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REVIEW ARTICLE Table of Contents   
Year : 2007  |  Volume : 4  |  Issue : 1  |  Page : 72-106
Complementary and alternative therapies in the treatment of chronic hepatitis B


1 Division of Research and Development, Development Center for Biotechnology, Xizhi City, Taipei County, 221, R.O.C, Taiwan
2 Department of Life Sciences and Institute of Biotechnology, National Tsing Hua University, Hsinchu, 30013, R.O.C, Taiwan

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   Abstract 

Hepatitis B virus (HBV) infects approximately more than 350 million people worldwide, especially in Asia, Africa, southern Europe and Latin America. Except for interferon-α, most anti-HBV drugs are derived from the anti-herpes and anti-HIV drugs. Because of the high cost of hepatitis B medications, herbs-also called 'complementary and alternative therapies' in modern Western science-are widely used for treatment of chronic hepatitis B in developing countries. Herbals confer their activities not only by inhibiting HBV secretion but also by building up immunity against viruses. After studying the anti-HBV mechanism of herbs, scientists were encouraged to find that novel anti-HBV drugs target viral secretion, whereas nucleoside analogues target viral polymerase. The complementary and alternative anti-HBV therapies published in scientific peer-reviewed journals are reviewed and discussed in this article.

Keywords: Chinese medicinal herbs, complementary and alternative medicine, hepatitis B, herbal medicine

How to cite this article:
Chang JM, Huang KL. Complementary and alternative therapies in the treatment of chronic hepatitis B. Hep B Annual 2007;4:72-106

How to cite this URL:
Chang JM, Huang KL. Complementary and alternative therapies in the treatment of chronic hepatitis B. Hep B Annual [serial online] 2007 [cited 2019 Jul 19];4:72-106. Available from: http://www.hepatitisbannual.org/text.asp?2007/4/1/72/45091



   Introduction Top


Hepatitis B virus (HBV) infection is known to produce chronic hepatitis, liver cirrhosis and hepatocellular carcinoma (HCC) and there is a high rate of HBV infection (more than 350 million) worldwide, especially in Asia, Africa, southern Europe and Latin America. [1] Although the natural history of HBV carriers is complicated and remains unclear, vaccination is still the most important strategy to protect healthy persons from becoming chronic HBV carriers. [2] On the other hand, the introduction of antiviral agents to people with chronic hepatitis B could attenuate or stop the fibrotic progression, thereby preventing the development of HCC and fulminant hepatitis. Before the first anti-HBV drug, 3TC, was approved by the US Food and Drug Administration (FDA) in 1998, there was no available small-molecule drug for treating chronic hepatitis B disease. Interferon was the only choice for treating this infection. Although interferon can reduce the activity of HBV, the side effects of interferon remain a concern to physicians with regard to its clinical use in treating chronic hepatitis B patients. Unfortunately, most anti-HBV drugs are derived from herpes and human immunodeficiency virus (HIV) drug development and only a few efficacious anti-HBV drugs are available for clinical use. The large repertoire of herbal compounds has shown potential in developing new ways to combat previously considered 'incurable' disease, provided that these compounds (or often, mixtures of compounds) can satisfy current government regulations. At present, alternative or traditional medical resources are used by more than 80% of the population in developing countries and by an increasing number of people in other parts of the globe. [3] For modern Western science, the use of herbs is termed 'complementary and alternative therapies'. These kinds of therapies for chronic hepatitis also are being extensively explored and the results appear promising. [4] The complementary and alternative anti-HBV therapies published in scientific peer-reviewed journals are reviewed and discussed in this article.


   Overview of HBV Life Cycle Top


HBV is a DNA virus that consists of a double-shelled structure (a nucleocapsid covered with surface/envelope proteins) enclosing a circular, partial double-strand DNA genome, also called 'Dane particle'. The HBV genome is approximately 3.2 kb and encodes the viral envelope (preS/S), core (preC/C), polymerase and X proteins. In the HBV replication cycle, the viral pregenomic RNA (pgRNA) and polymerase, together with cellular factors including chaperones and phosphorylated core proteins, are encapsidated by viral core proteins to form immature nucleocapsids. [5],[6],[7] Within the nucleocapsid, a complete HBV negative-strand DNA is first synthesized via reverse transcription of an RNA intermediate and then converted into partial double-strand DNA by viral polymerase to form mature nucleocapsids. These nucleocapsids are packaged by transmembrane envelope proteins in the post-endoplasmic reticulum/pre-Golgi membrane, where the assembled virions are secreted via the constitutive secretion pathway. [8] Alternatively, the mature nucleocapsids can return to the nucleus to amplify the intracellular genome copy number. [9] Excess middle- and small-surface proteins could self-assemble into subviral quasi-spherical or filamentous particles without envelopment of nucleocapsids that are secreted efficiently in relation to the virions. [10]


