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Phyllanthus species versus antiviral drugs for chronic hepatitis B virus infection

  1. Yun Xia1,2,
  2. Hui Luo1,
  3. Jian Ping Liu1,2,*,
  4. Christian Gluud2

Editorial Group: Cochrane Hepato-Biliary Group

Published Online: 30 APR 2013

Assessed as up-to-date: 5 DEC 2012

DOI: 10.1002/14651858.CD009004.pub2


How to Cite

Xia Y, Luo H, Liu JP, Gluud C. Phyllanthus species versus antiviral drugs for chronic hepatitis B virus infection. Cochrane Database of Systematic Reviews 2013, Issue 4. Art. No.: CD009004. DOI: 10.1002/14651858.CD009004.pub2.

Author Information

  1. 1

    Beijing University of Chinese Medicine, Centre for Evidence-Based Chinese Medicine, Beijing, China

  2. 2

    Copenhagen Trial Unit, Centre for Clinical Intervention Research, Department 7812, Rigshospitalet, Copenhagen University Hospital, The Cochrane Hepato-Biliary Group, Copenhagen, Denmark

*Jian Ping Liu, jianping_l@hotmail.com. jianping@fagmed.uit.no.

Publication History

  1. Publication Status: New
  2. Published Online: 30 APR 2013

SEARCH

 

Background

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. Contributions of authors
  12. Declarations of interest
  13. Sources of support
  14. Differences between protocol and review
  15. Index terms
 

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 more than 350 million people are chronically infected (WHO 2010). This constitutes a significant health and economic burden. In China, the HBV infection is highly endemic. It is estimated in China that there are 120 million chronically infected carriers; up to 12 million people suffer from chronic hepatitis B, and about 300,000 people die each year (Sun 2010). A study has shown that the total economic loss resulting from chronic hepatitis B-associated disease was probably in the range of US$ 8.5 to 15.6 billion in year 2001 (Shi 2004; Hu 2009).

There is a hepatitis B vaccine available, and the vaccine is found to be 95% effective in preventing HBV infection (Chen 2005; Lee 2006; Mathew 2008; WHO 2008). Most countries have included the 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 adults with chronic HBV infection. Hence, millions of patients are awaiting improvement in the treatment of this disease.

 

Description of the intervention

Currently approved therapies for chronic hepatitis B include immunomodulatory agents (interferon alpha and pegylated interferon alpha) and nucleoside analogues (lamivudine, telbivudine, entecavir, adefovir, and tenofovir) (EASL 2009). Interferon alpha treatment results in viral, biochemical, and histological remission in about 30% of the patients (EASL 2009). However, interferon alpha (conventional or pegylated) has the disadvantages of high cost and serious adverse events, 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 the additional benefit that viral drug resistance is uncommon (Marcellin 2003). Telbivudine is another potent inhibitor of HBV (EASL 2009). However, despite these advances, the use of these drugs may still be limited by cost, and by being effective in a limited number of patients only. In China, a large number of patients who cannot afford this 'standard therapy' seek help from traditional Chinese medicine.

Phyllanthus is the largest genus in Phyllanthaceae (Kathriarachchi 2005). The plants are widely distributed in most tropical and subtropical countries, and it is estimated that there are over 1200 species in the world (Kathriarachchi 2005). The plants of phyllanthus species are considered bitter, astringent, stomachic, diuretic, febrifuge, deobstruent, and antiseptic and have long been used in traditional Chinese medicine to treat chronic liver diseases (Calixto 1998). Studies carried out on extracts and main constituents that are isolated from different species of phyllanthus, seems to support most of the reported usages in folk medicine defining them as effective antiviral agents and hepatoprotective agents (Bagalkotkar 2006; Khatoon 2006; Lam 2006). In China, phyllanthus was added to the Pharmacopoeia of People's Republic of China in 1992, and subsequent clinical studies seem to have proven the therapeutic effects of phyllanthus for chronic hepatitis B virus infection (Chang 1995).

 

How the intervention might work

Substantial progress on the chemical and pharmacological properties of phyllanthus species has been made (Calixto 1998). Phytochemical studies carried out on these plants isolate have characterised a number of classes of compounds, including alkaloids, flavonoids, lignans, phenols, tannins, coumarins, and terpenes (Venateswaran 1987). These compounds seem to be mainly responsible for the pharmacological actions reported in relation to these plants. Most of these compounds were found to interact with most key enzymes, such as aldose reductase, angiotensin converting enzyme, mitochondrial ATPase, both cyclooxygenase and lipoxygenase, phospholipase A2, tyrosine kinase, reverse transcriptase, and phosphodiesterases (Chang 1995; Blumberg 1998). Many studies suggest that most plants of the phyllanthus species have a beneficial effect against HBV in vitro and in vivo (Liu 1997), possibly through inhibition of polymerase activity, mRNA transcription, and replication (Venateswaran 1987; Chang 1995; Lee 1996; Ott 1997).

 

Why it is important to do this review

A systematic review about genus phyllanthus for chronic hepatitis B virus infection showed potential effect on the clearance of serum HBsAg, HBeAg, HBV DNA, and on liver enzymes normalisation, as well as a better effect of the phyllanthus plus interferon alpha combination than interferon alpha alone on clearance of serum HBeAg and HBV DNA (Liu 2001). However, due to the limitations of the clinical trials included in that review (small number of patients and high risk of bias the included trials), there is currently still no strong evidence available on phyllanthus species for chronic hepatitis B. We recently reviewed systematically the randomised trials comparing phyllanthus species versus placebo or no intervention for patients with chronic hepatitis B and we did not find any high quality evidence to support phyllanthus species (Xia 2011). During the past several years, more clinical trials have been carried out comparing phyllanthus versus antiviral drugs for chronic hepatitis B. We have been unable to identify any meta-analyses or systematic reviews assessing phyllanthus versus antiviral drugs in chronic hepatitis B. Current uncertainties about the clinical effectiveness of phyllanthus species require a Cochrane systematic review to clarify the potential benefits and harms in the treatment of chronic hepatitis B.

