Nucleos(t)ide analogues to treat hepatitis B virus-related hepatocellular carcinoma after radical resection

Table 1 Characteristics of patients with hepatitis B virus-related hepatocellular carcinoma treated with nucleos(t)ide analogues or not after radical resection

Ref.	Country or region	No. of patient1	Mean age (yr)1	TNM stage (I/II/III/IV) (n)	Multiple tumor (%)1	Mean tumor size (cm)1	Portal vein invasion (%)1	Mean HBV-DNA level (log10 copies/mL)1	Mean ALT (U/L)1	Cirrhosis (%)1	Initial treatment for HCC, (Ope/RFA/PEI/TACE)	NA therapy	Mean antiviral treatment duration (mo)	Mean follow-up duration (mo)1
Piao et al[21]	Japan	30 vs 40	59 vs 58	31/25/11/3	N/A	2.3 vs 2.52	N/A	6.1 vs 6.52	88 vs 62	N/A	22/16/0/32	LAM	N/A	24
Shuqun et al[22]	Chinese mainland	16 vs 17	48.3 vs 48.5	N/A	N/A	≥ 5 cm: 56.2% vs 70.6%	37.5 vs 23.5	N/A	N/A	100 vs 94.1	33/0/0/0	LAM	12	12-36
Kuzuya et al[23]	Japan	16 vs 33	59.8 vs 61.1	25/19/5/0	N/A	N/A	N/A	6.2 vs 4.12	56.6 vs 54.2	N/A	31/18/0/0	LAM	22.7	38.0 vs 32.6
Kubo et al[24]	Japan	14 vs 10	55 vs 55	5/9/10/0	N/A	2.4 vs 2.8	28.6 vs 40.0	6.0 vs 6.0	53 vs 562	42.9 vs 40.0	24/0/0/0	LAM	32	36.7 vs 7.32
Hung et al[25]	Hong Kong	10 vs 62	N/A	N/A	N/A	N/A	N/A	N/A	N/A	N/A	72/0/0/0	LAM	N/A	18.92
Yoshida et al[26]	Japan	33 vs 71	57 vs 59	I + II: 57.6% vs 73.2%	N/A	2.6 vs 2.8	N/A	≥ 3.7: 100% vs 63%	54 vs 362	N/A	0/104/0/0	LAM	N/A	33 vs 47
Koda et al[27]	Japan	30 vs 20	59 vs 60	19/20/11/0	N/A	N/A	N/A	5.7 vs 5.2	78 vs 54	N/A	12/24/5/9	28LAM + 2ETV	28.6	28.6 vs 36.3
Chuma et al[28]	Japan	20 vs 30	55.7 vs 55.6	19/27/4/0	25.0 vs 23.3	1.7 vs 2.1	N/A	6.0 vs 5.92	43.1 vs 37.7	55.0 vs 53.3	10/10/0/0	15LMA + 5ETV	N/A	35.5 vs 49.22
