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Update on New Therapies
Alan Franciscus, Editor-in-Chief
March was a disappointing month for results from two new drugs in
clinical development to treat hepatitis C – Albuferon, and
Viramidine. Problems from side effects of another new therapy,
valopicitabine (NM 283) have prompted the company to revise the
clinical trial to allow a lower dose of the medication. However, all
three drugs are still considered strong potential treatment
candidates – but they will all require more studies at different
doses to establish safety and effectiveness.
Albuferon
Albuferon is a form of time-released interferon that is produced by
fusing human serum albumin to interferon. Preliminary results found
that Albuferon was safe and well-tolerated and had the potential to
treat hepatitis C in doses administered (by injection) every four
weeks instead of the once a week injection of pegylated interferon.
Unfortunately, preliminary results from a phase IIb study comparing
Albuferon plus ribavirin vs. pegylated interferon (Pegasys) plus
ribavirin found that one dose every 4 weeks of Albuferon plus daily
ribavirin produced lower treatment response rates than the once
weekly dosing of pegylated interferon (Pegasys) plus daily ribavirin.
However, there was a slightly higher treatment response in the group
that injected Albuferon every 2 weeks. Another disappointing result
was the higher drop-out rates in the high dose Albuferon group –
7.6% vs. 2.6% in the Pegasys group. However, the company is still
optimistic and will move forward with larger trials. The full
interim results will be presented at the upcoming European
Association for the Study of Liver Disease (EASL) 2006 Conference.
If two week dosing is effective it begs the
question – will one once every two weeks instead of once weekly be
enough to compete with the two well-established drugs (Pegasys and
Peg-Intron)?
Viramidine
Results from the Phase 3 VISER 1 trial of Viramidine (prodrug of
ribavirin) versus ribavirin (both in combination with Peg-Intron) in
treatment naïve patients (never received treatment) found that the
safety profile (hemolytic anemia) of Viramidine was superior to
ribavirin. The other study endpoint of effectiveness of Viramidine
vs. ribavirin didn’t fair as well.
In this study 970 patients (worldwide) were
treated with Peg-Intron plus a fixed dose of Viramidine (600 mg) vs.
a Peg-Intron plus weight based dose of ribavirin (1000/1200 mg).
Treatment duration was 48 weeks for participants with non-genotype 2
and 3 and 24 weeks for genotype 2 and 3 patients. Post treatment
follow-up was 24 weeks.
Results
Anemia: It was found that the anemia rates (hemoglobin less
than 10 g/dL) were statistically lower in patients treated with
Viramidine than in patients treated with ribavirin (5% vs. 24%,
p<0.0001).
Sustained Virological Response: In the
intent to treat (ITT) analysis of 637 patients treated with Peg-Intron
plus Viramidine vs. Peg-Intron plus ribavirin the SVR was 38% vs.
52% for the ribavirin group. When the data was broken down per
protocol the SVR rates were 51% (Viramidine) vs. 56% (ribavirin) in
North America and Europe. In these regions Viramidine met the
non-inferiority criteria. The company is questioning the data from
other areas which they think may have negatively affected the total
trial results. In addition, Valeant believes that if Viramidine was
weight dosed (like ribavirin in this trial) that Viramidine would
have produced similar SVR rates to ribavirin. The complete data set
(genotype, age, ethnicity and viral load) will be presented at the
EASL 2006 Conference in late April.
Another phase III study of Viramidine – VISER 2
is comparing Pegasys plus Viramidine to Pegasys plus ribavirin and
is currently underway. Preliminary data from this trial is expected
towards the middle of 2006. It will be interesting to see if the FDA
will approve Viramidine for marketing based on the superior safety
profile or if the FDA will require further testing of Viramidine in
higher doses or dosed by body weight. Valeant hopes to launch
Viramidine by the end of 2007.
