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

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.