a-
i eness by isk g oup o 0.3 means ha 30% o pa ne s
a e p e e en ially chosen wi hin he same sexual ac i i y
g oup while he emaining sexual pa ne s a e chosen
p opo ionally om all sexual ac i i y g oups depending
on hei size. As obus Ge man da a on pa e ns o sex-
ual beha iou we e lacking, we used da a om he ans-
mission model by Zechmeis e e al. [15], which had been
o iginally de i ed om B i ish and No wegian su eys o
sexual beha iou .
Na u al his o y
The ini ial alues o he epidemiological model pa am-
e e s ega ding he na u al his o y o ce ical cance
we e ob ained om he published li e a u e, pa icula ly
om p e ious modelling s udies [14, 16–20]. Whe eas
some pa ame e alues we e di ec ly inco po a ed in ou
model, o he alues we e de i ed h ough calib a ion.
De ails on he pa ame e alues used in ou model a e
p o ided in an a icle by Ho n e al. [12].
No e e y HPV in ec ion is ollowed by he de elop-
men o a ype-speci ic esis ance. Hence, we only allowed
a ac ion o he in ec ed popula ion o be immune a e
in ec ion o a ce ain pe iod o ime [21]. The p opo ion
o indi iduals expe iencing a se ocon e sion was es i-
ma ed o be 60% [22]. The ac ion o se ocon e ed indi-
iduals de eloping a na u ally acqui ed immuni y was
es ima ed o be 30% [23]. Waning o na u ally acqui ed
immuni y was assumed o be 10% pe yea esul ing in an
a e age ype-speci ic immuni y o 10yea s.
Well
(suscepble)
Well
( eco e ed)
HPV-in ec ed
CIN 1
CIN 2
CIN 3
FIGO IV
FIGO III
FIGO II
FIGO I
CIS
FIGO III
FIGO II
FIGO I
CIS
Ce icalcance
(unde ec ed)
Ce icalcance
(de ec ed)
FIGO IV
Benign hys e ec omy
Dea h
F om all non-
cance s a es
F om all s a es
Fig. 1 Simpli ied model s uc u e (adap ed om Ho n e al. [12])
Page 4 o 19
Damm e al. Cos E Resou Alloc (2017) 15:18
In ou model, he CIS s a e was subdi ided in o wo
compa men s as p oposed by Insinga e al. [24] o a oid
sho ansi ion imes om CIS o in asi e cance esul -
ing om he exponen ial dis ibu ion.
Sc eening p og amme
The sc eening module o ou model was cons uc ed o
e lec he cu en sc eening p ac ice in Ge many. We
applied age-speci ic sc eening co e age a es ha we e
ob ained om Ge man da a [25] and assumed he p o-
po ion o women who ne e pa icipa e in sc eening
o be 7% as done in o he modelling s udies [18, 19]. To
simula e he u u e e ec s o he s epwise inc ease in
sc eening co e age in Ge many du ing he 1990s and o
p e en an o e es ima ion o he accine-induced educ-
ion in ce ical cance - ela ed bu den o disease, we
inco po a ed his o ical changes in sc eening up ake in
ou model. Fo his pu pose, we combined he cu en
age-speci ic sc eening co e age a es wi h he obse ed
changes in pa icipa ion in ea ly cance de ec ion p o-
g ammes o e ime [26]. Diagnos ic ollow-up (including
managemen o abno mal ce ical cy ology and his ol-
ogy) was modelled by he use o in eg a ed decision ees.
The cons uc ion o hese decision ees was based on
clinical guidelines, empi ical s udies, heal h economic
models, and an in e iew wi h membe s o he Ge man
wo king g oup on ce ical pa hology and colposcopy ha
was conduc ed explici ly o his pu pose.
Vaccina ion
In he base case scena io, we analysed he cos -e ec-
i eness o accina ing 12-yea -old gi ls wi h h ee
doses. Vaccina ion co e age was assumed o be 50%
based on se e al s udies assessing HPV accine up ake
in Ge many [27–32]. In hese s udies, epo ed up ake,
de ined as eceip o a leas one HPV accine dose,
anged om 30 o 60%. When conside ing only hose
emales who ecei ed he ull cou se o h ee doses,
up ake anged om 27 o 48%. We assumed comple ion
o he 3-dose se ies o all gi ls who ini ia ed accina-
ion. All analyses we e ca ied ou o bo h he bi a-
len and quad i alen accines. Vaccine e icacy agains
HPV 16/18 in ec ion was es ima ed o be 98% o bo h
accines, and accine e icacy in p e en ing HPV 6/11
in ec ion was es ima ed o be 100% o he quad i alen
accine. C oss-p o ec ion agains non- accine onco-
genic HPV- ypes was no conside ed in he base case
scena io bu was explo ed in sensi i i y analysis aking
he di e en c oss-p o ec ion p o iles o he accines
in o accoun . Cu en ly, he maximum du a ion o ac-
cine p o ec ion is unknown. Clinical e icacy agains
ype-speci ic in ec ion and associa ed diseases has been
demons a ed up o 9.4yea s pos - accina ion [33], bu
long- e m pe sis ence o an ibody esponses has been
p edic ed by s a is ical modelling o indi idual an ibody
da a [34, 35]. Taking bo h he e idence based on lim-
i ed ollow-up o adolescen gi ls and women in clini-
cal ials and he p edic ions o s a is ical models in o
accoun , we decided o assume a 10yea s las ing ini ial
pe iod o sus ained accine p o ec ion ollowed by a
pe iod o waning immuni y using a waning a e o 10%
pe yea . This app oach esul ed in an a e age du a ion
o accine-induced immuni y o 20yea s. We sepa a ely
examined he impac o li elong p o ec ion as well as
he in luence o adminis e ing a boos e dose in sensi-
i i y analysis. While in he base case scena io accina-
ion was es ic ed o gi ls, immunisa ion o boys was
assessed in sensi i i y analysis. A 2-dose schedule was
also examined in sensi i i y analysis. All accina ion-
ela ed inpu da a a e p esen ed in Table1.
