Chronic hepatitis C virus infection is a global health problem, especially among renal transplant recipients. Herein, we present an overview of hepatitis C virus among renal transplant patients, with a focus on some updated aspects concerning types of viral genotypes, methods of diagnosis, the effects of renal transplant on hepatitis C virus infection, and summary of hepatitis C virus-related complications after renal transplant. We also discuss patient and graft survival rates and the present and future therapeutic options with special focus on new antiviral and possible interactions with immunosuppressive medications.

Key words : Management, New antiviral agents, Outcomes

Introduction

Chronic hepatitis C virus (HCV) infection is a global health problem that threatens almost 180 million people with cirrhosis and hepatocellular carcinoma (HCC); every year, there are an estimated 3 to 4 million new infections.¹ Unfortunately, low treatment uptake together with an aging population of HCV-infected patients has resulted in increased comp­lication rates. The number of HCV-infected individuals with established cirrhosis is estimated to double over the next decade,² with cases with HCC and liver failure to be tripled by 2030.³ These complications represent the foremost indications for liver transplant. ⁴

The hepatitis C virion measures 55 to 65 nm and has a single-stranded RNA virus that belongs to the flaviviridae family. Its RNA genome constitutes a single open-reading frame made of 9600-nucleotide bases long. It has envelope proteins E1 and E2 and structural and nonstructural proteins named NS1, NS2, NS3, NS4a, NS4b, NS5a, and NS5b.⁵ Seven genotypes exist for HCV isolates having a difference of 30% to 35% in their nucleotide sequences and multiple subtypes differing up to 20% to 25%.⁶ Genotypes 1a and 1b are the most prevalent in Western Europe and the United States followed by genotypes 2 and 3. Although genotype 4 is widespread in Egypt, genotype 5 is common in South Africa and genotype 6 in Southeast Asia.⁷ A seventh genotype has also been identified in patients from Canada and Belgium.⁸

Methods

A systematic literature search was conducted using PubMed, EMBASE, and the Cochrane Library for “HCV” and “renal transplant recipients,” as well as synonyms for “new antiviral.” A total of 110 studies were included in this review.

Transmission of hepatitis C infection
Most patients acquire infection through intravenous drug use or blood transfusion, with the following known risk factors⁹: intravenous drug use, blood transfusion, sex with an intravenous drug user, having been hit or cut with a bloody object, pierced ears or body parts, and immunoglobulin injection. Other factors identified among dialysis patients have included blood transfusions, the duration of dialysis, the type of dialysis (risk is the highest with in-hospital hemodialysis compared with peritoneal dialysis, especially with non-adherence to universal precautions), and the prevalence of HCV infection in the dialysis unit.¹⁰

Diagnostic approach to hepatitis C virus infection
According to the Kidney Disease Improving Global Outcome (KDIGO) 2009 guidelines, hemodialysis patients should be tested when they first start hemodialysis or when they transfer from another hemodialysis facility; however, for predialysis patients with chronic kidney disease, recom­mendations to test for HCV are not well-defined. However, dialysis patients who are candidates for kidney transplant should be screened, evaluated, and if necessary treated for HCV before placed on a wait list.¹¹ Initial testing with enzyme immunoassay or with nucleic acid testing is advocated, depending on prevalence of the virus in the country (particularly the hemodialysis unit). Currently, third-generation enzyme immunoassay has shown high sensitivity in dialysis patients.¹² As in the general population, it is practical to perform initial screening for HCV in hemodialysis patients with third-generation enzyme immunoassay, with confirmation by nucleic acid testing.¹³ The problem of negative anti-HCV antibodies among HCV patients can be solved using HCV-RNA by RT-PCR, which represents the most sensitive and specific assay for HCV detection as mentioned in the multicenter trial done from Hinrichsen and associates.¹⁴ Again, this approach depends on the prevalence of HCV and the financial status of the country.¹⁴

