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- Milk Thistle (Silybum marianum)
- Silymarin
- Chronic Hepatitis C
| Date:
09-14-2012 | HC# 081231-456
|
Re: Hepatitis C Interferon Treatment Non-responder Patients also Do Not Respond to Milk Thistle (60% Silymarin) Treatment
Fried
MW, Navarro VJ, Afdhal N, et al. Effect of silymarin (milk thistle) on liver
disease in patients with chronic hepatitis C unsuccessfully treated with
interferon therapy: a randomized controlled trial. JAMA. July 18, 2012;308(3):274-282.
Affecting
almost 3% of the world's population, chronic hepatitis C virus (HCV) infection
can lead to cirrhosis, hepatic failure, and hepatocellular carcinoma. Many
patients with HCV infection do not respond well to conventional therapies
(peginterferon and ribavirin) and others cannot use those therapies because of
medical comorbidities. Alternative medications with disease-modifying activity
may therefore be beneficial. Silymarin, an extract of milk thistle (Silybum marianum), is the botanical
treatment most commonly used for liver disorders in the United States: 33% of
patients with chronic HCV infection and cirrhosis reported current or past use
of silymarin to treat their disease.1 Clinical studies evaluating
milk thistle for various liver diseases have reported inconsistent results.
Because the data on dosing and pharmacokinetics of silymarin were limited,
these authors conducted an earlier dose-ranging study2 to identify
silymarin doses for further study in the trial reported in this article. Two
doses, 3 and 5 times higher than the customary dose, were selected based on the
earlier study. The aim of the randomized, double-blind, placebo-controlled,
multicenter trial reported here was to assess the safety and efficacy of
silymarin for treating chronic HCV infection among patients previously
unsuccessfully treated with conventional interferon (IFN)-based treatment.
Adult
patients with chronic HCV infection were eligible for the trial if they had
received previous IFN-based therapy without sustained virological response, had
quantifiable serum HCV RNA levels, and had an alanine aminotransferase (ALT)
level of ≥65 U/L at screening. Participants were recruited at 4 northeastern U.S.
clinical centers. Enrollment ran from May 2008 to May 2010. Follow-up continued
until March 2011.
The
154 eligible participants were randomly assigned to 1 of 3 groups to receive
the following: 420 mg silymarin (n=50), 700 mg silymarin (n=52), or matching
placebo (n=52) gelatin capsules administered for 24 weeks. Three times daily, the
participants took 5 capsules of silymarin (420 mg); 5 capsules of silymarin
(700 mg); 3 capsules of silymarin (420 mg) plus 2 of placebo; or 5 capsules of
placebo. The botanical product used was a dry extract of milk thistle fruit
marketed as Legalon® 140 (Rottapharm|Madaus; Monza, Italy).
Most
of the participants were men (70%); the median age was 54 years. Most
participants had HCV genotype 1 infection (91%). At baseline, the median HCV
RNA and serum ALT levels were similar among the groups. Participants were seen
at baseline, and at 6 follow-up visits scheduled 2 to 8 weeks apart throughout
the 24-week study, and subsequently at 4 and 23 weeks post-treatment.
The
primary outcome measure was a serum ALT level of ≤45 U/L (considered within the
normal range) or <65 U/L, provided the value was at least 50% less than the
baseline value. Secondary outcomes included significant changes in ALT levels,
HCV RNA levels, and quality-of-life measures.
An
analysis of changes in serum ALT levels from baseline to the end of treatment
revealed no statistically significant differences among the 3 groups: mean
declines were -4.3 U/L for placebo; -14.4 U/L for 420 mg silymarin; and -11.3 U/L
for 700 mg silymarin (P=0.75). The authors also report that there were no
significant differences in HCV RNA levels: mean changes were 0.07 log10
IU/mL for placebo; -0.03 log10 IU/mL for 420 mg silymarin; and 0.04 log10
IU/mL for 700 mg silymarin. No significant changes were reported in the physical
or mental health components of quality-of-life scores, in chronic liver disease
health-related quality-of-life assessments, or in depression scores.
Frequency
of adverse events reported by participants did not differ significantly among
the groups. The most frequent adverse events were gastrointestinal symptoms,
most of which were mild or moderate in severity.
The
authors state that this trial used a well-characterized silymarin product (not
described); focused on a specific liver disease; enrolled a large,
representative cohort across 4 different northeastern U.S. clinical sites;
included an adequate treatment duration; had excellent adherence to study
medication and visits; and used well-defined outcome measures.
They
conclude that oral silymarin, used in a higher than customary dose, did not
significantly alter biochemical or virological markers of disease activity in
patients with chronic HCV infection who had been treated previously with
IFN-based regimens and had not responded to treatment. For these participants,
with treatment-resistant HCV infection, silymarin did not provide a greater
benefit than placebo. ―Shari
Henson
References
1Seeff LB, Curto TM,
Szabo G, et al.; HALT-C Trial Group. Herbal product use by persons enrolled in
the Hepatitis C Antiviral Long-Term Treatment Against Cirrhosis (HALT-C) Trial.
Hepatology. 2008;47(2):605-612.
2Hawke
RL, Schrieber SJ, Soule TA, et al.; SyNCH Trial Group. Silymarin ascending
multiple oral dosing phase I study in
noncirrhotic patients with chronic hepatitis C. J Clin Pharmacol.
2010;50(4):434-449.
Peer Reviewer's
Comments:
The
primary inclusion criteria for this study were that the participants FAILED to respond
to "gold standard" conventional treatments. It is hardly surprising
that they also did not respond to herbal therapy. To overstate the obvious, these
subjects were not representative of the general U.S. HCV population.
Also, in both the result and discussion sections, the
authors claimed that compliance was very good ("despite a high pill
burden" – 5 capsules, three times a day); however, the methodology for
assessing compliance was not reported nor was there any indication whether these
unknown compliance evaluations were intended to measure medication intake or
adherence to the 3 times daily dosing schedule. As the authors point out, the
study medication is rapidly metabolized, so the 3 times daily dosing schedule
is critical to maintain effective, steady plasma levels.
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