Risk factors for hepatocellular carcinoma in patients with drug-resistant chronic hepatitis B

Table 1 Characteristics of patients with drug-resistant chronic hepatitis B stratified by hepatocellular carcinoma status n (%)

Variables	Patients with HCC (n = 57)	Patients without HCC (n = 375)	P-value
Gender (male)	42 (73.7)	267 (71.2)	0.755
Age (mean, yr)	57.44 ± 8.35	47.03 ± 12.25	< 0.001
Presence of cirrhosis	42 (73.7)	85 (22.7)	< 0.001
HBeAg positivity	36 (63.2)	314 (83.7)	0.003
Seroconversion of HBeAg	3 (5.3)	78 (20.8)	0.022
Initial HBV DNA (< 2000 IU)	2 (3.5)	27 (7.2)	0.61
Initial HBV DNA (> 20000 IU)	46 (80.7)	314 (83.7)	0.162
Complete virologic response	11 (19.3)	135 (36)	0.02
Partial virologic response	31 (54.4)	271 (72.3)	0.012
Platelet count (103/mm3) (median, range)	103 (35-380)	164.5 (34-330)	< 0.001
AST U/L (median, range)	79.5 (22-707)	63 (14-1494)	0.126
ALT U/L (median, range)	86.5 (11-590)	82 (9-2280)	0.770
AFP IU/mL (median, range)	7.58 (1.54-1890)	2.8 (0.65-980)	< 0.001
Child-Pugh score	5.51 ± 0.85	5.12 ± 0.71	0.002
Viral mutation
rtM204I	25 (43.9)	93 (24.8)	0.004
rtM204I/rtL180M	4 (7)	50 (13.3)	0.098
rtM204V/rtL180M	14 (24.6)	111 (29.6)	0.492
rtM204V + I/rtL180M	3 (5.3)	36 (9.6)	0.451
rtA181T	3 (5.3)	22 (5.9)	1
rtA181T/V	1 (1.8)	1 (0.26)	0.224
Duration of antiviral treatment (mo)	24.31 ± 15.28	31.43 ± 19.43	0.004

HCC: Hepatocellular carcinoma; ALT: Alanine aminotransferase; AFP: Alpha-fetoprotein; AST: Aspartate aminotransferase; HBV: Hepatitis B virus.

Table 2 Multivariate analysis of the clinical and virologic factors associated with hepatocellular carcinoma occurrence

Variables	HR	95%CI	P-value
Presence of cirrhosis	8.196	3.623-18.518	< 0.01
Age > 50 yr	3.426	1.445-8.123	< 0.01
Complete virologic response	0.164	0.054-0.276	< 0.01
Positivity of HBeAg	2.893	1.143-7.327	< 0.05
Presence of rtM204I mutation	3.412	1.54-6.440	< 0.01

Table 3 Comparison of tumor characteristics between patients with hepatocellular carcinoma with resistant chronic hepatitis B (R group) and hepatocellular carcinoma with chronic hepatitis B treated with antivirals (N group) n (%)

Variables	R group (n = 57)	N group (n = 119)	P-value
Gender (male)	42 (73.7)	100 (84)	0.158
Age (mean, yr)	57.44 ± 8.35	55.37 ± 10.61	0.161
Presence of cirrhosis	55 (96.5)	117 (98.3)	1
Portal vein thrombosis	8 (14)	43 (36.1)	0.004
Vascular invasion	20 (35.1)	47 (39.5)	0.623
Multi-nodular tumor type	21 (36.8)	55 (46.2)	0.259
CLIP score	0.75 ± 0.85	1.67 ± 1.43	< 0.001
Modified UICC stage (< IVA)	50 (87.7)	73 (61.3)	< 0.001
Modified UICC stage (I/II/III/IVA/IVB)	13/18/19/6/1	18/34/21/28/18
LN involvement	1 (2.1)	14 (11.7)	0.071
Distant metastasis	0 (0)	13 (10.9)	0.019
AST U/L (median, range)	48 (20-415)	61 (16-481)	0.022
ALT U/L (median, range)	39 (8-532)	44 (3-203)	0.616
Platelet count (103/mm3), (median, range)	103 (23-380)	126 (24-426)	0.009
CRP (mg/dL) (median, range)	0.34 ± 0.37	1.71 ± 2.75	< 0.001
AFP IU/mL (median, range)	48 (2-40591)	107 (2-50000)	0.003
Child-Pugh score	5.51 ± 0.85	5.91 ± 1.32	0.344
Duration of anti-viral Tx. (mo)	20 (0-72)	6 (1-276)	0.001
Mean tumor surveillance period (mo)	6.35 ± 1.69	8.71 ± 2.86	< 0.001
Total follow-up duration (d)	842.51 ± 702.57	801.74 ± 713.24	0.721

UICC: Union Internationale Contre le Cancer; CLIP: Cancer of the Liver Italian Program; LN: Lymph node; ALT: Alanine aminotransferase; AFP: Alpha-fetoprotein; AST: Aspartate aminotransferase; HBV: Hepatitis B virus; CRP: C-reactive protein.

Table 4 Comparison of tumor characteristics between patients with hepatocellular carcinoma with resistant chronic hepatitis B (R’ group) and hepatocellular carcinoma with chronic hepatitis B treated with antiviral treatment (N’ group): subgroup analysis based on tumor surveillance interval (≤ 6 mo) n (%)

Variables	R’ group (n = 37)	N’ group (n = 39)	P-value
Gender (male)	27 (73)	31 (79.5)	0.594
Age (mean, yr)	55.24 ± 7.94	56.08 ± 10.3	0.695
Presence of cirrhosis	36 (97.3)	39 (100)	1
Portal vein thrombosis	5 (13.5)	8 (20.5)	0.546
Vascular invasion	11 (29.7)	8 (20.5)	0.431
Multi-nodular tumor type	27 (73)	27 (69.2)	0.803
CLIP score	0.59 ± 0.72	0.97 ± 0.98	0.061
Modified UICC stage (< IVA)	34 (91.9)	35 (89.7)	1.0
Modified UICC stage (I/II/III/IVA/IVB)	11/11/12/3/0	11/15/9/2/2
LN involvement	0 (0)	2 (5.1)	0.496
Distant metastasis	0 (0)	1 (2.6)	1
AST U/L (median, range)	48 (20-141)	52 (16-481)	0.283
ALT U/L (median, range)	38 (8-199)	44 (11-150)	0.14
Platelet count (103/mm3) (median, range)	101 (23-232)	131 (24-260)	0.059
CRP (mg/dL) (median, range)	0.3 (0-2)	0.5 (0-16)	0.029
AFP IU/mL (median, range)	27 (2-737)	52 (3-16644)	0.039
Child-Pugh score	5.51 ± 0.85	5.91 ± 1.32	0.982
Duration of anti-viral Tx	21.5 (8-72)	7 (1-60)	< 0.001
Total follow-up duration	791.95 ± 643.06	1114.23 ± 646.84	0.033

UICC: Union Internationale Contre le Cancer; CLIP: Cancer of the Liver Italian Program; LN: Lymph node; ALT: Alanine aminotransferase; AFP: Alpha-fetoprotein; AST: Aspartate aminotransferase; HBV: Hepatitis B virus; CRP: C-reactive protein.