These forms can be picked up at any pharmacy.
Ontario Ministry of Health Trillium Drug Program
1-800-575-5386
(Treatment related financial assistance in
Ontario)
http://www.gov.on.ca/health/english/pub/drugs/trillium.html
C.A.R.E. is the reimbursement assistance number
for patients who were
prescribed Rebetron.
1-800-603-2754 10:00 a.m. to 6:00 p.m. EST
Monday to Friday.
The Canadian Advisory Reimbursement Exchange
P.O. Box 24512,
Brossard, Quebec, J4W 3J1
A
Dynamic Duo for Chronic HCV: Interferon and Ribavirin
By Roger Smith
May 8, 1998 --
Interferon alfa is the standard treatment for
chronic infection of hepatitis C virus (HCV), but it clears the virus, even
temporarily, from fewer than four American patients out of ten. Accordingly,
researchers are looking for a more effective remedy. Among the most promising
drugs that are available for testing is the antiviral agent ribavirin. Given
on its own, ribavirin has minimal power to eradicate chronic HCV, but taken
together, ribavirin and interferon alfa boost response rates significantly.
Preliminary drug trials have demonstrated that
the combination can cure patients who have relapsed after interferon monotherapy
and may even help some of those who did not respond at all. "Relapse
patients may have a cure rate of up to 60 percent," says Dr. Robert G.
Gish, Medical Director of the Liver Transplant Program at San Francisco's
California Pacific Medical Center. He adds that in the six-month clinical
trials conducted so far only about 10 percent of non-responders have been
cured; still, trials of 12-18 months are needed before doctors can be sure
how much the combined therapy improves upon interferon alone.
Interferon
The cells in the body naturally produce interferon,
a protein, when viruses infect them. Exactly how it works against HCV is not
yet known, but in some way it stops the virus from copying itself and spreading
-- the "interfere" of interferon. Scientists proposed that giving
the body extra interferon would stop even more viruses from replicating during
an infection. A great idea, and it works, but not nearly so well as researchers
hoped. The U.S. Federal Drug Administration (FDA) has approved three varieties
of genetically engineered interferon for HCV treatment: interferon alfa-2a,
interferon alfa-2b, and consensus interferon, a synthetic construct from several
interferon subtypes.
Patients are candidates for interferon therapy
when they meet three criteria. First, their blood tests positive for HCV antibodies,
and second, their blood serum contains markers of liver cell injury, alanine
aminotransferase (ALT), an enzyme produced by the liver. It is normal for
there to be some ALT in the bloodstream, but when liver cells are injured,
the ALT in them spills out and the concentration in the blood climbs. So a
level of ALT above the upper limit of normal indicates liver inflammation
and possible damage. Third, a liver biopsy shows chronic inflammation with,
in many cases, scarring of the liver.
Doctors measure the response to the therapy
by monitoring the patient's ALT levels and by a polymerase chain reaction
(PCR) assay, which detects HCV ribonucleic acid (RNA) particles in the blood.
After six months of therapy 40-50 percent of patients have normal ALT levels,
and 30-40 percent test negative for HCV RNA. But that is only the end-of-treatment
response (ETR). The key indicator of a cure is the sustained response (SR).
An SR means that patients have normal ALT levels and show no HCV RNA in the
blood for at least six months after their therapy ended.
Only 10-50 percent of patients have normal
ALT on interferon therapy and fewer still (15-20 percent) have normal ALT
six months after the end of treatment. Only 10-20 percent are still clear
of the virus off therapy. That means that about half of patients do not respond
to interferon alfa, and of those who do, about three out of five have a relapse.
The long-term response rates are so low partly because HCV comes in three
genetic types. Interferon is more effective against genotypes 2 and 3 than
against genotype 1. Unfortunately, 70-80 percent of patients in the United
States have genotype 1. Moreover, interferon alfa is most likely to help patients
younger than 45 years who have had chronic HCV for fewer than five years and
show little scarring of the liver, low levels of HCV RNA in the blood, and
low concentrations of iron in the liver. That leaves out a lot of patients,
particularly those with more advanced disease.
Sustained response rates have proven somewhat
better in clinical trials that administered interferon alfa for 12, 18, and
24 months: SRs of more than 25 percent. But the extended therapy also extends
the side effects, which can feel like the flu -- muscle aches, chills, nausea,
and diarrhea -- and cause weight loss and fatigue. Some patients lose hair,
have mood swings, and are depressed as well. Doctors can counteract most side
effects, but the additional drugs and the extended treatment drive up costs,
and the chance of a cure remains fairly low.
Ribavirin
and Combined Therapy
Cheaper than interferon, easier to use, and
proven as an antiviral agent, ribavirin initially looked like a possible replacement
therapy. It is a nucleoside analogue that appears to stimulate helper T cells
(a type of white blood cell) to combat viruses and may have some direct antiviral
effect, according to Dr. Gish. Ribavirin was first used to treat respiratory
infections, and beginning in 1994 it was tested on HCV patients for a year.
The results were disappointing. It temporarily lowered ALT levels but failed
to get rid of the virus.
Four pilot studies of combined interferon alfa-ribavirin
treatment had much more encouraging results.
In a New England Journal of Medicine review
article, Dr. Jay H. Hoofnagle and Dr. Adrian M. Di Bisceglie report that a
six-month course of combined therapy produces an SR of 40-77 percent, significantly
better than interferon (0-23 percent), ribavirin alone (0 percent) or no therapy
(6 percent). Two of the studies involved patients who had not responded to
interferon monotherapy or who had relapsed after treatment ceased; the two
other studies included patients who had no previous therapy ("treatment-naive"
in medical jargon). The improved response rate appears to come despite the
genotype of HCV, although the evidence is unclear for sub-genotype 1b. Why
the combination works better than either drug alone is unknown.
These findings inspired further studies, including
a large multinational trial comparing the combined therapy with interferon
alone. The course lasts up to 48 weeks. Patients receive the standard interferon
alfa dose, 3 million units injected three times each week, and 1,000 milligrams
of ribavirin daily, taken orally.
Dr. Sandra L. Wilborn, a gastroenterologist
at Health First Medical Group in Portland, Oregon, is recruiting patients
for the study. "It's a 'give people the drug and keep track of what happens'
kind of study," she says -- adding, "appropriately selected people."
That's the rub. Ribavirin is not for everyone.
It is known to cause hemolytic anemia, a condition in which red blood cells
burst. According to Dr. Gish, patients who already have anemia or ischemic
heart disease therefore should not take the drug. The study protocol also
warns that ribavirin can harm fetuses and infants, so pregnant women and nursing
mothers should not participate either.
