MAJOR ARTICLE
1204 • cid 2020:71 (1 Sep embe ) • Kama e al
Clinical In ec ious Diseases
Recei ed 23 Ma ch 2019; edi o ial decision 20 Augus 2019; accep ed 01 Oc obe 2019;
published online Decembe 3, 2019.
aP esen a ilia ion: Depa men o Medical Mic obiology, Uni e si y Medical Cen e U ech ,
The Ne he lands
Co espondence: N. Kama , Depa men o Neph ology and O gan T ansplan a ion, CHU
Toulouse Rangueil, TSA 50032, 31059 Toulouse Cedex 9, F ance (kama [email p o ec ed]).
Clinical In ec ious Diseases® 2020;71(5):1204–11
© The Au ho (s) 2019. Published by Ox o d Uni e si y P ess o he In ec ious Diseases Socie y
o Ame ica. All igh s ese ed. Fo pe missions, e-mail: [email p o ec ed].
DOI: 10.1093/cid/ciz953
Riba i in o Hepa i is E Vi us In ec ion A e O gan
T ansplan a ion: ALa ge Eu opean Re ospec i e
Mul icen e S udy
Nassim Kama ,1 Flo ence Ab a anel,2 Pa ick Beh end ,3 Jö g Ho mann,4 Geo gesPhillippe Pageaux,5 Ch is elle Ba be ,6 Valé ie Moal,7 Lionel Couzi,8
Thomas Ho a i s,9 Robe A. DeMan,10 Elisabe h Cassu o,11 AhmedM. Elsha kawy,12 Annelies Riezebos-B ilman,13,a Anne Scemla,14 Sophie Hillai e,15
Mhai iC. Donnelly,16 Syl ie Radenne,17 Johnny Sayegh,18 Cy il Ga ous e,19 Jé ôme Dumo ie ,20 F ançois Glowaki,21 Ma ie Ma ignon,22 Aud ey Coilly,23
Lucile Figue es,24 Ch is iane Mousson,25 Anne Minello,26 Sébas ien Dha ancy,27 JeanPhilippe Re olle,28 Pascal Leb ay,29 Isabelle E ienne,30
Peggy Pe in,31 Mi a Choi,4 Oli ie Ma ion,2 and Jacques Izope 2; o he Hepa i is E Vi us Riba i in S udy G oup
1Depa men o Neph ology, Dialysis and O gan T ansplan a ion, Cen e Hospi alie Uni e si ai e (CHU) Rangueil, Ins i u Na ional de la San é e de la Reche che Médicale (INSERM) U1043, Ins i u
Fédé a i de Reche che Bio-médicale de Toulouse (IFR–BMT), Uni e si y Paul Saba ie , Toulouse, F ance; 2Depa men o Vi ology, INSERM U1043, IFR–BMT, Uni e si y Paul Saba ie , Toulouse,
F ance; 3Depa men o Gas oen e ology, Hepa ology, and Endoc inology, Hanno e Medical School, and Ins i u e o Expe imen al Vi ology, TWINCORE, Cen e o Expe imen al and Clinical
In ec ion Resea ch, a join en u e be ween he Medical School Hanno e and he Helmhol z Cen e o In ec ion Resea ch, Ge man Cen e o In ec ion Resea ch, Hanno e , Ge many; 4Cha i é
Uni e si ä smedizin Be lin, Depa men o Neph ology and In ensi e Ca e and Ins i u e o Vi ology, Labo Be lin Cha i é-Vi an es-GmbH, Be lin, Ge many; 5Depa men o Hepa ology, Sain Eloi
Hospi al, Mon pellie , F ance; 6Depa men o Neph ology and Clinical Immunology, B e onneau Hospi al, Uni e si y Hospi al, Tou s, F ance; 7Aix Ma seille Uni e si é, Asis ance Publique Hôpi aux
de Ma seille, Ins i u Pou la Reche che Pou le Dé eloppemen , Mic obes, E olu ion, Phylogénie e In ec ion, Ins i u Hospi alo-Uni e si ai e–Médi e anée In ec ion, Hôpi al Concep ion, Cen e
de Néph ologie e T ansplan a ion Rénale, Ma seille, F ance; 8Depa men o Neph ology and T ansplan a ion, CHU Bo deaux, Bo deaux, F ance; 9Depa men o Medicine I, Uni e si y Medical
Cen e Hambu g-Eppendo , Hambu g, Ge many; 10Depa men s o Gas oen e ology and Hepa ology, E asmus Medical Cen e , Ro e dam, The Ne he lands; 11Depa men o Neph ology and
T ansplan a ion, CHU Nice, F ance; 12Li e Uni , Uni e si y Hospi als Bi mingham, Bi mingham, Uni ed Kingdom; 13Depa men o Medical Mic obiology, Uni e si y o G oningen, Uni e si y Medical
Cen e G oningen, G oningen, The Ne he lands; 14Se ice de néph ologie- ansplan a ion, Hôpi al Necke , Assi ance publique- Hôpi aux de Pa is (AP-HP), Pa is e Uni e si é Pa is Desca es, Pa is,
F ance; 15Depa men o Hepa ology, Hôpi al Foch, Su esnes, F ance; 16Depa men o Hepa ology and Sco ish Li e T ansplan Uni , Royal In i ma y o Edinbu gh, Edinbu gh, Uni ed Kingdom;
17Depa men o Hepa ology and Li e T ansplan a ion, CHU de la C oix Rousse, Lyon, F ance; 18Depa men o Neph ology and T ansplan a ion, CHU Ange s, Ange s, F ance; 19Depa men o
Neph ology, CHU Cle mon -Fe and, Cle mon -Fe and, F ance; 20Depa men o Hepa ology, Edoua d He io Hospi al, CHU Lyon, Lyon, F ance; 21Depa men o Neph ology, CHU Lille, Lille,
