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Saudi Journal of Kidney Diseases and Transplantation
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Year : 2017  |  Volume : 28  |  Issue : 5  |  Page : 1169-1174
Direct-acting antiviral drugs against hepatitis C virus in renal transplant recipients: Is it the dawn of an interferon-free Era?

Department of Nephrology, Kasturba Medical College, Manipal University, Manipal, Karnataka, India

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Date of Web Publication21-Sep-2017


Hepatitis C virus (HCV) is a significant problem among hemodialysis population, especially in India where renal transplant often gets delayed in the presence of live-related donors. An acceleration of liver cirrhosis and poor renal allograft outcomes are often witnessed in allograft recipients with high viral load. Use of interferon in the postrenal transplant setting for the treatment of hepatitis C viral infection was limited to a few grave situations, fearing the precipitation of allograft rejection and poor efficacy for sustained virological remission. However, the availability of newer direct-acting antivirals has opened a new tool box in the management of HCV in the postrenal transplant setting and in reducing the pretransplant waiting period.

How to cite this article:
Rangaswamy D, Nagaraju SP, Attur RP. Direct-acting antiviral drugs against hepatitis C virus in renal transplant recipients: Is it the dawn of an interferon-free Era?. Saudi J Kidney Dis Transpl 2017;28:1169-74

How to cite this URL:
Rangaswamy D, Nagaraju SP, Attur RP. Direct-acting antiviral drugs against hepatitis C virus in renal transplant recipients: Is it the dawn of an interferon-free Era?. Saudi J Kidney Dis Transpl [serial online] 2017 [cited 2021 Oct 21];28:1169-74. Available from: https://www.sjkdt.org/text.asp?2017/28/5/1169/215140

   Introduction Top

Currently, routine treatment of hepatitis C virus (HCV) infection in renal transplant recipients (RTRs) is not recommended for the potential risk of precipitating rejection with interferon (IFN)-based therapy.[1] Several cohort studies have shown long-term inferior graft and patient survival in patients with HCV infection when compared with non-HCV- infected RTRs.[2],[3],[4] Certain situations such as HCV-associated glomerulopathy (HCVGN) in the renal allograft, severe cholestatic hepatitis, and advanced histologic stages of liver disease warrant therapy for HCV infection.[1] In the last two years, multiple new oral direct-acting antiviral (DAA) drugs against HCV were developed. The success of their use in naïve and liver transplant recipients as an IFN-free regimen for the treatment of HCV infection is encouraging. Sofosbuvir, a NS5B nucleotide inhibitor, has been approved for the treatment of HCV infection without dose adjustment, in patients with an estimated glomerular filtration rate (eGFR) >30 mL/min/1.73 m2. Use of sofosbuvir in dialysis and RTR requires further clinical trials. We highlight a case of RTR being treated successfully with sofosbuvir-based regimen and review in brief about sofosbuvir and other DAAs which could be the future for HCV treatment in RTRs.

   Case Report Top

A 31-year-old female, hypertensive and diabetic with moderate nonproliferative diabetic retinopathy, was diagnosed as a case of chronic kidney disease stage 5 and initiated on hemodialysis three months back. She was referred to our center for a live renal transplant with her husband as a prospective donor. She had received multiple (14) units of blood transfusions in view of severe anemia during her dialysis sessions.

Her pretransplant screening for antibody to HCV with third-generation enzyme-linked immunosorbent assay was positive. On ultrasound abdomen, significant findings were the presence of bilateral small kidneys, partially distended gall bladder with sludge and calculi, normal liver echotexture, and portal vein diameter. Her liver enzymes were normal with no esophageal varices, and a quantitative ribo-nucleic acid (RNA) polymerase chain reaction (PCR) for HCV was 408 IU/mL. She was offered liver biopsy, pretransplant IFN therapy, and was explained about the need to treat HCV infection. However, the patient and her relatives advanced for renal transplant without consenting for therapy against HCV infection. Donor screening for antibody against HCV was negative. Pretransplant complement-dependent cytotoxicity cross-match done on two different occasions was negative and there was 6/6 human leukocyte antigen mismatch between the donor and the recipient.

