New and Emerging Evidence on the Use of Second-Generation Direct Acting Antivirals for the Treatment of Hepatitis C Virus in Renal Impairment

Abstract

Due to the intimate relationship between liver and kidney disease in hepatitis C virus (HCV) infection, treatment options for HCV-positive patients at any stage of chronic kidney disease (CKD) are essential. The availability of second-generation, direct-acting antiviral (DAA) combinations has allowed for the advent of interferon-sparing treatment regimens with shorter durations and minimal side effects. While many of the second-generation DAAs are principally metabolized by the hepatic system, dosing in severe renal impairment (creatinine clearance [CrCl] <30 mL/min) or dialysis has remained questionable due to limited experience. New evidence regarding the use of these agents in renal impairment continues to become available, as real-world experience with these treatment regimens is reported. Simeprevir, ledipasvir, paritaprevir, ombitasvir, dasabuvir, and daclatasvir have data to suggest safety in end-stage renal disease. While safety and efficacy with sofosbuvir remains uncertain, data are now available to support utilizing a dose adjustment when glomerular filtration rates are <30 mL/min. Upcoming regimens grazoprevir/elbasvir and daclatasvir/asunaprevir/beclavubir may provide further options for patients with advanced kidney disease, and ongoing studies will continue to provide guidance for this unique patient population. This article will review the currently available literature, including the newest emerging evidence, on the use of second-generation DAAs in CKD stages 3 to 5 and dialysis.

Keywords

hepatitis C direct acting antiviral agents renal disease chronic kidney disease dialysis

Introduction

Chronic hepatitis C virus (HCV) is estimated to have infected over 3 million people in the United States and more than 170 million people worldwide.^1
–3 While HCV primarily affects the liver, at least 40% of HCV-infected patients are reported to have at least 1 extra-hepatic manifestation.⁴ Progression to cirrhosis and hepatocellular carcinoma remains the major burden of disease; however, the development of renal dysfunction is also of significant concern for HCV-infected individuals.^5,6

The relationship between chronic kidney disease (CKD) and HCV is multifactorial and complex. Long-term hemodialysis is a risk factor for acquiring HCV infection due to repeated exposure to blood-borne pathogens, need for intravenous access, catheter manipulation, and close proximity to other patients.^7,8 The prevalence of HCV infection in hemodialysis units ranges from 10% to as high as 59% depending on the geographic area.^9,10 At the same time, HCV infection is itself an independent risk factor for CKD and end-stage renal disease (ESRD).^11
–13 In patients already diagnosed with CKD, the estimated 5-year cumulative incidence rate of progressing to ESRD is nearly 15% higher for HCV-infected individuals when compared to the general population.¹³ Importantly, HCV-positive patients with ESRD on dialysis appear to have higher rates of all-cause mortality, including liver-related death, than HCV-negative patients.¹⁴

Due to the intimate relationship between liver and kidney disease in HCV infection, treatment options for HCV-positive patients at any stage of CKD are essential. Over the past decade, the landscape of treatment options for HCV has been transformed. Interferon (IFN) and ribavirin (RBV), which were minimally effective and difficult to administer due to side effect profiles, were once the mainstays of therapy. Plasma concentrations and toxicity of IFN and RBV significantly increase in renal dysfunction, requiring dose reductions, frequent monitoring of hemoglobin, and potentially the addition of erythropoietin to offset severe anemia.¹⁵ Recently, the use of direct-acting antiviral (DAA) combinations have allowed for the advent of IFN-sparing treatment regimens with shorter durations and minimal side effects. These drugs have few contraindications to use, making more patients eligible for treatment than ever before.

Despite such advances, patients with renal impairment remain a unique patient population as identified by the American Association for the Study of Liver Diseases (AASLD), Infectious Disease Society of America (IDSA), and International Antiviral Society (IAS-USA) HCV treatment guidelines¹⁶ due to limited data surrounding recently approved regimens in regard to safety and efficacy in CKD (Table 1). Guidelines¹⁷ released by the European Association for the Study of Liver (EASL) in March 2015 recommend using these drugs with extreme caution in patients with severe renal disease and in extreme life-threatening situations only for patients on dialysis until more data are available.

Table 1.

AALSD/IDSA/IAS-USA HCV Treatment Guidelines for Unique Patient Populations: Patients With Renal Impairment.

