TREATMENT

Getting the proper treatment for hepatitis C is important. You must talk to your doctor about the best course to follow. He or she should recommend confirming a positive blood test with additional lab tests to rule out inaccurate results. No matter what option you choose, your doctor will regularly draw blood to test for virus levels and liver enzyme levels.

DRUG TREATMENT

Side effects

Treatment with interferon can cause side effects. The severity of these effects will vary individually and typically occur early in the treatment. The most common side effects include:

flu-like symptoms such as fever, chills, headache, and muscle and joint aches
fatigue
nausea or loss of appetite
anemia
Depression: Depression and mood swings are common after a hepatitis C diagnosis and especially common with treatment. Signs of depression include, among others, feelings of deep and constant sadness, hopelessness, mood changes, or loss of interest in things you once enjoyed. If you are experiencing changes in mood, emotion, attitude, and lifestyle that persist despite your efforts to "cheer up," you should talk to your doctor. There are anti-depressant medications that will help you.

During treatment, your doctor has to regularly draw blood to test for virus levels and liver enzyme levels. He or she will also monitor your liver function and viral loading. Being on treatment may mean taking time off from work. It can be difficult — not just for you but for your family.

Treatments Of The Future
http://www.hepatitiscaware.org/news/future.html
The future of Hepatitis treatment lies in the development of
specific inhibitors of HCV-derived enzymes such as protease,
helicase and polymerase inhibitors. Inhibitors will hopefully keep
the Hepatitis C virus from replicating in the body.
Drugs that inhibit other steps in HCV replication may also be used
in treating this disease, by blocking production of HCV antigens
from the RNA (IRES inhibitors), preventing the normal processing
of HCV proteins (inhibitors of glycosylation), or blocking entry
of HCV into cells (by blocking its receptor).
Molecular approaches in treating Hepatitis C are also worthy of
investigation; these consist of using ribozymes and anti-sense
oligonucleotides (which are small complementary segments of DNA
that bind to viral RNA and inhibit viral replication).
The crusade against Hepatitis C Virus is bound to produce results
for the millions affected by it.
While this may be very technical the important thing is that is
shows research is being done and from different approaches. The
outlook for "non-responders" may look a little more promising in
the near future

nterferon Improves Risk for Death and Cancer
New Ribavirin in Early Development

Interferon Improves Risk for Death and Cancer
New Ribavirin in Early Development
Normal ALT in African-Americans
Fats, Overweight, Diabetes in HCV
How Often Should You Do a Biopsy in HCV/HIV Coinfection

A Japanese research group reported that interferon therapy improves
the risk for developing HCC and death. This is not a new finding.
Several studies have reported this. But this study was a large one.
The study measured ALT response. Authors reported therapy was 4-12
months & presumably interferon alone. Responders and transient
responders improved risk but non-responders did not compared to
untreated patients. One of the key questions is if you take IFN+RBV
therapy and are a partial responder, relapser or nonresponder how
long will improved histology last after stopping therapy? I don't
think we know but anecdotal opinion is that histology can improve
while on IFN even if you're a nonresponder. After stopping therapy
progression starts up again but it may take a year to get back to
where you were before therapy. Opinion is that by staying on
interferon histology improvement is continued. Two large studies in
HCV monodisease are ongoing to prove this.

Levovirin is a second generation ribavirin being made by ICN
Pharmacueticals. In a poster today they reported that in monkeys
they found Levovirin gets into the red blood cell less than
ribavirin. This would suggest perhaps less side effects. RBV can
lead to reduced hemoglobin and fatigue. A study in HCV-infected
patients is planned and required to see if this new version of RBV
has antiviral activity as RBV does in combination with IFN.

A study reported today by Thelma Wiley from the University of
Illinois, Chicago reported finding that in African-Americans
compared to non-AAs cirrhosis was as likely to occur whether ALT is
normal or abnormal (25%). Among the general population, normal ALT
implies less progression in general. Although ALT is not a predictor
of non-progression. You could have nomal ALT and have moderate or
more advance liver disease. Wiley said African-Americans with normal
ALT are as likely to develop significant histologic disease as
whites with abnormal ALT.

Several posters associate overweight, elevated fats (cholesterol,
triglycerides), and sugar with HCV and progression. This is not new
information but is worth reporting because these are things that
patients can have some control over with dietm, exercise, and
medical intervention for lipids.

One poster suggested in HCV monodisease a follow-up biopsy should be
done 3-5 years after the first to evaluate progression. Since HIV
accelerates HCV perhaps a followup biopsy should be considered 1-2
years after the first, if HCV therapy was not started.

A San Diego group reported that HCV/HIV patients treated with HAART
& for HCV have better survival if they are compliant with taking
meds, participating in support groups, and in stopping alcohol. In
other words, good support systems are important.

HCV Therapy in HCV/HIV Coinfection

Reported by Jules Levin

There were a few studies reported today in posters on response to
HCV therapy by HCV/HIV coinfected patients. The data is preliminary
as I'll explain below but suggest that coinfected patients may not
respond as well to therapy as patients with HCV alone. Is this a
reason to not treat your HCV? I don't think so. A study was reported
by Thierry Poynard showing that interferon+ribavirin appears to
improve, slow, or stop liver damage even if there is no viral
response (non-responders). And yesterday the Japanese research group
reported from a large analysis that interferon improves disease
progression. Other studies have suggested that interferon can slow
disease progression even if there is little viral load response. In
speaking with French researchers here their experience is that
coinfected patients respond less by about 5-10% in terms of percent
achieving a sustained virologic response. It's my understanding that
genotype 1 is less prevalent in Europe (50%) while here in the USA
genotype 1 prevalence is 70%. Among IVDUs genotype 1 is reportedly
found 80% of the time. While several studies report over 90% of
African-Americans have genotype 1. So, one reason coinfected
patients don't respond as well is because they have a higher
percentage of genotype 1. However, there may be other factors. HIV
may impair the immune response. Evaluating a person's immunity by
their CD4 count is a crude way to assess the capacity of their
immune system. Inside liver cells there are CD4 cells. Researchers
have yet to examine inside liver cells in coinfected patients to see
if their immune response is impaired. Additionally, the overall
immune response in HIV is not well understood. More research is
needed to understand the role of HIV in perhaps limiting the
response to HCV therapy. Other factors may also be involved such-is
the HIV viral load undetectable which may improve response to HCV
therapy; alcohol intake; is HAART playing a role; do individual
drugs play a role; the length of time a person has had HCV.

