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Home : Digestive Diseases A-Z List of Topics and Titles: Hepatitis Series : Chronic Hepatitis C

Chronic Hepatitis C: Current Disease Management

On this page:

● Introduction

● Risk Factors and Transmission

● Clinical Symptoms and Signs

● Serologic Tests

● Liver Biopsy

● Serum Markers of Hepatic Fibrosis

● Diagnosis

● Treatment

● Hope Through Research

● Selected Review Articles and References

● Patient Education Materials

Introduction

The hepatitis C virus (HCV) is one of the most important causes of chronic liver 

disease in the United States. It accounts for about 15 percent of acute viral hepatitis, 

60 to 70 percent of chronic hepatitis, and up to 50 percent of cirrhosis, end-stage liver 

disease, and liver cancer. Almost 4 million Americans, or 1.8 percent of the U.S. 

population, have antibody to HCV (anti-HCV), indicating ongoing or previous infection 

with the virus. Hepatitis C causes an estimated 10,000 to 12,000 deaths annually in 

the United States.

A distinct and major characteristic of hepatitis C is its tendency to cause chronic liver 

disease. At least 75 percent of patients with acute hepatitis C ultimately develop 

chronic infection, and most of these patients have accompanying chronic liver 

disease.

Chronic hepatitis C varies greatly in its course and outcome. At one end of the 

spectrum are patients who have no signs or symptoms of liver disease and 

completely normal levels of serum liver enzymes. Liver biopsy usually shows some 

degree of chronic hepatitis, but the degree of injury is usually mild, and the overall 

prognosis may be good. At the other end of the spectrum are patients with severe 

hepatitis C who have symptoms, HCV RNA in serum, and elevated serum liver 

enzymes, and who ultimately develop cirrhosis and end-stage liver disease. In the 

middle of the spectrum are many patients who have few or no symptoms, mild to 

moderate elevations in liver enzymes, and an uncertain prognosis.

Chronic hepatitis C can cause cirrhosis, liver failure, and liver cancer. Researchers 

estimate that at least 20 percent of patients with chronic hepatitis C develop cirrhosis, 

a process that takes at least 10 to 20 years. After 20 to 40 years, a smaller 

percentage of patients with chronic disease develop liver cancer. Liver failure from 
chronic hepatitis C is one of the most common reasons for liver transplants in the 

United States. Hepatitis C is the cause of about half of cases of primary liver cancer 

in the developed world. Men, alcoholics, patients with cirrhosis, people over age 40, 

and those infected for 20 to 40 years are more likely to develop HCV-related liver 

cancer.

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Risk Factors and Transmission

HCV is spread primarily by contact with blood and blood products. Blood transfusions 

and the use of shared, unsterilized, or poorly sterilized needles and syringes have 

been the main causes of the spread of HCV in the United States. With the 

introduction in 1991 of routine blood screening for HCV antibody and improvements 

in the test in the mid-1992, transfusion-related hepatitis C has virtually disappeared. 

At present, injection drug use is the most common risk factor for contracting the 

disease. However, many patients acquire hepatitis C without any known exposure to 

blood or to drug use.

The major high-risk groups for hepatitis C are

● Injection drug users, including those who used drugs briefly many years ago. 

● People who had blood transfusions before June 1992, when sensitive tests for 

anti-HCV were introduced for blood screening. 

● People who have frequent exposure to blood products. These include patients 

with hemophilia, solid-organ transplants, chronic renal failure, or cancer 

requiring chemotherapy. 

● Infants born to HCV-infected mothers. 

● Health care workers who suffer needle-stick accidents. 

Other groups who appear to be at slightly increased risk for hepatitis C are

● people with high-risk sexual behavior, multiple partners, and sexually 

transmitted diseases 

● people who use cocaine, particularly with intranasal administration, using 

shared equipment 

Maternal-Infant Transmission

Maternal-infant transmission is not common. In most studies, only 5 percent of infants 

born to infected women become infected. The disease in newborns is usually mild 

and free of symptoms. The risk of maternal-infant spread rises with the amount of 

virus in the mother's blood and with complications of delivery such as early rupture of 

membranes and fetal monitoring. Breast-feeding has not been linked to spread of 

HCV.

