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Hepatitis C Virus Eradication in Kidney Transplant Recipients: A Single-Center Experience in Portugal
Hepatitis C Virus Eradication in Kidney Transplant Recipients: A Single-Center Experience in Portugal A. Weigerta,*, S. Queridoa, L. Carvalhob, L. Lebreb, C. Chagasb, P. Matiasa, R. Birnea, C. Nascimentoa, C. Jorgea, T. Adragãoa, M. Brugesa, and D. Machadoa a Nephrology Department, Hospital Santa Cruz, Centro Hospitalar de Lisboa Ocidental, Carnaxide, Portugal; and bGastroenterology Department, Hospital Santa Cruz, Centro Hospitalar de Lisboa Ocidental, Carnaxide, Portugal
ABSTRACT Introduction. Hepatitis C (HCV) is a major cause of liver impairment postekidney transplantation (KT). Anti-HCV direct-acting antivirals (DAA) made viral eradication possible. Methods. We performed a retrospective review of KT patients (n ¼ 23) who received DAA at our hospital. Sustained viral response (SVR) was defined as absence of viral detection 12 weeks after cessation of therapy. Results. From 1985 to September 2017, 1440 patients underwent transplantation at Hospital Santa Cruz. From a total of 32 HCV RNAþ KT recipients on follow-up, we describe the first 23 patients treated with DAA. They were 56.7 9.1 years old; 22 were white, 52.2% were males, they underwent transplantation 18.8 9.0 years ago, and 13 had genotype 1B, 21 were naïve, and 9 had stages F3/F4. All but 2 patients, treated with grazoprevir/elbasvir, received sofosbuvir (18 with ledispasvir, 2 with daclastavir, and 4 with simultaneous ribavirin). Pretreatment, intra-treatment, and post-treatment creatinine clearances were 61.4, 60.6, and 60.7 mL/min/1.73 m2, respectively (not significant [NS]). Cyclosporine A was the basis of immunosuppression in the majority [(n ¼ 14); pretreatment and intratreatment levels were 79.5 23.0 and 91.8 26.0 ng/mL, respectively (P ¼ .08)]; tacrolimus (n ¼ 8) and mammalian target of rapamycin (mTOR) levels (n ¼ 5) were also similar. One patient interrupted ribavirin after 7 weeks due to anemia; all other patients completed the treatment course without major side effects. Only 3 patients presented positive viral RNA at the fourth week of treatment and SVR was achieved in 100% of the patients 12 weeks after treatment. Conclusions. DAA therapy was well tolerated and effective in 100% of our treated patients, without significant impact on the renal function or on the immunosuppression.
A
LTHOUGH the prevalence of hepatitis C virus (HCV) infection has been decreasing both in hemodialysis patients and in recipients of kidney allografts, it is still a significant problem in both populations. With the introduction of direct-acting antivirals (DAA) against HCV, viral eradication in both groups of patients became possible. The prevalence of HCV has been decreasing; it is currently present in 3.4% of hemodialysis patients and 2.2% of peritoneal dialysis patients in our country [1]. However, this prevalence was much higher in past decades when HCV antibody evaluation was impossible (many patients were then labeled as having “nonA, nonB hepatitis”) and erythropoietin was not ª 2018 Elsevier Inc. All rights reserved. 230 Park Avenue, New York, NY 10169
Transplantation Proceedings, 50, 743e745 (2018)
available, reasons for an extensive use of unscreened blood transfusions. Fortunately this reality changed many years ago, but a large burden of HCV-seropositive patients was left from this period. Interferon and ribavirin-based treatments were not only poorly tolerated and frequently ineffective, they also had the potential to trigger rejection and severe anemia. Therefore, these treatments were only used in kidney
*Address correspondence to André Weigert, MD, PhD, Nephrology, Hospital de Santa Cruz, Av. Prof. Dr. Reinaldo dos Santos, Carnaxide, Portugal. E-mail: [email protected] 0041-1345/18 https://doi.org/10.1016/j.transproceed.2018.02.017
743
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WEIGERT, QUERIDO, CARVALHO ET AL