Moreover, the combined therapy may slightly
increase the intensity of side effects associated with interferon. Nonetheless,
says Dr. Wilborn, "I hope that with the addition of ribavirin, we'll
see a greater percentage of patients having a sustained response without a
significant increase in side effects." It is the trial's primary goal
to see if that hope can be realized.
No one expects interferon alfa-ribavirin combined
therapy to be the magic bullet for chronic HCV. It improves existing therapy
while researchers look for new approaches. These include other antiviral drugs
or combinations, protease inhibitors that prevent the construction of viruses,
and even gene-replacement therapy to insert counterfeit RNA into the virus,
deactivating it. Few such ideas have reached the testing stage, or will in
the near future. According to Dr. Gregory T. Everson, Director of Hepatology
at the University of Colorado Health Sciences Center, the federal government
allots only about $7.5 million each year for HCV research, an expenditure
of only about $2 for every infected American. Much more basic clinical research
is needed.
Bibliography
Robert G. Gish, MD, Medical Director of the
Liver Transplant Program, California Pacific Medical Center, San Francisco,
CA.
Sandra L. Wilborn, M.D., gastroenterologist,
Health First Medical Group, Portland, OR.
Living with Hepatitis C: A Survivor's Guide,
Gregory T. Everson and Hedy Weinberg, Hatherleigh Press, 1998.
Hepatitis C: A Personal Guide to Good Health,
Beth Ann Petro Roybal, Ulysses Press, 1997.
Management of Hepatitis C, NIH Consensus Statement,
Vol. 15, No. 3, March 24-26, 1997.
"Ribavirin and Interferon Alfa in Chronic
Hepatitis C," American Family Physician, Vol. 55 (March 1997), p. 1369.
"The Treatment of Chronic Viral Hepatitis,"
Jay H. Hoofnagle and Adrian M. Di Bisceglie, The New England Journal of Medicine,
Vol. 336 (January 30, 1997), pp. 347-356.
"Therapy of Hepatitis C: Consensus Interferon
Trials," Emmet B. Keeffe and F. Blaine Hollinger, Hepatology, Vol. 26,
No. 3, Suppl. 1 (September 1997), pp. 101S-107S.
"Ribavirin as Therapy for Chronic Hepatitis
C," Adrian M. Di Bisceglie, et al., Annals of Internal Medicine, Vol.
123, No. 12 (December 15, 1995), pp. 897-902.
Source: Exclusive SHN Report
Copyright © 1998 by Sapient Health Network. All rights reserved.
Ribavirin
Treatment Alone or in Combination With Interferon
Olle Reichard, M.D., Ph.D., and Ola Weiland,
M.D., Ph.D.Background
Only a small fraction of chronic hepatitis
C virus (HCV) infected patients will achieve long-term benefit with viral
eradication from standard interferon treatment. (1-3) Furthermore, patients
with autoimmune disorders, thyroid dysfunctions, decompensated cirrhosis,
thrombocytopenia, and posttransplant patients, usually are withheld from
interferon therapy due to the risk of serious adverse reactions. Thus, the
need for alternative treatments for chronic HCV infection is evident. Presently,
ribavirin (l-beta-D-ribofuranosyl-lH-1,2,4-triazole-3-carboxamide), a guanosine
analogue with a broad spectrum of activity against several RNA and DNA viruses
including the flavivirus family, is the most extensively evaluated and promising
alternative. (4) Ribavirin is usually well tolerated and has the advantage
of oral administration. The exact mode of action is poorly understood. Possible
mechanisms include depletion of the intracellular triphosphate pools through
the direct inhibition of inosine monophosphate dehydrogenase, inhibition
of the S'-cap structure of viral mRNA, and inhibition of the viral dependent
RNA polymerases. Moreover, it has recently been proposed that ribavirin
does not act as an antiviral drug, but rather as an inhibitor of macrophage
pro-inflammatory cytokines and as an immune modulator preserving the Th
1 and reducing the Th2 cytokine production. (5) Unfortunately, it is not
possible to test drugs including ribavirin for antiviral effect against
HCV in vitro, since no tissue culture system is readily available for HCV
replication.
Ribavirin
Monotherapy Studies
Ribavirin as therapy for chronic HCV infection
was first suggested 1991 in a pilot study from Sweden. (6) Ten HCV patients
were treated with oral ribavirin at a dose of 1000-1200 mg/day for 12 weeks.
A significant reduction of mean serum transaminase levels during treatment,
with a subsequent relapse when treatment was withdrawn, was seen. The effect
on HCV replication, as measured by polymerase chain reaction (PCR) in serum,
was disappointing. No patient cleared viremia during treatment in spite
of normalization of transaminases. (7) Several uncontrolled studies later
confirmed these initial results. (8,9)
Recently, two randomized, double-blind, placebo-controlled
ribavirin trials were reported.l? ll The results were consistent with previous
uncontrolled studies. Thus, a biochemical response with reduction of transaminase
levels during treatment was seen in ribavirin treated patients, whereas
no virological eradication was achieved (Table 1). However, a slight but
significant decline of serum HCV RNA levels during treatment as measured
by branched DNA assay was seen in the ribavirin group.ll
After treatment, rebound to pretreatment
levels was noted. The necro-inflammatory activity, particularly periportal
and intralobular inflammation, was significantly reduced for patients treated
with ribavirin when liver biopsies from before and at the end of treatment
were compared. The predominant adverse events noted were hemolysis (necessitating
a dose reduction in 13 percent of patients), nervous system disorders (fatigue,
depression, insomnia, and vertigo), gastrointestinal disorders (anorexia
and nausea), and skin disorders (pruritus, rash, and eczema).
TABLE 1 Treatment Results of Two Randomized
Placebo-Controlled Ribavirin Studies in Patients with Chronic Hepatitis
C
See URL:
http://gi.ucsf.edu/alf/CC/CCReichard.html
Interferon/Ribavirin
Combination Studies
In order to improve response rates
and to minimize drug resistance, combination therapy is of value in many
infectious diseases. The combination of interferon and ribavirin as therapy
for chronic HCV infection thus seemed reasonable. Pilot studies have shown
that approximately 80 percent of relapsers and 10-25 percent of nonresponders
to previous interferon therapy will have a sustained virological and biochemical
response when ribavirin is combined with interferon during a 24-week treatment
course. (12-14) In an Italian study, 45 interferon-naive chronic HCV patients
were randomized in three groups (1:1:1) to receive either alpha interferon
alone, ribavirin alone, or alpha interferon in combination with ribavirin.
