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The efficacy and safety of entecavir in patients

with chronic hepatitis B- associated liver failure: a meta-analysis

Xiaoguo Zhang,* Lu Liu,** Meng Zhang,* Shuchun Gao,* Yizhen Du,* Yong An,*** Shijun Chen*

* Division of Liver Disease, Jinan Infectious Disease Hospital, Shandong University, China. ** Shandong University School of Medicine, China.

*** Division of Liver Disease, Qianfoshan Hospital, Shandong University, China.

ABSTRACT

Background. The effectiveness of nucleoside analogue (NA) treatment in patients with chronic hepatitis B (CHB) -associated liver failure is still controversial. Severe lactic acidosis has been reported during enteca-vir (ETV) treatment in patients with impaired liver function. Aim. To investigate the rescuing efficacy and safety of ETV in patients with CHB-associated liver failure. Material and methods. A literature search was carried out to collect articles dated up to December, 2013 on ETV therapy for patients with CHB-associa-ted liver failure. Risk ratio (RR) and mean difference (MD) were used to measure the effects. Survival rate was used as the primary efficacy measure. The safety of ETV was assessed. Results. Six randomized contro-lled trials were selected. The overall analysis revealed ETV significantly improved survival at 4 weeks (RR = 1.35; 95% CI [1.16, 1.57]; p < 0.0001), 8 weeks (RR = 1.33; 95% CI [1.07, 1.64]; p = 0.009), 12 weeks (RR = 1.68; 95% CI [1.24, 2.28]; p = 0.0008). Pooled data also showed beneficial effects of antiviral therapy compared with control for HBV DNA negative change (RR = 5.35; 95% CI [2.06, 13.88]; p = 0.0006), TBIL and PTA impro-vement (TBIL: MD = -69.36; 95% CI [-134.37, -4.36]; p = 0.04. PTA: MD = 16.26; 95% CI [8.59, 23.94]; p < 0.0001). No adverse effect was identified in the examined studies. Conclusion. Our results showed that antiviral therapy with ETV improved the short-term survival of patients with CHB-associated liver failure. In addi-tion, ETV was well tolerated during the treatment period. Further studies are still needed to strengthen these results.

Key words. HBV. ETV. Severe hepatitis. Review.

Correspondence and reprint request: Professor Shijun Chen, Division of Liver Disease, Jinan Infectious Disease Hospital, Shandong University, 22029# Jinshi Road, Jinan 250021, China. E-mail: xiaoguolab@gmail.com.

Professor Yong An, Division of Liver Disease,

Qianfoshan Hospital, Shandong University, 16766# Jingshi Road, Jinan 250014, China. E-mail: 1330698021@qq.com

Manuscript received: April 01, 2014. Manuscript accepted: August 25, 2014.

INTRODUCTION

Chronic hepatitis B (CHB), caused by the hepati-tis B virus (HBV), is a serious health problem worldwide, especially in China, and other parts of Asia.1 Patients with chronic HBV infection are at

an increased risk of developing liver cirrhosis and hepatocellular carcinoma.2 In some cases, patients

may develop severe acute exacerbations, resulting in liver failure and death. Liver failure is the ina-bility of the liver to perform its normal synthetic,

metabolic, excretory and biotransformation func-tions, and usually manifests as coagulopathy, jaun-dice, ascites and hepatic encephalopathy.3 In

China, HBV infection is the leading cause of liver failure, and HBV-induced liver failure is usually se-vere, with a high mortality.4 Current treatments

for liver failure include supportive and symptomat-ic treatment-based comprehensive treatment, artifi-cial liver support systematic treatment, and liver transplant.5 Liver transplantation is the most

ef-fective therapy for liver failure;6,7 however, it is

limited by the availability of donor organs and high medical expense.

As we know, oral antiviral agents, nucleoside analogues (NAs), including lamivudine (LAM), adefovir dipivoxil (ADV), entecavir (ETV), telbivu-dine (LdT), and tenofovir disoproxil fumarate (TDF), have been licensed for the treatment of CHB patients.2,8 Recently NAs treatment has been

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• Previous diagnosis of CHB or HBV-associated cirrhosis.

