Kidney Transplantation Direct-acting Antivirals for the Treatment of Kidney Transplant Patients With Chronic Hepatitis C Virus Infection in Spain: A Long-term Prospective Observational Study Carmen González-Corvillo, MD,1 Isabel Beneyto, MD,2 Ana Sánchez-Fructuoso, MD,3 Manel Perelló, MD,4 Angel Alonso, MD,5 Auxiliadora Mazuecos, MD,6 Carlos Jiménez, MD,7 Sofía Zárraga, MD,8 Javier Paul, MD,9 Ricardo Lauzurica, MD,10 Domingo Hernández, MD,11 Luis Guirado, MD,12 Antonio Franco, MD,13 Juan Carlos Ruiz, MD, PhD,14 Santiago Llorente, MD,15 Marta Crespo, MD,16 Alberto Rodríguez-Benot, MD,17 María del Carmen de Gracia Guindo, MD,18 Carmen Díaz-Corte, MD,19 and Miguel Ángel Gentil, MD1 Background. Direct-acting antivirals (DAA) allow effective and safe eradication of hepatitis C virus (HCV) in most patients. There are limited data on the long-term effects of all-oral, interferon-free DAA combination therapies in kidney transplant (KT) patients infected with HCV. Here we evaluated the long-term tolerability, efficacy, and safety of DAA combination therapies in KT patients with chronic HCV infection. Methods. Clinical data from KT patients treated with DAA were collected before, during, and after the treatment, including viral response, immunosuppression regimens, and kidney and liver function. Results. Patients (N = 226) were mostly male (65.9%) aged 56.1 ± 10.9 years, with a median time from KT to initiation of DAA therapy of 12.7 years and HCV genotype 1b (64.6%). Most patients were treated with sofosbuvir-based therapies. Rapid virological response at 1 month was achieved by 89.4% of the patients and sustained virological response by week 12 by 98.1%. Liver function improved significantly after DAA treatment. Tacrolimus dosage increased 37% from the beginning of treatment (2.5 ± 1.7 mg/d) to 1 year after the start of DAA treatment (3.4 ± 1.9 mg/d, P < 0.001). Median follow-up was 37.0 months (interquartile range, 28.4–41.9) and death-censored graft survival was 91.1%. Adverse events resulting from DAA treatment, especially anemia, were reported for 31.0% of the patients. Conclusions. Chronic HCV infection can be treated efficiently and safely with DAA therapy in KT patients. Most patients retained stable kidney function and improved liver function. Tacrolimus dose had to be increased in most patients, potentially as a result of better liver function. (Transplantation Direct 2019;5: e510; doi: 10.1097/TXD.0000000000000954. Published online 18 November, 2019.) Received 2 October 2019. 18 Department of Nephrology, Hospital Universitario Virgen de las Nieves, Accepted 6 October 2019. Granada, Spain. 1 Department of Nephrology, Hospital Virgen del Rocío, Sevilla, Spain. 19 Department of Nephrology, Hospital Central de Asturias, REDinREN 2 Department of Nephrology, Hospital La Fe, Valencia, Spain. RD16/0009/0021, Asturias, Spain. 3 Department of Nephrology, Hospital Clínico San Carlos, Facultad de Medicina, Universidad Complutense, Madrid, Spain. All authors participated in research design and contributed with data from 4 Department of Nephrology, Hospital Vall d’Hebrón, Barcelona, Spain. their respective hospitals. J.C.R. collected data and performed the initial data 5 Department of Nephrology, Complejo Hospitalario A Coruña, A Coruña, Spain. analysis. All authors provided feedback on the data results. J.C.R. wrote draft of the manuscript and all authors contributed to and approved the final version. 6 Department of Nephrology, Hospital Universitario Puerta del Mar, Cádiz, Spain. The authors declare no conflicts of interest. 7 Department of Nephrology, Hospital La Paz, Madrid, Spain. This work was partially supported by a grant from the Instituto de Salud Carlos 8 Department of Nephrology, Hospital de Cruces, Vizcaya, Spain. III co-funded by the Fondo Europeo de Desarrollo Regional-FEDER, RETICS 9 Department of Nephrology, Hospital Miguel Servet, Zaragoza, Spain. (REDinREN RD16/0009). Astellas Pharma S.A. provided financial support for 10 Department of Nephrology, Hospital Germans Trías i Pujol, Barcelona, Spain. medical writing and editing of the manuscript. 