Review question
To assess the benefits and harms of Xiao Chai Hu Tang formula versus placebo or no intervention in people with chronic hepatitis B virus infection.
Background
Chronic hepatitis B virus infection is a common liver disease, associated with high morbidity (illness) and death. It causes psychological stress and is a burden to people with chronic hepatitis B and their families. Xiao Chai Hu Tang formula has been used for treating people with chronic hepatitis B as it is believed that it decreases discomfort and prevents the replication of the virus in people with chronic hepatitis B. However, the benefits and harms of Xiao Chai Hu Tang formula have never been established in reviews with rigorous review methodology.
Search date
The review includes trials published up to 1 March 2019.
Study characteristics
We included 10 randomised clinical trials (studies where people are randomly put into one of two or more treatment groups) with 934 participants. All trials compared Xiao Chai Hu Tang formula with no treatment. The trials assessed different formulas and doses for three to eight months. One trial included participants with tuberculosis (a disease of the lungs that can make you cough mucous), and one trial included participants with liver cirrhosis (scarring). Only five trials with 490 participants provided data for analysis
Study funding sources
Two of the 10 included trials reported receiving academic funding. None of the remaining eight trials reported information of support or funding.
Key results
None of the 10 included trials reported data on all-cause mortality (death from any cause), serious side effects (untoward medical occurrences that result in serious outcomes such as death or disability), health-related quality of life (a measure of physical, mental, emotional, and social functioning a measure of a person's satisfaction with their life and health), hepatitis B-related death, and hepatitis B-related morbidity. We are uncertain whether Xiao Chai Hu Tang formula versus no intervention has a positive or negative effect regarding side effects considered 'not to be serious', the proportion of people with detectable HBeAg (a hepatitis B viral protein that indicates active viral replication), and separately reported side effects considered 'not to be serious'. Xiao Chai Hu Tang formula compared with no intervention seems to reduce the proportion of people with detectable HBV-DNA (which is used to indicate how much hepatitis B virus is in the blood) but the reliability of this finding is low. Surrogate outcomes are markers that are used in research as a substitute for a clinically meaningful measure that directly measures patient outcomes. We cannot always be certain that such surrogate outcomes are reliable substitutes for important outcomes as they need to be officially examined. Caution is needed with this beneficial finding as the trials are at high risk of bias, and this outcome has not yet been proven relevant to patients. We identified an additional 47 studies as potential randomised clinical trials, but the data they reported were of no use. Accordingly, properly designed randomised clinical trials are needed before the benefits and harms of Xiao Chai Hu Tang formula for chronic hepatitis B can be determined.
Reliability of the evidence
The reliability of the evidence on the use of Xiao Chai Hu Tang formula in people with chronic hepatitis B virus in terms of its beneficial or harmful effects on death, health-related quality of life, risk of dying due to hepatitis B virus infection, and serious side effects cannot be determined as no trials aimed to explore these. The reliability of the evidence that Xiao Chai Hu Tang formula, when compared with no intervention, in terms of side effects considered 'not to be serious', the proportion of people with detectable HBV-DNA, and the proportion of people with detectable HBeAg is very low. These assessments of the reliability of the evidence are due to the poor design and reporting of the included trials.
The clinical effects of Xiao Chai Hu Tang formula for chronic hepatitis B remain unclear. The included trials were small and of low methodological quality. Despite the wide use of Xiao Chai Hu Tang formula, we lack data on all-cause mortality, serious adverse events, health-related quality of life, hepatitis B-related mortality, and hepatitis B-related morbidity. The evidence in this systematic review comes from data obtained from a maximum three trials. We graded the certainty of evidence as very low for adverse events considered not to be serious and the surrogate outcomes HBeAg and HBV-DNA. We found a large number of trials which lacked clear description of their design and conduct, and hence, these trials are not included in the present review. As all identified trials were conducted in China, there might be a concern about the applicability of this review outside China. Large-sized, high-quality randomised sham-controlled trials with homogeneous groups of participants and transparent funding are lacking.