PEGASYS

Roche reported very preliminary data on their study of coinfected
patients in the USA. 150 coinfected patients are being enrolled in
this study to receive Pegasys (pegylated interferon alfa-2a) 180 ug
by subcutaneous injection for 48 weeks. Patients receive Pegasys
momotherapy for 12 weeks and can add ribavirin if they have
detectable viral load at 12 weeks or do not achieve 2 or more log
reduction in HCV viral load. Patients could have CD4s as low as 100
for this study and detectable HIV-RNA. 106 patients enrolled; age
44; 82% male (women respond better); ALT 101; 59% had high viral
load (6 million); average HCV-RNA 6.3 log IU/mL; 80% genotype 1
(this is a high percentage of genotype 1); average HIV-RNA 2.3 log;
11% cirrhotic.

Cd4 at baseline was 513 and 436 at week 12. 63% had <50 copies/ml
HIV-RNA at baseline and 72% at week 12. 19.1% (17/89) had negative
HCV-RNA at week 12 (on Pegasys monotherapy). 33.7% (30/89) had a
reduction in HCV-RNA of 2 or more log. 9 patients (8.5%) have
discontinued therapy: 5 patients (4.7%) because of expected adverse
events and 4 because of refusal of treatment or failure to return.
The authors reported that no unexpected adverse effects of the study
meds were seen. The lowest post-baseline neutrophil count of grade 4
neutropenia (<500/mm3) occurred in 9 patients (8.5%); the lowest
post-baseline hemoglobin level grade 1 (8.0-9.4) occurred in 2
patients; and thrombocytopenia (platelet count <20,000 mm3) occurred
in 1 patient.

82% of patients experienced at least 1 AE: fatigue 35%; myalgia
(muscle aches) 27%; headache 22%; nausea 20%; pyrexia 19%; rigors
18%; arthralgia 12%; injection site inflammation 12%; depression
12%.

These results are obviously preliminary, at week 12. And we look
forward to further analysis.

Edmund Bini, from New York City, reported on a small study of
coinfected patients receiving standard interferon + ribavirin.
Consecutive HIV and HCV coinfected patients were treated with IFN
alfa-2b 3 million units three times per week with 800-1200mg/day of
RBV. The results in these patients were compared to a matched group
(similar characteristics) of patients with HCV alone. The duration
of therapy was 24 weeks if genotype 2/3 or up to 48 weeks in those
with genotype 1. Sustained virologic response was defined as <100
copies/ml 24 weeks after stopping therapy. In patients with genotype
1, treatment was discontinued if HCV was still detectable at week
24. All data was analyzed by an intent-to-treat analysis. 96
patients were included in the study- 32 with coinfection and 64 with
HCV alone.

Bini said there were no significant differences between the
coinfected patients and those with HCV alone. Treatment was
completed in 75% of the coinfected patients and 83% of those with
HCV alone (p=0.37). The coinfected patients had HIV for 7.5 years,
on average. CD4 count was 433. Average HIV viral load was <50
copies/ml (range <50 to 83,000). Average number of ART medications
was 3. Bini reported 84% had genotype 1in both groups. In both
groups, 40% had >2 million viral load. Average HCV-RNA was 1.5
million copies/ml. Histologic Activity Index (0-18) was 6.7 in HIV
group and 6.1 in HCV group (NS). Cirrhosis was 22% in each group.
Duration of HCV was 16.8 years in HIV group and 19 years in the HCV
group. So, these patients had HCV for much longer than they had HIV.
68-73% had IVDU as the risk factor for HCV. 56-65% were
African-American. 18-25% were Hispanic. 90% male. Age was 49 on
average.

The end-of-treatment viral response was 39% in the HCV alone group
and 34% in the coinfected group (p=0.66, NS). So, the 2 groups
responded the same. At the end of followup (sustained response)
26.6% in the HCV alone group and 21.9% in the coinfected group
(p=0.62, no difference) had a viral response. Response according to
genotype: genotype 1: 22% in HCV alone and 18.5% in coinfected;
genotype 2/3 Ð 50% in HCV group and 40% in the coinfected patients.
No coinfected patient with undetectable HIV viral load developed HIV
viremia during treatment or follow-up. Treatment with IFN+RBV did
not result in a significant CD4 count decrease. There were no
serious adverse events. Bini reported there was no difference
between the 2 groups in terms of dose reductions and other adverse
events. This is unusual. In real life, you would expect coinfected
patients to discontinue more often and have higher incidence of
reduced hemoglobin. Bini concluded that the response was the same
between coinfected patients and those with HCV alone.

