CHB patients commonly experience liver fibrosis, cirrhosis, HCC and death as the progression of disease [27, 28]. Although the current expert consensus showed that the effective anti-viral treatment to HBV is vital for improving prognosis and preventing complications in cirrhotic patients, the treatment to adverse reactions, immunosuppression and chronic systemic inflammation should not be ignored [29, 30]. In this meta-analysis, we assessed the efficacy and safety of ETV combined with Tα1 versus ETV monotherapy for treating HBV-related cirrhosis. Seven studies accorded with the inclusion criteria. Our results showed that ETV combined with Tα1 could increase the complete response and contribute to the reduction of adverse reactions, in comparison with ETV monotherapy. The subgroup analyses to type of adverse reactions indicated that ETV combined with Tα1 has no significance with ETV monotherapy in nause, vomit, dizzy and allergy, respectively.
Rehermann B and colleagues supported that the suppress and elimination of HBV depend mainly on the potent and diverse T cell immune response in host . In vitro experiments showed that Tα1 induced the maturation of thymocytes, stimulated differentiation into active T cells and functional recovery of T cells . In vivo experiments verified that Tα1 was associated with the up-regulating activity of natural killer cell in CHB patients . Our results demonstrated that ETV plus Tα1 combination therapy could provide additional benefits of the virological and serological response over ETV monotherapy, which is accorded with previous studies. Substantial heterogeneity was observed in undetectable HBV DNA and HBeAg negative conversion rate (I2 > 50%), and the subgroup and sensitivity analyses showed that duration of treatment is an important factor for the primary results.
The present meta-analysis showed that the biochemical variables, including ALT, ALB, AST, TBIL and A/G, which were significantly improved by combination therapy during Tα1 add-on, compared with ETV monotherapy, thus indicating that the combination treatment have a better effect on improving the function of hepatocytes and remission of hepatic damage. Yang XL  found that Tα1 could protect liver of rat against damage via down-regulating TNF-α and up-regulating IL-10, resulting in the relief to hepatic inflammation and hepatocyte apoptosis, which was also in line with our findings.
HBV-related cirrhosis is an important stage of progressive liver injury or fibrosis . Recovery of cirrhosis was related with degradation of fibrous septa, regeneration of hepatocytes to replace fibrotic tissue and restoration of a lobular architecture [34, 35]. Our current meta-analysis indicated the serum variables about hepatic fibrosis including HA, PC-Ⅲ, LN and C-Ⅳ in ETV plus Tα1 group were significantly reduced, reminded that the main components of liver fibrosis remains more degradation and less deposition in combination treatment during Tα1 add-on. However, the included trials was short and small sample size, which limited the ability to objectively analyze potential differences in clinical outcomes. More large, long-term and high-quality studies were still being executed.
In addition, HCC and the complications of cirrhosis included variceal hemorrhage, ascites, spontaneous bacterial peritonitis and hepatic encephalopathy, which have an important impact on the expected life of the human being . Although these endpoint outcomes were not analyzed, the study included from this meta-analysis showed that ETV plus Tα1 combination group has a lower incidence of HCC after treatment of 51 weeks, and yet has no benefits in terms of ascites, hepatic encephalopathy, variceal hemorrhage and liver stiffness, in comparison with ETV alone . The results were consistent with the study of Liang YR which reported that Tα1 therapy improves liver function, and obviously extend recurrence-free and overall survival in HBV-related HCC . Unfortunately, the participants of RCTs were from Chinese mainland. With a view to the diversity among people of different races and regions, more global multicenter randomized double-blind trials will need to be performed.
There were other possible limitations in this meta-analysis. First, the diagnostic criteria of HBV-related cirrhosis was inconsistent among the included studies, and the severity of cirrhosis patients was not exactly same. Second, the characteristic of included subjects were incomplete in some studies, the statistical sample size was sometimes too small to compare the treatment effects between monotherapy and combination therapy. Third, the heterogeneity was remarkable in biochemical and virological variables. Despite the subgroup analysis and sensitivity analysis were detected in this meta-analysis, the resource of heterogeneity was not well clarified. Fourth, the included individuals in RCTs were all from China, the results haven’t apply for people in other countries at present.