On the day of renal transplant surgery, the patient underwent an open cholecystectomy followed by a live ABO blood group-compatible renal transplant with her 34-year-old husband as donor. She was started on triple drug regimen of steroids, tacrolimus (FK-506), and mycophenolate mofetil and received basi-liximab induction. Her trough FK-506 level was targeted to be in the range of 9–11 ng/mL. Postoperatively, she had a good diuresis with a progressive decline in serum creatinine. On the third posttransplant day, the patient had a decline in urine output with a rise in her serum creatinine levels. After assessing her volume status and transplant renal artery, she underwent a renal biopsy. Graft biopsy was reported as a C4d-negative, acute vascular rejection with acute tubular injury with a Banff score of g1, i1, t0, v2, ptc1, cg0, ct0, ci0, cv0, mm0, ah0, and C4d0. In the next 1 week, the patient underwent four sessions of one volume plasma exchange followed by 200 mg/kg of intravenous immunoglobulin after each session. Her urine output improved and serum creatinine reached a nadir of 0.7 mg/dL at the end of her second posttransplant week (PTW).

In her 5th PTW, she had an asymptomatic elevation of her liver enzymes. A quantitative RNA PCR for HCV showed an increase of viral copies by 103 from her baseline value with an indeterminate genotype. She was counseled about her current condition, her increased risk for a progressive liver disease, and to develop HCVGN in the transplant kidney, the reasons for her not qualifying to receive IFN-based therapy according to the current guidelines, and the current available therapeutic options against HCV in India. A change of drug regimen to cyclosporine was not attempted, for an episode of acute rejection in her first PTW. The patient and her relatives insisted to be treated with the sofosbuvir and ribavirin regimen (SR). A detailed consent about lack of data for the use of sofosbuvir in RTR regarding its safety profile, drug interactions, efficacy in viral clearance, etc., was obtained before the start of the therapy. The patient’s baseline parameters at the time of start of therapy and at follow-up are summarized in [Table 1].
Table 1: Patient's baseline and follow-up hematological and biochemical parameters.

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She was started on 400 mg once-daily dose of sofosbuvir and 400 mg thrice-daily dose of ribavirin from her 6th PTW. By the end of two weeks of therapy with SR regimen, her liver enzymes had normalized with a stable graft function. Her dose of ribavirin was reduced to 400 mg twice daily from her 10th PTW in response to her declining hemoglobin levels and was continued at the same dose till completion of 12 weeks of her therapy. The patient’s hemoglobin had stabilized; her liver enzymes and renal function were in the normal range at the end of her 12-week therapy with SR regimen. A repeat HCV RNA quantitative PCR at the end of four and 12 weeks of therapy was reported as undetectable. She had no adverse events during her entire treatment course except for an asymptomatic decline in her hemoglobin levels. The patient has a good graft and liver function and a negative HCV RNA quantitative PCR after 12 weeks of her last dose of SR regimen.

   Discussion Top

HCV infection increases the risk for cirrhosis and death by two folds in dialysis patients.[5] Centers across India have an estimated average prevalence of 4%–30% of patients with HCV infection on hemodialysis.[6],[7] In India, where live-related renal transplant is the most common category, transplantation often gets delayed due to newly diagnosed cases for HCV infection in patients on hemodialysis. According to the Kidney Disease Improving Global Outcomes (KDIGO) guidelines, HCV infection is not a contraindication for renal transplant, but has suggested that HCV-infected kidney transplant candidates should be considered for treatment with standard IFN before trans-plantation.[1] The basis for such an approach is due to enough evidence for HCV-infected RTRs having worse patient and allograft survival when compared to their uninfected counterparts.[2],[3],[4] The KDIGO also cautions that an effort to achieve sustained virological remission (SVR) should not result in a missed opportunity for renal transplant.[1] India has a very high prevalence of 26%–56% for HCV infection in RTRs.[6]

In untreated or nonresponders to anti-HCV therapy, HCV loads increase by approximately 1.0–1.5 log10 IU/mL after transplantation accompanied by rise in serum alanine amino-transferase levels.[5] Worsening liver disease, in addition to several extrahepatic clinical events such as New Onset Diabetes After Transplant and HCVGN of the allograft, has been repor-ted.[8],[9],[10],[11],[12] The administration of IFN in RTRs can be deleterious to the allograft and should generally be avoided unless there is an indication of worsening hepatic injury on biopsy, clinically decompensating liver disease, or extrahepatic complications including HCVGN, where the potential benefits of treatment (in terms of eradicating virus and attenuating liver injury) outweigh the substantial risks of kidney allograft injury and graft loss due to the therapy.[1] Studies which have used pegylated IFN a2a with or without ribavirin have shown low incidence of acute rejection but require prolonged therapy for 24–48 months and at best achieve SVR in up to 50% of patients only.[13],[14],[15]