F ance; 22Assis ance Publique-Hôpi aux de Pa is, Neph ology and Renal T ansplan a ion Depa men , G oupe Hospi alie Hen i-Mondo /Albe -Chene ie , Uni e si é Pa is-Es -C é eil, Dépa emen
Hospi alo-Uni e si ai e Vi us-Immuni é-Cance , Ins i u Mondo de Reche che Biomédicale, Equipe 21, INSERM U 955, C é eil, F ance; 23Cen e Hépa o-Biliai e, Hôpi al Paul B ousse, AP-HP,
INSERM U1193, Uni e si é Pa is-Sud Pa is-Saclay, Villejui , F ance; 24Depa men o Neph ology and Clinical Immunology, CHU Nan es, Nan es, F ance; 25Depa men o Neph ology, CHU F ançois
Mi e and, Dijon, F ance; 26Depa men o Hepa ogas oen e ology and Diges i e Oncology, CHU F ançois Mi e and, Dijon, F ance; 27Hôpi al Claude Hu iez, Se ices Maladies de l’Appa eil
Diges i , INSERM Uni é 995, Lille, F ance; 28Depa men o Neph ology, CHU Limoges, Limoges, F ance; 29Depa men o Hepa ology, Pi ié Salpé iè e Hospi al, Pa is, F ance; 30Depa men o
Neph ology, CHU Rouen, Rouen, F ance; and 31Depa men o Neph ology, CHU S asbou g, S asbou g, F ance
(See he Edi o ial commen a y by c um-cian lone on pages 1212–4.)
Backg ound. Riba i in is cu en ly ecommended o ea ing ch onic hepa i is E i us (HEV) in ec ion. This e ospec i e
Eu opean mul icen e s udy aimed o assess he sus ained i ological esponse (SVR) in a la ge coho o solid o gan ansplan
(SOT) ecipien s wi h ch onic HEV in ec ion ea ed wi h iba i in mono he apy (N=255), o iden i y he p edic i e ac o s o
SVR, and o e alua e he impac o HEV RNA mu a ions on i ological esponse.
Me hods. Da a om 255 SOT ecipien s wi h ch onic HEV in ec ion om 30 Eu opean cen e s we e analyzed. Riba i in was gi en
a he median dose o 600 ( ange, 29–1200) mg/day (mean, 8.6±3.6mg/kg/day) o a median du a ion o 3 ( ange, 0.25–18) mon hs.
Resul s. A e a i s cou se o iba i in, he SVR a e was 81.2%. I inc eased o 89.8% when some pa ien s we e o e ed a second
cou se o iba i in. An inc eased lymphocy e coun a he ini ia ion o he apy was a p edic i e ac o o SVR, while poo hema o-
logical ole ance o iba i in equi ing i s dose educ ion (28%) and blood ans usion (15.7%) we e associa ed wi h mo e elapse
a e iba i in cessa ion. P e ea men HEV polyme ase mu a ions and de no o mu a ions unde iba i in did no ha e a nega i e
impac on HEV clea ance. Anemia was he main ad e se e en .
Conclusions. This la ge-scale e ospec i e s udy con i ms ha iba i in is highly e icien o ea ing ch onic HEV in ec ion in SOT
ecipien s and shows ha he p edominan HEV RNA polyme ase mu a ions ound in his s udy do no a ec he a e o HEV clea ance.
Keywo ds. o gan ansplan a ion; hepa i is E i us; iba i in; sus ained i ological esponse; anemia.
In immunosupp essed pa ien s, mainly in solid o gan ans-
plan (SOT) ecipien s, geno ype 3 hepa i is E i us (HEV)
can be esponsible o ch onic hepa i is ha can lead o apid
li e ib osis p og ession and ci hosis [1–3]. The educ ion
o immunosupp essan s a ge ing he T-cell esponse is con-
side ed as a he apeu ic op ion [4, 5]. I leads o HEV clea ance
in one- hi d o pa ien s wi h ch onic HEV in ec ion [5]; in he
emaining pa ien s, iba i in mono he apy is ecommended
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Riba i in o HEV In ec ion in SOT Recipien s • cid 2020:71 (1 Sep embe ) • 1205
[6]. In i o, iba i in inhibi s HEV eplica ion [7, 8]. In i o,
case epo s and small se ies showed ha iba i in was e icien
o ea ing ch onic HEV in ec ion [9–11]. A e ospec i e
mul icen e F ench s udy, which included 59 SOT ecipien s,
con i med his inding [12]. A e a i s cou se o iba i in
mono he apy, a sus ained i ological esponse (SVR) was ob-
se ed in 78% o pa ien s [12]. Re- ea ing elapses o a longe
pe iod gua an eed SVR in addi ional pa ien s, hus leading o
an SVR o 85% [12]. In some pa ien s who ailed o clea HEV,
HEV RNA polyme ase mu a ions we e de ec ed [13]. Howe e ,
he impac o hese mu a ions on an i i al esponse o iba i in
is s ill unknown [14, 15]. This e ospec i e mul icen e s udy
aims o assess he SVR in a la ge coho o SOT ecipien s wi h
ch onic HEV in ec ion ea ed wi h iba i in mono he apy, o
iden i y he p edic i e ac o s o SVR, and o e alua e he im-
pac o HEV RNA mu a ions on i ological esponse.
