2013 phyllantus species vs antiviral

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Phyllanthus species versus antiviral drugs for chronic hepatitisB virus infection (Review)

Xia Y, Luo H, Liu JP, Gluud C

This is a reprint of aCochrane review, preparedand maintained by The Cochrane Collaboration andpublished in The Cochrane Library 2013, Issue 4

http://www.thecochranelibrary.com

Phyllanthus species versus antiviral drugs for chronic hepatitis B virus infection (Review)Copyright 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
http://www.thecochranelibrary.com/http://www.thecochranelibrary.com/


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T A B L E O F C O N T E N T S

1HEADER . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .1 ABSTRACT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .2PLAIN LANGUAGE SUMMARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .2BACKGROUND . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

4OBJECTIVES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .4METHODS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .7RESULTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Figure 1. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7Figure 2. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8Figure 3. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9Figure 4. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11

11DISCUSSION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .12 AUTHORS CONCLUSIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .13 ACKNOWLEDGEMENTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .13REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .17CHARACTERISTICS OF STUDIES . . . . . . . . . . . . . . . . . . . . . . . . . . . . .26DATA AND ANALYSES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Analysis 1.1. Comparison 1 Phyllanthus versus antiviral drug, Outcome 1 Number of patients with detectable serumHBsAg. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27 Analysis 1.2. Comparison 1 Phyllanthus versus antiviral drug, Outcome 2 Number of patients with detectable serum H

DNA ( end of treatment ). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 28 Analysis 1.3. Comparison 1 Phyllanthus versus antiviral drug, Outcome 3 Number of patients with detectable serum H

DNA ( end of post-treatment follow-up ). . . . . . . . . . . . . . . . . . . . . . . . . 2 Analysis 1.4. Comparison 1 Phyllanthus versus antiviral drug, Outcome 4 Number of patients with detectable serum

HBeAg ( end of treatment ). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3 Analysis 1.5. Comparison 1 Phyllanthus versus antiviral drug, Outcome 5 Number of patients with detectable serum

HBeAg ( end of post-treatment follow-up ). . . . . . . . . . . . . . . . . . . . . . . . Analysis 1.6. Comparison 1 Phyllanthus versus antiviral drug, Outcome 6 Number of patients without HBeAg

seroconversion ( end of treatment ). . . . . . . . . . . . . . . . . . . . . . . . . . . 3 Analysis 2.1. Comparison 2 Phyllanthus versus antiviral drug according to antiviral drugs, Outcome 1 Number of patie

with detectable serum HBsAg. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3 Analysis 2.2. Comparison 2 Phyllanthus versus antiviral drug according to antiviral drugs, Outcome 2 Number of patie

with detectable serum HBV DNA ( end of treatment ). . . . . . . . . . . . . . . . . . . . Analysis 2.3. Comparison 2 Phyllanthus versus antiviral drug according to antiviral drugs, Outcome 3 Number of patie

with detectable serum HBeAg ( end of treatment ). . . . . . . . . . . . . . . . . . . . . . Analysis 2.4. Comparison 2 Phyllanthus versus antiviral drug according to antiviral drugs, Outcome 4 Number of patie

without HBeAg seroconversion (end of treatment). . . . . . . . . . . . . . . . . . . . . . 35 ADDITIONAL TABLES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .37 APPENDICES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .39CONTRIBUTIONS OF AUTHORS . . . . . . . . . . . . . . . . . . . . . . . . . . . . .39DECLARATIONS OF INTEREST . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .39SOURCES OF SUPPORT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .39DIFFERENCES BETWEEN PROTOCOL AND REVIEW . . . . . . . . . . . . . . . . . . . . .

iPhyllanthus species versus antiviral drugs for chronic hepatitis B virus infection (Review)Copyright 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.


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[Intervention Review]

Phyllanthus species versus antiviral drugs for chronic hepatitisB virus infection

Yun Xia 1, 2, Hui Luo1, Jian Ping Liu1, 2, Christian Gluud2

1Centre for Evidence-Based Chinese Medicine,Beijing University ofChinese Medicine,Beijing, China.2The Cochrane Hepato-Biliary Group, Copenhagen Trial Unit, Centre for Clinical Intervention Research, Department 7812, Rigshospitalet, Copenhagen UnHospital, Copenhagen, Denmark

Contact address: Jian Ping Liu, [email protected]. [email protected].

Editorial group: Cochrane Hepato-Biliary Group.Publication status and date: New, published in Issue 4, 2013.Review content assessed as up-to-date: 5 December 2012.

Citation: 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.

Copyright 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

A B S T R A C T

Background

Phyllanthus species for patients with chronic hepatitis B virus (HBV) infection have been assessed in clinical trials, but no cregarding their usefulness exists. When compared with placebo or no intervention, we were unable to identify convincing

that phyllanthus species are benecial in patients with chronic hepatitis B. Some randomised clinical trials have compared phyllanthus species versus antiviral drugs.

Objectives

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

Search methods

Searches were performed in The Cochrane Hepato-Biliary Gorup Controlled Trials Register, The Cochrane Central RegControlled Trials (CENTRAL) in The Cochrane Library , MEDLINE, EMBASE, Science Citation Index Expended, and the ChinesBiomedical CD Database, China Network Knowledge Information, Chinese Science Journal Database, TCM Online, and WDatabase. Conference proceedings in Chinese were handsearched. All searches were conducted until 31st October 2012.

Selection criteria

Randomised clinical trials comparing phyllanthus species with antiviral drugs for patients with chronic HBV infection. We includtrials irrespective of blinding, publication status, or language.

Data collection and analysis

Twoauthors selected thetrials andextractedthe dataindependently. TheRevMansoftwarewas usedfor statistical analysisof dichdata with risk ratio (RR) with 95% condence intervals (CI). We assessed the risk of bias to control for systematic errors. Wethe number of patients needed (required information size) to be randomised in order to make reliable conclusions. We asscumulative ndings with trial sequential analysis to control for random errors.

1Phyllanthus species versus antiviral drugs for chronic hepatitis B virus infection (Review)Copyright 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
mailto:jianpingchar%20%22A8penalty%20z@%[email protected]:[email protected]:[email protected]:jianpingchar%20%22A8penalty%20z@%[email protected]


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Main results

We identied ve randomised clinical trials with 290 patients. All trials were considered to have high risk of bias. Patieexperimental group received compound phyllanthus for three months to 12 months. Patients in the antiviral drug group receivelamivudine, interferon alpha, thymosin, or thymosin alpha 1. None of the trials reported mortality, hepatitis B-related moquality of life, or liver histology. Phyllanthus seemed to have a superior effect on clearance of serum HBeAg at the end of treatmenconventional meta-analysis (RR 0.76; 95% CI 0.64 to 0.91, P = 0.002; I2 = 0%), but not when trial sequential analysis was applied.Phyllanthus had no signicant effect on clearance of serum HBsAg (RR 1.00; 95% CI 0.93 to 1.08, P = 0.92; I2 = 0%) or HBV DNA (RR 0.83; 95% CI 0.53 to 1.31, P= 0.43; I2 = 70%) when compared with antiviral drugs. Data on HBeAgseroconversion was repoin one trial and no signicant difference was found comparing phyllanthus versus lamivudine (RR 0.89; 95% CI 0.71 to 1.11). No data were reported on adverse events in the ve trials.

