Chinese Herbal Medicine and Interferon in the Treatment of Chronic
Hepatitis B:
A Meta-Analysis of Randomized, Controlled Trials
By Michael McCulloch, LAc, MPH, Michael Broffman, LAc, Jin Gao,
MD, PhD, &
John M. Colford Jr, MD, PhD
Download the PDF version of this paper (215kb): [PDF]
Table of Contents
Abstract
Introduction
Methods
Results
Discussion
About the Authors
References
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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. (Am J
Public Health. 2002;92:1619–1627)
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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.1 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).2–4
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 in terferon alfa.5 Observational
studies have shown that such clearance occurs spontaneously in 4% to
29% of people with chronic infection.6–8 However,
patients can develop HBsAg-negative 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.9–12 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.13 Furthermore, patients
can also develop HBeAg-negative chronic infection, which, as with HbsAg
negative patients, signals a poor prognosis.1,13
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.14 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,3 with
low cost and low toxicity. Interferon alfa, by contrast has a very high
cost and significant toxicities.15–18
English-language
journals have published few randomized trials of Chinese herbal medicine
for the treatment of hepatitis.19–23 A far
larger body of literature exists in Chinese- language 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 (Traditional
Chinese Medicine Language Acquisition and Retrieval System, available
at www.cintcm.ac.cn)
now allows rapid searching of journal abstracts to quickly locate clinical
trials data published in China after 1984. TCMLARS contains more than
330000 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.
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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 (Centralized 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.50 When we found multiple reports
of the same patient data, we selected for review only the most recently
published data (n=1).
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.51–53
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 alfa19,24,38,43,45 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,54,55 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.26,33,37,48 In
calculating relative risk for these studies, the value 0.5 was added
to all 4 cells of the contingency table.56 Confidence
intervals for the relative risks were estimated by the Woolf method.57 Studies
with missing data were excluded from analysis (n=4). We used the Egger
et al. regression asymmetry test58 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 standalone 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.
We calculated the summary effect
estimates across the above-mentioned groups of studies as a weighted
average, using the random- effects model of DerSimonian and Laird.59 We
used a variance-based method to assess the heterogeneity of treatment
effect within subsets.60
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Results
In our initial screening, we identified 587 abstracts in which the title,
the abstract, or both mentioned the use of both Chinese herbal medicine
and interferon: 583 by electronic searches of the TCMLARS database, 2
by electronic searches of MEDLINE, 1 by hand-searching the bibliographies
of each of the identified journals, and 1 by electronic searches of EMBASE
(this reference was also identified by MEDLINE).
Of these 587 studies, 27 met our inclusion criteria (see “Methods” section).
All 27 were randomized, controlled trials of patients with chronic hepatitis
B, treated with Chinese herbal medicine treatment alone (vs interferon
alfa; n=15) or Chinese herbal medicine combined with interferon alfa
(vs interferon alfa; n=14), with interferon alfa administered at dosages
of at least 1 million units 3 times weekly. Two studies had a 3-arm design,
thus contributing data to both the treatment group using only Chinese
herbal medicine and the treatment group using Chinese herbal medicine
combined with interferon alfa.35,47 We identified
2 individual studies with data on the active component kurorinone19,24 and
2 individual studies with data on bufotoxin.38,45
All studies with the exception of the Lu et al.36
study used 1 of the 2 diagnostic standards for chronic hepatitis B currently
recognized in China: the 1990 Shanghai and 1995 Beijing diagnostic protocols,
which define chronic cases of hepatitis B infection as those in which
positive HBsAg and HBeAg serum markers and HBV DNA genetic marker persist
for 6 months or more.61 The Lu study used an older
diagnostic standard, the 1984 Hainan protocol, which also defines chronic
cases as those persisting for 6 months or more. All studies evaluated
patients for treatment outcomes at the end of 3 months of treatment.
Although we had hoped to find and report data on long-term follow-up,
only 1 study provided such data.21 Furthermore,
all studies were of low quality, and each study had a modified Jadad
scale score of 0 or 1.
Chinese Herbal Medicine as Sole Treatment
Patients using Chinese herbal medicine alone were significantly more
likely to achieve seroreversion of HBsAg levels than were control patients
receiving interferon alfa (Figure 1; Table 2) (relative risk [RR]=2.00;
95% confidence interval [CI]=1.35, 2.97). Our evaluation suggested that
Chinese herbal medicine used alone was equivalent to interferon alfa
with respect to seroreversion of HBeAg (RR=1.20; 95% CI=0.99, 1.49) and
HBV DNA (RR=0.94; 95% CI=0.80, 1.11).
Chinese Herbal Medicine Combined With Interferon Alfa
Patients receiving combined therapy were significantly more likely
than those receiving interferon alfa alone to achieve seroreversion (Figure
1; Table 3). This was true for all 3 outcomes: HBsAg (RR=2.08; 95% CI=1.45,
2.96), HBeAg (RR=1.64; 95% CI= 1.39, 1.94), and HBV DNA (RR=1.58; 95%
CI=1.35, 1.85).
Chinese Herbal Medicine Active Component Bufotoxin Combined With Interferon
Alfa
Patients receiving a combination of bufotoxin and interferon alfa were
significantly more likely than interferon alfa–treated control
patients to achieve seroreversion of HBeAg (RR=1.50; 95% CI=1.09, 2.08)
and HBV DNA (RR=1.75; 95% CI=1.24, 2.47), but not of HBsAg (RR=2.16;
95% CI=0.99, 4.65).
