Antiviral treatment of hepatitis C in renal transplant patients - safety issues

KEYWORDS:

• HCV
• kidney transplant
• antiviral treatment
• safety

Hemodialysis (HD) has long been listed as a major risk factor for nosocomial transmission of hepatitis C virus (HCV) infection, the prevalence of infection in these patients ranging from 2.6 to 22.9% in Western countries, definitively greater than that observed in the general population [1]. As expected, this translated also in an increased risk of chronic HCV infection among kidney transplant (KT) recipients, where 5–15% of all patients are chronically infected by the virus [2]. The clinical consequences of HCV infection in KT patients are relevant owing to enhanced risk of cardiovascular events, new onset of diabetes, infection rates, and graft loss that have been demonstrated in HCV populations worldwide, all these comorbidities translating in a worse survival expectancy compared to HCV-uninfected KT patients [3,4]. On top of this, the virus itself can be either an additional or a concomitant cause of kidney disease as a result of cryoglobulin-related and unrelated vasculitis that may lead to a variety of kidney damage including membranous proliferative glomerulonephritis [5,6]. All these morbidities have been shown to be either attenuated or reverted following HCV eradication, an objective that could rarely be achieved in the era of interferon therapy, whereas the arrival of interferon-free all oral regimens has dramatically changed cure options. The consolidated clinical benefits of HCV eradication, in fact, include attenuated progression of posttransplant hepatitis C, reduced risk of graft loss due to rejection or relapse of cryoglobulin-related glomerulopathy, and prevention of accelerated atherosclerotic diseases enhanced by the combination of virus infection and immunosuppressant drugs, a synergy that increases the chances of developing diabetes and cardiovascular events. Not surprisingly, therefore, all KT recipients with chronic HCV infection should be considered for antiviral treatment.

In the past, standard treatment of these patients with interferon-based regimens has been limited by low rates of treatment uptake due to poor tolerability and limited chances of therapeutic success. Indeed, interferon alone or in combination with ribavirin almost invariably resulted in an accentuated treatment-induced toxicity and low success in achieving viral eradication mostly due to higher treatment discontinuation rates for enhanced incidence of serious adverse events [7], not to mention that interferon could induce acute allograft rejection and serious infectious complications, whereas ribavirin, which is eliminated by the kidney, had enhanced side effects on bone marrow even when underdosed. The introduction of direct-acting antiviral agents (DAAs) has revolutionized the treatment of HCV with impressive cure rates greater than 90% and low incidence of adverse events. Despite these major advancements, treatment of KT patients with HCV remains a challenge due to an initial lack of efficacy and safety data in this patient population and the fact that the pioneer HCV DAA sofosbuvir (SOF) and its metabolite 007 are eliminated via renal clearance, making SOF regimens not indicated for patients with a GFR <30 mL/min, who can be treated with expert consultation only. The other classes of direct antivirals currently approved for the treatment of HCV infection are not restricted in renal patients, since these drugs have a negligible renal clearance, being primarily excreted in the feces and not requiring dosage adjustment in renal patients however they do not cover infection with genotype 2 and 3 of HCV.

1. DAA regimens approved for renal patients

SOF-based regimens are registered for treatment of renal patients with >30 ml creatinine/min × 1.73 mq body surface. This notwithstanding, data collected by the observational study TARGET indicates that 88% of 15 US patients with stage 4 or 5 kidney impairment were able to achieve an SVR in the face of an increased rate of adverse events and transient deterioration of renal function [8]. In that study, the SVR rate in 1495 patients with >45 IU/ml eGFR receiving SOF-based regimens were similar to that of 64 patients with <45 IU/ml eGFR, again with an increased rate of adverse events in patients with more deteriorated renal function. Data from a multicenter retrospective analysis of 50 patients with stage 4 or 5 CKD treated with SOF-containing regimens, including 35 on HD, 17 kidney transplanted patients, 11 liver transplanted patients, and 27 on waiting list for kidney transplantation, showed SVR12 rates of 86%. In HD patients SOF was given at lower dose, 400 mg three times a week or 400 mg every other day. SOF was combined with Simeprevir or Daclatasvir or PegIFN or RBV. 13 patients received RBV and dose ranging from 200 mg three times a week to 600 mg/day. No patients had to discontinue treatment due to adverse events, and in non-HD patients GFR was not modified during treatment [9].