The AmFar study in coinfected patients was reported but there are
some problems with this study. It was conducted at 21 sites
including Puerto Rico. 110 patients received either standard
interferon monotherapy 3 million units 3 times per week or IFN+RBV.
But, patients in the IFN/RBV arm received IFN monotherapy for 12
weeks and if detectable they could replace RBV placebo with RBV at
week 16 (in a blinded fashion). Although it wasn't stated in the
poster, I was told that patients who added RBV were still considered
non-responders. Patients were somewhat evenly divided between being
white, black, or hispanic. 85% were men. 75% had genotype 1 and
baseline HCV-RNA was 4.4 million copies/ml. Fibrosis was present in
84% of participants. 15% had cirrhosis. Hepatic necrosis was present
in 59%. Median HIV-RNA was 400 copies/ml and mean viral load was
37,000 in the IFN/RBV group. Average CD4 was 500. 56% had
undetectable HIV-RNA. 57% were on a PI regimen. 15% were not on any
ART. 26% were taking AZT and 54% were taking d4T. ALT was about 100.
RESULTS: at week 72, 8% receiving IFN/RBV had undetectable HCV-RNA.
But remember patients were initially randomized to 16 weeks of IFN
monotherapy. Although it wasn't mentioned in the poster and may not
be true, I was told that those who added RBV because they weren't
undetectable were considered failures (nonresponders). 0% (0/40)
with genotype 1 had a sustained response while 25% with other
genotypes had a sustained response. These results are strange. A
response rate of 0% in genotype 1 is unexpectly low. 28% were
African-American in the study and 36% were white. 21 patients (19%)
experienced an undetectable viral load during at least one
evaluation during the study. 3 of these patients were taking IFN
monotherapy at the time of being undetectable. The authors reported
that 50% of patients discontinued study drugs before prematurely.
And 20% reported premature discontinuation was due to an adverse
event. This is a high discontinuation rate. The most commonly
reported adverse events were Ð elevated ALT 32% (???); leukopenia
28%; elevated triglycerides 25%; anemia 24%; asthenia (fatigue 24%.
It sounds to me as if patient management was not handled well. 24
patients were reported to have bilirubinemia, 18 with depression. 15
with elevated amylase, 13 elevated lipase, 12 hypoglycemia. The
response rate at week 12 was 23% for those receiving IFN/RBV.

PEN-LABEL PHASE 1B STUDY OF HEPATITIS C VIRAL DYNAMICS WITH OMEGA
INTERFERON TREATMENT


Reported by Jules Levin

John G McHutchison, Paul J Pockros, Scripps Clinic, La Jolla, CA;
Peter Langecker, Dennis Blanchett, William - Lang, Mark Moran,
BioMedicines, Inc, Emeryville, CA

Background: Omega (w) interferon (IFN) is a type 1 IFN active in
vitro against DNA, RNA and retroviruses. In man w IFN increases IFN
response marker levels. Aims: To evaluate in patients who failed to
clear virus with alpha IFN alone, alpha IFN with ribavirin or
pegylated interferon: á hepatitis C viral dynamics á HCV RNA and ALT
response to increasing doses of w á safety, tolerability, and PK
characteristics of w IFN Study design: Three groups of 8 patients
(pts) received 15,30 or 60 mg of w IFN sc qd for 14 days. Initially
mean HCV RNA levels were >105 and ALT levels were elevated. HCV RNA
levels were measured at 2,4,7,10,14,19 and 24 hours after initial
dosing; 5,10 and 24 hours after dose 2; and every 1-2 days through
Day 14. Omega IFN blood levels were measured at 11 time points for
24 hours following the initial dose. Results: 16 males and 8 females
completed 14 days of daily therapy. Median half life of elimination
of w IFN was approximately 9 hours after a single 15 mg dose. Six
pts required dose reduction and one discontinuation after 14 days
for neutropenia (3/8 at 30 mg, 4/8 at 60 mg). One pt each
discontinued because of pyelonephritis and elevated ALT. Other side
effects were mild to moderate headache (60%), fever (45%) myalgia
(45%). Conclusions: Omega IFN reduces levels of HCV RNA within 48
hours in genotype 1 infected patients resistant to prior alpha IFN
therapy. Further reductions occur in 2 of the 3 groups at 14 days.
AE's with w IFN, even with daily dosing, are not worse than those of
other IFNs. Neutropenia may be dose limiting. Prospective trials are
required to further determine the role of Omega IFN for the
treatment of HCV infection.

OPEN-LABEL PHASE II STUDY OF OMEGA INTERFERON IN PREVIOUSLY
UNTREATED HCV INFECTED PATIENTS

Mathias Plauth, Stadisches Klinikum, Dessau Germany; Helga Meisel,
Inst fur Medizinische Virologie, Berlin Germany; Peter Langecker,
Mark Moran, William Lang, Dennis Blanchett, BioMedicines,
Emeryville, CA; Jens-Uwe Jetschmann, Campus Charite, Humboldt Univ,
Berlin Germany; Jochen Brack, Klinikum Nord, Betiebsteil Ochsenzoll,
Hamburg Germany; Peter Von Wussow, Privatdozent, Facharzt fur Innere
Medizin, Hannover Germany

Purpose: To measure in naive HCV infected patients - the safety and
tolerability of w interferon (IFN) - the effect of different doses
on ALT levels -the effect of different doses on HCV RNA levels
Background: Omega (w) interferon (IFN) is a type 1 IFN active in
vitro against DNA, RNA and retroviruses. Human administration of w
IFN increases IFN response markers. Study design: Each of three
groups of treatment naive HCV infected patients (pts) received
either 15, 30 or 45 m g of w IFN sc daily TIW for 12 weeks. All pts
had HCV RNA levels >105 and elevated ALT levels at study entry. Pts
were evaluated clinically, with hematology, chemistries and HCV RNA
assays at 6 time points between day 0 and week 16. HCV RNA assays
were also performed at Days 0,1,2,3,4 and 15. Dose escalation is
continuing to 60, 90 and 45 m g of w IFN sc TIW. Results: Data are
presented from 32 patients who have completed 4 weeks of therapy.
Results for HCV RNA and ALT testing are presented in the table.
Adverse events were similar to those seen with other IFNs.
Leukopenia required dose reduction in two pts at the 15 mg dose
level but none at higher doses. No patients discontinued treatment.
Conclusions: Omega IFN is active against type 1 HCV in IFN naive
patients. It induced undetectable HCV RNA levels in 10/30 pts and
normalized ALT in 12/32 pts during the first 28 days of treatment.
Omega IFN shows the characteristics of a clinically useful
interferon for the treatment of HCV infection and further evaluation
of higher doses and prolonged treatment is warranted.