The use of noninvasive testing or liver biopsy is recommended to assess the degree of hepatic fibrosis and hence the urgency of immediate treatment. Hepatitis C virus RNA testing should be performed in those with a positive antibody test,¹⁵ especially when antiviral treatment is being considered, and in those with unexplained liver disease and negative anti-HCV test, especially those who are immuno­compromised or suspected of having acute HCV infection. Hepatitis C virus genotype should be determined in all infected individuals before treatment to determine the duration of therapy and the likelihood of response.16 Repeated enzyme immunoassays should be considered every 6 to 12 months, with nucleic acid testing conducted in patients with unexplained elevations of aminot­ransferase levels, if there is suspicion of an outbreak of HCV in a hemodialysis unit, in patients on wait lists for transplant, and for monitoring of therapy.¹⁶

Other methods for chronic hepatitis C evaluation
Of major clinical importance is the documentation of chronic HCV severity in all patient settings, including for patients on dialysis. Novel noninvasive methods are used to validate hepatic fibrosis. Transient elastography (Fibroscan, a standard ultrasound machine with a new technology that assesses the stiffness of the liver) evaluates the degree of fibrosis by measuring liver stiffness,¹⁷ whereas aspartate aminotransferase-to platelet-index is a noninvasive alternative. In hemodialysis patients, elastography has shown hopeful results in 1 study, ¹⁸ but it will need to be authenticated in larger cohorts. On the other hand, this index has shown low diagnostic accuracy. ¹⁹ Thus, liver biopsy remains the criterion standard in the evaluation of chronic hepatitis C.

Despite the higher bleeding risk due to uremic platelet dysfunction, it has been shown that it can be safely performed also in hemodialysis patients.²⁰ Ideally, liver biopsy would be useful, at least initially, in all HCV-positive hemodialysis patients with sustained viremia to evaluate the severity of liver disease, the necessity of therapy, and the long-term prognosis. KDIGO guidelines have clearly defined dialysis patients waiting for kidney transplant as the only indication for liver biopsy. The rationale behind that recommendation is that a significant percentage of patients (up to 25%) may have subclinical precirrhotic disease, which could impede kidney transplant. In addition, patients with persistent viremia should be treated to attain sustained virological response (SVR) or at least low viremic load before transplant, as it may guide therapy and determine prognosis.¹⁷

Effect of renal transplant on HCV infection
Chronic liver disease after renal transplant depends on many risk factors, such as the pretransplant duration and the severity of HCV infection, liver histopathology, coinfection with hepatitis B virus, duration after transplant, and type of induction and maintenance immunosuppression.¹⁷ Some studies have shown no adverse effects of antibody induction on patient survival21 despite the increase of viral load up to 30 times compared with levels before transplant in HCV RNA-positive patients. This finding suggested that immunosuppressives have a role regarding this issue.

Mycophenolate mofetil²² and antithymocyte globulin increase HCV viremia, whereas cyclo­sporine inhibits the replication of HCV in cultured hepatocytes.²³ Apart from cases with fibrosing cholestatic hepatitis, HCV infection usually has a benign course after renal transplant,24 with normal transaminase levels in 20% to 51% of cases.25 In a meta-analysis, the cause-specific mortality due to chronic HCV hepatic disease complications (cirrhosis or HCC) in kidney transplant recipients was increased in most of the studies compared with HCV-negative cases (relative risk [RR] of 1.79).²¹ An increased risk of cirrhosis and HCC was reported among HCV-infected patients after kidney transplant compared with those infected before transplant; however, the progression of liver disease is slow and does not occur in all patients.²³ It was reported that faster progression of liver histologic activity and fibrosis in kidney transplant recipients compared with nonimmunocompromised patients infected by HCV, whereas Alric and associates 26 detected a slow progression of liver fibrosis in HCV-infected kidney transplant patients, a finding that was inferior to that observed in infected patients with a normal renal function. The use of different immunosuppressive protocols might explain these discrepancies.

