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Does Reducing Iron Levels Improve the Response to Treatment in Patients with Chronic Hepatitis C?

Small randomized study with alfa * interferon and iron reduction revealed some improvements six months after treatment, with some study limitations

by Harvey S. Bartnof, MD

Previously, patients with chronic hepatitis C have been shown to have an improved response to alfa * interferon monotherapy if they had lower levels of tests for iron in blood ("serum ferritin, transferrin saturation") and lower iron levels in liver. (Note that the current standard is combination therapy.) Also, iron reduction in patients with chronic hepatitis C leads to lower levels of liver enzymes (ALT, alanine aminotransferase and AST, aspartate aminotransferase) in blood. In addition, small pilot studies have determined that reducing iron levels in blood before therapy with high dose alfa interferon leads to improved responses in patients who previously had not responded to monotherapy alone. Two other small studies found improved responses with iron reduction before alfa interferon monotherapy in treatment-nave (no previous treatment) patients. Still other studies have shown that 30-40% of patients with chronic hepatitis C has increased blood (serum, no cells) levels of ferritin and transferrin saturation. In the current study, iron reduction was started before therapy with six months of alfa interferon and was continued to maintain low levels of iron.

A total of 82 persons in the US with chronic hepatitis C were enrolled into this randomized, controlled study. All were treatment-nave. Women comprised 60%, and 18% were non-Caucasian. HCV genotype 1 (the most difficult to treat) was present in 76%. The mean baseline HCV RNA viral load was 2.8 million copies per milliliter. The arm with interferon alone and the other arm with interferon plus iron reduction had comparable baseline levels of ALT, blood serum tests for iron and inflammation scores on liver biopsy. In spite of randomization, unfortunately the fibrosis scores on baseline liver biopsies were significantly lower in the arm that had iron reduction. This limits the results of the study somewhat.

Iron reduction was accomplished by removing blood ("therapeutic phlebotomy") in a similar manner as that used for blood donation. A total of 400-500 milliliters (approximately quart) of blood was removed every 1-2 weeks until a mild iron deficiency was measured in blood. The blood removal sessions started before and continued, if necessary, during alfa interferon therapy. Mild iron deficiency was defined as two out of three of the following: "prephlebotomy hematocrit" (percentage red cells) less than 35%, blood serum "ferritin" less than 10 nanograms per milliliter, and serum "transferrin" saturation less than 10%.

The Intron-A (alfa interferon) dose was 3 million units injected 3-times weekly for six months. This was standard at the time of the study. Currently, the standard is dual therapy with Rebetron (alfa interferon plus ribavirin or Rebetol) for 6-12 months.

Among all patients, 71% completed the study, with an equal percentage of discontinuations in both arms. The most common cause for discontinuation was virologic non-response at week 12.

The most significant result was that inflammation on liver biopsy was significantly lower after treatment in the interferon plus iron reduction arm than in the arm without iron reduction. Specifically, 18 patients in the iron reduction arm had significant improvements in two out of three inflammation scores from the "Knodell histological activity index (HAI)." In contrast, in 15 patients from the arm without iron reduction, there were no significant differences when comparing liver biopsies before and after treatment. (Note that a pre- and post-liver biopsies were only available for 45% of those in the iron reduction arm and 36% of those in the arm without iron reduction.) However, fibrosis and total HAI scores were unchanged in both arms. (Note the liver biopsy correlates with HCV disease progression, while HCV RNA and liver enzymes do not correlate with progression.)

The iron reduction arm did have significantly lower ALT levels during the follow-up period up to 24 weeks after interferon was stopped. During treatment, the iron reduction arm had significantly lower ALT levels for half of the measurements; the other half of measurements were lower, but did not reach statistical significance.

The HCV RNA results were somewhat mixed. The iron reduction arm did have a significantly lower viral load (approximately 1.4 million copies per milliliter) 24 weeks after therapy, when compared to the arm without iron reduction (approximately 3.4 million copies per milliliter). However, the percentage with an undetectable viral load at that time point was not significantly different by statistical analysis: 18% in the iron reduction arm and 7% in the arm without iron reduction.

The mean number of blood removal sessions in the iron reduction arm was significantly greater (nine) for the men than that for the women (six). Also, the mean amount of total blood removed was significantly greater for the men (4.3 liters) than for the women (2.8 liters). (Note 3.8 liters equals one gallon.) As has been shown in many studies previously, the baseline serum ferritin levels were significantly higher among men than women.

In a statistical "regression analysis" of all patients in the study, an undetectable HCV RNA viral load six months after the end of treatment was significantly inversely associated only with baseline blood serum transferrin saturation levels. That is, lower saturation levels at baseline was significantly associated with a higher percentage of viral load undetectability six months after treatment. Each of the following factors had no statistical association: gender (sex), race-ethnicity, HCV genotype, HCV RNA, baseline ALT, ferritin and total HAI score on liver biopsy.

The researchers found that therapeutic phlebotomy led to only a 5% rate of side effects from the procedure. Primarily, this was fatigue. The overall side effect profile was equal when comparing the two study arms.

There are a few limitations to the study. As mentioned above, despite randomization, the arm that had iron reduction had better baseline liver fibrosis scores. Another limitation was that despite randomization, the percentage of African Americans in the iron reduction arm was significantly less (3%) than those randomized to the arm without iron reduction (17%). Since a few studies have shown a lower response rate to therapy among African-Americans, this might have skewed the results. However, the authors state that their overall results were unchanged when controlling for baseline liver biopsy results and race-ethnicity.

Another limitation is that an older standard of therapy was used, even though it was standard at the time. The duration of treatment with alfa interferon today should be 12 months for patients with genotype 1 who have a virologic response at six months. Also, therapy today would include ribavirin. It is possible that the results would have been different if ribavirin were added to the alfa interferon. However, this adds a variable that makes the situation somewhat cloudy. "Hemolytic anemia" (low red cell count) is a common side effect of ribavirin that may require dose reduction, discontinuation, therapy with Procrit (epoetin) to increase the red cell count, or even blood transfusion. This would obviously have the opposite effect of therapeutic phlebotomy, which would be expected to decrease the hematocrit even more. Yet, even if ribavirin decreased the hematocrit, it would not necessarily decrease iron levels.

The authors conclude that studies with more patients are needed before any definitive advantages of therapeutic phlebotomy can be substantiated. Even considering the limitations of the study, the trend towards better disease markers and outcomes with lower iron levels in several studies suggests that this therapy is worth pursuing as an adjunct to medications. The lead author was Robert J. Fontana, MD, from the University of Michigan in Ann Arbor.

* Note that all generic versions use the spelling 'alfa' and not 'alpha' interferon.

04/06/00

References:
Fong TL and others. A pilot randomized, controlled trial of the effect of iron depletion on long term response to alfa interferon in patients with chronic hepatitis C. Journal of Hepatology 1998; 28:369-374.

Fontana RJ and others. Iron reduction before and during interferon therapy of chronic hepatitis C: results of a multicenter, randomized, controlled trial. Hepatology 2000; 31:730-736.

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