• Rapidly deepening jaundice, with total bilirubin (TBIL) 10 times greater than the upper limit of normality (≥ 171 μmol/L or 10 mg/dL), or a daily increase ≥ 17.1 μmol/L or 1 mg/dL.

• Hemorrhagic tendency with international nor-malized ratio (INR) ≥ 1.5 or prothrombin activity (PTA) ≤ 40%.

• HBV DNA > 103 copies/mL (approximately 200

IU/mL).20

• Interventional measure: routine comprehensive treatment in the control group; ETV (0.5 mg/d) combined with routine comprehensive treatment in the test group; and

• The neutrality and comparability of the two groups studied in terms of age, gender, and other biological or chemical predictors.

Exclusion criteria were:

• Patients with superinfection with hepatitis A, C, D, and E virus, Epstein-Barr virus, cytomegalovi-rus, human immunodeficiency vicytomegalovi-rus, and others; • Patients with other causes of chronic liver

fail-ure, like drug-induced liver injury, auto-immune liver disease, alcoholic liver disease, and inherit-ed metabolic disease, et al;

• Patients with malignant tumors and severe blood anomalies;

• Patients receiving antiviral therapy at the time recruited to the study or having received antivi-ral therapy in 6 months before the studies; • Patients receiving artificial liver treatment

dur-ing the studies;

• Non-convertible or unusable data in literature; and

• Literatures not published as full text.

Literature search

We searched Pubmed, MEDLINE, EMBASE, Co-chrane Library, the Chinese BioMedical Literature (CBM), Chinese National Knowledge Infrastructure (CNKI), Chinese Technological Journal of Database (VIP) and Wanfang databases for eligible articles published up to December, 2013 without language and publication restrictions. To search for publica-tions, we applied a free key word or mesh word search with the following terms: severe hepatitis B, chronic severe hepatitis B, liver failure, hepatic fail-ure, acute on chronic liver failfail-ure, acute exacerba-tion, severe acute exacerbaexacerba-tion, hepatitis B virus, to CHB.9-12 However, other studies found that NAs

treatment did not improve the short-term prognosis of patients with HBV-associated liver failure.13,14

What’s even worse is that ETV treatment has been reported to be associated with increased short-term mortality in patients with severe acute exacerbation of CHB.15 In Acute-on-chronic liver failure: consen-sus recommendations of the Asian Pacific Association for the study of the liver,16 NAs were recommended as

antiviral treatment. However, the level of evidence is only grade 3, meaning it is only based on the experi-ence and comments made by specialists or authori-ties. Thus, the benefits of NAs therapy for this condition remain controversial.

Currently, the four types of nucleoside drugs available in the Chinese market include LAM, LdT, ETV, and ADV. ETV is a potent nucleoside inhibitor of HBV polymerase with a high antiviral activity and a high genetic barrier to resistance, and it has been regarded as one of the first line drugs for hepatitis B.2 In Asian-Pacific consensus statement on the management of chronic hepatitis B: a 2012 update, ETV is recommended as the agent of choice for patients with obvious or impending hepatic decompensation.17 However, severe lactic

acidosis during treatment of CHB with ETV has been reported, occurring more often in patients with impaired liver function, especially in those with high model for end stage liver disease (MELD) scores and multi-organ failure.18 Thus,

the safety of ETV remains a concern for clinical doctors treating patients with liver failure. In this paper, we selected randomized controlled trials (RCTs), and investigated the efficacy and safety of ETV in the treatment of patients with CHB asso-ciated liver failure by performing a systematic review and meta-analysis.

MATERIAL AND METHODS

Inclusion and exclusion criteria

We included studies from randomized controlled trials that compared ETV treatment with no antivi-ral treatment for patients with CHB-associated liver failure. According to the Prevention and treatment scheme for virus related hepatitis released in 2000,19

and Guidelines for the diagnosis and treatment of liver failure released in 2012,4 we made a criteria for

the patients with CHB-associated liver failure in the selected studies.

