Hepatitis C and renal transplantation in era of new antiviral agents

Table 1 The four classes of direct acting antivirals agents

The four classes of DAAs	Mechanism of action	Drugs (targeted genotypes in brackets)
NS3/4A PIs (PIs)	Block a viral enzyme (protease) that enables the HCV to survive and replicate in host cells	Glecaprevir (1-6) Paritaprevir (1, 4) Voxilaprevir (1-6) Grazoprevir (1, 3, 4)
Nucleoside and nucleotide NS5B polymerase inhibitors	Target the HCV to stop it from making copies of itself in the liver. So doing block the virus from multiplying	Sofosbuvir (1-4)
NS5A inhibitors	Block a virus protein, NS5A, that HCV needs to reproduce and for various stages of infection	Ombitasvir (1, 4) Pibrentasvir (1-6) Daclatasvir (3) Elbasvir (1, 4) Ledipasvir (1) Ombitasvir (1) Velpatasvir (1-6)
Non-nucleoside NS5B polymerase inhibitors	Stop HCV from reproducing by inserting themselves into the virus so that other pieces of the HCV cannot attach to it	Dasabuvir (1)

PIs: Protease inhibitors; HCV: Hepatitis C virus.

Table 2 Available, approved direct acting antiviral-based regimens for treating hepatitis C virus in treatment-naive patients

Genotype 1a	Genotype 4
Ledipasvir + sofosbuvir Paritaprevir + ritonavir + ombitasvir + dasabuvir Sofosbuvir+ simeprevir ± ribavirin	Ledipasvir + sofosbuvir Paritaprevir + ritonavir + ombitasvir + dasabuvir + ribavirin Sofosbuvir + ribavirin + pegIFN Sofosbuvir + simeprevir + ribavirin
Genotype 1b	Genotype 5
Ledipasvir + sofosbuvir Paritaprevir + ritonavir + ombitasvir + dasabuvir Sofosbuvir + simeprevir	Sofosbuvir + ribavirin PegIFN + ribavirin
Genotype 2	Genotype 6
Sofosbuvir + ribavirin	Ledipasvir + sofosbuvir Sofosbuvir + ribavirin + pegIFN
Genotype 3	Pangenotype
Sofosbuvir + ribavirin Sofosbuvir + ribavirin + pegIFN	Glecaprevir + pibrentasvir Sofosbuvir + velatapasvir

pegIFN: Pegylated interferon.

Table 3 Recommended regimens for kidney transplant patients

Recommended	Duration	Rating
Recommended regimens listed by evidence level and alphabetically for treatment-naive and experienced kidney transplant patients with genotype 1 or 4 infection, with or without compensated cirrhosis
Daily fixed-dose combination of glecaprevir (300 mg)/pibrentasvir (120 mg)	12 wk	I, A1
		IIa, C2
Daily fixed dose combination of ledipasvir (90 mg)/sofosbuvir (400 mg)	12 wk	I, A
Recommended and alternative regimens for treatment-naïve and experienced kidney transplant patients with genotype 2, 3, 4, 5 or 6 infection, with or without compensated cirrhosis
Daily fixed-dose combination of glecaprevir (300 mg)/pibrentasvir (120 mg)	12 wk	I, A3
		IIa, C4
Alternative
Daily daclatasvir (60 mg) plus sofosbuvir (400 mg) plus low initial dose of ribavirin (600 mg; increased as tolerated)	12 wk	II, A

¹Patients without cirrhosis;

²Patients with compensated cirrhosis;

³Genotypes 2, 3 and 6;

⁴Genotype 5.

Table 4 Main literature studies with direct acting antiviral therapy in patients with chronic hepatitis C and renal dysfunction

Ref.	Title	Journal	Year
[62]	Efficacy of direct-acting antiviral combination for patients with HCV genotype 1 infection and severe renal impairment or end-stage renal disease	Gastroenterology	2016
[63]	Glecaprevir and Pibrentasvir in patients with HCV and severe renal impairment	N Engl J Med	2017
[64]	Grazoprevir plus elbasvir in treatment-naive and treatment-experienced patients with HCV genotype 1 infection and stage 4-5 chronic kidney disease (the C-SURFER study): A combination phase 3 study	Lancet	2015
[65]	Elbasvir plus grazoprevir in patients with HCV infection and stage 4-5 chronic kidney disease: clinical, virological, and health-related quality-of-life outcomes from a phase 3, multicentre, randomized, double-blind, placebo-controlled trial	Lancet Gastroenterol Hepatol	2017
[70]	Use of sofosbuvir-based direct-acting antiviral therapy for HCV infection in patients with severe renal insufficiency	Infect Dis	2015
[71]	Safety, efficacy and tolerability of half-dose sofosbuvir plus simeprevir in treatment of hepatitis C in patients with end stage renal disease	J Hepatol	2015
[72]	Sofosbuvir and simeprevir in hepatitis C genotype 1-patients with end-stage renal disease on haemodialysis or GFR < 30 mL/min	Liver Int	2016
[74]	Use of direct-acting agents for HCV-positive kidney transplant candidates and kidney transplant recipients	Transpl Int	2016
[75]	Safety and efficacy of sofosbuvir-containing regimens in hepatitis C-infected patients with impaired renal function	Liver Int	2016

HCV: Hepatitis C virus.

Table 5 American Association for the Study of Liver Diseases Recommendation for treating hepatitis C virus in patients with renal impairment

Recommended	Rating	Genotype	Duration
Recommendations for patients with CKD stage 1, 2 or 3
No dose adjustment is required when using (1) Daclatasvir (60 mg) (2) Daily fixed-dose combination of elbasvir (50 mg)/grazopevir (100 mg) (3) Daily fixed-dose combination of glecaprevir (300 mg)/pibrentasvir (120 mg) (4) Fixed-dose combination of ledipasvir (90 mg)/sofosbuvir (400 mg) (5) Fixed-dose combination of sofosbuvir (400 mg)/velpatasvir (100 mg) (6) Simeprevir (150 mg) (7) Fixed-dose combination of sofosbuvir (400 mg)/velpatasvir (100 mg)/voxilaprevir (100 mg) (8) Sofosbuvir (400 mg)	I, A
Recommendations for patients with CKD stage 4 or 5 (eGFR < 30 mL/min or ESRD
Daily fixed-dose combination of elbasvir (50 mg)/grazoprevir (100 mg)	I, B	1a, 1b, 4	12 wk
Daily fixed-dose combination of glecaprevir (300 mg)/pibrentasvir (120 mg)	I, B	1, 2, 3, 4, 5, 6	8 to 16 wk

CKD: Chronic kidney disease; ESRD: End-stage renal disease.

Table 6 European Association for the Study of the Liver Recommendations for treating hepatitis C virus in patients with reduced or absent renal function

Hemodialysis patients, particularly those who are suitable candidates for renal transplantation, should be considered for antiviral therapy (B1)

Hemodialysis patients should receive an IFN-free, if possible ribavirin-free regimen, for 12 wk in patients without cirrhosis, for 24 wk in patients with cirrhosis (B1)

Simeprevir, daclatasvir, and the combination of ritonavir-boosted paritaprevir, ombitasvir and dasabuvir are cleared by hepatic metabolism and can be used in patients with severe renal disease (A1)

Sofosbuvir should not be administered to patients with an eGFR < 30 mL/min per 1.73 m2 or with end-stage renal disease until more data is available (B2)