micb-11-564486 Sep embe 9, 2020 Time: 18:15 # 1
ORIGINAL RESEARCH
published: 11 Sep embe 2020
doi: 10.3389/ micb.2020.564486
Edi ed by:
Anna K am is,
Uni e si y o he Wi wa e s and,
Sou h A ica
Re iewed by:
Ma ia Guadalupe Vizoso Pin o,
Consejo Nacional de In es igaciones
Cien í icas y Técnicas (CONICET),
A gen ina
Anna Rosa Ga buglia,
Is i u o Nazionale pe le Mala ie
In e i e Lazza o Spallanzani (IRCCS),
I aly
Flo ence Ab a anel,
Cen e Hospi alie Uni e si ai e
de Toulouse, F ance
*Co espondence:
An onio Ri e o-Jua ez
[email p o ec ed];
[email p o ec ed]
†These au ho s ha e con ibu ed
equally o his wo k
‡The comple e membe ship o he
CoRIS coho can be ound in he
Acknowledgmen s
Special y sec ion:
This a icle was submi ed o
Vi ology,
a sec ion o he jou nal
F on ie s in Mic obiology
Recei ed: 21 May 2020
Accep ed: 18 Augus 2020
Published: 11 Sep embe 2020
Ci a ion:
Ri e o-Jua ez A, F ias M,
Lopez-Lopez P, Be engue J,
Ga cía F, Macias J, Alca az B,
Cas o-Iglesias A, Caballe o-Gomez J
and Ri e o A (2020) Hepa i is E 3 a
Geno ype In ec ion in People Li ing
Wi h HIV in Spain.
F on . Mic obiol. 11:564486.
doi: 10.3389/ micb.2020.564486
Hepa i is E 3 a Geno ype In ec ion in
People Li ing Wi h HIV in Spain
An onio Ri e o-Jua ez1*†, Ma io F ias1†, Ped o Lopez-Lopez1, Juan Be engue 2,
Fede ico Ga cía3, Juan Macias4, Begoña Alca az5, Angeles Cas o-Iglesias6,
Ja ie Caballe o-Gomez1,7 and An onio Ri e o1on behal o CoRIS Coho ‡
1Ins i u o Maimonides de In es igación Biomédica de Có doba, Hospi al Uni e si a io Reina So ía de Có doba, Uni e sidad
de Có doba, Có doba, Spain, 2Hospi al Gene al Uni e si a io G ego io Ma añón, Ins i u o de In es igación Sani a ia
G ego io Ma añón, Mad id, Spain, 3Hospi al Uni e si a io San Cecilio, Ins i u o de In es igación Biosan a ia Ibs, G anada,
Spain, 4Hospi al Nues a Seño a de Valme, Se ille, Spain, 5Hospi al Gene al Uni e si a io San a Lucía, Ca agena, Spain,
6Complejo Hospi ala io Uni e si a io a Co uña, A Co uña, Spain, 7Uni e si y o Có doba - Ag i ood Excellence In e na ional
Campus, Có doba, Spain
Backg ound: The objec i e o ou s udy was o assess he p e alence and incidence
o HEV in people li ing wi h HIV (PLWH) in a Spanish na ional coho .
Me hods: Re ospec i e longi udinal s udy including PLWH ec ui ed in he coho o
adul HIV-in ec ed pa ien s o he AIDS Resea ch Ne wo k in ollow-up a 28 Spanish
hospi als wi h a ailable se um samples in 2014 and 2015. All samples we e es ed o
HEV IgG, IgM, and RNA. Samples wi h de ec able HEV i al loads we e geno yped.
P e alence and incidence o HEV in ec ion we e calcula ed.
Resul s: The s udy sample comp ised 845 PLWH. A baseline, 101 pa ien s we e
posi i e o HEV IgG an ibodies (11.9%), none had HEV IgM an ibodies, and 2 p esen ed
de ec able HEV RNA (0.23%). Fo y- wo se ocon e ed o IgG, supposing a cumula i e
incidence o 5.7%. One subjec was posi i e o IgM (0.13%), and 2 showed de ec able
HEV RNA (0.27%). One case was in ec ed by he eme gen HEV geno ype 3 a.
Conclusion: Ou s udy iden i ies one case o HEV 3 a geno ype in ec ion, he main hos
o which is abbi , showing a po en ial zoono ic ole o his eme ging geno ype in Spain.
Keywo ds: hepa i is E, HIV, su ey, geno ype 3 a, se op e alence
INTRODUCTION
Hepa i is E i us (HEV) is an eme ging in ec ious disease wo ldwide. In Eu ope, he majo i y o
cases a e ela ed o local in ec ions, ep esen ed by HEV geno ype 3 (Aspinall e al., 2017). Al hough
HEV in ec ion by his au och honous geno ype usually p esen s as subclinical o sel -limi ing acu e
hepa i is, he e a e se e al ela ed complica ions ha subs an ially wo sen he p ognosis o he
in ec ion (Fabe e al., 2018). HEV geno ype 3 has opism o he pe iphe al and cen al ne ous
sys em, p oducing neu ological inju y, including se ious mani es a ions such as Guillen-Ba é
synd ome (Dal on e al., 2017). On he o he hand, immunosupp essed pa ien s in ec ed by HEV
geno ype 3 could de elop ch onic in ec ion (Kama e al., 2008). Cases o ch onic HEV in ec ion
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Ri e o-Jua ez e al. Zoono ic Risk o Rabbi HEV
ha e been desc ibed in ansplan ecipien s, leukemia pa ien s
ea ed wi h i uximab, pa ien s on he apy wi h an i- umo al
nec osis ac o d ugs, and subjec s in ec ed by HIV wi h a low
CD4 +cell coun (Ri e o-Juá ez e al., 2020). Finally, in he
con ex o unde lying li e disease, HEV in ec ion can igge
li e ailu e and may equi e li e ansplan a ion (F ias e al.,
2018). Consequen ly, he e a e subse s o pa ien s in whom
HEV could ha e a se ious ou come. Among he popula ion in
which HEV in ec ions may ha e a wo se p ognosis, pe sons
li ing wi h HIV (PLWH) ep esen a high-sensi i i y popula ion
because o he high a e o ad anced li e ib osis due o
common hepa o opic i us coin ec ion and he unde lying
immunosupp ession (Ri e o-Jua ez e al., 2019).
In Eu ope, he main HEV geno ype is 3 (Ab a anel e al.,
2017;Oese e al., 2019;Suin e al., 2019). Ne e heless, in
ecen yea s, an impo an numbe o new i al s ains ha e
eme ged ha encompass a g owing caseload in coun ies such as
Swi ze land, F ance, Belgium and Spain (Ab a anel e al., 2017;
Caballe o-Gómez e al., 2019;Oese e al., 2019;Suin e al., 2019).
