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Table of Contents
ORIGINAL ARTICLE
Year : 2020  |  Volume : 14  |  Issue : 2  |  Page : 111-115

Direct-acting antivirals in the treatment of hepatitis C virus infection in renal transplant recipients: A single-center experience from South India


Institute of Nephrology, Madras Medical College, Chennai, Tamil Nadu, India

Date of Submission09-Sep-2019
Date of Acceptance15-Mar-2020
Date of Web Publication06-Jul-2020

Correspondence Address:
Dr. T Sugan Gandhi
Institute of Nephrology, Madras Medical College, Chennai, Tamil Nadu
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ijot.ijot_46_19

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  Abstract 


Introduction: Direct-acting antivirals (DAAs) are widely used in the treatment of hepatitis C virus (HCV) infection in renal transplant recipients. Aim: The aim was to study the efficacy and safety of these drugs in our renal transplant recipients. Study Design, Subjects, and Methods: A retrospective observational study was performed among the renal transplant recipients > 18 years of age who were treated with DAA for HCV infection. The viral genotype, DAA regimen, the viral load at various time intervals, FibroScan score at the start and at the end of therapy, the changes in graft function (estimated glomerular filtration rate) and in the dosage of calcineurin inhibitors during therapy, and side effects if any during therapy were documented from history and transplant records. The viral remission rates and the safety of DAA were analyzed. Statistical analysis was done with Medcalc statistical software version 12.7.0.0. Results: Thirty-three recipients were included in the study. The DAA regimens were sofosbuvir + ledipasvir (n = 17), sofosbuvir + daclatasvir (n = 8), and sofosbuvir + ribavirin (n = 8). The most common genotype was genotype 1 (n = 30, 90.9%). End-of-therapy response and sustained viral remission (SVR) at 12 weeks of completion of therapy (SVR12) were 100% in all the three DAA regimens. About 75% (n = 6) of the patients who underwent ribavirin therapy developed anemia, unlike the ribavirin-free regimens which had no side effects. The graft function remained stable during DAA therapy. At a mean follow-up of 3 years after initiation of sofosbuvir + ribavirin therapy and 2 years after initiation of sofosbuvir + daclatasvir and sofosbuvir + ledipasvir therapy, the viral remission was sustained. Conclusion: DAAs are safe and effective in achieving and sustaining viral remission in renal transplant recipients.

Keywords: Direct-acting antivirals, efficacy and safety, hepatitis C virus, renal transplant recipients, South India


How to cite this article:
Gandhi T S, Natarajan G, Jayachandran D, Thanigachalam DK, Ramanathan S, Alavudeen SS. Direct-acting antivirals in the treatment of hepatitis C virus infection in renal transplant recipients: A single-center experience from South India. Indian J Transplant 2020;14:111-5

How to cite this URL:
Gandhi T S, Natarajan G, Jayachandran D, Thanigachalam DK, Ramanathan S, Alavudeen SS. Direct-acting antivirals in the treatment of hepatitis C virus infection in renal transplant recipients: A single-center experience from South India. Indian J Transplant [serial online] 2020 [cited 2020 Aug 6];14:111-5. Available from: http://www.ijtonline.in/text.asp?2020/14/2/111/289041




  Introduction Top


The prevalence of hepatitis C virus (HCV) infection among renal transplant recipients ranges from 1.8% to 8%[1] and posttransplant HCV infection is associated with decreased patient and graft survival.[2] Studies have revealed a sustained viral remission (SVR) rate of > 95% with direct-acting antivirals (DAAs) drugs in renal transplant recipients, with better safety and lesser drug interactions.[3],[4] There are only a few studies from India on the efficacy and safety of DAA therapy in renal transplant recipients.[5]


  Subjects and Methods Top


Subjects

All living-related and deceased-donor renal transplant recipients > 18 years of age, who were treated with DAA for HCV infection, were included in the study, irrespective of the time of transplant. We excluded those with hepatitis B virus coinfection and those who were not compliant with DAA therapy.

The viral genotype was determined. The HCV viral load was analyzed at the start of therapy, at the end of therapy, at 12 weeks after the completion of therapy, and at every 6 months after that. Quantitative HCV RNA was detected by real-time polymerase chain reaction-Roche COBAS Taqman assay with lower limit of quantification of <34 IU/ml.

The FibroScan score was detected at the start and at the end of therapy. Grading of fibroscan score was as follows: F0 ≤6.5 kPa, F1 = 6.5 − 8.0 kPa, F2 = 8.0 − 10 kPa, F3 = 10 − 12 kPa, and F4 ≥12 kPa. Complete blood count, renal function tests, and liver function tests were monitored during the course of therapy.

