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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, Centre for Evidence-Based Chinese Medicine, Beijing University of Chinese Medicine, 11 Bei San Huan Dong Lu, Chaoyang District, Beijing, 100029, China. jianping_l@hotmail.com. jianping@fagmed.uit.no.

Publication History

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

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Characteristics of included studies [ordered by study ID]
Ge 2005

MethodsTrial 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.


ParticipantsSetting: Lijin, Shandong province.

Origin of the patients: not specified.

Number of participants: 68. 36 participants received phyllanthus, 32 participants received lamivudine.

Sex ratio: 47 males (69%), 21 females (31%).

Mean age: 28.1 years (18 to 46 years).

Duration of hepatitis B: not specified.

Diagnostic criteria: Diagnostic criteria of chronic hepatitis B on National Conference on Infectious Diseases and Parasitic Disease, 2000, Xi'an.

Inclusion criteria: patients were treated by lamivudine and got HBV DNA conversion and Alanine transaminase (ALT) normalization before participation.

Exclusion criteria: not described.


InterventionsIntervention: 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.


OutcomesOutcome measure(s): HBV DNA and HBeAg conversion after treatment and follow-up; Alanine transaminase (ALT), total bilirubin, and Albumin (Alb) level before and after treatment; adverse events.


NotesSingle centre.

Species of phyllanthus were not described.

Sources of funding were not stated.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskDescribed as randomised, but the method was not described.

Allocation concealment (selection bias)Unclear riskNot described.

Blinding (performance bias and detection bias)
All outcomes
High riskIt appears the trial was not blind.

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskThe trial did not reported if there were withdrawals or dropouts. The number of patients analysed were the same as the number of patients randomised.

Selective reporting (reporting bias)Unclear riskNo trial protocol was identified. We were unable to contact the authors. It is unclear whether the trial reported all the outcomes which had been measured.

Other biasHigh riskThere are other factors in the trial that could put it at risk of bias.

Huang 2004

MethodsTrial 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.


ParticipantsSetting: Guangzhou, Guangdong province.

Origin of the patients: out-patients.

Number of participants: 60. 30 participants received phyllanthus, 30 participants received lamivudine.

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 on Infectious Diseases and Parasitic Disease, 2000, Xi'an.

Inclusion criteria: patients with serum HBsAg positive, or HBeAg positive or HBV DNA positive, Alanine transaminase (ALT) 1 time higher than the upper limit of normal level, age 16 to 55, no serious complications.

Exclusion criteria: patients allergic with lamivudine, pregnancy or breast-feeding.


InterventionsIntervention: compound phyllanthus capsule (Institute of tropical medicine preparation room of Guangzhou University of Traditional Chinese Medicine), 4 capsules, po, tid, 52 weeks.

Control: lamivudine tablets (GlaxoSmithKline), 100 mg, po, qd, 52 weeks.

Post treatment follow-up: no follow-up.


OutcomesOutcome measure(s): serum HBsAg, HBeAg, and HBV DNA conversion after treatment; Alanine transaminase (ALT), Aspartate transaminase (AST), and total bilirubin normalization.


NotesSingle centre.

Species of phyllanthus were not described.

Sources of funding were not stated.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskDescribed as randomised by Casio random number.

Allocation concealment (selection bias)Unclear riskNo information.

Blinding (performance bias and detection bias)
All outcomes
High riskIt appears the trial was not blind.

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskThe trial did not reported if there were withdrawals or dropouts. The number of patients analysed were the same as the number of patients randomised.

Selective reporting (reporting bias)Unclear riskNo trial protocol was identified. We were unable to contact the authors. It is unclear whether the trial reported all the outcomes which had been measured.

Other biasHigh riskThere are other factors that could put it at risk of bias.

Li 1998

MethodsTrial design: randomised, parallel group trial.

Language: Chinese.

Type of publication: journal article.

Year of trial: 1996, 3 to 1997, 7.

Judgement of the quality: high risk of bias.


ParticipantsSetting: Guangzhou, Guangdong province.

Origin of the patients: not specified.

Number of participants: 55. 30 participants received phyllanthus, 25 participants received interferon alpha 1 b.

Sex ratio: 43 males (78%), 12 females (22%).

Mean age: 31.8 years (15 to 55 years).