The emergence of multiple new DAAs has led to improved treatment outcomes, while minimizing adverse events in patients with chronic HCV infection. First-generation protease inhibitors (PIs), boceprevir and telaprevir, FDA approved in 2011 for patients infected with HCV genotype 1, are currently out of favor in view of their poor safety profile.[16] The current generation of NS3/4A PI and NS5B polymerase inhibitors have several benefits over the first-generation PIs, which include a higher barrier to resistance, better effectiveness on all genotypes, convenient dosing, reduced pill burden, shorter duration of treatment, and better safety and tolerability.[17] Most of these drugs are now recommended as firstline agents in patients with normal renal function and with moderate renal failure.[16],[18] IFN- free combinations are widespread in Europe and North America and have demonstrated SVR12 rates of >70%–90% across various genotypes. There has been encouraging results of its use in postliver transplant settings too. Use of simeprevir (NS3/4A protease inhibitor), ledipasvir, daclatasvir (NS5A replication inhibitor), and sofosbuvir (NS5B nucleoside inhi-bitor)-based regimens in postorthotropic liver transplant patients has resulted in undetectable viral load within four weeks of transplant and a SVR, without a change in immunosup-pression regimen.[17],[19],[20] Studies focusing on the pharmacokinetics of newer DAAs have emphasized the lack of clinically evident drug–drug interactions associated with its use alongside calcineurin inhibitors [Table 2].[21]
Table 2: Drug interactions between hepatitis C virus direct-acting antiviral and immunosuppressants.[13],[17]

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Sofosbuvir, a pangenotypic nucleotide analog inhibitor of HCV RNA-dependent RNA poly-merase, should be administered at the dose of 400 mg (one tablet) once per day. Approximately, 80% of sofosbuvir is renally excreted and the remaining 15% in feces. The majority of the sofosbuvir dose recovered in urine is the dephosphorylation-derived nucleoside metabolite GS-331007 (78%), with a large part actively secreted. For this, currently, sofos-buvir is not recommended for patients with an eGFR <30 mL/min/1.73 m2 due to higher exposures (up to 20 folds) of GS-331007. Except when used with amiodarone, sofos-buvir is not reported to have any serious adverse events and is well tolerated over 12–24 weeks of administration. The most common adverse events (≥20%) observed in combination with ribavirin were fatigue and headache. Marginal elevations of creatine kinase, amy-lase, and lipase without clinical impact are also observed. Sofosbuvir is not metabolized by cytochrome P450, but is transported by P- glycoprotein (P-gp). Drugs that are potent Pgp inducers significantly decrease sofosbuvir plasma concentrations and may lead to a reduced therapeutic effect.[16],[22] Currently, IFN- free regimen with SR though recommended for genotypes 2 and 3 for 12 and 24 weeks, respectively, in patients without cirrhosis and an eGFR >30 mL/min/1.73 m2 is not endorsed in RTRs.

Our patient had an indeterminate genotype, and a rise in viral load and liver enzymes by 103 copies/mL and by >3 times, respectively, from her baseline value. After starting therapy with SR, the patient’s viral load was undetec-table at four weeks with SVR at 12 and 20 weeks of follow-up. Her liver enzymes returned to baseline within two weeks of initiating SR therapy and had no significant side effects other than a moderate degree of anemia which improved with reduction in the dose of ribavirin.

DAAs have opened a new tool box for therapy against HCV in the posttransplant setting and with sofosbuvir not having any major interaction with immunosuppressants, the future looks bright for HCV-infected patients with the comfort for an all-oral therapy in patients with eGFR >30 mL/min/1.73 m2. However, the duration and the combination of DAA for differing genotypes resulting in maximum benefit with minimum side effects and drug interaction is a matter for further research. The finding of SVR in the absence of untoward events requires a much larger cohort of patients to truly gain an understanding of the potential nuances of DAA use postkidney transplantation and to advance our understanding.

Conflict of interest: None declared.

