Phyllanthus species versus antiviral drugs for chronic hepatitis B virus infection

  • Review
  • Intervention

Authors

  • Yun Xia,

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

    1. Beijing University of Chinese Medicine, Centre for Evidence-Based Chinese Medicine, Beijing, China
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  • Jian Ping Liu,

    Corresponding author
    1. Beijing University of Chinese Medicine, Centre for Evidence-Based Chinese Medicine, Beijing, China
    2. Copenhagen Trial Unit, Centre for Clinical Intervention Research, Department 7812, Rigshospitalet, Copenhagen University Hospital, The Cochrane Hepato-Biliary Group, Copenhagen, Denmark
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  • Christian Gluud

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

Background

Phyllanthus species for patients with chronic hepatitis B virus (HBV) infection have been assessed in clinical trials, but no consensus regarding their usefulness exists. When compared with placebo or no intervention, we were unable to identify convincing evidence that phyllanthus species are beneficial in patients with chronic hepatitis B. Some randomised clinical trials have compared phyllanthus species versus antiviral drugs.

Objectives

To evaluate the benefits 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 Register of Controlled Trials (CENTRAL) in The Cochrane Library, MEDLINE, EMBASE, Science Citation Index Expended, and the Chinese Biomedical CD Database, China Network Knowledge Information, Chinese Science Journal Database, TCM Online, and Wanfang Database. 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 included trials irrespective of blinding, publication status, or language.

Data collection and analysis

Two authors selected the trials and extracted the data independently. The RevMan software was used for statistical analysis of dichotomous data with risk ratio (RR) with 95% confidence intervals (CI). We assessed the risk of bias to control for systematic errors. We calculated the number of patients needed (required information size) to be randomised in order to make reliable conclusions. We assessed the cumulative findings with trial sequential analysis to control for random errors.

Main results

We identified five randomised clinical trials with 290 patients. All trials were considered to have high risk of bias. Patients in the experimental group received compound phyllanthus for three months to 12 months. Patients in the antiviral drug group received lamivudine, interferon alpha, thymosin, or thymosin alpha 1. None of the trials reported mortality, hepatitis B-related morbidity, quality of life, or liver histology. Phyllanthus seemed to have a superior effect on clearance of serum HBeAg at the end of treatment in conventional 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 significant 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 HBeAg seroconversion was reported in one trial and no significant 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 five trials.

Authors' conclusions

There is currently insufficient 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 beneficial and harmful effects and should primarily test the herb against placebo in addition to antiviral drugs that are known to offer more benefit than harm. Only in this way new interventions can be assessed without compromising personal ethical considerations.

Résumé scientifique

Espèces de phyllanthus versus médicaments antiviraux pour l'infection chronique par le virus de l'hépatite B

Contexte

Des espèces de Phyllanthus pour patients présentant une infection chronique par le virus de l'hépatite B (VHB) ont été évaluées dans des essais cliniques, mais il n'y a pas de consensus quant à leur utilité. Nous n'avons pas trouvé de preuves convaincantes que des espèces de phyllanthus, en comparaison avec un placebo ou l'absence d'intervention, soient bénéfiques chez les patients présentant une hépatite B chronique. Certains essais cliniques randomisés avaient comparé des espèces de phyllanthus à des médicaments antiviraux.

Objectifs

Évaluer les avantages et les inconvénients des espèces de phyllanthus par rapport aux médicaments antiviraux pour les patients présentant une infection chronique par le VHB.

Stratégie de recherche documentaire

Nous avons effectué une recherche dans le registre des essais contrôlés du groupe Cochrane sur les affections hépato-biliaires, le registre Cochrane des essais contrôlés (CENTRAL) in The Cochrane Library, MEDLINE, EMBASE, Science Citation Index Expanded, et dans les Chinese Biomedical CD Database, China Network Knowledge Information, Chinese Science Journal Database, TCM Online et Wanfang Database. Nous avons cherché manuellement dans des actes de conférences en chinois. Toutes les recherches ont été menées jusqu'au 31 octobre 2012.

