Impact of baseline hepatitis B virus viral load on the long-term prognosis of advanced hepatocellular carcinoma treated with immunotherapy

Table 1 Baseline characteristics of the hepatitis B virus-DNA > 2000 and hepatitis B virus-DNA ≤ 2000 groups, n (%)

Variable	Group		P value
	HBV-DNA > 2000, n = 54	HBV-DNA ≤ 2000, n = 66
HBV			0.614
Negative	37 (69)	48 (73)
Positive	17 (31)	18 (27)
Antiviral therapy			0.068
No	8 (15)	19 (29)
Yes	46 (85)	47 (71)
Child Pugh score			0.724
A	22 (41)	29 (44)
B	32 (59)	37 (56)
IVPTT			0.595
No	26 (48)	35 (53)
Yes	28 (52)	31 (47)
BCLC stage			0.776
B	21 (39)	24 (36)
C	33 (61)	42 (64)
Metastasis			0.632
No	31 (57)	35 (53)
Yes	23 (43)	31 (47)
AFP			0.271
> 1210	24 (44)	36 (55)
≤ 1210	30 (56)	30 (45)
Sex			0.925
Female	20 (37)	25 (38)
Male	34 (63)	41 (62)
Age			0.811
< 60	29 (54)	34 (52)
≥ 60	25 (46)	32 (48)
BMI			0.413
Low	36 (67)	37 (56)
Normal	2 (4)	6 (9)
Obese	1 (2)	4 (6)
Overweight	15 (28)	19 (29)
ECOG			0.271
0-1	29 (54)	42 (64)
2	25 (46)	24 (36)
Post operative			0.549
No	34 (63)	38 (58)
Yes	20 (37)	28 (42)
ALT			0.083
> 40	29 (54)	25 (38)
≤ 40	25 (46)	41 (62)
Total bilirubin			0.969
> 34	37 (69)	45 (68)
≤ 34	17 (31)	21 (32)
Diabetes			0.832
No	41 (76)	49 (74)
Yes	13 (24)	17 (26)
Hypertensive			0.920
No	16 (30)	19 (29)
Yes	38 (70)	47 (71)
Cirrhosis			0.753
No	31 (57)	36 (55)
Yes	23 (43)	30 (45)
Smoking			0.889
No	37 (69)	46 (70)
Yes	17 (31)	20 (30)
Alcohol			0.893
No	35 (65)	42 (64)
Yes	19 (35)	24 (36)
Virus reactivation			1.000
No	53 (98)	65 (98)
Yes	1 (1.9)	1 (1.5)

Data in brackets represent the percentages of patients. HBV: Hepatitis B virus; BMI: Body mass index; ECOG: Eastern Cooperative Oncology Group; AFP: Alpha-fetoprotein; ALT: Alanine aminotransferase; BCLC: Barcelona Clinic Liver Cancer; PVTT: Portal vein tumor thrombosis.

Table 2 Tumor response between the hepatitis B virus-DNA ≤ 2000 and hepatitis B virus-DNA > 2000 groups, n (%)

	RECIST 1.1		P value	mRECIST		P value
	HBV ≤ 2000, n = 66	HBV > 2000, n = 54		HBV ≤ 2000, n = 66	HBV > 2000, n = 54
CR	0	0	-	0	0	-
PR	13 (19.70)	17 (31.48)	0.14	15 (22.73)	18 (33.33)	0.20
SD	35 (53.03)	21 (38.89)	0.12	37 (56.06)	23 (42.59)	0.14
PD	18 (27.27)	16 (29.63)	0.78	14 (21.21)	13 (24.07)	0.71
ORR	13 (19.70)	18 (33.33)	0.09	15 (22.73)	22 (40.74)	0.03
DCR	48 (72.73)	40 (74.07)	0.87	52 (78.79)	41 (75.93)	0.71

Data in brackets represent the percentages of patients. HBV: Hepatitis B virus; CR: Complete responds; PR: Partial responds; SD: Stable disease; PD: Progression disease; ORR: Objective responds rates; DCR: Disease control rates.

Table 3 Subgroup analysis of tumour response according to whether or not they received antiviral therapy, n (%)

	Antiviral therapy (no), n = 25			Antiviral therapy (yes), n = 95
	HBV-DNA (HBV > 2000), n = 8	HBV-DNA (HBV ≤ 2000), n = 18	P value	HBV-DNA (HBV > 2000), n = 46	HBV-DNA (HBV ≤ 2000), n = 48	P value
PR	2 (29)	3 (17)	0.597	15 (32)	10 (21)	0.220
SD	3 (43)	11 (61)	0.656	18 (38)	24 (50)	0.251
PD	2 (29)	4 (22)	> 0.999	14 (30)	14 (29)	0.947
ORR	2 (29)	3 (17)	0.597	16 (34)	10 (21)	0.149
DCR	5 (71)	14 (78)	> 0.999	35 (74)	34 (71)	0.691
ORR (whole)	5 (20)		-	26 (27)		0.454
DCR (whole)	6 (24)		-	26 (27)		0.735

Data in brackets represent the percentages of patients. HBV: Hepatitis B virus; PR: Partial responds; SD: Stable disease; PD: Progression disease; ORR: Objective responds rates; DCR: Disease control rates.

