Over the past several decades there has been progressive reduction in the risk of transmission of HBV by transfusion based on the use of HBsAg tests with increased sensitivity and widespread use of the HBV vaccine. However, on the basis of modeling studies, HBV remains the most common clinically important viral infection transmitted by transfusion, with residual risk estimates several-fold greater than those for HIV and HCV. The recent FDA licensure of two manufacturers’ automated triplex (HIV-1/HCV/HBV) nucleic acid testing (NAT) assays, used either in minipools (MPs) of 6 or 16 donations, or for testing individual donations (ID), may offer an opportunity to further reduce this risk. Both licensed assay systems appear to perform adequately in terms of analytical sensitivity and specificity, and when applied to contemporary US donors they generate incremental yields of 1:300,000 to 1:600,000 HBV DNA-positive donations not detected by current serological tests (HBsAg and anti-HBc). This rate is similar to the yield rate of HCV MP NAT, and substantially higher than that for HIV MP NAT. The HBV yield donations tend to contain low copy numbers of HBV genome that are not detected by currently available ultrasensitive HBsAg assays. It has been shown that these HBV yield donations include two sample types. Firstly, there are seronegative window-period donations in unvaccinated donors that are likely to be infectious; such window-period donations have been found at a rate that is similar to that predicted by modeling. Secondly and unexpectedly, at least half of the NAT yield donations identified in all of the US clinical studies represent subclinical infections in vaccinated individuals, characterized by HBV DNA in the presence of low titers of anti-HBs. Acute HBV infection in these individuals occurred years after vaccination predominantly through contact with their sexual partner who was a chronic carrier. The possible finding of vaccinated HBV NAT yield donations was not included in the models and infectivity of these additional yield samples is unknown. Understanding the infectivity (by transfusion) of these vaccine breakthrough NAT yield cases is critical. It appears that the HBV MP NAT yield rate is higher than expected as a result of the widespread use of HBV vaccine and the resultant detection of vaccinated individuals. Of the yield donations presented in the Red Cross study of 3.8 million HBV NAT screened donations, two-thirds (6 of 9) were vaccine breakthrough cases all of which were detected by MP NAT using a pool size of 16. The total yield of the study was nine HBV DNA positive donors of which eight (89%) were detected by MP NAT with the single ID NAT-only donation not detectable in any pool size of four to 16. The data suggest that the efficient detection of the vaccine breakthrough cases by MP NAT is likely related to a low-level but prolonged viremic phase.
Modeling studies indicate that the maximum yield of HBV window-period donations can be achieved only through the use of ID NAT. In contrast, the clinical studies conducted have shown that the majority of HBV DNA-positive yield donations were detected by MP NAT. Thus, the adoption of HBV MP NAT will offer an incremental improvement in HBV transfusion safety by the detection of HBsAg and anti-HBc-nonreactive donations from donors with acute infection whether previously vaccinated or naive. At the present time neither HBsAg nor anti-HBc testing can be eliminated since these tests continue to detect donations that HBV NAT fails to detect (and vice versa). It is possible that eventually HBV NAT may displace one of these serological tests, but this will require additional large studies.
In summary, HBV MP NAT is now available in multiplexed, automated NAT screening assays, and these tests are able to detect a number of HBV DNA-positive individuals. Such expanded screening will have unknown clinical benefit. In addition, its use cannot be offset by the discontinuation of any current testing. Widespread adoption of HBV MP NAT is predicted to occur in the future in part as a consequence of the operational advantages of the fully automated triplexed NAT systems. The Roche automated system is already only available as a triplexed assay, and we expect that over time the same will be true of the Chiron system.
Based on these considerations, it is reasonable for FDA licensed blood establishments to implement HBV MP NAT on a voluntary basis until the FDA mandates such testing. This mandate should be consistent with FDA-approved labeling of the two manufacturers’ tests that allows NAT in MPs of up to 6 or 16 donations. There is no benefit to smaller MP sizes from either modeling studies or clinical trials. We oppose a mandate for ID NAT at this time due to the relatively small increased yield observed in the Red Cross study (only 1 of 9 cases), increased donor deferral and donation loss due to false positivity, logistics of a 6 to 16-fold increased in test volume and cost. We as an industry recognize the potential benefit of MP NAT for HBV, and therefore believe that this test should be adopted.
As a final comment, the absence of effective reimbursement mechanisms by which hospitals can recover the increased costs of blood safety initiatives, implemented voluntarily or after an FDA recommendation, remains a serious flaw in the regulatory process. HBV NAT is an example of such an initiative that will come as an unfunded mandate if FDA recommends its use.
AABB is an international association dedicated to advancing transfusion and cellular therapies worldwide. Our members include more than 1,800 hospital and community blood centers and transfusion and transplantation services as well as approximately 8,000 individuals involved in activities related to transfusion, cellular therapies and transplantation medicine. For more than 50 years, AABB has established voluntary standards for, and accredited institutions involved in, these activities. AABB is focused on improving health through the advancement of science and the practice of transfusion medicine and related biological therapies, and developing and delivering programs and services to optimize patient and donor care and safety.
The Red Cross is committed to the safety of donors and patients, and to meet the best interests of the public we serve. The Red Cross, through its 35 Blood Services regions, supplies approximately 40% of the nation's blood for transfusion needs.