   The Strategy of Chronic Hepatitis Treatment Top


The current hepatitis B treatments are categorized into two strategies to fight HBV viral infection: (1) Induction of certain cellular immune responses including activation of specific cytotoxic T lymphocytes that target infected cells and/or inhibition of virus replication in the infected cells by specific cytokines such as interferons. In addition, vaccines made of viral recombinant protein or viral DNA plasmid can induce specific immune responses involving both cellular and humoral immunity against HBV or HBV-infected cells via neutralization of anti-envelope antibodies or by destruction of infected liver cells. (2) Inhibition of viral replication by targeting viral molecules or by affecting cellular regulatory factors that are associated with HBV replication and the processes for viral nucleocapsid formation, envelopment and secretion. On the basis of the cellular and molecular mechanism of HBV replication, a number of potential targets for anti-HBV drugs were developed for chronic hepatitis B treatment summarized in [Figure 1] and are described as follows.


   The Immunomodulators Top


Alpha-interferon (IFN-α), the first drug approved by FDA for the treatment of chronic hepatitis B inhibits viral replication and acts as an immunomodulator. Treatment with IFN-α.achieves persistent loss of HBV in about 30% of patients with chronic hepatitis B. However, the disadvantages of interferon treatment include its limited efficacy, the fact that only about one third of patients with a sustained infection are eligible for trials, its low efficacy with respect to cost and its serious side effects. [11] Recently, a pegylated interferon, PEG-IFN-α2a was approved and this seems to be superior to IFN-α. PEG-IFN-α2a has a prolonged half-life in serum and is also effective against a broader range of cases than the other interferons. [2]


   The Viral Polymerase Inhibitors Top


HBV encodes multifunctional polymerase, which is a signal for viral pgRNA encapsidation; catalyzes RNA- and DNA-dependent DNA synthesis and has an intrinsic RNase H activity that degrades pgRNA during reverse transcription. [12] Therefore, it is already a promising target for antiviral agents and for the nucleoside or nucleotide analogues that target selectively the viral RNA-dependent DNA polymerase, which can suppress viral replication. [2] Lamivudine (3TC) was approved by FDA in 1998 for the treatment of chronic hepatitis B. However, short-term monotherapy is not sufficient to clear viral infection and long-term monotherapy has been associated with the emergence of resistant mutants in the tyrosine-methionine-aspartic acid-aspartic acid (YMDD) motif of the viral polymerase (during 2-3 years of 3TC administration). [13],[14] Recently, adefovir and entecavir were approved and used against 3TC-resistant viruses; unfortunately, resistances to these two drugs were reported in 3TC-resistant patients. [15],[16],[17] Research efforts are still ongoing to improve current antiviral drugs by developing novel nucleoside analogues. At present, two nucleotide analogues, emtricitabine and tenofovir, are at the phase III clinical trial stage.


   The Nucleocapsid Assembly Inhibitors Top


Two critical early steps in HBV replication, the initiation of reverse transcription, via protein priming and nucleocapsid assembly, take place in the cytoplasm of infected cells. Binding of the polymerase to e region, a short RNA signal located at the 5' end of pgRNA, leads to the selective incorporation of both polymerase and pgRNA together with the 90-kDa heat shock protein (Hsp90) chaperone complex into the viral core proteins. [18],[19],[20],[21] It has been reported that some host chaperones are involved in the assistance of viral protein folding and assembly in the viral life cycle. At present, three host chaperones are known to be required for the early steps in HBV replication. In a dynamic process that is dependent on ATP hydrolysis, Hsp90 facilitates HBV polymerase-pgRNA interaction and is associated with HBV polymerase conformational changes for replication, whereas Hsp60 activates HBV polymerase both in vitro and ex vivo. [5],[22],[23] The chaperone 94-kDa glucose-regulated protein (GRP94) is also involved in stabilization of HBV polymerase as an active form. [24] In light of the importance of HBV nucleocapsid as a process necessary for genome replication, an experimental approach that targets the HBV core protein to interfere with the nucleocapsid formation would possibly inhibit HBV production.