11 Department of Nephrology, Hospital Universitario Carlos Haya, IBIMA, Correspondence: Juan Carlos Ruiz, MD, Department of Nephrology, Hospital REDinREN RD16/0009/0006, Málaga, Spain. Marqués de Valdecilla, Av. Valdecilla, 25, 39008 Santander, Cantabria, Spain. 12 Department of Nephrology, Fundación Puigvert, REinREN RD16/0009/0019, (ruizjc@humv.es). Barcelona, Spain. Copyright © 2019 The Author(s). Transplantation Direct. Published by Wolters 13 Department of Nephrology, Hospital de Alicante, Alicante, Spain. Kluwer Health, Inc. This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 14 Department of Nephrology, Hospital Marqués de Valdecilla, IDIVAL, REDinREN (CCBY-NC-ND), where it is permissible to download and share the work provided RD16/0009/0027, Santander, Spain. it is properly cited. The work cannot be changed in any way or used commercially 15 Department of Nephrology, Hospital Virgen de la Arrixaca, Murcia, Spain. without permission from the journal. 16 Department of Nephrology, Hospital del Mar, Barcelona, Spain. ISSN: 2373-8731 17 Department of Nephrology, Hospital Universitario Reina Sofía, Córdoba, Spain. DOI: 10.1097/TXD.0000000000000954 Transplantation DIRECT ■ 2019 www.transplantationdirect.com 1 2 Transplantation DIRECT ■ 2019 www.transplantationdirect.com K idney transplant (KT) recipients who are hepatitis C virus (HCV)-positive have an increased risk of other infec- tions, new-onset diabetes mellitus, cardiovascular diseases, Although large cohort studies will be needed to assess the clinical and long-term benefits of DAAs in the KT patient population, the European Association for the Study of the liver fibrosis, graft loss, and mortality.1,2 The immunosuppres- Liver and the Spanish Association of the Liver and the Kidney sive regimen required after transplantation can promote viral encourage the use of DAA therapies for the treatment of HCV replication, leading to progression of liver disease or reactiva- infection in chronic kidney disease.11,27 tion of HCV infection and exacerbation of hepatitis. Active In this observational, prospective, multicenter study, we viral replication at transplantation is an independent risk fac- present our results of 226 cases of HCV-infected KT recipi- tor for graft failure in this type of patients.3 However, kidney ents treated with DAA. This analysis is an extension of a pre- transplantation is still recommended, as mortality is higher if vious preliminary report of 119 cases.18 Our main objective continuing on maintenance hemodialysis.4 here was to investigate the long-term tolerability, efficacy, and Antiviral therapy based on interferon (IFN) or ribavirin is safety of a variety of IFN-free DAA combination therapies not recommended in patients with impaired renal function currently used in Spanish reference hospitals. because both drugs are eliminated by the kidneys and reduced doses are required. In KT patients, the therapies based on IFN have been associated with poor efficacy, low tolerability, and MATERIALS AND METHODS increased risk of graft rejection.2,5 This observational, multicentric, prospective study included In recent years, the introduction of oral antiviral drugs that KT patients from 19 reference hospitals throughout Spain directly inhibit viral proteins have revolutionized the treat- from March 2013 to May 2017. All patients were ≥18 years ment of HCV-positive patients.6 The first IFN-free direct- old, HCV-positive at the time of transplant, and received acting antiviral (DAA) therapy implemented was sofosbuvir, DAA therapy. The study protocol was approved by the Ethics an inhibitor of the viral RNA polymerase, approved by the Committee of the Virgen del Rocío Hospital, Seville (Spain). US Food and Drug Administration in December 2013.7 All eligible patients provided written informed consent before Currently, there are 4 major classes of approved DAA drugs undergoing study-related procedures. The trial was conducted targeting 3 different nonstructural viral proteins: NS3/4A pro- in accordance with the