Hepatitis C: An Update
By Linda Bren (staff writer for FDA Consumer)
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, and people can go through their whole lives and never have a problem," says Leonard Seeff, M.D., a hepatologist at the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)." 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 percent of those infected with HCV have a short-term infection that goes away by itself and never returns. The other 85 percent 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, M.D., 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 percent to 20 percent of people with chronic HCV infection over a period of 20 to 30 years. Liver cancer develops in 1 percent to 5 percent.
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, M.D., 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 percent, to 36,000 reported cases. This decrease may be 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. Blood samples taken from the recruits between 1948 and 1956 were kept frozen and were tested for the presence of HCV in recent years, after testing became available. Seventeen of the recruits were determined to have acquired HCV at least 45 years earlier; these recruits 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 percent) 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 February 2001 issue of Hepatology, he reported on nearly 600 people who had received blood transfusions in the 1970s. Approximately 67 percent of the 222 people infected with HCV had died 25 years later, compared with 56 percent 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 FDA has approved one ribavirin product and four interferon products to treat HCV. Rebetol, the ribavirin product, is made by Schering-Plough Corp. of Kenilworth, N.J. The interferon products are: Intron A and PEG-Intron (made by Schering-Plough), Roferon-A (Hoffmann-La Roche Inc., Nutley, NJ), and Infergen (Amgen Inc., Thousand Oaks, Calif.). Intron A, Roferon-A, and Infergen are considered "conventional" interferons and are injected three times a week. PEG-Intron (a longer-acting form of interferon) is injected once a week. Only Intron A and PEG-Intron are approved for use in combination with ribavirin.
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.
There is no absolute way to know who will or won't respond to therapy. But health-care providers try to predict responsiveness using research tests to determine genotype and concentration of HCV in the blood, says John Ticehurst, M.D., a microbiologist and clinical laboratory faculty member at the Johns Hopkins Medical Institutions. HCV concentration in the blood is often referred to as "viral load."
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 United States, 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. Unfortunately, about 70 percent of HCV-infected people in the United States have genotype 1.
Genotyping also can be 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 usually sufficient. Patients with genotype 1 who have responded at the end of 24 weeks of treatment may benefit from an additional 24 weeks of treatment.
Historically, only 10 to 20 percent of those treated with conventional interferon alone had sustained responses, depending on the interferon product used. Combination therapy (conventional interferon plus ribavirin) showed better results, with 35 percent to 45 percent of those treated sustaining the response, depending on genotype.
Studies have shown that PEG-Intron used with Rebetol is slightly more effective than the conventional interferon Intron A with Rebetol. PEG-Intron with Rebetol caused the same types of side effects as Intron A with Rebetol, but some occurred more often. (See "Treatment Side Effects.")
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 HCV. 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 more than five 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."
"Side effects are variable," says Adrian Di Bisceglie, M.D., medical director of the American Liver Foundation and professor of internal medicine at St. Louis University. "About 10 percent of patients have virtually no side effects. Approximately 10 percent have very severe, almost disabling side effects and have to stop work or stop the drug. The remaining 80 percent have side effects--but they are tolerable."
For some people, the side effects decrease after the first few weeks of treatment. But many individuals have severe side effects through the duration of treatment; these side effects may persist for months after the treatment ends.
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."
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 for interferon products 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).
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 in female patients and female partners of male patients must 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, says DI Bisceglie. "Patient symptoms are a very unrelated guide to the severity of hepatitis C. 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:
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," she says. 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.
There is a 5 percent risk that an HCV-positive mother can give the virus to her unborn child. There is no evidence that HCV is transmitted from mother to child through breastfeeding.
Diagnosis and Vaccination
DI Bisceglie encourages everyone at risk--not just those with symptoms--to be tested for HCV. (See "You May Be at Risk for Hepatitis C".) The FDA has approved two types of test for HCV. One type, the enzyme immunoassay (EIA) test (also called enzyme-linked immunosorbent assay, or ELISA) is usually the first laboratory test used to determine if someone is infected with HCV. The EIA detects antibodies to the virus in a person's blood.
The EIA is not always accurate--it may show an infection when there really isn't one. So if the EIA test result is positive, an additional, more expensive test is used to make sure the person really is infected with HCV. Until recently, the only FDA-approved second test was the recombinant immunoblot assay, RIBA, made by Chiron Corporation, Emeryville, Calif. The EIA and RIBA tests may detect HCV infection, but do not tell if the infection is active or inactive.
In July 2001, the FDA approved two tests that do indicate if an infection is active. These similar tests, made by Roche Molecular Systems, Inc., of Pleasanton, Calif., are the Amplicor HCV Test, v2.0 and the Cobas Amplicor HCV Test, v2.0. Both are approved for people who have evidence of liver disease and antibody evidence of HCV infection and who are suspected to be actively infected with HCV. The tests detect HCV RNA, indicating that the virus is replicating and therefore active. Either the Amplicor or the Cobas Amplicor test may be used as a follow-up to an EIA positive test result, a RIBA positive result, or an EIA positive and a RIBA inconclusive result.
The FDA has also approved an over-the-counter home test system, called Hepatitis C Check. 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 2001, the FDA approved a combined hepatitis A and B vaccine called Twinrix, marketed by SmithKline Beecham Pharmaceuticals in Philadelphia.
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 health-care 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."
Gamache, who also joined a support group and volunteers at a hepatitis clinic, recommends leading a healthy lifestyle and keeping a positive attitude. "Anything you can do to help yourself, empower yourself, helps get rid of the sense of hopelessness," he says. "It doesn't have to be a death sentence."
Hepatitis C Study
Researchers are conducting a large study to try to prevent the development of cirrhosis and liver cancer in people with chronic hepatitis C. Called Hepatitis C Antiviral Long-Term Treatment Against Cirrhosis (HALT-C), the four-year study is being conducted at 10 research centers nationwide and involves more than 1,300 participants.
The goal is to learn whether long-term pegylated interferon plus ribavirin treatment will decrease liver damage over time in people with advanced fibrosis or cirrhosis who didn't respond to prior treatment. Pegylated interferon is a, longer-acting form of interferon than conventional interferons.
The study is sponsored by the National Institute of Diabetes and Digestive and Kidney Diseases. For additional information, see www.haltctrial.org.
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