supplementary material 1. methods

Supplementary material 1.

Methods.

Prospero.

To enable PROSPERO to focus on COVID-19 registrations during the 2020 pandemic,

this registration record was automatically published exactly as submitted. It has not

been checked for eligibility or for ILCA and EASL HCC summit were reviewed.

Systematic search

Systematic search for records up to 3rd April 2018 of PubMed Central/MEDLINE was

performed with the following keywords and combinations:

“hepatocellular carcinoma” AND “recurrence” AND “direct antiviral agents” [OR

“sofosbuvir”]. A second search was performed following “hepatocellular carcinoma”

AND “recurrence” AND “hepatitis C virus” with the data filter between April 2016

when the first paper was published until April 2018. Furthermore, abstracts presented in

onco-hepatology meetings such as EASL, AASLD, ESMO, ESMO-GI, starting DAAs

and also the prior history of HCC treatment (first treatment, type and number of

previous treatments); f) report the HCC stage before starting DAAs and the HCC status

at that time point (complete radiologic response [CRR] yes/no); g) report the date of

DAA initiation and finalization, SVR12 status; f) report the date of HCC recurrence,

HCC stage and treatment received at the time of HCC recurrence. If the patient did not

develop HCC recurrence, the date of the last radiology assessment was recorded. All the

additional data from each database was also be included in the analysis.

BMJ Publishing Group Limited (BMJ) disclaims all liability and responsibility arising from any relianceSupplemental material placed on this supplemental material which has been supplied by the author(s) Gut

doi: 10.1136/gutjnl-2020-323663–12.:10 2021;Gut, et al. Sapena V

Propensity Score model.

The PS model was constructed including age, gender (male/female), type of first HCC

treatment (Ablation, Resection, TACE or Others), Child-Pugh (A, B or C), INR,

creatinine, natural logarithm of creatinine, squared creatinine, AFP, natural logarithm of

AFP, cubed AFP, albumin, ALT, natural logarithm of ALT, squared ALT, total

bilirubin, MELD score, encephalopathy, extrahepatic spread, vascular vein invasion,

ECOG-PS (0, 1 or 2), ascites, tumour burden of first HCC (solitary nodule, <=3 nodules

<=3cm each or multifocal), number of previous HCC recurrences and natural logarithm

of previous HCC recurrences.



Supplementary Tables.

1.- Supplementary Table S1. Baseline Characteristics of the included patients before

starting DAA

2.- Supplementary Table S2. Characteristics of patients at HCC recurrence

3.- Supplementary Table S3. Regression models, subgroup and leave-one-out analysis

for HCC recurrence

A. Multivariate regression models

B. Subgroup analysis

C. Leave-one-out

4.- Supplementary Table S4. Subgroup analysis of HCC recurrence according to the

time between the last CR and DAA initiation

5.- Supplementary Table S5. Characteristics of DAA-exposed and unexposed patients

6.- Supplementary Table S6. Characteristics of matched population



1.- Supplementary Table S1. Baseline Characteristics of the included patients before starting DAA Patients, n 977

Age (Years) & 69.72 [60-76]

Gender (Male) & 618 (63.3)

Weight (kg) $ 67 [56.4-76]

Height (cm) $ 165 [158-170]

Genotype&

1 696 (71.2)

2 83 (8.5)

3 47 (4.8)

4 90 (9.2)

5 1 (0.1)

Previous or current alcohol consumption (Yes) # 175 (17.9)

Presence of HBV (Yes) & 16 (1.6)

Presence of HIV (Yes) & 8 (0.8)

Arterial hyper tension (Yes) # 247 (25.3)

Diabetes (Yes) $ 237 (24.3)

Cirrhosis (No) & 20 (2)

Child-Pugh &

A 860 (88)

B 78 (8)

C 15 (1.5)

Not applicable 20 (2)

ALBI score&

ALBI 1 848 (86.8)

ALBI 2 116 (11.9)

