Medicinal Herbs for HCV (oxymatrin)
This report contains several recent publications of a clinical studies in patients infected with hepatitis B and/or C and using for treatment a Chinese herb called oxymatrin in the Dec 2004 issue of World Journal of Gastroenterology. Following this full report is a journal article of a systematic review of randomized trials on medicinal herbs published in the American Journal of Gastroenterology in March 2003 prior to the recent Dec article on oxymatrine.
[Preliminary study on therapeutic effect of oxymatrine in treating patients with chronic hepatitis C]
[Article in Chinese]
Li J, Li C, Zeng M.Renji Hospital of Shanghai, Second Medical University, Shanghai 200001.
OBJECTIVE: To evaluate the efficacy of oxymatrine in treating chronic hepatitis C and its mechanism. METHODS: Forty-three patient were divided randomly into the treated group (20 cases) and the control group (23 cases). The treated group was given oxymatrine 600 mg per day intramuscularly, and the control group was given the general liver protective agents such as vitamins. The therapeutic course of both groups was 3 months. RESULTS: HCVRNA of 8 in 17 cases (47.1%) of the treated group converted to negative, while in 18 cases of the control group, the negative conversion only took place in 1 patient (5.6%), the negative conversion rate was significantly higher in the treated group than that in the control group (P < 0.05). The normalization rates of serum alanine transaminase (ALT) of the treated group after 1 month and 2 months treatment was higher than that of the control group, but after 3 months treatment, the normalization rates of the two groups were not different significantly. Plasma level of soluble interleukin-2 receptor and serum level of collagen type IV in the treated group were lowered significantly after treatment, but in the control group, there were no significant change, the difference between the two groups was significant (P < 0.01, P < 0.05).
CONCLUSION: Oxymatrine is effective in inhibiting proliferation of HCV, antagonisting liver fibrosis and regulating immune reaction of the host, so it could be a safe, effective drug in treating chronic hepatitis C.
[Oxymatrine in the treatment of chronic hepatitis B for one year: a multicenter random double-blind placebo-controlled trial.]
[Article in Chinese]
Lu LG, Zeng MD, Mao YM, Wan MB, Li CZ, Chen CW, Fu QC, Wang JY, She WM.
Shanghai Institute of Digestive Diseases, Renji Hospital, Shanghai Second Medical University, Shanghai 200001 China.
OBJECTIVE: To evaluate the efficacy and safety of oxymatrine in the treatment of chronic hepatitis B. METHODS: A multicenter randomized double-blind placebo-controlled trial was conducted. A total of 144 patients with chronic hepatitis B entered the study for 52 weeks; of them 72 received oxymatrine, and 72 received a placebo. Before and after the treatment, clinical symptoms, liver function, serum hepatitis B virus markers, and adverse drug reactions were observed. RESULTS: In 144 patients, 14 were dropped and excluded due to inconsistencies in the included standard. Therefore, the efficacy and safety of 130 patients were analyzed. After being treated for 52 weeks, 70.77% of the patients in the study group had a normal ALT level, and in 43.08% and 33.33% their HBV DNA and HBeAg became negative. In the placebo group, 39.68% had normal ALT level, and 12.31% and 3.33% had their HBV DNA and HBeAg become negative. The rates of complete response and partial response in the oxymatrine group were 23.08% and 58.46%, and in the placebo group they were 3.08% and 44.62%. They were significantly higher in the oxymatrine group than in the placebo group. In the oxymatrine treated patients, 12 weeks after its withdrawal, 60.00% had a normal ALT level, 41.54% and 23.33% had both HBV DNA and HBeAg negative. In the placebo group, 31.75% had a normal ALT level, 3.08% and 1.67% had both HBV DNA and HBeAg negative. The rates of complete response and partial response in the oxymatrine group were 21.54% and 47.69%, and in the placebo group they were 0 and 41.54%. They were significantly higher in the study group than in the placebo group. The adverse reaction rates of oxymatrine in the study and the placebo group were 7.69% and 6.15%, respectively, but there was no statistical significant difference between them. CONCLUSION: Oxymatrine is an effective and safe agent for the treatment of chronic hepatitis B.