Moderate renal impairment (CrCl 30-80 mL/min)

No dosage adjustment is required when using DCV, fixed dose combination of LDV (90 mg)/SOF (400 mg), or fixed dose combination of PTV (150 mg)/r (100 mg)/OBV (25 mg) with (or without for HCV genotype 4 infection) twice-daily dosed DBV (250 mg), SMV, or SOF to treat or retreat HCV in appropriate genotypes (class I, level A).

CrCl <30 mL/min for those who do not have cirrhosis but for who the urgency to treat (or retreat) is high and renal transplant is not an immediate option

For HCV genotype 1a infection, daily fixed dose combination of PTV (150 mg)/r (100 mg)/OBV (25 mg) plus twice-daily dosed DBV (250 mg) with RBV at reduced doses (200 mg thrice weekly to daily) is recommended (class IIb, level B).^a
For HCV genotype 1b infection, daily fixed dose combination of PTV (150 mg)/r (100 mg)/OBV (25 mg) with twice-daily dosed DBV (250 mg) is recommended (class IIb, level B).^b
For HCV genotype 4 infection, daily fixed dose combination of PTV (150 mg)/r (100 mg)/OBV (25 mg) is recommended (class IIb, level B).^b
For HCV genotype 2, 3, 5, or 6 infection, PEG-IFN and dose-adjusted RBV are recommended if treatment is necessary and transplantation cannot be performed (class IIb, level B).
For RBV intolerant or ineligible, consultation with an expert is recommended to assess the appropriateness of a SOF-containing regimen due to limited safety and efficacy data in this setting (class IIb, level C).

Abbreviations: AASLD/IDSA/IAS-USA, American Association for the Study of Liver Diseases/Infectious Disease Society of America/International Antiviral Society; HCV, hepatitis C virus; CrCl, creatinine clearance; DCV, daclatasvir; LDV, ledipasvir; SOF, sofosbuvir; PTV, paritaprevir; r, ritonavir; OBV, ombitasvir; DBV, dasabuvir; SMV, simeprevir; PEG-IFN, pegylated interferon; RBV, ribavirin.

^aCaution is recommended due to the potential for hemolysis in this population. RBV should be restricted to those with a baseline hemoglobin concentration above 10 g/d and should be discontinued if hemoglobin level declines by more than 2 g/dL, despite the use of erythropoietin.

^bRecommendation is based on limited data on safety and efficacy.

The objective of this review is to evaluate the efficacy and safety of recent DAAs in severe renal impairment (creatinine clearance <30 mL/min) or ESRD, including dialysis. The pharmacology, pharmacokinetic parameters, and renal dosing adjustments are briefly described for each currently available agent as well as several upcoming regimens.

Study Selection

For this review, the prescribing information of each second-generation DAA approved by the Food and Drug Administration (FDA) was consulted to obtain phase I to II pharmacokinetic studies used to support present-day renal dosing recommendations. Further studies, including the ongoing HCV-TARGET trial, were identified using sections of current AASLD/IDSA/IAS-USA¹⁶ and EASL HCV treatment guidelines¹⁷ pertaining to patients with renal impairment. As data are limited, no studies were excluded. All abstracts presented at the 2014 AASLD and 2015 EASL conferences were evaluated for inclusion, with all abstracts pertaining to DAA use in renal impairment selected for this article.

Sofosbuvir

Sofosbuvir (SOF) is an NS5B nucleotide RNA polymerase inhibitor. Following oral administration, SOF is absorbed and reaches peak concentrations at approximately 0.5 to 2 hours. The prodrug SOF is converted by the hepatic system into the pharmacologically active metabolite, GS-461203. The drug undergoes further metabolism to produce the predominant circulating metabolite, GS-331007, via dephosphorylation. GS-331007 lacks anti-HCV activity and reaches peak concentrations in 2 to 4 hours. SOF is roughly 61% to 65% bound to plasma proteins, whereas protein binding of GS-331007 is minimal. Elimination is primarily renal with approximately 80% of the drug recovered in the urine following the administration of 1 oral dose of 400 mg. The major metabolite recovered is GS-331007. SOF and GS-331007 have terminal half-lives of 0.4 and 27 hours, respectively. It is estimated that 18% of the drug is removed following a 4-hour hemodialysis session.¹⁸ Due to the extensive renal elimination, dosing SOF in renal impairment is an area of uncertainty as the drug and its metabolite may accumulate.

