The effect of antiviral therapy on patients with hepatitis B virus-related hepatocellular carcinoma after curative resection: a systematic review and meta-analysis

Figures & data

Figure 1 Flowchart of search strategy for meta-analysis study selection.

Abbreviations: HBV, hepatitis B virus; HCC, hepatocellular carcinoma; HDV, hepatitis D virus.

Table 1 Baseline characteristics of the studies included for meta-analysis

Study	Study type	NA type	Arms	Cases	Age (years)a	Gender (M/F)	HBV DNA level (log copies/mL)a	HBeAg (±)	Tumor size (cm)a	No of tumors (S/M)	Tumor stageb	Child–Pugh (A/B/C)	Follow-up duration (months)a	Quality score
Chan et al (2011)^Citation12	Pro–retro	LAM, ETV	Treatment	42	57	31/11	N/A	N/A	9.3	N/A	11/14/16/0 (AJCC)	42/0/0	N/A	4c
			Control	94	55	74/20	N/A	N/A	9.0	N/A	28/18/48/0 (AJCC)	84/10/0	N/A
Chen et al (2016)^Citation22	Retro	LAM, ETV	Treatment	192	47	172/20	N/A	48/144	4.7	176/16	151/41/0 (TNM)	192/0/0	74d	4c
			Control	253	49	218/35	N/A	35/218	5.4	232/21	215/38/0 (TNM)	253/0/0
Chen (2015)^Citation24	Pro	LAM	Treatment	45	52.2	39/6	N/A	N/A	N/A	37/8	38/5/2/0 (AJCC)	41/4/0	N/A	4c
			Control	40	51.9	36/4	N/A	N/A	N/A	35/5	34/5/1/0 (AJCC)	38/2/0	N/A
Cheng et al (2011)^Citation35	Retro	LAM	Treatment	50	45.3	38/12	5.56 (5.53–5.64)	N/A	N/A	N/A	N/A	N/A	N/A	4c
			Control	43	42.2	32/11	5.68 (5.50–5.83)	N/A	N/A	N/A	N/A	N/A	N/A
Chong et al (2015)^Citation13	Pro–retro	LAM, ETV	Treatment	254	55	222/32	N/A	42/212	3.5	198/56	168/50/34/2 (AJCC)	243/10/1	39.2 (0.2–163.9)	5c
		ADV, LdT	Control	150	56	125/25	N/A	12/138	3.8	118/32	97/26/27/0 (AJCC)	145/4/1	43.3 (0.1–151.2)
Ding et al (2014)^Citation36	Retro	ETV	Treatment	74	47.2	56/18	5.21	N/A	N/A	N/A	N/A	54/20/0	N/A	4c
			Control	39	46.5	30/9	5.02	N/A	N/A	N/A	N/A	31/8/0	N/A
Fang et al (2012)^Citation25	Retro	LAM	Treatment	26	48.9	20/6	6.38	N/A	N/A	N/A	N/A	N/A	41	4c
			Control	30	50.0	23/7	6.55	N/A	N/A	N/A	N/A	N/A	20
Huang et al (2015)^Citation14	RCT	ADV	Treatment	100	50.6	90/10	N/A	51/49	4.9	100/0	8/60/0 (BCLC [0/A/B])	100/0/0	60 (4–70)d	3e
			Control	100	50.5	89/11	N/A	50/50	5.1	100/0	8/59/0 (BCLC [0/A/B])	100/0/0
Huang et al (2016)^Citation26	Retro	LAM, ETV	Treatment	45	N/A	N/A	4.72	N/A	N/A	N/A	N/A	45/0/0	11 (3–34)d	4c
		ADV	Control	33	N/A	N/A	4.25	N/A	N/A	N/A	N/A	33/0/0
Ke et al (2013)^Citation15	Retro	LAM	Treatment	141	48.9	129/12	4.97	15/126	4.5	102/39	107/23/11 (BCLC [A/B/C])	141/0/0	24 (2–65)	5c
			Control	141	49.7	127/14	4.78	16/125	5.0	107/34	105/26/10 (BCLC [A/B/C])	141/0/0	23 (1–73)
Li et al (2010)^Citation16	Pro	LAM, ADV	Treatment	43	46	34/9	6.49 (4.04–7.38)	38/5	7.1	N/A	9/17/17 (TNM)	28/14/1	12	4c
