Designed By: Amet's Web Design © 98, 99
The United States blood supply is safer than ever.
This is a statement made by many: from blood industry
representatives to consumer rights advocates; from the
Blood Products Advisory Committee to the National
Hemophilia Foundation; from pharmaceutical companies
to even those suing them. "We should take pride in the
statement that blood has never been safer," says Dr.
Bernard Horowitz, Executive Vice President of Melville
Biologics, a subdivision of the New York Blood Center.
Just as the blood supply is safer, so are its
derivative products, like the factor concentrates we
infuse into our children. But to Glenn Pierce, former
NHF President and person with hemophilia, it is not
safe enough for those who, like him, must infuse the
blood of hundreds of thousands of donors.
Many manufacturers, Food and Drug Administration (FDA)
officials, health professionals, and even many consumers are
quite comfortable with the high level of safety demonstrated
by today1s products, and it can probably be stated with near
certainty that the blood supply today poses no grave danger
to society as a whole. But, for individual consumers, there
are still real risks; the controversy surrounds those viruses
that are resistant to current manufacturer methods used to
kill or inactivate viruses. These include hepatitis A virus,
parvovirus B19 and the agent for Creutzfeldt-Jakob Disease
(CJD).
How prevalent are these infectious agents in the blood
supply? Are they a serious risk? Do manufacturer1s methods
destroy them, and other viruses, including HIV and hepatitis
C? What can you do to protect your child and to improve
product safety?
What Makes Hepatitis A So Different?
When parents think of safety and factor products, they
may think of the more publicized threats: HIV and hepatitis C.
Actually, these viruses are not the current worries in the
minds of those monitoring the blood supply. HIV and hepatitis
C are viruses that have a lipid (fat) coating around them.
This lipid "envelope" protects the fragile virus. When the
coating is destroyed, the virus is destroyed.
But there are viruses with no lipid coat, the nonlipid-
enveloped viruses like hepatitis A and parvovirus B19. These
are the viruses, along with those yet undiscovered and
unnamed, that keep people like Dr. Glenn Pierce and his wife
Bea Pierce, RN and member of the Blood Products Advisory
Committee of the FDA, actively dogging the government and the
manufacturers to improve research that will find unknown
viruses, and to improve factor concentrate manufacturing
methods. "Over the past 15 years a number of new viral agents
have been identified that can be transmitted," noted Dr.
Pierce in a panel discussion in Philadelphia last October.
"We're up to hepatitis G, and we don't know where it will
end. Hepatitis G has been transmitted by the blood supply in
the past. For us to think that there is not another virus out
there that will get, or may already be, in the blood supply
is very naive."
No Transmission of HIV
"Even as we draw attention to our failures," notes Dr.
Horowitz, "we should recognize our achievements. Coagulation
factor concentrates have not transmitted HIV in the United
States since 1987." Can we expect this safety record to
continue in the future? In all likelihood, it will.
A multiple safety net helps to eliminate the risk of HIV
in the blood supply. For HIV to contaminate factor products,
multiple breakdowns would have to occur at the same time: the
screening of donors would have to fail to identify one or
more at-risk donors, and testing of the donor plasma would
have to fail to detect the presence of the virus. Then, the
complex purification and inactivation methods used by the
manufacturers would have to fail to eliminate the virus.
These safety procedures have been challenged under carefully
controlled conditions, and have proven very effective at
eliminating the fragile HIV virus. The likelihood of any such
catastrophic breakdown in the system is extremely low.
Still, Dr. Craig Kessler, Director of
Hematology/Oncology, and Director of the Hemophilia Treatment
Center at George Washington University, warned last October
at the National Hemophilia Foundation Annual Meeting in
Philadelphia, "In spite of safety nets, there is still a risk
of human error." He recalls that several years ago in Europe
there was a "miniepidemic" of HIV seroconversion in factor IX
concentrates. "No one understood why it happened," said
Kessler. "It was assumed to be human error in the
manufacturing process."