ALBI 3 2 (0.2)

MELD score & 8 [7-9]

Fibroscan (kPA) @ 19 [11.7-28.8]

Patient in radiological follow-up (Yes) $ 858 (87.8)

AST (UI/L) & 65 [45-92]

ALT (UI/L) & 57 [36-88]

Total bilirubin (mg/dl) & 0.9 [0.67-1.3]

Albumin (g/L) & 3.9 [3.5-4.3]

Haemoglobin basal (g/dl) & 13.4 [12.1-14.6]

Prothrombin time (%)& 83 [71-98.7]

International Normalized Ratio $ 1.09 [1-1.19]

Creatinine (mg/dl) & 0.8 [0.7-0.97]

GGT (UI/L) @ 55 [33-100]

Alkaline phosphatase (UI/L) @ 159.5 [93-298]



Leukocyte (x109) $ 4 [2-5.82]

Neutrophil (x109) @ 2.51 [1.65-3.61]

Platelets (x109) & 103 [62.5-153]

Number of HCC recurrence before the last complete response&

0 555 (56.8)

1 233 (23.9)

>1 181 (18.5)

Type of 1st HCC treatment&

Liver transplantation 7 (0.7)

Resection 303 (31)

Ablation 462 (47.3)

TACE 149 (15.3)

Combination of Locoregional treatments

34 (3.5)

Radio embolization 9 (0.9)

Others 9 (0.9)

Images used for CR assessment&

Computed Tomography 486 (49.7)

Contrast Ultrasound 40 (4.1)

Magnetic Resonance 317 (32.5)

More than one 29 (3)

Ultrasound 102 (10.4)

Last HCC treatment$

Liver transplantation 8 (0.8)

Resection 209 (21.4)

Ablation 383 (39.2)

TACE 143 (14.6)

Combination of Locoregional treatments

47 (4.8)

Radio embolization 10 (1)

Others 7 (0.7)

Ascites (Yes) & 75 (7.7)

Encephalopathy (Yes) # 12 (1.23)

Oesophageal varices (Yes) $ 296 (30.3)

Vascular Invasion (Yes) & 2 (0.2)

Tumor burden&

Solitary nodule 377 (38.6)

<=3 nodules and <=3cm each 516 (52.8)

Multifocal 69 (7.1)

Extrahepatic spread (Yes) & 2 (0.2)

ECOG-PS (0/1/2) & 888 (90.89) / 62 (6.35) / 5 (0.51)



Alpha-fetoprotein (ng/ml) & 9.05 [5-21.4]

Patient in waiting list for liver transplantation (Yes) &

25 (2.6)

Descriptive statistics are frequencies (%) or median [IQR: 25th – 75th percentile], as

appropriate.

HCV: Hepatitis C Virus; HBV: Hepatitis B Virus; HIV: human immunodeficiency virus; TACE: Trans Arterial Chemoembolization; HCC: Hepatocellular carcinoma; AST: Aspartate aminotransferase; ALT: Alanine aminotransferase; GGT: Gamma glutamyl transpeptidase; IQR: Interquartile range; ECOG-PS: Eastern Cooperative Oncology Group Performance Status. The rate of missingness was <10%&, 10-20%$, >20-30# or >30%@, as specified.



2.- Supplementary Table S2. Characteristics of patients at HCC recurrence

Recurrences, n 409

Gender (Male) & 272 (66.5)

Age (Years) & 67.5 [59.1 - 75.8]

MELD score$ 8 [7-10]

Fibroscan (kPA) @ 29 [15-40]

Sustained virologic response (Yes) & 347 (84.8)

Reason of early discontinuation of DAA&

DAA- related Adverse Events 8 (38)

History of Liver transplant 1 (5)

Others 12 (57)

Cirrhosis (Yes) & 380 (93)

Child-Pugh &

A 312 (76.3)

B 57 (14)

C 11 (2.7)

No cirrhosis 2 (0.5)

