Risk prediction of hepatitis B virus-related hepatocellular carcinoma in the era of antiviral therapy

Table 1 Risk factors for hepatitis B virus-related hepatocellular carcinoma

Host factors	Liver factors	Viral factors
Advanced age	Advanced fibrosis	High serum HBV DNA
Male gender	Cirrhosis	Positive HBeAg
Family history of HCC	Hypoalbuminemia	HBV genotype C
SNP at human genomic loci, e.g.	Hyperbilirubinemia	HBV subgenotype Ce
Chromosome 1p36.22	High ALT	Core promoter mutations
Chromosome 6 of HLA-DP/Q loci	Active necroinflammation	High serum HBsAg level
Chromosome 8p12	Concomitant liver diseases, e.g.
Immunosuppressed condition, e.g.	Hepatitis C virus co-infection
Human immunodeficiency virus co-infection	Hepatitis delta virus co-infection
	Alcoholic liver disease
	Nonalcoholic fatty liver disease

ALT: Alanine aminotransferase; HBeAg: Hepatitis B virus e antigen; HBsAg: Hepatitis B surface antigen; HBV: Hepatitis B virus; HCC: Hepatocellular carcinoma; HLA: Human leukocyte antigen; SNP: Single-nucleotide polymorphism.

Table 2 Components of the risk scores

Factor	Risk score
	CU-HCC	GAG-HCC (yr)	REACH-B
Age (yr)	≤ 50: 0		30-34: 0
	>50: 3		35-39: 1
			40-44: 2
			45-49: 3
			50-54: 4
			55-59: 5
			60-65: 6
Sex	NA	Male: 16	Male: 2
		Female: 0	Female: 0
Albumin (g/L)	≤ 35: 20	NA	NA
	> 35: 0
Bilirubin (mmol/L)	≤ 18: 0	NA	NA
	> 18: 1.5
ALT (U/L)	NA	NA	< 15: 0
			15-44: 1
			≥ 45: 2
HBeAg	NA	NA	Positive: 2
			Negative: 0
HBV DNA (copies/mL)	< 4 log: 0	3 × in log	< 4 log: 0
	4-6 log: 1		4-5 log: 3
	> 6 log: 4		5-6 log: 5
	(lack of maintained virologic suppression: 4)		≥ 6 log: 4 (lack of maintained virologic suppression: 4)
Cirrhosis	Presence: 15	Presence: 33	NA
	Absence: 0	Absence: 0

ALT: Alanine aminotransferase; HBeAg: Hepatitis B e antigen; NA: Not applicable; HCC: Hepatocellular carcinoma; HBV: Hepatitis B virus.

Table 3 Comparison of the CU-hepatocellular carcinoma, GAG-hepatocellular carcinoma and REACH-B scores

Score	Patients	Components	Cutoff value	Performance
CU-HCC	Clinic patients: 1005 in training cohort, 424 in validation cohort	Age, albumin, bilirubin, HBV DNA, cirrhosis	5	97% NPV at 10 yr
GAG-HCC	820 clinic patients (leave-one-out cross-validation method)	Age, gender, HBV DNA, cirrhosis	101	99% NPV at 10 yr
REACH-B	Non-cirrhotic patients: 3584 in training cohort, 1505 in validation cohort	Age, gender, ALT, HBV DNA, HBeAg	8	98% NPV at 10 yr

ALT: Alanine aminotransferase; HBeAg: Hepatitis B e antigen; HBV: Hepatitis B virus; HCC: Hepatocellular carcinoma; NPV: Negative predictive value.

Table 4 Dynamic changes in risk scores and 5-year risk of hepatocellular carcinoma

Risk score		HCC in 5 yr
Baseline	2 yr	CU-HCC	GAG-HCC	REACH-B1
Low	Low	0.4%	1.4%	0.0%
Low	High	0.0%	NA	0.0%
High	Low	2.1%	5.1%	0.0%
High	High	12.9%	26.4%	2.1%

¹Only patients without cirrhosis were analyzed for the REACH-B score. Results adopted from Wong et al[22]. HCC: Hepatocellular carcinoma; NA: Not available.