Hepatitis

Description

Hepatitis C

Each year about 30,000 new cases of hepatitis C occur. It is the most common blood-borne infection in the country. Until blood screening began in 1990, the primary mode of known transmission was through transfusions. It is also transmitted through contaminated needles and possibly through sexual transmission. The cause of transmission is unknown in 40% of cases.

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About 4 million Americans have had an initial HCV infection and an estimated 2.7 million are currently chronically infected. Hepatitis C also affects 170 million people worldwide. Most people with chronic HCV, however, are unaware that they have it and experts believe that over the next 20 years, there will be a fourfold increase in diagnosed cases in the US. It is currently 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.

Other High-Risk Groups. Some other specific groups are at higher than normal risk:

• Intravenous drug users. Intravenous drug use has been the greatest risk factor for HCV since the early 1980s. It accounts for 60% of new cases and 20% to 50% of chronic infections. Individuals who engage in this activity have a risk for infection that is between 50% and 80%. Intravenous drug use, particularly in people who also drink alcohol heavily, poses a higher risk for severe complications. Intranasal cocaine use also increases the danger. Needle exchange and educational programs have reduced the risk for HIV transmission and should have similar benefits for preventing HCV.
• People who had transfusions before 1992. Although transfused blood has been tested for both hepatitis B and C since the early nineties, individuals given transfusions before then, even decades before, may still be at risk. Such individuals are urged to be tested. Hepatitis C can exist for decades without symptoms, and nearly 300,000 people who had transfusions before 1992, including many who were children at the time, may have been infected. Of some reassurance was a 1999 study of people who had transfusions when they were children. After an average of 20 years, only 8% tested positive for hepatitis C and only three people showed signs of any liver abnormalities. These results suggest that the virus may be less aggressive in children than adults, but further observations are needed to learn if the infection remains mild beyond age 30.
• Among the homeless and people in prison the HCV prevalence may be as high as 40%.
• Infants of infected mothers. The risk for transmission to an infant during pregnancy is about 2% but increases to 4% to 7% during delivery. The highest rates of infection (20%) are in mothers who are also HIV positive. It is not clear if Cesarean section delivery in infected mothers offers protection. Avoiding fetal scalp monitoring and prolonged labor may reduce the risk. (Breastfeeding does not increase the risk.)
• Organ transplant recipients.
• Sexual transmission. Although HCV can be transmitted sexually, the risk is much less than with hepatitis B or other sexually transmitted diseases. For example, the risk for transmitting the HCV within a monogamous relationship is only about 2% to 3%. The risk is 4% to 6% for partners of people who have high-risk sex (e.g., those with multiple partners or sex workers). Of note, the risk for women becoming infected through sexual transmission may be three times that of men.
• Hospital workers. It should be strongly noted that health care providers in general are at very low risk. The risk of infection from a needle stick is now believed to be about 2%. (It is not yet clear if this poses any significant risk to patients.)
• Children who survive cancer.
• Possibly people who have had body piercing or tattoos with contaminated equipment.

Symptoms of Hepatitis C

Most patients with hepatitis C do not experience symptoms. If they appear at all, symptoms develop about a month or two 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. In fact, chronic hepatitis C can be present for 10 to 30 years and in some cases cirrhosis or liver failure can 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. Other nonspecific symptoms include abdominal discomfort, loss of appetite, depression and difficulty in concentration.

Outlook for Patients with Hepatitis C

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

Chronic Form. About 60% to 85% of infected people develop chronic hepatitis. This poses a risk for cirrhosis, liver cancer, or both.

• Overall, between 10% and 15% of patients with chronic hepatitis C develop cirrhosis. The risk varies widely, however.
• Of these patients, 4% eventually develop liver cancer. (Liver cancer rarely develops without cirrhosis first being present.)

It should be noted, however, that even in patients with cirrhosis, survival rates in one study were nearly 80% at ten years. Still, over 5,000 deaths are currently attributed annually to hepatitis C and the rate continues to climb. Furthermore 140,000 people were hospitalized in 1998 for HCV, leading many experts to believe that hepatitis C is indirectly responsible for many more deaths than reported. [See Well-Connected Report # 75 Cirrhosis.]

Patients with chronic hepatitis C may be also 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.

High-Risk Chronic Hepatitis C Patients. The risk for cirrhosis varies widely among different patient groups. The following factors influence risk for disease progression to cirrhosis.

