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Study Examines HCV & Mistletoe & Herbal Concoction, When Interferon Fails
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Three study abstracts on mistletoe were presented at DDW and follow this Reuters report. Although these pilot preliminary studies suggested benefit, the potential risks and harm associated with use of mistletoe are unknown and not recommended. Even for patients with limited options who may have not had a response to interferon/ribavirin therapy, use of mistletoe is risky as new HCV drugs are expected in several years and there are several therapeutic options that may be beneficial and be less risky such as maintenance interferon therapy and Consensus Interferon. At last year's DDW there was a report on the use of a tomatoe sauce concoction from researchers in Italy that appeared to show benefit as well.
By Karla Gale
NEW ORLEANS (Reuters Health) May 19 - Treatment with a mix of herbs that includes extracts of mistletoe and green tomato may lead to a sustained response in patients with hepatitis C (HCV) for whom treatment with pegylated interferon-alpha has failed or is contraindicated, according to findings presented here at Digestive Disease Week.
Dr. Harald Matthes and colleagues included 85 patients in their sample, 7 of whom withdrew from the study. Treatment included subcutaneous injections of mistletoe extract (Viscum album), and oral extracts of green tomato (Solanum lycopersicum) and Hepatodoron (Fragaria vesca and Tritis vinifer). After 12 months, 18% were complete responders, 49% were partial responders and 33% were nonresponders. After 1 more year of treatment and an additional 6 months' follow-up, the corresponding rates were 44%, 28% and 28%.
About 60% of patients exhibited local responses to the injection, but otherwise adverse events were mild and uncommon. The group etimates the cost to treat each patient who achieves a sustained response is $5,600 with the herbal extracts, compared with $28,000 for treatment with interferon.
In an interview with Reuters Health, Dr. Matthes, based at Charite University of Berlin in Germany, explained that the mistletoe extract activates CD4 T helper-1 cells to induce an HCV-specific immune response, and the Hepatodoron stimulates liver regeneration.
The green tomato contains alkaloids that induce apoptosis through the caspase 8 pathway. "This is important because HCV blocks heaptocyte apoptosis, which is required to clear infected cells from the liver," he said.
As a result, liver enzyme levels actually increase during the first 4 to 8 weeks of treatment, he added, but then drop to normal levels as liver inflammation and necrosis resolve.
He noted that mistletoe is used as an adjuvant to treat approximately 60% of oncology patients, so its safety profile is well established.
However, he would not recommend these agnts as first line treatment, since interferon is associated with a better response rate and requires only one year of treatment.
Dr. Paul Pockros, from Scripps Clinic in La Jolla, California, told Reuters Health he was concerned that herbal treatment could induce heaptocyte apoptosis, "which could be quite dangerous for patients with an impaired hepatic reserve." He also thinks it should not be recommended until its mechanism of action is better understood.
However, he agrees with Dr. Matthes that such treatment could be appropriate for patients who have no other choice of treatment for HCV.
But that remains a moot point in the U.S., he added, because subcutaneous injections of mistletoe are considered a drug rather than a dietary substance, and have not been approved by the FDA.
Digestive Disease Week is jointly sponsored by the American Association for the Study of Liver Diseases, the American Gastroenterological Association, the American Society for gastrointestinal Endoscopy, and th Society for Surgery of the Alimentary Tract.
OUTCOME STUDY ON HEPATITIS C THERAPY WITH MISTLETOE (VISCUM ALBUM L.; ABNOBAVISCUM) AND SOLANUM LYCOPERSICUM
Harald Matthes, Friedemann Schad, Burkhard Matthes, Silke Biesenthal-Matthes, Gesa Schenk
Combined therapy with pegylated Interferon-alpha and Ribaverin reaches sustained response rates of 45-70%, depending on the genotype. The wide range of side effects which often lead to an interruption of this therapy. In cases where Interferon- a therapy has failed and high rates of side effects occur a study on a complementary therapy with mistletoe extract (Abnobaviscum) in combination with Solanum lycopersicum (herbal extract of tomato plant) and Hepatodoron was initiated (herbal extract of fragaria vesca and vitis vinifera).