Declaration of Helsinki.28 tease inhibitors (eg, simeprevir, paritaprevir, grazoprevir, gle- Patients were followed prospectively and clinical, virologi- caprevir, voxilaprevir); NS5A replication complex inhibitors cal, and laboratory data were collected at a basal visit before (eg, ledipasvir, ombitasvir, elbasvir, daclatasvir, velpatasvir, the treatment started, 1 month after treatment start (before pibrentasvir); non-nucleoside NS5B polymerase inhibitors its finalization), and 1 month, 3 months, 1 year after the (eg, dasabuvir); and nucleoside NS5B polymerase inhibitors treatment ended. All data collected by the investigators were (sofosbuvir). Used in combinations and with/without riba- placed into a single database for further analysis. virin, they can often lead to sustained virological responses Efficacy of the therapy was defined as the SVR after 30, 90 (SVR) >90% in 12 weeks or less among patients that are treat- (SVR-12), and 365 days of treatment. Safety of the therapy ment naïve,8 compared with curation rates of 34% in 24–48 was assessed as a function of renal function (creatinine, esti- weeks with previous treatments.9 Compared with IFN-based mated glomerular filtration rate [eGFR]), proteinuria, immu- treatments, the safety of oral DAA therapies has been well nosuppression levels, and changes in the diabetes treatment tested on patients with renal dysfunction. Recently devel- for diabetic patients (as judged by the investigator). Risk of oped pangenotypic DAA combinations, such as glecaprevir/ recurrence was also evaluated. Fibrosis stage was evaluated by pibrentasvir, have emerged as major advances for patients transient elastography (FibroScan). Compliance with antiviral with severe kidney impairment.10,11 However, the long-term therapy and rate of adverse events were monitored through treatment effects are still poorly known,12 as drug–drug inter- the treatment duration and follow-up by review of clinical actions are a possibility in patients compromised by other charts by the clinicians at each of the hospitals. diseases. Statistical analysis was performed using the SPSS 22.0 sta- In KT patients with concomitant HCV infection, the ben- tistical software for Windows. All values were calculated from efits of DAA therapies include a reduced risk of graft rejec- the number of valid cases (N). Quantitative variables were tion compared with IFN-based therapies, as well as improved described as means and standard deviations or as medians liver function. HCV eradication with DAA treatments has with interquartile ranges (IQR). Categorical variables were been shown to improve significantly the quality of life of KT presented as lists of frequencies and proportions. Comparisons patients.13 Another advantage of DAA treatments is that more of numerical variables were performed using the paired t test HCV-infected kidneys will be available for transplants, thus or the Wilcoxon test. reducing waiting lists and time on hemodialysis for affected patients.14-16 It could also be expected that there will be a reduction in the number of severe renal impairment patients RESULTS that will require a dual kidney and liver transplant. Patient Population There is a growing body of evidence regarding the efficacy This study included 226 KT recipients with chronic HCV and safety of DAAs in KT recipients.17-25 The review of the infection. The basal demographic and clinical characteris- available data indicates that DAA therapies can cure HCV tics of the patients are shown in Table 1. Most patients were in most KT patients (>98%) with no major safety-associated male (65.9%) and the mean age was 56.1 ± 10.9 years, with concerns.17,26 They also highlighted the need for careful moni- a median time from KT to initiation of DAA therapy of 12.7 toring of immunosuppressive drug levels shortly after DAA years (IQR, 6.3–21.9). The median time of follow-up after treatment initiation, as well as the need for close collabora- initiation of antiviral therapy was 37.0 months (IQR, 28.4– tion between hepatologists and transplantation nephrologists. 