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 endstage 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. 

National Digestive Diseases Information Clearinghouse

National

Institute of

Diabetes and

Digestive 

and Kidney

Diseases

NATIONAL

INSTITUTES

OF HEALTH

Chronic Hepatitis C:

Current Disease Management

U.S. Department

of Health and

Human Services
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.

2 Chronic Hepatitis C: Current Disease Management
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.

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.

3 Chronic Hepatitis C: Current Disease Management

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.

HCV Viral Components

Envelope

(E1 and E2)

protein complex

Nucleocapsid

(core) protein

RNA

genome
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.

4 Chronic Hepatitis C: Current Disease Management
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.

5 Chronic Hepatitis C: Current Disease Management
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.

6 Chronic Hepatitis C: Current Disease Management

Biochemical Indicators of

Hepatitis C Virus Infection

• In chronic hepatitis C, increases in

the alanine and aspartate aminotransferases 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.
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

7 Chronic Hepatitis C: Current Disease Management
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. 

8 Chronic Hepatitis C: Current Disease Management
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.

9 Chronic Hepatitis C: Current Disease Management
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 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.

10 Chronic Hepatitis C: Current Disease Management
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 next page).

11 Chronic Hepatitis C: Current Disease Management
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

12 Chronic Hepatitis C: Current Disease Management
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

13 Chronic Hepatitis C: Current Disease Management
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 solidorgan 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.

14 Chronic Hepatitis C: Current Disease Management
15 Chronic Hepatitis C: Current Disease Management

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 lifethreatening. 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.
16 Chronic Hepatitis C: Current Disease Management

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.

17 Chronic Hepatitis C: Current Disease Management
18 Chronic Hepatitis C: Current Disease Management

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 longterm 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

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.

Genotype 1: Test for HCV RNA level immediately

before starting therapy (baseline level).

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: 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.
19 Chronic Hepatitis C: Current Disease Management

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.
20 Chronic Hepatitis C: Current Disease Management

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.
21 Chronic Hepatitis C: Current Disease Management

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.
Selected Review Articles

and References

Alter HJ, Seeff LB. Recovery, persistence,

and sequelae in hepatitis C virus infection:

a perspective on long-term outcome. Seminars in Liver Disease. 2000;20(1):17–35.

Armstrong GL, Wasley A, Simard EP, et al.

The prevalence of hepatitis C virus infection in the United States, 1999 through

2002. Annals of Internal Medicine.

2006;144:705–714.

Centers for Disease Control and Prevention. Hepatitis A to E. Available at:

www.cdc.gov/ncidod/diseases/hepatitis/

slideset/httoc.htm. Accessed November 25,

1996.

Centers for Disease Control and Prevention. Recommendations for prevention and

control of hepatitis C virus (HVC) infection and HVC-related chronic disease.

Morbidity and Mortality Weekly Report.

1998;47:1–39.

Conjeevaram HS, Fried MW, Jeffers LJ, et

al. Peginterferon and ribavirin treatment in

African American and Caucasian American

patients with chronic hepatitis C genotype 1.

Gastroenterology. 2006;131:470–477.

Fried MW, Shiffman ML, Reddy KR, et al.

Peginterferon alfa-2a plus ribavirin for

chronic hepatitis C infection. New England

Journal of Medicine. 2002;347:972–982.

Hadziyannis SJ, Sette H Jr, Morgan TR, et

al. Peginterferon alfa-2a and ribavirin combination therapy in chronic hepatitis C: a

randomized study of treatment duration

and ribavirin dose. Annals of Internal Medicine. 2004;140:346–355.

Liang TJ, Reherman B, Seeff LB, Hoofnagle JH. Pathogenesis, natural history, treatment, and prevention of hepatitis C.

Annals of Internal Medicine.

2000;132:296–305.

Manns MP, McHutchison JG, Gordon SC,

et al. Peginterferon alfa-2b plus ribavirin

compared with interferon alfa-2b plus ribavirin for initial treatment of chronic hepatitis C: a randomised trial. Lancet.

2001;358:958–965.

McHutchison JG, Gordon SC, Schiff ER,

et al. Interferon alfa-2b alone or in combination with ribavirin as initial treatment for

chronic hepatitis C. New England Journal

of Medicine. 1998;339(21):1485–1492.