Sexual Transmission

Sexual transmission of hepatitis C between monogamous partners appears to be 

uncommon. Surveys of spouses and monogamous sexual partners of patients with 

hepatitis C show that less than 5 percent are infected with HCV, and many of these 

have other risk factors for this infection. Spread of hepatitis C to a spouse or partner 
in stable, monogamous relationships occurs in less than 1 percent of partners per 

year. For these reasons, changes in sexual practices are not recommended for 

monogamous patients. Testing sexual partners for anti-HCV can help with patient 

counseling. People with multiple sex partners should be advised to follow safe sex 

practices, which should protect against hepatitis C as well as hepatitis B and HIV.

Sporadic Transmission

Sporadic transmission, when the source of infection is unknown, occurs in about 10 

percent of acute hepatitis C cases and in 30 percent of chronic hepatitis C cases. 

These cases are usually referred to as sporadic or community-acquired infections. 

These infections may have come from exposure to the virus from cuts, wounds, or 

medical injections or procedures.

Unsafe Injection Practices

In many areas of the world, unsafe injection practices are an important and common 

cause of hepatitis C (and hepatitis B as well). Use of inadequately sterilized 

equipment, lack of disposable needles and syringes, and inadvertent contamination 

of medical infusions are unfortunately well-documented causes of transmission of 

hepatitis C. Careful attention to universal precautions and injection techniques should 

prevent this type of spread. In the United States, multiple-use vials are a frequent 

culprit in leading to nosocomial spread of hepatitis C.

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 6 

major genotypes and more than 50 subtypes of HCV. 

The different genotypes have different geographic 

distributions. Genotypes 1a and 1b are the most 

common in the United States (about 75 percent of 

cases). Genotypes 2 and 3 are present in only 10 to 20 

percent of patients. There is little difference in the 

severity of disease or outcome of patients infected with 

different genotypes. However, patients with genotypes 

2 and 3 are more likely to respond to interferon 

treatment.

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Clinical Symptoms and Signs

Many people with chronic hepatitis C have no symptoms of liver disease. If symptoms 

are present, they are usually mild, nonspecific, and intermittent. They may include

● fatigue

● mild right-upper-quadrant discomfort or tenderness ("liver pain")

● nausea

● poor appetite

● muscle and joint pains
Similarly, the physical exam is likely to be normal or show only mild enlargement of 

the liver or tenderness. Some patients have vascular spiders or palmar erythema.

Clinical Features of Cirrhosis

Once a patient develops cirrhosis or if the patient has severe disease, symptoms and 

signs are more prominent. In addition to fatigue, the patient may complain of muscle 

weakness, poor appetite, nausea, weight loss, itching, dark urine, fluid retention, and 

abdominal swelling.

Physical findings of cirrhosis may include

● enlarged liver

● enlarged spleen

● jaundice

● muscle wasting

● excoriations

● 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

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Serologic Tests

Enzyme Immunoassay

Anti-HCV is detected by enzyme immunoassay (EIA). The third-generation test (EIA3) 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 EIA3. Additional or confirmatory testing is often helpful.
The best approach to confirm the diagnosis of hepatitis C is to test for HCV RNA 

using a sensitive assay such as polymerase chain reaction (PCR) or transcription 

mediated amplification (TMA). The presence of HCV RNA in serum indicates an 

active infection.

Testing for HCV RNA is also helpful in patients in whom EIA tests for anti-HCV are 

unreliable. For instance, immunocompromised patients may test negative for antiHCV despite having HCV infection because they may not produce enough antibodies 

for detection with EIA. Likewise, patients with acute hepatitis may test negative for 

anti-HCV when first tested. Antibody is present in almost all patients by 1 month after 

onset of acute illness; thus, patients with acute hepatitis who initially test negative 

may need followup testing. In these situations, HCV RNA is usually present and 

confirms the diagnosis.

Recombinant Immunoblot Assay

Immunoblot assays can be used to confirm anti-HCV reactivity as well. These tests 

are also called "Western blots"; serum is incubated on nitrocellulose strips on which 

four recombinant viral proteins are blotted. Color changes indicate that antibodies are 

adhering to the proteins. An immunoblot is considered positive if two or more proteins 

react and is considered indeterminate if only one positive band is detected. In some 

clinical situations, confirmatory testing by immunoblotting is helpful, such as for the 

person with anti-HCV detected by EIA who tests negative for HCV RNA. The EIA antiHCV 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 antiHCV reactivity. Indeterminate tests require further followup 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 

aminotransferases are normal or only slightly elevated, when anti-HCV is not present, 

or when several causes of liver disease are possible. This method also helps 

diagnose hepatitis C in people who are immunosuppressed, have recently had an 

organ transplant, or have chronic renal failure. A PCR assay has now been approved 

by the Food and Drug Administration for general use. This assay will detect HCV 

RNA in serum down to a lower limit of 50 to 100 copies per milliliter (mL) which is 

equivalent to 25 to 50 international units (IU). A slightly more sensitive TMA test is 

currently under evaluation and may soon become available. Almost all patients with 

chronic hepatitis C will test positive by these assays.