The eme gence o hese new s ains has an impo an clinical
implica ion because he in oduc ion o new i al s ains could
ha e a nega i e impac in e ms o an inc eased numbe o
symp oma ic and wo s p ognosis cases (Oese e al., 2019). In
addi ion, ecen ly, he e has been awa eness abou he zoono ic
beha io o se e al HEV i al s ains, he main hos o which a e
lagomo phs and oden s (Ab a anel e al., 2017;S idha e al.,
2018;Suin e al., 2019). These s ains ha e been desc ibed in
a high p opo ion o pa ien s wi h ch onic hepa i is, sugges ing
ha hose pa ien s wi h unde lying immunosupp ession could
be mo e sui able o in ec ion by hese eme ging i uses (S idha
e al., 2018;Sahli e al., 2019).
Fo hese easons, ou s udy assessed he p e alence and
incidence o HEV, as well as he p e alence o ch onic HEV
in ec ion, in a la ge na ional coho o PLWH, desc ibing he
HEV i al s ains.
MATERIALS AND METHODS
S udy Popula ion
The coho o adul HIV-in ec ed pa ien s o he AIDS Resea ch
Ne wo k (CoRIS) is an open, p ospec i e, mul icen e coho
o adul subjec s wi h con i med HIV in ec ion who a e naï e
o an i e o i al he apy (ART) a coho en y and who a e
ec ui ed o HIV ca e uni s o he Spanish Public Heal h Sys em
(Ca o-Mu illo e al., 2007), which cons i u es he s anda d place
o ea men o he g ea majo i y o pe sons in Spain. CoRIS was
launched in 2004. Each cen e ec ui s in o he coho all subjec s
seen o he i s ime a he cen e who mee he ollowing
c i e ia: con i med HIV diagnosis, and naï e o ART. W i en
in o med consen is ob ained om all pa ien s. Demog aphic,
clinical, labo a o y, mic obiological and ea men in o ma ion
is eco ded. The coho is linked o a cen alized BioBank,
whe e pa ien s’ blood samples a e p ocessed and c yop ese ed
immedia ely a e ecep ion and hen s o ed (Ga cía-Me ino
e al., 2009). Pa icipa ing cen e s a e encou aged o ob ain an
ini ial blood sample a en y in he coho , p e e en ially be o e
s a ing ART, and ollow-up samples p e e en ially annually,
o a leas biannually he ea e . The BioBank has ob ained
he UNE-EN-ISO 9001:2008 Sys ems o Quali y Managemen
Requi emen s. Fo he p oposed s udy, we included pa ien s
ec ui ed in he coho a ollow-up in 28 hospi als belonging
o 15 Spanish p o inces wi h a ailable se um samples in he
cen alized BioBank in 2014 (baseline) and 2015.
HEV Se ological and Molecula
De e mina ion
Fi s , all pa ien s we e es ed o HEV IgG and IgM an ibodies.
Se um samples we e es ed o an i-HEV IgG and IgM
(Wan ai HEV-IgM ELISAR
; Beijing Wan ai Biological Pha macy
En e p ise©LTD, Beijing, China). ELISA es s we e ca ied ou
in duplica e in acco dance wi h he ins uc ions p o ided by
he manu ac u e , using he au oma ed ELISA T i u us Sys em
(G i ols S. A, Ba celona, Spain). The cu -o alue o posi i e
samples was >1.1, ollowing he manu ac u e ’s ins uc ions.
Pa ien s who we e posi i e o HEV an i-IgG an ibody a baseline
(p e alence) we e no e alua ed o IgG an ibodies in he ollow-
up (incidence).
Second, all pa ien s we e es ed o HEV RNA using RT-
qPCR. RNA was ex ac ed om 400 µL o se um pools o 4
pa ien s using he comme cial QIAamp MinElu e Vi us Spin
Ki (QIAgen. Hilden, Ge many) and an au oma ed p ocedu e
(QIAcube. QIAgen, Hilden, Ge many). The pu i ied RNA was
elu ed in a o al elu ion olume o 30 µL. As a posi i e ex ac ion
con ol, 50 µL o he econs i u ed WHO S anda d HEV s ain
(supplied by he Paul-Eh lich-Ins i u e [code 6329/10]) was
dilu ed in 350 µL o AmbionR
DEPC- ea ed wa e (The mo
Fishe Scien i ics. Wal ham, MA, Uni ed S a es). RT-qPCR was
pe o med on all pooled samples using he CFX Connec (Bio-
Rad, He cules, Cali o nia), using p ime and p obe designed and
alida ed by ou g oup and desc ibed ecen ly (Caballe o-Gómez
e al., 2020). These p ime s and p obes we e ob ained by aligning
all whole-genome sequences o he O hohepe i idae A species
a ailable in GenBank. The p ocedu e was alida ed using he
WHO in e na ional e e ence panel o HEV RNA geno ypes
o nucleic acid ampli ica ion echnique (ıNAT)ı-based assays
(including geno ypes 1a, 1e, 3b, 3c, 3e, 3 , 3 a, 4c, 4g, and
2a) supplied by he Paul-Eh lich-Ins i u (code 8578/13). Fo
he eac ion, he QIAgen One-S ep PCR Ki (QIAgen, Hilden,
Ge many) was used using 25 µL o RNA empla e. An ex e nal
(in- un) s anda d cu e (using 18 dilu ions) was used o calcula e
he HEV i al load using he WHO S anda d HEV s ain (code
6329/10) wi h a uni age o 250,000 In e na ional Uni s/mL.
Posi i e pools we e indi idually e alua ed by he same RT-qPCR
p ocedu e. The sensi i i y o PCR in indi idual samples was 21
IU/mL, and in 4 samples-pools i was se a 350 IU/mL.
Samples wi h de ec able HEV i al loads we e geno yped
acco ding o he p o ocol desc ibed by HEVne . Fo phylogene ic
analysis, nes ed RT-PCR was pe o med, a ge ing he ORF2
egion (s uc u al p o eins), using p ime s HEV_5920S (50-
CAAGGHTGGCGYTCKGTTGAGAC-30) and HEV_6425A
(50-CAAGGHTGGCGYTCKGTTGAGAC-30) in he i s ound
and HEV_5930S (50-GYTCKGTTGAGACCWCBGGBGT-30)
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and HEV_6334A (50-TTMACWGTRGCTCGCCATTGGC-30)
in he second ound. The second ampli ica ion p oduc o 467 bp
was sequenced using he BigDye Te mina o Cycle Sequencing
Ready Reac ion Ki on an ABI PRISM 3100 Gene ic Analyze
(Applied Biosys ems, Fos e Ci y, CA, Uni ed S a es). SnapGene
so wa e (Ve sion 3.1; GSL Bio- ech, snapgene.com) was used o
sequence analysis. The consensus sequence was ob ained using
SeqMan So wa e SeqMan NGenR
Ve sion 12.0 (DNASTAR.
Madison, WI). Sub ype assignmen and phylogene ic analyses
we e pe o med using he HEVne geno yping ool1(Mulde
e al., 2019), and con i med by BLAST. Sequence alignmen s
we e gene a ed by he MAFFT online se ice: mul iple sequence
alignmen , in e ac i e sequence choice and isualiza ion.
Phylogene ic ees we e cons uc ed using he maximum
likelihood me hod using he p oposed HEV geno ype/sub ype
s anda d e e ence (Smi h e al., 2016). Re e ence sequences o
geno ype 4 we e included as an ou g oup o oo he ee. The
inal ee was ob ained wi h MEGA So wa e (Ve sion 6) using
he boo s ap me hod (boo s apped wi h 1000 eplica es).
