|
Chronic
Hepatitis C: Current
Disease Management
On this page:
The hepatitis C virus (HCV)
is one of the most
important causes of
chronic liver disease in
the United States. It
accounts for about 15
percent of acute viral
hepatitis, 60 to 70
percent of chronic
hepatitis, and up to 50
percent of cirrhosis,
end-stage liver disease,
and liver cancer. Of the
U.S.
population, 1.6 percent,
or an estimated 4.1
million Americans, have
antibody to HCV (anti-HCV),
indicating ongoing or
previous infection with
the virus. Hepatitis C
causes an estimated
10,000 to 12,000 deaths
annually in the United
States.
A distinct and major
characteristic of
hepatitis C is its
tendency to cause
chronic liver disease in
which the liver injury
persists for a prolonged
period if not for life.
About 75 percent of
patients with acute
hepatitis C ultimately
develop chronic
infection.
Chronic hepatitis C
varies greatly in its
course and outcome. At
one end of the spectrum
are infected persons who
have no signs or
symptoms of liver
disease and have
completely normal levels
of serum enzymes, the
usual blood test results
that indicate liver
disease. Liver biopsy
usually shows some
degree of injury to the
liver, but the extent is
usually mild, and the
overall prognosis may be
good. At the other end
of the spectrum are
patients with severe
hepatitis C who have
symptoms, high levels of
the virus (HCV RNA) in
serum, and elevated
serum enzymes, and who
ultimately develop
cirrhosis and end-stage
liver disease. In the
middle of the spectrum
are many patients who
have few or no symptoms,
mild to moderate
elevations in liver
enzymes, and an
uncertain prognosis.
Chronic hepatitis C can
cause cirrhosis, liver
failure, and liver
cancer. Researchers
estimate that at least
20 percent of patients
with chronic hepatitis C
develop cirrhosis, a
process that takes at
least 10 to 20 years.
Liver failure from
chronic hepatitis C is
one of the most common
reasons for liver
transplants in the
United States. After 20
to 40 years, a small
percentage of patients
develop liver cancer.
Hepatitis C is the cause
of about half of cases
of primary liver cancer
in the developed world.
Men, alcoholics,
patients with cirrhosis,
people over age 40, and
those infected for 20 to
40 years are at higher
risk of developing HCV-related
liver cancer.
Risk Factors and
Transmission
HCV is spread primarily
by contact with infected
blood and blood
products. Blood
transfusions and the use
of shared, unsterilized,
or poorly sterilized
needles, syringes and
injection equipment or
paraphernalia have been
the main routes of the
spread of HCV in the
United States. With the
introduction in 1991 of
routine blood screening
for HCV antibody and
improvements in the test
in mid-1992,
transfusion-related
hepatitis C has
virtually disappeared.
At present, injection
drug use is the most
common risk factor for
contracting the
infection. However, some
patients who acquire
hepatitis C do not have
a recognized risk factor
or known exposure to
infected blood or to
drug use.
The most common risk
factors for acquiring
hepatitis C are
-
injecting drugs,
including having
used injection drugs
only once many years
ago
-
having a blood
transfusion before
June 1992, when
sensitive tests for
anti-HCV were
introduced for blood
screening
-
receiving clotting
factor concentrates
(such as
anti-hemophilic
factor) before 1987,
when effective means
to inactive HCV were
introduced
-
hemodialysis for
kidney failure
-
birth to an HCV-infected
mother
-
suffering a
needle-stick
accident from a
person with
hepatitis C
Other risk factors that
have a slightly
increased risk for
hepatitis C are
-
having sex with
someone with
hepatitis C or
having multiple sex
partners
-
intranasal use of
cocaine using shared
equipment or
paraphernalia
Maternal-Infant
Transmission
Maternal-infant
transmission is not
common. In most studies,
less than 5 percent of
infants born to
HCV-infected mothers
become infected. The
disease in newborns is
usually mild and free of
symptoms. The risk of
maternal-infant spread
rises with the amount of
virus in the mother’s
blood, if the mother
also has human
immunodeficiency virus
(HIV) infection, or if
there are complications
of delivery such as
early rupture of
membranes and fetal
monitoring.
Breast-feeding has not
been linked to the
spread of HCV.
Sexual Transmission
Sexual transmission of
hepatitis C between
monogamous partners
appears to be uncommon.
Surveys of spouses and
monogamous sexual
partners of patients
with hepatitis C show
that fewer than 5
percent are infected
with HCV, and many of
these have other risk
factors for this
infection. Spread of
hepatitis C to a spouse
or partner in stable,
monogamous relationships
occurs in less than 1
percent of partners per
year. For these reasons,
changes in sexual
practices are not
recommended for
monogamous patients.
Testing sexual partners
for anti-HCV can help
with patient counseling.
People with multiple sex
partners should be
advised to follow safe
sex practices, which
should protect against
hepatitis C as well as
hepatitis B, HIV, and
other sexually
transmitted diseases.
Sporadic Transmission
Sporadic transmission,
when the source of
infection is unknown, is
the basis for about 10
percent of acute
hepatitis C cases and
for 30 percent of
chronic hepatitis C
cases. These cases are
usually referred to as
sporadic or
community-acquired
infections. These
infections may have come
from exposure to the
virus from cuts, wounds,
or medical injections or
procedures.
Unsafe Injection
Practices
In many areas of the
world, unsafe injection
practices in the
delivery of health care
are an important and
common cause of
hepatitis C (and
hepatitis B as well).
Use of inadequately
sterilized equipment,
reuse of needles and
syringes, and
inadvertent
contamination of medical
infusions are
unfortunately
well-documented causes
of transmission of
hepatitis C. Careful
attention to universal
precautions and
injection techniques
should prevent this type
of spread. In the United
States, multiple-use
vials are a frequent
culprit in leading to
medical-care linked
spread of hepatitis C.
The Hepatitis C Virus
HCV is a small (40 to 60
nanometers in diameter),
enveloped,
single-stranded RNA
virus of the family
Flaviviridae and genus
hepacivirus. Because the
virus mutates rapidly,
changes in the envelope
proteins may help it
evade the immune system.
There are at least six
major genotypes and more
than 50 subtypes of HCV.
The different genotypes
have different
geographic
distributions. Genotypes
1a and 1b are the most
common in the
United States (about 75
percent of cases).
Genotypes 2 and 3 are
present in only 10 to 20
percent of patients.
There is little
difference in the
severity of disease or
outcome of patients
infected with different
genotypes. However,
patients with genotypes
2 and 3 are more likely
to respond to interferon
treatment.