Recently, heteroaryldihydropyrimidines, bis-ANS and alkylated imino sugar were reported to reduce the virus production from the virus-producing cells by preventing the maturation of HBV nucleocapsids or by destabilizing the formed nucleocapsids. [25],[26],[27],[28],[29] In addition, suppression of Hsp90 or Hsp60 has similar anti-HBV effects in reducing the viral nucleocapsid formation. [5],[22] Targeting nucleocapsid formation may serve as a good approach for anti-HBV drug development.


   The Viral Envelopment Inhibitors Top


The HBV envelope consists of three structurally related HBV proteins, large-surface, middle-surface and small-surface proteins, which are individually translated from one open reading frame of the viral genome by using different translation initiations. [30] These proteins share a common carboxyl terminus. The large-surface protein contains additional pre-S1 and pre-S2 domains, whereas the middle-surface protein contains more pre-S2 domains than the small-surface protein. All these proteins are cotranslationally integrated into the endoplasmic reticulum (ER) membrane by the topogenic signals of the small-surface protein domain and are glycosylated as they are transported through the secretory pathway. [31] These glycoproteins are probably involved in virion assembly and secretion and/or infectivity. [32],[33] One glucosidase function is to remove terminal glucose residues from N-linked oligosaccharides attached to nascent glycoproteins, which in turn assists in protein folding via the interaction oflectin-like chaperone proteins (calnexin and calreticulin) with nascent glycoproteins. [34] The chemicals for the inhibition of the N-linked glycosylation pathway, such as N-butyl-deoxynojirimycin (NB-DNJ) for glucosidase I and II and N-nonyl-DNJ (NN-DMJ) for mannosidase I, can cause some proteins to misfold and be retained in the ER. [32],[35] NB-DNJ is also reported to suppress secretion of HBV particles and to cause intracellular retention of HBV DNA in HepG2 2.2.15 cells; site-directed mutagenesis experiments prove that virion secretion requires the glycosylation sequence in the pre-S2 domain of middle-surface proteins. [35],[36] This finding highlights the potential role in the glycosylation of the middle-surface protein with oligosaccharide, which may serve as a therapeutic target in the treatment of chronic hepatitis B.


   The Novel Target in the Secretion of HBV Top


The pre-S (pre-S1 plus pre-S2) domain of the large-surface protein is needed for the translocation process during HBV morphogenesis. [37] About half of large-surface proteins posttranslationally translocate their pre-S domains into the ER, whereas the other pre-S domains appear on the cytosolic side, which yields a dual topology maintained in the secreted viral and subviral particles. [38],[39],[40] The dual topology of pre-S domains of large-surface proteins may perform a different function in the viral lifecycle. Large-surface proteins containing pre-S domains oriented at the cytosolic site (external) participate in virus-host receptor binding and those with pre-S domains oriented at the luminal site (internal) are probably involved in envelopment of the nucleocapsid. [37],[41],[42] In addition, both large- and small-surface proteins are required for virion secretion. [43] Over-expression of large-surface proteins relative to small-surface proteins can inhibit virion secretion and restrict the subviral particles in the ER lumen, suggesting that a small relative ratio of large-surface proteins to middle- and small-surface proteins is crucial for virion secretion. [44],[45],[46] Recently, the GRP78 was found to play an important role in the suppression of HBV production by Boehmeria nivea. This finding also suggests that inhibiting the function of chaperones associated with HBV replication may alter the production of HBV virion.


   Combination Approach for Antiviral Therapy Top


At present, the major target of anti-HBV drug development is to emphasize inhibition of the HBV multifunctional viral polymerase. An objective to develop other nucleotide analogue drugs, with the expectation of a synergistic antiviral effect, may prevent or attenuate the emergence of resistant mutants and improve therapeutic effects. Clinically, the use of combination therapy, such as IFN-α plus 3TC, 3TC plus adefovir or 3TC plus entecavir, may yield additive or synergistic effects and/or reduce the emergence of resistance, even though the problems of serious side-effects and unsatisfactory efficacy are still arising. A high mutation rate of HBV results from the lack of a proofreading function in HBV polymerase, which is the main reason for drug resistance and suggests that combining drugs with different pharmacological action modes benefits the effectiveness of anti-HBV therapy. [47]


