Chronic Hepatitis C Current Disease Management: NIDDK
Article title: Chronic Hepatitis C Current Disease Management: NIDDK
Main condition: Chronic Hepatitis C
Conditions: Chronic Hepatitis C, Hepatitis C
Also see:
What Do I
Need To Know About Hepatitis C?
The hepatitis C virus (HCV) is one of the most
important causes of chronic liver disease in the United States. It
accounts for about 20 percent of acute viral hepatitis, 60 to 70 percent
of chronic hepatitis, and 30 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
8,000 to 10,000 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.
Researchers
estimate that at least 20 percent of patients with chronic hepatitis C
develop cirrhosis, a process that takes 10 to 20 years. After 20 to 40
years, a smaller percentage of patients with chronic disease develop liver
cancer.
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Chronic hepatitis C can cause cirrhosis, liver failure, and
liver cancer. About 20 percent of patients develop cirrhosis within
10 to 20 years of the onset of infection. Liver failure from chronic
hepatitis C is one of the most common reasons for liver transplants
in the United States. Hepatitis C might be the most common cause of
primary liver cancer in the developed world. In Italy, Spain, and
Japan, at least half of liver cancers could be related to HCV. 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 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
- 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.
- Health care workers who suffer needle-stick accidents.
- Injection drug users, including those who used drugs briefly many
years ago.
- Infants born to HCV-infected mothers.
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
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. Breast-feeding has not been linked to HCV's
spread.
Sexual Transmission
Sexual transmission of hepatitis C between
monogamous partners appears to be uncommon. Whether hepatitis C is spread
by sexual contact has not been conclusively proven, and studies have been
contradictory. 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. For
this reason, 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
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 also
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.
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The Hepatitis C Virus
HCV is a small
(40 to 60 nm in diameter), enveloped, single-stranded RNA
virus of the family Flaviviridae. Because the virus mutates
rapidly, changes in the envelope protein 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. 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 alpha
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
- Nausea
- Poor appetite
- Muscle and joint pains.
Similarly, the physical exam is likely to be normal or show only mild
hepatomegaly 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
- Ascites
- 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.
Enzyme Immunoassay
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 polymerase chain reaction (PCR) assay. 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 the physician first tests. 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.
Recombinant Immunoblot Assay
Immunoblot assays are used to
confirm anti-HCV reactivity, too. 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 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
without virus. 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 Amplification
PCR 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 by PCR 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. At
present, however, there are no PCR assays approved by the Food and Drug
Administration for general use, although commercial test systems are
available. Many commercial laboratories offer their own PCR assays, which
are not subject to strict independent quality controls. Thus, the
reliability and specificity of the PCR technique are not standardized. In
addition, it is expensive and prone to technical or laboratory error. When
ordering HCV RNA testing by PCR, the physician should use a high-quality
laboratory willing to document standardization of the test.
Biochemical Indicators of Hepatitis C Virus 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 levels are usually higher than
aspartate aminotransferase 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 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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Quantification of HCV RNA in Serum
Several methods are available
for measuring the titer 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
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.
Viral load does not correlate with the severity of the hepatitis or
with a poor prognosis (as it seems to 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 2 million copies
per milliliter (mL).
In addition, monitoring viral load 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 reliable guides to therapy. More sensitive and reliable methods of
quantitating HCV RNA in serum are needed. Until that time, these tests
should not be routinely used in practice.
Genotyping and Serotyping of HCV
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. 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 almost three times more likely to respond to therapy with
alpha interferon or the combination of alpha interferon and ribavirin.
Furthermore, when using combination therapy, the recommended duration of
treatment depends on the genotype. For patients with genotypes 2 and 3, a
24-week course of combination treatment is adequate, whereas for patients
with genotype 1, a 48-week course 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.
Normal Serum ALT Levels
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.
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.
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.
Immunostaining using polyclonal or monoclonal
antibodies to detect HCV antigens in the liver has been reported to be
useful. However, these tests are not commercially available, and, even in
the hands of research investigators, immunostaining detects HCV antigens
in liver tissue in only 60 to 70 percent of patients with chronic
hepatitis C--largely in those with high levels of HCV in serum. This test
also requires special handling of liver tissue and thus is not appropriate
for routine clinical use.
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 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 presents to the physician with symptoms.
In 30 to 40 percent of patients, anti-HCV is not detected until 2 to 8
weeks after onset of symptoms. Acute hepatitis C can also be diagnosed by
testing for HCV RNA, but another approach is to repeat the anti-HCV
testing a month after onset of illness.
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
- Medication-induced liver disease.
In the United States, two different regimens
have been approved as therapy for hepatitis C:
- Monotherapy with alpha interferon
- Combination therapy with alpha interferon and ribavirin.