Standard doses of interferon (3 million units [MU] thrice weekly) and ribavirin
(1,000-1,200 mg/day) were used. The sustained virological response rate
was *****0 percent in the ribavirin group, 13 percent in the interferon
group, and 47 percent in the combination group. (15) Similar results were
obtained in an open study from Sweden where 7/14 (50 percent) of interferon-naive
patients had a sustained response to combination treatment. (16) Furthermore,
a recent long-term followup study from Taiwan reported sustained virological
response 2 years after stopping treatment in 9/21 (43 percent) of patients
treated with interferon/ribavirin vs. only 1/19 (6 percent) of patients
treated with interferon alone (p=0.017). (17) A randomized double-blind
placebo-controlled study comprising 100 interferon-naive chronic HCV patients
has been performed by our group in Sweden. (18) All patients were treated
with interferon alfa-2b 3 MU thrice weekly, in combination with either ribavirin
1,000-2,000 mg/day (n=50) or placebo (n=50) for 24 weeks. The followup period
after treatment was 24 weeks. The study groups were comparable with regard
to age, gender, mode of transmission, liver histology, pretreatment ALT
level, pretreatment HCV RNA level, and genotype. Preliminary results confirmed
those of previous pilot studies. Thus the sustained virological response
rate was 45 percent in the combination group vs. 23 percent in the interferon
group (p<0.05). In the combination group, significantly more patients
either required reduction in dose or withdrew from treatment due to adverse
events, primarily anemia, fatigue, and depression. Moreover, in order to
prevent recurrent HCV in the posttransplant setting, ribavirin alone or
in combination with alpha interferon seems to offer promising results. (19,20)
Discussion
Ribavirin alone is apparently not the answer
to antiviral therapy for chronic HCV infection, since it does not achieve
eradication of the viremia. Nevertheless, ALT levels frequently normalize,
and more importantly, histological activity improves during therapy. Ribavirin
is also generally well tolerated, with a mild, dose-dependent, and reversible
hemolysis being the predominant adverse reaction. For nonresponders to interferon
therapy, and for patients where interferon cannot be used, maintenance therapy
with ribavirin could be an option. However, the long-term consequences of
continuous hemolysis have not been fully elucidated. Hemolyzed red blood
cells release iron, and significantly increased hepatic iron stores have
been noted after prolonged ribavirin therapy. (21)
Combination treatment with interferon and
ribavirin for 24 weeks is clearly associated with higher sustained response
rates than interferon alone. However, many questions remain to be solved.
Should all HCV patients receive combination treatment as a first choice,
regardless of genotype, pretreatment viral load, liver histology, or other
factors shown to be predictive of sustained response to interferon monotherapy?
What are the optimal dose and duration of combination therapy? Should relapsers
of 24 weeks of combination therapy receive prolonged combination treatment
courses? Do patients tolerate prolonged combination therapy? What is the
optimal treatment for nonresponders to combination therapy? Should patients
with unfavorable prognostic pretreatment factors like cirrhosis, genotype
1b, and/or high pretreatment viral loads receive more aggressive and prolonged
combination treatment courses? Is the risk for drug resistance diminished
by combination treatment?
Ongoing international, randomized, multicenter,
placebo-controlled studies comparing 24- and 48week treatment with interferon
alone vs. combination treatment, in naive, chronic HCV patients, will answer
some of these questions in the forthcoming years. Controlled combination
studies in relapsers after prior interferon treatment, and ribavirin dose-finding
studies, are also in progress.
References
1.Davis G, Balart L, Schiff E, et al. Treatment
of chronic hepatitis C with recombinant interferon alfa. A multicenter randomized
controlled trial. N Engl J Med 1989;321:1501 6. 2.Di Bisceglie A, Martin P,
Kassianides C, et al. Recombinant interferon alfa therapy for chronic hepatitis
C. A randomized, double-blind, placebo-controlled trial. N Engl J Med
1989;321:1506-10. 3.Tine F, Magrin S, Craxi A, Pagliaro L. Interferon for
non-A, non-B chronic hepatitis. A meta-analysis of randomized clinical
trials. J Hepatol 1991; 13 :192-9. 4.Patterson J, Fernandez-Larson R. Molecular
action of ribavirin. Rev Infect Dis 1990;12:1132 46. 5.Ning Q, Brown D, Parodo
J, et al. Ribavirin inhibits viral induced macrophages production of tumor
necrosis factor, interleukin I and procoagulant activity and preserves Thl
cytokine production, but inhibits Th2 cytokine response. Hepatology 1996;24:355A.
6.Reichard 0, Andersson J, Schvarez R, Weiland 0. Ribavirin treatment for
chronic hepatitis C. Lancet 1991;337:1058-61. 7.Reichard 0, Yun Z-B, Sonnerborg
A, Weiland 0. Hepatitis C viral RNA titers in serum prior to, during, and
after oral treatment with ribavirin for chronic hepatitis C. J Med Virol 1993;41:99-102.
8.Di Bisceglie A, Shindo M, Fong T-L, et al. Pilot study of ribavirin therapy
for chronic hepatitis C. Hepatology 1992;16:649-54. 9.Camps J, Garcia
N, Rieza-Boj J, Civiera M, Prieto J. Ribavirin in the treatment of chronic
hepatitis C unresponsive to alfa interferon. J Hepatol 1993;19:408-12. 10.Di
Bisceglie A, Conjeevaram H, Fried M, et al. Ribavirin as therapy for chronic
hepatitis C: a randomized, double-blind, placebo-controlled trial. Ann Intern
Med 1995;123:897-903. 11.Dusheiko G, Main J, Thomas HR, et al. Ribavirin treatment
for patients with chronic hepatitis C: results of a placebo-controlled study.
J Hepatol 1996;25:591-8. 12.Brillianti S, Garson J, Foli M, et al. A pilot
study of combination therapy with ribavirin plus interferon alfa for
interferon alfa-resistant chronic hepatitis C. Gastroenterology 1994;107:812-7.
13.Kakumu S, Yoshioko K, Wakita T, Ishikawa T, Takayanagi M, Higashi Y. A
pilot study of ribavirin and interferon beta for the treatment of chronic
hepatitis C. Gastroenterology 1993; 105 :507-12. 14.Schvarez R, Ando Y, Sonnerborg
A, Weiland 0. Combination treatment with interferon alfa-2b and ribavirin
for chronic hepatitis C in patients who have failed to achieve sustained response
to interferon alone: Swedish experience. J Hepatol 1995;23(suppl 2):17-21.
15.Chemello L, Cavaletto L, Bernardinello E, Guido M, Pontisso P, Alberti
A. The effect of interferon alfa and ribavirin combination therapy in naive
patients with chronic hepatitis C. J Hepatol 1995;23(suppl 2):8-12. 16.Braconier
J, Paulsen 0, Engman K, Widell A. Combined alpha-interferon and ribavirin
treatment for chronic hepatitis C virus infection. Scand J Infect Dis 1995;27:325-9.
