Alternative Therapies for Hepatitis C

The use of complementary and alternative medicine is widespread with approximately 40% of Americans using some form of this therapy.(1) Although most utilize this therapy as a supplement to conventional medicine, some have substituted alternative treatments for scientifically accepted treatment modalities. Some of the reasons why patients are turning to alternative therapies may include

	a perception that traditional therapies are not successful
	a desire to have more autonomy in choosing their treatments
	a perception that alternative therapies are safer or more natural
	a concern over the cost and side effects of conventional medicine
	a sense that they will be able to spend more time with practitioners than in a conventional medical setting

Many clinicians have a limited knowledge or understanding of the possible benefits and risks of alternative therapies. The primary criticism of alternative therapies is that claims of efficacy are often based solely on anecdotal or personal experience. In addition, there is a lack of standardization in preparation and formulation of these products whose use is not regulated by the Food and Drug Administration. Many patients with HCV infection are turning to alternative approaches for treatment and management of their infection. In particular, the use of herbs has become increasingly popular in patients who are non-responders to conventional HCV treatments. The following is a discussion of four of the most popular herbs that patients are taking for chronic hepatitis C infection. These four products were selected because they are cited the most in the literature on alternative treatments for hepatitis C. By no means should they be advocated for use until randomized, double-blinded, and placebo controlled studies with large numbers of patients are completed. Until these herbs are better evaluated, there is always the potential for harmful effects and drug interactions. A brief discussion of other non-herbal, alternative treatments used by patients with chronic hepatitis C concludes this section.

This herbal compound, extracted with 95% ethanol, is prepared from the leaves of the plant Silybum marianum, a member of the aster family, which encompasses daisies, thistles, and artichokes. The name "milk thistle" derives from its characteristic spiked leaves with white veins.

Milk Thistle has 3 active flavonoid components: silybin, silydianin, and silychristine. Silybin has the greatest degree of biologic activity and standard silymarin extracts contain 70% silybin.

Putative Hepatoprotective Properties

Acts as an antioxidant: Scavenges free radicals (superoxide anion radical and nitric oxide) produced by activated Kupffer cells to protect against genomic injury--in vitro concentrations were quite high (higher than the dose given therapeutically)(2) Inhibits lipid peroxidation: Stabilizes phospholipid composition of hepatocyte plasma membrane Protects against glutathione depletion Selectively inhibits leukotriene formation: Inhibits 5-lipooxygenase pathway at in vivo doses to protect against genomic injury Has anti-inflammatory effects: Stabilizes mast cells and inhibits neutrophil migration

Clinical Trials with Milk Thistle

In one study, 170 patients with cirrhosis (92 alcoholic, 78 nonalcoholic) were asked to abstain from alcohol and then randomized to receive either milk thistle (140 mg po tid) or placebo for 2-6 years.(3) Survival was higher in the treated group (77% vs. 67% overall, 82% vs. 68% at 2 years). Amongst patients who had abused alcohol, survival was the highest (p = 0.01). In another study, 60 patients with chronic hepatitis, with or without cirrhosis, were treated with either silymarin or placebo for 12 months.(4) No change in biochemical markers was noted in either group; however, there was a trend toward histological improvement. This study was limited by incomplete follow-up in 40% of the patients enrolled. A third, uncontrolled study of 2637 patients with chronic liver disease who were treated with high dose silymarin (560 mg po tid) for 8 weeks reported a decrease in symptoms in two-thirds of the patients.(5) Also, aminotransferase levels fell by approximately 35%; however, neither the type of viral hepatitis, nor the presence or absence or cirrhosis, was mentioned in this study.

Problems with Past Milk Thistle Trials

The population size, the variable etiologies and severity of liver disease within the groups have limited trials designed to test the efficacy of silymarin. Patients with chronic hepatitis B and C were often included in the same study under the broad heading of chronic viral hepatitis. In conventional medicine, the accepted definition of response to treatment involves the return of aminotransferase levels to normal and a loss of HCV RNA from the serum, indicating a resolution of viremia. To date, studies of milk thistle have only noted trends toward improvement, as evidenced by decreases in aminotransferase levels, improvements in liver histology, decreases in hospital stay, or subjective reports of symptom resolution. It is possible that these findings may have been the consequence of lifestyle changes and not related directly to milk thistle treatment. Most importantly, none of the studies to date of milk thistle in the treatment of hepatitis C have been randomized, double-blinded, and placebo controlled. Prospective, randomized, controlled trials with careful documentation of changes in aminotransferase levels, liver histology, and HCV RNA levels both during and after treatment must be performed to validate the efficacy of milk thistle as a treatment for chronic hepatitis C.