The DAA regimens were based on the viral genotype, stage of liver fibrosis, prior treatment history, prevailing guidelines (European Association for the Study of Liver/American Association for the Study of Liver Diseases), and the DAA that were available at our center at various time periods.

The regimens were sofosbuvir 400 mg once daily with ribavirin 1000 mg/day in divided doses for 24 weeks or with daclatasvir 60 mg once daily for 12 weeks or with ledipasvir 90 mg once daily for 12 weeks. If estimated glomerular filtration rate (eGFR) was <60 ml/min or if serum hemoglobin (Hb) drops to 8–10 g/dl, ribavirin dose was reduced by 50%, and if Hb drops to <8 g/dl, ribavirin was withheld.

Data were collected retrospectively from history and transplant records. Side effects, if any, experienced by the recipients during DAA therapy were also documented. End-of-therapy response (ETR) and SVR12 were defined as undetectable viral load at the end of therapy and at 12 weeks after the completion of therapy, respectively.

The patient consent has been taken for participation in the study and for publication of clinical details and images. Patients understand that the names, initials would not be published, and all standard protocols will be followed to conceal their identity. The study has been approved by Institutional Ethics Committee Madras Medical College Chennai Ethics Committee Reg. No. Ecr/270/Inst./TN/2013 (Ethics Committee Study Approval No. 10082018).

Statistical analysis

Statistical analysis was done with Medcalc statistical software version 12.7.0.0. Descriptive data were presented as proportions, mean ± standard deviation, or median (interquartile range [IQR]). Paired t-test was used for univariate analysis. The value of P < 0.05 was considered statistically significant.


  Results Top


Thirty-three (n = 33) renal transplant recipients had been treated with DAA at our center between 2015 and 2018. They were predominantly males (n = 21, 63.6%). The median age at the time of initiation of therapy was 43 years (range = 27–60 years). All of them were first renal transplant recipients. Majority of them were living-related renal transplant recipients (n = 25, 75.8%). Majority (n = 26, 78.8%) of them were transplanted between 2001 and 2010. All of them had received the graft from HCV-negative donors. Four of them had received induction therapy (anti-thymocyte globulin, n = 3 and basiliximab, n = 1).

The median dialysis vintage was 6 months (IQR: 3–12). Fourteen (42.4%) recipients had undergone dialysis in more than one center and 19 (57.57%) had received at least one blood transfusion pretransplant.

Ten (30.3%) recipients were detected to have HCV-infection pretransplant, out of which one had received interferon therapy pretransplant. He had attained remission with interferon therapy pretransplant and has had reinfection with another genotype posttransplant. Among the 23 recipients detected to have HCV infection posttransplant, 15 (65.22%) had clinical signs and symptoms and the remaining 8 (34.78%) were detected during screening. The median time of detection of HCV infection posttransplant was 6 years (IQR: 3.12–9.5). Baseline recipient characteristics are represented in [Table 1].
Table 1: Recipients baseline characteristics

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Genotype 1 was the most prevalent genotype (n = 30, 90.9%). The median viral load at the start of therapy was 15.0 lakhs IU/ml (IQR: 7.3–44.7). Twenty-four (72.72%) recipients had a high viral load of > 8 lakh IU/ml at the start of therapy.

Among the 33 recipients, 17 had received sofosbuvir + ledipasvir (n = 17), eight had received sofosbuvir + daclatasvir (n = 8), and eight had received sofosbuvir + ribavirin (n = 8). Fifteen recipients had been on calcineurin inhibitor (CNI) therapy (cyclosporin, n = 10 and tacrolimus, n = 5) at the start of DAA therapy.

FibroScan score was F0 in 13 recipients, F1 in seven, F2 in one, F3 in two, and F4 in ten. None had decompensated liver disease. The median time interval between renal transplantation and initiation of HCV treatment was 8 years (IQR: 6–12) and between the detection of HCV infection and initiation of therapy was 3 months (IQR: 1–60).

The median serum creatinine at the start of therapy was 1.30 mg/dl (range 0.8–2.7). The mean eGFR at the start of therapy was 64.3 ± 21.89 ml/min/1.73 m2, and none of our recipients had an eGFR of <30 ml/min/1.73 m2.

All of our recipients attained the ETR and SVR12 [Table 2]. Six recipients (75%) on sofosbuvir + ribavirin therapy (n = 8) developed anemia (defined as <12.0 g/dl in males, <11.0 g/dl in females), of which three (50%) developed severe anemia (Hb ≤8.0 g/dl) warranting blood transfusion. There were no reported side effects in the other two ribavirin-free regimens.
Table 2: Response to therapy

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There was no statistically significant change in eGFR during the DAA therapy period [Table 3]; however, there was a significant drop in FibroScan score post-DAA therapy [Table 3].
Table 3: Effects of therapy

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There was a statistically significant drop in the mean Hb with the sofosbuvir + ribavirin regimen unlike the other two regimens [Table 3].

