The following documents related to hepatitis B have been
elaborated for informative purpose only. They have been written by . 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.
Introduction
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 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.
Acylovir
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
. Suppression of has been demonstrated and clearance of
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)
FOSTER CITY, Calif., Sept 16 (Reuter) - Gilead Sciences Inc said Monday
its GS 840 drug produced "significant and sustained antiviral activity"
in a clinical test of 20 patients with chronic hepatitis B virus, 65
percent of whom also tested positive for the human immunodeficiency
virus, the virus that causes AIDS.
Gilead said that during four weeks of treatment, GS 840 resulted in
a statistically significant mean decline in levels of 97 percent from baseline numbers, compared with an
increase of seven percent in the placebo group. All treated patients
experienced a greater-than-90 percent decrease in HBV DNA versus none
of patients on placebo.
Levels of HBV DNA returned to baseline between one and six weeks after
the 28 days of GS 840 dosing. This underscored the antiviral effect
of drug treatment, the company said.
During the first eight weeks, one marker of hepatitis infection () became transiently undetectable in one patient. GS 840
was well tolerated with only mild to moderate reactions, including moderate
nausea in two patients, Gilead said.
GS 840 is an oral drug from a class of antiviral compounds known as
nucleotides that seek to prevent viral replication, Gilead said. The
drug is also being tested in combination with other drugs to treat HIV.
The company said that in its study, the mean time since hepatitis B
diagnosis was four years and 25 percent of the patients had failed hepatitis
B virus .
Antibody Therapy
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 , hepatitis B , 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.
Colchicine
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 .
ddI
Initial Trials indicate that is ineffective against HBV.
Famciclovir
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
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
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 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.
Fialuridine
This drugs was found to have severe and lethal toxicity.
Foscarnet (trisodium phosphonoformate)
This is an inhibitor of
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.
Gancilovir.
Given intravenously this drug inhibits HBV
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 ,
and may have promise particularly in patients with leukopenia, who would
otherwise benefit from
Interferon Beta
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
and loss of in 30% of
cases and seroconversion with the appearance of HBeAb in 19.4% of cases.
Interferon Gamma
Studies suggest that the antiviral activity of interferon gamma is half
that of .
Interlukin-2
Some transient inhibition of HBV has been observed and it could prove useful as it increases
lymphocyte counts and CD4 cells.
Interleukin-12
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.
Isoprinosine
This compound has antiviral and immunoregulatory activity and was reported
to induce a serocoversion of
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 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 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 ,
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
By Denise Mann. Medical Tribune.January 11, 1996.
Already used to treat HIV, the nucleoside analogue lamivudine also appears
to suppress the hepatitis B virus in the DNA of patients with the chronic
form of the disease, Harvard researchers report.
In the study of 32 chronic hepatitis B patients, traces of the virus
disappeared in the DNA of all patients who took 100-mg or 300-mg doses
daily of lamivudine (Epivir, 3TC, Glaxo Wellcome) for 12 weeks, according
to Jules L. Dienstag, M.D, of the Gastroenterology Unit and Liver-Biliary-Pancreas
Center at the Massachusetts General Hospital and the department of medicine
at Harvard Medical School in Boston.
Dr. Dienstag and colleagues noted that while hepatitis B virus (HBV)
DNA reappeared in most patients after completion of therapy, six patients
(19%), including five who had been unresponsive to interferon, had sustained
suppression of HBV DNA, along with a normalization of transaminase elevations.
Moreover, hepatitis B e antigen disappeared in four of these six patients
(12%), he said.
But a longer course of the drug could suppress the virus indefinitely
and prevent subsequent liver disease, said Raymond Koff, M.D., chairman
of medicine at MetroWest Hospital in Framingham, Mass. The findings
are "an exciting new observation, and in a small number of people,
we can start thinking about the notion of a cure," Dr. Koff said.
In the double-blind trial, the patients were assigned to either a 25-mg,
100-mg or 300-mg oral dose of lamivudine daily for 12 weeks. Levels
of the hepatitis B virus in genetic material became undetectable (≤
1.5 pg/ml) in 70% of the chronic hepatitis B patients who took 25-mg
doses of lamivudine, and 100 % of those taking the higher doses, Dr.
Dienstag reported in The New England Journal of Medicine (1995;333:
1657-1661).
"It may be premature to get extraordinarily excited," Dr.
Koff said. "But if longer term follow-up studies are done, we may
really be talking about a cure."
Though lamivudine was well-tolerated, all participants in the trial
experienced an increase in alanine aminotransferase. In the study, alanine
aminotransferase levels at least doubled in five patients given the
25-mg dose and eight patients given the 100- or 300-mg dose. "Although
this substance does have a toxic effect on the liver, in most cases
it is usually a mild [effect]," said Alfred Prince, M.D., director
of virology at the New York Blood Center in New York City.