The usual formulation contains 200 mg of glycyrrhizin (a major component of licorice root), 100 mg of cysteine, and 2000 mg of glycine in 100 cc of saline. Most studies have used daily IV injections of SNMC; however, more recent studies suggest that an oral form may have equivalent efficacy.

The reported beneficial effects of glycyrrhizin on liver tissue include

	stabilization of hepatic cellular membranes
	inhibition of production of PGE2
	augmentation of the effects of Interferon

Clinical Trials with SNMC

Suzuki in 1983 published the results of a randomized, controlled, double-blind study with 133 chronic hepatitis patients who were given either SNMC (40 cc IV QD) or placebo for 4 weeks.(6) Both ALT and AST levels were lower in the SNMC treated group when compared to the placebo group (p = 0.001) throughout the entire treatment period; however, within 2 weeks of follow-up, there was no longer a statistical difference in aminotransferases between the 2 groups. Also, HCV RNA remained present throughout treatment in both groups. In addition, this study did not distinguish between patients with hepatitis B and hepatitis C. These findings suggest that SNMC results in a decline in aminotransferase levels in patients with chronic liver disease, but that it has no lasting benefit once therapy is stopped. In another study, the combination of SNMC with interferon-a was evaluated in patients who had failed to respond to a course of interferon alone for 12 weeks.(7) No response was defined as persistently abnormal liver enzymes. The 28 patients in this study were randomized to receive either continued interferon-a alone or interferon in combination with SNMC for 12 more weeks. At the end of the treatment period, ALT levels had normalized in 33% of patients treated with interferon monotherapy versus 64% of patients treated with a combination of interferon and SNMC. Also, HCV RNA became undetectable in 13% of patients treated with interferon monotherapy versus 39% of patients treated with a combination of interferon and SNMC. Finally, post-treatment liver biopsies revealed a greater reversal of histological abnormality in patients treated with interferon and SNMC. These encouraging preliminary results on the combination warrant further evaluation in larger studies with longer follow-up.

This compound contains 19 different Chinese herbs used to treat chronic liver disease. This compound's mechanism of action is unknown.

A Clinical Trial on CH100

Batey in 1998 evaluated 40 patients with chronic hepatitis C, of whom 14 had relapsed after prior interferon treatment.(8) Of these 40 patients, 20 received CH100 tablets and 20 received placebo. The treatment duration was 6 months. Within the treatment group, ALT levels decreased significantly (p = 0.03) as compared with the placebo group. CH100 led to a 20% end-of-treatment biochemical response rate and a 5% sustained biochemical response rate. All patients remained viremic in both groups throughout treatment. Presently, CH100 remains to be proven as a clinically effective treatment for chronic HCV infection.

Oral thymus preparations include components such as bovine thymopoeitin and thymic humoral factor. The supposed immunological properties of thymus extracts include

	stimulation of interferon production
	enhancement of T-cell dependent antibody production
	enhancement of helper T-cell activity
	increased production of suppressor cells and natural killer cell activity

Clinical Trials with Thymus Extracts

Rsai in 1996 evaluated 16 patients with chronic hepatitis C in an open-label study.(9) 11 were treatment naïve and 5 were interferon non-responders. A sustained loss of HCV RNA with the combination of interferon and thymosin-a1 was noted in 5 of the 11 treatment naÂ¥ve patients and in 1 of the 4 interferon non-responder patients. In another study, Raymond reported the results of a randomized controlled trial of oral thymus extract for interferon non-responders.(10) Of the 38 patients, 36 had truly failed interferon and 2 were intolerant. Twenty patients were randomized to receive 6 tablets of thymus extract twice daily and eighteen patients were randomized to receive placebo. The treatment course was 12 weeks. All patients after 3 months were offered the option of continuing on thymus extract for another 3 months. By the end of the first 3 months, no patient in either group became HCV RNA negative. The average HCV RNA and ALT did not differ throughout treatment in the 2 groups. In those patients who went on to receive a total of 6 months of thymus extract, the results were similar. In conclusion, all studies to date have been hampered by the small sample size, the different forms of thymus extract used (oral versus parenteral), and the different doses and regimens. if a standardized formulation of thymus extract is developed and shown to have some effect in chronic hepatitis C, either by itself or in combination with interferon, further investigation with large controlled trials would be warranted.

