A review of direct-acting antivirals for the treatment of hepatitis C in patients with advanced chronic kidney disease Free

Historically, standard treatment of hepatitis C virus (HCV) infection in patients with renal impairment has been limited by low cure rates and poor tolerability. The introduction of direct-acting antivirals (DAAs) has revolutionized the treatment of HCV with impressive cure rates >90% and low rates of adverse events. Despite these major advancements, treatment of patients with HCV and advanced chronic kidney disease (CKD) is a major challenge due to the lack of efficacy and safety data in this patient population. The purpose of this review is to summarize the available data for efficacy and safety of the following DAAs in treating HCV patients with advanced Stage 4 and 5 CKD: simeprevir, sofosbuvir, ledipasvir, ombitasvir, paritaprevir, dasabuvir, grazoprevir, elbasvir and daclatasvir.

INTRODUCTION

Hepatitis C virus (HCV) infection is a leading cause of chronic liver disease, affecting >170 million people worldwide [1–3], and HCV infection in the setting of renal impairment is not uncommon. For more than a decade, standard treatment for HCV infection in patients with advanced chronic kidney disease [CKD Stage 4 or 5 with a glomerular filtration rate (GFR) <30 mL/min] consisted of peginterferon (PEG) alone or in combination with ribavirin (RBV) [4]. Unfortunately, both regimens have been associated with poor virologic response rates and intolerable adverse effects, requiring dosage adjustments and careful monitoring, especially in those with end-stage renal disease (ESRD) [1]. The use of RBV, which remains a component of some interferon-free antiviral regimens, is particularly challenging in advanced renal disease. RBV, which is renally eliminated, will accumulate in the setting of renal dysfunction, compounding its severe adverse events, including hemolytic anemia. RBV dosing, therefore, must be dramatically curtailed in advanced CKD from the standard dosages of 800–1200 mg/day to as little as 200 mg thrice weekly to daily [5, 6]. Moreover, RBV is poorly removed by hemodialysis (HD) [7].

Recently, there have been major advancements in the treatment of HCV with the development of new direct-acting antivirals (DAAs), which have shown impressive sustained virologic responses (SVRs) >90% and few adverse effects with as short as 8–12 weeks of therapy. Despite these major advancements, treatment of patients with HCV and advanced CKD remains a major challenge due to the lack of reported efficacy and safety data of DAAs in this patient population. Adding to this challenge is the high cost associated with DAAs, which may limit access to these medications. The purpose of this review is to summarize the currently available studies and provide clinicians with guidance in terms of efficacy and safety of the new DAAs in treating HCV patients with advanced CKD.

DATA SOURCES

A search was conducted using MEDLINE (1946–May 2015), Embase (1974–May 2015), International Pharmaceutical Abstracts (1970–May 2015), Google/Google Scholar and Clinicaltrials.gov, using the terms simeprevir (SMV), sofosbuvir (SOF), ledipasvir (LED), ombitasvir (OBV), paritaprevir (PTV), dasabuvir (DSB), grazoprevir (GZR), elbasvir (EBR) and daclatasvir (DCV), and combining them with the subject headings kidney failure/chronic kidney failure, kidney diseases and renal impairment to identify potential articles limited to the English language. As this search revealed a paucity of primary literature, abstracts, conference proceedings and product monographs were consulted. This review is a summary of all the available evidence to date.

CURRENT DAAS

Simeprevir

SMV is a second-generation HCV NS3/4A protease inhibitor that is administered at a dose of 150 mg once daily [8]. Renal elimination is negligible (<1%), as it is primarily excreted in the feces (>90%) [9]. In mild [estimated glomerular filtration rate (eGFR) 50–80 mL/min/1.73 m²] to moderate (eGFR 30–50 mL/min/1.73 m²) renal impairment, creatinine clearance (CrCl) was not found to influence the pharmacokinetic parameters of SMV [9]. Steady-state pharmacokinetics of SMV was evaluated in HCV-negative patients with severe renal impairment (eGFR < 29 mL/min/1.73 m²) [9]. Compared with subjects with normal renal function (eGFR > 80 mL/min/1.73 m²), maximum concentration (C_max) and area under the curve (AUC24h) exposures of SMV were 34 and 62% higher in patients with severe renal impairment. These increases appear to be not clinically significant, as there were no Grade 4 serious adverse events reported and no treatment-related discontinuations [10]. Dosage adjustments are not required for mild to severe renal impairment [9]. The current American Association for the Study of Liver Diseases (AASLD) and Infectious Diseases Society of America (IDSA) guidelines recommend the standard dose of SMV in patients with Stage 4 CKD, but not in those with Stage 5 CKD or those receiving renal replacement therapy, due to a lack of sufficient evidence [11]. The use of SMV in patients with advanced CKD will be further discussed in the next section under SOF.

