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FDA Consumer magazine
New Treatment Helps Some, But Cure Remains Elusive
by John Henkel
Elaine Moreland knew she wasn't imagining the symptoms. Fatigue, migraines, nausea, memory loss, anxiety, and dizziness all were wreaking havoc in her life. Yet doctor after doctor could find nothing wrong with her. Some said she was depressed. Others blamed hypochondria.
Finally, in 1992, after suffering for several years, she went to another doctor in tears. "I told him that I was not leaving his office until he found something," she says. Through extensive testing, he did. Moreland, then 32, had hepatitis C.
The nation's most common blood-borne infection, hepatitis C is estimated to affect some 4 million Americans in its chronic form. Eventually, as many as 70 percent of them will develop liver disease, according to the national Centers for Disease Control and Prevention.
In congressional testimony last year, former Surgeon General C. Everett Koop, M.D., called hepatitis C "a disease these millions will carry for a decade or more--possibly spreading to others--while it develops into a serious threat to their health."
Hepatitis C is one of five currently identified viruses--hepatitis A, B, C, D, and E--all of which can attack and damage the liver. Widely viewed as one of the most serious of the five, the hepatitis C virus (HCV) is spread primarily through contact with infected blood and can cause cirrhosis (irreversible and potentially fatal liver scarring), liver cancer, or liver failure. Hepatitis C is the major reason for liver transplants in the United States, accounting for 1,000 of the procedures annually. The disease is responsible for between 8,000 and 10,000 deaths yearly.
Some estimates say the number of HCV-infected people may be four times the number of those infected with the AIDS virus. "One of the main differences is that hepatitis C doesn't kill as quickly as AIDS," says Jay Hoofnagle, M.D., director of digestive diseases and nutrition at the National Institute of Diabetes and Digestive and Kidney Diseases.
Presently, there is no vaccine or other means of preventing hepatitis C infection. HCV exists in many different forms, called genotypes, confounding researchers in their quest to develop a vaccine effective for all variations. Also, HCV mutates frequently within infected patients, so even if an effective vaccine is developed, it could be rendered useless by a new strain of mutant virus.
Once HCV is contracted, treatment or the body's defenses can cure a small portion of patients. In most others, however, HCV's frequent mutations allow it to evade the immune system, defeating attempts to develop a cure. Some treatments are available, but they don't work for all patients. The most recent is one that combines a genetically engineered biological drug (interferon) with the drug ribavirin.
Who Is at Risk?
High-risk activities for acquiring hepatitis C include:
In the recent past, people receiving blood transfusions were a main risk group for HCV infections. That is because before 1990, there was no way to reliably screen the blood supply for the virus, so many were unwittingly infected. At the time, the risk of HCV infection was about 1 in 200 units of blood, says CDC. In May 1990, the Food and Drug Administration licensed an enzyme immunoassay (EIA) test for HCV, which indicates the presence of HCV antibodies in blood samples. But this test had a high rate of false positives (see "Identifying Recipients of Contaminated Blood."). Two years later, the agency approved a more sensitive and reliable EIA test, which has helped lower the odds of contracting hepatitis C from donated blood to 1 in 100,000 units. In February, FDA approved an improved test for confirming positive results from screening tests.
Acquiring HCV through sex between monogamous partners has not been conclusively demonstrated and appears to be rare. Studies have shown that less than 5 percent of spouses of patients with chronic hepatitis C become infected. But some of these studies include data from countries where hepatitis C is common in the general population. Likewise, transmission of HCV from infected mother to infant also is rare and results in infection of the infant in only about 5 percent of cases. There is no evidence that breast-feeding spreads HCV.