Authors conclusions

There is currently insufcient evidence to support or refute the use of phyllanthus for patients with chronic hepatitis B virus infection.Researchers who are interested in conducting further randomised clinical trials on phyllanthus ought to monitor both benecial andharmful effects and should primarily test the herb against placebo in addition to antiviral drugs that are known to offer morthan harm. Only in this way new interventions can be assessed without compromising personal ethical considerations.

P L A I N L A N G U A G E S U M M A R Y

Phyllanthus species versus antiviral drugs for chronic hepatitis B virus infection

Chronic hepatitis B virus (HBV) infection causes signicant mortality, morbidity, and it is an economic burden worldwide. the current approved therapies show benecial effects, response to treatment is not satisfactory, patients are at high risk of dviral resistance, and serious adverse events occur. The objective of this review was to evaluate the benets and harms of phyllanthus species compared with commonly used antiviral drugs for patients with chronic HBV infection. In a previous Cochrane HepaGroup systematic review we have compared phyllanthus species versus placebo or no intervention. In that review, we were unable nd convincing evidence to support the use of phyllanthus species for patients with chronic hepatitis B.

The ndings of this review are based on ve randomised clinical trials with 290 patients. Phyllanthus was tested versus antiviral drugs,

including lamivudine, interferon alpha, thymosin, or thymosin alpha 1 for three months to 12 months. The primary ndingreview are that phyllanthus seemed to have a superior effect on clearance of serum HBeAg at the end of treatment in convenmeta-analysis, but not when trial sequential analysis was applied. Phyllanthus had no signicant effect on clearance of serum HBsAg,serum HBV DNA, or HBeAg seroconversion when compared with antiviral drugs. No data were identied on mortality or madverse events, quality of life, or liver histology. However, the ndings in our review are inconclusive due to the small npatients and outcomes, risk of bias, and the study design. We need more randomised trials to conrm or reject the potential phyllanthus . We advocate that phyllanthus is primarily assessed against placebo. This can be done in randomised clinical trials in wall patients receive antiviral drugs that are known to offer more benet than harm and the patients are then randomised to phyllanthus versus placebo. If the effect of phyllanthus versus placebo is unequivocally demonstrated in such trials, it may be prudent to asseseffects of phyllanthus versus other antiviral drugs superior to placebo in such trials. The quality of trials regarding conduct andshould also be taken into account.

B A C K G R O U N D

Description of the condition

Chronic hepatitis B virus (HBV) infectionis oneof themost com-mon infectious diseases in the worldand may cause cirrhosis, hepatocellular carcinoma, and death. World-wide, hepatitis B viruscauses more than one million deaths every year, and more than



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350 million people are chronically infected ( WHO 2010). Thisconstitutes a signicant 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 12million peoplesuffer fromchronic hepatitisB, andabout 300,000

people die each year (Sun 2010). A study has shown that the totaleconomic loss resulting from chronic hepatitis B-associated dis-ease was probably in the range of US$ 8.5 to 15.6 billion in year2001 (Shi 2004; Hu 2009).There is a hepatitis B vaccine available, and the vaccine is foundto be 95% effective in preventing HBV infection (Chen 2005;Lee 2006; Mathew 2008; WHO 2008). Most countries have in-cluded the hepatitis B vaccine into their national infant immu-nisation programmes, and vaccination has markedly reduced thefrequency of chronic HBV infection (Chang 1997; WHO 2001).Furthermore, hepatitis B vaccine has been shown to be cost-effec-tive ( Aggarwal 2003). However, vaccination offers no benet foradults 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 im-munomodulatory agents (interferon alpha and pegylated inter-feron alpha) and nucleoside analogues (lamivudine, telbivudine,entecavir, adefovir, and tenofovir) (EASL 2009). Interferon alpha treatment results in viral, biochemical, and histological remissioninabout30%ofthepatients(EASL 2009).However,interferonal-pha (conventional or pegylated) hasthe disadvantages of high costand serious adverse events, which may lead to treatment discon-tinuation. Lamivudine is inexpensive, but patients are at high risk of developing viral resistance. New antiviral drugs characterisedby more potent antiviral effects, less toxicity, and minimal risk of resistance have been explored during the past decades. Entecavirand tenofovir are potent HBV inhibitors and have a high barrierto resistance (EASL 2009). Adefovir has most of the advantages of lamivudine, with the additional benet that viral drug resistanceis uncommon (Marcellin 2003). Telbivudine is another potent in-hibitor 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 largenumber of patients who cannot afford this standard therapy seek help from traditional Chinese medicine.Phyllanthus is the largest genus in Phyllanthaceae (Kathriarachchi2005). The plants are widely distributed in most tropical and sub-tropical countries, and it is estimated that there are over 1200species in the world (Kathriarachchi 2005). The plants of phyllan-thus species are considered bitter, astringent, stomachic, diuretic,febrifuge, deobstruent, and antiseptic and have long been used intraditionalChinesemedicinetotreatchronicliverdiseases(Calixto1998). Studies carried out on extracts and main constituents thatare isolated from different species of phyllanthus, seems to support

most of the reported usages in folk medicine dening them as effective antiviral agents and hepatoprotective agents (Bagalkotkar2006;Khatoon2006;Lam2006).InChina, phyllanthus wasaddedto the Pharmacopoeia of Peoples Republic of China in 1992, andsubsequent clinical studies seem to haveproven the therapeutic ef-

fects of phyllanthus for chronic hepatitis B virus infection (Chang 1995).

How the intervention might work

Substantial progress on the chemical and pharmacological prop-erties of phyllanthus species has been made (Calixto 1998). Phy-tochemical studies carried out on these plants isolate have char-acterised a number of classes of compounds, including alkaloidsavonoids, lignans, phenols, tannins, coumarins, and terpenes(Venateswaran 1987). These compounds seem to be mainly re-sponsible for the pharmacological actions reported in relation tothese plants. Most of these compounds were found to interactwith most key enzymes, such as aldose reductase, angiotensinconverting enzyme, mitochondrial ATPase, both cyclooxygenaseand lipoxygenase, phospholipase A2, tyrosine kinase, reverse transcriptase, and phosphodiesterases (Chang 1995; Blumberg 1998).Many studies suggest that most plants of the phyllanthus specieshave a benecial effect against HBV in vitro and in vivo (Liu1997), 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 hepatitisB virus infectionshowedpotentialeffecton the clearance of serumHBsAg, HBeAg,HBV DNA, andon liverenzymes normalisation,as well as a better effect of the phyllanthus plus interferon alpha combination than interferon alpha alone on clearance of serumHBeAg and HBV DNA (Liu 2001). However, due to the limi-tations of the clinical trials included in that review (small num-ber of patients and high risk of bias the included trials), there iscurrently still no strong evidence available on phyllanthus speciesfor chronic hepatitis B. We recently reviewed systematically thrandomised trials comparing phyllanthus species versus placebo orno intervention for patients with chronic hepatitis B and we didnot nd any high quality evidence to support phyllanthus species( Xia 2011). During the past several years, more clinical trials havebeen carried out comparing phyllanthus versus antiviral drugs forchronic hepatitis B. We have been unable to identify any meta-analyses or systematic reviews assessing phyllanthus versus antivi-ral drugs in chronic hepatitis B. Current uncertainties about theclinical effectiveness of phyllanthus species require a Cochrane sys-tematic review to clarify the potential benets and harms in thetreatment of chronic hepatitis B.