No rejection episodes were observed and none of the recipients required modification of CNI dose during the therapy period.

All 33 recipients were on regular follow-up and all of them had undetectable viral load (less than the lower limit of quantification of <34IU/ml) throughout the follow-up period after attaining SVR12. Hence, the viral remission was sustained at a mean follow-up of 36 ± 5 months from the start of therapy in the sofosbuvir + ribavirin group, 24.2 ± 9.6 months in the sofosbuvir + daclatasvir group, and 24.47 ± 8.02 months in the sofosbuvir + ledipasvir group [Table 4].
Table 4: Viral load on follow up

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  Discussion Top


HCV infection in the posttransplant period has deleterious effects on patient and graft survival. This is attributed to an increased risk of developing liver disease,[6] new-onset diabetes after transplant,[7] sepsis,[8],[9] cardiovascular disease,[2] or graft loss due to various causes such as rejection,[10] transplant glomerulopathy,[10] or de novo glomerulonephritis [11] than uninfected recipients. Interferon is generally not recommended in the posttransplant period except in the setting of fibrosing cholestatic hepatitis due to increased risk of rejection and allograft loss.[12] Initially, DAAs were used and were proved to be safe and efficacious in liver transplant recipients.[13],[14],[15] Later, they were used in renal transplant recipients [3],[4] and were found to have high efficacy.[3],[4] This is the first study from India involving a large number of recipients and the efficacy was high similar to the previous studies [Table 5].[3],[4] All of our recipients cleared the virus at the end of therapy and had sustained viral remission at 12 weeks after completion of therapy.
Table 5: Comparison of studies

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The most prevalent genotype and the DAA regimens studied by Kamar et al. and Sawinski et al. were similar to that of our study [Table 5]. Furthermore, the mean serum creatinine and mean eGFR at the start of therapy were comparable to our study.[3],[4] However, unlike our study, they had included combined kidney and liver transplant recipients as well as prior renal transplant recipients, and the mean age was higher compared to our study.

Sawinski et al. found DAA to be efficacious in 60% of the study population who had failed treatment with interferon-based therapy pretransplant.[4]

One of our patients who had attained remission with interferon therapy pretransplant had a reinfection with another genotype posttransplant and he remitted with DAA therapy.

In the Sawinski et al. study, 50% of the study population had advanced fibrosis (F3 or F4) in liver biopsy and SVR 12 was 100%.[4] Liver fibrosis was assessed with FibroScan in our study and all the 12 (36%) recipients with advanced fibrosis (F3 or F4) attained ETR and SVR 12.

The median time interval between renal transplantation and initiation of HCV treatment was higher in our study (8 years [IQR: 6–12]) than in other studies. This could be because DAA became available only in recent years.

Similar to the other studies,[3],[4],[5] a significant proportion of recipients on ribavirin therapy developed anemia in our study and none of the recipients in the other two treatment groups had any major or minor side effects.[3],[4],[5]

Graft function remained stable, and there were no rejection episodes during the therapy period, similar to the observations of previous studies.[3],[4] However, protocol biopsies were not done in our study to rule out subclinical rejections.

Studies have shown that the pharmacokinetics of CNI gets altered with exposure to DAA [Table 5]. They had observed that a decrease in CNI trough levels occurs after HCV clearance with DAA therapy, though no major changes in the dose of CNI were needed during DAA therapy.[3],[4],[5] CNI levels were not monitored in all of our recipients to draw any firm conclusions.

All the 33 recipients were on regular follow-up. At a mean follow-up of 3 years after initiation of sofosbuvir + ribavirin therapy and 2 years after initiation of sofosbuvir + daclatasvir and sofosbuvir + ledipasvir therapy, all the recipients were in viral remission.

FibroScan was repeated at the end of therapy in all the recipients, and a significant drop in the FibroScan score was noted post-DAA therapy.

The large sample size and a long follow-up period are the strength of our study; however, the limitations are that the efficacy and safety of DAA were not assessed in recipients with eGFR <30 ml/min, the CNI levels were not monitored during therapy, and it is a retrospective study.


