|Hepatitis B Version 4.1|
The following documents related to hepatitis B have been elaborated for informative purpose only. They have been written by Stuart Millinship. This report has not been written by the Health On the Net Foundation's team and the Foundation is not responsible for the content of the Hepatitis B report.
There are trials of new drugs being carried out by various pharmaceutical companies, hospitals and medical research teams and you may wish to consider joining one of these. Most of these studies are double blind. I.e. you will not know if you are taking the new drug or a placebo. Some studies also combine interferon with the new drug.
In considering to take an experimental drug you must make a decision regarding the possible gains (A cure) and the possible risks (unknown side effects) and should discuss things very thoroughly with your medical advisor.
Some of the drugs currently under study are shown below, I have also included details of drugs that have been found ineffective or unsuitable for reference purposes.
This drug which has an antiviral activity against the herpes simple virus was found ineffective against hepatitis B.
Adenene Arabinoside (ara-AMP)
This drug has been shown to be a potent inhibitor of hepatitis B virus DNA polymerase. Suppression of HBV DNA has been demonstrated and clearance of HBeAg was achieved in 33% of patients in a controlled study. Usually 8 weeks of treatment is required to effect loss of HBeAg and HBV DNA, unfortunately this drug showed serious neurotoxicity in many patients and was therefore deemed unsuitable as a therapeutic agent.
However a recent study (Hepatology April 1996) has shown that Adenine arabinoside monophosphate coupled to lactosaminated human albumin (L-HAS-ara-AMP) administered over a four week period exerted the antiviral activity of ara-AMP without producing neurotoxic effects. Unfortunately L-HAS-ara-AMP must be administered by intravenous infusion and this has prompted investigation of new ara-AMP conjugates which my be injected via the intramuscular route.
Adefovir Dipivoxil (GS 890)
In a Phase I/II trial of Protean Design Labs Human Anti-Hepatitis B Antibody in 12 patients with chronic hepatitis B, levels of key markers for hepatitis B disease such as hepatitis B surface antigen, hepatitis B DNA, and enzymes released into the blood by damaged liver cells declined at least temporarily during the treatment period by at least 50% in half or more of the patients who had elevated levels before treatment. Patients were treated for about 5 weeks. In addition, Boehringer Mannheim has conducted a Phase I study in 33 healthy volunteers, and determined that the antibody has a half life of approximately 20 days and was well-tolerated. While the Phase I and Phase I/II trial results are encouraging, the results of early clinical trials may not be predictive of results in larger later-stage trials for various reasons, including differences in patient populations, study size, and trial design, and there can be no assurance that the Phase II clinical trial will demonstrate safety or efficacy.
The Phase II/III trial is expected to begin in early 1997.
Colchine was not shown to improve survival rates in patients with chronic hepatitis B. However a more recent study showed that colchicine may be of benefit for those with cirrhosis.
Initial Trials indicate that is ineffective against HBV.
SmithKline Beecham is evaluating its antiherpes agent Famvir (famciclovir) in the treatment of hepatitis and has recently presented Phase II clinical data for the treatment of chronic hepatitis B infection, according to Datamonitor. The report notes that significant antiviral effect was observed in interferon unresponsive and refractory patients. These results may have an enormous impact in the treatment of chronic hepatitis patients, if Famvir's potential use in long-term therapy is proven.
In a recent double blind study (Nov 1996) involving 333 patients Famciclovir treatment resulted in a dose-dependent suppression of hepatitis B virus replication. A reduction of serum hepatitis B DNA levels was evident in all famciclovir treatment groups within one week and was maintained throughout the 16 week treatment period. In addition famciclovir reduced patients' levels of ALT and the normalisation of liver enzymes was sustained eight months after the 16 week treatment period in fifty percent of patients who took 500mg of famciclovir 500 three times a day. Loss of the "e" antigen was also observed and was significantly higher than that found in the placebo group.
Further clinical trials are taking place to determine famciclovir effectiveness as a therapy for hepatitis B.
This drugs was found to have severe and lethal toxicity.
Foscarnet (trisodium phosphonoformate)
This is an inhibitor of DNA polymerase which has been shown to have activity against hepatitis B in vitro. When administered by continuous intravenous infusion it can cause renal dysfunction and results obtained do not suggest an important role for this agent.
Given intravenously this drug inhibits HBV DNA but replication continues once treatment is stopped.
Granulocyte Macrophage colony-stimulating factor
A small pilot study of this therapy demonstrated an antiviral effect, as documented by a fall in serum HBV DNA, and may have promise particularly in patients with leukopenia, who would otherwise benefit from interferon therapy
Trials are in progress. One study on patients that failed to respond to interferon alpha showed after a 16-24 week treatment with 9 - 15m million units of interferon beta three times a week showed (after 6 months follow up) a sustained clearance of HBV DNA and loss of HBeAg in 30% of cases and seroconversion with the appearance of HBeAb in 19.4% of cases.
Studies suggest that the antiviral activity of interferon gamma is half that of interferon alpha.
Some transient inhibition of HBV DNA Polymerase has been observed and it could prove useful as it increases lymphocyte counts and CD4 cells.
