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• Introduction
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• Hepatitis A
• Hepatitis B and D
• Hepatitis C
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Hepatitis

Description

An in-depth report on the causes, diagnosis, treatment, and prevention of hepatitis.

Hepatitis C

Hepatitis C is spread by contact with infected human blood. It is the most common blood-borne infection in the country. Until blood screening began in 1990, the hepatitis C virus was primarily transmitted through blood transfusions. Now, hepatitis C is transmitted mainly through intravenous drug use and sharing needles. Recent studies estimate that nearly half of people infected with HCV have a history of injecting drugs. People who received a blood transfusion before 1992 are also at high risk, as are people who have had 20 or more sexual partners. Hepatitis C can also be passed from an infected mother to her baby during birth. (Breastfeeding does not increase the risk of transmission.)

About 4 million Americans have had an initial HCV infection and an estimated 3.2 million have chronic hepatitis C. Hepatitis C affects about 170 million people worldwide. Most people with chronic HCV are unaware that they have it. Currently, it is not possible to predict which patients will develop the chronic form of hepatitis C.

Ethnic Groups. In general, HCV occurs most commonly in non-Caucasian men between the ages of 30 and 49 years. Over 6% of African Americans are infected with HCV, which is about two to three times the risk for Caucasians.

Symptoms of Hepatitis C

Most patients with hepatitis C do not experience symptoms. If they appear at all, symptoms develop about 1 – 2 months after a person is infected. Symptoms of progressive chronic viral hepatitis may be very subtle. In some patients, itchy skin is the first symptom. Overall, fatigue is the most common symptom. Many patients do not experience any symptoms at all. Chronic hepatitis C can be present for 10 - 30 years, and cirrhosis or liver failure can sometimes develop before patients experience any clear symptom.

Some evidence suggests, however, that patients with chronic hepatitis C often experience an impaired quality of life, mostly from fatigue. Fatigue can impair daily function, vitality, and mood in ways that are similar to other chronic diseases. The severity of the fatigue is not necessarily related to the degree of liver injury. Some patients develop pain in small joints in the body (such as the hand) that may be nearly indistinguishable from symptoms of rheumatoid arthritis, fibromyalgia, or carpal tunnel syndrome. Recent research suggests that sexual dysfunction may be common among men with chronic hepatitis C. Other nonspecific symptoms include abdominal discomfort, loss of appetite, depression, and difficulty concentrating.

Outlook for Patients with Hepatitis C

Acute Form. Acute hepatitis C is rarely recognized, since there are no symptoms in up to 80% of patients. An estimated 15 - 30% of acute cases clear up on their own without becoming chronic. Early treatment with interferon drugs can significantly reduce the risk for progression to chronic hepatitis.

Chronic Form. About 55 - 85% of infected people develop chronic hepatitis. Chronic hepatitis C poses a risk for cirrhosis, liver cancer, or both.

• 5 - 20% of patients with chronic hepatitis C develop cirrhosis over a period of 20 – 30 years. The longer the patient has had the infection, the greater the risk. Patients who have had hepatitis C for more than 60 years have a 70% chance of developing cirrhosis.
• 70% of patients with chronic hepatitis C eventually develop chronic liver disease.
• Of these patients, 4% eventually develop liver cancer. (Liver cancer rarely develops without cirrhosis first being present.)

Even in patients with cirrhosis, survival rates in one study were nearly 80% at 10 years after diagnosis. Still, hepatitis C causes over 5,000 deaths a year, and the rate continues to climb. [See In-Depth Report # 75: Cirrhosis.]

Patients with chronic hepatitis C may also be at higher risk for non-liver disorders including the following:

• Cryoglobulinemia (a disorder in which protein clumps form in the blood). This can cause skin rash and ulcers, kidney problems, arthritis, and sensations (such as tingling or pain) in the hands and feet. People with such symptoms may have particular difficulties with interferon, which can have similar side effects.
• Porphyria cutanea tarda (a disorder which causes skin color and texture changes and sensitivity to light.)
• Certain autoimmune disorders, particularly hypothyroidism and rheumatoid arthritis.
• Some experts believe that hepatitis C may infect the central nervous system in certain patients, possibly accounting for the fatigue, depression, or both experienced by patients who have even relatively mild cases.
• Certain non-Hodgkin's lymphomas.

Specific Tests for Identifying Hepatitis C and Determining its Severity

Tests for Liver Enzymes. Blood tests showing elevated liver enzymes, particularly alanine aminotransferase (ALT), plus symptoms of hepatitis (jaundice, fatigue) are often first signs of acute hepatitis. In chronic hepatitis, however, liver enzymes may be normal or fluctuate. They also can be elevated even after the virus has cleared.

