Interferon-free regimens in patients with hepatitis C infection and renal dysfunction or kidney transplantation

Table 1 Main characteristics of the approved direct acting antivirals that are currently used for the treatment of hepatitis C

DAA (commercial name), dose	Category	Dose adjustment in renal impairment	Antiviral activity	CNIs co-administration
Sofosbuvir (Sovaldi®), tablet 400 mg, once daily	Nucleotide analogue NS5B polymerase inhibitor	Contraindicated in patients with GFR < 30 mL/min	Genotypes 1-6	No change
			High genetic barrier
Simeprevir (Olysio®), tablet 150 mg, once daily with food	NS3/4A protease inhibitor	No change in renal impairment	Genotypes 1,4	Contraindicated with cyclosporine
			Low genetic barrier
Daclatasvir (Daklinza®), tablet 60 mg, once daily	NS5A inhibitor	No change in renal impairment	Genotypes 1, 2, 3, 4	No change
			Low genetic barrier
Ledipasvir/sofosbuvir/(Harvoni®), tablet 90/400 mg, once daily	NS5A inhibitor + nucleotide analogue NS5B polymerase inhibitor	Contraindicated in patients with GFR < 30 mL/min	Genotypes 1, 4, 5, 6	No change
			High genetic barrier
Ombitasvir/paritaprevir/ritonavir (Viekirax®), tablet 12.5/75/50 mg, two once daily with food	NS5A inhibitor + NS3/4A protease inhibitor boosted by ritonavir boosted	No change in renal dysfunction	Genotypes 1, 4	Cyclosporine: 20% of pretreatment total daily dose; tacrolimus: 0.2 mg/72 h or 0.5 mg once weekly
			Genetic barrier depending on HCV genotype
Dasabuvir (Exviera®), tablet 250 mg, every 12 h	Non-nucleos(t)ide analogue NS5B polymerase inhibitor	No change in renal dysfunction	Genotype 1
			Low genetic barrier
Elbasvir/Grazoprevir (Zepatier®), tablet 100/50 mg, once daily	NS5A inhibitor + NS3/4A inhibitor	No change in renal dysfunction	Genotypes 1,4	Co-administration increases tacrolimus concentrations
Velpatasvir/sofosbuvir/(Epclusa®), tablet 100/400 mg, once daily	NS5A inhibitor + nucleotide analogue NS5B polymerase inhibitor	Contraindicated in patients with GFR < 30 mL/min	Genotypes 1-6	No change
			High genetic barrier

CNI: Calcineurin inhibitor; DAA: Direct acting antiviral; GFR: Glomerular filtration rate.

Table 2 Studies of interferon free regimens for treatment of hepatitis C virus patients with severe renal disease or under hemodialysis

