Spontaneous and treatment-induced viral clearance in acute hepatitis C
The management of acute hepatitis C needs to consider the high rate of
spontaneous viral clearance after the onset of symptomatic disease, find
researchers in the July issue of Gastroenterology.
Acute hepatitis C virus infection makes up about 20% of cases of acute
hepatitis.
In this study, researchers from Germany aimed to determine the natural
course of this disease, and to contribute to the development of treatment
strategies.
The team based their diagnosis on seroconversion to anti-hepatitis C virus
antibodies, or clinical and biochemical criteria, and the presence of
hepatitis C virus RNA in the first serum sample.
They included 60 patients with acute hepatitis C in their study.
Spontaneous clearance was observed in 52% of untreated patients.
Gastroenterology
Of these, 85% presented with symptomatic acute hepatitis C virus.
The team found that in untreated acute symptomatic hepatitis C, spontaneous
clearance was observed in 52% of patients. This usually occurred within 12
weeks of the onset of symptoms.
The team determined that all 9 patients who were asymptomatic developed
chronic hepatitis C.
Furthermore, antiviral therapy with interferon-alpha, either with or
without ribavirin, induced sustained viral clearance in 80% of patients.
Dr Tilman Gerlach's team concluded, "The management of acute hepatitis C
has to take into account the high rate of spontaneous viral clearance
within 12 weeks after the onset of symptomatic disease".
"Treatment of only those patients who remain hepatitis C virus RNA positive
for more than 3 months after the onset of disease led to an overall viral
clearance (self-limited and treatment induced) in 91% of patients, and
unnecessary treatment was avoided in those with spontaneous viral clearance".
"Patients with asymptomatic acute hepatitis C virus infection are unlikely
to clear the infection spontaneously and should be treated as early as
possible".
Gastroenterology 2003; 125(1): 80-88
11 July 2003
Cost-effectiveness of treatment for chronic hepatitis C infection
Newer treatment options for hepatitis C are reasonably cost-effective, but
results vary widely across patient subgroups and depend on quality-of-life
assumptions, find researchers in this week's issue of the Journal of the
American Medical Association.
Over 2.5 million people in the United States have chronic hepatitis C virus
(HCV) infection.
However, as public health campaigns are pursued, a growing number of
treatment candidates are likely to have minimal evidence of liver damage.
In this study, researchers examined the benefits and cost-effectiveness of
treatments for chronic hepatitis C infection in asymptomatic, HCV
sero-positive, but otherwise healthy individuals.
The team performed a cost-effectiveness analysis using a Markov model of
the natural history of HCV infection and impact of treatment.
Probability of developing cirrhosis over a 30-year period was between 13%
and 46% for men, and 1% and 29% for women.
Journal of the American Medical Association
They derived natural history parameters from an epidemiologic model. These
were empirically calibrated to provide a good fit to observed data on both
prevalence of HCV seropositivity and time trends in outcomes.
The researchers assessed cohorts of 40-year-olds who had elevated levels of
alanine aminotransferase, positive HCV RNA assays and serologic tests for
antibody to HCV. Subjects had no histological evidence of fibrosis on liver
biopsy.
The subjects were treated using either standard or pegylated interferon
alfa-2b, or combination therapy with standard or pegylated interferon plus
ribavirin.
The team evaluated the lifetime costs of treatment, life expectancy,
quality-adjusted life-years (QALYs), and incremental cost-effectiveness
ratios.
The researchers found that the probability of patients with chronic HCV
developing cirrhosis over a 30-year period was between 13% and 46% for men,
and 1% and 29% for women.
They determined that the incremental cost-effectiveness of combination
therapy with pegylated interferon for men was between $26,000 and $64,000
per QALY for genotype 1, and between $10,000 and $28,000 for other genotypes.
The cost-effectiveness for women was between $32,000 and $90,000 for
genotype 1, and between $12,000 and $42,000 for other genotypes.
The research team found that the benefits of treatment were largely
improvements in health-related quality of life, rather than prolonged
survivorship, meaning that cost-effectiveness ratios expressed as dollars
per year of life were substantially higher.
In addition, results were most sensitive to assumptions about the gains and
decrements in health-related quality of life associated with treatment.
Dr Joshua Salomon's team concluded, "While newer treatment options for
hepatitis C appear to be reasonably cost-effective on average, these
results vary widely across different patient subgroups and depend
critically on quality-of-life assumptions".
"As the pool of persons eligible for treatment for HCV infection expands to
the more general population, it will be imperative for patients and their
physicians to consider these assumptions in making individual-level
treatment decisions".
JAMA 2003; 290(2): 228-37
10 July 2003
Treatment with interferon alfa alone has yielded poor results in children with chronic hepatitis C and has not been generally recommended.