HCV Therapy Adherence; New drugs

Reported by Jules Levin

In this afternoon,s oral session on Novel Hepatitis C Therapies
Histamine showed nothing I or other observers in the audience could
see. The study of IL-12 was stopped for both lack of antiviral
activity against HCV and for adverse events, among them
thrombocytopenia (reduced platelets) and hemoglobin reduction. The
ISIS 14803 antisense showed antiviral activity in some patients (2/4
³ 1-log reduction in viral load) but was accompanied by high spikes
in liver enzymes as viral load reduced. The enzyme spikes resolved
when drug was stopped. Also a negative, ISIS drug is administered by
subcutaneous injection, I think 3 times per week by 2-hour
intravenous infusion (which is I think how the drug is administered
in the study beginning shortly), or by bolus subcutaneous injection
following, by at least 7 days, a single dose.

Peter Ferenci from Vienna gave an interesting presentation in his
talk on Early Prediction of Response to Peginterferon alfa-2a
(Pegasys) Plus Ribavirin in patients with HCV. An analysis on early
response was presented at DDW 2001 from the Pegasys/RBV study, which
reported that a patient,s viral load response by week 12 appears to
indicate the capacity to achieve a sustained virologic response.
This was explored further by Ferenci in an analysis from the same
study, which he presented today at AASLD. This is preliminary data
from a sort of pilot study. This is data that was generated after
the study. The study was not designed to look at these questions on
adherence and early response. The data do appear to make sense but
follow-up study is required. Ferenci also showed preliminary data
suggesting that a dose reduction may not reduce response rates. The
data previously reported at DDW showed that patients who fail to
achieve an early viral response (EVR) with Pegasys were highly
unlikely (negative predictive value=97%) to achieve a sustained
viral response (SVR).

The purpose of this study presented by Ferenci at AASLD was to
determine the effect of HCV genotype and adherence to study regimen
on positive and negative predictive values for sustained virologic
response using the EVR. They used study NV 15801 where patients were
treated with Pegasys once weekly and Ribavirin 1000-1200 mg per day
(Fried et al, DDW 2001).

Predictive value (PPV) is the probability that patients who achieve
an EVR will eventually achieve an SVR. Negative predictive value is
the probability that patients who do not achieve an EVR will not
achieve an SVR. This data is the first time its reported so it,s
preliminary. Further time may be needed to discuss and explore the
reliability of the data. Additional data and studies will continue
to look at these questions.

A brief summary of key points-

(1) The data presented by Ferenci suggests Adherence Matters:

· 86% (81% genotype 1) achieved undetectable viral load at week 12
in the Fried study of Pegasys+RBV. 65% of them achieved a sustained
virologic response. 86% with genotype 2/3 and fully adherent
achieved an SVR. This compares with a 76% SVR in the study for
genotype 2/3

· Adherence appeared matter more for genotype 1 to achieving a viral
response: 81% of patients with genotype 1 had an EVR. 67% (105/151)
of genotype 1 patients who were fully adherent achieved an SVR. This
compares with the 46% SVR for genotype 1 in the Pegasys/RBV studyÑan
improvement of 21%, and with 40% who were <80% adherent

(2) you will see from the discussion below that the data suggests
that (again, data is preliminary) perhaps atients may be able to
dose reduce and still maintain equal or close to equal chance of
achieving sustained viral response. Since the data is preliminary,
further research needs to be done before trying this. Do not try
dose reducing on your own. Read the details below.

Michael Fried reported at DDW that 86% (n=390) of patients at week
12 (total n=453) achieved an EVR. Again, the original study was not
designed to explore these questions. 65% (PPV) of those achieving
the EVR (n=253) achieved an SVR, and 35% (n=135) did not achieve an
SVR. So, if you had undetectable viral load by week 12 you had a 65%
chance of achieving an undetectable viral load 24 weeks after
stopping 48 weeks of therapy. 14% (n=63) did not achieve an EVR at
week 12, and 3% of them (n=2) achieved an SVR. 97% (NPV) (n=61) did
not achieve an SVR. So, if you had undetectable viral load at week
12 you had a 65% chance of achieving an SVR, and if you did not have
an EVR at week 12 you had a 97% chance of not achieving an SVR. This
suggests that, depending on other considerations, you may want to
stop therapy at week 12 if undetectable viral load was not reached.
However, if you are trying to improve histology you may want to
continue therapy for the full 48 weeks. As reported in yesterday,s
reports from this conference several new studies report what has
been previously reportedÑit appears as if interferon therapy
improves, slows, or stops liver disease progression. Perhaps
nonresponders may not accomplish this but the data indicate
transient viral responders and sustained viral responders achieved
this. Still, it,s my understanding that even nonresponders may
achieve stopping or slowing progression while on interferon therapy.
This has not been well established but two large studies are
exploring this now.

GENOTYPE

In the Fried study 81% (240/298) of patients with genotype 1 had an
EVR at week 12. The PPV was 57%. 137 patients (57%) achieved a SVR,
while 43% did not achieve an SVR. Not surprisingly genotype 2 did
better. 19% of patients with genotype 1 had no EVR at week 12. 2%
(n=1) had an SVR. 98% (n=57) had no SVR (NPV=98%).

The PPV for genotype 2/3 was 77%, as 97% had an EVR and 77% of them
had an SVR. 23% had no SVR. 3% (n=4) of genotype 2/3 had no EVR and
25% (n=1) had an SVR, while 3 patients (NPV=75%) had no SVR.

ADHERENCE MATTERS; IS DOSE REDUCTION OK?

For this discussion, full dose or full adherence in this analysis of
the Fried study equals taking 80% of drug and completing at least 38
weeks of therapy. Less than 80% adherence is due to early withdrawal
or dropout or dose reduction.