Ref.	Patients, n	Patient characteristics	Regimen: Patients number (dose of sofosbuvir)	Sustained virological response at 12 wk, n/N	Adverse events, n
Pockros et al[25]	20	GT1: 20 patients (1a: 13)	3D ± RBV: 20	18/20 (EOT-VR: 20/20)	Death from drug unrelated cause (cardiac arrest at 14 d after the end of therapy): 1
Gomez et al[26]	33	GT1: 29 (1a: 6)	3D ± RBV: 33	31/31	Serious adverse events: 5 (all unrelated to study drugs)
		Age: 57 yr
Basu et al[27]	36	GT1: 36 (1a: 23)	3D ± RBV: 36	34/36	No serious adverse event
Roth et al[28]	122	GT1: 122 patients	Elbasvir/grazoprevir: 122	115/122	Serious adverse events: 16
Czul et al[29]	28	GT1: 26 (1a: 16)	SOF + SMV: 26	21/25	Encephalopathy: 1
		Age: 58 yr	SOF + RBV: 2 (200 mg/eod-400 mg/d)		Uncontrolled diarrhea: 1
Beinhardt et al[30]	15	GT1: 11 patients	SOF + DCV: 9	1/1 (EOT-VR: 5/5)	Pancytopenia at week 7: 1 (change SOF from every 24 h to every 48 h)
		Age: 52 yr	SOF + SMV: 5
			SMV + DCV: 1 (400 mg/d)
Dumortier et al[31]	50	GT1: 28 patients	SOF + RBV: 7	24/26 (EOT-VR: 50/50)	No serious adverse event
		Age: 60 yr	SOF + RBV + PEG-IFN: 2
			SOF + DCV ± RBV: 30
			SOF + SMV ± RBV: 11
Gane et al[32]	10	GT1: 9 (1a: 7)	SOF + RBV: 10 (200 mg/d)	4/10	Serious adverse events: 2 (diabetic acidosis, angina)
		Age: 62 yr
Nazario et al[33]	40	GT1: 26 (1a: 26)	SOF + LDV: 9	29/29	Drug discontinuation: 1 (unknown reason)
		Age: 57 yr	SOF + DCV: 2
			SOF + SMV: 29 (400 mg/d)
Baliellas et al[34]	21 (10 on hemodialysis)	GT1: 20 patients (1a: 2)	SMV + DCV: 12	17/19	No serious adverse event
		Age: 57 yr	SMV + DCV + RBV: 9
Moreno et al[35]	42	GT1: 25 (1a: 8)	SOF + RBV: 5	32/42	Drug discontinuation: 11
		Age: 54 yr	LDV/SOF: 8
			SOF + DCV: 14
			SOF + SMV: 3
			SMV + DCV: 12
Saxena et al[36]	19	GT1: 16 (1a: 8)	SOF + SMV + RBV: 2	SOF + SMV + RBV: 2/2	Therapy discontinuation: 1
			SOF + SMV: 11	SOF + SMV: 8/10	Serious adverse events: 3
			SOF + RBV: 5	SOF + RBV: 4/4
			SOF + RBV + PEG-IFN: 1 (400 mg/d)	SOF + RBV + PEG: 1/1
Martin et al[37]	10	GT1: 8 patients	SOF + RBV: 10 (400 mg/d)	6/10	Acute respiratory failure - drug discontinuation: 1, hematemesis: 1
		Age: 58 yr

DCV: Daclatasvir; EOT-VR: End of treatment virological response; GT: Genotype; RBV: Ribavirin; LDV: Ledipasvir; PEG-IFN: Pegylated interferon-alfa; SMV: Simeprevir; SOF: Sofosbuvir; 3D: Ombitasvir/paritaprevir/ritonavir plus dasabuvir; eod: Every other day; HCV: Hepatitis C virus.

Table 3 Studies of interferon-free regimens for treatment of hepatitis C virus positive kidney transplant recipients

