Glycyrrhizin for chronic hepatitis B virus infection
Abstract
This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:
To evaluate the benefits and harms of glycyrrhizin preparations for patients with chronic HBV infection.
Background
Description of the condition
Chronic hepatitis B virus (HBV) infection is one of the most common infectious diseases in the world and may cause cirrhosis, hepatocellular carcinoma, and death. World‐wide, hepatitis B virus causes more than one million deaths every year, and about 350 million people are chronically infected (WHO 2008). This constitutes a significant health and economic burden. In China, the HBV infection is highly endemic. It is estimated that there are 120 million chronically infected carriers; up to 12 million people suffer from chronic hepatitis B, and 300,000 people die each year (Sun 2010). A study showed that the total economic loss resulted from chronic hepatitis B‐associated disease was probably in the range of US$ 8.5 to 15.6 billion in year 2001 (Hu 2009; Shi 2004).
Description of the intervention
Hepatitis B vaccine is 95% effective in preventing HBV infection (Chen 2005; Lee 2006; Mathew 2008; WHO 2008). Most countries have included hepatitis B vaccine into their national infant immunisation programmes, and vaccination has markedly reduced the frequency of chronic HBV infection (Chang 1997; WHO 2001). Furthermore, hepatitis B vaccine has been shown to be cost‐effective (Aggarwal 2003). However, vaccination offers no benefit for patients with chronic HBV infection. Hence, millions of patients are awaiting for advances in the treatment of the disease.
Currently, approved therapies for chronic hepatitis B include immunomodulatory agents like interferon alpha and pegylated interferon alpha as well as nucleoside analogues like lamivudine, telbivudine, entecavir, adefovir, and tenofovir (EASL 2009). Interferon alpha treatment results in viral, biochemical, and histological remission in about 30% of the patients. However, interferon alpha (conventional or pegylated) has the disadvantages of high cost and serious adverse events, both of which may lead to treatment discontinuation. Lamivudine is inexpensive but patients are at high risk of developing viral resistance. New antiviral drugs characterised by more potent antiviral effects, less toxicity, and minimal risk of resistance have been explored during the past decades. Entecavir and tenofovir are potent HBV inhibitors and have a high barrier to resistance (EASL 2009). Adefovir has most of the advantages of lamivudine, with an additional benefit that viral drug resistance is uncommon (Marcellin 2003). Telbivudine is another potent inhibitor of HBV (EASL 2009). Despite these advances, the use of these drugs may still be limited due to costs and effects only in a limited number of patients. In China, a large number of patients who cannot afford 'standard therapy' seek help from the traditional Chinese medicine.
Glycyrrhizin is a major component extracted from liquorice (Sato 1996). It is one of the earliest drugs developed for the treatment of chronic hepatitis B, both in China and Japan (Fujisawa 2000), and it is one of the most widely used herbal preparations for the treatment of chronic hepatitis B (Lee 2007). Randomised clinical trials suggest that glycyrrhizin improves the immune function, reduces hepatocellular damage in chronic hepatitis, and promotes the recovery of liver function (Yano 1991; Cao 2006; Fiore 2008). Preliminary and subsequent clinical trials have shown that glycyrrhizin products may lower aminotransferase activity and improve liver function (Hayashi 1989; Yano 1991; Guo 1994; Cao 2006; Fiore 2008).
The main products of glycyrrhizin for chronic hepatitis B include monoammonium glycyrrhizinate (ammonium glycyrrhizinate) and diammonium glycyrrhizinate (Zhang 1989; Li 1999; Ye 1999). In 1977, Japan was the first country to report the use of the glycyrrhizin for chronic hepatitis patients (Suzuki 1977; Suzuki 1983). In 1985, China succeeded in developing the preparation of glycyrrhizin and L‐amino acid (potenline), which is clinically effective for chronic hepatitis B (Li 1999). Since 1990, diammonium glycyrrhizinate has been widely used in China for chronic liver disease. It seems more effective than ammonium glycyrrhizinate (potenline) (Zhou 1993; Zhu 1998; Li 2001).
