Download Hepatitis B, hepatitis C and HIV transfusiontransmitted infections in

Vox Sanguinis (2011) 100, 92–98
ª 2010 The Author(s)
Vox Sanguinis ª 2010 International Society of Blood Transfusion
DOI: 10.1111/j.1423-0410.2010.01426.x
REVIEW
Hepatitis B, hepatitis C and HIV transfusion-transmitted
infections in the 21st century
D. M. Dwyre, L. P. Fernando & P. V. Holland
Department of Pathology, University of California Davis Medical Center, Sacramento, CA, USA
Received: 15 July 2010,
revised 22 September 2010,
accepted 25 September 2010
In the past, transfusion-transmitted virus (TTV) infections were not uncommon. In
recent years with advanced technologies and improved donor screening, the risk of
viral transfusion transmission has been markedly reduced. Hepatitis B virus (HBV),
hepatitis C virus (HCV) and human immunodeficiency virus (HIV) have all shown
marked reduction in transmission rates. However, the newer technologies, including
nucleic acid technology (NAT) testing, have affected the residual rates differently
for these virally transmitted diseases. Zero risk, which has been the goal, has yet to
be achieved. False negatives still persist, and transmissions of these viruses still
occur, although rarely. It is known that HBV serological testing misses some
infected units; likewise, HBV NAT–negative units have also been known to transmit
the virus. Similarly, HIV minipool NAT–negative units have transmitted HIV, as
recently as 2007; likely, these transmissions would have been prevented with single-unit NAT testing. Newer technologies, such as pathogen inactivation (PI), will
(ideally) eliminate these falsely test negative components, regardless of the original
testing method used for detecting the viruses.
Key words: hepatitis B, hepatitis C, HIV, pathogen inactivation, transfusiontransmitted infections.
Introduction
The first cases of transmission of a viral illness through
blood transfusion were reported in 1943 [1]. Laboratory
testing for viral transfusion-transmitted viruses began in
1969 with testing for hepatitis B surface antigen (HBsAg).
To reduce the risks of transmission of other viral illnesses
(e.g. non-A, non-B viral hepatitis), introduction of alanine
aminotransferase (ALT) testing and antibody to hepatitis B
core antigen (anti-HBc) testing began in the 1980s [2]. More
specific disease serological testing (anti-Hepatitis C virus
antibody and HIV antigen and antibody testing) followed
in the 1980s–1990s markedly reducing the risk of these
transfusion-transmitted viruses (TTV).
With the implementation of nucleic acid technology
(NAT) in 1999, there was further reduction in viral infections transmitted by blood transfusion. Using serological
Correspondence: Denis M. Dwyre, Department of Pathology, University of
California Davis Medical Center, 4400 V Street, Sacramento, CA 95817,
USA
E-mail: [email protected]
92
methods, the risk of Hepatitis B virus (HBV) is currently
estimated to be 1 in 282 000 to 1 in 357 000 with a
‘window period’ (time from infection to first reactive
test) of 30–38 days [3]. The current risk of transfusiontransmitted Hepatitis C virus (HCV) infection with NAT
testing in place along with serologic testing is estimated
to be 0Æ03–0Æ5 in 1 000 000 units [1]. For human immunodeficiency virus (HIV), transmission risk using NAT
and serologic testing is currently estimated to be 1 in
1Æ5 million to 1 in 4Æ3 million [4,5]. Although quite small
today, the risks for transfusion transmission of HBV,
HCV and HIV persist. So, efforts to reduce the risks to
zero continue.
Hepatitis B
After the discovery of widespread HBV infection became
evident in 1963 with the introduction of HBsAg testing,
HBV was noted to have a high prevalence in multiply transfused patients. However, it is now known that HBV is a very
common infection in the general population and that transfusion transmission accounts for a minority of those
Transfusion transmission of hepatitis B, hepatitis C, and HIV 93
infections. The prevalence of HBV differs by geography.