Clinical Symptoms and
Signs
Many people with chronic
hepatitis C have no
symptoms of liver
disease. If symptoms are
present, they are
usually mild,
nonspecific, and
intermittent. They may
include
-
fatigue
-
mild
right-upper-quadrant
discomfort or
tenderness (“liver
pain”)
-
nausea
-
poor appetite
-
muscle and joint
pains
Similarly, the physical
exam is likely to be
normal or show only mild
enlargement of the liver
or tenderness. Some
patients have vascular
spiders or palmar
erythema.
Clinical Features of
Cirrhosis
Once a patient develops
cirrhosis or if the
patient has severe
disease, symptoms and
signs are more
prominent. In addition
to fatigue, the patient
may complain of muscle
weakness, poor appetite,
nausea, weight loss,
itching, dark urine,
fluid retention, and
abdominal swelling.
Physical findings of
cirrhosis may include
-
enlarged liver
-
enlarged spleen
-
jaundice
-
muscle wasting
-
excoriations
(scratches or
abrasions on the
skin)
-
ascites
(fluid-filled belly)
-
ankle swelling
Extrahepatic
Manifestations
Complications that do
not involve the liver
develop in 1 to 2
percent of people with
hepatitis C; the most
common is
cryoglobulinemia, which
is marked by
-
skin rashes, such as
purpura, vasculitis,
or urticaria
-
joint and muscle
aches
-
kidney disease
-
neuropathy
-
cryoglobulins,
rheumatoid factor,
and low-complement
levels in serum
Other complications of
chronic hepatitis C are
-
glomerulonephritis
-
porphyria cutanea
tarda
Diseases that are less
well documented to be
related to hepatitis C
are
-
seronegative
arthritis
-
keratoconjunctivitis
sicca (Sjögren's
syndrome)
-
non-Hodgkin's type,
B-cell lymphomas
-
fibromyalgia
-
lichen planus
Serologic Tests
Enzyme Immunoassay
Persons suspected to
have hepatitis C should
be tested for anti-HCV
as an initial screening
test. Anti-HCV is
detected by enzyme
immunoassay (EIA). The
third-generation test
(EIA-3) used today is
more sensitive and
specific than previous
ones. As with all enzyme
immunoassays, however,
false-positive results
are occasionally a
problem with the EIA-3.
Additional or
confirmatory testing is
often helpful.
The best approach to
confirm the diagnosis of
hepatitis C is to test
for HCV RNA using a
sensitive assay such as
polymerase chain
reaction (PCR) or
transcription-mediated
amplification (TMA). The presence of HCV RNA in serum indicates an
active infection.
Testing for HCV RNA is
also helpful in patients
in whom EIA tests for
anti-HCV are unreliable.
For instance,
immunocompromised
patients may test
negative for anti-HCV
despite having HCV
infection because they
may not produce enough
antibodies for detection
with EIA. Likewise,
patients with acute
hepatitis may test
negative for anti-HCV
when first tested.
Antibody is present in
almost all patients by 1
month after onset of
acute illness; thus,
patients with acute
hepatitis who initially
test negative may need
follow-up testing. In
these situations, HCV
RNA is usually present
and confirms the
diagnosis.
Recombinant Immunoblot
Assay
Immunoblot assays can be
used to confirm anti-HCV
reactivity. These tests
are also called “Western
blots”; serum is
incubated on
nitrocellulose strips on
which four recombinant
viral proteins are
blotted. Color changes
indicate that antibodies
are adhering to the
proteins. An immunoblot
is considered positive
if two or more proteins
react and is considered
indeterminate if only
one positive band is
detected. In some
clinical situations,
confirmatory testing by
immunoblotting is
helpful, such as for the
person with anti-HCV
detected by EIA who
tests negative for HCV
RNA. The EIA anti-HCV
reactivity could
represent a
false-positive reaction,
recovery from hepatitis
C, or continued virus
infection with levels of
virus too low to be
detected (the last
occurs only rarely when
sensitive PCR or TMA
assays are used). If the
immunoblot test for
anti-HCV is positive,
the patient has most
likely recovered from
hepatitis C and has
persistent antibody. If
the immunoblot test is
negative, the EIA result
was probably a false
positive.
Immunoblot tests are
routine in blood banks
when an
anti-HCV-positive sample
is found by EIA.
Immunoblot assays are
highly specific and
valuable in verifying
anti-HCV reactivity.
Indeterminate tests
require further
follow-up testing,
including attempts to
confirm the specificity
by repeat testing for
HCV RNA.
Direct Assays for HCV
RNA
PCR and
TMA amplification can
detect low levels of HCV
RNA in serum. Testing
for HCV RNA is a
reliable way of
demonstrating that
hepatitis C infection is
present and is the most
specific test for
infection. Testing for
HCV RNA is particularly
useful when
aminotransferase levels
are normal or only
slightly elevated, when
anti-HCV is not present,
or when several causes
of liver disease are
possible. This method
also helps diagnose
hepatitis C in people
who are
immunosuppressed, have
recently had an organ
transplant, or have
chronic renal failure.
Currently available PCR
assays will detect HCV
RNA in serum down to a
lower limit of 50 to 100
copies per milliliter
(mL), which is
equivalent to 25 to 50
international units
(IU). A slightly more
sensitive
TMA test has recently become available. Almost all
patients with chronic
hepatitis C will test
positive by these
assays.
Biochemical Indicators
of Hepatitis C Virus
Infection
-
In chronic hepatitis
C, increases in the
alanine and
aspartate
amino-transferases
range from zero to
20 times (but
usually less than
five times) the
upper limit of
normal.
-
Alanine
aminotransferase (ALT) levels are usually higher than aspartate
aminotransferase
(AST) levels, but
that finding may be
reversed in patients
who have cirrhosis.
-
Alkaline phosphatase
and gamma glutamyl
transpeptidase are
usually normal. If
elevated, they may
indicate cirrhosis.
-
Low platelet and
white blood cell
counts and raised
levels of serum
globulins (including
immunoglobulins and
rheumatoid factor)
are frequent in
patients with severe
fibrosis or
cirrhosis, providing
clues to the
presence of advanced
disease.
-
The enzymes lactate
dehydrogenase and
creatine kinase are
usually normal.
-
Albumin levels,
bilirubin, and
prothrombin time are
normal until
late-stage disease.
-
Iron and ferritin
levels may be
slightly elevated.
Quantification of HCV
RNA in Serum
Several methods are
available for measuring
the concentration or
level of virus in serum,
which is an indirect
assessment of viral
load. These methods
include a quantitative
PCR and a branched
DNA (bDNA) test.
