Hepatitis c virus and chronic kidney disease

ABSTRACT

Introduction

Hepatitis C virus (HCV) infection is associated with an increased incidence and progression of chronic kidney disease (CKD), as well as higher mortality in CKD and renal transplant patients. Direct acting antiviral agents (DAAs) have revolutionized the treatment of HCV, with viral eradication attained in 90–100% of treated patients. DAAs have an excellent safety and tolerability profile in CKD and renal transplant patients.

Areas covered

In this review, we discuss the association of HCV with incidence and progression of CKD as well as its effect on outcomes and mortality. We also discuss the available treatment options in patients with CKD and renal transplant and in HCV-associated glomerular disease.

Expert opinion

The availability of newly available direct acting anti-viral agents has revolutionized the treatment of HCV in persons with advanced CKD and undergoing dialysis. With these regimens, viral eradication can be attained in 90–100% of the treated patients. The safety, tolerability, and efficacy of these drugs in renal transplant patients have also made it possible to use HCV-infected grafts and successful virus eradication at a later stage.

KEYWORDS:

• HCV
• CKD
• hemodialysis
• DAA
• Sofosbuvir
• renal transplant

1. Introduction

Approximately 71 million people are infected with hepatitis C virus (HCV) worldwide, resulting in over 399,000 deaths mainly from cirrhosis or hepatocellular carcinoma (HCC)[1]. HCV-related morbidity and mortality tend to be under-estimated as literature mainly focuses on liver-related complications, namely cirrhosis and HCC. A substantial proportion of patients with HCV develop a wide range of extrahepatic manifestations [2]. These include mixed cryoglobulinemia/cryoglobulinemia vasculitis, B-cell non-Hodgkin’s lymphoma (NHL), type 2 diabetes mellitus, glomerulonephritis, renal insufficiency, lichen planus, porphyria cutanea tarda, and cardiovascular disease events [3,4]. This review focuses on the association between chronic HCV infection and chronic kidney disease (CKD).

2. HCV and CKD

HCV has been associated with CKD from the time of its discovery [5]. The viral infection may be a cause or consequence of CKD [6]. The classic manifestation of glomerulonephritis caused by HCV has been well described [7], but the virus has been linked to CKD in a number of other ways [6]. Growing evidence confirms the association between HCV infection and development of incident CKD, and rapid progression of CKD to end-stage renal disease (ESRD) needing transplant or hemodialysis.

2.1. Prevalence of HCV infection in patients on dialysis

Prevalence of HCV infection is higher in persons on chronic hemodialysis compared with the general population [8]. HCV prevalence rates range from 4% to 9% in most high-income countries, but is significantly higher and varies widely across different countries in the Middle East, North and Sub-Sahara Africa, Asia, and Eastern Europe [9]. The mean HCV prevalence in the Dialysis Outcomes and Practice Patterns Study (DOPPS) study, a prospective, observational study of HCV prevalence and seroconversion rates among dialysis patients in high-income countries was 13.5%, ranging from 2.6% to 22.9% between different participating countries. Increased HCV prevalence was associated with longer time on dialysis, male gender, black race, diabetes, hepatitis B virus (HBV) infection, history of renal transplant, and alcohol or substance abuse. HCV seroconversion was associated with longer time on dialysis, human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS), HBV infection, and recurrent cellulitis or gangrene [10].

HCV spreads via parenteral route, primarily through percutaneous exposure to blood, making dialysis patients more prone to acquiring infection. In fact, nosocomial transmission is the main method of spread of HCV in dialysis units and patient to patient spread of HCV infection has been documented [11]. Current guidelines recommend screening all patients initiating chronic hemodialysis as well as those who transfer between dialysis facilities or dialysis modalities and routine surveillance testing every 6 months thereafter [9].

HCV prevalence and seroconversion rates have declined significantly following routine implementation of infection control practices and regular screening and follow up of dialysis patients for HCV infection [12,13]. Lapses in standard infection control practices, including sharing contaminated hemodialysis machines and multidose vials and breaches in cleaning and disinfection practices, are responsible for outbreaks of infection [14]. The identification of acute HCV infection in a patient on hemodialysis should be reported to the appropriate public health authorities and all patients in the same center must be screened again. Adherence to currently recommended infection control practices can effectively control this problem [9].