   Study Model for HBV Top


For the development of anti-HBV drugs, a number of in vitro and in vivo models of HBV infection are established for drug screening. In vitro cell culture models, including infection of primary hepatocytes and transient or established HBV DNA-transfected cell lines, have become widely used in the laboratory for antiviral research because of their convenient manipulation and maintenance. However, the disadvantages of in vitro cell culture models are the poor data for reproducibility of infection of hepatocytes with infected sera and non-natural viral production from chromosomally integrated viral cDNA of established cell lines. Because hepatitis viruses have a restricted host range, chimpanzee and tree shrews (Tupaia belangeri sinensis) are the few animal models for HBV infection. [48],[49] Chimpanzees develop acute hepatitis and evoke an immune response after HBV infection that could be used to evaluate the safety and immunogenicity of HBV vaccines, but the limited availability and the high cost of these primates severely restrict their use for such purposes. [50] In surrogate animal models, including the woodchuck, the Pekin duck and the ground squirrel, which can be infected by host-specific genus hepadnaviruses, are used to simulate the condition of human HBV infection to evaluate the efficacy of antiviral agents. [51],[52],[53] In 2002, Huang and his co-workers first introduced a novel murine model by using the transfection of HBV-expressing plasmid for studying human HBV replication, immunogenicity and control. [54] However, the major drawback of these animal models in testing antiviral agents is that they may produce aberrant results as a consequence of virus-specific differential susceptibility to the drugs. Transgenic mouse model and human-mouse chimeric liver model have been established as suitable laboratory small-animal models for investigators to study the immunopathogenesis of HBV infection. [55],[56] Although there is no particular cell culture model or animal model for studying all features of HBV, researchers can choose suitable models to investigate different aspects of pathology, prevention and therapy of HBV.


   Herbal Medicines used in Chronic Hepatitis B Treatment Top


Because chronic hepatitis B is widely spread in Asia, Africa, southern Europe and Latin America, it is urgent to develop anti-HBV drugs in these countries. One possibility is to find useful therapeutic agents from herbs for treating chronic hepatitis B. The empirical experiences of these medicinal substances have been widely used in folk medicine and studied as modern drugs by employing science-based methodology. Chemists continue to identify active compounds from plants and attempt to discover their lead compounds.

Before the etiology of chronic hepatitis B was understood, many plants and remedies were used to treat liver-related diseases, including hepatitis, cirrhosis and cancer. According to historical experiences, some of these treatments are highly relevant to alleviate "liver inflammation syndrome" no matter whether or not the hepatitis is caused by viruses. For the past decade, researchers have turned to systemically screening these medicinal plants for anti-HBV activity. The anti-HBV efficacy of these medicinal plants are investigated by using established in vitro and in vivo models; these results are summarized and listed in [Table 1]. Since the 1990s, many assay models have been developed for evaluating anti-HBV activity. The HepG2 2.2.15 cells can consistently secrete infectious viral particles that are acceptable for investigating anti-HBV herbals in vitro and DHBV-transfected ducks are promising for investigating the metabolism and efficacy of anti-HBV drugs in vivo. In some of these herbs, the active compounds that are responsible for their anti-HBV activities have been identified and some of them are still under investigation. The anti-HBV mechanism of these herbs remains mostly unclear; however they do inhibit the production of hepatitis B surface antigen (HBsAg) and hepatitis B e antigen (HbeAg) or HBV DNA in the HepG2 2.2.15 cell model or suppress the serum DHBV in the DHBV-transfected duck animal model. It is believed that these herbs may have anti-HBV action modes that differ from that of the nucleoside inhibitors which target viral polymerase.


