The most significant advancement in the treatment of hepatitis C in recent years is the antiviral drug ribavirin. The combination of pegylated interferon and ribavirin has reduced relapse rates to 20 percent from 50 percent (see “Two Ribavirin Advances,” Hepatitis, January – March 2006). But like most choices in life, the decision to treat hepatitis C virus (HCV) with interferon and ribavirin is one of risk versus reward. In addition to the possible side effects of interferon – including flu-like symptoms, fatigue, nausea, depression, anxiety, insomnia and mental confusion – patients who take ribavirin run the risk of becoming anemic.
 
As many as 10 percent to 15 percent of patients treated with interferon/ribavirin therapy become anemic, a condition that can be life threatening and typically requires adjustments to the medication.  A complete blood count (CBC) can be used to diagnose anemia because the test includes counts of red blood cells and of hemoglobin, the iron-containing protein in red blood cells that transports oxygen. The World Health Organization defines anemia as hemoglobin levels less than 13 grams per deciliter (g/dL) in men and less than 12 g/dL in nonpregnant women.
 
Hemolytic anemia is a disorder in which the red blood cells are destroyed faster than the bone marrow can produce them. There are two types of hemolytic anemia: intrinsic, which is the destruction of red blood cells due to a defect within the cells themselves, and extrinsic, which occurs when red blood cells are produced healthy but are later destroyed by infection or drugs.
 
Dr. Mark Sulkowski, associate professor of medicine at Johns Hopkins University School of Medicine and medical director of the Viral Hepatitis Center in Baltimore, Md., says that in general, hepatitis C infection is not associated with anemia in and of itself. “However, anemia may be found in persons with advanced liver disease and those with HIV/HCV coinfection,” he says. “In addition, the current standard of care for the treatment of HCV, peginterferon alfa and ribavirin, is commonly associated with significant reductions in hemoglobin and, in some patients, anemia.
 
“This is primarily due to the effect of ribavirin, which causes an extravascular hemolytic anemia, and to a lesser extent, due to bone marrow suppression with interferon,” says Dr. Sulkowski, who notes that the differential diagnosis for anemia is very broad and may be caused by many conditions both benign and serious.
 
“One of the most common types of anemia in the developed world is iron deficiency anemia,” he says. “However, this is quite different than what is observed in the treatment of hepatitis C, in which iron stores are typically adequate.”
 
In most cases, he says, the anemia subsides once the treatment is stopped. “This type of anemia is reversible following the discontinuation of these medications and is not typically a long-term problem,” Dr. Sulkowski says.
 
Hard to handle
Sara T. Welch of Versailles, Ky., became anemic while participating in a clinical trial for HCV treatment at the University of Louisville School of Medicine. The trial was blind, meaning she was not told whether she was receiving ribavirin or a placebo. “The clinical trial I participated in began late in 2004,” she says. “After being on medication for two months, my hemoglobin dropped from around 15 (g/dL) to around 10 (g/dL). I believe it rapidly dropped further to around 8 (g/dL), which is when it was decided to dose down one of the medications.”
 
To combat the anemia, the research coordinator cut the oral dosage (ostensibly the ribavirin) by half, leaving the injected dosage (interferon) at full strength. Welch says that although the trial was blind, she is pretty sure she was given the ribavirin rather than a placebo because of the anemia she experienced. She says the anemia left her extremely fatigued and made it difficult for her to maintain her livelihood.
 
Don Lyons of Gaston, Ore., knows about the fatigue. A veteran of treatment for his HCV, Lyons experienced his first bout with anemia when he went on a regimen of daily injections of interferon over the course of six months in 1992. He says his doctor monitored it closely and he kept up the treatment, although the anemia took its toll on him physically.
 
“I could not walk up a flight of stairs without resting,” he recalls. “Everything was tiring and I would have to stop and catch my breath often during any physical exertion. It would take me hours to do jobs that normally take minutes.”
 
While Lyons acknowledges that he experienced other side effects and cannot say with complete certainty that the anemia caused all of the fatigue, it was nevertheless debilitating. “I had to ask to be relieved of my management position at work until the treatment was complete. I completed the treatment (but) it failed to kill the virus,” he says.
 
When the first combination therapy was approved using ribavirin and interferon, Lyons started another regimen of treatment. Again, the side effects were debilitating.
 