2.2. HCV and the risk of incident

HCV infection is independently associated with microalbuminuria, and a higher risk and shorter time to development of CKD [15,16]. Studies have shown that HCV infection is associated with up to 2.2 fold higher mortality [17], and a progressive loss of kidney function leading to higher risk of developing ESRD [18]. The risk of developing CKD is higher in the younger population (age <50 years), men, and those with co-existing diabetes, hypertension (HTN), hyperlipidemia, or cirrhosis [19,20]. Multiple meta-analyses have confirmed these associations, with HCV infection being associated with up to 51% increase in the risk of proteinuria and 43% increase in incidence of CKD. Longer duration of infection and lower estimated glomerular filtration rate (eGFR) at baseline are associated with a higher risk [21–23].

The association of HCV with CKD is also evident among other patient groups. Co-infection with human immunodeficiency virus (HIV) increases the risk of CKD [24,25], with the risk linearly associated with HCV viral load [24,25]. Among patients with primary glomerulonephritis, HCV infection is associated with increased risk of progression of CKD [26], and in persons with diabetes, HCV is a predictor of poor renal survival leading to early ESRD development. This association is independent of age, race, sex, blood pressure, proteinuria, diabetes duration, and diabetic nephropathy [27,28].

2.3. HCV and CKD progression

HCV is also associated with an accelerated progression of CKD to ESRD needing hemodialysis (HD) and renal transplant. HCV prevalence is higher among persons with more advanced CKD [29], with ongoing viral replication being associated with rapid deterioration of kidney function (defined as >5 mL/min/year average eGFR decline) and doubling the risk of developing ESRD [18].

While persons with active viral replication experience a more rapid deterioration in renal function compared with those who are only HCV antibody positive without active viral replication [18,24,25,30], there is no clear association between HCV genotype and CKD development, and both genotype 1 and 2 have been shown to increase the risk of CKD [18,19,31].

2.4. HCV and CKD mortality

Persons with HCV infection undergoing maintenance hemodialysis are at a higher risk of death, hospitalizations, anemia requiring blood transfusions, and worsened quality of life compared with non-infected individuals [32]. Liver and cardiovascular diseases are the main reasons of excess mortality in dialysis patients with HCV infection [33]. HCV infection is closely associated with increased aortic stiffness and cardiovascular events in dialysis patients [34]. Patients with HCV infection also have higher burden of major cardiovascular co-morbidities, and concomitant diabetes and CKD confer excess mortality risk in this population [35].

Patients with HCV infection have poorer outcomes after kidney transplantation as compared to HCV negative patients. HCV infection post-renal transplant is associated with increased incidence of de novo immune‐mediated glomerulonephritis, especially type I membranoproliferative glomerulonephritis (MPGN) resulting in accelerated graft loss [36]. In renal transplant patients, HCV infection is associated with decreased long-term graft survival and increased mortality of recipients [37–39]. The increased mortality results from a higher risk of cardiovascular disease events, malignancy, and hepatic failure post-transplant, while glomerulonephritis and chronic allograft neuropathy being the main causes of graft failure [37,39]. There is higher risk of death during the first 6 months post-transplant owing to increased risk of infections, but overall transplant patients experience a survival benefit compared to patients on waiting list, attributable to sustained decrease in cardiovascular mortality [40]. Post-renal transplant, there is a marked increase in the risk of developing diabetes in HCV-positive recipients, and this may also contribute to the increased risk of mortality in these patients [41].

2.5. Other associated factors

Concomitant presence of hypertension, diabetes mellitus [28], genetic factors and use of nephrotoxic medicines can all contribute to increased risk of renal dysfunction in HCV infected patients [42]. Diabetes and hypertension are major independent risk factors for CKD, and HCV-associated chronic inflammation, increased insulin resistance, and accelerated atherosclerosis in renal vasculature can all potentiate the onset or exacerbation of CKD [43]. Conversely, persons with HCV also have two-fold higher risk of developing incident cardiovascular and cerebrovascular disease events [44,45] and a 1.5 fold higher risk of developing insulin resistance and diabetes mellitus compared with persons without HCV [28,46–48]. Patients with HCV-related cirrhosis are also at an increased risk of chronic kidney disease. In addition, to the risk of developing hepatorenal syndrome, increased prevalence of diabetes, and atherosclerosis-associated glomerulosclerosis contribute toward increased risk of CKD in cirrhotic patients [49]. Similarly, presence of HCV infection post-liver transplant is independently associated with incident CKD [50].