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O B J E C T I V E S

To evaluate thebenetsandharms of phyllanthus species comparedwith antiviral drugs for patients with chronic HBV infection.

M E T H O D S

Criteria for considering studies for this review

Types of studies

We included randomised clinical trials irrespective of publicationstatus, language, or blinding. We excluded studies using alterna-tion, date of birth, hospital record number, or other quasi-ran-dom methods ofallocation of treatment, exceptforthe assessmentof harms.

Types of participants

We included participants with chronic HBV infection. Patientswith chronic HBV infection were divided into HBeAg positiveand HBeAg negative according to HBeAg blood test. We used thedenition of chronic HBV infection of the individual trials. If indoubt which type of chronic hepatitisB infection(HBeAgpositiveor negative) the patient had, we used the following denitions,based on Lok 2009:

HBeAg-positive chronic hepatitis B infection dened asHBsAg and HBeAg positivity for more than six months, serumHBV 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 liverbiopsy ndings showing moderate or severe necroinammationcompatible with with chronic hepatitis B.

HBeAg-negative chronic hepatitis B infection dened asHBsAg positivity for more than six months without HBeAg positivity, serum HBV DNA positivity usually between 2000 to20,000 IU/ml, ie, 104 to 105 copies/ml, and persistent orintermittent elevation in activity of aspartate aminotransferase oralanine aminotransferase, and liver biopsy ndings showing moderate or severe necroinammation compatible with chronichepatitis B.

We included trials with both children and adult participants. Forthe purpose of this review we dened a child as aged 15 yearsor less and an adult as aged 16 years or older. We planned toinclude patients irrespective of whether they were treatment-naiveor had previously been treated unsuccessfully for chronic HBV infection with another drug. We planned to include patients withevidence 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 conditionsalso separately. We also planned to include patients with priorliver transplantation or with concomitant renal failure but againanalysed these patients groups separately.

Types of interventions

We considered trials eligible for inclusion if they assessed ansingle medicinal herb belonging to the plant species phyllanthus or any other compound from the plant species phyllanthus ver-sus antiviral drugs, including interferon, nucleoside analogues, oimmunomodulating agents. The plant species phyllanthus shouldhave been the only active constituent in the experimental com-pound, but other ingredients assumed to have no antiviral effectsmaybeaddedtothe phyllanthus species (so-calledcompound phyl-lanthus ). We did not consider trials for inclusion if they used decoctionsprepared with phyllanthus .

Types of outcome measures

The following outcome measures were sought at the end of treat-ment 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 orhepatocellular carcinoma).

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

4. Number of participants with serious and non-seriousadverse events in separate (as dened by the InternationalConference on Harmonisation Guideline for Good ClinicalPractice (ICH-GCP 1997)).

5. Quality of life (as dened 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-negativeparticipants).

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

5. Number of participants with worsened liver histology.



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Search methods for identication of studies

Electronic searches

We identied trials by electronic searches of The Cochrane Hep-ato-Biliary Group Controlled Trials Register ( Gluud 2011), TheCochrane Central Register of Controlled Trials (CENTRAL)in The Cochrane Library , MEDLINE, EMBASE, Science Cita-tion Index Expended (Royle 2003), and the Chinese BiomedicalCD Database (CBM), China Network Knowledge Information(CNKI), Chinese Science Journal Database (VIP), TCM Online,and Wanfang Database. All the databases above were searchedfrom their date of inception onwards until October 31, 2012 andirrespective 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 resourcesConference proceedings in Chinese were handsearched. Wescreened the reference lists of all retrieved randomised trials andreview articles for eligible trials.

Data collection and analysis

The methodology for data collection and analysis is based on TheCochrane Handbook of Systematic Reviews of Interventions (Higgins2009) and the Cochrane Hepato-Biliary Group Module (Gluud2011).

Selection of studies

Two authors (YX and HL) independently screened the titles andabstracts of studies identied by the literature search for eligibility accordingto theprespeciedselectioncriteria.Disagreementswereresolved by discussion with JL. The authors (YX and HL) werenot 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 resolvedby discussion with JL. The following characteristics and data wereextracted from each included trial.

Methods: trial design, the information needed to assess therisk of bias domains (listed below), sample size calculations, andlength of follow-up.

Participants: age, sex, ethnic origin, previous antiviraltreatment, duration of hepatitis B, diagnostic criteria, inclusionand exclusion criteria, number of patients randomised,

assessment of compliance, and withdrawals/losses to follow-up(reasons/description).

Interventions: species and origin of phyllanthus , dosage andduration of therapy, formulation, route of administration, andintervention 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 biafor each included randomised trial. Disagreements were resolvedby discussion with JL. We assessed the following domains (Schulz1995; Moher 1998; Jni 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, shufing cards and throwing dice aradequate if performed by an independent adjudicator.- Uncertain risk of bias: the trial is described as randomised, buthe method of sequence generation was not specied.- High risk of bias: the sequence generation method is not, ormaynotbe, random.Quasi-randomised studies, thoseusingdates,names, or admittance numbers in order to allocate patients areinadequate and will be excluded for the assessment of benets bunot for harms.

Allocation concealment - Low risk of bias: allocation was controlled by a central and independent randomisation unit, sequentially numbered, opaque andsealed envelopes or similar, so that intervention allocations couldnot have been foreseen in advance of, or during, enrolment.- Uncertain risk of bias: the trial was described as randomised buthe method used to conceal the allocation was not described, sothat intervention allocations may have been foreseen in advanceof, or during, enrolment.- High risk of bias: if the allocation sequence was known to theinvestigators who assigned participants or if the study was quasirandomised. Quasi-randomised studies will be excluded for theassessment of benets but not for harms.

Blinding - Low risk of bias: the trial was described as blinded, the partiethat were blinded, and the method of blinding was described, sothat knowledge of allocation was adequately prevented during thetrial.- Uncertain risk of bias: the trial was described as blind, but themethod of blinding was not described, so that knowledge of allo-cation was possible during the trial.- High risk of bias: the trial was not blinded, so that the allocationwas known during the trial.