Chinese Herbal Medicine Active Component Kurorinone Alone
The Chinese herbal medicine active component kurorinone, when used alone,
appeared to be equivalent to interferon alfa in its effect on seroreversion
of HBeAg (RR=0.93; 95% CI=0.68, 1.27) and HBV DNA (RR=0.88; 95% CI=0.66,
1.16). Neither of the 2 studies employing kurorinone19,24 reported
seroreversion data on HBsAg, so we were not able to include that endpoint
in this subanalysis.
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Discussion
Our meta-analysis data suggest that Chinese herbal medicine in the treatment
of chronic hepatitis B infection may have potential therapeutic value;
however, because the studies we found were of generally poor quality,
we are unable to make firm conclusions. Substantial limitations apply
to these findings. Published studies from China were found to be more
highly condensed than typical articles published in the Western literature,
with key details of study design omitted, especially details concerning
blinding of subjects and clinicians. We chose the Jadad scale to assess
study quality because its straightforward and simple design makes it
suitable for such studies.
In 22 of the 27 studies assessed in this meta-analysis, because the
treatment group received orally administered Chinese herbal medicine
and the control group received injected interferon alfa, blinding of
subjects and clinicians was not possible. In such a study design, blinding
could be achieved only if the treatment and control groups each received
both oral and injected trial medications (i.e., the treatment group could
receive true orally administered herbal medicine and placebo injection,
and the control group could receive placebo orally administered herbal
medicine and true interferon alfa injection).
Only 1 of our 27 studies39 described
the method of randomization used (unfortunately, this consisted of alternating
case record numbers, which is not a truly random method). None of the
other studies provided any details of the randomization method used,
an unfortunate oversight given the availability of low-cost computers
and free random number– generating software. Even more problematic
was the lack of discussion in any study about whether the investigators
knew which patients were randomized to receive treatment. However, failure
to fully describe randomization procedures is not limited to Chinese
medical journals. One study showed that as recently as 1994, 70% to 80%
of trials published in Western journals did not adequately describe randomization.62
In future trials, we propose that Chinese investigators employ relatively
simple measures such as random number–generating software for use
in randomization and placebo trial drugs for use in comparing different
therapies or in evaluating new and emerging extracted active components
of Chinese herbal medicines. More thorough reporting of patient characteristics
would also be helpful.
In
these studies, subjects in both herbal medicine and interferon groups
were treated for only 3 months. Because prior work has documented that
long-term treatment with interferon alfa can almost double response rates,63–65 future
investigations with Chinese herbal medicine or Chinese herbal medicine
combined with interferon alfa should examine longer treatment durations.
Our findings
suggest that Chinese herbal medicines administered in combination with
interferon alfa may augment the efficacy of interferon. However, a better
understanding of drug synergism between herbal medicines and interferon
alfa is needed. A small number of studies have shown drug synergism between
Chinese herbal medicines and interferons, suggesting, for example, that
herbal medicines may boost endogenous interferon production.66–68 These
initial studies and their positive findings of synergism are important
and can help inform future clinical investigations of combined-modality
therapy for chronic hepatitis B.
In a previous review by the Cochrane Collaboration,69 a
search of the Chinese medical literature was limited to Western databases
(which index few Chinese journals) and hand searching of 5 Chinese journals.
Because that review did not use the TCMLARS database, it did not identify
many of the primary trials found in this study. Our use of the TCMLARS
database allowed us to more completely search all medical journals published
in China, yielding 27 studies that focused specifically on comparing
herbal therapy with a known reference standard, interferon alfa. In our
review, TCMLARS was more effective than Western databases as a search
tool for locating clinical studies on Chinese medicine, yielding 583
potentially useful studies, compared with 2 obtained from MEDLINE. TCMLARS
may become an important new asset in literature review and meta-analysis
of Chinese herbal medicine.
The Chinese herbal medicine active components bufotoxin38,45 and
kurorinone19,24 used in the combination therapies
identified in this review appear to be promising initial targets for
further investigation. It is possible that further investigation in well-designed
trials may help answer the question of whether Chinese herbal medicine
can be effective for treating chronic hepatitis B. Given the significant
public health hazard of chronic hepatitis B and the high rates of nonresponse
to interferon therapy, continued and more carefully conducted research
could be helpful in identifying more effective therapies.
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About the the Authors
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. Requests for reprints should be sent to John
M. Colford Jr, MD, PhD, UC Berkeley School of Public Health. This article
was accepted June 11, 2002.
Contributors
M. McCulloch was involved in conception and design of the study; acquisition,
analysis, and interpretation of data; drafting and critical revisions
of the manuscript; and statistical expertise. M. Broffman was involved
in conception and design, analysis and interpretation of data, critical
revisions, and supervision. J. Gao was involved in acquisition, analysis,
and interpretation of data; critical revisions; and technical support.
J. M. Colford Jr was involved in conception and design, analysis and
interpretation of data, drafting and critical revisions of the manuscript,
statistical expertise, technical support, and supervision.
Acknowledgments
We thank Yvonne Wu, MD, MPH,
and Corinne Keet, MS, for technical assistance with analytic software.
Dylan Tierney, MPH, provided assistance with proofreading the manuscript.
Min-lin Fang introduced us to the TCMLARS database. This report was prepared
according to the guidelines established by the Quality of Reporting of
Meta-Analysis (QUOROM) Group.70,71
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Copyright © 2002 American Journal of Public Health. Reprinted
with permission.
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