2.6. Treatment improves survival and reduces complications

Treatment of HCV infection confers a survival benefit and a reduction in incidence of complications. It also reduces the risk of developing CKD and cardiovascular complications [51,52]. Effective treatment and viral eradication as measured by attainment of SVR also provide survival benefit. The benefit is most pronounced in patients without cirrhosis or hepatoma [53,54]. The achievement of SVR results in reduction of non-liver-related mortality [55,56], as well as reduced insulin resistance, and decreased incidence of diabetes mellitus [55], thus conferring protection for CKD development. It has also been demonstrated that treatment with DAAs leads to decrease in the rate of decline in GFR, as well as improvement in albuminuria [57].

2.7. HCV and glomerular disease

Mixed cryoglobulinemia (MC) is a small vessel vasculitis leading to immune complex deposition in kidneys, skin, liver, joints, and nerves [3,4]. HCV is a major risk factor for MC, accounting for more than 80% of cryoglobulinemia vasculitis (CryoVasc) cases, with type II IgM kappa MC being the most common form [2,3]. Renal manifestations are present in 20–35% [58–60] of the patients with MC, and type I membranoproliferative glomerulonephritis (MPGN) is the most common form of HCV-related glomerulopathy resulting as a consequence of type II mixed cryoglobulinemia (MC) [7,61–63]. Type I MPGN is characterized by sub-endothelial deposits of IgM and IgG in capillary loops, and cryoglobulins precipitate in glomerular endothelial cells [64]. Clinical presentation varies from isolated proteinuria with microscopic hematuria (30%), to nephritic (20%) and nephrotic syndromes (15%), and acute renal failure (10%) [65]. More than half of the patients with MC have a benign course [66]. Ten year survival in patients with MC associated MPGN is about 80%, with cardiovascular diseases being the main cause of death [65]. However, in patients with life-threatening cryoglobulinemia vasculitis (defined as biopsy-proven glomerulonephritis and renal failure as initial manifestation), mortality rates appear to be higher approaching 20% at 1 year [67].

Other less common glomerular lesions reported in association with HCV infection include membranous nephropathy [64,68], focal segmental glomerulosclerosis [69], renal thrombotic microangiopathy [70], fibrillary glomerulonephritis, immunotactoid glomerulopathy [71], IgA nephropathy, and interstitial nephritis [7].

There are two major mechanisms for HCV-related glomerular injury. First, immune-mediated tissue damage via cryoglobulins, and second direct cytotoxic effect of the virus itself. HCV antigens cause constant stimulation and activation of T- and B-lymphocytes leading to production of antibodies and immune complexes [7,62]. The pathophysiological mechanism probably involves E2–CD81 interaction. CD81 is a cellular receptor present on hepatocytes (involved in infection), and B-lymphocytes. The interaction of E2 protein of HCV with CD81 receptor of B-lymphocytes leads to activation and monoclonal proliferation, eventually resulting in HCV-related MC [72]. The renal deposition of these immune complexes is the primary mechanism of glomerular inflammation resulting in fibrinoid necrosis of glomerular vessels, endothelitis, and complement activation. The resultant capillary leak allows leakage of cryoglobulins into the urinary lumen resulting in formation of tubular casts and crescents [7,62,73,74]. In addition to the indirect effects, HCV can have direct cytotoxic effect on renal tissue, resulting in kidney function decline. HCV can directly infect renal leukocytes, endothelium, and tubular cells [68], with renal cells expressing CD81 receptor, facilitating virus entry into cells and resulting in apoptosis [72,75].

3. Treatment of HCV in CKD

Treatment of HCV infection has been revolutionized with the introduction of all-oral DAA regimens against HCV. The first generation DAAs (boceprevir and telaprevir) were introduced in 2011 and were inhibitors of the HCV nonstructural protein 3/4A (NS3/4A) serine protease and were given in combination with pegylated interferon and ribavirin to boost SVR. However, thrice daily administration and adverse effect profile predominantly related to interferon and ribavirin, coupled with development of more effective and safe second generation DAAs have obviated their use [6,76]. Since 2015, second generation DAAs are used in two or three drug combination for a period of 8–16 weeks. The regimen type and duration depend on several factors including stage of liver fibrosis, virus genotype and subtype, prior treatment history, co-morbid conditions, concomitant medicine usage, glomerular filtration rate (GFR), and kidney and liver transplant candidacy [77–80].

