Ribavirin for Hepatitis E Virus Infection After Organ Transplantation: A Large European Retrospective Multicenter Study.

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 Downloaded om h ps://academic.oup.com/cid/a icle/71/5/1204/5650877 by GBF Gesellscha ue Bio echnologische Fo schung mbH, -Biblio hek- use on 13 June 2022 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. Downloaded om h ps://academic.oup.com/cid/a icle/71/5/1204/5650877 by GBF Gesellscha ue Bio echnologische Fo schung mbH, -Biblio hek- use on 13 June 2022 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’ Downloaded om h ps://academic.oup.com/cid/a icle/71/5/1204/5650877 by GBF Gesellscha ue Bio echnologische Fo schung mbH, -Biblio hek- use on 13 June 2022 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. Downloaded om h ps://academic.oup.com/cid/a icle/71/5/1204/5650877 by GBF Gesellscha ue Bio echnologische Fo schung mbH, -Biblio hek- use on 13 June 2022 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. Downloaded om h ps://academic.oup.com/cid/a icle/71/5/1204/5650877 by GBF Gesellscha ue Bio echnologische Fo schung mbH, -Biblio hek- use on 13 June 2022 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. Downloaded om h ps://academic.oup.com/cid/a icle/71/5/1204/5650877 by GBF Gesellscha ue Bio echnologische Fo schung mbH, -Biblio hek- use on 13 June 2022 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). Downloaded om h ps://academic.oup.com/cid/a icle/71/5/1204/5650877 by GBF Gesellscha ue Bio echnologische Fo schung mbH, -Biblio hek- use on 13 June 2022 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. Re e ences 1. Kama N, Sel esJ, MansuyJM, e al. Hepa i is E i us and ch onic hepa i is in o gan- ansplan ecipien s. N Engl J Med 2008; 358:811–7. 2. onFeldenJ, Al icL, PischkeS, e al. The bu den o hepa i is E among pa ien s wi h haema ological malignancies: a e ospec i e Eu opean coho s udy. J Hepa ol 2019; 71:465–72. 3. F iebus-Ka dashJ, Eisenbe ge U, Acke mannJ, e al. P e alence o ac i e hepa- i is E i us in ec ion and e icacy o iba i in ea men in enal allog a ecipi- en s. T anspl In ec Dis 2019; 21:e13088. 4. Kama N, Ab a anelF, Sel esJ, e al. In luence o immunosupp essi e he apy on he na u al his o y o geno ype 3 hepa i is-E i us in ec ion a e o gan ansplan- a ion. T ansplan a ion 2010; 89:353–60. 5. Kama N, Ga ous eC, HaagsmaEB, e al. Fac o s associa ed wi h ch onic hep- a i is in pa ien s wi h hepa i is E i us in ec ion who ha e ecei ed solid o gan ansplan s. Gas oen e ology 2011; 140:1481–9. 6. Eu opean Associa ion o he S udy o he Li e . EASL clinical p ac ice guidelines on hepa i is E i us in ec ion. J Hepa ol 2018; 68:1256–71. 7. DebingY, Eme sonSU, WangY, e al. Riba i in inhibi s in i o hepa i is E i us eplica ion h ough deple ion o cellula GTP pools and is mode a ely syne gis ic wi h alpha in e e on. An imic ob Agen s Chemo he 2014; 58:267–73. 8. Wang Y, Zhou X, Debing Y, e  al. Calcineu in inhibi o s s imula e and mycophenolic acid inhibi s eplica ion o hepa i is E i us. Gas oen e ology 2014; 146:1775–83. 9. Malle  V, Nicand E, Sul anik P, e  al. B ie communica ion: case epo s o iba i in ea men o ch onic hepa i is E. Ann In e n Med 2010; 153:85–9. 10. Kama N, Ros aingL, Ab a anelF, e al. Riba i in he apy inhibi s i al eplica- ion in pa ien s wi h ch onic hepa i is E i us in ec ion. Gas oen e ology 2010; 139:1612–8. 