SOF was studied in HCV-negative subjects with varying degrees of renal dysfunction. Mild, moderate, and severe renal impairment were defined with estimated glomerular filtration rates (estimated glomerular filtration rate [eGFR] mL/min/1.73m²) of >50 to <80, >30 to <50, and <30. Those who required dialysis were considered ESRD. In comparison to healthy subjects with normal renal function, those with mild, moderate, and severe renal impairment experienced increases in SOF area under the curve (AUC_0-inf) of 61%, 107%, and 171%. Increases in GS-331007 were 55%, 88%, and 451%. When comparing subjects with ESRD to those with normal kidney function, the AUC_0-inf of SOF was 28% higher, while GS-331007 was increased by 1280%.¹⁹ While the concentrations of SOF and its GS-331007 metabolite are clearly increased in renal impairment, the effects of these elevated concentrations are unknown. Based on the observed pharmacokinetics, no dose adjustment is recommended for mild or moderate renal impairment (creatinine clearance [CrCl] >30 mL/min). There are currently no dosing recommendations in severe renal impairment, or ESRD as the safety, efficacy, and optimal dosing strategy has not yet been fully established. Since the approval of SOF, new data and pharmacokinetic studies have surfaced to allow greater insight on IFN-free treatment in renal impairment with the use of SOF-containing regimens.

In 2014, Gane et al^19,20 reported on the safety, efficacy, and pharmacokinetics of SOF in severe renal impairment. In this open-label study, 10 patients with severe renal impairment and ESRD on dialysis infected with genotype (GT) 1 or 3 HCV received low-dose SOF (200 mg) + RBV 200 mg by mouth daily for 24 weeks with sustained virological response (SVR) at 12 weeks after treatment (SVR12) as the primary end point. The results were compared to the historical cohort in the PHOTON-1 study, which was comprised of HIV/HCV coinfected patients with a CrCl >60 mL/min treated with full dose SOF (400 mg) + RBV 1000 to 1200 mg by mouth daily for 12 to 24 weeks. SVR12 was achieved in 40% of patients (including the 1 patient with GT 3), differing from the PHOTON-1 study which resulted in SVR12 rates of 76% (87 of 114) in GT 1.²¹ Although SVR12 rates differed from the historical cohort, rapid virologic decline was similar. By week 4 of treatment, 9 of 10 patients had an undetectable HCV RNA level. Despite this initial response, 5 patients relapsed. When comparing the serum concentrations, low-dose SOF in severe renal impairment resulted in similar concentrations to those observed with full-dose SOF in patients with normal kidney function. GS-331007 had approximately a 4-fold exposure increase, however, the adverse drug reactions (ADRs) reported were minimal (Figure 1). This study highlighted the need for a greater understanding of SOF treatment in renal impairment as SVR12 rates were unexpectedly low, even with rapid virologic decline and adequate SOF concentrations.

Figure 1.

SOF and GS-331007 pharmacokinetics in severe renal impairment. RI indicates renal impairment; SOF, sofosbuvir. Adapted from Gane et al.²⁰

At times, immediate HCV treatment is necessary, specifically in cases of liver and/or kidney transplants. Bhamidimarri et al reported 4 cases of urgent HCV treatment with SOF in GT 1-infected individuals with severe renal impairment.^22,23 Patients 1 and 2 had cirrhosis with ESRD (on dialysis) undergoing evaluation for a combined liver–kidney transplant, patient 3 was a liver transplant recipient who developed fibrosing cholestatic hepatitis with ascites and severe renal impairment requiring dialysis, and patient 4 was a post liver–kidney transplant recipient who developed acute antibody-mediated rejection of the kidney. Patients 1, 2, and 4 were treated with SOF 400 mg every other day plus simeprevir (SMV) 150 mg daily, while patient 3 was treated with SOF 400 mg daily plus RBV 200 mg every other day. Only patient 2 did not achieve SVR12. Additionally, patient 3 had normalization of hepatic function and no longer required dialysis following completion of therapy. These cases indicate that combining SOF with a second DAA, which does not undergo renal elimination, may be beneficial in those with severe kidney impairment.

To further investigate this concept, Czul et al went on to research the efficacy and safety of low-dose SOF in combination with SMV.²⁴ In this study, 19 patients with ESRD (GFR <15 mL/min/1.73 m²) requiring dialysis were treated with SOF 200 mg daily plus SMV 150 mg daily. In a per-protocol analysis, 14 (88%) of 16 achieved SVR12. The 2 relapsers both had compensated cirrhosis, a baseline HCV RNA level of 11 million IU/mL, and had previously failed treatment. Although studies of larger sample sizes may help validate these findings, reducing the dose of SOF in renal dysfunction resulted in high SVR12 rates when administered in conjunction with SMV.