Several DAA regimens are now approved for use, some of which are active against all genotypes [9,81–83]. These newer all-oral DAA regimens are better tolerated and are safer and more efficacious than pegylated interferon/ribavirin and boceprevir/telaprevir regimens. These regimens have also been highly successful in CKD population. Furthermore, their efficacy in real-life settings is comparable to that in randomized clinical trials, with SVR rates consistently exceeding 90–95% [84]. Table 1 summarizes different available DAAs, along with pharmacokinetics, pharmacodynamics, and significant drug–drug interactions especially with immunosuppressive medications used in renal transplant patients [76,81,83].

Table 1. Pharmacokinetic data of new direct-acting antiviral treatment in HCV patients and significant drug Interactions [76,81,83].

Drug - HCV targets	Metabolism	Elimination	Adjustment if GFR <30 ml/min/1.73 m2 or HD	Interaction with immunosuppressive medications	Important drug interactions
Sofosbuvir - NS5B	Mainly Renal oxidative metabolism and dephosphorylation	Urine (80%) Feces (15%)	No adjustment needed	No significant interaction	c-i with amiodarone Safe with antiretrovirals
Simeprevir - NS3/4A protease (co-formulation with sofosbuvir)	Hepatic	Biliary (91%) Urine (<1%)	No adjustment needed	Decreased Tacrolimus lvl, Increased CsA lvl Alters Sirolimus lvl	Significant interaction with triazole antifungals, digoxin, antiarrhythmics & anticonvulsants
Daclatasvir - NS5A replication Complex (co-formulation with sofosbuvir)	Hepatic	Feces (88%) Urine (7%	No adjustment needed	Not Clinically relevant	C-i with dexamethasone, St. John wart, rifampin, phenytoin and carbamazepine
Ledipasvir - NS5A (co-formulation with sofosbuvir)	Hepatic	Feces (>80%) Urine (<1%)	No adjustment needed	No change in levels of CsA, Tacrol and sirolimus	Use in caution with digoxin and dabigatran Not recommended with rosuvastatin
Velpatasvir - NS5A (co-formulation with sofosbuvir)	Hepatic	fecal 94% urine 0.4%	No adjustment needed	No significant interaction	Not recommended with efavirenz, etravirine and nevirapine.
Paritaprevir/ritonavir/ ombitasvir/ dasabuvir NS3/4A protease/ HIV protease/NS5A polymerase	Hepatic	Feces (>86%) Urine (2–11%)	No, if GFR 15–30 ml/min/1.73 m2 Caution for ESRD or HD	Reduce dose of Tacrolimus Decrease dose of CsA to 1/5^th Increase lvl of Sirolimus and everolimus (monitor)	Not recommended in Child B,C Cirrhosis
Grazoprevir/elbasvir NS3/4A protease/ NS5A	Hepatic (CYP3A)	Feces (>90%)	No adjustment needed	Increase tacrolimus level Increase lvl of Sirolimus and everolimus (monitor) Do not use with CsA	Not recommended with boosted protease inhibitors, some azole antifungal
Glecaprevir/Pibrentasvir NS3/4A protease/NS5A polymerase	Hepatic (CYP3A)	Feces (>90%)	No adjustment needed	Not recommended with CsA > 100 mg/day	c-i with atazanavir-containing HIV regimens

Protease inhibitor drugs (simeprevir, paritaprevir, grazoprevir, voxilaprevir) containing regimen are not recommended in Child B/C cirrhosis.

CsA: cyclosporin.

Tacrol: tacrolimus.

Lvl: level.

C-i: contra indication.

3.1. Goals of treatment

The goal of HCV therapy is to cure infection and to prevent virus-related hepatic (cirrhosis, decompensation, HCC) and extra-hepatic complications and death, and to improve quality of life and prevent transmission of virus. The endpoint of therapy is attainment of SVR, defined by undetectable HCV RNA in serum or plasma 12 weeks (SVR12) after the end of therapy. Treatment is recommended for all treatment-naïve and experienced patients with HCV infection, who are willing to be treated and who have no contraindications for treatment. Priority must be given to the patients with advanced fibrosis and/or cirrhosis and patients with certain conditions including but not limited to patients with diabetes, those on hemodialysis and clinically significant extra-hepatic manifestations e.g. symptomatic vasculitis associated with HCV-related mixed cryoglobulinemia (MC), HCV immune complex-related nephropathy and non-Hodgkin B-cell lymphoma [81,83] since these groups are likely to benefit the most from treatment.