Hepatitis C virus-related complications after renal transplant

Glomerular lesions
The most frequent glomerular lesions observed among HCV-positive kidney transplant recipients are cryoglobulinemic or noncryoglobulinemic mem­b­ranoproliferative glomerulonephritis (MPGN)27 and membranous glomerulonephritis (MGN)²⁸ and to a lesser extent transplant glomerulopathy, anticardiolipin-related thrombotic microangiopathy, ²⁹ and fibrillary glomerulonephritis.³⁰ The patho­genesis of MPGN and MGN may be due to deposition of immunocomplexes containing viral RNA in the glomerulus,³¹ as confirmed by detection of viral antigens by immunohistochemistry. Wornle and associates 32 assumed HCV-associated glome­rulonephritis to be due to abnormal Toll-like receptor proteins (expressed on immune and nonimmune cells as important components of the innate immunity), as they found that these receptors were elevated in the mesangial cells in HCV-related glomerulonephritis and associated with enhanced proinflammatory cytokines. However, an anti-CD20 antibody that targets B cells (rituximab) was effective in some cases of HCV-related posttransplant cryog­lobulinemia. Petrarca and associates had reported promising results using it among HCV-positive patients with extrahepatic manifestations. ³³

New-onset diabetes after transplant
Hepatitis C virus infection seems to be related to a higher incidence of new-onset diabetes after transplant (NODAT). Fabrizi and associates 34 reported in their meta-analysis with 13 observational studies (which included more than 30 000 renal transplant patients) significantly increased risk of NODAT in HCV-positive patients. In addition, tacrolimus in HCV-positive patients has been shown to increase the incidence of NODAT,³⁴ which may be one of the risk factors explaining lower patient and graft survival among HCV-positive patients.¹⁷

Insulin resistance is expected among these patients, mainly due to the inhibitory actions of the virus on hepatic insulin regulatory pathways and overexposure to tacrolimus (with impaired meta­bolism), especially during the first days after transplant.³⁵ Therefore, the 2008 KDIGO guidelines recommended an optimized immunosuppressive regimen for antirejection efficacy, while minimizing the risk of hyperglycemia.¹⁷

Acute rejection
With its inhibitory effects on the rate of naïve T-helper lymphocytes and proliferative responses to mitogens of T lymphocytes, HCV can induce a state of immunodeficiency, perhaps explaining the decreased incidence of acute rejection. A similar or even a higher incidence of acute rejection, including antibody-mediated rejection, has been reported in HCV-positive patients,³⁶ possibly due to longer history of renal disease, previous transplants, and blood transfusions, which are all risk factors for HCV infection in kidney transplant recipients. Similarly, in a Spanish series of 435 kidney transplant recipients (with protocol biopsies during the first 6 months after transplant), subclinical acute rejection with chronic allograft nephropathy and hepatitis C infection were both shown to be independent risk factors for graft loss.³⁶ Seron and associates³⁷ extrapolated the negative effects of HCV on rejection when they observed better graft outcomes with reduction of HCV infection (from 29% to 10%; P < .0001) and acute rejection (from 39% to 25%; P < .0001), despite worsening of renal quality (elderly donors) and poorer HLA matching among these patients. The clinical risk factors for HCV infection and acute rejection (14.5% over a 20-year period) included dialysis duration, previous transplants, and the number of blood transfusions. Other series have found a similar or even greater incidence of acute rejection among patients with HCV infection.¹⁷ Forman and associates found that HCV infection was no longer an independent risk factor for antibody-mediated acute rejection.³⁶

Posttransplant tuberculosis
Torres and associates38 reported HCV infection as the most important risk factor for posttransplant tuberculosis; they suggested that, in immuno­logically low-risk patients, either rapamycin-based or cyclosporine-based protocols should be used with steroid avoidance. However, the optimal immuno­suppressive regimen for HCV-infected patients has not yet been determined, especially with immuno­logically high-risk patients.