Valopicitabine
Valopicitabine is currently in two different phase III studies for
treating hepatitis C. Due to gastrointestinal-related adverse events
in the treatment naïve trial of the 800 mg dose of valopicitabine
plus Pegasys about 16% of patients discontinued treatment and
3patients developed serious adverse events. This represents 2% of
the valopicitabine-treated patients. In the second trial of
valopicitabine (used as a monotherapy and in combination with
Pegasys) for previously treated patients, 5% of valopicitabine
treated patients discontinued treatment due to gastrointestinal side
effects, and six serious adverse events were reported (4% of
valopicitabine treated patients). Due to the incidence of
gastrointestinal adverse events Indenix and the FDA have amended the
original clinical trial design to reduce the dosage of
valopicitabine to either 200 or 400 mg depending on the study group.
According to a company spokesperson, “While these modifications will
delay the valopicitabine development program, the primary purpose of
phase II studies is to identify the optimal dosing regimen with
respect to efficacy and safety. Meaningful data from these ongoing
trials, along with data from the planned ribavirin interaction study
and potential additional dose-ranging data, which is expected to be
available over the next six months, will provide us with necessary
safety and efficacy data to further define the phase III development
plan for valopicitabine.”
Bringing a new drug to market is a long and
expensive process. The reason for clinical trials is to provide
information about a drug’s safety and effectiveness. It is not
uncommon to find that doses have to be adjusted as more information
about the effectiveness and side effects of the drugs come to light.
The data from the three drugs above does not necessarily mean that
the new drugs will not be viable treatments for hepatitis C in the
future, but we will not know how effective the drugs are until data
from phase III trials is completed and submitted to the Food and
Drug Administration. Even then we may have to wait for a good period
of follow-up time to find out if the SVRs achieved are durable over
time.
http://www.hcvadvocate.org/news/newsLetter/2006/advocate0506.html#1
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Psychological and Social Aspects of
Hepatitis C Treatment
Liz Highleyman
Most studies of hepatitis C reported in the medical
literature concern various aspects of natural history, disease
progression, and treatment. But psychological and social factors can
also have a profound effect on people with hepatitis C. A few recent
journal articles have explored these issues.
Problems are Common During Treatment
A majority of patients with hepatitis C experience some type of
difficulty – physical, mental, or social – when using
interferon-based therapy. As reported in the April 2006 European
Journal of Gastroenterology and Hepatology, a team led by Susan
Zickmund, MD, a researcher at the University of Pittsburgh and the
Veterans Affairs Medical Center, interviewed 65 HCV patients. As is
typical for the population of hepatitis C patients seeking
treatment, the average age was 46 and about 62% were men. In this
group, 80% described moderate to severe problems associated with
treatment. Most were physical problems – 74% reported fatigue and
32% had flu-like symptoms – but more than one-third (38%)
experienced depression.
In addition, about one-third said they had to
quit their jobs or cut back on employment due to side effects.
One-fifth said side effects contributed to deteriorating
relationships with friends and family, and 22% said lifestyle
adjustments related to treatment (such as not drinking alcohol or
the need to rest more often) caused “friction” with friends. “To
encourage appropriate levels of adherence,” the researchers
concluded, “healthcare providers should seek information about these
indirect treatment effects as they monitor their patients on
therapy.”
In the March 2006 Journal of Hepatology,
Amy Dan of Inova Fairfax Hospital in Virginia and colleagues looked
at depression, anemia, and health-related quality of life (HRQOL) in
271 people with chronic HCV receiving pegylated interferon (Peg-Intron)
plus ribavirin. Similar to Zickmund’s study, the average age was 47
and 69% were men; nearly three-quarters were white. The researchers
found, as expected, that anemia and depression both led to decreased
HRQOL. Symptoms of depression tended to increase over the first half
of the course of treatment. Patients with cirrhosis, obese patients,
and women reported more quality-of-life impairment; however, age,
race/ethnicity, ALT levels, and HCV viral load levels where not
associated with differences in HRQOL. While HRQOL declined during
treatment, it typically returned to – or exceeded – the
pre-treatment level within 24 weeks after completion of therapy.