3.2. Patients with HCV infection and CKD stage 1–3

Patients with HCV infection and CKD with estimated glomerular filtration rate (eGFR) >30 ml/min/1.73 m2 can be treated with any of the approved regimens, similar to those with normal renal function. This typically consists of combination therapy with sofosbuvir plus daclatasvir or velpatasvir, sofosbuvir plus ledipasvir, or grazoprevir plus elbasvir for 8–12 weeks depending on the HCV genotype and subtype, and the extent of underlying liver injury (see Table 2)[9,81,83]. Regimens active against all genotypes, e.g. glecaprevir/pibrentasvir can be given for 8 weeks in patients without cirrhosis or for 12 weeks in patients with cirrhosis [78,81,83]. One recent study has demonstrated that a shorter 8-week regimen of glecaprevir/pibrentasvir is as effective as 12-week regimen against all genotypes in treatment-naïve chronic HCV patients with compensated cirrhosis [85]. Protease inhibitors (simeprevir, paritaprevir, grazoprevir, voxilaprevir) are contra-indicated in patients with decompensated cirrhosis [86] so sofosbuvir-containing regimen preferably sofosbuvir/ledipasvir or sofosbuvir/velpatasvir should be used with sofosbuvir and daclatasvir regimen remaining an acceptable alternative.

Table 2. Therapeutic options for treating hepatitis C virus infection [9,81,83].

CKD stage	HCV genotype	DAA regimens
Stages 1-3 (eGFR, 31-90 mL/min)	All (1-6)	Sofosbuvir + velpatasvir (8–12 weeks) or Sofosbuvir + velpatasvir + voxilaprevir (8 weeks for patients without cirrhosis; 12 weeks for patients with cirrhosis) or Glecaprevir + pibrentasvir(8 weeks for patients without cirrhosis; 12 weeks for patients with cirrhosis) or Sofosbuvir + Daclatasvir (12 weeks with dose escalating ribavirin)^a or Sofosbuvir + Ledipasvir (12 weeks)^b or Grazoprevir + elbasvir (8–12 weeks)^c
Stage 4 or 5 (eGFR, <30 mL/min or hemodialysis)	• 1a, 1b, 4 • All (1-6)	Elbasvir/grazoprevir Glecaprevir/pibrentasvir Sofosbuvir containing regimens since November 2019[83]

a: For genotype 1–4, Extend treatment duration to 24 weeks if ribavirin ineligible.

b: For genotype 1,4,5,6.

c: Approved for genotype 1a,1b, and 4.

The choice of therapy for HCV and duration of treatment depends on genotype, presence or absence of cirrhosis, and tolerability to ribavirin.

Protease inhibitor drugs (simeprevir, paritaprevir, grazoprevir, voxilaprevir) containing regimen are not recommended in Child B/C cirrhosis.

3.3. Patients with HCV infection and CKD stage 4–5

Protease inhibitors containing regimens may be used in advanced CKD, as they are metabolized mainly in liver and do not need dose adjustment for renal function. Similarly, NS5A inhibitors are also metabolized in liver and can be used in CKD stage 4,5 and dialysis patients. Earlier only two DAA regimens were approved by the Food and Drug Administration (FDA) to treat HCV infection in patients with CKD stage 4 or 5 and ESRD on hemodialysis: elbasvir/grazoprevir and glecaprevir/pibrentasvir. Sofosbuvir is predominantly renally cleared (80%) and was previously licensed for use only in individuals with GFR >30 ml/min per 1.73 m2 (CKD G1–G3b). Initial data suggested that the use of sofosbuvir in patients with advanced renal impairment was associated with serious adverse events, worsening of renal function, and higher rates of anemia [87]. More recently, growing evidence has suggested that the use of sofosbuvir is safe and effective in patients with moderate to severe renal impairment including dialysis patients [88,89]. In November 2019, the FDA amended the package inserts for sofosbuvir-containing regimens and allowed its use in patients with renal disease, including those with an eGFR ≤30 mL/min and those on dialysis [83]. The issue of sofosbuvir-based therapy in advanced renal impairment is still controversial and more data are needed on this subject. Different DAA regimen recommended according to stage of CKD are summarized in Table 2[9,81,83].

The C-SURFER trial evaluated the safety and efficacy of 12 weeks of the daily fixed-dose combination of elbasvir (50 mg)/grazoprevir (100 mg) versus placebo among genotype 1-infected patients with advanced CKD (eGFR <30 mL/min or on HD). The cure rate in modified intention to treat (mITT) group approached 99% and no serious adverse events were noted [90].