Unfortunately, these
assays are not well
standardized, and
different methods from
different laboratories
can provide different
results on the same
specimen. In addition,
serum levels of HCV RNA
can vary spontaneously
by 3- to 10-fold over
time. Nevertheless, when
performed carefully,
quantitative assays
provide important
insights into the nature
of hepatitis C. Most
patients with chronic
hepatitis C have levels
of HCV RNA (viral load)
between 100,000 (105)
and 10,000,000 (107)
copies per mL. Expressed
as IU, these averages
are 50,000 to 5 million
IU.
Viral levels as measured
by HCV RNA do not
correlate with the
severity of the
hepatitis or with a poor
prognosis (as in HIV
infection); but viral
load does correlate with
the likelihood of a
response to antiviral
therapy. Rates of
response to a course of
peginterferon and
ribavirin are higher in
patients with low levels
of HCV RNA. There are
several definitions of a
“low level” of HCV RNA,
but the usual definition
is below 800,000 IU (~ 2
million copies) per mL.
In addition, monitoring
HCV RNA levels during
the early phases of
treatment may provide
early information on the
likelihood of a
response. Yet because of
the shortcomings of the
current assays for HCV
RNA level, these tests
are not always reliable
guides to therapy.
Genotyping and
Serotyping of HCV
There are six known
genotypes and more than
50 subtypes of hepatitis
C. The genotype is
helpful in defining the
epidemiology of
hepatitis C. More
important, knowing the
genotype or serotype
(genotype-specific
antibodies) of HCV is
helpful in making
recommendations and
counseling regarding
therapy. Patients with
genotypes 2 and 3 are
two to three times more
likely to respond to
interferon-based therapy
than patients with
genotype 1. Furthermore,
when using combination
therapy, the recommended
dose and duration of
treatment depend on the
genotype. For patients
with genotypes 2 and 3,
a 24-week course of
combination treatment
using peginterferon and
800 milligrams (mg) of
ribavirin daily is
adequate, whereas for
patients with genotype
1, a 48-week course and
full dose of ribavirin
(1,000 to 1,200 mg
daily) is recommended.
For these reasons,
testing for HCV genotype
is clinically important.
Once the genotype is
identified, it need not
be tested again;
genotypes do not change
during the course of
infection.
Normal Serum ALT Levels
Up to 40 percent of
patients with chronic
hepatitis C have normal
serum alanine
aminotransferase (ALT) levels, even when tested on multiple
occasions. In this and
other situations in
which the diagnosis of
chronic hepatitis C may
be questioned, the
diagnosis should be
confirmed by testing for
HCV RNA. The presence of
HCV RNA indicates that
the patient has ongoing
viral infection despite
normal
ALT levels.
Liver Biopsy
Liver biopsy is not
necessary for diagnosis
but is helpful for
grading the severity of
disease and staging the
degree of fibrosis and
permanent architectural
damage. Hematoxylin and
eosin stains and
Masson’s trichrome stain
are used to grade the
amount of necrosis and
inflammation and to
stage the degree of
fibrosis. Specific
immunohistochemical
stains for HCV have not
been developed for
routine use. Liver
biopsy is also helpful
in ruling out other
causes of liver disease,
such as alcoholic liver
injury, nonalcoholic
fatty liver disease, or
iron overload.
HCV causes the following
changes in liver tissue:
-
Necrosis and
inflammation at the
edge of the portal
areas, so-called
“piecemeal necrosis”
or “interface
hepatitis”
-
Necrosis of
hepatocytes and
focal inflammation
in the liver
parenchyma
-
Inflammatory cells
in the portal areas
(“portal
inflammation”)
-
Fibrosis may exist
in an early stage,
being confined to
the portal tracts,
an intermediate
stage consisting of
expansion of the
portal tracts and
bridging between
portal areas or to
the central area, or
a late stage of
frank cirrhosis
characterized by
architectural
disruption of the
liver with fibrosis
and regeneration.
Several scales are
used to stage
fibrosis. One common
classification is a
scale from 0 to 4
where stage 0
indicates no
fibrosis; stage 1
indicates
enlargement of the
portal areas by
fibrosis; stage 2
indicates fibrosis
extending out from
the portal areas
with rare bridges
between portal
areas; stage 3
indicates many
bridges of fibrosis
that link up portal
and central areas of
the liver; and stage
4 indicates
cirrhosis.
By assigning scores for
severity, grading and
staging of hepatitis are
helpful in managing
patients with chronic
hepatitis. The degree of
inflammation and
necrosis can be assessed
as none, minimal, mild,
moderate, or severe. The
degree of fibrosis can
be similarly assessed.
Scoring systems are
particularly helpful in
clinical studies on
chronic hepatitis.
Noninvasive Tests
While liver biopsy is
considered the “gold
standard” for assessing
the severity of liver
disease, it is not
always accurate and has
several shortcomings.
Liver biopsy can under-
or over-estimate the
severity of hepatitis C,
particularly if the
biopsy is small and if
it is not read by a
knowledgeable expert. In
addition, liver biopsy
is an invasive procedure
that is expensive and
not without
complications. At least
20 percent of patients
have pain requiring
medications after liver
biopsy. Rare
complications include
puncture of another
organ, infection, and
bleeding. Significant
bleeding after liver
biopsy occurs in one out
of 100 to one out of
1,000 cases, and deaths
are reported in one out
of 5,000 to one out of
10,000 cases. Obviously,
noninvasive means of
grading and staging
liver disease would be
very helpful.
ALT levels, particularly if tested over an extended
period, are reasonably
accurate reflections of
disease activity. Thus,
patients with repeatedly
normal
ALT levels usually have
mild inflammation and
liver cell injury on
liver biopsy.
Furthermore, patients
who maintain
ALT levels above five times the upper limit of
normal usually have
marked inflammatory
activity. But for the
majority of patients
with mild to moderate
ALT elevations, the
actual level is not very
predictive of liver
biopsy findings.
More important is a
means to stage liver
disease and measure
fibrosis short of liver
biopsy. Unfortunately,
serum tests are not
reliable in predicting
fibrosis, particularly
earlier stages (0, 1,
and 2). When patients
develop bridging (stage
3) fibrosis and
cirrhosis (stage 4),
serum tests may be
helpful. The “danger
signals” that suggest
the presence of advanced
fibrosis include an
aspartate
aminotransferase (AST)
that is higher than ALT
(reversal of the ALT/AST
ratio), a high gamma
glutamyl transpeptidase
or alkaline phosphatase,
a decrease in platelet
count (which is perhaps
the earliest change),
elevations in serum
globulins, and, of
course, abnormal
bilirubin, albumin, or
prothrombin time.
Physical findings of a
firm liver, or enlarged
spleen or prominent
spider angionata or
palmar erythema, are
also danger signals.