17.Lai M-Y, Kao J-H, Yang P-M, et al. Long-term efficacy of ribavirin plus
interferon alfa in the treatment of chronic hepatitis C. Gastroenterology
1996;111:1307-12. 18.Reichard 0, Norkrans G, Fryden A, et al. Alfa-interferon
and ribavirin versus alfa-interferon alone as therapy for chronic hepatitis
C: a randomized, double-blind, placebo-controlled study. Hepatology 1996;24:356A.
19.Gane E, Lo S, Portman B, Lau J, Naoumov N, Williams R. A randomized study
of the safety and efficacy of ribavirin vs. interferon monotherapy for recurrent
HCV infection in liver transplant recipients. Hepatology 1996;24:293A. 20.Bizzolon
T, Palazzo U, Chevallier M, Dicerf C, Trepo C. HCV recurrence after OLT: a
pilot study of ribavirin therapy following initial combination with IFN. Hepatology
1996;24:293A. 21.Di Bisceglie A, Bacon B, Kleiner D, Hoofnagle J. Increase
in hepatic iron stores following prolonged therapy with ribavirin in patients
with chronic hepatitis C. J Hepatol 1994;21:1109-12.
American Liver Foundation 1425 Pompton Avenue
Cedar Grove, NJ 07009 1-800-GO LIVER (465-4837)
The American Liver Foundation is a national
voluntary health organization dedicated to preventing, treating, and curing
hepatitis and other liver and gallbladder diseases through research and education.
September
15: Update III
This month we will focus on newer treatments
for hepatitis C. Several exciting new therapies are available, or soon to
be released, which are changing the way we treat hepatitis C.
Interferon-(2b (Intron-A) combined with Ribavirin
is now being offered, under an experimental protocol, to patients who have
either relapsed or failed to respond to a previous course of interferon. This
protocol is not for the faint of heart, however, as it includes a very aggressive
interferon induction dose schedule. For qualified patients, treatment is initiated
with 10mu Intron-Adaily for 2 weeks, then 5mu daily for 2 weeks, then 5mu
three times a week for 11 months combined with oral Ribavirin. It is our feeling
that an aggressive induction schedule of interferon offers the best hope of
eradicating hepatitis C for these troublesome cases.
Consensus interferon (Infergen) is soon to
be approved by the FDA.
What is Infergen?
Infergen is a synthetic formulation of interferon
which has a "consensus" structure of 11 naturally-occurring interferons.
In the laboratory, it appears more potent than either Intron-A or Roferon-A.
The results of a large, U.S. multicenter trial have now been published and
indicate that 9 micrograms of Infergen is equivalent to 3mu (15 micrograms)
of Intron-A. Some patients with genotype 1, and those with higher levels of
virus, may respond better to Infergen. In patients who have failed a prior
course of interferon, Infergen given in slightly higher dosages (15 micrograms)
has been shown to be an effective therapy. Over 50% of patients who have relapsed
after a previous course of treatment can expect to have a sustained clearance
of the virus from the blood.
Finally, studies are continuing with two new
interferon formulations called "PEG-interferon". By attaching polyethylene
glycol (PEG) molecules to the interferon structure, a form of interferon is
created which has a much longer lifespan in the bloodstream (up to 7 days
or more). This has the advantage of delivering a more constant level of interferon
to the hepatitis C virus with once a week injections (rather than 3 times
a week or daily). Preliminary results of these studies are very encouraging.
Previously untreated hepatitis C
patients are now being evaluated for these
experimental studies ( Laura Weeden, RN at 312-942-8910 or Audrey Silver,
RN at 8470674-2087 if interested).
We are hopeful that these new therapies will
offer new hope to many individuals afflicted with the hepatitis C virus. We
are now rapidly approaching the time when "cure" of this disease
is a real possibility.
Managing
Side Effects: Update II
Most of the side effects of interferon are
mild and manageable. Careful education of patients about possible side effects
and their management can be extremely helpful in minimizing concern and apprehension.
Flu-like symptoms occur within hours of the first few injection and typically
dissipate by 6-8 hours. Administering the injections in the evening, and premedication
with acetaminophen, may allow the patient to sleep through much of this annoyance.
Advising patients to allow for increased rest during the first few weeks and
to increase their daily fluid intake (at least two liters) is also helpful.
Monitoring
of blood counts during the first few weeks will allow prompt recognition of
potentially severe cytopenias. In general, a temporary 50% interferon dose
reduction is indicated if platelet counts drop below 50,000/mm3, hemoglobin
declines to 10 gms, or granulocytes decrease below 1000/mm3.
A prior history of depression should necessitate
psychiatric evaluation prior to initiating treatment. Mild depression occurring
during treatment usually responds to anti-depressant therapy. If in doubt,
however, psychiatric consultation is suggested as suicides have occurred in
patients on interferon.
A
TSH level is obtained prior to therapy with interferon and at 3-6 month intervals
while on treatment. This is a sensitive indicator of thyroid dysfunction,
and any TSH abnormalities uncovered should prompt further endocrinologic evaluation.
Other metabolic disorders may also occur during interferon treatment. These
include hyperlipidemia and diabetes mellitus.
Certain side effects should mandate at least
temporary discontinuation of treatment. These include severe depression, other
severe psychological side effects (psychosis, delirium, paranoia, coma), sepsis
or other severe infection, cardiac abnormalities (arrhythmias, congestive
heart failure), hyperthyroidism, severe peripheral cytopenias, seizures, renal
disease, and exacerbation of liver disease.
In summary, interferon side effects are generally
mild and easily managed. Nonetheless, adequate patient education and monitoring
is essential if more severe problems are to be avoided.
(1)
Fattovich G, Giustina G, Favarato S, Ruol A, et al: A survey of adverse events
in 11,241 patients with chronic viral hepatitis treated with alfa interferon.
J Hepatol 1996;24:38-47,
(2) Poynard T, Leroy V, Cohard M, Thevenot
T, Mathurin P, Opolon P, Zarski J: Meta-analysis of interferon randomized
trials in the treatment of viral hepatitis C: Effect of dose and duration.
Hepatology 1996;24:778-789.
Interferon
Plus Ribavirin for Chronic Hepatitis C.
Subject(s): HEPATITIS C virus – United States;
UNITED States. – Food & Drug Administration; CHRONIC diseases – Treatment
Source: Medical Letter on Drugs & Therapeutics, 06/04/99, Vol. 41 Issue
1054, p53, 2p
INTERFERON PLUS RIBAVIRIN FOR CHRONIC HEPATITIS
C
Rebetron (Schering), a combination of injected
recombinant interferon alfa-2b (Intron A) with oral ribavirin (Rebetol) has
been approved by the FDA for treatment of chronic hepatitis C virus (HCV)
infection. Chronic hepatitis C is the most common chronic liver disease in
the United States and is the cause of about one third of liver transplants.