Serious Psychiatric Illness
While any patient taking interferon can experience reduced quality
of life, the risk is higher in certain groups including substance
users and people with pre-existing mental illness. Due to the
adverse mental side effects – especially depression – associated
with interferon, experts have traditionally recommended that
patients with serious pre-existing psychiatric illness should not be
treated, and these patients have been excluded from most clinical
trials of anti-HCV medications. However, just as studies have shown
that injection drug users can achieve good adherence and treatment
response rates (see “Treating Hepatitis C in Injection Drug Users”
in the
May 2005 HCV Advocate),
researchers are also finding that hepatitis C treatment can be
successful in people with pre-existing mental conditions.
In the April 2006 issue of Psychosomatics,
Lisa Mistler, MD, from Dartmouth College and associates presented a
comprehensive literature review of hepatitis C treatment in people
with severe mental illness and depression. While most studies
suggest that mild to moderate depression symptoms occur in 20%-40%
of patients treated with interferon, less than 10% develop severe
interferon-induced major depressive disorder. Studies to date offer
conflicting evidence as to whether interferon-induced depression is
more common in people with a history of psychiatric illness. While
changes in energy level (fatigue) typically occur within days of
starting treatment, changes in mood and cognition “tend to occur
weeks or months” after treatment begins.
Several studies have shown that antidepressant
medications are effective in preventing or relieving depression
during interferon therapy, both for those with and those without a
history of pre-existing mental illness. For example, in the June
2005 Journal of Hepatology, Martin Schaefer and colleagues
reported that patients with pre-existing psychiatric conditions who
started a selective serotonin reuptake inhibitor (SSRI)
antidepressant (citalopram or Celexa) before HCV treatment were
significantly less likely to develop major depression during the
first six months of interferon therapy, compared with those who did
not receive the antidepressant (14% vs 64%, respectively).
A smaller number of patients (2%-16% in various
studies) report new or worsening anxiety during treatment with
interferon. Studies suggest that most such patients can complete
treatment. Mistler and colleagues concluded that interferon-induced
anxiety “appears to be mild and uncommon.” Other psychiatric
conditions (including mania or psychosis) are rare among patients
taking interferon, and there is little data about whether problems
during HCV treatment are more common or more severe among patients
with pre-existing conditions. But it is clear that these conditions
usually abate when interferon is discontinued.
People with severe mental illness “can be
safely and effectively treated for hepatitis C virus,” the authors
concluded, and thus should be offered interferon-based therapy if
indicated based on degree of liver disease progression.
“[N]europsychiatric side effects are, in some cases, preventable,
and, in most cases, treatable,” they continued. “Severe
neuropsychiatric side effects due to [interferon] are uncommon and
reversible.”
Good Management is the Key
When conventional interferon monotherapy offered only about a 10%
chance of a cure for hepatitis C, many patients and healthcare
providers felt the reduction in quality of life related to treatment
was not worth the risk. But with today’s improved therapies, the
risk/benefit balance has shifted. Sustained response rates can reach
as high as 70%-80% for patients with HCV genotypes 2 or 3, and
50-60% for those with genotype 1. As such, it’s more important than
ever to find ways to help patients start and stick to treatment –
and there’s less justification for automatically excluding any
groups from therapy (although treatment may not be appropriate for
certain individuals within these groups).
In their overview, Mistler and colleagues
concluded that hepatitis C patients with severe mental illness could
achieve “good treatment adherence, low drop-out rates, and good
side-effect tolerability” provided they are offered “assertive
psychiatric management, close monitoring, and adjustment of
psychiatric medication to address the psychiatric side effects.” But
patients with no history of mental conditions or only mild
psychiatric problems should also be monitored for depression, given
that some studies suggest interferon-induced depression is just as
common among people without such a history.
One of the ironies of hepatitis C is that
sometimes you have to feel worse in order to feel better. If
depression, fatigue, or other treatment side effects are interfering
with your job, relationships, ability to care for children, or other
aspects of your daily life, talk to your healthcare provider. In
many cases, adjunct therapies (such as antidepressants, or EPO for
anemia) may allow you to stay on treatment. Sometimes social support
from family and friends is the best medicine. Many HCV positive
people find that peer support groups can be a lifeline before,
during, and even after treatment. To find a support group in your
area, see the HCV Advocate web site’s
Community and Support section.