41.9). Nineteen patients were recipients of a combined liver © 2019 The Author(s). Published by Wolters Kluwer Health, Inc. González-Corvillo et al TABLE 1. response after 1 month of treatment, with undetectable viral Basal demographic and clinical characteristics, N = 226 load. After completion of the 12-week DAA treatment, 203 patients (98.1%) achieved SVR-12. One year after the start of Age (y), mean ± SD 56.1 ± 10.9 treatment, there were no cases recorded of infection relapse or Gender (male), N (%) 149 (65.9) retreatment with antivirals. Primary cause of kidney disease, N (%) There were 12 patients (5.3%) who discontinued treatment; Glomerulonephritis 60 (26.5) half of them had been treated with the combination of ombi- Interstitial 35 (15.5) tasvir, ritonavir, paritaprevir, and dasabuvir. Discontinuation Polycystic kidney disease 20 (8.8) was due to pancytopenia in 2 patients, neural toxicity in 3 Diabetic nephropathy 16 (7.1) patients, hepatic toxicity in 2 patients, and gastrointestinal Systemic disease 7 (3.1) toxicity in 1 patient; in 1 patient, the reason was not regis- Unknown/other 78 (38.9) tered and there were 3 deaths: 2 due to sepsis and 1 due to Previous transplants, N (%) acute myocardial infarction. In these cases, the median treat- 0 150 (66.4) 1 64 (28.3) ment duration was 3.3 weeks (IQR, 1.9–12.2). 2–3 11 (5.3) Immunosuppressive treatment, N (%)a Graft Function and Immunosuppression Tacrolimus 153 (67.7) Clinical renal and hepatic parameters before and 1 year Mycophenolate 151 (66.8) after the start of DAA treatment are shown in Table 3. The Steroids 161 (71.2) indicators of kidney function worsened, as eGFR decreased Cyclosporine 37 (16.4) significantly (P = 0.003, paired t test). Renal function was not Azathioprine 12 (5.3) significantly different between DAA treatment regimens. All Everolimus 15 (6.6) indicators of liver function presented very significant improve- Rapamycin 11 (4.9) ments (P < 0.001). HCV genotype, N (%) All patients were on 1 or more immunosuppressive agents, 1 1 (0.4) of which tacrolimus was the most frequent (67.7%, Table 1). 1a 34 (15.0) Tacrolimus trough levels were reduced 1 year after the start of 1a/1b 1 (0.4) DAA therapy (7.2 ± 1.9 ng/mL at start versus 6.6 ± 2.3 ng/mL, 1b 146 (64.6) P = 0.041). The total daily dose of tacrolimus significantly 2 12 (5.3) increased 1 year after the start of the treatment (2.5 ± 1.7 3 11 (4.9) versus 3.4 ± 1.9 mg/d; P < 0.001). 3a 5 (2.2) During the median 37 months of follow-up, the death- 4 11 (4.9) censored graft survival was 96.9% after 1 year, 96.4% after 6 1 (0.4) 2 years, and 91.1% after 37 months. The causes of graft loss Unknown/no data 4 (1.7) were interstitial fibrosis plus tubular atrophy in 10 patients, Fibrosis, N (%) chronic humoral rejection in 3 patients, and cryoglobuline- 0–2 104 (46.1) mia in 3 patients. Patient survival (DAA-treated) was 96.4% 3–5 66 (29.2) after 1 year, 95.8% after 2 years, and 89.1% after 37 months. Unknown/no data 56 (24.8) Causes of death were cancer (lung and cholangiocarcinoma) Patients could have multiple treatments. in 6 patients, cardiovascular events in 6 patients, sepsis in 5 HCV, hepatitis C virus; SD, standard deviation. patients, liver failure due to cirrhosis in 2 patients, and other causes in 4 patients. and KT and 4 had simultaneous pancreatic and KTs. Seventy- four patients (32.7%) presented diabetes, which was treated Adverse Events with oral antidiabetics (8.4%), insulin (19.5%), or a combi- A total of 70 patients (31.0%) reported adverse events while nation of both (2.7%). on DAA treatment (Table 2). The most common adverse event Baseline viral genotypes are shown in Table 1. Genotype was anemia, which was serious in 25 of the cases and highly 1b was the most frequent (146 patients, 64.6%). Fifty-seven prevalent in patients treated with ribavirin (>60% of patients). patients (25.2%) had received previous HCV treatment. A decline of kidney function was observed in 17 patients Further, 8 and 6 patients tested positive for hepatitis B virus (7.5%). Neutropenia and thrombopenia