Hepatocellular carcinoma after direct-acting antiviral hepatitis C virus therapy: A debate near the end

Table 1 De novo hepatocellular carcinoma incidence after direct-acting antiviral treatment

Ref.	Type of study	Patient (n) and characteristics	Follow-up time	De novo HCC incidence
Conti et al[14]	Retrospective study	Cirrhotic patients treated with DAAs (n = 285)	Mean FU: 5.6 mo	3.16%
Ravi et al[33]	Retrospective study	Cirrhotic patients treated with DAAs (n = 66)	From SOT to 6 mo after EOT	9.1%
Singer et al[34]	Retrospective study	DAA-treated (n = 30183), IFN-treated (n = 12948), untreated (n = 137502)	Mean FU: 1.05 yr	1.18 per 100 PY
Nahon et al[43]	Retrospective study	All compensated cirrhotic patients DAA-treated (n = 336), IFN-treated with SVR (n = 495), IFN-treated without SVR (n = 439)	Median FU: 21.2 mo (IQR: 13.5-26.9)	2.6 per 100 PY
Ioannou et al[35]	Retrospective study	DAA-treated (n = 21948), IFN-treated (n = 35871), DAA + IFN treated (n = 4535)	Mean FU: 6.1 yr	1.32 per 100 PY
Kanwal et al[37]	Retrospective study	DAA-treated (n = 22500)	Mean FU: 1.02 yr	1.18 per 100 PY
Cheung et al[42]	Prospectivestudy	DAA-treated (n = 406), untreated (n = 261)	Median FU: 18 mo	4%
Calleja et al[38]	Retrospectivestudy	DAA-treated (n = 3325)	Mean FU: 18 mo	11.3%
Mettke et al[44]	Prospective study	DAA-treated (n = 158), untreated (n = 184)	Median FU: 440 d	2.90 per 100 PY
Carrat et al[45]	Prospectivestudy	DAA-treated (n = 7344), untreated (n = 2551)	Median FU: 33.4 mo (IQR: 24.0-40.7)	1.40 per 100 PY
Janjua et al[36]	Retrospective study	IFN-treated (n = 8871), DAA-treated (n = 3905)	Median FU: 1.0 yr	6.9 per 1000 PY
Poordad et al[46]	Prospective study	DAA-treated (n = 2211)	156 wk from EOT	1.4%
Sangiovanni et al[47]	Prospective study	DAA-treated (n = 1285)	Mean FU: 17 mo	3.1 per 100 PY
Kanwal et al[39]	Retrospective study	DAA-treated (n = 18076)	Mean FU: 2.9 yr	3%
Romano et al[48]	Prospective study	DAA-treated (n = 3917)	Median FU: 523 d, (IQR: 381-699 d)	0.97 per 100 PY
Tani et al[40]	Retrospective study	DAA-treated (n = 1088)	Median FU: 13.8 mo	2.38%
Watanabe et al[41]	Retrospective study	DAA-treated (n = 1438)	Median FU: 803 d	3.82%

DAA: Direct-acting antivirals; SOT: Start of treatment; FU: Follow-up; HCC: Hepatocellular carcinoma; HCV: Hepatitis C virus; IFN: Interferon; IQR: Interquartile range; PY: Person-year; EOT: End of treatment; SVR: Sustained viral response.

Table 2 Recurrent hepatocellular carcinoma incidence after direct-acting antiviral treatment