 

Objectives

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. Contributions of authors
  12. Declarations of interest
  13. Sources of support
  14. Differences between protocol and review
  15. Index terms

To evaluate the benefits and harms of phyllanthus species compared with antiviral drugs for patients with chronic HBV infection.

 

Methods

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. Contributions of authors
  12. Declarations of interest
  13. Sources of support
  14. Differences between protocol and review
  15. Index terms
 

Criteria for considering studies for this review

 

Types of studies

We included randomised clinical trials irrespective of publication status, language, or blinding. We excluded studies using alternation, date of birth, hospital record number, or other 'quasi-random' methods of allocation of treatment, except for the assessment of harms.

 

Types of participants

We included participants with chronic HBV infection. Patients with chronic HBV infection were divided into HBeAg positive and HBeAg negative according to HBeAg blood test. We used the definition of chronic HBV infection of the individual trials. If in doubt which type of chronic hepatitis B infection (HBeAg positive or negative) the patient had, we used the following definitions, based on Lok 2009:

  • HBeAg-positive chronic hepatitis B infection defined as HBsAg and HBeAg positivity for more than six months, serum HBV DNA usually positivity more than 20,000 IU/ml, ie, 105copies/ml, persistent or intermittent elevation in levels of aspartate aminotransferase or alanine aminotransferase, and liver biopsy findings showing moderate or severe necroinflammation compatible with with chronic hepatitis B.

  • HBeAg-negative chronic hepatitis B infection defined as HBsAg positivity for more than six months without HBeAg positivity, serum HBV DNA positivity usually between 2000 to 20,000 IU/ml, ie, 104 to 105 copies/ml, and persistent or intermittent elevation in activity of aspartate aminotransferase or alanine aminotransferase, and liver biopsy findings showing moderate or severe necroinflammation compatible with chronic hepatitis B.

We included trials with both children and adult participants. For the purpose of this review we defined a child as aged 15 years or less and an adult as aged 16 years or older. We planned to include patients irrespective of whether they were treatment-naive or had previously been treated unsuccessfully for chronic HBV infection with another drug. We planned to include patients with evidence of concomitant HIV infection, hepatitis C, hepatitis D, hepatocellular carcinoma, or other liver related co-morbidities, but we analysed the patients with and without these conditions also separately. We also planned to include patients with prior liver transplantation or with concomitant renal failure but again analysed these patients groups separately.

 

Types of interventions

We considered trials eligible for inclusion if they assessed any single medicinal herb belonging to the plant species phyllanthus or any other compound from the plant species phyllanthus versus antiviral drugs, including interferon, nucleoside analogues, or immunomodulating agents. The plant species phyllanthus should have been the only active constituent in the experimental compound, but other ingredients assumed to have no antiviral effects may be added to the phyllanthus species (so-called compound phyllanthus).

We did not consider trials for inclusion if they used decoctions prepared with phyllanthus.

 

Types of outcome measures

The following outcome measures were 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 serum HBsAg.
  2. Number of participants with detectable serum HBV DNA.
  3. Number of participants with detectable serum 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 identified trials by electronic searches of The Cochrane Hepato-Biliary Group Controlled Trials Register (Gluud 2011), The Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library, MEDLINE, EMBASE, Science Citation Index Expended (Royle 2003), and the Chinese Biomedical CD Database (CBM), China Network Knowledge Information (CNKI), Chinese Science Journal Database (VIP), TCM Online, and Wanfang Database. All the databases above were searched from their date of inception onwards until October 31, 2012 and irrespective of language or publication status.

The preliminary search strategies with the expected time span of the searches have been given in Appendix 1.

 

Searching other resources

Conference proceedings in Chinese were handsearched. We screened the reference lists of all retrieved randomised trials and review articles for 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 2011).

 

Selection of studies

Two authors (YX and HL) independently screened the titles and abstracts of studies identified by the literature search for eligibility according to the prespecified selection criteria. Disagreements were resolved by discussion with JL. The authors (YX and HL) were not blinded to the authors' names and institutions, journal of publication, or trial results.

 

Data extraction and management

Two authors (YX and HL) extracted data independently using a self-developed data extraction form. Disagreements were resolved by discussion with JL. The following characteristics and data were extracted from each included trial.

  • Methods: trial design, the information needed to assess the risk of bias domains (listed below), sample size calculations, and length of follow-up.
  • Participants: age, sex, ethnic origin, previous antiviral treatment, duration of hepatitis B, diagnostic criteria, inclusion and exclusion criteria, number of patients randomised, assessment of compliance, and withdrawals/losses to follow-up (reasons/description).
  • Interventions: species and origin of phyllanthus, dosage and duration of therapy, formulation, route of administration, and intervention in the control group.
  • Outcomes: as listed above under outcome measures.

 

Assessment of risk of bias in included studies

Two authors (YX and HL) independently assessed the risk of bias for each included randomised trial. Disagreements were resolved by discussion with JL. We assessed the following domains (Schulz 1995; Moher 1998; Jüni 2001; Kjaergaard 2001; Wood 2008; Lundh 2012; Savovic 2012a; Savovic 2012b):

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' judgements were based on the definitions of the above listed domains, and trials with adequate assessments in all of the above mentioned bias risks domains were considered as having low risk of bias. Otherwise, a trial was considered with high risk of bias.