were detected in and HIV, respectively. Thirty-five patients (15.5%) presented 3.1% and 5.3% of patients, respectively. In addition to the portal hypertension and 5 patients (2.2%) had hepatocellular adverse events shown in Table 2, there were also reported carcinoma. cases of asthenia (4 patients), nausea and vomiting (3 patients), headache (3 patients), skin rash (2 patients), tacrolimus toxic- Antiviral Treatments and Virological Response ity (2 patients), and hepatotoxicity (2 patients). Toxicity due to A total of 11 different antiviral regimens were prescribed tacrolimus was observed in 2 of the 16 patients treated with in our cohort study (Table 2). More than half of the patients ombitasvir, ritonavir, paritaprevir, and dasabuvir, but we found were treated with the combination of sofosbuvir and ledipas- no other cases of toxicity in any of the other DAA treatments. vir (118 patients, 52.2%). The combination of sofosbuvir and ribavirin, with or without other DAA, was used in 38 patients (16.8%). The median treatment duration was 12.3 weeks DISCUSSION (IQR, 11.9–15.7 wk). Of the 207 patients who completed the In this study, we describe the results of the medium to treatment, 185 (89.4%) patients achieved rapid virological long-term treatment of HCV-infected KT recipients with the 4 Transplantation DIRECT ■ 2019 www.transplantationdirect.com TABLE 2. DAA treatments and adverse events, N (%) Adverse eventsb,c Treatment Frequencya Discontinuedb Anemia Kidney function decline Neutropenia Thrombopenia Sofosbuvir, ledipasvir 118 (52.2) 2 (1.7) 4 (3.4) 9 (7.6) 0 3 (2.5) Sofosbuvir, simeprevir 23 (10.2) 1 (4.3) 0 2 (8.7) 1 (4.3) 1 (4.3) Sofosbuvir, daclatasvir 21 (9.3) 1 (4.8) 1 (4.8) 1 (4.8) 0 0 Sofosbuvir, ribavirin, ledipasvir 21 (9.3) 2 (9.5) 13 (61.9) 0 4 (19.0) 5 (23.8) Ombitasvir, ritonavir, paritaprevir, dasabuvir 16 (7.1) 6 (37.5) 6 (37.5) 3 (18.8) 1 (6.3) 2 (12.5) Sofosbuvir, rivabirin 8 (3.5) 0 6 (75.0) 0 1 (12.5) 0 Grazoprevir, elbasvir 7 (3.1) 0 0 0 0 0 Sofosbuvir, ribavirin, daclatasvir 5 (2.2) 0 3 (60.0) 1 (20.0) 0 1 (20.0) Sofosbuvir, ribavirin, simeprevir 4 (1.8) 0 1 (25.0) 0 0 0 Sofosbuvir 2 (0.9) 0 0 0 0 0 Simeprevir, daclatasvir, ribavirin 1 (0.4) 0 0 1 (100.0) 0 0 Totala 226 (100.0) 12 (5.3) 34 (15.0) 17 (7.5) 7 (3.1) 12 (5.3) Percentages calculated over total number of patients. a Percentages calculated over patients under this treatment. b More than 1 adverse event could occur in the same patient. c DAA, direct-acting antivirals. TABLE 3. Clinical parameters of kidney and liver function N Pretreatment Post-treatmenta Pb Creatinine (mg/dL) c 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 Proteinuriac (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 Total bilirubine (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 a Indicated post-treatment values are 1 year after start of direct-acting antiviral therapy. b Paired t test, unless otherwise stated. c Mean (SD). d Wilcoxon test. e Median (interquartile range). ALT, alanine transaminase; CKD-EPI, Chronic Kidney Disease Epidemiology Collaboration; eGFR, estimated glomerular filtration rate; GGT, gamma glutamyl transferase; SD, standard deviation. recently developed DAA therapies. The virological response that enhanced liver function is the result of improved metab- was very high (98.1% achieved SVR-12) and, after a median olism of the calcineurin inhibitors as a consequence of the follow-up of 26.6 months, patient and graft survival were DAA treatment. Proinflammatory cytokines may inhibit >95%. SVR was similar in double liver/kidney or pancreas/KT cytochrome P450 enzymes during HCV infection, which are patients, suggesting that immunosuppression did not affect then restored to normal function after virus clearance.32 This the effectiveness of the therapy. Additionally, we observed apparent DAA-induced reversibility of liver function could be no post-treatment relapses. One year after the antiviral treat- more pronounced in KT patients with lower degrees of fibro- ment, hepatic function experienced significant improvements sis compared