Oxymatrine therapy for chronic hepatitis B: a randomized double-blind and placebo-controlled multi-center trial.
World J Gastroenterol. 2003 Nov;9(11):2480-3.
Lu LG, Zeng MD, Mao YM, Li JQ, Wan MB, Li CZ, Chen CW, Fu QC, Wang JY, She WM, Cai X, Ye J, Zhou XQ, Wang H, Wu SM, Tang MF, Zhu JS, Chen WX, Zhang HQ.
Shanghai Institute of Digestive Disease, Renji Hospital, Shanghai Second Medical University, Shanghai 200001, China.
AIM: To evaluate the efficacy and safety of capsule oxymatrine in the treatment of chronic hepatitis B. METHODS: A randomised double-blind and placebo-controlled multicenter trial was conducted. Injection of oxymatrine was used as positive-control drug. A total of 216 patients with chronic hepatitis B entered the study for 24 weeks, of them 108 received capsule oxymatrine, 36 received injection of oxymatrine, and 72 received placebo. After and before the treatment, clinical symptoms, liver function, serum hepatitis B virus markers, and adverse drug reaction were observed. RESULTS: Among the 216 patients, six were dropped off, and 11 inconsistent with the standard were excluded. Therefore, the efficacy and safety of oxymatrine in patients were analysed. In the capsule treated patients, 76.47% became normal in ALT level, 38.61% and 31.91% became negative both in HBV DNA and in HBeAg. In the injection treated patients, 83.33% became normal in ALT level, 43.33% and 39.29% became negative both in HBV DNA and in HBeAg. In the placebo treated patients, 40.00% became normal in ALT level, 7.46% and 6.45% became negative both in HBV DNA and in HBeAg. The rates of complete response and partial response were 24.51% and 57.84% in the capsule treated patients, and 33.33% and 50.00% in the injection treated patients, and 2.99% and 41.79% in the placebo treated patients, respectively. There was no significance between the two groups of patients, but both were significantly higher than the placebo. The adverse drug reaction rates of the capsule, injection and placebo were 7.77%, 6.67% and 8.82%, respectively. There was no statistically significant difference among them. CONCLUSION: Oxymatrine is an effective and safe agent for the treatment of chronic hepatitis B.
Capsule oxymatrine in treatment of hepatic fibrosis due to chronic viral hepatitis: A randomized, double blind, placebo-controlled, multicenter clinical study
World J Gastroenterol 2004 November 15;10(22):3269-3273
Yi-Min Mao (Shanghai Institute of Digestive Disease, Renji Hospital, Shanghai Second Medical University, Shanghai 200001, China), Min-De Zeng, Lun-Gen Lu, Mo-Bin Wan, Cheng-Zhong Li, Cheng-Wei Chen, Qing-Chuen Fu, Ji-Yao Wang, Wei-Min She, Xiong Cai, Jun Ye, Xia-Qiu Zhou, Hui Wang, Shan-Ming Wu, Mei-Fang Tang, Jin-Shui Zhu, Wei-Xiong Chen, Hui-Quan Zhang
AIM: To evaluate the efficacy and safety of oxymatrine capsule in treatment of hepatic fibrosis in patients with chronic viral hepatitis.
METHODS: It was a randomized, double blind, placebo-controlled, multicenter clinical study. One hundred and forty-four patients were divided into oxymatrine capsule group(group A) and placebo group (group B).The course was 52 wk. Patients were visited once every 12 wk and the last visit was at 12 wk after cessation of the treatment. All patients had liver biopsy before treatment. part of them had a second biopsy at the end of therapy. Clinical symptoms, liver function test, serum markers of hepatic fibrosis were tested. Ultrasound evaluation was performed before, during and at the end of therapy.
RESULTS: One hundred and forty-four patients enrolled in the study. Of them 132 patients completed the study according to the protocol,49 patients had liver biopsy twice (25 patients in group A and 24 in group B). At the end of therapy, significant improvements in hepatic fibrosis and inflammatory activity based on Semi-quantitative scoring system (SSS) were achieved in group A. The total effective rate of the treatment was 48.00%, much higher than that of 4.17% in group B (P<0.05). Significant improvement in serum markers of hepatic fibrosis such as hyaluronic acid (HA) and type III procollagenic peptide (P III P) in group A was seen (P<0.05). The total effective rate of serum markers at the end of therapy in group A was 68.19%, much higher than that of 34.85% in group B (P<0.05). The total effective rate of noninvasive markers at the end of therapy in group A was 66.67%, much higher than that of 30.30% in group B (P<0.05). The rate of adverse events was similar in two groups.
