What is hepatitis C?
"Hepatitis" refers to inflammation of the liver. This can be the result of an infection, an autoimmune disorder, or a reaction to a drug, such as alcohol. When there is inflammation in the liver, your blood tests can be abnormal. The liver enzymes "leak" from the damaged liver cells into the blood stream and the levels become elevated to varying degrees depending on the severity of the hepatitis. The enzymes most frequently measured are the AST (aspartate aminotransferase) and the ALT (alanine aminotransferase). Other lab values may be elevated too (alkaline phosphatase and total bilirubin), but to a lesser degree.
Hepatitis C virus was formerly known as "Non-A, Non-B hepatitis." The virus was cloned in 1989-1990, and was determined to be a single strand of RNA (similar to DNA) that causes an infection of the liver in humans and primates (monkeys). The virus is also present in the blood stream, and the most common means of exposure to the virus are through blood transfusions, intravenous drug use, tattoos, promiscuous sexual behavior, or occupational exposure (as in the case of health care workers). Sexual (monogamous) and vertical transmission (from mother to infant) are rare.
Between 1970-1990, hepatitis C accounted for approximately 90-96% of the cases of post-transfusion hepatitis. Since the virus was cloned, a blood test has become available to test for infected individuals. Donated blood is now routinely checked for the hepatitis C virus, thereby reducing the risk of post-transfusion hepatitis from 1 per 10 units of blood transfused to 1 per 200,000 units of blood transfused.
The hepatitis C virus is unusual among the hepatitis viruses in that exposure to the virus leads to chronic infection in 80-85% of cases. In those chronically infected, 30% of less will have very little damage or inflammation. More significant chronic inflammation develops in >70% of those chronically infected. In this group, end-stage liver disease or cirrhosis can develop in 20-40%. This occurs over decades (10-30 years) and the rapidity with which damage to the liver occurs is variable from person to person. Alcohol use together with hepatitis C infection leads to liver damage much more quickly than either insult alone. Immunosuppression (drugs that can suppress the immune system or HIV) may lead to a more rapidly progressive illness. On the other hand, over 50% of patients never develop significant liver impairment. Unfortunately, we are not able to identify those individuals who will develop cirrhosis before the damage occurs. If a person develops cirrhosis, they have an increased risk of developing liver cancer. The majority of patients do not even know if cirrhosis is present.
How do I know if I am infected?
A simple blood test is all that is necessary to make the diagnosis of hepatitis C. A screening antibody test is performed and, if positive, is accurate in 90-95% of patients. It costs about $50.00. Further tests to confirm the diagnosis are available. The most sensitive indicator of a hepatitis C infection, however, is to test the blood for the presence of the actual virus by a specialized test called "polymerase chain reaction" or PCR. This test can detect virus levels as low as 100 copies of virus per cc of your serum. Remember, being positive for the virus and the antibody does not always translate into severe liver disease. The most accurate way of assessing the severity of the liver disease is by a liver biopsy (a sampling of the liver tissue).
What are the symptoms of hepatitis C?
Acute infection with hepatitis C usually has no symptoms ("asymptomatic"). Occasionally, patients may develop a flu-like illness with jaundice, but this is the rare case. The most common symptom of chronic hepatitis C infection is fatigue. Most patients with chronic hepatitis C are asymptomatic during the first 10-20 years. Other more unusual symptoms are itching, joint aches, or mild abdominal discomfort. Once cirrhosis develops, you may develop signs of fluid retention (swelling of the abdomen and extremities), jaundice, or confusion. If you have end-stage liver disease, you have an increased tendency for bleeding because of coagulation abnormalities or possible gastrointestinal bleeding.
What is the treatment for hepatitis C?
The FDA approved interferon alfa-2b (Intron® A) in late 1989 for use in the treatment of chronic hepatitis C. It is a drug that had been previously used to treat certain cancers (hairy-cell leukemia and Kaposi's sarcoma). Intron® A is a synthetic form of interferon alfa, which is produced naturally by your white blood cells. Its function in the body is to fight off viral infections, tumors, and to boost the function of the immune system. Because of its ability to kill viruses and boost the immune system, it is useful in treating chronic hepatitis C.
The initial studies using interferon in the treatment of chronic hepatitis C showed that a six month treatment course resulted in a sustained (long-term) remission of the hepatitis in about 10-15%. Since then, follow-up studies over the last 10 years have shown that 95%-100% of patients who achieved sustained remission remain in remission. To increase the percentage of patients with a sustained remission (normal lab tests and negative viral levels after treatment), treatment was increased to a year or more. This resulted in a long term response of about 25%.
