A randomized trial at multiple medical centers in Greece was conducted to assess the efficacy of interferon alfa (IFN) daily in combination with ribavirin in 301 naive patients with chronic hepatitis C (CHC).
Patients were randomized to receive ribavirin 1.2 g daily (QD) for 48 weeks with either IFN 5 MU (thrice weekly) TIW for 8 weeks followed by IFN 3 MU TIW for 40 weeks (IFN TIW, n = 154) or IFN 5 MU QD for 8 weeks followed by IFN 3 MU QD for 16 weeks followed by IFN 3 MU TIW for 24 weeks (IFN QD, n = 147).
Treatment discontinuation rates, because of adverse events, were similar in the two arms (14.9% in IFN TIW and 14.3% in IFN QD, P = 0.87).
The proportion of patients with sustained virological response (SVR) was 27.9% for patients treated TIW and 38.8% for those treated QD (P = 0.046). According to logistic regression analysis, patients in the IFN QD arm had 1.7 times higher probability of achieving SVR, than those receiving IFN TIW (P = 0.038).
Low baseline viral load (P
= 0.017) and genotype non-1 (P = 0.036) were associated with higher SVR
rates.
The authors conclude, “Combination of IFN/ribavirin for 48 weeks is more
effective when IFN is administered daily for the first 24 weeks in naive
patients with CHC.”
10/08/03
Reference
NC Tassopoulos and others (The Hellenic Viral Hepatitis Research Network).
A randomized trial to assess the efficacy of interferon-alpha daily in
combination with ribavirin in the treatment of naive patients with chronic
hepatitis C. Journal of Viral Hepatitis 10(5): 383-389. September
2003.
There are few options for therapy among patients with chronic hepatitis C who are nonresponders to treatment with interferon alfa (IFN-alfa) plus ribavirin. Several studies have explored the addition of amantadine to interferon alfa/ribavirin in the hope of eliciting more sustained virologic responses. Study results have varied.
In this German study, conducted at the Johann Wolfgang Goethe Clinic in Frankfurt, Germany, researchers evaluated the efficacy and safety of interferon-alfa (IFN-alfa)/ribavirin retreatment with or without amantadine sulphate in non-responders with chronic hepatitis C.
Two hundred twenty five consecutive nonresponders to previous antiviral treatment(s) with IFN-alfa alone or in combination with ribavirin or amantadine were treated with IFN-alfa 2b 5 MU daily for 4 weeks, 5 MU tiw for 20 weeks, followed by 3 MU tiw for additional 24 weeks combined with ribavirin 1000-1200 mg/d.
One hundred fifteen of 225 patients were randomized to receive amantadine 100 mg bid for 48 weeks. Treatment was discontinued in patients with detectable serum hepatitis C virus (HCV)-RNA at treatment week 24.
Study Results
An overall sustained virologic response with undetectable serum HCV-RNA levels was observed in 49/225 patients (22%). Patients infected with HCV-genotype non-1 (P<0.001), low viremia (P=0.011) and only one previous antiviral treatment (P=0.032) were more likely to respond to antiviral retreatment.
There was a trend towards higher sustained virologic response rates in patients receiving triple retreatment compared with those treated with IFN-alfa/ribavirin alone (25 versus 18%, P=0.172).
The authors conclude, “The addition of amantadine was well tolerated and led to an improvement of sustained virologic responses compared with retreatment with IFN-alfa/ribavirin alone, in particular in patients with low baseline viremia.”
10/08/03
Reference
G Teuber and others. Randomized, controlled trial with IFN-alpha combined
with ribavirin with and without amantadine sulphate in non-responders with
chronic hepatitis C.
Journal of Hepatology
39(4): 606-613. October 2003.
by Deena Beasley
|
From
Liver International
Impact of High-Dose
Interferon Induction and Ribavirin Therapy in Patients With Chronic
Hepatitis C Relapsing After or Not Responding to Interferon
Monotherapy
Posted 09/19/2003
Petra Steindl-Munda, Peter Ferenci, Harald Brunner, Karin Nachbaur,
Christian Datz, Michael Gschwantler, Harald Hofer, Rudolf Stauber,
Franz Hackl, Wolfgang Jessner, Martha Rosenbeiger, Alfred Gangl,
Wolfgang Vogel
|
Abstract and Introduction
Abstract
Background/Aims: Initial high-dose interferon-
induction therapy in combination with ribavirin improves sustained
response rates in treatment-naïve patients. This prospective,
randomized, controlled study tested whether non-responders or relapsers
to interferon monotherapy also benefit from induction therapy.