Tests to Identify the Virus . The standard first test for diagnosing hepatitis C is known as enzyme-linked immunosorbent assay (ELISA or EIA). The antibody for hepatitis C is used to identify the virus, but it may not show up for 6 weeks to 1 year after the onset of the disease, so its absence is not necessarily an indication of a healthy liver. A test called an immunoblot assay (called RIBA) may also be used to confirm the presence of the virus. An accurate home test (Hepatitis C Check) is now available. It supplies a lancet for obtaining a drop of blood, which is sent to the laboratory for EIA and possibly RIBA analysis. Results take about a week.

Tests to Identify Genetic Types and Viral Load . Additional tests called HCV RNA assays may be used to confirm the diagnosis. They use a polymerase chain reaction (PCR) to detect the RNA (the genetic material) of the virus. Such tests may be performed if there is some doubt about a diagnosis but the doctor still firmly believes the virus is present.

HCV RNA assays also determine virus levels (called viral load). Such levels do not reflect the severity of the condition or speed of progression, as they do for other viruses, such as HIV. However, high viral loads suggest a poorer response to treatment with interferons.

Such techniques may also be used to determine the genotype of the virus, which can be helpful in determining a treatment approach. There are six main genetic types of HCV and more than 90 subtypes. They do not appear to affect the rate of progression of the disease itself, but they can differ significantly in their effects on response to treatment. Genotype 1 is the most difficult to treat and is the cause of up to 75% of the cases in the U.S. The other common genetic types are types 2 (15%) and 3 (7%), which are more responsive to treatment.

Liver Biopsy . Only a biopsy can determine the extent of injury in the liver. Some experts now recommend biopsies for all patients with chronic hepatitis C, regardless of severity, because of the risk for liver damage even in patients without symptoms. If a biopsy does not show any scarring and liver enzymes are normal, patients can be assured that the outlook is very favorable.

Prevention of Hepatitis C

No vaccines are available, but immune globulin helps protect against developing hepatitis C after transfusions. Periodic doses of immune globulin in sexual partners of infected people also appear to confer protection. In infected people, preventing transmission is similar to those for hepatitis B.

Treatments for Chronic Hepatitis C

Interferons Alone and in Combination with Ribavirin. Pegylated (PEG) interferon combined with ribavirin (a nucleoside analogue) is now the gold standard treatment for chronic hepatitis C. Interferons are natural proteins that activate certain immune functions in the body and have antiviral properties. Ribavirin is poor at inducing initial responses alone, but it can double sustained response rates when combined with an interferon. Several natural and synthetic interferons are available:

• Natural interferons include interferon alpha-2a (Intron) and Interferon alpha-2b (Roferon). Rebetron is a combination of interferon alpha-2b and ribavirin.
• Pegylated interferons (PegINF) are long-acting formulations of interferon. They include alfa-2b (Peg-Intron) or alfa 2a (Pegasys). Rebetol is a combination of alfa-2b and ribavirin.
• Alfacon-1 (Infergen), also called consensus interferon, is a genetically modified interferon. A combination of alfacon-1 with ribavirin is proving to help some patients who were nonresponsive to ribavirin with interferon.

The combination of pegylated interferon alfa-2b with ribavirin (Rebetol) has achieved the best success rates to date of all interferons and their combinations. It also appears to be safe and effective for children. However, the combination can cause side effects, including anemia. A 2005 study suggested that some patients with hepatitis C genotypes 2 or 3 may be able to benefit from a shorter course of treatment (12 weeks) than the standard 24-week treatment duration. A shorter treatment time may reduce the risk of side effects.

PegINF combinations may help slow progression of scarring, and have even achieved improvement in some patients who already have cirrhosis. Whether the combination treatment protects against future liver cancer is still unclear. (A higher total dose, rather than a longer duration of treatment, may be the critical factor for protection.)

Side Effects of the Combination Treatment. The side effects of the combination include those of both interferon and ribavirin. Interferon side effects may occur more often in the combination treatment. Ribavirin used in the combination treatment adds the following specific side effects:

• Hemolytic anemia. This complication is reversible and usually stabilizes after 1 -2 months of treatment. However, some patients may become so anemic that they have to stop the medication. Since anemia can worsen heart disease, patients with a history of significant heart problems should not be treated with ribavirin. Other nucleoside analogues, including levovirin and viramidine, are under investigation that may have a lower risk for anemia than ribavirin.
• Skin disorders.
• Coughing and shortness of breath.
• Emotional and neurologic symptoms, such as severe sleep disturbances, depression, and anxiety.
• Gastrointestinal symptoms (heartburn, weight loss).
• Temporary thyroid dysfunction (either over- or under- activity). The presence of hypothyroidism (low activity) is, in fact, associated with long-term remission of hepatitis.