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hepatitis b virus infection, HBV, entecavir, ETV, baraclude, nucleoside analog* and nucleotide analog.* In addition, a manual search of abstracts of interna-tional liver meetings, reference lists of retrieved arti-cles and qualitative topic reviews was also performed.

Indicators of therapeutic efficacy

The primary efficacy endpoint was survival rate. Secondary efficacy endpoints were HBV DNA nega-tive change rate, TBIL and PTA changes. The safety of ETV treatment during the clinical course of liver failure was also assessed.

Data extraction and quality assessment

Two reviewers (Xiaoguo Zhang and Lu Liu) inde-pendently selected the studies and extracted the data and outcomes according to the inclusion and exclusion criteria. In cases of disagreement between the two re-viewers, a third reviewer (Shijun Chen) examined the

data and discussed the choices with the two initial re-viewers. The data were incorporated only when the three reviewers reached a consensus. The information collected included basic information on the studies, sample sizes, receiver characteristics (gender, age, TBIL, PTA, HBV DNA, etc.), and results.

Methodological quality assessment of the included studies was performed using the Cochrane risk of bias tool (Random sequence generation, Allocation concealment, Blinding of participants and person-nel, Blinding of outcome assessment, Incomplete outcome data, Selective reporting, Other sources of bias) as described in the Cochrane Reviewer’s Hand-book 5.1.0.

Statistical analysis

Analysis was performed with review manager ver-sion 5.2.7 (Rev Man 5.2.7 from Cochrane Collabora-tion). Risk ratio (RR) and 95% confidence interval (95% CI) were used to compare survival and HBV DNA negative change rates. Mean difference (MD)

* Analog is regarded as a word used for searching.

Figure 1. Flow-chart identifying eligible studies.

Records identified Additional records

through database identified through

searching (n = 1,485) other sources (n = 0)

Records after duplicates removed (n = 834)

Records Records excluded based

screened (n = 76) on title and abstract

screening (n = 758)

70 articles were excluded after full text review. 16 did no meet the criteria of chronic hepatitis B

associated liver failure we made or had no convertible data. 48 were without clear study designs.

1 contained no definite follow-up time.

Full-text articles assessed for 4 adopted artificial liver treatment for patient.

eligibility (n = 76) 1 did not have control group.

Studies included in qualitative synthesis (n = 6)

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and 95% CI were used to compare TBIL and PTA changes. The heterogeneity of the data collected was measured using Cochran’s Q test (Chi-square χ2

test) and I² tests. The fixed or random effect model was used depending on the presence or absence of significant heterogeneity. In our meta-analysis, P > 0.10 in Cochran’s Q test and I2 < 25% were

consid-ered indicators of no or low-level heterogeneity, and the fixed effects model was adopted when the data across studies was pooled. Otherwise, the random effects model was used. For all tests except heteroge-neity, P < 0.05 was considered statistically signifi-cant. Funnel charts, Egger’s test and Begg’s test were used to detect possible publication biases. Sen-sitivity analysis was performed to evaluate the va-lidity and reliability of the primary meta-analysis.

RESULTS

Characteristics of the included studies

A total of six studies comprising 536 patients ful-filled the criteria for this systematic review and meta-analysis.21-26 The strategy is summarized in

fig-ure 1. All selected studies originated from mainland China and were published in Chinese. One26 study

had three-arm design with two test groups: one us-ing ETV, and the other usus-ing LAM. All patients were given routine comprehensive treatment, in-cluding: intensive care monitoring, nutritional sup-plementation, intravenous drop infusion of albumin and plasma, maintenance water, and electrolyte and acid-base equilibrium. Detailed characteristics of the included studies are shown in table 1.

Effect of ETV treatment on the survival rate

Survival rate was used as the primary efficacy endpoint in the selected studies with 267 cases in the test group and 269 cases in the control group. In the heterogeneity test, χ2 = 5.00, df = 7, P = 0.66,

and I2 = 0% (Figure 2), suggesting that there was

no significant variability among the included stud-ies. Therefore, the fixed effect model was used to combine the effect measures using RR as indicator (RR = 1.41), and 95% CI was (1.26, 1.59). In the test for the overall effect, Z = 5.77 and P < 0.00001, suggesting that ETV treatment in patients with CHB-associated liver failure improved the sur-vival rate.

