Medicinal Herbs for Hepatitis C Virus Infection: A Cochrane Hepatobiliary Systematic Review of Randomized Trials

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NATAP - www.natap.orgMedicinal Herbs for Hepatitis C Virus Infection: A Cochrane Hepatobiliary Systematic Review of Randomized TrialsAmerican Journal of GastroenterologyVolume 98 Issue 3 Page 538 - March 2003Jianping LiuM.D., Ph.D. a, b * , ManheimerPh.D. c , Kiichiro TsutaniM.D. d , Christian GluudDr. Med. Sci. aObjective The aim of this study was to assess beneficial and harmful effects of medicinal herbs for hepatitis C virus (HCV) infection.Methods The databases of the Cochrane Collaboration, MEDLINE, EMBASE, and BIOSIS were searched combined with manual searches of five Chinese and one Japanese journals. We included randomized trials comparing medicinal herbs with placebo, no intervention, nonspecific treatment, other herbs, or interferon and/or ribavirin. Trials of herbs with or without other drug(s) were included. Methodological quality of the trials was evaluated by randomization, double blinding, and the Jadad scale.Results Thirteen randomized trials (n = 818) evaluated 14 medicinal herbs. Four trials had adequate methodology. Compared with placebo, none of the herbs showed effects on HCV RNA or liver enzyme, except for silybin, which showed a significant reduction of serum AST and gamma-glutamyltranspeptidase levels in one trial. Oxymatrine showed effects on clearance of HCV RNA (relative risk = 9.20, 95% CI = 1.26-67.35) compared with vitamins. The herbal mixture Bing Gan Tang plus interferon-alpha showed better effects on clearance of HCV RNA (relative risk = 2.54, 95% CI = 1.43-4.49) and on normalization of serum ALT (relative risk = 2.54, 95% CI = 1.43-4.49) than interferon-alpha alone. The herbal mixture Yi Zhu decoction showed better effects on clearance of HCV RNA and normalization of ALT compared with glycyrrhizin plus ribavirin. Yi Er Gan Tang showed effects on normalizing serum ALT compared with silymarin plus glucurolactone. The herbs were associated with adverse events.Conclusions There is no firm evidence supporting medicinal herbs for HCV infection, and further randomized trials are justified.INTRODUCTIONHepatitis C is an infectious disease of the liver caused by the hepatitis C virus (HCV) (1). Currently, an estimated 170 million persons worldwide are chronically infected with HCV (2). HCV infection may be self-limited (viral clearance) or persistent (3-5). Viral clearance occurs in about 15% of persons with HCV-specific antibodies (anti-HCV) when HCV RNA is undetectable in multiple tests (4-6). About 85% patients develop persistent HCV infection (7), and liver cirrhosis develops in about 20% patients with chronic hepatitis C within 20 yr (8, 9). Once cirrhosis is established, one fourth of them will ultimately suffer from liver cancer or liver failure (9, 10). However, other studies suggest that chronic HCV infection may have a much better prognosis (11-14).Presently, the most effective therapy for chronic hepatitis C is interferon (IFN)-alpha plus ribavirin (13, 14). Both of them demonstrated a significant effect on virological and histological responses. However, we do not yet know whether the effects on these surrogate outcome measures can be turned into patient-relevant outcomes such as quality of life and decreased mortality. Furthermore, IFN and ribavirin are connected with a plethora of adverse events and are costly. Therefore, new medications and approaches to treatment are needed. Complementary therapies are being used increasingly (15, 16). The number of randomized trials of complementary treatments has doubled every 5 yr, and The Cochrane Library now includes nearly 50 systematic reviews of complementary medicine interventions (16). Many people turn to this therapy when conventional medicine fails, or they believe strongly in the effectiveness of complementary medicine.Clinical trials have shown that some medicinal herbs might have therapeutic potential for chronic hepatitis C (17-22), or alleviating adverse effects of conventional therapy such as depression (23). On the other hand, there are reports about liver toxicity and other adverse events from some herbal products (24-26). Accordingly, the efficacy and safety of treating HCV infection using medicinal herbs should be evaluated systematically.Materials and methods This study is based on a previously published protocol for a Cochrane systematic review (27).SearchingEligible trials were identified through electronic searches (February, 2002) of the Controlled Trials Registers of the Cochrane