86% achieved EVR at week 12. 75% who took their full dose achieved
an SVR. 48% who were <80% adherent achieved an SVR. 145 patients
were <80% adherent. 94 of them (67%) dose reduced and 63 (67%)
achieved an SVR. Of the 145 patients who were not 80% adherent 51
withdrew early or dropped out. 12% (n=6) achieved an SVR. What is
the importance of this?? Perhaps a patient could dose reduce and
still achieve close to or equal to the response they would achieve
with full adherence. If a patient is not tolerating drugs, dose
reduction may help them stay on drug and maintain an equal or close
to equal chance for achieving an SVR. However, the analysis of this
data is new and so we don,t know yet whether patients dose reduced
the Peg IFN, RBV, or both. And we don,t know how much dose reduction
is ok. This data suggests a patient may be able to dose reduce to
600 mg per day RBV and still hold a good chance of achieving an SVR.
Here is the data further broken down by genotype 1 and 2.

81% (n=240) of patients with genotype 1 had an EVR. 67% (105/151)
who were fully adherent achieved an SVR. 40% who were <80% adherent
achieved an SVR. But, 56% who dose reduced (<80% adherence) were
still able to achieve an SVR. Genotype 2/3 did better. 97% achieved
an EVR (n=136). 86 were fully adherent and 76/86 (86%) achieved an
SVR. 50 patients had <80% adherence. 29 of the 50 dose reduced and
88% of them achieved an SVR.

These are preliminary data from 1 study. It,s premature to presume
it,s ok to reduce your dose of either Peg IFN or ribavirin. Further
analysis of these data are forthcoming and we should take a wait and
see approach.

Treatment of Chronic Hepatitis C
Howard J. Worman, M.D.
Treatment of chronic hepatitis C is presently based on the use of
interferon-alpha. Interferon-alpha is a protein that is given by
injection, usually three times a week. The addition of ribivirin, a
non-specific, orally administered anti-viral agent, improves the
efficacy of interferon-alpha. Although interferon-alpha with or
without ribivirin works for some patients with hepatitis C, most do
not achieve a "sustained response" of undetectable virus in blood 6
months after stopping therapy. Interferon-alpha is also associated
with myriad adverse events and is relatively expensive. Ribavirin
may also cause side effects. Better drugs are unequivocally needed
for the treatment of chronic hepatitis C. What will they likely be?
Longer Acting Interferon-alpha
The next drug available for the treatment of chronic hepatitis C
will be peginterferon-alpha (sometimes called "pegylated
interferon"). The active agent in peginterferon-alpha is the same
old interferon-alpha. However, the protein is attached to
polyethylene glycol (antifreeze), an inert compound that slows the
elimination from the body. More constant blood levels of
interferon-alpha are achieved with less frequent injections, usually
once a week. This results in enhanced compliance and clinically
superior anti-viral activity.
Published studies have shown that peginterferon-alpha alone results
in "sustained response" rates of 30% to almost 40%. The side effect
profile is similar to unmodified interferon-alpha. Preliminary data
show that addition of oral ribavirin to pegylated interferon-alpha
results in "sustained response" rates of approximately 50%. Hence,
pegylation enhances the efficacy of interferon-alpha for the
treatment of chronic hepatitis C.
The United States Food and Drug Administration (FDA) has recently
approved peginterferon-alpha-2b (Peg-Intron, Schering-Plough) for
the treatment of chronic hepatitis C. Peginterferon-alpha-2a
(Pegasys, Hoffmann La Roche) will likely be approved in the near
future. Within a year, the FDA will likely approve the combination
of peginterferon-alphas with ribavirin. Clinical trials of
peginterferon-alpha with a compound called VX-497 (Vertex
Pharmaceuticals) are also in progress. VX-497 has some features
similar to ribavirin and inhibits a cellular enzyme know as inosine
monophosphate dehydrogenase that may responsible for some of its
effects.
An even longer acting form on interferon-alpha is currently in early
stage clinical testing. This is a fusion protein between albumin and
interferon alpha (Albuferon, Human Genome Sciences). Data on its
clinical efficacy are not yet available. It is also probable that
other long acting preparations of interferon-alpha will be developed
in the next few years.
Drugs that Affect the Immune Response Against the Virus
Several drugs known as "immune modifiers" or "immunomodulators" that
alter the immune response are being tested in clinical trials for
chronic hepatitis C. Some are being studied along with
interferon-alpha. There drugs alter the inflammatory response
against liver cells infected with the virus; however, their
mechanisms of action are poorly understood. Compounds of this type
currently being tested in humans include thymosin-alpha-1 (Zadaxin,
SciClone Pharmaceuticals) and histamine dihydrocholoride (Ceplene,
Maxim Pharmaceuticals).
Therapeutic vaccines are also being developed to enhance the immune
response against the hepatitis C virus. In contrast to a preventive
vaccine, which is likely to be a very long way off for hepatitis C,
a therapeutic vaccine is administered to already-infected
individuals to stimulate the immune system to fight the infection.
Several therapeutic vaccines are in preclinical development for
hepatitis C. The most promising of these are DNA vaccines involving
injection of DNA copies of the hepatitis C virus's RNA genome, which
are taken up by certain immune system cells. These cells then
express viral proteins, stimulating an immune response against the
virus. These theoretically appealing therapeutic vaccine for
hepatitis C remain to be shown effective in human subjects
Specific Agents Against Hepatitis C Virus Proteins
A new generation of drugs to treat hepatitis C will be those
designed specifically to inhibit functions of the hepatitis C virus.
One target for such drugs is the hepatitis C virus RNA genome.
Ribozymes are catalytic RNA molecules, some of which can cut other
RNA molecules. A ribozyme (Hepatazyme, Ribozyme Pharmaceuticals) has
been designed to cleave the hepatitis C virus RNA genome in a region
that the virus needs to survive. Its efficacy in cutting hepatitis C
virus RNA has been established in the test tube and the drug is now
in early clinical trials. ISIS-14803 (Isis Pharmaceuticals) is a
antisense inhibitor complementary to a conserved sequence of the
hepatitis C virus RNA. This molecule binds to the viral RNA and
inhibits the expression of proteins required for replication.
ISIS-14803 is currently in early stage clinical trials. A small
molecule known as VP-50406 (ViroPharma) has also been demonstrated
to inhibit hepatitis C virus RNA in the laboratory and is in early
stage clinical development. Inhibitors of a unique structure of the
hepatitis C virus RNA necessary for protein synthesis, known as the
internal ribosome entry site or IRES, are also under study in the
laboratory.
Three favorite targets of the hepatitis C virus for pharmaceutical
chemists are its N3S RNA polymerase, NS3 RNA helicase and NS5B RNA
polymerase. Compounds directed against these targets are in various
stages of preclinical development. The targets are all enzymes
(proteins that catalyze chemical reactions) essential for hepatitis
C virus replication. They are expressed in cells infected with the
virus but not in mature viral particles themselves. Armed with
knowledge of the three-dimensional structures of these enzymes
deduced using X-ray crystallography, scientists can identify
molecules that inhibit their activities.
NS3 has two parts with distinct enzymatic activities. One part is a
protease that cuts a larger precursor protein encoded by the
hepatitis C virus RNA into smaller functional proteins. Inhibition
of NS3 would result in a failure of the virus to make the smaller
proteins necessary for its replication. The other part of NS3 is a
RNA helicase that unwinds the hepatitis C viral RNA. RNA unwinding
is necessary for its efficient replication and translation into
protein. Specific inhibitors of NS3's enzymatic activities would
theoretically not influence critical host cell functions, limiting
the side effect profiles. NS5B of the hepatitis C virus is an
essential RNA-dependent RNA polymerase that copies the virus's RNA
genome. Animal cells do not copy RNA; they make RNA copies from DNA.
Therefore, specific inhibitors of the NS5B should not affect host
cell processes.
Of course, one cannot accurately predict the adverse event profile
of a given drug until it is tested in human. Drugs designed as best
as possible against specific viral targets may still prove to have
side effects. However, well-designed drugs directed against the
hepatitis C virus RNA, NS3 protease, NS3 RNA helicase and NS5AB RNA
polymerase are very likely to be more effective and better tolerated
than currently available treatments for hepatitis C. The timeline
from the laboratory to the clinic is likely to be several years.