Sofosbuvir

SOF is an HCV NS5B nucleotide inhibitor that is dosed at 400 mg once daily. It is a prodrug that undergoes extensive intracellular metabolism to form the pharmacologically active metabolite GS-461203 via phosphorylation [12]. The active metabolite is then dephosphorylated into the inactive metabolite GS-331007, which is the predominant circulating metabolite following administration [12]. The majority of SOF is eliminated by the kidney (∼81%), where 78% is recovered as GS-331007 and 3.5% is SOF [12]. Approximately 15% is excreted in the feces [12].

A single 400 mg dose of SOF was studied in non-HCV-infected patients with varying degrees of renal function, including those with ESRD requiring dialysis [13]. It was found that no dosage adjustments are required for mild to moderate renal impairment [12]. Compared with subjects with normal renal function (eGFR > 80 mL/min), AUC∞ for SOF and GS-331007 was 171 and 451% higher in patients with severe renal impairment [13]. In patients with ESRD and requiring dialysis, the AUC∞ for SOF and GS-331007 was 28 and 1280% higher when dosed 1 h before hemodialysis (HD) compared with 60 and 2070% higher when dosed 1 h after HD [12]. HD can remove ∼50% of GS-331007, and a 4-h HD session can remove ∼18% of the administered dose [12].

In an ongoing open-label Phase IIb trial, the efficacy and safety of SOF were evaluated in patients with HCV genotypes 1 (N = 9) and 3 (N = 1) with severe renal impairment (eGFR < 30 mL/min/1.73 m²) [14]. SOF 200 mg once daily along with RBV 200 mg once daily was given for 24 weeks. None of the patients had cirrhosis, and the majority of patients (70%) were treatment naive. The primary outcome was a 12-week SVR (SVR12). Despite initial rapid on-treatment viral suppression, SVR12 rates were disappointing at 40%, with the majority of treatment failures being due to relapse [14]. Pharmacokinetic analysis showed comparable SOF exposure and an ∼4-fold higher GS-331007 exposure with SOF 200 mg daily when compared with a historical HCV-infected population receiving SOF 400 mg daily [14]. None of the patients discontinued SOF treatment due to adverse events and there were no Grade 4 adverse events reported during the treatment period. Approximately 50% of patients experienced anemia, one discontinued RBV at 8 weeks and four patients had their RBV dose reduced or interrupted. The mean RBV daily dose was 136 mg at the end of treatment. The authors concluded that although SOF and RBV were safe and relatively well tolerated in HCV-positive patients with severe renal impairment, SOF 200 mg is an inadequate dose given the suboptimal SVR rate of 40%. A study with SOF 400 mg daily in combination with RBV in both Stage 4 and 5 CKD patients is under way.

In a case series, the efficacy and safety of different SOF regimens were evaluated in four HCV genotype 1–infected patients with severe renal impairment (eGFR < 30 mL/min/1.73 m²), including those on HD [15]. Two patients had cirrhosis and ESRD on HD, and two patients were post liver transplant. Previous treatment history for HCV was not reported for any of the patients. Three patients received SOF 400 mg every other day and SMV 150 mg once daily, and one patient received SOF 400 mg once daily and RBV 200 mg every other day. Treatment durations were not reported for either regimen. The primary outcome was SVR12, which was achieved in three of four patients. The patient who did not achieve SVR12 was in the SOF and SMV group, and virologic failure was due to relapse. None of the patients discontinued treatment due to adverse events, and there were no Grade 4 serious adverse events reported during the treatment period, even when SOF was dosed at 400 mg daily.

HCV-Target is a large longitudinal observational study assessing the efficacy and safety of real-world use of different SOF regimens in patients with reduced renal function. In total, 1890 HCV-infected patients with various baseline renal functions, including those with ESRD requiring HD, were included [16]. Approximately 10% of the patients had advanced CKD (eGFR < 30 mL/min/1.73 m²), of which 3% were on dialysis and 42% had cirrhosis. Treatment regimens consisted of either SOF, PEG and RBV or SOF and RBV or SOF and SMV or SOF, SMV and RBV. SOF was given at a dose of 400 mg once daily to all patients, and when included in the regimen, RBV was renally adjusted. SVR12 rates were similar between mild and severe renal impairment groups ranging from 81 to 88% [16]. Serious adverse events were highest in the moderate renal impairment group (eGFR 31–45 mL/min/1.73 m²) at 24%. However, early treatment discontinuations were similar between the groups. One patient with a baseline eGFR <30 mL/min/1.73 m² died from worsening renal failure and hepatic decompensation while on treatment. Compared with patients with mild renal impairment, patients with severe renal impairment more frequently experienced anemia (31 versus 15%, P < 0.01), acute renal insufficiency (25 versus 1%, P < 0.01) and serious adverse events (19 versus 6%, P < 0.01) even when limited to patients receiving RBV-free regimens. The authors concluded that full-dose SOF regimens in patients with severe renal impairment did not influence SVR; however, frequent monitoring is warranted for patients with severe renal impairment.

