Age-male-albumin-bilirubin-platelet score stratifies hepatocellular carcinoma risk after sustained virological response in hepatitis C-related compensated advanced chronic liver disease

Table 1 Diagnostic criteria supporting compensated advanced chronic liver disease in the final study cohort

Diagnostic criterion supporting compensated advanced chronic liver disease	n (%)
Liver biopsy available	62 (10.9)
Histologic stage F3 fibrosis	19 (3.3)
Histologic stage F4 cirrhosis	43 (7.5)
Vibration-controlled transient elastography ≥ 10 kPa	293 (51.3)
Radiological features consistent with cirrhosis or portal hypertension	518 (90.7)
Clinical or endoscopic evidence of portal hypertension	77 (13.5)

Percentages were calculated using the final study cohort as the denominator (n = 571). Categories were not mutually exclusive and should not be summed. Histological stage F3 fibrosis and histological stage F4 cirrhosis were assigned only when liver biopsy data were available. Radiological features were used to support the presence of cirrhosis or portal hypertension and were not used to diagnose histological stage F3 fibrosis.

Table 2 Baseline characteristics, comorbidities, liver stiffness before direct-acting antiviral therapy, laboratory parameters at sustained virological response at 12 weeks after treatment completion, and noninvasive scoring systems, n (%)/median (interquartile range)

Characteristics	Overall	No HCC	De novo HCC	P value
Patients	571	493 (86.3)	78 (13.7)
Sex, male	267	225 (45.6)	42 (53.8)	0.177
Age (years), mean ± SD	59.75 ± 10.00	59.53 ± 10.24	61.18 ± 8.22	0.175
Comorbidities
T2DM	209	172 (34.9)	37 (47.4)	0.033
DLP	228	205 (41.6)	23 (29.5)	0.043
HT	315	270 (54.8)	45 (57.7)	0.629
Thalassemia	23	22 (4.5)	1 (1.3)	0.346
Esophageal varices without bleeding	87	67 (13.6)	20 (25.6)	0.006
Transient elastography
Baseline liver stiffness by VCTE (kPa)	15.8 (11.1-25.7)	15.1 (10.5-23.3)	21.3 (15.7-35.3)	< 0.001
SOF-based treatment	571 (100)	493 (86.3)	78 (13.7)	0.045
SOF/LDV	186 (32.6)	153 (31.0)	33 (42.3)
SOF/VEL	163 (28.5)	149 (30.2)	14 (17.9)
SOF/DAC	222 (38.9)	191 (38.7)	31 (39.7)
Laboratory parameters at SVR12
Total bilirubin (mg/dL)	0.71 (0.49-1.10)	0.71 (0.47-1.01)	0.90 (0.54-1.47)	0.028
Direct bilirubin (mg/dL)	0.31 (0.20-0.49)	0.28 (0.19-0.46)	0.37 (0.26-0.62)	0.046
AST (U/L)	30 (24-40)	30 (23-40)	34 (26-47)	0.006
ALT (U/L)	22 (16-31)	21 (16-31)	23.5 (17-31)	0.275
ALP (U/L)	91 (67.5-120.5)	91 (68-124)	85 (64-107)	0.193
GGT (U/L)	44.5 (27-92)	43 (27-92)	59 (59-59)	0.641
Platelet count (× 109/L)	140 (92-191)	149 (96-195)	88 (68-150)	< 0.001
Total protein (g/dL), mean ± SD	7.69 ± 0.74	7.71 ± 0.74	7.61 ± 0.71	0.393
Albumin (g/dL), mean ± SD	4.04 ± 0.56	4.08 ± 0.54	3.77 ± 0.56	< 0.001
Globulin (g/dL), mean ± SD	3.70 ± 0.71	3.68 ± 0.68	3.84 ± 0.85	0.170
Noninvasive scoring systems at SVR12
FIB-4	2.97 (1.81-4.97)	2.66 (1.76-4.51)	5.24 (2.79-7.46)	< 0.001
APRI	0.58 (0.35-1.08)	0.54 (0.34-0.96)	1.01 (0.51-1.65)	< 0.001
ALBI	-2.72 (-3.04 to -2.26)	-2.78 (-3.06 to -2.31)	-2.43 (-2.87 to -1.92)	0.001
aMAP	61.79 (56.59-66.22)	60.78 (55.45-65.31)	65.05 (62.29-68.57)	< 0.001

ALBI: Albumin-bilirubin score; ALP: Alkaline phosphatase; ALT: Alanine aminotransferase; aMAP: Age-male-albumin-bilirubin-platelet score; APRI: Aspartate aminotransferase-to-platelet ratio index; AST: Aspartate aminotransferase; DLP: Dyslipidemia; FIB-4: Fibrosis-4 index; GGT: Γ-Glutamyl transferase; HCC: Hepatocellular carcinoma; HT: Hypertension; IQR: Interquartile range; SD: Standard deviation; SOF: Sofosbuvir; DAC: Daclatasvir; LDV: Ledipasvir; VEL: Velpatasvir; SVR12: Sustained virological response at 12 weeks after treatment completion; T2DM: Type 2 diabetes mellitus; VCTE: Vibration-controlled transient elastography.

Table 3 Time-dependent diagnostic performance of four noninvasive scoring systems for predicting de novo hepatocellular carcinoma at 1-year, 3-year, 5-year, and 8-year follow-up

Noninvasive scoring system at SVR12	1-year FU AUC (95%CI)	3-year FU AUC (95%CI)	5-year FU AUC (95%CI)	8-year FU AUC (95%CI)
FIB-4	0.64 (0.49-0.78)	0.69 (0.59-0.79)	0.69 (0.60-0.78)	0.69 (0.61-0.78)
APRI	0.61 (0.46-0.75)	0.67 (0.57-0.77)	0.65 (0.56-0.75)	0.66 (0.57-0.75)
ALBI	0.59 (0.44-0.73)	0.67 (0.58-0.76)	0.66 (0.57-0.74)	0.65 (0.56-0.74)
aMAP	0.74 (0.62-0.85)	0.76 (0.68-0.83)	0.74 (0.67-0.82)	0.74 (0.67-0.80)

ALBI: Albumin-bilirubin score; aMAP: Age-male-albumin-bilirubin-platelet score; APRI: Aspartate aminotransferase-to-platelet ratio index; AUC: Area under the curve; CI: Confidence interval; FIB-4: Fibrosis-4 index; FU: Follow-up; SVR12, sustained virological response at 12 weeks after treatment completion.

Table 4 Exploratory age-male-albumin-bilirubin-platelet score strata for hepatocellular carcinoma risk

Risk of developing de novo HCC	aMAP	Annual HCC incidence % (95%CI)	Proportion of the cohort, %
Low	< 55	0.0	18.55
Intermediate	55 to < 60	2.42 (1.21-4.84)	22.96
High	≥ 60	6.42 (4.81-8.57)	58.49

aMAP: Age-male-albumin-bilirubin-platelet score; HCC: Hepatocellular carcinoma.

Table 5 Risk stratification based on previously validated age-male-albumin-bilirubin-platelet score thresholds

Risk of developing de novo HCC	aMAP score	Annual HCC incidence % (95%CI)	Proportion of the cohort, %
Low	< 50	0.0	6.60
Intermediate	50 to <60	1.58 (0.79-3.16)	34.91
High	≥ 60	6.42 (4.81-8.57)	58.49

aMAP: Age-male-albumin-bilirubin-platelet score; HCC: Hepatocellular carcinoma.