Duration of hepatitis B: 0.6 to 20 years (mean 6.3 years).

Diagnostic criteria: Diagnostic criteria of chronic hepatitis B National Conference on Infectious Diseases and Parasitic Disease, 1995, Beijing.

Inclusion criteria: patients with liver dysfunction, serum HBsAg positive, Alanine transaminase (ALT) 1 time higher than the upper limit of the normal level, age 15 to 55, no serious complications.

Exclusion criteria: patients allergic with interferon, pregnancy and breast-feeding.


InterventionsIntervention: compound phyllanthus capsule (Institute of tropical medicine preparation room of Guangzhou University of Traditional Chinese Medicine), 4 capsules, po, tid, 3 months.

Control: Interferon alpha 1 b (Shanghai Institute of Biological Products), 300 IU, IM, qod, 3 months.

Post treatment follow-up: no follow-up.


OutcomesOutcome measure(s): serum HBsAg, HBeAg, and HBV DNA conversion after treatment; Alanine transaminase (ALT), Aspartate transaminase (AST), and total bilirubin normalisation.


NotesSingle centre.

Species of phyllanthus were not described.

Sources of funding: Youth Fund project of State Administration of Traditonal Chinese Medicine.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskDescribed as randomised, but the method was not described.

Allocation concealment (selection bias)Unclear riskNo information.

Blinding (performance bias and detection bias)
All outcomes
High riskPhyllanthus capsule versus interferon alpha injection.

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskThe trial did not reported if there were withdrawals or dropouts. The number of patients analysed were the same as the number of patients randomised.

Selective reporting (reporting bias)Unclear riskNo trial protocol was identified. We were unable to contact the authors. It is unclear whether the trial reported all the outcomes which had been measured.

Other biasHigh riskThere are other factors that could put it at risk of bias.

Ouyang 1999

MethodsTrial 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.


ParticipantsSetting: Ziyang, Sichuan province.

Origin of the patients: not specified.

Number of participants: 89. 26 participants received phyllanthus, 21 participants received thymosin, 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 National Conference on Infectious Diseases and Parasitic Disease.

Inclusion criteria: not described.

Exclusion criteria: not described.


InterventionsIntervention: phyllanthus tablet (Pharmaceutical production in Dali, Yunnan province), 5 tablets tid, orally, 3 months.

Control: thymosin 10 mg qd, intramuscular, 3 months.

Post treatment follow-up: no follow-up.


OutcomesOutcome measure(s): number of patients with positive serum HBsAg, HBeAg and anti-HBc IgM after treatment.

Alanine transaminase (ALT), Aspartate transaminase (AST), and total bilirubin level were reported as effective rate referred to Ministry of Health guidelines for pharmaceutical clinical research.


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

Single centre.

Species of phyllanthus were not described.

Sources of funding were not stated.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskDescribed as randomised, but the method was not described.

Allocation concealment (selection bias)Unclear riskNo information about concealment.

Blinding (performance bias and detection bias)
All outcomes
High riskPhyllanthus was taken orally and thymosin was given intramuscularly.

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskThe trial did not reported if there were withdrawals or dropouts. The number of patients analysed were the same as the number of patients randomised.

Selective reporting (reporting bias)Unclear riskNo trial protocol was identified. We were unable to contact the authors. It is unclear whether the trial reported all the outcomes which had been measured.

Other biasHigh riskThere are other factors that could put it at risk of bias.

Zhu 2005

MethodsTrial 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.


ParticipantsSetting: The Third People's Hospital of Qidong, Jiangsu province.

Origin of patients: in-patients and out-patients.

Number of participants: 92. 30 participants received phyllanthus, 30 participants received thymosin, and 32 received phylanthus plus thymosin.

Sex 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 52 years).

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 the Tenth Viral Hepatitis Conference.

Inclusion criteria: patients without serious complications.

Exclusion criteria: patients of thymosin alpha 1 allergy sufferers; pregnancy or breast-feeding patients.


InterventionsIntervention: phyllanthus capsule (provided by Institute of Tropical Medicine preparation room of Guangzhou University of Traditional Chinese Medicine, Batch Number: 030112), 4 capsules tid, orally, 24 weeks.