CONCLUSION: Oxymatrine capsule is effective and safe in treatment of hepatic fibrosis due to chronic viral hepatitis.
Hepatic fibrosis is a kind of compensating and healing response in the liver to liver injury induced by a variety of causes and also a common pathological process of many chronic liver diseases characterized by hyperplasia and deposition of fibro-connective tissues. It is essential to block the genesis and progress of hepatic fibrosis[1-5,30,31]. Oxymatrine is a kind of alkaloid extracted from a Chinese herb Sophora alopecuraides L. which has been proved to have antihepatic fibrosis effect[6,7,18-20]. In this paper, we reported the clinical study data of oxymatrine capsule in treatment of hepatic fibrosis in patients with chronic viral hepatitis.
MATERIALS AND METHODS
This study was a clinical trial characterized by multicentre, randomization, double blinding, and placebo-control. Enrolled patients were randomly assigned into oxymatrine capsule group(group A) or vacant placebo control group (group B), with 72 cases in each group and a treatment course of 52 wk. This study was conformed to the Good Clinical Practice (GCP) of China. The research protocol was discussed and approved by the Ethic Committee of National Clinical Research Base of Drugs in the Institute of Digestive Disease of Renji Hospital. Informed consent was obtained from each patient.
Selection of subjects
Enrolled criteria were age: 18-65 years regardless of sex; positive serum markers of hepatitis B virus (HBV) and hepatitis C virus(HCV) for at least 6 mo before enrollment; abnormal serum value of alanine transaminase (ALT) twice or more within 6 mo before enrollment; liver biopsy examination during 1 mo before enrollment indicating the stage of hepatic fibrosis from 1 to 4 according to National Criteria of Grading and Staging for chronic viral hepatitis amended in 1995 and the scores of stage equal or more than 1 assessed by the semi-quantitative scoring system(SSS) of hepatic fibrosis; total serum bilirubin level less than or equal to 85.5 mmol/L; no history of administrating following drugs: antiviral drugs, immunoregulating drugs and other antifibrotic agents; promising not to receive other systemic antiviral agents, cytotoxic agents, immunoregulators, drugs capable of reducing serum enzyme activity and bilirubin level, and Chinese traditional medicines, etc. Following situations should be excluded: patients with positive laboratory test of HIV; uncompensable liver diseases; suggestive of autoimmune diseases with antinuclear antibody (ANA) titer greater than a 1:160 dilution; bone marrow inhibition; abnormality of serum creatinine with a value 1.5 times greater than normal; concurrence of other associated diseases which might affect the present treatment such as unstable diabetes, renal insufficiency, unstable angina pectoris, alcoholic liver disease, epilepsy, obvious manifestations of neurosis, drug abuser, psychosis, pancreatitis, disability of absorption and malignant disease, and so on; Having taken other drugs in clinical trial within 30 d before the first medication; hypersensitive to oxymatrine capsule; pregnancy and during breast-feeding period; female conceptive patients not adopting any contraceptives.
Treatment procedures and drugs
After completion of selection and assessment, qualified subjects were allocated into group A or B randomly. The patients in group A took 300 mg oxymatrine capsules orally 3 times a day, and 2 tablets of complex vitamins B and C at the same time for 52 wk. The patients in group B took 3 tablets of vacant capsules instead of oxymatrine capsules and complex vitamins B and C at the same frequency as described above for 52 wk. All patients received follow-up once every 12 wk during treatment and were followed up at out-patient department 12 wk after treatment. Oxymatrine capsule, vacant placebo capsule, complex vitamins B and C tablets were manufactured and provided by Ningxia Pharmaceutic Institute and Shanghai Green Valley Ecological Engineering Co.LTD.
