Direct-acting antivirals and hepatocellular carcinoma in chronic hepatitis C: A few lights and many shadows

Table 1 Main characteristics of the studies on hepatocellular carcinoma occurrence

Ref.	Journal, year	Country	Study design	Sample size	Median follow-up (mo)	HCC cumulative incidence (%)	Risk factors	Notes
Conti et al[8]	J Hepatol, 2016	Italy	Retrospective	207	6	3.1	cirrhosis, child class B, low platelet count	No control group
Cheung et al[15]	J Hepatol, 2016	United Kindom	Prospective	406	18	5.4 in SVR group	NA	Control groups: Non-SVR with HCC incidence of 11.3%
Kozbial et al[12]	J Hepatol, 2016	Austria	Retrospective	16	NA	6.6	NA	Letter to editor
Cardoso et al[10]	J Hepatol, 2016	Portugal	Retrospective	54	12	7.4	NA	Letter to editor
Kanwal et al[13]	Gastroenterology, 2017	United States	Retrospective	22500	NA	1.2	cirrhosis, alcohol use	HCC incidence: 0.9% in SVR, 2.9% in non-SVR
Zeng et al[18]	J Hepatol, 2016	China	Retrospective	21	15	0	NA	Letter to editor
Calleja et al[14]	J Hepatol, 2017	Spain	Retrospective	3325	18	0.93	NA	-
Ioannou et al[31]	J Hepatol, 2017	United States	Retrospective	21948	18	2	NA	HCC incidence: 1.4% in SVR, 8.1% in non-SVR
Mettke et al[17]	Aliment Pharmacol Ther, 2017	Germany	Prospective	158	15	3.7	MELD score, AFP level	HCC incidence in untreated: 7.6%
Nakao et al[9]	J Hepatol, 2017	Japan	Retrospective	242	15	2.8	NA	Letter to editor
Calvaruso et al[19]	Gastroenterology, 2018	Italy	PWrospective	2249	14	3.5	low albumin level, absence of SVR, low platelet count	The rate of HCC at 1 yr was 2.9%.

AFP: Alpha-fetoprotein; DAAs: Direct-acting antiviral agents; HCC: Hepatocellular carcinoma; HCV: Hepatitis C virus; LR: Liver resection; LRT: Local-regional therapy; LT: Liver transplantation; SVR: Sustained virological response; RFA: Radiofrequency ablation; TACE: Trans-catheter arterial chemoembolization; NA: Not available.

Table 2 Main characteristics of the studies on hepatocellular carcinoma recurrence

Ref.	Journal, year	Country	Study design	Sample size	Previous HCC treatment	Median follow-up (mo)	HCC recurrence rate (%)	Risk factors	Notes
Reig et al[7,37,38]	J Hepatol, 2016 and 2017 - Semin Liv Dis, 2017	Spain	Retrospective	77	Ablation, resection, TACE	11.2	27.3	NA	Updated cohort of the 58 patients reported in J Hepatol 2016
Conti et al[8]	J Hepatol, 2016	Italy	Retrospective	59	Ablation, resection, TACE	12	28.8	age, liver stiffness	-
ANRS - HEPATHER et al[43]	J Hepatol, 2016	France	Prospective	189	NA	20	12.7	NA	-
ANRS - CirVir et al[43]	J Hepatol, 2016	France	Prospective	13	Ablation, resection	16.5	7.7	NA	-
ANRS - CUPILT et al[43]	J Hepatol, 2016	France	Prospective	314	Bridge therapy before LT (Ablation, resection, TACE, chemotherapy)	7	2.2	NA	-
Calleja et al[14]	J Hepatol, 2017	Spain	Retrospective	70	NA	20	30	NA	-
Cabibbo et al[50]	APT, 2017	Italy	Prospective	143	Ablation, resection, TACE	9	21	previous recurrence, tumour size	-
Minami et al[55,56]	J Hepatol 2016 - Abs AASLD 2017	Japan	Retrospective	163	Ablation, resection, TACE, radiotherapy	14.5	54.4	AFP-L3, DCP, number of previous treatment for HCC, interval between last HCC treatment and DAA start	Abstract of AASLD 2017
Virlogeux et al[46]	Liver Int 2017	France	Retrospective	23	Ablation, resection, TACE	13	47.8	NA	-
Zeng et al[18]	J Hepatol, 2016	China	Retrospective	10	Ablation	15	0	NA	Letter to Editor
Ogawa et al[48]	Aliment Pharmacol Ther, 2017	Japan	Prospective	152	Ablation, resection, TACE, radiotherapy	17	16.5	cirrhosis, time from previous HCC treatment < 1 yr, non-curative HCC treatment (TACE, radiotherapy)	-
Cheung et al[15]	J Hepatol 2016	United Kingdom	Prospective	29	NA	15	6.8	NA	-
Torres et al[44]	J Hepatol 2016	United States	Prospective	8	Ablation, resection, proton therapy	12	0	NA	Letter to Editor
Yang et al[41]	J Hepatol 2016	United States	Prospective	18	Bridge therapy before LT: Ablation, TACE	NA	27.8	NA	Letter to Editor; untreated patients: 9.5%
Bielen et al[29]	J Viral Hepat 2017	Belgium	Retrospective	41	LT, ablation, resection, TACE	32	14.6	SVR	-
Ikeda et al[45]	Dig Dis Sci 2017	Japan	Retrospective	177	Ablation, resection, TACE, radiotherapy	20.7	34.5	multiple HCC treatment, AFP level, Prothrombin time	-
Kolly et al[39]	J Hepatol 2017	Germany, Belgium, Switzerland	Prospective	56	Ablation, resection, TACE	21	42.5	time from previous HCC treatment	Letter to Editor
Nagata et al[30]	J Hepatol 2017	Japan	Retrospective	83	Ablation, resection	27.6	29	SVR, AFP, WFA-M2BP	-
Shimizu et al[52]	Indian J Gastroenterol 2017	Indian	Retrospective	23	RFA, TACE, radiation	NA	43	HBcAb positivity, TACE	-
Mashiba et al[57]	Plos one 2018	Japan	Retrospective	368	NA	24	NA	AFP level, SVR, clinical stage of HCC	-

AFP: Alpha-fetoprotein; DAAs: Direct-acting antiviral agents; HCC: Hepatocellular carcinoma; HCV: Hepatitis C virus; LR: Liver resection; LRT: Local-regional therapy; LT: Liver transplantation; SVR: Sustained virological response; RFA: Radiofrequency ablation; TACE: Trans-catheter arterial chemoembolization; NA: Not available.