Table 4 Univariate and multivariate analyses of the prognostic factors for progression-free survival

Factors	Univariate		Multivariate
	HR (95%CI)	P value	HR (95%CI)	P value
AFP (≤ 1210 vs > 1210)	0.71 (0.46- 1.09)	0.121	-	-
Age (≥ 60 yr vs < 60 yr)	1.00 (0.65- 1.53)	0.984	-	-
Alcohol (Yes vs No)	0.93 (0.60- 1.45)	0.753	-	-
ALT (≤ 40 vs No)	0.81 (0.53- 1.24)	0.337	-	-
Antiviral therapy (Yes vs No)	0.61 (0.32- 1.16)	0.132	-	-
BCLC stage (C vs B)	0.55 (0.35 - 0.87)	0.011	0.57 (0.36-0.91)	0.017
BMI (Normal vs Low)	1.35 (0.61- 3.00)	0.457	-	-
BMI (Over obese vs Low)	0.46 (0.16- 1.31)	0.146	-	-
BMI (Weight vs Low)	0.87 (0.53- 1.44)	0.584	-	-
Child Pugh score (B vs C)	1.34 (0.86- 2.06)	0.192	-	-
Diabetes (Yes vs No)	1.02 (0.62 - 1.69)	0.929	-	-
Cirrhosis (Yes vs No)	0.99 (0.64- 1.52)	0.955	-	-
ECOG (2 vs 0-1)	1.92 (1.25- 2.96)	0.003	1.86 (1.21-2.86)	0.005
HBV (Positive vs Negative)	1.21 (0.76- 1.94)	0.417	-	-
HBV-DNA (HBV ≤ 2000 vs HBV > 2000)	1.04 (0.67- 1.60)	0.877	-	-
Hypertensive (Yes vs No)	0.97 (0.60- 1.56)	0.904	-	-
PVTT (Yes vs No)	1.36 (0.86- 2.13)	0.186	-	-
Post operative (Yes vs No)	0.78 (0.50- 1.22)	0.284	-	-
Metastasis (Yes vs No)	0.73 (0.47- 1.14)	0.164	-	-
Sex (male vs No)	0.83 (0.54- 1.28)	0.395	-	-
Smoking (Yes vs No)	0.95 (0.59- 1.53)	0.834	-	-
Total bilirubin (≤ 34 vs > 34)	0.92 (0.57- 1.48)	0.726	-	-
Virus reactivation (Yes vs No)	1.30 (0.18- 9.43)	0.798	-	-

HBV: Hepatitis B virus; BMI: Body mass index; ECOG: Eastern Cooperative Oncology Group; AFP: Alpha-fetoprotein; ALT: Alanine aminotransferase; BCLC: Barcelona Clinic Liver Cancer; PVTT: Portal vein tumor thrombosis.

Table 5 Univariate and multivariate analyses of the prognostic factors for overall survival

Factors	Univariate		Multivariate
	HR (95%CI)	P value	HR (95%CI)	P value
AFP (≤ 1210 vs > 1210)	0.57 (0.36-0.92)	0.020	0.95 (0.56-1.60)	0.849
Age (≥ 60 yr vs < 60 yr)	0.89 (0.57-1.39)	0.618	-	-
Alcohol (Yes vs No)	0.93 (0.59-1.46)	0.750	-	-
ALT (≤ 40 vs No)	1.29 (0.83-2.02)	0.256	-	-
Antiviral therapy (Yes vs No)	0.23 (0.12-0.44)	<0.001	0.43 (0.20-0.89)	0.024
BCLC stage (C vs B)	2.44 (1.48-4.05)	0.001	2.22 (1.27-3.86)	0.005
BMI (Normal vs Low)	0.61 (0.26-1.45)	0.265	-	-
BMI (Over obese vs Low)	2.86 (1.00-8.21)	0.051	-	-
BMI over (Weight vs Low)	0.83 (0.51-1.37)	0.469	-	-
Child Pugh score (B vs C)	1.01 (0.65-1.59)	0.952	-	-
Diabetes (Yes vs No)	0.97 (0.57-1.66)	0.922	-	-
Cirrhosis (Yes vs No)	1.16 (0.74-1.83)	0.515	-	-
ECOG (2 vs 0-1)	0.98 (0.63-1.53)	0.937	-	-
HBV (Positive vs Negative)	1.03 (0.63-1.66)	0.914	-	-
HBV-DNA (HBV ≤ 2000 vs HBV > 2000)	0.71 (0.45-1.12)	0.142	-	-
Hypertensive (Yes vs No)	1.07 (0.65-1.76)	0.781	-	-
PVTT (Yes vs No)	2.64 (1.61-4.31)	< 0.001	2.28 (1.29-4.05)	0.005
Post operative (Yes vs No)	1.18 (0.75-1.88)	0.472	-	-
Metastasis (Yes vs No)	0.65 (0.41-1.04)	0.071	-	-
Sex (male vs No)	1.00 (0.64-1.56)	0.994	-	-
Smoking (Yes vs No)	1.25 (0.77-2.04)	0.374	-	-
Total bilirubin (≤ 34 vs > 34)	0.86 (0.53-1.39)	0.533	-	-
Virus reactivation (Yes vs No)	1.29 (0.18-9.35)	0.803	-	-

