Blood, Vol. 91 No. 2 (January 15), 1998:
pp. 727-728
CORRESPONDENCE
High-Dose and Long-Term Therapy of 
Interferon in Hemophiliac
Patients With Chronic C Virus Hepatitis
 |
LETTER |
To the Editor:
We have read with interest the work by Rumi et al1
reporting very low success rates in the treatment with 
interferon in human immunodeficiency virus (HIV)-negative hemophilac patients with
chronic hepatitis C despite prolonged therapy.
Hepatitis C virus (HCV)-associated chronic liver disease is a major
complication in multitransfused persons with hemophilia and is
attributed to the use of coagulation concentrates introduced in the
early 1970s. Almost all hemophiliacs who have been treated with
non-virus-inactivated factor VIII or IX concentrates have evidence of
past or current HCV.
Interferon has been used to treat chronic HCV in both nonhemophiliacs
and hemophiliacs. Response to treatment has been assessed by serial
serum alanine transaminase (ALT) levels, clearance of viremia by
polymerase chain reaction (PCR), and direct assessment of liver
histology. Clearance of viremia is a prerequisite for a long-term
response rather than normalization of ALT. To date, there has only been
a few studies on the efficiency of interferon for the treatment of
HCV infection in individuals with hemophilia. Some of these
studies2-4 have suggested that the response to interferon
in hemophiliacs may be lower than in other groups infected with HCV.
Interestingly, response rates in the earliest studies are superior to
those performed more recently. This may be a reflection of the
relatively small number of patients studied or may have been caused by
progression of liver disease in cohorts of hemophiliacs leading to
diminished responses to interferon. The study of Rumi et
al1 is the first trial with randomized controlled study of
interferon therapy that has enrolled exclusively hemophilic patients
with chronic hepatitis C not coinfected with HIV-1. On the other hand,
it is the first time that interferon therapy has been extended to 12 months instead of the standard period of 6 months in hemophiliac
patients on the basis of previous reports in nonhemophiliac patients
that showed an increase of the chance of a sustained
response5 but at dose of 3 × 106 units
three times a week.
Among factors implicated by the investigators in the poor treatment
outcomes observed in the previous studies in hemophiliacs are HIV
disease,2-4 excess virus load,6,7 duration of
HCV infection,8 high prevalence of genotype 1 infection,9 and inadequate initial dose of interferon
therapy. It is believed that they are implicated in the low rates of
sustained remission achieved.
In this way, 3 years ago we began a pilot study (open label cohort
format) of treatment with high-dose and prolonged interferon treatment in patients with congenital coagulopathies and hepatitis C in
our Hemophilia Unit. We enrolled 26 patients with hemophilia A (17 patients), hemophilia B (4 patients), von Willebrand disease (3 patients), and other congenital coagulopathies (2 patients). The mean
age was 39 ± 10 years. All patients had serum anti-HCV, HCV-RNA
using a polymerase chain reaction (PCR) method, and ALT values greater
than twice the upper limit of normal range on three consecutive
occasions 6 months apart before enrollment. All patients were negative
for HIV antibody. Patients were monitored each month for serologic test
for HCV and HBV, liver function tests, and complete blood counts and
every 3 months for PCR for HCV-RNA. Genotypes were performed in the
pretreatment sera. It was not possible to perform the quantification
serum levels of HCV-RNA. Fourteen patients were undergoing transyugular
liver biopsy for assessement of liver histology (10 patients before and
4 after).
The schedule used was 6 million units of recombinant interferon 2a
or 2b administered by subcutaneous injections three times per week for 1 year. Patients who did respond to therapy were followed-up for at least 12 months after cessation of treatment.
According to the definition of response by Rumi et al,1 we
found the following results. Fifteen (58%) treated patients had a
complete biochemical and virologic response at the end of treatment (12 months). Ten (38%) had sustained complete remission and the end of
follow-up (24 months) and 5 (19%) had biochemical and virologic
relapse after cessation of interferon therapy. Four of these patients
received another course of interferon treatment at the same schedule
and 2 of the 4 achieved a sustained complete remission with a follow-up
of at least 6 months. Six of the total (23%) were nonresponses and 5 (19%) left the treatment (2 cases for interferon toxicity).
In addition, we found surprisingly higher complete response and
complete sustained response rates than rates reported until now in
hemophiliac patients treated with other schedules of interferon.
Factors that could be involved in these results were unknown until now.
Genotype distribution is the same as in other groups, with a high
prevalence of both genotype 1 infection and mixed infections. In our
group, it was not possible to perform the HCV-RNA quantification assay.
However, there is agreement that hemophiliac patients had higher levels
of HCV-RNA. This may result from several factors such as an impaired
immunologic status or an accumulation of multiple virus
strains.6 Moreover, our patients had a mean age higher than
that reported by Rumi et al1 and a longer duration of HCV
infection, another well-recognized predictor of poor response in
nonhemophiliac patients.8 The last issue is the high degree of genetic variations in HVR1 of HCV specimens isolated from
hemophiliacs compared with another population of HCV patients and the
biological significance of sequence diversity of the interferon
sensitivity determining region (ISDR). Both topics may have affected
the final results in our pilot study.10
No previous experience exists about treatment with high doses and
long-term treatment with interferon in hemophiliac patients. In
nonhemophiliac patients, previous reports5,11-14 showed
that sustained response rates may be improved by longer and higher-dose interferon courses.
We have begun an ongoing multicenter study in Spain to confirm these
results. Our intention is now to perform HCV-RNA quantification to
monitor the possible disappearance of HCV charge in long-term therapy.
Javier Pinilla
Manuel Quintana
Manuel Magallon
Hemophilia Unit
La Paz Hospital
Madrid,
Spain
| |
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