Critères de sélection

Des essais randomisés cliniques comparant des espèces de phyllanthus à des médicaments antiviraux pour les patients présentant une infection chronique par le VHB. Nous avons inclus des essais sans tenir compte de leur mise en aveugle, de leur statut de publication ou de la langue qu'ils avaient utilisée.

Recueil et analyse des données

Deux auteurs ont sélectionné les essais et extrait les données de manière indépendante. Le logiciel RevMan a été utilisé pour l'analyse statistique des données dichotomiques par le risque relatif (RR) avec des intervalles de confiance (IC) à 95%. Nous avons évalué le risque de biais pour neutraliser les erreurs systémiques. Nous avons calculé le nombre de patients à randomiser pour pouvoir tirer des conclusions fiables. Nous avons évalué les résultats cumulatifs par analyse séquentielle des essais afin de neutraliser les erreurs aléatoires.

Résultats principaux

Nous avons identifié cinq essais cliniques randomisés impliquant 290 patients. Tous les essais ont été considérés présenter un risque élevé de biais. Les patients du groupe expérimental avaient reçu un composé de phyllanthus pendant trois à 12 mois. Les patients dans le groupe de traitement antiviral avaient reçu de la lamivudine, de l'interféron alpha, de la thymosine ou de la thymosine alpha 1. Aucun des essais n'avait rendu compte de la mortalité, de la morbidité liée à l'hépatite B, de la qualité de vie ou de l'histologie hépatique. Le Phyllanthus semblait avoir un effet très net sur la clairance de l'AgHBe sérique à la fin du traitement dans la méta-analyse conventionnelle (RR 0,76 ; IC 95% 0,64 à 0,91 ; P = 0,002 ; I2 = 0%), mais pas avec l'analyse séquentielle des essais. Le Phyllanthus n'avait pas eu d'effet significatif sur la clairance de l'AgHBs sérique (RR 1,00 ; IC 95% 0,93 à 1,08 ; P = 0,92 ; I2 = 0%) ou de l'ADN de VHB (RR 0,83 ; IC 95% 0,53 à 1,31 ; P = 0,43 ; I2 = 70%) en comparaison avec les médicaments antiviraux. Les données sur les séroconversion de l'AgHBe avaient été rapportées dans un essai et aucune différence significative n'avait été observée dans la comparaison du phyllanthus à la lamivudine (RR 0,89 ; IC 95% 0,71 à 1,11). Dans les cinq essais, aucunes données n'avaient été rapportées sur les événements indésirables.

Conclusions des auteurs

Les données dont on dispose actuellement ne suffisent pas pour étayer ou réfuter l'utilisation de phyllanthus pour les patients présentant une infection chronique par le virus de l'hépatite B. Les chercheurs désireux d'effectuer de nouveaux essais cliniques randomisés sur le phyllanthus devraient s'intéresser à la fois aux effets bénéfiques et aux effets néfastes et devraient principalement comparer l'herbe à un placebo, en supplément aux médicaments antiviraux qui sont reconnus présenter plus d'avantages que d'inconvénients. Ce n'est qu'ainsi que de nouvelles interventions peuvent être évaluées sans compromis avec des considérations éthiques personnelles.

アブストラクト

慢性B型肝炎ウイルス感染に対するコミカンソウ種対抗ウイルス薬

背景

慢性B型肝炎ウイルス(HBV)感染患者に対するコミカンソウ種(Phyllanthus species)は、臨床試験で評価されてきたが、その有用性に関する一致した見解はない。プラセボや介入なしと比較して、コミカンソウ種が慢性B型肝炎患者で有益であることを示す確定的なエビデンスを特定できなかった。いくつかのランダム化臨床試験では、コミカンソウ種と抗ウイルス薬を比較していた。