Lamivudine, also known as 3TC and part of a new class of drugs called
nucleoside analogues, seems to be more effective in treating chronic
hepatitis B than interferon, which only works in about 40% of hepatitis
B patients. "It looks as if nucleoside analogues work in people
who fail to respond to interferon," Dr. Koff said, because 17 study
participants had no response to earlier therapy. Larger multicenter
trials involving 12-month courses of treatment with lamivudine are now
underway, the study authors noted. A trial involving the treatment combination
of interferon and lamivudine may yield interesting results as well,
Dr. Koff said.
Levamizole
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)
N-Acetyl-Cysteine (NAC)
ANTI-HEPATITIS-B VIRUS ACTIVITY OF N-ACETYL-L-CYSTEINE (NAC) - NEW
ASPECTS OF A WELL-ESTABLISHED DRUG
N-acetyl-L-cysteine (NAC) is commonly administered as an antidote against
acetaminophen (paracetamol) intoxication and is the preferred agent
in the treatment of pulmonary diseases. It is furthermore commonly considered
that it restrains human immunodeficiency virus (HIV) replication by
scavenging reactive oxygen intermediates (ROI) and thus suppressing
activation of nuclear factor kappa B (NF kappa B). We Show here that
NAC is in addition able to inhibit hepatitis B virus (HBV) replication,
but by a mechanism independent of the intracellular level of reactive
oxygen intermediates. Treatment of HBV-producing cell lines with NAC
resulted in an at least 50-fold reduction of viral DNA in the tissue
culture supernatant within 48 h. This decrease of viral DNA and thus
of virions in the tissue culture supernatant is caused by a disturbance
of the virus assembly, rather than by a reduction of viral transcripts.
Our data strongly suggest a potential use of this well-established,
non-toxic drug for the treatment of HBV infection. Since NAC, in contrast
to interferon, exerts its anti-HBV activity at a post transcriptional
level, a combination of NAC with the established interferon therapy
could also be considered.
PC1323
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 trial this compound normalised elevated
levels and induced loss ofin 11 out of 19 patients and loss of HBV DNA in 12 out of 19 patients.
(Hahm et al, 1994)
Reticulose
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.
Theradigm-HBV
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
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 .
This observation is potentially significant because the majority of patients
who ultimately clear chronic HBV infection as a result of 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
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
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
and loss of , 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.
Title: A RANDOMIZED CONTROLLED TRIAL OF THYMOSIN-ALPHA-1 VERSUS
INTERFERON-ALFA TREATMENT IN PATIENTS WITH HEPATITIS B E-ANTIGEN
ANTIBODY-POSITIVE AND HEPATITIS B VIRUS DNA-POSITIVE CHRONIC HEPATITIS
B
Abstract: It has recently been shown that thymosin-alpha 1 (T.alpha
1), a synthetic polypeptide of thymic origin, is able to promote disease
remission and inhibition of hepatitis B virus (HBV) replication in patients
affected by hepatitis B e antigen (HBeAg)-positive chronic active hepatitis.
We evaluated the efficacy and safety of T-alpha(1) treatment in patients
with hepatitis B e antibody (anti-HBe) and HBV -DNA-positive chronic
hepatitis. Thirty three patients were randomly assigned to receive either
T-alpha(1), 900 mu g/m(2) body surface area twice weekly (17 patients)
or 5 MU of interferon alfa (IFN-alpha) three times weekly (16 patients)
for 6 months. At baseline, both groups were comparable concerning age,
sex, liver histology, and alanine transaminase (ALT) levels. At the
end of treatment, complete response (defined as ALT normalisation and
HBV-DNA loss) occurred in 5 of 17 (29.4%) in the T-alpha(1) group and
in 7 of 16 (43.8%) in the IFN-alpha group (P = not significant). After
a follow -up period of 6 months, a complete response was observed in
7 of 17 (41.2%) in the T-alpha(1) group and in 4 of 16 (25%) in the
IFN-alpha group (P = n.s.). Compared with the results observed in a
group of 15 patients never treated with IFN-alpha and followed for 12
months, the rate of complete response was significantly higher in the
IFN-alpha group at the end of therapy (1 of 15 vs. 7 of 16, respectively;
P < .05) and in the T-alpha(1) group at the end of follow-up (1 of
15 vs. 7 of 17, respectively; P < .05). Unlike IFN-alpha T-alpha(1)
was well tolerated by all patients. The only side effect, reported by
some, was local discomfort at injection sites. The results of this trial
suggest that T-alpha>(1) is able to reduce HBV replication in patients
affected by anti-HBe positive chronic hepatitis, Furthermore, compared
with IFN-alpha, T-alpha(1) is better tolerated and seems to induce a
gradual and more sustained ALT normalisation and HBV-DNA loss. In conclusion,
T-alpha(1) appears to be a safe and effective alternative treatment
for anti-HBe-positive chronic hepatitis. The benefit of this agent in
producing long-term inhibition of HBV replication must be confirmed
by future trials.
Author: ANDREONE P, POLICLIN S ORSOLA, VIA MASSARENTI 9, I-40138 BOLOGNA,
ITALY
Source: HEPATOLOGY 1996 OCT;24(4):774-777
Thymopentin
Results indicate that this agent is ineffective.
Vaccine Therapy
Research has indicated that vaccines may have a use in the treatment
of chronic hepatitis B. See
