Future of liver disease in the era of direct acting antivirals for the treatment of hepatitis C

Table 1 Main features of antiviral targets and clinical indications of second-generation direct acting antivirals[17]

Molecule	Class	Target	Genotype	Associations
Sofosbuvir	Nucleotide polymerase inhibitor	NS5B RNA-dependent RNA polymerase	Pangenotypic	Ledipasvir
				Daclatasvir
				Simeprevir
				Velpatasvir
Dasabuvir	Non-nucleoside polymerase inhibitor	NS5B RNA-dependent RNA polymerase	Genotype 1	Ombitasvir + paritaprevir + ritonavir
Ombitasvir		NS5A	Genotype 1, 4	Paritaprevir + ritonavir with or without dasabuvir
Daclatasvir		NS5A	Genotype 1, 2, 3	Sofosbuvir
Ledipasvir		NS5A	Genotype 1, 4	Sofosbuvir
Velpatasvir		NS5A	Pangenotypic	Sofosbuvir
Elbasvir		NS5A	Genotype 1, 4	Grazoprevir
Paritaprevir		NS3/4A protease	Genotype 1, 4	Ombitasvir + ritonavir with or without dasabuvir
Simeprevir		NS3/4A protease	Genotype 1, 4	Sofosbuvir
Grazoprevir		NS3/4A protease	Genotype 1, 4	Elbasvir

Table 2 Main studies highlighting the effects of hepatitis C virus antiviral therapy on patients’ mortality, fibrosis regression and risk of hepatocellular carcinoma