How the intervention might work
Glycyrrhizin is reported to have liver protection, immune‐modulating, and biological response‐modifier activities (Zhang 1998; Hao 2001). A study indicates that increased production of interleukin 10 (IL‐10) by liver dendritic cells due to glycyrrhizin administration may be involved in down regulation of the levels of liver inflammation in mice with con A‐induced hepatitis (Abe 2003). The hepatoprotective mechanism of action of glycyrrhizin is associated with the ability to down‐regulate nuclear factor‐kappa B (NF‐kappaB) and to decrease pronecrotic and profibrotic cytokines (Muriel 2008). Glycyrrhizin inhibits the cytolytic activity of complement via the activation of both the classical and alternative pathways, while it has no effect on immune adherence, suggesting that it blocks component 5 (C5) or a later stage of the complement cascade. Further analysis reveals that glycyrrhizin inhibits the lytic pathway in which the membrane attack complex (MAC) is formed (Fujisawa 2000). This mechanism suggests that glycyrrhizin may prevent tissue injury caused by MAC in chronic hepatitis (Fujisawa 2000). Intravenous administration in guinea pigs has clarified the pharmacological basis for the effectiveness of glycyrrhizin. Glycyrrhizin modifies the intracellular transport and suppresses sialylation of HBV surface antigen (HBsAg) in vitro (Sato 1996). The results of in vivo experiments have also demonstrated that glycyrrhizin significantly enhances recovery of liver function and rapidly lowers serum transaminase activities (Kimura 2008).
Why it is important to do this review
Since 1980s, a large number of clinical trials studying the potential effects of glycyrrhizin products for chronic hepatitis B have been published, but the benefits and harms of glycyrrhizin products for patients with chronic hepatitis B have never been systematically reviewed.
Objectives
To evaluate the benefits and harms of glycyrrhizin preparations for patients with chronic HBV infection.
Methods
Criteria for considering studies for this review
Types of studies
We will include randomised clinical trials irrespective of publication status, language, or blinding. We will exclude studies using alternation, date of birth, hospital record number, or other 'quasi‐random' methods of allocation of treatment, except for assessment of harms.
Types of participants
We will include participants with chronic active HBV infection. As patients with chronic active HBV infection may be HBe‐Ag positive or HBe‐Ag negative, we will use the following definitions based on Lok 2007:
HBe‐Ag positive chronic hepatitis B infection defined as HBsAg positivity for more than six months, serum HBV DNA positivity more than 20,000IU/ml, ie, 105copies/ml, persistent or intermittent elevation in levels of aspartate aminotransferase or alanine aminotransferase, and liver biopsy findings showing chronic hepatitis B with moderate or severe necroinflammation.
HBe‐Ag negative chronic hepatitis B infection defined as HBsAg positivity for more than six months, serum HBV DNA positivity with lower values of 2000 to 20,000 IU/ml, ie, 104 to 105 copies/ml, and persistent or intermittent elevation in levels of aspartate aminotransferase or alanine aminotransferase, and liver biopsy findings showing chronic hepatitis B with moderate or severe necroinflammation.
We will include trials with both children and adult participants. For the purpose of this review we will define a child as aged 15 years or less and an adult as aged 16 years or older. Patients will be included irrespective of whether they are treatment‐naive or have previously been treated unsuccessfully for chronic HBV infection with another drug. We will include patients with evidence of concomitant HIV infection, hepatitis C, hepatitis D, hepatocellular carcinoma, or other liver related co‐morbidities, but we will analyse the patients with and without these conditions in separate. Patients with prior liver transplantation or those with concomitant renal failure will also be included, but again analysed separately.
Types of interventions
We will consider trials being eligible for inclusion if they assess any glycyrrhizin products used for chronic hepatitis B.
Glycyrrhizin products may include but will not be limited to monoammonium glycyrrhizinate, diammonium glycyrrhizinate, potenline, or the compound glycyrrhizin given as tablets or injections. We will consider interventions at any dose, formulation, route of administration, or length of treatment.
The control intervention may be no intervention or placebo.
We will allow co‐interventions if all intervention and control groups in the trial have received the same co‐intervention(s).