   Single Herb in the Treatment of Chronic hepatitis B Top


The genus Phyllanthus (Euphorbiaceae) is traditionally used for the treatment of virus-associated diseases and has been extensively investigated for its anti-HBV activity. [57] In China, herbs are permitted to be used clinically in treating chronic hepatitis B patients without precise chemical and manufacturing controls. Despite the poor quality of clinical trials on Phyllanthus herbs for chronic hepatitis, the authors of a review of information on the use of this genus of herbs alone or in combination with interferon in humans from 22 RCTs suggested that they may be effective against HBV. [58] In laboratory research, ellagic acid was identified from P. uriraria, which is not able to inhibit either HBV polymerase activity or HBV replication or block HBsAg secretion. [59],[60] Instead, ellagic acid blocks effectively HBeAg secretion in HepG2 2.2.15 cells and shows a low IC 50 (0.07 µg/ml). Kang and his co-workers concluded that the function of ellagic acid in treatment of chronic hepatitis B is to block the immune tolerance caused by HBeAg. [61] The ethanolic extract of Phyllanthus nanus has been studied for anti-HBV activity. [62] P. nanus suppresses the HBsAg secretion and HBsAg mRNA expression in HepG2 2.2.15 cells and the viral replication of DHBV in DHBV-infected primary duck hepatocytes. A microarray analysis consisting of 800 human cDNA clones showed that induction of annexin A7 can be correlated with the anti-HBV activity of this herb. [62] Later, Niu et al, demonstrated the utility of P. amarus in anti-HBV treatment. [63] The researchers in this field are interested in the anti-HBV activity of this herb and are starting to extensively investigate it. With the use of a different assay model, P. amarus was shown to suppress the gene expression of HbsAg [64],[65] and studies have shown that P. amarus suppresses hepatitis B virus by interrupting interactions between HBV enhancer I and cellular transcription factors. [64],[65] Recently, many active compounds were identified from this genus, such as niranthin, nirtetralin, hinokinin, geraniin, etc and all of them show anti-HBV activities. [66]

Radix Sophorae flavescentis is recorded in the Chinese Divine Husbandman's Classic of the Materia Medica and has been traditionally used in treatment of chronic liver diseases. [67] Recently, pharmacological studies have shown that S. flavescentis possesses anti-HBV activity. Clinical trials with S. flavescentis confirmed that this herb possessed antiviral activity, as this treatment achieved seroconversion of HBeAg to anti-HBe antibody and of HBV DNA from positive to negative. [68] The extract of S. flavescentis is also reported to improve the therapeutic effect of IFN-α. [69] The active ingredients identified from S. flavescentis, such as matrine, oxymatrine, sophoranol, anagyrine, sophocarpine and spophordine were studied for their individual anti-HBV activity. [70] Among these compounds, matrine has more potent anti-HBV activity and is being extensively studied for treatment of chronic hepatitis B in clinics. [71] No matter whether used alone or in combination with either IFN-α or other herbs, the outcomes are beneficial in the clearance of serum HBeAg. Another active compound, kurarinone, found in Sophora flavescens Ait, is also being investigated for its efficacy in clinical treatments of chronic hepatitis B. [69] The outcomes of clinical trials reveal that kurarinone used alone is equivalent to IFN-α; the seroconverion of HBeAg and HBV DNA was observed in chronic hepatitis B patients. [68],[72]

Glycyrrhiza uralensis is widely used in modulation or improvement of the other herbs in many Chinese prescriptions. The active compounds in G. uralensis are identified as glycyrrhizin, glycyrrhetic acid 3-O-monoglucuronide and glycyrrhetic acid. All these compounds have anti-HBV activity in PLC/PRF/5 cells that inhibits the expression of HBsAg and sialylation of HBsAg. [73] Because of its modest effect on the suppression of HBV, glycyrrhizin usually is used in combination with other potent anti-HBV drugs, such as 3TC. [74] In a pilot clinical trial, the combination of intravenous glycyrrhizin and oral lamivudine demonstrated safety and efficacy of anti-HBV activity. [75] Regardless of its anti-HBV activity, glycyrrhzin showed its effect on the modulation of the immune system, with enhanced interleukin-12 production in peritoneal macrophages. [76] Because of this characteristic, G uralensis is used widely in many complex remedies for supporting the immune system against infectious diseases, such as hepatitis B infection. [77]

Boehmeria nivea has been used therapeutically in China and Taiwan for diuretic and antipyretic purposes and for liver protection. [78] Recently, the anti-HBV activity of B. nivea was first demonstrated by Huang et al for the first time. [79] B. nivea strongly inhibits the HBV virion secretion in HepG2 2.2.15 cells, but this inhibitory effect was not related to its cytotoxicity or inhibition of viral DNA replication and RNA expression. Furthermore, B. nivea can also reduce the level of serum HBV DNA in a HepG2 2.2.15 tumor-bearing SCID model. [80] Similar to other anti-HBV herbs, B. nivea's primary mechanism of anti-HBV effect was not through inhibition of the viral polymerase. It was later demonstrated that B. nivea inhibits HBV virion secretion via down-regulation of a chaperone interacting with HBV surface proteins. [81]