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Incomplete outcome data- Low risk of bias: the numbers and reasons for dropouts andwithdrawals in all intervention groups were described or if it wasspecied 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 thiswas not specically stated.- High risk of bias: the number or reasons for dropouts and with-drawals were not described.

Selective outcome reporting - Lowriskof bias: pre-dened,or clinically relevantandreasonably expected outcomes are reported on.- Uncertain risk of bias: not all pre-dened, or clinically relevantand reasonably expected outcomes are reported on or are not re-ported fully, or it is unclear whether data on these outcomes wererecorded or not.- High risk of bias: one or more clinically relevant and reasonably

expected outcomes were not reported on; data on these outcomeswere likely to have been recorded.

Other biases- Low risk of bias: the trial appears to be free of other sources of bias (eg, conict of interest bias).- Uncertain risk of bias: there is insufcient information to assesswhether other sources of bias are present).-Highriskofbias:itislikelythatpotentialsourcesofbiasrelatedtospecicdesignused,early terminationduetosomedata-dependentprocess, lack of samplesize or power calculation,or other bias risksare present. Authors judgements were based on the denitions of the above

listed domains, and trials with adequate assessments in all of theabove 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 assummary risk ratio (RR) with 95% condence interval (CI).

Unit of analysis issues

Intervention groups of patients in randomised clinical trials. Alltrials 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 analysisas well as sensitivity analysis (missing individuals).

Assessment of heterogeneity

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

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

Data synthesis

Meta-analysesFor all analyses, we used the xed-effect model (DeMets 1987)as well as the random-effects model meta-analyses (DerSimonian1986). Incase there wasno difference in statistical signicance, wepresented the results of the random-effects analyses. Otherwisewepresentedtheresults ofboth analyses. Theanalyseswere carried

out using the latest Cochrane Review Manager software (RevMan2011).Meta-analysisisasummaryinterventioneffectestimationbasedona weightedaveragecalculation of the intervention effectsestimatedin theindividual trials. Onecannot conduct a meta-analysis if only one trial is identied. If only one trial assessed an outcome, we stilpresented thedata in a forestplot in order to give amore completeoverview, to prepare our review for future updates, and to obtainrelative risks with condence intervals. We are well aware that threlative risks and condence intervals may not be fully correct.Trial sequential analysis (TSA) We planned to perform trial sequential analysis (TSA) for all othe outcomes. Trial sequential analysis aims to reduce the risk o

random error in the setting of sparse data and repetitive testingof accumulating data, thereby improving the reliability of conclu-sions (Brok 2008; Wetterslev 2008; Wetterslev 2009; CTU 2011;Thorlund 2011). We planned to calculate the information size, providing an esti-mate of how many patients would be required in order to makea reliable conclusion. In our trial sequential analyses, the requireinformation size was based on the proportion of patients with theoutcome in the control group assumption of a plausible RR re-duction of 10% or on the RR reduction observed in the includedtrials with low risk of bias, a type I error of 5%, and a type II erroof 20% ( Wetterslev 2008). We planned to use control event ratesfrom 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 differ-ences in trials with low risk of bias compared to trials with highrisk of bias, among different species of phyllanthus , antiviral drugs,populations with different co-infections, and diseases.



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R E S U L T S

Description of studies

See:Characteristicsofincludedstudies;Characteristicsofexcludedstudies. We identied a total of 212 publications through electronicsearches and hand-searching. We excluded 174 duplicates among databases, clearly irrelevant publications or non-clinical studies.Thirtyeightpublications were retrievedfor furtherassessment. Of these, we excluded 33 which are listed under Characteristics of excludedstudies withreasonsforexclusion. Accordingly, vetrialsfullled our inclusion criteria and were included. For a summary of the search see Figure 1.

Figure 1. Flow diagram of the search.



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The ve randomised clinical trials were parallel group trials pub-lished as full articles. Three of the ve included trials had threearms which were phyllanthus , antiviral drugs, and a combinationof 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 phyllan-thus versus antiviral drugs were included into analyses of our re-view.One trial included both in-patients and out-patients (Zhu 2005).One trial included out-patients (Huang 2004). The other threetrials did not specify the origin of the patients (Ge 2005; Li 1998;Ouyang 1999). One trial included both children and adults (ageranging from 9 to 65 years) (Ouyang 1999). The remaining fourtrials included only adults (age ranging from 15 to 59 years). Alltrials reported the male/female ratio. There were 72% males and28% females. All trials reported that viral hepatitis diagnosed according to theNational Conference on Infectious Disease or Viral Hepatitits in

China. In the trial Ouyang 1999, 37 patients out of 47 wereHBeAg negative. In the trial Li 1998, 29 patients out of 55 wereHBeAg negative. In the remaining trials all patients included were

HBeAg positive. None of the trials reported any informations ofpatients with co-infections or diseases.Patients in the experimental group of the ve trials received compound phyllanthus. The antiviral drugs used in the control groupwere lamivudine, interferonalpha, thymosin, or thymosin alpha1.

All the dosage and duration of the antiviral drugs were in accordance with standards of international guidelines. The treatmentduration varied from three months to 12 months. Detailed infor-mation of the ve randomised trials and the source and adminis-tration of phyllanthus species and antiviral drugs were summarisedin Table 1, Table 2, and Table 3.The outcome measures reported in the ve trials were virologicamarkers and/or biochemical variables. None of the trials reportedmortality, hepatitis B-related morbidity, liver histology progress,or quality of life.Furtherdetails are listed in the table of Characteristicsof includedstudies.

Risk of bias in included studies

The risk of bias of included trials is summarised in Figure 2 andFigure 3. Following the risk of bias components, all trials includedwere classied as trials with high risk of bias.

Figure 2. Risk of bias graph: review authors judgements about each risk of bias item presented aspercentages across all included studies.



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Figure 3. Risk of bias summary: review authors judgements about each risk of bias item for each includedstudy.



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Allocation

Allocation sequence generationGeneration of the allocation sequence was adequately reported intwo trials (Huang 2004; Zhu 2005 ). In both trials, patients wererandomised 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 blindedto the intervention. As the different administration described be-tweentheinterventiongroupsof theincludedtrials,we consideredthat no blinding was performed in the ve trials.

Incomplete outcome data

None of the ve included trials reported if there were withdrawalsor dropouts.Thenumber ofpatients analysed were thesame as thenumber of patients randomised. It seems unlikely that no patientsdrop outduring the treatment(from three months to 12 months).However, wecould notgetconrmation on that as wewere unableto contact the authors.

Selective reporting

In the ve trials, none of the randomised patients were analysedfor the primary outcomes chosen for this systematic review. As nocontact 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 reportedall the outcomes which hadbeen measured.

Other potential sources of bias

None of the trials reported a sample size calculation. We alsoplanned to assess publication bias using a funnel plot. We did notmake this assessment due to the limited number of trials that wereincluded.

