Chronic Hepatitis C: Current Disease Management

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.

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 needlestick accidents.

Other groups that 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.

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

Serologic Tests Enzyme Immunoassay
Anti-HCV is detected by enzyme immunoassay (EIA). The third-generation test (EIA-3) used today is more sensitive and specific than previous ones. However, as with all enzyme immunoassays, falsepositive results are occasionally a problem with the EIA-3. Additional or confirmatory testing is often helpful.

The best approach to confirm the diagnosis of hepatitis C is to test for HCV RNA using a sensitive assay such as polymerase chain reaction (PCR) or transcription mediated amplification (TMA). The presence of HCV RNA in serum indicates an active infection.

Testing for HCV RNA is also helpful in patients in whom EIA tests for anti-HCV are unreliable. For instance, immunocompromised patients may test negative for anti-HCV despite having HCV infection because they may not produce enough antibodies for detection with EIA. Likewise, patients with acute hepatitis may test negative for anti-HCV when first tested. Antibody is present in almost all patients by 1 month after onset of acute illness; thus, patients with acute hepatitis who initially test negative may need followup testing. In these situations, HCV RNA is usually present and confirms the diagnosis.

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 anti-HCV reactivity could represent a false-positive reaction, recovery from hepatitis C, or continued virus infection with levels of virus too low to be detected (the last occurs only rarely when sensitive PCR or TMA assays are used). If the immunoblot test for anti-HCV is positive, the patient has most likely recovered from hepatitis C and has persistent antibody. If the immunoblot test is negative, the EIA result was probably a false positive.

Immunoblot tests are routine in blood banks when an anti-HCV-positive sample is found by EIA. Immunoblot assays are highly specific and valuable in verifying anti-HCV reactivity. Indeterminate tests require further followup testing, including attempts to confirm the specificity by repeat testing for HCV RNA.

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.

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.

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 mportant, 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.

Normal Serum ALT Levels
Some patients with chronic hepatitis C have normal serum alanine aminotransferase (ALT) levels, even when tested on multiple occasions. In this and other situations in which the diagnosis of chronic hepatitis C may be questioned, the diagnosis should be confirmed by testing for HCV RNA. The presence of HCV RNA indicates that the patient has ongoing viral infection despite normal ALT levels.

Liver Biopsy
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.

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.

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

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, long-term improvement in hepatitis C occurs only if HCV RNA disappears during therapy and stays undetectable once therapy is stopped. Among patients who become HCV RNA negative during treatment, a proportion relapse when therapy is stopped.

The relapse rate is lower in patients treated with combination therapy compared with monotherapy. Thus, a 48-week course of combination therapy using peginterferon and ribavirin yields a sustained response rate of approximately 55 percent. A similar course of peginterferon monotherapy yields a sustained response rate of only 35 percent.

A response is considered “sustained” if HCV RNA remains undetectable for 6 months or more after stopping therapy. The optimal duration of treatment varies depending on whether interferon monotherapy or combination therapy is used, as well as by HCV genotype. For patients treated with peginterferon monotherapy, a 48-week course is recommended, regardless of genotype. For patients treated with combination therapy, the optimal duration of treatment depends on viral genotype.
Patients with genotypes 2 and 3 have a high rate of response to combination treatment (70 to 80 percent), and a 24-week course of combination therapy yields results equivalent to those of a 48-week course. In contrast, patients with genotype 1 have a lower rate of response to combination therapy (40 to 45 percent), and a 48-week course yields a significantly better sustained response rate. Again, because of the variable responses to treatment, testing for HCV genotype is clinically useful when using combination therapy.

In addition, the optimal dose of ribavirin appears to vary depending on genotype. For patients with genotypes 2 or 3, a dose of 800 mg daily appears adequate. For
patients with genotype 1, the full dose of ribavirin (1,000 or 1,200 mg daily depending on body weight) appears to be needed for an optimal response.

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 56 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 coinfection, and end-stage liver disease has become an increasingly common cause of death in HIV-positive persons. For these reasons, therapy for hepatitis C should be recommended even in HIV-infected patients with early and mild disease. Once HIV infection becomes advanced, complications of therapy are more difficult and response rates are less. The decision to treat people co-infected with HIV must take into consideration the concurrent medications and medical conditions. The efficacy of peginterferon and ribavirin in HIV-infected people has been tested in only a small number of patients. Ribavirin may still have significant interactions with other antiretroviral drugs.

In many of these indefinite situations, the indications for therapy should be reassessed at regular intervals. In view of the rapid developments in hepatitis C today, better therapies may become available within the next few years, at which point expanded indications for therapy would be appropriate.

Patients with acute hepatitis C are a major challenge to management and therapy. Because such a high proportion of patients with acute infection develop chronic hepatitis C, prevention of chronicity has become a focus of attention. In small studies, 83 to 100 percent of persons treated within 1 to 4 months of onset have had resolution of the infection. What is unclear is what dose, duration, and regimen of treatment to use. A practical regimen is peginterferon monotherapy for 24 weeks. The possible role for ribavirin, for short courses of therapy, and for lower doses of peginterferon are under evaluation.

In patients with clinically significant extrahepatic manifestations, such as cryoglobulinemia and glomerulonephritis, therapy with alpha interferon can result in remission of the clinical symptoms and signs. However, relapse after stopping therapy is common. In some patients, long-term or maintenance alpha interferon therapy can be used despite persistence of HCV RNA in serum if clinical symptoms and signs resolve on therapy.

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 solidorgan 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 abuseproblems 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 combinationtherapy. 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. 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 fullyinformed 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 lly
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.

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 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 long-term “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.

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 fibrosiswould 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 aresmall 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.

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.
2002. Hepatitis A to E.
Available at http://www.cdc.gov/ncidod/diseases/hepatitis/slideset.
Centers for Disease Control and Prevention.
Recommendations for prevention and control of hepatitis C virus (HCV) infection and HCV-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, 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.
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, et al. Peginterferon alfa-2a in patients with chronic hepatitis C.
New England Journal of Medicine. 2000;343:1666-1672.

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 10038–4810
Phone: 1–800–GO–LIVER (465–4837)
or 1–888–443–7222 or 212–668–1000 or 1–800–676–9340
24-hour helpline (7 days/week):
1–800–465–4857 or 1–888–443–7222
Fax: 973–256–3214 or 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

Download a Fact Sheet:
Chronic Hepatitis C