supplementary material 1. methods
TRANSCRIPT
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.
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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.
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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
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doi: 10.1136/gutjnl-2020-323663–12.:10 2021;Gut, et al. Sapena V
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]
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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)
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doi: 10.1136/gutjnl-2020-323663–12.:10 2021;Gut, et al. Sapena V
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%$, >20-30# or >30%@, as specified.
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2.- Supplementary Table S2. Characteristics of patients at HCC recurrence
Recurrences, n 409
Gender (Male) & 272 (66.5)
Age (Years) & 67.5 [59.1 - 75.8]
MELD score$ 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]
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doi: 10.1136/gutjnl-2020-323663–12.:10 2021;Gut, et al. Sapena V
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)
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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.
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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
13 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) | Number of HCC recurrence before the
last complete response
21.18 (12.38 - 38.8)
48.72 (14.74 - 69.16)
0.01
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14 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 | 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
16 Ascites before DAA initiation | Oesophageal varices before DAA initiation | Child-Pugh
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
17 Ascites before DAA initiation | Oesophageal varices before DAA initiation | Child-Pugh
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
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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
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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
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doi: 10.1136/gutjnl-2020-323663–12.:10 2021;Gut, et al. Sapena V
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
<=6 months from CR to
DAA initiation
375 879 21.95 (15.18 -
32.78)
75.7 (63.3 -
83.9)
<0.001
>6 months from CR to
DAA initiation
34 98 10.17 (4.11 -
41.53)
0 (0 - 0) 0.6
<=12 months from CR to
DAA initiation
391 934 21.12 (14.66 -
31.39)
74.4 (61.3 -
83.1)
<0.001
>12 months from CR to
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)
I2 (95%CI) heterogeneity
test (p-value)
Time between CR
to DAA initiation
<=3 months from CR to
DAA initiation
113 286 19.4 (10.76 -
38.62)
50.93
(19.52 -
70.1)
0.01
>3 months from CR to
DAA initiation
21 91 10.9 (2.63 -
59.93)
0 (0 - 0) 0.7
<=6 months from CR to
DAA initiation
126 346 17.54 (9.76 -
35.36)
45.14 (11.4
- 66)
0.01
>6 months from CR to
DAA initiation
8 31 9.19 (2.45 -
69.55)
0 (0 - 0) >0.99
<=12 months from CR to
DAA initiation
130 366 16.81 (9.24 -
34.26)
42.1 (6.5 -
64.2)
0.02
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>12 months from CR to
DAA initiation
4 11 12.04 (NE) 0 (0 - 0) NE
<=3 nodules and <=3cm each
Subgroup 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
168 378 23.94 (14.38 -
44.56)
49.6 (18.1 -
69)
0.01
>3 months from CR to
DAA initiation
56 138 18.24 (8 -
49.37)
0 (0 - 0) 0.9
<=6 months from CR to
DAA initiation
205 464 23.86 (14.91 -
41.32)
52.5 (23.1 -
70.7)
0.01
>6 months from CR to
DAA initiation
19 52 12.36 (4.46 -
62.5)
0 (0 - 0) 0.9
<=12 months from CR to
DAA initiation
215 495 23.15 (14.55 -
39.42)
46.7 (14 -
66.9)
0.01
>12 months from CR to
DAA initiation
9 21 12.25 (10.43 -
33.83)
42.7 (0 -
71.3)
0.11
Multifocal
Subgroup 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
37 53 38.16 (19.51 -
87.29)
48.2 (9 -
70.5)
0.02
>3 months from CR to
DAA initiation
9 16 14.24 (9.47 -
38.71)
0 (0 - 0) >0.999
<=6 months from CR to
DAA initiation
39 57 37.25 (19.17 -
84.67)
52.7 (17.1 -
73)
0.01
>6 months from CR to
DAA initiation
7 12 13.15 (10.14 -
29.65)
0 (0 - 0) >0.9
<=12 months from CR to
DAA initiation
41 60 34.72 (17.37 -
82.46)
37.6 (0 -
64.3)
0.08
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
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)
>12 months from CR to
DAA initiation
5 9 11.49 (8.97 -
26.51)
0 (0 - 0) >0.9999
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
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)
<=3 nodules and <=3cm each
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
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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)
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<=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
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doi: 10.1136/gutjnl-2020-323663–12.:10 2021;Gut, et al. Sapena V
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.
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doi: 10.1136/gutjnl-2020-323663–12.:10 2021;Gut, et al. Sapena V
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.
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