Malignancies
Hepatitis C virus infection is one of a well-known risk factor of posttransplant lymphoproliferative disorders, such as Epstein-Barr virus, induction, and antirejection therapies. The overall prevalence is 0.8% in renal transplant recipients and is significantly higher in HCV-positive (3.6%) than in HCV-negative patients (1.2%). Neoplasia represents the third most common cause of death in HCV-infected transplant patients, exceeding the contribution by liver disease.⁹ Morales and associates reported that posttransplant lymphoproliferative disorder was the second most common posttransplant neoplasia in HCV-positive recipients. However, the incidence of HCV infection was higher in myeloma patients (with the American registry showing 66 169 recipients), suggesting a possible association between HCV infection and myeloma.³⁹

Patient survival after kidney transplant among hepatitis C virus-infected patients
The survival of HCV-positive renal transplant recipients is significantly better than matched patients who remain on dialysis,⁴⁰ although infection is associated with lower patient and graft survival compared with HCV-negative patients.⁴¹ However, the short-term outcome is similar in both HCV-infected and noninfected cases.Cardiovascular disease was more prevalent in patients who tested positive for HCV antibodies, and chronic HCV infection has been recognized as a risk factor for atherosclerosis.⁴² The high incidence of NODAT in HCV-positive recipients, especially for those maintained on tacrolimus, was suggested as a possible explanation for lower patient survival.⁴³ In a multivariate analysis, it was found that independent risk factors that adversely affect the long-term outcome included biopsy-proven cirrhosis, older age, and duration of transplant, with 21% of deaths caused by liver disease in HCV-positive patients.⁴⁴ A lesser outcome was partially related to an increase in liver disease-related deaths and the higher frequency of both hepatic and extrahepatic complications in HCV-positive versus HCV-negative recipients. Heavy immunosuppression could increase the risk of HCV viral replication after renal transplant, especially with the use of quadruple therapy with monoclonal or polyclonal antibodies. However, Luan and associates44 reported that antibody induction did not adversely affect patient surv ival with HCV infection. Therefore, all conventional current immunosuppressive drugs, especially cyclosporine with its viral inhibitory effects, can be used in HCV-positive patients.^17,26 The higher risk of NODAT can be minimized by low-dose tacrolimus combined with mycophenolate mofetil and with a steroid-free regimen. The influence of mammalian target of rapamycin inhibitors (sirolimus and everolimus) on patient survival after renal transplant is unknown.

Effect of hepatitis C virus infection on graft survival
Hepatitis C virus infection does not affect short-term graft survival. However, long-term graft survival is lower compared with that shown in HCV-negative patients,¹¹ possibly due to development of pro­teinuria because of chronic allograft nephropathy and/or HCV-associated glomerulonephritis and NODAT. The probability of proteinuria increases from 19.5% in HCV-positive versus 7.5% in HCV-negative patients at 1 year to 22.9% versus 10.7% at 3 years to 45.1% versus 13.1% at 5 years. This could be due to HCV-induced endothelial cell lesions. In another case study done in Mansoura, Egypt by Mahmoud and associates,²⁸ higher incidences of proteinuria and chronic rejection were shown in HCV-positive kidney transplant recipients. Post­transplant cryoglobulinemic and noncryoglo­bulinemic MPGN and MGN associated with HCV infection contribute to the development of graft failure.⁴⁰ Type 1 MPGN is associated with accelerated loss of the graft,²⁸ whereas, with MGN, the clinical course and the development of renal failure appear to be similar in patients with and without HCV infection.⁴⁵ Fabrizi and associates²¹ concluded in their meta-analysis (4 of 8 studies) that the presence of anti-HCV antibodies was an independent risk factor for graft failure (RR, 1.56). This finding was con­firmed by Rostami and associates⁴⁶ in their systematic review of 18 observational studies. The negative effect of HCV supports the hypothesis that HCV eradication may result in positive outcomes concerning patient and graft survival.⁴⁷

Transplant of kidneys from HCV-positive donors to HCV-positive recipients is currently considered a safe, long-term approach,¹⁷ as outcomes with transplant were better than remaining on dialysis.²⁴ Moreover, midterm outcomes of these patients was similar to that for HCV-positive recipients receiving transplants from HCV-negative donors in terms of patient and graft survival and HCV-related liver disease.⁴⁸ Hence, it can be a safe strategy to overcome organ shortage for transplant, but long-term assessment is still needed.⁴⁹