ALBI score&

ALBI 1 318 (77.8)

ALBI 2 46 (11.3)

ALBI 3 44 (10.8)

Images used for HCC recurrence assessment#

Contrast Ultrasound 1 (0.2)

Ultrasound 11 (2.7)

Computed Tomography 181 (44.3)

Magnetic Resonance 125 (30.6)

More than one image 5 (1.2)

AST (UI/L) # 33 [26-48]

ALT (UI/L) # 25 [17- 40]

Total bilirubin (mg/dl) $ 0.9 [0.68-1.3]

Direct Bilirubin (mg/dl) @ 0.3 [0.2-0.6]



Hemoglobin (g/dl) # 13 [11.7-14.45]

prothrombin time (%)& 83 [68-97]

International Normalized Ratio$ 1.1 [1-1.2]

Creatinine (mg/dl) $ 0.87 [0.7-1]

Albumin (g/L) $ 3.9 [3.5-4.3]

GGT (UI/L) @ 36 [22-69]

Alkaline phosphatase (UI/L) @ 186 [93-309]

Leukocyte (x109) # 4.9 [3.6-6.5]

Neutrophil (x109) @ 2.9 [2-4.4]

Platelets (x109) $ 115 [74-164]

Ascites (Yes) $ 43 (10.5)

Encephalopathy (Yes) $ 10 (2.4)

Alpha-fetoprotein (ng/ml) $ 10.4 [5-42.6]

Vascular invasion (Yes) & 35 (8.6)

Extrahepatic spread (Yes) & 29 (7.1)

ECOG-PS&

0 286 (69.9)

1 66 (16.1)

2 27 (6.6)

3 3 (0.7)

Tumor burden&

Solitary nodule 152 (37.2)

<=3 nodules and <=3cm each nodule 159 (38.9)

Multifocal 90 (22)

First Treatment of HCC recurrence after DAA$

Liver transplant 9 (2.2)

Resection 19 (4.6)

Ablation 157 (38.4)

TACE 112 (27.4)

Combination of Locoregional treatments 11 (2.7)

Systemic 21 (5.1)



Chemotherapy 5 (1.2)

Radio embolization 1 (0.2)

Others 21 (5.1)

Patient with history of liver transplantation (Yes) # 23 (5.6)

Decompensation (Yes) $ 55 (13.45)

If the patient had decompensation, type of the last

decompensation&

Ascites or Edema 42 (77.8)

Encephalopathy 5 (9.3)

Others 3* (5.5)

Renal failure 1 (1.9)

Variceal bleeding 3 (5.5)

Death (Yes/No) & 100 (24.45) / 309 (75.55)

Cause of death&

Adverse Events related with HCC or with

treatment

31 (31)

HCC 42 (42)

Not HCC related 14 (14)

Not available 13 (13)

Descriptive statistics are frequencies (%) or median [IQR: : 25th – 75th percentile], as

appropriate.

TACE: Trans Arterial Chemoembolization; HCC: Hepatocellular carcinoma; AST:

Aspartate aminotransferase; ALT: Alanine aminotransferase; GGT: Gamma glutamyl

transpeptidase; HCC: Hepatocelular carcinoma; ECOG-PS: Eastern Cooperative

Oncology Group Performance Status; DAA: Direct Antiviral Agents; *1 Jaundice and 2

Deteriorated liver functions

The rate of missingness was <10%&, 10-20%$, >20-30# or >30%@, as specified.