In an ongoing observational cohort study, HCV-TARGET, the real-world safety and efficacy of DAAs are being assessed. This study is comprised of 43 academic and 13 community medical centers in which data are being prospectively collected. Interim results for SOF-containing regimens in varying renal functions were presented at the 2015 EASL International Liver Conference.²⁵ Patients were divided into groups based on eGFR (mL/min/1.73 m²) of >60, 46 to 60, 31 to 45, and <30. For eGFR <30mL/min/1.73 m², the regimens utilized were SOF/SMV (58%), SOF/RBV(26%), SOF/SMV/RBV (11%), and SOF/PEG/RBV (5%) with preliminary SVR12 rates of 80%, 100%, 100%, and 100%, respectively. To date, SVR rates in SOF-containing regimens do not seem to be influenced by baseline renal function. Patients with renal impairment did have higher rates of anemia and changes in serum creatinine; however, discontinuations due to ADRs were similar among all groups.

The continuing results from the HCV-TARGET cohort, along with the other data reviewed above (Table 2), provide optimistic and insightful information on SOF-containing regimens for the treatment of HCV in those with renal impairment.

Table 2.

Summary of SOF Data in Renal Impairment.

Study	Regimen	N	Cirrhosis included	Dialysis included	SVR12 rates
Gane et al ^19,20	SOF 200 mg daily + RBV 200 mg daily × 24 weeks^a	10	N	Y	40%
Bhamidimarri et al^22,23	SOF 400 mg every other day + SMV 150 mg daily^b	3	Y	Y	75%
Bhamidimarri et al^22,23	SOF 400 mg daily + RBV 200 mg every other day^b	1	Y	Y	0%
Czul et al²⁴	SOF 200 mg daily + SMV 150 mg daily × 12-24 weeks	19	Y	Y	88%
Saxena et al²⁵	SOF/SMV^c	10	Y	Y	80%
	SOF/RBV^c	4			100%
	SOF/SMV/RBV^c	2			100%
	SOF/PEG/RBV^c	10			100%

Abbreviations: SVR, sustained virologic response; SOF, sofosbuvir; RBV, ribavirin; SMV, simeprevir; PEG, pegylated interferon; Y, yes; N, no; eGFR, estimated glomerular filtration rate; SVR12, sustained virological response at 12 weeks.

^aOnly results for subjects with eGFR <30 mL/min reported.

^bTreatment duration not reported.

^cTreatment doses and duration of therapy not reported.

Simeprevir

The HCV NS3/4A protease inhibitor SMV reaches peak plasma concentrations in 4 to 6 hours. Protein binding of SMV is extensive (>99.99%) and was shown to be unaltered in those with renal and/or hepatic impairment. The drug undergoes oxidative metabolism by the cytochrome P450 (CYP450) 3A enzyme, with elimination occurring primarily through biliary excretion. As renal elimination is nonsignificant, there is little concern when using SMV for those with renal impairment. In a pharmacokinetic analysis of HCV-infected subjects with mild and moderate kidney dysfunction, CrCl did not seem to influence the pharmacokinetics of SMV. Although the safety and efficacy have not been studied in ESRD, including those requiring dialysis, SMV exposure is not expected to be clinically altered in this setting.²⁶

Ledipasvir

Ledipasvir (LDV), an HCV NS5A protein inhibitor, is only available as a combination tablet with SOF. Peak concentrations of LDV occur within 4 to 4.5 hours after 1 dose of 90 mg, with >99.8% bound to plasma proteins. LDV undergoes oxidative metabolism through an unknown mechanism, as metabolism by the CYP450 system has not been identified. Following a 90 mg dose, approximately 70% of unchanged LDV is found in the feces, indicating that biliary excretion is the major route of elimination. The pharmacokinetics of the drug was studied in HCV-negative subjects with severe renal impairment (eGFR <30 mL/min). No clinically significant differences were found when comparing these patients to healthy subjects with normal kidney function. However, because LDV is coformulated with SOF, concern in renal impairment remains. The dosing recommendations for SOF, therefore, pertain to the SOF–LDV combination as well.²⁷