In the early screening of anti-HBV herbs, many active compounds were identified and proposed for hepatitis B treatment: costunolide and dehydrocostus lactone in Saussurea lappa Clarks, daphnoretin in Wikstroemia indica and osthole in Angelica pubescens. [64],[82] These compounds exert anti-HBV activities by inhibition of HBsAg gene expression and HBsAg secretion via protein kinase C activation or HBsAg glycosylation. [83] Wogonin, an active compound, from Scutellaria radix is reported to be able to inhibit secretion of HBsAg and reduce HBV DNA in HepG2 2.2.15 cells as well as serum DHBV and HBsAg levels in DHBV-infected ducks. [84]


   Complex Herb Formula in the Treatment of Chronic Hepatitis B Top


Although a single herb can be used to treat a disease, traditional physicians have been treating chronic hepatitis patients with complex herbs, a so-called decoction or remedy. Generally, different herbs with a consistent proportion are extracted with hot water and then evaporated to approximately 4-fold concentration. In traditional Chinese medical theory, each herb confers its activity to eliminate symptoms, enhances the therapeutic effect of the other herbs and supports the patients' tolerance to side effects or balances the body's milieu. Some decoctions or remedies have been studied for a novel 'indication' of not only reducing the levels of alanine transaminoferase or aspartate aminotransferase but also reducing the serum HBsAg, HBeAg and HBV DNA levels, which in turn reflects the suppression of replication of HBV. Because of the difficulties and complexities in the control of manufacturing, evaluation of the most complex remedies include only authentication of an individual herb with very limited chemical control. In addition, the remedy is designed for human use and there is no suitable assay model to evaluate the therapeutic efficacy. Many clinical trials have been conducted to evaluate the efficacy of these complex remedies for treatment of chronic hepatitis B [Table 2]. Most of these anti-HBV complex remedies, such as Hejie decoction, Bushen recipe and sho-saiko-to, are not designed to clear serum HBV but support patients in evoking an immune response against HBV. [85],[86] These remedies have been shown to reduce the serum HBV DNA of chronic patients in controlled and uncontrolled clinical trials. According to the results of these clinical trails, these remedies may stimulate the immune system via the expression of TCRVβ 7 in T cells or may polarize Th1 cytokine secretion followed by activation of cytotoxic T lymphocytes to eliminate HBV. [87],[88] In addition, the Bushen recipe combined with 3TC not only enhances the therapeutic effect but also reduces mutation of the YMDD motif. [86] This finding implies that the Bushen recipe prevents the mutation of HBV in long-term chronic hepatitis B treatment. The Chinese remedy xiao-chai-hu-tang, also called sho-saiko-to and TJ9 in Japan, has been extensively studied for its therapeutic purposes. In treatment of chronic hepatitis B, xiao-chai-hu-tang can eliminate the serum HBeAg in children infected with HBV and can induce anti-HBe antibody development in some chronic hepatitis patients. [89],[90] Experimental evidence has also revealed that xiao-chai-hu-tang improved the effect of vaccination in an HBV transgenic animal model. [91] Unfortunately, there are reports that xiao-chai-hu-tang may induce acute hepatitis and acute respiratory distress syndrome. [92],[93],[94],[95] Hejie decoction, a complex formula of Chinese traditional medicine, is composed of nine herbs and its composition is similar to that of Xiao-Chai-hu-Tang, which contains the additional herbs Polygonum cuspidatum, Morinda officinalis How and Hedyotis diffusa Willd instead of Zingiber officinale [Table 2]. Clinical trails reveal that Hejie decoction is effective for treating chronic hepatitis B; its effect in eliminating HBV is through activating T cells by increasing the expression of TCRVβ 7. [85],[87] So far, no observed adverse effect has been reported while chronic hepatitis B patients were treated with Hejie decoction. Although Hejie decoction, Bushen recipe and sho-saiko-to are designed to improve the immune system against infectious diseases, several kinds of complex formulas of herbs are designed to clear HBV, such as Denshao Huaxian capsule and New LivFit. Danshao Huaxian capsule contains five medicinal herbs that inhibited replication of HBV DNA and reduced serum HBV DNA in a 35-patient clinical trial. [96] New LivFit contains six medicinal herbs that demonstrate the effect of hepatic protection and eliminate circulating HBV DNA in end-stage renal disease patients with HBV infection. [97],[98] It is not surprising that the formulation contains more than one herb with effective anti-HBV activity. Other complex herbal formulas, such as VI-28 and KYH-1, are also being studied at the pre-clinical stage. VI-28 can up-regulate the level of IFN-g and IL-2Ra and can enhance both innate and acquired immunity, which is supposed to eliminate HBV. [99],[100] KYH-1 has been shown to inhibit HBV replication in HepG2 2.2.15 cells, expression of woodchuck hepatitis virus (WHV) RNA, pregenomic WHV RNA and WHV surface antigen mRNA in WHV-infected primary woodchuck hepatocytes and also inhibits the activity of HBV polymerase in an in vitro assay. [101]