PATIENTS AND METHODS
Du ch, English, F ench, Ge man, and Sco ish ansplan cen-
e s we e asked o pa icipa e in his e ospec i e s udy; 30 o
hem ag eed. We collec ed da a om 280 SOT ecipien s wi h
ch onic au och honous HEV in ec ion who we e ea ed wi h
iba i in mono he apy be ween Sep embe 2009 and Ma ch
2018. Ch onic hepa i is was de ined as a pe sis en eplica ion o
HEV o a leas 3mon hs. Pa ien s who had pe sis en inc ease
in li e enzyme le els las ing o >3mon hs be o e i s sc eening
o HEV and diagnosis and who we e ea ed be o e he hi d
mon h a e diagnosis we e conside ed o ha e ch onic hepa i is.
Pa ien s who we e ea ed du ing he acu e HEV phase and hose
wi hou a comple e ollow-up (ie, <6 mon hs’ ollow-up a e
iba i in cessa ion) we e excluded (n=25). Hence, da a om
255 pa ien s we e analyzed. O no e, da a om 57 pa ien s we e
al eady published [12]. Howe e , in he p e ious publica ion,
HEV RNA polyme ase mu a ions we e no analyzed. Fo his
eason, da a om hese pa ien s we e included o he p esen
s udy. De ails ega ding pa icipa ing cen e s and he numbe o
included pa ien s pe cen e a e p esen ed in he Supplemen a y
Ma e ials. The pa ien s’ cha ac e is ics a e p esen ed in Table
1. Da a we e eco ded anonymously. Acco ding o F ench and
Ge man laws, anonymous e ospec i e s udies do no equi e
ins i u ional e iew boa d (IRB) app o al. In o he coun ies, he
s udy was app o ed by he IRB o each hospi al.
Vi ological Pa ame e s
As p e iously desc ibed [16], HEV RNA in blood was de ec ed
and quan i ied by eal- ime polyme ase chain eac ion (PCR)
ha a ge ed he ORF3 gene (o ORF2 gene in 1 cen e ). Mos
samples we e cen alized and analyzed in he F ench e e ence
cen e o HEV in Toulouse. The limi o de ec ion o HEV
RNA was 100 copies/mL. SVR was de ined as unde ec able
HEV RNA in he se um a leas 6mon hs a e iba i in he apy
was comple ed [17]. The de ec ion o a ian s in he HEV pol-
yme ase was pe o med by he Sange me hod by sequencing a
1100-nucleo ide agmen co e ing he en i e HEV polyme ase
gene. A i s eal- ime PCR assay was pe o med using p ime s
designed acco ding o he HEV sub ype (Supplemen a y File 2).
Then, 3 o e lapping nes ed PCR assays we e pe o med o am-
pli y he whole gene. Nes ed PCR p oduc s we e sequenced on
bo h s ands by he dideoxy chain e mina ion me hod (P ism
Ready Reac ion AmpliTaq Fs and BigDye e mina o , Applied
Table 1. Pa ien Cha ac e is ics
Va iable N=255
Age, y 51±14
Sex, male/ emale, no. 189/66
Type o o gan ansplan a ion, no.
Kidney 153
Li e 56
Hea 14
Kidney-panc eas 10
Lung 9
Kidney-li e 6
Hea -kidney 3
Lung-kidney 2
Hea -li e 1
Panc eas 1
His o y o acu e ejec ion, % 26.3
Immunosupp ession a ini ia ion o RBV, %
Calcineu in inhibi o 87.7
Cyclospo ine A 13.2
Tac olimus 86.8
mTOR inhibi o 24.8
An ime aboli e 64.6
S e oids 74.1
Se um c ea inine le el a ini ia ion o RBV, µmol/L 134±60
eGFR (MDRD) a ini ia ion o RBV, mL/min/1.73 m255±23
Lymphocy e coun a ini ia ion o RBV, cells/μL1456±887
Hemoglobin le el a ini ia ion o RBV, g/dL 2.8±2
EPO use a ini ia ion o RBV, % 1. 6
Pla ele coun a ini ia ion o RBV, cells/μL186372±22428
An i-HEV IgG a ini ia ion o RBV, posi i e/nega i e, no.a160/42
An i-HEV IgM a ini ia ion o RBV, posi i e/nega i e, no.a190/17
Se um HEV RNA a ini ia ion o RBV, posi i e/nega i e, no. 255/0
HEV geno ype 3, no.b238
3 52
3chi 90
3e g 96
P e ea men HEV RNA polyme ase mu a ion, no. (%)c76/112 (68)
Time be ween ansplan a ion and RBV he apy, mo 74±64
Time be ween diagnosis and RBV he apy, mo, median
( ange)
4 (0.5–82)
Da a a e p esen ed as mean ± s anda d de ia ion unless o he wise indica ed.
Abb e ia ions: eGFR, es ima ed glome ula il a ion a e; HEV, hepa i is E i us; IgG, im-
munoglobulin G; IgM, immunoglobulin M; MDRD, modi ica ion in die o enal disease;
mTOR, mammalian a ge o apamycin; RBV, iba i in; EPO, ecombinan e y h opoie in.
aHEV se ology was no done in all pa ien s.
bTwo hund ed hi y-eigh o he 255 pa ien s we e in ec ed by HEV geno ype 3. HEV
geno yping was no done in he emaining 17 pa ien s.
cBaseline HEV RNA polyme ase mu a ions we e assessed in only 112 pa ien s.
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1206 • cid 2020:71 (1 Sep embe ) • Kama e al
Biosys ems, Pa is, F ance) on an ABI 3130XL analyze (Applied
Biosys ems, Fos e Ci y, Cali o nia) using he same sense and
an isense p ime s as used o ampli ica ion. Elec opho eg aphy
da a we e analyzed using Sequenche so wa e e sion 4.8
(Gene Codes Co po a ion, Ann A bo , Michigan).
