Hepatitis C virus infection is highly prevalent among kidney transplant recipients, occurring consequently to their previous treatment with hemodialysis. Hepatitis C virus infection has been associated with lower graft and patient survival compared with that shown in patients without infection. The lower survival has been associated with the posttransplant pro-gression of liver disease and increased risk for development of extrahepatic complications. The choice of immunosuppressive drugs could significantly affect the course of the infection with an accelerated viral replication after kidney transplant. Eradicating hepatitis C virus infection with antiviral treatment is imperative to increasing graft and patient survival after transplant. Antiviral treatment options include standard interferon-based therapy and new direct-acting antiviral agents. Interferon-based treatment is rarely used in kidney transplant recipients because it has been associated with high risk of interferon-induced acute graft rejection. Several novel studies have shown that the new direct-acting antiviral agents are highly efficacious for treatment of hepatitis C infection in kidney transplant patients.

Key words : Antiviral agents, Immunosuppression, Renal transplantation

Introduction

Hepatitis C virus (HCV) infection is relatively common among patients on hemodialysis and in kidney transplant recipients.¹ In developed countries, approximately 1.8% to 8% of the kidney transplant recipients are infected with HCV.^2,3 Hepatitis C virus infection has negative effects on both patient and graft survival.^2,4,5 A meta-analysis demonstrated that the presence of HCV antibodies was an independent and significant risk factor for death (risk ratio = 1.79; 95% confidence interval [CI], 1.57-2.03; P = .042) and graft failure (risk ratio = 1.56; 95% CI, 1.35-1.80; P = .019) after kidney transplant.6 The lower survival was related to the posttransplant progression of liver disease induced by the use of immunosuppressive regimens7,8 and increased risk for development of extrahepatic complications of HCV infection, including posttransplant de novo or recurrent glomerular disease and new-onset diabetes mellitus.^9,10 However, despite these risks, renal transplant is still recommended in HCV-positive patients, as survival is significantly better in those who undergo transplant versus infected patients who remain on hemodialysis.^11,12

Immunosuppressive drugs and hepatitis C virus infection
The natural course of HCV infection in kidney transplant patients is more complex than in non-transplant patients. The use of immunosuppressive drugs could promote viral replication in hepatocytes and enhance the progression of liver disease or lead to reactivation of the HCV infection, which presents as acute hepatitis.^13-15 Controversy remains regarding what is the optimal immunosuppressive regimen for kidney transplant recipients with HCV infection. The use of induction therapy is not contraindicated in HCV-positive kidney transplant recipients.¹⁶ Corticosteroid withdrawal might be an acceptable option in recipients with specific comorbidities such as diabetes mellitus or osteoporosis. The calcineurin inhibitor cyclosporine specifically suppresses HCV replication in vitro, at clinically achievable concentrations. The antiviral activity of cyclosporine is mediated through specific blockade of cyclophilins, which may have a role in supporting HCV RNA replication and viral protein expression.¹⁷ In a retrospective study, a group analyzed the effects of the widely used calcineurin inhibitors cyclosporine and tacrolimus on HCV replication, liver inflam-matory activity, development of liver fibrosis, and long-term renal graft function in HCV-infected kidney transplant recipients.¹⁸ During long-term immunosuppression, cyclosporine compared with tacrolimus showed no significant differences in viral kinetics and development of liver fibrosis. However, the hepatic inflammatory activity was less pro-nounced in patients who were given cyclosporine, although renal graft function was significantly better preserved in patients who received tacrolimus. The use of tacrolimus should be avoided or minimized in HCV-positive kidney transplant recipients with insulin resistance because of the increased risk for development of posttransplant diabetes mellitus. Mycophenolate mofetil has shown an inhibitory effect on viral replication in the nontransplant setting, and no convincing evidence has been presented of a specific deleterious effect of mycophenolate mofetil on either graft or patient outcomes in kidney transplant recipients with HCV infection.^19,20 Published information on the clinical use of mammalian target of rapamycin (mTOR) inhibitors (sirolimus and everolimus) in kidney transplant patients with HCV is scarce; therefore, the influence of mTOR inhibitors on patient survival after kidney transplant is unknown.²¹ Overall, immunosup-pressive regimens need to be individualized in kidney transplant recipients, according to the patient's immunologic risk, persistence of HCV infection, and other comorbidities.