Daclatasvir

Daclatasvir (DCV), another HCV NS5A inhibitor, reaches peak plasma concentrations within 2 hours of administration and has an oral bioavailability of 67%. It is highly protein bound (>99%) and hepatically metabolized via CYP3A. While DCV exhibits only 5% renal clearance, the pharmacokinetic profile displays slight changes in renal dysfunction.^28,29 In a study evaluating the pharmacokinetics of DCV in HCV-negative subjects, the predicted AUC_0-inf was estimated to be 26%, 60%, and 80% higher in subjects with a CrCl of 60, 30, and 15 mL/min, respectively, when compared to those with a CrCl of 90 mL/min. Similarly, the predicted AUC_0-inf of unbound DCV was 18%, 39%, and 51% higher for subjects with a CrCl of 60, 30, and 15 mL/min. Patients with ESRD requiring hemodialysis had a 27% increase in DCV AUC_0-inf and a 20% increase in unbound AUC_0-inf.³⁰ The observed differences in DCV concentration in patients with renal impairment are within the normal range of variability and have not been shown to result in increased adverse effects, as reported by the study authors.³⁰ Therefore, renal dose adjustment of DCV is not required.

Ombitasvir, Paritaprevir, Ritonavir, and Dasabuvir

Ombitasvir (OMB), an HCV NS5A inhibitor, paritaprevir (PTV), an HCV NS3/4A protease inhibitor, and ritonavir (RTV/r), a CYP3A inhibitor, are available as a combination tablet administered with dasabuvir (DAS), an HCV nonnucleoside NS5B polymerase inhibitor. The regimen may be administered with or without RBV based on AALSD/IDSA/IAS-USA guideline¹⁶ recommendations. OMB/PTV/r and DAS have a mean T_max of 4 to 5 hours after oral administration. Absolute bioavailability of DAS is 70%, however, the bioavailability of the other agents has not been evaluated. OMB is metabolized by amide hydrolysis, and oxidative metabolism, while PTV, RTV, and DAS are metabolized by various enzymes in the CYP450 system. The drug combination is primarily excreted in the feces, although minimal elimination into the urine does occur.³¹

Effects of renal impairment on the pharmacokinetics of OMB, PTV, RTV, and DAS were found to vary by individual drug when evaluated in HCV-negative subjects. Exposure to OMB remains unchanged in patients with renal impairment. Exposure to PTV, RTV, and DAS increases, however, the difference is not expected to be clinically relevant, and no dosage adjustment is required for patients with mild, moderate, or severe renal impairment.³¹

While this drug combination has been studied in renal impairment, there is minimal data available regarding its use in patients requiring dialysis. The ongoing RUBY-1 study of treatment-naive, GT 1 HCV-infected patients was designed to further investigate its use in ESRD. Of the 20 patients enrolled in the study, 13 required hemodialysis. Preliminary data analysis showed the drug combination to be well tolerated, with no serious treatment-related adverse events and no significant changes in renal function as a result of treatment. Pharmacokinetic data, available for 17 of the 20 study patients, also suggested that trough drug levels in study patients with CKD stage 4 or 5 were similar to trough drug levels observed in patients with normal renal function in 5 previous phase III trials. Mean C_trough values are reported in Table 3.³² No virologic failures had been observed at the time of presentation, although only SVR at 4 weeks after treatment (SVR4) results were available for reporting.

Table 3.

RUBY-1: Mean Trough Concentrations in Patients With Severe Renal Impairment Versus Patients With Normal Renal Function in 5 Previous Phase III Trials.³²

	Mean C_trough, ng/mL
	RUBY-1	Phase III trials
OMB	36	24-30
PTV	36	16-29
RTV	50	40-53
DAS	253	177-270

Abbreviations: DAS, dasabuvir; OMB, Ombitasvir; PTV, paritaprevir; RTV, ritonavir.

Any differences in drug concentration observed in this study were considered insignificant, consistent with current dosing recommendations. Management of patients with ESRD requiring hemodialysis remains uncertain, as the study is still ongoing and evaluates only a small number of participants.³²

Future Therapies

Grazoprevir/Elbasvir

Grazoprevir (GZR), an NS3/4A inhibitor, in combination with elbasvir (EBR), an NS5A inhibitor, for the treatment of HCV GT 1 was recently evaluated in an open-label trial, where more than 75% of study participants were hemodialysis dependent.³³ Both treatment-naive and treatment-experienced patients were included, with a small number of participants (6%) having compensated cirrhosis. The results of the immediate treatment group showed SVR12 rates of 99% due to 1 noncirrhotic patient who experienced viral relapse after completing 12 weeks of therapy. No renal dose adjustment was required, and the once-daily treatment was seen to be well tolerated in this study regardless of CKD stage.

