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 liver.
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 serious problem."
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 stomach pain.
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 persons.
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 with ribavirin.
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 alone) relapse.
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
load."
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 common.
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 more often.
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 without
success.
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."
Treatment Side Effects
"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 didn't work.
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
risk.
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 (ALT),
- 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 clear.
"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 C.
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 acupuncture.
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 the infectiousness."
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 blood.
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
inactive.
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 result.
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 identification number.
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
… if you have:
- had a blood transfusion before 1992 (when screening
blood for HCV antibodies started)
- shared needles for IV drug use (even if you injected
drugs just once, many years ago)
- 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.