S a is ical Analysis
Th ee ou come a iables we e es ablished: (i) posi i i y o IgG
an ibodies agains HEV, (ii) posi i i y o IgM an ibodies agains
HEV, and (iii) de ec ion o HEV RNA. These a iables we e
e alua ed a baseline. The p e alence o IgG, IgM, and HEV
RNA was calcula ed. Fo hose pa ien s who we e nega i e o
all ou come a iables, h ee ou come a iables we e e alua ed a
he end o he ollow-up: (i) se ocon e sion o IgG an ibodies
agains HEV, (ii) se ocon e sion o IgM an ibodies agains HEV,
and (iii) de ec ion o HEV RNA. The incidence a e o HEV
was calcula ed. The accumula ed incidence was exp essed as a
pe cen age. Con inuous a iables we e exp essed as he median
and qua iles (Q1–Q3). S uden ’s - es , he Welch es o he
Mann-Whi ney U- es was used o compa e wo independen
a iables, and a K uskal-Wallis es , one-way ANOVA o Welch
es was used o compa e mo e han wo independen a iables.
The mos app op ia e es was chosen based on a no mal
dis ibu ion (using he Shapi o-Wilk es ) o equali y o a iances
(using he Le ene es ). Ca ego ical a iables we e exp essed as
he numbe o cases (pe cen age) compa ed using he χ2- es
o Fishe ’s exac es . Signi icance was de e mined as a wo-
ailed p- alue o less han 0.05. Bi a ia e analysis compa ing
he p e alence and incidence a e be ween g oups was ca ied
ou o iden i y a iables ela ed o he di e en ou come
a iables. All analyses we e ca ied ou using he SPSS s a is ical
so wa e package e sion 18.0 (IBM Co po a ion, Some s, NY,
Uni ed S a es), G aphPad P ism e sion 7 (Mac OS X e sion;
G aphPad So wa e; San Diego, Cali o nia, Uni ed S a es) and
Winpepi so wa e e sion 11.36 (B ix on Heal h).
E hics
This s udy was designed and pe o med acco ding o he Helsinki
Decla a ion. The local and na ional Clinical T ial and E hical
Commi ee app o ed he s udy p o ocol.
1h ps://www. i m.nl/mp / yping ool/he /
RESULTS
S udy Popula ion and Baseline
Cha ac e is ics
A o al o 845 indi iduals we e included in he s udy. Se en
hund ed and i y-one (88.9%) we e male and had a median age o
36.9 yea s (30.7–45.2 yea s). Rega ding HIV- ela ed a iables, 616
(72.9%) we e men who had sex wi h men (MSM), and 80 (9.4%)
had p io AIDS-de ining condi ions, wi h a median CD4 +cell
coun o 574 cells/mL (413–787 cells/mL), and 410 (48.5%) wi h
de ec able HIV i al load. Because pa ien s a e included in he
coho i hey a e naï e o an i e o i al he apy, he popula ion
p esen s a high p opo ion o pa ien s wi h a de ec able i al load.
P e alence and Incidence o HEV
In ec ion
One hund ed and one pa ien s showed posi i i y o IgG agains
HEV (11.9%; 95% CI: 9.9–14.3%). The e we e no a iables
associa ed wi h IgG posi i i y in he uni a ia e and mul i a ia e
analyses (Table 1). Among he p e iously desc ibed isk ac o s
o HEV in HIV-in ec ed pa ien s, nei he men who had sex
wi h men (MSM) no CD4 +cell coun s we e associa ed
wi h a highe a e o HEV se op e alence. Any o he pa ien s
included in he s udy we e posi i e o IgM an i-HEV. Two
pa ien s showed de ec able HEV i al load (0.23%; 95% CI: 0.0–
0.9%). Bo h pa ien s we e male and we e nega i e o bo h IgG
and IgM an ibodies.
O he 744 pa ien s nega i e o IgG an ibodies a baseline, 733
(98.5%) had a ailable se um samples in he ollow-up. Fo y- wo
pa ien s showed se ocon e sion o IgG an ibodies a e 1 yea
o ollow-up, supposing a cumula i e incidence o 5.7% (95%
CI: 4.3–7.7%). Simila o he p e alence analysis, by uni a ia e
and mul i a ia e analysis, all ac o s we e no associa ed wi h
HEV se ocon e sion du ing he ollow-up (Table 2). One pa ien
showed bo h posi i e IgG and IgM an ibodies bu did no ha e
de ec able HEV RNA. HEV RNA was de ec ed in wo pa ien s,
bu hey we e nega i e o IgG and IgM an ibodies.
Phylogene ic Analysis
O he 4 pa ien s wi h de ec able i al load in he s udy, h ee we e
success ully geno yped. In wo cases, i al s ains we e consis en
wi h geno ype 3 (Genbank accession numbe s MN914126 and
MN914127). In e es ingly, in he o he pa ien , he isola ed i al
s ain was consis en wi h geno ype 3 a (Genbank accession
numbe MN537838) (Table 3). Phylogene ic analysis is shown
in Figu e 1. No pa ien had a de ec able HEV i al load in he
ollow-up, indica ing spon aneous i al clea ance.
DISCUSSION
The p e alence o HEV among PLWH s ongly depends on
he coun y o o igin and he immunoassays employed in he
s udy. In his sense, in high endemic a eas, such A ica o Asia,
he epo ed se op e alence is highe han 40%; in addi ion,
in o he egions, such as Eu ope, hese da a a y be ween 29
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TABLE 1 | Uni a ia e and mul i a ia e analysis o IgG an i-HEV a baseline.
Va iable IgG an i-HEV
posi i e (N= 101)
IgG an i-HEV
nega i e (N= 744)
Uni a ia e p- alue Adjus ed OR (95% CI) Mul i a ia e p- alue
Age (yea ), mean (SD) 36.2 (19.8) 36.3 (14.3) 0.926 0.997 (0.98–1.01) 0.652
Gende , n (%)
Male 86 (11.5) 665 (88.5) 0.236 1
Female 15 (16) 79 (84) 0.905 (0.37–2.21) 0.828
Coun y o o igin, n (%)
Wes e n Eu ope 84 (12.3) 599 (87.7) 0.917
Eas e n Eu ope 1 (5.6) 17 (94.4)
No h-Cen al Ame ica 0 6 (100)
Ca ibbean 3 (10) 27 (90)
Sou h Ame ica 10 (11.8) 75 (88.2)
Asia 0 4 (100)
A ica 3 (16.7) 15 (83.3)
HIV acquisi ion ou e, n (%)
He e osexual 24 (14.6) 140 (85.4) 0.643
MSM 67 (10.9) 549 (89.1)
PWID 5 (15.2) 28 (84.8)
O he 1 (20) 4 (80)
Unknown 4 (14.8) 23 (85.2)
HIV acquisi ion ou e, n (%)a
MSM 67 (10.9) 549 (89.1) 0.134 1
No MSM 34 (14.9) 172 (85.1) 0.738 (0.38–1.42) 0.363
AIDS de ining c i e ia, n (%)
No 88 (11.5) 677 (88.5) 0.207 1
Yes 13 (16.2) 67 (83.8) 2.02 (0.99–4.13) 0.052
Time since HIV diagnosis, mean (SD) 3.67 (4.5) 3.58 (3.8) 0.823
CD4 +cell coun , mean (SD)b586 (307) 611 (292) 0.474
CD4 +cell coun , n (%)b
<200 5 (9.6) 47 (90.4) 0.622
200–349 11 (16.7) 55 (83.3)
350–500 19 (12.8) 130 (87.2)
>500 50 (11.4) 389 (88.6)
CD4 +cell coun , n (%)b
<200 5 (9.6) 47 (90.4) 0.824 1
≥200 80 (12.2) 574 (87.8) 0.61 (0.22–1.67) 0.343
IgG, Immunoglobulin G; HEV, hepa i is E i us; OR, odds a io; SD, s anda d de ia ion; n, numbe o pa ien s; HIV, human immunode iciency i us; MSM, men who ha e
sex wi h men; PWID, people who injec d ugs. aTwen y-se en pa ien s wi h unknown acquisi ion ou es we e excluded om he analysis. bOne-hund ed and hi y nine
pa ien s did no ha e CD4 +cell alues.