The HEV polyme ase sequences we e de e mined in 112 pa-
ien s be o e iba i in ea men ini ia ion and in 26 pa ien s
who emained i emic a e 3mon hs o he apy o a elapse
a e iba i in cessa ion. We ailed o sequence HEV poly-
me ase a baseline o 4 pa ien s, as well as 1 pa ien in elapse.
Rega ding all emaining pa ien s, no samples we e a ailable o
sequence HEV polyme ase.
S a is ical Analyses
Da a a e p esen ed ei he as mean ± s anda d de ia ion o
median ( ange). P opo ions we e compa ed by he χ
2 es o
Fishe exac es . Quan i a i e a iables we e compa ed by he
nonpa ame ic F iedman es o se ial measu emen s and ei-
he S uden es o he Wilcoxon es . Independen ac o s
associa ed wi h a sus ained i ological esponse we e s udied
using a s epwise mul i a ia e logis ic eg ession model ha
used ini ial inclusion c i e ia ha had a signi icance o P<.05,
using S a iew so wa e (SAS Ins i u e, Ca y, No h Ca olina).
Fo his pu pose, pa ien s wi h an SVR we e compa ed o hose
wi hou an SVR (as de ined abo e). AP alue o <.05 was con-
side ed o be s a is ically signi ican .
RESULTS
Riba i in The apy
The median ime be ween HEV diagnosis and iba i in he apy
was 3 ( ange, 0–82) mon hs. The du a ion o iba i in he apy
a ied conside ably, om 0.25 o 18 (median, 3) mon hs.
Pa ien s we e gi en 1mon h o he apy o less (n=12), be-
ween 1 and 2mon hs (n=13), 3mon hs (n=128), 4mon hs
(n = 26), 5 mon hs (n = 21), 6 mon hs (n = 37), 7 mon hs
(n=4), 9mon hs (n=1), 10mon hs (n=5), 11mon hs (n=1),
12mon hs (n=2), 15mon hs (n=2), 17mon hs (n=1), o
18mon hs (n=2). Riba i in doses we e gi en a he disc e ion
o physicians and acco ding o kidney unc ion and iba i in
ole ance. The median dose o iba i in was 600 ( ange,
29–1200) mg/day (mean, 8.6±3.6mg/kg/day). Mos pa ien s
ecei ed 400mg/day (n=47), 600mg/day (n=72), o 800mg/
day (n=81). Thi y-one pa ien s we e gi en <400mg/day, and
32 pa ien s ecei ed >800mg/day. Twen y-eigh pe cen o pa-
ien s equi ed iba i in dose educ ion due o poo hema olog-
ical ole ance. In his subg oup o pa ien s, he mean iba i in
dose dec eased om 706±221mg/day o 399±194mg/day
(P<.0001). In he whole popula ion, mean iba i in dose de-
c eased sligh ly om 614 ± 241 mg/day o 572 ± 428 mg/
day (P=.13). Con e sely, i was inc eased in 10% o pa ien s.
Fu he mo e, no signi ican change in es ima ed glome ula
il a ion a e was obse ed— ha is, 55±29mL/minu e/1.73
m2 a he ini ia ion o iba i in, 55±29mL/minu e/1.73 m2 a
he end o he apy, and 53±27mL/minu e/1.73 m2 a 6mon hs
a e iba i in cessa ion (P=.33).
Vi ological Response
All pa ien s we e i emic a he ini ia ion o iba i in. One
mon h la e , HEV RNA was assessed in 221 o 255 pa ien s and
was ound o s ill be posi i e in 105 pa ien s (47.5%). A he end
o iba i in he apy, HEV RNA was s ill posi i e in he blood in
only 10 pa ien s (3.9%). Thei cha ac e is ics a e p esen ed in
Supplemen a y Table 1. A e iba i in cessa ion, HEV elapsed
in 38 pa ien s. Hence, SVR was achie ed a e a i s cou se o
iba i in in 207 o 255 pa ien s (81.2%; Figu e 1). The SVR a e
acco ding o he du a ion o iba i in he apy is p esen ed in
Figu e 2.
Thi y-six o 48 pa ien s who did no achie e SVR we e o e ed
a longe cou se o iba i in (Figu e 1). O hese, 18 achie ed
SVR a e ha ing been ea ed o 3mon hs (n=1), 4mon hs
(n=1), 5mon hs (n=2), 6mon hs (n=10), 12mon hs (n=2),
and 15mon hs (n=2). Se en o he pa ien s a e s ill cu en ly
unde he apy. The 11 emaining pa ien s did no achie e SVR:
1 o hem was unaccoun ed o du ing he ollow-up 1mon h
a e eini ia ing iba i in, ano he pa ien was conside ed a
non esponde and s opped iba i in, 4 pa ien s we e gi en
long- e m iba i in he apy because o pe sis ing eplica ion
(1 o hem, a hea ansplan ecipien , died om decompen-
sa ed ci hosis ela ed o HEV), and 5 pa ien s elapsed a e
ha ing been e- ea ed o 5mon hs (n=1), 6mon hs (n=1),
10mon hs (n=2), and 12mon hs (n=1) and s opped iba i in.
In e es ingly, 2 o he elapsed pa ien s unde going he second
cou se o iba i in clea ed he i us spon aneously a ew weeks
a e iba i in cessa ion, he e o e achie ingSVR.