Observation of indexes and assessment
Clinical symptoms and signs were divided into grades from 0 to 3 according to the symptomatic grading criteria , evaluated at each follow-up visit, and examined 24 and 52 wk after treatment and 12 wk after drug withdrawal.
Analysis of blood and urine routines and related liver function indexes
These indexes were evaluated at each follow-up visit and examined 52 wk after treatment and 12 wk after drug withdrawal.
Analysis of serum markers of hepatic fibrosis
Tests of serum hyaluronic acid (HA), laminin (LN), type III procollagenic peptide (p III p), type IV collagen-7S (IV-7S) were fulfilled by Military Clinical Immunologic Research Centre of Changzheng Hospital, Second Military Medical University. The above markers were evaluated before treatment, 24 and 52 wk after treatment,12 wk after drug withdrawal respectively, and examined 24 and 52 wk after treatment,12 wk after drug withdrawal, respectively.
Imaging examination (type B ultrasound)
The detection included 5 indexes: maximal oblique radius of right liver lobe, main trunk diameter of portal vein and its blood flow parameters per minute; width of spleen at the hilus and the diameter of spleenic vein. Ultrasound examination was performed on fixed machines and by fixed operators and the data were recorded and input in computers which were read by experts. All the indexes were evaluated before treatment and 52 wk after therapy, examined 52 wk after drug withdrawal.
Histopathological specimens were independently observed and assessed based on National Criteria of Grading and Staging for chronic viral hepatitis amended in 1995 and SSS by 3 pathologists from Department of Pathology, Medical College, Fudan University. The observed results were checked by another 3 pathologists who did not anticipate in the study by Kappa test. The reciprocal consistence among the above pathologists was satisfactory. The observed results in all patients were evaluated before therapy and part of them were evaluated 52 wk after therapy. All data were examined 52 wk after therapy.
During treatment and after therapy was terminated, the following events were recorded: combined medication, adverse reactions and the compliance of patients.
Assessment of therapeutic effects
Indexes of histopathology
The curative effect was evaluated based on SSS. Distinctly effective: the scores of hepatic fibrosis based on SSS from liver biopsy decreased at least 6 scores compared with that before treatment. Effective: the above scores decreased at least 2 scores. Ineffective: the effect did not meet the effective criteria.
Assessment of indexes of noninvasive tests
These indexes were evaluated comprehensively in terms of clinical manifestations, serum liver fibrotic markers and ultrasound detection data. Distinctly effective: any two values among serum liver fibrotic indexes decreased by at least 80% compared with that before treatment, at least the main trunk diameter of portal vein and splenic width returned to normal after treatment, clinical symptoms and signs disappeared or their total scores decreased by at least 75% compared with that before treatment. Effective: any two values among serum liver fibrotic indexes decreased by at least 40% compared with that before treatment, the main trunk diameter of portal vein and splenic width reduced after treatment, clinical symptoms and signs disappeared basically or their total scores decreased by at least 25% compared with that before treatment. Ineffective: the effect did not meet the effective criteria.
Assessment of safety
Any abnormal clinical manifestations and laboratory tests occurred during treatment were recorded and divided into 4 grades according to the criteria published by WHO and the Ministry of Public Health of China in 1994.
Statistical analyses were performed by professor Su BH and He QB from Department of Statistics, Shanghai Second Medical University, and SAS 6.12 software kit was used.
A total of 144 patients satisfied the selection criteria. Of them,12 cases withdrew or were excluded during treatment, 132 cases fulfilled the treatment course according to the required protocol(66 cases in group A and 66 cases in group B). Before treatment, the following general data between two groups were similar (P>0.05, respectively): sex, age, drinking history, duration of hepatitis, duration of abnormality of liver function and a more than 2-fold normal elevation of serum ALT, etc. Each qualified patient received liver biopsy before treatment. A total of 49 cases had a second liver biopsy (25 cases in group A and 24 cases in group B).
Analysis of observed indexes
Clinical symptoms and signs Clinical manifestations in group A were obviously improved 52 wk after therapy (P<0.05), except for epistaxis (P = 1.0000). Heptomegaly was also improved significantly after therapy (P = 0.0313), symptoms of gum bleeding and epistaxis were not improved obviously in group B (P>0.05). Signs of hepatomegaly, splenomegaly and liver palm were significantly improved in group B (P<0.05), improvement of anorexia in group A was greater than that in group B (P = 0.0263).
