| |
Complementary and alternative therapies in the treatment of chronic hepatitis C: a systematic review
|
| |
| |
Journal of Hepatology
Volume 40, Issue 3, Pages 491-500 (March 2004)
Joanna Thompson Coon Corresponding Author Information Send E-mail to Author＊ and Edzard Ernst
Abstract
Background/Aims
Hepatitis C is an escalating global health problem. The recommended treatment regimen is associated with considerable expense, adverse effects and poor efficacy in some patients. Complementary therapies are widely promoted for and used by patients with hepatitis C. The aim is to systematically assess the efficacy of complementary therapies in treating chronic hepatitis C.
Methods
Systematic searches were conducted in six databases, reference lists of all papers were checked for further relevant publications and information was requested from experts. No language restrictions were imposed.
Results
Twenty-seven eligible randomised clinical trials were located involving herbal products and supplements. No randomised clinical trials were identified for any other complementary therapy. In 14 of the trials, patients received interferon-α in combination with the complementary therapy. Less than half the trials (11/27) were of good methodological quality. Compared with the control group, significant improvements in virological and/or biochemical response were seen in trials of vitamin E, thymic extract, zinc, traditional Chinese medicine, Glycyrrhiza glabra and oxymatrine.
Conclusions
We identified several promising complementary therapies, although extrapolation of the results is difficult due to methodological limitations. More research is warranted to establish the role of these and other therapies in the treatment of hepatitis C.
Methods
Identification of clinical trials
In order to identify clinical trials involving complementary and alternative therapies in the treatment of hepatitis C, systematic literature searches were conducted in the following electronic databases: Medline (via Pubmed), Embase, CINAHL, Amed (Alternative and Allied Medicine Database, British Library Medical Information Centre), The Cochrane Library and the British Library Index of Conference Proceedings (all from their inception to October 2002).
Further relevant papers were located by hand searching the reference lists of all papers. In addition experts in the field were contacted to provide published and unpublished material. Finally our own extensive files were hand searched for further relevant publications.
Inclusion/exclusion criteria
Only randomised clinical trials of complementary therapies administered to patients with a diagnosis of hepatitis C or non-A, non-B chronic hepatitis were included. Trials in which several subgroups of patients with different hepatitis aetiologies were studied and those in which the hepatitis virus was not specified were excluded. Both placebo controlled and comparative trials were considered. All retrieved data including uncontrolled trials, case reports, pre-clinical and observational studies were reviewed for safety information. No language restrictions were imposed.
Data extraction and quality assessment
All articles were read in full. Data relating to sample size, diagnosis, genotype and gender of patients, previous interferon exposure, intervention and control, treatment duration, primary outcome measures and results were extracted by the first author and validated by the second. The methodological quality of each clinical trial was assessed using the Jadad scoring system [8]. This scale ranges from 0 (poorest) to 5 (highest) and assesses methods of randomisation and blinding and descriptions of withdrawals and dropouts.
Results
The search strategy generated a total of 3085 references, of which 142 were considered to be potentially relevant. We did not locate any unpublished trials. A total of 67 clinical trials were retrieved for further evaluation of which 27, involving 1709 patients, were eligible for inclusion (Table 1). Reasons for exclusion included no specific hepatitis diagnosis, trials in which patients with both hepatitis B and C were included, trials in which only interim results have been published, or which did not measure clinical endpoints and trials which were not randomised.
Supplements
Antioxidants
Seven randomised clinical trials of antioxidants were located including a total of 463 patients [9--15]. In six trials, antioxidants were administered in combination with interferon-α No significant differences in virological response were seen between treatment regimens in any of the trials. Details of biochemical parameters were not provided in all reports but appear to correlate with virological responses. One trial compared vitamin E treatment with placebo; statistically significant reductions in alanine aminotransferase (ALT) were seen during treatment but reductions did not occur in all patients nor did complete normalisation of ALT levels occur. No virological effects were seen.
Safety
At the doses studied, these antioxidants appear to be well tolerated, with no specific adverse events reported in any of the trials. However, very large oral doses of N-acetyl cysteine used to treat paracetamol overdose are commonly associated with nausea and vomiting [16] and intravenous administration of N-acetyl cysteine can result in anaphylactoid reactions, which may be more common in patients with chronic liver disease [17]. Over a prolonged period, selenium at doses as low as 900 mg/day can produce signs of toxicity, such as depression, nervousness, emotional instability, nausea and vomiting, in some people [18]. In extreme cases excess levels of selenium have been associated with pathologic nail bed changes and the loss of finger nails, temporary hair loss and fatigue [19]. No further information regarding adverse events associated with vitamin E was identified.
