Nucleos(t)ide analogs in the prevention of hepatitis B virus related hepatocellular carcinoma

Table 1 Summary of controlled studies investigating the effect of nucleos(t)ide analogues on hepatocellular carcinoma risk among treated and untreated patients with chronic hepatitis B

Ref.	Country/region	Study type	Treatment	No. ofpatients (T/C)	Patient cohort	Follow-up (T/C), mean or median (yr)	Treatment outcome
Liaw et al[30]	Asia	RCT	Lamivudine (100 mg/d)	436/215	Advanced fibrosis or cirrhosis	2.7/2.7	Reduced HCC risk
Manolakopoulos et al[80]	Greece	Case-control	Lamivudine (100 mg/d)	30/30	Decompensated cirrhosis	1.5/1.8	No risk reduction
Matsumoto et al[33]	Japan	Retrospective cohort	Lamivudine (100 mg/d)	377/377	Chronic hepatitis B (any stage)	2.7/5.3	Reduced HCC risk
Papatheodoridis et al[40]	Greece	Retrospective cohort	Lamivudine (adefovir switch or add-on when required)	201/195	HBeAg-negative chronic hepatitis B	3.8/6.1	Better overall survival. Reduced risk of major events including HCC
Chan et al[32]	China	RCT	Lamivudine (100 mg/d)	89/47	HBeAg-negative chronic hepatitis B	2.5/2.5	No risk reduction
Yuen et al[34]	China	Prospective cohort	Lamivudine (25-100 mg/d)	142/124	HBeAg-positive chronic hepatitis B	7.5/9.0	Reduced cirrhosis/HCC risk
Lee et al[36]	South Korea	Retrospective cohort	Lamivudine (100 mg/d)	589/589	Chronic hepatitis B (any stage)	2.9/5.3	Reduced HCC risk
Ma et al[35]	China	Prospective cohort	Lamivudine (100 mg/d)	41/176	Cirrhosis	3.16/NS	Reduced HCC risk
Das et al[39]	India	Case-control	Lamivudine or adefovir	151/102	Decompensated cirrhosis	4.0/3.8	Less HCC rate in treated group
Eun et al[37]	South Korea	Retrospective cohort	Lamivudine (100 mg/d)	872/699	Chronic hepatitis B (any stage)	4.7/5.7	Reduced HCC risk in cirrhotic patients with SVS
Kim et al[38]	South Korea	Retrospective cohort	Lamivudine and/or adefovir, or entecavir	240/481	Cirrhosis	3.9/4.3	Better overall survival. Reduced HCC risk (borderline significance)
Hosaka et al[46]	Japan	Retrospective cohort	Entecavir (0.5 mg/d)	316/316	Chronic hepatitis B (any stage)	3.3/7.6	Reduced HCC risk
Wong et al[47]	China	Retrospective cohort	Entecavir (0.5 mg/d)	1446/424	Chronic hepatitis B (any stage)	3.0/9.5	Reduced HCC risk in cirrhotic patients
Kumada et al[81]	Japan	Retrospective cohort	Lamivudine ± adefovir, entecavir	117/117	Chronic hepatitis B (any stage)	12.3/11.6	Reduced HCC risk
Sievert et al[49]	Reg. trial (abstract)	Prospective cohort	Tenofovir (300 mg/d)	641	Chronic hepatitis B (any stage)	6	Reduced HCC risk compared to estimated risk (REACH-B model)
Su et al[48]	Taiwan	Prospective cohort	Entecavir (0.5 mg/d)	1123/503	Cirrhosis (HBVDNA > 2000 IU/mL)	3.6/6.8
Wu et al[44]	Taiwan	Retrospective nationwide cohort	Lamivudine, adefovir or entecavir	21595/21595	Chronic hepatitis B (any stage)	3.5/5.2	Reduced HCC risk
Gordon et al[82]	United States	Retrospective cohort	94% received NAs, remaining received IFNs	820/1851	Chronic hepatitis B (any stage)	5.2	Reduced HCC risk
Coffin et al[83]	United States	Retrospective cohort	NAs	322	Chronic hepatitis B (any stage)	3.2	Reduced HCC risk compared to estimated risk (REACH-B model)

NAs: Nucleos(t)ide analogues; HCC: Hepatocellular carcinoma; T: Treatment group; C: Control group; RCT: Randomized-controlled trial; HBeAg: Hepatitis B e antigen; SVS: Sustained virological suppression; IFNs: Interferons.

Table 2 Systematic review and meta-analyses investigating hepatocellular carcinoma risk reduction in patients receiving nucleos(t)ide analogues vs untreated controls

Ref.	No. of studies	No. of patients (T/C)	OR (95%CI)	P
Papatheodoridis et al[51]	3	1313 (779/534)	0.43 (0.25-0.74)	0.002
Zhang et al[52]	6	3644 (2035/1609)	0.26 (0.15-0.47)	< 0.00001
Singal et al[53]	6	6877 (3306/3571)	0.48 (0.38-0.61)	< 0.00001
Sung et al[54]	5	2289 (1267/1022)	0.22 (0.10-0.50)	0.0003

T: Treatment group; C: Control group.