Aims of study are to achieve HCV-RNA-PCR negativity after 1 or 2 years of treatment and 6 months of follow up, documentation of side effects, fibrosis -parameter (PIIIP) and the quantitative course of HCV-RNA-PCR.
Up to now 85 patients with chronic hepatitis C (> 6 months) with increased transaminases and positive HCV-RNA-PCR values are included. 43 patients had a liver biopsy before therapy; 27 patients failed Interferon therapy before. Genotype was determined in all patients. Initially mistletoe was administered 3x per week subcutaniously, concomitantly Hepatodoron 3x2 tablets were given. After 14 days Solanum lycopersicum Herba D3-4 tablets were applied. Duration of therapy was 12 (78 patients) - 24 months (64 patients).
Of the 85 study patients, 67% were genotype 1, 25% genotype 3, 6% genotype 2, and 2% genotype 4.
78 of 85 patients completed >12 months therapy. 7 patients dropped out, were non-compliant. 14 patients (18%) were HCV-RNA-PCR negative after 12 months, 38 patients (49%) were partial responders, and 26 patients (33%) were nonresponders. After 24 months and 6 months followup 34 patients (44%) showed a sustained response. 44 patients (56%) were non-responders (28% partial response & 28% nonresponders). Partial response=HCV RNA PCR reduced >3 log or ALT reduced 1/3 of starting level. No essential side effects were observed. Transaminases and PIIIP-values decreased significantly during therapy (p<0,05). Virus load did not decrease continously but in those patients with HCV-RNA-PCR negativity it decreased below the detection limit, independent of the initial level. 2 patients had shown a so-called 'break through' phenomenon.
The authors did not provide clear response rate analysis by genotype but said 3 patients with genotype 1 had sustained response after 12 months. Based on 67% being genotype 1 at baseline my figuring is about 55 patients had genotype 1, showing a low response rate for genotype 1. The authors did not present a break down of response by genotype after 2 years therapy except to say in summary that responses were better for G2/3 than G1/4.
Side Effects
Mistletoe: local redness, local itching often >60%; fever seldom <4%; allergic reaction (very seldom) <1%; in case of overstimualtion increasing fatigue.
Solarium lycopersicum herba: nausea 2.4%; restlessness 1.4%; muscular tension: 2.4%.
Hepatoderm: not known (ev light flatulence).
Nonresponders (n=27) of IFN & RBV showed a decreased sustained response rate (4 patients after 2 years=14%) compared to naïve after mistletoe combination therapy.
80% showed increase quality of life.
Genotype 2/3 response was better than genotype 1 response. Of the 14 patients (18%) with SVR after 12 months, 3 had genotype 1, 6 genotype 3, and 5 genotype 2.
HAI -- Score / Fibrosis Score
Results from 8 patients before & after >=12 months: total HAI mean 7.75 before treatment & 5.25 after (p<0.05); fibrosis HAI 2.375 before & 1.375 after treatment (p<0.05).
Responders showed initial increase in ALT after 4-8 weeks following start of treatment.
The authors concluded combined therapy of mistletoe and Solanum lycopersicum showed a virus elimination and sustained response in chronic hepatitis C. The responder rates of combination therapy lay below the results of the standard therapy. Advantage of mistletoe therapy is the absence of side effects and its cost effectiveness Total per year=$1,056). Therefore mistletoe therapy could be an alternative in non-responders of standard therapy or in patients with relative or absolute contraindications of Interferon therapy. Further studies will be necessary to optimise the therapy and to verify the results.
VISCUM ALBUM IN THE THERAPY OF PRIMARY INOPERABLE HEPATOCELLULAR CARCINOMA (HCC).