HBV: Hepatitis B virus; BMI: Body mass index; ECOG: Eastern Cooperative Oncology Group; AFP: Alpha-fetoprotein; ALT: Alanine aminotransferase; BCLC: Barcelona Clinic Liver Cancer; PVTT: Portal vein tumor thrombosis.

Table 6 Comparison of training set and validation set features, n (%)

Characteristic	Training cohort, n = 84	Internal test cohort, n = 36	P value
HBV-DNA			0.749
> 2000	37 (44)	17 (47)
≤ 2000	47 (56)	19 (53)
HBV			0.001
Negative	67 (80)	18 (50)
Positive	17 (20)	18 (50)
Antiviral therapy			0.806
No	18 (21)	7 (19)
Yes	66 (79)	29 (81)
Child Pugh score			0.022
A	30 (36)	21 (58)
B	54 (64)	15 (42)
PVTT			0.780
No	42 (50)	19 (53)
Yes	42 (50)	17 (47)
BCLC stage			0.690
B	41 (49)	19 (53)
C	43 (51)	17 (47)
Metastasis			0.936
No	46 (55)	20 (56)
Yes	38 (45)	16 (44)
AFP			0.035
> 1210	48 (57)	13 (36)
≤ 1210	36 (43)	23 (64)
Sex			0.837
Female	31 (37)	14 (39)
Male	53 (63)	22 (61)
Age			0.968
< 60	44 (52)	19 (53)
≥ 60	40 (48)	17 (47)
BMI			0.333
Low	48 (57)	25 (69)
Normal	5 (6.0)	3 (8.3)
Obese	5 (6.0)	0 (0)
Overweight	26 (31)	8 (22)
ECOG			0.491
0-1	48 (57)	23 (64)
2	36 (43)	13 (36)
Post operative			0.569
No	49 (58)	23 (64)
Yes	35 (42)	13 (36)
ALT			0.262
> 40	35 (42)	19 (53)
≤ 40	49 (58)	17 (47)
Total bilirubin			0.049
> 34	62 (74)	20 (56)
≤ 34	22 (26)	16 (44)
Diabetes			0.066
No	59 (70)	31 (86)
Yes	25 (30)	5 (14)
Hypertensive			0.827
No	24 (29)	11 (31)
Yes	60 (71)	25 (69)
Cirrhosis			0.245
No	44 (52)	23 (64)
Yes	40 (48)	13 (36)
Smoking			0.365
No	56 (67)	27 (75)
Yes	28 (33)	9 (25)
Alcohol			0.228
No	51 (61)	26 (72)
Yes	33 (39)	10 (28)
Virus reactivation			0.512
No	83 (99)	35 (97)
Yes	1 (1)	1 (3)

Data in brackets represent the percentages of patients. HBV: Hepatitis B virus; BMI: Body mass index; ECOG: Eastern Cooperative Oncology Group; AFP: Alpha-fetoprotein; ALT: Alanine aminotransferase; BCLC: Barcelona Clinic Liver Cancer; PVTT: Portal vein tumor thrombosis.

Table 7 Treatment-related adverse events in patients with hepatocellular carcinoma, n (%)

Variable	Group		P value
	HBV-DNA > 2000, n = 54	HBV-DNA ≤ 2000, n = 66
Rash	4 (7)	6 (9)	> 0.999
Nausea	7 (13)	13 (20)	0.325
Diarrhea	5 (9)	5 (8)	0.752
Fatigue	4 (7)	6 (9)	> 0.999
Myocarditis	6 (11)	6 (9)	0.714
Hyperbilirubinemia	5 (9)	8 (12)	0.616
Hypertension	5 (9)	7 (11)	0.807
Leukopenia	6 (11)	8 (12)	0.864
Thrombocytopenia	7 (13)	10 (15)	0.732
RCCEP	23 (43)	31 (47)	0.632
Neutropenia	4 (7)	7 (11)	0.752
Proteinuria	14 (26)	18 (27)	0.868
Hypothyroidism	5 (9)	5 (8)	0.752
Elevated ALT	4 (7)	7 (11)	0.752
Elevated AST	7 (13)	6 (9)	0.497

Data in brackets represent the percentages of patients. HBV: Hepatitis B virus; RCCEP: Reactive cutaneous capillary endothelial proliferation; AST: Aspartate aminotransferase; ALT: Alanine aminotransferase.