Thymic extracts
A total of five trials of thymic extracts were identified [20--24]; four involved the synthetic polypeptide thymosin alpha 1 (Tα1) and in one, patients received Complete Thymic Formula which contains bovine glandular extracts of thymosin, thymopoeitin and thymic humoral factors with various herbs, vitamins, enzymes and minerals.
Of the three trials in which patients received Tα1 in combination with interferon, the number of patients experiencing a complete virological or biochemical response at the end of treatment was significantly higher during treatment with the combination than with either interferon alone or placebo. There were also significant differences in the number of patients with a sustained response at 6 or 12 months after cessation of treatment. However, there were no significant differences in biochemical or virological response between treatment and placebo groups in the two trials in which patients received Tα1 or Complete Thymic Formula alone.
Safety
Treatment with thymic extracts appears to be well tolerated. It is possible that administering two drugs with potential immunostimulatory properties might increase the incidence of immune-associated adverse events, but there does not appear to be any evidence of this from the literature. Adverse events were reported in detail in one trial; whilst the frequency of adverse events was high, only nausea and vomiting were more common with combination treatment than with interferon-α. In another study, Tα1 was associated with local discomfort at the injection site in two patients [23], and complete thymic extract was associated with severe thrombocytopenia in one patient who was also receiving naproxen [24].
Zinc
One clinical trial of zinc supplementation in combination with interferon-α was identified [25]. Overall significantly more patients in the combination group were complete or incomplete responders (18/32 vs 8/36; ) with the effect being most evident in those patients with less than 5×105 copies of HCV RNA/ml, although there were far more patients with a higher viral load in the interferon-only group (23 vs 8).
Safety
In this trial, a total of seven patients withdrew because of side effects; four from the interferon-α-alone group (erythema multiforme, severe fatigue with headache and an attack of loss of consciousness) and three from the combination group (loss of sleep, serious headache and interstitial pneumonia). The side-effect profile was similar in both groups and included flu-like symptoms and a mild reduction in platelet and white blood cell counts. Toxic effects of zinc supplementation tend to occur following prolonged intake at levels greater than 150 mg/day; effects can include copper deficiency anemia, reduced HDL cholesterol levels and depressed immune function. [26]
Other supplements
One randomised clinical trial was identified involving Adelavin (an injectable hepatoprotective mixture containing liver extract and flavin adenin dinucleotide) [27]. The trial was of poor methodological quality and whilst the results appear promising, no statistical analyses were performed.
One randomised clinical trial of oral enzyme therapy was identified, again this trial was of poor methodological quality [28]. The lack of methodological, analytical and statistical details provided makes interpretation of the results very difficult.
No data relating to the safety profile of these supplements was located.
Herbal medicinal products
Traditional Chinese medicine
We located a total of seven randomised clinical trials of traditional Chinese medicine in the treatment of hepatitis C [29--35]. The methodological quality of six of the trials was considered poor, scoring only one out of a maximum of five on the Jadad scale.
In two trials of herbal formulations in combination with interferon-α, there was some suggestion of greater clearance of HCV RNA and ALT normalisation with the combination treatment compared with patients receiving monotherapy. In the only placebo-controlled trial of sole therapy with traditional Chinese medicine, there was a significant reduction in ALT levels during treatment in those receiving the herbal compound. No virological effects were seen. Two studies compared a traditional Chinese medicine with interferon-α; there were no significant differences between groups in either study. The remaining studies used less common treatment regimens in the control group. Although these results are promising, interpretation is difficult due to the unknown effects of the control treatment regimens.
Safety
Detailed descriptions of adverse events were not provided. In the only placebo-controlled trial [31], four patients experienced adverse events: palpitations [36], diarrhoea [37], abdominal discomfort [36]; all of them were taking the herbal formulation. Further assessment of the safety of these medicines is complicated, due to the individualised nature of many of the herbal compounds involved, the large number of different herbs in each formulation and the relatively small number of patients within each clinical trial.
