Hepatitis C: An Update
It's often portrayed as a virus causing an incurable disease--a killer with
few outward warning signs that lurks inside the body and slowly ravages the
For some, the hepatitis C virus (HCV) is deadly, but for most of the nearly
4 million Americans infected with the virus, it is not life-threatening.
"Some cases are mild, and people
can go through their whole lives
and never have a problem," says
Leonard Seeff, M.D., a hepatologist
at the National Institute of Diabetes
and Digestive and Kidney Diseases
(NIDDK)." For others who develop
severe liver disease, it is a terribly
HCV is responsible for 8,000 to 10,000 deaths per year in the United States,
according to the Centers for Disease Control and Prevention (CDC). The virus
is spread mainly through contact with the blood of an infected person. Most
people don't know they carry the virus because they have either no symptoms
or vague ones--extreme tiredness is the most common. Other common symptoms are
"flu-like": muscle and joint pain, nausea, poor appetite, and mild
Only about 15 percent of those infected with HCV have a short-term infection
that goes away by itself and never returns. The other 85 percent become chronically
infected, meaning the virus stays in the liver, replicates, and may slowly attack
the organ over a period of decades.
Despite many years of chronic infection, the majority of people infected with
HCV do not develop severe liver disease, and some may not need treatment, says
William Schwieterman, M.D., chief of the immunology and infectious diseases
branch in the Food and Drug Administration's Center for Biologics Evaluation
and Research (CBER). Most studies report that cirrhosis (advanced liver scarring)
develops in 10 percent to 20 percent of people with chronic HCV infection over
a period of 20 to 30 years. Liver cancer develops in 1 percent to 5 percent.
Those who do need treatment have more and better therapies today than were
available just a few years ago. Although treatments come with the risk of serious
side effects, many individuals with HCV infection are benefiting from them.
Disease in Decline
"The number of new cases is
going down precipitously," says
Jay Hoofnagle, M.D., director of
the division of digestive diseases
and nutrition at the NIDDK. During
the 1980s, an average of 230,000
new infections occurred each year
in the United States, according to
CDC estimates. But between 1989 and
1996, the annual number of new infections
declined by more than 80 percent,
to 36,000 reported cases. This decrease
may be explained by the introduction
of routine blood screening for HCV
antibodies in 1991 and improved testing
for the virus in 1992--lowering significantly
the risk of transmitting the virus
through blood transfusions.
Individuals who have the virus and are otherwise healthy may be at less risk
for severe liver damage than previously thought. Several studies led by Seeff
have shown that serious illness and death from liver disease in people infected
with HCV is by no means inevitable.
In a study published in the Jan.
18, 2000, issue of Annals of Internal
Medicine, Seeff examined the
records of more than 8,000 U.S. military
recruits. Blood samples taken from
the recruits between 1948 and 1956
were kept frozen and were tested
for the presence of HCV in recent
years, after testing became available.
Seventeen of the recruits were determined
to have acquired HCV at least 45
years earlier; these recruits had
similar hospital admission rates
over the 45-year period as those
who were HCV-negative. After 45 years,
only two of the 17 (11.8 percent)
showed evidence of liver disease;
one of these died from liver disease
42 years after initial testing.
In Seeff's more recent study, published
in the February 2001 issue of Hepatology,
he reported on nearly 600 people
who had received blood transfusions
in the 1970s. Approximately 67 percent
of the 222 people infected with HCV
had died 25 years later, compared
with 56 percent of the 377 non-infected
people who had died. Although these
numbers reflect deaths from all causes,
a liver-related cause for death was
more common among the HCV-infected
Treatments and Their Success
For some people with mild hepatitis C, the only treatment needed may be eating
a nutritious diet, avoiding alcohol, exercising regularly, and visiting a doctor
regularly to monitor the disease. But for others with hepatitis C, drug therapy
may be appropriate.
The FDA has approved two different
treatment regimens for chronic hepatitis
C: monotherapy (using a single drug,
interferon) and combination therapy
(using two drugs, interferon and
ribavirin). Interferon, which is
injected into the bloodstream, works
by bolstering the immune response
to HCV. Ribavirin, which is taken
orally, may work by preventing the
virus from reproducing (viral replication).
Taken alone, ribavirin does not effectively
suppress levels of the virus in the
bloodstream. But studies have shown
that the interferon and ribavirin
combination, approved in 1998, is
more effective than interferon alone.