Ref.	Patients, n	Patient characteristics	Regimen: Patients number	Sustained virological response at 12 wk, n/N	Adverse events, n
Huard et al[39]	17	GT1: 16 patients (1a: 5) Age: 65 yr	SOF + RBV: 17 (400 mg/d)	1/6	Therapy discontinuation: 4 (3 due to pruritus, myalgia, anemia, 1 unclarified) Anemia: 8
Lin et al[40]	15	GT1: 14 (1a: 10) Age: 55.8 yr	SOF + SMV ± RBV: 12 (SOF + SMV: 9)	13/15	No serious adverse events under therapy (1 died by massive hemorrhage 4 wk after therapy) Proteinuria: 2
			SOF + RBV: 2 SOF + LDV: 1		Bradycardia under amiodarone (pacemaker placement): 1
Bhamidimarri et al[41]	14	GT1: 14 (1a: 12)	SOF + LDV: 13	13/14	No serious adverse events
		Age: 54 yr	(in 9 plus RBV)		Therapy discontinuation: 1
			SOF + SMV: 1		Anemia: 7
Hussein et al[42]	3	GT4: 3	SOF + RBV	3/3	No serious adverse events
			(400 mg/d)
Sawinski et al[43]	20	GT1: 17 (1a: 7)	SOF + SMV: 9	20/20	No serious adverse events
		Age: 57 yr	SOF/LDV: 7
			SOF + RBV: 3
			SOF + DCV: 1
			(400 mg/d)
Moreno et al[44]	12	GT1: 11 (1a: 4)	SOF + SMV: 1	11/12	Therapy discontinuation: 1
		Age: 53 yr	SOF/LDV: 8
			SOF + DCV: 3
			(400 mg/d)
El-Halawany et al[45]	11	GT1: 10 (1a: 10)	SOF + SMV: 2	10/11	No serious adverse events
		Age: 57.6 yr	SOF/LDV: 8
			SOF + RBV: 1
Londono et al[46]	74	GT1: 61 (1a: 6)	SOF/LDV ± RBV: 37	45/46	Rejection episodes: 3
		Age: 54 yr	SOF + DCV ± RBV: 15
			SOF + SMV ± RBV: 6
			SMV + DCV ± RBV: 7
			SOF + RBV: 4
			3 “D” or 2 “D”: 5
Colombo et al[47]	114	GT1: 104	SOF/LDV	112/114	Therapy discontinuation: 1
					Serious adverse events: 12
Reddy et al[48]	50		SOF/LDV ± RBV: 42	10/10	Rejection episode: 1
			SOF + DCV ± RBV: 1
			3 “D”: 7

DCV: Daclatasvir; GT: Genotype; RBV: Ribavirin; LDV: Ledipasvir; PEG-IFN: Pegylated interferon-alfa; SMV: Simeprevir; SOF: Sofosbuvir; 3D: Ombitasvir/paritaprevir/ritonavir plus dasabuvir; 2 “D”: Ombitasvir/paritaprevir/ritonavir.

Table 4 Recommended regimens from the American Association for the Study of Liver Diseases and European Association for the Study of the Liver for patients with chronic hepatitis C and severe renal impairment (glomerular filtration rate < 30 mL/min) who need urgent hepatitis C virus therapy and renal transplantation is not an immediate option

HCV genotype	AASLD recommended regimen	EASL recommended regimen3
1	Elbasvir/grazoprevir for 12 wk (for 1a or 1b) or ombitasvir/paritaprevir/ritonavir plus dasabuvir1 (for 1b) for 12 wk	Elbasvir/grazoprevir or ombitasvir/paritaprevir plus dasabuvir (for 1a or 1b), for 12 wk (plus RBV 200 mg/d for 1a if the haemoglobin level is > 10 g/dL at baseline)
2, 3, 5 or 6	Pegylated interferon-alfa plus dose-adjusted ribavirin (200 mg daily)2	Sofosbuvir/velpatasvir or sofosbuvir plus daclatasvir (plus ribavirin if the haemoglobin level is > 10 g/dL at baseline for genotype 3) for 12 wk (or for 24 wk without ribavirin for genotype 3)4
4	Elbasvir/grazoprevir for 12 wk	Elbasvir/grazoprevir for 12 wk or ombitasvir/paritaprevir plus dasabuvir plus ribavirin (if the haemoglobin level is > 10 g/dL at baseline) for 12 wk

¹For HCV genotype 1a: Ombitasvir/paritaprevir/ritonavir plus Dasabuvir plus ribavirin at reduced doses (200 mg thrice weekly to daily) may be also used;

²Ribavirin should be discontinued when hemoglobin decreases by > 2 g/dL despite use of erythropoietin (or in case of severe anaemia (haemoglobin < 8.5 g/dL according to EASL guidelines);

³According to EASL guidelines: (1) antiviral therapy is indicated in those without an indication for kidney transplantation otherwise after kidney transplantation may be preferred; and (2) sofosbuvir should be used with caution (no dose recommendation can currently be given for these patients) and with careful monitoring of renal function;

⁴If treatment is urgently needed. HCV: Hepatitis C virus; AASLD: American Association for the Study of Liver Diseases; EASL: European Association for the Study of the Liver.