 

Measures of treatment effect

For dichotomous data, such as mortality, we presented results as summary risk ratio (RR) with 95% confidence interval (CI).

 

Unit of analysis issues

Intervention groups of patients in randomised clinical trials. All trials included were with the parallel design.

 

Dealing with missing data

We planned to seek missing data by contacting the trials’ authors. In case the data was still lacking, we put the trial to high risk of bias (missing outcomes) and conducted intention-to-treat analysis as well as sensitivity analysis (missing individuals).

 

Assessment of heterogeneity

We planned to use the chi-square statistic to assess heterogeneity and I-square statistic to measure inconsistency (Higgins 2009).

 

Assessment of reporting biases

We planned to use the funnel plot to investigate reporting biases if there were more than ten included trials.

 

Data synthesis

Meta-analyses
For all analyses, we used the fixed-effect model (DeMets 1987) as well as the random-effects model meta-analyses (DerSimonian 1986). In case there was no difference in statistical significance, we presented the results of the random-effects analyses. Otherwise, we presented the results of both analyses. The analyses were carried out using the latest Cochrane Review Manager software (RevMan 2011).

Meta-analysis is a summary intervention effect estimation based on a weighted average calculation of the intervention effects estimated in the individual trials. One cannot conduct a meta-analysis if only one trial is identified. If only one trial assessed an outcome, we still presented the data in a forest plot in order to give a more complete overview, to prepare our review for future updates, and to obtain relative risks with confidence intervals. We are well aware that the relative risks and confidence intervals may not be fully correct.

Trial sequential analysis (TSA)
We planned to perform trial sequential analysis (TSA) for all of the outcomes. Trial sequential analysis aims to reduce the risk of random error in the setting of sparse data and repetitive testing of accumulating data, thereby improving the reliability of conclusions (Brok 2008; Wetterslev 2008; Wetterslev 2009; CTU 2011; Thorlund 2011).

We planned to calculate the information size, providing an estimate of how many patients would be required in order to make a reliable conclusion. In our trial sequential analyses, the required information size was based on the proportion of patients with the outcome in the control group assumption of a plausible RR reduction of 10% or on the RR reduction observed in the included trials with low risk of bias, a type I error of 5%, and a type II error of 20% (Wetterslev 2008). We planned to use control event rates from our own results to do these calculations. We adjusted the information size for diversity (Wetterslev 2009).

 

Subgroup analysis and investigation of heterogeneity

We had planned to conduct subgroup analyses to explore differences in trials with low risk of bias compared to trials with high risk of bias, among different species of phyllanthus, antiviral drugs, populations with different co-infections, and diseases.

 

Results

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. Contributions of authors
  12. Declarations of interest
  13. Sources of support
  14. Differences between protocol and review
  15. Index terms
 

Description of studies

See: Characteristics of included studies; Characteristics of excluded studies.

We identified a total of 212 publications through electronic searches and hand-searching. We excluded 174 duplicates among databases, clearly irrelevant publications or non-clinical studies. Thirty eight publications were retrieved for further assessment. Of these, we excluded 33 which are listed under 'Characteristics of excluded studies' with reasons for exclusion. Accordingly, five trials fulfilled our inclusion criteria and were included. For a summary of the search see Figure 1.

 FigureFigure 1. Flow diagram of the search.

The five randomised clinical trials were parallel group trials published as full articles. Three of the five included trials had three arms which were phyllanthus, antiviral drugs, and a combination of phyllanthus and antiviral drugs (Huang 2004; Ouyang 1999; Zhu 2005). The data from the two arms comparing phyllanthus alone versus antiviral drug alone were included in this review.

Two hundred and ninety patients randomly allocated to phyllanthus versus antiviral drugs were included into analyses of our review.

One trial included both in-patients and out-patients (Zhu 2005). One trial included out-patients (Huang 2004). The other three trials did not specify the origin of the patients (Ge 2005; Li 1998; Ouyang 1999). One trial included both children and adults (age ranging from 9 to 65 years) (Ouyang 1999). The remaining four trials included only adults (age ranging from 15 to 59 years). All trials reported the male/female ratio. There were 72% males and 28% females.

All trials reported that viral hepatitis diagnosed according to the National Conference on Infectious Disease or Viral Hepatitits in China. In the trial Ouyang 1999, 37 patients out of 47 were HBeAg negative. In the trial Li 1998, 29 patients out of 55 were HBeAg negative. In the remaining trials all patients included were HBeAg positive. None of the trials reported any informations of patients with co-infections or diseases.

Patients in the experimental group of the five trials received compound phyllanthus. The antiviral drugs used in the control group were lamivudine, interferon alpha, thymosin, or thymosin alpha1. All the dosage and duration of the antiviral drugs were in accordance with standards of international guidelines. The treatment duration varied from three months to 12 months. Detailed information of the five randomised trials and the source and administration of phyllanthus species and antiviral drugs were summarised in  Table 1,  Table 2, and  Table 3.

The outcome measures reported in the five trials were virological markers and/or biochemical variables. None of the trials reported mortality, hepatitis B-related morbidity, liver histology progress, or quality of life.

Further details are listed in the table of 'Characteristics of included studies'.

 

Risk of bias in included studies

The risk of bias of included trials is summarised in Figure 2 and Figure 3. Following the risk of bias components, all trials included were classified as trials with high risk of bias.