with those with severe fibrosis or cirrhosis.33 In in most patients. the non-KT population, the biochemical parameters of liver The SVR-12 observed in our study is comparable to that function improve shortly after DAA therapy,35 with regression found in other series, which range from 91% to 100% in this of fibrosis, normalization of portal hypertension and liver patient population.20-22,25,29-31 In our study, some patients devel- stiffness, and increase in skeletal muscle mass.36-38 oped mild allograft dysfunction and some patients required Independent of intervention, some functional deterioration immunosuppression dose adjustment. One year after initia- is expected in KT patients followed in time, as reflected in tion of DAA treatment, our study showed that tacrolimus dose their clinical parameters. In our study, we could not determine had to be significantly increased to maintain levels within tar- if there had been a prior decline in renal function, or even an get ranges. Immunosuppressive dose adjustment in KT or liver improvement, as no data were available before DAA treat- transplant recipients receiving DAA has been observed previ- ment. The observed variation in renal function was not clini- ously.32-34 It has been suggested that drug–drug interactions cally significant and the survival of the transplanted kidney could develop during DAA therapy, as the NS3/4A protease censored for death, 91.1% after a median follow-up of 37.0 inhibitors are degraded in the liver by cytochrome P450, which months, was high. Likely the elimination of the virus sup- also metabolizes calcineurin inhibitors. However, in our study, presses or limits its negative impact, improving the survival of only 50 patients (22%) received NS3/4A protease inhibitors the patient and the transplanted organ until it equals or nears simeprevir, paritaprevir, or grazoprevir. Another possibility is that of the negative HCV receptors. Our study and others © 2019 The Author(s). Published by Wolters Kluwer Health, Inc. González-Corvillo et al were not designed to assess the functional evolution of the 4. Ingsathit A, Kamanamool N, Thakkinstian A, et al. Survival advan- kidney in the same patient before and after treatment (com- tage of kidney transplantation over dialysis in patients with hepa- titis C: a systematic review and meta-analysis. Transplantation. paring the slope of loss of eGFR as a predictor of its long- 2013;95:943–948. term survival). Possibly this issue cannot be resolved directly 5. Fabrizi F, Lunghi G, Dixit V, et al. Meta-analysis: anti-viral therapy and conclusively, although large registries could be used to of hepatitis C virus-related liver disease in renal transplant patients. develop retrospective studies by following large cohorts of Aliment Pharmacol Ther. 2006;24:1413–1422. 6. Fabrizi F, Messa P. Treatment choices for hepatitis C in patients with patients. kidney disease. Clin J Am Soc Nephrol. 2018;13:793–795. DAA therapy was well tolerated, as in previously reported 7. Noell BC, Besur SV, deLemos AS. Changing the face of hepatitis C series,17-19,21-25 with only 5.3% of the patients discontinu- management - the design and development of sofosbuvir. Drug Des ing treatment. Most common adverse event was anemia in Devel Ther. 2015;9:2367–2374. 8. Pawlotsky JM. New hepatitis C virus (HCV) drugs and the hope for patients treated with ribavirin, a well-known effect of this a cure: concepts in anti-HCV drug development. Semin Liver Dis. antiviral.39 The highest proportion of discontinuation due to 2014;34:22–29. DAA adverse effects was seen for patients taking the com- 9. Fabrizi F, Penatti A, Messa P, et al. Treatment of hepatitis C after kid- bination of ombitasvir, ritonavir, paritaprevir, and dasabu- ney transplant: a pooled analysis of observational studies. J Med Virol. vir (6 patients, 37.5% of all discontinuations). We did not 2014;86:933–940. 10. Zeuzem S, Foster GR, Wang S, et al. Glecaprevir-pibrentasvir for register the emergence of serious infections that required 8 or 12 weeks in HCV genotype 1 or 3 infection. N Engl J Med. hospitalization. 