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. 2018 Aug 9;2018(8):CD008957. doi: 10.1002/14651858.CD008957.pub2

Sophorus species for chronic hepatitis B virus infection

Yu Feng Wu 1, Xing Liao 1, Jian Ping Liu 1,✉
PMCID: PMC6513607

Abstract

This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:

To assess the beneficial and harmful effects of extracts of the Chinese herbs belonging to the Sophorus species, as matrine and oxymatrine, in patients with chronic hepatitis B.

Background

Description of the condition

Hepatitis B virus (HBV) is the most severe type of viral hepatitis. About 2 billion people have been infected with HBV worldwide, of whom more than 350 million are chronically infected. Between 500,000 and 700,000 people die annually from HBV infection (WHO 2009; World Hepatitis Alliance 2009). In China, for example, the incidence of viral hepatitis in 2008 was 106.54 (ie, 1 in every 100,000) in total, and the incidence rate of hepatitis B alone was 88.52 (ie, 1 in every 100,000) (MOH 2009). People with chronic HBV infection have a 15% to 25% risk of dying prematurely from HBV‐related cirrhosis and liver cancer (WHO 2009).

Hepatitis B is a viral infection producing inflammation of the liver. It can be contracted by vertical transmission, from mother to baby during birth or during the neonatal period, or through infected blood through wounds, contaminated injection equipment (blood transfusions, re‐use of contaminated needles and syringes, etc), or by unprotected sexual contact. All persons who have hepatitis B surface antigen (HBsAg) are potentially infectious. Human beings are generally susceptible to HBV. Only people who have been vaccinated successfully or those who have developed anti‐HBs antibodies after HBV infection are immune to HBV infection. Hepatitis B virus infection may either be acute or chronic. Persons with acute infection may clear the infection spontaneously within several weeks to months. The risk of getting chronically infected depends on the age when someone initially becomes infected: the risk for chronic infection for newborns is about 90% and for children from 1 to 5 years old around 25% to 50% (WHO 2002). Less than 5% of the older children and adults infected with HBV develop chronic hepatitis B. In the Western Pacific Region, around 40% of all chronic infections with hepatitis B begin at birth (WHO 2002).

Description of the intervention

Several antiviral drugs are now available for the treatment of chronic hepatitis B. They include conventional interferon alpha, pegylated interferon alpha, and nucleoside/nucleotide analogues (NUCs). There are three classes of NUCs: L‐nucleosides (lamivudine, telbivudine, and emtricitabine), deoxyguanosine analogues (entecavir), and acyclic nucleoside phosphonates (adefovir and tenofovir). Interferon alpha (conventional or pegylated) has the property of obtaining a sustained virological response off‐treatment and a chance of HBsAg reduction in patients who achieve and maintain undetectable HBV DNA. However, the main disadvantages are frequent adverse effects and subcutaneous injections (EASL 2009). Patients with decompensated HBV‐related cirrhosis, autoimmune disease, and those with uncontrolled severe depression or psychosis have all contraindications towards infections. Lamivudine is an inexpensive drug for HBV infection but induces very high proportion of patients with resistance towards this drug. Entecavir and tenofovir have a high barrier to resistance, but they are expensive for some patients. Adefovir is even more expensive than tenofovir, is less efficacious, and causes higher rates of resistance. Telbivudine is a potent inhibitor of HBV, but it also has high resistance (EASL 2009). These disadvantages hinder the usage of these drugs, especially in developing countries.

Herbal medicine is the main part of Traditional Chinese Medicine, which has a more than 3000 years of history and forms a holistic system of combination of medicinal herbs, acupuncture, massage, moxibustion, food, and physical therapy for both treatment and prevention of disease (Fulder 1996). Chinese herbal medicines are widely used for chronic hepatitis B for more than 2000 years. Clinical trials on herbs for hepatitis B have reported positive findings (Cai 1997; Luo 1997; Luo 2005; CSH 2006). Among them, we find many trials that adopted matrine and oxymatrine as an experimental intervention.