Glycyrrhiza glabra (licorice)
Four randomised clinical trials of glycyrrhizin (all administered as Stronger Neo Minophagen C (SNMC) comprising of 0.2% glycyrrhizin, 0.1% cysteine and 2.0% glycine in physiological saline solution) were located. In two trials, patients received SNMC in combination with interferon-α [38,39]; there were no significant differences between treatments in the number of patients achieving biochemical or virological response in either study. In the only European randomised clinical trial of glycyrrhizin, there were some reductions in ALT levels during treatment, compared with placebo but this was not sustained after cessation of treatment and there were no significant effects on HCV RNA levels [40]. In the final trial, there were statistically significant differences in liver enzyme levels between treatment groups during treatment, however, these were not sustained at follow-up and there were no virological effects [41]. There was no placebo group in this trial; the comparison treatment was a combination of SNMC and ursodeoxycholic acid, the effects of which are unknown. These results are therefore difficult to interpret.
Safety
Hypokalemia, sodium retention, increase in body weight, elevated blood pressure and retention of sodium are all expected adverse effects of glycyrrhizin treatment [42]. However, there is no evidence for an increased occurrence of these during SNMC treatment in these studies. Two publications provide a thorough analysis of the adverse events experienced during the trial [40, p. 1165]; there were no significant differences between groups in the number of patients reporting an adverse event, although in the study by van Rossum et al. significantly more patients reported cold/flu symptoms in the 160 mg group compared with placebo. Suzuki et al. reported one adverse event (bleeding in the fundus) which occurred during combination treatment with glycyrrhizin and interferon-α [39]. In the final study, no patients complained of drug related symptoms or developed signs of an adverse reaction during the treatment period [41].
Oxymatrine (derived from Sophora japonica)
One open, randomised, parallel group clinical trial of mediocre methodological quality in which patients were treated with oxymatrine or with general liver protective agents was identified [43]. At the end of treatment there were statistically significant differences in the number of patients with normalised HCV RNA levels between groups. No further information regarding the safety of oxymatrine was located.
Discussion
Several herbal medicinal products and supplements have been identified with potential virological and/or biochemical effects in the treatment of chronic hepatitis C infection. Studies of thymic extract, zinc and Bing Gan decoction in combination with interferon-α and oxymatrine alone have demonstrated greater clearance of the hepatitis C virus than control treatment. Normalisation of liver enzymes has been greater during treatment with vitamin E, Glycyrrhiza glabra, CH100, Yi Zhu decoction and Yi Er Gan Tang decoction than with the control treatment.
However, interpretation and extrapolation of the results is difficult for several reasons.
First, few of the studies measured the sustained virological response at 6 months after cessation of treatment. This has become the optimum outcome measure in trials of conventional therapy since studies of interferon-α treatment indicate that 92% of patients with a sustained virological response at 6 months will remain seronegative for up to 6 years [44]. There is also evidence that a sustained virological response may be associated with regression of fibrosis [45]. Of the studies that did include this endpoint, only one trial, of the combination of interferon-α and zinc, reported a significant effect above interferon-α alone [25]. Secondly, the current recommended duration of interferon-α treatment is 48 weeks in patients with hepatitis virus genotype 1 [46], none of the trials included a treatment period of longer than 26 weeks and some were as short as 4 weeks. The control group did not receive currently accepted optimum interferon-α treatment in many of the comparative studies; therefore results from these trials cannot be extrapolated to standard treatment comparisons. Thirdly, it is recognised that an individual's response to interferon-α treatment will be affected by several factors e.g. hepatitis C virus genotype, gender, baseline viral level and previous exposure to interferon-α therapy [47]. Whether these are also important for predicting treatment response to complementary interventions is unclear, but they may have influenced the selection of patients for inclusion into trials with included patients already having failed to respond to a course of interferon-α, for example. And finally, there were methodological limitations with over half the trials, the most common being lack of blinding and incomplete reporting of randomisation methods and withdrawals.
Attempts were made to obtain data from unpublished trials and we are aware of several studies which have not been published in full, however, we were not able to obtain the unpublished results. There is evidence to suggest that studies with significant positive results are more likely to be published [48] and this may be more pronounced with unfamiliar complementary therapies [49]. It is possible that we did not locate all the trials on traditional Chinese medicine, as we did not search any Chinese language databases. A recent systematic review of herbal medicinal products for the treatment of hepatitis B located an additional 18 trials from Chinese language sources [50]. We decided not to perform searches in Chinese language databases as previous experience suggests that the resulting references do not provide sufficient detail to reliably assess methodological quality and consequently do not add significantly to the evidence base [51].