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 

alpha interferon and ribavirin are higher in patients with low levels of HCV RNA. 

There are several definitions of a "low level" of HCV RNA, but the usual definition is 

below 1 million IU (2 million copies) per mL.

In addition, monitoring HCV RNA levels during the early phases of treatment may 

provide early information on the likelihood of a response. Yet because of the 

shortcomings of the current assays for HCV RNA level, these tests are not always 

reliable guides to therapy.

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. More 

important, knowing the genotype or serotype (genotype-specific antibodies) of HCV is 

helpful in making recommendations and counseling regarding therapy. Patients with 

genotypes 2 and 3 are two to three times more likely to respond to interferon-based 

therapy than patients with genotype 1. Furthermore, when using combination therapy, 

the recommended dose and duration of treatment depend on the genotype. For 

patients with genotypes 2 and 3, a 24-week course of combination treatment using 

interferon and 800 milligrams (mg) of ribavirin daily is adequate, whereas for patients 

with genotype 1, a 48-week course and full dose of ribavirin (1,000 to 1,200 mg daily) 

is recommended. For these reasons, testing for HCV genotype is often clinically 

helpful. Once the genotype is identified, it need not be tested again; genotypes do not 

change during the course of infection.

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 (ALT) levels are usually higher than aspartate 

aminotransferase (AST) levels, but that finding may be reversed in patients 

who have cirrhosis. 

● Alkaline phosphatase and gamma glutamyl transpeptidase are usually 

normal. If elevated, they may indicate cirrhosis. 

● Rheumatoid factor and low platelet and white blood cell counts are 

frequent in patients with severe fibrosis or cirrhosis, providing clues to the 

presence of advanced disease. 

● The enzymes lactate dehydrogenase and creatine kinase are usually 

normal. 

● Albumin levels and prothrombin time are normal until late-stage disease. 

● Iron and ferritin levels may be slightly elevated. 
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.

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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 or iron overload.

HCV causes the following changes in liver tissue:

● Necrosis and inflammation around the portal areas, so-called "piecemeal 

necrosis" or "interface hepatitis." 

● Necrosis of hepatocytes and focal inflammation in the liver parenchyma. 

● Inflammatory cells in the portal areas ("portal inflammation"). 

● Fibrosis, with early stages being confined to the portal tracts, intermediate 

stages being expansion of the portal tracts and bridging between portal areas 

or to the central area, and late stages being frank cirrhosis characterized by 

architectural disruption of the liver with fibrosis and regeneration. Several 

scales are used to stage fibrosis, most commonly a scale from 0 to 4 where 0 

indicates none and 4 indicates cirrhosis. Stage 1 and 2 fibrosis is limited to the 

portal and periportal areas. Stage 3 fibrosis is characterized by bridges of 

fibrosis bands linking up portal and central areas. 

Grading and staging of hepatitis by assigning scores for severity are helpful in 

managing patients with chronic hepatitis. The degree of inflammation and necrosis 

can be assessed as none, minimal, mild, moderate, or severe. The degree of fibrosis 

can be similarly assessed. Scoring systems are particularly helpful in clinical studies 

on chronic hepatitis.

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Serum Markers of Hepatic Fibrosis

Liver biopsy is an invasive procedure that is expensive and not without complications. 

At least 20 percent of patients have pain requiring medications after liver biopsy. 

More uncommon complications include puncture of another organ, infection, and 

bleeding. Significant bleeding after liver biopsy occurs in 1/100 to 1/1,000 cases, and 

deaths are reported in 1/5,000 to 1/10,000 cases. Obviously, noninvasive means of 

grading and staging liver disease would be very helpful.
ALT levels, particularly if tested over an extended period, are reasonably accurate 

reflections of disease activity. Thus, patients with repeatedly normal ALT levels 

usually have mild necroinflammatory activity on liver biopsy. Furthermore, patients 

who maintain ALT levels above 5 times the upper limit of normal usually have marked 

necroinflammatory activity. But for the majority of patients with mild-to-moderate ALT 

elevations, the actual level is not very predictive of liver biopsy findings.