With over 300 million carriers of HBV worldwide, the
infection, as measured by HBV surface antigen (HBsAg)
positivity, remains endemically high in Africa, parts of
Asia, the Middle East and parts of South America, ranging
from 8% to 15% of those populations. In low prevalence
areas, such as the United States, western and northern
Europe, Canada and parts of South America, the prevalence
is estimated to be < 2% [1]. Acute infection with HBV,
whether transmitted via transfusion, intravenous drug use,
perinatally or via sexual contact, may be asymptomatic or
cause clinical viral hepatitis with nonspecific constitutional
symptoms, including jaundice. Rarely, acute infections,
including acute infections from transfusion-transmitted
HBV, can cause fulminant liver failure and death [6].
After transmission of HBV, HBV DNA is the first marker
to be present in the blood. After viral replication in the
liver, HBV viral load can attain 108–1010 viral particles per
millilitres of serum [1]. Viremia during the window period,
however, is exponentially lower; infectivity, incidentally,
in also lower in the WP, most likely related to antibodies
(anti-HBc and anti-HBs) formed after acute infection [7].
Testing for those infected with HBV historically involves
detection of HBsAg. HBsAg is present in the serum of
infected individuals from weeks to months after onset of
infection and before symptoms begin. Some infected individuals never test positive for HBsAg, but generally will
produce an antibody response to Hepatitis B core antigen
(HBcAg): anti-HBc. The fact that there are some false-negative tests for HBsAg is the reason for testing for anti-HBc in
some countries. However, determination of HBsAg-negative ⁄ anti-HBc-positive distant HBV infections in individuals, such as healthy blood donors without a history of
hepatitis, testing falsely positive for anti-HBc has been a
persistent problem for blood donor collection facilities.
Generally, two positive anti-HBc tests will result in permanent deferral from donating blood in the United States.
Recently, however, an algorithm for re-entry of these
donors has been approved by the US Food and Drug
Administration (F.D.A.) [8].
Unlike HCV and HIV testing, NAT HBV DNA testing has
not eliminated the necessity for serological testing for HBV
carrier donors. Where instituted, it was hoped that NAT
testing for HBV would 1) reduce the window period for
HBV, 2) identify low-level carriers of HBV, 3) provide
another mechanism for re-entry of HBsAg false-positive
donors and 4) ultimately replace serological testing. NAT
testing for HBV DNA has been implemented to a variable
extent in industrialized countries in Europe, North America,
Asia, Australia and Africa. Occult HBV infections (HBsAg
negative, HBV NAT positive) have been identified in all
studies, in the range of 1 ⁄ 2000–1 ⁄ 107 000 [9]. Japan was
in the higher part of the range with the difference possibly
being related to the use of larger pools for their NAT testing
[9].
It has been shown that occult HBV infections can transmit the virus via blood transfusions, but the infectivity is
not 100% [10], and the level of viremia needed to infect has
not been determined in humans. However, in chimpanzees,
it may be related to HBV genotype [11]. NAT testing for
HBV varies by country and varies by blood centre within
countries. HBV NAT testing is mandated in some countries
[12]. Single-unit NAT testing can detect very low levels of
HBV DNA (< 100 IU ⁄ ml). With the availability of multiplex
testing of small pools of donor sera, more blood centres are
implementing HBV NAT, along with HCV and HIV. However, without single-unit NAT HBV DNA testing, the window period may not be shortened that much, compared to
the sensitive tests available today for HBsAg (like
PRISM ⁄ Abbott Park, IL, USA). This can be explained by the
relatively slower doubling time of HBV in the window period, resulting in a lower viral load. Thus far the consensus
is that NAT should be used in conjunction with serological
testing to identify low-level infections as well as infections
that are at the ends of the window periods of detection.
There is no consensus either on whether single-donor NAT
or what size pool NAT is optimal, and it may depend on the
prevalence of HBV in the country. Additionally, HBV infectivity may depend upon the immunosuppressive state of
the recipient of the blood component.
