Hepatitis C: An Update

It's often portrayed as a virus causing an incurable disease--a killer with few outward warning signs that lurks inside the body and slowly ravages the liver. For some, the hepatitis C virus (HCV) is deadly, but for most of the nearly 4 million Americans infected with the virus, it is not life-threatening.

"Some cases are mild," says Leonard Seeff, MD, a hepatologist at the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), "and people can go through their whole lives and never have a problem. For others who develop severe liver disease, it is a terribly serious problem."

HCV is responsible for 8,000 to 10,000 deaths per year in the United States, according to the Centers for Disease Control and Prevention (CDC). The virus is spread mainly through contact with the blood of an infected person. Most people don't know they carry the virus because they have either no symptoms or vague ones--extreme tiredness is the most common. Other common symptoms are "flu-like": muscle and joint pain, nausea, poor appetite, and mild stomach pain.

Only about 15% of those infected with HCV have a short-term infection that goes away by itself and never returns. The other 85% become chronically infected, meaning the virus stays in the liver, replicates, and may slowly attack the organ over a period of decades.

Despite many years of chronic infection, the majority of people infected with HCV do not develop severe liver disease, and some may not need treatment, says William Schwieterman, MD, chief of the immunology and infectious diseases branch in the Food and Drug Administration's Center for Biologics Evaluation and Research (CBER). Most studies report that cirrhosis (advanced liver scarring) develops in 10% to 20% of people with chronic HCV infection over a period of 20 to 30 years. Liver cancer develops in 1 % to 5%.

Those who do need treatment have more and better therapies today than were available just a few years ago. Although treatments come with the risk of serious side effects, many individuals with HCV infection are benefiting from them.

Disease in Decline

"The number of new cases is going down precipitously."says Jay Hoofnagle, MD, director of the division of digestive diseases and nutrition at the NIDDK. During the 1980s, an average of 230,000 new infections occurred each year in the United States, according to CDC estimates. But between 1989 and 1996, the annual number of new infections declined by more than 80 %, to 36,000 reported cases. This decrease is explained by the introduction of routine blood screening for HCV antibodies in 1991 and improved testing for the virus in 1992--lowering significantly the risk of transmitting the virus through blood transfusions.

Individuals who have the virus and are otherwise healthy may be at less risk for severe liver damage than previously thought. Several studies led by Seeff have shown that serious illness and death from liver disease in people infected with HCV is by no means inevitable.

In a study published in the Jan. 18, 2000, issue of Annals of Internal Medicine, Seeff examined the records of more than 8,000 U.S. military recruits. Seventeen who had tested positive for HCV 45 years earlier had similar hospital admission rates over the 45-year period as those who were HCV-negative. After 45 years, only two of the 17 (11.8 %) showed evidence of liver disease; one of these died from liver disease 42 years after initial testing.

In Seeff's more recent study, published in the Feb. 2001 issue of Hepatology, he reported on nearly 600 people who had received blood transfusions in the 1970s. Approximately 67 % of the 222 people infected with HCV had died 25 years later, compared with 56 % of the 377 non-infected people who had died. Although these numbers reflect deaths from all causes, a liver-related cause for death was more common among the HCV-infected persons.

Treatments and Their Success

For some people with mild hepatitis C, the only treatment needed may be eating a nutritious diet, avoiding alcohol, exercising regularly, and visiting a doctor regularly to monitor the disease. But for others with hepatitis C, drug therapy may be appropriate.

The FDA has approved two different treatment regimens for chronic hepatitis C: monotherapy (using a single drug, interferon) and combination therapy (using two drugs, interferon and ribavirin). Interferon, which is injected into the bloodstream, works by bolstering the immune response to HCV. Ribavirin, which is taken orally, may work by preventing the virus from reproducing (viral replication). Taken alone, ribavirin does not effectively suppress levels of the virus in the bloodstream. But studies have shown that the interferon and ribavirin combination, approved in 1998, is more effective than interferon alone.

The goal of treatment is sustained response--meaning that the virus is not measurable in the blood after drug therapy is completed. Those who continue to have measurable levels of the virus after treatment are considered non-responders. Relapsers "clear" the virus during therapy or shortly thereafter, but the virus returns after therapy ends. About half of the people who initially respond to monotherapy (interferon alone) relapse. Only 10 % to 20 % of those treated with monotherapy have a sustained response, depending on the type of interferon used.

Early reports on a modified version of interferon monotherapy, PEG-Intron (pegylated interferon), made by Schering-Plough Corp. of Kenilworth, N.J., show a slightly higher sustained response rate-up to 25 %. The FDA approved PEG-Intron in January as a monotherapy for treating chronic hepatitis C in adult patients not previously treated with interferon and whose livers are still working normally.

Combination therapy (conventional interferon plus ribavirin) shows better results: about 55 % of patients initially respond, and 35 % to 45 % of those treated sustain the response. The FDA is currently reviewing data on the safety and effectiveness of a combination of PEG-Intron and ribavirin.

In addition to PEG-Intron, three other interferon products for HCV have been approved by the FDA: Intron A (made by Schering-Plough), Roferon-A (Hoffmann-La Roche Inc.), and Infergen (Amgen Inc.). These three products are injected three times a week; PEG-Intron is injected once a week.

