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. 2018 Sep 5;2018(9):CD003182. doi: 10.1002/14651858.CD003182.pub2

Comparison of medicinal herbs for chronic hepatitis B virus infection

Jian Ping Liu 1,✉, Hui Lin 2, Christian Gluud 3
PMCID: PMC6513022

Abstract

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

The primary objective of this review was to assess the efficacy and safety of a medicinal herb (single herb or compound of herbs) compared with another medicinal herb for chronic HBV infection.

Background

Hepatitis B is an infectious disease of the liver caused by hepatitis B virus (HBV). Worldwide more than two billion people alive today have been infected (WHO 2008) and approximately 350 million people are chronically infected carriers of the virus (Purcell 1993; WHO 2008). These carriers are at high risk of getting serious illness and more than one million carriers worldwide die from cirrhosis of the liver and liver cancer each year (WHO 2008).

HBV is transmitted by body fluids, such as blood and serum, and it can be passed from mother to child. The virus belongs to the family hepadnaviridae (Gitlin 1997). The virus has a round structure (42 nm diameter), called the Dane particle, which has an outer coat and an inner core. A protein on the surface, hepatitis B surface antigen (HBsAg) is a standard marker of infection when found in a patient's serum. The inner core is made of nucleocapsid protein (HBcAg) which encloses the virus DNA (HBV DNA). There is another core protein, called hepatitis B 'e' antigen (HBeAg), which is used as a marker of infection and virus replication.

With the availability of a safe and effective vaccine, the incidence of new HBV carriers in children has decreased in high endemic areas, but in areas with low endemicity, high risk group immunization strategy is not leading to a significant reduction of HBV infection on a national or international scale (WHO 2008). Hence, millions of patients are awaiting improvement in treatment of this disease. Currently, interferon (IFN) and lamivudine are the only two drugs licensed worldwide for treatment of chronic HBV infection. Alfa‐IFN is recommended in patients with chronic hepatitis who have HBsAg in serum together with HBeAg, HBV DNA, and raised aminotransferase (two to five times the upper normal limit) (Saracco 1999; Liaw 2000). Lamivudine is also recommended for these patients as well as for chronic hepatitis B patients who are HBsAg and HBV DNA positive, but HBeAg negative (so called precore mutant infections) (Liaw 2000). Further, lamivudine is recommended for chronic hepatitis B with an alanine aminotransferase (ALT) level over five times the upper normal limit (Liaw 2000). However, both alfa‐IFN and lamivudine are associated with a high incidence of recurrence, serious side effects, and substantial costs; hence they are not widely used in developing countries.

Herbal medicine forms part of Traditional Chinese Medicine, which is a 3000 year‐old holistic system of medicine combining medicinal herbs, acupuncture, food therapy, massage, and therapeutic exercise for both treatment and prevention of disease (Fulder 1996). Medicinal herbs have been widely used for more than 2000 years to treat liver disease, including HBV infection (Wang 2000). Based on systematic reviews of randomised clinical trials (RCTs) on medicinal herbs for asymptomatic HBV carriers (Liu 2001a) and chronic hepatitis B (Liu 2001b), medicinal herbs seem to be superior to placebo or no intervention or non‐specific interventions with regard to clearance of HBsAg, HBeAg, and HBV DNA. Further, medicinal herbs plus IFN had significantly better efficacy on clearance of HBsAg, HBeAg and HBV DNA than IFN alone (Liu 2001b). However, the majority of the trials in these systematic reviews had low methodological quality, which may be associated with biased estimates (Schulz 1995; Moher 1998; Kjaergard 2001; Wood 2008). Second, the trials had a number of other methodological problems (Liu 2001b). Third, the trials showed significant funnel plot asymmetry (Liu 2001b). Finally, most of the medicinal herbs were only tested once or a couple of times in individual RCTs. Accordingly, we do not yet have firm evidence enabling us to recommend one or more types of herbs for HBV infection. On the other hand, most of the RCTs in the two reviews (Liu 2001a; Liu 2001b) were small and could have overlooked important effects. As recommended (Liu 2001a; Liu 2001b), we need more well designed RCTs of high methodological quality comparing different medicinal herbs versus placebo for HBV infection.

During our search for RCTs, we noticed a large number of RCTs comparing one medicinal herb versus another medicinal herb. As we do not have compelling evidence that any of these herbs are effective for HBV when tested against placebo or no intervention, such comparisons may be highly misleading. On the other hand, a systematic review of these RCTs could cast further light on which type of herbs that may seem to work such a systematic review could supplement ongoing ethnobotanical and laboratory efforts to identify plants possessing antiviral activity (Blumberg 1998). In order to identify potential promising medicinal herbs, we therefore performed a systematic review of RCTs comparing one medicinal herb versus another medicinal herb for chronic HBV infection.