The FDA has approved one ribavirin
product and four interferon products
to treat HCV. Rebetol, the ribavirin
product, is made by Schering-Plough
Corp. of Kenilworth, N.J. The interferon
products are: Intron A and PEG-Intron
(made by Schering-Plough), Roferon-A
(Hoffmann-La Roche Inc., Nutley,
NJ), and Infergen (Amgen Inc., Thousand
Oaks, Calif.). Intron A, Roferon-A,
and Infergen are considered "conventional"
interferons and are injected three
times a week. PEG-Intron (a longer-acting
form of interferon) is injected once
a week. Only Intron A and PEG-Intron
are approved for use in combination
The goal of treatment is sustained response--meaning that the virus is not
measurable in the blood after drug therapy is completed. Those who continue
to have measurable levels of the virus after treatment are considered non-responders.
Relapsers "clear" the virus during therapy or shortly thereafter,
but the virus returns after therapy ends.
About half of the people who initially
respond to monotherapy (interferon
There is no absolute way to know
who will or won't respond to therapy.
But health-care providers try to
predict responsiveness using research
tests to determine genotype and concentration
of HCV in the blood, says John Ticehurst,
M.D., a microbiologist and clinical
laboratory faculty member at the
Johns Hopkins Medical Institutions.
HCV concentration in the blood is
often referred to as "viral
An HCV genotype, which is also determined by a blood test, reflects the variation
in the genetic makeup of the virus. At least six different genotypes and many
more subtypes of HCV exist. In the United States, genotypes 1, 2 and 3 are most
People with genotypes 2 and 3 are almost three times more likely to respond
to therapy than those with genotype 1, according to NIDDK researchers. Unfortunately,
about 70 percent of HCV-infected people in the United States have genotype 1.
Genotyping also can be used to determine
the duration of treatment for many
people. For those with genotype 2
or 3, a 24-week course of combination
therapy is usually sufficient. Patients
with genotype 1 who have responded
at the end of 24 weeks of treatment
may benefit from an additional 24
weeks of treatment.
Historically, only 10 to 20 percent
of those treated with conventional
interferon alone had sustained responses,
depending on the interferon product
used. Combination therapy (conventional
interferon plus ribavirin) showed
better results, with 35 percent to
45 percent of those treated sustaining
the response, depending on genotype.
Studies have shown that PEG-Intron used with Rebetol is slightly more effective
than the conventional interferon Intron A with Rebetol. PEG-Intron with Rebetol
caused the same types of side effects as Intron A with Rebetol, but some occurred
Ken Gamache, of Middletown, Md.,
was diagnosed with hepatitis C in
1995, but believes that he became
infected over 30 years ago after
an operation. Gamache has genotype
1 HCV. He was treated initially with
monotherapy, and when that failed,
he tried combination therapy, again
When first told he needed a liver
transplant, Gamache thought it was
a death sentence. Now, after more
than five years on a waiting list
for a liver, he has more hope. "I
caught it early in the cirrhosis
process and am doing whatever I can
to prevent further damage,"
he says. Gamache still gets tired
and run down, but has learned to
pace himself. "I exercise regularly,
but don't overextend myself. I'm
careful to get enough sleep, eat
right, and take vitamins, and I don't
drink or smoke."
"Side effects are variable,"
says Adrian Di Bisceglie, M.D., medical
director of the American Liver Foundation
and professor of internal medicine
at St. Louis University. "About
10 percent of patients have virtually
no side effects. Approximately 10
percent have very severe, almost
disabling side effects and have to
stop work or stop the drug. The remaining
80 percent have side effects--but
they are tolerable."
For some people, the side effects
decrease after the first few weeks
of treatment. But many individuals
have severe side effects through
the duration of treatment; these
side effects may persist for months
after the treatment ends.
Patricia Buchanan of Brooklyn Park, Minn., suffered severe side effects throughout
the 19 months she was in treatment--first in a 24-week clinical trial with monotherapy,
and then in a 52-week treatment course with combination therapy after the monotherapy
Buchanan clearly remembers the completion of her therapy on Nov. 6, 1999. "When
you do chemotherapy for over a year, you remember the date of your last injection,"
she says. "I lived on my couch because of the extreme fatigue. I lost two-thirds
of my hair and I had nausea, fever, chills, body aches and terrible depression.
I went from having diarrhea to being constipated."
Because of interferon's potentially
serious side effects, the products
come with an FDA-approved medication
guide written for patients. Under
regulations that became effective
in 1999, pharmacists must distribute
a medication guide with products
that the FDA has determined pose
a serious risk and for which patient
guidelines can help prevent that
The guide for interferon products
lists both the common, less serious
side effects, and the rarer but potentially
life-threatening ones. The common
side effects include "flu-like"
symptoms, extreme fatigue, nausea
and loss of appetite, thyroid problems,
high blood sugar, hair loss, and
skin reactions (such as redness and
itching at the injection site). Possible
serious side effects are psychoses
or suicidal behavior, heart problems
(low blood pressure, heart attack),
other internal organ damage, blood
problems (blood counts falling dangerously
low), and new or worsening autoimmune
disease (such as rheumatoid arthritis).