Hepatobiliary Group, the Cochrane Complementary Medicine Field, The Cochrane Library, MEDLINE, EMBASE, BIOSIS, Chinese biomedical databases, and Japanese databases. Five Chinese journals, one Japanese journal, conference proceedings, and the references of identified trials were handsearched.SelectionInclusion criteria were randomized clinical trials comparing medicinal herbs with placebo, no intervention, nonspecific treatments, such as vitamins, other medicinal herbs, or IFN (no limitation regarding IFN type or regimen), and/or ribavirin. Trials on medicinal herbs plus IFN and/or ribavirin versus IFN and/or ribavirin alone were also included. Cointerventions were allowed as long as both arms of the randomized allocation received the same intervention(s). There were no limits on blinding, publication status, language, age, gender, or ethnic origin of patients with acute or chronic HCV infection. The main outcomes were virological response (loss of detectable HCV RNA) at the end of treatment and at maximal follow-up after completion of the treatment, liver fibrosis, cirrhosis, cancer, and liver-related mortality (28). Secondary outcomes were biochemical response (normalization of serum transaminases), improvement of histological activity index (29), quality of life, cost, and adverse events (30). Trials on patients coinfected with HIV were excluded. Two reviewers independently selected the trials.Validity assessmentMethodological quality was assessed by the adequacy of generation of the allocation sequence, allocation concealment, double blinding (31-33), and the Jadad scale (32-34).Data extractionData were extracted independently by two reviewers and validated by a third party. The following data were extracted: primary author, study design, mean age, gender and ethnicity of patients, numbers of patients randomized and lost during follow-up, inclusion and exclusion criteria, dosage and duration of intervention, outcome measures, and adverse events. The missing data were sought by correspondence with the principle investigator.Data synthesisDichotomous data were presented as relative risk and continuous outcomes as weighted mean difference (WMD), both with 95% CIs. For dichotomous outcomes, patients with incomplete or missing data were included in sensitivity analysis by counting them as treatment failures to explore the possible effect of loss to follow-up on the findings ("worst-case" scenario). Meta-analysis was performed in Review Manager 4.1 (The Cochrane Collaboration, Oxford, England, 2000) within comparisons of the same medicinal herb versus the same controls. The random effects model was used when there was heterogeneity ( p< 0.1) among trials. If a sufficient number of trials were identified, we planned to perform sensitivity analyses according to their methodological quality. Potential biases were investigated according to Egger et al. (35).Identification of trialsOur initial searches identified 110 references, 90 from the electronic searches and 20 from the handsearches. After reading titles and abstracts, 59 of these articles were excluded. A total of 51 references published in three languages (Chinese, English, and Japanese) were retrieved for further assessment. Of these, 37 were excluded, and the reasons for exclusion were listed under "characteristics of excluded studies" (36). One abstract was excluded because of duplication of an included trial (37). The remaining 13 randomized trials reported random allocation of patients (n = 818) with mainly chronic hepatitis C to medicinal herbs versus placebo in four trials, nonspecific drug (vitamin) in one trial, IFN in five trials, other herbal medicines in two trials, and herb plus ribavirin in one trial (Table 1). All patients were adults (mean age 38 yr), and the proportion of men was 69%. The average size per trial was 69 patients (range 20-192). Four trials confirmed the diagnosis by liver biopsy (38-41). Ten trials included patients with chronic hepatitis C (85%), one in patients with acute and chronic hepatitis C (42), and another two in undefined patients with hepatitis C (43, 44). Nine trials were tested in Chinese patients and one each in Australians, Italians, Americans, and Europeans.Fourteen medicinal herbs were tested in the trials, without one tested twice (Table 1). The median duration of treatment was 17 wk (1-24 wk). No trial reported mortality, liver cirrhosis or cancer, quality of life, or cost. The reported outcomes were viral and biochemical responses, liver histology, symptoms, and adverse effects.Of 13 included trials, one trial had adequate generation of allocation