目的

慢性HBV感染患者を対象としてコミカンソウ種を抗ウイルス薬と比較した場合の有益性および有害性を評価すること。

検索戦略

Cochrane Hepato-Biliary Gorup Controlled Trials Register、コクラン・ライブラリにおけるCochrane Central Register of Controlled Trials(CENTRAL)、MEDLINE、EMBASE、Science Citation Index Expended、Chinese Biomedical CD Database、China Network Knowledge Information、Chinese Science Journal Database、TCM OnlineおよびWanfang Databaseを検索した。 中国語の議事録をハンドサーチした。すべての検索は、2012年10月31までに実施した。

選択基準

慢性HBV感染患者を対象にコミカンソウ種と抗ウイルス薬を比較するランダム化臨床試験。 盲検化、公表状態や言語に制限を設けずに試験を選択した。

データ収集と分析

2名の著者が独立して試験を選択し、データを抽出した。リスク比(RR)と95%信頼区間(CI)で示した二項データについて、RevManソフトウェアを用いて統計学的解析を行った。システマティックな誤差を調整するため、バイアスのリスクを評価した。信頼性の高い結論を導くため、ランダム化されるべき患者数(必要情報量)を算出した。ランダム化誤差について調整するため、試験逐次解析を用いて累積結果を評価した。

主な結果

290例の患者を対象としたランダム化臨床試験を5件特定した。すべての試験について、バイアスのリスクが高いと判定された。実験群の患者は、コミカンソウ化合物を3~12カ月間投与されていた。 抗ウイルス薬群の患者は、ラミブジン、インターフェロンα、サイモシンやサイモシンα1を投与されていた。いずれの試験も、死亡率、B型肝炎関連の罹病率、QOL、肝組織像について報告していなかった。従来のメタアナリシスでは、治療終了時における血清HBeAgのクリアランスにコミカンソウの効果の優越性が認められたが(RR 0.76;95% CI 0.64~0.91、 P = 0.002;I2 = 0%)、試験逐次解析では認められなかった。 抗ウイルス薬と比較してコミカンソウには、血清HbsAg(RR 1.00;95% CI 0.93~1.08、P = 0.92;I2 = 0%)またはHBV DNA(RR 0.83;95% CI 0.53~1.31、P = 0.43;I2 =70%)のクリアランスに対する有意な効果は認められなかった。 HbeAgセロコンバーションに関するデータは1試験で報告されており、コミカンソウとラミブジンとを比較した際の有意差は認められなかった(RR 0.89;95% CI 0.71~1.11)。 5試験で、有害事象に関するデータは報告されていなかった。

著者の結論

現時点でエビデンスが不十分であるため、慢性B型肝炎ウイルス感染患者に対して、コミカンソウの使用を支持したり否定したりできない。 コミカンソウに関するランダム化臨床試験を今後実施しようと考えている研究者は、有益な作用および有害な作用の双方を検証するべきであり、有害性よりも有益性が認められている抗ウイルス薬に加えてプラセボを対照にコミカンソウを第一に試験するべきである。 個人の倫理的な考慮事項を損なうことなく、このように新たな介入法を評価するべきである。

訳注

《実施組織》厚生労働省「「統合医療」に係る情報発信等推進事業」(eJIM:http://www.ejim.ncgg.go.jp/)[2016.1.9]
《注意》この日本語訳は、臨床医、疫学研究者などによる翻訳のチェックを受けて公開していますが、訳語の間違いなどお気づきの点がございましたら、eJIM事務局までご連絡ください。なお、2013年6月からコクラン・ライブラリーのNew review, Updated reviewとも日単位で更新されています。eJIMでは最新版の日本語訳を掲載するよう努めておりますが、タイム・ラグが生じている場合もあります。ご利用に際しては、最新版(英語版)の内容をご確認ください。

Plain language summary

Phyllanthus species versus antiviral drugs for chronic hepatitis B virus infection