Side effects of ribavirin, the oral
part of the combination therapy,
include anemia, fatigue, irritability,
skin rash, nasal stuffiness, sinusitis,
and cough. Ribavirin can also cause
birth defects, so pregnancy in female
patients and female partners of male
patients must be avoided during treatment
and for six months afterward.
To Treat or Not to Treat
"If we had a treatment that was safe, good, and not unpleasant, we should
treat everybody," says Seeff. Unfortunately, the length of treatment required,
the low rate of success, and the current treatments' side effects--the severity
of which is unpredictable from patient to patient--don't warrant treating everybody.
Treatment decisions should not be
based on symptoms, says DI Bisceglie.
"Patient symptoms are a very
unrelated guide to the severity of
hepatitis C. Someone can be feeling
very well and have severe hepatitis
on a liver biopsy. Some patients
have very profound symptoms, such
as fatigue, but HCV is trivial in
severity based on blood tests and
a liver biopsy."
The NIH and CDC recommend treating people with HCV infection who are at greatest
risk for progression to cirrhosis. These include individuals with four characteristics:
- a positive test for antibodies to HCV (meaning they were, or still are,
infected with HCV),
- persistently elevated blood levels of a liver enzyme called alanine aminotransferase
- a positive test for HCV RNA
(ribonucleic acid), which detects
virus in the blood, and
- a liver biopsy that shows either advanced fibrosis or moderate degrees
of inflammation and necrosis (death of living tissue).
For those with less severe liver damage, indications for treatment are less
"Patients, along with their physicians, need to carefully evaluate the
stage of their disease and other risk factors before deciding whether or not
to undergo treatment with interferon-based therapies," says the FDA's Schwieterman.
After discussing the pros and cons of interferon treatment with her doctor,
Helen Clark of Minnetonka, Minn., decided against it. Clark had acquired the
virus in 1970 during treatment for a severe form of dysentery she contracted
in Cozumel, Mexico. Following 18 life-saving blood transfusions, Clark continued
to feel ill for years, but doctors could find nothing wrong. They dismissed
her symptoms, telling her she was tired because she was a busy mother, or she
was menopausal. Some said that it was "all in her head" and that she
should see a psychiatrist. Finally, in 1997, a doctor diagnosed her with hepatitis
Clark has genotype 1 (the most resistant to treatment) and a high "viral
load." Her liver biopsy did not show any fibrosis after 27 years of infection.
So Clark decided she could live with the disease if she could do something about
her fatigue and other debilitating symptoms. "Now I pace myself, take naps,
and find ways to remove stress from my life."
Clark avoids red meat, which she
claims gives her liver pains after
eating. "And I haven't had a
drop of alcohol since diagnosis,"
she says. Alcohol is toxic to the
liver and can advance the progression
to cirrhosis. Clark also attributes
her decrease in symptoms to some
alternative therapies, including
Along with experiencing symptoms of the virus, individuals with HCV infection
often experience discrimination, says Clark. "People think you're an alcoholic
or drug addict. And they're afraid of you--there's such a misconception about
HCV is not spread through coughing, kissing, hugging, or casual contact. It
is spread only by contact with blood and possibly other body fluids.
People with HCV infection should cover any open wounds, and be careful not
to share personal care items such as toothbrushes, razors, and nail files.
It's possible to get the virus through unprotected sex with an infected partner.
However, studies--which have focused mainly on long-term monogamous couples--have
shown that transmission through sexual contact is rare.
There is a 5 percent risk that an HCV-positive mother can give the virus to
her unborn child. There is no evidence that HCV is transmitted from mother to
child through breastfeeding.
Diagnosis and Vaccination
DI Bisceglie encourages everyone at risk--not just those with symptoms--to
be tested for HCV. The FDA has approved two types of test for HCV. One type,
the enzyme immunoassay (EIA) test (also called enzyme-linked immunosorbent assay,
or ELISA) is usually the first laboratory test used to determine if someone
is infected with HCV. The EIA detects antibodies to the virus in a person's
The EIA is not always accurate--it
may show an infection when there
really isn't one. So if the EIA test
result is positive, an additional,
more expensive test is used to make
sure the person really is infected
with HCV. Until recently, the only
FDA-approved second test was the
recombinant immunoblot assay, RIBA,
made by Chiron Corporation, Emeryville,
Calif. The EIA and RIBA tests may
detect HCV infection, but do not
tell if the infection is active or
In July 2001, the FDA approved two
tests that do indicate if an infection
is active. These similar tests, made
by Roche Molecular Systems, Inc.,
of Pleasanton, Calif., are the Amplicor
HCV Test, v2.0 and the Cobas Amplicor
HCV Test, v2.0. Both are approved
for people who have evidence of liver
disease and antibody evidence of
HCV infection and who are suspected
to be actively infected with HCV.