More important is a means to stage liver disease short of liver biopsy. Unfortunately, 

serum tests are not reliable in predicting fibrosis, particularly earlier stages (0, 1, and 

2). When patients develop bridging (stage 3) fibrosis and cirrhosis (stage 4), serum 

tests may be helpful. The "danger signals" that suggest the presence of advanced 

fibrosis include an aspartate aminotransferase (AST) that is higher than ALT (reversal 

of the ALT/AST ratio), a high gamma glutamyl transpeptidase or alkaline 

phosphatase, a low platelet count (which is perhaps the earliest change), rheumatoid 

factor, elevations in globulins, and, of course, abnormal bilirubin, albumin or 

prothrombin time. Physical findings of a firm liver, or enlarged spleen or prominent 

spider angionata or palmar erythema, are also danger signals. While none of these 

findings are perfect, their presence should raise the suspicion of significant fibrosis 

and lead to evaluation for treatment earlier rather than later.

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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 on the basis of symptoms such as jaundice, fatigue, 

and nausea, along with marked increases in serum ALT (usually greater than 10-fold 

elevation), and presence of anti-HCV or de novo development of anti-HCV.

Diagnosis of acute disease can be problematic because anti-HCV is not always 

present when the patient develops symptoms and sees the physician. In 30 to 40 

percent of patients, anti-HCV is not detected until 2 to 8 weeks after onset of 

symptoms. In this situation, testing for HCV RNA is helpful, as this marker is present 

even before the onset of symptoms and lasts through the acute illness. Another 

approach to diagnosis of acute hepatitis C is to repeat the anti-HCV testing a month 

after onset of illness. Of course, a history of an acute exposure is also helpful in 

establishing the diagnosis.

Chronic Hepatitis C

Chronic hepatitis C is diagnosed when anti-HCV is present and serum 

aminotransferase levels remain elevated for more than 6 months. Testing for HCV 

RNA (by PCR) confirms the diagnosis and documents that viremia is present; almost 

all patients with chronic infection will have the viral genome detectable in serum by 

PCR.

Diagnosis is problematic in patients who cannot produce anti-HCV because they are 

immunosuppressed or immunoincompetent. Thus, HCV RNA testing may be required 

for patients who have a solid-organ transplant, are on dialysis, are taking 

corticosteroids, or have agammaglobulinemia. Diagnosis is also difficult in patients 

with anti-HCV who have another form of liver disease that might be responsible for 
the liver injury, such as alcoholism, iron overload, or autoimmunity. In these 

situations, the anti-HCV may represent a false-positive reaction, previous HCV 

infection, or mild hepatitis C occurring on top of another liver condition. HCV RNA 

testing in these situations helps confirm that hepatitis C is contributing to the liver 

problem.

Differential Diagnosis

The major conditions that can be confused clinically with chronic hepatitis C include

● autoimmune hepatitis

● chronic hepatitis B and D

● alcoholic hepatitis

● nonalcoholic steatohepatitis (fatty liver)

● sclerosing cholangitis

● Wilson's disease

● alpha-1-antitrypsin-deficiency-related liver disease

● drug-induced liver disease

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Treatment

The therapy for chronic hepatitis C has evolved steadily since alpha interferon was 

first approved for use in this disease more than 10 years ago. At the present time, the 

optimal regimen appears to be a 24- or 48-week course of the combination of 

pegylated alpha interferon and ribavirin.

Alpha interferon is a host protein that is made in response to viral infections and has 

natural antiviral activity. Recombinant forms of alpha interferon have been produced, 

and several formulations (alfa-2a, alfa-2b, consensus interferon) are available as 

therapy for hepatitis C. These standard forms of interferon, however, are now being 

replaced by pegylated interferons (peginterferons). Peginterferon is alpha interferon 

that has been modified chemically by the addition of a large inert molecule of 

polyethylene glycol. Pegylation changes the uptake, distribution, and excretion of 

interferon, prolonging its half-life. Peginterferon can be given once weekly and 

provides a constant level of interferon in the blood, whereas standard interferon must 

be given several times weekly and provides intermittent and fluctuating levels. In 

addition, peginterferon is more active than standard interferon in inhibiting HCV and 

yields higher sustained response rates with similar side effects. Because of its ease 

of administration and better efficacy, peginterferon has been replacing standard 

interferon both as monotherapy and as combination therapy for hepatitis C.

