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The hepatitis B virus is a member of the Hepadnaviridae family of viruses. It is a 42 nm partially double-stranded DNA virus, composed of a 27 nm nucleocapsid core (hepatitis B core antigen, HBcAg), surrounded by an outer lipoprotein coat (also called envelope) containing the surface antigen (hepatitis B surface antigen, HBsAg).
Hepatitis B virus (HBV) is the causative agent for the potentially life-threatening liver infection hepatitis B. HBV is a highly infectious blood-borne virus (50-100 times more infectious than HIV) and is transmissible by transfusion.
Worldwide, hepatitis B is a major health problem and the most serious type of viral hepatitis. HBV can cause chronic liver disease and sufferers have a high risk of death from cirrhosis of the liver and liver cancer. It is estimated that more than two billion people have been infected with HBV, and more than 350 million of these have chronic (long-term) liver infections.(1)
It is mandatory for the Blood Service to screen every blood donation it collects for the presence of HBV as well as a number of other infectious viruses including human immunodeficiency virus (HIV), hepatitis C virus (HCV) and human T-lymphotropic virus (HTLV). The Blood Service uses two complementary assays to screen every donation for HBV; a serological assay for detecting HBsAg and a NAT assay for detecting HBV DNA.
NAT assays are used to detect viral genetic material which may be DNA or RNA, depending upon the virus in question. The detection of viral genetic material in a test sample indicates that the corresponding donation is potentially infectious for the virus. NAT assays are very sensitive and able to detect very small amounts of viral DNA or RNA.
Because viral nucleic acid is detectable earlier in infection than antigens or antibodies, NAT assays are able to shorten the testing window period, which is the time between infection and the first detectable viral marker in the blood of an infected person.
NAT assays work by making millions of copies of (ie, amplifying) the viral DNA or RNA present in the sample taken from an infected donor. This amplification process makes the viral nucleic acid easier to detect.
Compared to serological tests for HBsAg, HBV DNA assays have a shorter window period and therefore can detect recently infected donors earlier. In addition, some people with chronic HBV infection lack detectable HBsAg and therefore would not be identified without the HBV NAT assay. These advancements in the detection of HBV infection mean improved safety for the transfusion recipient.
Due to the complexity of HBV infection, there are at least three important reasons to maintain a dual testing strategy incorporating HBsAg screening in addition to HBV NAT on all donations.
Firstly, during the very early stages of acute HBV infection, HBV DNA can be detected for a short period before HBsAg becomes detectable.
Secondly, during the course of early or chronic HBV infection, some individuals may have periods when HBV DNA becomes undetectable but HBsAg can still be detected.
Thirdly, during late chronic infection HBsAg may become undetectable although HBV DNA can still be detected (refer to section on occult hepatitis B below).
In July 2010, the Blood Service introduced a fully automated testing system, comprising the Procleix Tigris platform and a new triplex assay (Procleix Ultrio Assay).
The fully automated testing platform used for HBV NAT allows for rapid screening of individual donations and provides the following major benefits:
The fully automated Novartis Tigris system used by the Blood Service is the most advanced NAT technology currently available for donor screening and enables us to maintain international best practice in business efficiency and safety when testing blood donations.
Since September 2010, all red cells, platelets and clinical plasma (i.e. fresh frozen plasma, cryoprecipitate and cryodepleted plasma) supplied by the Blood Service have been tested for HBV DNA using the Procleix Ultrio NAT assay.
Plasma-derived products, such as immunoglobulins, albumin and coagulation factors concentrates, are subjected to two specific pathogen inactivation and/or removal steps during manufacture by CSL Biotherapies, which result in significant (multiple log) reduction in the number of potential pathogens.
Additionally, the fractionation process includes physical separation using precipitation and chromatography steps which also contributes to non-specific reduction of viruses and other pathogens.
No confirmed transmission of viral agents has occurred from plasma-derived products used in
Due to the manufacturing and fractionation processes already in place at CSL, there has been no change to the risk profile of plasma-derived products following the introduction of HBV NAT in July 2010. CSL have since introduced HBV NAT screening of their manufacturing plasma pools to ensure consistency with their current processes for HIV and HCV NAT screening of these pools.
The introduction of HBV NAT has reduced the residual risk of transfusion-transmitted HBV infection by:
Serologic and clinical patterns observed during acute HBV infection
Source: Hollinger (2008).(2)
HBV NAT on individual donations reduces the testing window period for HBV from approximately 38 days to approximately 24 days.
Acute HBV infection is self-limiting in approximately 97% of immunocompetent adults, leading to recovery and immunity.
However, in 3% of cases, individuals remain chronically infected, usually testing HBsAg positive and positive for antibodies to HBcAg (anti-HBc).
Some of these chronically infected individuals can have very low and/or intermittently detectable levels of HBV DNA with undetectable HBsAg. Upon testing, they are found to be HBsAg negative, anti-HBc positive, HBV DNA positive or negative, and positive or negative for antibodies to HBsAg (anti-HBs). This is known as occult HBV infection (OBI).
OBI can be detected by either HBV DNA or anti-HBc testing. Prior to the implementation of HBV DNA, the Blood Service detected a proportion of donors with OBI as a consequence of anti-HBc testing conducted as an additional test for donors who reported a history of hepatitis or jaundice.
However, only 30–50% of HBV infections are associated with clinical symptoms and therefore most donors with a previous HBV infection would not be aware of the infection, would not report a history of hepatitis and would not be tested for anti-HBc. Therefore, the sensitivity of this approach is at best 50%. The addition of HBV DNA markedly improves detection of OBI but, because of the very low and fluctuating levels of virus in some donors, even the most sensitive DNA test is not able to detect all donors with OBI.
The prevalence of OBI in blood donors varies markedly by region. One study of Asian blood donors quotes a median prevalence of 1% with a range of 0 to 4.6% of donors.(3)
Synthesised data from international studies for cases of confirmed HBV transfusion-associated transmission showed the rate of HBV transmission by components collected from donors in the window period of acute HBV infection was greater than that of components collected from donors with OBI (81% versus 19%, respectively).(4)
The following table shows the change in window period, the percentage of window period closure and the residual risk estimates for HBV since HBV NAT was implemented.
The 37.6% reduction in the testing window period for HBV, in addition to the ability to identify donors with OBI, has reduced the residual risk of transfusion-transmitted HBV from approximately 1 in 739,000 to approximately 1 in 1,170,000 per unit transfused.
|Virus||Assay||NAT Pool Size||Infectious WP* (Days)||% WP* Closure||
Estimate of Residual Risk (per unit)
|HBV||HBsAg||No NAT||38||1 in 739,000|
Less than 1 in 1 million
|Note: *WP = window period|
The current Blood Service residual risk estimate for transfusion-transmitted HBV (based on data from 1 Jan 2009 to 31 Dec 2010) is lower than most comparable international blood services.
Residual risk estimate for transfusion transmitted HBV
|Australia||Approximately 1 in 739,000||Seed et al (2009–2010)|
|USA||1 in 205,000 to 488,000||Zou et al (2009)|
|Canada||1 in 1,700,000||O’Brien et al (2011)|
|Germany||1 in 360,000||Houfar et al (2008)|
|France||1 in 640,000||Pillonel and Laperche (2005)|
|UK||1 in 320,000||UK NHSBT (2010)|
All donors identified as having OBI are notified of their test results, counselled and referred for further medical follow up.
Blood component recall and lookback investigations are undertaken as required on their previous donations.