Objectives

The primary objective of this review was to assess the efficacy and safety of a medicinal herb (single herb or compound of herbs) compared with another medicinal herb for chronic HBV infection.

Methods

Criteria for considering studies for this review

Types of studies

Only RCTs will be included irrespective of blinding, publication status, language and period of patient inclusion.

Types of participants

Male or female patients, of any age or ethnic origin, who had chronic HBV infection (including asymptomatic carriers of HBV and chronic hepatitis B). Asymptomatic HBV carriers (formerly known as 'healthy' chronic HBsAg carriers) are patients with serum HBsAg positivity for more than six months, normal ALT level, and no symptoms of liver disease. Chronic hepatitis B is defined as serum HBsAg and/or HBeAg positivity for more than six months, with elevated ALT and/or aspartate aminotransferase (AST) levels, and with or without a liver biopsy finding compatible with chronic hepatitis (Dusheiko 1999).

Types of interventions

Medicinal herb (a single herb or a compound of herbs) is compared with another medicinal herb (a single herb or a compound of herbs). Co‐interventions are allowed as long as both arms of the RCT receives the same co‐intervention(s). Trials that compare the same herb or compound of herbs in different dosage or route of administration are also included.

Types of outcome measures

The following outcome measures will be sought at the end of treatment as well as at maximal follow‐up:

1. Mortality (primary outcome measure).

2. Incidence of hepatic fibrosis, cirrhosis or liver cancer.

3. Viral response. ‐ Loss of serum HBsAg. ‐ Loss of serum HBeAg. ‐ Loss of serum HBV DNA. ‐ Seroconversion of HBeAg to anti‐HBe (antibody against HBeAg). ‐ Loss of serum anti‐HBc IgM. Anti‐HBc IgM is a typical serological marker in acute hepatitis B. But with the onset of serum aminotransferase abnormalities in chronic hepatitis B, anti‐HBc (both IgG and IgM) arises and the existence of anti‐HBc IgM may demonstrate an active HBV replication and/or the 'flare‐up' of the disease. The determination of anti‐HBc IgM can be used for monitoring of antiviral treatment (Trepo 1993; Dusheiko 1999).

Viral response should be measured by validated methods. Serum HBsAg, HBeAg, anti‐HBe, anti‐HBc were measured by either enzyme immunoassay or radial immunoassay and serum HBV DNA by molecular hybridisation or polymerase chain reaction assay.

4. Biochemical response. Normalisation of ALT and/or AST (less than 40 IU/L) or a decrease of ALT and/or AST levels. In case other liver biochemical variables like serum bilirubin, gamma‐glutamyltranspeptidase, alkaline phosphatase, albumin and globulin were measured, these outcomes will also be analysed.

5. Liver histology. The inflammatory severity and degree of liver fibrosis will be analysed.

6. Quality of life.

7. Adverse events. Two types of adverse events will be analysed, serious adverse events and adverse events not considered serious. The serious adverse events are any untoward medical occurrence that resulted in death, was life‐threatening, required hospitalisation or prolongation of hospitalisations, resulted in persistent or significant disability, was a congenital anomaly/birth defect or was an event that may jeopardise the patient or required intervention to prevent one of the former serious adverse events (ICH‐GCP 1997). All other adverse events are considered non‐serious.

Search methods for identification of studies

Electronic searches The Cochrane Hepato‐Biliary Group Controlled Trials Register, The Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library, and the register of The Cochrane Complementary Medicine Field will be searched. MEDLINE, EMBASE and BIOSIS will be searched from their date of inception onwards. The MeSH terms will include hepatitis‐B, carrier‐state, medicine‐traditional, herbal‐medicine, plants‐medicinal, drugs‐herbal, plants extracts, herbs‐medicinal, drugs‐non‐prescription, medicine‐alternative, medicine‐complementary, and herbs.

Handsearches Chinese Journal of Infectious Diseases, Chinese Journal of Hepatology, Chinese Journal of Clinical Hepatology, Chinese Journal of Integrated Traditional and Western Medicine, and Journal of Integrated Traditional and Western Medicine on Liver Diseases will be handsearched from the first publication date onwards by the contact reviewer. Conference proceedings in Chinese will also be handsearched. Results of handsearching will be submitted to The Cochrane Hepato‐Biliary Group.

The bibliographic references of identified RCTs and review articles will be checked in order to find RCTs not identified by the electronic searches and handsearches. The principal authors of the identified RCTs will be approached and inquired about additional RCTs they might know.

Data collection and analysis

Selection of trials for inclusion Two reviewers will independently select the trials to be included in the review according to the prespecified selection criteria. Disagreement is resolved by discussion.