transplantation (KT) patients in life-saving situations. Similarly, patients on dialysis were rarely treated due to the side effects and reduced efficacy. The appearance of DAAs and overcoming the economic barriers to access this expensive medication within the Portuguese National Health System made the aim of HCV eradication possible. Thus, we describe the experience of our first 23 KT patients treated with DAA. METHODS All HCV-positive patients were simultaneously followed at the Post-Transplant Outpatient Clinic and at the Hepatology Clinic of Hospital Santa Cruz, Centro Hospitalar de Lisboa Ocidental, Carnaxide, Portugal. Chart and database review was the basis of data collection. Data was analyzed using Microsoft Office Excel 2011. HCV RNA was measured through COBAS AmpliPrep/COBAS TaqMan HCV Quantitative Test version 2.0 (with lower limit of detection of 15 IU/mL) and genotyping through SIEMENS VERSANT HCV LiPA 2.0. Liver fibrosis was evaluated before therapy using real-time elastography (Hitachi HI-VISION Avius) and stages F3 and F4 were identified, although treatment length was only different in stage 4. All patients were included in the Portuguese Database on the Treatment of Hepatitis C (“Portal da Hepatite C”) and informed consent was obtained for this treatment with the understanding that the generated data would be critically analyzed. Patients in stage F1/F2/F3 were treated for 12 weeks, whereas the 3 patients in stage F4 (with hepatic cirrhosis) were treated for 24 weeks. Sustained viral response (SVR) was defined as absence of viral detection 12 weeks after cessation of therapy (SVR12). In addition, in a subgroup of patients (n ¼ 14), confirmation of undetectable viral RNA was obtained 24 weeks after cessation of therapy (SVR24).
RESULTS
Demographic data are detailed in Table 1. Eighteen patients initiated dialysis between 1979 and 1996 (i.e., at least 20 years ago). The following genotypes were present: 1A (5), 1B (13), 3A (3), and 4 (2). Twenty-one were treatment naive (91.3%). Table 1. Demographic and Clinical Data From Patients Patients
N ¼ 23
Male (n/%) Age (y) White (n/%) CKD etiologies (n/%) Chronic glomerulonephritis Unknown Hereditary nephropathy Diabetic nephropathy Other etiologies Diabetes (n/%) Co-infection with HBV (n/%) Living KT (n/%) Time since initiation of dialysis (median/min/max)/mo Length of follow-up post-KT (median/min/max)/mo
12/52.2 56.7 9.1 (40e71) 22/95.7% 9 (39.1%) 7 (30.4%) 2 (8.7%) 2 (8.7%) 3 (13.1%) 4/17.4 5/21.7 1/4.3 370 (range, 30e469) 214 (range, 29e368)
Abbreviations: CKD, chronic kidney disease; HBV, hepatitis B virus; min, minimum; max, maximum.
Seven had Stage F3 or F4 by real-time elastography. Five patients were co-infected with hepatitis B, but all were human immunodeficiency virus (HIV)-negative. All but 2 patients received sofosbuvir associated with ledispasvir in 15, daclastavir in 2, and ribavirin in 4. The 2 remaining patients were treated with grazoprevir and elbasvir because they had a creatinine clearance level < 30 mL/min.1.73 m2. No significant variation was detected in glomerular filtration rate during the exposure to DAA and post-therapy. Pretreatment, intra-treatment, and post-treatment clearances were 61.4, 60.6, and 60.7 mL/min/ 1.73 m2, respectively (using the Chronic Kidney Disease Epidemiology Collaboration [CKD EPI] formula; not significant [NS]). Cyclosporine (CsA) was the basis of immunosuppression in the majority (n ¼ 14) of the patients, reflecting the period when transplanted; intra-treatment levels were slightly higher although not significantly different than pretreatment levels (91.8 26.0 and 79.5 23.0 ng/mL, respectively [P ¼ .08]); likewise, tacrolimus preand intra-DAA levels (n ¼ 8; 4.5 0.87 ng/mL and 4.7 1.96) and everolimus levels (n ¼ 5; 6.8 0.5 and 6.8 1.2 ng/mL; P ¼ .5) were not significantly different pretreatment and posttreatment. One patient interrupted ribavarin 7 weeks after initiation due to anemia, but, other than that, all the other patients completed the treatment course (12 weeks in 14 patients or 24 weeks in 9 patients). No other major side effects were reported. Only 3 patients still presented positive viral RNA at the fourth week of treatment and SVR was achieved in 100% of the patients 12 weeks post-cessation of therapy. Two patients died more than 6 months after achieving SVR 12, one with disseminated prostatic cancer and another one with hepatocellular carcinoma. DISCUSSION
As soon as DAAs became available and reimbursed, an effort was initiated to eradicate HCV both in dialysis patients on the waiting list and in patients who had already undergone transplantation and were under immunosuppression. This article only addresses the latter group. Because our KT program started in 1985, many patients seropositive for HCV received kidney allografts. As presented in Table 1, it is noteworthy that the majority of patients underwent dialysis for many years prior to undergoing transplantation; furthermore, most have very long post-transplantation follow-ups, with extremely long cumulative periods in end-stage renal disease (ESRD). HCV RNA evaluation was only extensively obtained after 2000 and, therefore, many of the HCV-seropositive patients were KT patients in the early years of our program and died or lost allograft function before HCV RNA evaluation became available. We recently evaluated among the 1334 KT patients in the “Antonio Pina” Renal Transplant Unit who underwent transplantation until December 31, 2015 160 patients who were seropositive for HCV and 60 of them had HCV RNAþ [2]. We reviewed the experience of our hospital with the HCV RNAþ KT patients prior to the availability of DAAs and we found that, unlike other series, the survival was similar to the