Drugs that Affect the Liver's Response to Injury
Chronic hepatitis (inflammation of the liver) can lead to fibrosis
(scarring) and cirrhosis (fibrosis plus abnormal regeneration of
liver cells). Virtually all of the serious complications of chronic
hepatitis C result from cirrhosis. For this reason, several groups
are developing drugs to prevent fibrosis and cirrhosis. Recent data
suggest that fibrosis, and perhaps even early cirrhosis, may be
reversible to some extent.
Very little is known about why the liver becomes fibrotic in
response to chronic inflammation. Furthermore, it is not known why
some individuals infected with the hepatitis C virus develop
significant fibrosis or cirrhosis while others never do. Some drugs
that may prevent liver fibrosis and cirrhosis are in early clinical
trials. IP-501 (Interneuron Pharmaceuticals) is an orally
administered anti-fibrotic compound being tested for the treatment
of including alcoholic and hepatitis C-induced cirrhosis. Animal
models suggest that IP-501 is effective in preventing the
development of alcohol-induced cirrhosis, however the exact
mechanism by which this compound works is not fully understood.
Clinical trials of IP-501 in alcohol-induced liver disease and
chronic hepatitis C are underway. Preliminary studies in humans have
also shown that interleukin-10 (Schering-Plough) may prevent liver
fibrosis in chronic hepatitis C. Clinical trials of interleukin-10
need to be carried out on a larger scale to demonstrate safety and
efficacy. Increasing scientific effort is being devoted to the study
of liver fibrosis in response to injury and exciting new drugs to
prevent it will hopefully be available someday.
Re-grow a Damaged Liver?
When a liver is damaged beyond repair, the only hope today is
orthotopic liver transplantation. However, considerable research
effort is being devoted to the study of stem cells. Stem cells are
undifferentiated cells, such as those in the early embryo that can
be directed to form many different tissues of the body. In the past
few of years, investigators have shown that liver stem cells reside
in the bone marrow. Theoretically, these bone marrow stem cells can
be isolated and grown into hepatocytes and bile duct cells in the
laboratory. Some animal studies have also shown that expression of
the enzyme telomerase in liver cells enhance their ability to
regenerate. Although considerable challenges remain to be overcome,
this early stage research provides promise that liver
transplantation may someday be a thing of the past.
Pharacogenomics
Some drugs work in some patients but not in others. Similarly, some
drugs have side effects in some patients while others tolerate them
well. For example, less than half of patients with chronic hepatitis
C have a "sustained response" to treatment with interferon-alpha and
many experience intolerable side effects. Most of this is a result
of different individuals' different genetic make-ups.
Pharmacogenomics is the science of understanding the correlation
between an individual patient's genetic make-up and response to a
drug. The discipline is evolving rapidly as a result of the
extensive work recently completed on sequencing the entire human
genome. Phamacogenomics aims to identify genetic markers that
predict response to a drug. The genetic markers commonly assessed
are known a single nucleotide polymorphisms (SNPs) and haplotypes.
SNPs are changes at a single base of DNA between individuals.
Haplotypes are linear arrays of slightly different forms of
particular genes on a chromosome. By studying populations of
patients and their responses to a drug, inheritance of a collection
of SNPs or different haplotypes can be correlated with successful
treatment, unsuccessful treatment or development of side effects.
This knowledge can them be used to "customize" drug therapy for a
particular patient based on first examining their DNA.
New HCV Drug in Phase I
Idun Pharmaceuticals' Clinical Trial Demonstrates Safety Of
Liver Disease Drug
- Phase I Trial Demonstrates Safety and Opens the Door To
Treat Multiple Liver Diseases -

SAN DIEGO, Jan. 31 /PRNewswire/ --
Idun Pharmaceuticals, Inc. today announced the results of its
Phase 1 clinical trial of IDN-6556. The drug was safe and well
tolerated in a clinical study involving 50 normal adults.
Evaluation of patients with mild hepatic impairment is
ongoing. In the Phase 1 study, IDN-6556 was administered in
both single doses and for a week of therapy with various
doses. The drug was well tolerated in all groups of subjects.

