Interferon-free regimens for the treatment of hepatitis C virus in liver transplant candidates or recipients

Table 1 Main characteristics of the approved direct acting antivirals that are currently used in interferon-free regimens for the treatment of hepatitis C

DAA (commercial name), dose	Category	Dose adjustment in liver or renal impairment	Antiviral activity	CNIs co-administration	Co-administration should be avoided
Sofosbuvir (Sovaldi®), tablet 400 mg, once daily	NUC NS5B polymerase inhibitor	No change in hepatic impairment Contraindicatedin patients with GFR < 30 mL/min	Genotypes 1-6, High genetic barrier	No change	P-glycoprotein inducers (Anticonvulsants: carbamazepine, oxcarbazepine, phenobarbital, phenytoin; Antimycobacterials: rifampin, rifabutin, rifapentin; St. John’s wort; HIV drugs: Tipranavir/ritonavir)
Simeprevir (Olysio®), tablet 150 mg, once daily with food	NS3/4A protease inhibitor	Contraindicated in Child class C No change in renal impairment	Genotypes 1, 4, Low genetic barrier	Contraindicated with cyclosporine	Inhibitors or inducers of CYP3A4 (Antifungals: fluconazole, itraconazole, ketoconazole, posaconazole, voriconazole; Antibiotics: clarithromycin, erythromycin, telithromycin; Dexamethasone; Cicapride; HIV drugs: cobicistat, efavirenz, delavirdine, etravirine, nevirapine, ritonavir and any HIV protease inhibitor)P-glycoprotein inducers
Daclatasvir(Daklinza®), tablet 60 mg, once daily	NS5A inhibitor	No change in liver or renal impairment	Genotypes 1,3,4, Low genetic barrier	No change	Strong inducers of CYP3A4 and/or P-glycoprotein (e.g., phenytoin, carbamazepine, oxcarbazepine, phenobarbital, rifampicin, rifabutin, rifapentine, dexamethasone, St John’s wort; HIV drugs: darunavir, lopinavir, etravirine)
Ledipasvir/Sofosbuvir/(Harvoni®), tablet 90/400 mg, once daily	NUC NS5B polymerase inhibitor + NS5A Inhibitor	No change in hepatic impairment Contraindicated in patients with GFR < 30 mL/min	Genotypes 1,3,4, High genetic barrier	No change	P-glycoprotein inducers, rosuvastatin, simeprevir
Paritaprevir/Ritonavir/Ombitasvir (Viekirax®), tablet 75/50/12.5 mg, x 2 once daily with food	Ritonavir boosted NS3/4A protease inhibitor/NS5A inhibitor	No safety and efficacy data in Child class B, Contraindicated in Child class C No change in renal dysfunction	Genotypes 1, 4, Genetic barrier depending on HCV genotype	Cyclosporine: 20% of pretreatment total daily dose; tacrolimus: 0.2 mg/72 h or 0.5 mg once weekly	P-glycoprotein inducers, gemfibrozil, lovastatin, simvastatin, oral midazolam, triazolam, pimozide, ethinyl estradiol-containing oral contraceptives, sildenafil for pulmonary hypertension
Dasabuvir (Exviera®), tablet 250 mg, every 12 h	Non-NUC NS5B polymerase inhibitor		Genotype 1, Low genetic barrier

NUC: Nucleos(t)ide analogue; CNI: Calcineurin inhibitor.

Table 2 Studies of interferon-free regimens for treatment of hepatitis C virus positive liver transplant candidates

Ref.	No. of patients	Severity of liver disease based on CP score	Antiviral scheme (duration)	Virological response
Curry et al[16]	61	≤ 7	SOF + RBV (for 48 wk or until LT)	69% (12 wk after LT)
Afdhal et al[17]	40	5-10	SOF + RBV (48 wk)	100% and 93% for Child class A and B, respectively at 24 wk under treatment
Gane et al[18]	20	7-9	SOF + Ledipasvir ± RBV(12 wk)	89%
Flamm et al[19]	108	Decompensated cirrhosis (CP score range: 7-12)	Ledipasvir/SOF + RBV(12 or 24 wk)	87% and 89% (for 12 and 24 wk, respectively)

CP: Child-Pugh; SOF: Sofosbuvir; RBV: Ribavirin.