and 10% (Wo ld Heal h O ganiza ion [WHO], 2014). Ou s udy
ound a Spanish se op e alence o HEV in ec ion o 11.9% and
a cumula i e incidence o 5.9% in 1 yea . These esul s sugges
widesp ead ci cula ion o HEV among PLWH in Spain.
The main ou e o ansmission o he HEV geno ype 3 is
he consump ion o aw o unde cooked mea , including game
species and po k (Aspinall e al., 2017;Fabe e al., 2018). In
wo la ge case se ies epo ed in F ance and Swi ze land, he
majo sub ype belonged o clade 3e g and he eme ging sub ype
3s, espec i ely (Ab a anel e al., 2017;Sahli e al., 2019). In a
la ge empo al se ies in Belgium, he majo i y o pa ien s we e
in ec ed by geno ype 3 (Suin e al., 2019). In e es ingly, hese
s udies ound se e al cases o HEV in ec ion due o he i al
geno ype 3 a, whose main hos a e abbi s. Ou s udy iden i ied
one case o HEV in ec ion by geno ype 3 a, con i ming he
zoono ic ole o his geno ype and he i s desc ip ion o a case
o i s ype in Spain. I should be highligh ed ha he i al s ain
iden i ied in ou s udy shows a high simila i y wi h wo i al
s ains isola ed in F ance (MG211750 and MG211751; Figu e 1),
sugges ing he widesp ead o his s ain in Eu ope. Rema kably,
none o he cases ound in F ance and Swi ze land documen ed
he consump ion o abbi mea o we e in con ac wi h hem
(Ab a anel e al., 2017;Sahli e al., 2019). We canno de e mine
he sou ce o in ec ion because o he e ospec i e cha ac e o
he analysis o he s udy. Fu he in es iga ions a e needed o
e alua e o he possible ou es o in ec ion o his geno ype in
addi ion o consump ion o con ac wi h abbi s. Rema kably,
in hese se ies, he a e o ch onic in ec ion among pa ien s
in ec ed wi h geno ype 3 a is highe han hose obse ed in o he
sub ypes. P esen ly, se e al cases o ch onic HEV in ec ion ha e
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TABLE 2 | Uni a ia e and mul i a ia e analysis o IgG an i-HEV se ocon e sion du ing ollow-up.
Va iable IgG an i-HEV
posi i e (N= 42)
IgG an i-HEV
nega i e (N= 691)
Uni a ia e p- alue Adjus ed OR (95% CI) Mul i a ia e p- alue
Age (yea ), mean (SD) 36 (21) 36 (14) 0.279 0.99 (0.96–1.02) 0.735
Gende , n (%)
Male 37 (5.6) 619 (94.4) 0.794 1
Female 5 (6.5) 72 (93.5) 0.99 (0.21–4.67) 0.998
Coun y o o igin, n (%)
Wes e n Eu ope 34 (5.8) 557 (94.2) 0.463
Eas e n Eu ope 0 17 (100)
No h-Cen al Ame ica 0 2 (100)
Ca ibbean 3 (11.5) 23 (88.5)
Sou h Ame ica 4 (5.5) 69 (94.5)
Asia 1 (25) 3 (75)
A ica 0 15 (100)
HIV acquisi ion ou e, n (%)
He e osexual 9 (6.5) 129 (93.5) 0.518
MSM 30 (5.5) 511 (94.5)
PWID 1 (3.6) 27 (96.4)
O he 1 (25) 3 (75)
Unknown 1 (4.5) 21 (95.5)
HIV acquisi ion ou e, n (%)a
MSM 30 (5.5) 511 (94.5) 0.652 1 0.205
No MSM 11 (6.5) 159 (93.5) 0.44 (0.12–1.56)
AIDS de ining c i e ia, n (%)
No 38 (5.7) 628 (94.3) 0.788 1
Yes 4 (6) 63 (94) 2.11 (0.56–7.92) 0.267
Time since HIV diagnosis, mean (SD) 5.4 (6.9) 3.5 (3.8) 0.081 1.05 (0.96–1.16) 0.245
CD4 +cell coun , mean (SD)b630 (238) 672 (280) 0.662
CD4 +cell coun , n (%)b
<200 1 (7.1) 13 (92.9) 0.909
200–349 1 (3.4) 28 (96.6)
350–500 6 (6.5) 86 (93.5)
>500 19 (5.2) 344 (94.8)
CD4 +cell coun , n (%) b
<200 1 (7.1) 13 (92.9) 0.547
≥200 26 (5.4) 458 (94.6)
IgG, Immunoglobulin G; HEV, hepa i is E i us; OR, odds a io; SD, s anda d de ia ion; n, numbe o pa ien s; HIV, human immunode iciency i us; MSM, men who ha e
sex wi h men; PWID, people who injec d ugs. aSix een pa ien s wi h unknown acquisi ion ou es we e excluded om he analysis. bTwo-hund ed and i y-one pa ien s
did no ha e CD4 +cell alues.
TABLE 3 | Cha ac e is ics o pa ien s wi h de ec able HEV RNA.
ID Ci y Coun y o o igin Yea o sampling Gende Age HEV i al load (IU/mL) HEV geno ype
545 Mad id Ge many 2014 Male 43 10,376 3
85 Ta agona Spain 2014 Male 52 217,024 3 a
420 Mad id Spain 2015 Male 43 24,387 3
466 Mu cia Nige ia 2015 Female 36 3,197 Ungeno yped
ID, iden i ica ion numbe ; HEV, hepa i is E i us; IU/mL, In e na ional Uni pe millili e .
been epo ed in PLWH (Ri e o-Jua ez e al., 2019). In ou s udy,
none o he pa ien s wi h de ec able HEV i al loads de eloped
ch onic in ec ions, including hose in ec ed wi h eme gence
geno ype 3 a. The e o e, ch onic HEV in ec ion seems o be a
a e e en in PLWH.