   Strategy of Herbal Medicines Against HBV Top


To fight HBV infection, one must adopt two strategies: inhibit HBV replication and evoke immunity against HBV infection. Unlike nucleoside analogue drugs that target viral polymerase, herbal medicines may confer their anti-HBV activity in any step of the HBV lifecycle. Because of the high mutation rate of viral polymerase, the use of nucleoside analogue drugs, such as 3TC, will select the resistant mutation clone. Nevertheless, there are other targets that could affect the

lifecycle, including viral encapsidation, assembly, envelopment and so forth. Herbal medicines elicit an unknown mechanism to inhibit replication and secretion of HBV, which is reflected in the reduction of HBsAg, HBeAg and HBV DNA. Because of the lack of a drug-screening system for anti-HBV effect, the herbal medicines still languish in the early stage of anti-HBV drug development. Although the mechanism of anti-HBV remains unclear, the effectiveness of these herbal medicines encourages scientists to identify the novel anti-HBV drug components from herbs that differ from the nucleoside analogues. In fact, once a novel viral target of the HBV lifecycle can be established, the herbs could be screened by using this target to facilitate the development of an anti-HBV drug. Of the traditional herbal medicines, some may confer an important function in promotion of immunity against HBV. By means of increasing the antigen presentation or inducing the expression of immune-related genes, the herbs could even substitute the costly IFN-α therapy. Moreover, the herbs that are used as immunomodulators may yield additive or synergistic effects in combination with vaccinations or drugs in different pharmacological action modes. [69],[86],[90]


   Crude Mixture Versus Active Compounds Top


Among the herbals studied against HBV infection in the past decades, some of them have known chemical constituents. Some active compounds have been identified and reported for their potent anti-HBV activity. However, continued research on these potent compounds is no longer pursued, which implies that inhibition of HBV by medicinal plants in the studies is not reproducible or is not feasible for pharmaceutical purposes. In fact, medicinal plants or herbs exhibit their anti-HBV as a result of a mixture of their constitutive components. When scientists try to fractionate the extract of herbs into partial purified fractions or to identify the single active compounds, such action results in loss of the synergistic effects from a set of similar compounds. In most cases, this finding also explains the fact that herbs in crude extract form are effective and partially purified fractions are less effective.


   Combination of Herbal Medicine and Current Anti-HBV Drug Top


So far, there is no generally effective therapy for chronic hepatitis B because most of the present clinical regimens for treatment, such as interferon and nucleoside analogues, have had limited success. [47] Therefore, some scientists are putting in a lot of effort into searching for novel anti-HBV agents from the empirically traditional herbal medicines. Medicinal herbs are widely used in the treatment of chronic hepatitis B in developing countries and many clinical trials are being conducted to verify the anti-HBV efficacy and safety of these herbal medicines individually or combined with current therapeutic drugs. [68],[69],[72],[86],[102] The quality of these clinical trials on herbal medicines for hepatitis B is poor in that they do not follow the randomized, placebo-controlled, double-blind model, suggesting that the results may lead to misunderstandings. [103] There are obstacles in conducting a good double-blind and placebo-controlled clinical trial because of the taste, flavor and color of herbal medicine products. However, the outcomes of these limited clinical trials have encouraged physicians and guided scientists to continue the search for active compounds or the optimal formula for the treatment of chronic hepatitis B.


