Preoperative Antiviral Therapy and Long-Term Outcomes for Hepatitis B Virus-Related Hepatocellular Carcinoma After Curative Liver Resection: A Multicenter Analysis

Figures & data

Figure 1 Selection of the study population.

Table 1 Baseline Characteristics of the Patients in the Two Cohorts

N (%)	Total (N = 565)	Without Preoperative Regular Antiviral Therapy (N = 375)	With Preoperative Regular Antiviral Therapy (N = 190)	P value
Clinicalpathologic Characteristics
Age, years	55±12	55±13	55±11	0.869
Male	478 (84.6)	317 (84.5)	161 (84.7)	1.000
ASA score>2	94 (16.6)	66 (17.6)	28 (14.7)	0.406
Body mass index > 24 Kg/m^2	278 (49.2)	180 (48.0)	98 (51.6)	0.475
HBsAg seroclearance	34 (6.0)	24 (6.4)	10 (5.3)	0.709
HBeAg positive	122 (21.6)	68 (18.1)	54 (28.4)	0.005
Cirrhosis	384 (68.0)	252 (67.2)	132 (69.5)	0.651
Portal hypertension	108 (19.1)	67 (17.9)	41 (21.6)	0.344
ALBI grade 2/3	106 (18.8)	77 (20.5)	29 (15.3)	0.130
Child-Pugh grade B	25 (4.4)	20 (5.3)	5 (2.6)	0.139
Preoperative ALT level > 40 U/L	138 (24.4)	117 (31.2)	21 (11.1)	<0.001
Preoperative AST level > 40 U/L	108 (19.1)	93 (24.8)	15 (7.9)	<0.001
Preoperative AFP level > 400 μg/L	133 (23.5)	95 (25.3)	38 (20.0)	0.173
Preoperative HBV DNA level > 2000 IU/mL	211 (37.3)	197 (52.5)	14 (7.4)	<0.001
BCLC tumor stage
BCLC 0/A	484 (85.6)	308 (82.1)	176 (92.6)	0.003
BCLC B	36 (6.4)	30 (8.0)	6 (3.2)
BCLC C	45 (8.0)	37 (9.9)	8 (4.2)
Largest tumor diameter > 5 cm	205 (36.3)	157 (41.9)	48 (25.3)	<0.001
Multiple Tumors	57 (10.1)	39 (10.4)	18 (9.5)	0.770
Microvascular invasion	202 (35.8)	139 (37.1)	63 (33.2)	0.411
Satellites	56 (9.9)	48 (12.8)	8 (4.2)	0.001
Poor tumor differentiation	516 (91.3)	345 (92.0)	171 (90.0)	0.432
Incomplete tumor encapsulation	391 (69.2)	264 (70.4)	127 (66.8)	0.442
Operative Variables
Operation time	115 (90–145)	120 (95–153)	105 (88–135)	0.001
Intraoperative blood loss > 400 mL	119 (21.1)	86 (22.9)	33 (17.4)	0.155
Intraoperative blood transfusion	26 (4.6)	22 (5.9)	4 (2.1)	0.054
Major liver resection	90 (15.9)	72 (19.2)	18 (9.5)	0.002
Non-anatomical liver resection	482 (85.3)	310 (82.7)	172 (90.5)	0.012
Resection margin < 1cm	387 (68.5)	267 (71.2)	120 (63.2)	0.065
Perioperative Outcomes
Postoperative 30-day morbidity	178 (33.6)	125 (35.5)	53 (30.0)	0.189
Minor morbidity	142 (25.1)	98 (26.1)	44 (23.2)	0.441
Major morbidity	36 (6.4)	27 (7.2)	9 (4.7)	0.281
Postoperative 30-day mortality	1 (0.2)	1 (0.3)	0 (0.0)	1.000
Postoperative 90-day mortality	2 (0.4)	2 (0.5)	0 (0.0)	0.553
Postoperative hospital stays, days	7 (7–8)	7 (7–9)	7 (7–8)	0.606

Abbreviations: AFP, Alpha-fetoprotein; ASA, American Society of Anesthesiologists; ALBI, albumin-bilirubin; AST, aspartate transaminase; ALT, alanine aminotransferase; HBsAg, hepatitis B surface antigen; HBeAg, hepatitis B e antigen.