3.- Supplementary Table S3. Regression models, subgroup and leave-one-out analysis for HCC recurrence A. Multivariate regression models

model Adjust co-variables Recurrence rate per 100PY (95%CI)

I2 (95%CI) p-value

1 Gender 20.03 (13.76 - 30.19)

73.48 (59.65 - 82.57)

<0.001

2 Age (Years) 19.97 (13.7 - 30.16)

72.96 (58.78 - 82.26)

<0.001

3 Gender | Age (Years) 20 (13.56 - 30.51) 72.24 (57.57 - 81.84)

<0.001

4 Tumor burden before DAA initiation 20.14 (13.69 - 30.69)

72.05 (57.25 - 81.72)

<0.001

5 Child-Pugh before DAA initiation 20.16 (13.41 - 31.77)

72.82 (58.54 - 82.18)

<0.001

6 Genotype (type 1 grouped) 20.2 (13.89 - 30.65)

73.13 (58.2 - 82.72)

<0.001

7 Oesophageal varices before DAA initiation 20.05 (13.8 - 30.31)

76.8 (64.04 - 85.03)

<0.001

8 Ascites before DAA initiation 20.42 (14.29 - 30.43)

77.03 (64.85 - 84.99)

<0.001

9 Arterial hyper tension before DAA initiation 20.39 (14.39 - 30.2)

79.15 (67.67 - 86.56)

<0.001

10 Arterial hyper tension before DAA initiation 20.39 (14.39 - 30.2)

79.15 (67.67 - 86.56)

<0.001

11 History of previous HCC recurrence 20.1 (13.85 - 30.25)

72.08 (57.31 - 81.74)

<0.001

12 Tumor burden before DAA initiation | Treatment of last HCC treatment before

starting DAA (Radio embolization grouped with Combination) | Vascular Invasion

before DAA initiation | Child-Pugh before DAA initiation | Genotype (type 1 grouped) |

Gender | Age (Years)

20.99 (12.38 - 38.21)

58.53 (31.99 - 74.72)

<0.001


starting DAA (Radio embolization grouped with Combination) | Vascular Invasion before DAA initiation | Child-Pugh before DAA initiation | Genotype

(type 1 grouped) | Gender | Age (Years) | Number of HCC recurrence before the

last complete response

21.18 (12.38 - 38.8)

48.72 (14.74 - 69.16)

0.01




starting DAA (Radio embolization grouped with Combination) | Vascular Invasion

before DAA initiation | Child-Pugh before DAA initiation | Genotype (type 1 grouped) |

Gender | History of previous HCC recurrence | Age (Years)

21.2 (12.44 - 38.73)

55.2 (26.09 - 72.84)

0.01

15 Ascites before DAA initiation | Oesophageal varices before DAA initiation | Child-Pugh

before DAA initiation | Tumor burden before DAA initiation | History of previous

HCC recurrence

20.34 (12.95 - 33.9)

67.36 (46.94 - 79.92)

<0.001


before DAA initiation | Tumor burden before DAA initiation | History of previous

HCC recurrence | Age (Years)

20.3 (12.77 - 34.21)

65.53 (43.67 - 78.91)

<0.001


before DAA initiation | Tumor burden before DAA initiation | Age (Years) |

Number of HCC recurrence before the last complete response

20.28 (12.72 - 34.28)

66.02 (44.55 - 79.18)

<0.001

B. Subgroup analysis

parameter Group Number of

events

N at

risk

Recurrence rate per 100PY

(95%CI)

I2 (95%CI)

p-value

Gender Female 137 359 17.82 (10.36 - 33.12)

44.04 (8.71 - 65.7)

0.01

Male 272 618 21.34 (13.51 - 35.55)

59.83 (36.44 - 74.61)

<0.001

Treatment of last HCC treatment

before starting DAA

Liver transplant 1 8 3.57 (NE - NE)

NE NE

Ablation 159 383 21.28 (14.82 - 34.46)

54.35 (23.64 - 72.71)

0.01

Resection 67 209 15.21 (7.52 - 34.95)

0 (0 - 0) 0.5

TACE 84 143 29.26 (15.66 - 62.23)

16.41 (0 - 46.28)

0.3



Combination of Locoregional

treatments

26 57 19.03 (8.36 - 50.05)

0 (0 - 0) 0.9

Others 3 7 41.19 (2.91 - 100)