 FigureFigure 2. Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
 FigureFigure 3. Risk of bias summary: review authors' judgements about each risk of bias item for each included study.

 

Allocation

Allocation sequence generation 

Generation of the allocation sequence was adequately reported in two trials (Huang 2004; Zhu 2005 ). In both trials, patients were randomised by Casio random number.

Allocation concealment

Allocation concealment was not described in any of the trials.

 

Blinding

None of the trials actually stated that the patients were blinded to the intervention. As the different administration described between the intervention groups of the included trials, we considered that no blinding was performed in the five trials.

 

Incomplete outcome data

None of the five included trials reported if there were withdrawals or dropouts. The number of patients analysed were the same as the number of patients randomised. It seems unlikely that no patients drop out during the treatment (from three months to 12 months). However, we could not get confirmation on that as we were unable to contact the authors.

 

Selective reporting

In the five trials, none of the randomised patients were analysed for the primary outcomes chosen for this systematic review. As no contact information was given in the trials, we tried, but were not able to contact any of the authors of the included trials. Therefore, It is unclear whether the trial reported all the outcomes which had been measured.

 

Other potential sources of bias

None of the trials reported a sample size calculation. We also planned to assess publication bias using a funnel plot. We did not make this assessment due to the limited number of trials that were included.

 

Effects of interventions

Mortality and morbidity

None of the trials reported on mortality or morbidity.

Adverse events

Only one trial reported that adverse events were observed Ge 2005. Data of adverse events were not reported. The type of adverse events reported in the trial was mild gastrointestinal symptoms. Joint pain, leukopenia and/or thrombocytopenia, depression, and poor sleep were reported in the lamivudine group. The trial reported that none of the patients who experienced these adverse events required dose modification, interruption or prolonged hospitalisation.

Quality of life

None of the trials reported on quality of life.

Number of patients with detectable serum HBsAg

Four trials provided data for serum HBsAg after treatment (Huang 2004; Li 1998; Ouyang 1999; Zhu 2005). The meta-analysis showed no statistically significant difference between phyllanthus and antiviral drugs (RR 1.00; 95% CI 0.93 to 1.08, P = 0.92; I2 = 0%). The antiviral drugs used in the five trials were lamivudine, interferon alpha, thymosin, or thymosin alpha 1.

According to the subgroup analyses, there was no statistically significant difference of phyllanthus on clearance of serum HBsAg when compared with lamivudine (RR 1.04; 95% CI 0.89 to 1.21), interferon alpha (RR 1.01; 95% CI 0.87 to 1.18), or thymosin (RR 0.99; 95% CI 0.89 to 1.09, P = 0.79; I2 = 0%).

Number of patients with detectable serum HBV DNA

Four trials reported data for serum HBV DNA after the end of treatment (Ge 2005; Huang 2004; Li 1998; Zhu 2005). Combining results of these five trials showed that there was no statistically significant difference between phyllanthus and antiviral drugs (RR 0.83; 95% CI 0.53 to 1.31, P = 0.43; I2 = 70%).

One trial also reported data after six months' post-treatment follow-up (Ge 2005). There was no significant difference between phyllanthus and lamivudine on clearance of serum HBV DNA (RR 0.53; 95% CI 0.25 to 1.14).

According to the subgroup analyses, phyllanthus showed no significant difference of effect on clearance of serum HBV DNA when tested against lamivudine (RR 0.87; 95% CI 0.21 to 3.57, P = 0.85; I2 = 93%), interferon alpha (RR 1.17; 95% CI 0.61 to 2.24), or thymosin (RR 0.86; 95% CI 0.59 to 1.25).

Number of patients with detectable serum HBeAg

All of the five trials reported this outcome. Combining results of these trials showed that phyllanthus had a superior effect on clearance of serum HBeAg at the end of treatment between phyllanthus and antiviral drugs in traditional meta-analysis (RR 0.76; 95% CI 0.64 to 0.91, P = 0.002; I2 = 0%).

However, trial sequential analysis on data for detectable serum HBeAg after treatment does not support a 10% relative risk reduction (RRR) in the phyllanthus group compared with antiviral drug group (Figure 4). The required information size of 1574 was calculated based on a control event proportion of 75.8%, a relative risk reduction of 10%; a risk of type I error of 5%, a power of 80%, and a diversity of 30%. Although the cumulated Z-curve (blue curve) crossed the traditional boundary of 5% significance (horizontal red line), it did not cross the trial sequential monitoring boundary (red curve), implying that firm evidence was not reached.

 FigureFigure 4. Figure 4: Trial sequential analysis with a type 1 error of 5% on phyllanthus species versus antiviral drugs for patients with chronic hepatitis B on clearance of serum HBeAg. Trial sequential analysis of five trials (marked with black squares), illustrating that the cumulative Z-curve (blue curve) did not cross the monitoring boundaries (red inward sloping curves), which is needed to obtain firm evidence controlling for the risk of random error. The required information size (RIS) is calculated to be 1574 patients (vertical line) based on a relative risk reduction (RRR) of 10%, event proportion of 75.8% in the control group (PC), type I error (α) of 5%, type II error (β) of 20%, and diversity (D) of 30%.

No statistically significant difference was seen after 6 months' post treatment follow-up which was reported in the trial Ge 2005 (RR 0.70; 95% CI 0.26 to 1.88).

