Impact of new treatment options for hepatitis C virus infection in liver transplantation

Table 1 Expected benefits of new treatments for hepatitis C virus infection

Target population	Main objectives	Outcome
General population with chronic HCV infection	Achieve excellent SVR rates for all genotypes, reduce side effects, shorten treatment duration, simplify regimen schedules	Reduced ESLD incidence and indication for LT
Patients on LT waiting list	Achieve pre-transplant undetectable HCV-RNA; improve MELD scores	Reduced post-LT HCV recurrence; improved clinical conditions
Recipients of LT with HCV recurrence	Increase SVR rates, reduce side effects and dropouts, decrease drug-drug interactions, simplify regimen schedules	Increased patients and grafts survival
HIV/HCV-coinfected patients and coinfected LT recipients	Increase SVR rates, reduce side effects and dropouts, decrease drug-drug interactions, simplify regimen schedules	Increased patients and grafts survival

HCV: Hepatitis C virus; SVR: Sustained virological response; ESLD: End stage liver disease; LT: Liver transplant; MELD: Model for end-stage liver disease; HIV: Human immunodeficiency virus.

Table 2 Sustained virological response among recent clinical trials of new treatment regimens for hepatitis C virus including patients with cirrhosis

Ref.	Trial	Population	Drug	Overall SVR12	SVR12 in cirrhosis
Jacobson et al[143], 2014	Fusion	G2, G3 experienced	SOF/RBV 12 vs 16 wk	G2 86% vs 94%	G2 60% vs 78%
		34% cirrhotic		G3 62% vs 30%	G3 19% vs 61%
Lawitz et al[33], 2015	Fission	G2, G3 naïve	SOF/RBV 12 wk vs Peg-IFN/RBV 24 wk	G2 97% vs 78%	G2 92% vs 62%
		20% cirrhosis		G3 56% vs 63%	G3 30% vs 34%
Jacobson et al[143], 2014	Positron	G2, G3 naïve and experienced IFN ineligible	SOF/RBV	G2 93%, G3 61%	G2 92%, G3 21%
Zeuzem et al[144], 2014	Valence	G3 extended 24 wk 21% cirrhosis	SOF/RBV	G2 94%, G3 91%	G2 82%, G3 68%
Lawitz et al[42], 2015	Lonestar-2	G 2 and 3	SOF/RBV/Peg-IFN	G2 96%, G3 83%	G2 93%, G3 83%
Bourliere et al[43], 2015	Sirius	G1 with compensated cirrhosis, NR previous treatment	SOF/LDV 24 wk vs SOF/LDV/RBV 12 wk	N/A	97% vs 96%
Lawitz et al[36], 2014	Cosmos	G1 NR, 52% F3-F4	SOF/SMV ± RBV 12 or 24 wk	92%	94%
Gane et al[114], 2014	Electron II	G1 naïve, experienced and decompensated, G3 naïve, 15% cirrhosis	LDV/RBV 12 wk	G1 100%, G3 64%	G1 65%

Peg-IFN: Pegylated interferon; RBV: Ribavirin; SVR12: Sustained virological response; G: Genotype; LDV: Ledipasvir; SOF: Sofosbuvir; SMV: Simeprevir; NR: Non responder.

Table 3 Pros and cons of hepatitis C virus treatment before and after liver transplant

	Before LT	After LT
Aim	Prevention of HCV recurrence	Treatment of HCV recurrence
Advantages	Undetectable HCV-RNA at transplantation correlates with low rates of post-LT HCV recurrence	Increased tolerance to treatment
Disadvantages	Low eligibility due to compromised baseline conditions	High rates of adverse effects
	High rates of serious side effects and discontinuation rates	Moderate SVR rates
	Low SVR rates	Drug-drug interactions

HCV: Hepatitis C virus; LT: Liver transplant; SVR: Sustained virological response.