Infectious disease testing on donated blood is of great
importance in the reduction in risk for TT HBV infection.
Other processes may also reduce the risk of HBV from blood
components. For example, optimization of donor screening
pre-donation is where most of the potential infected donors
can be eliminated from the donor pool. This screening process could and should be individualized by country and
even community. On the other end of the process, postdonation, pathogen inactivation (PI) may be almost 100%
effective in eliminating the risk of HBV TTD from platelets
and plasma in countries where it has been implemented.
The role of effective testing remains critical, at this time,
because of the lack of availability of PI for red blood cell
components and whole blood. Finally, the role of vaccination for HBV also has the potential of almost completely
eliminating the potential risk of HBV by blood transfusion;
the reduction in risk that widespread vaccination can provide would be large in countries where the virus is endemic
and access to vaccinations is currently limited.
Hepatitis C
After the discovery of hepatitis A virus (HAV) and HBV, a
significant number of patients testing negative for HAV
and HBV and with clinical presentation or laboratory evidence of viral hepatitis were identified; these patients were
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94 D. M. Dwyre et al.
presumed infected with what was initially termed non-A,
non-B (NANB) viral hepatitis. Most of these NANB viral
hepatitis patients had a history of intravenous drug use.
The majority of patients with NANB hepatitis later tested
positive for HCV after testing for anti-HCV became widespread in the 1990s. After testing was available, it was also
verified that blood transfusion was another significant
mode of transmission of HCV. The infection is present
worldwide with lower incidence rates in North America,
Australia and Europe (approximately 2%) and a higher rate
in Egypt (> 5%).
Once infected with HCV, the virus travels via the blood
to the liver where it replicates. Viremia occurs usually with
few symptoms. Similar to HBV, fulminant lethal acute HCV
infection can occur rarely. More typically, patients do not
clear the virus on their own, so HCV develops into a chronic
hepatitis and the patients become chronic carriers of the
virus.
Because many HCV infections are asymptomatic in the
acute setting, the diagnosis is often made during the
chronic phase. After exposure to HCV, usually parenterally, Hepatitis C antigen is present initially, then anti-HCV
develops in the weeks following infection. The specific
diagnosis of HCV infection requires serological and ⁄ or
molecular-based (NAT) assays. In rare instances, anti-HCV
may not develop; in these cases, a definitive diagnosis of
HCV requires molecular-based (NAT) assays. Spontaneous
recovery from HCV infection occurs in 15–45% of infected
individuals with recovery in the higher range occurring in
women given anti-D immunoglobulin contaminated with
HCV [13,14]. NAT of plasma intended for fractionation
and of blood donations for HCV RNA began in the late
1990s when methodologies became available. NAT for
HCV is now required in many countries. As anti-HCV testing is also generally performed in addition to NAT,
infected units from donors with spontaneous recovery
from HCV would also be eliminated from the blood supply.
Further reduction in transfusion-transmitted HCV, as
well as any TTV, begins with improved donor screening.
Recent data from the American Red Cross have shown that
HCV positivity in blood donors has increased from a rate of
1Æ96 ⁄ 100 000 to 2Æ98 ⁄ 100 000 from 2005 to 2008. The
increase has been primarily in Caucasian donors, especially
in those donors over 50 years of age [4]. Donor screening,
i.e. focusing donor questions on risk factors and on certain
racial ⁄ age populations may aid in eliminating potentially
infected donors prior to donation. A major risk factor identified in population screening is sharing of needles, especially in use of drugs, as well as reuse of non-sterilized
needles. Having had surgery in a developing country (with
unknown exposure to one of the blood) may be a risk factor
as noted in a study from Mexico where risk factors to HCV
infection was noted to be having had surgery or a prior
blood transfusion [15].
It is known that there are presumed false-positive
HCV donors (anti-HCV positive, HCV NAT negative).