While none of these
findings are completely
reliable, their presence
should raise the
suspicion of significant
fibrosis and lead to
evaluation for treatment
sooner rather than
later.
Recently, x-ray and
imaging studies have
been developed that may
be able to separate
different degrees of
fibrosis in the liver.
At present, these
techniques are
experimental and of
unproven accuracy,
particularly in
detecting early stages
of fibrosis. The most
promising technique is “elastrography,”
in which sound or
magnetic waves are
passed through the liver
and the speed with which
they return is measured,
which provides an index
of the elasticity and
stiffness of the liver.
Liver stiffness is used
as an indirect measure
of liver fibrosis. Most
importantly, measuring
the relative stiffness
of the liver over time
may provide a
noninvasive way to
monitor the development
of fibrosis and help
guide recommendations
for when therapy should
be recommended.
Ultrasound elastrography
is currently under
evaluation for its
reliability in measuring
the degree of fibrosis
in the liver in patients
with hepatitis C.
Ultimately,
elastrography may be
able to replace liver
biopsy as a way of
monitoring the
progression of disease
in chronic hepatitis C.
Diagnosis
Hepatitis C is most
readily diagnosed when
serum aminotransferases
are elevated and anti-HCV
is present in serum. The
diagnosis is confirmed
by the finding of HCV
RNA in serum.
Acute Hepatitis C
Acute hepatitis C is
diagnosed in persons who
have symptoms such as
jaundice, fatigue, and
nausea, together with
marked increases in
serum ALT (usually
greater than 10-fold
elevation), and the
presence of anti-HCV or
de novo development of anti-HCV.
Diagnosis of acute
disease can be
problematic because
anti-HCV is not always
present when the patient
develops symptoms and
sees the physician. In
30 to 40 percent of
patients, anti-HCV is
not detected until 2 to
8 weeks after onset of
symptoms. In this
situation, testing for
HCV RNA is helpful, as
this marker is present
even before the onset of
symptoms and lasts
through the acute
illness. Another
approach to diagnosis of
acute hepatitis C is to
repeat the anti-HCV
testing a month after
onset of illness. Of
course, a history of an
acute exposure is also
helpful in suggesting
the diagnosis.
Chronic Hepatitis C
Chronic hepatitis C is
diagnosed when anti-HCV
is present and serum
aminotransferase levels
remain elevated for more
than 6 months. Testing
for HCV RNA (by
PCR) confirms the diagnosis and documents that
viremia is present;
almost all patients with
chronic infection will
have the viral genome
detectable in serum by
PCR.
Diagnosis is problematic
in patients who cannot
produce anti-HCV because
they are
immunosuppressed or
immunoincompetent. Thus,
HCV RNA testing may be
required for patients
who have a solid-organ
transplant, are on
dialysis, are taking
corticosteroids, or have
agammaglobulinemia.
Diagnosis is also
difficult in patients
with anti-HCV who have
another form of liver
disease that might be
responsible for the
liver injury, such as
alcoholism, iron
overload, or
autoimmunity. In these
situations, the anti-HCV
may represent a
false-positive reaction,
previous HCV infection,
or mild hepatitis C
occurring on top of
another liver condition.
HCV RNA testing in these
situations helps confirm
that hepatitis C is
contributing to the
liver problem.
Differential Diagnosis
The major conditions
that can be confused
clinically with chronic
hepatitis C include
-
autoimmune hepatitis
-
chronic hepatitis B
and D
-
alcoholic hepatitis
-
nonalcoholic
steatohepatitis
(fatty liver)
-
sclerosing
cholangitis
-
Wilson’s disease
-
alpha-1-antitrypsin-deficiency-related
liver disease
-
drug-induced liver
disease
Treatment
Alpha Interferon
The therapy for chronic
hepatitis C has evolved
steadily since alpha
interferon was first
approved for use in this
disease more than 10
years ago. At the
present time, the
optimal regimen appears
to be a 24- or 48-week
course of the
combination of pegylated
alpha interferon and
ribavirin.
Alpha interferon is a
host protein that is
made in response to
viral infections and has
natural antiviral
activity. Recombinant
forms of alpha
interferon have been
produced, and several
formulations (alfa-2a,
alfa-2b, consensus
interferon) are
available as therapy for
hepatitis C. These
standard forms of
interferon, however, are
now being replaced by
pegylated interferon (peginterferon).
Peginterferon is alpha
interferon that has been
modified chemically by
the addition of a large
inert molecule of
polyethylene glycol.
Pegylation changes the
uptake, distribution,
and excretion of
interferon, prolonging
its half-life.
Peginterferon can be
given once weekly and
provides a constant
level of interferon in
the blood, whereas
standard interferon must
be given several times
weekly and provides
intermittent and
fluctuating levels. In
addition, peginterferon
is more active than
standard interferon in
inhibiting HCV and
yields higher sustained
response rates with
similar side effects.
Because of its ease of
administration and
better efficacy,
peginterferon has
replaced standard
interferon both as
monotherapy and as
combination therapy for
hepatitis C.
Ribavirin
Ribavirin is an oral
antiviral agent that has
activity against a broad
range of viruses. By
itself, ribavirin has
little effect on HCV,
but adding it to
interferon increases the
sustained response rate
by two- to three-fold.
For these reasons,
combination therapy is
now recommended for
hepatitis C, and
interferon monotherapy
is applied only when
there are specific
reasons not to use
ribavirin.
Combination Therapy
Combination therapy
leads to rapid
improvements in serum
ALT levels and
disappearance of
detectable HCV RNA in up
to 70 percent of
patients. However,
long-term improvement in
hepatitis C occurs only
if HCV RNA disappears
during therapy and stays
undetectable once
therapy is stopped.
Among patients who
become HCV RNA negative
during treatment, some
will relapse when
therapy is stopped. The
relapse rate is lower in
patients treated with
combination therapy
compared with
monotherapy. Thus, a
48-week course of
combination therapy
using peginterferon and
ribavirin yields a
sustained response rate
of about 55 percent. A
similar course of
peginterferon
monotherapy yields a
sustained response rate
of only 35 percent. A
response is considered
“sustained” if HCV RNA
remains undetectable for
6 months or more after
stopping therapy.
Dosing
Two forms of
peginterferon have been
developed and studied in
large clinical trials:
peginterferon alfa-2a
(Pegasys: Hoffman La
Roche, Nutley, NJ) and
peginterferon alfa-2b
(Pegintron:
Schering-Plough
Corporation, Kenilworth,
NJ). These two products
are roughly equivalent
in efficacy and safety,
but have different
dosing regimens.