0 (0 - 0) 0.9

System in which the CR was evaluated

Magnetic Resonance 134 317 18.54 (10.82 - 36.46)

55.55 (27.57 - 72.72)

0.01

Computed Tomography

212 486 22.36 (14.45 - 37.4)

40.46 (2.79 - 63.54)

0.03

Ultrasound 36 102 16.68 (8.03 - 40.51)

0 (0 - 0) 0.9

Contrast Ultrasound 15 40 16.85 (5.92 - 86.07)

0 (0 - 0) 0.6

More than one 12 29 15.62 (8.74 - 27.91)

NE NE

Tumor burden before DAA

initiation

Solitary nodule (<=2cm)

134 377 16.54 (9.12 - 33.47)

38.5 (0.53 - 61.97)

0.04

<=3 nodules and <=3cm each

224 516 21.92 (13.71 - 37.53)

50.78 (20.94 - 69.35)

0.01

Multifocal 46 69 29.61 (14.79 - 75.22)

19.57 (0 - 49.94)

0.2

Genotype (type 1

grouped)

1 269 696 19.65 (13.31 - 30.36)

69.91 (51.48 - 81.34)

<0.001

2 30 83 19.73 (7.93 - 72.56)

0 (0 - 0) 0.6

3 22 47 18.34 (7.89 - 67.56)

0 (0 - 0) >0.999

4 73 90 27.69 (20.51 - 42.82)

1.2 (0 - 6.97) 0.4

History of previous HCC

recurrence

No 187 555 15.72 (9.53 - 27.98)

59.58 (34.63 - 75.01)

<.0001

Yes 219 414 26.6 (17.41 - 42.83)

56.55 (28.48 - 73.6)

0.01

AFP <10 176 494 17.87 (10.4 - 32.68)

66.54 (47.93 - 78.5)

<0.001

[10-20) 91 197 21.09 (11.13 - 46.53)

22.93 (0 - 51.43)

0.2

[20-200) 121 234 24.92 (13.14 - 53.07)

0 (0 - 0) 0.5

>400 7 14 33.95 (2.89 - >100)

0 (0 - 0) >0.999



C. Leave-one-out Excluded Pooled Effect

(95%CI) I2 (95%CI)

p-value

Rec

urr

ence

ra

te p

er 1

00

PY

Merchante N. et al, 201826 20.13 (14.08 - 29.76) 75.76 (63.08 - 84.08) <0.001

Tsai PC. et al., 2017 (L)31 20.13 (14 - 30.06) 75.49 (62.63 - 83.92) <0.001

Abdelaziz AO. et al., 201834 19.55 (13.46 - 29.52) 72.71 (57.93 - 82.29) <0.001

Cavalletto L. et al., 2017 (*)37 19.95 (13.95 - 29.56) 76.23 (63.88 - 84.36) <0.001

Villani R. et al., 2017 (*)32 19.63 (13.76 - 28.94) 71.23 (55.42 - 81.43) <0.001

Toyoda H. et al., 201830 20.64 (14.28 - 31.02) 70.69 (54.5 - 81.12) <0.001

Masetti C. et al., 2018 (**)25 20.14 (14.07 - 29.87) 75.6 (62.82 - 83.99) <0.001

Singal A. et al., 20199 19.88 (13.99 - 29.3) 76.8 (64.83 - 84.7) <0.001

Kohla M. et al., 2017 (††)23 19.56 (13.53 - 29.38) 71.97 (56.69 - 81.86) <0.001

Zavaglia C. et al., 2017 (L)33 20.28 (14.15 - 30.15) 74.85 (61.56 - 83.55) <0.001