For practical tips on dealing with depression
and fatigue, see the Hepatitis C Support Project’s booklet
Coping with Depression and Hepatitis C
and
A Guide to Understanding and Managing
Fatigue.
http://www.hcvadvocate.org/news/newsLetter/2006/advocate0506.html#4
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HEPATITIS: THE SILENT PANDEMIC
Press
Contact: Lenore Neier
212-668-1000 x137
lneier@liverfoundation.org
More Than 500 Million
People Worldwide Are Infected by These Killer Viruses
New York, NY—The threat of avian flu may dominate the media, but its impact
on human lives is miniscule compared to the reality of hepatitis B and C,
the two most common forms of chronic liver disease. Together, they infect
nearly five million people in the United States and, according to a World
Health Organization estimate, more than 500 million people around the world.
Without global intervention, the U.S. Centers for Disease Control and
Prevention predicts that the impact of the disease will double over the next
ten years.
Yet these viruses, which are one of the top ten causes of death
nationwide, are often preventable. Although a vaccine is available for
hepatitis B, few people are immunized. Fewer still are aware that the
vaccine exists.
As for Hepatitis C—considered a “silent killer” because it often produces no
symptoms during its long incubation period—there is no vaccine, but
infection can be avoided through common-sense precautions such as using
sterile needles for tattoos or body piercing, not injecting drugs, and
practicing safer sex.
“It is imperative that patients speak with their doctor about getting tested
for hepatitis B and C and consider treatment options that will help preserve
liver health,” said James L. Boyer, MD, who is Chairman of the Board of
Directors of the American Liver Foundation, a nonprofit organization founded
30 years ago in order to promote liver health and disease prevention.
“Although many people shy away from it, testing can allow for early
diagnosis and treatment, preventing the virus from developing into cirrhosis
of the liver or cancer.”
“Too often,” Dr. Boyer explained, “people are ashamed to be tested because
of long ago drug habits or sexual activities. But shame is a terrible reason
for dying an unnecessary and painful death.”
Shame and ignorance go hand in hand, according to Frederick G. Thompson,
President and Chief Executive Officer of the American Liver Foundation. He
pointed to a recent survey conducted by the organization, which revealed
that half the U.S. population did not even know that hepatitis was a liver
disease.
In order to heighten understanding of the illness and its causes, volunteers
from the 25 local chapters will present special programs during the month of
May for the annual Hepatitis Awareness Month. A key weapon in this year’s
Hepatitis Awareness Month is a Liver Wellness Toolkit. The kit
consists of a professional slide presentation, complete with handouts and
instructions, for use by medical and nursing staff, volunteers and
healthcare educators. For more information about this presentation, call
1-800-GO-LIVER.
http://www.liverfoundation.org/db/pressrelease/66
Duration of Peginterferon Therapy in Acute Hepatitis C
Spontaneous resolution of acute hepatitis C virus infection cannot be
predicted, and chronic evolution of the disease occurs in a majority of
cases. To assess the efficacy and safety of
peginterferon alfa-2b (PegIntron) administered for 8, 12, or 24 weeks in
patients with acute hepatitis C virus infection, a total of 161 patients
were identified with acute hepatitis C virus infection.
Results
 Of these 161
patients, 30 refused treatment but were retained in the study as a
nonrandomized comparison group.
Of the 131
patients who consented to treatment, 29 patients spontaneously resolved,
leaving 102 patients randomly assigned to
peginterferon alfa-2b (1.5 microgram/kg) for 8 weeks (group A; n
= 34), 12 weeks (group B; n = 34), and 24 weeks (group C; n = 34).
The primary
end point was
sustained virologic response.
An
intent-to-treat analysis was used for efficacy and safety end points.
Sustained
virologic response was achieved in 23/34
(67.6%), 28/34 (82.4%), and 31/34 (91.2%) of patients in groups A, B,
and C, respectively.