-
Peginterferon
alfa-2a is given
subcutaneously in a
fixed dose of 180
micrograms (mcg) per
week.
-
Peginterferon
alfa-2b is given
subcutaneously
weekly in a
weight-based dose of
1.5 mcg per kilogram
(kg) per week (thus
in the range of 75
to 150 mcg per
week).
Ribavirin is an oral
medication, given twice
a day in 200-mg capsules
for a total daily dose
based upon body weight.
The standard dose of
ribavirin is 1,000 mg
for patients who weigh
less than 75 kg (165
pounds) and 1,200 mg for
those who weigh more
than 75 kg. In certain
situations, an 800-mg
dose (400 mg twice
daily) is recommended
(see
Duration).
Duration
The optimal duration of
treatment varies
depending on whether
interferon monotherapy
or combination therapy
is used, as well as by
HCV genotype. For
patients treated with
peginterferon
monotherapy, a 48-week
course is recommended,
regardless of genotype.
For patients treated
with combination
therapy, the optimal
duration of treatment
depends on viral
genotype. Patients with
genotypes 2 and 3 have a
high rate of response to
combination treatment
(70 to 80 percent), and
a 24-week course of
combination therapy
yields results
equivalent to those of a
48-week course. In
contrast, patients with
genotype 1 have a lower
rate of response to
combination therapy (40
to 45 percent), and a
48-week course yields a
significantly better
sustained response rate.
Again, because of the
variable responses to
treatment, testing for
HCV genotype is
clinically useful when
considering starting
combination therapy.
In addition, the optimal
dose of ribavirin
appears to vary
depending on genotype.
For patients with
genotypes 2 or 3, a dose
of 800 mg daily appears
adequate. For patients
with genotype 1, the
full dose of ribavirin
(1,000 or 1,200 mg daily
depending on body
weight) appears to be
needed for an optimal
response.
There is little
information on the
optimal regimen of
peginterferon and
ribavirin for patients
with the rare genotypes
4, 5, and 6. These
patients should probably
receive the regimen of
peginterferon and
ribavirin that is
recommended for genotype
1.
Many attempts have been
made to identify
patients who have a
rapid response to
treatment and who might
be able to stop
peginterferon and
ribavirin early and be
spared the further
expense and side effects
of prolonged therapy.
Patients who test HCV
RNA negative within 4
weeks of starting
therapy are considered
“rapid responders.” In
several studies, rapid
responders with
genotypes 2 and 3 have
been found to be able to
stop therapy after 12 to
16 weeks (12 to 8 weeks
early) and still achieve
a high rate of response.
Similarly, rapid
responders with genotype
1 may be able to stop
therapy at 24 weeks (24
weeks early) and achieve
an excellent response
rate. The consequence of
early stopping, however,
is a higher relapse rate
and this approach of
abbreviating therapy in
rapid responders must be
individualized based
upon tolerance.
Who should be treated?
Patients with anti-HCV,
HCV RNA, elevated serum
aminotransferase levels,
and evidence of chronic
hepatitis on liver
biopsy, and with no
contraindications,
should be offered
therapy with the
combination of
peginterferon and
ribavirin. The National
Institutes of Health
Consensus Development
Conference Panel
recommended that therapy
for hepatitis C be
limited to those
patients who have
histological evidence of
progressive disease.
Thus, the panel
recommended that all
patients with fibrosis
or moderate to severe
degrees of inflammation
and necrosis on liver
biopsy should be treated
and that patients with
less severe histological
disease be managed on an
individual basis.
Patient selection should
not be based on the
presence or absence of
symptoms, the mode of
acquisition, the
genotype of HCV RNA, or
serum HCV RNA levels.
Between 30 and 40
percent of patients with
chronic hepatitis C have
normal serum
aminotransferase levels.
These patients usually
have mild disease that
is unlikely to progress.
Nevertheless, such
patients may wish to be
treated and, indeed,
response rates to
peginterferon and
ribavirin appear to be
independent of serum
aminotransferase levels.
Patients who prefer not
to be treated at present
should be monitored as
advances in the field
may ultimately lead to
more effective and
better tolerated
therapies. When
questions arise
regarding treatment,
liver biopsy can be
helpful in documenting
the level of disease
activity and liver
fibrosis and thus the
advisability of waiting
for future improvements
in therapy.
Patients with cirrhosis
can be offered therapy
if they do not have
signs of decompensation,
such as ascites,
persistent jaundice,
wasting, variceal
hemorrhage, or hepatic
encephalopathy. However,
combination therapy has
not been shown to
improve survival or the
ultimate outcome in
patients with
pre-existing cirrhosis.
The role of
peginterferon and
ribavirin therapy in
children with hepatitis
C remains uncertain.
Ribavirin has yet to be
evaluated adequately in
children, and pediatric
doses and safety have
not been established.
Thus, if children with
hepatitis C are treated,
monotherapy is
recommended, and
ribavirin should not be
used outside of
controlled clinical
trials.
People with both HCV and
HIV infection should be
offered therapy for
hepatitis C as long as
there are no
contraindications.
Indeed, hepatitis C
tends to be more rapidly
progressive in patients
with HIV co-infection,
and end-stage liver
disease has become an
increasingly common
cause of death in
HIV-positive persons.
For these reasons,
therapy for hepatitis C
should be recommended
even in HIV-infected
patients with early and
mild disease. Once HIV
infection becomes
advanced, complications
of therapy are more
difficult and response
rates are less. The
decision to treat people
co-infected with HIV
must take into
consideration the
concurrent medications
and medical conditions.
In particular, ribavirin
may have significant
interactions with
anti-retroviral drugs
used to treat HIV
infection. In patients
with co-infection,
control of the HIV
infection should be the
first priority; in
persons who are
inadequately treated for
HIV or who have low CD4
counts, therapy of
concurrent HCV is
unlikely to be
successful and may have
serious complications.
In many of these
indefinite situations,
the indications for
therapy should be
reassessed at regular
intervals. In view of
the rapid developments
in hepatitis C today,
better therapies may
become available within
the next few years, at
which point expanded
indications for therapy
would be appropriate.
Patients with chronic
hepatitis C should be
advised on the
likelihood of a
beneficial outcome to
antiviral therapy. For
patients with genotypes
2 and 3, the likelihood
of a sustained
virological response is
70 to 80 percent. In
patients with genotype
1, the likelihood of a
sustained virological
response is between 40
and 55 percent, but the
individual likelihood
correlates with several
viral and patient
factors. The major
predictive factor for a
response is the level of
HCV RNA in serum:
response rates being
higher if HCV RNA levels
are lower—levels less
than 800,000 IU/ml
generally being
considered low.