Effects of interventions

Mortality and morbidity None of the trials reported on mortality or morbidity. Adverse eventsOnly onetrialreportedthatadverse eventswereobservedGe2005.Data of adverse events were not reported. The type of adverseevents 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 re-ported that none of the patients who experienced these adverseevents required dose modication, interruption or prolonged hos-pitalisation.Quality of lifeNone of the trials reported on quality of life.Number of patients with detectable serum HBsAg Four trialsprovided data forserumHBsAgafter treatment(Huang 2004; Li 1998; Ouyang 1999; Zhu 2005). The meta-analysisshowed no statistically signicant 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 ve trials were lamivudineinterferon alpha, thymosin, or thymosin alpha 1. According to the subgroup analyses, there was no statistically signicant difference of phyllanthus on clearance of serum HBsAg whencomparedwith lamivudine (RR1.04;95%CI0.89 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 DNAFour trials reported data for serum HBV DNA after the end of treatment (Ge 2005;Huang 2004;Li 1998;Zhu2005). Combin-ing results of these ve trials showed that there was no statisticalsignicant 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 fol-low-up (Ge 2005). There was no signicant difference between phyllanthus andlamivudineon clearanceofserum HBV DNA(RR 0.53; 95% CI 0.25 to 1.14). According to the subgroup analyses, phyllanthus showed no signif-

icant difference of effect on clearance of serum HBV DNA whentested against lamivudine (RR 0.87; 95% CI 0.21 to 3.57, P =0.85; I2 = 93%), interferon alpha (RR 1.17; 95% CI0.61to 2.24),or thymosin (RR 0.86; 95% CI 0.59 to 1.25).Number of patients with detectable serum HBeAg All of the ve trials reported this outcome. Combining results othese trials showed that phyllanthus had a superior effect on clear-ance of serum HBeAg at the endof treatment between phyllanthus and antiviral drugs in traditional meta-analysis (RR 0.76; 95% CI0.64 to 0.91, P = 0.002; I2 = 0%).However, trial sequential analysis on data for detectable serumHBeAg after treatment does not support a 10% relative risk re-duction (RRR) in the phyllanthus group compared with antiviral

drug group (Figure 4). The required information size of 1574 wascalculated based on a control event proportion of 75.8%, a relativerisk reduction of 10%; a risk of type I error of 5%, a power of80%, and a diversity of 30%. Although the cumulated Z-curve(blue curve) crossed the traditional boundary of 5% signicance(horizontal red line), it did not cross the trial sequential moni-toring boundary (red curve), implying that rm evidence was not

reached.



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Figure 4. Figure 4: Trial sequential analysis with a type 1 error of 5% on phyllanthus species versus antiviraldrugs for patients with chronic hepatitis B on clearance of serum HBeAg. Trial sequential analysis of ve 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 rm evidence controlling for the risk of random error. The required information size (RIS) is calculated to be 1574 patients (vertical line) based on arelative risk reduction (RRR) of 10%, event proportion of 75.8% in the control group (PC), type I error ( ) of

5%, type II error ( ) of 20%, and diversity (D) of 30%.

No statistically signicant difference was seenafter 6months posttreatment 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 bettereffect on clearance of serum HBeAg when tested against lamivu-dine (RR 0.68; 95% CI 0.53 to 0.87, P = 0.002; I2 = 0%). Phyl-lanthus showed no signicant difference when compared with in-terferon 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 seroconversionOnly one trial reported data for HBeAg seroconversion Ge 2005.Phyllanthus showed no signicant difference of effect on HBeAg seroconversion when testedagainst lamivudine at the end of treat-ment (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 ve trials and all of the trialwere with high risk of bias. Based on the information given in thtrials, we were only able to perform subgroup analyses accordinto different antiviral drugs used in the control groups.

D I S C U S S I O NSummary of main results

There was no convincing evidence that phyllanthus was superiorcompared with antiviral drugs regarding virological outcomes. Itwould take much more patients to prove equivalence or non-infe-riority. Based on the present ndings as well as the ndings in ou



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previous review assessing phyllanthus versus placebo or no inter-vention,we conclude that there iscurrentlynoevidence to supportor refute the use of phyllanthus species for patients with chronichepatitis B.For the primary outcomes chosen in our review, no data were

identied from the ve trials. With regard to potential adverseevents, there was only one trial reporting on this outcome. Only the type of adverse events were reported in that trial and no pa-tients required dose modication, interruption or prolonged hos-pitalisation. However, insufcient evidence for adverse events of phyllanthus from randomised trials cannot lead to the conclusionthat phyllanthus does not cause harm.For thesecondary outcomes,therewasonly oneoutcomeforwhichtraditional meta-analysis revealed a statistically signicant benetinthe phyllanthus group. Theclearanceof serum HBeAgforwhichthe results from ve trials showed a RR (risk ratio) of 0.76 (95%CI 0.64 to 0.91). However, the trial sequential analysis does notsupport the nding from the traditional meta-analysis, implying

that rm evidence was not reached. In addition, there are fourthings we should keep in mind. First, this potential benet is onan outcome which is only a putative surrogate outcome (Gluud2007). Second, oursystematic reviewhasa major limitation whichis a small number of trials included. This increases the risks of random errors. In accordance, trial sequential analysis suggestedthat theobserved interventioneffect couldbedueto randomerror.Fourth, all of the ve trials were considered to have high risk of bias. This increases the risk of systematic errors.For the other ve secondary outcomes, meta-analyses showed nostatistically signicant differences between phyllanthus and antivi-ral drug groups. However, the fact that we did not nd signi-cantdifferencesbetween phyllanthus comparedwith antiviral drugs

cannot be taken as evidence that phyllanthus does work. First, wehave been unable to nd high quality evidence from randomisedclinical trials supporting phyllanthus versusplacebo orno interven-tion ( Xia 2011). Second, the fact that we observed no differencebetween phyllanthus versus antiviral drugs does not suggest activ-ity 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 ade-quacy of the treatments need to be evaluated. The evidence of theuse of lamivudine and interferon alpha has been elaborated in thesection of Descriptionof the intervention in thebackground. Forthe use of thymosin, a controlled, blinded study suggested thatthymosin might be effective on clearance of theHBV virus for pa-

tients with chronic active hepatitis B virus infection (Mutchnick 1988). Thymosin alpha 1, a biologically active peptide isolatedfrom thymosin fraction 5 (TF5) which is a partially puried ex-tractof bovine thymus, is one of the rst-linedrugs recommendedby APASL (Asian Pacic Association for the Study of Liver) fortreating chronic hepatitis B (Liaw 2003; Liaw 2005; Liaw 2008).Now thymosin alpha 1 has been approved in 35 countries for thetreatment of chronic hepatitis B (Garaci 2007; Goldstein 2009).