Radix Sophorae flavescentis (botanical name Sophora flavescens, Chinese name Ku Shen) is an ancient Chinese herb. The function of Radix Sophorae flavescentis is to remove heat and damp, treat jaundice and skin diseases (such as colpitis, psoriasis, eczema, etc) (Chinese Pharmacopoeia 2005). There are many studies that have proved that Radix Sophorae flavescentis could be used for treatment of chronic hepatitis B (Liu 2003). Matrine and oxymatrine are derived from Radix Sophorae flavescentis. The molecular formula of matrine is C15H24N2O, and the molecular formula of oxymatrine is C15H24N2O2. In 1998, matrine and oxymatrine were approved for treatment of chronic hepatitis B in China (Zheng 2007). There are more and more laboratory and clinical studies on matrine and oxymatrine in treating chronic hepatitis B, and even liver cirrhosis. Kushenin is another name for matrine in China (Luo 2005).

How the intervention might work

Basic and clinical research have shown that oxymatrine has the following pharmacological effects: it is antiviral, protects hepatocytes, has antifibrotic properties, and regulates the immune system (Lu 2002; Yang 2002; Shen 2008). The fact that Th1 cytokines are increased while at the same time Th2 cytokines are decreased suggests that oxymatrine therapy may trigger the change of immune response to hepatitis B infection in transgenic mice which leads to improved HBV inhibitory activities (Dong 2002). Oxymatrine can reduce the contents of HBsAg and HBcAg in transgenic mice liver (Chen 2001). There was a strong relationship between serum leveI of MMP‐2 (matrix metalloprotein‐2) and TIMP‐2 (tissue inhibitor of metalloprotein‐2), and the Ievels of Iiver cirrhosis indexes. Oxymatrine also could decrease the levels of MMP‐2, HA (hyaluronate), LN (laminin), and IV C (IV collagen) in patients with severe or moderate chronic hepatitis B and liver cirrhosis of Child‐Pugh A, B, and C grades compared with the data before treatment (P < 0.05) (Liu 2005). The inhibitory effects of matrine and oxymatrine on HepG2.2.15 cells under the concentration of 0.001 mol/L was lower(< 25%). When concentration was between 1000μmol/L and 0.1μmol/L, the inhibition ratios for either matrine or oxymatrine were more than 50% for secreting HBsAg but lower than 50% for HBeAg. At the concentration of 0.001 mol/L, the inhibitory rates of matrine and oxymatrine on hepatitis B Pre‐S1 antigen were 53.58% and 59.33% respectively.Their inhibitory effects on HBsAg and Pre‐S1 are superior to lamivudine (Nie 2008). The inhibitory effect of oxymatrine on HBsAg and HBeAg increased in a dose‐dependent manner from 0.125 to 1 g/L. Oxymatrine‐baicailin compound had good inhibitory effect on hepatitis B viral antigens secretion, and the inhibition effect of the compound on HBeAg was superior to the effect on HBsAg. Oxymatrine at concentrations between 0.125 and 1 g/L had little toxicity on cells, but oxymatrine at 2 g/L and 4 g/L had much more toxicity on cells (Cheng 2006). A clinical study suggested that intramuscular matrine was safe, economical, and efficacious drug for the treatment of chronic hepatitis B (Long 2004).

Why it is important to do this review

The goal of therapy in hepatitis B virus infection is to improve survival and quality of life by preventing progression of the disease to cirrhosis, decompensated cirrhosis, end‐stage liver disease, hepatocellular carcinoma (HCC), and death (EASL 2009). The many millions of people around the world who become HBV carriers are a new constant source of infections for those who have never contracted HBV (Robinson 1995). During our search for matrine for HBV infection, we noticed a large number of randomised clinical trials that had compared matrine (oxymatrine) with other therapies. As we still have no compelling evidence whether matrine or oxymatrine have the same effects and less adverse events, or have better effects than other therapies including placebo and no intervention, a systematic review of these randomised trials could identify the potential benefits and harms of matrine or oxymatrine or kushenin for hepatitis B. We could not identify any meta‐analyses with trials testing Sophorus species for chronic hepatitis B virus infection.

Objectives

To assess the beneficial and harmful effects of extracts of the Chinese herbs belonging to the Sophorus species, as matrine and oxymatrine, in patients with chronic hepatitis B.

