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Managing therapy-related problems in hepatitis C: timing is key.

BALTIMORE -- The hematologic side effects of using ribavirin and interferon to treat hepatitis C infections can be managed successfully with the timely use of complete blood counts and appropriate interventions, Dr. Jorge L. Herrera said at the annual meeting of the American College of Gastroenterology.

The risk of side effects such as anemia, neutropenia, and thrombocytopenia must be balanced against the benefits obtained from combination therapy with ribavirin and interferon, he noted.

* Anemia. This is "probably the most common hematologic side effect of combination therapy that you will see in your patients," said Dr. Herrera of the University of South Alabama, Mobile.

About 10% of patients will develop a hemoglobin count of less than 10 g/dL at some point during treatment with combination therapy. In 50% of males and 90% of females, the hemoglobin count will drop below 12 g/dL. For females, the risk of anemia is more than four times higher than for males.

The magnitude of the drop in hemoglobin is important as well. "That in itself can result in symptoms, even if the new, lower hemoglobin is not truly drastic when you're looking at the report," Dr. Herrera noted.

A drop in hemoglobin of 2-3 g/dL from baseline levels is generally expected during combination treatment, but the drop will exceed 3 g/dL in 60% of men and 40% of women.

The crucial period to be on the lookout for anemia is the first 2-8 weeks of treatment, he said.

"My preference is to check complete blood counts every 2 weeks, and if I see a dramatic drop I may do it on a weekly basis thereafter. After 8 weeks, the drop may be more gradual but you need to be just as careful in watching them," Dr. Herrera advised.

The "traditional explanation" for anemia is the hemolytic effect of ribavirin on red blood cells. Red blood cells have no nucleus, so they have no enzymes to break down ribavirin as it enters the cells. A high concentration of oxidized ribavirin in the red blood cell is thought to cause damage to the cell's membrane. Ribavirin also is known to affect the bone marrow of rhesus monkeys.

Even though ribavirin induces anemia, it protects against thrombocytopenia by stimulating an increase in the production of megakaryocytes.

Antioxidants are "probably the simplest and cheapest" therapies for dealing with antiviral-induced anemia, he said, but the small trials that have examined the therapy suggest it provides only a modest benefit, if any, and it must be started with the ribavirin treatment.

Another option is to reduce the dose of ribavirin if a patient's hemoglobin levels drop below 10 g/dL or if there is a greater than 2 g/dL decrease in hemoglobin from the baseline level in patients with heart disease.

Dose reductions, however, entail a 4- to 8-week lag time in response. Patients may even continue to have a decline in hemoglobin prior to recovery.

In this case, if the dose reduction is started too late, the patient may have to discontinue treatment or even get an infusion of blood.

The most one can really expect from a dose reduction of ribavirin is about a 1 g/dL increase in hemoglobin, Dr. Herrera said.

He advised using a growth factor such as erythropoietin to improve hemoglobin levels instead of reducing the dose of ribavirin. Erythropoietin has a shorter lag time--2 weeks--than dose reduction. Patients report an improvement in their quality of life even before hemoglobin levels begin to rise.

Furthermore, the timing of the single weekly dose of erythropoietin has no bearing on the treatment. Most importantly, erythropoietin increases hemoglobin levels by about 3 g/dL.

In one trial, 34 patients who received erythropoietin plus dose reductions of ribavirin had significantly higher hemoglobin levels after 16 weeks than 28 patients who received only dose reductions (14 g/dL vs. 11 g/dL). The patients who took erythropoietin also did not reduce their ribavirin dose as much as the other patients.

* Neutropenia. Around 15%-20% of patients develop this condition, most commonly from the use of pegylated interferon. In most cases of neutropenia, the drop in neutrophils occurs within the first 2-3 weeks of therapy. Patients who experience a decrease in neutrophils usually have a stable count thereafter, or even an increase.

In Dr. Herrera's experience, it's best to do a complete blood count no sooner than day 5 or 6 after an injection of interferon. All the lab work should be done on the day before or day of the next injection. If the count is performed before then, the "numbers will look ugly," he said. The late blood count allows white blood cells to recover prior to the next cycle of interferon. At this check, only scrutinize the neutrophil count and ignore the white blood cell count.

The oncology literature suggests intervening when the neutrophil count dips below 750/[mm.sup.3], but a range of 500/[mm.sup.3] to 750/[mm.sup.3] may be safe in noncirrhotic, otherwise healthy hepatitis C patients, advised Dr. Herrera, who noted that he discusses this departure from the standard of care with his patients.

A dose reduction of interferon will increase the number of neutrophils but also may reduce the effectiveness of treatment. When the neutrophil count drops to between 500/[mm.sup.3] and 700/[mm.sup.3] or less, consider using a granulocyte colony-stimulating factor such as filgrastim, Dr. Herrera suggested.

* Thrombocytopenia. Interferon monotherapy is the main cause of this condition because ribavirin is somewhat protective against its occurrence in combination therapy. Patients who experience thrombocytopenia have a 10%-50% decline in platelet count. It's rare for a patient to have thrombocytopenia if he or she has a pretreatment platelet count of 75,000/[mm.sup.3] or more, he said, but if the count is less than 75,000/[mm.sup.3] before combination therapy then thrombocytopenia probably will occur. Patients with thrombocytopenia should be counseled to stay away from nonsteroidal anti-inflammatory drugs.

In practice, Dr. Herrera believes that platelet counts of 35,000/[mm.sup.3] or higher are probably safe. Once the platelet count has dropped below 35,000/[mm.sup.3], it's best to reduce the dose of interferon. He has never treated thrombocytopenia with oprelvekin--synthetic interleukin-11, which helps to make platelets--because it can cause fluid retention.
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Title Annotation:Gastroenterology
Author:Evans, Jeff
Publication:Internal Medicine News
Date:Feb 1, 2004
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