Methods: Patients with chronic hepatitis C who had not responded
to (n=75) or relapsed (n=80) after previous interferon therapy were
randomized to receive three different interferon doses during the first
14 weeks of therapy (A: 10 MU IntronA®/day for 2 weeks,
followed by 10 MU/2 days for 12 weeks; B:5 MU/d for 14 weeks; C: 5 MU/2
days for 14 weeks) followed in all by 5 MU/2 days for 24 weeks. All
patients received 1-1.2 g ribavirin/day throughout the whole study.
Results: The rates of viral clearance at any time on treatment
were similar in all groups. Sustained response rates were also not
different among the groups in interferon nonresponders (A 32%, B 29%, C
31%) and relapsers (A 64%, B 68%, C 71%), respectively, as well as in
patients with different genotypes. As expected, sustained response rates
were higher in patients with genotype non-1 than in those with genotype
1.
Conclusion: High-dose induction therapy does not improve the
outcome of interferon/ribavirin therapy in interferon nonresponders or
relapsers.
Introduction
The outcome of antiviral therapy of chronic hepatitis C has improved
considerably over the last decade, but the results are still
unsatisfactory. Interferon-
(IFN) monotherapy has a limited efficacy in naïve patients[1]
as well as for re-treatment of nonresponders with higher doses of IFN.[2]
Combination of IFN with ribavirin improved response rates considerably
in de novo patients,[3, 4] in relapsers after
interferon therapy, and in interferon non-responders.[5-9]
Nevertheless, the majority of interferon nonresponders fail to respond
to standard combination therapy. Therefore, further strategies to
improve response rates are needed. One possible approach would be to use
high-dose interferon induction therapy in combination with ribavirin.
This concept is based on studies of the kinetics of virus clearance[10]
and was tested in naïve patients in an Austrian multicenter trial.[11]
High-dose interferon induction therapy (with 10 MU interferon-2b/daily
for 14 days followed by 10 MU every other day for 12 weeks) increased
sustained response rates in genotype 1 patients.[11]
The initial virologic response to interferon is rapid and dose-dependent.[10] Patients infected with IFN-sensitive viral strains clear the virus rapidly from blood and have a high probability to achieve a sustained response.[12] However, patients infected with viral strains that can only be partially suppressed by IFN include nonresponders, partial responders and relapsers to 'standard' IFN therapy. A large proportion of relapsers respond to IFN/ribavirin combination therapy.[5] In contrast, the rate of sustained responders in IFN-nonresponders receiving standard dose interferon/ribavirin combination therapy is unsatisfactory. Even with increasing doses of IFN to 10 MU/TIW, only 8.6% of nonresponders to a 3-month course of 3 MU/TIW IFN monotherapy became sustained responders.[8] Therefore, in this trial the impact of two different induction schedules in combination with ribavirin was compared with standard interferon/ribavirin therapy in nonresponders and relapsers to IFN (using the same protocol as for IFN-naïve patients). In affluent countries this patient group may not exist anymore, since interferon/ribavirin combination therapy is the accepted standard since 1999.[13] However, many patients in Eastern and Central Europe are still treated with interferon monotherapy. Furthermore, the response to daily interferon together with ribavirin may help to design studies using pegylated interferons in this very difficult patient group.
|
2
test, as appropriate. Primary outcome measures were the rates
of virus elimination measured by a qualitative PCR at 2, 14
and 38 weeks of therapy, and 6 months after the end of therapy
(week 62). The statistical evaluation strategy was based on
the intention-to-treat principle and was in accordance with
the relevant EU directives. The efficacy of the three
treatment arms was compared by univariate analysis using
Fisher's exact test. The prediction of successful therapy
based on viral response at various time points was evaluated
by the
Taming Hepatitis C: High stakes but low odds
By
JANE E. BRODY
c.2003 New York Times News Service
For once, there is some good news to report about a blood-borne virus that has infected 4 million Americans and 170 million people worldwide.
The disease, hepatitis C, will eventually debilitate the livers of many of its sufferers, but new cases of it have declined 80 percent since the virus was identified in 1988 and blood banks started screening for contaminated donations four years later.
But -- and this is no small but -- the annual death toll from the long-term consequences of this infection is 10,000 a year in the United States, and scientists expect deaths to triple by 2010 before that statistic begins to decline, unless new treatments are developed to eliminate the virus or at least keep its complications at bay indefinitely.
Several such treatments are being studied, and expert hope they will work as well as those that have radically improved the control of HIV infections. If their early promise holds up in clinical trials, most hepatitis C infections may be cured or at least rendered virtually harmless. Current therapies are lengthy, expensive and can cause devastating side effects. Further, they work in only slightly more than half the patients.