Ref.	HCV genotype	Fibrosis stage	Treatment	SVR rate	Mortality (n, pts)	Survival	Other outcomes
Veldt et al[47], 2007	G1: 280/474 (59%)	Ishak score 4: 120 (25%)	Duration of treatment, 26 wk (21-48)	142/280 (50.7%)	SVR: 2/280 (0.7%)	-	SVR associated with reduction in the hazard of events (adjusted HR = 0.21, 95%CI: 0.07-0.58; P < 0.003)
		Ishak score 5: 94 (20%)	IFN: 131 (27%)		Non-SVR: 24/280 (8.6%)
		Ishak score 6: 265 (55%)	IFN + RBV: 130 (27%)
			PEG-IFN: 10 (2.1%)
			PEG-IFN + RBV: 208 (43%)
Yoshida et al[64], 1999	G1: 1177/2400 (49%)	F0: 45 (1.9%)	IFN-α: 84%	789/2400 (32.8%)	-	-	Risk of HCC for IFN therapy: Adjusted risk ratio = 0.516, 95%CI: 0.358-0.742 (P < 0.001); risk of HCC for SVR pts: risk ratio = 0.197, 95%CI: 0.099-0.392 (P < 0.002)
	G2: 496/2400 (20.6%)	F1: 665 (27.7%)	IFN-β: 14%
		F2: 896 (37.7%)	Combination of IFN-α and IFN-β: 2%
		F3: 564 (23.5%)
		F4: 230 (9.6%)
Veldt et al[41], 2004	SVR	SVR:	Recombinant IFN α2a, α2b, or natural IFN monotherapy for 39 wk	286	SVR	SVR group: Comparable with the general population	29% regression and 5% progression of fibrosis in SVR group
	G1: 112/286 (39.2%)	F4: 15 (5.2%)			6/286 (2.1%)
	Not specified: 174/286 (60.8%)	Non-SVR:			3/50 (6%)
	Non-SVR	F4: 11 (22%)
	G1: 21/50 (42%)
	Not specified: 29/50 (58%)
Maruoka et al[42], 2012	Treated (577):	Treated:	IFN (not specified)	221/577 (38.3%)	Untreated: 37/144 (25.7%)	-	Risk ratio of overall death and liver-related death reduced to 0.173 (95%CI: 0.075-0.402)
	G1: 383/577 (66.2%)	F0: 15 (2.6%)			Non-SVR
	G2: 144/577 (24.8%)	F1: 290 (503%)			74/356 (20.8%)
	Untreated (144)	F2: 132 (22.9%)			SVR 10/221 (4.5%)
		F3: 82 (12.2%)
		F4: 58 (10.1%)
		Untreated:
		F0: 2 (1.4%)
		F1: 64 (44.4%)
		F2: 32 (22.2%)
		F3: 18 (12.5%)
Bruno et al[49], 2016	G1: 88/181 (48.6%)	F4: 100%	IFN mono-therapy or IFN (pegylated or not) + RBV	181	18/181 (9.9%)	-	-
		CPT A5: 154/181 (85.1%)
		CPT A6: 27/181 (14.9%)
Cardoso et al[44], 2010	G1: 60%	F4: 54%	PEG-IFN + RBV: 252 (82%), PEG-IFN: 22 (7%), IFN ± RBV: 33 (11%)	103/307 (33.5%)	21/307 (6.8%)	-	-
	G2: 8%
	G3: 16%
	G4: 13%
Tada et al[46], 2016	G1: 1476/2743 (53.8%)	-	IFN (not specified)	587/2267 (25.9%)	137/2267 (6%)	-	-
	G2: 789/2743 (28.3%)
	Unknown: 478/2743 (17.4%)
Van der Meer et al[48], 2012	G1: 340/498 (68.3%)	Ishak 4: 143/498 (27%)	IFN: 175 (33%)	192/498 (38.5%)	SVR: 13	-	SVR reduced all-cause mortality (HR = 0.265, 95%CI: 0.14-0.49; P < 0.001)
	G2: 48/498 (9.6%)	Ishak 5: 101/498 (19%)	IFN + RBV: 148 (28%)		Non-SVR: 100
	G3: 88/498 (17.7%)	Ishak 6: 22/498 (4%)	PEG-INF: 176 (33%)
	G4: 22/498 (4.4%)		PEG-IFN + RBV: 176 (33%)
D’Ambrosio et al[52], 2012	G1: 11/38 (28.9%)	Only cirrhotic patients	IFN + RBV: 10/38 (26.3%)	-	-	-	SVR reduced area of fibrosis by 2.3% (P < 0.0001), with a median individual decrease of 71.8%
	G2: 24/38 (63.2%)		PEG-IFN + RBV:
	G3: 3/38 (7.9%)		28/38 (73.6%)
			Duration of treatment 24 mo (24-48)