According to the subgroup analyses, phyllanthus showed a better effect on clearance of serum HBeAg when tested against lamivudine (RR 0.68; 95% CI 0.53 to 0.87, P = 0.002; I2 = 0%). Phyllanthus showed no significant difference when compared with interferon alpha (RR 1.05; 95% CI 0.63 to 1.76), or thymosin (RR 0.78; 95% CI 0.59 to 1.03, P = 0.08; I2 = 0%).

Number of participants without HBeAg seroconversion

Only one trial reported data for HBeAg seroconversion Ge 2005. Phyllanthus showed no significant difference of effect on HBeAg seroconversion when tested against lamivudine at the end of treatment (RR 0.89; 95% CI 0.71 to 1.11).

Number of participants with worsened liver histology

None of the trials reported data on this outcome measure.

Subgroup analyses

All of our meta-analyses were based on five trials and all of the trials were with high risk of bias. Based on the information given in the trials, we were only able to perform subgroup analyses according to different antiviral drugs used in the control groups.

 

Discussion

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. Contributions of authors
  12. Declarations of interest
  13. Sources of support
  14. Differences between protocol and review
  15. Index terms
 

Summary of main results

There was no convincing evidence that phyllanthus was superior compared with antiviral drugs regarding virological outcomes. It would take much more patients to prove equivalence or non-inferiority. Based on the present findings as well as the findings in our previous review assessing phyllanthus versus placebo or no intervention, we conclude that there is currently no evidence to support or refute the use of phyllanthus species for patients with chronic hepatitis B.

For the primary outcomes chosen in our review, no data were identified from the five trials. With regard to potential adverse events, there was only one trial reporting on this outcome. Only the type of adverse events were reported in that trial and no patients required dose modification, interruption or prolonged hospitalisation. However, insufficient evidence for adverse events of phyllanthus from randomised trials cannot lead to the conclusion that phyllanthus does not cause harm.

For the secondary outcomes, there was only one outcome for which traditional meta-analysis revealed a statistically significant benefit in the phyllanthus group. The clearance of serum HBeAg for which the results from five trials showed a RR (risk ratio) of 0.76 (95% CI 0.64 to 0.91). However, the trial sequential analysis does not support the finding from the traditional meta-analysis, implying that firm evidence was not reached. In addition, there are four things we should keep in mind. First, this potential benefit is on an outcome which is only a putative surrogate outcome (Gluud 2007). Second, our systematic review has a major limitation which is a small number of trials included. This increases the risks of random errors. In accordance, trial sequential analysis suggested that the observed intervention effect could be due to random error. Fourth, all of the five trials were considered to have high risk of bias. This increases the risk of systematic errors.

For the other five secondary outcomes, meta-analyses showed no statistically significant differences between phyllanthus and antiviral drug groups. However, the fact that we did not find significant differences between phyllanthus compared with antiviral drugs cannot be taken as evidence that phyllanthus does work. First, we have been unable to find high quality evidence from randomised clinical trials supporting phyllanthus versus placebo or no intervention (Xia 2011). Second, the fact that we observed no difference between phyllanthus versus antiviral drugs does not suggest activity of the former. The trials are too small to exclude a difference. Moreover, the trials of the present review had high risk of bias.

With regard to the treatments used in the control groups, the adequacy of the treatments need to be evaluated. The evidence of the use of lamivudine and interferon alpha has been elaborated in the section of ‘Description of the intervention’ in the background. For the use of thymosin, a controlled, blinded study suggested that thymosin might be effective on clearance of the HBV virus for patients with chronic active hepatitis B virus infection (Mutchnick 1988). Thymosin alpha 1, a biologically active peptide isolated from thymosin fraction 5 (TF5) which is a partially purified extract of bovine thymus, is one of the first-line drugs recommended by APASL (Asian Pacific Association for the Study of Liver) for treating chronic hepatitis B (Liaw 2003; Liaw 2005; Liaw 2008). Now thymosin alpha 1 has been approved in 35 countries for the treatment of chronic hepatitis B (Garaci 2007; Goldstein 2009). However, this approval has not been given to other thymosin products (Lin 2009). In China, thymosin products have been used in clinical practice as antiviral agents for more than 20 years (Lin 2009) and the Guideline of Prevention and Treatment of Chronic Hepatitis B published in 2005 in China explicitly approved the usage of thymosin alpha 1 (Chinese guideline on chronic hepatitis B 2005). One protocol of Cochrane systematic review was identified to evaluate the beneficial and harmful effects of thymosin alpha 1 (Saconato 2009), however, the full review has not been finished yet. Therefore, convincing evidence of thymosin alpha 1 or other thymosin products is still needed.

There might be biases in the process of our review. Although we made extensive searches, only five trials were identified. We may still have missed potentially eligible trials which were published in a particular language or indexed in databases which are not accessible. This precludes exploration of reporting bias. All the five trials were conducted in China and all the patients included were Chinese. Accordingly, the findings from our review may not apply to other populations. In addition, our review researchers were not blinded to the authors of the included trials.

A systematic review of genus phyllanthus for chronic hepatitis B virus infection was published in 2001 (Liu 2001), in which phyllanthus was compared with placebo, no intervention, general nonspecific treatment, other herbal medicine, or interferon treatment for patients with chronic hepatitis B and chronic hepatitis B carriers. In that review, no robust conclusion could be drawn for the use of genus phyllanthus due to the low methodological quality of included trials and the variations of the herb. In our present review, trials testing phyllanthus in chronic hepatitis B carriers were not included, and phyllanthus were compared only with antiviral drugs. But our results as well as recommendations are basically in accordance with the former systematic review.