Table 2 Long-Term Outcomes After Excluding Postoperative Early Deaths (Postoperative 90-Day Mortality)

N (%)	Total (N = 563)	Without Preoperative Regular Antiviral Therapy (N = 373)	With Preoperative Regular Antiviral Therapy (N = 190)	P value
Recurrence during the follow-up	291 (51.7)	209 (56.0)	82 (43.2)	0.004
Intrahepatic recurrence	270 (92.8)	192 (91.9)	78 (95.1)	0.348
Extrahepatic recurrence	5 (1.7)	5 (2.4)	0 (0.0)
Intra- and extrahepatic recurrence	16 (5.5)	12 (5.7)	4 (4.9)
BCLC stage of initial recurrence	291 (51.7)	209 (56.0)	82 (43.2)	0.004
BCLC A stage	182 (62.5)	127 (60.8)	55 (67.1)	0.378
BCLC B stage	72 (24.7)	52 (24.9)	20 (24.4)
BCLC C stage	37 (24.8)	30 (14.3)	7 (8.5)
Mortality during the follow-up	190 (33.7)	147 (39.4)	43 (22.6)	<0.001
Cancer-specific mortality	155 (81.6)	122 (83.0)	33 (76.7)	0.371
Non-cancer-specific mortality	35 (18.4)	25 (17.0)	10 (23.3)
Median overall survival (OS), 95% CI	61 (47–69)	61 (42–68)	61 (53–70)	0.005
1-year OS rate, %	95.7	96.0	95.3	<0.001
3-year OS rate, %	81.9	77.8	89.5
5-year OS rate, %	68.6	63.4	79.0
Median time-to-recurrence (TTR), 95% CI	48 (13–64)	61 (12–64)	61 (19–66)	0.007
1-year TTR rate, %	24.2	27.3	17.9	0.002
3-year TTR rate, %	41.5	45.9	32.8
5-year TTR rate, %	50.1	54.3	41.9

Figure 2 Curves comparisons of survival (A) and recurrence (B) between two groups in the whole cohort (calculated by Log rank test).

Table 3 Univariable and Multivariable Cox Regression Analyses of Preoperative Predictive Factors for Survival

Variables	HR Comparison	UV HR (95% CI)	UV P	MV HR (95% CI)	MV P
Age	> 60 vs ≤ 60 years	1.467 (1.094–1.967)	0.010	NA	0.935
Sex	Male vs Female	1.182 (0.781–1.788)	0.428
ASA score	> 2 vs ≤ 2	1.797 (1.288–2.505)	0.001	1.706 (1.216–2.394)	0.002
Body mass index	> 24 vs ≤ 24 Kg/m^2	0.675 (0.506–0.901)	0.008	0.743 (0.555–0.996)	0.047
Cirrhosis	Presence vs Absence	1.697 (1.221–2.360)	0.002	1.700 (1.204–2.402)	0.003
Portal hypertension	Presence vs Absence	1.018 (0.708–1.463)	0.925
ALBI score	2/3 vs 1 grade	1.800 (1.305–2.483)	< 0.001	NA	0.270
Preoperative ALT level	> 40 vs ≤ 40 U/L	1.783 (1.320–2.409)	< 0.001	1.394 (1.016–1.913)	0.040
Preoperative AST level	> 40 vs ≤ 40 U/L	1.754 (1.269–2.423)	0.001	NA	0.969
Preoperative AFP level	> 400 vs ≤ 400 μg/L	1.629 (1.194–2.222)	0.002	NA	0.191
Preoperative HBV-DNA level	≥ 2000 vs < 2000 IU/mL	1.336 (1.003–1.779)	0.048	NA	0.693
Largest tumor diameter	> 5 vs ≤ 5 cm	2.711 (2.037–3.610)	< 0.001	2.328 (1.729–3.135)	< 0.001
Tumor number	Multiple vs Solitary	1.883 (1.260–2.813)	0.001	2.051 (1.363–3.085)	0.001
Microvascular invasion	Yes vs no	1.917 (1.441–2.549)	0.002	1.688 (1.261–2.260)	< 0.001
Satellites	Yes vs no	2.392 (1.635–3.499)	< 0.001	NA	0.617
Poor tumor differentiation	Yes vs no	2.926 (1.375–6.225)	0.005	2.235 (1.090–5.004)	0.029
Incomplete tumor encapsulation	Yes vs no	1.429 (1.034–1.975)	0.031	1.545 (1.112–2.145)	0.009
Intraoperative blood loss	> 400 vs ≤ 400 mL	1.730 (1.262–2.372)	0.001	NA	0.198
Extent of liver resection	Major vs ≤ Minor	2.162 (1.553–3.008)	< 0.001	NA	0.487
Non-anatomical liver resection	Yes vs no	0.847 (0.576–1.244)	0.397
Resection margin	< 1 vs ≥ 1 cm	2.193 (1.519–3.167)	< 0.001	1.712 (1.179–2.484)	0.005
Preoperative antiviral therapy	Yes vs no	0.513 (0.365–0.721)	< 0.001	0.691 (0.484–0.986)	0.042

Abbreviations: AFP, Alpha-fetoprotein; ASA, American Society of Anesthesiologists; ALBI, albumin-bilirubin; AST, aspartate transaminase; ALT, alanine aminotransferase; CI, Confidence interval; HR, Hazard ratio; MV, multivariate; UV, univariate; NA, not available.