HCV ERADICATION
general population of KT patients [2]. In this series of 60 patients, 5 died with functioning grafts, 19 lost graft function and needed dialysis, 14 developed liver disease of variable degree, 10 had new-onset diabetes mellitus, and 4 had cancer, none of which was hepatocellular cancer (8). Between January 1, 2016 and September 2017, only 3 HCV-seropositive patients (1 coinfected with HIV) underwent transplantation, all previously treated with DAA and already RNA-negative. Since 2011, 8 additional HIV-positive patients underwent transplantation, 2 of whom were seropositive for HCV but RNA-negative; they were similarly treated with DAA prior to “wait listing” for transplantation because the results of KT are inferior in HIV/ HCV co-infected patients [3]. Until September 2017, from the 1440 KTs performed in our hospital, we currently are following 832 patients (608 died with functioning graft, lost allograft function and returned to dialysis, or were transferred to the care of other physicians). Currently, despite the presence of anti-HCV antibodies in 98 patients, only 32 had detectable HCV RNA and in this article we analyzed the results of the first 23 patients who underwent treatments with DAA; 2 patients are receiving DAA and 2 additional patients are about to initiate treatment; the remaining 5 are still being studied. Although other groups recently published their experiences on the treatment of HCV in organ transplant recipients [4e8], the experience is, like in our series, only descriptive and we are unaware of a similar series analyzed in our country, thus reflecting our specific reality. There is a single randomized clinical trial, but the randomized variable is the length of treatment (12 versus 24 weeks) and there is no placebo arm, understandable given the high efficiency, reduced side effects of the treatments, and potential severity of untreated HCV infection [9]. There are some controversies on the effect of DAAs on allograft function and their interaction with immunosuppression [4e9], which were also analyzed in our population. Therefore, we believe this article will add to the current understanding of HCV treatment in KT patients. Treatment with DAAs achieved excellent results (100% SVR) without significant side effects, except for 1 patient with severe anemia, which improved after ribavirin interruption. However, as previously mentioned, we must report a rather disturbing situation that became evident several months after the interruption of DAA therapy and without recurrence of detectable HCV RNA: 1 patient previously with F3 stage based on elastography developed hepatocellular carcinoma; this stresses that if damage is already caused prior to the treatment, we must continue follow-up as recommended by the European Association for the Study of the Liver (EASL) Guidelines [10]. An additional patient died with disseminated prostatic cancer. Because the information on the relationship of DAA and subsequent
745
development of cancer is very limited, we can neither establish nor exclude a causal relation. No episode of rejection was detected and no significant variation either in creatinine clearance or immunosuppressive drug levels, albeit a small and nonsignificant increase in CsA levels, was detected in our analysis in contrast to other authors who report variations in both parameters [7e9]. It is important to mention that all but 2 patients had an initial creatinine clearance level >30 mL/min/1.73 m2 and, as such, treatment with sofosbuvir was possible; 2 patients with inferior clearances were successfully treated with grazoprvir/elbasvir. No patient received ritonavir-boosted paritaprevir/ombitasvir/dasabuvir regimen with predictable interference in both calcineurin and mammalian target of rapamycin (mTOR) metabolism as CYP3A4 is extensively blocked by ritonavir. In conclusion, therapy with DAA proved to be safe and 100% effective in our initial 23 patients. However, despite viral eradication, one of these patients subsequently died with hepatocellular carcinoma.