 

Authors' conclusions

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. Contributions of authors
  12. Declarations of interest
  13. Sources of support
  14. Differences between protocol and review
  15. Index terms

 

Implications for practice

There is insufficient evidence from randomised trials to support or refute the use of phyllanthus for patients with chronic hepatitis B virus infection. There is no conclusive evidence of benefit due to the limited number of trials conducted, the small number of patients and outcomes, the design and the risk of bias of included trials, and the insufficient power to provide robust conclusions.

 
Implications for research

The reviewed results of the five clinical trials do not show firm evidence for a beneficial effect of phyllanthus. However, due to the small number of trials and few patients included, further trials may be considered. If such trials are performed, then both beneficial and harmful effects ought to be monitored and reported. It will also be necessary to report the species and preparations of phyllanthus. Any further trials should contain enough patients in accordance with the sample size estimation, primary outcome measures closely relevant to patients, and long-term follow up to observe potential improvement in liver histology. Future trials ought to be reported according to the Consort Statement (www.consort-statement.org).

The choice of the control treatment in a clinical trial should be justified, and methodological and ethical arguments should be taken into account. When no final conclusion can be reached due to the study design, it is not ethically no acceptable to perform the trial. We advocate that phyllanthus is primarily assessed against placebo. This can be done in randomised clinical trials in which all patients received antiviral drugs that are known to offer more benefit than harm and the patients are then randomised to phyllanthus versus placebo (the so called 'add-on' trials). Only when the effect of phyllanthus is unequivocally demonstrated as superior to placebo, it is prudent to assess the effects of phyllanthus versus other antiviral drugs superior to placebo in future randomised clinical trials (Scaglione 2012).

 

Acknowledgements

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. Contributions of authors
  12. Declarations of interest
  13. Sources of support
  14. Differences between protocol and review
  15. Index terms

We greatly thank Dimitrinka Nikolova and Sarah Klingenberg for expert assistance during the preparation of this review.

Peer Reviewers: S Pol, France; Luit Penninga, Denmark.
Contact Editor: Bodil Als-Nielsen, Denmark.

 

Data and analyses

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. Contributions of authors
  12. Declarations of interest
  13. Sources of support
  14. Differences between protocol and review
  15. Index terms
Download statistical data

 
Comparison 1. Phyllanthus versus antiviral drug

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Number of patients with detectable serum HBsAg4222Risk Ratio (M-H, Random, 95% CI)1.00 [0.93, 1.08]

 2 Number of patients with detectable serum HBV DNA ( end of treatment )4219Risk Ratio (M-H, Random, 95% CI)0.83 [0.53, 1.31]

 3 Number of patients with detectable serum HBV DNA ( end of post-treatment follow-up )135Risk Ratio (M-H, Random, 95% CI)0.53 [0.25, 1.14]

 4 Number of patients with detectable serum HBeAg ( end of treatment )5271Risk Ratio (M-H, Random, 95% CI)0.75 [0.63, 0.89]

 5 Number of patients with detectable serum HBeAg ( end of post-treatment follow-up )135Risk Ratio (M-H, Random, 95% CI)0.7 [0.26, 1.88]

 6 Number of patients without HBeAg seroconversion ( end of treatment )168Risk Ratio (M-H, Random, 95% CI)0.89 [0.71, 1.11]

 
Comparison 2. Phyllanthus versus antiviral drug according to antiviral drugs

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Number of patients with detectable serum HBsAg4222Risk Ratio (M-H, Random, 95% CI)1.00 [0.93, 1.08]

    1.1 Phyllanthus versus lamivudine
160Risk Ratio (M-H, Random, 95% CI)1.04 [0.89, 1.21]

    1.2 Phyllanthus versus interferon alpha
155Risk Ratio (M-H, Random, 95% CI)1.01 [0.87, 1.18]

    1.3 Phyllanthus versus thymosin
2107Risk Ratio (M-H, Random, 95% CI)0.99 [0.89, 1.09]

 2 Number of patients with detectable serum HBV DNA ( end of treatment )4229Risk Ratio (M-H, Random, 95% CI)0.92 [0.52, 1.62]

    2.1 Phyllanthus versus lamivudine
2128Risk Ratio (M-H, Random, 95% CI)0.87 [0.21, 3.57]

    2.2 Phyllanthus versus interferon alpha
141Risk Ratio (M-H, Random, 95% CI)1.17 [0.61, 2.24]

    2.3 Phyllanthus versus thymosin
160Risk Ratio (M-H, Random, 95% CI)0.86 [0.59, 1.25]

 3 Number of patients with detectable serum HBeAg ( end of treatment )5271Risk Ratio (M-H, Random, 95% CI)0.75 [0.63, 0.89]

    3.1 Phyllanthus versus lamivudine
2128Risk Ratio (M-H, Random, 95% CI)0.68 [0.53, 0.87]

    3.2 Phyllanthus versus interferon alpha
146Risk Ratio (M-H, Random, 95% CI)1.05 [0.63, 1.76]

    3.3 Phyllanthus versus thymosin
297Risk Ratio (M-H, Random, 95% CI)0.78 [0.58, 1.03]

 4 Number of patients without HBeAg seroconversion (end of treatment)1Risk Ratio (M-H, Random, 95% CI)Subtotals only

    4.1 Phyllanthus versus lamivudine
168Risk Ratio (M-H, Random, 95% CI)0.89 [0.71, 1.11]

 

Appendices

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. Contributions of authors
  12. Declarations of interest
  13. Sources of support
  14. Differences between protocol and review
  15. Index terms
 