Hepatitis C virus-related complications after renal transplant
HCV infection is associated with an increased risk for development of posttransplant liver disease and extrahepatic complications.^14,22 The most frequent extrahepatic complications are de novo or recurrent glomerular disease and new-onset diabetes mellitus.¹

Hepatitis C virus-related liver disease after kidney transplant
The risk of developing posttransplant liver disease depends on the severity of the liver disease before transplant, liver pathology, coinfection with hepatitis B virus, and the immunosuppressive regimen.9 Immunosuppression could promote viral replication in hepatocytes, enhancing the progression of liver disease. Posttransplant liver disease includes fibrosing cholestatic hepatitis, liver cirrhosis, hepatocellular carcinoma, and hepatic failure.¹⁴ Hepatitis C virus-positive kidney transplant recipients have an increased risk for development of posttransplant liver disease of approximately 7.14-fold.²² It is considered the fourth most important cause of mortality after kidney transplant.²² Fibrosing cholestatic hepatitis is a rapidly progressive form of liver injury, and, as a rare disease, it occurs only in 1.5% of the patients with HCV infection.¹⁴ Kidney recipients with HCV infection have an approximately 18-fold increased risk of developing liver cirrhosis after transplant.²² Also, HCV-positive kidney trans-plant recipients have an approximately 4-fold increased risk (hazard ratio = 4.40; 95% CI, 1.85-10.5) for development of hepatocellular carcinoma compared with those without HCV infection.²² However, approximately half of the transplanted patients with HCV infection have slow progression of the liver disease, with normal liver function tests, despite the detectable serum levels of HCV RNA.¹⁴ Hepatitis C virus-positive kidney transplant patients should be carefully monitored. The liver function tests should be performed every 3 months, and viral load should be examined every 6 months.²³

Hepatitis C virus-related de novo glomerular disease after kidney transplant
Hepatitis C virus infection does not affect short-term graft survival. However, long-term graft survival has been shown to be lower than that shown in HCV-negative patients, which is linked to the development of glomerular disease in kidney transplant recipients. The most frequent glomerular lesion associated with HCV infection is memb-ranoproliferative glomerulopathy, with or without type II mixed cryoglobulinemia.²⁴ The less frequently described renal lesions include membranous glomerulopathy,²⁵ fibrillary or immunotactoid glo-merular diseases,²⁶ and thrombotic microangiopathy.²⁷ The pathogenesis of HCV-related de novo glomerular disease could be explained by the deposition of immunocomplexes that contain HCV RNA in the glomerulus, which paradoxically occurs in immuno-suppressed patients.²⁸ The most frequent renal lesions related to HCV infection (membranoproliferative and membranous glomerulopathy) present with develop-ment of proteinuria with or without microhematuria or nephrotic syndrome.

Hepatitis C virus-infected kidney transplant recipients should be tested at least every 6 months for proteinuria. Graft biopsy is indicated if proteinuria is greater than 1 g on multiple occasions. Pathologic examination should include immunofluorescence and electron microscopy. When transplant glomerulopathy is suspected, electron microscopy is mandatory to make the differential diagnosis with HCV-related membranoproliferative glomerulopathy. For HCV-related glomerular disease, antiviral therapy is indicated. In severe HCV-related cryoglobulinemic membranoproliferative glomerulopathy, in addition to antiviral therapy, rituximab and plasmapheresis should be considered.^9,29

Hepatitis C virus-related new-onset diabetes mellitus after kidney transplant
Hepatitis C infection has been linked to an increased incidence of new-onset diabetes mellitus after kidney transplant.²⁴ The mechanisms proposed for development of posttransplant diabetes include increased insulin resistance, direct cytopathic action of the virus on pancreatic beta cells, and adverse effects from immunosuppressive drugs.30 Occurrence of new-onset diabetes mellitus after kidney transplant also impairs renal graft function.³¹ An association between HCV infection and post-transplant diabetes was shown in a retrospective study involving records from 427 kidney recipients who had no diabetes before transplant.³² The potential interaction between HCV and the use of tacrolimus as maintenance immunosuppressive therapy on the odds for the development of posttransplant diabetes was also examined. Overall, posttransplant diabetes occurred more frequently in HCV-positive than in HCV-negative patients (39.4% vs 9.8%; P = .0005). By multivariate logistic regression, HCV infection (odds ratio [OR] = 5.58; 95% CI, 2.63-11.83; P = .0001), weight at transplant (OR = 1.028; 95% CI, 1.00-1.05; P = .001), and the use of tacrolimus (OR = 2.85; 95% CI, 1.01-5.28; P = .047) were associated with development of posttransplant diabetes. Among the HCV-positive kidney transplant patients, posttransplant diabetes occurred more often in tacrolimus-treated patients than in cyclosporine-treated patients (57.8% vs 7.7%; P = .0001). Posttransplant diabetes rates in HCV-negative patients were similar between the 2 groups of patients treated with different calcineurin inhibitors (rates for tacrolimus vs cyclosporine were 10.0% vs 9.4%; P = .521).