All had
undetectable hepatitis C virus RNA 48 weeks after the end
of therapy.
Treatment
for 8 or 12 weeks was effective in
genotypes 2, 3, and
4, whereas
genotype 1 required 24 weeks of therapy.
The 8- and
12-week regimens were associated with fewer adverse events compared with
the 24-week regimen. |
In conclusion, the authors write, “Peginterferon
alfa-2b effectively induces high sustained virologic
response rates in patients with acute hepatitis C virus infection, thus
preventing development of chronic hepatitis C.”
“Duration of treatment should be further
optimized based on genotype and
rapid
virologic response at week 4.
05/09/06
Reference
S M
Kamal, K N Moustafa,
J Chen, and others.
Duration of peginterferon therapy in acute
hepatitis C: A randomized trial. Hepatology
43(5): 923-931. May 2006.
http://www.hivandhepatitis.com/hep_c/news/2006/050906_a.html |
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Factors That
Predict a Rapid Virological Response at Week 4 and a Sustained Virological
Response at Week 24
Approximately one third of hepatitis C virus (HCV) genotype 1 patients
achieved a sustained virological response (SVR) after 24 weeks of treatment
with peginterferon alfa-2a (Pegasys) plus ribavirin in a randomized,
multinational trial.
In the present study, researchers aimed to identify factors associated with
a rapid virological response (RVR) at week 4 (HCV
RNA <50 IU/mL) and a SVR (HCV RNA <50 IU/mL
at the end of follow-up) in these patients.
Stepwise multiple logistic regression analysis
was used to explore the prognostic factors for a RVR and SVR in genotype 1
patients treated for 24 weeks.
Results
Fifty-one of 216
(24%) genotype 1 patients in the 24-week treatment groups had a RVR.
SVR rates
were considerably higher in patients without a RVR (89% vs. 19%,
respectively) were more likely to achieve a
RVR than those with HCV RNA greater than 600,000 IU/mL.
HCV subtype (1b vs.
1a) was also independently associated with.
RVR and
baseline HCV RNA less than 200,000 IU/mL
were significant and independent predictors of SVR in patients treated
for 24 weeks. |
In conclusion, the authors write, “Patients infected with HCV genotype 1 and
treated with peginterferon alfa-2a plus
ribavirin sustained a RVR 24% of the time. This
portends an 89% probability of a SVR after 24 weeks of treatment.”
05/09/06
Reference
D M Jensen, T R Morgan, P
Marcellin
and others.
Early identification of HCV genotype 1 patients responding to 24 weeks
peginterferon alfa-2a
(40 kd)/ribavirin
therapy. Hepatology 43(5): 954-960.
NATAP
http://natap.org/
SUSTAINED VIROLOGIC
RESPONSE (SVR) TO INTERFERON-ALFA-2B+/- RIBAVIRIN THERAPY AT 6
MONTHS RELIABLY PREDICTS LONG-TERM CLEARANCE OF HCV AT 5-YEAR FOLLOW
UP
J.G. McHutchison, Division of Gastroenterology and DCRI, Duke
University, Durham, NC
The primary aim of this study was to determine long-term SVR and
clinical outcomes in patients treated with interferon-alfa-2b+/-ribavirin.
1071 patients treated with interferon-alfa-2b+/-ribavirin from six
clinical trials were followed up to five years with annual measures
of hematology, biochemistry, GI/liver examination and quantification
of HCV RNA by PCR with sensitivity of 100 copies/ml (National
Genetics Institute) and after 3/01 by Taqman (Schering-Plough:
sensitivity of 29IU/ml).
492 sustained responders (SR) and 579 non-responders (NR) entered
the trial and were followed for a mean of 283 and 131 weeks,
respectively, after the standard 24 week follow-up period. 61% of SR
(302) and 28% of NR (160) patients completed at least five years of
follow-up.
Only 5 patients in the SR group relapsed in the 5 year
follow-up. All relapsed within the first year and had
elevated ALT and >4 log increase in viral load. The Kaplan-Meier
estimate for continued sustained response over 5 years was 99+/-1%.