Combination therapy consistently yields higher rates of
sustained response than monotherapy. Combination treatment is more
expensive and is associated with more side effects than monotherapy, but,
in most situations, it is preferable. At present, interferon monotherapy
should be reserved for patients who have contraindications to the use of
ribavirin.
Several forms of alpha interferon are available (alfa-2a, alfa-2b, and
consensus interferon). These interferons are given subcutaneously three
times weekly in doses of 3 million units (MU) or, in the case of consensus
interferon, 9 µg per injection. Ribavirin, in contrast, is an oral
antiviral agent that is given twice a day in 200-mg capsules for a total
daily dose of 1,000 mg for patients who weigh less than 75 kilograms (165
pounds) or 1,200 mg for those who weigh more than 75 kilograms.
Treatment with interferon alone or combination therapy with interferon
and ribavirin leads to rapid improvements in serum ALT levels in 50 to 75
percent of patients and the disappearance of detectable HCV RNA from the
serum in 30 to 50 percent. However, a long-term improvement in liver
disease usually occurs only if HCV RNA disappears during therapy and stays
undetectable when therapy is stopped.
A response is considered to be "sustained" if HCV RNA remains
undetectable for 6 months or more after therapy stops. With interferon
monotherapy, 30 to 35 percent of patients become HCV RNA negative with
treatment, but almost half of these relapse when treatment stops: The
sustained response rate, therefore, averages only 15 to 20 percent.
Combination therapy with interferon and ribavirin, however, leads to loss
of HCV RNA on treatment in 50 to 55 percent of patients and a sustained
loss in 35 to 45 percent. Thus, combination treatment results in both a
higher rate of loss of HCV RNA on treatment and a lower rate of relapse
when treatment is stopped.
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 interferon 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 (60 to 70 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 (25 to 35 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.
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 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.
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.
In people with both HCV and HIV infection, benefits of therapy for
hepatitis C have only recently been evaluated. The decision to treat
people co-infected with HIV must take into consideration the concurrent
medications and medical conditions. If CD4 counts are normal or minimally
abnormal (> 400/mL), responses are similar in frequency to those in
patients who are not infected with HIV. The efficacy of combination
therapy 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.
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,
continual, long-term alpha interferon 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.
- 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. Patients with continuing problems of
alcohol or substance abuse should only be treated in collaboration with
alcohol or substance abuse specialists or councilors. Patients can be
successfully treated while on methadone.
Alpha interferon therapy can induce autoantibodies, and a 6- to
12-month 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.
Ribavirin causes red cell hemolysis to a variable degree in almost all
patients. Therefore, patients with a preexisting hemolysis or anemia
(hemoglobin < 11 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.
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/dL should
not be treated with ribavirin.
Finally, ribavirin causes birth defects in animal studies and should
not be used in women 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.
Side Effects of Treatment
Common side effects of alpha interferon
(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, and side effects may be less troublesome if interferon is taken in
the evening. 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.
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 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.
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
monotherapy may respond to a 24-week course of combination therapy,
particularly if they became and remained HCV RNA negative during the
period of monotherapy. Another approach is the use of long-term or
continual interferon, which is feasible only if the interferon is well
tolerated and has a clear-cut effect on serum aminotransferases and liver
histology, despite lack of clearance of HCV RNA. New medications and
approaches to treatment are needed. Most promising for the immediate
future are newer forms of "long-acting" interferons, which are alpha
interferons that are modified by polyethylene glycol (PEG) so that they
can be given once a week and yet provide a sustained level of interferon.
These "pegylated" formulations may avoid the peaks and troughs of
interferon levels and interferon side effects that occur when it is given
three times a week. Pegylated interferons and other experimental drugs
such as recombinant interleukin 10 (IL-10), are now being evaluated in
prospective controlled trials. Other promising approaches are the use of
other cytokines and the development 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, and chronic hepatitis shown by liver biopsy.
| |
|
| Assess for suitability of
therapy and contraindications.
| |
| |
|
|
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| Discuss side effects and
possible outcomes of
treatment. | |
| |
| Start therapy with alpha
interferon 3 million units by subcutaneous injection
thrice weekly and oral ribavirin 1,000 or 1,200 mg
daily. | |
| |
| 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. | |
| |
| At 24 weeks, assess
aminotransferase levels and HCV RNA. In patients with
genotypes 2 and 3, stop therapy. In patients with
genotype 1, stop therapy if HCV RNA is still positive,
but continue therapy for a total of 48 weeks if HCV RNA
is negative, retesting for HCV RNA at the end of
treatment. | |
| |
| After therapy, assess
aminotransferases at 2- to 6-month intervals. In
responders, repeat HCV RNA testing 6 months after
stopping. | | |
| Before Starting Therapy |
- Do a liver biopsy to confirm the diagnosis of
hepatitis C virus (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.