Reig M. et al., 20161 19.64 (13.76 - 29.11) 77 (65.16 - 84.81) <0.001

Degasperi E. et al., 201939 20.31 (14.06 - 30.51) 74.09 (60.28 - 83.1) <0.001

HEPADAT, 201729 20.52 (14.3 - 30.6) 74.92 (61.68 - 83.59) <0.001

Cabibbo G. et al., 20172 20.58 (14.21 - 31.02) 74.91 (61.65 - 83.58) <0.001

ANRS, 201635 20 (13.9 - 29.83) 74.64 (61.59 - 83.26) <0.001

El Kassas M. et al., 201740 20.05 (14.09 - 29.58) 76.25 (63.91 - 84.37) <0.001

Minami T. et al., 2016 (L)27 18.17 (11.85 - 28.82) 68.52 (50.79 - 79.86) <0.001

Conti F. et al., 201638 20.44 (14.2 - 30.55) 73.78 (59.74 - 82.92) <0.001

Calleja JL. et al., 201736 20.04 (13.96 - 29.77) 75.76 (63.09 - 84.08) <0.001

Kolly P. et al., 2017 (L)24 19.87 (13.85 - 29.59) 75.46 (62.59 - 83.91) <0.001

Nagata H. et al., 201728 20.14 (14.12 - 29.71) 75.85 (63.23 - 84.13) <0.001

AFP: Alpha-fetoprotein; DAA: Direct Antiviral Agents; 95%CI: 95% Confidence Interval; CR: Complete response; HCC: Hepatocelular carcinoma



4.- Supplementary Table S4. Subgroup analysis of HCC recurrence according to the time between the last CR and DAA initiation

Groups Events Patients

at risk

Recurrence

rate per 100PY

(95%CI)

I2 (95%CI) heterogeneity

test (p-value)

Time between CR

to DAA initiation

<=3 months from CR to

DAA initiation

322 728 22.75 (15.27 -

35.28)

73.2 (59.2 -

82.4)

<0.001

>3 months from CR to

DAA initiation

87 249 14.35 (6.67 -

36.55)

0.2 (0 - 1.5) 0.5


DAA initiation

375 879 21.95 (15.18 -

32.78)

75.7 (63.3 -

83.9)

<0.001


DAA initiation

34 98 10.17 (4.11 -

41.53)

0 (0 - 0) 0.6


DAA initiation

391 934 21.12 (14.66 -

31.39)

74.4 (61.3 -

83.1)

<0.001


DAA initiation

18 43 10.39 (6.19 -

34.25)

33.5 (0 -

63.5)

0.14

Solitary Nodule

Subgroup Events Patients

at risk

Recurrence

rate per 100PY

(95%CI)


test (p-value)

Time between CR

to DAA initiation


DAA initiation

113 286 19.4 (10.76 -

38.62)

50.93

(19.52 -

70.1)

0.01


DAA initiation

21 91 10.9 (2.63 -

59.93)

0 (0 - 0) 0.7


DAA initiation

126 346 17.54 (9.76 -

35.36)

45.14 (11.4

- 66)

0.01


DAA initiation

8 31 9.19 (2.45 -

69.55)

0 (0 - 0) >0.99


DAA initiation

130 366 16.81 (9.24 -

34.26)

42.1 (6.5 -

64.2)

0.02




DAA initiation

4 11 12.04 (NE) 0 (0 - 0) NE



at risk

Recurrence

rate per 100PY

(95%CI)


test (p-value)

Time between CR

to DAA initiation


DAA initiation

168 378 23.94 (14.38 -

44.56)

49.6 (18.1 -

69)

0.01


DAA initiation

56 138 18.24 (8 -

49.37)

0 (0 - 0) 0.9


DAA initiation

205 464 23.86 (14.91 -

41.32)

52.5 (23.1 -

70.7)

0.01


DAA initiation

19 52 12.36 (4.46 -

62.5)

0 (0 - 0) 0.9


DAA initiation

215 495 23.15 (14.55 -

39.42)

46.7 (14 -

66.9)

0.01


DAA initiation

9 21 12.25 (10.43 -

33.83)

42.7 (0 -

71.3)

0.11

Multifocal


at risk

Recurrence

rate per 100PY

(95%CI)


test (p-value)