• Overall the risk for progression is highest in men -- particularly African Americans -- who were older at the time of infection. The risk is much lower in women and children (2% to 4%).
• Moderate to heavy alcohol users. (Alcohol may actually promote viral replication. Even one or two alcoholic drinks a day increase the risk for liver injury in HCV patients.)
• Co-infection with hepatitis B. Co-infection with B significantly affects the outcome of these patients and may be more common than previously believed. This co-condition may cause superinfections with very serious consequences, reduce these patients responses to interferon therapy, and increase their risk of liver cancer. Patients with hepatitis C should be immunized against hepatitis B.
• Co-infection with HIV.
• A history of transfusions. (In one report, the risk in middle-aged patients with a history of transfusions was 20% to 30%.)
• Having type 2 diabetes.
• Having large iron stores in the liver.
• High exposure to toxic chemicals or environmental contaminants.

Because there are millions of Americans now infected with chronic hepatitis C, experts have been justifiably concerned that there will be a significant number of cases of liver failure and liver cancer in the coming years. Computer analyses have suggested that mortality rates from HCV-related cirrhosis or liver cancer will double or triple over the next twenty years. Fortunately, improved therapies may significantly reduce these discouraging estimates.

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 (e.g., 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 virus but it may not show up for six weeks to a 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 physician 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 three quarters of the cases in the US. 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 are now recommending biopsies for all chronic hepatitis C patients, 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 Hepatitis C

Interferons Alone and in Combination with Ribavirin for Hepatitis C. The current gold standard for treating chronic hepatitis C is a once-weekly injection of the interferon called pegylated interferon in combination with oral ribavirin (a nucleoside analogue). Patients are typically treated for 24 to 48 weeks depending on certain factors, such as the genotype. Interferons are also used for patients with acute hepatitis C to prevent the development of the chronic form.

Interferons are natural proteins that activate certain immune functions in the body and have anti-viral properties. Ribavirin is poor at inducing initial responses alone but it can double sustained response rates when combined with an interferon.

A number of natural and synthetic interferons are available:

• Natural interferons were the first used for HCV and include interferon alpha-2a (Intron) and interferon alpha-2b (Roferon). Rebetron is the 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). Both are now available in combination with ribavirin. (Rebetol is the alfa-2b combination.) The combination is now considered the gold standard for treating HCV. Response rates of up to 51% with genotype 1 and over 80% with genotype 2 and 3 have been reported. PegINFs may even help patients with 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.)
• 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.

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 a month or two of treatment. However, some patients may become so anemic that they have to withdraw. 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, and 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 (e.g., 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% to 14% of patients. The most frequent reason cited in the US is depression. Of note, combination of both drugs poses a very high risk for birth defects in children whose mothers used the drugs while pregnant.

Determining Treatment Success. Physicians gauge treatment success and approaches based on the patients 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 sustained response.)
• Sustained Response. Patients who are free of the virus longer than six 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 occurs most likely because of the development of mutant strains that may be resistant to the drugs used 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 24 weeks of combination therapy. Retreating these patients has achieved only a 15% response. Those who achieved a-called breakthrough at some point in the initial treatment may be more likely to response. (During a breakthrough there is a temporary reduction in liver enzymes or disappearance of the virus.) Alfacon-1 (Infergen) may be beneficial for some nonresponding patients. Patients should also ask their physician about any clinical trials that might be appropriate.

People at Risk for Poor Response to Combination Treatment. The following patients have a higher chance for a lower response to combination treatment with interferon and ribavirin:

• People who are at high risk in the first place for aggressive hepatitis C.
• Having a high viral count.
• Having a specific genetic type of the virus affects the response to treatment. Those with genotypes 2 or 3 who are given the current standard treatment (pegylated interferon plus ribavirin) can now achieve a sustained response of over 80%. Unfortunately, the response is lower in those with genotype 1. In one 2003 study, the sustained response rates in patients with genotype 1 were 39% in Caucasian patients and 26% in African Americans (which were the highest response rates reported at that time for this latter group). Young people with type 1 have a much higher response rate than older patients.
• Being African American also poses a risk for poor response. African Americans are less responsive to treatment than Caucasians and 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 the following:

• Interferon dose is 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. Also of note, there is some evidence that interferon still reduces liver scarring and may even 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 early 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 then is ongoing to find better solutions. Some showing promise include the following:

• IMPDH Inhibitors. Mycophenylate mofetil and VX-497 are agents 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 agent 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 agents are based on molecular therapies that target proteins involved in viral reproduction.

Other agents 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 agents would 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. In any case, liver transplantation is not a cure for hepatitis C. The virus nearly always returns. One study of patients with hepatitis C reported five-year risks for viral recurrence of 80% and for cirrhosis of 10%. Retreatment with antiviral agents at this point is being investigated.