REFERENCES [1] Macário F. Relatórios Anuais 2016. Sociedade Portuguesa de Nefrologia. http://spnefro.pt/tratamento_da_doenca_renal_terminal/ 2016. Accessed September 3, 2017. [2] Fernandes AR, Laranjinha IJ, Birne R, et al. HCV-infected renal transplant recipients: our experience before the availability of new antiviral drugs. Int J Org Transplant Med 2017;8(2):104e9. [3] Sawinski D, Forde KA, Eddinger K, et al. Superior outcomes in HIVepositive kidney transplant patients compared with HCVeinfected or HIV/HCVecoinfected recipients. Kidney Int 2015;88(2):341e9. [4] Suarez Benjumea A, Gonzalez-Covillo C, Sousa JM, et al. Hepatitis C virus in kidney recipients: a problem on the path to eradication. Transplant Proc 2016;48(9):2938e40. [5] Lin MV, Sise ME, Pavlakis M, et al. Efficacy and safety of direct acting antivirals in kidney transplant recipients with chronic hepatitis C virus infection. PLoS One 2016;11(7):e0158431. [6] Sawinski D, Kaur N, Ajeti A, et al. Successful treatment of hepatitis C in renal transplant recipients with direct-acting antiviral agents. Am J Transplant 2016;16(5):1588e95. [7] Saxena V, Khungar V, Verna AC, et al. Safety and efficacy of current DAA regimens in kidney and liver transplant recipients with hepatitis C: results from the HCV-TARGET Study. Hepatology 2017;66(4):1090e101. [8] Fernández I, Muñoz-Gómez R, Pascasio JM, et al. Efficacy and tolerability of interferon-free antiviral therapy in kidney transplant recipients with chronic hepatitis C. J Hepatol 2017;66(4): 718e23. [9] Colombo M, Aghemo A, Liu H, et al. Treatment with LedipasvireSofosbuvir for 12 or 24 weeks in kidney transplant recipients with chronic hepatitis C virus genotype 1 or 4 infection: a randomized trial. Ann Intern Med 2017;166(2):109e17. [10] EASL Recommendations on Treatment of Hepatitis C 2016. J Hepatol 2017;66(1):153e94.
ABSTRACT Introduction. Hepatitis C (HCV) is a major cause of liver impairment postekidney transplantation (KT). Anti-HCV direct-acting antivirals (DAA) made viral eradication possible. Methods. We performed a retrospective review of KT patients (n ¼ 23) who received DAA at our hospital. Sustained viral response (SVR) was defined as absence of viral detection 12 weeks after cessation of therapy. Results. From 1985 to September 2017, 1440 patients underwent transplantation at Hospital Santa Cruz. From a total of 32 HCV RNAþ KT recipients on follow-up, we describe the first 23 patients treated with DAA. They were 56.7 9.1 years old; 22 were white, 52.2% were males, they underwent transplantation 18.8 9.0 years ago, and 13 had genotype 1B, 21 were naïve, and 9 had stages F3/F4. All but 2 patients, treated with grazoprevir/elbasvir, received sofosbuvir (18 with ledispasvir, 2 with daclastavir, and 4 with simultaneous ribavirin). Pretreatment, intra-treatment, and post-treatment creatinine clearances were 61.4, 60.6, and 60.7 mL/min/1.73 m2, respectively (not significant [NS]). Cyclosporine A was the basis of immunosuppression in the majority [(n ¼ 14); pretreatment and intratreatment levels were 79.5 23.0 and 91.8 26.0 ng/mL, respectively (P ¼ .08)]; tacrolimus (n ¼ 8) and mammalian target of rapamycin (mTOR) levels (n ¼ 5) were also similar. One patient interrupted ribavirin after 7 weeks due to anemia; all other patients completed the treatment course without major side effects. Only 3 patients presented positive viral RNA at the fourth week of treatment and SVR was achieved in 100% of the patients 12 weeks after treatment. Conclusions. DAA therapy was well tolerated and effective in 100% of our treated patients, without significant impact on the renal function or on the immunosuppression.