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

The findings of this review are based on five 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 findings of this review are that phyllanthus seemed to have a superior effect on clearance of serum HBeAg at the end of treatment in conventional meta-analysis, but not when trial sequential analysis was applied. Phyllanthus had no significant effect on clearance of serum HBsAg, serum HBV DNA, or HBeAg seroconversion when compared with antiviral drugs. No data were identified on mortality or morbidity, adverse events, quality of life, or liver histology. However, the findings in our review are inconclusive due to the small numbers of patients and outcomes, risk of bias, and the study design. We need more randomised trials to confirm or reject the potential effects of phyllanthus. We advocate that phyllanthus is primarily assessed against placebo. This can be done in randomised clinical trials in which all patients receive antiviral drugs that are known to offer more benefit 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 assess the effects of phyllanthus versus other antiviral drugs superior to placebo in such trials. The quality of trials regarding conduct and report should also be taken into account.

Résumé simplifié

Espèces de phyllanthus versus médicaments antiviraux pour l'infection chronique par le virus de l'hépatite B

L'infection chronique par le virus de l'hépatite B (VHB) provoque une mortalité importante, de la morbidité, et a un impact économique important dans le monde entier. Bien que les thérapies actuellement approuvées montrent des effets bénéfiques, la réponse au traitement n'est pas satisfaisante, les patients ont un risque élevé de développer une résistance virale, et des événements indésirables graves se produisent. L'objectif de cette revue était d'évaluer les avantages et les inconvénients des espèces de phyllanthus par rapport aux médicaments antiviraux couramment utilisés chez les patients présentant une infection chronique par le VHB. Dans une revue systématique précédente du groupe Cochrane sur les affections hépato-biliaires, nous avions comparé des espèces de phyllanthus à un placebo ou à l'absence d'intervention. Dans cette revue, nous ne sommes pas parvenus à trouver des preuves convaincantes étayant l'utilisation d'espèces de phyllanthus pour les patients atteints d'hépatite B chronique.

Les résultats de cette revue sont fondés sur cinq essais cliniques randomisés impliquant 290 patients. Le Phyllanthus avait été testé par rapport à des médicaments antiviraux, notamment la lamivudine, l'interféron alpha, la thymosine ou la thymosine alpha 1, pendant trois à 12 mois. Les principales conclusions de cette revue sont que le phyllanthus semble avoir eu un effet très net sur la clairance de l'AgHBe sérique à la fin du traitement dans la méta-analyse conventionnelle, mais pas avec l'analyse séquentielle des essais. Le Phyllanthus n'avait pas eu d'effet significatif sur la clairance de l'AgHBs sérique ou de l'ADN de VHB sérique, ou la séroconversion de l'AgHBe, par rapport aux médicaments antiviraux. Aucune donnée n'a été identifiée sur la mortalité ou la morbidité, les effets indésirables, la qualité de vie ou l'histologie du foie. Les résultats de notre revue ne sont toutefois pas concluants en raison du nombre restreint de patients et de critères de résultat, du risque de biais et de la conception des études. Nous avons besoin d'essais randomisés supplémentaires pour confirmer ou infirmer les effets potentiels du phyllanthus. Nous préconisons que le phyllanthus soit principalement évalué par rapport à un placebo. Cela peut être fait dans des essais cliniques randomisés dans lesquels tous les patients reçoivent des médicaments antiviraux reconnus pour présenter plus d'avantages que d'inconvénients, et où les patients sont ensuite randomisés au phyllanthus ou à un placebo. Si l'effet du phyllanthus par rapport au placebo est démontré sans équivoque dans de tels essais, il pourra être prudent d'évaluer les effets du phyllanthus par rapport à d'autres médicaments antiviraux supérieurs au placebo dans de tels essais. La qualité de réalisation et de compte-rendu des essais devra également être prise en compte.

Notes de traduction

Traduit par: French Cochrane Centre 17th May, 2013
Traduction financée par: Pour la France : Minist�re de la Sant�. Pour le Canada : Instituts de recherche en sant� du Canada, minist�re de la Sant� du Qu�bec, Fonds de recherche de Qu�bec-Sant� et Institut national d'excellence en sant� et en services sociaux.