Li et al[29]	Chinese mainland	43 vs 36	46 vs 45	13/27/39/0	N/A	7.1 vs 8.5	30.2 vs 27.8	6.5 vs 7.3	60.8 vs 56.5	55.8 vs 69.4	79/0/0/0	LAM	N/A	12 vs 12
Chan et al[30]	Hong Kong	42 vs 94	57 vs 552	39/32/64/0	N/A	9.3 vs 9.02	11.9 vs 18.1	N/A	58.0 vs 42.52	73.8 vs 56.4	136/0/0/0	38LAM + 4ETV	N/A	N/A
Wu et al[31]	Tai Wan	518 vs 4051	54.4 vs 54.6	N/A	N/A	N/A	N/A	N/A	N/A	48.6 vs 38.7	4569/0/0/0	159LAM + 292ETV + 36LdT + 31Combined	17.4	31.7 vs 26.2
Urata et al[32]	Japan	46 vs 13	57 vs 58	N/A	28.3 vs 61.5	2.8 vs 3.4	34.8 vs 46.2	4.7 vs 6.1	46.8 vs 58.0	45.7 vs 30.8	59/0/0/0	22LAM + 24ETV	N/A	36.22
Ke et al[33]	Chinese mainland	141 vs 141	48.9 vs 49.7	N/A	27.7 vs 24.1	4.5 vs 5.02	7.8 vs 7.1	4.9 vs 4.7	39 vs 42	81.6 vs 81.6	282/0/0/0	LAM	12	24 vs 23
Yin et al[38]	Chinese mainland	81 vs 82	47.9 vs 49.3	N/A	12.3 vs 22.0	≥ 3 cm: 86.4% vs 93.9%	3.7 vs 7.3	4.9 vs 4.6	47.3 vs 37.5	24.7 vs 28.0	163/0/0/0	LAM	N/A	39.92
		215 vs 402	50.1 vs 50.2	N/A	14.4 vs 12.7	≥ 3 cm: 89.3% vs 92.3%	14.0 vs 15.4	4.5 vs 3.8	> 42: 48.8% vs 36.8%	47.0 vs 35.8	617/0/0/0	LAM	N/A	23.82
Su et al[34]	Tai Wan	62 vs 271	52 vs 582	N/A	22.6 vs 46.9	2.7 vs 4.22	11.3 vs 20.0	5.9 vs 5.52	45 vs 422	33.7 vs 45.8	333/0/0/0	40LAM + 19ETV + 3PEG-IFN	N/A	45.92
Yan et al[35]	Chinese mainland	35 vs 25	45 vs 47	22/29/9/0	N/A	4.7 vs 5.0	65.7 vs 68.0	> 5: 54.3% vs 72.0%	41.5 vs 35.8	N/A	60/0/0/0	LAM	N/A	N/A
Hann et al[37]	The United States	16 vs 9	57 vs 532	N/A	0 vs 0	2.7 vs 3.02	0 vs 0	5.4 vs 6.92	N/A	N/A	3/4/2/8/others3	8(LAM + TDF) + 3(LAM + ADV) + 2(TLV + TDF) + 2TDF + 1LAM	N/A	60.2
Huang et al[39]	Chinese mainland	100 vs 100	50.6 vs 50.5	N/A	17 vs 16	4.9 vs 5.1	0 vs 0	> 3.3: 100% vs 100%	52.6 vs 51.4	N/A	200/0/0/0	ADV	N/A	602