However, this approvalhasnot been givento other thymosinprod-ucts (Lin 2009). In China, thymosin products have been used inclinical practice as antiviral agents for more than 20 years (Lin2009) and the Guideline of Prevention and Treatment of ChronicHepatitis B published in 2005 in China explicitly approved the

usage of thymosinalpha 1 (Chinese guideline on chronichepatitisB 2005). One protocol of Cochrane systematic review was iden-tied to evaluate the benecial and harmful effects of thymosinalpha 1 (Saconato 2009), however, the full review has not beennished yet. Therefore, convincing evidence of thymosin alpha 1or other thymosin products is still needed.There might be biases in the process of our review. Although wmade extensive searches, only ve trials were identied. We mastill have missed potentially eligible trials which were publishein a particular language or indexed in databases which are notaccessible.Thisprecludesexploration of reportingbias. All thevtrials were conducted in China and all the patients included wereChinese. Accordingly, the ndings from our review may not apply

to other populations. In addition, our review researchers were notblinded to the authors of the included trials. A systematic review of genus phyllanthus for chronic hepatitis Bvirus infection was published in 2001 (Liu 2001), in which phyl-lanthus was compared with placebo, no intervention, general non-specic treatment, other herbal medicine, or interferon treatmentfor patients with chronic hepatitis B and chronic hepatitis B car-riers. In that review, no robust conclusion could be drawn for theuse of genus phyllanthus due to the low methodological quality of included trials and the variations of the herb. In our present re-view, trials testing phyllanthus in chronic hepatitis B carriers werenot included, and phyllanthus were compared only with antiviraldrugs. But our results as well as recommendations are basically i

accordance with the former systematic review.

A U T H O R S C O N C L U S I O N S

Implications for practice

There is insufcient evidence from randomised trials to supportor refute the use of phyllanthus for patients with chronic hepatitisB virus infection. There is no conclusive evidence of benet duto 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 insufcient power to provide robust conclusions.

Implications for research

The reviewed results of the ve clinical trials do not show rmevidence for a benecial effect of phyllanthus . However, due to thesmall numberof trialsand fewpatients included, further trialsmay be considered. If such trials are performed, then both benecialand harmful effects ought to be monitored and reported. It will



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also be necessary to report the species and preparations of phyllan-thus . Any further trials should contain enough patients in accor-dance with the sample size estimation, primary outcome measuresclosely relevant to patients, and long-term follow up to observepotential improvement in liver histology. Future trials ought to

be reported according to the Consort Statement (www.consort-statement.org).

Thechoiceof thecontrol treatmentin a clinical trial shouldbe jus-tied, and methodological and ethical arguments should be takeninto account. Whenno nal conclusion can be reached due to thestudy 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 patientsreceived antiviral drugs that are known to offer more benet thanharm and the patients are then randomised to phyllanthus versus

placebo (the so called add-on trials). Only when the effect o phyllanthus is unequivocally demonstrated as superior to placebo,it is prudent to assess the effects of phyllanthus versus other antivi-ral drugs superior to placebo in future randomised clinical trials(Scaglione 2012).

A C K N O W L E D G E M E N T S

We greatly thankDimitrinka Nikolova and Sarah Klingenberg forexpert assistance during the preparation of this review.

Peer Reviewers: S Pol, France; Luit Penninga, Denmark.

Contact Editor: Bodil Als-Nielsen, Denmark.

R E F E R E N C E S

References to studies included in this review

Ge 2005 {published data only}Ge X, Song WL, Heng SX, Yang WD. Therapeuticeffect observation of phyllanthus tablet for patients withlamivudine resistant hepatitis B. Chinese Journal of Integrated Traditional and Western Medicine on Liver Diseases 2005;15(1):502.

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 hepatitisB. Journal of New Chinese Medicine 1998;30(6):456.

Ouyang 1999 {published data only}Ouyang L. Thymosin and phyllanthus tablets for chronichepatitis 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):1656.

References to studies excluded from this review

Cai 2006 {published data only}Cai XM. Phyllanthus tablets and lamivudine for chronichepatitis B in 32 cases. Chinese Journal of Integrated Traditional and Western Medicine on Liver Disease 2006;16(6):3689.

Chan 2003 {published data only}Chan HLY, Sung JJY, Fong WF, Chim AML, Yung PP,Hui AY, et al.Double-blinded placebo-controlled study of phyllanthus urinaris for the treatment of chronic hepatitisB. Alimentary Pharmacology and Therapeutics 2003;48(3):33945.

Cheng 2005 {published data only}Cheng SL, Yin SS, Liu CY, Zhang JY. Compoundphyllanthus tablet and Interferon for children with chronichepatitis B in 30 cases. Chinese Journal of Integrated Traditional and Western Medicine on Liver Disease 2005;15(1):59.

Cui 1998 {published data only}Cui YJ, Gao WJ, Qiao HC. Phyllanthusnirud Linn forpatients with chronic hepatitis B virus infection. Chinese Journal of Traditional Chinese Medicine and Pharmacy 1998;13(5):74.

Gu 2005 {published data only}Gu HH, Chen QW, Zhou X, Wu WY, Zhao GG.Phyllanthus and vidarabine for chronic hepatitis B in 34cases. Chinese Journal of Integrated Traditional and Western Medicine on Digestion 2005;13(5):3323.

He 2008 {published data only}He LF. Therapeutic effect observation of adefovir dipivoxiland phyllanthus for chronic hepatitis B. Sichuan Medical Journal 2008;29(4):4356.

Huang 1993 {published data only}Huang ZR, Zhong JP, Zhu GL, Chen YD, Wang GQ.Therapeutic effect observation of phyllanthus for patientswith chronic hepatitis B. Chinese Journal of Clinical Hepatology 1993;9(2):10810.



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Huang 1999 {published data only}Huang L, Zhang FX, Li CQ. Compound phyllanthusand Interferon for chronic hepatitis B. Shanxi Journal of Traditional Chinese Medicine 1999;20(4):1467.

Huang 1999a {published data only}Huang KM. Phyllanthus for patients with chronic hepatitisB in 38 cases. Information of Traditional Chinese Medicine 1999;6:32.

Ma 1993 {published data only}Ma FX, Zhang Y. Clinical observation of compoundphyllanthus for asymptomatic carriers of hepatitis B. Journal of Shanghai Traditional Chinese Medicine 1993;5:89.

Qian 2008 {published data only}Qian HQ. Phyllanthus tablet and adefovir dipivoxil tabletfor 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 observationof phyllanthus capsule for chronic hepatitis B in 98 cases.Shandong Medical Journal 2007;47(23):978.

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):1467.

Tian 2004 {published data only}Tian GJ, Feng TB, Tang MZ, Wang XH. Short-termeffect 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):2579.

Wang 2000 {published data only} Wang SH, Xia SL, Zhang Y, Su Z, Wang LJ, Li DT. Clinicalstudy of phyllanthus for patients with chronic hepatitis B. Journal of Infectious Disease Pharmacy 2000;10(2):313.

Wang 2009 {published data only} Wang WX, Zhou WH, Shen LJ. Phyllanthus and adefovirdipivoxil tablets for chronic hepatitis B in 20 cases. Herald of Medicine 2009;28(1):745.

Yan 2008 {published data only} Yan J, Liu XQ, Du M, Chen LY. Therapeutic effectobservation interferon alpha and phyllanthus capsule forchronic hepatitis B. Journal of Clinical Hepatology 2008;11(1):378.