11. PischkeS, Ha dk eS, BodeU, e al. Riba i in ea men o acu e and ch onic hep- a i is E: a single-cen e expe ience. Li e In 2013; 33:722–6. 12. Kama N, Izope J, T iponS, e al. Riba i in o ch onic hepa i is E i us in ec ion in ansplan ecipien s. N Engl J Med 2014; 370:1111–20. 13. DebingY, GisaA, Dallmeie K, e al. A mu a ion in he hepa i is E i us RNA polyme ase p omo es i s eplica ion and associa es wi h iba i in ea men ailu e in o gan ansplan ecipien s. Gas oen e ology 2014; 147:1008–11 e7; quiz e15–6. 14. Lhomme S, Kama  N, Nico  F, e  al. Mu a ion in he hepa i is E i us poly- me ase and ou come o iba i in he apy. An imic ob Agen s Chemo he 2015; 60:1608–14. 15. Tod D, GisaA, RadonicA, e al. In i o e idence o iba i in-induced mu agen- esis o he hepa i is E i us genome. Gu 2016; 65:1733–43. 16. Ab a anel F, Sand es-Saune K, Lhomme S, Dubois M, Mansuy JM, Izope  J. Geno ype 3 di e si y and quan i ica ion o hepa i is E i us RNA. J Clin Mic obiol 2012; 50:897–902. 17. Ma ionO, LhommeS, Ab a anelF, Izope J, Kama N. Should 12- o 24-week pos - iba i in ollow-up be conside ed o de ine sus ained i ological esponse in ansplan pa ien s ea ed o ch onic hepa i is E i us in ec ion? T anspl In ec Dis 2019; 21:e13065. 18. DebingY, Ramie eC, Dallmeie K, e al. Hepa i is E i us mu a ions associa ed wi h iba i in ea men ailu e esul in al e ed i al i ness and iba i in sensi- i i y. J Hepa ol 2016; 147:1008–11. 19. Tod  D, Meis e  TL, S einmann E. Hepa i is E i us ea men and iba i in he apy: i al mechanisms o non esponse. Cu Opin Vi ol 2018; 32:80–7. 20. Nico F, JeanneN, Roule A, e al. Di e si y o hepa i is E i us geno ype 3. Re Med Vi ol 2018; 28:e1987. 21. Kama N, Izope J, Pa ioN, e al. Hepa i is E i us in ec ion. Na Re Dis P ime s 2017; 3:17086. 22. Kama N, Ros aingL, Ab a anelF, e al. Pegyla ed in e e on-alpha o ea ing ch onic hepa i is E i us in ec ion a e li e ansplan a ion. Clin In ec Dis 2010; 50:e30–3. 23. Ros aingL, Izope J, Ba onE, Du au M, PuelJ, Du andD. T ea men o ch onic hepa i is C wi h ecombinan in e e on alpha in kidney ansplan ecipien s. T ansplan a ion 1995; 59:1426–31. 24. DaoThiVL, DebingY, WuX, e al. So osbu i inhibi s hepa i is E i us epli- ca ion in i o and esul s in an addi i e e ec when combined wi h iba i in. Gas oen e ology 2016; 150:82–5.e4. 25. DonnellyMC, ImlachSN, Ab a anelF, e al. So osbu i and dacla as i an i- i al he apy ails oclea HEV i emia and es o e eac i e T cells in a HEV/HCV co-in ec ed li e ansplan ecipien . Gas oen e ology 2017; 152:300–1. 26. Mazzola A, T an Minh M, Cha lo e F, e  al. Ch onic hepa i is E i al in ec- ion a e li e ansplan a ion: a eg ession o ib osis a e an i i al he apy. T ansplan a ion 2017; 101:2083–7. 27. Kama N, LhommeS, Ab a anelF, e  al. An ea ly i al esponse p edic s he i ological esponse o iba i in in hepa i is E i us o gan ansplan pa ien s. T ansplan a ion 2015; 99:2124–31. 28. Sunee ha PV, Pischke S, Schlapho  V, e  al. Hepa i is E i us (HEV)–speci ic T-cell esponses a e associa ed wi h con ol o HEV in ec ion. Hepa ology 2012; 55:695–708. 29. Ab a anelF, LhommeS, Ros aingL, Kama N, Izope J. P o ac ed ecal shedding o HEV du ing iba i in he apy p edic s ea men elapse. Clin In ec Dis 2015; 60:96–9. 30. Ma ionO, LhommeS, DelBelloA, e al. Moni o ing hepa i is E i us ecal shed- ding o op imize iba i in ea men du a ion in ch onically in ec ed ansplan pa ien s. J Hepa ol 2019; 70:206–9. 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