Disappointingly, we found no evidence for the use of complementary therapies in clinically important subgroups of patients who have often been denied access to therapy with interferon-alpha in the past (e.g. patients with HIV co-infection or psychiatric problems). Nor were we able to locate any randomised clinical trials of any other complementary therapies, including several herbal medicinal products such as Silybum marianum which are very popular with patients. A survey of patients with hepatitis C attending an out-patient clinic found that 36% (42/117) were taking herbs, of which 14 (33%) were taking Silybum marianum; 67% of responders attributed benefit to their herbal therapy [52].
The safety profiles of the interventions discussed within this systematic review look encouraging at the doses studied. However, the long-term safety for use in the treatment of hepatitis C, either alone or in combination with conventional medicines, has not been established. Comparative and placebo-controlled trials suggest that patients experience no more adverse events with these interventions than with placebo or comparative medications, although short-term clinical trials are not designed to detect rare or delayed adverse events.
There is an undoubted need for further research into the treatment of hepatitis C, and this review has identified several promising interventions. A more detailed understanding both of the pharmacology of herbal medicinal products and supplements in relation to the hepatitis C virus and of the patient characteristics which might be important in predicting a favourable response to treatment would facilitate the design of future clinical trials. Anecdotal evidence suggests that many more complementary therapies are currently available to and popular with patients and further research into these interventions is warranted to establish their role in the treatment of chronic hepatitis C infection.
References [1]. World Health Organization . Report of a WHO consultation in collaboration with the Viral Hepatitis Prevention Board, Antwerp, Belgium. Global surveillance and control of hepatitis C. J Viral Hepat. 1999;6:35-47
[2]. Department of Health . Hepatitis C strategy for England. August 2002;
[3]. Chander G, Sulkowski MS, Jenckes MW, Torbenson MS, Herlong HF, Bass EB, et al. Treatment of chronic hepatitis C: a systematic review. Hepatology. 2002;36:S135-S144
[4]. Baker DE. Pegylated interferon plus ribavirin for the treatment of chronic hepatitis C. Rev Gastroenterol Disord. 2003;3:93-109
[5]. Liang TJ, Rehermann B, Seeff LB, Hoofnagle JH. Pathogenesis, natural history, treatment and prevention of hepatitis C. Ann Intern Med. 2000;132:296-305
[6]. Falck-Ytter Y, Kale H, Mullen KD, Sarbah SA, Sorescu L, McCullough AJ. Surprisingly small effect of antiviral treatment in patients with hepatitis C. Ann Intern Med. 2002;136:288-292
[7]. Seeff LB, Lindsay KL, Bacon BR, Kresina TF, Hoofnagle JH. Complementary and alternative medicine in chronic liver disease. Hepatology. 2001;34:596-603
[8]. Jadad AR, Moore A, Carroll D, Jenkinson C, Reynolds DJ, Gavaghan DJ, et al. Assessing the quality of reports of randomised clinical trials: is blinding necessary?. Control Clin Trials. 1996;17:1-12
[9]. Look MP, Gerard A, Rao GS, Sudhop T, Fischer H-P, Sauerbruch T, et al. Interferon/antioxidant combination therapy for chronic hepatitis C—a controlled pilot trial. Antiviral Res. 1999;43:113-122
[10]. Neri S, Ierna D, Antoci S, Campanile E, D'Amico RA, Noto R. Association of alpha-interferon and acetyl cysteine in patients with chronic C hepatitis. Panminerva Med. 2000;42:187-192 MEDLINE
[11]. Andreana A, Zampino R, Tonziello A, Adinolfi LE, Utili R, Ruggiero G. Treatment with N-acetyl cysteine (NAC) or ofloxacin (OFLO) as adjunct to IFN failed to achieve response in chronic hepatitis C patients non-responding to IFN alone: a phase II study. Hepatology. 1997;26:218A
