Impact of direct acting antivirals on occurrence and recurrence of hepatocellular carcinoma: Biologically plausible or an epiphenomenon?

Table 1 Possible factors contributing to hepatocellular carcinoma after hepatitis C virus eradication by direct acting antivirals

Down regulation of IFN genes

Presence of fibrosis

Sudden disruption of chronic inflammatory state

Impaired immune response by NK cells

T cell dysfunction

Decreased microRNA-122

IFN: Interferon; NK: Natural killer.

Table 2 Studies showing an increased incidence of hepatocellular carcinoma in direct acting antivirals treated patients

Ref.	Treatment groups	Country/sample size	Male gender n (%)	Age (yr)	Genotype n (%)	Duration of follow up	Cirrhosis n (%)	History of HCC n (%)	HCC occurrence	HCC recurrence
Reig et al[8]	All DAA treated	Spain n = 58	40 (69)	Median 66.3 (45-83)	G1a = 8 (13.8%), G1b = 45 (77.6%), G3 = 2 (3.4%), G4 = 3 (5.2%)	median 5.7 mo	55 (94.8)	58 (100)	Not applicable	16 (27.6%)
Conti et al[18]	All DAA treated	Italy n = 344	207 (60.2)	Median = 63 (29-85)	G1= 237 (69), G2= 40 (11.6), G3= 38 (11), G4= 29 (8.4)	24 wk	All cirrhotic	59 (17)	9 of 285 patients (3.16%, 95%CI: 1.45–5.90)	17 of 59 patients (28.81%, 95%CI: 17.76–42.07)
Cardoso et al[26]	All DAA treated	Portugal n = 54	> 70%	No HCC: 59 yr (41-81). Patients with HCC = 58 yr (55-72)	No HCC: G1 = 78%, G3 = 18%. Patients who developed HCC: G1 = 75%, G3 = 25%	Median = 12.0 mo (9.4-12.5 mo)	All cirrhotic	0 (0)	4 (7.4%)	Not applicable
Ida et al[28]	All DAA treated	Japan n = 100	46 (46)	Median 72.5 (26-87)	G1 = 100 (100)	15 mo		26 (26)	5 (5)	12 (12)
Kozbial et al[29]	All DAA treated	Austria	-	56-74 yr	G1a = 3 (15.8), G1b = 13 (68.4), G3a = 2 (10.5), G4 = 1 (5.2)			3 (15.8)	6.60%	3 patients
Issachar et al[30]	All DAA treated	Israel n = 273	-	-	-	15 mo	-	-	6 (2.1)	3 (1.05)
Kwong et al[31]	patients divided into 3 eras: IFN era (2003-2010), protease inhibitor era (2011-2013), and DAA era (2014-2015)	United States n = 48158	29858 (62)	Median 55 (49-60) yr		Median 493 d	All cirrhotic		Incidence Rate of HCC was 49% higher in the DAA era (IR 6.6/100 person-years [py], 95%CI: 5.6-7.9) vs the IFN era (4.5/100 py, 95%CI: 4.2-4.7; IRR 1.49, 95%CI: 1.24-1.79, P < 0.001).	Not applicable
Strazulla et al[32]	daclatasvir and simeprevir for 24 weeks to reach SVR	Italy n = 1 case report	1 male	53	G1	24 wk	Decompe-nsated cirrhosis	Treated	Not applicable	1 recurrence
Bielen et al[27]	PEG-IFN+ DAA = 77 (13.5), DAAs only = 490 (86.4)	Belgium n = 567	PEG IFN + DAA group: 55 (71.4) DAA only group: 307 (62.7)	PEG IFN + DAA group age : 52 ± 9, DAA only group: 59 ± 12	PEG IFN + DAA group: all genotype 1. DAA only: G1 = 69%, G4 = 14.7%	6 mo	Metavir fibrosis score F3/F4 included only	PEG IFN + DAA = 1/77 (1.3%),DAA alone: 41/490 (8.4%)	Early occurrence rate of HCC = 1.7% and 1.1% in patients treated with DAA with and without PEG-IFN, respectively	Early recurrence rate was 0% in patients treated with PEG-IFN+DAA and 15.0% in patients treated with DAA without PEG-IFN

DAAs: Direct acting antivirals; IFN: Interferon; HCC: Hepatocellular carcinoma.

