Chronic hepatitis B (CHB) is a major global health problem. Worldwide, more than two billion people have been infected the hepatitis B virus (HBV), and approximately 400 million people are chronic carriers of the virus. Chronic infection with HBV can significantly impair the quality of life and life expectancy of patients because of the potential for disease progression, which can lead to fibrosis, cirrhosis, liver failure, and hepatocellular carcinoma. It is estimated that worldwide more than 600,000 individuals die from HBV-related liver disease each year 1
. In China alone, there are at least 120,000,000 individuals carrying HBV 2
Traditional Chinese Medicines and Liver Diseases in China
The ‘Yellow Emperor’s Internal Classic’, an ancient book containing records of traditional Chinese medicines (TCM), indicates that TCM have been used to treat chronic liver disease in China at least since 475 BCE. Today, TCM are still used extensively for the treatment of CHB in China. Thousands of different herbs have been used in numerous TCM formulations (mixtures of different herbs) for the treatment of CHB. These TCM formulations are based on the collective wisdom of Chinese clinicians and practitioners, coupled with centuries of accumulated experience working with these herbs.
The general philosophical underpinning of Chinese medicine and use of TCM is that of ‘holistic medicine’. Thus clinicians in China pride themselves on treating the person as a whole, including body, mind, and spirit. TCM formulations are typically selected based upon the purported individual properties of the herbs, and their abilities to work in complementary fashion with other herbs in the mixture. For example, a wide-spread strategy underlying TCM treatment of CHB is to: (i) relieve anxiety and symptoms and improve the quality of life of the patients; (ii) alleviate inflammation; (iii) arrest hepatic fibrosis; (iv) improve immune function; and (v) improve lipid metabolism. Somewhat analogous is the recent recommendation of the “polypill” to manage cardiovascular disorders and risk factors3
Standard Modern Medical Treatments for CHB
Currently, the approved remedies worldwide for patients with CHB are interferon (IFN) and lamivudine (LAM) or other nucleoside analogues (e.g. adefovir, entecavir, tenofovir) 4
. However, the overall therapeutic efficacy of IFN is limited by its inconvenient parenteral route of administration, unpleasant side effects, and expense. Although patients treated with lamivudine or other nucleoside analogues generally respond well to the medication and experience fewer side effects, in many cases the HBV replication increases markedly as soon as the treatment is stopped. Furthermore, the emergence of drug resistance and viral variation limit their efficacy as therapeutic agents for CHB, and the newer nucleoside analogues are prohibitively expensive for many patients. Thus, currently, in mainland China, IFN and LAM are the most commonly used Western remedies.
Goals of the Review
Despite the availability of IFN and/or nucleoside analogues, almost 80% of the patients with CHB in China rely on TCM therapy. In recent decades, a number of clinical trials have been performed in China to assess the therapeutic efficacy and safety of TCM for treating CHB infection. Studies have assessed the effects of TCM on CHB, both alone, and in combination with medicines of western origin. Results from the trials suggest that some TCM may indeed be effective therapeutic agents for the treatment of CHB. These encouraging findings have prompted investigations in both Asian and western countries to explore the potential of TCM in the treatment of liver diseases.
The goals of this review are to summarize and analyze results of recent RCTs employing TCM in the treatment of CHB. Furthermore, a search was performed to determine which individual herbs are used most frequently in TCM formulations, and which appear to have the greatest efficacy in treating CHB. This information may be used to begin to determine which herbs or combinations of herbs possess the most therapeutic potential for treatment of CHB. A portion of this review has appeared in abstract form (available on line at http://www.isvhld2009.org/secondary.php?section=Abstracts
) and was presented at the 13th
International Symposium on Viral Hepatitis and Liver Disease, March 22, 2009, Washington, DC [oral presentation 92].
Data Bases Searched and Search Criteria
Searches of publications in the China National Knowledge Infrastructure (CNKI) and in PubMed were performed. Both searches were limited to trials reported between Jan., 1998 and June, 2008. The search key words used were combinations of TCM, herbs, single herb, herbal extract, plant and hepatitis B. All publications, which were written in either Chinese or English, were downloaded, read and critically reviewed.
Clinical trials studied included randomized controlled trials (RCTs), non-randomized controlled clinical trials (non-RCTs), and summaries of clinical experience. The diagnostic criteria for CHB were positivity for serum HBsAg and/or HBeAg for more than six months, with elevated levels of serum alanine aminotransferase (ALT). Studies were selected for analysis if they named the individual herbs in the TCM formulation, and if there was an objective outcome measure (normalization in serum ALT, loss of serum HBeAg, and/or clearance of serum HBV DNA). If the studies matched the criteria outlined above, the names of the herbs were input into a database. The number of times individual herbs were used in different TCM formulations was recorded to determine the frequency with which particular herbs were used in TCM formulations used to treat CHB.
For assessing the effectiveness of TCM formulations in the treatment of CHB, the effects of TCM on CHB were compared to the effects of IFN and LAM on CHB. Use of IFN required therapy at a dose of at least 3 million units, administered three times a week for at least three months. Because of the existence of different forms of IFN, we included studies in which not only IFN α, but also IFN α-1b, IFN α -2b, or IFN α -2a were used. Use of LAM required its administration at a dose of at least 100 mg, administered once daily for at least thirty consecutive days. The review summarizes not only the effects of TCM on CHB, but also any reported side effects associated with therapy.
Due to the length limitations of this review, studies that assessed single herbs, or single herbal extracts in the treatment of CHB are not included. Although we used single herb and herbal extract as one of our search terms, these were used mainly to determine the total number of publications related to TCM and CHB that have been published in the past decade. We plan to write a review regarding the effects of single herbs as well as single herbal extracts in the treatment of CHB at a later date.
RCTs in humans were included, regardless of whether they were single blind, double blind or not blinded, which compared the therapeutic efficacy of (i) TCM formulations only versus IFN or LAM or (ii) TCM formulations plus IFN or LAM versus IFN or LAM on CHB. We focused on comparing the results of the virological response (loss of serum HBeAg and/or clearance of serum HBV DNA) and normalization of serum ALT levels at the end of treatment among the groups under comparison.
Methodological Quality and Statistical Analysis of RCTs
The methodological quality of the RCTs included in our study was assessed by the method of Jadad 5
. The scores range from one to five, one or two being considered as low quality trials, and three to five as high quality. The Review Manager statistical software package (version 4.2, Biostat, Englewood, NJ) was used for the statistical analysis. According to usual standards for fitting to random-effects model [i.e., when the p value of heterogeneity of the results between two group trials is less than 0.1, or even when the p value is greater than 0.1, but the I2
parameters between two groups is greater than 50 ~ 70%], we chose the random-effects model to perform data analysis. Dichotomous data were presented as odds ratios (OR) and continuous outcomes as weighted mean differences, both with 95% confidence intervals (CI).