"We are excited to have completed this Phase 1 stage of the
drug's development," said Dr. David Shapiro, Chief Medical
Officer and Executive Vice President at Idun. "This drug may
prove to be useful in multiple liver diseases and we will
shortly start Phase 2 studies to evaluate its effects on
different groups of hepatic patients. We will conduct Phase 2
trials of individuals with hepatitis C virus (HCV) infections,
alcoholic liver disease and, subsequently, additional trials
of individuals experiencing acute alcoholic hepatitis. HCV
affects about 4 million Americans and another 200 million
people worldwide. Acute alcoholic hepatitis is an often-lethal
condition that affects about 85,000 people in the U.S. alone
and for which there is no effective treatment. We believe that
IDN-6556 can play an important role in the standard care for
people with HCV, acute alcoholic hepatitis, and many other
liver diseases."

"There are literally more than a half-billion people in the
world suffering with liver diseases that may benefit from this
drug," added Dr. Steve Mento, Idun's President and CEO. "The
success of the Phase 1 trial of our caspase inhibitor is the
first clinical step to a new and important therapy for
patients with liver disease. It also validates Idun's approach
to small molecule drug development and the role that apoptosis
modulators can play in the treatment of a number of diseases.
We've always believed that caspase inhibitors would be
effective drugs for a number of diseases. IDN-6556 is the
first broad-spectrum caspase inhibitor to be studied in
humans.

"This is just the beginning of many exciting new opportunities
that can come from Idun's technology. We have programs in
earlier stages of development in cardiovascular disease,
inflammation, central nervous system diseases, and cancer with
just as much potential."

Idun Pharmaceuticals, Inc. is a biopharmaceutical company
located in San Diego, CA, creating innovative human
therapeutics with a primary focus on controlling apoptosis, or
programmed cell death. Apoptosis is a genetically controlled
normal physiological process mediated by a cascade of
intra-cellular proteins. Too much, inappropriate, or too
little apoptosis is believed to play a role in many important
human diseases. Idun believes that controlling the cell death
process will have utility in treating cancer,
neurodegenerative diseases, ischemic disorders and
cardiovascular disease. The company has adopted a
commercialization strategy encompassing strategic
collaborations with major pharmaceutical companies; internal,
independent development of selected small molecule
therapeutics; and out-licensing of diagnostics, gene
therapies, and bioproduction technologies. Idun has an
extensive patent portfolio covering the fundamental and core
technologies involved in the regulation of cell death and has
established partnerships with Abbott Laboratories in cancer,
with Elan Corporation, plc in stroke, and Becton Dickinson and
Company in research reagents.

Some of the statements in this press release are
forward-looking statements and do not guarantee future
performance and involve risks and uncertainties. Actual
results may differ substantially from the results that the
forward-looking statements suggest for various reasons. These
forward- looking statements are made only as of the date of
this press release.

SOURCE Idun Pharmaceuticals, Inc.

Rivarin-High Dose Interferon Combination Improves Responses
In Hepatitis C
A DGReview of :"A randomized trial of high-dose interferon
alpha-2b, with or without ribavirin, in chronic hepatitis C
patients who have not responded to standard dose interferon"
Alimentary Pharmacology & Therapeutics

03/18/2002
By David Loshak


Patients with hepatitis C who do not respond to standard doses
of conventional interferon might benefit from higher doses
plus ribavirin.

This combination was well tolerated among patients in a pilot
study reported by specialists at the University of Texas
Southwestern Medical Center, Dallas, Texas, United States.
They pointed out that conventional interferon monotherapy
fails to achieve virological clearance in most patients
infected by hepatitis C.

However, the specialists conjectured, high-dose induction
regimens might improve the initial clearance of virus. Also
ribavirin might improve sustained response rates once
clearance was achieved.

The specialists recruited 25 chronic hepatitis C patients who
had not responded to standard dose interferon monotherapy. The
study compared the efficacy and safety of re-treatment with an
induction regimen of high-dose interferon alpha-2b either
alone or with ribavirin.

Previous virological non-responders to standard dose
interferon (3-5 MU three times weekly for 12 weeks) were
randomised to receive one of two open-label regimens for 36
weeks.

Ten patients (Group A) received interferon alpha-2b 10 MU
daily for 10 days followed by 5 MU daily for 74 days and then
5 MU three times weekly for 24 weeks. A further 15 patients
(Group B) received the same regimen plus ribavirin 1000-1200
mg/day at day 11. All 25 patients were followed up for 24
weeks.

At the end of treatment, virological response was noted in one
group A patient and in eight Group B patients. The sole
responder in group A and three in group B relapsed on
follow-up.

The apparent difference between the groups, with a 33 percent
sustained response rate in Group B compared with none in Group
A, nearly reached statistical significance.

Alimentary Pharmacology & Therapeutics 2002; 16(3):381-388. "A
randomized trial of high-dose interferon alpha-2b, with or
without ribavirin, in chronic hepatitis C patients who have
not responded to standard dose interferon"