Time between CR

to DAA initiation


DAA initiation

37 53 38.16 (19.51 -

87.29)

48.2 (9 -

70.5)

0.02


DAA initiation

9 16 14.24 (9.47 -

38.71)

0 (0 - 0) >0.999


DAA initiation

39 57 37.25 (19.17 -

84.67)

52.7 (17.1 -

73)

0.01


DAA initiation

7 12 13.15 (10.14 -

29.65)

0 (0 - 0) >0.9


DAA initiation

41 60 34.72 (17.37 -

82.46)

37.6 (0 -

64.3)

0.08



DAA: Direct Antiviral Agents; CR: Complete Response; 95%CI: 95% confidence interval 5.- Supplementary Table S5. Characteristics of DAA-exposed and unexposed patients

All DAA Un-exposed (ITA.LI.CA)

DAA exposed (SURE)

STD (%)

Patients, n 1305 328 977

Age (Years) 70.1 [61-76.4] 72.1 [64.4-76.85] 69.72 [60-76] 14.1%

Gender (Male) 835 (64) 217 (66.2) 618 (63.3) 6.1%

Meld Score 8.09 [7.12-9.58] 8.47 [7.5-9.74] 7.98 [7.08-9.51] 4.2%

Child-Pugh (A / B / C) 1191 (91.3) / 99 (7.6) / 15 (1.1)

307 (93.6) / 21 (6.4) / 0 (0)

884 (90.5) / 78 (8) / 15 (1.5)

21.9%

Total bilirubin (mg/dl) 0.9 [0.69 -1.3] 0.9 [0.7-1.2] 0.9 [0.67-1.3] 14.4%

ALT (UI/L) 57 [34-86] 56 [30-75] 58 [36-88] 29%

Albumin (g/L) 3.8 [3.4-4.1] 3.7 [3.4-4] 3.8 [3.4-4.1] 14.2%

Creatinine (mg/dl) 0.81 [0.7-0.97] 0.8 [0.7-1] 0.81 [0.7-0.95] 15.1%

International Normalized Ratio

1.1 [1-1.2] 1.1 [1-1.2] 1.1 [1-1.15] 6.1%

Number of previous recurrences

0 [0-1] 0 [0-0] 0 [0-1] 74.5%

Ascites (No/Yes) 1128 (93.8) / 75 (6.2) 328 (100) / 0 (0) 800 (91.4) / 75 (8.6) 43.3%

missing 102 0 102

Encephalopathy (No/Yes) 1088 (98.9) / 12 (1.1) 328 (100) / 0 (0) 760 (98.4) / 12 (1.6) 17.8%

missing 205 0 205

Vascular invasion (No/Yes)

1292 (99.8) / 2 (0.2) 328 (100) / 0 (0) 964 (99.8) / 2 (0.2) 6.4%

missing 11 0 11

Extra-hepatic spread (No/Yes)

1247 (99.8) / 2 (0.2) 328 (100) / 0 (0) 919 (99.8) / 2 (0.2) 6.6%

missing 56 0 56

ECOG-PS (0 / 1 / 2) 1216 (94.8) / 62 (4.8) / 5 (0.4)

328 (100) / 0 (0) / 0 (0)

888 (93) / 62 (6.5) / 5 (0.5)

38.8%

missing 22 0 22

Alpha-fetoprotein (ng/ml) 11 [5-34] 23 [6-49] 9.68 [5-24.1] 5.1%

Type of previous HCC treatment

80.5%

Ablation 702 (53.8) 240 (73.2) 462 (47.3)

Resection 391 (30) 88 (26.8) 303 (31)


DAA initiation

5 9 11.49 (8.97 -

26.51)

0 (0 - 0) >0.9999



Chemoembolization 149 (11.4) 0 (0) 149 (15.3)

Other 63 (4.8) 0 (0) 63 (6.4)

Tumor Burden 112.7%

Solitary nodule 658 (51) 281 (85.7) 377 (39.2)


563 (43.6) 47 (14.3) 516 (53.6)

Multifocal 69 (5.3) 0 (0) 69 (7.2)

missing 15 0 15

Descriptive statistics are frequencies (%) or median [IQR: 25th – 75th percentile], as

appropriate.