			Control	36	45	30/6	7.27 (3.45–8.32)	27/9	8.5	N/A	4/10/22 (TNM)	21/12/3	12
Lin et al (2016)^Citation27	Retro	ETV	Treatment	35	54.2	26/9	7.48	N/A	N/A	N/A	N/A	28/7/0	54	4c
			Control	25	2.5	20/5	6.94	N/A	N/A	N/A	N/A	20/5/0	38
Qian et al (2016)^Citation28	Retro	LAM, ADV	Treatment	70	N/A	58/12	6.70	N/A	6.5	N/A	N/A	70/0/0	N/A	4c
			Control	65	N/A	52/13	6.71	N/A	6.6	N/A	N/A	65/0/0	N/A
Su et al (2013)^Citation17	Retro	LAM, ETV	Treatment	62	52	56/6	5.89 (4.83–7.15)	9/53	2.7	48/14	40/15/5 (BCLC [A/B/C])	N/A	N/A	4c
			Control	271	58	232/39	5.48 (4.09–7.83)	28/243	4.2	144/127	142/83/44 (BCLC [A/B/C])	N/A	N/A
Tian et al (2015)^Citation29	Retro	LAM, ETV	Treatment	29	57.8	18/11	4.7	N/A	2.8	11/18	N/A	25/4/0	28.6d	4c
		ADV	Control	21	58.3	14/7	6.1	N/A	3.4	8/13	N/A	18/3/0
Wang et al (2015)^Citation30	Retro	LAM, ETV	Treatment	76	53.7	58/18	5.46	N/A	6.1	64/12	35/30/11 (TNM)	N/A	30.3	4c
		ADV	Control	80	51.3	57/23	5.40	N/A	5.5	71/9	32/28/10 (TNM)	N/A	18.4
Wei et al (2016)^Citation23	Retro	LAM, ADV	Treatment	86	50.8	79/7	6.9 (2.0–8.8)	14/72	8.0	27/59	0/36/50 (TNM)	82/4/0	30.6 (3.3–73.2)d	4c
			Control	40	50.0	35/5	5.7 (2.0–6.7)	6/34	8.9	15/25	0/22/18 (TNM)	39/1/0
Wu et al (2012)^Citation18	Retro	LAM, ETV	Treatment	518	54.4	435/83	N/A	N/A	N/A	N/A	N/A	N/A	32	4c
		LdT	Control	4,051	54.6	3,335/716	N/A	N/A	N/A	N/A	N/A	N/A	26
Xu et a1 (2016)^Citation31	Retro	N/A	Treatment	29	N/A	N/A	N/A	N/A	N/A	N/A	N/A	N/A	N/A	4c
			Control	82	N/A	N/A	N/A	N/A	N/A	N/A	N/A	N/A	N/A
Yang et al (2010)^Citation32	Retro	LAM	Treatment	30	22/8	N/A	N/A	N/A	N/A	N/A	27/2/1 (TNM)	29/1/0	26.2d	4c
			Control	30	23/7	N/A	N/A	N/A	N/A	N/A	21/7/2 (TNM)	26/4/0
Yang et al (2012)^Citation19	Pro	LAM, ETV	Treatment	142	N/A	N/A	N/A	N/A	N/A	N/A	N/A	N/A	49.1d	4c
		ADV	Control	188	N/A	N/A	N/A	N/A	N/A	N/A	N/A	N/A
Yao et al (2016)^Citation33	Retro	LAM, ADV	Treatment	76	53.9	54/22	5.43	N/A	N/A	N/A	N/A	N/A	30.4	4c
			Control	80	52.3	55/25	5.40	N/A	N/A	N/A	N/A	N/A	18.5
*Yin et al (2013a)^Citation20	Pro	LAM, ETV	Treatment	215	50.1	194/21	4.51	80/135	N/A	184/31	6/159/50 (BCLC [0/A/B])	209/6/0	24d	5c
		ADV	Control	402	50.3	336/66	3.82	100/302	N/A	351/51	6/296/98 (BCLC [0/A/B])	392/10/0
*Yin et al (2013b)^Citation20	RCT	LAM, ETV	Treatment	81	47.9	74/7	4.88	41/40	N/A	71/10	4/67/10 (BCLC [0/A/B])	80/1/0	40d	3e
		ADV	Control	82	49.4	70/12	4.57	26/56	N/A	64/18	2/58/22 (BCLC [0/A/B])	82/0/0
Zhang (2015)^Citation34	Pro	LAM	Treatment	45	52.2	39/6	N/A	N/A	N/A	37/8	38/5/2 (TNM)	41/4/0	N/A	4c
			Control	40	51.9	36/4	N/A	N/A	N/A	35/5	34/5/1 (TNM)	38/3/0	N/A
Zhang et al (2014)^Citation21	Retro	ETV	Treatment	40	N/A	26/14	N/A	N/A	4.6	40/0	N/A	33/6/1	N/A	5c
			Control	47	N/A	31/16	N/A	N/A	4.8	47/0	N/A	37/10/0	N/A