Resou ce u ilisa ion anddi ec heal h ca e cos s
Ou model akes in o accoun esou ce use associa ed
wi h accina ion, sc eening, managemen o abno mal
cy ological sc eening esul s, managemen and ea -
men o biopsy-con i med CIN, and ea men o ce ical
cance and geni al wa s. Di ec heal h ca e cos s we e
calcula ed conside ing all ele an cos componen s ha
a e eimbu sed by he s a u o y heal h insu ance. These
componen s include medica ion, physician consul a-
ions, ou pa ien diagnos ic p ocedu es, labo a o y es -
ing, he apeu ic appliances and ou pa ien heal h ca e
se ices p o ided by non-physicians (i.e. medical com-
p ession igh s and manual lympha ic d ainage as pa o
lymphoedema ea men ), and hospi alisa ions.
T ea men pa e ns and ela ed esou ce consump ion
we e mainly de i ed om clinical guidelines and pub-
lished s udies on he cu en managemen o ce ical
cance and i s p ecu so s [36–39]. Li e a u e-based e i-
dence was supplemen ed by expe opinion o accoun
o missing da a o Ge many and a ia ion in clinical
p ac ice. Fo ins ance, he expe s we e asked o es ima e
he s age-speci ic equency o u ilisa ion o di e en
ou pa ien and inpa ien ea men p ocedu es o ce ical
cance . A o al o six expe in e iews wi h gynaecolo-
gis s we e conduc ed by elephone o in w i en o m.
Table2 gi es an o e iew o he assumed ea men pa -
e ns and esou ce u ilisa ion in he ea men and pos -
ea men ollow-up o ce ical cance .
Mos uni cos s we e based on o icial Ge man p ice
lis s, ee scales, o ca alogues. Vaccine p ices and d ug
cos s we e ob ained om he pha maceu ical da abase
LAUER-TAXE® [40]. The cos pe dose o bo h accines
was es ima ed a €150.41. The mean accine adminis a-
ion ee was calcula ed o be €7.50 pe dose, based on
a e iew o he immunisa ion ee scales o all egional
Page 5 o 19
Damm e al. Cos E Resou Alloc (2017) 15:18
Associa ions o S a u o y Insu ance Physicians in Ge -
many. Cha ges o ou pa ien isi s as well as ou pa ien
diagnos ic and ea men p ocedu es we e based on he
physician ee scale (Einhei liche Bewe ungsmaßs ab,
EBM) o he s a u o y heal h insu ance. Hospi alisa ion
cos s we e e ie ed om he Ge man diagnosis- ela ed
g oup (DRG) ca alogue using a base a e o €2935.78
and he cos weigh s o a ious DRGs (N01A, N01E,
N03B, N09Z, N15Z, and N60A). Cos s o inpa ien pal-
lia i e ca e and ea men we e calcula ed assuming a
leng h o s ay o 30days and combining he DRG N60B
wi h a supplemen a y ee o pallia i e ca e (ZE60.01). All
di ec cos s we e adjus ed o pa ien co-paymen s. Cos
es ima es o ea ing CIN 3 and CIS we e aken om a
Ge man esou ce use s udy p o iding in e en ion cos s
associa ed wi h a PAP IV diagnosis o he Munich Cy o-
logical Classi ica ion, which co esponds o se e e dys-
plasia and CIS [41]. Cos s o ea ing geni al wa s we e
based on own calcula ions using da a om a Ge man
cos -o -illness s udy [42]. All cos s a e epo ed in 2010
eu os. Whe e 2010 p ices we e no a ailable, p ices we e
in la ed o 2010 alues using he Ge man consume p ice
index (CPI). The base case alues o he agg ega ed di ec
heal h ca e cos s a e summa ised in Table3.