EXPEDITION-4 trial evaluated the safety and efficacy of 12 weeks of the pan-genotypic regimen glecaprevir/pibrentasvir in patients with CKD including ESRD on HD. The reported SVR rates in intention to treat (ITT) and mITT approached 98% and 100%, respectively, [91].

RUBY-1 Trial in 2015 evaluated paritaprevir, ritonavir, and ombitasvir with or without dasabuvir and/or ribavirin of patients with HCV genotype 1 infection and stage 4–5 CKD including dialysis patients. The trial reported high SVR rates in response to combination therapy, although the sample size was small [92]. RUBY-II trial also reported high SVR rates in advanced CKD patients, without the use of Ribavarin [93]. Although not currently FDA approved, Paritaprevir/ritonavir/ombitasvir/dasabuvir (PrOD) combination can be considered as an option for treatment of HCV genotype 1 infections in places where Glecaprevir/pibrentasvir, and elbasvir/grazoprevir are not available.

3.4. Treatment of HCV-associated glomerulonephritis

Given the role of HCV in pathogenesis of CryoVasc, use of antiviral therapy for eradication of the virus remains crucial to ameliorate the renal injury [94]. Currently, DAAs are recommended as the first-line treatment for patients with HCV-related glomerular disease showing stable kidney function and/or non-nephrotic proteinuria [9]. Attainment of SVR is associated with remission of hematuria, proteinuria, reduction in cryoglobulin levels and improvement of GFR [95–97], and also restores immune tolerance by improving disturbances in peripheral B- and T-cell homeostasis [98]. In addition, control of proteinuria using angiotensin-converting enzyme inhibitors/angiotensin receptor blockers and control of blood pressure by diuretics is also recommended. Overall DAA therapy is associated with high rate of complete clinical response and low rates of serious adverse events in HCV-cryoglobulinemia vasculitis, but cryoglobulins may persist even after successful eradication of the virus [99], and there may be a dissociation between virologic and clinical responses to treatment [100,101], with some patients relapsing in the long-term necessitating regular monitoring and long term follow up of the patients [102–104].

For patients with cryoglobulinemic flare, nephrotic syndrome, or rapidly progressive kidney failure, immune-suppressive therapy with or without plasmapheresis is recommended, with rituximab as the immunosuppressive agent of choice [9]. Rituximab is also recommended as first-line agent for patients with histologically active HCV-associated glomerular disease in DAA non-responders [9], as the superiority of rituximab monotherapy vs. conventional immunosuppressive therapy has been demonstrated [59,105]. Successful eradication of HCV by DAAs allows safe usage of immunosuppressive and immunomodulatory therapies in these patients, with benefits for glomerular disease and no increased risk of HCV replication [106].

3.5. Effect of DAAs on GFR

DAAs are effective and well tolerated in CKD patients, including patients with advanced kidney disease [89] and SVR rates in patients with advanced CKD are similar to those without CKD. However, use of DAAs may lead to a modest decline in eGFR. This decline in renal function tends to reverse after completion of treatment except with sofosbuvir-containing regimens [107,108]. Age more than 65 years, baseline eGFR ≥60 mL/min/1.73 m² and liver transplantation are significant risk factors for deterioration in renal function. Recently, one study has shown that on-treatment and overall eGFR decline is more significant in sofosbuvir-containing DAAs as compared with sofosbuvir-free DAA regimen with eGFR evolution following a quadratic trend showing decline during treatment and improvement after the end of treatment [109]. Although the clinical implication of this decline remains uncertain, regular monitoring of renal function of patients at higher risk including elderly patients, those with liver transplant or risk factors for chronic kidney disease, during and after treatment seems reasonable.

4. Special populations

4.1. HCV in renal transplant patients

It has been shown that renal transplantation in HCV infected persons with ESRD confers long-term survival benefit, compared to the patients on the waitlist [40]. Until 2014, interferon-based regimens were the mainstay of treatment for patients with HCV undergoing renal transplant. Owing to the risk of graft dysfunction, or interferon-mediated humoral rejection, patients were treated only before transplant [110]. The introduction of DAAs has revolutionized the transplant field as well and opened the door for treatment of HCV post-transplant. The efficacy, tolerability, and safety of DAAs in post-transplant patients have been demonstrated [111,112].

However, optimal timing of treatment in renal transplant candidates is still unclear. Factors to consider include severity of liver fibrosis, living donor vs deceased donor, wait-list times by donor type, and government and center-specific policies [6,9]. If an HCV-positive living donor is available and immediate transplantation is expected to improve survival in the short term, HCV treatment should be deferred until after transplantation [9]. Transplanting kidney from HCV-positive donor to HCV-positive recipient decreases time to transplantation [113]. Treatment of such patients after transplant with DAA has shown promising results [114,115] and has also been shown to be cost-effective and increases quality-adjusted life years [115,116].

