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Traditional Chinese Medicine May Perform Better than Interferon or Lamivudine for Chronic Hepatitis B

Various traditional Chinese medicine (TCM) formulations were found to work as well as or better than the pharmaceutical drugs interferon and lamivudine for people with chronic hepatitis B, according to a joint U.S./Chinese review of clinical trials published in the February 2010 issue of Hepatology. While many of these studies were considered to be of poor quality according to Western drug testing standards, the review authors concluded that some TCM remedies appear effective and warrant further study.

Chronic hepatitis B is major global health problem, but its impact is especially great in Asia. In China, it is estimated that approximately 120,000,000 people have chronic HBV infection. For centuries, the disease has been treated with traditional medicines.

Lingyi Zhang, Herbert Bonkovsky, and colleagues performed a meta-analysis of clinical trials of TCM formulations for treatment of chronic hepatitis B reported in China from 1998 through 2008.

An ancient book called the Yellow Emperor's Internal Classic indicates that TCM remedies have been used to treat chronic liver disease in China at least since 475 BCE, the authors noted as background. Today, TCM is still used extensively for the treatment of chronic hepatitis B in China, with some 80% of patients relying on Chinese remedies. While interferon alpha and lamivudine (Epivir-HBV) are often available, newer nucleoside/nucleotide analog drugs such as adefovir (Hepsera), entecavir (Baraclude), and tenofovir (Viread) are "prohibitively expensive" and not widely used, they noted.

Thousands of different herbs have been used in TCM formulations for liver disease, including astragalus (Huang Qi), bupleurum (Chai Hu), licorice root (Gan Cao), red sage (Dan Shen), rhubarb (Da Huang), and schisandra (Wu Wei Zi). "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 researchers wrote.

The review authors searched electronic databases (China National Knowledge Infrastructure and PubMed) to identify studies that either compared TCM formulations versus interferon (alpha-1b, alpha-2a, or alpha-2b, at least 3 million units administered 3 times per week for at least 3 months) or lamivudine (at least 100 mg administered once-daily for at least 30 consecutive days), or that added Chinese remedies to interferon or lamivudine to see if the combination worked better than the Western drugs alone. They also looked at which specific Chinese herbs are used most often.

The initial search included both randomized controlled trials (RCTs) -- the "gold standard" for Western drug testing -- and other types of studies that reported objective outcome measures such as serum alanine aminotransferase (ALT) normalization, HBV DNA viral load clearance, or hepatitis B "e" antigen (HBeAg) loss.

A total of 643 reports were selected for inclusion (596 in Chinese, 47 in English). Of these, 487 were clinical trials (356 RCT and 131 non-RCT), 80 were pre-clinical experimental studies, and 76 were summaries of non-randomized clinical experience.

Out of these studies, the researchers identified 53 RCTs that reported random allocation of patients with chronic hepatitis B to treatment with TCM formulations; these trials met the inclusion criteria and were used in the meta-analysis. The studies used a variety of TCM formulations, with an average of 9 ingredients, but approximately 50%-60% of the herbs overlapped across different formulations.

Overall, the quality of studies was judged to be "poor"; 16 (27%) of the 53 RCTs had Jadad scores (a standard algorithm for assessing trials) of 3, while the rest (73%) had scores of 2. None of the reports described methods used for randomization or whether they were double-blind, single-blind, or unblinded.

Among the 53 selected RCTs, 16 (1918 total participants) compared responses in patients receiving TCM formulations alone versus interferon, 6 RCTs (723 total participants) compared TCM alone versus lamivudine,18 trials (1738 total participants) compared TCM plus interferon versus interferon alone, and another 14 trials (1548 total participants) compared TCM plus lamivudine versus lamivudine alone

Results

• A total of 203 different herbs were included in 230 TCM formulations for the treatment of chronic hepatitis B.
• TCM formulations alone had a significantly greater beneficial effect than interferon for ALT normalization (odds ratio [OR] 2.42, or 2.4-fold greater; P = 0.0003).
• Chinese formulations and interferon had a statistically similar likelihood of reducing HBeAg (OR 1.60; P = 0.07).
• TCM and interferon also performed similarly with regard to HBV viral load clearance (OR 1.31; P = 0.20).
• TCM formulations were significantly more effective than lamivudine for normalizing ALT (OR 1.96, or nearly twice as effective; P = 0.01).
• TCM and lamivudine showed no significant difference in likelihood of reducing HBeAg (OR 1.57; P = 0.36).
• Again, TCM and lamivudine were about equally likely to produce HBV DNA clearance (OR 1.20; P = 0.59).
• When used in combination, TCM plus interferon enhanced antiviral activity and liver function improvement compared with interferon alone:
• ALT normalization: OR 3.07, or about 3-fold greater benefit (P < 0.00001);
• HBeAg reduction: OR 2.17, or about twice the benefit (P < 0.00001);
• HBV DNA clearance: OR 2.05, again about twice the benefit (P < 0.00001). 
• TCM formulations plus lamivudine were also significantly more effective than lamivudine alone:
• ALT normalization: OR 3.40 (P < 0.00001). 
• HBeAg reduction: OR 2.54 (P < 0.00001);HBV DNA clearance:
• OR 3.20 (P < 0.00001);
• In a similar analysis of the 16 RCTs of higher technical quality (Jadad scores of 3), the pattern of the results were similar.
• Among 20 RCTs that included information about adverse events, no serious adverse side effects of TCM formulations were reported.

Based on these findings, the review authors concluded, "Some TCMs seem effective as alternative remedies for patients with chronic hepatitis B, suggesting that further study of TCMs in the treatment of chronic hepatitis B is warranted, both in preclinical models of HBV infection and in higher quality RCTs worldwide."

"Our meta-analysis suggests that in patients with chronic hepatitis B, (1) TCMs have a similar curative effect as interferon/lamivudine on antiviral activity as evidenced by the loss of serum HBeAg and HBV DNA; (2) TCMs have a better effect on normalization of serum ALT; and (3) TCMs enhance interferon and lamivudine antiviral activity and improvement of liver function," they elaborated in their discussion.

"It is noteworthy that there were no reported serious adverse events associated with the combinations of TCM studied," they added. "As used in China, these formulations seem to be very well tolerated, although many reports did not include data on adverse effects of therapy."

Liver-Biliary-Pancreatic Center and the Liver, Digestive Diseases, and Metabolism Laboratory, NC; McColl-Lockwood Laboratory, Carolinas Medical Center, Charlotte, NC; Institute of Clinical Medical Science, China-Japan Friendship Hospital, Beijing, China; Department of Biology, University of North Carolina at Charlotte, Charlotte, NC; Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC; Departments of Medicine and Molecular, Microbial & Structural Biology, University of Connecticut Health Center, Farmington, CT.

4/6/10

Reference
L Zhang, G Wang, W Hou, and others. Contemporary clinical research of traditional Chinese medicines for chronic hepatitis B in China: An analytical review. Hepatology 51(2): 690-698 (Free full text). February 2010.