AST: Aspartate aminotransferase; ALT: Alanine aminotransferase enzyme; HCC: Hepatocelular carcinoma; ECOG-PS: Eastern Cooperative Oncology Group Performance Status; IQR: Interquartile range



6.- Supplementary Table S6. Characteristics of matched population.

All DAA Un-exposed

(ITA.LI.CA)

DAA exposed

(SURE)

STD (%)

Patients, n 334 167 167

Age (Years) 71.25 [61-76.2] 72 [62.9-76.4] 70.15 [60–76] 3.4%

Gender (Male) 220 (65.9) 110 (65.9) 110 (65.9) 0%

Meld Score 7.89 [6.79-9.38] 8.41 [6.43-9.37] 7.7 [6.87-9.44] 0.3%

Child-Pugh (A/B) 320 (95.8) / 14 (4.2) 160 (95.8) / 7 (4.2) 160 (95.8) / 7

(4.2)

0%

Total bilirubin (mg/dl) 0.9 [0.6-1.2] 0.9 [0.6-1.1] 0.8 [0.6-1.2] 0.04%

ALT (UI/L) 58 [31-85] 58 [30-90] 59 [34-82] 3.2%

Albumin (g/L) 3.8 [3.5-4.1] 3.8 [3.5-4] 3.8 [3.5-4.1] 2.3%

Creatinine (mg/dl) 0.8 [0.7-0.97] 0.8 [0.7-1] 0.81 [0.71-0.93] 8.3%

International Normalized

Ratio

1.1 [1-1.19] 1.1 [1-1.2] 1.08 [1-1.14] 5%

Number of previous

recurrences

0 [0-0] 0 [0-0] 0 [0-0] 0%

Ascites (No) 334 (100) 167 (100) 167 (100) 0%

Encephalopathy (No) 334 (100) 167 (100) 167 (100) 0%

Vascular invasion (No) 334 (100) 167 (100) 167 (100) 0%

Extra-hepatic spread

(No)

334 (100) 167 (100) 167 (100) 0%

ECOG-PS (0) 334 (100) 167 (100) 167 (100) 0%

Alpha-fetoprotein

(ng/ml)

10.1 [5-39] 9 [5-45] 11 [5.6-34] 8.5%

Type of previous HCC

treatment

2.6%

Ablation 226 (67.7) 114 (68.3) 112 (67.1)

Resection 108 (32.3) 53 (31.7) 55 (32.9)

Tumor Burden 8%

Solitary nodule 238 (71.3) 122 (73.1) 116 (69.5)



<=3 nodules and <=3cm

each

96 (28.7) 45 (26.9) 51 (30.5)

Descriptive statistics are frequencies (%) or median [IQR: : Interquartile range p25th –

p75th], as appropriate.

AST: Aspartate aminotransferase; ECOG-PS: Eastern Cooperative Oncology Group

Performance Status; STD; Standardized mean difference; SURE: HCC recurrence after

Direct-acting Antivirals treatment. Meta-analysis of individual participant data

; ITA.LI.CA: Italian Liver Cancer; DAA: Direct Antiviral Agents



Supplementary Figure S1. Forest plot of pooled effect for HCC recurrence per 100PY in Original publications. Lines represent the 95%CI for HCC recurrence rate per 100PY of each study. Size of squares represent the weight of each study. Diamond represents the pooled effect.



Supplementary Figure S2. Forest plot of pooled effect for HCC recurrence per 100PY in Editorial, Letter or Meeting presentations. Lines represent the 95%CI for HCC recurrence rate per 100PY of each study. Size of squares represent the weight of each study. Diamond represents the pooled effect.



supplementary material 1. methods

Documents