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Herbal product use by persons enrolled in the hepatitis C Antiviral Long-Term Treatment Against Cirrhosis (HALT-C) Trial
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Hepatology Dec 21, 2007
"...There was no evidence, however, that silymarin showed antiviral activity against HCV infection. Moreover, the observation of better scores in a small number of symptoms among silymarin users than in non-users is insufficient to support the value of this alternative therapy.."
Leonard B. Seeff 1 *, Teresa M. Curto 2, Gyongyi Szabo 3, Gregory T. Everson 4, Herbert L. Bonkovsky 5, Jules L. Dienstag 6, Mitchell L. Shiffman 7, Karen L. Lindsay 8, Anna S. F. Lok 9, Adrian M. Di Bisceglie 10, William M. Lee 11, Marc G. Ghany 12, HALT-C Trial Group
1Division of Digestive Diseases and Nutrition, National Institutes of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Department of Health and Human Services, Bethesda, MD
2New England Research Institutes, Watertown, MA
3Hepatology and Liver Center, Division of Gastroenterology, Department of Medicine, University of Massachusetts Medical School, Worcester, MA
4Section of Hepatology, Division of Gastroenterology and Hepatology, University of Colorado School of Medicine, Denver, CO
5Departments of Medicine and Molecular & Structural Biology and The Liver-Biliary-Pancreatic Center, University of Connecticut Health Center, Farmington, CT
6Gastrointestinal Unit (Medical Services), Massachusetts General Hospital and the Department of Medicine, Harvard Medical School, Boston, MA
7Hepatology Section, Virginia Commonwealth University Medical Center, Richmond, VA
8Division of Gastrointestinal and Liver Diseases, Keck School of Medicine, University of Southern California, Los Angeles, CA
9Division of Gastroenterology, University of Michigan Medical Center, Ann Arbor, MI
10Division of Gastroenterology and Hepatology, Saint Louis University School of Medicine, St. Louis, MO
11Division of Digestive and Liver Diseases, University of Texas Southwestern Medical Center, Dallas, TX
12Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Department of Health and Human Services, Bethesda, MD
Abstract
Herbal products, used for centuries in Far Eastern countries, are gaining popularity in western countries. Surveys indicate that persons with chronic hepatitis C (CHC) often use herbals, especially silymarin (milk thistle extract), hoping to improve the modest response to antiviral therapy and reduce side effects. The Hepatitis C Antiviral Long-Term Treatment Against Cirrhosis (HALT-C) Trial, involving persons with advanced CHC, nonresponders to prior antiviral therapy but still willing to participate in long-term pegylated interferon treatment, offered the opportunity to examine the use and potential effects of silymarin.
Among 1145 study participants, 56% had never taken herbals, 21% admitted past use, and 23% were using them at enrollment. Silymarin constituted 72% of 60 herbals used at enrollment. Among all participants, 67% had never used silymarin, 16% used it in the past, and 17% used it at baseline. Silymarin use varied widely among the 10 participating study centers; men were more frequent users than women, as were non-Hispanic whites than African Americans and Hispanics. Silymarin use correlated strongly with higher education. No beneficial effect of silymarin was found on serum alanine aminotransferase or hepatitis C virus (HCV) RNA levels. Univariate analysis showed significantly fewer liver-related symptoms and better quality-of-life parameters in users than nonusers, but after reanalysis adjusted for covariates of age, race, education, alcohol consumption, exercise, body mass index, and smoking, only fatigue, nausea, liver pain, anorexia, muscle and joint pain, and general health remained significantly better in silymarin users. In conclusion, silymarin users had similar alanine aminotransferase and HCV levels to those of nonusers but fewer symptoms and somewhat better quality-of-life indices. Because its use among these HALT-C participants was self-motivated and uncontrolled, however, only a well-designed prospective study can determine whether silymarin provides benefit to persons with chronic hepatitis C.
Discussion
The data in this survey of a population of study subjects who volunteered to participate in a trial of long-term interferon-based therapy for histologically advanced hepatitis C reveal that levels neither of HCV RNA nor of serum alanine aminotransferase - virological and biochemical markers of virus activity and hepatic inflammation - were improved in those taking herbals, particularly silymarin, when compared with those who had never used herbal products. The absence of an identified positive relationship between silymarin and the virological and biochemical parameters of chronic HCV infection is consistent with the prevailing belief about these products, but is not surprising in view of the uncertainty of the product purity, the dose used, and the duration of use among those questioned at baseline, coupled with the fact that this particular cohort, nonresponders to accepted standard antiviral therapy, are a group especially difficult to cure. Nevertheless, those who were using silymarin did have findings of lower frequencies of a limited number of non-liver-specific symptoms.