   References Top

Management of HCV-infected patients before and after kidney transplantation. KDIGO clinical practice guidelines. Kidney Int 2008;73 (Suppl 109):S53-68.  Back to cited text no. 1
Breitenfeldt MK, Rasenack J, Berthold H, et al. Impact of hepatitis B and C on graft loss and mortality of patients after kidney transplantation. Clin Transplant 2002;16:130-6.  Back to cited text no. 2
Bruchfeld A, Wilczek H, Elinder CG. Hepatitis C infection, time in renal-replacement therapy, and outcome after kidney transplantation. Transplantation 2004;78:745-50.  Back to cited text no. 3
Mathurin P, Mouquet C, Poynard T, et al. Impact of hepatitis B and C virus on kidney transplantation outcome. Hepatology 1999;29: 257-63.  Back to cited text no. 4
Terrault NA, Adey DB. The kidney transplant recipient with hepatitis C infection: Pre-and post-transplantation treatment. Clin J Am Soc Nephrol 2007;2:563-75.  Back to cited text no. 5
Mukhopadhyaya A. Hepatitis C in India. J Biosci 2008;33:465-73.  Back to cited text no. 6
Jasuja S, Gupta AK, Choudhry R, et al. Prevalence and associations of hepatitis C viremia in hemodialysis patients at a tertiary care hospital. Indian J Nephrol 2009;19:62-7.  Back to cited text no. 7
[PUBMED]  [Full text]  
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. 8
Morales JM, Pascual-Capdevila J, Campistol JM, et al. Membranous glomerulonephritis associated with hepatitis C virus infection in renal transplant patients. Transplantation 1997; 63:1634-9.  Back to cited text no. 9
Roth D, Cirocco R, Zucker K, et al. De novo membranoproliferative glomerulonephritis in hepatitis C virus-infected renal allograft recipients. Transplantation 1995;59:1676-82.  Back to cited text no. 10
Abbott KC, Lentine KL, Bucci JR, et al. Impact of diabetes and hepatitis after kidney transplantation on patients who are affected by hepatitis C virus. J Am Soc Nephrol 2004;15: 3166-74.  Back to cited text no. 11
Bloom RD, Rao V, Weng F, Grossman RA, Cohen D, Mange KC. Association of hepatitis C with post-transplant diabetes in renal transplant patients on tacrolimus. J Am Soc Nephrol 2002;13:1374-80.  Back to cited text no. 12
Pageaux GP, Hilleret MN, Garrigues V, et al. Pegylated interferon-alpha-based treatment for chronic hepatitis C in renal transplant recipients: An open pilot study. Transpl Int 2009; 22:562-7.  Back to cited text no. 13
Aljumah AA, Saeed MA, Al Flaiw AI, et al. Efficacy and safety of treatment of hepatitis C virus infection in renal transplant recipients. World J Gastroenterol 2012;18:55-63.  Back to cited text no. 14
Sanai FM, Mousa D, Al-Mdani A, et al. Safety and efficacy of peginterferon-a2a plus ribavirin treatment in renal transplant recipients with chronic hepatitis C. J Hepatol 2013;58:1096-103.  Back to cited text no. 15
European Association for Study of Liver. EASL recommendations on treatment of hepatitis C 2015. J Hepatol 2015;63:199-236.  Back to cited text no. 16
Protopapas GF, Rao KV, Pyrsopoulos N. Management of Hepatitis C in the Pre-and Post-Transplant Setting: Then and Now. Gastroenterol Hepatol Open Access 2014;1:19.  Back to cited text no. 17
Recommendations for Testing, Managing, and Treating Hepatitis C. Available from: http://www.hcvguidelines.org. (Last accessed 14/08/2017)  Back to cited text no. 18
Gane EJ, Agarwal K. Directly acting antivirals (DAAs) for the treatment of chronic hepatitis C virus infection in liver transplant patients: “A flood of opportunity”. Am J Transplant 2014;14:994-1002.  Back to cited text no. 19
Fontana RJ, Hughes EA, Bifano M, et al. Sofosbuvir and daclatasvir combination therapy in a liver transplant recipient with severe recurrent cholestatic hepatitis C. Am J Transplant 2013;13:1601-5.  Back to cited text no. 20
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Sovaldi-Gilead Sciences, Inc. Available from: http://www.gilead.com/~/media/Files/pdfs/me dicines/liver-disease/sovaldi/sovaldi_pi.pdf. (Last accessed 14/08/2017).  Back to cited text no. 22

Correspondence Address:
Dharshan Rangaswamy
Department of Nephrology, Kasturba Medical College, Manipal University, Madhavnagar, Manipal, Udupi - 576 104, Karnataka
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