Sweden Approves Expanded Use of Naturally-Derived Alpha Interferon
PLANTATION, FL -- January 17, 2002 -- Viragen, Inc. and Viragen
International, Inc. today announced the approval of its application
to Swedish regulatory authorities to expand the use of Viragen's
natural alpha interferon.
This broadened approval extends use of the drug to include the
treatment of patients afflicted with any and all diseases in which
patients were or became resistant to treatments using recombinant
(synthetic) interferon. The most common maladies treated with
interferons include hepatitis C, multiple sclerosis and certain
cancers.
Viragen's natural alpha interferon had previously been approved in
Sweden and certain other countries for the treatment of patients
with hairy cell leukemia (HCL) and chronic myelogenous leukemia
(CML) who did not respond to recombinant interferon regimens. Global
interferon sales are estimated to exceed $2 billion per year.
Viragen's newly appointed chief medical officer, Professor Orjan
Strannegard, MD, stated, "Recombinant interferon products are the
dominant treatment for a broad range of chronic viral and malignant
diseases. However, a significant percentage of patients cannot
tolerate the adverse side-effects typically associated with
recombinant regimens or fail the therapy, probably due to the
formation of neutralizing antibodies. For those patients that do
fail, there are few safe and effective alternatives. Our expanded
Swedish approval provides further evidence that it may be
advantageous for a patient to be treated with Viragen's
naturally-derived interferon. This drug has been demonstrated to
have excellent effects in various viral diseases and cancers. It is
well tolerated by the treated patients and it is able to elicit a
renewed response in patients that have been resistant to recombinant
interferons."
Natural interferon, produced by white blood cells, is part of the
human immune system. It is one of the body's natural defensive
responses to foreign substances such as viruses, and is so named
because it "interferes" with viral growth. Recombinant interferons,
which currently dominate the interferon market, are genetically
engineered and are sometimes recognized as "foreign" by the body's
immune system. Recombinant interferons usually contain only one
subtype of interferon as compared to multiple subtypes produced by
human white blood cells.
SOURCE Viragen, Inc

Hepatitis C Treatments in Current Clinical Development
Brian D. Klein, MA, LMSW
Hepatitis C Action & Advocacy Coalition
March 20, 2002
There are many potential targets being pursued for drugs to treat
HCV. A number of compounds for these targets are in early
“test-tube” development or pre-clinical “animal” development phases.
Most of these compounds, however, will never make it to trials in
humans (clinical studies). Some drugs that do make it to clinical
trials are withdrawn from further study for safety or other reasons.
Therefore, every effort has been made to focus this list only on
treatments that are known to be in current active clinical
development.
When a company is ready to proceed to clinical trials, it files an
Investigational New Drug Application (IND) with the Food and Drug
Administration (FDA). Most clinical trials are designated as phases
I, II, or III, and sometimes IV based on the type of questions that
the study is seeking to answer.
Study Phases
In Phase I clinical trials, researchers test a new drug or
treatment in a small group of people (20-80) for the first time to
evaluate its safety, determine a safe dosage range, and identify
side effects.
In Phase II clinical trials, the study drug or treatment is given
to a larger group of people (100-300) to see if it is effective and
to further evaluate its safety.
In Phase III studies, the study drug or treatment is given to
large groups of people (1,000-3,000) to confirm its effectiveness,
monitor side effects, compare it to commonly used treatments, and
collect information that will allow the drug or treatment to be used
safely.
In Phase IV studies, the drug is already on the market for a
particular indication, but is now being tested for a different
indication, use, or disease.

The following table will be updated as clinical developments move
forward:
Table of Hepatitis C Drugs in Current Clinical Development
Drug CategoryDrug NamePharmaceutical CompanyClinical
PhaseComments
Long acting interferonPEGASYS
pegylated interferon alfa –2aRochePhase IIIUsed alone or in
combination with ribavirin. FDA approval is expected Fall,
2002
Interferon, Long acting interferonINFERGEN
interferon alfacon-1InterMunePhase IVProduct acquired from
Amgen, now re-launched and in post-marketing trial for combo
use with ribavirin. Company expects to make a pegylated
version later.
Interferon, Long acting interferonOMNIFERON
natural interferonViragenPhase IICompany is making long-acting
pegylated version of product as well in cooperation with
Valantis.
Longer acting interferonALBUFERONHuman Genome SciencesPhase
IFusion of the genes for human interferon and albumin
InterferonREBIF
interferon beta-1aAres-SeronoPhase II
InterferonOmega InterferonBioMedicinePhase IINew formulation
intended to target the liver specifically to avoid side
effects in other tissues
Oral InterferonOral Interferon alphaAmarillo BiosciencesPhase
ITesting low dose oral administration of alpha interferon
absorbed through mucosal membranes.
Anti-fibrotic Interferon gamma- 1bInterMunePhase IIMay reverse
fibrosis
Anti-fibroticInterleukin-10Schering-PloughPhase IITo slow and
prevent fibrosis
Anti-fibroticIP-501InterneuronPhase IIIAnti-fibrotic agent to
treat/prevent cirrhosis. Seems to stimulate collagenase to
breakdown collagen a component of scar tissue
IMPDH inhibitor
(inosine monophosphate dehydrogenase)Merimebodib
VX-497VertexPhase IIAnti-viral and anti-inflamatory effects
similar to ribavirin
Broad Antiviral AgentAMANTADINE
SymmetrelEndo Labs
SolvayPhase IVAnti-flu agent on the market, has shown mixed
results of efficacy in combo with interferons
RNA inhibitor using RibozymesHEPTAZYMERPIPhase IICleaves HCV
RNA at a point to interrupt life cycle of virus. Phase III
expected to start in 2003. Drug to be used in combo with
interferon.
Polyclonal AntibodyCIVACIRNABIPhase IIUnder investigation for
Post--transplant prevention of HCV
VaccineHCV/MF59ChironPhase II
Therapeutic vaccine InnogeneticsPhase IIPhase III expected
2003-2005
Nucleoside AnalogueLEVOVIRINICNPhase IDifferent structural
version of ribavirin. Projected approval is 2005
Nucleoside AnalogueVIRAMIDINEICNPhase IPro-drug that results
in a version of ribavirin that specifically targets the liver
cells. Projected approval in 2006
ImmunomodulatorZADAXIN
thymosin alfa-1SciClonePhase IIIBoosts the immune system. Use
in combo with interferons
ImmunomodulatorCEPLENE
histamine dihydrochlorideMaximPhase IIMay boost efficacy of
interferons in combination use
Protease InhibitorVX 950 /
LY 570310Vertex / Eli LillyPhase IPhase I expected to start
2003
Antisense
ISIS 14803Isis / ElanPhase IIGenetically inhibits translation
(production) of disease- causing proteins
Polymerase InhibitorJTK 003AKROS PharmaPhase IInhibits HCV
genotype 1 polymerase