Despite careful screening and testing procedures, HIV is
still in the blood supply. It is conservatively estimated
that about fifty people a year in the nationwide population
are still being infected with HIV through blood or blood
components. There is a high probability that some
contaminated plasma does get into the initial pool from which
factor products are derived. However, the purification and
inactivation procedures used by manufacturers should be more
than adequate to eliminate these small amounts of virus.
Good Track Record for Hepatitis C
Like HIV, hepatitis C virus (HCV) is a lipid-enveloped
virus. Like HIV, HCV is a deadly virus that is transmitted
primarily through direct blood contact or by contaminated
blood products. Like HIV, HCV was widely transmitted to
patients receiving factor products before the initiation of
testing and inactivation procedures. However, as with HIV,
there have been no documented cases of HCV transmission since
the implementation of testing and inactivation procedures.
Currently, both viruses are part of the donor screening and
testing procedures, and because both are lipid-coated
viruses, each is highly susceptible to the inactivation
procedures used today. None of the monoclonal products
currently available (Hemofil M®, Monoclate-P® or the Red
Cross1s Method M®) has ever been found to transmit hepatitis
C.
However, anecdotal reports continue to circulate of HCV
transmission among patients using monoclonally purified
factor products. Maria, mother of a nine-year-old with
hemophilia, was shocked several years ago to learn that her
son tested positive for hepatitis C. He had used only
monoclonals since birth. "I wondered how could this be?" Her
son was tested again, and again tested positive. This seemed
to fuel the belief that the blood supply and inactivation
methods were not safe. But, as with many reports of hepatitis
C transmission, it turned out that Maria1s son had been
tested using an inferior test. "In the last two years my son
was retested twice, and both tests were negative," Maria
reports. "My hematologist said that the newer hepatitis C
tests are more sensitive. The old ones were likely to give a
false positive."
Dr. Garrett Bergman, Senior Director, Medical/Scientific
Affairs at Centeon, finds this anecdotal report echoed
throughout the community. "The first generation tests for
hepatitis C were less accurate than those used today. They
led to many false positive results. We've received 18 to 20
reports of hepatitis C transmission through monoclonals," he
states. "We've found that in each case, either other products
were used at some point, or the second-generation, more
accurate tests, developed after 1990, yielded negative
results." Conversely, some children tested negative for
hepatitis C in the late 1980s, and later, using the more
accurate tests, tested positive. This led some parents to
conclude falsely that their child received hepatitis from a
recent product, even a monoclonal. "An initial negative
result, using the first generation tests, followed by a
positive result, using the second generation test or the more
accurate RIBA tests, does not mean that the child received
hepatitis C from the clotting factor they were using at the
time of the second testing," Dr. Bergman advises. A child may
have received hepatitis years before, while using
intermediate products or even from other sources in the
general environment. Bergman notes that since the newer tests
were developed, the issue of monoclonals and hepatitis C
transmission has faded.
Despite the difficulties of connecting an isolated case
of hepatitis C with any specific lot of factor, or even
determining whether it was caused by factor products
(patients who do develop hepatitis C may have contracted it
from sources other than factor products), each case is
investigated. Dr. Pierce points out that the NHF, the Centers
for Disease Control and Prevention (CDC) and the FDA have
collaborated for several years on the Seroconversion
Surveillance Project (SSP). The SSP looks actively for cases
of viral transmission by clotting factor. It has developed
guidelines for investigating the possible transmission of
HCV, which include investigating possible community sources
of infection and lot numbers of factor concentrate used by
patients. None of the cases investigated has indicated that
clotting factor transmitted HCV. In clinical studies using
today1s monoclonal products, where patients have been closely
monitored over long periods, no cases of factor-associated
HCV transmission have been found. But buyer beware: this is no
guarantee that a future case of a contaminated product could
not occur. Even Maria, whose son tested negative for HCV,
switched from monoclonal to recombinant factor, "because it
makes us feel better. Every year they come up with something
that wasn1t there before."
More Immediate Threats to the Blood Supply
Dr. Kessler reminds us that blood safety requires
constant vigilance, not just dispelling anecdotal reports.