Assessment of methodological quality Concealment of the allocation sequence is scored A (adequate), B (unclear) or C (inadequate), following criteria adopted from the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2008), The Cochrane Hepato‐Biliary Group Module (Gluud 2008), and Schulz et al. (Schulz 1995) as follows: A ‐ Adequate measures to conceal allocations such as central randomisation; serially numbered, opaque, sealed envelopes; or other description that contained convincing elements of concealment. B ‐ Unclearly concealed trials, in which the authors either did not report an allocation concealment approach at all, or reported an approach that did not fall into one of the categories in (A). C ‐ Inadequately concealed trials, in which method of allocation was not concealed, such as alteration methods or use of case record numbers. The later trials were excluded.

The blinding method is described and assessed as adequate or inadequate.

Further, the RCTs will be assessed by the Jadad scale (Jadad 1996): The scale awards one to five points to a RCT. RCTs with one or two points were considered as low quality and RCTs with three to five points as high quality (Moher 1998; Kjaergard 2001).

Data extraction The following characteristics and data of all included RCTs will be extracted independently by two reviewers using a self‐developed data extraction form. Disagreement will be resolved by discussion. Papers not in Chinese, Danish, English, French, German or Spanish will be translated with the help of The Cochrane Hepato‐Biliary Group. Data on the number of patients with each outcome event, by allocated treatment group, irrespective of compliance or follow‐up, will be sought to allow an intention‐to‐treat analysis. If the above data are not available in the trial reports, further information will be sought by correspondence with the principal investigator.

‐ Methods: randomisation procedure, concealment of allocation, blinding procedure, withdrawal and reasons, protection against contamination, power calculation, sample representativeness, length of follow‐up, Jadad quality score. ‐ Participants: age, gender, ethnic origin, diagnostic procedures, liver biopsy, HBV virological status, number of patients randomised. ‐ Interventions: preparations of medicinal herbs, dosage and duration of therapy, route of administration, and any co‐interventions. ‐ Outcomes: mortality, incidence of hepatic fibrosis, cirrhosis or liver cancer, viral response, liver biochemical response, liver histological activity, quality of life, and adverse events.

Data synthesis The statistical package RevMan 2008 provided by The Cochrane Collaboration will be used.

Dichotomous data will be presented as relative risk (RR) and continuous outcomes as weighted mean difference (WMD), both with 95% confidence intervals (CI). Analyses were performed on intention‐to‐treat basis where possible. Data were combined only when trials compared the same intervention(s) of medicinal herbs. For dichotomous outcomes, patients with incomplete or missing data were included in sensitivity analyses by counting them as treatment failures ('worst‐case' scenario analysis) to explore the possible effect of loss to follow‐up on the findings.

The following subgroup analyses will be performed within comparison of the same interventions: ‐ asymptomatic HBV carriers or chronic hepatitis B; ‐ chronic hepatitis B with versus without liver biopsy confirmation; ‐ ethnic origin; ‐ age at time of infection. Age is a major factor in determining the outcome of HBV infection as children and adults exhibit different patterns of disease outcome. Young children rarely develop symptomatic HBV infection, but about 25% infected under the age of seven become HBsAg carriers. After the age of seven, children exhibit an adult pattern of disease outcome with about 5 to 10% becoming HBsAg carriers (WHO 1999); ‐ duration of follow‐up. The spontaneous evolution of chronic hepatitis B disease is difficult to predict and a definitive assessment of the effects of treatment requires long‐term follow‐up (Liaw 1997). Accordingly we analysed RCTs with less than three months of follow‐up versus RCTs with a follow‐up of three months or more after the end of treatment.

Sensitivity analyses If a sufficient number of trials is found, sensitivity analyses will be performed as follows: ‐ excluding trials with inadequate or unclear concealment of allocation (Schulz 1995); ‐ excluding non‐blinded trials; ‐ excluding trials of lower quality score as assessed by Jadad's scale (score one and two).

Potential biases (Vickers 1998) will be investigated with funnel plot analyses according to Egger et al. (Egger 1997).

What's new

Date Event Description
5 September 2018 Amended The protocol is withdrawn as new, more focused reviews are under preparation.
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Contributions of authors

Jianping Liu drafted and revised the protocol, developed the search strategy and performed handsearches and data extraction. Hui Lin performed handsearches, retrieved papers and extracted data. Christian Gluud conceived the idea for the review and revised the protocol.

Sources of support

Internal sources

  • The Copenhagen Trial Unit, Denmark.

External sources

  • The 1991 Pharmacy Foundation, Denmark.

  • The Danish Medical Research Council Grant on Getting Research into Practice (GRIP), Denmark.

  • The Copenhagen Hospital Coporation's Research Council Grant on Getting Research into Practice (GRIP), Denmark.

  • The Danish Council for Development Research, Denmark.

Declarations of interest

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

Notes

The protocol is abandoned by the authors as the identified studies are of poor quality and of unmanageable number. Thus, new reviews, with specific medicinal herbs for chronic hepatitis B virus infection, are in progress.

Withdrawn from publication for reasons stated in the review

References

Additional references

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