“That caused the worst anemia by far,” he says. “I was lethargic, slept 12 to 14 hours a day and could not do physical activity without losing my breath and having to rest.” While his red blood cell count never got low enough to alter the treatment, he did suspend it after 10 months because his liver function tests and viral count spiked. “At that point, my doctor and I decided it was not worth the side effects if it was not working,” he says.
 
A biopsy showed that the damage to his liver had been abated somewhat by the treatments he endured. Determined to fight the virus, Lyons would resume treatments over the years as new drugs and protocols were introduced. In 2002, he started a short-lived regimen of pegylated interferon and ribavirin. “When Pegasys came out, my doctor and I decided to try combo treatment again. I had not ever used (pegylated interferon) so we thought it might have a different effect,” he says. “I only lasted two months. My body could no longer take the side effects as well as I had when I was younger. I had had enough.”
 
Serious business
In some cases, anemia can be a much more serious matter that requires close supervision by doctors. “In subjects with underlying heart disease, anemia can be life threatening and induce a heart attack,” says Dr. Howard J. Worman, an associate professor of medicine, anatomy and cell biology at the Columbia University College of Physicians and Surgeons in New York City. “For this reason, people with risk factors for coronary artery disease are recommended to be evaluated before receiving interferon alpha and ribavirin for hepatitis C.” Because of this risk, he advises that complete blood counts be obtained at baseline and at weeks two and four of therapy, or more frequently if clinically indicated.
 
Dee Jones of Memphis, Tenn., says the anemia she developed two months into the combo treatment not only left her tired, but made her prone to bruising as well. “That was my first suspicion,” she says. “I told the docs and they said ‘Yes, you have been anemic the whole time.’”
 
Jones says her doctors decided not to alter her treatment during the year-long regimen, although to battle the anemia they did suggest that she take injections of epoetin alfa (Epogen, Procrit) – a drug that has the same biological effects as endogenous erythropoietin, a glycoprotein produced in the kidneys that stimulates red blood cell production in the bone marrow.
 
“I refused,” she says. “It would have meant another shot.” Jones says she is a sustained responder to the treatment since April 2005 but that her anemia persists.
 
A shot in the arm
Like many, Alisha Ford of New Jersey battled the fatigue associated with anemia while on the combination therapy. “I felt like my life was out of control,” she says. “I couldn’t do basic things like folding clothes without becoming exhausted.”
 
Rather than cut back on the medication, her doctor chose to put her on Procrit, which is approved by the Food and Drug Administration for treatment of anemia in patients undergoing chemotherapy, those with chronic kidney disease, HIV/AIDS patients being treated with the antiviral drug AZT, and select surgery patients. As a specific treatment for HCV patients, however, there has not been enough study to prove its efficacy. That, however, may change.
 
“The standard approach to the management of HCV-treatment-associated anemia is to reduce the dose of ribavirin,” says Dr. Sulkowski. “There are no adjuvant medications approved by the FDA for the treatment of anemia in this setting. However, several clinical trials support the use of recombinant human erythropoietin for the treatment of anemic HCV-infected patients receiving peginterferon plus ribavirin. Although little data is available, it is anticipated that a similar medication, darbepoetin alfa (Aranesp), will also be effective in this setting.”
 
The effectiveness of the Procrit was a blessing for Ford, but she was battling other side effects that ultimately forced her to stop treatment.  “Procrit actually helped tremendously. It gave me motivation to continue the treatment. I started to feel like myself again,” she says. “The reason I stopped the treatment is because I was losing too much weight and I was severely depressed.”
 
Despite the debilitating side effects, Ford doesn’t think others should be discouraged by her experience. To fight the disease, she says, they should take advantage of the treatment options available, but they should keep close tabs on what the powerful drugs are doing to their bodies.
 
“I would tell people to be prepared for what anemia really means. It means that you may get tired very easily; you may not be able to function as usual. Walking up a flight of stairs or across the room can be extremely exhausting,” she says. “A person has to make arrangements to have others help with regular activities. I think it is worth the pain for a few months, if you get the results you want from the treatment.”
 
Lyons says he has to look no farther than the loved ones around him for the source of his perseverance. “All the interferon I have taken over the years has at least bought me time. Even though the quality of life was pretty poor, I was given enough time to raise all my children to adults, and that was worth it even though the treatment was not successful at killing the virus,” he says. “I would do it all again – without a second thought – for the chance to raise my children.”