Direct-Acting Antivirals for the Treatment of Kidney Transplant Patients with Chronic Hepatitis C Virus Infection in Spain: A Long-Term Prospective Observational Study

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Accep ed 6 Oc obe 2019. 1 Depa men o Neph ology, Hospi al Vi gen del Rocío, Se illa, Spain. 2 Depa men o Neph ology, Hospi al La Fe, Valencia, Spain. 3 Depa men o Neph ology, Hospi al Clínico San Ca los, Facul ad de Medicina, Uni e sidad Complu ense, Mad id, Spain. 4 Depa men o Neph ology, Hospi al Vall d’Heb ón, Ba celona, Spain. 5 Depa men o Neph ology, Complejo Hospi ala io A Co uña, A Co uña, Spain. 6 Depa men o Neph ology, Hospi al Uni e si a io Pue a del Ma , Cádiz, Spain. 7 Depa men o Neph ology, Hospi al La Paz, Mad id, Spain. 8 Depa men o Neph ology, Hospi al de C uces, Vizcaya, Spain. 9 Depa men o Neph ology, Hospi al Miguel Se e , Za agoza, Spain. 10 Depa men o Neph ology, Hospi al Ge mans T ías i Pujol, Ba celona, Spain. 11 Depa men o Neph ology, Hospi al Uni e si a io Ca los Haya, IBIMA, REDinREN RD16/0009/0006, Málaga, Spain. 12 Depa men o Neph ology, Fundación Puig e , REinREN RD16/0009/0019, Ba celona, Spain. 13 Depa men o Neph ology, Hospi al de Alican e, Alican e, Spain. 14 Depa men o Neph ology, Hospi al Ma qués de Valdecilla, IDIVAL, REDinREN RD16/0009/0027, San ande , Spain. 15 Depa men o Neph ology, Hospi al Vi gen de la A ixaca, Mu cia, Spain. 16 Depa men o Neph ology, Hospi al del Ma , Ba celona, Spain. 17 Depa men o Neph ology, Hospi al Uni e si a io Reina So ía, Có doba, Spain. Di ec -ac ing An i i als o he T ea men o Kidney T ansplan Pa ien s Wi h Ch onic Hepa i is C Vi us In ec ion in Spain: A Long- e m P ospec i e Obse a ional S udy Ca men González-Co illo, MD,1 Isabel Beney o, MD,2 Ana Sánchez-F uc uoso, MD,3 Manel Pe elló, MD,4 Angel Alonso, MD,5 Auxiliado a Mazuecos, MD,6 Ca los Jiménez, MD,7 So ía Zá aga, MD,8 Ja ie Paul, MD,9 Rica do Lauzu ica, MD,10 Domingo He nández, MD,11 Luis Gui ado, MD,12 An onio F anco, MD,13 Juan Ca los Ruiz, MD, PhD,14 San iago Llo en e, MD,15 Ma a C espo, MD,16 Albe o Rod íguez-Beno , MD,17 Ma ía del Ca men de G acia Guindo, MD,18 Ca men Díaz-Co e, MD,19 and Miguel Ángel Gen il, MD1 Kidney T ansplan a ion Backg ound. Di ec -ac ing an i i als (DAA) allow e ec i e and sa e e adica ion o hepa i is C i us (HCV) in mos pa ien s. The e a e limi ed da a on he long- e m e ec s o all-o al, in e e on- ee DAA combina ion he apies in kidney ansplan (KT) pa ien s in ec ed wi h HCV. He e we e alua ed he long- e m ole abili y, e icacy, and sa e y o DAA combina ion he apies in KT pa ien s wi h ch onic HCV in ec ion. Me hods. Clinical da a om KT pa ien s ea ed wi h DAA we e collec ed be o e, du ing, and a e he ea men , including i al esponse, immunosupp ession egimens, and kidney and li e unc ion. Resul s. Pa ien s (N = 226) we e mos ly male (65.9%) aged 56.1 ± 10.9 yea s, wi h a median ime om KT o ini ia ion o DAA he apy o 12.7 yea s and HCV geno ype 1b (64.6%). Mos pa ien s we e ea ed wi h so osbu i -based he