Acupuncture is the art and science of manipulating the flow of qi and other essential substances through the organ channels of the body. Approximately one million Americans utilize acupuncture annually, primarily for the relief of chronic pain.(11) One popular theory explaining how acupuncture modulates pain is the neurohumoral hypothesis, which states that the pain relieving properties of acupuncture are, in part, mediated by a cascade of endorphins and monoamines that are activated by stimulating 'De qi', a sensation of numbness and fullness.(12) "De qi" is associated with the stimulation of A-delta afferents, which set the cascade in motion. Acupuncture has been tried in the treatment of pain associated with chronic pancreatitis.(13) Yet, no studies addressing acupuncture in the treatment of pain associated with cirrhosis or fibrosis from chronic hepatitis C have been published to date. Ironically, the potential for acupuncture to transmit hepatitis C infection is well recognized.(14) As such, providers should caution patients about this mode of treatment.

Yoga advocates controlled breathing, concentration of mind, mastery over senses, and intense meditation. In addition, certain postures or exercises for psychosomatic harmony are involved.(15) Although yoga has been recommended by clinicians for those with chronic hepatitis C, no studies to date have been published demonstrating any effect of yoga on HCV RNA levels. Consequently, yoga cannot be recommended as a conclusive treatment for chronic hepatitis C.

Qi Gong is the traditional Chinese discipline that focuses on breathing and movement of Qi to increase physical harmony and strength and establish spiritual and emotional peace.(16) Recent studies indicate that patients with symptoms or complications associated with HCV, such as excessive fatigue, portal hypertension, cirrhosis, or fluid retention should avoid stressful activities. The energy-conserving, Qi-channeling practice of Qi Gong is perfectly designed to keep an individual in shape without causing stress and exhaustion. However, again no studies to date have been published demonstrating and effect of Qi Gong on HCV RNA levels.

1. Eisenberg, DM, Davis RB, Ettner SL, et al. Trends in alternative medicine use in the United States, 1990-1997: results of a follow-up national survey. JAMA 1998; 280:1569-75.

2. Dehmlow C, Erhard J, de Groot H. Inhibition of Kupffer cell functions as an explanation for the hepatoprotective properties of silbin. Hepatology 1996; 23:749-54.

3. Ferenci P, Dragosics B, Dittrich H, et al. Randomized controlled trial of silymarin treatment in patients with cirrhosis of the liver. J Hepatol 1989; 9:105-113.

4. Kiesewetter E, Leodolter I, Thaler H. Ergebnisse zweier Doppelblindstudien zur Wirksamkeit von Silymarin bie chronischer Hepatitis. Leber Magen Darm 1977; 7:318-323.

5. Albrecht M, Frerick H, et al. Therapy of toxic liver pathologies with Legalon. Z Klin Med 1992; 47:87-92.

6. Suzuki H, Ohta T, Takino T, Fujisawa K, Hirayama C. Effects of glycyrrhizin on biochemical tests in patients with chronic hepatitis: double-blind trial. Asian Med J 1983; 26:423-38.

7. Abe Y, Ueda T, Kato T, Kohli Y. Effectiveness of interferon, glycyrrhizin combination therapy in patients with chronic hepatitis C. Nippon Rinsho 1994; 52:1817-22.

8. Batey RG, Bensoussan A, Fan Y, Ballipo S, Hossian MA. Preliminary report of a randomized, double-blind, placebo-controlled trial of a Chinese herbal medicine preparation CH-100 in the treatment of chronic hepatitis C. J Gastroenterol Hepatol 1998; 13:244-7.

9. Rasi G, DiVirgilio D, Mutchnick MG, et al. Combination thymosin-alpha 1: a lymphoblastoid interferon treatment in chronic hepatitis C. Gut 1996; 39:679-83.

10. Raymond RS, Fallon MB, Abrahms GA. Oral thymic extract for chronic hepatitis C in patients previously treated with interferon: a randomized, double-blind, placebo-controlled trial. Ann Intern Med 1998; 129:797-800.

11. Bullock ML, Phaley AM, Kiresuk TJ, Lenz SJ, Culliton PD. Characteristics and complaints of patients seeking therapy at a hospital-based alternative medicine clinic. J Altern Complement Med 1997; 3:31-37.

12. Pomeranz B. Acupuncture in America. APSJ 1994;3:96-104.

13. Ballegaard S, Christophersen SJ, Dawids SG, Hesse J, Olsen NV. Acupuncture and transcutaneous electric nerve stimulation in the treatment of pain associated with chronic pancreatitis: a randomized study. Scand J Gastroenterol 1985;20:1249-1254.

14. Norheim AJ. Adverse effects of acupuncture: a study of the literature for the years 1981-1994. J Alternative Complementary Med 1996;2:291-297.

15. Subbarayappa BV. Siddha medicine: an overview. Lancet 1997;350:1841-1844.

16. Cohen MR. Qi Gong: Exercise and Meditation. In: Cohen MR and Gish RG, editors. The Hepatitis C Help Book, New York: St. Martin's Press, 2000.