Side Effects Minimized with Combination Therapy in Hard-to-Treat Patients
In a study of an all-oral drug regimen, a majority of volunteers
with liver damage due to hepatitis C virus (HCV) infection were cured
following a six-month course of therapy that combined an experimental
drug, sofosbuvir, with the licensed antiviral drug ribavirin. The
results showed that the regimen was highly effective in clearing the
virus and well tolerated in a group of patients who historically have
had unfavorable prognoses.
Scientists from the National Institute of Allergy and Infectious
Diseases (NIAID) and the NIH Clinical Center, parts of the National
Institutes of Health, led the Phase II trial. The findings appear in the
Aug. 28 issue of the Journal of the American Medical Association (JAMA).
More than 3 million Americans have chronic HCV infection, a condition
that is a major cause of cirrhosis (liver tissue scarring) and liver
cancer, and a leading reason for liver transplantation. Deaths from
HCV-related liver disease number about 15,000 every year. Standard
treatment for HCV can last up to a year and usually involves weekly
injections of pegylated interferon-alpha given with the oral drug
ribavirin and an HCV protease inhibitor. Side effects from this
treatment can be severe, notably from interferon-alpha, and can include
depression, flu-like symptoms and anemia.
“There is a pressing need for hepatitis C virus treatments that are
less burdensome to the patient, have fewer side effects and take less
time to complete. Building on previous work, this trial provides
compelling evidence that interferon-free regimens can be safe and
effective,” said NIAID Director and study co-author Anthony S. Fauci,
The current study involved 60 volunteers with genotype-1 HCV, which
tends to be less responsive to interferon-based treatment. Fifty of the
60 participants were African-American.
“While African-Americans make up about 13 percent of the U.S.
population, they represent more than 22 percent of people with chronic
HCV infection and, compared to whites, have lower cure rates with
traditional HCV therapy,” said NIAID researcher Shyam Kottilil, M.D.,
Ph.D., the principal investigator of the trial. “Several recently
completed trials testing interferon-free regimens have yielded promising
results, but most volunteers in those studies were white.”
The new study also differs from many previous trials because it
enrolled people with severe liver damage as well as those with mild or
moderately scarred livers.
The study was divided into two parts. The first part enrolled 10
people with mild or moderate liver fibrosis. Volunteers received oral
ribavirin at a dosage based on their weight along with the experimental
drug sofosbuvir, also in pill form, taken daily for six months. Gilead
Sciences, Inc., of Foster City, Calif., manufactures sofosbuvir and
supplied it to the study physicians.
Nine volunteers completed the course of therapy. Virus was
undetectable in all nine volunteers 12 weeks after the end of therapy
and continued undetectable when they were tested again 24 weeks after
finishing therapy. HCV does not integrate itself into human DNA. If the
virus cannot be detected for a period of 12 weeks after stopping
therapy, the patient is considered cured, Dr. Kottilil said.
The second part of the trial enrolled 50 volunteers, 13 of whom had
liver damage rated as serious. Twenty-five received ribavirin based on
their weight, and 25 received a low dose (600 milligrams per day). All
“Because ribavirin can cause serious side effects, including anemia, we
wanted to compare response rates in patients taking low-dose ribavirin
with results from patients on a weight-based dosage,” said Dr. Kottilil.
At four, 12 and 24 weeks after the end of treatment, volunteers were
tested for the presence of HCV. HCV levels were undetectable in 24 of
the volunteers in the weight-based arm when treatment ended. Of those,
17 continued to have undetectable virus levels 24 weeks later and were
considered cured of infection. In the low-dose arm, three volunteers
dropped out of the study. Of the remaining 22, all responded to the
treatment, but only 12 were considered cured at 24 weeks after the end
“We saw an overall cure rate of about 70 percent using regimens that
did not include interferon,” said Dr. Kottilil. “This is an encouraging
result, especially considering the proportion of volunteers who had
characteristics—such as being male, having HCV genotype-1 infection,
being African-American and having advanced liver damage—that are
recognized as predictors of poor response to treatment.”
Additional trials are underway to further determine if regimens
without interferon or ribavirin can help people with chronic HCV
infection, particularly those who have both HIV and HCV infections, said
Dr. Kottilil. These trials include two studies in which volunteers with
or without HIV infection take a combination of HCV drugs (but no
interferon or ribavirin) for periods of three months or less.
Information about these trials is available at clinicaltrials.gov using
the identifiers NCT01805882 and NCT01878799.
Further information about the HCV trial described in the current issue of JAMA is available at clinicaltrials.gov using the trial identifier NCT01441180.
A Osinusi et al.
Sofosbuvir and ribavirin for hepatitis C genotype 1 in patients with
unfavorable treatment characteristics: A randomized clinical trial. JAMA DOI: 10.1001/JAMA.2013.109309 (2013).
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