apies. Rapid i ological esponse a 1 mon h was achie ed by 89.4% o he pa ien s and sus ained i ological esponse by week 12 by 98.1%. Li e unc ion imp o ed signi ican ly a e DAA ea men . Tac olimus dosage inc eased 37% om he beginning o ea men (2.5 ± 1.7 mg/d) o 1 yea a e he s a o DAA ea men (3.4 ± 1.9 mg/d, P < 0.001). Median ollow-up was 37.0 mon hs (in e qua ile ange, 28.4–41.9) and dea h-censo ed g a su i al was 91.1%. Ad e se e en s esul ing om DAA ea men , especially anemia, we e epo ed o 31.0% o he pa ien s. Conclusions. Ch onic HCV in ec ion can be ea ed e icien ly and sa ely wi h DAA he apy in KT pa ien s. Mos pa ien s e ained s able kidney unc ion and imp o ed li e unc ion. Tac olimus dose had o be inc eased in mos pa ien s, po en ially as a esul o be e li e unc ion. (T ansplan a ion Di ec 2019;5: e510; doi: 10.1097/TXD.0000000000000954. Published online 18 No embe , 2019.) 18 Depa men o Neph ology, Hospi al Uni e si a io Vi gen de las Nie es, G anada, Spain. 19 Depa men o Neph ology, Hospi al Cen al de As u ias, REDinREN RD16/0009/0021, As u ias, Spain. All au ho s pa icipa ed in esea ch design and con ibu ed wi h da a om hei espec i e hospi als. J.C.R. collec ed da a and pe o med he ini ial da a analysis. All au ho s p o ided eedback on he da a esul s. J.C.R. w o e d a o he manusc ip and all au ho s con ibu ed o and app o ed he inal e sion. The au ho s decla e no con lic s o in e es . This wo k was pa ially suppo ed by a g an om he Ins i u o de Salud Ca los III co- unded by he Fondo Eu opeo de Desa ollo Regional-FEDER, RETICS (REDinREN RD16/0009). As ellas Pha ma S.A. p o ided inancial suppo o medical w i ing and edi ing o he manusc ip . Co espondence: Juan Ca los Ruiz, MD, Depa men o Neph ology, Hospi al Ma qués de Valdecilla, A . Valdecilla, 25, 39008 San ande , Can ab ia, Spain. ( uizjc@hum .es). Copy igh © 2019 The Au ho (s). T ansplan a ion Di ec . Published by Wol e s Kluwe Heal h, Inc. This is an open-access a icle dis ibu ed unde he e ms o he C ea i e Commons A ibu ion-Non Comme cial-No De i a i es License 4.0 (CCBY-NC-ND), whe e i is pe missible o download and sha e he wo k p o ided i is p ope ly ci ed. The wo k canno be changed in any way o used comme cially wi hou pe mission om he jou nal. 10.1097/TXD.0000000000000954 2 T ansplan a ion DIRECT ■ 2019 www. ansplan a iondi ec .com Kidney ansplan (KT) ecipien s who a e hepa i is C i us (HCV)-posi i e ha e an inc eased isk o o he in ec- ions, new-onse diabe es melli us, ca dio ascula diseases, li e ib osis, g a loss, and mo ali y.1,2 The immunosupp es- si e egimen equi ed a e ansplan a ion can p omo e i al eplica ion, leading o p og ession o li e disease o eac i a- ion o HCV in ec ion and exace ba ion o hepa i is. Ac i e i al eplica ion a ansplan a ion is an independen isk ac- o o g a ailu e in his ype o pa ien s.3 Howe e , kidney ansplan a ion is s ill ecommended, as mo ali y is highe i con inuing on main enance hemodialysis.4 An i i al he apy based on in e e on (IFN) o iba i in is no ecommended in pa ien s wi h impai