Table 4 Univariable and Multivariable Cox Regression Analyses of Preoperative Predictive Factors for Recurrence

Variables	HR Comparison	UV HR (95% CI)	UV P	MV HR (95% CI)	MV P
Age	> 60 vs ≤ 60 years	1.146 (0.895–1.465)	0.273
Sex	Male vs Female	1.314 (0.934–1.848)	0.117
ASA score	> 2 vs ≤ 2	1.204 (0.895–1.618)	0.220
Body mass index	> 24 vs ≤ 24 Kg/m^2	0.831 (0.660–1.046)	0.115
Cirrhosis	Presence vs Absence	1.787 (1.363–2.345)	< 0.001	1.611 (1.219–2.130)	0.001
Portal hypertension	Presence vs Absence	1.162 (0.874–1.545)	0.300
ALBI grade	2/3 vs 1 grade	1.529 (1.165–2.009)	0.002	NA	0.371
Preoperative ALT level	> 40 vs ≤ 40 U/L	1.547 (1.204–1.988)	0.001	NA	0.192
Preoperative AST level	> 40 vs ≤ 40 U/L	1.509 (1.146–1.986)	0.003	NA	0.501
Preoperative AFP level	> 400 vs ≤ 400 μg/L	1.282 (0.984–1.672)	0.066	NA	0.849
Preoperative HBV-DNA level	≥ 2000 vs < 2000 IU/mL	1.466 (1.163–1.848)	0.001	1.361 (1.076–1.721)	0.010
Largest tumor diameter	> 5 vs ≤ 5 cm	2.052 (1.628–2.588)	< 0.001	1.782 (1.401–2.265)	< 0.001
Tumor number	Multiple vs Solitary	2.113 (1.522–2.932)	< 0.001	2.135 (1.531–2.977)	< 0.001
Microvascular invasion	Yes vs no	1.409 (1.114–1.782)	0.004	1.332 (1.050–1.690)	0.018
Satellites	Yes vs no	2.828 (2.058–3.885)	< 0.001	1.830 (1.310–2.556)	< 0.001
Poor tumor differentiation	Yes vs no	1.862 (1.155–3.155)	0.011	NA	0.052
Incomplete tumor encapsulation	Yes vs no	1.209 (0.939–1.557)	0.142
Intraoperative blood loss	> 400 vs ≤ 400 mL	1.327 (1.010–1.743)	0.043	NA	0.765
Extent of liver resection	Major vs ≤ Minor	1.527 (1.138–2.049)	0.005	NA	0.847
Non-anatomical liver resection	Yes vs no	1.014 (0.708–1.362)	0.915
Resection margin	< 1 vs ≥ 1 cm	1.677 (1.280–2.198)	< 0.001	1.355 (1.029–1.783)	0.030
Preoperative antiviral therapy	Yes vs no	0.674 (0.522–0.870)	0.002	NA	0.371

Abbreviations: AFP, Alpha-fetoprotein; ASA, American Society of Anesthesiologists; ALBI, albumin-bilirubin; AST, aspartate transaminase; ALT, alanine aminotransferase; CI, Confidence interval; HR, Hazard ratio; MV, multivariate; UV, univariate; NA, not available.

Table 5 Independent Risk Factors Associated with Overall Survival (OS) and Time-to-Recurrence (TTR) in Patients Not Receiving AVT After Liver Resection for HBV-Related Hepatocellular Carcinoma

Independent Risk Factors	MV HR (95% CI)	MV P
Overall Survival
ASA score>2	1.582 (1.076–2.327)	0.020
Microvascular invasion	1.829 (1.303–2.568)	< 0.001
Multiple Tumors	2.179 (1.371–3.463)	0.001
Preoperative AFP level > 400 μg/L	1.444 (1.006–2.073)	0.046
Largest tumor diameter > 5 cm	2.233 (1.598–3.121)	< 0.001
Incomplete tumor encapsulation	1.852 (1.254–2.736)	0.002
Cirrhosis	2.102 (1.408–3.139)	< 0.001
Time-to-recurrence
Microvascular invasion	1.335 (1.005–1.773)	0.046
Multiple Tumors	2.231 (1.503–3.310)	< 0.001
Satellites	1.793 (1.237–2.598)	0.002
Largest tumor diameter > 5 cm	1.798 (1.353–2.390)	< 0.001
Incomplete tumor encapsulation	1.370 (1.004–1.870)	0.047
Cirrhosis	1.938 (1.380–2.722)	< 0.001
Preoperative HBV DNA level > 2000 IU/mL	1.362 (1.026–1.810)	0.032

Figure 3 Curves comparisons of survival (A) and recurrence (B) between two groups in the non-AVT cohort (calculated by Log rank test).