Treatment of hepatitis C virus infection in renal transplant recipients
The primary goal of HCV therapy is to achieve eradication of the HCV infection, which is currently determined by a sustained viral response (SVR). Sustained viral response is defined as undetectable HCV RNA in serum 12 weeks (SVR12) or 24 weeks (SVR24) after completion of treatment.³³ The antiviral treatment of HCV infection includes standard interferon-based therapy and new direct-acting antiviral (DAA) agents.

Until recently, interferon-based treatment was considered the mainstay of therapy for HCV infection. However, interferon has been rarely used in kidney transplant recipients because it has been associated with low efficacy (18% to 34%), poor tolerability (drop-out rate of 25% to 35%), and high risk of interferon-induced acute graft rejection (12% to 51%).^34,35 The immunostimulatory effects of interferon, affecting both the innate and the adaptive immune system, could lead to an increased risk of acute graft rejection. Interferon-induced graft rejection is frequently steroid resistant, and its use has been associated with graft loss.³⁶ A meta-analysis of clinical trials with interferon-based therapy (interferon alone or with ribavirin) in kidney transplant recipients with chronic HCV infection showed that the summary estimate for SVR24 rate was 18.0% (95% CI, 7.0% to 29%) with a drop-out rate of 35% (95% CI, 20% to 50%).³⁵ The most frequent adverse event requiring therapy discontinuation was acute graft rejection refractory to corticosteroid therapy. Therefore, the Kidney Disease: Improving Global Outcomes guidelines from 2008 have recommended administration of interferon-based therapy only to kidney transplant recipients with HCV in whom the benefits of the treatment clearly outweigh the risks.²³ The risks include rapid progression of liver fibrosis, fibrosing cholestatic hepatitis, severe vasculitis, and de novo cryoglobulinemic glomerulonephritis.^9,23,37

Direct-acting antiviral agents are new oral drugs that target viral modulators of the HCV life cycle.38 Since 2014, several DAAs have been approved for interferon-free antiviral treatment with high SVR rates and shorter duration of treatment (12-24 wk). The efficacy of DAAs used with ribavirin or in combination with one another yields SVR12 rates higher than 90% among patients who were treatment naïve.³⁹ The approved DAAs consist of 3 groups. The first group is directed against the viral protease NS3/4A (protease inhibitors; names ending with “previr”), the second group is directed against the viral RNA-dependent RNA-polymerase NS5B (polymerase inhibitors; names ending with “buvir”), and the third group is directed against the viral protein, which is involved in the formation of the replicon complex NS5A (NS5A-inhibitors; names ending with “asvir”).⁴⁰ Simeprevir is a second-generation protease inhibitor with clinically relevant antiviral effects against HCV genotypes 1, 4, and 6.⁴¹ Sofosbuvir is an inhibitor of the NS5B polymerase with a pan-genotypic effectiveness and a high-resistance barrier.⁴² Sofosbuvir has renal elimination abilities and may only be given to patients with glomerular filtration rates (GFRs) above 30 mL/min/1.73 m². Ledipasvir is an NS5A inhibitor with antiviral activity, particularly against genotype 1 and partially against other genotypes such as 4 and 6. Ledipasvir is only available as a fixed-dose combination with sofosbuvir. Daclatasvir is an NS5A inhibitor with antiviral activity against genotypes 1, 2, 3, and 4. Biliary excretion of simeprevir, ledipasvir, and daclatasvir is a major route of elimination, with renal excretion being a negligible pathway.⁴³

A 3D combination is available consisting of paritaprevir/ritonavir plus ombitasvir, with or without dasabuvir. Paritaprevir is an NS3/4A inhibitor that is boosted by ritonavir to optimize its pharmacokinetics. Ombitasvir is an NS5A inhibitor, whereas dasabuvir is a nonnucleotide polymerase inhibitor. Paritaprevir and ombitasvir are available at fixed-dose combinations and have antiviral activity against genotypes 1 and 4, whereas dasabuvir is only effective against genotype 1.