DRUGS
FOR HEPATITIS C -- Interferon alfa,
which inhibits viral replication in virus-infected cells, has been the drug
of choice for treatment of chronic hepatitis C. It is available as recombinant
alfa-2b, alfa-2a (Roferon A - Roche), or interferon alfacon-1 (Infergen -Amgen).
All of these have been about equally effective against hepatitis C. Six months'
treatment with interferon alfa leads to normalization of serum aminotransferase
activity in 40% to 50% of patients with chronic hepatitis C and loss of serum
HCV RNA in 30% to 40%. Six months later, however, only 15% to 20% of patients
still have normal aminotransferase values and only 6% to 12% are still free
of HCV RNA. Treatment for 12 months leads to similar results, except that
six months after the end of treatment the percentage of patients with aminotransferase
normalization increases to 20% to 30% and the percent free of HCV RNA increases
to 13% to 19% (MMWR Morb Mortal Wkly Rep, 47 RR-19:1, 1998).
Ribavirin,
a nucleoside analog with broad-spectrum antiviral activity, was not previously
approved by the FDA for treatment of hepatitis C and was commercially available
only as an aerosol (Virazole) for treatment of respiratory syncytial virus
(RSV) infection in young children. As a single agent, oral ribavirin transiently
lowers serum aminotransferase activity into the normal range in about 40%
of patients with chronic hepatitis C, but does not affect the level of HCV
RNA.
CLINICAL
TRIALS -- Ribavirin given in combination
with interferon alfa-2b for 24 or 48 weeks resulted in sustained (for six
months after treatment) normalization of serum aminotransferase activity and
loss of detectable HCV RNA in 30% to 50% of previously untreated patients
(JG McHutchison et al, N Engl J Med, 339:1485, 1998; T Poynard et al, Lancet,
352:1426, 1998). The response to the combination depended, however, on the
viral genotype. After 48 weeks' treatment, 30% of patients with HCV genotype
1 infection (the most prevalent by far in the USA) and 70% of those with genotypes
2 and 3 had a sustained virologic response. A sustained response was more
likely if patients with genotype 1 were treated for one year rather than for
six months (28% versus 16% in one study); for patients with genotype 2 or
3, six months of treatment was about as effective as 12 months.
Patients who had relapsed after responding
to interferon monotherapy also responded to combination therapy; among 173
patients treated for 24 weeks, 81 (47%) had a sustained response with normal
aminotransferase activity and no detectable viral RNA (GL Davis et al, N Engl
J Med, 339:1493, 1998). The combination of interferon and ribavirin appears
to be less effective in patients who did not respond to previous interferon
monotherapy (G Barbaro et al, Am J Gastroenterol, 93:2445, 1998), but more
data are needed.
ADVERSE
EFFECTS -- More than 50% of patients
treated with interferon alone develop flu-like symptoms, including fever,
chills, headache, myalgia, nausea and diarrhea. These symptoms usually occur
early, respond to acetaminophen, and diminish with continued treatment. Within
the first months of treatment, granulocytes and platelets may decrease, but
usually increase when the dosage of interferon is lowered or the drug is stopped.
Later in treatment, fatigue, depression, alopecia, rash, retinal hemorrhages
and autoimmune thyroid disorders have occurred. Oral ribavirin often causes
hemolytic anemia. It isteratogenic and embryolethal in animals and mutagenicin
mammalian cells. Patients of either sex who could conceive children should
not do so during treatment and for six months afterwards.
The combination of the two drugs has generally
been well tolerated, but the number of adverse events has been higher than
with interferon alone. The most common reason for discontinuation has been
emotional disturbance, mainly depression. Hemolytic anemia usually responds
to reduction in the dosage of ribavirin. When the combination is continued
for 48 weeks, 20% or more of patients drop out of treatment.
DOSAGE
-- Interferon alfa-2b is given subcutaneously
in a dose of 3 million units (one single-dose vial) three times per week (e.g.
Monday, Wednesday, and Friday) regardless of patient weight. Ribavirin, which
is supplied in 200-mg capsules, is taken orally every day in dosage of 400
mg in the morning and 600 mg in the evening; patients weighing more than 75
kg should take 600mg b.i.d. If hemolytic anemia develops, the dosage can be
reduced to 600 mg per day in divided doses.
COST
-- The cost of Rebetron with 1000
mg/day of ribavirin is $7,819 for a 24-week supply, according to wholesale
prices (AWP) listed in Drugs Topics Red Book Update, May 1999. The cost of
24 weeks of Intron A is $2,442.
CONCLUSION
-- Interferon alfa-2b plus ribavirin is now the treatment of choice for chronic
hepatitis C, but it is expensive and in the type of disease most prevalent
in the USA, only 30% of patients have had a sustained response to the combination.
Copyright of Medical Letter on Drugs &
Therapeutics is the property of Medical Letter, Inc. and its content may not
be copied without the copyright holder's express written permission except
for the print or download capabilities of the retrieval software used for
access. This content is intended solely for the use of the individual user.
Source: Medical Letter on Drugs & Therapeutics, 06/04/99, Vol. 41 Issue
1054, p53, 2p. Item Number: 1921584
Expanded
Indications Bring More Complications in Hepatitis C Treatment
New Patients Receive Strong Warnings
about Potential Risk to Fetus with Combination Therapy
February 8, 1999 (Philadelphia) - After just
six months on the market, revised safety information tells doctors and patients
to be even more cautious in the use of combination therapy to treat hepatitis
C. A "black box" warning in the revised prescribing information
for Rebetron (Schering-Plough) warns that patients and their partners must
use two forms of contraception because of the risk of birth defects or loss
of a pregnancy from combination therapy.
Even if only one partner is taking Rebetron,
both members of the couple need to use adequate contraception during therapy
and for six months after the end of treatment. Rebetron consists of interferon-alfa
plus ribavirin. It is the ribavirin component that is blamed for the risks
to the fetus.
The U.S. Food and Drug Administration recently
approved Rebetron combination therapy for patients with hepatitis C who had
never been treated before. Previously, only people who had failed a previous
treatment could receive Rebetron. But at the same time as it allowed wider
use, the FDA increased the warnings to reflect the danger of the combination
therapy during pregnancy. Ever since Rebetron was first approved, Schering-Plough
has maintained a registry to track people on the therapy who become pregnant.