Wi h espec o he 12 emaining pa ien s who elapsed a e
he i s cou se o iba i in and who ha e no been e- ea ed,
immunosupp ession was s opped and dialysis ini ia ed in 1
pa ien , which allowed him o achie e SVR. Ano he pa ien
clea ed he i us spon aneously 2mon hs a e HEV elapse and
be o e being e- ea ed. He achie ed SVR. Eigh pa ien s we e
s ill i emic and we e no o e ed addi ional he apy. Finally, 2
pa ien s died om ca dio ascula disease and lung cance while
i emic.
Hence, SVR was achie ed in 22 pa ien s who elapsed a e
he i s cou se o iba i in. Consequen ly, o e all, SVR was ob-
se ed in 229 o he 255 pa ien s (89.8%).
P edic i e Fac o s o SVR
Resul s o uni a ia e analysis a e p esen ed in Table 2.
In e es ingly, he de ec ion o HEV RNA in he blood a week
4 a e he ini ia ion o he apy was no associa ed wi h mo e
equen elapses a e iba i in cessa ion. The ollowing a i-
ables we e included in a mul i a ia e analysis model: ecipien s’
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Riba i in o HEV In ec ion in SOT Recipien s • cid 2020:71 (1 Sep embe ) • 1207
sex, alanine amino ans e ase le el, o al lymphocy e coun ,
an i-HEV immunoglobulin G, and he use o ac olimus ( s cy-
clospo ine A) a he ini ia ion o iba i in, as well as he use o
ecombinan e y h opoie in ( EPO) du ing he apy, iba i in
dose educ ion, and he need o blood ans usion unde he apy.
High lymphocy e coun a he ini ia ion o he apy was iden i ied
Figu e 2. Sus ained i ological esponse a e acco ding o he du a ion o iba i in he apy.
Figu e 1. Ou comes o solid o gan ansplan ecipien s ea ed wi h iba i in. Abb e ia ions: IS, immunosupp essan s; SVR,sus ained i ological esponse.
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1208 • cid 2020:71 (1 Sep embe ) • Kama e al
Table 2. P edic i e Fac o s o Sus ained Vi ological Response (N=255)
Va iable Pa ien s Wi h SVR (n=207) Pa ien s Wi hou SVR (n=48) P Value
Uni a ia e analysis
Age, y 52±14 49±13 .15
Sex, male/ emale, n 159/48 30/18 .05
Li e ansplan ecipien , yes/no, n 51/156 12/36 >.99
Rejec ion his o y, % 25.1 31.2 .46
CNIs a RBV ini ia ion, % 87.3 89.4 .81
Tac olimus a RBV ini ia ion, % 84 97 .02
mTOR inhibi o a RBV ini ia ion, % 21.2 18.8 .84
An ime aboli e a RBV ini ia ion, % 70.2 68.1 .86
S e oids a RBV ini ia ion, % 73.4 78.7 .58
AST le el a RBV ini ia ion, IU/La68 (19–1448) 79 (23–480) .41
ALT le el a RBV ini ia ion, IU/La120 (10–1733) 100 (32–373) .03
γGT le el a RBV ini ia ion, IU/La122 (19–914) 129 (22–1015) .04
Bili ubin le el a RBV ini ia ion, µmol/La11 (2–186) 13 (4–102) .16
C ea inine le el a RBV ini ia ion, µmol/L 136±62 129.5±49 .52
eGFR (MDRD) a RBV ini ia ion, mL/min/1.73 m254±22 57±26 .45
Hemoglobin le el a RBV ini ia ion, g/dL 12.9±1.9 12.4±2 .08
Lymphocy e coun a RBV ini ia ion, cells/μL1529±895 1095±758 .02
Tac olimus ough le el a RBV ini ia ion, ng/mL 6.3±2.8 7.2±29 .07
Pla ele coun a RBV ini ia ion, cells/μL185160±104539 191550±149320 .7
Time be ween ansplan a ion and RBV, mo 76±66 62±50 .18
Time be ween diagnosis and RBV, moa4 (0.5–82) 6 (0.5–50) .49
Du a ion o RBV he apy, moa3 (0.25–18) 3 (0.75–12) .92
Du a ion o RBV he apy <3 mo, yes/no, n 18/189 7/41 .27
Du a ion o RBV he apy ≤3 mo, yes/no, n 124/83 29/19 .99
Du a ion o RBV he apy 3 mo, yes/no, n 106/101 22/26 .52
Du a ion o RBV he apy >3 and <6 mo, yes/no, n 40/167 7/41 .54
Du a ion o RBV he apy ≤6 mo, yes/no, n 194/13 43/5 .35
Du a ion o RBV he apy o 6 mo, yes/no, n 30/177 7/41 .99
Du a ion o RBV he apy ≥6 mo, yes/no, n 43/164 12/36 .56
Ini ial RBV dose, mg/d a600 (29–1200) 600 (200–1000) .47
Ini ial RBV dose, mg/kg/d 8.6±3.7 8.6±3.5 .97
Cumula i e RBV dose, mg 71 280±53 828 67 626±44 743 .67
RBV ough le el a mon h 1 2.14±1.38 (n=54) 2.25±1.26 (n=19) .75
RBV dose <400mg/d a EOT, % 20.9 22.5 .83
RBV dose educ ion, % 24.3 46.8 .004
Use o EPO du ing RBV he apy, % 41.9 61.7 .02
Blood ans usion, % 10.9 36.2 <.0001
Hemoglobin le el a EOT, g/dL 11.7±2.3 9.8±2.3 .001
Posi i e an i-HEV IgG a RBV ini ia ion, yes/no, nb135/26 25/16 .002
Posi i e an i-HEV IgM a RBV ini ia ion, yes/no, nb156/12 34/5 .32
HEV RNA concen a ion a RBV ini ia ion, IU/mLa599 500 (200–166 000 000) 1 444 000 (200–37 000 000) .96
HEV geno ype 3chi/3e g, n 68/81 22/15 .14
Posi i e HEV RNA a mon h 1, yes/no, nb82/95 23/21 .5
P e ea men HEV polyme ase mu a ions, yes/no, nb57/25 19/11 .65
Mul i a ia e analysis OR (95% CI) P Value
Sex, male 1008 (.35–2.9) .99
ALT a baseline 2.22 (.65–7.58) .19
Cyclospo ine A( s ac olimus) … … .99
An i-HEV IgG a baseline (posi i e) 1. 7 (.6–4.8) .31
EPO du ing he apy (Y) 1.41 (.49–4.03) .52
Highe lymphocy e coun a baseline 1. 0 01 (1–1.02) .04
RBV dose educ ion (Y) 0.34 (.14–.84) .02
T ans usion du ing he apy (Y) 0.3 (.1–.84) .02
Da a a e p esen ed as mean ± s anda d de ia ion unless o he wise indica ed. Numbe s a e bold co espond o s a is ically signi ican di e ences.