Treatment protocols for HCV are currently changing with the emergence of new antiviral agents for dialysis patients waiting for transplant, resulting in shortened times on wait lists, possible treatment options after transplant, and possible increases in the organ pool with acceptance of HCV-positive donors (living or deceased).⁵⁰

Hepatitis C virus infection in renal transplant recipients: Therapeutic options between history and future
Antiviral treatment is recommended for all patients with chronic HCV infection, except those with limited life expectancy due to nonhepatic causes.¹⁵ Hesitancy in using interferon-based regimens in renal transplant recipients may be due to its association with increased risk of allograft rejection either with or without functioning grafts.^47,51

Interferon-based antiviral regimens have immu­nostimulant effects because they enhance cytokine gene expression, increase cell surface expression of HLA antigens, and stimulate natural killer cells, cytotoxic T cells, and monocytes. The rejection episode may be irreversible. Results regarding the use of interferon-α therapy for HCV-related cryo­globulinemia or de novo or recurrent glomerular disease in renal transplant recipients are limited. Posttransplant monotherapies with ribavirin and/or amantadine have no apparent effects on HCV viremia or liver histology.⁵²

Some recent studies have suggested that the risk is only about 5% in renal transplant recipients.⁷⁹ In life-sustaining transplants, interferon-based therapy is not recommended, and the risks and benefits must be weighed before use in renal transplant recipients.⁵³

Pretransplant interferon-based regimens have only been used in a minority of the eligible population, as they are poorly tolerated and have resulted in only a small proportion of patients being able to complete treatment and achieve sustained viral response SVR.⁵⁴

Antiviral therapy after renal transplant
The viral response rate in a meta-analysis from Fabrizi and associates⁵⁵ showed improvement versus that previously reported (18%),⁵⁶ which may reflect the tendency to use combined antiviral therapy (interferon plus ribavirin, with higher efficacy) and the use of pegylated interferon, which displays a longer half-life than either recombinant or interferon-α.⁵⁷

Frequency of graft dysfunction has been reported to range between 12% and 51% of patients and results in an interruption of treatment.⁵⁵ Rejection episodes occurred regardless of either high or low doses of recombinant interferon-α in patients also undergoing treatment with any other immuno­suppressive regimen, thus illustrating the high sensitivity of interferon-α. Interferon-induced graft rejection is steroid resistant and is usually irrever­sible; therefore, KDIGO guidelines recommend administration of interferon-based therapy to kidney graft recipients with HCV infection only in cases where the benefits of antiviral treatment outweigh the risks as in case of fibrosing cholestatic hepatitis, established cirrhosis, or de novo cryoglobulinemic glomerulonephritis.17

New anti-hepatitis C virus agents
Understanding the mechanisms of HCV entry and release into hepatocytes and the characterization of viral proteins involved in HCV replication have led to improvements of anti-HCV drugs. New anti-HCV drugs are divided into 2 categories: (1) direct-acting antiviral agents (DAAs) that target viral modulators of the HCV life cycle and (2) host-directed agents that attack components of the host cell that are essential for the HCV life cycle.⁵⁸

Some DAAs have already been approved by the US Food and Drug Administration (Table 1), with 12 having reached phase II or III clinical trials.⁵⁹ The NS3/4A protease inhibitors telaprevir and boceprevir, which are specific for HCV genotype 1, target the initial developmental stage of the viral life cycle with a high antiviral efficacy. Both have been approved in 2011 by the Food and Drug Admi­nistration for their combined use with pegylated interferon and ribavirin, with sustained viral response (SVR) rates up to 75% among naive patients. However, the complexity of such regimens and the development of new, more effective, and tolerable drugs have resulted in them no longer being recommended for use according to American and German guidelines (in January 2014).⁶⁰