Indi ec cos s
Indi ec cos s in e ms o p oduc ion losses we e con-
side ed when adop ing a socie al pe spec i e. Da a
on absence om wo k due o HPV-associa ed illness
we e ob ained om he s a is ics o a Ge man sickness
und [43] using yea 2008 in o ma ion. Indi ec cos s
we e calcula ed by he ic ion cos  app oach assum-
ing he ic ion pe iod equal o he a e age du a ion o a
acan job posi ion. Acco ding o a epo o he Fede al
Employmen Agency [44], his pe iod was assumed o be
63days. Cos pe wo k day los was es ima ed a €85.13
using 2010 da a on mone a y compensa ion and num-
be o employees in Ge many om he Fede al S a is i-
cal O ice [45]. Indi ec cos s due o CIN and ce ical
cance we e weigh ed by age-speci ic employmen a es
o women o a oid an o e es ima ion o he p oduc ion
losses. All indi ec cos inpu s a e summa ised in Table4.
Heal h s a e u ili ies
In he absence o u ili y alues ha a e speci ic o Ge -
many, he da a o calcula ing quali y-adjus ed li e yea s
(QALYs) we e aken om he in e na ional li e a u e and
p e ious heal h economic models. These s udies applied
di e en me hods o elici ing QALY weigh s including
he use o he EQ-5D ques ionnai e [46], he ime ade-
o echnique [47], and an expe -based applica ion o he
Heal h U ili y Index (HUI) Ma k II [48]. The selec ion o
u ili y alues was guided by he model s uc u e. The u il-
i y alues used in ou model a e p esen ed in Table5. We
assumed he baseline u ili y alue o no mal heal h o be
1.0. Es ima es o he du a ion o educ ions in quali y o
li e we e mainly based on expe opinion. QALY losses
associa ed wi h Pap smea -based sc eening and diagnos-
ic ollow-up o cy ological and his ological esul s we e
no conside ed in ou modelling app oach.
Discoun ing
In he base case analysis, u u e cos s and heal h e ec s
we e discoun ed a an annual a e o 3% as ecommended
by guidelines o he Ins i u e o Quali y and E iciency
in Heal h Ca e [49] and he STIKO [10]. O he Ge man
ecommenda ions on heal h economic e alua ion, also
e e ed o as Hano e Consensus, a ou a discoun a e
Table 1 Vaccina ion- ela ed inpu a iables
HPV human papilloma i us
Pa ame e Value Sou ce
Vaccine e icacy HPV 16/18 in emales 98% [81, 82]
HPV 6/11 in emales (quad i alen accine only) 100% [83]
HPV 16/18 in males 90.4% [84]
HPV 6/11 in males (quad i alen accine only) 90.4% [84]
C oss-p o ec ion p o ided by he quad i alen accine
(conside ed in sensi i i y analysis only) HPV 31/33/35/39/45/51/52/56/58/59 32.5% [85, 86]
C oss-p o ec ion p o ided by he bi alen accine
(conside ed in sensi i i y analysis only) HPV 31/33/35/39/45/51/52/56/58/59 68.4% [86]
Du a ion o ull p o ec ion 10 yea s Assump ion
Waning (a e he du a ion o ull p o ec ion) 0.1 pe yea Assump ion
Vaccina ion co e age 50% Assump ion
Age a accina ion 12 yea s Assump ion
Boos e accina ion No boos e accina ion in he base case analysis Assump ion

Page 6 o 19
Damm e al. Cos E Resou Alloc (2017) 15:18
o 5% [50], which was conside ed in sensi i i y analysis.
In addi ion, we assessed he impac o di e en ial dis-
coun ing (3% o cos s and 1.5% o heal h e ec s) [51].