Lastly, in a trial that is still under way, SMV and SOF are being evaluated in HCV genotype 1–infected patients with ESRD on HD or GFR < 30 mL/min/1.73 m² (N = 17) [17]. Baseline characteristics reveal that 82% of patients are treatment naive, 47% are cirrhotic and 88% require HD. The regimen consists of SMV 150 mg once daily and SOF 400 mg once daily for 12 weeks. The primary outcome is SVR12, which has been attained in 100% of patients (N = 11) that have completed treatment. However, the results are still preliminary, as some patients have not yet completed treatment (N = 3) or have not reached SVR12 (N = 3). There have been no serious adverse events reported and no treatment-related discontinuations thus far. Final results from this study will need to be confirmed before further recommendations can be made. The current AASLD and ISDA HCV guidelines state that SOF-containing regimens can be considered for patients with CrCl < 30 mL/min with expert consultation, as efficacy and safety data are not yet available [11].

Ledipasvir

LED is an HCV NS5A inhibitor that is co-formulated as a fixed-dose combination of LED 90 mg and SOF 400 mg taken once daily [18]. The majority of LED is excreted in the feces (∼86%), with 1% eliminated by renal excretion. The pharmacokinetics of a single dose of LED 90 mg was studied in HCV-negative patients with severe renal impairment (eGFR < 30 mL/min/1.73 m²) [18]. There were no clinically significant differences in LED pharmacokinetics between patients with severe renal impairment and healthy subjects with normal renal function (eGFR > 90 mL/min/1.73 m²). No dosage adjustments are required for patients with mild to severe renal impairment [18]. There are currently no data on the efficacy and safety of LED in patients with advanced CKD including those with ESRD. Although it is unlikely that dosage adjustments will be required given the elimination pathway of LED, studies need to be conducted in patients with advanced CKD to support its use in this population. From a practical perspective, as LED is always used in combination with SOF and is not formulated as a stand-alone agent, these studies would most likely need to be combination studies. The current AASLD and ISDA HCV guidelines do not make any dosing recommendations for LED use in patients with severe renal impairment including ESRD requiring HD [11].

Fixed-dose ombitasvir, paritaprevir, ritonavir and dasabuvir (3D regimen)

The 3D regimen is an all-oral regimen that is comprised of three DAAs often used in combination with RBV. OBV an NS5A inhibitor, PTV, an NS3/4A protease inhibitor, and ritonavir (RTV), a booster to increase the exposure of PTV, are co-formulated into one tablet, and DSB, a non-nucleoside NS5B inhibitor, is a separate tablet. This regimen is dosed at two tablets once daily of the co-formulated OBVPTV/RIT (12.5/75/50 mg) in addition to DSB 250 mg twice a day [8]. All components of this regimen are primarily excreted in the feces (>86%), with <11.3% renal elimination [19]. The pharmacokinetics of a single dose of OBVPTV/RTV with and without DSB was evaluated in subjects with mild (CrCl 60–89 mL/min) to severe (CrCl 15–29 mL/min) renal impairment. AUC values for the co-formulated OBVPTV/RTV and DSB were <1, 45, 114 and 50% higher in subjects with severe renal impairment compared with subjects with mild renal impairment [19]. However, these increases were not clinically significant and therefore no dosage adjustment is required for mild to severe renal impairment.

The interim analysis of the RUBY-I trial, an ongoing multicenter, open-label, Phase IIIb study assessing the safety and efficacy of the 3D regimen in HCV genotype 1–infected patients with Stage 4 or 5 CKD, was recently presented at the European Association for the Study of the Liver International Liver Congress [20]. A total of 20 HCV genotype 1 treatment-naive, non-cirrhotic patients with advanced CKD (65% receiving HD) were treated with OBVPTV/DSB with or without RBV. RBV (in those with HCV genotype 1a only) was dosed 4 h before HD and monitored with weekly hemoglobin assessments. RBV doses were suspended for a ≥2 g/dL decrease in hemoglobin level and resumed when the hemoglobin level normalized. Preliminary results have revealed that 10 of 10 patients achieved SVR4, and of those, 2 patients reached SVR12. As expected, the use of RBV was associated with an increased drop in hemoglobin levels, and 8 of 13 patients required interruption of RBV dosing. Four of eight patients also required erythropoietin treatment during the first 7 weeks of therapy. The mean drug concentrations (C_trough) of all drugs were measured, and levels were within the range that was observed with previous pharmacokinetic studies in healthy volunteers. Although the preliminary results look promising, final study results are required before a recommendation can be made regarding the safety and efficacy of the 3D regimen with or without RBV in patients with advanced CKD. As such, the current AASLD and ISDA guidelines state that although the 3D regimen can achieve viral suppression in most CKD patients, further data are required before making a recommendation for its use in this population [11].