Mallet et al[53], 2008	G1: 51/96 (53.1%)	F4: 100%	IFN or PEG-IFN, with or without RBV	39/96 (40.6%)	SVR: 4 (10.2%)	-	Regression of fibrosis (according to METAVIR score): Stage 4: 69 (71.9%); stage 3: 9 (9.4%); stage 2: 10 (10.4%); stage 1: 7 (7.3%); stage 0: 1 (1%)
					Non-SVR: 17 (29.8%)
Reichard et al[56], 1999	G1: 41/100 (41%)	F0-3: 22	IFN alpha2b: 73	27/100 (27%)	-	-	Reduction of portal inflammation (P < 0.0002), piecemeal necrosis (P < 0.0004), lobular necrosis (P < 0.0005), fibrosis (P < 0.0008) after SVR
	G2: 27/100 (27%)	F4: 4	Human leucocyte IFN alpha: 42
	G3: 23/100 (23%)
	Mixed: 9/100 (9%)
Arif et al[57], 2003	Naive (52):	Naive	IFN alpha2b	Naive	-	-	Reduction in fibrosis score in both groups: responders = -0.91 (P = 0.038), non-responders = -0.48 (P = 0.021)
	G1a: 64%			21/52 (40.4%)
	G1b: 19%	Fibrosis score: 2.91 ± 1.64	Duration of treatment:
	G2: 6%		12-24 wk: 10	Experienced
	G3: 10%		24 wk: 56	18/79 (22.8%)
	G4: 1%		36 wk: 8
			48 wk: 30
	Experienced (79):
	G1a: 55%
	G1b: 26%
	G2: 7%
	G3: 10%
	G4: 2%	Fibrosis score: 2.83 ± 1.62
George et al[58], 2009	G1: 75/141 (53%)	Fibrosis stage ≥ 2: 116	IFN alpha2b + RBV: 146 (97%)	100%	-	1	39/49 (79.6%) reduction in fibrosis stage (according to Ishak score) 16/49 (32.6%) pts had 2 point or greater decrease in stage
	G2: 49/141 (35%)	Fibrosis stage = 4: 16	PEG-IFN alpha2a + RBV:
	G3: 14/141 (10%)		4 (3%)
	G4: 3/141 (2%)	According to Scheuer
Poynard et al[59], 2002	-	Standard:	Standard:	Standard:	-	-	Decrease in fibrosis index score in SVR group compared with non-responders: From 0.33 ± 0.06 at baseline to 0.18 ± 0.06 at 72 wk vs from 0.41 ± 0.03 at baseline to 0.44 ± 0.03 at 72 wk (P < 0.001)
		F0: 12 (15%)	IFN alpha2a 3 MU	3/78 (3.8%)
		F1: 42 (54%)	TIW for 24 wk
		F3: 24 (31%)	Reinforced: IFN alpha2a 6 MU daily for 12 d followed by thrice weekly for 22 wk, then 3 MU thrice weekly for 24 wk	Reinforced:
		F4: 0 (0%)		14/87 (16%)
		Reinforced:
		F0: 16 (18%)
		F1: 41 (47%)
		F3: 30 (35%)
		F4: 0
Shiratori et al[60], 2000	-	SVR:	IFN alpha2a or	183/487 (37.6%)	-	-	SVR group: Rate of fibrosis progression -0.28 ± 0.03 unit/year (regression)
		F0: 3 (2%)	IFN alpha2b or
		F1: 42 (23%)	Natural IFN alpha weekly for 3 to 6 mo
		F2: 69 (37%)					Non-SVR group: Rate of fibrosis progression: 0.02 ± 0.02 unit/year
		F3: 45 (25%)	IFN alpha 6-7 times per wk for 8 wk
		F4: 24 (13%)
		Non-SVR:					P < 0.001
		F0: 3 (1%)
		F1: 95 (31%)
		F2: 109 (36%)
		F3: 67 (22%)
		F4: 30 (10%)
Maylin et al[62], 2008	G1: 21/210 (39%)	F0-1: 121 (38%)	IFN alpha: 3 (1%)	100%	-	-	Fibrosis stage improved in 56%, stable in 32%, deteriorated in 12%; regression of cirrhosis observed in 9 of 14 (64%)
	G2: 55/210 (18%)	F2: 111 (35%)	IFN-lymphoblastoid: 5 (1%)
	G3: 101/210 (32%)	F3: 56 (17%)	IFN-hybrid: 9 (3%)
	G4-5: 33/210 (11%)	F4: 31 (10%)	IFN alpha2a: 18 (5%)
			IFN alpha2a + RBV: 5 (2%)
			PEG-IFN alpha2a + RBV: 27 (8%)
			IFN alpha2b: 22 (6%)
			IFN alpha2b + RBV: 41 (12%)
			PEG-IFN alpha2b + RBV: 214 (62%)