Experts have learned enough about the virus and how it is transmitted to alert those at risk of the need to be tested, to take steps that can forestall complications and to prevent transmission to others.
Unlike HIV, the hepatitis C virus is rarely transmitted through sexual contact. Its primary route to a new bloodstream has been through contaminated needles shared by drug users and by blood transfusions. People with hemophilia and others who received blood products before the testing for the virus began may also be infected.
Low rates of transmission affect health care workers exposed to contaminated blood through needle-stick accidents, men who have sex with men and babies born to infected women.
Fatal cases have resulted from organs inadvertently transplanted from a contaminated donor.
Household contacts and sexual partners in monogamous relationships are rarely affected. But people who engage in high-risk sexual behavior with multiple partners and people who have sexually transmitted diseases face increased risk.
Although those receiving tattoos and body piercings in other countries can be at risk, there is as yet no evidence for transmission by those routes in the United States.
A blood test for the virus relies on the presence of antibodies to it, but antibodies may not appear for weeks after the infection. A more sensitive genetic test can detect the presence of the virus itself.
Testing is recommended for people who have had blood transfusions or organ transplants before July 1992 or were treated for clotting problems with blood products made before 1987, those who have been on long-term kidney dialysis and those who have injected street drugs, even once many years ago.
Not everyone infected becomes ill. Some people seem to eliminate the virus, and a chronic infection never develops.
Others who remain chronically infected may be free of symptoms indefinitely.
In most cases, however, as with HIV, the virus can linger in the body for a long time -- even decades -- before symptoms of liver damage appear.
The most serious consequences are severe cirrhosis, a scarring of the liver, liver failure and liver cancer, which have made hepatitis C the leading reason for liver transplants.
Symptoms, when they appear, are usually mild, intermittent and easily attributed to other causes. The symptoms may include fatigue, nausea, poor appetite, muscle and joint pains and mild discomfort or tenderness in the right upper abdomen.
Those who develop cirrhosis or severe liver disease may, in addition to complaining about those symptoms, experience weight loss, itching, dark urine, fluid retention and abdominal swelling.
No vaccine against the virus has been developed, and prospects for one are not promising because there are at least six major genetic types and more than 50 subtypes of the virus. And, it changes rapidly. The possibility of a vaccine depends on finding an exposed part of the virus that remains stable even as its protein coat mutates.
The main goal of treatment is to eradicate the virus to prevent progressive liver disease. Existing therapies are most effective in patients with Genotypes 2 and 3, which represent about 25 percent of patients in the United States. The most common ones, Genotypes 1a and 1b, affect about 75 percent of patients and are the most difficult to treat.
Two main therapies have been developed. One involves injections of interferon, usually long-acting pegylated interferon, which is injected weekly, and the other an oral antiviral drug called ribavirin.
Therapy is most successful when the treatments are used simultaneously. But each can cause serious problems in certain patients. Interferon should not be prescribed for people with serious psychiatric illness, unstable heart disease or poorly controlled diabetes. People with anemias, heart disease, stroke and kidney disease should avoid ribavirin, as should pregnant women.
Patients with the Type 1 virus are treated for 48 weeks; those with Types 2 and 3 do well with 24 weeks. The combination therapy is effective in slightly more than half the cases, in 42 percent of those with Type 1 and 80 percent for those with Types 2 or 3.
The side effects can be quite miserable, at least at the outset. But they subside with time and disappear when the treatment ends. Patients report that the drugs commonly cause flulike symptoms. They can seriously disrupt sleep and create havoc with sexual response and personality.
People tend to become irritable, forgetful and seriously depressed, and they may lose considerable weight. Even when treatment seems to have eliminated the virus, it can sometimes rebound, requiring a second round of therapy.
While some experts recommend that everyone who has chronic hepatitis C infection be treated, others suggest that each patient, in consultation with physicians, carefully weigh the likelihood that the disease will progress and the benefits and risks of therapy, as well as its considerable cost.
In a recent article in The Journal of the American Medical Association, Dr. Joshua A. Salomon and colleagues at the Harvard Center for Population and Development Studies noted that "30 percent to 70 percent of infected individuals may never progress to cirrhosis before dying from other causes."
The authors further pointed out that progression of the infection was highly variable and unpredictable. The probability of developing cirrhosis over 30 years ranges from 13 to 46 percent for men and 1 to 29 percent for women, they stated. Also, the progression of the infection to serious liver disease is less common among patients who are infected when they are young. They seem better able to fend off the virus or keep it under wraps.
With or without treatment, people infected with the virus should take steps to protect their livers from further damage. The steps include avoiding alcohol, getting vaccinated for hepatitis A and consulting physicians before taking any new medicines, including over-the-counter and herbal remedies