Ribavirin is an oral antiviral agent that has activity against a broad range of viruses. 

By itself, ribavirin has little effect on HCV, but adding it to interferon increases the 

sustained response rate by two- to threefold. For these reasons, combination therapy 

is now recommended for hepatitis C, and interferon monotherapy is applied only 

when there are specific reasons not to use ribavirin.

Two forms of peginterferon have been developed and studied in large clinical trials: 

peginterferon alfa-2a (Pegasys: Hoffman La Roche: Nutley, NJ) and peginterferon 

alfa-2b (Pegintron: Schering-Plough Corporation, Kenilworth, NJ). These two 

products are roughly equivalent in efficacy and safety, but have different dosing 

regimens. Peginterferon alfa-2a is given subcutaneously in a fixed dose of 180 

micrograms (mcg) per week. Peginterferon alfa-2b is given subcutaneously weekly in 

a weight-based dose of 1.5 mcg per kilogram per week (thus in the range of 75 to 150 

mcg per week).
Ribavirin is an oral medication, given twice a day in 200-mg capsules for a total daily 

dose based upon body weight. The standard dose of ribavirin is 1,000 mg for patients 

who weigh less than 75 kilograms (165 pounds) and 1,200 mg for those who weigh 

more than 75 kilograms. In certain situations, an 800-mg dose (400 mg twice daily) is 

recommended (see below).

Combination therapy leads to rapid improvements in serum ALT levels and 

disappearance of detectable HCV RNA in up to 70 percent of patients. However, longterm improvement in hepatitis C occurs only if HCV RNA disappears during therapy 

and stays undetectable once therapy is stopped. Among patients who become HCV 

RNA negative during treatment, a proportion relapse when therapy is stopped. The 

relapse rate is lower in patients treated with combination therapy compared with 

monotherapy. Thus, a 48-week course of combination therapy using peginterferon 

and ribavirin yields a sustained response rate of approximately 55 percent. A similar 

course of peginterferon monotherapy yields a sustained response rate of only 35 

percent. A response is considered "sustained" if HCV RNA remains undetectable for 

6 months or more after stopping therapy.

The optimal duration of treatment varies depending on whether interferon 

monotherapy or combination therapy is used, as well as by HCV genotype. For 

patients treated with peginterferon monotherapy, a 48-week course is recommended, 

regardless of genotype. For patients treated with combination therapy, the optimal 

duration of treatment depends on viral genotype. Patients with genotypes 2 and 3 

have a high rate of response to combination treatment (70 to 80 percent), and a 24-

week course of combination therapy yields results equivalent to those of a 48-week 

course. In contrast, patients with genotype 1 have a lower rate of response to 

combination therapy (40 to 45 percent), and a 48-week course yields a significantly 

better sustained response rate. Again, because of the variable responses to 

treatment, testing for HCV genotype is clinically useful when using combination 

therapy.

In addition, the optimal dose of ribavirin appears to vary depending on genotype. For 

patients with genotypes 2 or 3, a dose of 800 mg daily appears adequate. For 

patients with genotype 1, the full dose of ribavirin (1,000 or 1,200 mg daily depending 

on body weight) appears to be needed for an optimal response.

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. However, even patients in their late 

seventies have been successfully treated for hepatitis C.

The role of interferon therapy in children with hepatitis C remains uncertain. Ribavirin 

has yet to be evaluated adequately in children, and pediatric doses and safety have 

not been established. Thus, if children with hepatitis C are treated, monotherapy is 

recommended, and ribavirin should not be used outside of controlled clinical trials.

People with both HCV and HIV infection should be offered therapy for hepatitis C as 

long as there are no contraindications. Indeed, hepatitis C tends to be more rapidly 

progressive in patients with HIV co-infection, and end-stage liver disease has become 

an increasingly common cause of death in HIV-positive persons. For these reasons, 

therapy for hepatitis C should be recommended even in HIV-infected patients with 

early and mild disease. Once HIV infection becomes advanced, complications of 

therapy are more difficult and response rates are less. The decision to treat people coinfected with HIV must take into consideration the concurrent medications and 

medical conditions. The efficacy of peginterferon and ribavirin in HIV-infected people 

has been tested in only a small number of patients. Ribavirin may still have significant 

interactions with other antiretroviral drugs.

