Risk for hepatocellular carcinoma in the course of chronic hepatitis B virus infection and the protective effect of therapy with nucleos(t)ide analogues

Table 1 Summary of studies and meta-analyses evaluating the effect of antiviral therapy on the incidence of hepatocellular carcinoma in chronic hepatitis B patients

Ref.	Total no. of patients, trx/untrx	Type of study	NUC used	F-up (median) trx/untrx	Cumulative incidence of HCC % trx/% untrx	RR or SIR (95%CI)	P value
Liaw et al[56]	436/215	RCT, prospective	LAM vs placebo	2.7 yr	3.9/7.4	RR: 0.49	0.047
Yuen et al[57]	142/104	Prospective	LAM	8.2 yr	0.7/2.4	RR: 0.20 (CI: 0.03-2.76)	0.005
Matsumoto et al[58]	657/2138	Retrospective	LAM vs placebo	2.7/5.3 yr	1.1/13.3	RR: 0.08 (CI: 0.03-0.22)	< 0.001
Eun et al[59]	872/699	Retrospective	LAM vs placebo	5.1 ± 2.7/6.1 ± 4.3 yr	Annual incidence: 0.95 (VR with LAM)/4.1 (controls)/2.18 (R)	RR: 0.14 (0.006-0.34)	0.005 (CIR), 0.123 (non-CIR)
Papatheodoridis et al[60]	201/195	Retrospective	LAM, LAM + ADV	3.8 ± 1.4 yr	2.48/7.7	RR: 0.32 (0.12-0.87)	0.01
Papatheodoridis et al[63]	818	Retrospective	LAM, ADV (add-on), switch to ADV or ETV upon R	4.7 yr	6% (2.5%/yr)	RR: 1 (VR) RR: 2.04 (0.49-8.3) (no VR)	0.322
Kurokawa et al[64]	293	Retrospective	LAM	67.6 ± 27.4 mo	3 (CHB)/30 (CIR)
Hosaka et al[65]	316 (ETV)/316 (untrx)/182 (LAM)	Retrospective	LAM, ETV	5.4 yr	ETV/untrx 3.7/13.7	HCC reduction by 63% with ETV HR: 0.37 (0.15-0.91)	< 0.001
Kobashi et al[66]	ETV/LAM 129/127	Prospective	ETV, LAM	4.25 yr	12.4		No difference ETV vs LAM
Papatheodoridis et al[67]	ETV/LAM 321/818	Retrospective	ETV, LAM	30 mo	ETV/LAM 4.8/5.6		0.096
Lim et al[69]	LAM/ETV 3374/2000	Retrospective	LAM, ETV	LAM: 3.1 yr ETV: 8.7 yr	137/2000 (6.85)/234/3374 (6.9)	ETV/LAM HR: 1.01 (CI: 0.8-1.24)	0.95
Wu et al[70]	21595/21595	Retrospective	LAM, ETV, LdT vs controls	7 yr	7.32/22.7	CI: 6.77-7.87/22.1-23.3	< 0.001
Kim et al[71]	641	Prospective roll-over	TDF	5.52 yr	56% reduction in CIR after the 5th year	SIR:0.55 (0.32-0.94) at 5.52 yr
Lampertico et al[72]	418	Retrospective/prospective	ETV	58 mo	4 (CHB)/13/(CIR)
Arends et al[73]	744	Prospective	ETV	167 wk	Cumulative (5-yr) 2.1 (non-CIR)/10.9 (CIR)		CIR/non-CIR < 0.001
Papatheodoridis et al[74]	1666	Retrospective	ETV, TDF	39 mo	1.3(1st year), 3.4 (3d year), 8.7 (5th year)		No difference from untrx published cohorts
Sung et al[61]	5 studies 1267/1022	Meta-analysis	LAM			RR: 0.22 (0.10-0.50)	< 0.001
						HBeAg (-): RR: 0.25 (0.06-1.06)	NS
Papatheodoridis et al[62]	21 studies 3881/534	Systematic review	LAM		2.8/6.4		0.003
Singal et al[68]	49 studies 10025/3571	Meta-analysis	LAM, ADV, ETV, LdT, TDF		Pooled HCC incidence rate: 1.3 (1.1-1.6)/100 person-years	LAM vs untrx RR: 0.48 (0.38-0.61)	< 0.001 No difference between NA

Trx: Treated; Untrx: Untreated; RR: Relative risk; SIR: Standardized incidence ratio; LAM: Lamivudine; VR: Virological remission; R: Resistance; CIR: Cirrhosis; ADV: Adefovir; CHB: Chronic hepatitis B; ETV: Entecavir; HR: Hazard ratio; LdT: Telbivudine; TDF: Tenofovir; NS: Non-significant; HCC: Hepatocellular carcinoma; NA: Nucleoside analogues; RCT: Randomized controlled trial.

Table 2 Risk scoring system for hepatocellular carcinoma in chronic hepatitis B

CU-HCC score[76]		GAG-HCC score[75]		REACH-B score[77]
Variable	Points	Variable	Points	Variable	Points
Age		Age		Age
> 50 yr	3	Per year	1	Per 5 years over 30	1
Albumin		Gender		Gender
< 3.5 g/dL	20	Male	16	Male	2
Bilirubin		BCP mutations		ALT (IU/L)
> 1.1 mg/dL	1.5	Present	19	15-44	1
Cirrhosis		Cirrhosis		≥ 45	2
Presence	15	Presence	30	HBeAg (+)	2
HBV-DNA		HBV-DNA		HBV-DNA
4-6 log10	1	Per log10	3	< 4log10	0
> 6 log10	4			4 - < 5log10	3
				5 - < 6log10	5
				≥ 6log10	4
Risk category		Risk category		Risk category
Low	< 5	Low	< 101	A 17 point risk scale
Intermediate	5-20	High	≥ 101
High	> 20

CU-HCC: Chinese University-Hepatocellular Carcinoma Score; GAG-HCC: Guide with Age, Gender, HBV-DNA, Core Promoter Mutations and Cirrhosis; REACH-B: Risk Estimation for Hepatocellular Carcinoma in Chronic Hepatitis B; BCP: Basic core promoter; ALT: Alanine transaminase.