A total of 419 citations were identified by initial search, 348 duplicated or irrelevant records were later removed. According to the inclusion/exclusion criteria, 45 literature was further excluded, and final 26 studies (n= 2374) were included for our analysis (Figure 1).
The study and patient characteristics were summarized in Table 1. 24 observational studies and 2 RCT were included. 21 of them were presented in manuscript, and 5 in conference abstract. 18 studies were conducted in Asia, 3 in Europe, 3 in North America,1 in Australia, and 1 across continents. 15 studies enrolled patients with HBV viremia and 5 included patients with HDV superinfection. HCC was a major indication for LT, responsible for 13.6% to 80% of the surgical cases. Considerable follow-up period was ensured across the studies, with 84.6% (22/26) over 24 months and 30.7% (8/26) over 48 months.
Table 1
Identified studies for systematic review and meta-analysis
First Author
|
Year
|
Study design
|
NOS score/
RoB
|
Pre-transplant HBV DNA positivity (%)
|
Pre-transplant HDV superinfection (%)
|
HCC before LT (%)
|
HP NAs-based regimen
|
Median/mean
Follow-up period (month)
|
Definition of HBV recurrence
|
HBV recurrence
|
HBV-recurrence related mortality
|
All cause-mortality
|
Xi ZF[28]
|
2009
|
RC
|
6
|
60.0
|
NA
|
41.6
|
ETV + HBIG
|
34
|
reappearance of both HBsAg and HBV DNA
|
0/30
|
NA
|
4/30
|
Cai CJ[29]
|
2012
|
RC
|
6
|
Mean level 8.74×106 cp/ml
|
NA
|
29.9
|
ETV+HBIG
|
41.2
|
reappearance of HBsAg
|
0/63
|
NA
|
NA
|
Teperman LW[30]
|
2013
|
RCT
|
Unclear risk of bias
|
NA
|
0
|
NA
|
FTC/TDF±HBIG
|
18
|
HBV viremia
|
0/37
|
0/37
|
1/37
|
Yi NJ[31]
|
2013
|
PC
|
5
|
NA
|
0
|
72.4
|
Sequential ETV following HBIG+ETV
|
32.6
|
reappearance of HBsAg
|
1/29
|
0/29
|
1/29
|
Kim YK[32]
|
2013
|
RC
|
4
|
26.0
|
0.6
|
NA
|
ETV+HBIG
|
28
|
reappearance of HBsAg
|
5/154
|
0/154
|
21/154
|
Perrillo R[33]
|
2013
|
PC
|
6
|
0
|
NA
|
36.9
|
ETV+HBIG
|
18
|
HBV viremia
|
0/61
|
NA
|
5/61
|
Ueda Y[34]
|
2013
|
RC
|
5
|
46.0
|
NA
|
53.9
|
ETV+HBIG
|
25.1
|
reappearance of HBsAg and/or HBV DNA
|
0/26
|
0/26
|
7/26
|
Elsiesy H[35]
|
2013
|
RC
|
4
|
40.0
|
NA
|
NA
|
ETV+HBIG, TDF+HBIG
|
32
|
reappearance of HBsAg or HBV DNA
|
0/15
|
NA
|
NA
|
Cholongitas E[36]
|
2014
|
PC
|
5
|
0
|
28.0
|
50.0
|
Sequential ETV, TDF following HBIG+ETV or HBIG+TDF
|
18
|
reappearance of HBsAg and/or HBV DNA
|
0/28
|
0/28
|
2/28
|
Na GH[37]
|
2014
|
RC
|
5
|
74.9
|
NA
|
54.0
|
ETV+HBIG
|
49
|
reappearance of HBsAg
|
4/262
|
NA
|
NA
|
Hu TH[38]
|
2014
|
PC
|
6
|
NA
|
NA
|
NA
|
ETV+HBIG
|
36
|
reappearance of HBsAg
|
2/145
|
NA
|
NA
|
Gao Y[39]
|
2014
|
RC
|
6
|
69.1
|
NA
|
39.1
|
ETV+HBIG
|
57.1
|
reappearance of both HBsAg and HBV DNA
|
0/84
|
NA
|
0/84
|
Fernández I[40]
|
2015
|
PC
|
5
|
26.0
|
17.0
|
38.0
|
Sequential ETV, TDF following HBIG+ETV or HBIG+TDF
|
28
|
reappearance of HBsAg and/or HBV DNA
|
0/58
|
0/58
|
1/58
|
Choudhary NS[41]
|
2015
|
PC
|
5
|
76.0
|
0
|
22.7
|
Sequential ETV, TDF following HBIG+ETV or HBIG+TDF
|
43
|
reappearance of HBsAg and/or HBV DNA
|
1/175
|
NA
|
NA
|
Shen S[42]
|
2015
|
RC
|
5
|
34.2
|
NA
|
46.4
|
ETV + HBIG
|
45.8
|
reappearance of HBsAg or HBV DNA
|
5/491
|
NA
|
57/491
|
Chen G[43]
|
2015
|
PC
|
6
|
NA
|
NA
|
21.5
|
ETV+HBIG
|
36
|
reappearance of both HBsAg and HBV DNA
|
5/102
|
NA
|
11/102
|
Idilman R[44]
|
2016
|
PC
|
6
|
29.0
|
29.2
|
41.9
|
ETV+HBIG, TDF+HBIG
|
46
|
reappearance of HBsAg
|
1/89
|
NA
|
4/89
|
Togashi J[45]
|
2016
|
RC
|
4
|
30.0
|
NA
|
NA
|
ETV+HBIG
|
64
|
reappearance of HBsAg or HBV DNA
|
0/12
|
NA
|
0/12
|
Nolan A[46]
|
2016
|
RC
|
4
|
51.7
|
NA
|
NA
|
Sequential ETV, TDF following HBIG+ETV or HBIG+TDF
|
28
|
NA
|
0/17
|
0/17
|
1/17
|
Fung J[47]
|
2017
|
PC
|
5
|
61.0
|
NA
|
36.6
|
ETV
|
59
|
reappearance of HBsAg or HBV DNA
|
14/242
|
9/242
|
37/242
|
Gane E[48]
|
2018
|
RCT
|
Unclear risk of bias
|
NA
|
NA
|
NA
|
TDF, sequential TAF following TDF
|
12
|
HBV viremia
|
0/48
|
NA
|
NA
|
Saab S[49]
|
2019
|
RC
|
5
|
37.0
|
NA