Table 3 Studies that do not report an increased risk of hepatocellular carcinoma with direct acting antivirals

Ref.	Treatment N /sample size	Country	Male gender n (%)	Age (yr)	Genotype n (%)	Duration of follow up	Cirrhosis n (%)	History of HCC n (%)	HCC occurrence	HCC recurrence
Ioannou et al[33]	IFN only = 35871 (58%), DAA + IFN = 4535 (7.2%), DAA only = 21948 (35%) n = 62354	United States	96.60%	Mean 55.8 ± 7.6	G1 = 77.4 %, G2 = 13.5%, G3 = 8.3%, G4 = 0	Mean follow-up DAA only group = 1.53 years, DAA+IFN group= 3.6 yr, IFN only group = 9.1 yr	Cirrhosis: 16.8%, decompe-nsated cirrhosis: 4.7%	None	Total 3271 incident cases. IFN group = 0.81/100 person years, DAA + IFN = 1.06 /100 py, DAA only = 1.32/100 py	Not applicable
Kanwal et al[34]	All DAA treated n = 22500	United States	21761 (96.7%)	Mean 61.6 ± 6.1	G1 = 19531 (86.8%), G2 = 1422 (6.3%), G3 = 940 (4.2%), G 4-6 = 217 (1%)	22963 person years of follow-up	8766 (39.0%)	None	271 (1.2)	Not applicable
ANRS CO22 HEP ATH-ER et al[35]	DAA group = 189, no DAA = 78 n =267	France	DAA group = 147 (78%)	DAA group = 62 ± 9 yr, no DAAs = 66 ± 10 yr	65 % genotype 1	Median: 20.2 mo after DAA initiation and 26.1 mo for untreated patients	Cirrhosis: DAA group = 152 (80%), no DAAs = 55 (72 %)	All treated	Not Applicable	DAA group = 24 (12.7%), no DAAs = 16 (20.5%)
ANRS CO12 CIRVIR et al[35]	DAA group = 13, no DAA = 66 n = 79	France	DAA group = 11 (85%), no DAA = 39 (59%)	DAA group = 61 ± 10 yr, no DAA = 65 ± 9 yr	Genotype 1: DAA group = 11 (85%), no DAA group = 53/63 (84 %)		All cirrhotic	All treated	Not Applicable	DAA group = 1 (7.7%), no DAAs = 31 (47%)
ANRS CO23 CUPILT et al[35]	All DAA treated n = 314	France	257 (82%)	61 ± 8 yr	212 (67.5%) genotype 1		49 (15.6%)	Treated	Not Applicable	7 (2.2%)
Cabibbo et al[36]	All DAA treated n = 143	Italy	80 (60.1)	Mean 70.4 ± 8.9	G1a: 9 (6.3), 1b: 114 (79.7), G2: 9 (6.3), G3: 7 (4.9), G4: 4 (2.8)	6, 12 and 18 mo	All cirrhotic	All treated	Not applicable	6-, 12- and 18-mo HCC recurrence rates were 12%, 26.6% and 29.1%, respectively
Nagata et al[37]	IFN-based: 1145. IFN-free DAA group: 752 n = 1897	Tokyo	IFN group: 621 (54), IFN free: 340 (45)	Median: IFN group: 59 (19-79); IFN free: 69 (24-87)	IFN group: G1a = 8 (7), G1b = 833 (73), G2a = 182 (16), G2b = 105 (9), G3 = 1 (0)	Median for IFN group: 6.8 (0.2-22.0); IFN free: 1.8 (0.1–7.7)		5% of IFN group, 11% of IFN free group	IFN group: 18 (2.5%). IFN-free group: 7 (1.1%)	IFN group: 18 (53%). IFN-free group: 22 (29%)
Ikeda et al[38]	All DAA treated n = 177	Japan	M:F = 52: 37 in each group	DAA group: 71 (39-85)		Median 20.7 mo		All treated	Not applicable	HCC recurrence rates at 1st and 2nd year were 18.1 and 25.0% in pts with DAA therapy and 21.8 and 46.5% in those without DAAs, (P = 0.003)