A heterogeneity test in the subgroup analysis was conducted during the treatment course (4 weeks, 8 weeks and 12 weeks). Of the selected studies,

Table 1.

Characteristics of the six studies included in the meta-analysis.

Study year Study Blinding Region Language Patients Sex (M/F)

Age (mean ± SD years)

Follow-up

design

(n

)

(weeks)

Haimin Yang, 2008

RC T NA China Chinese 11 0 72 / 38 28.5 ± 8.9 4

Yuxiang Guo, 2008

RC T NA China Chinese 82 56 / 26 35.5 ± 8.9 8

Biao Wu, 2008

RC T NA China Chinese 11 0 10 4 / 6 41 ± 15 12

Zhaohui Wang, 2011

RC T NA China Chinese 42 30 / 12 45.4 ± 11.0 12

Dan Lv, 2011

RC T NA China Chinese 72 42 / 30 NA 12

Lei Fan, 2013

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three21-23 reported 4-weeks’ survival for 302 patients

(147 patients received ETV). The assessment of heter-ogeneity produced P = 0.54 in Cochran’s Q test and I2 = 0%, which indicated that there was no

signifi-cant variability between these studies. The fixed ef-fect model was therefore used, and the estimated pooled RR for these studies showed a significant in-crease in survival rate for patients receiving antiviral therapy (RR = 1.35; 95% CI [1.16, 1.57]; p < 0.0001). Two studies22,23 reported 8-weeks’ survival for

192 patients (92 patients received ETV). The assess-ment of heterogeneity produced p = 0.82 in Co-chran’s Q test and I2 = 0%, which indicated that

there was no significant variability between these 2 studies. The fixed effect model was therefore used, and the estimated pooled RR for these studies showed a significant increase in survival rate for pa-tients receiving antiviral therapy (RR = 1.33; 95% CI [1.07, 1.64]; p = 0.009).

Three studies23-25 reported 12-weeks’ survival for

224 patients (115 patients received ETV). The assessment of heterogeneity produced P = 0.42 in Cochran’s Q test and I2 = 0%, which indicated that

there was no significant variability between these studies. The fixed effect model was therefore used, and the estimated pooled RR for these studies showed a significant increase in survival rate for patients receiving antiviral therapy (RR = 1.68; 95% CI [1.24, 2.28]; p = 0.008).

Comparison of HBV DNA negative change rate between test

and control groups

Three studies21,22,26 reported HBV DNA negative

change at 4 weeks, and two22,26 studies reported

HBV DNA negative change at 8 weeks. A heteroge-neity test showed that χ2 = 17.21, P = 0.002, and

Figure 2. Overall effect of ETV treatment on the survival rate.

0.01 0.1 1 10 100

Favour Favour

(control) (test)

Risk ratio M-H, Fixed, 95% CI

Test Control Risk Ratio

Study or Subgroup Events Total Events Total Weight M-H, Fixed, 95% CI Year

1.6.1 Comparison of the 4 weeks’ survival rate

Yuxiang Guo 2008 33 37 32 45 16.0% 1.25(1.01, 1.56) 2008

Biao Wu 2008 45 55 35 55 19.4% 1.29(1.02, 1.63) 2008

Haimin Yang 2008 40 55 26 55 14.4% 1.54(1.11, 2.12) 2008

Subtotal (95% CI) 147 155 49.9% 1.35(1.16, 1.57)

Total events 118 93

Heterogeneity: χ2 = 1.23, df = 2 (P = 0.54); I2 = 0%

Test for overall effect Z = 3.91 (P < 0.0001)

1.6.2 Comparison of the 8 weeks’ survival rate

Biao Wu 2008 34 55 25 55 13.9% 1.36(0.95, 1.94) 2008

Yuxiang Guo 2008 32 37 30 45 15.0% 1.30(1.02, 1.65) 2008

Subtotal (95% CI) 92 100 28.9% 1.33(1.07, 1.64)