Analy ic s a egy andsensi i i y analysis
To de e mine he cos -e ec i eness o he in oduc ion o
HPV accina ion in Ge many, we calcula ed inc emen al
Table 2 T ea men pa e ns and esou ce u ilisa ion in he ea men andpos - ea men ollow-up o ce ical cance
(pe cen ages a e a e age alues based onexpe s’ esponses)
FIGO In e na ional Fede a ion o Gynecology and Obs e ics
Ce ical cance s age (FIGO
classi ica ion) o ea men phase T ea men pa e ns and esou ce u ilisa ion
FIGO IA1 Conisa ion 60%
Conisa ion wi h pel ic lymph node dissec ion 10%
Simple hys e ec omy 20%
Simple hys e ec omy wi h pel ic lymph node dissec ion 10%
FIGO IA2 Conisa ion wi h pel ic lymph node dissec ion 20%
Radical achelec omy wi h pel ic lymph node dissec ion 10%
Simple hys e ec omy 10%
Simple hys e ec omy wi h pel ic lymph node dissec ion 60%
FIGO IB1 Radical hys e ec omy wi h pel ic lymph node dissec ion 64%
Radical hys e ec omy wi h pel ic lymph node dissec ion and adju an chemo adio he apy 16%
Radical achelec omy wi h pel ic lymph node dissec ion 5%
Chemo adio he apy 15%
FIGO IB2 Radical hys e ec omy wi h pel ic and pa aao ic lymph node dissec ion 49%
Radical hys e ec omy wi h pel ic and pa aao ic lymph node dissec ion and adju an chemo adio-
he apy 21%
Chemo adio he apy 30%
FIGO IIA Radical hys e ec omy wi h pel ic and pa aao ic lymph node dissec ion 35%
Radical hys e ec omy wi h pel ic and pa aao ic lymph node dissec ion and adju an chemo adio-
he apy 15%
Chemo adio he apy 50%
FIGO IIB Radical hys e ec omy wi h pel ic and pa aao ic lymph node dissec ion 12%
Radical hys e ec omy wi h pel ic and pa aao ic lymph node dissec ion and adju an chemo adio-
he apy 18%
Chemo adio he apy 70%
FIGO IIIA Radical hys e ec omy wi h pel ic and pa aao ic lymph node dissec ion 2%
Radical hys e ec omy wi h pel ic and pa aao ic lymph node dissec ion and adju an chemo adio-
he apy 8%
Chemo adio he apy 90%
FIGO IIIB Radical hys e ec omy wi h pel ic and pa aao ic lymph node dissec ion 2%
Radical hys e ec omy wi h pel ic and pa aao ic lymph node dissec ion and adju an chemo adio-
he apy 8%
Chemo adio he apy 90%
FIGO IVA Radical hys e ec omy wi h pel ic and pa aao ic lymph node dissec ion 2%
Radical hys e ec omy wi h pel ic and pa aao ic lymph node dissec ion and adju an chemo adio-
he apy 8%
Chemo adio he apy 80%
Exen e a ion 2%
Exen e a ion and adju an chemo adio he apy 8%
FIGO IVB Chemo adio he apy 40%
Pallia i e chemo he apy 60%
Pos - ea men ollow-up Ou pa ien isi s, Pap-smea s, and pel ic and abdominal ul asonog aphy 100%
Ho mone eplacemen he apy (women <50 yea s) 50%
Manual lympha ic d ainage and medical comp ession igh s 10–30%
Page 7 o 19
Damm e al. Cos E Resou Alloc (2017) 15:18
Table 3 Di ec heal h ca e cos s
Pa ame e Di ec cos s (€, 2010 p ice le el)
Vaccina ion cos s
Vaccine (ini ial se ies o 3 doses) 451.23
Adminis a ion (ini ial se ies o 3 doses) 22.50
Boos e sho (pe dose) 150.41
Adminis a ion o boos e sho (pe dose) 7.50
Cos s o sc eening, managemen o abno mal cy ological sc eening esul s, and obse a ional ollow-up o CIN 1 and CIN 2
Cy ological sc eening (Pap smea ) 25.23
Follow-up smea (including qua e ly Gynaecologis ’s ee and op ional colposcopy) ≤59 yea s 20.15
60+ yea s 20.33
HPV es (including qua e ly Gynaecologis ’s ee) ≤59 yea s 44.77
60+ yea s 44.94
HPV es and ollow-up smea (including qua e ly Gynaecologis ’s ee) ≤59 yea s 50.55
60+ yea s 50.73
Colposcopy (including qua e ly Gynaecologis ’s ee) ≤59 yea s 14.37
60+ yea s 14.54
Biopsy and his ology 129.47
Cos s o CIN/CIS ea men and pos - ea men ollow-up
Conisa ion o he ce ix (CIN 1 and CIN 2) ≤39 yea s 525.05
40–59 yea s 531.22
60+ yea s 534.17
T ea men o CIN 3 and CIS 1621.53
Pos - ea men ollow-up o CIN/CIS (yea 1 and 2 a e ea men ) ≤59 yea s 70.71
60+ yea s 71.06
Cos s o ce ical cance ea men and pos - ea men ollow-up
Diagnos ics o symp om-de ec ed ce ical cance ≤59 yea s 323.03
60+ yea s 324.08
Diagnos ics o sc een-de ec ed ce ical cance ≤59 yea s 179.18
60+ yea s 180.06
T ea men o ce ical cance (FIGO I) ≤59 yea s 7586.98
60+ yea s 7591.22
T ea men o ce ical cance (FIGO II) ≤59 yea s 11,455.22
60+ yea s 11,456.94
T ea men o ce ical cance (FIGO III) ≤59 yea s 12,380.21
60+ yea s 12,380.70
T ea men o ce ical cance (FIGO IV) ≤59 yea s 10,615.72
60+ yea s 10,616.21
Pos - ea men ollow-up o ce ical cance (yea 1 a e ea men ) ≤49 yea s 841.53
50–59 yea s 835.65
60+ yea s 836.35
Pos - ea men ollow-up o ce ical cance (yea 2 a e ea men ) ≤49 yea s 428.13
50–59 yea s 422.25
60+ yea s 422.95
Pos - ea men ollow-up o ce ical cance (yea 3 a e ea men ) ≤49 yea s 352.42
50–59 yea s 346.54
60+ yea s 347.24
Pos - ea men ollow-up o ce ical cance (yea 4 and 5 a e ea men ) ≤49 yea s 282.50
50–59 yea s 276.62
60+ yea s 276.97
Page 8 o 19
Damm e al. Cos E Resou Alloc (2017) 15:18
cos -e ec i eness a ios (ICERs) using li e yea s (LYs)
gained and QALYs gained as ou come measu es. The base
case analysis was ca ied ou om he Ge man heal h ca e
paye pe spec i e, which is he pe spec i e o he s a u-
o y heal h insu ance unds ( aking accoun o eimbu sed
di ec cos s only), and om he socie al pe spec i e (con-
side ing eimbu sed di ec cos s as well as indi ec cos s).
