Other Drugs
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.
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.
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 HBV DNA 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 (Hbe
antigen) 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
treatment with interferon-alpha.
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.
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.
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)
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
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.
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)
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.
Please see the section on complimentary
medicine for more information on NAC.
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.
In a small trial this compound normalised elevated ALT
levels and induced loss of HBeAg in
11 out of 19 patients and loss of HBV DNA in 12 out of 19 patients. (Hahm et
al, 1994)
In a small study this did not have a significant benefit for patients infected
with Hepatitis B.
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.
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.
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
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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