Appendix 1. Search strategies


DatabaseTime spanSearch strategy

The Cochrane Hepato-Biliary Group Controlled Trials RegisterOctober 31, 2012.phyllanthus

The Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane LibraryOctober 31, 2012.#1 phyllanthus
#2 CHRONIC HEPATITIS B explode all trees (MeSH)
#3 (chronic next hepatitis next B)
#4 (#1 and (#2 or #3))

MEDLINE (Ovid SP)1950 to October 31, 2012.1 phyllanthus.mp. [mp=title, original title, abstract, name of substance word, subject heading word, unique identifier]
2 explode "Hepatitis-B-Chronic"/ all subheadings
3 chronic hepatitis B.mp. [mp=title, original title, abstract, name of substance word, subject heading word, unique identifier]
4 1 and (2 or 3)

EMBASE (Ovid SP)1980 to October 31, 2012.1 phyllanthus.mp. [mp=title, original title, abstract, name of substance word, subject heading word, unique identifier]
2 explode "Hepatitis-B-Chronic"/ all subheadings
3 chronic hepatitis B.mp. [mp=title, original title, abstract, name of substance word, subject heading word, unique identifier]
4 1 and (2 or 3)

Science Citation Index Expanded (http://apps.isiknowledge.com )1900 to October 31, 2012.#1 TS=phyllanthus
#2 TS=chronic hepatitis B
#4 #1 and #2

Chinese Biomedical CD Database (CBM)
(http://sinomed.imicams.ac.cn/)
1978 to October 31, 2012.Search strategy in Chinese.
#1 phyllanthus
#2 hepatitis B
#3 random
#4 #1 AND #2
#5 #3 AND #4

China Network Knowledge Information (CNKI)
(http://www.cnki.net/)
1994 to October 31, 2012.Search strategy in Chinese.
#1 phyllanthus
#2 hepatitis B
#3 random
#4 #1 AND #2
#5 #3 AND #4

Chinese Science Journal Database (VIP)
(http://www.cqvip.com/)
1989 to October 31, 2012.Search strategy in Chinese.
#1 phyllanthus
#2 hepatitis B
#3 #1 AND #2

TCM Online (http://www.cintcm.com/opencms/opencms/index.html)1984 to October 31, 2012.Search strategy in Chinese.
#1 phyllanthus
#2 hepatitis B
#3 random
#4 #1 AND #2
#5 #3 AND #4

Wanfang Database (http://www.wanfangdata.com.cn/)1982 to October 31, 2012.Search strategy in Chinese.
#1 phyllanthus
#2 hepatitis B
#3 random
#4 #1 AND #2
#5 #3 AND #4



 

Contributions of authors

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. Contributions of authors
  12. Declarations of interest
  13. Sources of support
  14. Differences between protocol and review
  15. Index terms

Yun Xia: protocol development, trial identification, data extraction, data analysis, and drafting the review.
Hui Luo: trial identification and data extraction.
JianPing Liu: protocol development, providing methodological perspectives, and protocol and review revision.
Christian Gluud: protocol and review revision and providing methodological perspectives.

All authors commented and agreed on the final version of the review.

 

Declarations of interest

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. Contributions of authors
  12. Declarations of interest
  13. Sources of support
  14. Differences between protocol and review
  15. Index terms

None known.

 

Sources of support

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. Contributions of authors
  12. Declarations of interest
  13. Sources of support
  14. Differences between protocol and review
  15. Index terms
 

Internal sources

  • Centre for Evidence-Based Chinese Medicine, Beijing University of Chinese Medicine, China.
  • Copenhagen Trial Unit, Centre for Clinical Intervention Research, Denmark.

 

External sources

  • National Basic Research Program of China (973 Program) (2006CB504602), China.
  • International Cooperation Project of the Ministry of Science and Technology (2009DFA31460), China.
  • State Scholarship Fund of Chinese Scholarship Council (2010655001), China.
  • Grant number R24 AT001293 from the National Center for Complementary and Alternative Medicine (NCCAM), USA.

 

Differences between protocol and review

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. Contributions of authors
  12. Declarations of interest
  13. Sources of support
  14. Differences between protocol and review
  15. Index terms

In order to control for risks of random errors, we performed trial sequential analyses (TSA) for the dichotomous outcomes of number of patients with detectable serum HBeAg.

We updated our searches to October 31, 2012 in accordance with instructions of the Cochrane Handbook of Systematic Reviews of Interventions and the Cochrane Hepato-Biliary Group Module.

References

References to studies included in this review

  1. Top of page
  2. AbstractRésumé
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. Contributions of authors
  13. Declarations of interest
  14. Sources of support
  15. Differences between protocol and review
  16. Characteristics of studies
  17. References to studies included in this review
  18. References to studies excluded from this review
  19. Additional references
Ge 2005 {published data only}
  • Ge X, Song WL, Heng SX, Yang WD. Therapeutic effect observation of phyllanthus tablet for patients with lamivudine resistant hepatitis B. Chinese Journal of Integrated Traditional and Western Medicine on Liver Diseases 2005;15(1):50-2.
Huang 2004 {published data only}
  • Huang ZC, Zhu BX, Zheng QJ, Yang SL, Tan B, He JY, et al. A comparative study on phyllanthus compound and lamivudine in the treatment of chronic hepatitis B. Journal of Guangzhou University of Traditional Chinese Medicine 2004;21(3):161--3.
Li 1998 {published data only}
  • Li CQ, Wang XH, Li GQ, Fang HX. Clinical observation of compound phyllanthus for patients with chronic hepatitis B. Journal of New Chinese Medicine 1998;30(6):45-6.
Ouyang 1999 {published data only}
  • Ouyang L. Thymosin and phyllanthus tablets for chronic hepatitis B in 42 cases. Chinese Journal of Traditional and Western Medicine on Liver Disease 1999;9(5):44.
Zhu 2005 {published data only}
  • Zhu YC. Therapeutic effect observation of compound phyllanthus and thymosin alpha 1 for chronic hepatitis B. Anti Infection Pharmacy 2005;2(4):165-6.

