Characteristics of studies
We totally identified 416 publications through database searching. Seven studies were lastly included for our meta-analyses [20-26] (Fig. 1). The types of disease included HBV-related cirrhosis (HBC), compensated HBV-related cirrhosis (CHBC) and decompensated HBV-related cirrhosis (DHBC). Only two studies contained patients with the unclassified types of HBC. Patients with DHBC were pointed out in one study, and patients with CHBC were mentioned in other studies included. Three studies were based on Guidelines for Prevention and Treatment of Chronic Hepatitis B in 2010 or 2015, and only one study followed the Diagnostic Criteria of HBV in 2000. Diagnostic criteria were not mentioned in 3 other studies. ETV (0.5 mg) per day were orally administrated by the subjects of monotherapy group. In combination therapy group, ETV (0.5 mg) per day were orally administrated and Ta1 (1.6 mg) subcutaneously injected twice per week. The detailed characteristics of studies were summarized in Table 1.
Fig 1. Flow chart for selection of relevant publications. The figures represent the number of articles included per stage.
Characteristics of patients
Five of 7 studies included the mean age of subjects, which ranged from 32 to 69 years old. Gender was provided in 6 studies, of which the percentage of males ranged from 43.3% to 76.0% in the ETV alone group, and it was from 50.0% to 80.0% in ETV plus Tα1 group. At least three baseline measures of ALT, TBIL, AST, ALB and A/G were mentioned in each study. Characteristics of patients were summarized in Additional file 5: Table S1.
Risk of bias
In the assessment of random sequence generation, 3 studies had a low risk. The allocation concealment, performance bias and detection bias remained unclear. All bias items of incomplete outcome data and 85% (6/7) bias items of selective reporting had a low risk. Other risks of bias were not estimated becsuse of their inefficient information in each study included. The judgements about each risk of bias items presented as percentages across all studies included were summarized in Additional file 1: Fig S1.
Complete and no response
Three studies with 270 subjects were included in the meta-analysis with regarding complete and no response. A higher complete response was observed in the combination therapy group (RR = 1.18; 95% CI, 1.07-1.30, P = 0.001). No significant heterogeneity was found between the two treatment groups (P = 0.49, I2 = 0%) (Fig. 2A). Furthermore, the rate of no response in the ETV plus Tα1 group was significantly lower than that of ETV alone group (RR = 0.32; 95% CI, 0.16-0.66, P = 0.002). No significant heterogeneity was observed in the two therapies (P = 0.59, I2 = 0%) (Fig. 2B).
Fig 2. Relative risk of the efficacy to HBV-related patients with cirrhosis in ETV plus Tα1 group and ETV alone group. (A) meta-analysis for the effective response; (B) meta-analysis for no response. Blue boxes indicate the dichotomous data in the forest plots. CI, confidence interval; M-H, Mantel-Haensel.
The HBV DNA undetectable rate
In the meta-analysis, six studies reported the virological response of 1090 patients after treatment of 24 weeks, 48 weeks and 52 weeks. We divided the eligible six studies into two subgroups. Subgroup 1 contained four trials with 310 patients (155 in ETV plus Tα1 group and 155 in ETV alone group) treated for 24 weeks. The sub-analysis suggested that the HBV DNA undetectable rate of the combination therapy was higher than that of ETV monotherapy (RR = 1.91; 95% CI, 1.56 - 2.35, P < 0.00001) (Fig. 3A and 3B). There was no significant heterogeneity in subgroup 1 (P = 0.40, I2 = 0%).
Subgroup 2 contained three studies with 780 patients (396 in ETV plus Tα1 group and 384 in ETV alone group) treated for 48 and 52 weeks. The sub-analysis indicated that the HBV DNA undetectable rate in ETV plus Tα1 group was no significant difference with ETV alone group (RR = 1.07; 95% CI, 0.96 - 1.18, P = 0.22) (Fig 3 and Additional file 2: Fig S2). There was no significant heterogeneity in subgroup 2 (P = 0.35, I2 = 0%).
Fig 3. Summary of pooled results about the HBV DNA undetectable rate in ETV plus Tα1 group and ETV alone group. The duration of treatment in subgroup analyses included both less than or equal to 24 weeks and more than 24 weeks. “Events” represents the number of subjects undetected with HBV DNA. “Total” represents the number of subjects in that group. “Test for overall effect” represents the pooled estimate of risk ratio after comprehensive analysis of all studies. Blue boxes indicate the dichotomous data in the forest plots. CI, confidence interval; M-H, Mantel-Haensel.
The HBeAg Loss Rate
723 subjects were involved in the six studies, through which the HBeAg loss rate was reported. The heterogeneity of overall tests was significant so that random-effect model was used to analyze the overall effects (P = 0.005, I2 = 70%). The HBeAg loss rate of the combination therapy group was higher than that of the monotherapy group among those studies (RR = 1.52; 95% CI, 1.16 - 2.01, P = 0.003) (Fig 4 and Additional file 3: Fig S3).