Methods

Criteria for considering studies for this review

Types of studies

Randomised clinical trials will be included irrespective of blinding, publication status, language, or year of publication.

Types of participants

We will include participants with chronic active HBV infection. As patients with chronic active HBV infection may be HBe‐Ag positive and HBe‐Ag negative, we will follow the following definitions 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. All participants need to have evidence of chronic hepatitis B as defined by the trialists. 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 separately from those 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

Sophorus species, matrine (kushenin) or oxymatrine, compared with no intervention or placebo. Sophorus species, matrine (kushenin) or oxymatrine compared with other antiviral treatments, immunomodulation agents, or other non‐specific medical treatments. Sophorus species, matrine (kushenin) or oxymatrine of different dosages, or mode, or duration of administration will be analysed. Co‐intervention(s) will be allowed as long as all intervention and control groups of the randomised clinical trials 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

  1. All‐cause mortality.

  2. Hepatitis B‐related mortality (caused by morbidities or decompensation of the liver such as liver cirrhosis or hepatocellular carcinoma).

  3. Hepatitis B‐related morbidity (decompensation of the liver such as liver cirrhosis or hepatocellular carcinoma).

  4. 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)).

  5. Quality of life (as defined by the trialists).

Secondary outcomes

  1. Number of participants with detectable HBsAg.

  2. Number of participants with detectable HBV DNA.

  3. Number of participants with detectable HBeAg (this outcome measure is not relevant for the HBeAg‐negative participants).

  4. Number of participants without HBeAg seroconversion (this outcome measure is not relevant for the HBeAg‐negative participants).

  5. 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) inThe 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), TCMOnline, and Wanfang Database. All the databases above will be searched from their date of inception onwards and irrespective of language or publication status.

The MeSH terms will cover chronic hepatitis B, Sophorus species, matrine, oxymatrine, medicine, Chinese traditional. Other relative free‐text terms will be: Radix Sophorae flavescentis, Ku Shen, Ke Su, and Gan Yi Ning.

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. The bibliographic references of identified randomised trials and review articles will be checked in order to find whether there were any randomised trials not identified by electronic and hand searches. The contact author of the identified trials will be approached and inquired about additional randomised trials they might know of.

Data collection and analysis

The methodology for data collection and analyses will be 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 (WY and LX) will independently select the trials to be included in the review according to the prespecified selection criteria. Disagreement will be resolved by discussion. The authors will not be blinded to the study authors' names and their institutions, journal of publication, or study results at any stage of the review.

Data extraction and management

The following characteristics and data of all included randomised trials will be extracted independently by two authors using a self‐developed data extraction form. Disagreement will be resolved by discussion. Papers not in Chinese or English will be translated with the help of the Cochrane Hepato‐Biliary Group.

  1. Methods: trial design, the information needed to assess the risk of bias domains (listed below), sample size calculations, withdrawals and reasons for withdrawal, protection against contamination, sample representativeness, length of follow‐up.

  2. Paticipants: number of patients randomised, age, sex, ethnic origin, diagnostic procedures, liver biopsy, serum HBV virological status.

  3. Interventions: administration of sophorus species, matrine (oxymatrine), formulation, dosage and duration of therapy, and other co‐interventions.

  4. Outcomes data: all data that are needed in order to assess the outcome measures of our review. The outcomes in each of the included study will also be recorded.

Assessment of risk of bias in included studies

Two authors will independently assess the methodological quality of the trials in terms of bias risk. Disagreements will be resolved by consensus. The domains for risk of bias and their definitions according to which we will judge the risk of bias in each individual included trial are as follows (Moher 1998; Kjaergard 2001; Jüni 2001; Schulz 1995; Wood 2008; Gluud 2010).

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).

We will group the trials into 'trials with low risk of bias' and 'trials with high risk of bias', depending on the judgements. The 'trials with high risk of bias' will also encompass the 'trials with uncertain risk of bias'.

We will report whether the trials had a sample size calculation.

Measures of treatment effect

Dichotomous variables will be presented as relative risk (RR) and continuous variables as mean difference (MD), both with 95% confidence intervals (CI).