References to studies excluded from this review

  1. Top of page
  2. AbstractRésumé
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. Contributions of authors
  13. Declarations of interest
  14. Sources of support
  15. Differences between protocol and review
  16. Characteristics of studies
  17. References to studies included in this review
  18. References to studies excluded from this review
  19. Additional references
Cai 2006 {published data only}
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Chan 2003 {published data only}
Cheng 2005 {published data only}
  • Cheng SL, Yin SS, Liu CY, Zhang JY. Compound phyllanthus tablet and Interferon for children with chronic hepatitis B in 30 cases. Chinese Journal of Integrated Traditional and Western Medicine on Liver Disease 2005;15(1):59.
Cui 1998 {published data only}
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Gu 2005 {published data only}
  • Gu HH, Chen QW, Zhou X, Wu WY, Zhao GG. Phyllanthus and vidarabine for chronic hepatitis B in 34 cases. Chinese Journal of Integrated Traditional and Western Medicine on Digestion 2005;13(5):332-3.
He 2008 {published data only}
  • He LF. Therapeutic effect observation of adefovir dipivoxil and phyllanthus for chronic hepatitis B. Sichuan Medical Journal 2008;29(4):435-6.
Huang 1993 {published data only}
  • Huang ZR, Zhong JP, Zhu GL, Chen YD, Wang GQ. Therapeutic effect observation of phyllanthus for patients with chronic hepatitis B. Chinese Journal of Clinical Hepatology 1993;9(2):108-10.
Huang 1999 {published data only}
  • Huang L, Zhang FX, Li CQ. Compound phyllanthus and Interferon for chronic hepatitis B. Shanxi Journal of Traditional Chinese Medicine 1999;20(4):146-7.
Huang 1999a {published data only}
  • Huang KM. Phyllanthus for patients with chronic hepatitis B in 38 cases. Information of Traditional Chinese Medicine 1999;6:32.
Ma 1993 {published data only}
  • Ma FX, Zhang Y. Clinical observation of compound phyllanthus for asymptomatic carriers of hepatitis B. Journal of Shanghai Traditional Chinese Medicine 1993;5:8-9.
Qian 2008 {published data only}
  • Qian HQ. Phyllanthus tablet and adefovir dipivoxil tablet for chronic hepatitis B in 42 cases. Chinese Journal of Integrated Traditional and Western Medicine on Liver Disease 2008;18(2):115.
Song 2007 {published data only}
  • Song XA, Ma XL, Liu YM. Therapeutic effect observation of phyllanthus capsule for chronic hepatitis B in 98 cases. Shandong Medical Journal 2007;47(23):97-8.
Su 2004 {published data only}
  • Su BL, Xu PR, Lu J. Therapeutic effect observation of phyllanthus tablet and lamivudine for chronic hepatitis B. Hebei Journal of Chinese Medicine 2004;26(2):146-7.
Tian 2004 {published data only}
  • Tian GJ, Feng TB, Tang MZ, Wang XH. Short-term effect of phyllanthus compound and lamivudine in treating chronic hepatitis B: an observation of 30 cases. Journal of Guangzhou University of Traditional Chinese Medicine 2004;21(4):257-9.
Wang 2000 {published data only}
  • Wang SH, Xia SL, Zhang Y, Su Z, Wang LJ, Li DT. Clinical study of phyllanthus for patients with chronic hepatitis B. Journal of Infectious Disease Pharmacy 2000;10(2):31-3.
Wang 2009 {published data only}
  • Wang WX, Zhou WH, Shen LJ. Phyllanthus and adefovir dipivoxil tablets for chronic hepatitis B in 20 cases. Herald of Medicine 2009;28(1):74-5.
Yan 2008 {published data only}
  • Yan J, Liu XQ, Du M, Chen LY. Therapeutic effect observation interferon alpha and phyllanthus capsule for chronic hepatitis B. Journal of Clinical Hepatology 2008;11(1):37-8.
Zhang 2006 {published data only}
  • Zhang MJ, Dong P, Yong J, Teng J, Li ZX. Therapeutic effect observation of phyllanthus for patients with chronic hepatitis B. Journal of Ningxia Medical College 2006;28(5):451-2.
Zhang 2009 {published data only}
  • Zhang HF, Zhu SX, Dong Y, Xu ZQ, Chen DW, Jia WZ, et al. The effect and safety assessment of phyllanthus capsule and adefovir dipivoxil tablet for chronic hepatitis B. Shandong Medical Journal 2009;49(28):60-1.
Zhong 2000 {published data only}
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Zhu 1992 {published data only}
  • Zhu FM, Zhang JQ, Zhang XZ, Zhang XM. Clinical observation of phyllanthus on hepatitis B viral markers. Chinese Journal of Integrated Traditional Chinese and Western Medicine 1992;2(2):10-1.

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  2. AbstractRésumé
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. Contributions of authors
  13. Declarations of interest
  14. Sources of support
  15. Differences between protocol and review
  16. Characteristics of studies
  17. References to studies included in this review
  18. References to studies excluded from this review
  19. Additional references
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