Total events 66 55

Heterogeneity: χ2 = 0.05, df = 1 (P = 0.82); I2 = 0%

Test for overall effect Z = 2.60 (P < 0.009)

1.6.3 Comparison of the 12 weeks’ survival rate

Biao Wu 2008 29 55 17 55 9.4% 1.71(1.07, 2.72) 2008

Zhaohui Wang 2011 12 22 4 20 2.3% 2.73(1.05,7.09) 2011

Dan Lv 2011 25 38 16 34 9.4% 1.40(0.92, 2.14) 2008

Subtotal (95% CI) 115 109 21.2% 1.68(1.24, 2.28)

Total events 66 37

Heterogeneity: χ2 = 1.72, df = 2 (P = 0.42); I2 = 0%

Test for overall effect Z = 3.37 (P < 0.0008)

Total (95% CI) 354 364 100.0% 1.41(1.26, 1.59)

Total events 250 185

Heterogeneity: χ2 = 5.00, df = 7 (P = 0.66); I2 = 0%

Test for overall effect Z = 5.77 (P < 0.00001)

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Figure 3. Overal effect of ETV treatment on the HBV-DNA negative change rate.

Figure 4. Effect of ETV on the TBIL change after 4 weeks’ treatment.

I2 = 77%, suggesting the existence of heterogeneity

among these studies. The random effect model was therefore used to combine the overall effects, and the estimated pooled RR showed a high HBV DNA negative rate for patients receiving ETV therapy

(RR = 5.35; 95% CI [2.06, 13.88]; p = 0.0006) (Fig-ure 3). Heterogeneity in the subgroup analysis exist-ed during the treatment course (4 and 8 weeks), so the random effect model was used, and the resulting RRs were 3.68 and 9.31 respectively, and the 95%

0.01 0.1 1 10 100

Favour Favour

(control) (test)

Risk ratio M-H, Random, 95% CI

-100 -50 0 50 100

Favour Favour

(control) (test)

Mean difference IV, Random, 95% CI

Figure 5. Effect of ETV on the PTA change after 4 weeks’ treatment.

-100 -50 0 50 100

Favour Favour

(control) (test)

Mean difference IV, Random, 95% CI

Test Control Mean Difference

Study or Subgroup Mean SD Total Mean SD Total Weight IV, Random, 95% CI Year

Haimin Yang 2008 42.3 20.1 40 30.5 18.5 26 43.5% 11.80 (2.35, 21.25) 2008

Yuxiang Guo 2008 58.4 18.2 33 38.7 12.8 32 56.5% 19.70 (12.07, 27.33) 2008

Total (95% CI) 73 58 100.0% 16.26 (8.59, 23.94)

Heterogeneity: Tau2 = 11.99, χ2 = 1.62, df = 1 (P = 0.20); I2 = 38%

Test for overall effect Z = 4.15 (P < 0.0001)

Test Control Risk Ratio

Study or Subgroup Events Total Events Total Weight M-H, Random, 95% CI Year

1.8.1 Comparison of the 4 weeks’ HBV-DNA negative change rate.

Haimin Yang 2008 37 40 10 26 28.0% 1.75 (1.03, 2.99) 2008

Yuxiang Guo 2008 26 33 5 32 25.0% 5.04 (2.21, 11.50) 2008

Lei Fan 2013 11 56 0 49 8.4% 20.18 (1.22, 333.72) 2013

Subtotal (95% CI) 129 107 61.4% 3.68 (1.16, 11.68)

Total events 64 15

Heterogeneity: Tau2 = 0.67, χ2 = 7.88, df = 2 (P = 0.02); I2 = 75%

Test for overall effect Z = 2.22 (P < 0.003)

1.8.2 Comparison of the 8 weeks’ HBV-DNA negative change rate.

Yuxiang Guo 2008 30 32 5 30 25.2% 5.63 (2.51, 12.58) 2008

Lei Fan 2013 28 56 1 49 13.4% 24.50 (3.46, 173.49) 2013

Subtotal (95% CI) 88 79 38.6% 9.31 (2.06, 42.17)