Abb e ia ions: ALT, alanine amino ans e ase; AST, aspa a e amino ans e ase; CI, con idence in e al; CNI, calcineu in inhibi o ; eGFR, es ima ed glome ula il a ion a e; EOT, end o
he apy; γGT, gamma-glu amyl anspep idase; HEV, hepa i is E i us; IgG, immunoglobulin G; IgM, immunoglobulin M; MDRD, modi ica ion in die o enal disease; mTOR, mammalian
a ge o apamycin; N, no; OR, odds a io; RBV, iba i in; EPO, ecombinan e y h opoie in; SVR, sus ained i ological esponse; Y, yes.
aMedian ( ange).
bHEV se ology a baseline, quan i a i e HEV RNA concen a ion a baseline, p e ea men HEV polyme ase mu a ions, and HEV RNA a mon h 1 we e no ob ained o all pa ien s.
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Riba i in o HEV In ec ion in SOT Recipien s • cid 2020:71 (1 Sep embe ) • 1209
as an independen p edic i e ac o ha was associa ed wi h SVR.
Con e sely, iba i in dose educ ion and blood ans usions we e
independen p edic i e ac o s associa ed wi h no achie emen o
SVR (Table 2).
E ec o HEV RNA Mu a ions on Vi ological Response
HEV RNA mu a ions we e assessed in 112 pa ien s be o e he
ini ia ion o iba i in. HEV polyme ase mu a ions we e de-
ec ed in 76 pa ien s (67.9%). V1479I was he mos common
mu a ion de ec ed (n=75), ollowed by G1634R (n=10). The
ollowing mu a ions and combina ions we e obse ed: V1479I
alone (n=64), V1479I and G134R (n=9), V1479I and Y1320H
(n = 1), V1479I and D138G/N (n = 1), and G1634R alone
(n=1). The p esence o p e ea men mu a ion did no impac
SVR. P e ea men mu a ions we e obse ed in 57 o 82 pa ien s
(69.5%) who achie ed SVR and 19 o 30 pa ien s (63.3%) who
did no (P=.65). The ype o mu a ion did no ha e any impac
on SVR (Table 3). Among 19 pa ien s who had p e ea men
mu a ions and who did no achie e SVR, 17 pa ien s we e
e- ea ed wi h iba i in: 13 achie ed SVR and 4 a e s ill unde
he apy. The 2 emaining pa ien s we e no e- ea ed: 1 o hem
spon aneously clea ed he i us be o e being e- ea ed.
HEV polyme ase mu a ions we e assessed in 26 pa ien s who
did no achie e SVR a e he i s cou se o iba i in. Twen y
pa ien s had de no o mu a ions: 5 did no ha e any mu a ion
be o e he apy whe eas all 15 emaining pa ien s al eady had
o he mu a ions be o e he apy. Among hese 20 pa ien s who
de eloped de no o mu a ions unde he apy, 16 pa ien s we e
e- ea ed wi h iba i in: 12 achie ed SVR and 4 a e s ill unde
he apy. The emaining 4 pa ien s we e no e- ea ed.
Riba i in Tole ance
Anemia was he main side e ec obse ed unde iba i in
he apy. Unde iba i in he apy, EPO was equi ed in 45.6%
o pa ien s. A ini ia ion o he apy, 21.6% we e al eady e-
cei ing EPO a he median dose o 12 000 ( ange, 1000–
120000) IU/week. A he end o he apy, 38% we e gi en EPO
(P<.0001, compa ed o baseline) a he median dose o 20000
( ange, 1000–320000) IU/week (P=.0003, compa ed o base-
line). A ew pa ien s equi ed only ansien use o EPO. Blood
ans usions we e equi ed o 15.7% o pa ien s. In pa ien s who
equi ed inc eased doses o EPO, he in oduc ion o EPO, o
blood ans usion, iba i in was ini ia ed a a sligh ly lowe dose
(581±243mg/day) compa ed o hose who did no equi e any
in e en ion (636±238mg/day) (P=.07). Howe e , a base-
line, hey had a signi ican ly lowe eGFR a e (47.5±19.3 s
60.6±22mL/minu e/1.73 m2, P<.0001), had a signi ican ly
lowe hemoglobin le el (12.5±1.6g/dL s 13.1±2.25g/dL,
P = .009), and mo e equen ly ecei ed o en mycophenolic
acid (79.3% s 57.7%, P=.0005).