"At the National Health Institute Conference in December 1994
there was a request on the part of industry to eliminate
certain serum markers in lab studies for liver disease. As
physicians we object to this. The blood banking stance is
that there are a lot of false positives in these enzymes
markers which would eliminate a large number of potential
[blood] donors. As a physician, this makes me nervous."
Especially when there is proof that viruses exist that elude
the safety nets and the inactivation processes designed to
keep factor concentrate safe. These include nonlipid-
enveloped viruses such as hepatitis A and parvovirus B19, as
well as the agent for CJD. What threat do they pose for the
average parent infusing a young child with factor made from
blood products?
Hepatitis A
The hemophilia community was shocked into reality again
when it was learned last December (1995) that a batch of
Alphanate was contaminated with hepatitis A (HAV). Many asked
how this could have happened. Hepatitis A is a nonlipid-enveloped
virus, less susceptible to inactivation methods, particularly
solvent-detergent. Available data indicates that heat treatment,
especially pasteurization, is effective against HAV.
Infection with HAV usually results in a short-term
illness without lasting effects. However, a person with HCV
or HVB who contracts HAV will have a more severe, potentially
lethal, illness. The presence of HAV in factor concentrates
strikes fear in parents who ask, "What will be next?" If
future cases of factor-associated hepatitis A transmission do
occur, they will most likely be associated just with products
that employ only a solvent-detergent inactivation step and
are not monoclonally purified.
Other Hepatitis Viruses
The list of viruses that can cause some form of hepatitis
is expanding; the latest strain to be identified is hepatitis
G (HGV). Historically hepatitis B virus has been a major
concern for hemophilia patients, but it is another lipid-
enveloped virus that is effectively removed by the current
manufacturing methods. All plasma is tested for the presence
of hepatitis B, and as with HIV and HCV, there does not seem
to be a problem with transmission through current products.
Several other hepatitis viruses have been discovered, and
there may be still more that have not been identified. At
least one, HGV, has been transmitted by blood products in the
past. At present, none of these appears to be a grave threat,
but each needs to be recognized and further studied.
Parvovirus
Parvovirus has become the "poster" virus for Glenn
Pierce's relentless drive to safeguard the blood supply. "It
has been highlighted in Europe that parvovirus B19 should be
assumed to be in all plasma derived concentrates. There is
evidence that it has been transmitted to individuals with
bleeding disorders who have taken plasma derived
concentrates," Pierce reported soberly last October. Dr.
Bergman counters this by noting, "Recent data published by
Dr. Margaret Ragni from Pittsburgh should help alleviate the
exaggerated fears among persons with hemophilia that
parvovirus B19 represents anything more than a theoretical
risk."
Like HAV, parvovirus does not have a lipid envelope and
is not destroyed by current inactivation methods. It has been
detected in both solvent-detergent and heat treated products,
including monoclonals. Without testing or effective
inactivation procedures available, it is likely that
parvovirus will continue to be a frequent contaminant in
blood-derived factor products.
The danger of parvoviral contaminants is unknown.
Parvovirus antibodies are found more often in those with
hemophilia than in the general population, although
parvovirus is present in high levels throughout the
population. It usually does not lead to serious illness.
However, two known adverse effects of parvovirus are
arthropathy (joint pain) and aplastic anemia. It has been
postulated but not proved that parvovirus could contribute to
the widespread joint problems among those with hemophilia,
and aplastic anemia could be particularly troublesome for
those with hemophilia and HIV. Dr. Pierce warns, "It is not a
benign virus."
Creutzfeldt-Jakob Disease
Much has been written lately about Creutzfeldt-Jakob
Disease (CJD), largely due to some cases in England that have
been linked in the press to mad cow disease. The risk of CJD
transmission through factor products is totally theoretical
at this point. It is generally thought that CJD is not caused
by a virus, but by an agent called a "prion", although no one
really knows what prions are or how they work. Prions are
thought to be variants of normal human proteins that can lead
to progressively degenerative neurological diseases. They are
not able to multiply like viruses or bacteria, but may over
time be able to convert normal protein into the "prion" form.