Zanetto et al[39]	DAA treated= 23, control = 23 n = 46	Italy		DAA group = 59 (49-69), controls= 58 (46 -70)	DAA group: G1a = 5 (22), Gb = 9 (39), G2 = 1 (4), G3 = 5 (22), G4 = 3 (13)	Median= DAA group = 10 mo, Control group = 7 mo	All cirrhotic	All treated	Not applicable	12.5% of DAA-treated patients and 8.3% of control group had HCC recurrence (P = 0.60)
Zavaglia et al[40]	All DAA treated n = 31	Italy	20 (64.5)	Mean 65 ± 8	G1a = 4 (13), G1b = 23(74), G2 = 2 (6.5), G4 = 2 (6.5)	Median 8 mo	All cirrhotic	All treated	Not applicable	1 (3.2)
Ogata et al[41]	All DAA treated n = 1170	Japan	493 (42)	Median = 67 (21-88)	All genotype 1	Time from the end of DAA therapy until last visit: 1.3 yr		None	22 cases (1.8%)	Not applicable
Minami et al[42]	DAA group = 27, IFN group = 38, Controls = 861 n = 926	Japan	DAA group: 18 (67), IFN group: 27 (71), Controls: 489 (57)	Median age: DAA group = 71 (48-82) IFN group = 66 (49-79), Control = 71 (44–91)	Genotype 1: DAA = 21 (78), IFN = 29 (76), Controls = 633 (74). Genotype 2: DAA= 6 (22), IFN= 9 (24), Control= 147 (17)	1 and 2 yr		All treated	Not applicable	Cumulative recurrence rates at 1 and 2 yr were 21.1% and 29.8%, respectively, in the DAA group, 26.3% and 52.9%, respectively, in the IFN group, and 30.5% and 61.0%, respectively, in the control group
Deterding et al[43]	n = 974	Germany			G1 = 743 (76.2)		All had advanced cirrhosis		12 (1.2)
Degasperi et al[44]	n = 565	Italy	60%	Median age = 65 (30-87) yr	G1a = 15%, G1b = 49%, G2 = 13%, G3 = 11%, G4 = 12%, G5 = 1%	Median 42 wk for occu-rrence, 39 wk for recurrence	All cirrhotic	48 (8%)	20 (4%) estimated annual incidence of 1.6%	9 (19%), annual incidence of 7 .7%
Bourliere et al[45]	DAA + RBV ± PEG IFN = 21%. IFN free DAA therapy = 79% n = 1393			47 (19-79) yr		2.5 (0.6-4.3) yr			0 (0)	0 (0)
Nagaoki et al[46]	PEG-IFN/ RBV = 244, DCV/ASV = 154 n = 398	Japan			All genotype 1	Median for PEG-IFN/RBV = 96 (10–196) and DCV/ASV group = 23 (4–78) mo			PEG-IFN/RBV = 13 (5.3%), DCV/ASV group = 7 (4.5%)
Cheung et al[47]	All DAA	United Kingdom			198 (48.8) 171 (42.1)	15 mo	All decompensated cirrhosis	29 (71.4%)	17 (5%)	2
Mettke et al[48]	158 DAA treated, 184 controls	Germany				Median = 440 (91–908) and 592 (90-1000) d	All cirrhotic		6 and 14 patients during follow-up, resulting in an HCC incidence of 2.9 (AVT) and 4.48 (Con) per 100 py, respectively
Ji et al[49]		China	51%	Mean age 51	82.2% genotype 1b	Median 14 (3-35) mo	48% cirrhotic	None		Not applicable
Innes et al[50]		Scotland				1.8 yr		None	44 (5.1%)	Not applicable
Torres et al[51]	All DAA treated	United States	7 (87.5%)	Median 64 (57-87) years	G1 = 6 (75%), mixed genotype = 2 (25%)	12 mo	7 (87.5%)	All treated	Not applicable	0 (0)

DAAs: Direct acting antivirals; IFN: Interferon; HCC: Hepatocellular carcinoma.

Table 4 Factors predisposing to hepatocellular carcinoma in hepatitis C virus patients treated with direct acting antivirals after sustained virologic response

Past history of hepatocellular carcinoma[18,28,36]

Male gender[28]

Cirrhosis[34]

Hypoalbuminemia[41]

Thrombocytopenia[41]

Raised AFP levels[41]