Control: thymosin alpha 1 (Hainan Shuangcheng Pharmaceutical Co. Ltd, Bantch Number: 20030612; Formulations: powder) 1.6 mg intramuscular, twice a week, 24 weeks.


OutcomesOutcome measure(s): Changes of HBV virological markers after treatment.

Alanine transaminase (ALT), protein A/G, and total bilirubin level were reported as recovery rate.


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

Single centre.

Species of phyllanthus were not described.

Sources of funding were not stated.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskDescribed as randomised by Casio random number.

Allocation concealment (selection bias)Unclear riskNo information about concealment.

Blinding (performance bias and detection bias)
All outcomes
High riskPhyllanthus was taken orally and thymosin was given intramuscularly.

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskThe trial did not reported if there were withdrawals or dropouts. The number of patients analysed were the same as the number of patients randomised.

Selective reporting (reporting bias)Unclear riskNo trial protocol was identified. We were unable to contact the authors. It is unclear whether the trial reported all the outcomes which had been measured.

Other biasHigh riskThere are other factors that could put it at risk of bias.

 
Characteristics of excluded studies [ordered by study ID]

StudyReason for exclusion

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

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

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

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

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

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

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

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

Huang 1999aRandomised clinical trial tested phyllanthus versus conventional treatment (a combination of inosine and vitamin C), without known antiviral effect.

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

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

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

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

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

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

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

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

Zhang 2006A randomised clinical trial on hepatitis B carriers. It does not meet our inclusion criteria.

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

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

Zhu 1992A randomised clinical trial on hepatitis B carriers. It does not meet our inclusion criteria.

 
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]

 
Table 1. Table 1: Random clinical trials of phyllanthus species

Study IDnMean age

(years)
Male sex

(male)
Phyllanthus groupControl groupLengthPost treatment / follow-up

Ge 20056818 to 4669%Phyllanthus tabletLamivudine tablets6 months6 months

Huang 20046016 to 5555%Phyllanthus capsuleLamivudine tablets52 weeksNo

Li 19985515 to 5578%Phyllanthus capsuleInterferon alpha 1 b3 monthsNo

Ouyang 1999479 to 6570%Phyllanthus tabletThymosin90 daysNo

Zhu 20056017 to 5383%Phyllanthus capsuleThymosin alpha 124 weeksNo

 
Table 2. Table 2: Source and administration of compound phyllanthus

Study IDSource and preparationSpeciesPart of the phyllanthus plantDoseLength

Ge 2005Tablet, but no detailNo data availableNo data available4 to 6 tablets, po, tid6 months

Huang 2004Capsule, prepared by Institute of Tropical Medical preparation room of Guangzhou University of Traditional Chinese Medicine, other ingredients assumed to have no antiviral effects included Astragalus membranaceus, Panax Notoginseng, etc.No data availableNo data available4 capsules, po, tid52 weeks

Li 1998Capsule, prepared by Institute of Tropical Medical preparation room of Guangzhou University of Traditional Chinese Medicine, other ingredients assumed to have no antiviral effects included Panax Notoginseng, etc.No data availableNo data available4 capsules, po, tid3 months

Ouyang 1999Tablet, produced by Pharmaceutical production in Dali, Yunnan provincePhyllanthus urinaria L.No data available5 tablets, po, tid90 days

Zhu 2005Capsule, prepared by Institute of Tropical Medical preparation room of Guangzhou University of Traditional Chinese Medicine, other ingredients assumed to have no antiviral effects included Astragalus membranaceus, Panax Notoginseng, etc.No data availableNo data available4 capsules, po, tid24 weeks

 
Table 3. Table 3: Administration of antiviral drugs

Study IDPreparationDoseLength

Ge 2005Lamivudine tablets, but no details100 mg, po, qd6 months

Huang 2004Lamivudine tablets, produced by GlaxoSmithKline100 mg, po, qd52 weeks

Li 1998Interferon alpha 1 b, produced by Shanghai Institute of Biological Products300 IU, IM, qod3 months

Ouyang 1999Thymosin, but no details10 mg, IM, qd90 days

Zhu 2005Thymosin alpha 1, produced by Hainan Shuangcheng Pharmaceutical Co. Ltd, powder formulation1.6 mg IM, twice a week24 weeks

 po = orally;
qd = every day;
qod = every other day;
tid = three times a day;
IM = intramuscular.