2018;378:354–369. Currently, the European Association for the Study of the 11. EASL Recommendations on Treatment of Hepatitis C 2018. J Hepatol. Liver recommends a fixed-dose combination of sofosbuvir 2018;69:461–511. 12. Jakobsen JC, Nielsen EE, Feinberg J, et al. Direct-acting antivirals for and ledipasvir (genotypes 1, 4, 5, and 6) without the need chronic hepatitis C. Cochrane Database Syst Rev. 2017;9:CD012143. for immunosuppressant drug dose adjustments in case of 13. Sabbatini M, Capuano I, Camera S, et al. Eradication of HCV in renal KT patients with acceptable kidney function.11 However, the transplant recipients and its effects on quality of life. Biomed Res Int. fixed-dose combination of glecaprevir and pibrentasvir for 12 2018;2018:8953581. weeks, with immunosuppressant drug adjustments as needed, 14. Franco A, Moreso F, Merino E, et al. Renal transplantation from sero- positive hepatitis C virus donors to seronegative recipients in Spain: a is recommended for patients with severe kidney impairment prospective study. Transpl Int. 2019;32:710–716. (eGFR <30 mL/min/1.73 m2).11 Although current therapeutic 15. Durand CM, Bowring MG, Brown DM, et al. Direct-acting antiviral protocols for KT patients seem highly effective and safe, it is prophylaxis in kidney transplantation from hepatitis C virus-infected likely that novel combination DAA therapies will be devel- donors to noninfected recipients: an open-label nonrandomized trial. Ann Intern Med. 2018;168:533–540. oped in the future for those patients with comorbidities or 16. Goldberg DS, Abt PL, Blumberg EA, et al. Trial of transplantation refractory to treatment. of HCV-infected kidneys into uninfected recipients. N Engl J Med. To date, this multicentric observational study of 226 2017;376:2394–2395. patients reflecting current clinical practices is the largest of 17. Chen K, Lu P, Song R, et al. Direct-acting antiviral agent efficacy its kind in Europe and with the longest follow-up (37 mo). and safety in renal transplant recipients with chronic hepatitis C virus infection: a PRISMA-compliant study. Medicine (Baltimore). However, the study was limited by patient heterogeneity (eg, 2017;96:e7568. genotypes, degree of fibrosis) and diversity in DAA regimes, 18. Gentil MA, González-Corvillo C, Perelló M, et al. Hepatitis C which prevented comparative and statistically significant treatment with direct-acting antivirals in kidney transplant: pre- analysis of effectiveness or safety. liminary results from a multicenter study. Transplant Proc. 2016;48:2944–2946. 19. Goel A, Bhadauria DS, Kaul A, et al. Experience with direct acting anti- CONCLUSIONS viral agents for treating hepatitis C virus infection in renal transplant recipients. Indian J Gastroenterol. 2017;36:137–140. Our study confirms that HCV infection can be success- 20. Fernández I, Muñoz-Gómez R, Pascasio JM, et al. Efficacy and toler- fully and safely treated after kidney transplantation with a ability of interferon-free antiviral therapy in kidney transplant recipients with chronic hepatitis C. J Hepatol. 2017;66:718–723. 12-week course of treatment with DAAs. After a median fol- 21. Kamar N, Marion O, Rostaing L, et al. Efficacy and safety of sofos- low-up of 37 months, most patients improved liver function buvir-based antiviral therapy to treat hepatitis C virus infection after and retained clinically stable kidney activity. Patients required kidney transplantation. Am J Transplant. 2016;16:1474–1479. a significant increase in tacrolimus dose to maintain trough 22. Lin MV, Sise ME, Pavlakis M, et al. Efficacy and safety of direct acting antivirals in kidney transplant recipients with chronic hepatitis C virus levels without changes in other immunosuppressive drugs. infection. PLoS One. 2016;11:e0158431. 23. Reddy S, Sharma RK, Mehrotra S, et al. Efficacy and safety of sofos- buvir-based antiviral therapy to treat hepatitis C virus infection after ACKNOWLEDGMENTS kidney transplantation. Clin Kidney J. 2018;11:429–433. 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