平易な要約

慢性B型肝炎ウイルス感染に対するコミカンソウ種と抗ウイルス薬

慢性B型肝炎ウイルス(HBV)感染は、顕著な死亡率および罹病率の原因となり、世界的に経済的な負担となっている。現在承認されている治療法には有益な効果が認められているが、治療への反応は満足度の高いものではなく、患者にはウイルス耐性が現れる高いリスクがあり、重篤な有害事象も起こる。本レビューの目的は、慢性HBV感染患者を対象にコミカンソウ種と一般的に使用されている抗ウイルス薬を比較した際の有益性および有害性を評価することとした。 過去のCochrane Hepato-Biliary Groupシステマティック・レビューでは、コミカンソウ種とプラセボまたは非介入とを比較した。 同レビューでは、慢性B型肝炎患者にコミカンソウ種を使用する根拠となる確定的なエビデンスをみつけることができなかった。

今回のレビューの結果は、290例の患者を対象とした5件のランダム化臨床試験に基づく。コミカンソウは、ラミブジン、インターフェロンα、サイモシンやサイモシンα1などの抗ウイルス薬と3~12カ月間検証された。本レビューの主な結果としては、従来のメタアナリシスでは、治療終了時における血清HBeAgのクリアランスにコミカンソウの効果の優越性が認められたが、試験逐次解析では認められなかった。 抗ウイルス薬と比較してコミカンソウは、血清中HbsAg、血清中HBV DNAのクリアランス、HBeAgセロコンバーションに対して有意な効果を示さなかった。死亡率、罹病率、有害事象、QOL、肝組織像に関するデータは認められなかった。しかし、本レビューの結果は、患者数やアウトカムの数が少ないこと、バイアスのリスクおよび試験デザインの問題のために確定的ではない。コミカンソウの効果を確定または否定するためのランダム化試験をさらに行う必要がある。 まずコミカンソウとプラセボを比較評価することを推奨する。 このことは、有害性よりも有益性が知られている抗ウイルスをすべての患者に投与し、その後コミカンソウ群またはプラセボ群に患者をランダム化するランダム化臨床試験で行うことができる。 プラセボに対するコミカンソウの効果がこのような試験で明白に示されれば、同様の試験でプラセボよりも優れているその他の抗ウイルス薬に対するコミカンソウの効果を評価すると良いであろう。 実施および報告に関する試験の質も考慮すべきである。

訳注

《実施組織》厚生労働省「「統合医療」に係る情報発信等推進事業」(eJIM:http://www.ejim.ncgg.go.jp/)[2016.1.9]
《注意》この日本語訳は、臨床医、疫学研究者などによる翻訳のチェックを受けて公開していますが、訳語の間違いなどお気づきの点がございましたら、eJIM事務局までご連絡ください。なお、2013年6月からコクラン・ライブラリーのNew review, Updated reviewとも日単位で更新されています。eJIMでは最新版の日本語訳を掲載するよう努めておりますが、タイム・ラグが生じている場合もあります。ご利用に際しては、最新版(英語版)の内容をご確認ください。

Background

Description of the condition

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

There is a hepatitis B vaccine available, and the vaccine is found to be 95% effective in preventing HBV infection (Chen 2005; Lee 2006; Mathew 2008; WHO 2008). Most countries have included the hepatitis B vaccine into their national infant immunisation programmes, and vaccination has markedly reduced the frequency of chronic HBV infection (Chang 1997; WHO 2001). Furthermore, hepatitis B vaccine has been shown to be cost-effective (Aggarwal 2003). However, vaccination offers no benefit for adults with chronic HBV infection. Hence, millions of patients are awaiting improvement in the treatment of this disease.