Daclatasvir/Asunaprevir/Beclavubir

A pharmacokinetics study was performed in HCV-negative individuals to determine the impact of renal impairment on daclatasvir, asunaprevir (NS3/4A inhibitor), and beclavubir (nonnucleoside NS5B inhibitor) administered twice daily as a 30 mg/200 mg/75 mg fixed dose combination (DCV-TRIO).³⁴ Renal excretion represents <10% elimination for each of these agents. The study was completed by 39 subjects, 8 of which were on hemodialysis. Although C_max and AUC_tau were suggested to increase with decreasing CrCl for all 3 drugs, the regimen was concluded to be well tolerated across all levels of renal impairment. No renal dosing adjustment is recommended except for subjects with CrCl ≤15 mL/min not on hemodialysis, where daily dosing of DCV-TRIO is recommended instead of twice daily.

Summary

Renally impaired patients, particularly those with CrCl <30 mL/min, have historically been difficult to treat, as safe and highly efficacious HCV therapies were unavailable for this population prior to the development of IFN-sparing DAA combination regimens. Table 4 provides a summary of dosing and administration recommendations for each FDA-approved DAA discussed here. Although evidence for the use of low-dose SOF with CrCl <30 mL/min has been presented, we recommend awaiting the results of the HCV-TARGET study prior to use in this population except in life-threatening situations requiring immediate treatment. In the dialysis setting, there is not currently a complete treatment regimen which may be safely utilized. The results of the RUBY-1 study may help to fill this clinical gap if PTV/OMB/RTV with DAS is shown to achieve acceptable SVR12 rates. Additionally, non-FDA approved regimens GZR/EBR and DCV-TRIO appear to be safe for use in the dialysis setting. These study results and future therapies are highly anticipated. For now, degree of renal impairment should remain a significant comorbidity to consider when choosing the ideal HCV treatment regimen.

Table 4.

Summary of DAAs.

Drug	Dose	Administration	Renal impairment	Hepatic impairment
Sofosbuvir	400 mg by mouth daily	With or without food	Not recommended if eGFR <30 mL/min/1.73 m²	No dose adjustment necessary
Simeprevir	150 mg by mouth daily	With food	No dose adjustment necessary	Not recommended with CTP class B or C disease
Ledipasvir	90 mg by mouth daily	With or without food	No dose adjustment necessary^a	No dose adjustment necessary
Daclatasvir	60 mg by mouth daily	With or without food	No dose adjustment necessary	No dose adjustment necessary
Ombitasvir^b	12.5 mg by mouth daily	With food	No dose adjustment necessary^c	CTP class B disease: Not recommended CTP class C disease: Contraindicated
Paritaprevir^b	75 mg by mouth daily
Dasabuvir^b	250 mg by mouth twice daily

Abbreviations: eGFR, estimated glomerular filtration rate; ESRD, end-stage renal disease; CPT, Child-Turcotte-Pugh; DAA, direct-acting antiviral.

^aAvailable as a coformulated tablet with sofosbuvir. Not recommended to use if eGFR <30mL/min/1.73 m².

^bOmbitasvir, paritaprevir, and ritonavir are available in fixed dose combination tablets packaged with dasabuvir tablets.

^cAuthors recommend avoiding this regimen in dialysis until more data are available.

Footnotes

Declaration of Conflicting Interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.

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. C-SURFER: Grazoprevir plus Elbasvir in Treatment-Naive and Treatment-Experienced Patients with Hepatitis C Virus Genotype 1 Infection and Chronic Kidney Disease. Paper presented at: 2015 Annual Meeting of the European Association for the Study of the Liver; April 22–26, 2015: Vienna, Austria.

34.

Adamczyk

Sims

Hesney

. The Effect of Renal Impairment on Multiple-Dose Pharmacokinetics of the Fixed-Dose Combination of Daclatasvir/Asunaprevir/Beclavubir. Paper presented at: 2015 Annual Meeting of the European Association for the Study of the Liver; April 22–26; 2015: Vienna, Austria.