There has never been a documented case of CJD transmission
through blood products, and there is no hard scientific data
to indicate that CJD would ever contaminate factor products.
There are 200 new cases of CJD each year in the U.S.
While it is not clear whether plasma can transmit CJD,
3plasma has not been shown not to transmit it,2 according to
Dr. Pierce. Much is unknown about CJD, and the CDC is
researching CJD's prevalence and mode of transmission.
Definitive results should be available in the next few years.
Safer Than Ever Is Not Enough
Current blood-derived factor products are considerably
safer than factor products of ten years ago. The introduction
of monoclonal antibody technology, improved screening
techniques and the implementation of very effective
inactivation procedures have drastically reduced the
potential risk of viral transmission by factor products.
Manufacturers have taken a product that was routinely
contaminated with deadly and debilitating viruses twenty
years ago, and transformed it into a product with only
minimal risk. For the generation of children born in the late
1980s, this dramatic transformation has resulted in treatment
alternatives that combine effectiveness with a high degree of
safety. But while it is important to recognize the progress
that has been made, it is imperative that the hemophilia
community
continues to monitor blood safety, and remains alert to real
and potential dangers that still exist in blood products.
Dr. Bruce Evatt, Chief of the Hematological Diseases
Branch of the CDC, commented last October, "The products are
very good now. But they can be better." Dr. Pierce agrees.
"It's highly unlikely, for example, that CJD is a problem.
But...I think it's a matter of other unknown agents. If we
don't hold the line on known agents in the blood supply that
can potentially transmit disease, then where does it stop?
How can we predict what the next agent will be? We can't."
The bottom line, Pierce stresses, is that "we don't want
known infectious agents in the blood supply. That includes
CJD even though it probably is not transmitted."
Based on current data, none of the viruses described
above is considered a major threat to the community, but
together they cast doubt upon the safety of blood-derived
factor products. The closer we look at blood-derived factor
products, the more questions arise. Risks, some real and some
theoretical, seem to lurk around every corner. HIV, hepatitis
B and hepatitis C all seem to be under control, but each is a
life-threatening virus that could have catastrophic effects
if it did break through the safeguards currently in place.
Hepatitis A is a less dangerous virus, but it has broken
through and therefore must be considered a real threat. It
also appears that parvovirus B19 is present in at least some
factor preparations, although the results of parvovirus
infection among those with hemophilia are not well
documented. On the other hand, it is unlikely that CJD and
other "prion diseases" are transmitted through blood
products, but the lack of scientific knowledge about these
diseases makes any conclusion about their pattern of
infection tentative at best. It is an open question whether
other known viruses, such as recently discovered forms of
hepatitis, or yet unidentified viruses also have the
potential to contaminate blood. So while blood-derived
factors may be described justifiably as generally safe, it is
also accurate to describe them as having some risk.
The manufacturers have taken blood-derived factor to an
exceptional level of safety considering the risks. And in the
future, there could be new viral inactivation methods, or
double inactivation methods, or albuminless factor
concentrates. Perhaps the key question is this: with
recombinant factor VIII available, does it make sense to
continue supporting production of blood-derived products?
"Medically speaking, no," says Dr. Pierce. "There was
concern about inhibitors at one time but that was put to rest
a couple of years ago." Dr. Kessler also remarked at a
symposium last spring in Maryland, "I want all of my patients
away from human products and on recombinant." While
recombinants, the genetically-derived, expensive alternative
to plasma-derived products, are hailed as theoretically
virus-free, they nonetheless use albumin, a blood product.
The bottom line is that all products have inherent risks, and
consumers need to make informed decisions about which product
they choose.
And consumers should never surrender their power as
consumers. "All of us as a community," urges Dr. Kessler,
"need to constantly remind the manufacturers that even though
we realize that there may never be a zero risk related to any
therapeutic intervention a physician may prescribe, there's
no reason why we can't continue to strive for it."
Designed By: Amet's Web Design © 98, 99