On he o he hand, he e a e se e al a iables ela ed o
HIV in ec ion ha could be associa ed wi h a highe isk o
HEV in ec ion in his popula ion. In his sense, he associa ion
be ween he CD4 +cell coun and he se op e alence o HEV
is con o e sial. The e a e s udies ha ound no di e ences in
he a e o HEV IgG an ibodies and he CD4 +cell coun
(Pineda e al., 2014;Ri e o-Jua ez e al., 2015;Zeng e al.,
2017). O he s udies ound ha his a iable could in luence a
highe o lowe a e o in ec ion (Ken ak-Foguena e al., 2011;
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Ri e o-Jua ez e al. Zoono ic Risk o Rabbi HEV
FIGURE 1 | Molecula phylogene ic analysis by Maximum Likelihood me hod. The e olu iona y his o y was in e ed by using he Maximum likelihood me hod based
on he Tamu a-Nei model. The boo s ap consensus ee in e ed om 1000 eplica es is aken o ep esen he e olu iona y his o y o he axa analyzed. B anches
co esponding o pa i ions ep oduced in less han 50% boo s ap eplica es a e collapsed. Ini ial ee(s) o he heu is ic sea ch we e ob ained au oma ically by
applying he Neighbo -Joining and BioNJ algo i hms o a ma ix o pai wise dis ances es ima ed using he Maximum Composi e Likelihood (MCL) app oach and hen
selec ing he opology wi h supe io log likelihood alue. The analysis in ol ed 120 nucleo ide sequences. The codon posi ions included we e
1s + 2nd + 3 d + Non-coding. All posi ions con aining gaps and missing da a we e elimina ed. No el sub ypes sequences p oposed by HEVne a e e e ed in he
ee as p.
Zhou e al., 2018). Ou s udy did no ind any associa ion
be ween he CD4 +cell coun , using di e en cu -o s, and
he p esence o IgG an ibody, ei he in he baseline o du ing
he ollow-up. In he same way, i is con o e sial whe he
MSM cons i u ed a isk popula ion o HEV in ec ion. S udies
conduc ed in Eu ope epo a highe HEV se op e alence in
MSM han in non-MSM popula ions (Payne e al., 2013;Lanini
e al., 2015). In ou s udy, MSM showed a simila HEV
se op e alence and se oincidence o non-MSM. This inding is
consis en wi h a ecen s udy conduc ed in Asia, whe e MSM
did no show a highe isk o HEV in ec ion in compa ison
wi h non-MSMs (Lin e al., 2019), unlike o he en e ic i uses,
such as hepa i is A.
Se e al limi a ions should be no ed. Fi s , despi e he high
numbe o hospi als in ol ed in he p esen s udy, he e is a
lack o pa ien s om di e en egions. The e o e, ou s udy
lacks he powe o iden i y di e ences in p e alence be ween
egions. Finally, due o he anonymous cha ac e o he samples,
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Ri e o-Jua ez e al. Zoono ic Risk o Rabbi HEV
addi ional pa ien da a (such epidemiological a iables ela ed o
isk o HEV acquisi ion) canno be e alua ed.
CONCLUSION
In conclusion, ou s udy ound ha HEV in ec ion in PLWH
om Spain is equen , showing a ela i ely high annual
incidence. Despi e he numbe o acu e in ec ions iden i ied in
ou s udy, none o he cases in ol ed ch onic in ec ion. We
iden i ied one case o in ec ion by he HEV geno ype 3 a, he
main hos o which is he abbi , con i ming he zoono ic ole o
his eme ging geno ype.
DATA AVAILABILITY STATEMENT
The aw da a suppo ing he conclusions o his a icle will be
made a ailable by he au ho s, wi hou undue ese a ion o, any
quali ied esea che .
ETHICS STATEMENT
The s udies in ol ing human pa icipan s we e e iewed and
app o ed by he Comi é de É ica de la In es igación de Có doba.
Po al de É ica de la In es igación Biomédica de Andalucia. The
pa ien s/pa icipan s p o ided hei w i en in o med consen o
pa icipa e in his s udy.
AUTHOR CONTRIBUTIONS
AR-J and AR: concep and design. JB, FG, JM, BA, AC-I, and
AR: collec ion o samples. MF, PL-L, and JC-G: EIA analysis.
MF, PL-L, JC-G, and AR-J: RNA ex ac ion and HEV-PCR. PL-L
and AR-J: sequencing and phylogene ic analysis. AR-J, AR, and
MF: d a he manusc ip . All au ho s: c i ical e ision o he
manusc ip . Funding: AR-J, AR, and MF.
FUNDING
The RIS coho (CoRIS) was suppo ed by he Ins i u o de
Salud Ca los III h ough he Red Temá ica de In es igación
Coope a i a en Sida (RD16/0025/0017; RD16/0025/0034;
RD16/0025/0040) as pa o he Plan Nacional I +D+i and
co inanced by ISCIII-Subdi ección Gene al de E aluación and
he Fondo Eu opeo de Desa ollo Regional (FEDER). This wo k
was suppo ed by he Minis e io de Sanidad (RD12/0017/0012)
in eg a ed in he Plan Nacional de I +D+I and co inanced by
he ISCIII-Subdi ección Gene al de E aluación and he Fondo
Eu opeo de Desa ollo Regional (FEDER), Fundación pa a la
In es igación en Salud (FIS) del Ins i u o Ca los III (PI16/01297),
and Fundación P og eso y Salud de la Jun a de Andalucía (PIN-
0477-2017). AR-J was awa ded wi h he I P emio de Jó enes
In es igado es de GeSIDA, which bene i s we e used o und
he p esen wo k. AR-J was he ecipien o a Miguel Se e
Resea ch Con ac by he Minis e io de Ciencia, P omoción y
Uni e sidades o Spain (CP18/00111). MF is he ecipien o a
Sa a Bo ell con ac by he Minis e io de Ciencia, P omoción y
Uni e sidades o Spain (CD18/00091). JC-G was suppo ed by
an FPU g an om he Spanish Minis y o Educa ion, Cul u e
and Spo (FPU17/01319). The unde s did no play any ole in
he design, conclusions o in e p e a ion o he s udy.
ACKNOWLEDGMENTS
We a e g a e ul o Ismael Za a and Lau a Ruiz o hei
echnical suppo .
Funding: A Ri e o-Jua ez, A Ri e o and Ma io F ias.
Cen e s and in es iga o s in ol ed in CoRIS
Execu i e commi ee: San iago Mo eno, Inma Ja ín, Da id
Dalmau, Ma ia Luisa Na a o, Ma ia Isabel González, Jose Luis
Blanco, Fede ico Ga cia, Ra ael Rubio, Jose An onio I iba en,
Félix Gu ié ez, F ancesc Vidal, Juan Be engue , Juan González.
Fieldwo k, da a managemen and analysis: Belén Alejos,
Vic o ia He nando, C is ina Mo eno, Ca los Inies a, Luis Miguel
Ga cia Sousa, Nie es Sanz Pe ez.