Pa ien co-paymen s we e no included in bo h pe spec-
i es since no all ele an sou ces p o ided su icien
de ails on ha aspec .
We e alua ed he long- e m heal h and economic e ec s
o accina ing 12-yea -old gi ls agains HPV alongside
he cu en cy ology-based ce ical cance sc eening p o-
g amme compa ed o an exclusi e con inua ion o he
cy ological sc eening p og amme. De e minis ic sensi i -
i y analyses we e pe o med o es he obus ness o he
esul s o changes in model inpu da a and assump ions.
The impac o a ying single model pa ame e s was exam-
ined by one-way sensi i i y analyses. Pa ame e s a ied
we e cha ac e is ics o he accina ion p og amme, cos s,
u ili ies, and he discoun a e. Fu he mo e, we assessed
he implica ion o inco po a ing accine-speci ic c oss-p o-
ec ion and e alua ed he addi ional impac o accina ing
boys. Since a 2-dose schedule showed equi alen an ibody
esponse and simila e icacy o he s anda d 3-dose egi-
men [52–54], we also analysed he cos -e ec i eness o
adminis e ing only wo doses a he age o 12yea s assum-
ing he same le el o p o ec ion. Mul i a ia e sensi i i y
analyses we e ca ied ou in e ms o bes -case (6/11/16/18
e icacy: 100%; accine-speci ic c oss-p o ec ion: 32.5 o
68.4%; li elong p o ec ion; 20% inc ease in sc eening and
ea men cos ; 20% inc ease in quali yo li e de imen s;
socie al pe spec i e) and wo s -case (6/11/16/18 e icacy:
80%; no c oss-p o ec ion; a e age du a ion o p o ec ion:
15yea s; 20% dec ease in sc eening and ea men cos ;
20% dec ease in quali yo li e de imen s; heal h ca e paye
pe spec i e) analyses.
Model calib a ion and alida ion
Model calib a ion is he p ocess o adjus ing inpu
pa ame e alues un il he simula ion ou pu ma ches
empi ical da a. Ou model was calib a ed o e lec
obse a ions on age-speci ic p e alence o HPVin ec-
ion [55–59], age-speci ic p e alence o CIN [60], age-
speci ic incidence and mo ali y o ce ical cance [61],
as well as HPV ype-dis ibu ion in di e en ce ical
disease s a es [57, 62–65]. When da a o Ge many we e
no a ailable, we used da a om o he coun ies. The
modi ica ion o pa ame e alues and he subsequen
compa ison o he simula ion esul s wi h he obse ed
da a we e pe o med manually. Fu he mo e, we used
age-speci ic adjus men ac o s o ou g oups o
pa ame e s (p og ession p obabili ies o cance , eg es-
sion p obabili ies, de ec ion o cance by symp oms, and
mo ali y o ce ical cance ) o achie e a be e i o he
obse ed da a. Mo e de ails ega ding bo h he model
calib a ion p ocess and he esul s o he model alida-
ion ha e been p e iously published [12].
Sys ema ic li e a u e e iew
We pe o med a sys ema ic li e a u e e iew o compa e
ou esul s wi h indings o p e iously published s udies
on he cos -e ec i eness o HPV accina ion in Ge many.
A PubMed-based li e a u e sea ch was conduc ed using
he ollowing sea ch e ms: (“HPV” OR “human papillo-
ma i us”) AND (“ accine” OR “ accina ion” OR “immu-
nisa ion” OR “immuniza ion”) AND (“cos -e ec i eness”
OR “economic”) AND “Ge many”. This sea ch was com-
plemen ed by scanning e e ence lis s o p e iously iden-
i ied ull- ex a icles. A s udy was included i i me he
ollowing c i e ia: (i) i was an economic e alua ion o
HPV accina ion in Ge many, (ii) i was conduc ed om
a heal h ca e paye o a socie al pe spec i e, (iii) i was
w i en in English o Ge man, and (i ) i was published as
a ull- ex a icle.