DISCUSSION
Riba i in mono he apy was ound o be e icien o ea ing
ch onic geno ype 3 and 4 HEV in ec ion [12]. Mos esul s
we e ob ained in SOT ecipien s, mainly om a e ospec i e
mul icen e F ench s udy ha included 59 pa ien s [12]. In
he p esen s udy, we aimed o assess he e iciency and sa e y
o iba i in in a la ge coho o SOT ecipien s and o assess
he impac o HEV polyme ase mu a ions on i ological e-
sponse. Ou indings we e 4- old: (1) A e a i s cou se o
iba i in, he SVR a e was 81.2%; his a e inc eased o 89.8%
when some pa ien s we e o e ed a second cou se o iba i in.
(2) Inc eased lymphocy e coun a ini ia ion o he apy was
a p edic i e ac o o SVR, while poo hema ological ol-
e ance o iba i in equi ing i s dose educ ion and blood
ans usion we e associa ed wi h mo e equen elapses a e
iba i in cessa ion. (3) P e ea men HEV polyme ase mu a-
ions and de no o mu a ions unde iba i in did no ha e a
nega i e impac on HEV clea ance. (4) Anemia was he main
ad e see en .
Table 3. Hepa i is E Vi us Polyme ase Mu a ions
Mu a ion
Pa ien s Who
Achie ed
SVR A e
Fi s RBV Cou se
(n=57)
Pa ien s Who
Did No
Achie e
SVR A e Fi s
RBV Cou se
(n=19) P Value
P e ea men combina ions .39
V1479I 49 15
V1479I+G1634R 6 3
V1479I+Y1320 H 1 0
V1479I+D1384G/N 0 1
G1634R 1 0
P e ea men mu a ions
V1479I 56 19 .99
G1634R 7 3 .7
Y1320 H 1 0 >.99
D138G/N 0 1 .25
De no o mu a ions
a e he apy (n=20)
K1383N 1
G1634R 3
D1384N o G 2
K1383N+D1384G 2
K1383N+K1398R 1
K1383N+G1634R 1
K1383N+Y1587Y 1
D1384G+K1398R 1
D1384G+ G1634R 2
K1383N+D1384G+G1634R 2
Y1320H+D1384G+G1634R 1
K1383N+Y1587Y/F 
+G1634G/R
1
K1383N+D1384G+Y1587F
+G1634R
1
K1383N+K1398R+Y1587F
+G1634R
1
Abb e ia ions: RBV, iba i in; SVR, sus ained i ological esponse.
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1210 • cid 2020:71 (1 Sep embe ) • Kama e al
In he p esen s udy, in a la ge coho , he SVR a e was 81.2%,
and was qui e simila o he one epo ed p e iously (78%) [12].
In addi ion, simila o ou p e ious s udy, ea ing elapsed pa-
ien s o a longe pe iod esul ed in he achie emen o SVR in
a leas 50% o epo ed cases. Un o una ely, ea men ailu e
unde iba i in can be obse ed. Debing e al ha e p e iously
de ec ed G1634R mu a ions in he HEV RNA polyme ase o 2
pa ien s who ailed o clea HEV wi h iba i in he apy [13].
La e on, in case epo s and small case se ies, o he mu a ions
such as K1383N, D1384G, V1479I, and Y1587F we e iden i ied
[15, 18, 19]. They we e de ec ed in some pa ien s be o e iba i in
he apy o appea ed unde iba i in in elapsed pa ien s [14,
15, 18]. In he p esen s udy, HEV polyme ase mu a ions we e
assessed—no in all, bu in a la ge numbe o pa ien s. As p e-
iously epo ed by Lhomme e al in a se ies ha included 63
pa ien s, p e ea men G1634R mu a ion did no impac SVR
[14]. Howe e , o he mu a ions in he polyme ase could play a
ole [20]. In he p esen s udy, hese mu a ions, analyzed alone
o in combina ion, did no ha e any impac on i ological e-
sponse. Fu he mo e, he majo i y o elapsed pa ien s and pa -
ial esponde s o iba i in (77%) de eloped de no o mu a ions
a e a i s cou se o iba i in he apy. Mos o hem achie ed
SVR a e e- ea men . Hence, HEV RNA polyme ase mu a-
ions do no seem o ha e an impac on HEV clea ance. This
is in line wi h in i o da a acco ding o which mu a ions may
imp o e iba i in an i i al ac i i y, bu hey may also inc ease
HEV eplica ion [15].
In non esponde s o subjec s who elapsed a e e- ea men ,
no exis ing he apy seems ele an [21], excep pegyla ed in e -
e on, which can only be used in li e ansplan a ion [22] be-
cause i inc eases he isk o acu e ejec ion [23]. So osbu i has
shown a syne gis ic e ec wi h iba i in in i o [24]. Howe e ,
his was no con i med in i o [25]. Simila o wha has been
done in some pa ien s in he cu en s udy, i has been sug-
ges ed ha main aining iba i in long- e m may ha e a bene-
icial e ec on p e en ing he p og ession on li e ib osis [26].
The main issue is he hema ological ole ance o iba i in. The
educ ion o iba i in doses and blood ans usion we e inde-
penden p edic i e ac o s o non-SVR. In a p e ious s udy, we
did no obse e a ela ionship be ween iba i in le els and SVR
[27]. In he p esen s udy, iba i in le els we e no assessed in
mos pa ien s. The e o e, we we e no able o assess hei impac
on SVR. Howe e , as p e iously epo ed, we ound ha a high
lymphocy e coun a baseline was a p edic i e ac o o SVR
[12]. This inding is in line wi h p e ious epo s sugges ing ha
HEV pe sis s in immunosupp essed pa ien s [28]. Ab a anel
e al had p e iously obse ed ha pa ien s wi h pe sis en HEV
RNA shedding in he s ools despi e unde ec able HEV RNA in
he blood a he end o scheduled du a ion o iba i in he apy
we e a inc eased isk o elapsing a e iba i in cessa ion [29].
