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.

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.

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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 strategy: 

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.

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