Is Hepatitis B Immunoglobulin Necessary in Prophylaxis of Hepatitis B Recurrence after Liver Transplantation? A Meta-Analysis

<div><p>Background & Aims</p><p>Application of nucleoside analogues and hepatitis B immunoglobulin (HBIG) has reduced hepatitis B virus (HBV) recurrence rate after liver transplantation (LT) dramatically. Recent data suggests therapy without HBIG is also effective. We sought to evaluate the necessity of HBIG in prophylaxis of HBV recurrence after LT.</p><p>Methods</p><p>A meta-analysis was performed. PubMed/MEDLINE, Web of Knowledge and other databases were searched for eligible literatures. The major end points were recurrence rate, patient survival, and YMDD mutant. Risk difference (RD) or risk ratio (RR) was calculated to synthesize the results.</p><p>Results</p><p>Nineteen studies with a total of 1484 patients were included in this analysis. Application of HBIG was helpful to reduce HBV recurrence [P<0.001; RD = 0.16; 95% confidence interval (CI)(0.12, 0.20)] and virus mutants [P<0.001; RR = 3.13; 95%CI (1.86–5.26)], it also improved patients' 1-year [P = 0.03; RD = 0.08; 95%CI (0.01, 0.15)] and 3-year survival rates [P = 0.005; RD = 0.17; 95%CI(0.05, 0.28)]. No significant difference was found for patients' 5-year survival [P = 0.46; RD = −0.06; 95%CI (−0.21, 0.10)]. Sub-group analysis showed that in patients with positive pre-operative HBV DNA status, HBIG was necessary to reduce HBV recurrence rate (P<0.001; RD = 0.42; 95%CI (0.32, 0.52)). In patients with negative HBV DNA, combined therapy gained no significant advantages (P = 0.18; RD = 0.06; 95%CI (−0.03, 0.14)). Non-Lamivudine (non-LAM) antiviral drugs performed as well as combination therapy in prophylaxis of HBV recurrence after LT (P = 0.37; RD = 0.06; 95%CI (−0.02, 0.14)).</p><p>Conclusions</p><p>HBIG with nucleoside analogues is helpful to reduce HBV recurrence and virus mutants. The necessity of HBIG in prophylaxis of HBV recurrence after LT when using new potent nucleoside analogues, especially for patients with negative pre-transplant HBV DNA status remains to be evaluated.</p></div

Literature search and selection flow: an overview of the methods used during the literature search.

<p>Literature search and selection flow: an overview of the methods used during the literature search.</p

Figure 2

<p><b>Transfection efficiency and </b><b><i>in vivo</i></b><b> bioluminescence imaging.</b> (A) Expression of miR-26a after transfection with different concentrations of Ad5-anti-miR-26a-LUC, Ad5-LUC, or no transfection (control). (B) Expression of miR-26a after transfection with different concentrations of Ad5-miR-26a-LUC, Ad5-LUC, or no transfection (control). The degree of bioluminescence was the greatest in Ad5-anti-miR-26a-LUC (AA) group (C), less in Ad5-LUC (AL) group (E), and the weakest in Ad5-miR-26a-LUC (AM) group (D). The mice in control group showed no bioluminescence image (F). ^*<i>P</i><0.05, ^**<i>P</i><0.01, ^***<i>P</i><0.001.</p

Figure 4

<p><b>CCND2 and CCNE2 are potential targeted genes of miR-26a.</b> (A) Anti-miR-26a expression increased the mRNA expression of CCND2 and CCNE2 as shown by qRT-PCR. Conversely, miR-26a over-expression declined the mRNA expression of the two genes. The mRNA expression of CCNE1 and CDK6 showed no obvious change. (B) Anti-miR-26a expression up-regulated the protein expression of CCND2 and CCNE2. In contrast, miR-26a over-expression down-regulated the protein expression of CCND2 and CCNE2. The protein expression of CCNE1 and CDK6 showed no obvious change. (C and D) Expression of CCND1 and CCND3 in both mRNA and protein level showed no obvious changes. ^*<i>P</i><0.05, ^**<i>P</i><0.01, ^***<i>P</i><0.001.</p

Quality assessment of included studies.

<p>(1) End points: A, Endpoints appropriate to the aim of the study; B, no description about endpoints; C, endpoints inappropriate to the aim of the study. (2) Follow-up period: A, follow-up appropriate to the aim of the study; B, follow-up was not mentioned; C, follow-up in appropriate to the aim of the study. (3) Loss to follow-up: A, loss to follow-up less than 5%; B, no description about the loss; C, loss to follow-up over than 5%; (4) Control group: A, an adequate control group; B, no description about control group; (5) Contemporary groups: A, control and studied groups were managed during the same time period; B, no description about the time period of groups; C, control and studied groups were historical comparison. (6) Baseline of groups: A, groups were similar regarding the criteria other than the studied endpoints (like age, sex); B, no description about the baselines; C, baseline unequal among groups. (7) Statistical analyses: A, adequate statistical analyses; B, inadequate statistical analyses.</p

Characteristics of trials included*

<p>*LAM, lamivudine; HBIG, hepatitis B immunoglobulin; ADV: adefovir dipivoxil; FTC,emtricitabine; TDF, tenofovir disoproxil fumarate</p

Primers used in reverse transcription and quantitative real-time PCR.

<p>Primers used in reverse transcription and quantitative real-time PCR.</p

Antiviral drugs or antiviral drugs combined with HBIG in prophylaxis of hepatitis B recurrence after liver transplantation: results of a meta-analysis: 1-year/3-year/5-year patient survival rate.

<p>(Columns represent the risk difference of each study. Diamonds represent the overall effect size, and diamond widths represent the overall 95% confidence interval.)</p

Antiviral drugs or antiviral drugs combined with HBIG in prophylaxis of hepatitis B recurrence after liver transplantation: results of a meta-analysis: YMDD mutants.

<p>(Columns represent the risk ratio of each study. Diamonds represent the overall effect size, and diamond widths represent the overall 95% confidence interval.)</p

Figure 3

<p><b>Anti-miR-26a expression promotes liver regeneration and improves liver function in mice.</b> (A) LBWR of mice transfected with Ad5-anti-miR-26a-LUC (AA), Ad5-miR-26a-LUC (AM) and Ad5-LUC (AL). There was an increased LBWR in AA group compared to AL group (<i>P</i><0.001), and a decreased LBWR in AM group can be seen compared with AL group at 120 h (<i>P</i><0.001). (B) The Ki-67 proliferation index (PI) after 70% PH and transfection, was significantly higher in AA group compared with AL group (<i>P</i><0.001), while lower in AM group in comparison with AL group (<i>P</i><0.001). (C-E) Liver function tests after transfection, worse liver functions could be observed in AM group compared with AL group. ^*<i>P</i><0.05, ^**<i>P</i><0.01, ^***<i>P</i><0.001.</p