Pharmacokinetic data have shown the possibility of using 3D regimens in patients with severe renal impairment. Serum levels of the 3D drugs were comparable with those shown in HCV patients without renal impairment.⁴⁴ Grazoprevir is an NS3/4A inhibitor, whereas elbasvir is an NS5A inhibitor, and their combination was a breakthrough therapy for the treatment of HCV genotype 1 infection in patients with renal impairment.⁴⁵ Combining DAAs, which target different steps of viral replication, should provide possibly synergistic antiviral potency with prevention of drug resistance.⁴⁶

Limited data exist on the use of DAA agents for the treatment of HCV infection in kidney transplant recipients. Most early clinical trials with DAAs have excluded kidney transplant recipients or patients with chronic kidney disease with GFRs of less than 30 mL/min. Protease inhibitors are associated with significant risks of drug-drug interactions with calcineurin inhibitors and mTOR inhibitors. These immunosuppressive drugs and protease inhibitors are metabolized in the liver by the cytochrome P450 and P-glycoprotein metabolic pathways, resulting in substrate competition with possible increases or decreases in serum levels of immunosuppressive drugs, with consequential risk of toxicity or graft rejection. No significant interactions between polymerase inhibitors and calcineurin inhibitors or protease inhibitors and mycophenolate mofetil have been described, but close monitoring of serum levels of immunosuppressive drugs is mandatory during antiviral treatment.^9,47

Several recent reports have described successful outcomes with DAA therapy in kidney transplant patients with HCV infection. A pilot study was conducted to assess the efficacy and safety of a sofosbuvir-based regimen to treat chronic HCV infection in 25 kidney transplant recipients (HCV genotype 1 in 76%). The median GFR was 64 mL/min (range, 43-85 mL/min). Patients were given combinations of sofosbuvir plus ribavirin (n = 3), sofosbuvir plus daclatasvir (n = 4), sofosbuvir plus simeprevir with (n = 1) or without ribavirin (n = 6), sofosbuvir plus ledipasvir with (n = 1) or without ribavirin (n = 9), and sofosbuvir plus pegylated-interferon with ribavirin (n = 1). Sofosbuvir was given at a daily dose of 400 mg, daclatasvir at a daily dose of 60 mg, and simeprevir at a daily dose of 150 mg. Pegylated interferon was given at a dose of 135 μg/week. Ribavirin was added to the DAAs only in cases of rapidly progressing liver fibrosis. Ribavirin doses were adapted to the GFR. Ribavirin daily doses were as follows: 400 mg (n = 1), 600 mg (n = 3), and 800 mg (n = 2). Most patients (n = 19) were treated for 12 weeks. Antiviral therapy was given for 24 weeks in 6 patients because of fibrosing cholestatic hepatitis (n = 1), rapid progression of liver fibrosis (n = 1), genotype 3 infection (n = 1), and genotype 1-infected patients treated with sofosbuvir and daclatasvir (n = 3). Treatment was well tolerated without any discontinuations, dose reductions, graft rejections, or changes in serum creatinine levels, and no drug interactions with calcineurin inhibitors were observed. All patients had achieved SVR12 after completion of DAA therapy.⁴⁸

Another group of 20 HCV-positive kidney transplant recipients (88% with genotype 1, half with advanced liver fibrosis, and 60% treatment experienced) were treated with a sofosbuvir-based regimen. The most commonly used combination was sofosbuvir (400 mg) with simeprevir (150 mg), administered once daily. The achieved SVR12 rate was 100%. There were no episodes of graft rejection during the treatment, and less than half of the patients required dose reduction of their calcineurin inhibitor. Only 3 patients were treated with ribavirin, and 2 of them required dose reduction due to anemia, including 1 patient who required a blood transfusion for symptomatic anemia.⁴⁹