[12]. Grant PR, Black A, Garcia N, Prieto J, Garson JA. Combination therapy with interferon-alpha plus N-acetyl cysteine for chronic hepatitis C: a placebo controlled double blind multicentre study. J Med Virol. 2000;61:439-442
[13]. Bernhard MC, Junker E, Hettinger A, Lauterburg BH. Time course of total cysteine, glutathione and homocysteine in patients with chronic hepatitis C treated with interferon-alpha with and without supplementation with N-acetylcysteine. J Hepatol. 1998;28:751-755
[14]. Ideo G, Bellobuono A, Tempini S, Mondazzi L, Airoldi A, Benetti G, et al. Antioxidant drugs combined with alpha-interferon in chronic hepatitis C not responsive to alpha-interferon alone: a randomised, multicentre study. Eur J Gastroenterol Hepatol. 1999;11:1203-1207
[15]. von Herbay A, Stahl W, Niederau C, Sies H. Vitamin E improves the aminotransferase status of patients suffering from viral hepatitis C: a randomised, double blind, placebo-controlled study. Free Radic Res. 1997;27:599-605
[16]. Kelly GS. Clinical applications of N-acetyl cysteine. Altern Med Rev. 1998;3:114-127
[17]. Jones AL, Jarvie DR, Simpson D, Hayes PC, Prescott LF. Pharmacokinetics of N-acetyl cysteine are altered in patients with chronic liver disease. Aliment Pharmacol Ther. 1997;11:787-791 MEDLINE
[18]. Murray MT, ed. Selenium. Encyclopedia of nutritional supplements. Rocklin, CA: Prima 1996:222-228
[19]. Leads from the MMWR . Selenium intoxication—New York. J Am Med Assoc. 1984;251:1938
[20]. Sherman KE, Sjogren M, Creager RL, Damiano MA, Fremman S, Lewey S, et al. Combination therapy with thymosin alpha 1 and interferon for the treatment of chronic hepatitis C infection: a randomised, placebo-controlled double blind trial. Hepatology. 1998;27:1128-1135
[21]. Moscarella S, Buzzelli G, Romanelli RG, Monti M, Giannini C, Careccia G, et al. Interferon and thymosin combination therapy in naive patients with chronic hepatitis C: preliminary results. Liver. 1998;18:366-369
[22]. Sherman KE, Sjogren M, Creager RL, Freeman S, O'Brian J, Root S, et al. Hepatitis C RNA response to combined therapy with thymosin alpha-1 and interferon. Hepatology. 1994;20:207A
[23]. Andreone P, Cursaro C, Gramenzi A, Buzzi A, Covarelli MG, Di Giammarino L, et al. A double blind, placebo controlled, pilot trial of thymosin alpha 1 for the treatment of chronic hepatitis C. Liver. 1996;16:207-210
[24]. Raymond RS, Fallon MB, Abrams GA. Oral thymic extract for chronic hepatitis C in patients previously treated with interferon. A randomised, double blind, placebo controlled trial. Ann Intern Med. 1998;129:797-800
[25]. Takagi H, Nagamine T, Abe T, Takayama H, Sato K, Otsuka T, et al. Zinc supplementation enhances the response to interferon therapy in patients with chronic hepatitis C. J Viral Hepat. 2001;8:367-371
[26]. Murray MT, ed. Zinc. Encyclopedia of nutritional supplements. Rocklin, CA: Prima 1996:181-189
[27]. Fujisawa K, Suzuki H, Yamamoto S, et al. Therapeutic effects of liver hydrolysate preparations on chronic hepatitis-A double blind, controlled study. Asian Med J. 1983;26:497-526
[28]. Stauder G, Kabil S. Oral enzyme therapy in hepatitis C patients. Int J Immunother. 1997;13:153-158
[29]. Han GP, Wang ZY, Peng SL. Binggan capsule combined with interferon for treatment of 30 cases of hepatitis C. Henan J Tradit Chin Med. 1997;12:43-44
[30]. Pei ZG, Liu YL, Zhao SM. Therapeutic observation of Binggan decoction combined with interferon in 46 cases of hepatitis C. Pract J Integrating Chin Mod Med. 1996;9:444
[31]. Batey RG, Bensoussan A, Fan YY, Bollipo S, Hossain MA. Preliminary report of a randomised, double blind placebo controlled trial of a Chinese herbal medicine preparation CH100 in the treatment of chronic hepatitis C. J Gastroenterol Hepatol. 1998;13:244-247