A
LTHOUGH the prevalence of hepatitis C virus (HCV) infection has been decreasing both in hemodialysis patients and in recipients of kidney allografts, it is still a significant problem in both populations. With the introduction of direct-acting antivirals (DAA) against HCV, viral eradication in both groups of patients became possible. The prevalence of HCV has been decreasing; it is currently present in 3.4% of hemodialysis patients and 2.2% of peritoneal dialysis patients in our country [1]. However, this prevalence was much higher in past decades when HCV antibody evaluation was impossible (many patients were then labeled as having “nonA, nonB hepatitis”) and erythropoietin was not ª 2018 Elsevier Inc. All rights reserved. 230 Park Avenue, New York, NY 10169
Transplantation Proceedings, 50, 743e745 (2018)
available, reasons for an extensive use of unscreened blood transfusions. Fortunately this reality changed many years ago, but a large burden of HCV-seropositive patients was left from this period. Interferon and ribavirin-based treatments were not only poorly tolerated and frequently ineffective, they also had the potential to trigger rejection and severe anemia. Therefore, these treatments were only used in kidney
*Address correspondence to André Weigert, MD, PhD, Nephrology, Hospital de Santa Cruz, Av. Prof. Dr. Reinaldo dos Santos, Carnaxide, Portugal. E-mail: [email protected] 0041-1345/18 https://doi.org/10.1016/j.transproceed.2018.02.017
743
744
WEIGERT, QUERIDO, CARVALHO ET AL
transplantation (KT) patients in life-saving situations. Similarly, patients on dialysis were rarely treated due to the side effects and reduced efficacy. The appearance of DAAs and overcoming the economic barriers to access this expensive medication within the Portuguese National Health System made the aim of HCV eradication possible. Thus, we describe the experience of our first 23 KT patients treated with DAA. METHODS All HCV-positive patients were simultaneously followed at the Post-Transplant Outpatient Clinic and at the Hepatology Clinic of Hospital Santa Cruz, Centro Hospitalar de Lisboa Ocidental, Carnaxide, Portugal. Chart and database review was the basis of data collection. Data was analyzed using Microsoft Office Excel 2011. HCV RNA was measured through COBAS AmpliPrep/COBAS TaqMan HCV Quantitative Test version 2.0 (with lower limit of detection of 15 IU/mL) and genotyping through SIEMENS VERSANT HCV LiPA 2.0. Liver fibrosis was evaluated before therapy using real-time elastography (Hitachi HI-VISION Avius) and stages F3 and F4 were identified, although treatment length was only different in stage 4. All patients were included in the Portuguese Database on the Treatment of Hepatitis C (“Portal da Hepatite C”) and informed consent was obtained for this treatment with the understanding that the generated data would be critically analyzed. Patients in stage F1/F2/F3 were treated for 12 weeks, whereas the 3 patients in stage F4 (with hepatic cirrhosis) were treated for 24 weeks. Sustained viral response (SVR) was defined as absence of viral detection 12 weeks after cessation of therapy (SVR12). In addition, in a subgroup of patients (n ¼ 14), confirmation of undetectable viral RNA was obtained 24 weeks after cessation of therapy (SVR24).
RESULTS
Demographic data are detailed in Table 1. Eighteen patients initiated dialysis between 1979 and 1996 (i.e., at least 20 years ago). The following genotypes were present: 1A (5), 1B (13), 3A (3), and 4 (2). Twenty-one were treatment naive (91.3%). Table 1. Demographic and Clinical Data From Patients Patients
N ¼ 23
Male (n/%) Age (y) White (n/%) CKD etiologies (n/%) Chronic glomerulonephritis Unknown Hereditary nephropathy Diabetic nephropathy Other etiologies Diabetes (n/%) Co-infection with HBV (n/%) Living KT (n/%) Time since initiation of dialysis (median/min/max)/mo Length of follow-up post-KT (median/min/max)/mo
12/52.2 56.7 9.1 (40e71) 22/95.7% 9 (39.1%) 7 (30.4%) 2 (8.7%) 2 (8.7%) 3 (13.1%) 4/17.4 5/21.7 1/4.3 370 (range, 30e469) 214 (range, 29e368)
Abbreviations: CKD, chronic kidney disease; HBV, hepatitis B virus; min, minimum; max, maximum.