Ve y ecen ly, Ma ion e al ound ha in pa ien s who es ed
posi i e o HEV in he s ools a he end o he apy, p olonging
he du a ion o iba i in he apy signi ican ly imp o ed he
SVR a e [30]. In he p esen s udy, HEV RNA was no sys em-
a ically assessed in he s ools a he end o he apy.
In ou p e ious mul icen e s udy, in uni a ia e analysis, we
ound ha posi i e HEV RNA in he blood a e 1mon h o
he apy was associa ed wi h SVR [12]. This was no con i med
in he p esen s udy. Finally, in a small case se ies ha included
35 pa ien s, we obse ed ha a dec ease o HEV RNA concen-
a ion ≥0.5 log a day 7 a e s a ing iba i in was an inde-
penden p edic i e ac o o SVR [27]. In he p esen s udy,
da a ega ding HEV RNA a day 7 we e no collec ed.
Due o i s e ospec i e na u e, ou s udy has se e al limi-
a ions. The du a ion o iba i in a ied conside ably ac oss
di e en cen e s. We canno exclude ha in some pa ien s he
du a ion o iba i in was de e mined acco ding o hei immu-
nological s a us o o he e olu ion o i al load unde iba i in,
especially hose who we e gi en >6mon hs o he apy. Howe e ,
only 5% o pa ien s ecei ed iba i in o >6mon hs. In addi-
ion, he SVR a e did no di e be ween pa ien s who we e in-
i ially gi en ≤3mon hs o >3mon hs. Because HEV RNA was
no collec ed a day 7, and since i was no assessed in he s ools
a he end o scheduled he apy, we canno ecommend an op-
imal du a ion o he apy. Howe e , based on ecen esul s by
Ma ion e al [30], we sugges a 3-mon h cou se o he apy a e
which, in case o pe sis en HEV RNA in he s ools, we sugges
p olonging he apy o 3 mo e mon hs. Ano he limi a ion o
his s udy is he lack o assessmen o HEV RNA polyme ase
mu a ions in all pa ien s. Howe e , i has been done in 44% o
hem, and no impac o hese mu a ions on i ological esponse
was obse ed. Finally, iba i in ough le els we e no sys em-
a ically assessed in all pa ien s. Fu he s udies a e equi ed o
be e de e mine he op imal dose o iba i in.
In summa y, his la ge-scale e ospec i e Eu opean s udy
con i ms ha iba i in is highly e icien o ea ing ch onic
HEV in ec ion in ansplan ecipien s. Re- ea ing elapsed
pa ien s o a longe pe iod allows clea ing he i us. The p e-
dominan HEV RNA polyme ase mu a ions ound in his s udy
do no a ec he a e o HEV clea ance. Finally, he e is s ill an
unme need o hose pa ien s who ail o clea he i us wi h
iba i in.
Supplemen a yDa a
Supplemen a y ma e ials a e a ailable a Clinical In ec ious Diseases online.
Consis ing o da a p o ided by he au ho s o bene i he eade , he pos ed
ma e ials a e no copyedi ed and a e he sole esponsibili y o he au ho s,
so ques ions o commen s should be add essed o he co esponding au ho .
No es
Hepa i is E Vi us Riba i in S udy G oup. J.Belliè e, O.Coin aul , A.Del
Bello, L.Espos io, A.L. Heb al, L.La ayssiè e, S.Lhomme, J.M. Mansuy
(Toulouse); H. Wedemeye (Hanno e ); P. Nickel (Be lin); M. Bismu h
(Mon pellie ); K. S e ic, M. Büchle , L. D’Al e oche (Tou s); P. Colson
(Ma seille); S. Bu on (Bi mingham); C. Ramiè e (Lyon); P. T imoule
(Bo deaux); S. Pischke (Hambu g); E. Todesco; R. Sbe o Soussan;
C.Legend e, V.Malle (Pa is); I.Johannessen, K.Simpson (Edinbu gh).
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Riba i in o HEV In ec ion in SOT Recipien s • cid 2020:71 (1 Sep embe ) • 1211
Au ho con ibu ions. N.K.designed he s udy, collec ed he da a, did
he s a is ical analyses, and w o e he manusc ip . O.M.collec ed he da a.
F.A.and J.I.did he i ological wo kup and e iewed he manusc ip . All
o he au ho s p o ided pa ien s om di e en cen e s and e iewed he
manusc ip .
Po en ial con lic s o in e es . N.K. epo s pe sonal ees om AbbVie,
Amgen, As ellas, Chiesi, F esenius, Gilead, Medical Ca e, Me ck Sha p &
Dohme, Neo ii, No a is, Roche, Sano i, and Shi e. C.L. epo s lec u e ees
om Hansa Medical and a el suppo om CSL Beh ing. G.P. P. epo s
g an s om No a is and pe sonal ees om In e cep , AbbVie, and Gilead.
V.M. epo s g an s, pe sonal ees, and non inancial suppo om AbbVie,
as well as pe sonal ees and non inancial suppo om Gilead. All o he
au ho s epo no po en ial con lic s o in e es . All au ho s ha e submi ed
he ICMJE Fo m o Disclosu e o Po en ial Con lic s o In e es . Con lic s
ha he edi o s conside ele an o he con en o he manusc ip ha e been
disclosed.
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