Table 3 con inued
Pa ame e Di ec cos s (€, 2010 p ice le el)
Pos - ea men ollow-up o ce ical cance ( om yea 6 a e ea men onwa ds) ≤49 yea s 262.35
50–59 yea s 256.47
60+ yea s 256.65
Inpa ien pallia i e ca e and ea men 7518.09
Cos s o geni al wa s ea men
T ea men o geni al wa s in emales 572.14
T ea men o geni al wa s in males 396.69
CIN ce ical in aepi helial neoplasia, CIS ca cinoma insi u, FIGO In e na ional Fede a ion o Gynecology and Obs e ics
Page 9 o 19
Damm e al. Cos E Resou Alloc (2017) 15:18
Table 4 Indi ec cos s
CIN ce ical in aepi helial neoplasia, CIS ca cinoma insi u, FIGO In e na ional Fede a ion o Gynecology and Obs e ics
a A e age du a ion o absence om wo k in pa ien s who missed wo k because o illness
b Weigh ed by age-speci ic employmen a es o women
c No weigh ed by age-speci ic employmen a es as he ac ion o geni al wa s pa ien s who missed wo k was es ima ed di ec ly on he basis o a Ge man s udy
[42]
Pa ame e A e age absence omwo k (days)aIndi ec cos s (€, 2010 p ice le el)b
T ea men o CIN 1 and CIN 2 15.9 15–19 yea s 336.50
20–24 yea s 835.26
25–29 yea s 965.33
30–34 yea s 977.31
35–39 yea s 1009.89
40–44 yea s 1063.18
45–49 yea s 1060.82
50–54 yea s 1010.30
55–59 yea s 853.97
60–64 yea s 410.89
T ea men o CIN 3 and CIS 21.3 15–19 yea s 450.79
20–24 yea s 1118.93
25–29 yea s 1293.18
30–34 yea s 1309.23
35–39 yea s 1352.87
40–44 yea s 1424.25
45–49 yea s 1421.10
50–54 yea s 1353.42
55–59 yea s 1144.00
60–64 yea s 550.44
T ea men o ce ical cance (all FIGO s ages) 44.4 15–19 yea s 939.67
20–24 yea s 2332.42
25–29 yea s 2695.65
30–34 yea s 2729.11
35–39 yea s 2820.06
40–44 yea s 2968.87
45–49 yea s 2962.30
50–54 yea s 2821.22
55–59 yea s 2384.68
60–64 yea s 1147.39
Dea h due o ce ical cance (all FIGO s ages) 63 ( ic ion pe iod) 15–19 yea s 1333.31
20–24 yea s 3309.52
25–29 yea s 3824.91
30–34 yea s 3872.38
35–39 yea s 4001.44
40–44 yea s 4212.58
45–49 yea s 4203.26
50–54 yea s 4003.08
55–59 yea s 3383.67
60–64 yea s 1628.06
T ea men o geni al wa s in emales 7.7 15–64 yea s 30.81c
T ea men o geni al wa s in males 8.7 15–64 yea s 28.14c
Page 16 o 19
Damm e al. Cos E Resou Alloc (2017) 15:18
Compa ison wi ho he models
In o he models e lec ing he Ge man heal h ca e se -
ing, he cos pe QALY o quad i alen HPV accina ion
wi h h ee doses anged be ween €10,000 and €20,000
om a heal h ca e paye pe spec i e when assuming a
20yea s las ing du a ion o p o ec ion and conside ing
e ec s on CIN, ce ical cance , and geni al wa s [67,
69]. Ou es ima e o €14,711 pe QALY alls wi hin his
ange o es ima es. When adop ing a socie al pe spec i e,
quad i alen HPV accina ion o 12-yea -old gi ls wi h
wo doses esul ed in cos sa ings in ou model. This also
compa es well wi h p e ious indings [66]. In con as ,
he s udy by Soe gel e al. [68] allows no di ec compa i-
son wi h ou es ima es because i ocussed on conisa ion-
associa ed neona al mo bidi y and mo ali y. Howe e ,
Soe gel e al. [68] showed ha accina ing gi ls agains
HPV 16/18 migh e en be cos -e ec i e wi hou consid-
e ing he impac on ce ical cance .
S eng hs andlimi a ions
An impo an s eng h o ou s udy is ha we p esen ed
esul s o a wide ange o scena ios a ying he a ge
g oup ( emale accina ion s. no accina ion; emale and
male accina ion s. emale accina ion), co e age a e,
and numbe o accine doses. Ano he s eng h is ha we
used a dynamic ansmission model o es ima e he cos -
e ec i eness o HPV accina ion in Ge many. Compa ed
o s a ic models, which accoun only o di ec e ec s o
accina ion, dynamic models also cap u e indi ec e ec s
in e ms o he d p o ec ion [75]. Fu he mo e, we included
he impac o his o ical changes in pa icipa ion a es o
he cy ological ce ical cance sc eening in Ge many. This
is one eason why ou model migh p o ide mo e accu a e
esul s han he dynamic model om Schobe e al. [67].