Interest in the use of CAM and especially in the use of herbal products has grown considerably in the United States in recent years. In a national survey conducted in 1999, an estimated 9.6% of the U.S. population stated that they had used herbals.[15] A similar analysis of data in the 2002 National Health Interview Survey revealed that 18.6% of 31,044 adult respondents (double the 1999 figure) had used herbs or supplements in the previous 12 months.[16] Based on this figure, 38.2 million adults in the United States were estimated to have used herbals for the treatment of various health-related conditions.[16] Most reported that herbals were important to their health and well-being, and many were reluctant to inform their physicians of this use.[16]
Herbals are often used simply in an effort to improve well-being and QOL, but they are also commonly employed to treat medical ailments, particularly for chronic diseases.[16][17-24] Not surprisingly, therefore, herbals are used commonly by persons with chronic liver diseases, especially those with chronic viral hepatitis B and C.[11][12][25-27] Indeed, clinic-based surveys suggest that the frequency of CAM use among persons with chronic liver disease ranges between 40% and 50%.[5][6]
Thus, the results of the current survey are in close agreement with previously reported experiences; 44% of the study participants had either previous or current experience with herbals; 23% continued to take a variety of herbals even at the time of enrollment; and 17% were using silymarin either on its own or together with other herbals. Reliance on herbal remedies might have been unexpected in this selected study population who had received conventional antiviral therapy previously - some more than once - and now were prepared to commit themselves to an additional 31/2 to 4 years of conventional pegylated interferon-based antiviral therapy.
In keeping with past reports,[15][28-30] sex and racial/ethnic differences in the use of herbals were observed in this study population. Also noted was a wide disparity in silymarin use among patients enrolled at the 10 different centers, ranging from a low of 8% to a high of 33%; silymarin use was reported most frequently among patients in Colorado, Michigan, and Southern California and least frequently among those in Maryland and Massachusetts. The reason for these regional differences and those reported by others[5] is unknown; demographic differences in herbal use across the centers in sex, race, or education did not explain the wide regional disparities in herbal use (data not shown). Conceivably, local and cultural differences among the populations might have accounted for the variations in the use of alternative medications, as might the influence of the medical staff across sites whose attitudes toward CAM practices might have differed.
Study participants reported using 60 or more herbal preparations, but silymarin was by far the most commonly used herbal. The popularity of silymarin among patients with liver disease may derive from the belief that it has a protective effect in liver injury resulting from Amanita phalloides poisoning.[31][32] Also, despite failure of clinical trials to demonstrate silymarin efficacy in any type of liver disease,[33][34] silymarin has been postulated to have numerous metabolic effects that might be hepatoprotective.[35-46] Comprehensive analyses of published data on CAM in general[5][6][12][47][48] and silymarin in particular[49][50] for the treatment of liver diseases including viral hepatitis,[51-53] however, provide little convincing support for the efficacy of such therapies in chronic viral hepatitis, with the exception of a recent study undertaken in humans[54] as well as an in vitro study using hepatoma Huh 7 cells.[55] A possible reason for the absence of demonstrable silymarin efficacy in viral hepatitis and other liver disorders is that silymarin formulations studied have not been standardized and that doses administered may have been inadequate. To address these issues, a multicenter group of investigators is conducting a clinical trial with standardized formulations and doses of silymarin to assess its efficacy in chronic hepatitis C and nonalcoholic steatohepatitis (ClinicalTrials.gov Identifier NCT000389376).
An association was noted was between symptoms and measures of QOL among the silymarin users, who, after adjustment for the covariates of age, race, education, exercise, body mass index, and smoking, had lower symptom scores for fatigue, nausea, liver pain, anorexia, and muscle and joint pains and a higher QOL general health domain, 1 of 8 domains analyzed. Because these observations do not represent a prospective and randomized analysis of CAM use in the study subjects, a definitive conclusion cannot be reached that the differences encountered in these symptom scores between silymarin users and non-users reflect a clinically meaningful impact of silymarin.
An issue not explored in this survey is whether liver injury might have occurred as a result of use of the herbals. Rich literature exists in regard to herbal hepatotoxicity,[10][56] and indeed, 1 of the herbal products claimed to have been used by a small number of study participants, kava kava, has been clearly implicated as a cause of drug-induced liver injury.[57] The HALT-C trial was, however, not designed to detect evidence of hepatotoxicity. Moreover, there is great difficulty in establishing a diagnosis of drug-induced liver injury when the biochemical abnormalities of chronic liver disease already exist.