Pts: Patients; IFN: Interferon; PEG: Pegylated; SVR: Sustained virological response; HCC: Hepatocellular carcinoma; RBV: Ribavirin.

Table 3 Main studies evaluating the effects of direct acting antivirals in patients with advanced cirrhosis and/or listed for liver transplantation

Ref.	HCV genotype	Fibrosis stage	Treatment	SVR rate	Observed improvement
Charlton et al[98], 2015	Cohort A	Child A: 1/108 (1%)	LDV/SOF + RBV 12 or 24 wk	Child B:	-
	G1a: 74/108 (68.5%)	Child B: 65/108 (60.2%)		-12 wk 26/30 (87%)
	G1b: 31/108 (28.7%)	Child C: 42/108 (38.9%)		-24 wk 24/27 (89%)
	G4: 3/108 (2.8%)
				Child C:
				-12 wk 19/22 (86%)
				-24 wk 20/23 (87%)
Belli et al[97], 2016	G1a: 20/103 (19.4%)	Child A: 0	SOF/RBV: 52/103 (50.4%)	SOF/RBV (24-48 wk): RVR 61%	MELD: - 3.4 points
	G1b: 40/103 (38.8%)	Child B: 46/103 (44.7%)	SOF/LDV ± RBV: 9/103 (8.7%)	EVR 98%
	G2: 3/103 (3%)	Child C: 57/103 (55.3%)	SOF/DCV ± RBV: 35/103 (33.9%)		Child: -2 points
	G3: 20/103 (19.4%)		SOF/SMV ± RBV: 7/103 (6.8%)	SOF + 2nd DAA (12-24 wk):
	G4: 20/103 (19.4%)			RVR 67%	Delisting: 20%
				EVR 98%
					Improvement in refractory ascites that became treatable with diuretics
Munoz et al[107], 2015	-	Only cirrhosis	SOF/LDV + RBV (12-24 wk): 230	SVR 84%	MELD: -2.9 + - 0.1
			DCV/SOF + RBV (12 wk): 56		Child B to Child A: 35%
			GRZ/ELB (12 wk): 27		Child C to Child B: 48%
			SOF/LDV/DCV ± RBV (12 wk): 220
Manns et al[101], 2016	G1a: 50/107 (46.7%)	Child A: 2/107 (2%)	LED/SOF + RBV 12 or 24 wk	genotype 1	MELD improvement in 72%
	G1b: 47/107 (43.9%)	Child B: 60/107 (56%)		Child B: 12 wk 20/23 (87%); 24 wk 22/23 (96%)	Child B to Child A: 28%
	G4: 10/107 (9.4%)	Child C: 45/107 (42%)		Child C: 12 wk 17/20 (85%); 24 wk 18/23 (78%), 1/2 (50%)	Child C to Child B: 68%
				Genotype 4
				Child B: 12 wk 2/3 (67%); 24 wk 100%
				Child C: 12 wk 0%
				24 wk
Poordad et al[100], 2016	G1a: 34/60 (56.7%)	Child A: 12/60 (20%)	DCV/SOF + RBV 12 or 24 wk	Child A: 11/12 (92%)	MELD improvement in 47% of pts
	G1b: 11/60 (18.3%)	Child B: 32/60 (53.3%)		Child B: 30/32 (94%)	Child improvement in 60% of pts
	G2: 5/60 (8.3%)	Child C: 16/60 (27.7%)		Child C: 9/16 (56%)
	G3: 6/60 (10%)
	G4: 4/60 (6.7%)
Jacobson et al[99], 2015	Part 1	Only Child B cirrhosis	GRZ/ELB 12 wk	SVR 27/30 (90%)	MELD improvement in 11/30 (36.7%) pts
	G1a: 27/30 (90%)
	G1b: 3/30 (10%)
Curry et al[26], 2015	G1a: 159/267 (59.6%)	Child A: 16/267 (6%)	SOF/VEL 12 or 24 wk	SOF/VEL 12 wk: 75/90 (83%)	MELD improvement in 51% of pts
	G1b: 48/267 (18%)	Child B: 240/267 (89.9%)	SOF/VEL + RBV 12 wk	SOF/VEL + RBV 12 wk: 82/87 (94%)	Child improvement in 47% of pts
	G2: 12/267 (4.5%)	Child C: 11/267 (4.1%)		SOF/VEL 24 wk: 77/90 (86%)
	G3: 39/267 (14.6%)
	G4: 8/267 (3%)
	G6: 1/267 (0.3%)
Gray et al[106], 2016	G1a: 29/101 (28.7%)	Child A: 15/101 (14.8%)	SOF/LDV ± RBV 12 wk	74.3%	No significant differences from baseline
	G1b: 19/101 (18.8%)	Child B: 67/101 (66.3%)			Mortality rate 7.9% (6% Child B, 21% Child C)
	G1 (no subtype): 27/101 (26.7%)	Child C: 19/101 (18.8%)
	G2: 0
	G3: 24/101 (23.8%)
	G4: 1/101 (1%)
	Mixed: 1/101 (1%)
Aquel et al[103], 2015	G1a: 82/119 (69%)	Child A: 84/119 (70%)	SMV/SOF ± RBV 12 wk	RVR: 82/119 (69%)	MELD improvement in 61/92 (66.4%) pts that achieved SVR 12
	G1b: 24/119 (20%)	Child B: 34/119 (29%)		SVR 12: 92/118 (78%; Child A: 83%, Child B: 68%) (1 pts died after achieving SVR4)
	G1 (no subtype): G13/119 (11%)	Child C: 1/119 (1%)
Saxena et al[104], 2015	1a: 98/160 (62%)	Child A: 101/160 (65%)	SMV/SOF ± RBV 12 wk	Child A (37% with RBV): 91%	No significant differences from baseline
	1b: 62/160 (38%)	Child B: 49/160 (31%)		Child B/C (35% with RBV): 73%
		Child C: 6/160 (4%)

