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“The only thing necessary for these diseases to the triumph is for good people and governments to do nothing.”

 

Chinese Herbal Medicine and Interferon in the Treatment of Chronic Hepatitis B: A Meta-Analysis of Randomized, Controlled Trials

October 2002, Vol 92, No. 10 | American Journal of Public Health 1619-1628
© 2002

Michael McCulloch, LAc, MPH, Michael Broffman, LAc, Jin Gao, MD, PhD and John M. Colford, Jr, MD, PhD

Michael McCulloch and Michael Broffman are with the Pine Street Clinic, San Anselmo, Calif. Michael McCulloch and Jin Gao are with the Institute of Biophysics, China Academy of Sciences, Beijing, China. Michael McCulloch and John M. Colford Jr, are with the School of Public Health, University of California at Berkeley.

Correspondence: Requests for reprints should be sent to John M. Colford Jr, MD, PhD, UC Berkeley School of Public Health, 140 Warren Hall MC 7360, Berkeley, CA 94720 (e-mail: jcolford@socrates.berkeley.edu).

ABSTRACT
 
Objectives. This meta-analysis was conducted to examine the effectiveness of Chinese herbal medicine (either alone or with interferon alfa) in treating chronic hepatitis B.

Methods. We searched the TCMLARS, AMED, CISCOM, EMBASE, MEDLINE, and Cochrane Collaboration databases and then hand-searched the articles’ bibliographies.

Results. Chinese herbal medicine significantly increased seroreversion of HBsAg and was equivalent to interferon alfa in seroreversion of HBeAg and hepatitis B virus (HBV) DNA; Chinese herbal medicine combined with interferon alfa significantly increased seroreversion of HBsAg, HBeAg, and HBV DNA. The Chinese herbal medicine active component bufotoxin combined with interferon alfa significantly increased HBeAg and HBV DNA seroreversion. The Chinese herbal medicine active component kurorinone was equivalent to interferon alfa in seroreversion of HBeAg and HBV DNA.

Conclusions. Although the quality of existing studies was poor, these data suggest that further trials of Chinese Herbal Medicine and interferon in chronic hepatitis B infection are justified.

INTRODUCTION

Traditional Chinese medicine is an established segment of the health care delivery system in China. In planning for allocation of health care resources, an important question for China’s health care authorities is whether traditional Chinese medicine functions best as a stand-alone therapy or in close integration with allopathic medical care. However, little formal assessment of its clinical effectiveness has been conducted. In this study, we sought to evaluate the clinical evidence for its effectiveness in the treatment of chronic hepatitis B and to examine the quality of the published data.

As one of the core techniques used within traditional Chinese medicine, Chinese herbal medicine is commonly used in China in the treatment of hepatitis. In this meta-analysis of randomized, controlled trials we examined the effectiveness of Chinese herbal medicine in the treatment of chronic hepatitis B when used as a stand-alone therapy and when used in combination with interferon alfa. The control group in each case was patients treated with interferon alfa alone.

Infection with hepatitis B virus is a significant public health concern. Worldwide, an estimated 2 billion people are infected with the hepatitis B virus (HBV).1 A total of 350 million people have the chronic form of hepatitis B infection, 75% of whom live in Asia.1 Chronic infection increases the risk for primary liver cancer. Endemic hepatitis B infection in Asia’s large population contributes to primary liver cancer’s position as the fourth leading cause of cancer death worldwide (after lung, stomach, and colorectal cancers).

Successful treatment of hepatitis B infection has long been defined as loss of detection of hepatitis B surface antigen (HBsAg). Meta-analysis has shown that HBsAg clearance occurs in only 6% of patients with chronic hepatitis B who are treated with interferon alfa.5 Observational studies have shown that such clearance occurs spontaneously in 4% to 29% of people with chronic infection. However, patients can develop HBsAgnegative chronic infection, a clinical course with a more serious prognosis than that of patients who are HBsAg positive.1 Therefore, some authors support the use of hepatitis B e antigen (HBeAg) and HBV DNA as markers of active viral replication and infectivity. HBeAg clearance occurs in 18% to 40% of patients with chronic hepatitis B who are treated with interferon alfa and spontaneously in 15% to 60% of people with chronic infection. Furthermore, patients can also develop HBeAg-negative chronic infection, which, as with HBsAgnegative patients, signals a poor prognosis.