ed enal unc ion because bo h d ugs a e elimina ed by he kidneys and educed doses a e equi ed. In KT pa ien s, he he apies based on IFN ha e been associa ed wi h poo e icacy, low ole abili y, and inc eased isk o g a ejec ion.2,5 In ecen yea s, he in oduc ion o o al an i i al d ugs ha di ec ly inhibi i al p o eins ha e e olu ionized he ea - men o HCV-posi i e pa ien s.6 The i s IFN- ee di ec - ac ing an i i al (DAA) he apy implemen ed was so osbu i , an inhibi o o he i al RNA polyme ase, app o ed by he US Food and D ug Adminis a ion in Decembe 2013.7 Cu en ly, he e a e 4 majo classes o app o ed DAA d ugs a ge ing 3 di e en nons uc u al i al p o eins: NS3/4A p o- ease inhibi o s (eg, simep e i , pa i ap e i , g azop e i , gle- cap e i , oxilap e i ); NS5A eplica ion complex inhibi o s (eg, ledipas i , ombi as i , elbas i , dacla as i , elpa as i , pib en as i ); non-nucleoside NS5B polyme ase inhibi o s (eg, dasabu i ); and nucleoside NS5B polyme ase inhibi o s (so osbu i ). Used in combina ions and wi h/wi hou iba- i in, hey can o en lead o sus ained i ological esponses (SVR) >90% in 12 weeks o less among pa ien s ha a e ea - men naï e,8 compa ed wi h cu a ion a es o 34% in 24–48 weeks wi h p e ious ea men s.9 Compa ed wi h IFN-based ea men s, he sa e y o o al DAA he apies has been well es ed on pa ien s wi h enal dys unc ion. Recen ly de el- oped pangeno ypic DAA combina ions, such as glecap e i / pib en as i , ha e eme ged as majo ad ances o pa ien s wi h se e e kidney impai men .10,11 Howe e , he long- e m ea men e ec s a e s ill poo ly known,12 as d ug–d ug in e - ac ions a e a possibili y in pa ien s comp omised by o he diseases. In KT pa ien s wi h concomi an HCV in ec ion, he ben- e i s o DAA he apies include a educed isk o g a ejec- ion compa ed wi h IFN-based he apies, as well as imp o ed li e unc ion. HCV e adica ion wi h DAA ea men s has been shown o imp o e signi ican ly he quali y o li e o KT pa ien s.13 Ano he ad an age o DAA ea men s is ha mo e HCV-in ec ed kidneys will be a ailable o ansplan s, hus educing wai ing lis s and ime on hemodialysis o a ec ed pa ien s.14-16 I could also be expec ed ha he e will be a educ ion in he numbe o se e e enal impai men pa ien s ha will equi e a dual kidney and li e ansplan . The e is a g owing body o e idence ega ding he e icacy and sa e y o DAAs in KT ecipien s.17-25 The e iew o he a ailable da a indica es ha DAA he apies can cu e HCV in mos KT pa ien s (>98%) wi h no majo sa e y-associa ed conce ns.17,26 They also highligh ed he need o ca e ul moni- o ing o immunosupp essi e d ug le els sho ly a e DAA ea men ini ia ion, as well as he need o close collabo a- ion be ween hepa ologis s and ansplan a ion neph ologis s. Al hough la ge coho s udies will be needed o assess he clinical and long- e m bene i s o DAAs in he KT pa ien popula ion, he Eu opean Associa ion o he S udy o he Li e and he Spanish Associa ion o he Li e and he Kidney encou age he use o DAA he apies o he ea men o HCV in ec ion in ch onic kidney disease.11,27 In his