For patients without living donor available, timing of treatment is primarily decided by extent of liver fibrosis. Patients with early fibrosis should receive treatment after transplant, while patients with advance liver fibrosis should receive treatment before transplantation, especially if anticipated wait time for organ availability is more than 6 months [5,117]. This pre-transplant treatment approach may offer more life years when compared with post-transplant treatment group [118] but would limit the availability of HCV-infected kidney donors. Hence, each case has to be decided on individual basis and best option would vary by region and candidate [117].

Despite increasing demand for transplant kidneys worldwide, underutilization of HCV infected kidneys remains an issue. Also, transplant of HCV infected kidneys into HCV negative recipients has been an uncharted territory previously. One study demonstrated that 29% of the patients without HCV infection will consider HCV infected donor kidney under all scenarios, while 53% of the patients showed conditional acceptance. Older patients (age>60 years) and prior renal transplant recipients showed greater willingness to accept an HCV-infected organ while black patients were the least likely to accept the offer [119]. HCV infection is independently associated with increased risk of mortality after renal transplantation [37–39]. Recently, two trials have evaluated the outcomes of kidney transplant from HCV-positive donor to HCV negative recipients. The THINKER trial (Transplanting Hepatitis C Kidneys into Negative Kidney Recipients) and EXPANDER‐1 trial (Exploring Renal Transplants Using Hepatitis‐C Infected Donors for HCV‐Negative Recipients) studied the efficacy and safety of this approach. In THINKER trial [120] treatment was started after detection of viremia, while in EXPANDER-1 trial [121], it was initiated just before transplant. In both trials, patients achieved SVR, and renal graft function was unaffected at 1 year. These trials highlight a potential strategy to increase organ donor base and to reduce mortality and morbidity of kidney transplant candidates [121].

5. HCV in CKD patients – Beginning of the end?

The availability of several DAA regimen that can be used in advanced stages of CKD represents a major advance in management of HCV in this population. Current data clearly demonstrate that the use of newer agents in CKD and renal transplant patients improves mortality and morbidity [9]. World Health organization aims to achieve 90% reduction in the incidence of new viral hepatitis infections and 65% reduction in mortality by 2030. While the high price of new medicines had been a hurdle initially restricting their access, measures such as government supported treatment programs with minimal copayments, negotiating substantial price reductions and voluntary licensing agreements for generic versions in low to middle income countries, have ensured the availability of effective treatment at a reduced price [6]. People on dialysis represent a good target for HCV diagnosis by regular screening, and transmission of virus and re-infection after successful eradication can be controlled by adhering to standard infection control procedures [9].

6. Conclusion

The relationship between Hepatitis C virus and chronic kidney disease is bi-directional, with HCV being both a cause and consequence of CKD. Prevalence of HCV is higher among patients with advanced CKD and those on dialysis, and at the same time HCV is associated with higher risk and accelerated progression to CKD. HCV infection is associated with increased risk of mortality in CKD patients and poorer outcomes after renal transplantation. Successful treatment of HCV and achieving SVR reduces the risk of CKD development, has beneficial effects on extra-hepatic manifestations and confers a survival benefit. New all-oral DAA regimens can be used safely and effectively in patients with advanced renal disease including those on dialysis patients and renal transplant recipients. The efficacy, tolerability, and safety of DAAs in renal transplant patients have allowed the treatment to be deferred until after transplant, thus reducing the time to renal transplantation. Also, this strategy has the potential of transplanting HCV infected grafts into HCV negative recipients and eradicating infection later on. Elimination of HCV in CKD population remains a challenge and will require multi-disciplinary approach to increase patients and clinician’s awareness, increasing access to treatment and prevention of reinfection.