Dr. Enrique Molina, a hepatologist and assistant
professor of clinical medicine at the Center for Liver Diseases, University
of Miami, Florida, says no patients with pregnancy-related complications from
Rebetron treatment have been referred to his practice yet. However, he feels
physicians need to counsel patients carefully before prescribing Rebetron
and says, "If a patient is not willing to practice strict contraception,
that's certainly a contraindication for ribavirin. It makes a bigger difference
for younger patients than for older ones. Many of our patients are 40 or 50
and already practicing contraception so it's not a big issue for them, but
for those that are younger, it's definitely an important point for physicians
to stress."
Dr. Molina also considers other potential risk
factors before prescribing the combination therapy. He is particularly concerned
about the anemia that ribavirin can cause. "A patient at high risk for
cardiac disease or hemolysis or one with existing severe anemia that might
be complicated by ribavirin is better off starting on Infergen." Infergen
is a newer bioengineered interferon that differs from standard interferons,
such as Intron A.
The side effects of combination treatment should
also be reviewed carefully with each patient, according to Dr. Molina. "I
explain that side effects at the beginning of interferon therapy are worse
in some patients-not only the headaches, fever and flu-like illness, but general
fatigue and malaise-and are probably made even worse by the addition of anemia
from ribavirin. The patients with the worst anemia are the patients with the
worst fatigue. There is an additive effect, and the two drugs together cause
worse side effects," he says.
"Patients should know that during the
first week or two of treatment, the side effects are going to be at their
worst no matter how mild or how bad, but by the end of a month they'll be
tolerable," Dr. Molina says. "Most patients will be able to carry
on normal lives with some limitations, and they will be able to continue treatment.
"When patients are taking Rebetron, it's
vital they are tested every two weeks at the beginning of treatment, especially
their CBC [complete blood count] and platelets, not only to monitor efficacy
but also side effects. Liver chemistry should be checked monthly, but tests
for anemia are the most important," Dr. Molina says. He recommends patients
have ANA [antinuclear antibody test] and thyroid tests before beginning treatment,
especially if they have an autoimmune background. These tests should be rechecked
after three months.
According to Dr. Molina, treatment should last
for a year. "At the end of three months of interferon monotherapy, we
recheck to see if the treatment is effective. When a patient is on combination
therapy, we should probably wait longer than three months to decide whether
he is responding or not. Many patients respond to Rebetron after the three-month
mark."
Distributed by: Patients NewsWire Check with
the FDA Online page for updated Rebetron warnings: http://www.fda.gov/cder/approval/index.htm
GASTROENTEROLOGY 1998;115:255-256 GASTROENTEROLOGY
NEWS
New
Therapy Packs Powerful One-Two Punch Against HCV
A leading hepatologist refers to the recently
approved combination antiviral therapy for chronic hepatitis C (HCV) as a
significant breakthrough. Rebetron, manufactured by Schering-Plough Corp.,
(Kenilworth, NJ) consists of a 6-month course of interferon injections combined
with ribavirin capsules. It was approved by the FDA in June for adult hepatitis
C patients who initially respond to and later relapse with standard treatment
(interferon alone).
An estimated 4 million Americans are believed
to be infected with HCV. The virus is responsible for about 10,000 deaths
a year in this country, and is the leading indication for liver transplantation.
Interferon alone eliminates the virus in only 10%-20% of patients, but another
25%-40% respond and subsequently relapse. In patients for whom the FDA approved
the therapy, nearly half experienced a sustained remission (6 months or more)
when administered the interferon/ribavirin combination in trials held in both
the United States and Europe, roughly 10-fold better than the patients who
received interferon alone.
Although the FDA approved the therapy specifically
for the subgroup of patients who relapse after responding to interferon alone,
physicians will be able to prescribe the treatment for patients as a first
course. While the FDA has not yet reviewed the data, Willis C. Maddrey of
the University of Texas Southwestern Medical Center in Dallas notes that published
results out of Europe suggest that naive patients respond better to the combination.
>From 20% to 40% of HCV patients develop cirrhosis, but the clinical complications
often take as many as 20 years to present.
Maddrey points out that patients who are not
cirrhotic have shown a substantially higher response rate to the treatment
than those who are in a later stage of the disease. “I cannot see a
patient right now and accurately predict that he will or won’t develop cirrhosis
in 20 years,” Maddrey says. “But I can say that if you take your chances and
don’t get treated, and you develop cirrhosis, you’re going to be much more
resistant to treatment.”
Of course, the new treatment won’t be for everyone.
The side effects of the combination therapy are potentially serious, because
ribavirin causes a nonimmune hemolytic anemia, with an average drop in hemoglobin
of about 2 g. “It’s important for physicians to plan for that, to test patients’
hemoglobin levels before treatment and at 2 and 4 weeks, and not to use this
drug in anyone who couldn’t stand a moderate drop in hemoglobin,” says Maddrey.
The combination therapy is also expensive, estimated
at $6400-$8600 for the 6-month course. But Maddrey suspects that cost-efficacy
studies will ultimately support the new therapy’s use. As for the slight majority
of HCV patients who don’t respond to the Rebetron, Maddrey predicts that the
next breakthrough will come with the addition, not substitution, of another
antiviral drug, possibly a protease inhibitor, to the combination treatment.
“It’s similar to what occurred in AIDS, where we did
well with AZT for awhile, but the real breakthrough came when we added a protease
inhibitor to the AZT,” he says. “We feel that multidrug therapy is the wave
of the future, and that hitting this virus in two or three sites gives us
a much better chance of eradication.”
Hepatitis
C virus dynamics in vivo:effect
of ribavirin and interferon alfa on viral turnover.
Zeuzem S, Schmidt JM, Lee JH, von Wagner
M, Teuber G, Roth WK
Medizinische Klinik II, Klinikum der Johann
Wolfgang Goethe-Universitat, Frankfurt a.M., Germany.
[Medline record in process]
Treatment of patients with chronic hepatitis
C with recombinant interferon alfa (rIFN-alpha) can cause a decrease of
serum transaminases and hepatitis C virus (HCV) RNA. Recent trials evaluating
combination therapy of IFN-alpha and ribavirin suggested a potential synergistic
effect. From serial measurements of serum HCV RNA concentrations following
treatment-induced perturbation of the balance between virus production and
clearance, we compared the antiviral efficacy of both IFN-alpha alone and
IFN-alpha in combination with ribavirin. Chronically HCV-infected patients
were treated with either 3 x 3 MU or 3 x 6 MU rIFN-alpha per week or 3 x
6 MU rIFN-alpha plus 14 mg/kg of body weight ribavirin per day. The time-dependent
HCV RNA concentrations during antiviral treatment were analyzed by iterative
least-squares regression. After initiation of antiviral therapy, HCV RNA
declined exponentially below the detection limit of the reverse-transcription
polymerase chain reaction assay (1,000 HCV RNA molecules per milliliter)
in 10 of 26 (39%), 10 of 19 (53%), and 10 of 18 patients (56%) treated with
3 x 3 MU, 3 x 6 MU rIFN-alpha without and with ribavirin, respectively.