obse a ional, p ospec i e, mul icen e s udy, we p esen ou esul s o 226 cases o HCV-in ec ed KT ecipi- en s ea ed wi h DAA. This analysis is an ex ension o a p e- ious p elimina y epo o 119 cases.18 Ou main objec i e he e was o in es iga e he long- e m ole abili y, e icacy, and sa e y o a a ie y o IFN- ee DAA combina ion he apies cu en ly used in Spanish e e ence hospi als. MATERIALS AND METHODS This obse a ional, mul icen ic, p ospec i e s udy included KT pa ien s om 19 e e ence hospi als h oughou Spain om Ma ch 2013 o May 2017. All pa ien s we e ≥18 yea s old, HCV-posi i e a he ime o ansplan , and ecei ed DAA he apy. The s udy p o ocol was app o ed by he E hics Commi ee o he Vi gen del Rocío Hospi al, Se ille (Spain). All eligible pa ien s p o ided w i en in o med consen be o e unde going s udy- ela ed p ocedu es. The ial was conduc ed in acco dance wi h he Decla a ion o Helsinki.28 Pa ien s we e ollowed p ospec i ely and clinical, i ologi- cal, and labo a o y da a we e collec ed a a basal isi be o e he ea men s a ed, 1 mon h a e ea men s a (be o e i s inaliza ion), and 1 mon h, 3 mon hs, 1 yea a e he ea men ended. All da a collec ed by he in es iga o s we e placed in o a single da abase o u he analysis. E icacy o he he apy was de ined as he SVR a e 30, 90 (SVR-12), and 365 days o ea men . Sa e y o he he apy was assessed as a unc ion o enal unc ion (c ea inine, es i- ma ed glome ula il a ion a e [eGFR]), p o einu ia, immu- nosupp ession le els, and changes in he diabe es ea men o diabe ic pa ien s (as judged by he in es iga o ). Risk o ecu ence was also e alua ed. Fib osis s age was e alua ed by ansien elas og aphy (Fib oScan). Compliance wi h an i i al he apy and a e o ad e se e en s we e moni o ed h ough he ea men du a ion and ollow-up by e iew o clinical cha s by he clinicians a each o he hospi als. S a is ical analysis was pe o med using he SPSS 22.0 s a- is ical so wa e o Windows. All alues we e calcula ed om he numbe o alid cases (N). Quan i a i e a iables we e desc ibed as means and s anda d de ia ions o as medians wi h in e qua ile anges (IQR). Ca ego ical a iables we e p esen ed as lis s o equencies and p opo ions. Compa isons o nume ical a iables we e pe o med using he pai ed es o he Wilcoxon es . RESULTS Pa ien Popula ion This s udy included 226 KT ecipien s wi h ch onic HCV in ec ion. The basal demog aphic and clinical cha ac e is- ics o he pa ien s a e shown in Table1. Mos pa ien s we e male (65.9%) and he mean age was 56.1 ± 10.9 yea s, wi h a median ime om KT o ini ia ion o DAA he apy o 12.7 yea s (IQR, 6.3–21.9). The median ime o ollow-up a e ini ia ion o an i i al he apy was 37.0 mon hs (IQR, 28.4– 41.9). Nine een pa ien s we e ecipien s o a combined li e © 2019 The Au ho (s). Published by Wol e s Kluwe Heal h, Inc. González-Co illo e al and KT and 4 had simul aneous panc ea ic and KTs. Se en y- ou pa ien s (32.7%) p esen ed diabe es, which was ea ed wi h o al an idiabe ics (8.4%), insulin (19.5%), o a combi- na ion o bo h (2.7%). Baseline i al geno ypes a e shown