In the first multicenter study of HCV-positive kidney transplant recipients who used DAAs, the SVR12 rate was 91% in 24 recipients. Hepatitis C virus genotype 1a was the cause of infection in 58% of patients. The median GFR was 71.9 mL/min (range, 47-96 mL/min). All patients received sofosbuvir, and this agent was paired with simeprevir in 12 patients, ledipasvir in 8 patients, and ribavirin in 4 patients. The dose of sofosbuvir was 400 mg, administered once daily. Simeprevir was prescribed at 150 mg and administered once daily. Ledipasvir was in coformulation with sofosbuvir 400 mg, with a dose of 90 mg once daily. The dose of ribavirin was prescribed according to body weight (1000 mg/d in patients with body weight of < 75 kg and 1200 mg/d in patients with body weight > 75 kg). The treatment duration varied between 12 and 24 weeks, based on HCV genotype, the stage of underlying liver fibrosis, and prior treatment history. Calcineurin inhibitor trough levels did not significantly change during the antiviral treatment. Adverse events were reported in 11 patients (46%) with no discontinuation of DAA therapy. Adverse effects of treatment were higher in patients who received ribavirin, and it was discontinued in 2 patients. One patient who received antiviral treatment with sofosbuvir and simeprevir had atrial fibrillation in the early posttransplant period and was treated with amiodarone. The patient had a treatment-related serious adverse event (symptomatic bradycardia) that necessitated pacemaker placement, which occurred approximately 10 months before the US Food and Drug Administration black box warning on the potential cardiac events (life-threatening symptomatic bradycardia) associated with the coadministration of sofosbuvir and amiodarone.⁵⁰

A clinical trial was performed that reported the safety and efficacy of the ledipasvir-sofosbuvir regimen in 114 HCV-positive kidney transplant recipients (91% with HCV genotype 1). Median GFR was 56 mL/min (range, 35-135 mL/min). Patients were randomly assigned 1:1 to receive co-formulation of ledipasvir (90 mg) and sofosbuvir (400 mg) for 12 or 24 weeks. The most frequent adverse events were headache (19%), asthenia (14%), and fatigue (10%). Serious adverse events were reported in 13 patients (11%), with the most frequent being syncope, pul-monary embolism, and increased serum creatinine. All treated patients achieved SVR, and SVR12 was 100%.⁵¹

In a Spanish multicenter study that included 119 HCV-positive transplant recipients (9 with combined liver-kidney transplants, 80% with HCV genotype 1), patients were treated mainly with sofosbuvir-based regimen (sofosbuvir combined with ledipasvir, simeprevir, or daclatasvir). Ribavirin was used as a coadjuvant in 18% of the patients. A paritaprevir-ritonavir-ombitasvir-dasabuvir combination was used in 9 patients (7%). More than half of the patients had GFRs between 30 and 59 mL/min. The mean duration of the DAA treatment was 14.1 ± 5 weeks. Ninety-four patients (79%) completed the treatment, and SVR12 was 97.8%. There was a significant improvement in liver function, with no change in renal function and proteinuria. Adverse events were reported in 23.5% of the treated patients. The treatment was discontinued in 7 patients because of the development of neurotoxicity caused by drug interaction (3D therapy and tacrolimus) or ribavirin-induced anemia.⁵²

Another Spanish study reported the results of DAA treatment in 103 HCV-positive kidney transplant recipients (26 with combined liver-kidney transplants and 4 with combined pancreatic-kidney transplants). Hepatitis C virus genotype 1 was the cause of infection in 83% of patients. More than half of the patients had GFRs between 30 and 59 mL/min. Treatment was mainly with sofosbuvir-based regimens, either sofosbuvir (400 mg) with ledipasvir (90 mg) or sofosbuvir (400 mg) with daclatasvir (60 mg). Ribavirin was used as a coadjuvant in 41% of patients. Treatment duration was 12 or 24 weeks. The most frequent adverse events were anemia (mainly ribavirin induced) in 23 patients (22%) and liver dysfunction in 17 patients (16%) (most of them with cirrhosis). There was no treatment discon-tinuation due to adverse events. More than half of the patients (56%) required dose adjustment of their calcineurin inhibitor, with SVR12 rate of 98%.⁵³

Conclusions

Hepatitis C virus infection is common among kidney transplant recipients, and it has been associated with lower patient and graft survival. The lower survival has been shown to be related to the posttransplant progression of liver disease and increased risk for development of extrahepatic complications. Treatment experience with the various DAA regimens in kidney transplant recipients is limited, but these antiviral drugs are very promising and can be safely used for highly efficacious eradication of HCV.

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