Chronic hepatitis B is associated with high morbidity and mortality. Chronic hepatitis B requires long-term management aiming at reduction of the risks of hepatocellular inflammatory necrosis, liver fibrosis, decompensated liver cirrhosis, liver failure, and liver cancer, and improving health-related quality of life. The Chinese herbal medicine formula Xiao Chai Hu Tang has been used to decrease discomfort and replication of the virus in people with chronic hepatitis B. However, the benefits and harms of Xiao Chai Hu Tang formula have never been established with rigorous review methodology.
To assess the benefits and harms of Xiao Chai Hu Tang formula versus placebo or no intervention in people with chronic hepatitis B.
We searched The Cochrane Hepato-Biliary Group Controlled Trials Register, CENTRAL, MEDLINE Ovid, Embase Ovid, and seven other databases to 1 March 2019. We also searched the World Health Organization International Clinical Trials Registry Platform (www.who.int/ictrp), ClinicalTrials.gov (www.clinicaltrials.gov/), and the Chinese Clinical Trial Registry for ongoing or unpublished trials to 1 March 2019.
We included randomised clinical trials, irrespective of publication status, language, and blinding, comparing Xiao Chai Hu Tang formula versus no intervention or placebo in people with chronic hepatitis B. We included participants of any sex and age, diagnosed with chronic hepatitis B according to guidelines or as defined by the trialists. We allowed co-interventions when the co-interventions were administered equally to all the intervention groups.
Review authors independently retrieved data from reports and after correspondence with investigators. Our primary outcomes were all-cause mortality, serious adverse events, and health-related quality of life. Our secondary outcomes were hepatitis B-related mortality, hepatitis B-related morbidity, and adverse events considered 'not to be serious'. We presented the meta-analysed results as risk ratios (RR) with 95% confidence intervals (CI). We assessed the risks of bias using risk of bias domains with predefined definitions. We used GRADE methodology to evaluate our certainty in the evidence.
We included 10 randomised clinical trials with 934 participants, but only five trials with 490 participants provided data for analysis. All the trials compared Xiao Chai Hu Tang formula with no intervention. All trials appeared to have been conducted and published only in China. The included trials assessed heterogeneous forms of Xiao Chai Hu Tang formula, administered for three to eight months. One trial included participants with hepatitis B and comorbid tuberculosis, and one trial included participants with hepatitis B and liver cirrhosis. The remaining trials included participants with hepatitis B only. All the trials were at high risk of bias, and the certainty of evidence for all outcomes that provided data for analyses was very low. We downgraded the evidence by one or two levels because of outcome risk of bias, inconsistency or heterogeneity of results (opposite direction of effect), indirectness of evidence (use of surrogate outcomes instead of clinically relevant outcomes), imprecision of results (the CIs were wide), and publication bias (small sample size of the trials). Additionally, 47 trials lacked the necessary methodological information needed to ensure the inclusion of these trials in our review.
None of the included trials aimed to assess clinically relevant outcomes such as all-cause mortality, serious adverse events, health-related quality of life, hepatitis B-related mortality, or hepatitis B-related morbidity. The effects of Xiao Chai Hu Tang formula on the proportion of participants with adverse events considered 'not to be serious' is uncertain (RR 0.43, 95% CI 0.02 to 11.98; I2 = 69%; very low-certainty evidence). Only three trials with 222 participants reported the proportion of people with detectable hepatitis B virus DNA (HBV-DNA), but the evidence that Xiao Chai Hu Tang formula reduces the presence of HBV-DNA in the blood (a surrogate outcome) is uncertain (RR 0.62, 95% CI 0.45 to 0.85; I2 = 0%; very low-certainty evidence). Only two trials with 160 participants reported the proportion of people with detectable hepatitis B virus e-antigen (HBeAg; a surrogate outcome) (RR 0.72, 95% CI 0.50 to 1.02; I2 = 38%; very low-certainty evidence) and the evidence is uncertain. The evidence is also uncertain for separately reported adverse events considered 'not to be serious'.
Funding: two of the 10 included trials received academic funding from government or hospital. None of the remaining eight trials reported information on funding.