BioBanK HIV: Hospi al Gene al Uni e si a io G ego io
Ma añón: M Ángeles Muñoz-Fe nández, Isabel Ma ía Ga cía-
Me ino, I ene Consueg a Fe nández, Co al Gómez Rico, Jo ge
Gallego de la Fuen e, Paula Palau Concejo.
Pa icipa ing cen es
Hospi al Gene al Uni e si a io de Alican e (Alican e): Joaquín
Po illa, Espe anza Me ino, Se gio Reus, Vicen e Boix, Li ia
Gine , Ca men Gadea, I ene Po illa, Ma ía Pampliega, Ma cos
Díez, Juan Ca los Rod íguez, José Sánchez-Payá.
Hospi al Uni e si a io de Cana ias (San C is obal de la
Laguna): Juan Luis Gómez, Jeho ana He nández, Ma ía
Remedios Alemán, Ma ía del Ma Alonso, Ma ía Inmaculada
He nández, Felici as Díaz-Flo es, Dácil Ga cía, Rica do Pelazas.,
Ana López Li ola.
Hospi al Uni e si a io Cen al de As u ias (O iedo): José Sanz
Mo eno, Albe o A anz Caso, C is ina He nández Gu ié ez,
Ma ía No ella Mena.
Hospi al Uni e si a io 12 de Oc ub e (Mad id): Ra ael
Rubio, Fede ico Pulido, O ilia Bisbal, Asunción He nando,
Lou des Domínguez, Da id Rial C es elo, Lau a Be mejo,
Mi eia San ac eu.
Hospi al Uni e si a io de Donos ia (Donos ia-San Sebas ián):
José An onio I iba en, Julio A izabalaga, Ma ía José A ambu u,
Xabie Camino, F ancisco Rod íguez-A ondo, Miguel Ángel
on Wichmann, Lidia Pascual Tomé, Miguel Ángel Goenaga, Ma
Jesús Bus induy, Ha kai z Azkune, Maialen Iba gu en, Ai zibe
Liza di, Xabie Ko aja ena.
Hospi al Gene al Uni e si a io De Elche (Elche): Félix
Gu ié ez, Ma Masiá, Se gio Padilla, And és Na a o, Fe nando
Mon olio, Ca alina Robledano, Joan G ego i Colomé, A aceli
Adsua , Ra ael Pascual, Ma a Fe nández, Elena Ga cía., José
Albe o Ga cía, Xa ie Ba be .
Hospi al Uni e si a i Ge mans T ias i Pujol (Can Ru i)
(Badalona): Robe o Muga, A an za San isens, Daniel Fus e .
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Ri e o-Jua ez e al. Zoono ic Risk o Rabbi HEV
Hospi al Gene al Uni e si a io G ego io Ma añón (Mad id):
Juan Be engue , Juan Ca los López Be naldo de Qui ós, Isabel
Gu ié ez, Ma ga i a Ramí ez, Belén Padilla, Paloma Gijón,
Te esa Aldamiz-Eche a ía, F ancisco Teje ina, F ancisco José
Pa as, Pascual Balsalob e, C is ina Diez, Lei e Pé ez La o e.
Hospi al Uni e si a i de Ta agona Joan XXIII (Ta agona):
F ancesc Vidal, Joaquín Pe ai e, Consuelo Viladés, Se gio Veloso,
Mon se a Va gas, Miguel López-Dupla, Mon se a Olona,
Anna Rull, Es he Rod íguez-Gallego, Ve ónica Alba.
Hospi al Uni e si a io y Poli écnico de La Fe (Valencia): Ma a
Mon e o Alonso, José López Aldegue , Ma ino Blanes Juliá,
Ma ía Tasias Pi a ch, I án Cas o He nández, E a Calabuig
Muñoz, Sand a Cuélla To a , Miguel Sala e Lle í, Juan
Fe nández Na a o.
Hospi al Uni e si a io La Paz/IdiPAZ: Juan González-ga cia,
F ancisco A nalich, José Ramón A ibas, Jose Ignacio Be na dino
de la Se na, Juan Miguel Cas o, Luis Escosa, Ped o He anz,
Vic o Hon añón, Sil ia Ga cía-Bujalance, Milag os Ga cía
López-Ho elano, Alicia González-Baeza, Ma ia Luz Ma ín-
Ca bone o, Ma io Mayo al, Ma ia Jose Mellado, Ra ael Es eban
Micán, Rocio Mon ejano, Ma ía Luisa Mon es, Vic o ia Mo eno,
Ignacio Pé ez-Vale o, Be a Rodés, Talia Sainz, Elena Sendago a,
Na alia S ella Alcá iz, Eulalia Valencia.
Hospi al San Ped o Cen o de In es igación Biomédica de La
Rioja (CIBIR) (Log oño): José Ramón Blanco, José An onio O eo,
Val ane a Iba a, Luis Me ola, Me cedes Sanz, Lau a Pé ez-
Ma ínez.
Hospi al Uni e si a io Miguel Se e (Za agoza): Piedad A azo,
Glo ia Sampé iz.
Hospi al Uni e si a i Mu uaTe assa (Te asa): Da id
Dalmau, Angels Jaén, Mon se Sanma í, Mi eia Cai ó, Ja ie
Ma inez-Lacasa, Pablo Velli, Rose Fon , Ma iona Xe ca ins,
Noemí Alonso.
Complejo Hospi ala io de Na a a (Pamplona): Ma ía Ri e o,
Jesús Repá az, Ma ía G acia Ruiz de Alda, Ma ía Te esa de León
Cano, Bea iz Pie ola Ruiz de Gala e a.
Co po ació Sani à ia Pa c Taulí (Sabadell): Fe án Segu a,
Ma ía José Amengual, Gemma Na a o, Mon se a Sala, Manuel
Ce an es, Valen ín Pineda, Sonia Calzado, Ma a Na a o.
Hospi al Uni e si a io de La P incesa (Mad id): Ignacio de
los San os, Jesús Sanz Sanz, Ana Salas Apa icio, C is ina Sa iá
Cepeda, Lucio Ga cia-F aile F aile, En ique Ma ín Gayo.
Hospi al Uni e si a io Ramón y Cajal (Mad id): San iago
Mo eno, José Luis Casado, Fe nando D onda, Ana Mo eno,
Ma ía Jesús Pé ez Elías, C is ina Gómez Aye be, Ca olina
Gu ié ez, Nadia Mad id, San os del Campo Te ón, Paloma
Ma í, Uxua Ansa, Se gio Se ano, Ma ía Jesús Vi ancos.
Hospi al Gene al Uni e si a io Reina So ía (Mu cia): En ique
Be nal, Al edo Cano, An onia Alca az Ga cía, Joaquín B a o
U bie a, Ángeles Muñoz, Ma ia Jose Alca az, Ma ia del
Ca men Villalba.
Hospi al Nue o San Cecilio (G anada): Fede ico Ga cía, José
He nández, Alejand o Peña, Leopoldo Muñoz, Paz Casas, Ma a
Al a ez, Na alia Chueca, Da id Vinuesa, Cla a Ma inez-Mon es.