in Table1. Geno ype 1b was he mos equen (146 pa ien s, 64.6%). Fi y-se en pa ien s (25.2%) had ecei ed p e ious HCV ea men . Fu he , 8 and 6 pa ien s es ed posi i e o hepa i is B i us and HIV, espec i ely. Thi y- i e pa ien s (15.5%) p esen ed po al hype ension and 5 pa ien s (2.2%) had hepa ocellula ca cinoma. An i i al T ea men s and Vi ological Response A o al o 11 di e en an i i al egimens we e p esc ibed in ou coho s udy (Table2). Mo e han hal o he pa ien s we e ea ed wi h he combina ion o so osbu i and ledipas- i (118 pa ien s, 52.2%). The combina ion o so osbu i and iba i in, wi h o wi hou o he DAA, was used in 38 pa ien s (16.8%). The median ea men du a ion was 12.3 weeks (IQR, 11.9–15.7 wk). O he 207 pa ien s who comple ed he ea men , 185 (89.4%) pa ien s achie ed apid i ological esponse a e 1 mon h o ea men , wi h unde ec able i al load. A e comple ion o he 12-week DAA ea men , 203 pa ien s (98.1%) achie ed SVR-12. One yea a e he s a o ea men , he e we e no cases eco ded o in ec ion elapse o e ea men wi h an i i als. The e we e 12 pa ien s (5.3%) who discon inued ea men ; hal o hem had been ea ed wi h he combina ion o ombi- as i , i ona i , pa i ap e i , and dasabu i . Discon inua ion was due o pancy openia in 2 pa ien s, neu al oxici y in 3 pa ien s, hepa ic oxici y in 2 pa ien s, and gas oin es inal oxici y in 1 pa ien ; in 1 pa ien , he eason was no egis- e ed and he e we e 3 dea hs: 2 due o sepsis and 1 due o acu e myoca dial in a c ion. In hese cases, he median ea - men du a ion was 3.3 weeks (IQR, 1.9–12.2). G a Func ion and Immunosupp ession Clinical enal and hepa ic pa ame e s be o e and 1 yea a e he s a o DAA ea men a e shown in Table3. The indica o s o kidney unc ion wo sened, as eGFR dec eased signi ican ly (P = 0.003, pai ed es ). Renal unc ion was no signi ican ly di e en be ween DAA ea men egimens. All indica o s o li e unc ion p esen ed e y signi ican imp o e- men s (P < 0.001). All pa ien s we e on 1 o mo e immunosupp essi e agen s, o which ac olimus was he mos equen (67.7%, Table1). Tac olimus ough le els we e educed 1 yea a e he s a o DAA he apy (7.2 ± 1.9 ng/mL a s a e sus 6.6 ± 2.3 ng/mL, P = 0.041). The o al daily dose o ac olimus signi ican ly inc eased 1 yea a e he s a o he ea men (2.5 ± 1.7 e sus 3.4 ± 1.9 mg/d; P < 0.001). Du ing he median 37 mon hs o ollow-up, he dea h- censo ed g a su i al was 96.9% a e 1 yea , 96.4% a e 2 yea s, and 91.1% a e 37 mon hs. The causes o g a loss we e in e s i ial ib osis plus ubula a ophy in 10 pa ien s, ch onic humo al ejec ion in 3 pa ien s, and c yoglobuline- mia in 3 pa ien s. Pa ien su i al (DAA- ea ed) was 96.4% a e 1 yea , 95.8% a e 2 yea s, and 89.1% a e 37 mon hs. Causes o dea h we e cance (lung and cholangioca cinoma) in 6 pa ien s, ca dio ascula e en s in 6 pa ien s, sepsis in 5 pa ien s, li e ailu e due o ci hosis in 2 pa ien s, and o he causes in 4 pa ien s. Ad e se E en s A o al o 70 pa ien s (31.0%) epo ed ad e se e en s while on DAA ea men (Table2). The mos common ad e se e en was anemia, which