With further complex methods evaluating for immunological response to HCV (not ready for routine screening
testing) [16–18], it is known that some of these donors
are truly negative, some of those negative because of
seasonal viral infections [19] and some of the donors
being positive having recovered from the infection. However, it is not believed that these positive donations are
capable of transmitting HCV. Unsafe endoscopy practices
at a US endoscopic clinic may have exposed patients to
viral infections [20]. In the absence of other risk factors,
these patients would not have been identified as higher
risk for HCV in donor screening.
With the use of anti-HCV antibody testing only, before
HCV NAT testing, the risk of transfusion transmission of
HCV was reduced considerably. The window period for
HCV was approximately 70 days [1]. With the introduction
of NAT, the window period has been reduced to approximately 12 days [1,21]. NAT HCV testing is mandated in
many industrialized countries. Combined antibody ⁄ antigen
testing is available, but this combination still is not as sensitive as NAT [22]. Generally, pooled NAT testing identifies
virtually all HCV-infected units because of the high levels
of HCV RNA [23,24]. In a South African study, single-unit
testing was performed, and only one window period HCV
NAT–positive unit was identified. It should be noted that
South Africa has a low incidence of HCV. In a German
study, multipool NAT was used (10–96 donations per pool),
and only one documented case of transfusion-transmitted
HCV was missed with multipool NAT over a 5-year period.
All three main genotypes were detected. Individual NAT
testing may not improve upon the multipool testing; however, as noted in a case study, also from Germany, HCV was
transmitted from a red cell unit that was negative by individual NAT HCV testing [21].
NAT testing has markedly improved the detection of
HCV in donor units, as well as dramatically reduced the
window period. However, the risk persists, albeit low. PI has
been shown to virtually reduce the risk of HCV transmission to zero in vitro. This has great potential, especially in
light of the fact that, unlike HBV, an effective vaccine
against HCV is not available. PI is not currently universally
available. PI would be of great benefit in developed countries where it could potentially reduce testing and the costs
associated with testing. PI would be of greater utility in
developing countries where universal testing is not available; testing for many infections would not be needed. The
major limitation is that PI is only available for plasma and
platelet products, and not for red blood cells. As noted in
the just-mentioned case study of individual NAT failure to
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Transfusion transmission of hepatitis B, hepatitis C, and HIV 95
identify a low-level case of infectious HCV, the component
transmitting the HCV was a red blood cell unit.
HIV
In June 1981, the landmark report of five cases of Pneumocystis jiroveci (then P. carini) Pneumonia in otherwise
healthy young men heralded a new disease eventually
named acquired immune deficiency syndrome (AIDS) [25].
Shortly thereafter, AIDS was also reported in IV drug users
and a few patients with Haemophilia. In December 1982,
AIDS was diagnosed in a San Francisco baby who had
received a platelet transfusion from a gay man who died of
AIDS [26]. The realization that we had a new infectious
agent (possibly a retrovirus) that had started to infiltrate
the blood supply mobilized all blood collection agencies
throughout the Western world to do everything possible to
prevent potentially infected individuals from donating
blood. The advent of AIDS also mobilized the research community to identify the causative agent and develop a test
for it.
In the United States, the first donor deferral guidelines
were put in effect in January 1983. Those early efforts to
indefinitely defer prospective blood donors at risk and their
sexual partners helped decrease the incidence of transfusion-associated AIDS by an estimated 90% [27]. The human
immunodeficiency virus (HIV) (originally named HTLV-III)
was described by Gallo and Montagnier [28] in 1984, and
the first ELISA antibody test was available to blood banks
in April, 1985. It is estimated that in the early 80s, the risk
of being infected by a blood transfusion was in the order of
1:100 in some US cities, like San Francisco [27]. The focus,
as well as the public perception, of transfusion medicine
was changed forever.