Given the limited clinical experience with combination therapy in children, the aim of the current study was to evaluate the efficacy and tolerability of interferon alfa-2b (PEG-Intron) in combination with ribavirin in these patients with different routes of viral transmission.
In an uncontrolled pilot study, 41 children and adolescents ranging from 3 to 16 years were treated with interferon alfa at a dose of 3 or 5 MU/m2 3 times weekly in combination with oral ribavirin (15 mg/kg/d) for 12 months.
The mode of infection was unknown in 4, parenterally transmitted in 16, and vertically transmitted in 21 children. Forty patients completed the study. Eleven children, who remained hepatitis C virus (HCV)-RNA positive 6 months after the beginning, discontinued therapy. One boy stopped treatment because of side effects.
At the end of treatment, 25 patients were HCV-RNA negative (61%). All individuals remained HCV-RNA negative during the 6-month follow-up period. Nine of 15 children with parenteral (56.3%), 14 of 21 with vertical (66.6%), and 2 of 4 with unknown route of infection responded.
Side effects included minor clinical signs such as fever, flu-like symptoms, anorexia, and more severe signs (21.4%), such as the development of thyroid autoantibodies and impairment of thyroid function.
In conclusion, combination of alfa-interferon with ribavirin seems to be an important advance in the treatment of chronic hepatitis C in children and adolescents. This also is true for both vertically infected patients and for individuals with normal transaminase levels before therapy.
07/11/03
Reference
S Wirth and others. Recombinant alfa-interferon plus ribavirin therapy in
children and adolescents with chronic hepatitis C. Hepatology 36(5):
1280-1284. November 2002.
High Rate of Spontaneous and Treatment-Induced Clearance of Acute Hepatitis C Infection
A DGReview of :"Acute hepatitis C: High rate of both spontaneous and treatment-induced clearance
Gastroenterology
07/23/2003
By Mary Beth Nierengarten
A high rate of viral clearance in patients with acute hepatitis C infection
was seen both in patients who were not treated within 12 weeks of symptom
onset and in patients who received antiviral therapy, report researchers
from Germany.
Acute hepatitis C virus (HCV) accounts for nearly 20% of all current cases
of acute hepatitis and carries significant morbidity and mortality. A better
understanding of the natural course of disease is therefore needed to
develop and improve treatment, the researchers write.
J. Tilman Gerlach, MD and colleagues, from General Hospital München
Schwabing, in München, conducted a study of 60 patients diagnosed with acute
HCV to determine the course of disease and to identify the best time to
initiate treatment.
Of the 35 women and 25 men, 85% presented with symptoms of disease that
included jaundice in 68%, flu-like symptoms in 55%, dark urine and white
stool in 39%, nausea in 34%, and abdominal pain in 25%. There were eight
asymptomatic patients who were diagnosed with acute HCV after physical
examination for various other conditions.
Six of the 60 patients were given immediate interferon therapy with or
without ribavirin. Therefore, the authors were able to study the natural
course of acute HCV in the remaining 54 untreated patients. In 68% of these,
the virus spontaneously cleared between 1 and 26 weeks (mean of 8.4 weeks)
after diagnosis. However, 44% of the 54 patients remained cleared of the
virus as indicated by RNA negativity at a median of 27 month follow-up, and
24% relapsed after a median of 18 weeks. A total of 31% patients developed
chronic HCV infection.
Overall, 24 patients achieved self-limited HCV infection (i.e., achieved
spontaneous clearance) and 30 developed chronic disease. Women were
significantly more likely than men to have self-limiting disease (18 vs. 6,
respectively; p<0.034). Patients who presented with disease symptoms were
also significantly more likely to achieve spontaneous viral clearance than
patients who presented without symptoms (p<0.007).
For the patients treated with antiviral therapy, 6 immediately after
diagnosis and 20 after 12 weeks of disease onset, 80% achieved sustained
viral clearance.
Because of the high rate of spontaneous viral clearance within 12 weeks of
symptomatic disease in this cohort of patients, the authors recommend that
antiviral treatment should be initiated only in patients who remain HCV
positive after 12 weeks of onset of symptomatic disease. For asymptomatic
patients, treatment should begin as soon as possible since these patients
are unlikely to achieve spontaneous clearance of the virus.
Gastroenterology 2003;125:1:80-88.
"Acute hepatitis C: High rate of both spontaneous and
treatment-induced viral clearance."
Alcohol Ups Hepatitis C Virus Replication
Tue July 22, 2003 06:02 PM ET
NEW YORK (Reuters Health) - Alcohol increases the replication of hepatitis C
virus (HCV), and it interferes with the effectiveness of interferon used to
treat hepatitis C.
That warning comes from an article in the medical journal Hepatology. The authors -- Dr. Wen-Zhe Ho from The Children's Hospital of Philadelphia, Pennsylvania and associates -- examined the effects of alcohol on HCV-infected cells in lab dishes.
