Safety of Products Used in Treatment
A number of major efforts focused at different levels in the production of replacement products
for hemophiliacs have resulted in a substantially lower risk of transfusion-transmitted agents for
the hemophilia community. Blood donors are carefully screened to eliminate those likely to have
been exposed to hepatitis or HIV. In addition, the plasma used to prepare factor concentrates and
factor concentrate products are tested for known bacterial and viral contaminants to eliminate
transmission by transfusion. Finally, solvent/detergent and heat treatment processes are in use to
inactivate viruses in plasma pools utilized in the preparation of clotting factors. As a result of
these practices, millions of doses of coagulation factor concentrates have been infused since 1987
without a single documented case of HIV, HCV, or HBV. In further efforts, research supported
by the National Heart, Lung, and Blood Institute (NHLBI) is underway to develop tests for HIV
and hepatitis nucleic acids to replace the current antibody tests. Successful implementation will
more than double safety of transfusion. The NHLBI is using still another approach to augment
safety of transfused products, that is through the support of research to inactivate non-enveloped
viruses such as parvovirus B-19 and hepatitis A virus that might contaminate plasma and plasma
derivatives. These viruses are not inactivated by solvent/detergent treatment and tend to be heat
stable. A recently developed photochemical treatment appears to be effective against viruses in
this class. It is expected that this newer viral elimination procedure, in combination with
established virucidal procedures, will further ensure the safety of coagulation factor concentrates..
Over the last few years, improved procedures have led to high purity plasma-derived factor VIII and factor IX products which appear to be safer when subjected to viral inactivation procedures than were the previous lower potency materials. "First generation" recombinant factor VIII, produced without human plasma, became available in 1992. This added a measure of safety especially from non-enveloped viruses, although the need for human albumen to stabilize the factor left a tiny and currently hypothetical risk of human infectious agent transmission. The first recombinant factor IX preparation is now in clinical trials. It is a "second generation" product which is manufactured and packaged without any human or animal plasma proteins. A similarly produced factor VIII concentrate is under development.
Although most individuals with hemophilia can use replacement products repeatedly without problems, about 20% develop neutralizing antibodies that make the product less effective. Antibody inhibitors are more likely to occur in individuals with severe hemophilia. At this time, it is not possible to predict who will develop the antibody inhibitors, but there is some evidence for genetic predisposition for an immune response. The treatment for people with inhibitors can be complex and expensive. Often more than one approach is tried before the bleeding is arrested. The decreased ability to control bleeding in the joints can lead to earlier development of arthritis. In some cases, immune tolerance can be induced which allows standard treatment to again be effective. Studies are being conducted to avoid or modify the immune response and to prepare recombinant factor VIII proteins with reduced antigenicity.
The Goal
The goal of having all hemophilia treatment products completely free of human blood products
with no possibility of transmitting infectious agents from human donors has not yet been achieved.
Despite the advances described above, approximately 60% of hemophilia treatment is still with
blood-derived products. Therefore, vigilance in maintaining the safety of the blood supply
remains critical. Current screening of donors, testing of donated blood and inactivating enveloped
viruses have essentially removed the danger of transmitting HIV, HBV, and HCV by hemophilia
treatment concentrates. There remains a small risk from non-enveloped viruses, such as hepatitis
A and parvo virus, that escape current inactivation procedures. These infections are rarely
transmitted by plasma products and generally result in self-limited relatively mild illnesses, unless
the patient also has immune deficiency. There is now concern about Creutzfeldt-Jakob Disease
(CJD), a rare nervous system disease. At this time the transmission of CJD through blood or
blood products is theoretical although the possibility is being reevaluated by combined efforts of
NIH, CDC, and FDA. Results from some critical studies should be available later this year. In
the meantime, the FDA has made recommendations that plasma not be taken from donors at
increased risk for developing CJD and that products made from pools that include plasma from
one or more donors who developed CJD at some time after donating be quarantined and
destroyed.
Future Directions
Gene therapy providing continuous production of the deficient clotting factor could be the next
major advance in hemophilia treatment. Studies that explore different viral and non-viral gene
transfer methods for the delivery of the factor VIII and factor IX gene continue. Efficient
expression and secretion of biologically functional protein is critical to the development of
effective gene therapy. Basic research studies are unraveling the complex mechanisms that
control the production of modified genes which increase the expression levels and enhance
biological activity of these coagulation factors. Significant progress has been made in obtaining,
modifying and inserting hemophilia genes in animals. Mice with hemophilia, deficient in either the
factor VIII or factor IX gene, which exhibit bleeding problems seen in the human deficiency are
now available. These small animal models provide valuable tools for testing multiple gene therapy
procedures more rapidly than in the larger animal models available previously. Important needs
remain to increase the level and duration of gene expression in animals before these procedures
are ready for human use.
Conclusion
In summary, the current high level of safety of the blood supply has resulted from many years of
targeted efforts to eliminate transfusion-transmitted agents at various stages - from improved
methods of donor selection, through products that are purer and have been subjected to better
viral inactivation methods, and through the development and marketing of first and second
generation recombinant products that are increasingly free of human plasma proteins. Continued
vigilance is necessary to guard against the introduction of new agents into the blood supply.
Despite improved factor replacement treatment, the morbidity and mortality of hemophilia from
arthropathy and critical hemorrhage will continue unless a cure can be effected. The promise of
gene therapy as that cure still exists although the transfer of results in small and large animals to
man constitute formidable problems. The original goal of availability before the turn of the
century may have been overly optimistic. Nevertheless, slow and careful progress continues to be
made toward this critical goal.
February 5, 1997
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