Studies have indicated that interlukin-12 may be beneficial in modulating the antibody and cellular response to hepatitis B and improve clearance of hepatitis B.
This compound has antiviral and immunoregulatory activity and was reported to induce a serocoversion of HBeAg positive patients in a small trial (Par et al. 1989)
Lamivudine or 3TC
This drug is a potent inhibitor of the hepatitis B virus by inhibition of DNA synthesis. Studies to date show it can decrease HBV DNA but in most cases HBV DNA reappeared once treatment was stopped although sustained suppression of HBV DNA and the disappearance of HBeAg has been observed.
Lamivudine has a fairly quick-acting therapeutic effect in many patients and longer therapy is expected to produce more lasting results. The drug is well-tolerated and may be safe for long-term or even indefinite use. To date, over 1,000 patients have received lamivudine for hepatitis B indications. Glaxo Wellcome is currently conducting 12 trials in 22 countries using lamivudine alone and in combination with alpha-interferon, suggesting that the company believes the drug has considerable potential for hepatitis B. Most of these are Phase III studies testing the drug for one year using the 100 mg/day dosage. Lamivudine is taken orally, has negligible side effects and is expected to be rather affordable for long-term therapy, possibly under $1,000/year. In contrast, conventional alpha-interferon treatment requires injections three times/week for months, has significant side effects, a course of treatment costs up to 5-times more and has only about a 25%-30% cure rate. Lamivudine eventually may show sufficient long-term efficacy to be used on its own or in combination with interferon or other drugs in development.
Extract From:HIV Drug Works Against Hepatitis B
This was claimed to inhibit HBV replication in up to 60% of patients (Fattovich et al, 1986) but the results were not proved to be reproducible. Combined trials of levamizole with interferon revealed a higher response rate in those treated with interferon alone(38%) than those treated with the combination (10%) (Fattovich et al, 1992)
KIRKLAND, Wash., Dec 15 (Reuters) - ProCyte Corp said it presented findings showing the company's PC1323 compound inhibits the hepatitis B virus by preventing release of the virus from infected cells.
PC1323 is an isomer, or restructured compound, of ProCyte's BCDS-copper compound, which the company is studying for its antiviral effects. "We are continuing to find that this family of proprietary compounds appears to inhibit specific viruses related to the outer core, or envelope, of the virus, said ProCyte principal scientist Andrew Branca, in a statement.
Polyadencyclic polyuridylic acid.
In a small study this did not have a significant benefit for patients infected with hepatitis B.
T cell vaccine
Still in the pilot study phase is the use of a vaccine which takes advantage of a T cell epitope for CTL in subjects with HLA-A2.1. It is hoped that this vaccine will induce sufficient immune recognition to initiate viral eradication by cell-mediated mechanisms and immune clearance, without inducing massive hepatocellular necrosis. It is possible that this vaccine may convert the carrier in the inactive `immune tolerant' phase of their hepatitis B to an active phase which seems to be a prelude to viral eradication.
Cytel Corporation, announced some preliminary results from a phase II trial, of 27 patients, of their therapeutic vaccine, Theradigm-HBV.
It appears that Theradigm-HBV stimulated an immune response in patients chronically infected with hepatitis B. These flares were dose dependent and no flares had been observed prior to the first injection or in those recieving a 50mg dose. Out of 10 patients in the 500 microgram dose group, 2 flares were observed (20%) while 5 of the 12 patients (42%) in the 5000 microgram dose group exhibited flares in their ALT. This observation is potentially significant because the majority of patients who ultimately clear chronic HBV infection as a result of interferon therapy produce a flare in their ALT prior to viral clearance. Another indication of a potential clinical effect is normalization of ALT. Normalization was achieved in 3 of 12 subjects (25%) in the 5000 microgram dose group, and in none of the patients in the 50 and 500 microgram dose groups.
A dose dependent drop in HBV DNA was also observed, despite the high viral burden of the patients in the study group. A drop in the level of HBV DNA at 2 or more time points during the study was defined as a potentially useful clinical effect. None of the 5 patients at the 50 microgram dose level had a 50% or greater drop in DNA, while 2 of 10 (20%) at the
500 microgram dose level and 3 of the 12 (25%) at the 5000 microgram dose level had decreases in HBV DNA greater than 50%. In addition, one patient in the 5000 microgram dose group showed total clearance of HBV DNA and HBeAg.
Thymosin Alpha (Zadaxin)
This drug, produced by SciClone pharmaceuticals has been licensed for the treatment of hepatitis B in the Philippines, the republic of China and Singapore , SciClone has also filed new drug applications for permission to market Zadaxin in Hong Kong, India, Indonesia, Malaysia, Mexico and Cyprus.
Thymosin is an immune stimulator known to enhance suppresser T cell activity and synthesis of IgG. Given by subcutaneous injection tymosin has been shown to induce clearance of HBV DNA and loss of HBeAg, rates as high as 54% have been reported and rates as high as 76% when used in conjunction with interferon.
The drug is reported to have few side effects and the results from phase III trials are now starting to appear and show promise for Thymosin Alpha as a therapy for hepatitis B.
Results indicate that this agent is ineffective.
Research has indicated that vaccines may have a use in the treatment of chronic hepatitis B. See Theradigm-HBV
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