  Conclusion Top


DAAs are safe and effective in treating HCV infection in renal transplant recipients, and they can sustain the viral remission for a prolonged period after completion of therapy. They are effective in treating HCV infection in the recipients with advanced fibrosis and are capable of reducing the stage of liver fibrosis. They have no adverse effects and do not adversely affect the graft function.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
Baid-Agrawal S, Schindler R, Reinke P, Staedtler A, Rimpler S, Malik B, et al. Prevalence of occult hepatitis C infection in chronic hemodialysis and kidney transplant patients. J Hepatol 2014;60:928-33.  Back to cited text no. 1
    
2.
Scott DR, Wong JK, Spicer TS, Dent H, Mensah FK, McDonald S, et al. Adverse impact of hepatitis C virus infection on renal replacement therapy and renal transplant patients in Australia and New Zealand. Transplant 2010;90:1165-71.  Back to cited text no. 2
    
3.
Kamar N, Marion O, Rostaing L, Cointault O, Ribes D, Lavayssière L, et al. Efficacy and safety of sofosbuvir-based antiviral therapy to treat hepatitis C virus infection after kidney transplantation. Am J Transplant 2016;16:1474-9.  Back to cited text no. 3
    
4.
Sawinski D, Kaur N, Ajeti A, Trofe-Clark J, Lim M, Bleicher M, et al. Successful treatment of hepatitis C in renal transplant recipients with direct-acting antiviral agents. Am J Transplant 2016;16:1588-95.  Back to cited text no. 4
    
5.
Reddy S, Sharma RK, Mehrotra S, Prasad N, Gupta A, Kaul A, et al. Efficacy and safety of sofosbuvir-based antiviral therapy to treat hepatitis C virus infection after kidney transplantation. Clin Kidney J 2018;11:429-33.  Back to cited text no. 5
    
6.
Espinosa M, Martin-Malo A, de Lara AL, Aljama P. Risk of death and liver cirrhosis in anti-HCV postive long term hemodialysis recipients. Nephrol Dial Transplant 2001;16:1669-74. AVailable from: https://academic.oup.com/ndt/article/16/8/1669/1826594. [Last accessed on 2020 April 22].  Back to cited text no. 6
    
7.
Bloom RD, Rao V, Weng F, Grossman RA, Cohen D, Mange KC. Association of hepatitis C with posttransplant diabetes in renal transplant patients on tacrolimus. J Am Soc Nephrol 2002;13:1374-80.  Back to cited text no. 7
    
8.
Roth D, Gaynor JJ, Reddy KR, Ciancio G, Sageshima J, Kupin W, et al. Effect of kidney transplantation on outcomes among patients with hepatitis C. J Am Soc Nephrol 2011;22:1152-60.  Back to cited text no. 8
    
9.
López-Medrano F, Fernández-Ruiz M, Morales JM, San-Juan R, Cervera C, Carratalá J, et al. Impact of hepatitis C virus infection on the risk of infectious complications after kidney transplantation: Data from the RESITRA/REIPI cohort. Transplant 2011;92:543-9.  Back to cited text no. 9
    
10.
Baid-Agrawal S, Farris AB 3rd, Pascual M, Mauiyyedi S, Farrell ML, Tolkoff-Rubin N, et al. Overlapping pathways to transplant glomerulopathy: Chronic humoral rejection, hepatitis C infection, and thrombotic microangiopathy. Kidney Int 2011;80:879-85.  Back to cited text no. 10
    
11.
Cruzado JM, Carrera M, Torras J, Grinyó JM. Hepatitis C virus infection and de novo glomerular lesions in renal allografts. Am J Transplant 2001;1:171-8.  Back to cited text no. 11
    
12.
Kidney Disease: Improving Global Outcomes (KDIGO). KDIGO clinical practice guidelines for the prevention, diagnosis, evaluation, and treatment of hepatitis C in chronic kidney disease. Kidney Int. 2008;73(Suppl 109):S1-S99.  Back to cited text no. 12
    
13.
Forns X, Charlton M, Denning J, McHutchison JG, Symonds WT, Brainard D, et al. Sofosbuvir compassionate use program for patients with severe recurrent hepatitis C after liver transplantation. Hepatol 2015;61:1485-94.  Back to cited text no. 13
    
14.
Charlton M, Gane E, Manns MP, Brown RS Jr., Curry MP, Kwo PY, et al. Sofosbuvir and ribavirin for treatment of compensated recurrent hepatitis C virus infection after liver transplantation. Gastroenterol 2015;148:108-17.  Back to cited text no. 14
    
15.
Curry MP, Forns X, Chung RT, Terrault NA, Brown R Jr., Fenkel JM, et al. Sofosbuvir and ribavirin prevent recurrence of HCV infection after liver transplantation: An open-label study. Gastroenterol 2015;148:100-70.  Back to cited text no. 15
    



 
 
    Tables

  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5]



 

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