Pts: Patients; LDV: Ledipasvir; SOF: Sofosbuvir; RBV: Ribavirin; DCV: Daclatasvir; SMV: Simeprevir; RVR: Rapid virological response (HCV-RNA < 15 UI after 4 wk of treatment); EVR: Early virological response (HCV-RNA < 15 UI after 12 wk of treatment); GRZ: Grazoprevir; ELB: Elbasvir; VEL: Velpatasvir; FCH: Fibrosing cholestatic hepatitis.

Table 4 Studies evaluating the effects of direct acting antivirals in liver transplant recipients

Ref.	HCV genotype	Fibrosis stage	Treatment	SVR12 rate	Observed improvement
Charlton et al[98], 2015	Cohort B	No cirrhosis: 111/229 (48.5%)	LDV/SOF + RBV 12 or 24 wk	No cirrhosis:	-
	G1a: 164/229 (71.6%)	Child A: 51/229 (22.3%)		12 wk 53/55 (96) 24 wk 55/56 (98)
	G1b: 63/229 (27.5%)	Child B: 52/229 (22.7%)		Child A:
	G4: 2/229 (0.9%)	Child C: 9/229 (3.9%)		12 wk 25/26 (96%)
		FCH: 6/229 (2.6%)		24 wk 24/25 (96%)
				Child B:
				12 wk 22/26 (85%)
				24 wk 23/26 (88%)
				Child C:
				12 wk 3/5 (60%)
				24 wk 3/4 (75%)
				FCH:
				12 and 24 wk 100%
Manns et al[101], 2016	Cohort B	No cirrhosis: 101/226 (44.7%)	LDV/SOF + RBV 12 or 24 wk	Genotype 1:	MELD improved in 58%
	G1a: 113/226 (50%)	Child A: 71/226 (31.4%)		No cirrhosis: 12 wk: 42/45 (93%)
	G1b: 86/226 (38%)	Child B: 40/226 (17.7%)		24 wk: 44/44 (100%)	Child B to A: 52%
	G4: 27/226 (12%)	Child C: 9/226 (4%)		Child A:	Child C to B: 60%
		FCH: 5/226 (2.2%)		12 wk: 30/30 (100%)
				24 wk: 27/28 (96%)
				Child B:
				12 wk: 19/20 (95%)
				24 wk: 20/20 (100%)
				Child C:
				12 wk: 1/2 (50%)
				24 wk: 4/5 (80%)
				FCH:
				12 and 24 wk: 100%
				Genotype 4:
				No cirrhosis:
				12 and 24 wk 100%
				Child A:
				12 wk 3/4 (75%)
				24 wk 100%
				Child B:
				12 and 24 wk 100%
				Child C:
				12 wk 0%
Poordad et al[100], 2016	G1a: 31/53 (58.5%)	F0: 6	DCV/SOF + RBV 12 and 24 wk	50/53 (94%)	-
	G1b: 10/53 (18.9%)	F1: 10
	G2: 0	F2: 7
	G3: 11/53 (20.7%)	F3: 13
	G4: 0	F4: 16
	G6: 1/53 (1.9%)	ND: 1
Brown et al[111], 2016	G1a: 87/151 (57.6%)	Cirrhosis: 97/151 (64.2%)	SMV/SOF ± RBV	133/151 (88%)	-
	G1b: 42/151 (27.8%)			SMV/SOF 105/119 (88%)
	G1 (unspecified): 22/151 (14.6%)			SMV/SOF + RBV 28/32 (88%)

LDV: Ledipasvir; SOF: Sofosbuvir; RBV: Ribavirin; DCV: Daclatasvir; SMV: Simeprevir; RVR: Rapid virological response (HCV-RNA < 15 UI after 4 wk of treatment); EVR: Early virological response (HCV-RNA < 15 UI after 12 wk of treatment); GRZ: Grazoprevir; ELB: Elbasvir; VEL: Velpatasvir; FCH: Fibrosing cholestatic hepatitis; HCV: Hepatitis C virus.