Furthermore, response
rates are higher in
women than men, in
younger than older
persons, in persons with
normal body weight
compared with those who
are overweight or obese,
and in persons with
lesser degrees of
fibrosis on liver
biopsy. Strikingly,
response rates are also
higher among Caucasian
Americans and Asian
Americans than among
African American
patients. Thus, average
overall response rates
in persons with HCV
genotype 1 infection are
50 to 60 percent among
Caucasian Americans, but
only 25 to 30 percent
among African American
patients. The reasons
for these racial
differences are not
known.
Patients with acute
hepatitis C are a major
challenge to management
and therapy. Because
such a high proportion
of patients with acute
infection develop
chronic hepatitis C,
prevention of chronicity
has become a focus of
attention. In small
studies, 83 to 100
percent of persons
treated within 1 to 4
months of onset have had
resolution of the
infection. What is
unclear is when to
initiate treatment, at
what dose, for what
duration, and with which
regimen. A practical but
rigorous approach is to
start peginterferon (in
usual doses) and
ribavirin (800 mg daily)
for 24 weeks if HCV RNA
is still detected 3
months after onset of
infection. The role of
ribavirin and the use of
shorter courses of
therapy are currently
under evaluation.
In patients with
clinically significant
extrahepatic
manifestations, such as
cryoglobulinemia and
glomerulonephritis,
therapy with interferon
can result in remission
of the clinical symptoms
and signs. However,
relapse after stopping
therapy is common. In
some patients, long-term
or maintenance
peginterferon therapy
can be used despite
persistence of HCV RNA
in serum if clinical
symptoms and signs
resolve on therapy.
Who should not be
treated?
Therapy is inadvisable
outside of controlled
trials for patients who
have
-
clinically
decompensated
cirrhosis because of
hepatitis C
-
kidney, liver,
heart, or other
solid-organ
transplant
-
specific
contraindications to
either monotherapy
or combination
therapy
Contraindications to
peginterferon therapy
include severe
depression or other
neuropsychiatric
syndromes, active
substance or alcohol
abuse, autoimmune
disease (such as
rheumatoid arthritis,
lupus erythematosus, or
psoriasis) that is not
well controlled, bone
marrow compromise, and
inability to practice
birth control.
Contraindications to
ribavirin and thus
combination therapy
include marked anemia,
renal dysfunction, and
coronary artery or
cerebrovascular disease,
and inability to
practice birth control.
Peginterferon has
multiple
neuropsychiatric
effects. Prolonged
therapy can cause marked
irritability, anxiety,
personality changes,
depression, and even
suicide or acute
psychosis. Patients
particularly susceptible
to these side effects
are those with
pre-existing serious
psychiatric conditions
and patients with
neurological disease.
Strict abstinence from
alcohol is recommended
during therapy of
hepatitis C.
Peginterferon therapy
can be associated with
relapse in people with a
previous history of drug
or alcohol abuse.
Therefore, interferon
should be given with
caution to a patient who
has only recently
stopped alcohol or
substance abuse.
Typically, a 6-month
abstinence is
recommended before
starting therapy, but
this should be applied
only to patients with a
history of alcohol
abuse, not to social
drinkers. Patients with
continuing alcohol or
substance abuse problems
should only be treated
in collaboration with
alcohol or substance
abuse specialists or
counselors. Patients can
be successfully treated
while on methadone or in
an active substance
abuse program. Indeed,
the rigor and regular
monitoring that
accompany methadone
treatment provide a
structured format for
combination therapy. The
dose of methadone may
need to be modified
during
peginterferon-based
therapy for hepatitis.
Peginterferon therapy
can induce
autoantibodies, and a
24- to 48-week course
triggers an autoimmune
condition in about 2
percent of patients,
particularly if they
have an underlying
susceptibility to
autoimmunity (high
titers of antinuclear or
antithyroid antibodies,
for instance).
Exacerbation of a known
autoimmune disease (such
as rheumatoid arthritis
or psoriasis) occurs
commonly during
peginterferon therapy.
Peginterferon has bone
marrow suppressive
effects. Therefore,
patients with bone
marrow compromise or
cytopenias, such as a
low platelet count (<
75,000 cells/mm3) or
neutropenia (< 1,000
cells/mm3), should be
treated cautiously and
with frequent monitoring
of cell counts. These
side effects appear to
be more common with
peginterferon than
standard interferon.
Ribavirin causes red
cell hemolysis to a
variable degree in
almost all patients.
Therefore, patients with
a pre-existing hemolysis
or anemia (hemoglobin <
11 grams [g] or
hematocrit < 33 percent)
should not receive
ribavirin. Similarly,
patients who have
significant coronary or
cerebral vascular
disease should not
receive ribavirin, as
the anemia caused by
treatment can trigger
significant ischemia.
Fatal myocardial
infarctions and strokes
have been reported
during combination
therapy with alpha
interferon and
ribavirin.
Growth factors such as
erythropoietin to raise
red blood cell counts or
granulocyte stimulating
factor to raise
neutrophil counts have
been used successfully
to treat patients with
cytopenias during
combination therapy. The
proper role, dose, and
side effects of these
adjunctive therapies
have yet to be defined.
Ribavirin is excreted
largely by the kidneys.
Patients with renal
disease can develop
hemolysis that is severe
and even
life-threatening.
Patients who have
elevations in serum
creatinine above 2.0 mg
per deciliter (dL)
should not be treated
with ribavirin.
Finally, ribavirin
causes birth defects in
animal studies and
should not be used in
women or men who are not
practicing adequate
means of birth control.
Peginterferon also
should not be used in
pregnant women, as it
has direct antigrowth
and antiproliferative
effects.
Combination therapy
should therefore be used
with caution. Patients
should be fully informed
of the potential side
effects before starting
therapy.
A common question is
whether liver biopsy is
necessary before
starting treatment of
hepatitis C. The answer
is that it is not
necessary but is prudent
and provides rationale
for whether therapy is
critical. Nevertheless,
the major use of liver
biopsy is to help in the
decision of whether to
initiate treatment or to
delay until there are
further advances in the
field. In some
situations, liver biopsy
may not be very helpful.
Patients with genotype 2
and 3, for instance,
have a high rate of
response and might be
offered therapy
regardless of the
severity of hepatitis
shown by liver biopsy.
Furthermore, patients
with genotype 1 who have
laboratory or clinical
evidence of advanced
fibrosis can be assumed
to have progressive
liver disease, and
therapy can be
recommended without
biopsy documentation.
Finally, some patients
wish to be treated
regardless of severity
of the underlying
hepatitis and the liver
biopsy results will not
alter medical care. As
response rates to
therapy of hepatitis C
improve, liver biopsy
will play a lesser role
in management.