Types of outcome measures
The following outcome measures will be sought at the end of treatment as well as at maximal follow‐up.
Primary outcomes
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All‐cause mortality.
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Hepatitis B‐related mortality (caused by morbidities or decompensation of the liver such as liver cirrhosis or hepatocellular carcinoma).
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Hepatitis B‐related morbidity (decompensation of the liver such as liver cirrhosis or hepatocellular carcinoma).
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Number of participants with serious and non‐serious adverse events in separate (as defined by the International Conference on Harmonisation Guideline for Good Clinical Practice (ICH‐GCP 1997)).
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Quality of life (as defined by the trialists).
Secondary outcomes
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Number of participants with detectable HBsAg.
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Number of participants with detectable HBV DNA.
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Number of participants with detectable HBeAg (this outcome measure is not relevant for the HBeAg‐negative participants).
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Number of participants without HBeAg seroconversion (this outcome measure is not relevant for the HBeAg‐negative participants).
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Number of participants with worsened liver histology.
Search methods for identification of studies
Electronic searches
We will identify trials by electronic searches of The Cochrane Hepato‐Biliary Group Controlled Trials Register (Gluud 2010), The Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library, MEDLINE, EMBASE, Science Citation Index Expended (Royle 2003), and Chinese Biomedical CD Database (CBM), China Network Knowledge Information (CNKI), Chinese Science Journal Database (VIP), TCM Online, and Wanfang Database. All the databases above will be searched from their date of inception onwards and irrespective of language or publication status.
The preliminary search strategies with the expected time span of the searches are given in Appendix 1. As the review progresses, we will improve the search strategies if necessary.
Searching other resources
Conference proceedings in Chinese will be handsearched. We will screen the reference lists of all retrieved randomised trials and review articles for other eligible trials.
Data collection and analysis
The methodology for data collection and analysis is based on the Cochrane Handbook of Systematic Reviews of Interventions (Higgins 2009) and the Cochrane Hepato‐Biliary Group Module (Gluud 2010).
Selection of studies
Two authors will independently screen the titles and abstracts of studies identified by the literature search for eligibility according to the prespecified selection criteria. Disagreements will be resolved by consensus. We will try the best to retrieve eligible studies in full to confirm whether or not they fulfil the inclusion criteria. The authors will not be blinded to the authors' names and institutions, journal of publication, or study results at this or any stage of the review.
Data extraction and management
Two authors will extract data independently using a self‐developed data extraction form. Disagreement will be resolved by consensus. The following characteristics and data will be extracted from each included trial:
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Methods: trial design, the information needed to assess the risk of bias domains (listed below), sample size calculations, and length of follow‐up.
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Participants: age, sex, ethnic origin, duration of hepatitis B, forms of transmission, previous anti‐viral treatment, diagnostic criteria, number of patients randomised, similarity of groups at entry into the trial, assessment of compliance, and withdrawals/losses to follow‐up (reasons/description).
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Interventions: type of glycyrrhizin preparation, dosage and duration of therapy, route of administration, formulation, intervention in the control group, and any co‐interventions.
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Outcomes: as listed above under outcome measures.
If more than one publication on each randomised clinical trial is identified, data will be extracted from the most recent or most explicit publication.
Assessment of risk of bias in included studies
Two authors will independently assess the risk of bias for each included randomised trial. Disagreements will be resolved by consensus. We will assess the following domains (Schulz 1995; Moher 1998; Jüni 2001; Kjaergaard 2001; Wood 2008):
Allocation sequence generation
‐ Low risk of bias: sequence generation was achieved using computer random number generation or a random number table. Drawing lots, tossing a coin, shuffling cards and throwing dice are adequate if performed by an independent adjudicator.
‐ Uncertain risk of bias: the trial is described as randomised, but the method of sequence generation was not specified.
‐ High risk of bias: the sequence generation method is not, or may not be, random. Quasi‐randomised studies, those using dates, names, or admittance numbers in order to allocate patients are inadequate and will be excluded for the assessment of benefits but not for harms.