Proceedings of the June 10–12 “Management of Hepatitis C: 2002. National Institutes of Health Consensus Development

Conference Update.” Hepatology.

2002;36(5, part 2).

Strader DB, Wright T, Thomas DL, Seeff

LB. Diagnosis, management, and treatment of hepatitis C. Hepatology.

2004;39:1147–1171.

22 Chronic Hepatitis C: Current Disease Management
Patient Education Materials

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

Phone: 1–800–891–5389

Fax: 703–738–4929

Email: nddic@info.niddk.nih.gov

Internet: www.digestive.niddk.nih.gov

Patient education materials are also available from

American Liver Foundation

75 Maiden Lane, Suite 603

New York, NY 10038

Phone: 1–800–GO–LIVER (465–4837) 

1–888–4HEP–USA (443–7222) 

212–668–1000

Fax: 212–483–8179

Email: info@liverfoundation.org

Internet: www.liverfoundation.org

Centers for Disease Control 

and Prevention 

1600 Clifton Road NE

Mail Stop G37

Atlanta, GA 30333

Phone: 404–371–5900

Fax: 404–371–5488

Internet: www.cdc.gov

Viral Hepatitis and Injection Drug Users

fact sheet available at

www.cdc.gov/idu/hepatitis/index.htm

Hepatitis Foundation International

504 Blick Drive

Silver Spring, MD 20904–2901

Phone: 1–800–891–0707 or 301–622–4200

Email: hepfi@hepfi.org

Internet: www.hepfi.org

23 Chronic Hepatitis C: Current Disease Management

The U.S. Government does not endorse or favor

any specific commercial product or company.

Trade, proprietary, or company names appearing

in this document are used only because they are

considered necessary in the context of the information provided. If a product is not mentioned,

the omission does not mean or imply that the

product is unsatisfactory.

You may also find additional information on this

topic using the following databases:

The NIDDK Reference Collection is a collection

of thousands of materials produced for patients

and health care professionals, including fact

sheets, brochures, and audiovisual materials.

Visit www.catalog.niddk.nih.gov/resources.

MedlinePlus is the consumer version of 

MEDLINE with easy access to medical journal

articles, medical dictionaries, directories, drug

and supplement lists, interactive patient tutorials,

publications, and the latest health news. Visit

www.medlineplus.org.

This publication may contain information about

medications used to treat a health condition.

When this publication was prepared, the NIDDK

included the most current information available.

Occasionally, new information about medication

is released. For updates or for questions about

any medications, please contact the U.S. Food

and Drug Administration at 1–888–INFO–FDA

(463–6332), a toll-free call, or visit their website

at www.fda.gov. Consult your doctor for more

information.
U.S. DEPARTMENT OF HEALTH 

AND HUMAN SERVICES

National Institutes of Health

NIH Publication No. 07–4230

November 2006

National Digestive Diseases

Information Clearinghouse

2 Information Way

Bethesda, MD 20892–3570

Phone: 1–800–891–5389

Fax: 703–738–4929

Email: nddic@info.niddk.nih.gov

Internet: www.digestive.niddk.nih.gov

The National Digestive Diseases Information

Clearinghouse (NDDIC) is a service of the

National Institute of Diabetes and Digestive and

Kidney Diseases (NIDDK). The NIDDK is

part of the National Institutes of Health of 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. The

NDDIC answers inquiries, develops 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 by both NIDDK scientists

and outside experts. This fact sheet was reviewed

by Beth Bell, M.D., Centers for Disease Control

and Prevention, Atlanta; Marc Ghany, M.D.,

NIDDK, NIH; Jay Hoofnagle, M.D., NIDDK;

David Kleiner, M.D., National Cancer Institute,

NIH; Jake Liang, M.D., NIDDK, NIH; John

McHutchison, M.D., Duke University; and

Leonard Seeff, M.D., NIDDK, NIH. 

This publication is not copyrighted. The

Clearinghouse encourages users of this fact

sheet to duplicate and distribute as many

copies as desired.

This fact sheet is also available at 

www.digestive.niddk.nih.gov.