Table 3 Studies of sofosbuvir plus simeprevir with or without ribavirin in recipients with hepatitis C recurrence after liver transplantation

Ref.	No. of patients	Patient characteristics	Antiviral Scheme, (duration)	On treatment virological response (%)	SVR (%)
Pungpapong et al[28]	55	Fibrosis 3-4: 29%, Decompensated cirrhosis: 4%, Cholestatic recurrence: 15%	SOF + SMV ± RBV(12 wk)	98 (EOT)	91
Brown et al[29]	143	Cirrhosis: 60%, MELD score > 10: 14%Previous DAA failure: 9%	SOF + SMV ± RBV (12-24 wk)	-	90
Satokar et al[30]	59	Fibrosis F3/F4: 51%,Treatment experience: 71%	SOF + SMVSOF + SMV + RBVSOF + RBV	62 50 43 (4 wk)	-
Gordon et al[31]	17	Fibrosis: range: 0-4	SOF + SMV(12 wk)	100 (EOT)	-
Gutierrez et al[32]	32	-	SOF + SMV ± RBV(12 wk)	93 (EOT)	-
Punzalan et al[37]	10	Median Fibrosis: 2.5,Treatment experience: 40%	SOF + SMV ± RBV(12 wk)	100 (EOT)	100
Lutchman et al[33]	41	Treatment experience: 56%	SOF + SMV orSOF + RBV(12-24 wk)	100 (8 wk)	-
Nair et al[34]	22	All patients with fibrosis ≥ 3 or decompensated cirrhosis	SOF + SMV ± RBV(12 wk)	100 (EOT)	-
Ripper et al[35]	25	Treatment experience: 64%	SOF + SMV ± RBV(12 wk)	100 (8 wk)	75
O'Dell et al[38]	16	-	SOF + SMV ± RBV	100 EOT	100
Alsabbagh et al[36]	17	Fibrosis F3-4: 40%, Treatment experience: 41%	SOF + SMV (n = 11)SOF + RBV (n = 6)(24 wk)	100 (4 wk)	-

EOT: End of treatment; CTP: Child-Pugh score; DAA: Direct acting antiviral.

Table 4 Studies of sofosbuvir plus daclatasvir with or without ribavirin in recipients with hepatitis C recurrence after liver transplantation

Authors	No. of patients	Patient characteristics	Antiviral Scheme (duration)	On treatment virological response (%)	SVR (%)
Leroy et al[39], (CUPILT study)	21	FCH: 100%, Treatment experience: 67%	SOF + Daclatasvir ± RBV (n = 13)SOF + RBV (n = 6)(24 wk)	95 (12 wk)	-
Conti et al[40]	55	Fibrosis F3-F4: 33%,FCH: 7%	SOF + Daclatasvir(24 wk)	85 (8 wk)	-

FCH: Fibrosing cholestatic hepatitis.

Table 5 Main strategies of interferon-free antiviral combinations in liver transplant candidates and recipients with chronic hepatitis C virus infection

Antiviral scheme (duration)	Antiviral activity
SOF + RBV (× 12 or 24 wk)	Genotype 2 or 3 (perhaps 5, 6)
SOF + Simeprevir ± RBV (× 12 or 24 wk)	Genotypes 1, 4
SOF + Daclatasvir ± RBV (× 12 or 24 wk)	Genotypes 1, 3, 4
Ledipasvir/SOF ± RBV (× 12-24 wk)	Genotypes 1, 3, 4, 6
Paritaprevir/Ritonavir/Ombitasvir + Dasabuvir ± RBV (× 12 or 24 wk)	Genotype 1
Paritaprevir/Ritonavir/Ombitasvir ± RBV (× 12 or 24 wk)	Genotype 4

SOF: Sofosbuvir; RBV: Ribavirin.