Other new antiviral agents, approved in the United States in December 2013 and in Europe in February 2014, have included nucleotide and nonnucleotide NS5B polymerase inhibitors (sofosbuvir), NS5A viral replication complex inhibitors, and second-generation protease inhibitors (simeprevir and daclatasvir), which were developed to target the second stage of the HCV life cycle. With these new agents, we have 4 treatment options (Table 2), with less pill burden and shorter duration of therapy, for treatment of chronic HCV with or without interferon.60,61 Interferon-containing regi­mens include the triple combination of pegylated interferon-α, ribavirin, and simeprevir or sofosbuvir. Interferon-free options include the combination of sofosbuvir and ribavirin for 12 or 24 weeks, with SVR rates of 76% for genotype 1, 93% for genotype 2, and 85% for genotype 3.⁶²

The DAA regimen of ombitasvir (an NS5A inhibitor), dasabuvir (an NS5B inhibitor), and paritaprevir (an HCV-specific protease inhibitor) enhanced with ritonavir is associated with SVR rates above 90%; this regimen became available in December 2014 for treatment of HCV genotype 1 (Table 2). Although dose adjustment is not necessary in patients with renal impairment, 47 this combina­tion has not been studied in dialysis patients or kidney transplant recipients. Simeprevir is most often used in combination with sofosbuvir for the treatment of HCV genotype 1 infection and is associated with SVR rates greater than 91%.⁶³

One of the most promising DAA regimens is the combination tablet of sofosbuvir and ledipasvir, with SVR rates greater than 95% for treatment of HCV genotype 1. In kidney transplants, this combination is well tolerated and associated with potentially manageable interactions with immunosuppressant medications. It is worth noted that tacrolimus may increase ledipasvir levels.⁶⁴ Therefore, it is an attractive regimen for these patients, and it is likely that clinical trials will demonstrate safety and efficacy. Another clinical trial with grazoprevir (formerly MK-5172, a protease inhibitor) and elbasvir (an NS5A inhibitor) for treatment of genotype 1 HCV infection in patients with chronic kidney disease is currently ongoing.⁶⁵

With the introduction of ledipasvir and sofo­sbuvir, the infection cure rates have improved to more than 90% with possible exclusion of interferon and ribavirin.⁶⁰ After excellent results were shown with DAAs in naïve, uncomplicated patients,66 clinical trials are being conducted to evaluate these agents in difficult to treat patients, such as those previously treated for HCV infection (Table 3),⁶⁶ patients with cirrhosis, liver transplant recipients, patients coinfected with HIV, chronic kidney disease patients, and patients with multidrug resistant viral infection.Limited evidence exists regarding the use of these agents in patients with chronic kidney disease, including renal transplant recipients.⁶⁷ A report on 4 patients on hemodialysis with HCV infection showed that, after failure of pegylated interferon plus ribavirin therapy to induce a response, a second course of treatment that included telaprevir resulted in undetectable HCV RNA in 3 patients. Mild adverse effects with ribavirin treatment included anemia, which required an increased dose of erythropoietin. The dose of ribavirin ranged from 200 mg administered 3 times per week to 200 mg administered once daily. No information was provided regarding the SVR.⁶⁷

Sofosbuvir, simeprevir, and daclatasvir will need dose modification in patients with chronic kidney disease. The appropriate dose of sofosbuvir has not yet been determined for individuals with severe renal impairment (estimated glomerular filtration rate < 30 mL/min/1.73 m²) or patients undergoing hemodialysis. Although simeprevir is primarily metabolized by the liver, the safety of this drug has not been evaluated in patients with stage 4 and 5 chronic kidney disease.⁴⁷ There are no published data on simeprevir use in kidney transplant recipients, and its use is complicated because of interactions with calcineurin inhibitors despite its successful use with sofosbuvir in liver transplant recipients.⁶⁸