Harald Matthes, Friedemann Schad, Gesa Schenk
BACKROUND: Hepatocellular carcinoma (HCC) is a frequent complication in chronic hepatitis. Only few patients are cured by operation (hemihepatectomie). Most of the patients can only be treated in a palliative manner. One common therapeutic option is the percutanious ethanol injection (PEI) of HCC. This cytotoxic treatment induces necrosis and causes a reduction of the HCC tumor. Viscum album is known as a cytotoxic, immune stimulating and immune modulating agent. Therefore we studied the combination effect of Viscum album with cytotoxic and immune modulating effects by intralesional injection in HCC.
AIMS: The aim of the study was to assess the effect of Viscum album (Abnobaviscum) as an immune-therapeutic and cytotoxic agent on inoperable HCC by intralesional injection to induce remission or partial remission and to measure its effect on quality of life.
METHOD: 18 inoperable HCC patients were treated by intralesional (ultrasonographic controlled) Viscum album injections 1-3 times per week. Starting dose was 1 ampoule Abnobaviscum (Viscum album) per injection and dosis escalating in steps of 1 ampoule by every injection until the maximal dose of 5 ampoules per injection were reached . The main end point was complete remission of the tumor mass.
RESULTS: In 18 elegible patients, overall tumor response was 77,7 % according to the WHO response criteria. 27,7% showed complete remission and 33,3 % partial remission (tumor reduction >50 %). In 16,6 % of the patients the disease was stationary and 22,2 % showed disease progression. At 6, 12 and 24 months the overall cumulative survival was 100% (6 months) , 77,8% (12 months) and 53,6% (24 months). No major toxicity was observed. In 8 cases fever > 38,50C was observed 1-4 hours after intralesional injection. One case of disease progression under therapy was a fibrolamellar HCC of a young woman (22 years old). Quality of life (SF 36) improved even in stationary cases.
CONCLUSION: Intralesional injection of Viscum album (Abnobaviscum; mistletoe) in inoperable HCC is able to induce in 27,7% remission and in 33,3 % partial remission. Historical studies by ethanol injection (PEI) demonstrated lower response rates. Therefore the combination of cytotoxicity and immune stimulating factors by Viscum album (mistletoe) will be useful and safe in treatment of inoperable HCC. Quality of life increased after intralesional injections of Viscum album in more than 70 %. Further multicenter randomised controlled studies will be necessary to confirm these remarkable results in inoperable HCC.
VISCUM ALBUM L AND SOLANUM LYCOPERSICUM INHIBIT FIBROSIS IN CHRONIC HEPATITIS C (HCV): A PILOT STUDY
Friedemann Schad, Burkhard Matthes, Silke Biesenthal-Matthes, Dirk Buchwald, Harald Matthes
INTRODUCTION: Untreated HCV leads to liver cirrhosis and hepatocellular carcinoma in 20-30% of cases after 25 years of infection. No treatment is known in failure or contraindications to standard therapy (pegylated interferon and ribavirin). We investigated the effect on fibrosis in a pilot study using a complementary concept with mistletoe and herbal extracts of Solanum lycopersicum, Fragaria vesca/Vitis vinifera (Hepatodoron).
METHODS: 8 patients with HCV (genotype 1) were treated with Viscum album (ABNOBAviscum aceris or Helixor M) 3 x weekly 1 Amp. sc., Solanum lyc. D4-D6 2-6 Tbl. and Hepatodoron 2-6 Tbl. daily. A liver biopsy was conducted before and 6-10 months after treatment and the HAI score was calculated.
RESULTS: In 8 patients (5 female, 3 male; mean age 43, mean duration of HCV 20.5 years) the HAI score before treatment was 7.75; after 18 - 23 months (12 months of treatment and 6-11 months follow-up) the score was 5.25 (p=0.05). The fibrosis stage decreased from 2.5 to 1.375 (p=0.05). In 5 patients, fibrosis decreased by 1-3 score points, 1 patient increased by 1 scored point and 2 were stable.
DISCUSSION: Viscum album and the herbal extract were able to inhibit and reduce fibrosis in liver biopsies scored by HAI. This therapy concept might be beneficial to non-responders and patients not compliant with standard HCV therapy. Further studies are necessary to confirm this preliminary data.
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