Other interferons have also been FDA-approved for use in the treatment of Hepatitis C. These are Infergen® and Roferon®. Their side effects are similar to Intron® A.
Infergen® is a non-natural interferon produced by scanning many interferon-alfa molecules and using the most common amino acids found to generate a "consensus" molecule. Infergen® at the 9 mcg dose has similar sustained response rates to Intron A® and Roferon® in patients who've never been treated before. Infergen® at the higher dose of 15 mcg may have an advantage in patients who have previously relapsed after interferon monotherapy and in patients with Genotype 1. There may also be a slight advantage in patients who were prior non-responders to monotherapy, but this is also still being studied. The higher dose has similar side effects to the 3 mU dose of Intron A®.
Interferon has many side effects, most of which resolve when treatment has been withdrawn. The majority of patients experience flu-like symptoms (fever, chills, muscle and joint aches, headache) with the first few injections, but they usually abate somewhat further into a treatment course. Tylenol can also be taken to counteract these side effects. Fatigue is also quite common and may last throughout the entire treatment course. Gastrointestinal side effects such as nausea, loss of appetite, abdominal pain, and diarrhea may occur but are less common. Neuropsychiatric side effects can occur with depression or worsening of depression, irritability, and mood swings. Interferon can worsen a pre-existing seizure disorder and cause blurriness of vision in patients with significant hypertension and diabetes. The blurriness of vision may not be reversible. Forgetfulness and difficulty concentrating may also occur. Autoimmune side effects such as thyroid disease or arthritis can occur. Hair loss, if it occurs, is generally minimal and never results in complete baldness. Bone marrow suppression can occur, but reverses when interferon is stopped. Numbness and tingling in the hands and feet, ringing in the ears and muscle weakness may occur, but rarely.
In the mid-1990s, a new drug was added to the arsenal. This is ribavirin (Rebetron®). Ribavirin is an antiviral drug which has been used in children to treat a serious lung virus. It was approved by the FDA in 1998 for use in patients with Hepatitis C. Ribavirin does not work when used alone - it requires combination therapy with interferon to see a response. The most important use of ribavirin is it's apparent ability to keep patients who respond to the interferon in a sustained response (40-50%!). Not everyone can take ribavirin, however. The drug causes a fairly severe anemia (low red blood cells), which can complicate high blood pressure, diabetes, or heart disease.
Patients with low virus levels in the blood (less than 2 million) and who do not have Genotype 1 seem to have a much better response to combination therapy than those with high levels and/or Genotype 1. Their sustained response is 75% to 80%. Also, non-genotype 1 patients only need about 6 months of therapy, rather than a full year.
Long-Acting (Pegylated; PEG) Interferons
As we worked with treating hepatitis C patients, it became clear that 3 times a week dosing was probably inadequate and daily dosing was more affective. Giving injections daily is less convenient, so long-acting molecules were developed. Pegylated IFN is a molecule that consists of standard IFN that has a polyethylene glycol (PEG) molecule attached to it. This delays its removal from the body and lengthens the time in the blood system. Pegylated IFN is given by subcutaneous injection once weekly. There are two types: Pegasys® (Roche Pharmaceuticals) and PEG-Intron® (Schering-Plough Biotech). Data is very encouraging. Pegylated interferon monotherapy has shown an improved response rate when compared with thrice weekly dosing of interferon monotherapy, and is similar to/slightly better than 3-times a week combination interferon/ribavirin therapy. Data is available using PEG in association with Ribavirin is also slightly better than standard combination therapy.
Standard IFN/Riba PEG/Riba All Genotypes 47% 54% Genotype 1 33% 42% Genotype 2/3 79% 82%
PEG-Intron® monotherapy and PEG-Intron/Ribavirin® have both been FDA-approved. Pegasys® and Pegasys/Ribavirin® are still pending FDA approval. Neither are available yet clinically (as of August 2001.
What if treatment fails?
If treatment fails, then there are often research protocols available at the University of Washington testing new drug combinations or differing doses of drug combinations. With research in this area being very active, newer drugs will soon be on the horizon. It is important to know, however, that research studies for Hepatitis C are not free. The patient and their insurance carrier remain responsible for the cost of the FDA-approved drug, lab studies, and clinic visits. For the studies, the physicians donate their time.
For those patients who develop liver failure (end-stage liver disease) resulting from chronic hepatitis C, liver transplantation is a potential option.