"As demonstrated in our study, alcohol not only induced HCV replicon expression but also compromised anti-HCV effect of interferon alfa," Dr. Ho told Reuters Health. "These findings provide practical guidance toward the reduction of risk factors that interfere with interferon-based therapy and promote HCV disease progression."
Other experiments showed that naltrexone, a drug used to treat opiate addiction, blocked the enhancing effect of alcohol on HCV. This suggests that "there might be an additional benefit for treating HCV-infected alcohol abusers with naltrexone," Dr. Ho added.
However, Dr. Ho stressed that all this was determined in laboratory research, not patients. Whether it is meaningful in clinical practice "needs to be confirmed by epidemiological investigations, which is what we would like to do in the future."
SOURCE: Hepatology, July 2003.
Drugs Now In Pipeline May Shorten, Ease Hepatitis C Treatment
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April 17, 2003 -- The central mystery of hepatitis C now is solved. A new finding promises more effective, shorter, and easier hepatitis C treatments.
What Michael Gale Jr., PhD, and colleagues discovered is how hepatitis C virus establishes lifelong infection. They found that the virus makes a key that lets it turn off a cell's anti-virus machinery. And they found that a type of drug -- already in development by several companies -- robs the virus of this key. Without it, the anti-viral machinery comes to life. It churns out a chemical called interferon that rids the cell of the hepatitis C virus.
"The beauty of [this type of drug] is it can clear persistently infected cells," Gale tells WebMD. "The cells rid themselves of hepatitis C virus within an average time of four to five days."
Gale and colleagues at University of Texas Southwestern Medical Center, Dallas, wondered why hepatitis C virus is able to cause long-lasting infection. Most viruses can't do that. Gale guessed that hepatitis C virus must somehow disable a crucial immune response -- some part of the innate immune system that's part of almost every cell in the body.
A crucial clue came from the McGill University lab of John Hiscott, PhD, in Montreal. Hiscott was studying the molecular switches that trigger interferon release inside a cell. One of these triggers is called interferon regulatory factor 3 or IRF-3. He gave Gale some IRF-3 to work with.
Gale's lab then found that a protein made by hepatitis C virus blocks IRF-3.
"By blocking it completely, hepatitis C virus prevents the cell from mounting an immune response," Gale says. "That lets the virus get a foothold soon after infection. Once it has this foothold, it never lets go."
The IRF-3 blocking protein is an enzyme called protease. Like hepatitis C virus, the AIDS virus also makes a kind of protease. Drugs that disable protease -- protease inhibitors -- revolutionized AIDS treatment. Several inhibitors of hepatitis C protease are now in the drug pipeline. Schering-Plough Corp. gave Gale some of its experimental drug, which he calls SCH6.
"We found that SCH6 not only inhibits hepatitis C protease, but also allows restoration of this cellular immune response," Gale says. "We could restore the ability of infected cells to respond to the virus, and naturally clear the virus on its own."
There's more good news. Gale's lab worked with genotype 1. It's the most common type of hepatitis C in the U.S. -- and the hardest kind to treat. Yet the protease inhibitor knocked it out.
By attacking the virus and also turning on antiviral immunity, hepatitis C protease inhibitors would have a dual action. And there's likely a third kind of action. Protease inhibitors likely would make current interferon treatments work better, at lower and less toxic doses. That's an exciting idea to Leslye Johnson, PhD, chief of the enteric and hepatic diseases branch at the National Institute of Allergy and Infectious Diseases.
"If a compound like this goes forward into clinical trials, it has the potential for dual activities and may work better than what's out there now," Johnson tells WebMD. "It might also allow people to use decreased doses of interferon. This finding opens new possibilities that are important for drug development. What it says for patients is that a hepatitis C protease inhibitor, as long as it is safe and everything else, could have multiple ways of getting rid of the virus. That is really the bottom line."
At least three drug companies are working on hepatitis C protease inhibitors. Farthest along appears to be BILN 2061 from Boehringer Ingelheim Pharma. It's already being tested in humans. The Schering-Plough product is not yet ready for human tests, says Schering spokesman Robert Consalvo.
Gale's findings appear in the April 17 issue of the online journal Sciencexpress. Also appearing in the same issue is an article by Hiscott's lab, offering new insights into how viruses trigger a cells antiviral immune response. That finding may lead to drugs effective not only against hepatitis C, but all viruses.
SOURCES: Sciencexpress, April 17, 2003. Michael Gale Jr., PhD, University of Texas Southwestern Medical Center, Dallas. Leslye Johnson, PhD, chief, enteric and hepatic diseases branch, National Institute of Allergy and Infectious Diseases. Robert Consalvo, director of external communications, Schering-Plough Corp.