| Chronic carriers of hepatitis B virus cause a disease burden for global public health.Liver fibrosis is a wound-healing response which results from chronic impairment due to pathogenic factors and may aggravate to cirrhosis.However,no specific treatment method has been found from conventional medicine.Many patients may resort to Chinese herbal medicine.This study aimed to systematically assess the effect and safety of Chinese herbal medicine in the whole,in order to update the evidence,which basing the clinical practice and guideline.In addition,we detected the conclusion bias of trials included in the two systematic reviews.This study can be separated into four parts.Part 1 was about literature review.Part 2 and Part 3 were two Cochrane systematic reviews about chronic carriers of HBV and liver fibrosis and/or cirrhosis.Part 4 was a methodology study focusing on the bias in conclusion of the original studies,to detect if there was spin or interpretive bias.Methods:In Part 2 and Part 3,we systematically searched randomized controlled trials in 10 databases.For Part 2,the eligibility criterion was chronic carriers of HBV;for Part 3 was diagnosed liver fibrosis and cirrhosis.Intervention was restricted as Chinese herbal medicine.Control therapy may contain no treatment,placebo,non-specific treatment,as well as etiological or symptomatic treatment.Outcome measures were all-cause mortality,hepatic complication occurrence,liver biopsy,transient elastography value,quality of life,serious and non-serious adverse events,serological response and virological response.We performed meta-analysis by Revman 5.3 and TSA to calculate the sample sized needed for it.In Part 4,after data extraction,we used a tool for the assessment of conclusion bias,which contain four aspects and 15 items to classify the conclusion bias,to detect if there was conclusion bias or its type for the included trials.Results:Part2:we included 27 RCT and 3412 participants were involved.All the studies were assessed as high risk of bias.None of them has reported the all-cause mortality or HBV-related complications.Three studies(174 participants involved)intervened by compound herbs reported a higher score of quality of life(SF-36,subjective well-being,social support and WHOQOL)compared with no treatment or non-specific treatment.14 studies(1712 participants involved)reported serious adverse event did not occure,whereas 95 participants reported with non-serious adverse events including gastrointestinal symptoms.In meta-analysis,for HBsAg clearance,Chinese herbal medicine had no significant difference compared with no treatment(two studies,FE,RR=0.96,95%CI[0.91,1.02],200 participants).Chinese herbal medicine had no significant difference compared with placebo(FE,RR=0.99,95%CI[0.98,1.01],1203 participants).Trial sequential analysis supported this meta-analysis.Combination with Chinese herbal medicine was superior to non-specific treatment alone(two studies,FE,RR=0.95,95%CI[0.91,0.98],443 participants).Combination with interferon was superior to interferon alone(two studies,FE,RR=0.83,95%CI[0.72,0.96],121 participants).For HBeAg clearance,Chinese herbal medicine was superior to no treatment(four studies,RE,RR=0.72,95%CI[0.60,0.87],453 participants).Chinese herbal medicine has no significant difference compared with placebo(six studies,FE,RR=0.99,95%CI[0.96,1.02],869 participants).Chinese herbal medicine was superior to non-specific treatment(four studies,FE,RR=0.81,95%CI[0.69,0.94],346 participants).Chinese herbal medicine was superior to interferon(two studies,FE,RR=0.79,95%CI[0.69,0.91],189 participants).Combination with Chinese herbal medicine has no significant difference compared with interferon alone(two studies,RE,RR=0.47,95%CI[0.20,1.12],121 participants).For HBeAg seroconversion,Chinese herbal medicine was superior to no treatment(two studies,FE,RR=0.93,95%CI[0.87,0.99],218 participants).Chinese herbal medicine was superior to placebo(three studies,FE,RR=0.97,95%CI[0.94,1.00],490 participants).For HBV-DNA clearance,Chinese herbal medicine was superior to no treatment(four studies,RE,RR=0.74,950%CI[0.62,0.89],438 participants).Trial sequential analysis supported this meta-analysis.Chinese herbal medicine had no significant difference compared with non-specific treatment(four