Total events 58 6

Heterogeneity: Tau2 = 0.73, χ2 = 2.26, df = 1 (P = 0.13); I2 = 56%

Test for overall effect Z = 2.90 (P < 0.004)

Total (95% CI) 217 186 100.0% 5.35 (2.06, 13.88)

Total events 122 21

Heterogeneity: Tau2 = 0.77, χ2 = 17.21, df = 4 (P = 0.002); I2 = 77%

Test for overall effect Z = 3.45 (P < 0.0006)

Test for subgroup differences: χ2 = 0.91, df = 1 (P = 0.34), I2 = 0%

Test Control Mean Difference

Study or Subgroup Mean SD Total Mean SD Total Weight IV, Random, 95% CI Year

Haimin Yang 2008 51.2 20.8 40 90.7 25.1 26 55.2% -39.50 (-51.10, -27.90) 2008

Yuxiang Guo 2008 176.4 85.2 33 282.6 94.7 32 44.8% -106.20 (-150.04, -62.36) 2008

Total (95% CI) 73 58 100.0% -69.36 (-134.37, -4.36)

Heterogeneity: Tau2 = 1956.81, χ2 = 8.31, df = 1 (P = 0.004); I2 = 88%

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0% CIs were (1.16, 11.60) and (2.04, 42.17) respectively.

In the test for the overall effect, Z = 3.45 and P = 0.0006, which indicated a significant statistical difference. Thus, ETV treatment significantly inhib-ited HBV DNA replication.

TBIL and PTA

comparison between test and control groups

We also evaluated the impact of antiviral therapy on TBIL and PTA changes. There were only two studies21,22 that reported TBIL and PTA changes at

4 weeks and heterogeneity was found among these groups (TBIL: χ2 = 8.31, df = 1, P = 0.004, and I2 =

88% [Figure 4]; PTA: χ2=1.62, df = 1, P = 0.20,

and I2 = 38% [Figure 5]). The random effect model

was therefore used to combine the overall effects us-ing MD as the indicator. Our results showed that ETV decreased the TBIL level (MD = -69.36; 95% CI [-134.37, -4.36]; p = 0.04) and increased PTA levels (MD = 16.26; 95% CI [8.59, 23.94]; p < 0.0001) at the 4 weeks after antiviral therapy. Lei Fan’s study26 reported TBIL and PTA changes at 24

weeks. In that study, liver function in the test group was significantly better than that in the con-trol group.

Safety

No studies reported patients developing drug-re-lated adverse events or drug redrug-re-lated viral mutation.

Sensitivity analysis

To confirm the stability of the primary analysis, we conducted a sensitivity analysis by excluding studies one by one and found that the overall sur-vival rate did not change significantly with the ex-clusion of any single study.

Risk of bias in included studies

The overall quality of the studies included in this meta-analysis was suboptimal. Each of the six studies was a RCT, of which four did not report how the allo-cation sequences were generated. Five studies did not report the methods of the allocation concealment, and one study took an open random allocation sched-ule. Five studies did not report the blinding of the study participants and personnel. Because different follow-up times and different outcomes were reported, often without full statistical details, it was not

possi-ble to meta-analyze all the data. Risk of bias graph and summary are shown in figures 6 and 7.

Publication bias

A funnel plot of the studies used in the meta-anal-ysis reporting on the survival rate is shown in fig-ure 8. Egger’s test and Begg’s test were also used to evaluate the possibility of publication bias. No evi-dence of publication bias was found in our study.

DISCUSSION

CHB-associated liver failure, once named severe chronic hepatitis B, represents one of the most diffi-cult to treat liver diseases with a high mortality rate. The mechanisms involved in this disease are rather complicated and remain unclear, but one of the important known mechanisms is an overactive immune response, particularly the cytotoxic T lym-phocyte reaction to infected hepatocytes, due to the high level of HBV replication and protein antigen ex-pression on target cell surfaces. This mechanism is necessary for HBV clearance and causes significant apoptosis and necrosis of hepatocytes.2,27-29 In

Zhao’s study on the cause and outcome of chronic and acute liver failure, HBV replication and

muta-Figure 6.Risk of bias graph: Review authors’ judgments about each risk of bias item for each included study.