¹Patients who received postoperative NA treatment vs patients who received no postoperative NA treatment;

²Median values;

³Two patients received resection and RFA for their initial treatment; Three patients received RFA and TACE; One patient received RFA, PEI and TACE; Two patients received cryoablation. Boldfaced data come from randomized controlled trials in our review[38,39]. ADV: Adefovir dipivoxil; ETV: Entecavir; LAM: Lamivudine; LdT: Telbivudine; N/A: Not available; Ope: Operation; PEI: Percutaneous ethanol injection; RFA: Radiofrequency ablation; TACE: Transarterial chemoembolization; NA: Nucleos(t)ide analogue.

Table 2 Survival outcomes of patients with hepatitis B virus-related hepatocellular carcinoma treated with nucleos(t)ide analogues or not after radical resection

Year ofpublication	Ref.	Group	n	Overall survival rate (%)				Recurrence-free survival rate (%)
				1 yr	3 yr	5 yr	P	1 yr	3 yr	5 yr	P
2005	Piao et al[21]	NAs	30	100	91.3	N/A	0.12	75	46	N/A	> 0.05
		Control	40	92.4	66	N/A		58	22	N/A
2006	Shuqun et al[22]	NAs	16	24	N/A	N/A	0.0053	19.7	N/A	N/A	> 0.05
		Control	17	0	N/A	N/A		4.5	N/A	N/A
2007	Kuzuya et al[23]	NAs	16	100	100	N/A	0.063	86.5	64.9	N/A	0.622
		Control	33	86.6	46.8	N/A		86.6	46.8	N/A
2007	Kubo et al[24]	NAs	14	N/A	N/A	N/A	N/A	90	90	78	0.0086
		Control	10	N/A	N/A	N/A		55	28	28
2008	Hung et al[25]	NAs	10	N/A	N/A	N/A	N/A	90	N/A	N/A	0.03
		Control	62	N/A	N/A	N/A		75	N/A	N/A
2008	Yoshida et al[26]	NAs	33	100	80	59	> 0.05	N/A	N/A	N/A	> 0.05
		Control	71	100	85	70		N/A	N/A	N/A
2009	Koda et al[27]	NAs	30	96	76	76	0.02	65	15	N/A	> 0.05
		Control	20	86	48	32		72	30	N/A
2009	Chuma et al[28]	NAs	20	N/A	N/A	N/A	N/A	90	55	45	> 0.05
		Control	64	N/A	N/A	N/A		85.9	50	43.7
2010	Li et al[29]	NAs	43	41.9	N/A	N/A	0.0094	23.3	N/A	N/A	0.072
		Control	36	33.3	N/A	N/A		8.3	N/A	N/A
2011	Chan et al[30]	NAs	42	88.1	79.1	71.2	0.005	66.5	51.4	51.4	0.05
		Control	94	76.5	47.5	43.5		48.9	33.8	33.8
2012	Wu et al[31]	NAs	518	94	81	73	0.002	87	66	54	< 0.001
		Control	4051	91	74	62		78	56	47
2012	Urata et al[32]	NAs	46	100	97.1	89.7	0.0025	71.6	56.8	42.6	0.0478
		Control	13	84.6	68.4	59.8		61.5	19.2	19.2
2013	Ke et al[33]	NAs	141	92.1	84.4	79.1	0.009	73.1	54.7	44.5	0.503
		Control	141	89.6	66.3	52.1		68.8	47.8	43
2013	Yin et al[38]	NAs	81	98	88	N/A	< 0.001	81	46	N/A	< 0.001
		Control	82	86	51	N/A		50	20	N/A
		NAs	215	84	60	N/A	0.04	52	37.5	N/A	< 0.001
		Control	402	75	50	N/A		43	21	N/A
2013	Su et al[34]	NAs	62	99	96	89	< 0.001	90	64	58	< 0.001
		Control	271	84	64	49		64	44	34
2013	Yan et al[35]	NAs	35	N/A	N/A	N/A	N/A	74.3	11.4	N/A	0.283
		Control	25	N/A	N/A	N/A		80	0	N/A
2014	Hann et al[37]	NAs	16	100	93.8	86.5	< 0.001	81.3	81.3	81.3	< 0.001
		Control	9	55.6	0	0		11.1	0	0
2014	Huang et al[39]	NAs	100	96	77.6	63.1	0.001	85	50.3	46.1	0.026
		Control	100	94	67.4	41.5		84	37.9	27.1

Boldfaced data come from randomized controlled trials in our review[38,39]. N/A: Not applicable; NA: Nucleos(t)ide analogue.

Table 3 Mutations of the hepatitis B virus polymerase gene arising after initial therapy with one nucleos(t)ide analogue and resulting in cross-resistance to other nucleos(t)ide analogues

Initial NA therapy	Mutational sites after initial NA therapy	Cross-resistance data
		LAM	LdT	ETV	ADV	TDF
	Wild-type	S	S	S	S	S
LAM or LdT	M204I/V	R	R	I	S	S
ADV	N236T	S	S	S	R	I
LAM or LdT or ADV	A181T/V	R	R	S	R	I
ADV or TDF	A181T/V + N236T1	R	R	S	R	R
ETV	L181M + M204V/I ± I169 ± T184 ± S202 ± M250V2	R	R	R	S	S

¹Resistance to ADV or TDF is associated with the substitution A181T/V and/or N235T in HBV polymerase gene;

²Resistance to ETV is associated with substitutions at I169, T184, S202 or M250V, and with the simultaneous substitutions at L181M plus M204V/I in HBV polymerase gene. Data come from ref. [11]. ADV: Adefovir dipivoxil; ETV: Entecavir; I: Intermediate; LAM: Lamivudine; LdT: Telbivudine; NA: Nucleos(t)ide analogue; R: Resistant; S: Sensitive; TDF: Tenofovir disoproxil fumarate.