Side Effects of
Treatment
Common side effects of
alpha interferon and
peginterferon (occurring
in more than 10 percent
of patients) include
-
fatigue
-
muscle aches
-
headaches
-
nausea and vomiting
-
skin irritation at
the injection site
-
low-grade fever
-
weight loss
-
irritability
-
depression
-
mild bone marrow
suppression
-
hair loss
(reversible)
Most of these side
effects are mild to
moderate in severity and
can be managed. They are
worse during the first
few weeks of treatment,
especially with the
first injection.
Thereafter, side effects
diminish. Acetaminophen
or a nonsteroidal
anti-inflammatory drug
(NSAID) such as
ibuprofen or naproxen
may be helpful for the
muscle aches and
low-grade fever. Fatigue
and depression are
occasionally so
troublesome that the
dose of peginterferon
should be decreased or
therapy stopped early.
Depression and
personality changes can
occur on peginterferon
therapy and be quite
subtle and not readily
admitted by the patient.
These side effects need
careful monitoring.
Patients with depression
may benefit from
antidepressant therapy
using selective
serotonin reuptake
inhibitors. Generally,
the psychiatric side
effects resolve within 2
to 4 weeks of stopping
combination therapy.
Ribavirin also causes
side effects, and the
combination is generally
less well tolerated than
peginterferon
monotherapy. The most
common side effects of
ribavirin are
-
anemia
-
fatigue and
irritability
-
itching
-
skin rash
-
nasal stuffiness,
sinusitis, and cough
Ribavirin causes a
dose-related hemolysis
of red cells; with
combination therapy,
hemoglobin usually
decreases by 2 to 3 g/dL
and the hematocrit by 5
to 10 percent. The
amount of decrease in
hemoglobin is highly
variable. The decrease
starts between weeks 1
and 4 of therapy and can
be precipitous. Some
patients develop
symptoms of anemia,
including fatigue,
shortness of breath,
palpitations, and
headache.
The sudden drop in
hemoglobin can
precipitate angina
pectoris in susceptible
people, and fatalities
from acute myocardial
infarction and stroke
have been reported in
patients receiving
combination therapy for
hepatitis C. For these
important reasons,
ribavirin should not be
used in patients with
pre-existing anemia or
with significant
coronary or cerebral
vascular disease. If
such patients require
therapy for hepatitis C,
they should receive
peginterferon
monotherapy.
Ribavirin has also been
found to cause itching
and nasal stuffiness.
These are histamine-like
side effects; they occur
in 10 to 20 percent of
patients and are usually
mild to moderate in
severity. In some
patients, however,
sinusitis, recurrent
bronchitis, or
asthma-like symptoms
become prominent. It is
important that these
symptoms be recognized
as attributable to
ribavirin, because dose
modification (by 200 mg
per day) or early
discontinuation of
treatment may be
necessary.
Uncommon side effects of
alpha interferon,
peginterferon, and
combination therapy
(occurring in less than
2 percent of patients)
include
-
autoimmune disease
(especially thyroid
disease)
-
severe bacterial
infections
-
marked
thrombocytopenia
-
marked neutropenia
-
seizures
-
depression and
suicidal ideation or
attempts
-
retinopathy
(microhemorrhages)
-
hearing loss and
tinnitus
Rare side effects
include acute congestive
heart failure, renal
failure, vision loss,
pulmonary fibrosis or
pneumonitis, and sepsis.
Deaths have been
reported from acute
myocardial infarction,
stroke, suicide, and
sepsis.
A unique but rare side
effect is paradoxical
worsening of the
disease. This effect is
assumed to be caused by
induction of autoimmune
hepatitis, but its cause
is really unknown.
Because of this
possibility,
aminotransferases should
be monitored. If
ALT
levels rise to greater
than twice the baseline
values, therapy should
be stopped and the
patient monitored. Some
patients with this
complication have
required corticosteroid
therapy to control the
hepatitis.
Options for Patients Who
Do Not Respond to
Treatment
Few options exist for
patients who either do
not respond to therapy
or who respond and later
relapse. Patients who
relapse after a course
of interferon or
peginterferon
monotherapy may respond
to a course of
peginterferon and
ribavirin combination
therapy, particularly if
they became and remained
HCV RNA negative during
the period of
monotherapy. The
response rates and
optimal dose (800 vs.
1,000 mg to 1,200 mg of
ribavirin) and duration
(24 or 48 weeks) of
peginterferon and
ribavirin for relapse or
previous nonresponder
patients have not been
defined. The algorithm
for treatment given
above is for treatment
of naive patients.
An experimental approach
to treatment of
nonresponders is the use
of long-term or
maintenance
peginterferon, which is
feasible only if the
peginterferon is well
tolerated and has a
clear-cut effect on
serum aminotransferase
levels or liver
histology, despite lack
of clearance of HCV RNA.
This approach is now
under evaluation in
long-term clinical
trials in the United
States. New medications
and approaches to
treatment are needed.
Most promising for the
future are the use of
newer antivirals, such
as RNA polymerase,
helicase, or protease
inhibitors.
Algorithm for Treatment
Make the diagnosis based on aminotransferase
elevations, anti-HCV,
and HCV RNA in serum.
Assess for suitability of therapy and
contraindications.
Discuss side effects and
the likelihood of a
beneficial treatment
outcome.
Test for HCV genotype.
Consider doing a liver
biopsy to assess the
severity of the
underlying hepatitis and
need for current
therapy.
Genotype 1:
Test for HCV RNA level
immediately before
starting therapy
(baseline level).
Genotype 1:
Start therapy with
peginterferon alfa-2a in
a dose of 180 mcg weekly
or peginterferon alfa-2b
in a dose of 1.5 mcg per
kg weekly in combination
with oral ribavirin in
two divided doses of
1,000 mg daily if body
weight is < 75 kg (165
lbs) or 1,200 mg daily
if > 75 kg.
Genotype 2 or 3:
Start therapy with
peginterferon alfa-2a in
a dose of 180 mcg weekly
or with alfa-2b in a
dose of 1.5 mcg per kg
weekly and oral
ribavirin 800 mg daily
in two divided doses.
All patients:
At weeks 1, 2, and 4 and
then at intervals of
every 4 to 8 weeks
thereafter, assess side
effects, symptoms, blood
counts, and
aminotransferase levels.
Genotype 1:
At week 12, retest for
HCV RNA level. If HCV
RNA is negative or has
decreased by at least
two log10
units (such as from 2
million IU to 20,000 IU
or from 500,000 IU to
5,000 IU or less),
continue therapy for a
full 48 weeks,
monitoring symptoms,
blood counts, and ALT at
4- to 8-week intervals.