Random sequence generation (selection bias) Allocation concealment (selection bias) Blinding of participants and personnel (performance bias) Blinding of outcome assessment (detection bias) Incomplete outcome data (attrition bias) Selective reporting (reporting bias) Other bias Biao Wu 2008

Dan Lv 2011 Haimin Yang 2008 Lei Fan 2013 Yuxiang Guo 2008 Zhaohui Wang 2011

+ – – + + +

+ + +

+ + + +

+ + +

+ + +

+ + +

?

? ? ? ?

? ? ?

? ? ? ?

? ? ? ?

? ? ? ?

+

?

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tion were the primary causes of severe hepatitis B.30

Therefore, a reasonable solution for treating CHB-associated liver failure is to inhibit HBV replication within the body and relieve immune hyperactivity using antiviral drugs.

LAM has been reported to decrease HBVDNA lev-els in the serum, improve liver function and en-hance survival rate of patients with severe CHB.31

There is no doubt that ETV is superior to LAM in the treatment of CHB,32 but is ETV also effective in

treatment for severe CHB or CHB-associated liver failure? Several reports have reviewed the use of ETV in the treatment of HBV-related decompensated liver disease, and ETV is considered to be one of the first-line therapies for patients with this disease.33-35

A retrospective matched cohort study by Ke Ma, et al.36 evaluated the survival rates of patients with

Hepatitis B related ACLF receiving ETV treatment and found that the 1 and 3 month survival rates of patients in the ETV treated group (n = 124) were 72.58 and 61.29%, respectively, significantly higher than that in the NA free group (n = 124), which were 53.23 and 45.97%, respectively. In Tianyan Chen’s report on the efficacy of NA treatment in pa-tients with HBV-related ACLF,37 42 patients were

treated with 0.5 mg ETV daily (ETV group), and 34 patients did not take any NA (non-NA group). After 3 months of treatment, the non NA group had a sig-nificantly higher mortality compared with the ETV group (64.7 vs. 33.3%, χ 2 = 7.163, P = 0.007).

Bingliang Lin’s study38 showed that ETV treatment

for patients with acute on chronic hepatitis B liver failure significantly improved disease severity scores with a marked reduction in mortality and suppres-sion in HBV DNA to undetectable levels at week 48. Moreover, the survival benefit was noted in ETV treated patients as early as week 3.

However, other studies drew different conclu-sions. Jun Chen13 collected data on 129 chronic

se-vere hepatitis B patients: 55 were treated with ETV, and the remaining 74 were not treated with NAs. The results showed that although ETV greatly re-duced HBV replication (P < 0.001), the MELD score, liver function and short-term survival rate showed no significant differences between test and control group. Yaoli Cui’s data14 also indicated that

NAs (including ETV) treatment did not improve the short-term prognosis of patients with HBV-associat-ed ACLF, although it was efficacious and safe in the management of HBV DNA levels. A study from Hong Kong even found that ETV treatment was as-sociated with increased short-term mortality in pa-tients with severe acute exacerbation.15

The effectiveness of ETV for treating chronic CHB-associated liver failure has been demonstrated by many trials, such as those discussed above. How-ever, most were not randomized controlled trials. We wished to obtain a more stringent, conclusive result. In the present study, RCTs conducted before December 2013 were collected. Our primary pooling results demonstrated that ETV treatment improved the short-term survival rate of patients with CHB-associated liver failure. The strategy of subgroup analysis was adopted in our statistical analysis. We found that the 4, 8 and 12 week survival rates of the test groups were higher than those of the control groups. Thus, ETV appeared to improve the survival rate of patients at weeks 4, 8 and 12 during the treatment course. Because different outcomes were reported, often without full statistical details, we presented the HBV DNA negative change rate at weeks 4 and 8, TBIL and PTA changes at week 4. Our results showed that ETV inhibited HBV replica-tion and improved liver funcreplica-tion.