In many of these indefinite situations, the indications for therapy should be 

reassessed at regular intervals. In view of the rapid developments in hepatitis C 

today, better therapies may become available within the next few years, at which 

point expanded indications for therapy would be appropriate.

Patients with acute hepatitis C are a major challenge to management and therapy. 

Because such a high proportion of patients with acute infection develop chronic 

hepatitis C, prevention of chronicity has become a focus of attention. In small studies, 

83 to 100 percent of persons treated within 1 to 4 months of onset have had 

resolution of the infection. What is unclear is what dose, duration, and regimen of 

treatment to use. A practical regimen is peginterferon monotherapy for 24 weeks. The 

possible role for ribavirin, for short courses of therapy, and for lower doses of 

peginterferon are under evaluation.

In patients with clinically significant extrahepatic manifestations, such as 

cryoglobulinemia and glomerulonephritis, therapy with alpha interferon can result in 

remission of the clinical symptoms and signs. However, relapse after stopping 

therapy is common. In some patients, long-term or maintenance alpha interferon 

therapy can be used despite persistence of HCV RNA in serum if clinical symptoms 

and signs resolve on therapy.

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, but this should be applied 

only to patients with a history of alcohol abuse, not to social drinkers. Patients with 

continuing alcohol or substance abuse problems should only be treated in 

collaboration with alcohol or substance abuse specialists or counselors. Patients can 

be successfully treated while on methadone or in an active substance abuse 

program. Indeed, the rigor and regular monitoring that accompany methadone 

treatment provide a structured format for combination therapy. The dose of 

methadone may need to be modified during interferon-based therapy for hepatitis.

Alpha interferon therapy can induce autoantibodies, and a 24- to 48-week course 

triggers an autoimmune condition in about 2 percent of patients, particularly if they 

have an underlying susceptibility to autoimmunity (high titers of antinuclear or 

antithyroid antibodies, for instance). Exacerbation of a known autoimmune disease 

(such as rheumatoid arthritis or psoriasis) occurs commonly during interferon therapy.

Alpha interferon has bone marrow suppressive effects. Therefore, patients with bone 

marrow compromise or cytopenias, such as low platelet count (< 75,000 cells/mm3) 

or neutropenia (< 1,000 cells/mm3) should be treated cautiously and with frequent 

monitoring of cell counts. These side effects appear to be more common with 

peginterferon than standard interferon.

Ribavirin causes red cell hemolysis to a variable degree in almost all patients. 

Therefore, patients with a preexisting hemolysis or anemia (hemoglobin < 11 grams 

[g] or hematocrit < 33 percent) should not receive ribavirin. similarly, patients who 

have significant coronary or cerebral vascular disease should not receive ribavirin, as 

the anemia caused by treatment can trigger significant ischemia. fatal myocardial 

infarctions and strokes have been reported during combination therapy with alpha 

interferon and ribavirin.

Growth factors such as erythropoietin to raise red blood cell counts or granulocyte 

stimulating factor to raise neutrophil counts have been used successfully to treat 

patients with cytopenias during combination therapy. The proper role, dose, and side 

effects of these adjunctive therapies have yet to be defined.

Ribavirin is excreted largely by the kidneys. Patients with renal disease can develop 

hemolysis that is severe and even life-threatening. Patients who have elevations in 

serum creatinine above 2.0 mg per deciliter (dL) should not be treated with ribavirin.

Finally, ribavirin causes birth defects in animal studies and should not be used in 

women or men who are not practicing adequate means of birth control. Alpha 

interferon also should not be used in pregnant women, as it has direct antigrowth and 

antiproliferative effects.

Combination therapy should therefore be used with caution. Patients should be fully 

informed of the potential side effects before starting therapy.
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 may be helpful for the 

muscle aches and low-grade fever. Fatigue and depression are occasionally so 

troublesome that the dose of interferon should be decreased or therapy stopped 

early. Depression and personality changes can occur on interferon therapy and be 

quite subtle and not readily admitted by the patient. These side effects need careful 

monitoring. Patients with depression may benefit from antidepressant therapy using 

selective serotonin reuptake inhibitors. Generally, the psychiatric side effects resolve 

within 2 to 4 weeks of stopping combination therapy.

Ribavirin also causes side effects, and the combination is generally less well tolerated 

than interferon monotherapy. The most common side effects of ribavirin are

● anemia

● fatigue and irritability

● itching

● skin rash

● nasal stuffiness, sinusitis, and cough

Ribavirin causes a dose-related hemolysis of red cells; with combination therapy, 

hemoglobin usually decreases by 2 to 3 g/dL and the hematocrit by 5 to 10 percent. 