If HCV RNA has not
fallen by two log10 units, stop therapy.
Genotype 2 or 3:
At 24 weeks, assess
aminotransferase levels
and HCV RNA and stop
therapy.
All patients:
After therapy, assess
aminotransferase levels
at 2- to 6-month
intervals. In
responders, repeat HCV
RNA testing 6 months
after stopping.
Considerations: Before,
During, and After
Therapy
Before Starting Therapy
-
Do a liver biopsy to
confirm the
diagnosis of HCV,
assess the grade and
stage of disease,
and rule out other
diagnoses. In
situations where a
liver biopsy is
contraindicated,
such as clotting
disorders,
combination therapy
can be given without
a pretreatment liver
biopsy.
-
Test for serum HCV
RNA to document that
viremia is present.
-
Test for HCV
genotype (or
serotype) to help
determine the
duration of therapy
and dose of
ribavirin.
-
Measure blood counts
and aminotransferase
levels to establish
a baseline for these
values.
-
Counsel the patient
about the relative
risks and benefits
of treatment. Side
effects should be
thoroughly
discussed.
During Therapy
-
Measure blood counts
and aminotransferase
levels at weeks 1,
2, and 4 and at 4-
to 8-week intervals
thereafter.
-
Adjust the dose of
ribavirin downward
(by 200 mg at a
time) if significant
anemia occurs
(hemoglobin less
than 10 g/dL or
hematocrit < 30
percent) and stop
ribavirin if severe
anemia occurs
(hemoglobin < 8.5
g/dl or hematocrit <
26 percent).
-
Adjust the dose of
peginterferon
downward if there
are intolerable side
effects such as
severe fatigue,
depression, or
irritability or
marked decreases in
white blood cell
counts (absolute
neutrophil count
below 500 cells/mm3)
or platelet counts
(decrease below
30,000 cells/mm3).
When using
peginterferon
alfa-2a, the dose
can be reduced from
180 to 135 and then
to 90 mcg per week.
When using
peginterferon
alfa-2b, the dose
can be reduced from
1.5 to 1.0 and then
to 0.5 mcg per kg
per week.
-
In patients with
genotype 1, measure
HCV RNA levels
immediately before
therapy and again
(by the same method)
at week 12. Therapy
can be stopped early
if HCV RNA levels
have not decreased
by at least two log10
units, as studies
have shown that
genotype 1 patients
without this amount
of decrease in HCV
RNA are unlikely to
have a sustained
response (likelihood
is < 1 percent). In
situations where HCV
RNA levels are not
obtainable, repeat
testing for HCV RNA
by PCR (or TMA)
should be done at 24
weeks and therapy
stopped if HCV RNA
is still present, as
a sustained response
is unlikely.
-
Reinforce the need
to practice strict
birth control during
therapy and for 6
months thereafter.
-
Measure
thyroid-stimulating
hormone levels every
3 to 6 months during
therapy.
-
Patients with
genotypes 2 or 3 can
stop therapy at 24
weeks. Patients with
genotype 1 who are
HCV RNA negative at
24 weeks should
continue therapy to
a full 48 weeks.
-
At the end of
therapy, test HCV
RNA by
PCR
to assess whether
there is an
end-of-treatment
response.
After Therapy
-
Measure
aminotransferase
levels every 2
months for 6 months.
-
Six months after
stopping therapy,
test for HCV RNA by
PCR (or TMA). If HCV
RNA is still
negative, the chance
for a long-term
“cure” is excellent;
relapses have rarely
been reported after
this point.
Hope Through Research
Basic Research
A major focus of
hepatitis C research has
been to develop a tissue
culture system that will
enable researchers to
study HCV outside the
human body. This goal
was achieved in part in
2005 when three
different laboratories
reported tissue culture
systems using HCV,
genotype 2. These
systems are now being
improved and used to
study how the virus
infects cells and
whether spread can be
blocked by antibodies
and by different
antiviral drugs. Animal
models and molecular
approaches to the study
of HCV are also
important. Understanding
how the virus replicates
and how it injures cells
would be helpful in
developing a means of
controlling it and in
screening for new drugs
that would block it.
Diagnostic Tests
More sensitive and less
expensive assays for
measuring HCV RNA and
antigens in the blood
and liver are needed.
Although current tests
for anti-HCV are quite
sensitive, a small
percentage of patients
with hepatitis C test
negative for anti-HCV
(false-negative
reaction), and a
percentage of patients
who test positive are
not infected
(false-positive
reaction). Also, there
are patients who have
resolved the infection
but still test positive
for anti-HCV. Convenient
tests to measure HCV in
serum and to detect HCV
antigens in liver tissue
would be helpful.
Clinically, noninvasive
tests such as ultrasound
elastrography that would
reliably predict liver
fibrosis would be a very
valuable advance.
New Treatments
Most critical for the
future is the
development of new
antiviral agents for
hepatitis C. Most
interesting will be
specific inhibitors of
HCV-derived enzymes such
as protease, helicase,
and polymerase
inhibitors. Drugs that
inhibit other steps in
HCV replication may also
be helpful in treating
this disease, by
blocking production of
HCV antigens from the
RNA (IRES inhibitors),
preventing the normal
processing of HCV
proteins (inhibitors of
glycosylation), or
blocking entry of HCV
into cells (by blocking
its receptors). In
addition, nonspecific
cytoprotective agents
might be helpful for
hepatitis C by blocking
the cell injury caused
by the virus infection.
Further, molecular
approaches to treating
hepatitis C are worthy
of investigation; these
consist of using
ribozymes, which are
enzymes that break down
specific viral RNA
molecules, and antisense
oligonucleotides, which
are small complementary
segments of DNA that
bind to viral RNA and
inhibit viral
replication. The serious
nature and the frequency
of hepatitis C in the
population make the
search for new therapies
of prime importance.
Prevention
At present, the only
means of preventing new
cases of hepatitis C are
to screen the blood
supply, encourage health
professionals to take
precautions when
handling blood and body
fluids, and inform
people about high-risk
behaviors. Programs to
promote needle exchange
offer some hope of
decreasing the spread of
hepatitis C among
injection drug users.
Furthermore, all drug
users should receive
instruction in safer
injection
techniques—simple
interventions that can
be life-saving. Vaccines
and immunoglobulin
products do not exist
for hepatitis C, and
development seems
unlikely in the near
future because these
products would require
antibodies to all the
genotypes and variants
of hepatitis C.
Nevertheless, advances
in immunology and
innovative approaches to
immunization make it
likely that some form of
vaccine for hepatitis C
will eventually be
developed.
|