Description of the intervention

Currently approved therapies for chronic hepatitis B include immunomodulatory agents (interferon alpha and pegylated interferon alpha) and nucleoside analogues (lamivudine, telbivudine, entecavir, adefovir, and tenofovir) (EASL 2009). Interferon alpha treatment results in viral, biochemical, and histological remission in about 30% of the patients (EASL 2009). However, interferon alpha (conventional or pegylated) has the disadvantages of high cost and serious adverse events, which may lead to treatment discontinuation. Lamivudine is inexpensive, but patients are at high risk of developing viral resistance. New antiviral drugs characterised by more potent antiviral effects, less toxicity, and minimal risk of resistance have been explored during the past decades. Entecavir and tenofovir are potent HBV inhibitors and have a high barrier to resistance (EASL 2009). Adefovir has most of the advantages of lamivudine, with the additional benefit that viral drug resistance is uncommon (Marcellin 2003). Telbivudine is another potent inhibitor of HBV (EASL 2009). However, despite these advances, the use of these drugs may still be limited by cost, and by being effective in a limited number of patients only. In China, a large number of patients who cannot afford this 'standard therapy' seek help from traditional Chinese medicine.

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

How the intervention might work

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

Why it is important to do this review

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

Objectives

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

Methods

Criteria for considering studies for this review

Types of studies

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

Types of participants

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

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

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

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

Types of interventions

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

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

Types of outcome measures

The following outcome measures were sought at the end of treatment as well as at maximal follow-up.

Primary outcomes
  1. All-cause mortality.

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

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

  4. Number of participants with serious and non-serious adverse events in separate (as defined by the International Conference on Harmonisation Guideline for Good Clinical Practice (ICH-GCP 1997)).

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

Secondary outcomes
  1. Number of participants with detectable serum HBsAg.

  2. Number of participants with detectable serum HBV DNA.

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

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

  5. Number of participants with worsened liver histology.

Search methods for identification of studies

Electronic searches

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

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

Searching other resources

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

Data collection and analysis

The methodology for data collection and analysis is based on The Cochrane Handbook of Systematic Reviews of Interventions (Higgins 2009) and the Cochrane Hepato-Biliary Group Module (Gluud 2011).

Selection of studies

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

Data extraction and management

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

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

  • Participants: age, sex, ethnic origin, previous antiviral treatment, duration of hepatitis B, diagnostic criteria, inclusion and exclusion criteria, number of patients randomised, assessment of compliance, and withdrawals/losses to follow-up (reasons/description).

  • Interventions: species and origin of phyllanthus, dosage and duration of therapy, formulation, route of administration, and intervention in the control group.

  • Outcomes: as listed above under outcome measures.

Assessment of risk of bias in included studies

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

Allocation sequence generation 
- Low risk of bias: sequence generation was achieved using computer random number generation or a random number table. Drawing lots, tossing a coin, shuffling cards and throwing dice are adequate if performed by an independent adjudicator.
- Uncertain risk of bias: the trial is described as randomised, but the method of sequence generation was not specified.
- High risk of bias: the sequence generation method is not, or may not be, random. Quasi-randomised studies, those using dates, names, or admittance numbers in order to allocate patients are inadequate and will be excluded for the assessment of benefits but not for harms.

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

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

Incomplete outcome data
- Low risk of bias: the numbers and reasons for dropouts and withdrawals in all intervention groups were described or if it was specified that there were no dropouts or withdrawals.
- Uncertain risk of bias: the report gave the impression that there had been no dropouts or withdrawals, but this was not specifically stated.
- High risk of bias: the number or reasons for dropouts and withdrawals were not described.

Selective outcome reporting
- Low risk of bias: pre-defined, or clinically relevant and reasonably expected outcomes are reported on.
- Uncertain risk of bias: not all pre-defined, or clinically relevant and reasonably expected outcomes are reported on or are not reported fully, or it is unclear whether data on these outcomes were recorded or not.
- High risk of bias: one or more clinically relevant and reasonably expected outcomes were not reported on; data on these outcomes were likely to have been recorded.