Eradication of HCV before renal transplant in the presence of severe liver fibrosis minimizes the risk of liver complications during surgery and in the initial posttransplant period.⁷ The most effective thera­peutic regimen for use in patients with severe fibrosis remains to be established. Patients without advanced pretransplant liver fibrosis who receive renal transplants can be administered an interferon-free protocol after transplant and after restoration of normal renal function. The combination of sofosbuvir with either simeprevir or ribavirin was successful in 8 renal transplant recipients without exhibition of organ rejection (RD Bloom, personal communication). The combined administration of pegylated interferon, ribavirin, and sofosbuvir for 24 weeks controlled the progression of fibrosing cholestatic hepatitis in a patient who had undergone a combined liver-kidney transplant procedure. Clearance of HCV was observed by week 4 of treatment with excellent tolerance.⁶⁹ The US Food and Drug Administration have approved a combination of ledipasvir and sofosbuvir, the first once-daily single tablet regimen for the treatment of chronic infection with HCV genotype 1.70

The development of these new drugs might change the present course of HCV infection in dialysis and renal transplant patients. The current limitations include the absence of evidence to support the use of DAAs in the setting of renal transplant in addition to their high economic cost.

The effectiveness of the new antiviral therapies against chronic HCV monoinfection has improved dramatically over the past decade. For patients infected with HCV genotype 1, the addition of 1 of the 2 recently approved first-generation protease inhibitors (telaprevir and boceprevir) to pegylated-interferon/­ribavirin for 48 weeks has increased SVR rates from 45% to 75% and allowed shortened duration of therapy in most patients to 24 to 28 weeks.⁷¹

New antiviral agents and immunosuppressive medications
The choice of maintenance immunosuppression may affect outcomes of HCV antiviral therapy. Several studies have reported higher SVR rates in patients who receive cyclosporine versus those who receive tacrolimus because of a lower risk of relapse. The proposed mechanism is thought to be from a direct antiviral effect of cyclosporine through inhibition of NS5B binding to cyclophilin B. However, there is no strong evidence supporting the switch of patients to cyclosporine before commencement of antiviral therapy.⁷² Data on the use of telaprevir in healthy volunteers resulted in a significant increase in cyclosporine (5-fold) and tacrolimus levels (70-fold) due to the inhibition of the cytochrome P4503A metabolic pathway. The required reduction in tacrolimus dosing (80%-95%) is greater than that for cyclosporine (50%-75%).⁷³ An early report demo­nstrated significant drug-drug interactions between calcineurin inhibitors and boceprevir in 5 liver transplant patients. Reductions in cyclosporine dose by 50% and up to 80% reductions in tacrolimus dose were required, with steady levels being accom­plished by 4 days. Meticulous management of immunosuppression agents with protease inhibitor-based therapy avoids graft dysfunction and rejection.

Combining DAAs, which target different steps of viral replication, should provide possibly synergistic antiviral potency, preventing the emergence of DAA resistance and consequently removing the need for IFN.⁷⁴ However, before they can be used to treat transplant recipients with recurrent HCV infection (Table 3), extensive drug-drug interaction studies with the calcineurin inhibitors are required because both the protease inhibitors and the non-nucleoside ns5b polymerase inhibitors are substrates and inhibitors of CYP3A4 and P-glycoprotein metabolic pathways. In contrast to the other DAA classes, the nucleotide polymerase inhibitors (chain terminators of HCV RNA synthesis) do not require dose adjust­ment in patients receiving calcineurin inhibitors. The addition of an NS5A inhibitor (either daclatasvir or ledipasvir) to sofosbuvir increased the SVR rate to 100% across different patient populations, including cirrhotic and prior nonresponders to both pegylated-interferon/ribavirin and triple therapy with telaprevir or boceprevir.⁷⁵ Adopted measures have been recommended before starting HCV treatment regarding the use of antiviral drugs (Table 4).¹⁵

In an open-label phase II study, 30 liver transplant recipients with compensated recurrent hepatitis C (HCV genotype 1 only) were treated with triple DAA regimen combined with ribavirin for 24 weeks.⁷⁶ Careful adjustment of the calcineurin inhibitor dose was required because of the inhibition of CYP3A4 by the ritonavir.

Conclusions

With the fast evolution of antiviral agents, we are expecting more therapeutic modalities among kidney transplant recipients, which will be reflected in patient and graft outcomes.

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