was se ious in 25 o he cases and highly p e alen in pa ien s ea ed wi h iba i in (>60% o pa ien s). A decline o kidney unc ion was obse ed in 17 pa ien s (7.5%). Neu openia and h ombopenia we e de ec ed in 3.1% and 5.3% o pa ien s, espec i ely. In addi ion o he ad e se e en s shown in Table 2, he e we e also epo ed cases o as henia (4 pa ien s), nausea and omi ing (3 pa ien s), headache (3 pa ien s), skin ash (2 pa ien s), ac olimus oxic- i y (2 pa ien s), and hepa o oxici y (2 pa ien s). Toxici y due o ac olimus was obse ed in 2 o he 16 pa ien s ea ed wi h ombi as i , i ona i , pa i ap e i , and dasabu i , bu we ound no o he cases o oxici y in any o he o he DAA ea men s. DISCUSSION In his s udy, we desc ibe he esul s o he medium o long- e m ea men o HCV-in ec ed KT ecipien s wi h he TABLE 1. Basal demog aphic and clinical cha ac e is ics, N = 226 Age (y), mean ± SD 56.1 ± 10.9 Gende (male), N (%) 149 (65.9) P ima y cause o kidney disease, N (%) Glome uloneph i is 60 (26.5) In e s i ial 35 (15.5) Polycys ic kidney disease 20 (8.8) Diabe ic neph opa hy 16 (7.1) Sys emic disease 7 (3.1) Unknown/o he 78 (38.9) P e ious ansplan s, N (%) 0 150 (66.4) 1 64 (28.3) 2–3 11 (5.3) Immunosupp essi e ea men , N (%)a Tac olimus 153 (67.7) Mycophenola e 151 (66.8) S e oids 161 (71.2) Cyclospo ine 37 (16.4) Aza hiop ine 12 (5.3) E e olimus 15 (6.6) Rapamycin 11 (4.9) HCV geno ype, N (%) 1 1 (0.4) 1a 34 (15.0) 1a/1b 1 (0.4) 1b 146 (64.6) 2 12 (5.3) 3 11 (4.9) 3a 5 (2.2) 4 11 (4.9) 6 1 (0.4) Unknown/no da a 4 (1.7) Fib osis, N (%) 0–2 104 (46.1) 3–5 66 (29.2) Unknown/no da a 56 (24.8) Pa ien s could ha e mul iple ea men s. HCV, hepa i is C i us; SD, s anda d de ia ion. 4 T ansplan a ion DIRECT ■ 2019 www. ansplan a iondi ec .com ecen ly de eloped DAA he apies. The i ological esponse was e y high (98.1% achie ed SVR-12) and, a e a median ollow-up o 26.6 mon hs, pa ien and g a su i al we e >95%. SVR was simila in double li e /kidney o panc eas/KT pa ien s, sugges ing ha immunosupp ession did no a ec he e ec i eness o he he apy. Addi ionally, we obse ed no pos - ea men elapses. One yea a e he an i i al ea - men , hepa ic unc ion expe ienced signi ican imp o emen s in mos pa ien s. The SVR-12 obse ed in ou s udy is compa able o ha ound in o he se ies, which ange om 91% o 100% in his pa ien popula ion.20-22,25,29-31 In ou s udy, some pa ien s de el- oped mild allog a dys unc ion and some pa ien s equi ed immunosupp ession dose adjus men . One yea a e ini ia- ion o DAA ea men , ou s udy showed ha ac olimus dose had o be signi ican ly inc eased o main ain le els wi hin a - ge anges. Immunosupp essi e dose adjus men in KT o li e ansplan ecipien s ecei ing DAA has been obse ed p e i- ously.32-34 I has been sugges ed ha d ug–d ug in e ac ions could de elop du ing DAA he apy, as he NS3/4A p o ease inhibi o s a e deg aded in he li e by cy och ome P450, which also me abolizes calcineu in inhibi o s. Howe e , in ou s udy, only 50 pa ien s (22%) ecei ed NS3/4A p o ease inhibi o s simep e i , pa i ap e i , o g