In 2005, it was estimated by the WHO that 38 million
people were living with HIV world wide, that 4Æ1 million
were newly infected and 2Æ8 million had died of AIDS. The
vast majority of AIDS cases were not because of transfusions, however. In sub-Saharan Africa alone 24 million
people are infected. The first generation ELISA tests for
anti-HIV were able to detect the great majority of asymptomatic HIV carriers, but the window period (time to
seroconversion) in newly infected individuals was approximately 56 days. Second and third generation anti-HIV tests
reduced the window to 33 and 22 days, respectively. The
HIV P-24 antigen test was introduced in March, 1996 with
the hope of further reducing the window period.
Transmission of HIV involving three different donors
negative for both anti-HIV and P-24 antigen testing was
documented in 1986 [29], 1987 [30] and 2007 [31]. The first
one was a frequent platelet donor who infected three recipients 11 and 4 days (double donation) prior to becoming
HIV P24 antigen positive. Subsequent NAT testing was
positive on the )4 day donation, but negative for the
)11 day one. The second one involved transmission of HIV
by both platelets and RBCs. NAT on the undiluted donor
plasma was positive, but detection was inconsistent in the
1:16 and 1:24 dilutions (the usual pool sizes in the USA).
On the third case, a retained sample from a donation
4 months earlier tested positive with individual NAT, but
had tested negative on a 96 sample minipool. Following
this case, individual donation (ID) NAT testing for HIV,
HCV and HBV was implemented in Denmark. Minipool
NAT testing for HIV and HCV was introduced in US blood
collection centres in 1999, reducing the HIV window of
infectivity to 11 days. Minipool NAT testing had already
been implemented in some European Countries (like
Germany).
Five cases of HIV transmission by donations negative by
NAT minipool testing have been reported in the United
States from four donors [32, 33], one in Germany [5] and
one in France [34]. In working up these transmissions in
detail, there are several common findings: The viral load
was too low to be detected by pooled testing which generally requires > 90 copies ⁄ ml. By look back, it was determined that these donors’ seroconversions were recent, thus
explaining the low viral load. More important, further
questioning of the involved donors revealed risk factors,
specifically recent male to male sexual contact, that were
denied in the original screening interview. Retesting of
stored donor samples with ID NAT was reactive in the cases
where it was performed.
The importance of viral load is further illustrated by a
report by Ferreira and Nel [35]. In January 2003, a 52-yearold male tested HIV antibody positive on his 55th blood
donation to the South African National Blood Service. Look
back on his earlier, HIV-negative donation from October
2002 showed that three components were made from it:
RBCs, transfused 12 days after collection to a 20-year-old
patient; platelets, transfused as part of a pool to a 12-year
old patient 5 days after collection; and fresh frozen plasma,
originally sent for fractionation but retrieved for further
testing. The viral load was estimated to be only 12
copies ⁄ ml. The sample tested negative for anti-HIV and HIV
p-24 antigen. It tested positive, however, by NAT. The assay
used has a sensitivity between 16Æ7 and 25 copies ⁄ ml.
In January 2003, the recipient of the platelet pool tested
positive for HIV antibody and HIV p-24 antigen. Phylogenetic analysis of donor and recipient samples confirms the
transmission from donor to recipient. The recipient of the
red cells was tested for HIV antibody in March 2003 and
found to be negative. Again in July 2003, he remained
negative for HIV antibody, and NAT for RNA, the same
test found positive in the platelet recipient.
In the United States, American Red Cross’ 10 years
experience (1999–2008) after NAT minipool testing was
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96 D. M. Dwyre et al.
implemented revealed the following: Of 66 million donations tested, mostly pools of 16, there were 32 positive
HIV NAT yield samples with an incidence of 1:2 060 000.