[32]. Chen J, Han XY, Miao YX, Zhang SX, Fu SX, Liu ZM, et al. Clinical study of Bingganling for treatment of hepatitis C. Hebei J Tradit Chin Med. 1998;20:137-138
[33]. Jiang YH. Treatment of 20 cases of hepatitis C using a self-prescribed Yizhu oral liquid. J Nanjing Univ Tradit Chin Med. 1999;15:256
[34]. Xiao HQ, Luo RY, Wu WF, Deng TT. Effect of Gansu capsule on chronic hepatitis C. J Guangzhou Univ Tradit Chin Med. 1999;16:24-27
[35]. Yu WJ. Yi Er Gan decoction for treatment of 40 cases of hepatitis C. New J Tradit Chin Med. 1995;27:47
[36]. Bahrke MS, Morgan WP. Evaluation of the erogenic properties of ginseng. Sports Med. 2000;29:113-133
[37]. Vogler BK, Pittler MH, Ernst E. The efficacy of ginseng. A systematic review of randomised clinical trials. Eur J Clin Pharmacol. 1999;55:567-575
[38]. Fujiyama S, Chikazawa H, Honda Y, Kukida T, Iida S, Kawakami T, et al. Treatment of chronic active hepatitis C with interferon alpha 2b-alone and in combination with Stronger Neo Minophagen C. Biother Jpn. 1998;12:1495-1513
[39]. Suzuki Y, Ikeda K, Saitoh S, Kobayashi M, Tsubota A, Koida I, et al. A prospective randomised administration of Stronger Neo Minophagen C as an adjuvant therapy for chronic hepatitis type C treated with interferon. Acta Hepatol Jpn. 1996;37:363-367
[40]. van Rossum TGJ, Vulto AG, Hop WC, Brouwer JT, Niesters HG, Schalm SW. Intravenous glycyrrhizin for the treatment of chronic hepatitis C: a double blind, randomised, placebo controlled phase I/II trial. J Gastroenterol Hepatol. 1999;14:1093-1099
[41]. Tsubota A, Kumada H, Arase Y, Chayama K, Saitoh S, Ikeda K, et al. Combined ursodeoxycholic acid and glycyrrhizin therapy for chronic hepatitis C virus infection: a randomized controlled trial in 170 patients. Eur J Gastroenterol Hepatol. 1999;11:1077-1083
[42]. Conn JW, Rovner DR, Cohen EL. Licorice-induced pseudoaldosteronism. J Am Med Assoc. 1968;205:492-496
[43]. Li J, Li C, Zeng M. Preliminary study on therapeutic effect of oxymatrine in treating patients with chronic hepatitis C. Zhongguo Zhng Xi Yi Jie He Za Zhi. 1998;48:227-229
[44]. Marcellin P, Boyer N, Gervais A, Martinot M, Pouteau M, Castelnau C, et al. Long term histologic improvement and loss of detectable intrahepatic HCV RNA in patients with chronic hepatitis C and sustained response to interferon alpha therapy. Ann Intern Med. 1997;127:875-881
[45]. Poynard T, McHutchison J, Davis GL, Esteban-Mur R, Goodman Z, Bedossa P, et al. Impact of interferon alfa-2b and ribavirin on progression of liver fibrosis in patients with chronic hepatitis C. Hepatology. 2000;32:1131-1137
[46]. Di Bisceglie AM, Hoofnagle JH. Optimal therapy of hepatitis C. Hepatology. 2002;36:S121-S127
[47]. Lindsay KL. Introduction to therapy of hepatitis C. Hepatology. 2002;36:S114-S120
[48]. Easterbrook PJ, Berlin JA, Gopalan R, Matthews DR. Publication bias in clinical research. Lancet. 1991;337:867-872
[49]. Schmidt K, Pittler MH, Ernst E. Bias in alternative medicine is still rife but is diminishing. Br Med J. 2001;323:1071
[50]. McCulloch M, Broffman M, Gao J, Colford JM. Chinese herbal medicine and interferon in the treatment of chronic hepatitis B: a meta-analysis of randomised, controlled trials. Am J Public Health. 2002;92:1619-1627
[51]. Tang J-L, Zhan S-Y, Ernst E. Review of randomised controlled trials of traditional Chinese medicine. Br Med J. 1999;319:160-161
[52]. Peyton BG, Spears TL, Lindsey A, Lindsey J, Sharma VK, Raufmann J-P. A survey of use of herbal medicine in patients with hepatitis C. Hepatology. 1999;30:191A
[53]. Sato A, Mizuno H, Tominaga T, Suga M, Suemori S, Suzuki H, et al. Efficacy of combination therapy with interferon and adelavin in patients of chronic hepatitis C with hepatitis C in viral (HCV) genotype 1b. Ther Res. 1998;19:295-298
|
|
| |
| |
|
|
|