In the subgroup analyses, the duration of treatment included 24 weeks, 48 weeks and 52 weeks. The results of Subgroup 1, which contained three studies with 314 patients treated for 24 weeks, reported that the HBeAg loss rate of ETV plus Tα1 group was greater than that of ETV alone group (RR = 2.05; 95% CI, 1.62 - 2.60, P < 0.00001). There was a significant heterogeneity (P = 0.12, I2 = 53%). Another three studies involving 409 patients treated for 48 and 52 weeks were included in the Subgroup 2. The results showed that the HBeAg loss rate was similar between the two groups (RR = 1.17; 95% CI, 0.89 - 1.55, P = 0.26). There was no significant heterogeneity (P = 0.88, I2 = 0%). (Fig 4 and Additional file 3: Fig S3)
Fig 4. Summary of pooled results about the HBeAG loss rate in ETV plus Tα1 group and ETV alone group. The duration of treatment in subgroup analyses included both less than or equal to 24 weeks and more than 24 weeks. “Events” represents the number of subjects experiencing a HBeAG loss. “Total” represents the number of subjects in that group. “Test for overall effect” refers to the pooled estimate of risk ratio after comprehensive analysis of all studies. Blue boxes indicate the dichotomous data in the forest plots. CI, confidence interval; M-H, Mantel-Haensel.
The HBsAg Loss Rate
Only one trial including 615 subjects reported the HBsAg loss rate in post-treatment [24]. After the treatment for 52 weeks, the HBsAg loss rate of ETV plus Tα1 group was no significance with that of ETV alone group (RR = 1.03; 95% CI, 0.15 - 7.26, P = 0.98) (Fig 5).
Fig 5. Summary of pooled results including the HBsAG loss rate in ETV plus Tα1 group and ETV alone group. “Events” represents the number of subjects experiencing a HBsAG loss. “Total” represents the number of subjects in that group. “Test for overall effect” represents the pooled estimate of risk ratio after comprehensive analysis of all studies. Blue boxes indicate the dichotomous data in the forest plots. CI, confidence interval; M-H, Mantel-Haensel.
Biomedical and clinical variables
Biomedical and clinical variables, including ALB, AST, ALT, TBIL and A/G, were extracted from six eligible studies involving 454 participants. The results of meta-analyses were summarized in Table 2. Serum levels of ALB, AST, ALT, TBIL and A/G were significantly enhanced after treatment with ETV plus Tα1 or ETV alone. Compared with ETV alone, ETV plus Tα1 significantly increased the levels of AST and ALT, while there was no obvious difference in the serum levels of ALB, TBIL and A/G. The significant heterogeneity was found in the most meta-analyses regarding biomedical and clinical variables. The results of sensitivity analyses were summarized in Table S2. Heterogeneity remained significant.
The results of meta-regression analyses were summarized in Table S3. Heterogeneity about serum ALT was relevant with the criteria of diagnostic in ETV plus Tα1 combination group or ETV alone group (P = 0.150; P = 0.050). Heterogeneity about serum TBIL was not related to the criteria of diagnostic, year of publication or types of cirrhosis in ETV plus Tα1 combination group or ETV alone group.
Serum variables about hepatic fibrosis
Liver fibrosis is a prominent pathological feature in patients with cirrhosis. Serum levels of HA, PC-Ⅲ, LN and C-Ⅳ have an impact on the synthesis and degradation about collagen, proteoglycan and glycoprotein in liver extracellular matrix. In this meta-analysis, serum variables about hepatic fibrosis were only reported one trial involving 120 subjects, including HA, PC-Ⅲ, LN and C-Ⅳ. Besides of the serum LN level, we found that serum levels of HA, PC-Ⅲ and C-Ⅳ in patients treated with ETV plus Tα1 were obviously decreased in comparison with ETV alone (Table 3). The more RCTs about the effect of ETV plus Tα1 combination therapy on liver fibrosis in HBV-related cirrhosis should be conducted to test the results.
Adverse events
It was reported in three eligible studies involving 270 subjects that 35 patients experienced the adverse events including nausea, vomit, allergy and dizziness. The results of meta-analysis showed that ETV plus Tα1 combination therapy led to a significant decrease in the number of adverse events, compared with ETV monotherapy (RR = 0.48; 95% CI, 0.24 - 0.95, P = 0.03) (Fig 6 and Additional file 4: Fig S4). No significant heterogeneity was found (P = 0.98, I2 = 0%). However, no significant difference was observed between the two groups in nausea, vomit, allergy or dizziness, respectively.
Fig 6. Summary of pooled results including adverse advents in ETV plus Tα1 group and ETV alone group. Meta-analysis for the incidence of adverse reactions included nausea, vomit, allergy or dizziness. “Test for overall effect” represents pooled estimate of risk ratio after comprehensive analysis of all studies. Blue boxes indicate the dichotomous data in the forest plots. CI, confidence interval; M-H, Mantel-Haensel.