In about 10 percent of acute hepatitis C cases and 30 percent of chronic cases, the source of the infection cannot be identified. These "sporadic" infections, says the National Institute of Diabetes and Digestive and Kidney Diseases, are likely caused by infection through contamination of cuts, wounds or medical injections with the blood or body fluids of infected persons. Also, some infected patients may not provide truthful information about potential exposure, especially regarding past drug abuse. Further, some health experts say there may be an as-yet unknown pathway for the virus. Most experts agree, however, that HCV cannot be acquired through casual contact with an infected person such as shaking hands, hugging, or even kissing. It also is not spread by sneezing, coughing, or sharing eating utensils or drinking glasses.
Treating the Disease
Some patients learn they have hepatitis C through a routine physical or when they donate blood and a blood test shows elevated liver enzymes. Others have symptoms (see "Hepatitis C: Types and Symptoms."). Further testing for HCV antibodies using the EIA test and a supplemental test such as the "Western blot" or HCV-RNA detection can positively identify the infection. A liver biopsy shows disease manifested by damage already done to the liver.
Once diagnosed, CDC recommends the following:
One of the only approved treatments for chronic hepatitis C, especially for patients with consistently elevated liver enzymes or mild-to-moderate liver damage, is the biological drug interferon alpha, marketed as Intron A by Schering Corp. and Roferon-A by Roche Laboratories Inc. Amgen Inc. also has an approved drug derived from interferon alpha called Infergen. Hepatitis C patients must inject interferon themselves, usually three times a week. In about 25 percent of patients, the drug has a pronounced effect, reducing HCV to very low levels in the blood. However, if the drug is ineffective after three months, doctors probably will discontinue it.
Doctors also may prescribe Rebetron, a Schering product that combines interferon with the antiviral drug ribavirin. Approved last June for patients who have relapsed after interferon therapy and expanded in December to include patients never treated with interferon, this combination therapy appears to suppress blood levels of HCV more effectively than a first or repeat course of interferon alone. In clinical trials, about 45 percent of relapsed patients treated with the combination sustained reduced HCV levels for six months after discontinuing therapy, compared with 5 percent of relapsed patients who were retreated with interferon alone. These results were reinforced by a study published last Nov. 19 in the New England Journal of Medicine showing the combination to be significantly more effective in suppressing HCV levels.
"We've learned from research in other viral diseases that combination therapies rather than [a single drug] may offer the best potential for effective treatment," says John Hutchison, M.D., medical director of liver transplantation at Scripps Clinic and Research Foundation.
Bill Ruttman, 44, a Lansdale, Pa., hepatitis C patient, has taken the combination treatment since last October. As a result, his HCV levels have dropped to undetectable levels, and his once-elevated liver enzyme levels have "normalized," which he says is good news because for now, he feels the disease has been slowed down. "I'm extremely happy in that regard," he says.
Ruttman's successful therapy has come at a price, however, because of Rebetron's side effects. He suffers from extreme fatigue and has to nap often during the day, and he sleeps restlessly at night. He also has bouts of depression and is currently unable to work. His side effects are typical of those experienced by patients taking interferon alone as well as the combination therapy.
Because side effects can be serious, patients should be closely monitored by their doctors. Ribavirin can cause anemia, and interferon is associated with both psychosis and suicidal behavior, though the latter occurs in 1 to 2 percent of patients. Both interferon and ribavirin present significant potential risks for pregnant women, including possible fetal death or malformations. Female patients and female partners of male patients must not become pregnant while receiving this therapy and for six months after completing therapy.
Some patients who take interferon or the combination complain of flu-like side effects such as fever, chills and body aches. Many side effects, such as muscle aches and low-grade fever, can be managed. Some side effects may be reduced by giving the drug at night or lowering the dosage. Side effects are often more severe during the first few weeks of treatment, especially after the first injection.
Patient Elaine Moreland says her interferon therapy caused "just about every one of the [side effects] listed in the drug handout sheets--severe muscle cramps, hair loss, nervousness, heart palpitations, fatigue, sweating, headaches, and blurry vision." Ultimately, she says, treatment was stopped because it wasn't working. Because of the potential side effects, she is holding off on further therapy in the hope that improved treatments may soon be available. "I'm waiting to see what comes down the pike unless signs start to point to serious progression of my disease."
