Hepatitis
C
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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. Almost 4 million Americans, or 1.8
percent of the U.S. population, 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. At least 75 percent of
patients with acute hepatitis C ultimately develop chronic
infection, and most of these patients have accompanying chronic
liver disease.
Chronic hepatitis C varies greatly in its course and outcome. At
one end of the spectrum are patients who have no signs or symptoms
of liver disease and completely normal levels of serum liver
enzymes. Liver biopsy usually shows some degree of chronic
hepatitis, but the degree of injury 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, HCV RNA in serum, and
elevated serum liver 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. After 20 to 40 years, a smaller percentage of
patients with chronic disease develop liver cancer. Liver failure
from chronic hepatitis C is one of the most common reasons for liver
transplants in the United States. 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 more likely to develop HCV-related
liver cancer.
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HCV is spread primarily by contact with blood and blood products.
Blood transfusions and the use of shared, unsterilized, or poorly
sterilized needles and syringes have been the main causes 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 the mid-1992, transfusion-related hepatitis C has virtually
disappeared. At present, injection drug use is the most common risk
factor for contracting the disease. However, many patients acquire
hepatitis C without any known exposure to blood or to drug use.
The major high-risk groups for hepatitis C are
- Injection drug users, including those who used drugs briefly
many years ago.
- People who had blood transfusions before June 1992, when
sensitive tests for anti-HCV were introduced for blood
screening.
- People who have frequent exposure to blood products. These
include patients with hemophilia, solid-organ transplants, chronic
renal failure, or cancer requiring chemotherapy.
- Infants born to HCV-infected mothers.
- Health care workers who suffer needle-stick
accidents.
Other groups who appear to be at slightly increased risk for
hepatitis C are
- people with high-risk sexual behavior, multiple partners, and
sexually transmitted diseases
- people who use cocaine, particularly with intranasal
administration, using shared equipment
Maternal-infant transmission is not common. In most studies, only
5 percent of infants born to infected women 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 and with complications of delivery such as early
rupture of membranes and fetal monitoring. Breast-feeding has not
been linked to spread of HCV.
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 less 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 and
HIV.
Sporadic transmission, when the source of infection is unknown,
occurs in about 10 percent of acute hepatitis C cases and in 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.
In many areas of the world, unsafe injection practices are an
important and common cause of hepatitis C (and hepatitis B as well).
Use of inadequately sterilized equipment, lack of disposable 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 nosocomial
spread of hepatitis C.
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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 6 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. | |
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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.
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
- ascites
- ankle swelling
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
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Anti-HCV is detected by enzyme immunoassay (EIA). The
third-generation test (EIA-3) used today is more sensitive and
specific than previous ones. However, as with all enzyme
immunoassays, 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 followup
testing. In these situations, HCV RNA is usually present and
confirms the diagnosis.
Immunoblot assays can be used to confirm anti-HCV reactivity as
well. 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 followup testing, including
attempts to confirm the specificity by repeat testing 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
aminotransferases 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. A PCR assay has now been approved by the Food
and Drug Administration for general use. This assay 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 is currently under
evaluation and may soon become available. Almost all patients with
chronic hepatitis C will test positive by these assays.
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
alpha interferon 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 1 million 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.
There are 6 known genotypes and more than 50 subtypes of
hepatitis C. The genotype of infection 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 interferon 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 often clinically helpful. Once
the genotype is identified, it need not be tested again; genotypes
do not change during the course of infection.
- In chronic hepatitis C, increases in the alanine and
aspartate aminotransferases range from 0 to 20 times (but
usually less than 5 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.
- Rheumatoid factor and low platelet and white blood cell
counts 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 and prothrombin time are normal until
late-stage disease.
- Iron and ferritin levels may be slightly elevated.
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Some 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.
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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 or iron
overload.
HCV causes the following changes in liver tissue:
- Necrosis and inflammation around 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, with early stages being confined to the portal
tracts, intermediate stages being expansion of the portal tracts
and bridging between portal areas or to the central area, and late
stages being frank cirrhosis characterized by architectural
disruption of the liver with fibrosis and regeneration. Several
scales are used to stage fibrosis, most commonly a scale from 0 to
4 where 0 indicates none and 4 indicates cirrhosis. Stage 1 and 2
fibrosis is limited to the portal and periportal areas. Stage 3
fibrosis is characterized by bridges of fibrosis bands linking up
portal and central areas.
Grading and staging of hepatitis by assigning scores for severity
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.
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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. More uncommon
complications include puncture of another organ, infection, and
bleeding. Significant bleeding after liver biopsy occurs in 1/100 to
1/1,000 cases, and deaths are reported in 1/5,000 to 1/10,000 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
necroinflammatory activity on liver biopsy. Furthermore, patients
who maintain ALT levels above 5 times the upper limit of normal
usually have marked necroinflammatory 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 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 low
platelet count (which is perhaps the earliest change), rheumatoid
factor, elevations in 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 perfect,
their presence should raise the suspicion of significant fibrosis
and lead to evaluation for treatment earlier rather than later.
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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 is diagnosed on the basis of symptoms such as
jaundice, fatigue, and nausea, along with marked increases in serum
ALT (usually greater than 10-fold elevation), and 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 establishing the
diagnosis.
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.