Daclatasvir

DCV is an HCV NS5A inhibitor that is currently available in Europe and Japan. The usual adult dose is 60 mg once daily. It is predominantly eliminated through the feces (88%), and renal elimination is minimal (6.6%) [21]. The pharmacokinetics of a single 60 mg dose of DCV was studied in HCV-negative individuals with renal impairment including ESRD requiring HD [22]. Compared with matched healthy subjects with normal renal function (CrCl > 90 mL/min), the AUC of DCV was 60 and 80% higher for patients with severe renal impairment and ESRD. For patients with ESRD requiring HD, the AUC of DCV was 27% higher compared with their matched healthy controls [23]. There were no serious adverse events reported. It was concluded that increased DCV exposures were within exposures observed in population pharmacokinetics and safety assessments, showing no correlation between higher exposures and serious adverse events [22]. The European Medicines Compendium for DCV states that no dosage adjustments are required for patients with any degree of renal impairment. DCV, however, is administered as part of combination therapy with other DAAs (e.g. SOF), and clinical efficacy in this renally impaired population will depend on the other agents. As DCV is newly licensed by the US Food and Drug Administration for genotype 3 infection, it is not included in the current AASLD and ISDA HCV guidelines.

DAAS CURRENTLY IN CLINICAL TRIALS

Grazoprevir/elbasvir

Phase III trials are currently under way for a co-formulated combination of GZR (100 mg) and EBR (50 mg) in HCV genotype 1 and 4. GZR is a second-generation HCV NS3/4A protease inhibitor and EBR is an NS5A inhibitor. Less than 1% of both drugs are renally eliminated. The safety and tolerability of co-formulated GZREBR (100/50 mg) were assessed in an open-label, multiple-dose study in HCV-negative patients with severe renal impairment including patients with ESRD and those on HD (N = 24) [24]. Compared with subjects with normal renal function (eGFR > 80 mL/min/1.73 m²), the AUCs of GZREBR were 1.65 and 1.86 higher in patients with severe renal impairment. Patients with ESRD receiving HD experienced similar GZREBR exposures when comparing HD with non-HD days and when compared with matched subjects with normal renal function. Due to high plasma protein binding of both GZR and EBR, removal of either medication via dialysis was negligible (0.5% for GZR and 0% for EBR). There were no serious adverse events reported during the study period and no treatment-related discontinuations.

The C-Surfer Study, a randomized, parallel-group, multicenter, placebo-controlled Phase II/III trial, evaluated the efficacy and safety of GZREBR in HCV genotype 1–infected patients with Stage 4 or 5 CKD including patients on dialysis (N = 224) [25]. Patients were randomized to receive either immediate or deferred treatment with GZREBR (100/50 mg) once daily for 12 weeks. Patients randomized to the deferred treatment arm first received 12 weeks of placebo before starting GZREBR. The majority of patients were treatment naive (∼80%), 6% were cirrhotic, ∼81% had Stage 5 CKD and ∼76% were on dialysis [25]. The primary end point was SVR12, which was achieved in 99% of patients who completed treatment. SVR12 was 94% in the intention-to-treat analysis. Serious adverse events were similar between the immediate treatment group and deferred treatment group (14.4 versus 16.8%). One serious adverse event (elevated lipase level) in the immediate treatment group was considered treatment related [25]. There were four deaths in total: one patient in the immediate treatment group from cardiac arrest unrelated to the treatment and three patients from the deferred treatment arm due to aortic aneurysm, pneumonia and an unknown cause. None of the patients in the immediate treatment group discontinued treatment, whereas 4.4% discontinued treatment in the deferred treatment group. It appears that the combination of GZREBR is a safe and effective option in patients with advanced CKD. GZREBR is expected to become available on the market in 2016.

