Hemophilia Update 1997: NHLBI
Article title: Hemophilia Update 1997: NHLBI
Conditions: Hemophilia
Source: NHLBI
HEMOPHILIA UPDATE: 1997
Background
Advances in treatment over the last three decades have permitted a near-normal lifestyle and life-span for many individuals with hemophilia. The introduction of factor VIII concentrate products in the 1970s allowed treatment at home and largely replaced the need for transfusion of whole blood or plasma in the hospital. An unfortunate result of increased freedom from bleeding as a cause of disability and death was infection with hepatitis from products made from pooled plasma. This culminated in the early 1980s with the unexpected and devastating infection of about 70 % of severe hemophiliac patients with HIV, the cause of AIDS. Since then, the development and improvement of methods for inactivating viruses with lipid envelopes in plasma, including factor VIII and IX concentrates, has improved the safety of transfused products to the point where the threat of infection with HIV, hepatitis B(HBV) or hepatitis C (HCV) viruses has been essentially eliminated.
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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