Cen o Sani a io Sando al (Mad id): Jo ge Del Rome o,
Ca men Rod íguez, Te esa Pue a, Juan Ca los Ca ió, Ma Ve a,
Juan Balles e os, Oska Aye di.
Hospi al Clínico Uni e si a io de San iago (San iago de
Compos ela): An onio An ela, Elena Losada.
Hospi al Uni e si a io Son Espases (Palma de Mallo ca):
Melcho Rie a, Ma ía Peña anda, Ma ía Leyes, MaAngels Ribas,
An oni A Campins, Ca men Vidal, F ancisco Fanjul, Ja ie
Mu illas, F ancisco Homa .
Hospi al Uni e si a io Vi gen de la Vic o ia (Málaga): Jesús
San os, C isi ina Gómez Aye be, Isabel Viciana, Rosa io Palacios,
Ca men Ma ía González.
Hospi al Uni e si a io Vi gen del Rocío (Se illa): Pompeyo
Viciana, Nu ia Espinosa, Luis Fe nando López-Co és.
Hospi al Uni e si a io de Bell i ge (Hospi ale de Llob ega ):
Daniel Podzamcze , Elena Fe e , A kai z Imaz, Juan Ti aboschi,
Ana Sil a, Ma ía Saumoy.
Hospi al Uni e si a io Valle de Heb ón (Ba celona): Es eban
Ribe a, Ad ian Cu an.
Hospi al Cos a del Sol (Ma bella): Julián Olalla, Al onso del
A co, Ja ie de la o e, José Luis P ada, José Ma ía Ga cía de
Lomas Gue e o, Ja ie Pé ez S achowski.
Hospi al Gene al Uni e si a io San a Lucía (Ca agena):
Ono e Juan Ma ínez, F ancisco Jesús Ve a, Lo ena Ma ínez,
Jose ina Ga cía, Begoña Alca az, Amaya Jimeno.
Complejo Hospi ala io Uni e si a io a Co uña (Chuac)
(A Co uña): Angeles Cas o Iglesias, Be a Pe nas Sou o,
Al a o Mena de Cea.
Hospi al Uni e si a io Basu o (Bilbao): Jose a Muñoz, Mi en
Zu iñe Zube o, Josu Mi ena Ba aia-E xabu u, So ía Iba a
Uga e, Osca Luis Fe e o Benei ez, Jose ina López de Munain,
MaMa Cáma a López, Mi eia de la Peña, Mi iam Lopez.
Hospi al Uni e si a io Vi gen de la A ixaca (El Palma ):
Ca los Gale a, Helena Albendin, Au o a Pé ez, Asunción Ibo a,
An onio Mo eno, Ma ia Angus ias Me los, Asunción Vidal.
Hospi al de la Ma ina Baixa (La Vila Joiosa): Concha Amado ,
F ancisco Pasquau, Ja ie Ena, Concha Beni o, Vicen a Fenoll.,
Concepcion Gil Angui a, Jose Tomas Algado Rabasa.
Hospi al Uni e si a io In an a So ia (San Sebas ian de
los Reyes): Inés Suá ez-Ga cía, Edua do Malmie ca, Pa icia
González-Ruano, Dolo es Ma ín Rod igo, MaPila Ruiz Seco.
Complejo Hospi ala io de Jaén (Jaén): Mohamed Oma
Mohamed-Balgha a, Ma ía Ampa o Gómez Vidal.
Hospi al San Agus ín (A ilés): Miguel Albe o de Za aga.
Hospi al Clínico San Ca los (Mad id): Vicen e Es ada Pé ez,
Ma ia Jesus Téllez Molina, Jo ge Ve gas Ga cía, Juncal Pé ez-
Soma iba Mo eno.
Hospi al Uni e si a io Fundación Jiménez Díaz
(Mad id): Miguel Gó golas., Al onso Cabello., Bea iz
Ál a ez., Lau a P ie o.
Hospi al Uni e si a io P íncipe de As u ias (Alcalá de
Hena es): José Sanz Mo eno, Albe o A anz Caso, C is ina
He nández Gu ié ez, Ma ía No ella Mena.
Hospi al Clínico Uni e si a io de Valencia (València): Ma ía
José Galindo Pue o, Ramón Fe nando Vilal a, Ana Fe e
Ribe a.
Hospi al Reina So ía (Có doba): An onio Ri e o Román,
Ma ia Te esa B ie a He e o, An onio Ri e o Juá ez, Ped o
López López, Isabel Machuca Sánchez, Ma io F ías Casas, José
Peña Ma ínez.
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Ri e o-Jua ez e al. Zoono ic Risk o Rabbi HEV
Hospi al Uni e si a io Se e o Ochoa (Leganés): Miguel Ce e o
Jiménez, Ra ael To es Pe ea, Juan José Jusdado Ruiz-Capillas.
Nues a Seño a de Valme: Juan A Pineda, Juan Macías Sánchez,
Nicolás Me chan e Gu ié ez, Pila Rincón.
REFERENCES
Ab a anel, F., Lhomme, S., El Cos a, H., Sch a z, B., Pe on, J. M., Kama , N., e al.
(2017). Rabbi Hepa i is E i us in ec ions in humans. F an. Eme g. In ec . Dis
23, 1191–1193. doi: 10.3201/eid2307.170318
Aspinall, E. J., Cou u ie , E., Fabe , M., Said, B., Ijaz, S., Ta oschi, L., e al. (2017).
Hepa i is E i us in ec ion in Eu ope: su eillance and desc ip i e epidemiology
o con i med cases, 2005 o 2015. Eu o. Su eill. 22:30561.
Caballe o-Gómez, J., Ga cía Bocaneg a, I., Gómez-Guillamón, F., Camacho-
Sille o, L., Zo illa, I., Lopez-Lopez, P., e al. (2020). Absence o Hepa i is E i us
ci cula ion in wild abbi s (O yc olagus cuniculus) and Ibe ian ha es (Lepus
g ana ensis) in Medi e anean ecosys ems in Spain. T ansbound. Eme g. Dis.
67, 1422–1427. doi: 10.1111/ bed.13478
Caballe o-Gómez, J., Jiménez-Ruiz, S., Lopez-Lopez, P., Vicen e, J., Risalde, M. A.,
Cano-Te iza, D., e al. (2019). Eme gen sub ype o hepa i is E i us geno ype
3 in wild boa in Spain. T ansbound. Eme g. Dis. 66, 1803–1808. doi: 10.1111/
bed.13251
Ca o-Mu illo, A. M., Cas illa, J., Pé ez-Hoyos, S., Mi ó, J. M., Podzamcze , D.,
Rubio, R., e al. (2007). Coho e RIS de pacien es con in ección po VIH sin
a amien o an i e o i al p e io (CoRIS): me odología y p ime os esul ados
[Spanish coho o naï e HIV-in ec ed pa ien s (CoRIS): a ionale, o ganiza ion
and ini ial esul s]. En e m. In ecc. Mic obiol. Clin. 25, 23–31. doi: 10.1157/
13096749
Dal on, H. R., an Eijk, J., Cin as, P., Madden, R. G., Jones, C., Webb, G. W., e al.