In addi ion, we applied a mo e comp ehensi e calib a ion
app oach han he a o emen ioned model and used age-
speci ic epidemiological da a o se e al calib a ion a ge s.
We acknowledge ha ou model also has se e al limi a-
ions. Fi s , we did no include o he cance s han ce ical
cance . O he modelling s udies showed ha conside -
ing he impac on aginal, ul a , penile, anal, and head
and neck cance could imp o e he cos -e ec i eness o
HPV accina ion [76, 77]. Howe e , ou model e lec s
he goal o he cu en Ge man HPV immunisa ion ec-
ommenda ion, which is de ined (by STIKO) as he educ-
ion in disease bu den caused by ce ical cance . Second,
ou model e alua ed he cos -e ec i eness o he bi alen
and quad i alen accines, bu did no include he new
9- alen HPV accine, which was in oduced in Ge many
a e comple ion o his s udy. Howe e , we in es iga ed
he impac o including accine-speci ic c oss-p o ec ion
agains non- accine high- isk HPV ypes in sensi i -
i y analyses, and co esponding esul s migh gi e an
imp ession o he cos -e ec i eness o highe - alen ac-
cines. We ecommend including he 9- alen HPV ac-
cine in u u e modelling s udies. Thi d, ou model did no
accoun o po en ial c oss-p o ec ion o he bi alen ac-
cine agains low- isk HPV ypes. Resul s o an ecological
s udy sugges ha he e migh be a mode a e c oss-p o-
ec i e e ec o he bi alen accine agains geni al wa s
since he a es o geni al wa s ha e declined a e he
in oduc ion o a na ional HPV accina ion p og amme
using he bi alen accine in England [78]. In addi ion, a
pos hoc analysis o a clinical ial showed ha he bi alen
accine p o ides a mode a e e icacy agains pe sis en
in ec ion wi h low- isk HPV ypes [79]. Ne e heless, he
unde lying biological mechanisms o hese indings ha e
no ye been cla i ied conclusi ely. Fou h, in ou base
case analysis, we assumed a accina ion age o 12yea s in
o de o ensu e compa abili y wi h o he s udies al hough
mos gi ls in Ge many ha e ecei ed he i s dose in he
age o 13 o 14yea s [28]. Howe e , he upda ed immuni-
sa ion ecommenda ion a ou s a younge accina ion age
( om 9 yea s), which migh impac u u e heal h and eco-
nomic e ec s o HPV accina ion. Fi h, modelling o ce -
ical cance sc eening was based on cy ological sc eening,
which p edominan ly e lec s he cu en sc eening p ac-
ice in Ge many. Howe e , u u e changes o ce ical
cance sc eening may in ol e p ima y HPV es ing [80].
Six h, inpu da a on sexual beha iou we e based on su -
eys om o he Eu opean coun ies, and ac ual beha iou
in Ge many migh di e om ha in o he coun ies.
Se en h, due o he lack o Ge man-speci ic u ili y al-
ues, he u ili y es ima es we used in ou model we e
aken om in e na ional s udies wi h some o hem es -
ing on expe opinion. Fu he mo e, we assumed a base-
line u ili y alue o 1.0 in he absence o HPV-associa ed
diseases, which migh lead o a po en ial o e es ima ion
o HPV- ela ed QALY losses. Howe e , sensi i i y analy-
ses showed ha a ia ions in u ili ies had limi ed impac
on he esul s. Eigh h, since we used a s able popula ion
app oach, ou model did no ake accoun o demog aphic
ends and hei implica ions.
Conclusions
Conside ing he o en-ci ed h eshold o €50,000 pe
QALY, ou model esul s sugges ha ou ine HPV acci-
na ion o 12-yea -old gi ls wi h h ee doses is likely o be
cos -e ec i e in Ge many. Due o he addi ional impac
on HPV 6/11- ela ed diseases (mos ly geni al wa s), he
quad i alen accine appea ed o be mo e cos -e ec i e
han he bi alen accine, e en when conside ing he
highe c oss-p o ec ion o he bi alen accine. Mos o
hese indings a e consis en wi h esul s p edic ed by
p e iously published indus y- unded models o HPV
accina ion in Ge many. Ou model also showed ha a

Page 17 o 19
Damm e al. Cos E Resou Alloc (2017) 15:18
2-dose schedule o he quad i alen accine could esul
in cos sa ings when assuming an equi alen le el o p o-
ec ion and adop ing a socie al pe spec i e. Addi ional
accina ion o boys was ound o be a cos -e ec i e s a -
egy in scena ios wi h low co e age in gi ls. Howe e ,
he e is a need o an ex ended e sion o his model ha
also accoun s o he po en ial impac on non-ce ical
cance ypes in bo h gende s since he conside a ion o
his aspec migh lead o mo e a ou able esul s ega d-
ing he addi ional accina ion o boys in scena ios wi h
mode a e o high co e age in gi ls.