Table 3 Summary of controlled studies investigating the efficacy of nucleos(t)ide analogues in prevention of hepatocellular carcinoma recurrence after curative treatments

Ref.	Country	Study type	Antiviral treatment	No. ofpatients (T/C)	HCCtreatment	Follow-up (T/C),mean/median (yr)	Treatment outcome
Piao et al[69]	Japan	Retrospective cohort	Lamivudine (100 mg/d)	30/40	Resection or ablation/TACE	Not specified	No risk reduction for HCC recurrence
							Better overall survival
Shuqun et al[70]	China	Retrospective cohort	Lamivudine (100 mg/d) + thymosin α1	17/16	Resection	1-3	Reduced HCC recurrence (NS)
Kuzuya et al[71]	Japan	Retrospective cohort	Lamivudine (100 mg/d)	16/33	Resection or RFA	3.2/2.7	No risk reduction
Kubo et al[72]	Japan	Retrospective cohort	Lamivudine (100 mg/d)	14/10	Resection	2.1	Higher tumor-free survival
Yoshida et al[84]	Japan	Retrospective cohort	Lamivudine (100 mg/d)	33/71	RFA	2.8/3.9	No risk reduction
Hung et al[85]	China	Retrospective cohort	Lamivudine (100 mg/d)	10/62	Resection	1.6	Reduced HCC recurrence
Koda et al[86]	Japan	Retrospective cohort	Lamivudine or entecavir	30/20	Resection or ablation/TAE	2.4/3.0	No risk reduction for HCC recurrence
							Better overall survival
Chuma et al[87]	Japan	Retrospective cohort	Lamivudine (100 mg/d)	39/64	Resection or RFA	2.9/4.4	Reduced HCC recurrence
Li et al[74]	China	Prospective cohort	Lamivudine ± adefovir	43/36	Resection	1.0	No risk reduction
Chan et al[73]	China	Retrospective cohort	Lamivudine or entecavir	42/94	Resection	Not specified	Reduced HCC recurrence
Urata et al[88]	Japan	Retrospective cohort	Not specified	46/242	Resection	3.1	Tumor-free survival is better vs patients with high viral load
Yang et al[89]	China	Prospective cohort	Lamivudine, adefovir or entecavir	142/188	Resection	4.0	Reduced HCC recurrence
Wu et al[75]	Taiwan	Retrospective nationwide cohort	Nucleoside analogue(s)	518/4051	Resection	2.6/2.2	Reduced HCC recurrence
Huang et al[90]	China	Prospective cohort	Lamivudine, adefovir or entecavir	865/175	Resection (HBVDNA > 2000 IU/mL)	3.5	Better disease-free survival (borderline significance)
							Better overall survival
Huang et al[68]	China	Retrospective cohort	Lamivudine, adefovir or entecavir	150/1459	Resection (HBVDNA < 2000 IU/mL)	2.9-3.3	Better disease-free survival
Ke et al[91]	China	Retrospective cohort	Lamivudine (100 mg/d)	141/337	Resection	2.0/1.9	No risk reduction for HCC recurrence
							Better overall survival
Su et al[92]	Taiwan	Retrospective cohort	Lamivudine, entecavir or pegylated interferon	62/271	Resection	3.8	Reduced HCC recurrence
							Better overall survival
Yin et al[76]	China	2 cohorts (RCT and NRC)	Lamivudine1 (100 mg/d)	RCT: 81/82; NRC: 215/402	Resection	RCT: 3.3; NRC: 1.98	Reduced HCC recurrence and better overall survival in both cohorts
Yeh et al[93]	Taiwan	Retrospective cohort	Entecavir, lamivudine, telbivudine, or combination	490/3369	Resection, RFA, PEI	3.3/3.3	No benefits for HCC progression or overall survival
Zhang et al[94]	China	Retrospective cohort	Entecavir (0.5 mg/d)	40/47	Resection	2.6	Reduced recurrence if HCC ≤ 3 cm
Hann et al[95]	United States	Retrospective cohort	NAs	16/9	Resection, RFA, PEI, TACE	5.0	Reduced HCC recurrence
							Better overall survival
Nishikawa et al[96]	Japan	Retrospective cohort	Lamivudine, adefovir or entecavir	99/32	Resection, RFA, PEI	3.5/4.0	No risk reduction for HCC recurrence
							Better overall survival
Huang et al[77]	China	RCT	Adefovir (10 mg/d)	100/100	Resection	5.0	Reduced HCC recurrence
			Switch to entecavir (18 patients)				Better overall survival
Chong et al[97]	China	Retrospective-prospective cohort	Nucleoside analog(s)	254/150	Resection	3.3/3.6	No risk reduction for HCC recurrence
							Better overall survival

¹Adefovir ± lamivudine or entecavir for drug resistance;

²13 patients with high viral load, 11 patients with low viral load. HCC: Hepatocellular carcinoma; T: Treatment group; C: Control group; NS: Not significant; TACE: Transarterial chemoembolization; TAE: Transarterial embolization; RFA: Radiofrequency ablation; PEI: Percutaneous ethanol injection; NAs: Nucleos(t)ide analogues; RCT: Randomized-controlled trial; NRC: Non-randomized cohort.

Table 4 Summary of meta-analyses which investigated preventive effect of nucleos(t)ide analogues on hepatocellular carcinoma recurrence in patients who underwent curative treatments

Ref.	No. of studies	No. of patients (T/C)	OR (95%CI)	P
Miao et al[98]
1 yr recurrence	2	119 (46/73)	0.59 (0.24-1.43)	0.24
2 yr recurrence	2	119 (46/73)	0.82 (0.34-1.74)	0.60
Wong et al[65]	9	555 (204/347)	0.59 (0.35-0.97)	0.04
Sun et al[78]	13	6350 (1227/5123)	0.66 (0.54-0.80)	< 0.0001
Zhou et al[79]	8	6127 (NS)	0.69 (0.59-0.80)	< 0.00001

NS: Not significant; T: Treatment group; C: Control group.