DISCUSSION

HCV therapy in the setting of renal dysfunction has always been challenging. In the era of PEG and RBV, treatment achieved nominal success at the expense of intolerable adverse events. Although DAAs have revolutionized the treatment of HCV infection with superior cure rates, tolerable adverse event profiles and short treatment durations, their use in patients with CKD has been limited to those with mild to moderate renal dysfunction. Until recently, there were limited data regarding their use in patients with Stage 4 or 5 CKD. In this review, we attempted to summarize the exciting upcoming therapies for this underserved population. Although preliminary in nature, the data clearly reveal a changing therapeutic landscape, with more DAAs becoming available for treating HCV in patients with advanced renal impairment.

Many DAAs, with the exception of SOF, are predominantly eliminated via biliary excretion (>86%), hence renal dosing is most likely not required for these agents. SOF is renally excreted and accumulates in renal dysfunction, therefore its use is not recommended in patients with GFR < 30 mL/min/1.73 m². A Phase II study showed that decreasing the SOF dose by 50%, to 200 mg daily, in addition to RBV 200 mg daily for 24 weeks in patients with severe renal impairment significantly compromises virologic efficacy, resulting in an SVR12 of only 40% [14]. Data from case series and prospective observational cohorts have revealed that full-dose SOF may in fact be safe and effective in patients with severe renal dysfunction (GFR < 30 mL/min/1.73 m²), although data in patients with ESRD on HD are scarce. Based on the available evidence, dosage adjustments for SOF are likely not required for severe renal impairment, and a 400 mg dose of SOF is most likely required in terms of optimizing virologic success. For patients with ESRD requiring dialysis, data are scant, and until higher-quality studies are conducted, concrete recommendations cannot be made.

Based on their pharmacokinetic properties and the present available literature, SMV, LED, DCV and the 3D regimen do not require dosage adjustments for severe renal impairment (eGFR 15–29 mL/min/1.73 m²). In ESRD including those requiring dialysis (eGFR < 15 mL/min/1.73 m²), SMV and LED likely do not require dosage adjustments, although this has not been substantiated in clinical trials. The preliminary results of the RUBY-1 trial indicate that the 3D regimen is likely safe in advanced CKD patients including those with ESRD, although the efficacy results are not yet available. As LED and DCV are always prescribed with SOF, combination studies will need to be conducted to determine their safety and efficacy in patients with ESRD. The GZREBR combination has the best evidence for use in patients with advanced CKD. In a multicenter, randomized, placebo-controlled, Phase III trial, GZREBR achieved 94% SVR in HCV genotype 1 and 4 patients with Stage 4 or 5 CKD. This regimen will be available in the near future. Tables 1 and 2 are a summary of the current and future DAAs, including their elimination pathways and their use in renal impairment.

Although the current and future treatment options for CKD patients with HCV genotypes 1 and 4 seem promising, treatment of patients with genotypes 2 and 3 remains a challenge. The only interferon-free regimen for these patients is the combination of SOF and RBV, both of which are renally eliminated. Table 3 is a summary of the current AASLD and ISDA treatment recommendations in CKD Stages 4 and 5 for each HCV genotype.

The major limitation of this review was the paucity of published data and reliance on conference abstracts and product monographs in guiding treatment recommendations. It should be recognized that these DAAs have not been adequately assessed in high-quality clinical trials to treat HCV in the CKD population. The majority of available data are based on pharmacokinetic studies (many were single dose) enrolling only a small number of HCV-negative individuals with severe renal impairment. Greater variability is expected in larger sample sizes, and potentially in the target HCV-infected population. There was a dearth of studies with regard to the use of these DAAs in patients with ESRD requiring dialysis. With the exception of the 3D regimen, for which results are still pending, further post-marketing studies are warranted for SMV, SOF and LED in this patient population. The availability of GZREBR in the near future will provide a very safe and efficacious option for treating HCV genotype 1 and 4 patients with advanced CKD.

Although the current and future treatment options for CKD patients with HCV genotypes 1 and 4 seem promising, treatment of patients with genotypes 2 and 3 still remains a challenge. The only interferon-free regimen for these patients is the combination of SOF and RBV, both of which are renally eliminated. Future studies are needed to address this difficult to treat population with limited therapeutic options.

CONFLICT OF INTEREST STATEMENT

The authors declare that this review has not been published previously in whole or in part. E.M.Y. has been an investigator of clinical trials sponsored by Gilead Sciences, Janssen, Merck, AbbVie, Hoffman LaRoche, Boerringher Ingleheim and Vertex. He has received honoraria for CME lectures from Gilead Canada and Merck Canada. He has received honoraria for advisory board lectures from Boerringher Ingleheim Canada and AbbVie Canada. A.M., T.H., S.R.E. and V.M.A. do not have any disclosures.

REFERENCES