Currently, chronic hepatitis C patients who do not respond to therapy have few options. In many, cirrhosis or other damage will eventually cause the liver to stop functioning. In these cases, a liver transplant is the only recourse. However, even new livers often become infected with the virus. But because HCV usually progresses slowly, says Jay Hoofnagle, many transplant recipients can live normal lives for many years despite the infection.
On the Horizon
A major focus of hepatitis C research is development of a cell culture through which scientists can study HCV outside the human body. By understanding how the virus replicates and how it injures cells, researchers may be able to develop ways to control the virus as well as drugs to block it.
Several drugs currently under study show some promise as future treatments for the disease. They include thymosin, amantadine, and other forms of interferon.
"What we really need, of course, is a vaccine against this disease," Surgeon General David Satcher, M.D., told a congressional committee last year. "However, we cannot underestimate the complexity of this task, particularly because of the rapid rate at which the virus mutates." Researchers at the National Institute of Allergy and Infectious Diseases say a vaccine is likely 10 years away.
One research hurdle was cleared in 1997 when NIAID scientists and FDA researcher Stephen Feinstone, M.D., independently cloned an infectious hepatitis C virus. NIAID director Anthony Fauci, M.D., says the work "will enable scientists to better understand the factors and mechanisms that determine whether the virus is cleared from the body or produces a chronic infection."
Another obstacle to research progress is the need for more funding. Though hepatitis C has taken a back seat in recent years to appropriations for many other more visible public health problems such as AIDS, the situation is improving. Direct funding for hepatitis C research at the National Institutes of Health was $25.3 million in 1997, but has increased to over $34 million in 1999. Private efforts have bolstered funding as well. For example, country music entertainer Naomi Judd, herself a hepatitis C patient who was forced to retire in 1991, started the Naomi Judd Research Fund to help find a cure for the disease. Through the fund, she has helped the American Liver Foundation raise over a million dollars.
Meanwhile, federal and private groups are escalating efforts to educate primary care physicians and the public about the disease. And through the Internet and local support groups, hepatitis C sufferers are finding what patient Bill Ruttman calls "a community."
As for those just diagnosed with the disease, patient Elaine Moreland has this advice: "Try to find a good doctor who is knowledgeable about HCV. Become active in your own medical treatment. Read all you can about the disease. Above all, try to keep a positive attitude and know you're not alone in the fight."
John Henkel is a staff writer for FDA Consumer.
Scientists have currently identified five different hepatitis viruses. All are serious infections that can attack and damage the liver. (The information below is also available as a 7K PDF file.)
How It Is Spread: By drinking water or eating food contaminated with fecal material that contains the virus.
Symptoms: Flu-like symptoms such as fatigue, nausea, vomiting, abdominal discomfort, dark urine, and jaundice (yellowing of the skin and eyes). Liver tests may be elevated.
Treatment: Bed rest and avoidance of intimate contact. Can last between three weeks and six months. Two approved vaccines: immune globulin for short-term protection and for patients already exposed, and hepatitis A vaccine for long-term protection.
How It Is Spread: Exposure to infected blood, unprotected sex with an infected person, sharing contaminated needles, and travel to countries with a high rate of infection. Infected mothers also may infect newborns.
Symptoms: Loss of appetite, nausea, vomiting, fever, fatigue, abdominal pain, dark urine, or jaundice. No symptoms in some people.
Treatment: Interferon alpha. A vaccine--recommended for newborns, infants, and teenagers--provides immunity for at least five years.
How It Is Spread: Direct contact with human blood, which can occur from being pricked accidentally by a contaminated needle, injecting illegal drugs, and sharing razors or toothbrushes with an infected person.
Symptoms: More than half have no symptoms. Others have appetite loss, fatigue, nausea, fever, dark-yellow urine, and jaundice. Liver tests may be elevated.