Zhang 2006 {published data only}Zhang MJ, Dong P, Yong J, Teng J, Li ZX. Therapeuticeffect observation of phyllanthus for patients with chronichepatitis B. Journal of Ningxia Medical College 2006;28(5):4512.

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 phyllanthuscapsule and adefovir dipivoxil tablet for chronic hepatitis B.Shandong Medical Journal 2009;49(28):601.

Zhong 2000 {published data only}Zhong JP, Zhu GL, Huang ZR, Shu ZM, Fei YM, Tang JL, Wang GQ, Chen BC. Therapeutic effect observation of phyllanthus for patients with chronic hepatitis B. Journal of Clinical Hepatology 2000;16(3):1867.

Zhu 1992 {published data only}Zhu FM, Zhang JQ, Zhang XZ, Zhang XM. Clinicalobservation of phyllanthus on hepatitis B viral markers.Chinese Journal of Integrated Traditional Chinese and Western Medicine 1992;2(2):101.

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Scaglione 2012Scaglione SJ, Lok ASF. Effectiveness of hepatitis B treatmentin clinical practice. Gastroenterology 2012;142(6):13608.

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Indicates the major publication for the study



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C H A R A C T E R I S T I C S O F S T U D I E S

Characteristics of included studies [ordered by study ID]

Ge 2005

Methods Trial design: randomised, parallel group trial.Language: Chinese.Type of publication: journal article. Year of trial: 2001,11 to 2003,8. Judgement of the quality: high risk of bias.

Participants Setting: Lijin, Shandong province.Origin of the patients: not specied.Numberof participants:68.36 participants received phyllanthus , 32participants receivedlamivudine.Sex ratio: 47 males (69%), 21 females (31%).

Mean age: 28.1 years (18 to 46 years).Duration of hepatitis B: not specied.Diagnostic criteria: Diagnostic criteria of chronic hepatitis B on National Conferenon Infectious Diseases and Parasitic Disease, 2000, XianInclusion criteria: patients were treated by lamivudine and got HBV DNA conversiand Alanine transaminase (ALT) normalization before participationExclusion criteria: not described.

Interventions Intervention: phyllanthus tablet, 4 to 6 tablets, po, tid, 6 months.Control: lamivudine tablets, 100 mg, po, qd, 6 months.Post treatment follow-up: 6 months.

Outcomes Outcome measure(s): HBV DNA and HBeAg conversion after treatment and folloup; Alanine transaminase (ALT), total bilirubin, and Albumin (Alb) level before anafter treatment; adverse events

Notes Single centre.Species of phyllanthus were not described.Sources of funding were not stated.

Risk of bias

Bias Authors judgement Support for judgement

Random sequence generation (selectionbias)

Unclear risk Described as randomised, but the methodwas not described.

Allocation concealment (selection bias) Unclear risk Not described.

Blinding (performance bias and detectionbias) All outcomes

High risk It appears the trial was not blind.



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Ge 2005 (Continued)

Incomplete outcome data (attrition bias) All outcomes

Unclear risk The trial did not reported if there werewithdrawals or dropouts. The number of

patientsanalysedwerethesameasthenum-ber of patients randomised

Selective reporting (reporting bias) Unclear risk No trial protocol was identied. We wunable to contact the authors. It is unclearwhether the trial reported all the outcomeswhich had been measured

Other bias High risk There are other factors in the trial thatcould put it at risk of bias

Huang 2004

Methods Trial design: randomised, parallel group trial.Language: Chinese.Type of publication: journal article. Year of trial: 1998 to 2002. Judgement of the quality: high risk of bias.

Participants Setting: Guangzhou, Guangdong province.Origin of the patients: out-patients.Numberof participants:60.30 participants received phyllanthus , 30participants receivedlamivudine.Sex ratio: 33 males (55%), 27 females (45%).Mean age: 37 years (16 to 55 years).Duration of hepatitis B: 0.8 to 14.2 years (mean 3.5 years).Diagnostic criteria: Diagnostic criteria of chronic hepatitis B National Conference oInfectious Diseases and Parasitic Disease, 2000, XianInclusioncriteria: patientswith serumHBsAgpositive,orHBeAg positive orHBV DNpositive, Alanine transaminase (ALT) 1 time higher than the upper limit of normal levage 16 to 55, no serious complicationsExclusion criteria: patients allergic with lamivudine, pregnancy or breast-feeding

Interventions Intervention: compound phyllanthus capsule (Institute of tropical medicine preparationroom of Guangzhou University of Traditional Chinese Medicine), 4 capsules, po, ti52 weeksControl: lamivudine tablets (GlaxoSmithKline), 100 mg, po, qd, 52 weeksPost treatment follow-up: no follow-up.

Outcomes Outcome measure(s): serum HBsAg, HBeAg, and HBV DNA conversion after trment; Alanine transaminase (ALT), Aspartate transaminase (AST), and total bilirubnormalization

Notes Single centre.Species of phyllanthus were not described.Sources of funding were not stated.



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Li 1998 (Continued)

Interventions Intervention: compound phyllanthus capsule (Institute of tropical medicine preparationroom of Guangzhou University of Traditional Chinese Medicine), 4 capsules, po, tid

monthsControl: Interferon alpha 1 b (Shanghai Institute of Biological Products), 300 IU, IMqod, 3 monthsPost treatment follow-up: no follow-up.

Outcomes Outcome measure(s): serum HBsAg, HBeAg, and HBV DNA conversion after trment; Alanine transaminase (ALT), Aspartate transaminase (AST), and total bilirubnormalisation

Notes Single centre.Species of phyllanthus were not described.Sources of funding: Youth Fund project of State Administration of Traditonal ChinesMedicine

Risk of bias




Allocation concealment (selection bias) Unclear risk No information.


High risk Phyllanthus capsule versus interferon alpha injection.


Unclear risk The trial did not reported if there werewithdrawals or dropouts. The number of patientsanalysedwerethesameasthenum-ber of patients randomised


Other bias High risk There are other factors that could put it atrisk of bias.



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Ouyang 1999

Methods Trial design: randomised, parallel group trial.Language: Chinese.Type of publication: journal article. Year of trial: not stated. Judgement of the quality: high risk of bias.

Participants Setting: Ziyang, Sichuan province.Origin of the patients: not specied.Numberof participants:89.26 participants received phyllanthus , 21participants receivedthymosin, and 42 received phyllanthus plus thymosin.Sex ratio: 63 males (70%), 26 females (30%).Mean age: 37.2 years (9 to 65 years).Duration of hepatitis B: 3 to 23 years (mean 5.6 years).Diagnostic criteria: Diagnostic criteria of chronic hepatitis B on the Fifth NationConference on Infectious Diseases and Parasitic DiseaseInclusion criteria: not described.Exclusion criteria: not described.