Table 4 Outcome of pre-transplant hepatitis C virus therapy in studies with different regimens

Ref.	Population	n	Treatment regimen	Outcome	Adverse effects
Everson et al[74], 2005	63% decompensated cirrhosis (MELD 11 ± 3.7)	124	IFN (5 MU 3/wk) or Peg-IFN (0.75 μg/kg per week)/RBV (600 mg/d escalated)	SVR 13% (G1), 50% (other genotypes) 53% relapse 29% completed course	13% discontinuations and SAE (2 deaths)
Crippin et al[75], 2002	LT waiting list	15	IFN (3 MU 3/wk or 1 MU/d) ± RBV 400 bid	SVR 33%	1.3 SAE/patient (one death)
Forns et al[145], 2003	LT waiting list	30	IFN (3 MU/d)/RBV 800 mg/d	SVR 20% (3 relapse after LT)	63% dose reduction
Thomas et al[76], 2003	LT waiting list	21	IFN (5 MU/d)	SVR 20% (8 relapse after LT)	No SAE
Carrión et al[78], 2009	LT waiting list	51	Peg-IFN/RBV	SVR 20%	39% bacterial infections
Everson et al[79], 2013	LT waiting list	59	Peg-IFN/RBV (from 0.75 μg/kg per week and 600 mg/d escalated)	SVR12 22% (G 1-4), 29% (G 2-3), 50% if > 16 wk	68% (2.7 SAE/patient)
Verna et al[11], 2015	LT waiting list	29	PI-based triple therapy (93% TVR, 7% BOC)	SVR 52%	31% SAE; one death 28% hospitalizations
Curry et al[81], 2015	LT waiting list for HCC (CTP < 7)	43	Sofosbuvir 400/d plus RBV 1000-1200 up to 48 wk	SVR pre-LT maintained in 69% LT	18% SAE 2 discontinuation
Charlton et al[82], 2015	Decompensated cirrhosis	108	LDV/SOF/RBV (600 mg/d escalating) 12 vs 24 wk	SVR 87% vs 89%, CTP B 87% vs 89%, CTP C 86% vs 87%	26% SAE 3 discontinuation
Poordad et al[85], 2015	Advanced cirrhosis (70% CTP B-C)	60	DCV/SOF/RBV 12 wk	SVR 83%, CTP A 91%, CTP B 92%, CTP C 50%	No SAE

LT: Liver transplant; HCC: Hepatocellular carcinoma; CTP: Child-Turcotte-Pugh; IFN: Interferon; Peg-IFN: Pegylated interferon; RBV: Ribavirin; SVR: Sustained virological response; G: Genotype; SAE: Serious adverse effects; MELD: Model for End-Stage Liver Disease; PI: Protease inhibitor; TVR: Telaprevir; BOC: Boceprevir; LDV: Ledipasvir; SOF: Sofosbuvir; DCV: Daclatasvir.

Table 5 Anti-hepatitis C virus therapy in liver transplant recipients with recurrent hepatitis C virus infection: Outcome of main studies from the past 10 years