sequence, two trials had adequate allocation concealment, and four trials had adequate double blinding. Four trials reported the numbers of patients withdrawn and the reasons (38, 40, 45, 46). The four double-blind trials obtained high Jadad scores (>=3) (38-40, 45), and nine obtained low scores (<=2) (41-44, 46-50). No trial reported sample size estimation or stated that intention-to-treat analysis was used.End-of-treatment responsesCompared with placebo, herbal medicine CH-100 and glycyrrhizin showed no significant effect on clearance of serum HCV RNA or normalization of serum ALT level (38, 40). Complete Thymic Formula showed no significant effect on clearance of HCV RNA and on serum AST level compared with placebo (45). Compared with placebo, silybin showed a significant effect on reducing serum AST level (WMD = -24.60 U/L, 95% CI = -34.28 to -14.92 U/L) and serum gamma-glutamyltranspeptidase level (WMD = -18.40 U/L, 95% CI = -23.78 to -13.02 U/L) after treatment for 7 days, but no significant effect on serum ALT or bilirubin level (39). Compared with vitamins, herbal extract oxymatrine showed a significant effect on clearance of HCV RNA (46), but no significant effect on normalizing ALT level (Table 2). Compared with IFN-alpha, the herbal compound Bing Gan Ling had no significant difference on the clearance of HCV RNA and normalization of ALT level at the end of a 3-month treatment (41). Another herbal compound, Bing Gan Ning granule, showed no significant difference on the clearance of HCV RNA and on ALT normalization compared with IFN-alpha (42). The herbal compound Bing Gan Tang plus IFN-alpha showed a significant effect on the clearance of HCV RNA and ALT normalization compared with IFN-alpha alone (43). Compared with IFN alone, the combinations of herbal compound Bing Gan capsules with IFN and Gansu capsules with IFN showed no significantly better effect on clearance of HCV RNA and ALT normalization (44, 50).Compared with glycyrrhizin plus ribavirin, Yi Zhu decoction showed significant effects on clearance of HCV RNA and ALT normalization at the end of a 3-month treatment (49). Compared with silymarin plus glucolactone, the herbal compound Yi Er Gan Tang showed a significant effect on ALT normalization (48). Compared with no intervention, the herbal compounds Qinggan granule and Bushen granule showed no significant effect on reducing AST, ALP, and gamma-glutamyltranspeptidase levels (47).One trial evaluated histological outcome through liver biopsy using inflammatory grade and fibrotic stage indexes (47). A semiquantitative score (Chevallier's system) (51) showed that the score of liver fibrosis decreased significantly (WMD = -3.51, 95% CI = -6.97 to -0.05, p = 0.05) using the herbal compound Qinggan compared with no intervention; however, there was no significant difference between Bushen and no intervention. For the score of inflammatory grade, Qinggan or Bushen showed no significant effect.Sustained responses and clinical effectsSustained responses could not be assessed because of inadequate reporting in seven trials with follow-up. The outcome of symptoms could not be assessed because of inadequate reporting in the trials. Adverse events were reported in seven trials (38-41, 44-46). Four patients experienced adverse events during herbal therapy with CH-100, in which one patient developed palpitation, two had diarrhea, and one had abdominal discomfort (38). Cold or "flu-like" symptoms, rash, itching, diarrhea, and nausea were observed in patients treated with glycyrrhizin (40). One patient developed severe thrombocytopenia during the fifth month of therapy with Complete Thymic Formula (45).The limited number of trials prevented us from doing meaningful sensitivity analyses or funnel plot analysis.DISCUSSIONThis systematic review demonstrates that there is insufficient evidence for treating HCV infection with any of the examined medicinal herbs because of the small number of randomized trials conducted, the paucity of patients having entered these trials, and the low methodological quality of the trials.The majority of the 13 trials included had low methodological quality. They provided very limited description of generation of the allocation sequence, allocation concealment, and only four were double blinded. Methodologically less rigorous trials showed larger treatment effects than those conducted with better rigor (31-33). No large randomized clinical trials were identified. They examined different herbal medicines in different formulations (tablet, capsule, injection, or decoction). Therefore, it is not possible to infer