There is no absolute way to know who will or won't respond to therapy. But healthcare providers try to predict responsiveness using research tests to determine viral load and genotype, says John Ticehurst, MD, a medical officer in the FDA's Center for Devices and Radiological Health. Testing for "viral load" determines the concentration of virus in the blood. An HCV genotype, which is also determined by a blood test, reflects the variation in the genetic makeup of the virus. At least six different genotypes and many more subtypes of HCV exist. In the US, genotypes 1, 2 and 3 are most common.

People with genotypes 2 and 3 are almost three times more likely to respond to therapy than those with genotype 1, according to NIDDK researchers. About 70 % of HCV-infected people in the United States have genotype 1. Genotyping also is used to determine the duration of treatment for many people. For those with genotype 2 or 3, a 24-week course of combination therapy is appropriate, but for genotype 1, a 48-week treatment is usually prescribed.

Ken Gamache, of Middletown, Md., was diagnosed with hepatitis C in 1995, but believes that he became infected over 30 years ago after an operation. Gamache has genotype 1. He was treated initially with monotherapy, and when that failed, he tried combination therapy, again without success. When first told he needed a liver transplant, Gamache thought it was a death sentence. Now, after nearly six years on a waiting list for a liver, he has more hope. "I caught it early in the cirrhosis process and am doing whatever I can to prevent further damage," he says. Gamache still gets tired and run down, but has learned to pace himself. "I exercise regularly, but don't overextend myself. I'm careful to get enough sleep, eat right, and take vitamins, and I don't drink or smoke."

Treatment Side Effects

"Side effects are variable," says Adrian Di Bisceglie, MD, medical director of the American Liver Foundation and professor of internal medicine at St. Louis University. "About 10 % of patients have virtually no side effects. Approximately 10 % have very severe, almost disabling side effects and have to stop work or stop the drug. The remaining 80 % have side effects--but they are tolerable."

Patricia Buchanan of Brooklyn Park, Minn., suffered severe side effects throughout the 19 months she was in treatment; first in a 24-week clinical trial with monotherapy, and then in a 52-week treatment course with combination therapy after the monotherapy didn't work.

Buchanan clearly remembers the completion of her therapy on Nov. 6, 1999. "When you do chemotherapy for over a year, you remember the date of your last injection," she says. "I lived on my couch because of the extreme fatigue. I lost two-thirds of my hair and I had nausea, fever, chills, body aches and terrible depression. I went from having diarrhea to being constipated."

For some people, the side effects decrease after the first few weeks of treatment. But many individuals experience severe side effects through the duration, which may persist for months after the therapy ends.

Because of interferon's potentially serious side effects, the products come with an FDA-approved medication guide written for patients. Under regulations that became effective in 1999, pharmacists must distribute a medication guide with products that the FDA has determined pose a serious risk and for which patient guidelines can help prevent that risk. The guide lists both the common, less serious side effects, and the rarer but potentially life-threatening ones. The common side effects include "flu-like" symptoms, extreme fatigue, nausea and loss of appetite, thyroid problems, high blood sugar, hair loss, and skin reactions (such as redness and itching at the injection site). Possible serious side effects are psychoses or suicidal behavior, heart problems (low blood pressure, heart attack), other internal organ damage, blood problems (blood counts falling dangerously low), and new or worsening autoimmune disease (such as rheumatoid arthritis and a form of lupus).

Side effects of ribavirin, the oral part of the combination therapy, include anemia, fatigue, irritability, skin rash, nasal stuffiness, sinusitis, and cough. Ribavirin can also cause birth defects, so pregnancy should be avoided during treatment and for six months afterward.

To Treat or Not to Treat

"If we had a treatment that was safe, good, and not unpleasant, we should treat everybody," says Seeff. Unfortunately, the length of treatment required, the low rate of success, and the current treatments' side effects--the severity of which is unpredictable from patient to patient--don't warrant treating everybody.

Treatment decisions should not be based on symptoms. "Patient symptoms are a very unrelated guide to the severity of hepatitis C," says Di Bisceglie. "Someone can be feeling very well and have severe hepatitis on a liver biopsy. Some patients have very profound symptoms, such as fatigue, but HCV is trivial in severity based on blood tests and a liver biopsy."

The NIH and CDC recommend treating people with HCV infection who are at greatest risk for progression to cirrhosis. These include individuals with four characteristics:

a positive test for antibodies to HCV (meaning they were, or still are, infected with HCV), persistently elevated blood levels of a liver enzyme called alanine aminotransferase (ALT), a positive research test for HCV RNA (ribonucleic acid, which detects virus in the blood), and a liver biopsy that shows either advanced fibrosis or moderate degrees of inflammation and necrosis (death of living tissue). For those with less severe liver damage, indications for treatment are less clear.

"Patients, along with their physicians, need to carefully evaluate the stage of their disease and other risk factors before deciding whether or not to undergo treatment with interferon-based therapies," says the FDA's Schwieterman.