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
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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 interferons
(peginterferons). 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 been replacing standard
interferon both as monotherapy and as combination therapy for
hepatitis C.
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 threefold. 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.
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 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
kilograms (165 pounds) and 1,200 mg for those who weigh more than 75
kilograms. In certain situations, an 800-mg dose (400 mg twice
daily) is recommended (see below).
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, a proportion 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 approximately 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.
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 using
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.
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 alpha interferon 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.
Patients with cirrhosis found through liver biopsy can be offered
therapy if they do not have signs of decompensation, such as
ascites, persistent jaundice, wasting, variceal hemorrhage, or
hepatic encephalopathy. However, interferon and combination therapy
have not been shown to improve survival or the ultimate outcome in
patients with preexisting cirrhosis.
Patients older than 60 years also should be managed on an
individual basis, since the benefit of treatment in these patients
has not been well documented and side effects appear to be worse in
older patients. However, even patients in their late seventies have
been successfully treated for hepatitis C.
The role of interferon 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. The efficacy of peginterferon
and ribavirin in HIV-infected people has been tested in only a small
number of patients. Ribavirin may still have significant
interactions with other antiretroviral drugs.
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 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 what dose,
duration, and regimen of treatment to use. A practical regimen is
peginterferon monotherapy for 24 weeks. The possible role for
ribavirin, for short courses of therapy, and for lower doses of
peginterferon are under evaluation.
In patients with clinically significant extrahepatic
manifestations, such as cryoglobulinemia and glomerulonephritis,
therapy with alpha 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 alpha
interferon therapy can be used despite persistence of HCV RNA in
serum if clinical symptoms and signs resolve on therapy.
Therapy is inadvisable outside of controlled trials for patients
who have
- clinically decompensated cirrhosis because of hepatitis C
- normal aminotransferase levels
- a kidney, liver, heart, or other solid-organ transplant
- specific contraindications to either monotherapy or
combination therapy
Contraindications to alpha interferon 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, again, inability to practice birth
control.
Alpha interferon 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
preexisting serious psychiatric conditions and patients with
neurological disease.
Strict abstinence from alcohol is recommended during therapy with
interferon. Interferon therapy can be associated with relapse in
people with a previous history of drug or alcohol abuse. Therefore,
alpha 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 interferon-based therapy for hepatitis.
Alpha interferon 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 interferon therapy.
Alpha interferon has bone marrow suppressive effects. Therefore,
patients with bone marrow compromise or cytopenias, such as 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 preexisting
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. Alpha interferon 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.
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 may be helpful for the muscle aches
and low-grade fever. Fatigue and depression are occasionally so
troublesome that the dose of interferon should be decreased or
therapy stopped early. Depression and personality changes can occur
on interferon 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 interferon 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 preexisting anemia or with
significant coronary or cerebral vascular disease. If such patients
require therapy for hepatitis C, they should receive alpha
interferon 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 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.
|
| Make the diagnosis based on aminotransferase
elevations, anti-HCV and HCV RNA in serum, and
chronic hepatitis shown by liver
biopsy. | |
 |
| Assess for suitability of therapy and
contraindications. Discuss side effects and
possible treatment
outcomes. | |
|
|
|
|
| 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 mg weekly
or peginterferon alfa-2b in a dose of 1.5 mg/kg
weekly in combination with oral ribavirin in two
divided doses of 1,000 mg daily if body weight is
< 75 kilograms (165 lbs.) or 1,200 mg daily if
body weight is > 75
kilograms. | |
|
| 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 kilogram
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
aminotransferases. | |
|
| 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
aminotransferases at 2- to 6-month intervals. In
responders, repeat HCV RNA testing 6 months after
stopping. | | |
|
- 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 aminotransferases
to establish a baseline for these
values.
- Counsel the patient about the relative risks
and benefits of treatment. Side effects should
be thoroughly discussed.
| |
|
|
- Measure blood counts and aminotransferases
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 kilogram per week.
- In patients with genotype 1, measure HCV RNA
level 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 and a drop in
HCV RNA by 12 weeks should continue therapy for
48 weeks.
- At the end of therapy, test HCV RNA by PCR
to assess whether there is an end-of-treatment
response.
| |
|
|
- Measure aminotransferases every 2 months for
6 months.
- Six months after stopping therapy, test for
HCV RNA by PCR. If HCV RNA is still negative,
the chance for a long-term "cure" is excellent;
relapses have rarely been reported after this
point.
| | |
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 monotherapy may respond to a course of
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 non-responders is the
use of long-term or maintenance interferon, which is feasible only
if the peginterferon is well tolerated and has a clear-cut effect on
serum aminotransferases 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 other cytokines and the development of newer
antivirals, such as RNA polymerase, helicase, or protease
inhibitors.
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A major focus of hepatitis C research is developing a tissue
culture system that will enable researchers to study HCV outside the
human body. 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.
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 that
would reliably predict liver fibrosis would be a very valuable
advance.
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 receptor). 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. All of these
approaches remain experimental and few have been applied to humans.
The serious nature and the frequency of hepatitis C in the
population make the search for new therapies of prime
importance.
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.
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Patient education materials are available from:
American Liver
Foundation (ALF)
Centers for Disease Control
and Prevention
Hepatitis Foundation International
(HFI)
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