Progression of liver disease occurred in 2 patients in the SR and 5
in the NR group. 3 SR and 8 NR patients died during the follow-up
period. Only 2 deaths were related to liver disease progression (HCC).
Only 1 of 71 SAEs was 'possibly' related to interferon/ribavirin
therapy. 13 SR and 5 NR patients had a liver biopsy performed >5
years with hepatic HCV RNA testing in ten. Of this group, all 8 SR
patients were negative for hepatic HCV RNA while the two NR patients
were positive. Post-treatment values of hepatic activity (Knodell
I+II+III) increased in the 5 NR patients (mean 6.0 pre-Tx to 5.0
post-Tx to 7.8 FU) undergoing liver biopsy while the 12 SR
patients remaining HCV RNA negative showed little change.(8.8 to
3.0 to 2.7).
The authors concluded that this large study confirms that sustained
loss of serum HCV RNA 6 months following the completion of
interferon-alfa-2b +/-ribavirin treatment is an excellent predictor
of long-term clearance of the virus from the serum and may predict
clearance of hepatic infection and maintenance of histological
improvement. |
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Comparison of 48 vs 72 Weeks of Treatment with Peginterferon
Alfa-2a plus Ribavirin in Patients with HCV Genotype 1
In order to improve treatment
outcomes of
chronic hepatitis C (CHC)
among individuals with HCV genotype 1 it is necessary to employ
innovative strategies. One possible approach is to extend the period
of treatment of CHC beyond 48 weeks.
Researchers
at the University of Berlin conducted a comparative study of the
safety and efficacy of treatment with
peginterferon alfa-2a (Pegasys) 180
microgram/wk plus ribavirin (Copegus) 800 mg daily for 48
weeks (group A, 230 pts) vs 72 weeks (group B, 225 pts). All study
participants had HCV genotype 1 and all were treatment-naïve.
On-treatment
and sustained virologic response (SVR) 24 weeks after stopping
treatment was assessed by qualitative reverse-transcription
polymerase chain reaction assay (sensitivity 50 IU/mL).
Results
Overall, no significant differences were observed in the treatment
outcome between the two groups.
End-of-treatment and SVR rates in
groups A and B were 71% vs 63% and 53% vs 54%, respectively.
Patients with undetectable HCV-RNA levels at weeks 4 and 12 had
excellent SVR rates ranging from 76% to 84% regardless of
treatment group, whereas patients shown to be still HCV-RNA
positive at week 12 achieved significantly higher SVR rates when
treated for 72 instead of 48 weeks (29% vs 17%, P = .040).
A particular benefit from extended treatment duration was seen in
patients with low-level viremia (<6000 IU/mL) at week 12.
The frequency and intensity of
adverse events was similar
between the 2 groups.
Based on
these findings, the authors conclude, "Extended treatment duration
generally is not recommended in HCV type 1 infection and should be
reserved only for patients with slow virologic response defined as
HCV-RNA positive at week 12 but negative at week 24."
05/16/05
Reference
T Berg, M von Wagner, S Nasser, and others. Extended Treatment
Duration for Hepatitis C Virus Type 1: Comparing 48 Versus 72 Weeks
of Peginterferon-Alfa-2a Plus Ribavirin. Gastroenterology
130(4): 1086-1097. April 2006.
Suggested Reading
M von Wagner, M Huber M, T Berg, and others. Peginterferon-alpha-2a
(40KD) and ribavirin for 16 or 24 weeks in patients with genotype 2
or 3 chronic hepatitis C. Gastroenterology 129(2): 522-527.
August 2005.
P Ferenci P,
M W Fried, M L Shiffman, and others. Predicting sustained
virological responses in chronic hepatitis C patients treated with
peginterferon alfa-2a (40 KD)/ribavirin. Journal of Hepatology
43(3): 425-433. September 2005.
http://www.hivandhepatitis.com/hep_c/news/2006/051606_b.htm |
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