|
80.0
|
Sequential TAF following HBIG
|
57.4
|
reappearance of HBsAg
|
0/32
|
NA
|
NA
|
Lee WC[50]
|
2019
|
RC
|
4
|
NA
|
NA
|
54.7
|
Sequential ETV following HBIG+ETV
|
42.2
|
reappearance of HBsAg
|
8/80
|
NA
|
NA
|
Teegen EM[51]
|
2019
|
RC
|
5
|
NA
|
12.2
|
20.5
|
ETV+HBIG, TDF+HBIG
|
166.8
|
reappearance of HBsAg or HBV DNA
|
0/22
|
NA
|
NA
|
Darweesh SK[52]
|
2019
|
RC
|
6
|
NA
|
NA
|
13.6
|
ETV± HBIG
|
72
|
reappearance of both HBsAg and HBV DNA
|
0/34
|
NA
|
NA
|
Muthiah MD[53]
|
2020
|
RC
|
5
|
50.0
|
NA
|
62.0
|
ETV± HBIG, TDF±HBIG
|
79
|
HBV viremia
|
2/38
|
NA
|
3/38
|
PC: prospective cohort; RC: retrospective cohort; RCT: randomized controlled trial; HP NAs: high potent nucleot(s)ide analogues; ETV: entecavir; TDF: tenofovir disoproxil fumarate; TAF: tenofovir alafenamide; HBIG: hepatitis B immune globulin
No observational studies scored under 4 or above 6, indicating all of them having fair quality. Both RCT had unclear risk of bias because the process of random sequence generation or blinding outcome assessment was not described.
3.2 HBV recurrence rate
The overall HBV recurrence rate was 0.92% (95% CI 0.47%-1.48%, I2 =44%) (Figure 2). HBV recurrence rate did not differ significantly between studies with and without detectable HBV DNA patients (0.87% vs 0.00%, p= 0.25), or studies with and without HDV superinfected patients (1.00% vs 0.63%, p=0.69) (Figure S1, S2).
Subgroup analysis demonstrated the preventive effect of ETV-based, TDF-based and TAF-based therapies were comparable, and in this analysis episode of transient recurrence was counted as recurrence event (p= 0.27) (Figure S3). The frequency of HBV reactivation was inconsistent among patients receiving indefinite combination (0.48%, 95% CI 0.10%–1.06%), NAs plus finite course of HBIG (1.05%, 95% CI 0.00%–4.38%) and HP NAs alone (5.00%, 95% CI 2.57%-8.07%) (p=0.001) (Figure 3). Further comparison suggested that the reactivation rate under indefinite combination was lower than that under HP NAs monotherapy (p=0.0003) and similar to that under NAs plus finite course of HBIG (p=0.53). For studies which enrolled viremia or HDV superinfected patients, HBV recurrence were comparable between indefinite and finite combination subgroups (p=0.65, p=0.16) (Figure S4, S5). For patients received finite combination, the risk of reinfection didn’t change significantly regardless of combination period (i.e. ≤6m vs >6m) (p=0.31) or the administration route of HBIG (i.e. IM vs change from IV to IM) (p=0.26). There was no difference between studies under finite combination and monoprophylaxis (p=0.101).
3.3 All-cause mortality and HBV-recurrence related mortality
Patient survival was reported in 16 studies, and the pooled death rate was 7.29% (95% CI 4.42%–10.71%, I2 =73%) (Figure S6). Based on detailed information of death from 8 studies, HBV-recurrence related death was 0.17% (95% CI 0.00%-1.51%, I2 =37%) (Figure 4).
3.4 HCC recurrence rate
19 studies included patients with pre-transplant HCC, and 5 reported information relevant to HCC recurrence. The aggregated HCC recurrence rate was 5.34% (95% CI 0.78%–12.48%, I2 =52%) (Figure 5).
3.5 Renal function
10 trials measured renal function, among which 3 observed significant eGFR/creatinine clearance deterioration (1 TDF based, 2 ETV based) 30, 33, 47. Another 2 studies demonstrated a trend toward improved eGFR/CKD stage under sequential TAF treatment following TDF or HBIG+NAs 48, 49. The renal function remained at a stable level in other trials 35, 36, 40, 41, 52.
3.6 Sensitivity analysis
After ruling out the abstracts and studies with follow-up period less than 24 months, the aggregated HBV recurrence was 1.37% (95%CI 0.46-2.60%). A proportion of original studies defined HBV recurrence by reappearance of HBsAg, and others defined by detectable HBV DNA. We compared the HBV recurrence under abovementioned two standards (i.e. HBsAg (or HBV DNA) vs HBV DNA (and HBsAg)) and found no significant difference between them (p=0.49).