The European Association of the Study of the Liver recommends two regimens based on protease inhibitors of HCV for the treatment of patients with stage 4 and 5 renal impairment [10]. One such regimen is the fixed-dose ombitasvir (OBV), paritaprevir/ritonavir (PTV/RTV) and dasabuvir (DSB), the so-called 3D regimen that is recommended for genotype 1 and 4, the latter requiring the DSB-free regimen 2D. Both 3D and 2D regimens, however, require expert management because of significant interactions expected when used in combination with immunosuppressive drugs and other drugs (see Table 1 below). The second regimen is the combination of Grazoprevir (GZR) and Elbasvir (EBR), also registered for the treatment of HCV genotype 1 and 4. Both regimens are restricted to the treatment of patients with compensated liver disease with the exclusion of patients with a previous history of decompensation to avoid drug-related liver toxicity. The best study evaluating DAA in renal failure is the placebo-controlled trial C-Surfer, where 111 patients infected with HCV-1,-4, and -6 were randomized to receive immediate treatment and 113 to receive deferred treatment with GZR/EBR (100/50 mg without ribavirin) once daily for 12 weeks. A sustained viral response (SVR) at week 12 was achieved in 99% of patients who completed treatment, which fell to 94% in the intention-to-treat analysis [11]. While serious adverse events were rare and similar between the immediate treatment group and deferred treatment group (14.4 % vs. 16.8%), a few cases of elevated lipase level were reported in the immediate treatment group only. Noticeably, there was no consistent change in mean glomerular filtration rate (GFR) or serum creatinine in either treatment group. While none of the patients in the immediate treatment group discontinued treatment, 4.4% did it in the deferred treatment group, making the combination of GZR/EBR to appear as a safe and effective option in patients with advanced chronic kidney disease.

Table 1. Table of potential drug-drug interactions.

Less robust is the data stemming from the open-label study RUBY-1 evaluating the safety and efficacy of 3D regimen with or without ribavirin in HCV-1 and -4 patients with a stage 4 or 5 CKD. All patients were treatment naïve, genotype 1a patients received 12 weeks of 3D associated with RBV 200 mg QD, genotype 1b patients received 12 weeks of 3D alone [12]. Out of the 20 patients who received the study drug, nobody had to discontinue treatment due to adverse events, whereas 9 (69%) genotype 1a patients developed anemia requiring RBV dosage adjustment. SVR12 was 90% (18/20), 1 patient relapsed at week 4 of follow-up and 1 patient died 14 days after treatment discontinuation for causes not related to study drug. These outcomes were reproduced in a small study of 20 patients with HCV-1a or 4, where 3D and 2D combinations led to 100% and 80% SVR rates, respectively, without any safety signal [13].

2. Treatment of KT patients

Though encouraging data came from the liver-transplanted patients successfully treated with all oral regimens, data on antiviral treatment in HCV-positive kidney recipients came later than the marketing of HCV drugs. Early experiences concerned real-life case series from centers in France and the USA like the first pilot study published in 2015, where Kamar et al. reported results obtained in the treatment of 25 kidney transplanted patients [14]. All patients received an SOF-based therapy, differently combined with at least another drug including ribavirin, daclatasvir, simeprevir, or ledipasvir with a median time from kidney transplantation at initiation of DAA of 146 months (range 1–329), a majority of patients with genotype 1 (76%), and an estimated GFR >30 ml/min. Interestingly, all patients achieved an SVR12 at week 12 after treatment discontinuation while no serious adverse events were reported in this small study, especially no significant changes in kidney function nor acute rejection episodes or need for adapting immunosuppression . Another study [15] in 20 patients (88%, HCV-1) with a median time from kidney transplantation to antiviral treatment initiation of 888 days (range 341–1621), reported 100% rates of SVR 12 to SOF-based regimens, with excellent safety profile, no adverse events were reported, but almost half (45%) of patients requiring an adjustment of immunosuppression during antiviral treatment, however, without any episode of cellular rejection or graft loss. The real breakthrough, however, was the multinational phase II study demonstrating that KT recipients chronically infected by HCV genotype 1 or 4 could safely and effectively be treated with 12-week Ledipasvir/SOF only [16]. In the study comparing 12 vs. 24 weeks 114 patients, 15% had compensated cirrhosis and the majority had HCV 1 infection and a median time from kidney transplantation to start of antiviral therapy of 12 years (range 0.5–42.0) with a median eGFR at baseline of 56 mL/min (range 35–135). The rates of SVR-12 were 100% both in 12-weeks than in 24-weeks treatment group, with a few adverse events being observed, similar to those reported in premarketing studies of Ledipasvir/SOF. Three treatment-related serious adverse events occurred, but in one case only permanent therapy discontinuation was deemed necessary without compromising the chances of SVR. In the majority of patients, renal function remained stable during study period and after treatment discontinuation; in 21 cases immunosuppressive treatment needed to be adjusted, yet nobody experienced acute cellular rejection. The excellent outcome of DAA therapy of HCV in KT patients was confirmed by real-life practice studies, one above all the Spanish registry of 103 kidney-transplanted patients treated with a variety of SOF-based regimens [17], 35% with a diagnosis of compensated cirrhosis and a median time from kidney transplantation and start of antiviral treatment ranging from 1 to 561 months. Interestingly, 101 patients (98%) achieved an SVR 12 while regimens were well tolerated, except that in patients receiving ribavirin, who experienced higher rates of anemia. Though graft rejection was observed in three patients (3%), the complication evolved favorably with case-by-case medical management; half of the patients required adjustments of immunosuppression and 16% experienced a worsening of serum creatinine >25% during treatment. This not withstanding, all patients, except 4, recovered renal function at the end of follow-up period. In another real-life study [18], 31 kidney-transplanted patients were treated with SOF-based regimens after 101–10,404 days from KT, leading to SVR rates of 97% without any significant change in GFR and no cases of cellular rejection observed.