Indexes of liver function in group A were significantly improved 52 wk after treatment (P<0.05) except for serum gamma glutamino transpeptidase (GGT) and TB (P>0.05). In group B, indexes such as serum ALT, AST, TB and alkaline phosphatase (ALP) had no obvious difference before and after therapy (P>0.05). Compared with group B, the improvement of ALT and AST in group A was much greater (P = 0.0007 and 0.0025). Fifty-two wk after therapy, the normalization rate of ALT in group A was 70.77%, much higher than 39.68% in group B (P = 0.0003). In groups A and B, 14 out of 46 cases (30.43%) and 12 out of 25 cases (48.00%) had their serum ALT levels returned to normal 52 wk after treatment ,and their serum ALT levels became abnormal again after drug withdrawal.
Liver histologic examination
Evaluation of hepatic fibrosis based on SSS: In group A, the scores of hepatic fibrosis after therapy were 4.72±5.63, much smaller than 6.76±6.67 before therapy (P = 0.0001), while the scores in group B after therapy increased significantly (P = 0.0009). There was an obvious difference between two groups (P = 0) (Table 1). Evaluation of histolgic inflammatory activity based on SSS: In group A, the scores of histologic activity decreased from 46.08±3.84 before treatment to 4.00±2.97 after therapy (P = 0.0002), while the scores in group B after therapy did not decrease obviously (P = 0.2344). There was an obvious difference between two groups (P = 0008) (Table 2).
Evaluation of serum markers of hepatic fibrosis
In group A, serum levels of HA, LN, p III p and IV-7S decreased significantly 24 and 52 wk after treatment (P<0.05). In group B, serum levels of LN, p III p and IV-7S also decreased obviously after treatment(P<0.05). However, degrees of improvement in HA and p III p between two groups were distinctly different (P<0.05). In group A, except for LN (P = 0.1493), the other 3 liver fibrotic markers increased significantly 12 wk after drug withdrawal compared with that 52 wk after treatment (P<0.05). In group B, except for HA (P = 0.4212), the other markers also increased obviously 12 wk after drug withdrawal compared with that 52 wk after treatment(P<0.05). The increase of HA in group A was more than that in group B (P = 0.0002) and the increase of IV-7S in group B was more than that in group A (P = 0.0048).
After treatment, the average values of main trunk diameters of portal vein and splenic width in group A obviously decreased (P<0.05). However, in group B, the above two parameters and the parameters of blood flow volume per minute of portal vein and diameters of splenic vein all increased significantly compared with those before therapy (P<0.05). The changes in main trunk diameters of portal vein and splenic width between two groups were statistically significant (P<0.05).
Analysis of therapeutic effect
Assessment of histopathology based on SSS
After treatment, the rates of distinct effectiveness and effectiveness in group A were both 24.00%, and the total effective rate was 48.00%. In group B, none achieved distinct effectiveness and the effective rate was only 4.17%; Comparison of the rates of distinct effectiveness and effectiveness between two groups had a significant difference (P = 0.004) (Table 3).
Assessment of serum markers of hepatic fibrosis
The total effective rate of group A 24 and 52 wk after therapy was 57.43% and 68.19%, more than 24.24% and 34.85% of group B (P = 0.0002 and 0.0004, respectively). Twelve weeks after treatment, the total effective rate of group A was 50.00%, more than 15.16% of group B (P =0.00).
Assessment of noninvasive indexes of hepatic fibrosis
After treatment, the rates of distinct effectiveness and effectiveness in group A were respectively 3.03% and 63.64%, and the total effective rate was 66.67%. In group B, the rates of distinct effectiveness and effectiveness were respectively 0% and 30.30%, and the total effective rate was 30.30%. The comparison of the above statistics between two groups had a significant difference (P = 0.0001) (Table 4).
In group A, there were 5 patients who suffered from adverse drug reactions and the incidence was 6.94%. The adverse drug reactions mainly included nausea, rash, chest discomfort, fever, epigastric comfort, diarrhea and poor taste, and most of them were mild or moderate. None of the patients withdrew because of adverse drug reactions. In group B, adverse effects occurred in 7 patients and the incidence was 9.72%. The manifestations were similar to those in group A and 1 patient withdrew because of weakness, anorexia, epigastric discomfort after taking drugs.