The amount of decrease in hemoglobin is highly variable. The decrease starts 

between weeks 1 and 4 of therapy and can be precipitous. Some patients develop 

symptoms of anemia, including fatigue, shortness of breath, palpitations, and 

headache.

The sudden drop in hemoglobin can precipitate angina pectoris in susceptible people, 

and fatalities from acute myocardial infarction and stroke have been reported in 

patients receiving combination therapy for hepatitis C. For these important reasons, 

ribavirin should not be used in patients with preexisting anemia or with significant 

coronary or cerebral vascular disease. If such patients require therapy for hepatitis C, 

they should receive alpha interferon monotherapy.

Ribavirin has also been found to cause itching and nasal stuffiness. These are 

histamine-like side effects; they occur in 10 to 20 percent of patients and are usually 

mild to moderate in severity. In some patients, however, sinusitis, recurrent 

bronchitis, or asthma-like symptoms become prominent. It is important that these 

symptoms be recognized as attributable to ribavirin, because dose modification (by 
200 mg per day) or early discontinuation of treatment may be necessary.

Uncommon side effects of alpha interferon, peginterferon, and combination therapy 

(occurring in less than 2 percent of patients) include

● autoimmune disease (especially thyroid disease)

● severe bacterial infections

● marked thrombocytopenia

● marked neutropenia

● seizures

● depression and suicidal ideation or attempts

● retinopathy (microhemorrhages)

● hearing loss and tinnitus

Rare side effects include acute congestive heart failure, renal failure, vision loss, 

pulmonary fibrosis or pneumonitis, and sepsis. Deaths have been reported from 

acute myocardial infarction, stroke, suicide, and sepsis.

A unique but rare side effect is paradoxical worsening of the disease. This is 

assumed to be caused by induction of autoimmune hepatitis, but its cause is really 

unknown. Because of this possibility, aminotransferases should be monitored. If ALT 

levels rise to greater than twice the baseline values, therapy should be stopped and 

the patient monitored. Some patients with this complication have required 

corticosteroid therapy to control the hepatitis.

Algorithm for Treatment

Make the diagnosis based on aminotransferase elevations, antiHCV and HCV RNA in serum, and chronic hepatitis shown by 

liver biopsy.

Assess for suitability of therapy and contraindications. Discuss 

side effects and possible treatment outcomes.

Test for HCV genotype.

Genotype 1: Test for HCV RNA level immediately before 

starting therapy (baseline level).

Genotype 1: Start therapy with peginterferon alfa-2a in a dose 

of 180 mg weekly or peginterferon alfa-2b in a dose of 1.5 mg/kg 

weekly in combination with oral ribavirin in two divided doses of 

1,000 mg daily if body weight is < 75 kilograms (165 lbs.) or 

1,200 mg daily if body weight is > 75 kilograms.

Genotype 2 or 3: Start therapy with peginterferon alfa-2a in a 

dose of 180 mcg weekly or with alfa-2b in a dose of 1.5 mcg per 

kilogram weekly and oral ribavirin 800 mg daily in two divided 

doses.
All patients: At weeks 1, 2, and 4 and then at intervals of every 

4 to 8 weeks thereafter, assess side effects, symptoms, blood 

counts, and aminotransferases.

Genotype 1: At week 12, retest for HCV RNA level. If HCV RNA 

is negative or has decreased by at least two log10 units (such as 

from 2 million IU to 20,000 IU or from 500,000 IU to 5,000 IU or 

less), continue therapy for a full 48 weeks, monitoring 

symptoms, blood counts, and ALT at 4- to 8-week intervals. If 

HCV RNA has not fallen by two log10 units, stop therapy.

Genotype 2 or 3: At 24 weeks, assess aminotransferase levels 

and HCV RNA and stop therapy.

All patients: After therapy, assess aminotransferases at 2- to 6-

month intervals. In responders, repeat HCV RNA testing 6 

months after stopping.

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 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). 

● Adjust the dose of peginterferon downward if there are 

intolerable side effects such as severe fatigue, 

depression, or irritability or marked decreases in white 

blood cell counts (absolute neutrophil count below 500 
cells/mm3) or platelet counts (decrease below 30,000 cells/

mm3). When using peginterferon alfa-2a, the dose can be 

reduced from 180 to 135 and then to 90 mcg per week. 