The tests detect HCV RNA, indicating
that the virus is replicating and
therefore active. Either the Amplicor
or the Cobas Amplicor test may be
used as a follow-up to an EIA positive
test result, a RIBA positive result,
or an EIA positive and a RIBA inconclusive
The FDA has also approved an over-the-counter
home test system, called Hepatitis
C Check. Made by Home Access Health
Corp. of Hoffman Estates, Ill., the
product allows a person to take a
sample of blood at home and mail
it to a designated laboratory for
analysis with EIA and, when appropriate,
RIBA testing. The results are available
anonymously by phone through a unique
A liver biopsy to examine tissue from the liver is not necessary for diagnosing
HCV infection. "However, a biopsy is the only accurate way to check the
severity and stage of liver disease," says the NIDDK's Seeff.
Hepatitis C patients--whether they decide to get treated or not--should be
monitored regularly by their doctors. Patients not in treatment should have
a blood test approximately every six months to check liver functioning. A baseline
liver biopsy is recommended to establish the severity of HCV infection, and
the biopsy should be repeated in three to five years. Patients on treatment
will have additional and more frequent tests.
There is no vaccine for hepatitis
C, but there are vaccines for hepatitis
A and B. The CDC recommends these
vaccines, particularly the hepatitis
A vaccine, for HCV-positive individuals.
Becoming infected with hepatitis
A virus can be life threatening for
someone with HCV infection. In May
2001, the FDA approved a combined
hepatitis A and B vaccine called
Twinrix, marketed by SmithKline Beecham
Pharmaceuticals in Philadelphia.
An Individual Disease
"The progression of disease varies from person to person," says the
NIDDK's Hoofnagle. "Therapies are getting better, and some people have
time to wait."
Afraid they were running out of
time, Gamache and Buchanan sought
interferon treatment. For Gamache,
it didn't work, but Buchanan remains
"clear" (shows no detectable
virus in the blood). Clark is waiting,
hoping she won't need interferon
treatment or that something better
will come along. She is due for a
liver biopsy this year. Ultimately,
the decision to get treated or not
for HCV infection is up to the individual
and his or her health-care provider.
"We insist people be educated about their treatment options and the risks
involved," says Clark, who runs a support group with Buchanan to help people
with hepatitis learn more about their disease. The support group also helps
them deal with feelings of isolation, contamination, and fear. "It can
be very scary," says Clark. "It puts you face to face with your own
mortality and gives you a whole different perspective on life."
Gamache, who also joined a support group and volunteers at a hepatitis clinic,
recommends leading a healthy lifestyle and keeping a positive attitude. "Anything
you can do to help yourself, empower yourself, helps get rid of the sense of
hopelessness," he says. "It doesn't have to be a death sentence."
Hepatitis C Study
Researchers are conducting a large
study to try to prevent the development
of cirrhosis and liver cancer in
people with chronic hepatitis C.
Called Hepatitis C Antiviral Long-Term
Treatment Against Cirrhosis (HALT-C),
the four-year study is being conducted
at 10 research centers nationwide
and involves more than 1,300 participants.
The goal is to learn whether long-term
pegylated interferon plus ribavirin
treatment will decrease liver damage
over time in people with advanced
fibrosis or cirrhosis who didn't
respond to prior treatment. Pegylated
interferon is a, longer-acting form
of interferon than conventional interferons.
The study is sponsored by the National Institute of Diabetes and Digestive
and Kidney Diseases.
You May Be at Risk for Hepatitis C
- had a blood transfusion before 1992 (when screening blood for HCV antibodies
- shared needles for IV drug use (even if you injected drugs just once, many
- shared straws for inhaling cocaine
- had body (including ear) piercing and tattoos with unsterile equipment
- had hemodialysis (used a kidney machine)
- had frequent exposure to blood
products (have hemophilia, or had
chronic renal failure, cancer requiring
chemotherapy, or an organ transplant)
- had a needle-sticking accident (mainly a risk for health-care workers)
- used an infected person's toothbrush, razor or other item that may have
blood on it
- engaged in high-risk sexual behavior, such as having multiple partners
or failing to use condoms.