azop e i . Ano he possibili y is ha enhanced li e unc ion is he esul o imp o ed me ab- olism o he calcineu in inhibi o s as a consequence o he DAA ea men . P oin lamma o y cy okines may inhibi cy och ome P450 enzymes du ing HCV in ec ion, which a e hen es o ed o no mal unc ion a e i us clea ance.32 This appa en DAA-induced e e sibili y o li e unc ion could be mo e p onounced in KT pa ien s wi h lowe deg ees o ib o- sis compa ed wi h hose wi h se e e ib osis o ci hosis.33 In he non-KT popula ion, he biochemical pa ame e s o li e unc ion imp o e sho ly a e DAA he apy,35 wi h eg ession o ib osis, no maliza ion o po al hype ension and li e s i ness, and inc ease in skele al muscle mass.36-38 Independen o in e en ion, some unc ional de e io a ion is expec ed in KT pa ien s ollowed in ime, as e lec ed in hei clinical pa ame e s. In ou s udy, we could no de e mine i he e had been a p io decline in enal unc ion, o e en an imp o emen , as no da a we e a ailable be o e DAA ea - men . The obse ed a ia ion in enal unc ion was no clini- cally signi ican and he su i al o he ansplan ed kidney censo ed o dea h, 91.1% a e a median ollow-up o 37.0 mon hs, was high. Likely he elimina ion o he i us sup- p esses o limi s i s nega i e impac , imp o ing he su i al o he pa ien and he ansplan ed o gan un il i equals o nea s ha o he nega i e HCV ecep o s. Ou s udy and o he s TABLE 2. DAA ea men s and ad e se e en s, N (%) T ea men F equencyaDiscon inuedb Ad e se e en sb,c Anemia Kidney unc ion decline Neu openia Th ombopenia So osbu i , ledipas i 118 (52.2) 2 (1.7) 4 (3.4) 9 (7.6) 0 3 (2.5) So osbu i , simep e i 23 (10.2) 1 (4.3) 0 2 (8.7) 1 (4.3) 1 (4.3) So osbu i , dacla as i 21 (9.3) 1 (4.8) 1 (4.8) 1 (4.8) 0 0 So osbu i , iba i in, ledipas i 21 (9.3) 2 (9.5) 13 (61.9) 0 4 (19.0) 5 (23.8) Ombi as i , i ona i , pa i ap e i , dasabu i 16 (7.1) 6 (37.5) 6 (37.5) 3 (18.8) 1 (6.3) 2 (12.5) So osbu i , i abi in 8 (3.5) 0 6 (75.0) 0 1 (12.5) 0 G azop e i , elbas i 7 (3.1) 0 0 0 0 0 So osbu i , iba i in, dacla as i 5 (2.2) 0 3 (60.0) 1 (20.0) 0 1 (20.0) So osbu i , iba i in, simep e i 4 (1.8) 0 1 (25.0) 0 0 0 So osbu i 2 (0.9) 0 0 0 0 0 Simep e i , dacla as i , iba i in 1 (0.4) 0 0 1 (100.0) 0 0 To ala226 (100.0) 12 (5.3) 34 (15.0) 17 (7.5) 7 (3.1) 12 (5.3) aPe cen ages calcula ed o e o al numbe o pa ien s. bPe cen ages calcula ed o e pa ien s unde his ea men . cMo e han 1 ad e se e en could occu in he same pa ien . DAA, di ec -ac ing an i i als. TABLE 3. Clinical pa ame e s o kidney and li e unc ion N P e ea men Pos - ea men aPb C ea ininec (mg/dL) 147 1.36 (0.51) 1.50 (1.02) 0.016 eGFR (CKD-EPI)c (mL/min/1.73 m2) 198 61.40 (21.45) 58.75 (22.30) 0.003 P o einu iac (mg/24 h) 184 355.18 (538.12) 813.68 (3524.03) 0.586d GGTe (U/L) 136 60 (34–126) 22 (16–42) <0.001 To al bili ubine (mg/dL) 136 0.61 (0.50–0.87) 0.50 (0.40–0.80) <0.001 ALTe (U/L) 136 52.5 (31.3–84.5) 17 (13.0–25.0) <0.001 aIndica ed pos - ea men alues a e 1 yea a e s a o di ec -ac ing an i i al he apy. bPai ed es , unless o he wise s a ed. cMean (SD). dWilcoxon es . eMedian (in e qua ile ange). ALT, alanine ansaminase; CKD-EPI, Ch onic Kidney Disease Epidemiology Collabo a ion; eGFR, es ima ed glome ula il a ion a e; GGT, gamma glu amyl ans e ase; SD, s anda d de ia ion. © 2019 The Au ho (s). Published by Wol e s Kluwe Heal h, Inc. González-Co illo e al we e no designed o assess he unc ional e olu ion o he kidney in he same pa ien be o e and a e ea men (com- pa ing he slope o loss o eGFR as a p edic o o i s long- e m su i al). Possibly his issue canno be esol ed di ec ly and conclusi ely, al hough la ge egis ies could be used o de elop e ospec i e s udies by ollowing la ge coho s o pa ien s. DAA he apy was well ole a ed, as in p e iously epo ed se ies,17-19,21-25 wi h only 5.3% o he pa ien s discon inu- ing ea men . Mos common ad e se e en was anemia in pa ien s ea ed wi h iba i in, a well-known e ec o his an i i al.39 The highes p opo ion o discon inua ion due o DAA ad e se e ec s was seen o pa ien s aking he com- bina ion o ombi as i , i ona i , pa i ap e i , and dasabu- i (6 pa ien s, 37.5% o all discon inua ions). We did no egis e he eme gence o se ious in ec ions ha equi ed hospi aliza ion. Cu en ly, he Eu opean Associa ion o he S udy o he Li e ecommends a ixed-dose combina ion o so osbu i and ledipas i (geno ypes 1, 4, 5, and 6) wi hou he need o immunosupp essan d ug dose adjus men s in case o KT pa ien s wi h accep able kidney unc ion.11 Howe e , he ixed-dose combina ion o glecap e i and pib en as i o 12 weeks, wi h immunosupp essan d ug adjus men s as needed, is ecommended o pa ien s wi h se e e kidney impai men (eGFR <30 mL/min/1.73 m2).11 Al hough cu en he apeu ic p o ocols o KT pa ien s seem highly e ec i e and sa e, i is likely ha no el combina ion DAA he apies will be de el- oped in he u u e o hose pa ien s wi h como bidi ies o e ac o y o ea men . To da e, his mul icen ic obse a ional s udy o 226 pa ien s e lec ing cu en clinical p ac ices is he la ges o i s kind in Eu ope and wi h he longes ollow-up (37 mo). Howe e , he s udy was limi ed by pa ien he e ogenei y (eg, geno ypes, deg ee o ib osis) and di e si y in DAA egimes, which p e en ed compa a i e and s a is ically signi ican analysis o e ec i eness o sa e y. CONCLUSIONS Ou s udy con i ms ha HCV in ec ion can be success- ully and sa ely ea ed a e kidney ansplan a ion wi h a 12-week cou se o ea men wi h DAAs. A e a median ol- low-up o 37 mon hs, mos pa ien s imp o ed li e unc ion and e ained clinically s able kidney ac i i y. Pa ien s equi ed a signi ican inc ease in ac olimus dose o main ain ough le els wi hou changes in o he immunosupp essi e d ugs. ACKNOWLEDGMENTS The au ho s hank F ancisco López de Sa o, PhD, o medi- cal w i ing suppo wi h he p epa a ion o his a icle. REFERENCES 1. Heo NY, Mannali ha a A, Kim D, e al. Long- e m pa ien and g a su i al o kidney ansplan ecipien s wi h hepa i is C i us in ec ion in he Uni ed S a es. T ansplan a ion. 2018;102:454–460. 2. Fab izi F, Ma in P, Dixi V, e al. 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