   Regulation of Complementary and Alternative Medicines Top


Complementary and alternative medicine (CAM), also termed 'herbal medicines', has a long history of use worldwide; even in Western countries, ancient people used herbs to treat many diseases. In China, multiple herbs are used to treat diseases, especially to cure a 'syndrome', whereas Western industries emphasize use of a single herb to treat the etiology of a disease. Traditionally, appropriate herbs are combined to synergize the therapeutic effects and reduce adverse effects. However, the use of multiple herbs may lead to quality-control problems in manufacturing. In developing countries, patients can visit traditional physicians and accept the medication in herb forms. Most herbs are brought home to make a decoction or have already been made into capsule, solution and tablet form by a pharmaceutical company. Unfortunately, it is difficult to achieve consistency in these botanical products from the initial control of botanical raw materials to standardization of active ingredients. This problem may invoke a question: Do physicians use uncertain drugs to treat patients? In the treatment of chronic hepatitis B, complex herbs have been used clinically in treating patients and have yielded good therapeutic effects in clinical trials. In fact, CAM can be used as an adjuvant or adjunctive therapy; for example, Bushen recipe synergizes the therapeutic effect of 3TC and Sophora flavescens Ait synergizes the function of IFN-α. [67],[69],[86] Most herbs exert antiviral activity in the treatment of chronic hepatitis B in a manner different to that of nucleotide drugs [Figure 1]. In China, many clinical trials have been conducted and regulated by the State Administration of Traditional Chinese Medicine (under the Ministry of Public Health) and a number of herbal medicines are already approved and commercially available. Although these herbal medicines have effects on the clearance of HBV markers and/or the restoration of liver function in patients with chronic hepatitis B, their reliability is still doubted because of the poor methodological qualities of the trials. Moreover, the organic chemicals contained in the herbs vary substantially because of many factors including the growth condition of the plant, the method of extraction and the type of formulation, which is correlated highly with the effectiveness of botanical products. Therefore, herbal medicines should be subject to more stringent regulation to meet the requirements of the Western pharmaceutical market.

In 1998, the National Center for Complementary and Alternative Medicine (NCCAM), was founded in the United States. This medical institute published a book titled Complementary and Alternative Medicine in the United States, which stated that more than one third of American adults had used CAM and that visits to CAM providers each year exceeded those to primary care physicians. [104] About 19% of the people surveyed in the United States used natural products. This implies that CAM has already been accepted by technology-rich countries or areas. For regulation of natural products, FDA published guidance on botanical drug products in June 2004, which formally opened the regulatory door for the approval of botanical drugs. According to a 2005 report from the FDA Center for Drug Evaluation and Research (CDER) on preclinical issues and the status of botanical drug products in the United States, 192 botanical drugs were submitted as investigational new drugs (INDs) compared with 50 botanical IND drugs in 2000, showing that the number of botanical IND drugs has gradually increased in recent years. For the global pharmaceutical market, the herbal medicine manufactures would have to meet the FDA regulations for chemistry, manufacturing and controls (CMC), toxicology and pharmacology to provide the world with evidence-based, science-based, clinically-driven and verifiable botanical drugs.


   Conclusions Top


Because of the low response rate of 3TC therapy and the serious side-effects of IFN treatment, the development of herbal medicines is assuming greater importance. Herbal medicines not only inhibit HBV replication but also lower the mutation rate in the YMDD sequence. Most herbs inhibit replication of the HBV virus but unlike 3TC, which inhibits only the viral polymerase, multiple herbal compounds in addition affect multiple intracellular targets to elicit synergistic anti-HBV effect. It is also believed that a combination of two anti-HBV drugs with different pharmacological actions will improve the therapeutic effect in the treatment of chronic hepatitis B. In many clinical trials, the effectiveness of herbs combined with IFN has been intensively evaluated and verified. The results suggest that herbs can be integrated into the current Western anti-HBV therapy to achieve a good therapeutic effect. For this purpose, a novel type of anti-HBV herb or drug should be developed as the leading drug for the treatment of chronic hepatitis B.

 
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Correspondence Address:
Jia-Ming Chang
Division of Research and Development, Development Center for Biotechnology, Xizhi City, Taipei County, 221 R.O.C
Taiwan
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0972-9747.45091

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    Abstract
    Introduction
    Overview of HBV...
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    The Immunomodulators
    The Viral Polyme...
    The Nucleocapsid...
    The Viral Envelo...
    The Novel Target...
    Combination Appr...
    Study Model for HBV
    Herbal Medicines...
    Single Herb in t...
    Complex Herb For...
    Strategy of Herb...
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