Other biases
- Low risk of bias: the trial appears to be free of other sources of bias (eg, conflict of interest bias).
- Uncertain risk of bias: there is insufficient information to assess whether other sources of bias are present).
- High risk of bias: it is likely that potential sources of bias related to specific design used, early termination due to some data-dependent process, lack of sample size or power calculation, or other bias risks are present.

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

Measures of treatment effect

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

Unit of analysis issues

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

Dealing with missing data

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

Assessment of heterogeneity

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

Assessment of reporting biases

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

Data synthesis

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

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

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

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

Subgroup analysis and investigation of heterogeneity

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

Results

Description of studies

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

Figure 1.

Flow diagram of the search.

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

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

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

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

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

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

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

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

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

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

Risk of bias in included studies

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

Figure 2.

Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.

Figure 3.

Risk of bias summary: review authors' judgements about each risk of bias item for each included study.

Allocation

Allocation sequence generation 

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

Allocation concealment

Allocation concealment was not described in any of the trials.

Blinding

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

Incomplete outcome data

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

Selective reporting

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

Other potential sources of bias

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

Effects of interventions

Mortality and morbidity

None of the trials reported on mortality or morbidity.

Adverse events

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

Quality of life

None of the trials reported on quality of life.

Number of patients with detectable serum HBsAg

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

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

Number of patients with detectable serum HBV DNA

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

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

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

Number of patients with detectable serum HBeAg

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

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

Figure 4.

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

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

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

Number of participants without HBeAg seroconversion

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

Number of participants with worsened liver histology

None of the trials reported data on this outcome measure.

Subgroup analyses

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

Discussion

Summary of main results

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

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

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

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

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

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

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

Authors' conclusions

Implications for practice

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

Implications for research

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

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

Acknowledgements

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

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

Data and analyses

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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]
Analysis 1.1.

Comparison 1 Phyllanthus versus antiviral drug, Outcome 1 Number of patients with detectable serum HBsAg.

Analysis 1.2.

Comparison 1 Phyllanthus versus antiviral drug, Outcome 2 Number of patients with detectable serum HBV DNA ( end of treatment ).

Analysis 1.3.

Comparison 1 Phyllanthus versus antiviral drug, Outcome 3 Number of patients with detectable serum HBV DNA ( end of post-treatment follow-up ).

Analysis 1.4.

Comparison 1 Phyllanthus versus antiviral drug, Outcome 4 Number of patients with detectable serum HBeAg ( end of treatment ).

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 ).

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 lamivudine160Risk Ratio (M-H, Random, 95% CI)1.04 [0.89, 1.21]
1.2 Phyllanthus versus interferon alpha155Risk Ratio (M-H, Random, 95% CI)1.01 [0.87, 1.18]
1.3 Phyllanthus versus thymosin2107Risk 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 lamivudine2128Risk Ratio (M-H, Random, 95% CI)0.87 [0.21, 3.57]
2.2 Phyllanthus versus interferon alpha141Risk Ratio (M-H, Random, 95% CI)1.17 [0.61, 2.24]
2.3 Phyllanthus versus thymosin160Risk 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 lamivudine2128Risk Ratio (M-H, Random, 95% CI)0.68 [0.53, 0.87]
3.2 Phyllanthus versus interferon alpha146Risk Ratio (M-H, Random, 95% CI)1.05 [0.63, 1.76]
3.3 Phyllanthus versus thymosin297Risk Ratio (M-H, Random, 95% CI)0.78 [0.58, 1.03]
4 Number of patients without HBeAg seroconversion (end of treatment)1 Risk Ratio (M-H, Random, 95% CI)Subtotals only
4.1 Phyllanthus versus lamivudine168Risk Ratio (M-H, Random, 95% CI)0.89 [0.71, 1.11]
Analysis 2.1.

Comparison 2 Phyllanthus versus antiviral drug according to antiviral drugs, Outcome 1 Number of patients with detectable serum HBsAg.