Seven had Stage F3 or F4 by real-time elastography. Five patients were co-infected with hepatitis B, but all were human immunodeficiency virus (HIV)-negative. All but 2 patients received sofosbuvir associated with ledispasvir in 15, daclastavir in 2, and ribavirin in 4. The 2 remaining patients were treated with grazoprevir and elbasvir because they had a creatinine clearance level < 30 mL/min.1.73 m2. No significant variation was detected in glomerular filtration rate during the exposure to DAA and post-therapy. Pretreatment, intra-treatment, and post-treatment clearances were 61.4, 60.6, and 60.7 mL/min/ 1.73 m2, respectively (using the Chronic Kidney Disease Epidemiology Collaboration [CKD EPI] formula; not significant [NS]). Cyclosporine (CsA) was the basis of immunosuppression in the majority (n ¼ 14) of the patients, reflecting the period when transplanted; intra-treatment levels were slightly higher although not significantly different than pretreatment levels (91.8 26.0 and 79.5 23.0 ng/mL, respectively [P ¼ .08]); likewise, tacrolimus preand intra-DAA levels (n ¼ 8; 4.5 0.87 ng/mL and 4.7 1.96) and everolimus levels (n ¼ 5; 6.8 0.5 and 6.8 1.2 ng/mL; P ¼ .5) were not significantly different pretreatment and posttreatment. One patient interrupted ribavarin 7 weeks after initiation due to anemia, but, other than that, all the other patients completed the treatment course (12 weeks in 14 patients or 24 weeks in 9 patients). No other major side effects were reported. Only 3 patients still presented positive viral RNA at the fourth week of treatment and SVR was achieved in 100% of the patients 12 weeks post-cessation of therapy. Two patients died more than 6 months after achieving SVR 12, one with disseminated prostatic cancer and another one with hepatocellular carcinoma. DISCUSSION
As soon as DAAs became available and reimbursed, an effort was initiated to eradicate HCV both in dialysis patients on the waiting list and in patients who had already undergone transplantation and were under immunosuppression. This article only addresses the latter group. Because our KT program started in 1985, many patients seropositive for HCV received kidney allografts. As presented in Table 1, it is noteworthy that the majority of patients underwent dialysis for many years prior to undergoing transplantation; furthermore, most have very long post-transplantation follow-ups, with extremely long cumulative periods in end-stage renal disease (ESRD). HCV RNA evaluation was only extensively obtained after 2000 and, therefore, many of the HCV-seropositive patients were KT patients in the early years of our program and died or lost allograft function before HCV RNA evaluation became available. We recently evaluated among the 1334 KT patients in the “Antonio Pina” Renal Transplant Unit who underwent transplantation until December 31, 2015 160 patients who were seropositive for HCV and 60 of them had HCV RNAþ [2]. We reviewed the experience of our hospital with the HCV RNAþ KT patients prior to the availability of DAAs and we found that, unlike other series, the survival was similar to the
HCV ERADICATION
general population of KT patients [2]. In this series of 60 patients, 5 died with functioning grafts, 19 lost graft function and needed dialysis, 14 developed liver disease of variable degree, 10 had new-onset diabetes mellitus, and 4 had cancer, none of which was hepatocellular cancer (8). Between January 1, 2016 and September 2017, only 3 HCV-seropositive patients (1 coinfected with HIV) underwent transplantation, all previously treated with DAA and already RNA-negative. Since 2011, 8 additional HIV-positive patients underwent transplantation, 2 of whom were seropositive for HCV but RNA-negative; they were similarly treated with DAA prior to “wait listing” for transplantation because the results of KT are inferior in HIV/ HCV co-infected patients [3]. Until September 2017, from the 1440 KTs performed in our hospital, we currently are following 832 patients (608 died with functioning graft, lost allograft function and returned to dialysis, or were transferred to the care of other physicians). Currently, despite the presence of anti-HCV antibodies in 98 patients, only 32 had detectable HCV RNA and in this article we analyzed the results of the first 23 patients who underwent treatments with DAA; 2 patients are receiving DAA and 2 additional patients are about to initiate treatment; the remaining 5 are still being studied. Although other groups recently published