SAMe Improves Early Response to Pegylated Interferon/ribavain in Small Study

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SAMe Improves Early Response to Pegylated Interferon/ribavain in Small Study By Liz HighleymanAbout half of patients with genotype 1 chronic hepatitis C virus (HCV) infection do not achieve a sustained response to standard interferon-based therapy, and researchers have explored other types of treatment. In addition to directly-targeted "STAT-C" agents such as HCV protease and polymerase inhibitors, some have also studied various alternative or complementary therapies.

S-adenosyl methionine (SAMe) is a compound made from adenosine triphosphate and methionine. Sold as a dietary supplement, marketed brand names include Adomet, Admethionine, Heptral, and Samyr; it is available as a prescription drug in some countries. SAMe has been promoted for a variety of ailments, including depression, osteoarthritis, Alzheimer's disease, and liver disease, and several clinical trials have demonstrated some benefit.

In a small study presented at the recent 59th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD 2008) in San Francisco, researchers assessed the effect of SAMe on interferon signaling and early HCV viral kinetics, to see whether it might have promise as an adjunct therapy in combination with interferon-based therapy.

As background, the investigators noted that SAMe has been shown to enhance interferon signaling in cell culture and animal models by acting as a methyl donor to transcription factor STAT1, leading to improved STAT1-DNA binding.

The study included 9 chronic hepatitis C patients with HCV genotype 1 who were non-responders to prior therapy with pegylated interferon plus ribavirin. Participants were given pegylated interferon alfa-2a (Pegasys) plus ribavirin for 2 weeks to establish baseline responses (Course A). Treatment was stopped for a 1-month washout period, after which patients received 1600 mg SAMe daily for 2 weeks, at which point pegylated interferon/ribavirin was restarted along with SAMe for a planned duration of 48 weeks (Course .

Early HCV viral kinetics and interferon-stimulated gene (ISG) expression in peripheral blood mononuclear cells (PBMCs) were compared during periods with and without SAMe. Interim results were presented after all 9 patients completed Course A, and a subset were partially through Course B.

Results

• HCV RNA decline from time 0 to 48 hours after starting treatment (phase 1 kinetics) was similar during Course A and B. • There was a significant improvement in the second phase slope of viral decline in 8 of 9 patients and in the group taking SAMe (-0.11 vs -0.33 log/week for Courses A and B, respectively; P = 0.007). • 5 of 7 patients -- all previous non-responders -- achieved early virological response (EVR) at week 12 of Course B, including 3 with undetectable HCV RNA.• ISG-15 induction in PBMCs was significantly greater in 6 of 9 patients, and for the group as a whole, during treatment with SAMe (area under the curve 133 vs 187 RU for Course A and B, respectively; P = 0.001). • ISG-15 fold induction was greater at all time points, with the greatest difference seen at 24 hours (171 vs 350 RU respectively; P = 0.04). • A similar pattern was observed with gene MxA. • ISG15 and MxA expression were greater at time 0 in Course B than in Course A, after receiving 2 weeks of SAMe monotherapy. • During the 2 weeks of SAMe monotherapy, ALT values decreased significantly (mean change 37 U/ml; P = 0.004).• HCV RNA levels, however, increased slightly during SAMe monotherapy (mean change 0.22 log; P = 0.05).

Based on these findings, the researchers concluded, "SAMe appears to improve early viral kinetics in interferon non-responders and the observation that it leads to greater ISG induction suggests that the effect may be through improved interferon signaling."12/12/08