In conclusion, in the HALT-C trial, involving persons with chronic HCV infection and advanced liver disease who had failed to respond previously to 1 or more episodes of antiviral therapy and were now willing to embark on a new long-term antiviral treatment trial, approximately one fifth chose also to use herbals concomitantly. There was no evidence, however, that silymarin showed antiviral activity against HCV infection. Moreover, the observation of better scores in a small number of symptoms among silymarin users than in non-users is insufficient to support the value of this alternative therapy. Currently in progress, therefore, is a properly designed prospective, randomized, controlled trial in which a fully characterized, purified, and standardized silymarin formulation is being evaluated.
Results
Among the 1145 study participants who were questioned, 641 (56%) reported that they had never used herbals, 235 (21%) stated that they had used them in the past only, and 269 (23%) admitted to current use at the time of the baseline evaluation (Fig. 1). Although patients reported using 60 different herbals, many in combinations, 195 (72%) of the 269 baseline herbal users reported taking silymarin, by far the most common single herbal used (Table 1). Focusing on silymarin, 772 (67%) indicated they had never used it, 178 (16%) admitted to taking it in the past, and 195 (17%) used it at the baseline visit (Fig. 1). The frequency of use of all herbal products as well as of silymarin varied widely among the different participating centers. As shown in Fig. 2, baseline use of all herbals ranged from 12% and 13% at the Bethesda, Maryland, and Boston, Massachusetts, sites to 29% and 42% at the Los Angeles, California, and Denver, Colorado, sites. Similarly, silymarin use ranged from 8% and 9% at the Bethesda and Boston locations to 22% and 33% at the Ann Arbor, Michigan, and Denver sites.
Among the 195 patients who were using silymarin at baseline, their mean age was 50.8 years, not significantly different from those who never used this herbal. Silymarin was used more frequently by men than women (18.4% versus 13.5%; P = 0.05) and by non-Hispanic whites than both African Americans and Hispanics (19.4% versus 8.6% and 10.4%, respectively; P = 0.0005) (Table 2). The highest formal education received was significantly greater among those who were using silymarin at baseline than among those who had never used silymarin (P < 0.0001) as well as among the users of the other herbal products combined when compared with the never users (0.0024); higher education was also associated strongly with white race (P < 0.0001).
Statistical comparisons presented are between persons using silymarin at the baseline (enrollment) visit and those who had never used herbals. The levels of HCV RNA were not significantly different between silymarin users and non-users; the mean HCV RNA levels were 6.5 log10IU/mL in silymarin users at baseline compared with 6.4 log10 IU/mL in those who had never used silymarin (Table 3). Similarly, no significant difference between baseline silymarin users and non-users was noted for mean aspartate aminotransferase (91.6 U/L versus 87.4 U/L) or total serum bilirubin levels (0.8 mg/dL for both). The mean serum alanine aminotransferase level was significantly higher in silymarin users than nonusers (124.5 U/L versus 109.5 U/L; P = 0.04), whereas the mean serum alkaline phosphatase level was significantly (P = 0.0004) lower in users than in non-users (88.5 U/L versus 99.7 U/L); both, however, were in the normal range. Measures of hepatic synthetic function (serum albumin and prothrombin time) did not differ between the 2 groups. Baseline silymarin users had lower white blood cell counts (5.6 X 103/mm3 versus 6.0 X 103/mm3; P = 0.03) and higher hemoglobin levels (15.4 g/dL versus 15.0 g/dL; P < 0.0001) than nonusers; however, the level of statistical significance in the hemoglobin level was lowered after excluding the Denver site from the analysis (P = 0.01), presumably a consequence of the low oxygen tension present at the high altitude of the Denver site.
Univariate analysis of symptoms at baseline between silymarin users and non-users revealed a significantly lower frequency among silymarin users of fatigue (P = 0.004), nausea (P < 0.0001), pain over the liver (P = 0.002), anorexia (P < 0.0001), headaches (P = 0.05), muscle and joint pains (P
Similarly, quality-of-life (QOL) domains were measured and compared between silymarin users and non-users. Significantly higher QOL scores among silymarin users were found for 6 of 8 QOL domains and 2 of 3 summary scales: physical functioning (P = 0.002), body pain (P = 0.005), general health (P = 0.002), vitality (P = 0.03), social functioning (P = 0.0004), mental health (P = 0.04), physical summary scale (P = 0.003), and the sexual summary scale (P = 0.05) (Table 6). All of these items became nonsignificant, however, except general health (P = 0.04) when adjusted for the same covariates of age, race, education, total alcohol consumed, exercise, body mass index, and smoking.
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