Herbal medicine is in common use in many parts of the world. A 1997 survey estimated that 34% of the American public use alternative medicine; among the survey respondents, 12% reported the use of herbal medicine within the prior 12 months.In China, Chinese herbal medicine is used as a treatment adjunct or alternative to interferon alfa and accounts for 30% to 50% of total medicine consumption, with low cost and low toxicity. Interferon alfa, by contrast has a very high cost and significant toxicities.

English-language journals have published few randomized trials of Chinese herbal medicine for the treatment of hepatitis. A far larger body of literature exists in Chineselanguage journals. For centuries, textbooks have discussed treatment strategies handed down in the oral and literary tradition of Chinese herbal therapy. Over the past 50 years, modern Chinese-language medical journals have more formally assessed the effectiveness of these treatment strategies. From case reports came observational studies and, over the past decade, randomized, controlled trials. Although these medical journals report only studies from the past 50 years, these data represent a distillation of the accumulated historical experience of the body of traditional Chinese medicine. The field has grown substantially, from 1 published randomized, controlled trial of Chinese herbal medicine for the treatment of chronic hepatitis B in 1991 to 221 in 1999. Until recently, however, time-consuming searching by hand was the only means of accessing Chinese-language data sources.

Online availability of the Chinese-language TCMLARS database now allows rapid searching of journal abstracts to quickly locate clinical trials data published in China after 1984. TCMLARS contains more than 330 000 references and abstracts to literature on traditional Chinese medicine, drawn from more than 600 Chinese biomedical journals and 100 specialty journals. Searching is straightforward, and scanned articles can be ordered via e-mail. Approximately 10% of the abstract database has been translated into English.

Using TCMLARS and searches of Western medical literature, we examined 2 hypotheses: (1) that treatment with Chinese herbal medicine could serve as an alternative therapy when interferon alfa is not available or acceptable, and (2) that Chinese herbal medicine used in combination with interferon alfa could enhance the effectiveness of interferon alfa. We were interested in assessing the effectiveness of Chinese herbal medicine when used either as a stand-alone therapy or in combination with interferon alfa and also in examining the quality of the published data.

METHODS
 
Study Selection
We searched for articles in TCMLARS (1984–2000), MEDLINE (1966–2000), the Cochrane Database of Systematic Reviews (Cochrane Collaboration, 1992–2000), CISCOM (Centralised Information Service for Complementary Medicine), EMBASE (Excerpta Medica, 1974–2000), and AMED (Allied & Complementary Medicine Resources, 1985–2000), with articles in all languages included for consideration. We used the following keywords and medical subject headings: hepatitis B; hepatitis B, chronic; drugs, Chinese herbal; medicine, Chinese traditional; medicine, oriental traditional; interferon; and interferons. These resources were supplemented by the hand-searching of articles’ bibliographies, nonindexed medical and professional journals, and the Chinese-language and English-language libraries and files of the authors. Two authors (M. M. and M. B.) translated the Chinese-language articles. We searched for additional data, both published and unpublished, through communications with a senior investigator and collaborator at the China Academy of Sciences (J. G.). To define a standardized control regimen, we included only studies in which the control group used interferon alfa at a dosage of at least 1 million units administered 3 times weekly; we excluded studies in which the control group used very low doses of interferon alfa, different comparison treatments such as gamma interferon, other drugs, or other herbal treatments.

In the first stage of our systematic review, we identified studies describing the use of Chinese herbal medicine and interferon alfa in the title or abstract (n = 587). We retained for further review studies in which interferon alfa was administered to the control group (n = 49). For the meta-analysis, we retained only those 27 studies (1) that were randomized, controlled trials of Chinese herbal medicine alone (vs interferon alfa) or Chinese herbal medicine combined with interferon alfa (vs interferon alfa) for the treatment of hepatitis B (Table 1) and (2) that provided data on the number of responders and nonresponders for any of the 3 endpoints: HBsAg (n = 18 studies), HBeAg (n = 27), and HBV DNA (n = 20). We defined Chinese herbal medicine as the 311 botanical and animal-product medicines that are commonly used in clinical practice by practitioners of traditional Chinese medicine and enumerated in a current herbal medical textbook used at the Shanghai University of Traditional Chinese Medicine. When we found multiple reports of the same patient data, we selected for review only the most recently published data (n = 1).