Analysis 2.2.

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

Analysis 2.4.

Comparison 2 Phyllanthus versus antiviral drug according to antiviral drugs, Outcome 4 Number of patients without HBeAg seroconversion (end of treatment).

Appendices

Appendix 1. Search strategies

DatabaseTime spanSearch strategy
The Cochrane Hepato-Biliary Group Controlled Trials RegisterOctober 31, 2012.phyllanthus
The Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane LibraryOctober 31, 2012.#1 phyllanthus
#2 CHRONIC HEPATITIS B explode all trees (MeSH)
#3 (chronic next hepatitis next B)
#4 (#1 and (#2 or #3))
MEDLINE (Ovid SP)1950 to October 31, 2012.1 phyllanthus.mp. [mp=title, original title, abstract, name of substance word, subject heading word, unique identifier]
2 explode "Hepatitis-B-Chronic"/ all subheadings
3 chronic hepatitis B.mp. [mp=title, original title, abstract, name of substance word, subject heading word, unique identifier]
4 1 and (2 or 3)
EMBASE (Ovid SP)1980 to October 31, 2012.1 phyllanthus.mp. [mp=title, original title, abstract, name of substance word, subject heading word, unique identifier]
2 explode "Hepatitis-B-Chronic"/ all subheadings
3 chronic hepatitis B.mp. [mp=title, original title, abstract, name of substance word, subject heading word, unique identifier]
4 1 and (2 or 3)
Science Citation Index Expanded (http://apps.isiknowledge.com )1900 to October 31, 2012.#1 TS=phyllanthus
#2 TS=chronic hepatitis B
#4 #1 and #2
Chinese Biomedical CD Database (CBM)
(http://sinomed.imicams.ac.cn/)
1978 to October 31, 2012.Search strategy in Chinese.
#1 phyllanthus
#2 hepatitis B
#3 random
#4 #1 AND #2
#5 #3 AND #4
China Network Knowledge Information (CNKI)
(http://www.cnki.net/)
1994 to October 31, 2012.Search strategy in Chinese.
#1 phyllanthus
#2 hepatitis B
#3 random
#4 #1 AND #2
#5 #3 AND #4
Chinese Science Journal Database (VIP)
(http://www.cqvip.com/)
1989 to October 31, 2012.Search strategy in Chinese.
#1 phyllanthus
#2 hepatitis B
#3 #1 AND #2
TCM Online (http://www.cintcm.com/opencms/opencms/index.html)1984 to October 31, 2012.Search strategy in Chinese.
#1 phyllanthus
#2 hepatitis B
#3 random
#4 #1 AND #2
#5 #3 AND #4
Wanfang Database (http://www.wanfangdata.com.cn/)1982 to October 31, 2012.Search strategy in Chinese.
#1 phyllanthus
#2 hepatitis B
#3 random
#4 #1 AND #2
#5 #3 AND #4

Contributions of authors

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

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

Declarations of interest

None known.

Sources of support

Internal sources

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

  • Copenhagen Trial Unit, Centre for Clinical Intervention Research, Denmark.

External sources

  • National Basic Research Program of China (973 Program) (2006CB504602), China.

  • International Cooperation Project of the Ministry of Science and Technology (2009DFA31460), China.

  • State Scholarship Fund of Chinese Scholarship Council (2010655001), China.

  • Grant number R24 AT001293 from the National Center for Complementary and Alternative Medicine (NCCAM), USA.

Differences between protocol and review

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

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

Characteristics of studies

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 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.

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.

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.
Notes

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 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

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.

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.

Interventions

Intervention: 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.
Notes

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.
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

Methods

Trial 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.

Participants

Setting: 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.

Interventions

Intervention: 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.
Notes

Single 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

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 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.

Interventions

Intervention: 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.

Outcomes

Outcome 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.

Notes

This 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

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 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.

Interventions

Intervention: 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.

Outcomes

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

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

Notes

This 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.

Ancillary