Abb e ia ions
BCR: bene i –cos a io; CBA: cos –bene i analysis; CEA: cos -e ec i eness
analysis; CIN: ce ical in aepi helial neoplasia; CIS: ca cinoma in si u; CPI:
consume p ice index; CUA: cos -u ili y analysis; DRG: diagnosis- ela ed g oup;
EBM: Einhei liche Bewe ungsmaßs ab; FIGO: In e na ional Fede a ion o
Gynecology and Obs e ics; HPV: human papilloma i us; HUI: Heal h U ili y
Index; ICER: inc emen al cos -e ec i eness a io; QALY: quali y-adjus ed li e
yea ; MSM: men who ha e sex wi h men; RKI: Robe Koch Ins i u e; SIRS:
suscep ible-in ec ious- eco e ed-suscep ible; STIKO: S ändige Imp kommis-
sion (S anding Vaccina ion Commi ee).
Au ho s’ con ibu ions
OD and JH designed he s udy, de eloped he model, pe o med he da a col-
lec ion, ca ied ou he analyses, and in e p e ed he esul s. OD conduc ed he
in e iews wi h clinical expe s, pe o med he cos calcula ions, and d a ed he
manusc ip . JH p og ammed and calib a ed he model. AMK and YD helped o
selec he model inpu alues and p o ided clinical expe ad ice. MEEK con ib-
u ed o he s udy design and p o ided me hodological expe ad ice. RTM and
WG con ibu ed o he s udy design, pa icipa ed in he in e p e a ion o he
esul s, and supe ised he p ojec . All au ho s c i ically e iewed he ini ial d a .
All au ho s ead and app o ed he inal manusc ip .
Au ho de ails
1 Depa men o Heal h Economics and Heal h Ca e Managemen , School
o Public Heal h, Biele eld Uni e si y, Uni e si ä ss aße 25, 33615 Biele eld,
Ge many. 2 Epidemiological and S a is ical Me hods Resea ch G oup, Helm-
hol z Cen e o In ec ion Resea ch, B aunschweig, Ge many. 3 Hanno e Medi-
cal School, Hanno e , Ge many. 4 Ge man Cen e o In ec ion Resea ch, Si e
Hanno e -B aunschweig, Hanno e /B aunschweig, Ge many. 5 Julius Cen e
o Heal h Sciences and P ima y Ca e, Uni e si y Medical Cen e U ech , U e-
ch , The Ne he lands. 6 Cen e o In ec ious Disease Con ol, RIVM, Bil ho en,
The Ne he lands. 7 Gynecologic Tumo Immunology, Clinic o Gynecology,
Cha i é-Uni e si ä smedizin Be lin, Be lin, Ge many. 8 P axis Löse /Kaden/
Dele é/Knappe, Be lin, Ge many. 9 Immunisa ion Uni , Robe Koch Ins i u e,
Be lin, Ge many. 10 Depa men o Public Heal h Medicine, School o Public
Heal h, Biele eld Uni e si y, Biele eld, Ge many.
Acknowledgemen s
We hank Ma hias W. Beckmann (Uni e si y Hospi al E langen, E langen,
Ge many), Ch is ian Dannecke (Hospi al o he Ludwig-Maximilians-Uni e si y
München, München, Ge many), Ingke Hagemann (ab s + pa ne , Kiel, Ge -
many), Pe e Hillemanns (Hanno e Medical School, Hanno e , Ge many), Ka l
U. Pe y (Wol sbu g Clinic, Wol sbu g, Ge many), Achim Schneide (Cha i é-
Uni e si ä smedizin Be lin, Be lin, Ge many) and he membe s o he Ge man
wo king g oup on ce ical pa hology and colposcopy o pa icipa ing in he
expe in e iews. We also hank Julian Wi e (Biele eld Uni e si y, Biele eld,
Ge many) o his assis ance in collec ing uni cos da a. We acknowledge sup-
po o he A icle P ocessing Cha ge by he Deu sche Fo schungsgemein-
scha and he Open Access Publica ion Fund o Biele eld Uni e si y.
Compe ing in e es s
OD and WG ha e conduc ed s udies o Sano i Pas eu MSD and GlaxoSmi h-
Kline un ela ed o he cu en s udy. All o he au ho s ha e no compe ing
in e es s o decla e.
A ailabili y o da a and ma e ials
No applicable.
Consen o publica ion
No applicable.
E hics app o al and consen o pa icipa e
No applicable.
Funding
The s udy was ully unded by Robe Koch Ins i u e (P ojec Numbe :
1362/1-927).
Publishe ’s No e
Sp inge Na u e emains neu al wi h ega d o ju isdic ional claims in pub-
lished maps and ins i u ional a ilia ions.
Recei ed: 8 Sep embe 2016 Accep ed: 23 Augus 2017
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