TABLE 1 —Chinese Herbal Medicine (CHM) for Chronic Hepatitis B: Study Diagnoses and Herbal Medicines Used

Author

Quality Scorea

Diagnosis

CHM or CHM + IFN-{alpha} Group, Average Age ± Range

IFN-{alpha} Group, Average Age ± Range

Herbal Treatment


Cai24 (1997)

0

CAH, CPH, CAH + LC

31.5 ± 10.3

35.4 ± 9.9

Kurorinone

Chen19 (2000)

1

CHB

NS

NS

Kurorinone

Dai25 (1998)

1

CAH, CPH

NS

NS

Artemesia capillaris, Astragalus membranaceus, Peonia rubra, Polygonum multiflorum, Poria cocos, Pseudostellaria heterophylla

Fu26 (1997)

0

CHB

NS

NS

Agrimonia, Astragalus membranaceus, Atractylodes alba, Carthamus tinctorum, Ligusticum wallichium, Codonopsis pilosula, Gardenia jasminoidis, Gentiana scabra, Glycyrrhiza uralensis, Imperata cylindrica, Peonia alba, Peonia rubra, Prunus persica, Poria cocos, Pueraria lobata, Rheum officinale, Salvia multiorrhiza, Sparganium longifolium, Schisandra chinensis, Curcuma longazedoaria, Zingiberis officinalis, Zizyphus jujuba

Hao27 (1996)

1

CHB, CPH

NS

NS

Ganpi jiaonang combination (ingredients not specified)

Huang28 (1999)

1

CHB

32.5 ± 6.7

30.8 ± 5.6

Phyllanthus, pseudoginseng

Huang29 (2000)

1

CHB

35.7 ± 11.3

37.2 ± 11.7

Artemesia capillaris, Atractylodes alba, bupleurum, Glycyrrhiza uralensis, Hypericum japonicum, Magnolia officinalis, Polygonum cuspidatum, Polyporus umbellatus, Poria cocos, Rheum officinale, Salvia multiorrhiza

Jing30 (2000)

1

CHB

28.7 (NS)

27.6 (NS)

Cuscuta chinensis, Ganoderma lucidum, Juglans regia, Sophora subprostata

Li31 (1998)

1

CHB

30.8 ± 5.7

32.8 ± 6.9

Phyllanthus, pseudoginseng

Li32 (1999)

0

CHB

NS

NS

Phyllanthus, Polygonum cuspidatum, Schisandra chinensis

Li33 (1997)

1

CAH

NS

NS

Agrimonia pilosa, Isatis indigotica, Scutellaria barbata, Scutellaria baicalensis, Nidus vespae, Oldenlandia diffusa, Polygonum cuspidatum, Smilax glabra

Li34 (2000)

1

CHB

33.7 ± 7.8

31.0 ± 7.8

Alpinia, Atractylodes alba, bupleurum, Coix lachryma-jobii, Curcuma longa, Dryopteris crassirhizo, Eclipta prostrate, Oldenlandia diffusa, Isatis indigotica, Loranthus parasiticus, Magnolia officinalis, Patrinia villosa, Pinellia ternata, baijiangcao, Scutellaria baicalensis

Liu35 (1999)

1

CHB

CHM group: 32.6 ± 14.6; CHM + IFN-{alpha} group: 34.6 ± 17.8

35.7 ± 20.5

Agrimonia pilosae, Bruca javanica, litchi, Dryopteris crassirhizo, Punica granatum, Prunus mume, Siegesbeckia orientalis, Stemonia japonica

Lu36 (1992)

1

CAH, CPH

NS

NS

Achyranthis bidentata, aloe, Amyda sinensis, Artemesia capillaris, Astragalus membranaceus, Atractylodes alba, Citrus medica, Curcuma longa, Eclipta prostrate, Gallus gallus domesticus, Gardenia jasminoidis, Gentiana macrophylla, Imperata cylindrica, Isatis indigotica, Lithospermum arnebia, Loranthus parasiticus, mouton, Oldenlandia diffusa, Peonia rubra, Polygonum cuspidatum, Salvia multiorrhiza