Hepatic fibrosis, a precuror of cirrhosis, is a consequence of sever liver damage that occurred in many patients with chronic liver disease, and involves the abnormal accumulation of extracellular matrix[3,4,11,12]. Liver fibrosis represents a major worldwide healthcare burden. Current therapy is limited to removing the causal agent. This approach has been successful in some diseases, particularly in haemochromatosis and chronic viral hepatitis[9,10,17,28]. However, for many patients treatment was not possible, while other patients presenting to medical attention were at an advanced stage of fibrosis[8,9]. There is therefore a great need for novel therapies for liver fibrosis. Tremendous insights into the understanding of hepatic fibrosis have taken place over the past ten years. Foremost among these is the recognition that hepatic stellate cells (formerly known as lipocytes, Ito cells, or fat-storing cells) play a central role based on their ability to undergo activation following liver injury of any cause[11,15,16,29]. Hepatic stellate cells have been recognised to be responsible for most of the excess extracellular matrix observed in chronic liver fibrosis. The detailed understanding of hepatic stellate cell biology has allowed the rational design of novel antifibrotic therapies. Effective therapy for hepatic fibrogenesis would probably also be multifactorial, based on the basic mechanisms underlying the fibrogenic process[13,14,21-23].
At present, it is considered that treatment of hepatic fibrosis and antihepatic fibrosis are two different concepts and antifibrotic drugs should act on various parts of the genesis and development of hepatic fibrosis. Firstly, as for etiological treatment, oxymatrine could effectively treat chronic viral hepatitis and promote the serum markers of hepatitis B virus (HBV) and hepatitis C virus(HCV) in chronic hepatitis B and C to convert to negative and reduce serum level of ALT[6,7]. Secondly, oxymatrine could inhibit the proliferation of hepatic stellate cells (HSC) at the concentrations of 0.5-16 mg/mL in vitro. In addition, oxygen stress and lipid peroxidation are important mechanisms responsible for hepatic injury and hepatic stellate cell activation. Therefore, inhibition of lipid peroxidation is an essential strategy of antihepatic fibrosis[12-16]. By establishing D-galactosamine-induced rat liver fibrosis model, we observed the effect of oxymatrine on serum and tissue biochemical indexes, content of liver hydroxyline, expression of TGFb1 mRNA and changes of tissue pathology, the results showed oxymatrine had prophylactic and therapeutic effects on D-galactosamine induced rat liver fibrosis. This was partly by protecting hepatocytes and suppressing fibrosis accumulation through anti-lipoperoxidation. In present study, We found that the scores of hepatic fibrosis after therapy in group A were 4.72±5.63, much smaller than 6.76±6.67 before therapy, and the scores in group B after therapy increased significantly. There was an obvious difference between two groups. The scores of histological inflammatory activity in group A decreased from 46.08±3.84 before treatment to 4.00±2.97 after therapy, and the scores in group B after therapy did not decrease obviously. There was an obvious difference between two groups both in improvement of histopathology and in improvement of noninvasive indexes such as clinical manifestations, serum markers of hepatic fibrosis[24-27]. Associated indexes of liver function and imaging detection indicated that oxymatrine was an ideal drug of antihepatic fibrosis. It is valuable to pay more attentions to the basic and clinical research of oxymatrine in order to explore the accurate mechanisms of its effect on antihepatic fibrosis.
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Medicinal Herbs for Hepatitis C Virus Infection: A Cochrane Hepatobiliary Systematic Review of Randomized Trials
American Journal of Gastroenterology
Volume 98 Issue 3 Page 538 - March 2003
Jianping LiuM.D., Ph.D. a, b * , Eric ManheimerPh.D. c , Kiichiro TsutaniM.D. d , Christian GluudDr. Med. Sci. a
Objective 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.
Hepatitis 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).
Eligible 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.
Inclusion 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.
Methodological 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 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.
Dichotomous 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 trials
Our 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.
Compared 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 effects
Sustained 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.
This 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).
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