Viral clearance from serum was faster in patients treated with 3 x 6 MU
rIFN-alpha (t1/2 = 0.23 +/- 0.15) compared with patients treated with 3
x 3 MU rIFN-alpha per week (0.67 +/- 0.36 days) (P < .004). However,
half-lives of viral clearance were similar in patients treated with rIFN-alpha
or rIFN-alpha plus ribavirin. For virus release from infected hepatocytes,
absence and presence of ribavirin yielded half-lives of t1/2 = 2.54 +/-
2.10 and t1/2 = 1.99 +/- 1.70, respectively, indicating that ribavirin does
not significantly inhibit HCV production. In conclusion, the data of the
present study indicate that higher rIFN-alpha doses accelerate viral clearance
from serum. Ribavirin (14 mg/kg/d), however, lacks synergistic antiviral
effects in the treatment of chronic hepatitis C with 3 x 6 MU rIFN-alpha
per week.
PMID: 9657119, UI: 98319201
Am J Clin Pathol
2000 Jan;113(1):35-9
Increased
Hepatitic Iron Deposition
Fiel
MI, Schiano TD, Guido M, Thung SN, Lindsay KL, Davis GL, Lewis JH, Seeff LB,
Bodenheimer HC Jr
Lillian and
Henry M. Stratton-Hans Popper Department of Pathology, Mount Sinai Medical
Center, City University of New York, NY 10029, USA.
Increased
levels of hepatic iron may impair the response of patients with chronic hepatitis
C to treatment with interferon-alfa, but combination therapy with ribavirin
has demonstrated efficacy in the treatment of hepatitis C. When used alone
or with interferon-alfa, ribavirin may cause a dose-dependent reversible hemolytic
anemia. We compared the extent and cellular localization of iron deposition
in liver tissue from biopsy specimens obtained before and after 36 weeks of
therapy with ribavirin or placebo for 59 patients with chronic hepatitis C.
Paired slides were available for review from 26 ribavirin and 27 placebo recipients.
Iron deposition was assessed using coded slides stained with Perls Prussian
blue and was semi-quantitated in hepatocytes, Kupffer cells, and areas of
fibrosis. The overall iron score fell by 0.96 in the placebo group and increased
1.69 in the ribavirin recipients. Iron was deposited mainly in hepatocytes;
the hepatocyte iron score increased from 2.19 to 3.81 in the ribavirin group.
The amount of iron staining in Kupffer cells declined in the placebo group
and increased slightly in the ribavirin group. Iron changes in areas of fibrosis
were minor and did not differ between groups. Increased total hepatic iron
deposition occurred during a 9-month course of ribavirin. Ribavirin-associated
hemolysis deposits iron preferentially in hepatocytes. This increased deposition
of hepatic iron does not seem to affect the biochemical or histologic response
to ribavirin therapy but may have implications for hepatocyte susceptibility
to future injury.
PMID:
10631856, UI: 20097474
Increase
in hepatic iron stores following prolonged therapy
with ribavirin in patients with chronic hepatitis C.
J Hepatol 1994 Dec;21(6):1109-12
Di Bisceglie AM, Bacon BR, Kleiner DE, Hoofnagle
JH
Liver Diseases Section, National Institute
of Diabetes and Digestive and Kidney Diseases, National Institutes of Health,
Bethesda, Md 20892.
Ribavirin,
an oral nucleoside analogue being evaluated as therapy for chronic hepatitis
C, is associated with hemolysis. Other hemolytic conditions are known to be
associated with accumulation of iron within the liver. We therefore examined
hepatic iron stores before and after 6 to 12 months of therapy with ribavirin
in 15 patients with chronic hepatitis C. Although there were no significant
changes in serum iron or ferritin levels, hepatic iron staining increased
in almost all patients. Using a ranking system to quantitate the amount of
hepatic iron staining, we found that the mean rank increased from 3.9 to 8.5
after therapy (p < 0.01). In six patients in whom hepatic tissue was available
for determination of hepatic iron, concentrations also increased in all cases
from a mean of 826 to 1857 micrograms/g dry weight (p < 0.01). The average
rate of iron accumulation in these six patients was approximately 1500 micrograms/g
per year. Thus hepatic iron concentrations might enter the range clearly associated
with hepatic fibrosis after approximately 15 years of continuous therapy.
PMID: 7699235, UI: 95213561
How
to Open a Ribavarin Blister Pack
From Jim: lnterwebpc@aol.com
1) Gingerly hold 6 pill blister
packet and gently bend it back and forth
across the perforated line until
it separates in half.
2) Now carefully tear the 3 pill
half card into three individual single
pieces with 1 pill in small packet.
3) Carefully examine the small
packet and you will notice each one has a
small slit in the packet.
4) Now with your index finger and
thumb pinch the 1 pill packet on either
side of the slit and with a sort
of a gentle twisting motion pull the packet
in half along the slit.
5) Wipe the water on floor up and
pick up the pieces of the vase while
making
a mental note to glue the pieces
back later, then pick up the 1 pill packet
from the floor.
6) Get two pairs of pliers and
pinch on either side of the slit and briskly
pull the packet apart.
7) Get Band-Aid from medicine cabinet
for blood blister on index finger and
get pill out of wastebasket.
8) Put packet on a kitchen chair
with half hanging over the edge of the seat
and your foot holding it down.
9) Get big wooden spoon and with
a thrusting motion stab in to the packet.
10) Put the two pieces of the wooden
spoon back in the kitchen drawer and
make note to call floor technician
to repair tear in linoleum, get packet
off
of ceiling light fixture.
11) Scold the cat and dog for laughing
at you with their eyes.
12) Go into the garage and put
the stupid packet in workbench vise.
13) Get 5 pound sledgehammer and
swing hammer down sharply and strike the
hellish packet in the vise.
14) After getting home from the
Emergency Room to remove pill fragments from
eyes call kids in to inform them
there is a new house punishment now, and it
is called the "Riba Packet
Opening Duty"
--jim--
I patterned it after something
I found on the Internet "How To Give a Pill
To a Cat"
ps, there are 3 things I have come
to learn since having Hepatitus C, 1)
Humor makes the medicine go down,
in the most delightful way. 2) Open up
youreyes
and see whats REALLY important in life. 3) NEVER run with an uncapped
loaded syringe, OUCH!