Qian37 (1999)

1

CAH

37.4 (NS)

36.4 (NS)

Carthamus tinctorum, Ligusticum wallichium, Lithospermum arnebia, Polygonum cuspidatum, pseudoginseng, Salvia multiorrhiza, Scutellaria baicalensis

Shen38 (2000)

1

CHB

31.2 (NS)

32.3 (NS)

Bufotoxin

Song39 (1994)

0

CHB

15.6 (NS)

14.8 (NS)

Aconite carmichaeli, Agastache rugosa, Amomum cardamom, Astragalus membranaceus, Atractylodes alba, Citrus reticulata, Epimedium, Glycyrrhiza uralensis, Panax ginseng, Poria cocos, Rehmannia glutinosa

Wang40 (1997)

1

CAH, CPH

NS

NS

Astragalus membranaceus, Cassia tora, chouteng, dibo, guicao, huangpi, longye, Salvia multiorrhiza

Wang41 (2000)

1

CHB

38.5 (NS)

36.4 (NS)

Eupolyphaga, hirudo, qichan, tabanus

Wang42 (2000)

1

CHB

33.4 (NS)

35.0 (NS)

Astragalus membranaceus

Wu43 (1997)

1

CHB

38.2 ± 6.5

36.4 ± 7.9

Salvia multiorrhiza

Wu44 (1998)

1

CHB

36.5 (NS)

36.0 (NS)

Atractylodes alba, Amyda sinensis, bupleurum, amomum, Citrus reticulata, Dioscorea opposita, Glycyrrhiza uralensis, Lycium chinensis, Panax ginseng, Pinellia ternata, Peonia alba, Poria cocos, Rheum officinale, Scutellaria barbata, Trionyx sinensis

Zhang45 (1999)

1

CHB

28.4 (NS)

27.6 (NS)

Bufotoxin

Zhang46 (1997)

1

CHB

36 (NS)

34.5 (NS)

Long dan xie gan tang (ingredients not specified)

Zhang47 (1999)

1

CHB

20–50 (NS) for both CHM & CHM+ IFN-{alpha} groups

20–50 (NS)

Bupleurum, erhoutao, Hypericum japonicum, Imperata cylindrica, Panax ginseng, jixueteng, tianwangye, wuahuaxueteng

Zhao48 (1996)

1

CAH; CPH

36.0 ± 11.1

34.2 ± 13.4

Astragalus membranaceus, Prunus persica, Curcuma longa zedoaria

Zhou49 (1999)

1

CHB

36.2 ± 10.3

35.6 ± 11.0

Atractylodes alba, Astragalus membranaceus, Crinis carbonisatus, Prunus persica, Phyllanthus, Polygonum multiflorum, Poria cocos, Rehmannia glutinosa, Salvia multiorrhiza, Schisandra chinensis, Taraxacum mongolicum

Note. CAH = chronic active hepatitis B; CHB = chronic hepatitis B; CPH = chronic persistent hepatitis B; IFN-{alpha} = interferon alfa; LC = liver cancer; NS = not specified.

aPoints awarded for modified Jadad scale criteria (how studies randomized patients and handled dropouts or withdrawals): low score = 0 or 1; high score = 2 or 3; maximum possible total score = 3.

 
We retained studies that reported the use of different forms of interferon alfa (interferon alfa, n = 20 studies; interferon alfa-1b, n = 2; interferon alfa-2a, n = 3; interferon alfa-2b, n = 2) in the treatment or control groups. Previous research has documented similarities in the effectiveness of the different forms of interferon alfa in the treatment of hepatitis B.

 

Data Abstraction
Two reviewers (M. M. and M. B.), who were blinded to author, affiliation, and journal title, reviewed the 27 studies. The following data were abstracted through standardized forms: publication year; diagnosis; average patient age; definition of diagnosis used; Chinese herbal medicine treatment used; type of interferon alfa used; interferon alfa doses; whether the treatment arm involved Chinese herbal medicine alone or Chinese herbal medicine combined with interferon alfa; the total number of subjects in each treatment arm; and the number of treatment responders in each treatment arm for any of the endpoints HBsAg, HBeAg, and HBV DNA. Any disparities in data abstraction were resolved through a consensus process in which a third investigator served as arbitrator (J. M. C.).