(2017). Hepa i is E i us in ec ion and acu e non- auma ic neu ological inju y:
a p ospec i e mul icen e s udy. J. Hepa ol. 67, 925–932. doi: 10.1016/j.jhep.
2017.07.010
Fabe , M., Aska , M., and S a k, K. (2018). Case-con ol s udy on isk ac o s o
acu e hepa i is E in Ge many, 2012 o 2014. Eu o. Su eill. 23:e100469.
F ias, M., López-López, P., Ri e o, A., and Ri e o-Jua ez, A. (2018). Role o
Hepa i is E Vi us In ec ion in Acu e-on-Ch onic Li e Failu e. Biomed. Res.
In e n. 2018:9098535.
Ga cía-Me ino, I., de Las Cue as, N., Jiménez, J. L., Gallego, J., Gómez, C., P ie o,
C., e al. (2009). The Spanish HIV BioBank: a model o coope a i e HIV
esea ch. Re o i ology 6:27. doi: 10.1186/1742-4690-6-27
Kama , N., Sel es, J., Mansuy, J. M., Ouezzani, L., Pé on, J. M., Gui a d, J., e al.
(2008). Hepa i is E i us and ch onic hepa i is in o gan- ansplan ecipien s.
N. Engl. J. Med. 358, 811–817.
Ken ak-Foguena, A., Schöni-A ol e , F., Bü gisse , P., Wi eck, A., Da ling, K. E.,
Ko a i, H., e al. (2011). Hepa i is E Vi us se op e alence and ch onic in ec ions
in pa ien s wi h HIV, Swi ze land. Eme g. In ec . Dis. 17, 1074–1078. doi:
10.3201/eid/1706.101067
Lanini, S., Ga buglia, A. R., Lapa, D., Pu o, V., Na a a, A., Pe gola, C., e al. (2015).
Epidemiology o HEV in he Medi e anean basin: 10-yea p e alence in I aly.
BMJ Open 5:e007110. doi: 10.1136/bmjopen-2014-007110
Lin, K. Y., Lin, P. H., Sun, H. Y., Chen, Y. T., Su, L. H., Su, Y. C., e al. (2019).
Hepa i is E i us in ec ions among human immunode iciency i us-posi i e
indi iduals du ing an ou b eak o acu e hepa i is a in Taiwan. Hepa ology 70,
1892–1902. doi: 10.1002/hep.30771
Mulde , A. C., K oneman, A., F anz, E., Vennema, H., Tulen, A. D., Takkinen, J.,
e al. (2019). HEVne : a One Heal h, collabo a i e, in e disciplina y ne wo k
and sequence da a eposi o y o enhanced hepa i is E i us molecula yping,
cha ac e isa ion and epidemiological in es iga ions. Eu o. Su eill. 24:1800407.
Oese , C., Vaughan, A., Said, B., Ijaz, S., Tedde , R., Haywood, B., e al. (2019).
Epidemiology o Hepa i is E in England and Wales: a 10-Yea e ospec i e
su eillance s udy, 2008-2017. J. In ec . Dis. 220, 802–810. doi: 10.1093/in dis/
jiz207
Payne, B. A., Medhi, M., Ijaz, S., Valappil, M., Sa age, E. J., Gill, O. N., e al.
(2013). Hepa i is E i us se op e alence among men who ha e sex wi h men,
Uni ed Kingdom. Eme g. In ec . Dis. 19, 333–335. doi: 10.3201/eid1902.121174
Pineda, J. A., Ci uen es, C., Pa a, M., Me chan e, N., Pé ez-Na a o, E., Ri e o-
Juá ez, A., e al. (2014). Incidence and na u al his o y o hepa i is E i us
coin ec ion among HIV-in ec ed pa ien s. AIDS 28, 1931–1937. doi: 10.1097/
qad.0000000000000378
Ri e o-Juá ez, A., Aguile a, A., A ellón, A., Ga cía-Del o o, M., Ga cía, F.,
Go aza , C., e al. (2020). Execu i e summa y: consensus documen o he
diagnosis, managemen and p e en ion o in ec ion wi h he hepa i is E i us:
s udy G oup o Vi al Hepa i is (GEHEP) o he Spanish Socie y o In ec ious
Diseases and Clinical Mic obiology (SEIMC). En e m. In ecc. Mic obiol. Clin.
38, 28–32. doi: 10.1016/j.eimc.2018.06.014
Ri e o-Jua ez, A., Lopez-Lopez, P., F ias, M., and Ri e o, A. (2019). Hepa i is
E in ec ion in HIV-in ec ed pa ien s. F on . Mic obiol. 10:1425. doi: 10.3389/
micb.2019.01425
Ri e o-Jua ez, A., Ma inez-Dueñas, L., Ma inez-Peinado, A., Camacho, A.,
Ci uen es, C., Go don, A., e al. (2015). High hepa i is E i us se op e alence
wi h absence o ch onic in ec ion in HIV-in ec ed pa ien s. J. In ec . 70, 624–
630. doi: 10.1016/j.jin .2014.10.016
Sahli, R., F aga, M., Semela, D., Mo adpou , D., and Gou enoi e, J. (2019). Rabbi
HEV in immunosupp essed pa ien s wi h hepa i is E acqui ed in Swi ze land.
J. Hepa ol. 70, 1023–1025. doi: 10.1016/j.jhep.2019.01.025
Smi h, D. B., Simmonds, P., Izope , J., Oli ei a-Filho, E. F., Ul ich, R. G., Johne, R.,
e al. (2016). P oposed e e ence sequences o hepa i is E i us sub ypes. J. Gen.
Vi ol. 97, 537–542. doi: 10.1099/jg .0.000393
S idha , S., Yip, C., Wu, S., Cai, J., Zhang, A. J., Leung, K. H., e al. (2018). Ra
Hepa i is E Vi us as cause o pe sis en hepa i is a e li e ansplan . Eme g.
In ec . Dis. 24, 2241–2250. doi: 10.3201/eid2412.180937
Suin, V., Klame , S. E., Hu se, V., Wau ie , M., Jacques, M., Abady, M., e al. (2019).
Epidemiology and geno ype 3 sub ype dynamics o hepa i is E i us in Belgium,
2010 o 2017. Eu . Commun. Dis. Bull. 24:1800141.
Wo ld Heal h O ganiza ion [WHO] (2014). The Global P e alence o Hepa i is E
Vi us In ec ion and Suscep ibili y: A Sys ema ic Re iew. Gene a: Wo ld Heal h
O ganiza ion.
Zeng, H., Wang, L., Liu, P., Liao, L., Wang, L., and Shao, Y. (2017). Se op e alence
o hepa i is E i us in HIV-in ec ed pa ien s in China. AIDS 31, 2019–2021.
doi: 10.1097/qad.0000000000001585
Zhou, S., Ren, L., Xia, X., Miao, Z., Huang, F., Li, Y., e al. (2018). Hepa i is E i us
in ec ion in HIV-in ec ed pa ien s: a la ge coho s udy in Yunnan p o ince,
China. J. Med. Vi ol. 90, 1121–1127. doi: 10.1002/jm .25060
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