Overall, the significant side effects of the combination treatment include flu-like symptoms, blood disorders (hemolytic anemia and low white blood cell counts), and psychologic and neurologic symptoms (particularly depression). Side effects from the combination result in treatment discontinuation in 10 - 14% of patients. The most frequent reason cited in the U.S. is depression. In addition, combination treatment in pregnant women poses a very high risk for birth defects.

Determining Treatment Success. Doctors measure treatment success and approaches based on the patient’s response to the treatments:

• Early Response. These are patients who respond to the drug right away. This means that their viral count drops very rapidly within the first few weeks of treatment and is still undetectable at 12 weeks. (One difficulty in deciding when to stop treatment, even in responders, is the inability to predict at 12 weeks which of these patients will relapse and which ones will have a sustained response.)
• Sustained Response. Patients who are free of the virus longer than 6 months are considered to be sustained responders. The overall sustained response rates with the current standard combination of pegylated interferon and ribavirin is over 50%, with certain factors predicting higher or lower response rates.
• Relapse. In relapse, the virus comes back again and requires retreatment. This is usually due to the development of mutant strains that are resistant to the drugs or because the original dose was too low.
• Nonresponse. Patients are considered to be nonresponders if the virus is still detectable 12 weeks after interferon alone or after 24 weeks of combination therapy. Treating these patients again has achieved only a 15% response.

People at Risk for Poor Response to Combination Treatment. The following patients have a greater risk for not responding to combination treatment with interferon and ribavirin:

• People at high risk for aggressive hepatitis C.
• Having a high viral count.
• Having a specific genetic type of the virus. Patients with genotype 1 do not respond as well to combination treatment as patients with genotypes 2 or 3.
• Older age (especially older than 60 years).
• African Americans are less responsive to treatment than Caucasians or Asians. The reasons for this are unclear.

Failure can be due to other, modifiable factors, which should be assessed before stopping treatment, particularly in patients who had interferon alone. They include:

• Interferon dose was too low
• Patient did not comply fully with the treatment
• Patient was consuming alcohol
• Treatment time was too short. Some evidence suggests that response can significantly improve for many patients with genotype 1 if treatment time is extended to 48 weeks.

Even if viral levels persist, there is some evidence the interferon treatment may still have benefits. For example, patients with normal liver enzyme levels appear to have almost no risk for liver damage, even if viral levels persist after treatment. Evidence also suggests that interferon reduces liver scarring and may reduce the risk for liver cancer in some patients, even if the treatment does not eliminate the virus. More research is needed, however, to confirm these findings.

Investigative Drugs for Hepatitis C. The current drugs used for HCV still do not meet the needs of all patients. They are expensive, have significant side effects, do not work in half the patients who take them, and are unsuitable in many others. Investigation is ongoing to find better solutions. Drugs showing promise include:

• Nucleoside analogs. Several new nucleoside analogs are in clinical development. Viramidine is a drug related to ribavirin. It is being studied in Phase III trials alone and in combination with pegylated interferon-alfa. Valopicitabine (NM283) is being tested in Phase II trials as alone and in combination with pegylated interferons.
• Albuferon. This long-acting form of interferon-alfa may have fewer side effects and require less dosing than pegylated interferons. It is currently being tested in Phase II trials for patients who have not been treated with or have not responded to standard interferon-alfa.
• IMPDH Inhibitors. Mycophenolate mofetil and VX-497 are drugs that inhibit an enzyme known by its brief name, IMPDH, which may block replication of the hepatitis C virus. If effective, they would most likely be used in combination with interferon and ribavirin.
• Amantadine (Symmetrel) is an anti-viral drug being investigated in various combinations. For example, triple therapy with amantadine, pegylated interferon, and ribavirin is showing particular promise. In some cases, the side effects of amantadine can be severe, and include vertigo, insomnia, nervousness, and depression. They are particularly disabling among older patients who receive inappropriately high doses.
• Thymosin Alpha 1 (Zadaxin), also called thymalfasin, is a synthetic version of a peptide derived from the thymus gland (which is responsible for maturation of immune factors call T-cells). It is being used for hepatitis B and is under investigation for hepatitis C in combinations with natural interferons and pegylated interferon.
• Protease Inhibitors. Novel protease inhibitors (similar to those used for HIV) are under investigation for hepatitis C patients who fail other treatments. These drugs are based on molecular therapies that target proteins involved in viral reproduction.

Other drugs under investigation include vaccines, genetic therapies known as antisense oligonucleotides or monoclonal antibodies, and drugs that will help prevent or reduce progression of liver scarring or progression to liver cancer. Even if successful, none of these drugs will be available for some years.

Of interest are studies using phlebotomy (which is simply drawing blood) to reduce iron levels. In one study, maintenance therapy with this procedure reduced liver inflammation and possible slowed progression of cirrhosis.