Unit of analysis issues

Intervention groups of patients in randomised clinical trials. We will give special attention to the cross‐over design of the randomised clinical trial. We will only include data from the first period of the randomised cross‐over trial, following the suggestions of the Cochrane Handbook of Systematic Reviews of Interventions (Higgins 2009).

Dealing with missing data

We will try to get in touch with the authors and request missing data. If no information is received, then we will use the intention‐to‐treat analyses.

Assessment of heterogeneity

We will use the chi‐square statistics test to check the heterogeneity and I‐square measures for inconsistency (Higgins 2009).

Assessment of bias

Potential biases will be analysed with funnel plot analyses in case a minimum of ten trials are included in the review (Egger 1997).

Data synthesis

Data will be combined if trials compare the same interventions regardless of the route of administration and dosage. We will perform both the fixed‐effect model (Demets 1987) and the random‐effects model (DerSimonian 1986) meta‐analyses. In case of statistical differences between the results of the meta‐analyses of the two models, we will present the data from both models. Otherwise, the data from the random‐effects model will be presented. The analyses will be carried out using the Cochrane Review Manager software (RevMan 2008).

Subgroup analysis and investigation of heterogeneity

If a sufficient number of randomised trials are identified and data are available, we will perform the following subgroup analyses within a comparison of the same interventions:

  • Trials with low risk of bias compared to trials with high risk of bias.

  • Matrine compared to oxymatrine.

  • Age of acquiring the HBV infection. Age is a major factor in determining the outcome of HBV infection as children and adults show different outcomes. The risk of becoming chronically infected depends on the age at the time of initial infection: for newborns the risk can be about 90%, for 1 to 5 years children around 25% to 50%. Less than 5% of the older children and adults infected with hepatitis B may develop chronic hepatitis (WHO 2002).

  • Duration of follow‐up. Chronic hepatitis B is a dynamic process. Its natural history can be schematically divided into five phases, but are not necessarily sequential. This makes it difficult to anticipate each patient's outcome in a short follow‐up. Therefore, a long‐term follow‐up is needed. Accordingly, we will analyse the randomised trials with less than three months of follow‐up compared to the randomised trials with a follow‐up of three months or longer after the end of treatment.

Acknowledgements

We would like to acknowledge the staff at The Cochrane Hepato‐Biliary Group (CHBG) who helped us revise and finalise this protocol. Peer Reviewers: Luit Penninga, Denmark. Contact Editor: Christian Gluud, Denmark.