anything on the applicability of these herbs in different populations. Ideally, we should evaluate well-defined herbal constituents, dosage, duration, and control intervention in two or more independently conducted randomized trials when evaluating the efficacy of medicinal herbs. We were limited in this respect by the small number of identified trials. When dealing with efficacy and adverse events of medical herbs, one should apply the same rigorous criteria in the evaluation of interventions as internationally required for pharmaceutical products (52). Many factors may affect the impact of herbs, including species, geographical origin, harvest season, preparation, storage, and extraction procedures, as well as dosage and duration of therapy (53, 54). In clinical trials on herbs, it is, therefore, important to mention specific botanical identification of a plant material, its geographical source, and the condition under which the plant substances are obtained. When the plant preparation is described in a monograph of a national or international Pharmacopoeia, all the quality control requirements should be fulfilled (55). If a monograph concerning the plant preparations does not exist, the manufacturer should write a protocol dealing with the above quality control requirements (53).In four trials obtaining high Jadad scores, only one small, short-term trial suggests that silybin (a milk thistle preparation) may have a liver-protecting effect (39). One should be aware that this beneficial effect came from a trial with only 20 patients treated for 1 wk and without any follow-up. A recent health technology assessment on milk thistle products for liver disease patients concluded that there is not substantial evidence supporting these herbal products (56). In nine low-score trials, oxymatrine seemed to be better than vitamins in clearance of HCV RNA; Yi Er Gan Tang seemed to be better than silymarin plus glucurolactone in normalizing ALT. Yi Zhu decoction seemed to be better than glycyrrhizin plus ribavirin in clearing HCV RNA and normalizing ALT. Neither glycyrrhizin nor ribavirin have demonstrated significant beneficial effects for chronic hepatitis C (14). Bing Gan Tang plus IFN may have positive effects on clearance of HCV RNA and on ALT normalization compared with IFN alone. The potential benefit of these herbs in chronic hepatitis C could justify further trials. Herbs with a potential benefit can be tested against placebo in chronic hepatitis C patients who do not respond to IFN and ribavirin treatment or who have contraindications to the standard treatment or in combination with these interventions (13). However, some of the herbs led to the occurrence of adverse events. Safety monitoring of medicinal herbs in hepatitis C is important through adequate recording and reporting of adverse events in clinical trials.It is likely that certain medicinal herbs contain substances that may interact with viral load and/or prevent further liver injury. It is a difficult question, however, to point to which trials we need to conduct in the future. The field of medicinal herbs is more difficult than the traditional development of pharmaceutical interventions. First, we are dealing with a vast plethora of substances that have been brought to us from ancient times. Second, even focusing on one single medicinal herb raises the problems of its components and how they work in consort. Third, despite the fact that we may not have a plausible biological reason for using some of the herbs, the use of these herbs is widespread in the East as well as in the West (53). To find medicinal herbs that work and to prevent patients from taking herbs that have no efficacy or may cause detrimental effects, we need to conduct randomized trials, which can reveal the true benefits and harms these herbs may cause.In future trials, it is necessary to have a much better description of the medicinal herbs being tested, e.g., plant species, geographical origin, harvest season, preparation procedures, and quality control. In patients with HCV infection, it is necessary to have information on clinical and/or histological stage of liver disease, the presence or absence of cirrhosis, the genotype of HCV, and other well-proven prognostic indicators when assessing the efficacy of medicinal herbs. Rigorously designed, randomized, multicenter clinical trials are required to evaluate medicinal herbs with potential efficacy for hepatitis C, and such trials should be reported following the guidelines of the CONSORT Statement (www.consort-statement.org).REFERENCES posted in article on NATAP website