In a small study in Germany, 15 KT recipients treated with Ledipasvir/SOF combination showed SVR rates and safety profile similar to these reported so far [19], i.e. SVR of 100%, stable eGFR, no episodes of rejection, while 6 patients (55%) required an adjustment in immunosuppressive drug dosage. Pooling data from the literature, more than 300 KT patients in the last 2 years received SOF-based regimes to treat chronic HCV infection: even though reported data were heterogeneous, antiviral treatments showed excellent response rates and an acceptable safety profile. SOF-based regimens are the most prescribed therapies but all patients treated should have a creatinine clearance level more than 30 ml/min and at present there is not yet a good treatment option in kidney-transplanted recipient with impaired renal function. The ideal time of antiviral treatment after kidney transplantation is not yet defined, ideally ‘as soon as possible’ could be the answer but it is not clear if a period of ‘stability’ in immunosuppression and graft function is helpful in avoid antiviral-treatment complications and the risk of graft loss. Needless to say, treatment of HCV in this special population requires a multidisciplinary approach to guarantee a careful monitoring of graft function and immunosuppressive therapy by the attending nephrologists during antiviral treatment and in the first six months after treatment discontinuation, that should be entrusted to expert hepatologists independently of liver disease severity.

3. Conclusions

Despite significant steps forward in treatment of HCV, not all patients with severely impaired renal function and chronic hepatitis C can safely be treated with interferon-free DAA regimens. Patients infected with HCV-2 and -3 and in general all patients with advanced liver disease are not eligible to first-generation protease inhibitor-based regimens, the first as a consequence of the limited genotypic activity of the protease inhibitor-based regimens, the second because of increased risk of liver toxicity induced by protease inhibitors. SOF-based regimens still stand as the most widely prescribed therapy of HCV, with the restriction that all patients should have a creatinine clearance level higher than 30 ml/min while a safe multi-genotypic treatment option is not yet available for patients with impaired renal function or during the first weeks following KT. The latter reflects also a lack of data on the ideal time to start antiviral treatment after transplantation: while ideally ‘as soon as possible’ could be the answer, it is still unclear if a period of ‘stabilization’ of immunosuppression and graft function is necessary to prevent autoimmune reactions and graft rejection resulting from impaired immune surveillance caused by a swift removal of HCV and recovering of metabolic function of the liver.

The marketing of a second-generation combination of a protease inhibitor and a NS5A inhibitor such as Grecaprevir/Pribentavir (GP) is expected to substantially improve the therapeutic scenario of patients with advanced kidney failure, as it will allow treatment of patients with any HCV genotype. In the EXPEDITION IV study, 104 patients infected with HCV 1–6, including previous non responders to SOF-based regimens, achieved a 98% rate of SVR to 12 week therapy with GP in the absence of any significant adverse events [20]. In the setting of kidney-transplanted patients, safe and effective interferon-free treatments resulted in an expanded access to donated kidneys from HCV-infected donors, who in the USA represent 4.2% of the entire donor pool, with a 2.4% of HCV RNA-positive individuals [21]. The pilot trial Thinker at the University of Pennsylvania was to some extent anticipating the future scenario: 10 patients grafted with infected kidneys and treated with GZR/EBR for 12 weeks, safely recovered from HCV without any arm of the graft, this study potentially being the foundation for a significant change in the policy in kidney transplantation, with the expected benefit of a wait list dropping to a few months from the currently years (https://www.pennmedicine.org).

Declaration of interest

Massimo Colombo has served on advisory committees for: Merck, Roche, Novartis, Bayer, BMS, Gilead Science, Tibotec, Vertex, Janssen Cilag, Achillion, Lundbeck, GSK, GenSpera, AbbVie, AlfaWasserman, Jennerex Speaking and teaching: Tibotec, Roche, Novartis, Bayer, BMS, Gilead Science, Vertex, Merck, Janssen, Sanofi, AbbVie. The authors have no other 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 apart from those disclosed.

Additional information

Funding

This paper has not been funded.