Appendices

Appendix 1. Search Strategies

Database Time Span Search Strategies
The Cochrane Hepato‐Biliary Group Controlled Trials Register Date will be given at the review stage. Sophorus species OR Radix Sophorae flavescentis OR matrine OR oxymatrine
The Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library Latest issue. #1 Sophorus species #2 Radix Sophorae flavescentis #3 matrine #4 oxymatrine #5 #1 MeSH descriptor Hepatitis B, Chronic explode all trees #6 ((#1 or #2 or #3 or #4) and #5)
MEDLINE (Ovid SP) 1950 to the date when the search is performed. #1 Sophorus species.mp. [mp=title, abstract, subject headings, heading word, drug trade name, original title, device manufacturer, drug manufacturer] #2 Radix Sophorae flavescentis.mp. [mp=title, abstract, subject headings, heading word, drug trade name, original title, device manufacturer, drug manufacturer] #3 matrine.mp. [mp=title, abstract, subject headings, heading word, drug trade name, original title, device manufacturer, drug manufacturer] #4 oxymatrine.mp. [mp=title, abstract, subject headings, heading word, drug trade name, original title, device manufacturer, drug manufacturer] #5 exp Hepatitis B, Chronic/ #6 ((#1 or #2 or #3 or #4) and #5)
EMBASE (Ovid SP) 1980 to the date when the search is performed. #1 Sophorus species.mp. [mp=title, abstract, subject headings, heading word, drug trade name, original title, device manufacturer, drug manufacturer] #2 Radix Sophorae flavescentis.mp. [mp=title, abstract, subject headings, heading word, drug trade name, original title, device manufacturer, drug manufacturer] #3 matrine.mp. [mp=title, abstract, subject headings, heading word, drug trade name, original title, device manufacturer, drug manufacturer] #4 oxymatrine.mp. [mp=title, abstract, subject headings, heading word, drug trade name, original title, device manufacturer, drug manufacturer] #5 exp hepatitis B/ #6 ((#1 or #2 or #3 or #4) and #5)
Science Citation Index Expanded (http://www.isiknowledge.com/?DestApp=WOS&locale=en_US.) 1900 to the date when the search is performed. #1TS=Sophorus species #2 TS=Radix Sophorae flavescentis #3 TS=matrine #4 TS=oxymatrine #5 TS=chronic hepatitis B #6 ((#1 or #2 or #3 or #4) and #5)
Google scholar Available on line. Sophorus species, Radix Sophorae flavescentis, matrine, oxymatrine Chronic hepatitis B
CBM (Chinese Biomedical Database)(http://sinomed.imicams.ac.cn/) 1978 to the date when the search is performed. #1Sophorus species #2 Radix Sophorae flavescentis #3 matrine #4 oxymatrine #5 Ku Shen #6 Ke Su #7 Gan Yi Ning #8 chronic hepatitis B explode all trees (MeSH) #9 ((#1 or #2 or #3 or #4 or #5 or #6 or #7) and #8)
CNKI (China National Knowledge Infrastructure)(http://www.cnki.net/) 1994 to the date when the search is performed. #1Sophorus species #2 Radix Sophorae flavescentis #3 matrine #4 oxymatrine #5 Ku Shen #6Ke Su #7 Gan Yi Ning #8 chronic hepatitis B explode all trees (MeSH) #9 ((#1 or #2 or #3 or #4 or #5 or #6 or #7) and #8)
Wanfang Database (http://www.wanfangdata.com.cn/) 1982 to the date when the search is performed. #1Sophorus species #2 Radix Sophorae flavescentis #3 matrine #4 oxymatrine #5 Ku Shen #6Ke Su #7 Gan Yi Ning #8 chronic hepatitis B explode all trees (MeSH) #9 ((#1 or #2 or #3 or #4 or #5 or #6 or #7) and #8)
VIP (http://www.cqvip.com) 1989 to the date when the search is performed. #1Sophorus species #2 Radix Sophorae flavescentis #3 matrine #4 oxymatrine #5 Ku Shen #6Ke Su #7 Gan Yi Ning #8 chronic hepatitis B explode all trees (MeSH) #9 ((#1 or #2 or #3 or #4 or #5 or #6 or #7) and #8)
TCM Online (http://www.cintcm.com/opencms/opencms/index.html) 1984 to the date when the search is performed. #1Sophorus species #2 Radix Sophorae flavescentis #3 matrine #4 oxymatrine #5 Ku Shen #6Ke Su #7 Gan Yi Ning #8 chronic hepatitis B explode all trees (MeSH) #9 ((#1 or #2 or #3 or #4 or #5 or #6 or #7) and #8)
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What's new

Last assessed as up‐to‐date: 17 November 2010.

Date Event Description
7 August 2018 Amended This protocol is withdrawn because it is outdated. This review title has been split into two new review titles: 'Radix Sophorae flavescentis for chronic hepatitis B' and 'Radix Sophorae flavescentis versus antiviral drugs for chronic hepatitis B'. See Liang et al 2018.
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Contributions of authors

Yufeng Wu drafted the protocol and developed the search strategy. Jianping Liu conceived the idea for the review and revised the protocol, supervised development of the protocol, and provided methodological perspectives.

Sources of support

Internal sources

  • Beijing University of Chinese Medicine, China.

External sources

  • Supported by the National Basic Research Program (973 Program, No. 2006CB504602), China.

  • Supported by the international cooperation project (grant number 2009DFA31460), China.

  • Partially supported by the '111' Project (No. B08006), China.

Declarations of interest

We certify that we have no affiliations with or involvement in any organisation or entity with a direct financial interest in this subject of the review (eg, employment, consultancy, stock ownership, honoraria, expert testimony).

Notes

This protocol is withdrawn because it is outdated. This review title has been split into two new review titles: 'Radix Sophorae flavescentis for chronic hepatitis B' and 'Radix Sophorae flavescentis versus antiviral drugs for chronic hepatitis B'. See Liang et al 2018.

Withdrawn from publication for reasons stated in the review

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