studies,FE,RR=0.87,95%CI[0.75,1.02],326 participants).Combination with Chinese herbal medicine was superior to non-specific treatment alone(three studies,FE,RR=0.82,95%CI[0.75,0.90],409 participants).Chinese herbal medicine was superior to interferon(two studies,FE,RR=0.88,95%CI[0.78,0.99],189 participants).Combination with Chinese herbal medicine has no significant difference compared with interferon alone(two studies,FE,RR=0.71,95%CI[0.47,1.07],91 participants).Part 3:we included 50 RCTs and 5274 participants were involved.44 studies were assessed as high risk of bias.16 studies(1532 participants involved)reported no serious adverse events occurred and 19 participants had non-serious adverse events including gastrointestinal symptoms.In meta-analysis,for all-cause mortality,the compound herbs was superior to placebo(two studies,FE,RR=0.40,95%CI[0.16,0.99],236 participants).Combination with compound herbs was superior to anti-virus alone(four studies,FE,RR=0.53,950%CI[0.36,0.77],238 participants).Combination with compound herbs was superior to conventional medicine alone(three studies,FE,RR=0.54,95%CI[0.31,0.95],375 participants).For hepatic carcinoma occurrence,combination with compound herbs had no significant difference compared with anti-virus alone(three studies,FE,RR=0.56,95%CI[0.12,2.54],178 participants).For quality of life,six studies(1080 participants involved)all reported that participants with compound herbs had a higher score(p<0.05).Among them,two studies showed that combination with compound herbs was superior to anti-virus alone(FE,MD=10.11,95%CI[6,81,13.41],234 participants).For complication occurrence,combination with compound herbs was superior to conventional medicine alone(two studies,FE,RR=0.56,95%CI[0.35,0.91],169 participants).For fibrosis degree in liver biopsy,compound herbs was superior to placebo,either in qualitative synthesis(four studies,FE,RR=0.70,95%CI[0.62,0.80],475 participants)or in quantitative analysis(two studies,FE,MD=-2.62,95%CI[-4.03,-1.21],205 participants).For transient elastography value,combination with compound herbs was superior to anti-virus alone(14 studies,FE,MD=-3.21,95%CI[-3.57,-2.84],1220 participants).Trial sequential analysis supported this meta-analysis.Part 4:For the assessment of conclusion bias of the 71 included trials,only two of them reported conclusion without missing information.55 of them did not report the security of intervention therapy.48 of them did not recommend as its clinical meaning in practice.The most frequently observed conclusion biases were "drawing a conclusion without supporting data of corresponding outcome"(62.34%),"use of linguistic spin"(48.05%),"extrapolation without consideration of safety"(32.47%)and "seeing 'no adverse events' as 'no side effect'"(25.97%).Conclusion:for chronic carriers of HBV,judging from present studies,Chinese herbal medicine may not have a specific effect in eradication of HBsAg,HBeAg and HBV-DNA.Compound herbs may improve the quality of life.No serious adverse event has been observed in this kind of herbal medicine treatment.However,limited by methodological quality and sample size,the strength of this evidence is low.Chinese herbal medicine can be used as a complimentary therapy in the improvement of quality of life for this disease.For liver fibrosis and/or cirrhosis,combination with compound herbs may decrease the all-cause mortality and hepatic carcinoma occurrence,improve the quality of life,remit the pathological status,and soften hardness.No serious adverse event has been observed in this kind of herbal medicine treatment.However,limited by methodological quality and sample size,the strength of this evidence is low.Chinese herbal medicine can be used as a complimentary therapy in the improvement of quality of life for this disease.Ninety nine percent of included above trials had interpretative conclusion bias,mainly concentrated on drawing a conclusion without observation of corresponding outcome,use of linguistic spin,extrapolation without consideration of safety and extrapolation to a larger population.We suggested the conclusion report should be correspondence with outcomes.Authors should report the conclusion objectively and take safety into consideration before extrapolation. |
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