- Measure serum HCV RNA by polymerase chain reaction
(PCR) to document that viremia is present.
- Test for HCV genotype (or serotype) to help
determine the duration of therapy.
- 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.
| |
|
| During Therapy |
- 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).
- Measure HCV RNA by PCR at 24 weeks. If HCV RNA is
still present, stop therapy. If HCV RNA is negative
and patient had genotype 1 (1a or 1b), continue
therapy for another 24 weeks.
- 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.
- At the end of therapy, test HCV RNA by PCR to
assess whether there is an end-of-treatment
response.
| |
|
| After Therapy |
- 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.
| | |
Basic Research
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 the virus 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.
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 receptor).
Nonspecific cytoprotective agents might also 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 have not 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.
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. 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.
Alter, M. J. (1996). Epidemiology of hepatitis C.
European Journal of Gastroenterology & Hepatology, 8(4), 319-323.
American Medical Association. (1995). Prevention, diagnosis, and
management of viral hepatitis: A guide for primary care physicians[Fact
sheet]. Chicago, IL.
Centers for Disease Control and Prevention. (Accessed 1996, November 25).
Hepatitis A to E. http://www.cdc.gov/ncidod/diseases/hepatitis/slideset/httoc.htm
Centers for Disease Control and Prevention. (1998). Recommendations for
prevention and control of hepatitis C virus (HCV) infection and HCV-related
chronic disease. Morbidity and Mortality Weekly Report, 47,1-39.
Hoofnagle, J. H., & Di Bisceglie, A. M. (1997). The treatment of chronic
viral hepatitis. New England Journal of Medicine, 336(5), 347-356.
Lemon, S. M., & Thomas, D. L. (1997). Vaccines to prevent viral
hepatitis. New England Journal of Medicine, 336(5), 196-204.
McDonnell, W. M., & Lok, A. S. (1996). Testing for hepatitis C virus RNA
in serum: When and how? Viral Hepatitis Reviews, 2(2), 81-83.
McHutchison, J. G., Gordon, S. C., Schiff, E. R., et al. (1998). Interferon
alfa-2b alone or in combination with ribavirin as initial treatment for chronic
hepatitis. New England Journal of Medicine, 339(21), 1485-1492.
Proceedings of the National Institutes of Health Consensus Development
Conference (1997). Management of hepatitis C. Hepatology, 26(Supplement
1).
Strader, D. B., & Seeff, L. B. (1996). The natural history of chronic
hepatitis C infection. European Journal of Gastroenterology & Hepatology,
8(4), 324-328.
The National Digestive Diseases Information Clearinghouse (NDDIC)
has patient education materials on hepatitis C. To obtain free copies, contact
the clearinghouse at
NDDIC
2 Information Way
Bethesda, MD 20892-3570
Tel:
(301) 654-3810
Fax: (301) 907-8906
E-mail: National Digestive
Diseases Information Clearinghouse
Home page: www.niddk.nih.gov/health/digest/digest.htm
Patient education materials are also available from
American Liver Foundation
75 Maiden Lane, Suite 603
New
York, NY 10038
Tel: (800) GO-LIVER (465-4837)
E-mail: info@liverfoundation.org
Home
page: www.liverfoundation.org/
Hepatitis Foundation International
30 Sunrise Terrace
Cedar Grove, NJ
07009-1423
Tel: (800) 891-0707 or (201) 239-1035
Home page: www.hepfi.org/
National Digestive Diseases Information Clearinghouse
2 Information Way
Bethesda, MD 20892-3570
Tel: (301)
654-3810
Fax: (301) 907-8906
E-mail: National Digestive
Diseases Information Clearinghouse
The National Digestive Diseases Information Clearinghouse (NDDIC) is a
service of the National Institute of Diabetes and Digestive and Kidney Diseases
(NIDDK). NIDDK is part of the National Institutes of Health under the U.S.
Department of Health and Human Services. Established in 1980, the clearinghouse
provides information about digestive diseases to people with digestive disorders
and to their families, health care professionals, and the public. NDDIC answers
inquiries; develops, reviews, and distributes publications; and works closely
with professional and patient organizations and Government agencies to
coordinate resources about digestive diseases.
Publications produced by the clearinghouse are carefully reviewed for
scientific accuracy, content, and readability.
This e-text is not copyrighted. The clearinghouse encourages users of this
e-pub to duplicate and distribute as many copies as desired.
NIH Publication No. 99-4230
May 1999
Updated: November 2000
