Table 1.

Recent data on HCV direct-acting agent use in renal patients [74]

Drug class	Metabolism and elimination	Regular daily dosage	Dosage in CKD or dialysis	Published dataa
Sofosbuvir [75] NS5B inhibitor	Prodrug: extensive intracellular metabolism (pharmacologically active metabolites GS-461203 via phosphorylation) Dephosphorylated into inactive metabolite GS-331007 Elimination: kidney (78% GS-331007 and 3.5% sofosbuvir); feces (15%)	400 mg once daily	No drug dosage adaptation if GFR >30 ml/min/1.73 m2	After one single dose of 400 mg, an increase AUC (171% and 451%, respectively for SOF and GS-331007) was observed in non-HCV-patients with severe renal impairment [75] In HCV non-cirrhotic, treatment-naïve patients with eGFR <30 ml/min/1.73 m2, a fourfold exposure to GS-331007 with 200 mg SOF daily was observed. Two patients discontinued because of AE (grade 2 fatigue and grade 3 renal failure and pneumonia). One initiated dialysis while under treatment. Overall, 2 grade 3 and 1 grade 4 increase in creatinine under treatment. SOF exposure was 136% and GS-331007 603% compared to HCV patients without renal failure [76] 1890 HCV patients in real-life conditions (longitudinal target study) received SOF regimens (10% of which exhibited CKD and 3% needed dialysis), 42% cirrhotic. Serious adverse events were highest in patients with GFR 31–45 ml/min/1.73 m2 (23%). Compared to patients with mild renal impairment, those with severe impairment more frequently experienced anemia, acute renal failure and serious adverse effects even in ribavirin-free regimen patients [77] SOF 400 mg plus SIM 150 mg daily for 12 weeks in 17 dialysis or stage 4 CKD patients with hepatitis C (47% cirrhotic): treatment was overall well tolerated with no treatment discontinuations reported. Four (24%) patients reported mild AE [73]
Simeprevir NS3/4A protease inhibitor	Metabolism: hepatic; saturable, first pass Elimination: biliary excretion (91%); renal (<1%)	150 mg oral daily with food	No drug dosage adaptation if GFR >30 ml/min/1.73 m2	In HCV-negative patients with severe renal impairment (GFR <29 ml/min/1.73 m2) receiving SIM, Cmax and AUC24 h were 34 and 62% higher compared to patients with normal renal function [78]
Ledipasvir NS5A inhibitor (co-formulation with Sofosbuvir)	Metabolism: hepatic, minimal, not CYP450 mediated Elimination: feces (70%); urine (<1%)	90 mg oral daily	No drug dosage adaptation if GFR >30 ml/min/1.73 m2	In HCV-negative patients with severe renal impairment (GFR <30 ml/min/1.73 m2) receiving LED (single dose) no differences in pharmacokinetics parameters were found [79]
Daclatasvir NS5A replication complex inhibitor	Metabolism: hepatic Elimination: feces (88%); urine (7%)	60 mg oral daily	No drug dosage adaptation if GFR >30 ml/min/1.73 m2	A single dosage in HCV-negative individuals with CKD or ESRD showed a 60 and 80% higher AUC of DCV, respectively) In patients in dialysis; no serious adverse events were observed despite a 27% increase in AUC compared to matched healthy controls [80]
Paritaprevir/ritonavir/ombitasvir/dasabuvir NS3/4A HCV protease inhibitor/ HIV protease inhibitor/ NS5A inhibitor + non-nucleoside HCV polymerase inhibitor	Metabolism: hepatic Elimination: feces (>86%); renal (11.3%)	Two tablets of 75 mg/50 mg/12.5 mg oral daily + 250 mg twice daily	No drug dosage adaptation if GFR >30 ml/min/1.73 m2	A single-dose pharmacokinetic study showed no clinically significant changes in any of the four drugs in severe renal impairment patients despite increase in AUC24hour [81, 82] Ruby-1 trial: 20 patients naïve, HCV, non-cirrhotic, with advanced CKD (stage 4, n = 7) or dialysis (n = 13); most adverse events were mild to moderate; no study discontinuation, no treatment-related serious adverse event [83]
Grazoprevir 2nd generation HCV NS3/4A protease inhibitor Elbasvir NS5A inhibitor	Elimination: <1% of both drugs renally eliminated	GZR 100 mg and EBR 50 mg co-formulation	No drug dosage adaptation in case of renal failure	Healthy volunteers with severe renal impairment and dialysis; the treatment showed 65% and 86% increase in AUC, respectively for GZR and EBR. Dialysis patients showed same GZR/EBR exposure as matched subjects with normal renal function [84] Placebo-controlled trial (C-Surfer study) 224 patients were randomized to immediate or deferred treatment with GZR/EBR. All patients on inclusion had a GFR <30 ml/min or in dialysis. The overall safety of the HCV therapy was very good with no discontinuation of study drug due to adverse events. AEs such as headache, nausea, diarrhea, etc., were equally distributed between patients receiving study drug versus placebo [85]

HCV hepatitis C virus, CKD chronic kidney disease, ESRD end-stage renal disease, AE adverse event, GFR glomerular filtration rate, SOF sofosbuvir, LED ledipasvir, SIM simeprevir, DCV daclatasvir, GZR grazoprevir, EBR elbasvir

^aMost studies were designed to evaluate efficacy as a primary endpoint—low number of patients