Experimental Botanical Therapies for Hepatitis C
By Liz Highleyman Given
that current standard therapy for chronic hepatitis C (pegylated interferon alpha plus ribavirin)
does not cure about half of all patients, and that there are no proven effective treatments
for liver fibrosis,
researchers have explored a wide range of complementary and alternative (CAM)
therapies for management of the disease. Two studies presented at the recent 58th Annual Meeting of the American Association
for the Study of Liver Diseases in Boston
(November 2-6, 2007) looked at botanical therapies for patients with hepatitis
C. Glycyrrhizin
Glycyrrhizin,
derived from licorice root (Glychyrrhiza glabra), has long been used in traditional Asian medicine
to treat liver conditions. In Japan, it has been used as a treatment
for hepatitis C for more than 20 years. However, there is less data on the use
of glycyrrhizin in non-Asian patients. M.P.
Manns and colleagues conducted a study to assess the safety
and efficacy of glycyrrhizin in chronic hepatitis C patients in Western and Eastern Europe who did not achieve sustained response to
standard combination anti-HCV therapy.
Efficacy was defined in terms of biochemical response (ALT reduction) and histological
response (improvement of necroinflammation), not virological
response (HCV viral load reduction). All
374 participants were non-responders or relapsers to
prior treatment with conventional or pegylated interferon
plus ribavirin. At baseline, they had detectable HCV
RNA and abnormal ALT (mean 77 IU/L); 73% had HCV genotype 1. The mean necroinflammation
score was 7.6 and the mean fibrosis score was 3.1. Liver biopsy results were available
at study entry or performed within 6 months. The
trial consisted of 2 phases. Phase 1 was a randomized, double-blind, placebo-controlled
comparison of intravenous injections
of 200 mg glycyrrhizic acid 5 or 3 times per week, or
placebo 5 times per week, for 12 weeks. The following Phase 2 was a randomized,
open-label comparison of 200 mg glycyrrhizin
administered 5 or 3 times per week for an additional 40 weeks, with no placebo
arm. Results •
30%
of patients in the 5 times weekly glycyrrhizin arm and 32% in the 3 times weekly
glycyrrhizin arm had ≥50% ALT reduction after 12 weeks, significantly higher
than the 6% in the placebo arm. •
Based on evaluable
biopsies taken before and at the end of treatment (n=249), 45% of patients experienced
histological improvement (defined as at least 1 point difference in necroinflammation
score) and 17% had stable histology (that is, 62% had no histological worsening). •
About 4% of patients discontinued
therapy due to treatment-related adverse events. •
Favorable
results were also seen in secondary endpoints, including quality of life. The
investigators concluded that, “Glycyrrhizin appears to be effective and well tolerated
in the treatment of chronic hepatitis C [patients] not responding to interferon
alpha or pegylated interferon plus ribavirin therapy.” CEE,
PharmaPart AG, Thalwil, Zurich,
Switzerland; Hannover Medical School, Hanover, Germany;
Military Therapy, Moscow City Hospital No. 29, Moscow, Russian Federation; Moscow
Hepatology Center, Moscow Clinical Hospital for Infectious
Diseases No. 1, Moscow, Russian Federation; Lugansk Medical University, Lugansk,
Ukraine; University Hospitals Leuven, Belgium; University
Hospital of Cologne, Germany; Minophagen Pharmaceutical
Co., Ltd, Tokyo, Japan; PharmaPart AG, Thalwil,
Zurich, Switzerland. Silymarin and Sho-saiko-to In
the second study, S.J. Polyak and colleagues examined
the mechanism of action of 2 botanical therapies widely used for liver conditions,
silymarin (derived from milk thistle, Silybum
marianum) and sho-saiko-to,
a combination of several herbs based
on a traditional Chinese medicine formula. The
activity of the 2 therapies was studied in the laboratory in human hepatoma liver cell lines (Huh 7 and Huh 7.5.1) infected with
JFH-1, a genotype 2a strain of HCV that can replicate in vitro. Results •Silymarin inhibited expression of TNF-alpha in anti-CD3 stimulated human
peripheral blood mononuclear cells and NF-kappa-B dependent transcription in Huh7
cells. • Both
silymarin and sho-saiko-to
inhibited infection of Huh7 and Huh7.5.1 cells by JFH-1 virus in a dose-dependent
manner. • Both
compounds also displayed prophylactic
and therapeutic effects against JFH-1 infection. • When
combined with interferon alpha, both
silymarin and sho-saiko-to
inhibited HCV replication more than interferon alone. • The
antiviral effects induced by silymarin involved both
JAK-STAT pathway dependent and independent signaling. • Sho-saiko-to enhanced interferon-stimulated response element (ISRE) transcription
via p38 MAP kinase activation. • High
performance liquid chromatography fractionation of the herbal preparations permitted
identification of specific components
eliciting antiviral actions. “The
data demonstrate that standardized silymarin and sho-saiko-to have antiviral action against in vitro
HCV infection, and that silymarin has immunomodulatory and anti-inflammatory actions,” the researchers
concluded. “Therefore, CAM-based approaches may assist in the management patients
with chronic hepatitis C.” Laboratory of Medicine, University
of Washington, Seattle,
WA; Harvard
University, Cambridge, MA. 12/04/07 References
MP Manns,
IG Bakulin, NP Blokhina, and others. A 52 week multi-centre, randomized, double-blind
placebo-controlled trial evaluating the efficacy and safety of glycyrrhizin in
patients with chronic hepatitis C not responding to IFN alpha or PEG-IFN plus
ribavirin therapy. 58th Annual Meeting of the American Association for the Study
of Liver Diseases (AASLD 2007). Boston, MA, November 2-6, 2007. Abstract 1326. SJ
Polyak, J Wagoner, O Kane, and others. Botanical Medicines for Hepatitis C. AASLD
2007. Abstract 1383.
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