Ref.	Type of study	Patient (n) and characteristics	Follow-up time	Recurrent HCC incidence
Reig et al[13]	Retrospective study	DAA-treated (n = 103)	Mean FU: 5.7 mo	27.6%
Conti et al[14]	Retrospective study	DAA-treated (n = 59)	Mean FU: 5.6 mo	28.8%
ANRS CO22 HEPATHER[64]	Prospective study	DAA-treated (n = 189), untreated (n = 78)	Mean FU: 20.2 mo	0.73 per 100 person-months
ANRS CO12 CirVir[64]	Prospective study	All biopsy proven cirrhotic patients, DAA-treated (n = 13), untreated (n = 66)	Median FU: 21.3 mo (IQR: 13.0-33.5)	1.11 per 100 person-months
ANRS CO23 CUPILT[64]	Prospective study	LT recipients for HCC, treated with DAA (n = 314)	Mean FU: 70 ± 64 mo after LT	2.2%
Cabibbo et al[65]	Prospective study	DAA-treated (n = 143)	Mean FU: 8.7 mo	20.3%
Lin et al[59]	Retrospective study	DAA-treated (n = 60), untreated (n = 47)	Median FU: 20 mo	37.1%
Singal et al[60]	Retrospectivestudy	DAA-treated (n = 304), IFN-treated (n = 489)	Median FU: 10.4 mo (IQR: 5.3-20.8) since complete remission	DAA treated 42.1%, untreated 52.9%
Nagata et al[62]	Retrospectivestudy	DAA-treated (n = 83), IFN-treated (n = 60)	Mean FU: IFN 81.6 mo, DAA 21.6 mo	IFN-treated 54.2%, DAA- treated 45.1%
Imai et al[63]	Retrospective study	DAA-treated (n = 13), IFN-treated (n = 34), untreated (n = 70)	N/A

DAA: Direct-acting antivirals; FU: Follow-up; HCC: Hepatocellular carcinoma; IFN: Interferon; IQR: Interquartile range; LT: Liver transplant; N/A: Not available.

Table 3 Risk factors for de novo and recurrent hepatocellular carcinoma after direct-acting antiviral therapy

Ref.	Type of study	Patient (n) and characteristics	Risk factors
Conti et al[14]	Retrospective study	Cirrhotic patients treated with DAAs (n = 285)	No associated factor for de novo HCC, older age, liver stiffness for HCC recurrence
Singer et al[34]	Retrospective study	DAA-treated (n = 30183), IFN-treated (n = 12948), untreated (n = 137502)	Older age, male gender, cirrhosis, thrombocytopenia, portal hypertension, diabetes, tobacco use, alcoholic liver disease
Ioannou et al[35]	Retrospective study	DAA-treated (n = 21948), IFN-treated (n = 35871), DAA + IFN treated (n = 4535)	Non-SVR, cirrhosis
Kanwal et al[37]	Retrospective study	DAA-treated (n = 22500)	Non-SVR, alcohol use, non-African Americans, cirrhosis
Hanafy et al[71]	Prospectivestudy	All decompensated cirrhotic patients, DAA-treated (n = 160), untreated (n = 80)	An adequate baseline liver volume measured by ultrasound was associated with less HCC occurrence and better short-term survival
Kanwal et al[39]	Retrospective study	DAA-treated (n = 18076)	High FIB-4/APRI, alcohol use, older age, genotype 3
Watanabe et al[41]	Retrospective study	DAA-treated (n = 1438)	High FIB-4 index, AFP
Nagata et al[62]	Retrospective study	DAA-treated (n = 83), IFN-treated (n = 60)	IL-28 genetic polymorphism, post-treatment WFA+M2BP, AFP (> 5.4 ng/mL)
Ide et al[68]	Prospectivestudy	CHC DAA-treated (n = 2552)	Age ≥ 62 yr, male gender, FIB-4 index ≥ 4.6, GGTP level ≥ 44 IU/L
Calvaruso et al[69]	Prospective study	HCV cirrhosis DAA-treated (n = 2249)	Albumin < 3.5 g/dL, platelets < 120 × 109/L, absence of SVR
Romano et al[48]	Prospective study	CHC > F3 DAA-treated (n = 3917)	HBsAg+, APRI ≥ 2.5, CPT B, treatment failure
Sangiovanni et al[47]	Retrospective study	1161 HCC-free HCV cirrhotics, DAA treated, 124 HCV cirrhotics who had received a curative treatment for an HCC DAA treated	De novo HCC: Ascites, AFP, recurrent HCC: History of alcohol abuse, history of HCC recurrence

DAA: Direct-acting antivirals; FU: Follow-up; HCC: Hepatocellular carcinoma; SVR: Sustained virological response; IFN: Interferon; IQR: Interquartile range; LT: Liver transplant; CHC: Chronic hepatitis C; APRI: Aspartate aminotransferase to platelet ratio index; CPT: Child-Pugh-Turcotte; SVR: Sustained viral response; AFP: Alpha-fetoprotein; WFA⁺M2BP: Wisteria floribunda agglutinin positive Mac-2 binding protein; HCV: Chronic hepatitis C; GGTP: Gamma-glutamyl transpeptidase.