Liver Transplantation for Hepatitis C. If the disease progresses to the point where it becomes life-threatening, liver transplantation may be an option. In fact, nearly 40% of liver transplant patients are infected with hepatitis C. However, liver transplantation is not a cure for hepatitis C. The virus nearly always returns. One study of patients with hepatitis C reported 5-year risks for viral recurrence of 80% and for cirrhosis of 10%. A 2004 study found that the hepatitis C virus recurs with more severity with liver donations from living donors than livers taken from cadavers. Retreatment with antiviral drugs is being investigated.

Description of Interferons Interferons are natural proteins that activate certain immune functions in the body and have anti-viral properties. The natural interferons used for chronic hepatitis B and C are called type I interferons. They are given by injection, need to be taken three times a week, and include the following: Interferon alpha 2b (Intron A). Used for both hepatitis B and C. Interferon alpha 2a (Roferon-A). Mostly used for hepatitis C. Interferon alfa-n1 (Wellferon). Approved but mostly used in Canada for hepatitis C. Newer synthetic interferons have been developed that are showing some advantages over the natural forms: Pegylated interferon (PegINF). Pegylated interferons use a small molecule called polythelene glycol (PEG), which attaches to a protein and extends the activity of the interferon. This action allows the drug to be taken only once a week. Drugs available include pegylated interferon alfa-2b (Peg-Intron) and alfa-2a (Pegasys). Interferon alfacon-1 (Infergen). This drug is called a consensus interferon (CIFN) because it was genetically developed using the most commonly occurring amino acid sequences from each of the natural type 1 alpha interferons. It is 5 - 10 times more biologically active than natural type 1 interferons. CIFN is usually given three times a week when used as initial treatment. Interferon Candidates The best candidates for interferon treatments are those at greatest risk for cirrhosis. Factors suggesting a higher risk for cirrhosis include: Detectable virus levels as determined by an assay test High levels of aminotransferase enzyme for more than 6 months Indication of liver scarring on biopsy Patients who are not good candidates for interferon and are usually ineligible include: Women who are pregnant or planning to become pregnant soon. Patients with advanced cirrhosis. (It is unclear if the drug improves survival in patients with advanced cirrhosis and, in any case, it may be dangerous for them.) Patients with fluid in the abdomen. Patients with anemia or risk factors for anemia should not take the combination treatments, although they may be candidates for interferon alone. Several kinds of patients are ineligible for treatment because of the high risk for noncompliance and because of the severe psychiatric effects of the drugs. They include patients with psychiatric and medical problems and substance abusers. Some experts believe that these patients could benefit from treatment. Disease Recurrence In both hepatitis B and C, the disease often persists or returns despite treatment. The virus continually generates many “mutant viruses” that differ just slightly from the parent virus. These mutated viruses may be resistant to interferons and so, over time, the drugs become ineffective. Side Effects and Complications Common side effects of any interferon are flu-like symptoms (fever, chills, muscle aches) that usually occur within 6 hours and gradually decline over 1 - 2 weeks. (Pegylated interferon may pose a higher risk for these symptoms than the natural interferons.) Chronic or more serious effects include: Emotional and mental changes. Depression can be very severe, and cases of suicidal thoughts have been reported. Other mental and emotional symptoms include anxiety, amnesia, confusion, irritability, impaired concentration, decreased alertness, memory problems, and mental slowing. Changes in sensation Weight loss Skin rashes Hair loss Gastrointestinal problems including nausea, vomiting, and diarrhea, and, in severe cases intestinal bleeding and ulcers Fatigue and general weakness Back pain Complications in the lungs, including worsening of asthma. In severe cases, interferon can cause shortness of breath, inflammation in the lungs, and pneumonia. Possible negative effects on cholesterol and lipid levels Heart rhythm disturbances, which, in rare cases, can be serious Mild anemia Drop in platelet and white blood cell counts, increasing susceptibility to bacterial infections May trigger an autoimmune response, possibly causing anemia, diabetes, lupus-like symptoms, hypothyroidism, or even autoimmune hepatitis Complications in the eye, including bleeding that, in some cases, may lead to loss of vision if not detected promptly Rare reports of acute pancreatitis In children, interferon therapy temporarily disrupts growth. Patients have a difficult time with prolonged therapy. Over 20% drop out if treatment lasts longer than 2 years. Depression is the most common reason for withdrawal. Several different methods of delivering interferons are under investigation to help reduce some of the problems with injections. They include oral compounds and the use of pumps, controlled release implants, and other methods.

• Review Date: 8/17/2006
• Reviewed By: Harvey Simon, MD, Editor-in-Chief, In-Depth Reports; Associate Professor of Medicine, Harvard Medical School; Physician, Massachusetts General Hospital

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