Treatment of chronic hepatitis C in liver transplant candidates and recipients: Where do we stand?

Table 1 Direct acting antivirals commenced on patients with decompensated cirrhosis or recipients after liver transplantation

Approved protease inhibitors
Boceprevir	NS3-4A serine protease inhibitors
Telaprevir	Second-wave NS3/4A protease inhibitor
Simeprevir
Approved NS5A inhibitors
Daclatasvir	NS5A inhibitor
Approved NS5B RNA-dependent RNA polymerase nucleotide inhibitor
Sofosbuvir	NS5B RNA-dependent RNA polymerase nucleotide inhibitor
Newer DAAs evaluated in combination regimens without Peg-IFN
Ledipasvir (formerly GS-5885)	NS5A inhibitor
ABT-450	NS3/4A protease inhibitor
Ombitasvir (formerly ABT-267)	NS5A inhibitor
Dasabuvir (formerly ABT-333)	Non-nucleoside NS5B polymerase inhibitor

Peg-IFN: Pegylated interferon.

Table 2 Doses of antivirals in liver transplant candidates and recipients

Peg-IFN-α 2a	180 μg/wk, subcutaneous	Renal adjustment
Peg-IFN-α 2b	Weight-based 1.5 μg/kg per week, subcutaneous	No CNI adjustment
Ribavirin	Weight-based, 1000 mg in patients < 75 kg, 1200 mg in patients ≥ 75 kg, orally twice a day
Boceprevir	800 mg orally three times a day	No renal adjustment
Telaprevir	1125 mg orally twice a day	CNI adjustment
Sofosbuvir	400 mg daily, orally
Daclatasvir	60 mg daily, orally	No renal adjustment1
Simeprevir	150 mg daily, orally	No CNI adjustment2

¹Sofosbuvir only in patients with glomerular filtration rate > 30 mL/min;

²Simeprevir should not be given with cyclosporine. CNI: Calcineurin inhibitor; Peg-IFN: Pegylated interferon.

Table 3 Treatment of liver transplant candidates with hepatitis C[6]

Cirrhosis CP A, all HCV genotypes
Sofosbuvir + RBV until LT	Peg-IFN + RBV + sofosbuvir for 12 wk	RBV + sofosbuvir + daclatasvir for 12 wk
Cirrhosis CP B and C, all HCV genotypes
Sofosbuvir + RBV until LT	IFN contraindicated	RBV + sofosbuvir + daclatasvir for 12 wk

CP: Child-Pugh; HCV: Hepatitis C virus; LT: Liver transplant; RBV: Ribavirin; Peg-IFN: Pegylated interferon.

Table 4 Major studies of interferon-free regimens for treatment of hepatitis C virus positive liver transplant candidates reported in 2014

Ref.	n	CP score	Antiviral scheme	Virological response
Curry et al[37]	61	≤ 7	SOF + RBV for 48 wk or until LT	69% (12 wk after LT)
Gane et al[39]	20	7-9	SOF ± RBV + ledipasvir for 12 wk	89% (SVR 4 wk)
Flamm et al[40]	108	Decompensated cirrhosis (range: 7-12)	SOF + RBV + ledipasvir for 12 or 24 wk	87% and 89%, respectively (SVR 12 wk)
Afdhal et al[38]	50	5-10	SOF + RBV for 48 wk	100% CP class A
				93% CP class B at 24 wk under treatment

n: Number of patients; CP: Child-Pugh; SOF: Sofosbuvir; RBV: Ribavirin; SVR: Sustained virological response.

Table 5 Treatment of hepatitis C virus recurrence post liver transplant

IFN-free: Sofosbuvir + RBV (HCV genotype 2 for 12-24 wk); sofosbuvir + daclatasvir ± RBV (HCV genotypes 1, 3-6 for 12-24 wk); sofosbuvir + simeprevir ± RBV (HCV genotypes 1, 4 for 12 -24 wk)
In case of restriction applying first generation DAAs
Fibrosis metavir stage 3-4	Genotype 2/3	Genotype 1
Genotype 1a		Fibrosis metavir stage 2
IL-28B polymorphism		Predictors of poor response
Fibrosing cholestatic hepatitis	Peg-IFN plus RBV	Peg-IFN plus RBV plus boceprevir or telaprevir
Non responders to previous treatments	Monitor closely Hb, WBC, PLTs CNI levels, renal function
	Consider
	Administration of blood transfusions, EPO, CSGF
	Decrease of RBV dose
	Renal dose adjustment
	Decrease of CNI dose

IFN: Interferon; RBV: Ribavirin; CNI: Calcineurin inhibitor; HCV: Hepatitis C virus; Peg-IFN: Pegylated interferon; DAA: Direct antiviral agent; WBC: White cells blood count; PLTs: Platelets; EPO: Erythropoietin; CSGF: Granulocyte-colony stimulating factor.

Table 6 Major studies tested the efficacy of first generation direct antiviral agents combined with peg-interferon and ribavirin in liver transplant recipients

Ref.	Year of publication	No. of patients	Sustained virological response
Coilly et al[73]	2013	37	50% (20% for telaprevir and 71% for boceprevir)
Pungpapong et al[74]	2013	60	56% (67% for telaprevir and 45% for boceprevir)
Werner et al[75]	2012	9	89%
Stravitz et al[76]	2013	122	28%
Ann Brown et al[77]	2013	46	60%
Faisal et al[78]	2014	76	59.5%
Werner et al[79]	2014	14	50%

Table 7 Major studies of sofosbuvir with other novel direct antiviral agents with or without ribavirin for treatment of hepatitis C virus positive liver transplant recipients reported in 2014

Ref.	n	Patient characteristics	Antiviral scheme	Virological response	SVR	Duration (wk)
Pungpapong et al[85]	55	Fibrosis 3-4 (29%)	SOF + simeprevir ± RBV	98% (EOT)	91%	12
		Decompensated cirrhosis (4%)
		Cholestatic recurrence (15%)
Leroy et al[87] (CUPILT)	21	Fibrosing cholestatic hepatitis	SOF + daclatasvir ± RBV (n = 13)	95% HCV RNA < 15 IU/mL	-	24
			SOF + RBV (n = 6)	81% were not detectable (at week 12 under treatment)
Conti et al[86]	55	Fibrosis 3-4 (33%)	SOF + daclatasvir	85% (at week 8 under treatment)	-	24
		Fibrosing cholestatic hepatitis (7%)
Kwo et al[89] (CORAL I)	34	Fibrosis 0-2	Paritaprevir + ritonavir + ombitasvir + dasabuvir + RBV	100% (EOT)	97%	24
Reddy et al[88]	223	Fibrosis 0-3, CP A-C	SOF + ledipasvir + RBV	-	96%-98% (CP A: 9% CP B: 83%-85% CP C: 60%-67%)	12-24

n: Number of patients included in the study; RBV: Ribavirin; SOF: Sofosbuvir; EOT: End of treatment; SVR: Sustained virological response; CP: Child-Pugh; HCV: Hepatitis C virus.

Table 8 Major drug-drug interactions of the newer direct acting antivirals for hepatitis C

DAA	Co-administration should be avoided
Sofosbuvir	P-glycoprotein inducers
	Anticonvulsants: Carbamazepine, oxcarbazepine, phenobarbital, phenytoin; antimycobacterials: Rifampin, rifabutin, rifapentin; St. John's wort; HIV drugs: Tipranavir/ritonavir
Simeprevir	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	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
Sofosbuvir/ledipasvir	P-glycoprotein inducers, rosuvastatin, simeprevir

DAA: Direct acting antiviral; HIV: Human immunodeficiency virus.