their experiences on the treatment of HCV in organ transplant recipients [4e8], the experience is, like in our series, only descriptive and we are unaware of a similar series analyzed in our country, thus reflecting our specific reality. There is a single randomized clinical trial, but the randomized variable is the length of treatment (12 versus 24 weeks) and there is no placebo arm, understandable given the high efficiency, reduced side effects of the treatments, and potential severity of untreated HCV infection [9]. There are some controversies on the effect of DAAs on allograft function and their interaction with immunosuppression [4e9], which were also analyzed in our population. Therefore, we believe this article will add to the current understanding of HCV treatment in KT patients. Treatment with DAAs achieved excellent results (100% SVR) without significant side effects, except for 1 patient with severe anemia, which improved after ribavirin interruption. However, as previously mentioned, we must report a rather disturbing situation that became evident several months after the interruption of DAA therapy and without recurrence of detectable HCV RNA: 1 patient previously with F3 stage based on elastography developed hepatocellular carcinoma; this stresses that if damage is already caused prior to the treatment, we must continue follow-up as recommended by the European Association for the Study of the Liver (EASL) Guidelines [10]. An additional patient died with disseminated prostatic cancer. Because the information on the relationship of DAA and subsequent
745
development of cancer is very limited, we can neither establish nor exclude a causal relation. No episode of rejection was detected and no significant variation either in creatinine clearance or immunosuppressive drug levels, albeit a small and nonsignificant increase in CsA levels, was detected in our analysis in contrast to other authors who report variations in both parameters [7e9]. It is important to mention that all but 2 patients had an initial creatinine clearance level >30 mL/min/1.73 m2 and, as such, treatment with sofosbuvir was possible; 2 patients with inferior clearances were successfully treated with grazoprvir/elbasvir. No patient received ritonavir-boosted paritaprevir/ombitasvir/dasabuvir regimen with predictable interference in both calcineurin and mammalian target of rapamycin (mTOR) metabolism as CYP3A4 is extensively blocked by ritonavir. In conclusion, therapy with DAA proved to be safe and 100% effective in our initial 23 patients. However, despite viral eradication, one of these patients subsequently died with hepatocellular carcinoma.
REFERENCES [1] Macário F. Relatórios Anuais 2016. Sociedade Portuguesa de Nefrologia. http://spnefro.pt/tratamento_da_doenca_renal_terminal/ 2016. Accessed September 3, 2017. [2] Fernandes AR, Laranjinha IJ, Birne R, et al. HCV-infected renal transplant recipients: our experience before the availability of new antiviral drugs. Int J Org Transplant Med 2017;8(2):104e9. [3] Sawinski D, Forde KA, Eddinger K, et al. Superior outcomes in HIVepositive kidney transplant patients compared with HCVeinfected or HIV/HCVecoinfected recipients. Kidney Int 2015;88(2):341e9. [4] Suarez Benjumea A, Gonzalez-Covillo C, Sousa JM, et al. Hepatitis C virus in kidney recipients: a problem on the path to eradication. Transplant Proc 2016;48(9):2938e40. [5] Lin MV, Sise ME, Pavlakis M, et al. Efficacy and safety of direct acting antivirals in kidney transplant recipients with chronic hepatitis C virus infection. PLoS One 2016;11(7):e0158431. [6] Sawinski D, Kaur N, Ajeti A, et al. Successful treatment of hepatitis C in renal transplant recipients with direct-acting antiviral agents. Am J Transplant 2016;16(5):1588e95. [7] Saxena V, Khungar V, Verna AC, et al. Safety and efficacy of current DAA regimens in kidney and liver transplant recipients with hepatitis C: results from the HCV-TARGET Study. Hepatology 2017;66(4):1090e101. [8] Fernández I, Muñoz-Gómez R, Pascasio JM, et al. Efficacy and tolerability of interferon-free antiviral therapy in kidney transplant recipients with chronic hepatitis C. J Hepatol 2017;66(4): 718e23. [9] Colombo M, Aghemo A, Liu H, et al. Treatment with LedipasvireSofosbuvir for 12 or 24 weeks in kidney transplant recipients with chronic hepatitis C virus genotype 1 or 4 infection: a randomized trial. Ann Intern Med 2017;166(2):109e17. [10] EASL Recommendations on Treatment of Hepatitis C 2016. J Hepatol 2017;66(1):153e94.