7. Expert opinion

The treatment of hepatitis C virus (HCV) infection has been revolutionized in the last decade with the approval of all-oral direct acting anti-viral agents (DAAs). Compared with the older interferon-based regimens, these regimens are more tolerable, safer and more efficacious with sustained virologic response (SVR) rates routinely exceeding 90–95%. These DAA regimens can also be used safely and effectively in persons with advanced chronic kidney disease (CKD) and those on dialysis. This has allowed the broadening of the treatment eligibility criteria of patients with HCV, including those previously considered difficult to treat. Some observational studies have demonstrated an improvement in renal function after treatment and attainment of SVR, as well as a reduction in overall mortality in this population. However, the long-term impact of HCV elimination on extra-hepatic manifestations remains unclear, and long-term follow-up data are needed. In patients with HCV-related glomerular diseases, attainment of SVR with DAA regimens is associated with a marked improvement in cryoglobulinemia-associated manifestations, but the long-term follow-up showed relapse of vasculitis despite achieving SVR. Randomized control trials testing effective treatment strategy and giving evidence-based recommendations are lacking in this field, and currently treatment strategies are guided clinically by degree of proteinuria and severity of renal failure.

Treatment with DAAs, especially sofosbuvir-containing regimens may result in modest decline in eGFR, which does not return to normal after cessation of therapy. The long-term clinical implications of this association are unclear. Prospective clinical studies following up these patients for proteinuria and eGFR measurement are needed in this regard.

Even before FDA approval, growing evidence suggested that sofosbuvir can be utilized safely at full or reduced doses, in CKD stages 4 and 5, with careful clinical monitoring of the patients [89,122,123]. In November 2019, sofosbuvir was approved by the FDA for use in patients with advanced renal disease including those on dialysis. This holds promise for areas where other approved regimens (elbasvir/grazoprevir and glecaprevir/pibrentasvir) are either not available, or affordable. Similarly, more and more evidence is accumulating regarding comparable efficacy and safety profile of generic DAAs for HCV treatment [124,125]. The generic drugs are more cost-effective and affordable enabling treatment coverage on a larger scale, especially in developing world and helping in achieving World Health Organization (WHO) target of reducing viral hepatitis-related mortality by 65% and reducing new infections by 80% by 2030, compared with 2015 rates.

In patients with renal transplant, the efficacy, safety, and tolerability of DAAs have been well documented. However, the optimal timing of the treatment remains debatable. Successful virus eradication post-transplant has made possible the use of HCV infected grafts, thus reducing the waiting time on transplant list and helping to overcome the ever-increasing problem of donor organ shortage. As HCV can be safely treated post-renal transplant with the new DAA regimens, HCV infected patients may be able to delay their treatment, hence making them eligible to receive HCV infected organs. However, given the unpredictability of time to transplantation, and deleterious effects of HCV in advanced CKD patients, as well as concerns about impact of DAAs on the graft function in long term, it is expected that many physicians will be reluctant to defer the treatment of patients until after transplant and would be inclined to treat the patients at the earliest. Large scale studies are needed to assess the impact of this strategy of delaying HCV treatment upon HCV-induced liver disease, overall morbidity and patient survival, as well as examining the long-term effects of DAAs on renal grafts. These results will serve to strengthen the confidence of treating physicians in favor of deferring HCV treatment post-transplant and hence providing their patients opportunity to receive HVC infected grafts.

Lastly, the novel strategy of transplanting HCV infected grafts into HCV negative recipients has been tested recently to overcome the problem of shortage of donor organs. Two pilot studies have reported excellent outcomes in HCV negative patients receiving HCV infected renal grafts, and virus eradication post-transplant. Future large-scale studies are needed on this subject to corroborate these initial encouraging results.

Article highlights

• HCV prevalence is higher in persons with chronic kidney disease (CKD) and those on dialysis, though the prevalence in dialysis patients has declined over the years.

• HCV is associated with 51% increase in the risk of proteinuria and 43% increased incidence of CKD and mixed cryoglobulinemia glomerulonephritis.

• HCV infection is also associated with increased risk of all cause and cardiovascular mortality in dialysis patients and accelerated graft loss in renal transplant patients.

• Active viral replication is directly associated with a higher risk of complications, which decreases in those patients who achieved successful virus eradication.

• Currently approved direct acting anti-viral (DAA) regimens lead to a sustained virologic response (SVR) in more than 90% of patients with advance CKD.

• Waiting time for renal transplant candidates can be reduced by using HCV infected donor kidneys. HCV infection can be treated safely post-transplant with newly available DAAs.

• Treatment with DAA regimens is associated with a small but significant decline in renal function that tends to reverse after completion of treatment except with sofosbuvir-containing regimens; long-term effect of DAAs on renal function is not known.

• HCV transmission can be prevented in dialysis units through strict adherence to infection control and hygiene policies and regular screening. This coupled with DAAs hold potential for significant reduction of HCV prevalence from CKD patients in future.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

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Funding

The publication of this article was funded by the Qatar National Library.