Notes:

a Mean, median, or median (range).

b Tumor stage containing AJCC with form (I/II/III/IV), TNM with form (I/II/III), and BCLC (0/A/B or A/B/C).

c Modified Newcastle–Ottawa scale (0–6 stars).

d The follow-up duration of all patients in the study.

e Jadad scale (0–5 points).

* Study of Yin et al (2013)²⁰ was a two-stage longitudinal clinical study which included a first stage pro study and a second stage RCT. Therefore, the first stage pro study was defined as Yin et al (2013a)²⁰ and the second stage RCT was defined as Yin et al (2013b)²⁰.

Abbreviations: ADV, adefovir dipivoxil; AJCC, American Joint Committee on Cancer; BCLC, Barcelona clinic Liver Cancer; ETV, entecavir; HBeAg, Hepatitis B e-antigen; HBV, hepatitis B virus; LAM, lamivudine; LdT, telbivudine; M/F, male/female; NA, nucleoside analog; N/A, not available; Pro, prospective; RCT, randomized controlled trial; Retro, retrospective; S/M, single/multiple.

Figure 2 Forest plots for postoperative survival outcomes.

Notes: (A) Meta-analysis of OS. (B) Meta-analysis of RFS. *Study of Yin et al (2013)²⁰ was a two-stage longitudinal clinical study which included a first stage pro study and a second stage RCT. Therefore, the first stage pro study was defined as Yin et al (2013a)²⁰ and the second stage RCT was defined as Yin et al (2013b)²⁰.
Abbreviations: CI, confidence interval; HR, hazard ratio; IV, inverse variance; OS, overall survival; RFS, recurrence-free survival; SE, standard error.

Figure 3 Stratified meta-analysis of OS according to the type of NAs.

Note: *Study of Yin et al (2013)²⁰ was a two-stage longitudinal clinical study which included a first stage pro study and a second stage RCT. Therefore, the first stage pro study was defined as Yin et al (2013a)²⁰ and the second stage RCT was defined as Yin et al (2013b)²⁰.
Abbreviations: CI, confidence interval; HR, hazard ratio; IV, inverse variance; NAs, nucleoside analogs; OS, overall survival; SE, standard error.

Figure 4 Stratified meta-analysis of postoperative survival outcomes according to viral load (baseline HBV DNA level ≥20,000 IU/mL versus <20,000 IU/mL).

Notes: (A) Meta-analysis of OS. (B) Meta-analysis of RFS.
Abbreviations: CI, confidence interval; HBV, hepatitis B virus; HR, hazard ratio; IV, inverse variance; OS, overall survival; RFS, recurrence-free survival; SE, standard error.

Figure 5 Subgroup analysis on patients with fully preserved hepatic function (Child class A).

Notes: (A) Meta-analysis of OS. (B) Meta-analysis of RFS.
Abbreviations: CI, confidence interval; HR, hazard ratio; IV, inverse variance; OS, overall survival; RFS, recurrence-free survival; SE, standard error.

Figure 6 Stratified meta-analysis of RFS according to the type of NAs.

Note: *Study of Yin et al (2013)²⁰ was a two-stage longitudinal clinical study which included a first stage pro study and a second stage RCT. Therefore, the first stage pro study was defined as Yin et al (2013a)²⁰ and the second stage RCT was defined as Yin et al (2013b)²⁰.
Abbreviations: CI, confidence interval; HR, hazard ratio; IV, inverse variance; NAs, nucleoside analogs; RFS, recurrence-free survival; SE, standard error.

Figure 7 Funnel plot for the results from included studies comparing RFS in HBV-related HCC patients who received antiviral therapy or no treatment.

Abbreviations: HBV, hepatitis B virus; HCC, hepatocellular carcinoma; HR, hazard ratio; RFS, recurrence-free survival; SE, standard error.

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