Figure 7. Risk of bias graph: Review authors’ judgments about each risk of bias item presented as percentages across all included studies.

Low risk of bilas. Unclear risk of bilas. High risk of bilas

0 25 50 75 100

(%)

0% 25% 50% 75%

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ETV can inhibit the activity of HBV DNA polymerase. This inhibition decreases HBV replica-tion, thereby reducing the viral load in the liver and blood, decreasing the target antigen expression on the surface of liver cells and reducing CTL attack on infected liver cells. Lu’s study39 demonstrated that

ETV could regulate the function of dendritic cells in CHB patients, so the immune modulation may be an-other mechanism by which ETV treatment improves survival rate of patients with CHB- associated liver failure. Thus, it appears reasonable to use ETV for treating CHB-associated liver failure.

To investigate the optimal timing for therapeutic efficacy of ETV for HBV-related ACLF in hepatitis B e antigen negative patients, 109 patients were col-lected by Yan Y40 and divided into three groups

ac-cording to MELD score: high (≥ 30); intermediate (22-30); and low (≤ 22). When ETV was added to comprehensive therapy, the mortality of patients with a high MELD score was 95.83%, while the mortality of patients with a low MELD score was 3.23%. Yan Y’s study suggested that ETV treatment for CHB-associated liver failure should be initiated as early as possible.

The safety of ETV in the included studies was also assessed. No studies reported the development of drug-related adverse events, drug-related viral mutation or the need for dose modification or early discontinuation.

In the end, we are obliged to mention the several limitations of our meta-analysis. First, the number of included studies was small, and some did not

in-clude all of the outcome parameters which we want-ed to analyze at the different follow-up time points. As mentioned above, NAs therapy has been recom-mended as antiviral treatment for patients with HBV-associated liver failure. It seemed unethical to perform a controlled trial using no antiviral treat-ment, which limited the conduct of RCTs. Second, the quality of included studies was not optimal. Most of the studies did not report how the allocation sequences were generated and did not report the methods of the allocation concealment. Risk of bias may therefore exist in the included studies. Third, all of the included studies were conducted in China, thus the conclusion may not be generalizable to oth-er populations. Finally, although the assessment of publication bias was not significant in our analysis, the possibility of publication bias may exist in any research because negative and small sample studies are less likely to be published. These limitations have all affected the reliability of research results. Therefore, future studies should assess high-quality, well-designed, multicenter RCTs with larger sample sizes.

CONCLUSION

In conclusion, our results showed that antiviral therapy with ETV improved the short-term survival rate of patients with CHB-associated liver failure. In addition, ETV was well tolerated during the treat-ment period. Further studies are still needed to in-crease the weight of these findings.

Figure 8. Funnel plots for studies evaluating 4 weeks, 8 weeks and 12 weeks survival. The x-axis represents the treatment effect (RR) and the y-axis represents the study size( stan-dard error of logRR). The dashed line indicates the overall risk estimate.

0

0.1

0.2

0.3

0.4

0.5

SE (log[RR])

0.01 0.1 1 10 100

RR Subgroups

Comparison of the 4 weeks’ survival rate.

Comparison of the 8 weeks’ survival rate.

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AUTHORS’ CONTRIBUTIONS

Study conception and design: SC and YA. Data acquisition and analysis: XZ, LL, MZ and SG. Writ-ing of the paper: XZ. Critical revision: YD and SC. All authors read and approved the final manuscript.

ACKNOWLEDGMENTS

The authors would like to thank the members of Prof. Shijun Chen’s Laboratory for their helpful dis-cussion and critical reading of the manuscript.

CONFLICT OF INTEREST STATEMENT

The authors declare that they have no conflict of interests.

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Figure

Figure 1. Flow-chart identifying eligible studies.
Figure 2. Overall effect of ETV treatment on the survival rate.
Figure 5. Effect of ETV on the PTA change after 4 weeks’ treatment.
Figure 6.Risk of bias graph: Review authors’ judgments about each risk of bias item for each included study.
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