Allocation concealment
‐ Low risk of bias: allocation was controlled by a central and independent randomisation unit, sequentially numbered, opaque and sealed envelopes or similar, so that intervention allocations could not have been foreseen in advance of, or during, enrolment.
‐ Uncertain risk of bias: the trial was described as randomised but the method used to conceal the allocation was not described, so that intervention allocations may have been foreseen in advance of, or during, enrolment.
‐ High risk of bias: if the allocation sequence was known to the investigators who assigned participants or if the study was quasi‐randomised. Quasi‐randomised studies will be excluded for the assessment of benefits but not for harms.
Blinding
‐ Low risk of bias: the trial was described as blinded, the parties that were blinded, and the method of blinding was described, so that knowledge of allocation was adequately prevented during the trial.
‐ Uncertain risk of bias: the trial was described as blind, but the method of blinding was not described, so that knowledge of allocation was possible during the trial.
‐ High risk of bias: the trial was not blinded, so that the allocation was known during the trial.
Incomplete outcome data
‐ Low risk of bias: the numbers and reasons for dropouts and withdrawals in all intervention groups were described or if it was specified that there were no dropouts or withdrawals.
‐ Uncertain risk of bias: the report gave the impression that there had been no dropouts or withdrawals, but this was not specifically stated.
‐ High risk of bias: the number or reasons for dropouts and withdrawals were not described.
Selective outcome reporting
‐ Low risk of bias: pre‐defined, or clinically relevant and reasonably expected outcomes are reported on.
‐ Uncertain risk of bias: not all pre‐defined, or clinically relevant and reasonably expected outcomes are reported on or are not reported fully, or it is unclear whether data on these outcomes were recorded or not.
‐ High risk of bias: one or more clinically relevant and reasonably expected outcomes were not reported on; data on these outcomes were likely to have been recorded.
Other biases
‐ Low risk of bias (the trial appears to be free of other sources of bias (eg, conflict of interest bias).
‐ Uncertain risk of bias (there is insufficient information to assess whether other sources of bias are present).
‐ High risk of bias (it is likely that potential sources of bias related to specific design used, early termination due to some data‐dependent process, lack of sample size or power calculation, or other bias risks are present).
Authors' judgement will be based on the definitions of the above listed domains, and the trials will be grouped into 'trials with low risk of bias' and 'trials with high risk of bias', the latter encompassing also the 'trials with uncertain risk of bias'.
We will also report whether the trials had a sample size calculation.
Measures of treatment effect
For dichotomous data, such as mortality, we will present results as summary risk ratio (RR) with 95% confidence interval (CI).
Unit of analysis issues
Intervention groups of patients in randomised clinical trials. We will give special attention to randomised cross‐over trials. For reasons stated in the Cochrane Handbook of Systematic Reviews of Interventions (Higgins 2009), only data from the first period of the randomised trial will be included into the meta‐analyses.
Dealing with missing data
We will seek missing data by contacting authors. Sensitivity analyses will be conducted if data are still lacking. For dichotomous data, analyses will be carried out based on 'best‐case' and 'worst‐case' scenarios (Gamble 2005).
Assessment of heterogeneity
We will use the chi‐square statistic to assess heterogeneity and I‐square statistic to measure inconsistency (Higgins 2009).
Assessment of reporting biases
We will use the funnel plot to investigate bias if there are at least ten included trials. Other possible reasons for bias, such as high risk of bias and true heterogeneity, will be explored for funnel plot asymmetry as asymmetric funnel plots are not necessarily caused by publication bias (Egger 1997).
Data synthesis
We will conduct both fixed‐effect (Demets 1987) and random‐effects (DerSimonian 1986) models meta‐analyses, but we will present the results with the fixed‐effect model only if there is no significant difference between the two analyses. In case of difference in results, we will present the results obtained with both models meta‐analyses. The analyses will be carried out using the Cochrane Review Manager software (RevMan 2008).
Subgroup analysis and investigation of heterogeneity
We plan to conduct subgroup analysis to explore differences in trials with low risk of bias compared to trials with high risk of bias, among different glycyrrhizin products, and populations with different co‐infections and diseases.
