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
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-naïve (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-naïve. 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 ½ 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
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.)
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.
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
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'
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;
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.