Further analysis of the data revealed some disturbing
trends: While in the years 2005 ⁄ 2006, 67 incident HIV
positive tests (both NAT and serology) were found, in the
years 2007 ⁄ 2008 there were 92, with an increase of 25
cases. The number of 16- to 19-year-old males in both
groups went from 6 to 21, a statistically significant
increase (P < 0Æ01). A preponderance of non-Caucasian
donors was also noted [4]. These demographics parallel
the incidence of HIV in the community. While there was
no suggestion of test seeking behaviour when analysing
the US data, a 2006 Brazilian study showed that donors
still use the blood donation process to obtain HIV testing
[36]. These finding underscore the importance of the initial donor history questionnaire, along with effective
donor education, to ensure its veracity.
ID NAT testing is out of reach, as is pooled NAT testing,
in many countries such as many in sub-Saharan Africa,
where the incidence of HIV in the general population is
expressed in double % digits. To significantly improve the
safety of transfused blood, new technologies, such as PI,
must be added to the already extensive battery of strategies
[37]. Such systems have proven successful in preventing
viral transmission when plasma and platelet components
are treated [38]. They have been implemented in several
European and Middle East countries, and FDA approval is
being sought in the United States. So far, there is no available way to apply PI methods to red cells. The cost of such
intervention has yet to be determined, but it will be
undoubtedly quite high for the marginal increase in safety
from HIV, HBV and HCV; but it may be worthwhile for
emerging transfusion transmissible infections, especially
for those agents for which we do not have effective tests or
means to decrease their risks.
Less common viruses
Rarely, other identified viral infections have caused transfusion-transmitted infections. HAV is a food-borne illness
that generally causes an acute clinical picture. As virtually
all HAV infections are symptomatic, potential infectious
donors would be eliminated by blood donor screening.
There have been documented cases of transfusion-transmitted HAV [1], including remote cases involving transmission
via contaminated factor VIII. HAV is not inactivated by solvent ⁄ detergent treatment, but HAV vaccines are available.
Hepatitis E virus (HEV) infection, like HAV, is another
enterovirus generally caused by fecally contaminated
water. The presentation of HEV infection is similar to HAV,
but subclinical infections are reported. Transfusion-transmitted HEV is rare, but has been reported. Antibody testing
for HEV infection is generally used to test for infection, but
PCR testing is available. A recent study from Japan showed
the prevalence of anti-HEV in qualified blood donors to be
3Æ4% [39], slightly higher than that reported in the United
States and Europe [1]. Like HAV, solvent-detergent treatment is not effective. Theoretically, PI would inactivate
HEV as well as HAV.
Conclusion
Careful donor screening has been shown to eliminate the
vast majority of HBV, HCV and HIV transfusion-transmitted viral infections over the past four decades. With viral
specific antigen and antibody testing, viral-transmitted
infections have been reduced another log. With NAT testing over the past decade, the risk of transmitting these
infections through transfusion has been reduced further in
the range of 1 in 300 000 for HBV to 1 in 2 million for
HIV. For maximum reduction in risk, testing of units may
not be able to reduce the rates of infection further. The
best opportunity for near zero risk is treatment of the
blood components directly, such as with PI. Although not
approved worldwide, this technology has been shown to
reduce the rate to near zero with the potential of eliminating extensive testing of all units [40]. PI has not been fully
adopted and needs further investigation into the quantifying of pathogen reduction and toxicity. It has been suggested that, in addition to infectious disease testing which
has reduced window period and established infections, PI
could reduce transfusion-transmitted viral infections by
reducing pre-NAT window period and occult infections
[41]. Clinical studies proving this have not yet been performed.
As PI does not rely on specific disease testing, it allows
elimination of risk for yet unknown emerging infections.
Furthermore, PI has been shown not to affect protein composition or clotting capacity [42]. A major limitation on this
technology, however, is that is not available for use in red
blood cells, although it has been suggested that treatment
of whole blood before fractionation could assist in resolving this issue [43–45]. The challenge persists to develop a
method capable of achieving the near zero risk of TTV from
red blood cells. Careful donor selection remains the best
way to prevent TTV before the unit is even collected and
tested.
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