Treatment: Interferon or a combination of interferon and the drug ribavirin. No vaccine.
How It Is Spread: Contact with infected blood. Requires the hepatitis B virus to replicate, so it infects either at the same time as hepatitis B or those who already have hepatitis B.
Symptoms: Same as for hepatitis B but typically more severe: appetite loss, fatigue, nausea, vomiting, abdominal pain.
Treatment: Interferon alpha for hepatitis B may have some effect.
How It Is Spread: Water contaminated with fecal material, especially in developing countries, and contaminated uncooked shellfish, fruits and vegetables.
Symptoms: Abdominal pain, dark urine, fever, jaundice, nausea, and vomiting.
Treatment: Bed rest. No drug treatment or vaccine.
Before 1992, tests to detect antibodies to the hepatitis C virus in the nation's blood supply were unreliable or nonexistent. As a result, many patients who received blood then may have contracted the virus unknowingly. To identify them so they can receive treatment, the Department of Health and Human Services is sponsoring a "lookback" program that is tracking down and informing about 300,000 people who received suspected HCV-contaminated blood before 1992. HHS agencies, including FDA and the Health Care Financing Administration, will ensure that recipients of blood that initially tested negative for antibodies to HCV, but was collected from donors who later tested positive for the antibodies, are informed by letter that they may have received blood containing HCV. As part of the lookback program, the national Centers for Disease Control and Prevention is leading educational programs for health-care professionals and the public to bring greater awareness of the disease.
Infection with hepatitis C may cause symptoms right away, not for years, or sometimes not at all. With the acute form of the disease, symptoms such as fatigue, nausea, and dark urine typically show up within six months. About one-fourth of patients with acute hepatitis C recover completely with treatment. But according to the National Institute of Diabetes and Digestive and Kidney Diseases, the other estimated 75 percent of these patients will progress eventually to the long-term, or chronic, form of the disease, with detectable HCV in their blood.
Chronic hepatitis C, however, varies widely in its severity and outcome. It can lie dormant for 10 years or more before symptoms appear. Some patients will have no symptoms of liver damage, and their liver enzymes will stay at normal levels (elevated enzymes are one indication of liver disease). A liver biopsy, in which the doctor removes a tiny piece of liver with a needle, may show some degree of chronic hepatitis, but it may be mild.
Other patients, however, will have severe hepatitis C, with detectable HCV in their blood, liver enzymes elevated as much as 20 times more than normal, and a prognosis of ultimately developing cirrhosis and end-stage liver disease. Another group of patients falls somewhere in the middle, with few or no symptoms, mild- to-moderate elevation of liver enzymes, but with an uncertain prognosis.
According to the National Institute of Diabetes and Digestive and Kidney Diseases, at least 20 percent of chronic hepatitis C patients develop cirrhosis, but this process can take 10 to 20 years from the onset of infection. As many as 5 percent of chronic patients, after 20 to 40 years, develop liver cancer. Other studies show that those with cirrhosis develop liver cancer within 17 years.
Patients with no symptoms sometimes learn they have the disease when a routine physical or blood donation shows elevated levels of liver enzymes, which can indicate hepatitis C, as well as other liver disorders.
Other patients, however, have symptoms that prompt them to seek medical attention, including:
Contact any of the following organizations for more on hepatitis C, its treatment, support groups, and Internet mailing lists.
American Liver Foundation
1425 Pomptom Ave.
Cedar Grove, NJ 07009
1-800-GO LIVER (1-800-465-4837)
Hepatitis C Foundation
1502 Russett Drive
Warminster, PA 18974
Hepatitis Foundation International
30 Sunrise Terrace
Cedar Grove, NJ 07009-1423
National Digestive Diseases Information Clearinghouse
2 Information Way
Bethesda, MD 20892-3570
In addition, two helpful publications are available on-line from the national Centers for Disease Control and Prevention or by calling CDC at (404) 332-4555:
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