The
Future of Hepatitis C Reseach
Basic Research
A major focus of hepatitis C
research is developing a tissue culture system that will enable researchers
to study HCV outside the human body. Animal models and molecular approaches
to the study of HCV are also important. Understanding how the virus replicates
and how it injures cells would be helpful in developing a means of controlling
the virus and in screening for new drugs that would block it.
Diagnostic Tests
More sensitive and less expensive assays for measuring HCV RNA and antigens
in the blood and liver are needed. Although current tests for anti-HCV are
quite sensitive, a small percentage of patients with hepatitis C test negative
for anti-HCV (false-negative reaction), and a percentage of patients who test
positive are not infected (false-positive reaction). Also, there are patients
who have resolved the infection but still test positive for anti-HCV. Convenient
tests to measure HCV in serum and to detect HCV antigens in liver tissue would
be helpful.
New Treatments
Critical for the future is the development of new antiviral agents for hepatitis
C. Most interesting will be specific inhibitors of HCV-derived enzymes such
as protease, helicase, and polymerase inhibitors. Drugs that inhibit other
steps in HCV replication may also be helpful 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).
Nonspecific cytoprotective agents
might also be helpful for hepatitis C by blocking the cell injury caused by
the virus infection. Further, molecular approaches to treating hepatitis C
are worthy of investigation; these consist of using ribozymes, which are enzymes
that break down specific viral RNA molecules, and antisense oligonucleotides,
which are small complementary segments of DNA that bind to viral RNA and inhibit
viral replication.
All of these approaches remain
experimental and have not been applied to humans. The serious nature and the
frequency of hepatitis C in the population make the search for new therapies
of prime importance.
Prevention
At present, the only means of preventing new cases of hepatitis C are to screen
the blood supply, encourage health professionals to take precautions when
handling blood and body fluids, and inform people about high-risk behaviors.
Programs to promote needle exchange offer some hope of decreasing the spread
of hepatitis C among injection drug users. Vaccines and immunoglobulin products
do not exist for hepatitis C, and development seems unlikely in the near future
because these products would require antibodies to all the genotypes and variants
of hepatitis C. Nevertheless, advances in immunology and innovative approaches
to immunization make it likely that some form of vaccine for hepatitis C will
eventually be developed.
NIH Publication No. 99-4230 May
1999
e-text last updated: 4 May 1999
NDA Submitted
a. Interferon alpha-2a, recombinant (Roferon-A); Hoffman-LaRoche -
FDAapproved 11/96
b. Consensus Interferon (Infergen), Amgen -FDA and Health Canada Approved
c. Lymphoblastoid Interferon (Welferon); Glaxo-Welcome - FDA and Health
Canada Approved
In
Trials
a. Beta interferons, recombinant
SeronoLabs; Phase I/II
Chiron Corp.; Phase III
Biogen Corp.; Phase III?
b. Natural-source interferon, Alpha-n3 (human leukocyte-derived) (AlferonN):
Phase III
Combination Strategies
a. Intron-A (Interferon alpha 2b) + Ribavirin (Schering-PloughPharmaceuticals)
b. Thymosin alpha 1 (Zadaxin; SciClone Pharmaceuticals) + Intron-A;
PhaseIII trials
Other Strategies
a. Antisense-based therapies (Antivirals, Inc., Hybridon, IsisPharmaceuticals,
Lynx Therapeutics)
b. Pegylated Interferons (Hoffman-LaRoche, Schering Plough); trials
inprogress
c. Interferon/iron reduction (Schering Plough): trials in progress
d, Granulocyte macrophage colony stimulating factor (GMCSF) (Immunex)
e. Ribozyme gene therapy (Immunol Inc., RiboGene)
f . Vaccine-based therapies (Cytel Corp., Chiron Viagene, Univax Biologies,Vical)
g. Protease inhibition (Vertex Pharmaceuticals, Agouron Pharmaceuticals,
Roche Pharmaceuticals, Glaxo-Wellcome, others)
HCV protease is one of the proteins that catalyze critical steps in the viral
life cycle of hepatitis C. Recent efforts have focused on the
molecular mechanism of hepatitis C replication as this has proven tobe a successful
approach in the treatment of HIV. The combination
of HIV protease inhibitors and nucleoside analogs have been the first major
breakthrough in the treatment of AIDS. There are similarities between the
HIV and hepatitis C viruses as they are both RNA viruses which have a tendency
to mutate. The HIV protease inhibitors are
aspartate proteinases whereas the HCV protease is serine-based. This makes
it unlikely that any of the current drugs being used for
HIV would be effective in patients with hepatitis C.
Particular attention is being focused on the NS3 protease domain of the hepatitis
C virus as this is an enzyme considered essential
for replication of the hepatitis C virus. Recently the crystal structure of
the hepatitis C virus NS3 protease domain was reported by two
separate groups in the journal, Cell. This will no doubt lead to rapid development
of protease inhibitor drugs by a number of biotechnology
and pharmaceutical companies who are racing to accomplish this. Other logical
targets for inhibition are the NS3 helicase and the NS5b
polymerase enzymes as these are also essential for viral replication. It is
likely that a number of inhibitor drugs will reach clinical testing
phase in the next 18 to 36 months. (As of yet there are no protease inhibitors
in clinical trials.)
Antisense drugs are large, highly charged molecules which form DNA-RNA or
RNA -RNA hybrids with the target RNA receptor.
In the case of hepatitis C this hybrid would form with the hepatitis C RNA
which is the viral replicative material. This occurs by simple
Watson-Crick base pairing. Once an anti-sense DNA hybrid has been formed it
inactivates the viral replication process. Ribozymes
are enzymes which have the ability to cause a catalytic cleavage of a targeted
RNA. Ribozymes directed against the hepatitis C virus
RNA have been developed which have the ability to destroy the virus' replicative
material. Although these compounds have been produced
using recombinant bench techniques they have not yet been proven safe or effective
in vivo. It is anticipated that these compounds may
have unpredictable and non-specific effects on other cells and therefore may
be potentially toxic. More work is needed on these drugs before they will
reach the clinic.
In summary, a number of new therapies for hepatitis C are emerging in clinical
practice. Tile first of these are new Interferon products
which have already reached market or will be doing so in the next 12 to 18
months. Combination approaches of Interferon and Ribavirin are currently being
tested and will likely prove to be beneficial. We anticipate other similar
nucleoside analog therapies will be tested with Interferon in the near future.
In addition, other combination approaches with Interferon may improve efficacy.
Within two to three years we expect to see a whole new class of drugs which
will be oral, have low toxicities, and improved efficacy. These drugs will
likely need to be taken lifelong and may need to be taken in combination with
each other as is currently the case in HIV disease.