Interventions Intervention: phyllanthus tablet (Pharmaceutical production in Dali, Yunnan province),5 tablets tid, orally, 3 monthsControl: thymosin 10 mg qd, intramuscular, 3 months.Post treatment follow-up: no follow-up.

Outcomes Outcome measure(s): number of patients with positive serum HBsAg, HBeAg and aHBc IgM after treatment Alanine transaminase(ALT), Aspartate transaminase (AST), and total bilirubinlevel wereported as effective rate referred to Ministry of Health guidelines for pharmaceuticlinical research

Notes This is a trial with 3 arms. Two arms comparing phyllanthus versus thymosin wereincluded in our systematic review for analysesSingle centre.Species of phyllanthus were not described.Sources of funding were not stated.

Risk of bias




Allocation concealment (selection bias) Unclear risk No information about concealment.


High risk Phyllanthus was taken orally and thymosinwas given intramuscularly.



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Ouyang 1999 (Continued)


Unclear risk The trial did not reported if there werewithdrawals or dropouts. The number of

patientsanalysedwerethesameasthenum-ber of patients randomised


Other bias High risk There are other factors that could put it atrisk of bias.

Zhu 2005

Methods Trial design: randomised, parallel group trial.Language: Chinese.Type of publication: journal article. Year of trial: 2003, 6 to 2004, 6. Judgement of the quality: high risk of bias.

Participants Setting: The Third Peoples Hospital of Qidong, Jiangsu provinceOrigin of patients: in-patients and out-patients.Numberof participants:92.30 participants received phyllanthus , 30participants receivedthymosin, and 32 received phylanthus plus thymosinSex ratio: phyllanthus capsule group - 22 males (73%), 8 females (27%); thymosin group- 24 males (80%), 6 females (20%); phyllanthus plus thymosin group - 22 males (69%),

10 females (31%).Mean age: phyllanthus - (38.2 9.2) years (18 to 59 years); thymosin group - (37.2 8.1) years (16 to 53 years); phyllanthus plus thymosin group - (35.2 6.8) years (18 to 52years).Duration of hepatitis B: phyllanthus - (9 to 41) years; thymosin group - (8 to 14.2) years; phyllanthus plus thymosin group - (7 to 13.8) years.Diagnostic criteria: Diagnostic criteria of Viral Hepatitis Prevention Programme on tTenth Viral Hepatitis ConferenceInclusion criteria: patients without serious complications.Exclusion criteria: patients of thymosin alpha 1 allergy sufferers; pregnancy or brefeeding patients

Interventions Intervention: phyllanthus capsule (provided by Institute of Tropical Medicine prepara-

tion room of Guangzhou University of Traditional Chinese Medicine, Batch Numbe030112), 4 capsules tid, orally, 24 weeksControl: thymosinalpha1 (HainanShuangchengPharmaceuticalCo.Ltd,BantchNum-ber: 20030612; Formulations: powder) 1.6 mg intramuscular, twice a week, 24 week

Outcomes Outcome measure(s): Changes of HBV virological markers after treatment Alanine transaminase (ALT), protein A/G, and total bilirubin level were reported recovery rate



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Zhu 2005 (Continued)

Notes This is a trial with 3 arms. Two arms comparing phyllanthus versus thymosin alpha 1were included in our systematic review for analyses

Single centre.Species of phyllanthus were not described.Sources of funding were not stated.

Risk of bias



Low risk Described as randomised by Casio randomnumber.

Allocation concealment (selection bias) Unclear risk No information about concealment.


High risk Phyllanthus was taken orally and thymosinwas given intramuscularly.


Unclear risk The trial did not reported if there werewithdrawals or dropouts. The number of patientsanalysedwerethesameasthenum-ber of patients randomised

Selective reporting (reporting bias) Unclear risk No trial protocol was identied. We wunable to contact the authors. It is unclearwhether the trial reported all the outcomes

which had been measuredOther bias High risk There are other factors that could put it at

risk of bias.

Characteristics of excluded studies [ordered by study ID]

Study Reason for exclusion

Cai 2006 Randomised clinical trial tested phyllanthus plus antiviral drugs versus antiviral drugs alone. It was included in theCochrane systematic review entitled Phyllanthus species for chronic hepatitis B virus infection.

Chan 2003 Randomised clinical trial tested phyllanthus plus antiviral drugs versus antiviral drugs alone. It was included in theCochrane systematic review entitled Phyllanthus species for chronic hepatitis B virus infection.

Cheng 2005 Randomised clinical trial tested phyllanthus plus antiviral drugs versus antiviral drugs alone. It was included in theCochrane systematic review entitled Phyllanthus species for chronic hepatitis B virus infection.



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(Continued)

Cui 1998 Randomised clinical trial tested phyllanthus plus antiviral drugs versus antiviral drugs alone. It was included in theCochrane systematic review entitled Phyllanthus species for chronic hepatitis B virus infection.

Gu 2005 Randomised clinical trial tested phyllanthus plus antiviral drugs versus antiviral drugs alone. It was included in theCochrane systematic review entitled Phyllanthus species for chronic hepatitis B virus infection.

He 2008 Randomised clinical trial tested phyllanthus plus antiviral drugs versus antiviral drugs alone. It was included in theCochrane systematic review entitled Phyllanthus species for chronic hepatitis B virus infection.

Huang 1993 A randomised clinical trial on hepatitis B carriers. It does not meet our inclusion criteria

Huang 1999 Randomised clinical trial tested phyllanthus plus antiviral drugs versus antiviral drugs alone. It was included in theCochrane systematic review entitled Phyllanthus species for chronic hepatitis B virus infection.

Huang 1999a Randomised clinical trial tested phyllanthus versus conventional treatment (a combination of inosine and vitaminC), without known antiviral effect

Ma 1993 A randomised clinical trial on hepatitis B carriers. It does not meet our inclusion criteria

Qian 2008 Randomised clinical trial tested phyllanthus plus antiviral drugs versus antiviral drugs alone. It was included in theCochrane systematic review entitled Phyllanthus species for chronic hepatitis B virus infection.

Song 2007 Randomised clinical trial tested phyllanthus plus antiviral drugs versus antiviral drugs alone. It was included in theCochrane systematic review entitled Phyllanthus species for chronic hepatitis B virus infection.

Su 2004 Randomised clinical trial tested phyllanthus plus antiviral drugs versus antiviral drugs alone. It was included in theCochrane systematic review entitled Phyllanthus species for chronic hepatitis B virus infection.

Tian 2004 Randomised clinical trial tested phyllanthus plus antiviral drugs versus antiviral drugs alone. It was included in theCochrane systematic review entitled Phyllanthus species for chronic hepatitis B virus infection.

Wang 2000 A randomised clinical trial on hepatitis B carriers. It does not meet our inclusion criteria

Wang 2009 Randomised clinical trial tested phyllanthus plus antiviral drugs versus antiviral drugs alone. It was included in theCochrane systematic review entitled Phyllanthus species for chronic hepatitis B virus infection.

Ya

2013 phyllantus species vs antiviral

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