Quality Scoring
Five of these trials compared an injected active ingredient extracted from a Chinese herbal medicine with injected interferon alfa and thus could have included double-blinding within the study design. However, in the remaining 22 studies, blinding was obviously not possible because those studies compared an orally administered Chinese herbal medicine with injected interferon alfa. Thus, we created a modified scale based on the method of Jadad, limiting our assessment of study quality to how studies randomized patients and handled dropouts or withdrawals (low score = 0 or 1; high score = 2 or 3; maximum possible total score = 3).

Statistical Analysis
We used the Stata statistical software package (version 6.0; Stata Corp, College Station, Tex) for data management and analysis. We calculated relative risk of cure from the data in the original studies for use in the meta-analysis. These relative risks were calculated as the probability of seroreversion in the treated group divided by the probability of seroreversion in the control group. Thus, relative risk values greater than 1.0 are consistent with a beneficial effect of Chinese herbal medicine used alone (vs interferon alfa) or Chinese herbal medicine in combination with interferon alfa (vs interferon alfa). In 4 of the studies, we encountered individual contingency table cells with no patients. In calculating relative risk for these studies, the value 0.5 was added to all 4 cells of the contingency table. Confidence intervals for the relative risks were estimated by the Woolf method. Studies with missing data were excluded from analysis (n = 4). We used the Egger et al. regression asymmetry test to examine our meta-analysis data for publication bias

We constructed our groupings for meta-analysis as follows: (1) to assess the effectiveness of Chinese herbal medicine as a stand-alone therapy, all studies of Chinese herbal medicine alone (vs interferon alfa) were analyzed together (Figure 1; Table 2); (2) to assess the effectiveness of Chinese herbal medicine as an adjunct to interferon alfa, all studies of Chinese herbal medicine combined with interferon alfa (vs interferon alfa) were analyzed together (Figure 1; Table 3); (3) to examine the effectiveness of specific active components extracted from Chinese herbal medicines, subanalyses of those active components were conducted when 2 or more studies reporting use of the same active component were available. Within each of these groupings, the outcome we studied was seroreversion of 3 dichotomous endpoints: HBsAg, HBeAg, and HBV DNA. Using these endpoints, we calculated the treatment effect of Chinese herbal medicine alone (vs interferon alfa) and Chinese herbal medicine combined with interferon alfa (vs interferon alfa); we report these results as relative risk of cure, with 95% confidence intervals. A relative risk of cure > 1 indicates effectiveness of the treatment evaluated.



FIGURE 1 —Meta-analysis forest plots for seroreversion among patients with chronic hepatitis B infection treated with Chinese herbal medicine: pooled relative risks and 95% confidence intervals, by trial.

TABLE 2 —Seroreversion in Chronic Hepatitis B: Chinese Herbal Medicine (CHM) Alone vs Interferon Alfa (IFN-{alpha})

 

Seroconversion, No. of Responders/Total No. of Patients in Group


 

Study

IFN-{alpha}

CHM

RR (95% CI)


Hepatitis B surface antigena

Dai25 (1998)

  2/15

  2/15

1.00 (0.16, 6.20)

Li31 (1998)

  2/25

  2/30

0.83 (0.13, 5.50)

Li32 (1999)

  1/32

  3/38

2.53 (0.28, 23.1)

Li33 (1997)

  0/40

  1/40

3.00 (0.13, 71.5)

Lu36 (1992)

 15/79

 33/97

1.79 (1.05, 3.05)

Song39 (1994)

  5/30

 20/50

2.40 (1.01, 5.72)

Wang40 (1997)

  2/11

 33/64

2.84 (0.79, 10.1)

Zhao48 (1996)

  0/30

 10/30

21.0 (1.29, 342)

Overall

 27/262

104/364

2.00 (1.35, 2.97)

Hepatitis B e antigenb

Cai24 (1997)

 23/50

 28/63

0.97 (0.64, 1.45)

Chen19 (2000)

 17/29

 15/29

0.88 (0.55, 1.41)

Dai25 (1998)

  7/15

  5/15