When using peginterferon alfa-2b, the dose can be 

reduced from 1.5 to 1.0 and then to 0.5 mcg per kilogram 

per week. 

● In patients with genotype 1, measure HCV RNA level 

immediately before therapy and again (by the same 

method) at week 12. Therapy can be stopped early if HCV 

RNA levels have not decreased by at least two log10 

units, as studies have shown that genotype 1 patients 

without this amount of decrease in HCV RNA are unlikely 

to have a sustained response (likelihood is < 1 percent). in 

situations where hcv rna levels are not obtainable, repeat 

testing for hcv rna by pcr (or tma) should be done at 24 

weeks and therapy stopped if hcv rna is still present, as a 

sustained response is unlikely. 

● Reinforce the need to practice strict birth control during 

therapy and for 6 months thereafter. 

● Measure thyroid-stimulating hormone levels every 3 to 6 

months during therapy. Patients with genotypes 2 or 3 can 

stop therapy at 24 weeks. Patients with genotype 1 and a 

drop in HCV RNA by 12 weeks should continue therapy 

for 48 weeks. 

● At the end of therapy, test HCV RNA by PCR to assess 

whether there is an end-of-treatment response.

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 longterm "cure" is excellent; relapses have rarely been 

reported after this point. 

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 course of combination therapy, particularly if they became and remained 

HCV RNA negative during the period of monotherapy. The response rates and 

optimal dose (800 vs. 1,000 mg to 1,200 mg of ribavirin) and duration (24 or 48 

weeks) of peginterferon and ribavirin for relapse or previous nonresponder patients 

have not been defined. The algorithm for treatment given above is for treatment of 

naive patients.

An experimental approach to treatment of non-responders is the use of long-term or 

maintenance interferon, which is feasible only if the peginterferon is well tolerated and 

has a clear-cut effect on serum aminotransferases or liver histology, despite lack of 

clearance of HCV RNA. This approach is now under evaluation in long-term clinical 

trials in the United States. New medications and approaches to treatment are 
needed. Most promising for the future are the use of other cytokines and the 

development of newer antivirals, such as RNA polymerase, helicase, or protease 

inhibitors.

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Hope Through Research

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 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 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 

receptor). In addition, nonspecific cytoprotective agents might be helpful for hepatitis 

C by blocking the cell injury caused by the virus infection. Further, molecular 

approaches to treating hepatitis C are worthy of investigation; these consist of using 

ribozymes, which are enzymes that break down specific viral RNA molecules, and 

antisense oligonucleotides, which are small complementary segments of DNA that 

bind to viral RNA and inhibit viral replication. All of these approaches remain 

experimental and few have been applied to humans. The serious nature and the 

frequency of hepatitis C in the population make the search for new therapies of prime 

importance.

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.

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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.

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

gov/ncidod/diseases/hepatitis/slideset/httoc.htm (accessed Nov. 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.

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.

Lauer GM, Walker BD. Hepatitis C virus infection. New England Journal of Medicine. 

2001;345:41-52.

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, Rustgi VK, Shiffman M, Reindollar R, 

Goodman ZD, Koury K, Ling M, Albrecht JK. 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, Shiffman ML, Lee WM, Rustgi VK, 

Goodman ZD, Ling M-H, Cort S, Albrecht JK. 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).

Zeuzem S, Feinman SV, Rasenack J, Heathcote EJ, Lai M-Y, Gane E, O'Grady J, 

Reichen J, Diago M, Lin A, Hoffman J, Brunda MJ. Peginterferon alfa-2a in patients 

with chronic hepatitis C. New England Journal of Medicine. 2000;343:1666-1672.

[Top]

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 or (301) 654-3810 

Fax: (301) 907-8906 

Email: nddic@info.niddk.nih.gov

Internet: http://digestive.niddk.nih.gov

Patient education materials are also available from

American Liver Foundation (ALF)

75 Maiden Lane, Suite 603 

New York, NY 10038 

Phone: 1-800-GO-LIVER (465-4837), 

1-888-4HEP-USA (443-7222), 

or (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 (HFI)

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

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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, this does not mean or imply that the product 

is unsatisfactory.

National Digestive Diseases Information Clearinghouse

2 Information Way 

Bethesda, MD 20892-3570 

Email: nddic@info.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 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 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 Jay Hoofnagle, M.D., 

NIDDK.

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. 03-4230 

February 2003

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