After discussing the pros and cons of interferon treatment with her doctor, Helen Clark of Minnetonka, Minn., decided against it. Clark had acquired the virus in 1970 during treatment for a severe form of dysentery she contracted in Cozumel, Mexico. Following 18 life-saving blood transfusions, Clark continued to feel ill for years, but doctors could find nothing wrong. They dismissed her symptoms, telling her she was tired because she was a busy mother, or she was menopausal. Some said that it was "all in her head" and that she should see a psychiatrist. Finally, in 1997, a doctor diagnosed her with hepatitis C.

Clark has genotype 1 (the most resistant to treatment) and a high "viral load." Her liver biopsy did not show any fibrosis after 27 years of infection. So Clark decided she could live with the disease if she could do something about her fatigue and other debilitating symptoms. "Now I pace myself, take naps, and find ways to remove stress from my life."

Clark avoids red meat, which she claims gives her liver pains after eating. "And I haven't had a drop of alcohol since diagnosis," says Clark. Alcohol is toxic to the liver and can advance the progression to cirrhosis. Clark also attributes her decrease in symptoms to some alternative therapies, including acupuncture. Along with experiencing symptoms of the virus, individuals with HCV infection often experience discrimination, says Clark. "People think you're an alcoholic or drug addict. And they're afraid of you--there's such a misconception about the infectiousness."

HCV is not spread through coughing, kissing, hugging, or casual contact. It is spread only by contact with blood and possibly other body fluids. People with HCV infection should cover any open wounds, and be careful not to share personal-care items such as toothbrushes, razors, and nail files.

It's possible to get the virus through unprotected sex with an infected partner. However, studies-which have focused mainly on long-term monogamous couples--have shown that transmission through sexual contact is rare.

Diagnosis and Vaccination

Di Bisceglie encourages everyone at risk--not just those with symptoms--to be tested for HCV. The FDA has approved two types of test for detecting antibodies to HCV in a person's blood, providing evidence of infection. If a person is suspected of having HCV infection, the doctor should first obtain a blood sample for the enzyme immunoassay (EIA) test (also called enzyme-linked immunosorbent assay, or ELISA). If this test result is negative, no further testing is needed.

But if the result is positive, an additional, more expensive test is used to rule out a "false positive." If this second test, the recombinant immunoblot assay (RIBA, made by Chiron Corporation), yields a positive result, the person is considered to have been, or to currently be, infected. If the RIBA result is negative, the person is considered not to have been infected.

The FDA approved an over-the-counter home test system, called Hepatitis C Check, in 1999. Made by Home Access Health Corp. of Hoffman Estates, Ill., the product allows a person to take a sample of blood at home and mail it to a designated laboratory for analysis with EIA and, when appropriate, RIBA testing. The results are available anonymously by phone through a unique identification number.

A liver biopsy to examine tissue from the liver is not necessary for diagnosing HCV infection. "However, a biopsy is the only accurate way to check the severity and stage of liver disease," says the NIDDK's Seeff.

Hepatitis C patients--whether they decide to get treated or not--should be monitored regularly by their doctors. Patients not in treatment should have a blood test approximately every six months to check liver functioning. A baseline liver biopsy is recommended to establish the severity of HCV infection, and the biopsy should be repeated in three to five years. Patients on treatment will have additional and more frequent tests.

There is no vaccine for hepatitis C, but there are vaccines for hepatitis A and B. The CDC recommends these vaccines, particularly the hepatitis A vaccine, for HCV-positive individuals. Becoming infected with hepatitis A virus can be life threatening for someone with HCV infection. In May, the FDA approved a combined hepatitis A and B vaccine called Twinrix.

An Individual Disease

:"The progression of disease varies from person to person," says the NIDDK's Hoofnagle. "Therapies are getting better, and some people have time to wait."

Afraid they were running out of time, Gamache and Buchanan sought interferon treatment. For Gamache, it didn't work, but Buchanan remains "clear" (shows no detectable virus in the blood). Clark is waiting, hoping she won't need interferon treatment or that something better will come along. She is due for a liver biopsy this year. Ultimately, the decision to get treated or not for HCV infection is up to the individual and his or her healthcare provider.

"We insist people be educated about their treatment options and the risks involved," says Clark, who runs a support group with Buchanan to help people with hepatitis learn more about their disease. The support group also helps them deal with feelings of isolation, contamination, and fear. "It can be very scary," says Clark. "It puts you face to face with your own mortality and gives you a whole different perspective on life."

Hepatitis C Study

Researchers are now recruiting individuals infected with hepatitis C virus (HCV) to be part of the largest HCV study ever conducted. Called Hepatitis C Antiviral Long-Term Treatment Against Cirrhosis (HALT C), the eight-year study will be conducted at 10 research centers nationwide and will involve 1,350 participants. The goal is to learn whether long-term pegylated interferon plus ribavirin treatment in individuals who didn't respond to prior treatment will decrease liver damage over time. Pegylated interferon is a new, longer-acting form of interferon. The study is sponsored by the National Institute of Diabetes and Digestive and Kidney Diseases.

For additional information, contact the NIH clinical center's patient recruitment and public liaison office at (800) 411-1222.

Source: FDA Consumer

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