The Licorice Class Preparation And Phyllanthus In The Treatment Of Chronic Hepatitis B System

BACKGROUNDChronic hepatitis B virus infection is a serious public health problem with high prevalence all over the world, especially in China. Cochrane systematic review based on randomized clinical trials with high quality is the gold standard of evaluating the effect of interventions, and simultaneously provides the best evidence for clinical practice. Clinical practice guideline is the best conscience of clinical practice and management. Although the Chinese guideline of prevention and treatment for chronic hepatitis B updated according to the approval of new antiviral agents, there is still absence of the evidence of Chinese medicine for treating chronic hepatitis B virus infection.OBJECTIVESTo evaluate the efficiency and harms of glycyrrhizin and phyllanthus species for chronic hepatitis B virus infection in Cochrane systematic reviews. To discuss the methodology problems of the current published clinical trials on chronic hepatitis B virus infection. To introduce the principles of designing hepatic randomized trials.METHODSWe did systematic and unbiased electronic search and hand-search. We included randomised clinical trials testing glycyrrhizin and phyllanthus species separately versus placebo, or no intervention. Co-interventions were also allowed. In the experiment group we were looking at any trials that using glycyrrhizin or phyllanthus species in any form. We chose primary clinical outcomes which were all cause mortality, hepatitis B related motality or morbidity, serious or non-serious adverse events or qulity of life, and we put all the surrogate outcomes as secondary outcomes, which were number of patients with detectable serum HBsAg, number of patients with detectable serum HBV DNA, number of patients with detectable HBeAg, number of patients without HBeAg seroconversion or number of patients with worsened liver histology. We published our protocol before conducting this review. We conducted our review following the recommendations of the Cochrane handbook. We considered the methodological quality of the trials according to the 6 domains based on the Cochrane handbook and the Cochrane hepato-biliary group module. Only the trials with adequate description of all the domains were assessed as low risk of bias. We measured the effect using risk ratio with 95% confidence interval. We used the I square statistic to assess heterogeneity. For meta-analysis we used fixed effect model and random effect model according to the I square statistic. We performed trial sequential analysis to reduce the risk of random errors.RESULTSWe searched 5 international databases and 5 Chinese databases from start to Oct 2010. Handsearching was performed for more eligible trials. In the systematic review of glycyrrhizin for chronic hepatitis B virus infection,29 randomized trials were included comparing glycyrrhizin plus antiviral drugs with the same antiviral drugs alone. The antiviral drugs used were alpha interferon, lamivudine, adefovir dipivoxil, thymosin, vidarabine, or conventional treatment. No trials were identified comparing glycyrrhizin with placebo or no intervention. All trials were considered as high risk of bias. For the primary outcomes, no trials reported mortality, morbidity or quality of life. No trials reported serious adverse events. Six trials reported general adverse events with data of both groups, the result of meta-analysis showed that there was no significant difference (RR 0.89; 95% CI 0.78 to 1.02, P= 0.11; 12= 30%). For the secondary outcomes, when glycyrrhizin plus antiviral drugs with antiviral drugs alone, we did not find statistical significant difference between group regarding to clearance of serum HBsAg (RR 0.98; 95% CI 0.95 to 1.01, P= 0.11; 12= 31%); we found statistical significant difference on clearance of serum HBV DNA (RR 0.81; 95%CI 0.68 to 0.96, P= 0.01; 12= 95%); we found statistical significant difference on clearance of serum HBeAg (RR 0.82; 95% CI 0.71 to 0.94, P =0.004; 12=91%); and we found no statistical significant difference on seroconversion from HBeAg to anti-HBe (RR 0.89; 95% CI 0.78 to 1.02, P=0.11;12 =30%).In the systematic review of phyllanthus species for chronic hepatitis B virus infection,20 publications which described 16 different trials were included. Of the 16 trials,1 trial compared phyllanthus with placebo and the remaining 15 compared phyllanthus plus antiviral drugs with the same antiviral drugs alone. All of the 1326 participants were Chinese and 72% of them were male.12 trials used single herb of phyllanthus and 4 trials used compound phyllanthus. These were the antiviral drugs included in trials. The mean treatment duration was 6 months. All trials were considered with high risk of bias. For the primary outcomes, we did not have any data on the three outcomes of mortality, hepatitis B related mortality or morbidity and quality. We did have data about adverse events. They looked at general adverse events, there were 100 patients and no significant difference was found(RR 1.04; 95% CI 0.66 to 1.63, P=0.86; 12=0%). But we did have quite a bit data with regard to the secondary outcomes. Let's look at the secondary outcomes which you will also call as surrogate outcomes.4 trials reported the number of patients with detectable HBsAg after treatment. We didnot find significant differences between the groups for this outcome (RR 0.95; 95% CI 0.90 to 1.00, P=0.07;12=0%);12 trials reported the data under this outcome. We found significant differences between the groups (RR 0.69; 95% CI 0.52 to 0.91, P=0.008; 12=71%); 15 trials reported data on this outcome. We did find statistical significant differences between groups (RR 0.70; 95% CI 0.60 to 0.81,12= 68%); Seroconversion from HBeAg to HBe antibody was reported in 8 trials. We found significant differences between the intervention groups (RR 0.77; 95%CI 0.63 to 0.92, P=0.005; 12=78%).In summary, with regard to the primary outcomes, we don't have any information about mortality, morbidity or quality of life. We have some information about the adverse events, but the small number we have showed no significant differences. We do have information on secondary outcomes, and we found statistically significant results by conservative methods or TSA. But we have to keep in mind that they were surrogate outcomes coming from trials with high risk of bias, so if we have something to suggest that might be evidence, we clearly need to do more research to confirm it.CONCLUSIONThere is still absence of the evidence of the efficiency and harms of glycyrrhizin and phyllanthus for chronic hepatitis B virus infection, according to the results of Cochrane systematic reviews. The uncertainty for the clinical use of these two Chinese medicines needs confirmation urgently in randomized clinical trials with high quality. There is a series of methodology problems in the current published clinical trials of Chinese medicine. Clinical trials in future should be improved in implementing and reporting of methodology. Clinical relevant outcomes are supposed to be observed in the future trials in order to highlight the advantages of interventions of Chinese medicine.