Ref.	Population	n	Treatment regimen	SVR	Adverse effects
Interferon (IFN) or pegylated interferon (Peg-IFN) plus ribavirin (RBV) regimens
Fernández et al[95], 2006	LTR with recurrent HCV	47	Peg-IFN/RBV	23%	21% SAE
Carrión et al[77], 2008	LTR with mild recurrence (F0-F2)	27	Peg-IFN/RBV	48%	56% discontinuation
Berenguer et al[92], 2008	LTR with recurrent HCV	89	IFN/RBV vs Peg-IFN/RBV	16% vs 48%	20% decompensation; 15% deaths
Hanouneh et al[93], 2008	LTR with recurrent HCV	53	Peg-IFN/RBV	35%	23% SAE
Ueda et al[146], 2010	LTR with recurrent HCV (G1)	34	Peg-IFN alfa-2b + RBV	50%	18% discontinuation
DAA triple therapy with Peg-IFN/RBV plus boceprevir (BOC) or telaprevir (TVR)
Verna et al[109], 2015	Advanced fibrosis (F > 3) and 9 FCH	49	Peg-IFN/RBV/TVR or BOC	51% AF 44% CH	22% AF and 33% CH decompensation
Pungpapong et al[108], 2013	LTR with recurrent HCV	60	Peg-IFN/RBV/TVR (35) or BOC (25)	67% TVR 45% BOC	12% decompensation, 2 deaths
Coilly et al[107], 2014	LTR with recurrent HCV	37	Peg-IFN/RBV/TVR (19) or BOC (18)	20% TVR 71% BOC	14% SAE, 27% infection, 3 deaths
IFN-free DAA regimens
Forns et al[111], 2015	Post-LT decompensated cirrhosis and FCH	92	SOF/RBV ± Peg-IFN 24-48 wk	59%	46% SAE
Charlton et al[110], 2015	LTR with recurrent HCV	40	SOF/RBV 24 wk	70%	No SAE
Reddy et al[44], 2015	Post LT recurrence (121 CPT B and C)	223	LDV/SOF/RBV 12 vs 24 wk	94% (60% CTP C)	4% SAE, 3% discontinuation
Gutierrez et al[118], 2015	Post LT recurrence	61	SOF/SMV ± RBV	93%	No SAE
Pungpapong et al[119], 2015	Post LT recurrence	123	SOF/SMV ± RBV	90%	1 death possibly related to treatment
Kwo et al[103], 2014	Post LT recurrence (G1)	34	Paritaprevir/r/Ombitasvir and Dasabuvir/RBV	97%	1 discontinuation
Poordad et al[85], 2015	Post LT recurrence	53	DCV/SOF/RBV 12 wk	94%	1 discontinuation (SVR); no SAE

LTR: Liver transplant recipients; SVR: Sustained virological response; CTP: Child-Turcotte-Pugh; SAE: Serious adverse event; FCH: Fibrosing cholestatic hepatitis; SOF: Sofosbuvir; SMV: Simeprevir; LDV: Ledipasvir; r: Ritonavir; DCV: Daclatasvir.

Table 6 American Association for the Study of Liver Diseases 2014 recommendations for therapy in recurrent hepatitis C virus post liver transplant

Rating	Population	CPT B and C	Regimen	Daily Dose
IB-recommended	G 1, 4 experienced and naïve	RBV 600 mg, increased as tolerated1	LDV/SOF/RBV 12 wk	90 mg/400 mg/weight-based2
IB-alternative	G 1, 4 naïve, RBV intolerant	Not recommended	LDV/SOF 24 wk	90 mg/400 mg
IB-alternative	G1	Not recommended	SOF/SMV ± RBV 12 wk	400 mg + 150 mg ± weight-based2
IB-alternative	G1	Recommended only for non-cirrhosis	Paritaprevir/r/rombitasvir/dasabuvir + RBV for 24 wk	150 mg/100 mg/25 mg/250 mg bid/weight-based2
IIB-recommended	G2 experienced and naïve	600 mg/d,	SOF/RBV 24 wk	400 mg/weight-based2
		increased as tolerated1
IB-recommended	G3 experienced and naïve	600 mg, increased as tolerated1	SOF/RBV 24 wk	400 mg/weight-based2
IIIA Not recommended: Regimens containing PEG-IFN, monotherapy with PEG-IFN, RBV, or a DAA; TVR or BOC-based regimens

¹e.g., increased monthly by 200 mg/d;

²1000 mg < 75 kg, 1200 mg > 75 kg. Recommendations are graded according the level of the evidence and strength of the recommendation. G: Genotype; RBV: Ribavirin; LDV: Ledipasvir; SOF: Sofosbuvir; RBV: Ribavirin; r: Ritonavir; DCV: Daclatasvir; DAA: Direct active antiviral; TVR: Telaprevir; BOC: Boceprevir.