Donor screening for hepatitis B: hepatitis B surface antigen—a belt, suspenders, and another belt?

The authors of this commentary, being of a certain age, recall (at least one of us anyway) the excitement that attended the discovery of the Australia antigen in patients with serum hepatitis, that is, hepatitis B, followed by its association with posttransfusion hepatitis and the implementation of tests for surface antigen (HBsAg) in blood center laboratories reviewed in Block et al.1 We were less enthusiastic about bringing tests for antibody to the hepatitis B core antigen (anti-HBc) to bear, mainly because of the nonspecificity of surrogate testing. However, the test's value emerged with a clearer understanding of the burden of non-A, non-B posttransfusion hepatitis and, subsequently, an appreciation for the potential impact of occult hepatitis B virus (HBV) infections.2, 3 HBV was the first application of an orthogonal dual-testing algorithm (HBsAg with anti-HBc) that combined direct pathogen detection with antibody testing. This approach was used to overcome the critical limits of the individual tests, namely, the infectious window before detectability of an immune response to a chronic pathogen and the relative insensitivity of direct detection with immune modulation of chronic infection. We now use antibody testing, that is, detection of an immune response, combined with direct pathogen detection by minipool nucleic acid testing (MP-NAT) for hepatitis C and human immunodeficiency virus (HIV). For HBV we apply triple testing using an antibody assay (anti-HBc) and two direct viral detection assays (HBsAg and MP-NAT). Estimates for residual risk from all three of these classic transfusion-transmitted pathogens cluster around one missed donation per 2 million in the United States,4 which we accept as manageable and tolerable. We now ask whether HBsAg is redundant in this algorithm and if it adds any efficacy to anti-HBc plus NAT. The study by Dodd and colleagues5 in this issue of TRANSFUSION suggests any such value is minimal.

The authors have reviewed routine donor testing (HBsAg, anti-HBc, and MP-NAT) on more than 22 million donations, using sensitive individual-donation NAT (ID-NAT) to isolate the positive donations from positive minipools and potentially infective units from seroreactive donations with negative MP-NAT. At the end of all this testing, they identified six HBsAg-positive donations that were both anti-HBc negative and detected only with ID-NAT. These represent the maximum true “yield” of HBsAg testing within the three-assay algorithm. Even among these six donations, the authors note that HBsAg signal-to-cutoff ratios were quite low and that DNA testing was inconsistent. Follow-up testing on new samples was not clearly described, and the infectivity of such donations, those that are being found only by HBsAg, is not known, but will not be 100%. Only one of five qualified prior donations that were ID-NAT positive for HBV, found by looking back from a current donation detected by MP-NAT, transmitted in a Japanese study.6 It is worth recognizing further that the remaining risk for transfusion-transmitted HBV will only decrease with time, as donors subject to universal HBV immunization in childhood, as recommended by the Centers for Disease Control and Prevention in 1991,7 come to dominate the pool of eligible US donors. In 2016, vaccine coverage among adults at least 19 years was 24.8%,8 but among children 19 to 35 months it was 90.5%.9 If there was no opportunity for cross-contamination of these samples, their conclusion that removal of HBsAg testing will allow distribution of less than one additional potentially infectious donation per 4 million tested is likely conservative.

Cost is not, in fact, an important driver. Contemporary contract information is proprietary, but we believe, based on prior experience in our respective blood center laboratories, that the current price of HBsAg is in the range of $1.00 to $1.50/donation tested. Since there were 14 to 15 million whole blood plus apheresis RBC and apheresis PLT donations collected in 2015,10 this represents only approximately $15 to $22.5 million, which is not serious money in the overall costs of maintaining and using a robust blood supply. Recall, for example, that we are spending an estimated $137 million on Zika testing annually.11

Nonspecificity (nonconfirmed, repeatedly reactive HBsAg) is not really an issue. The lower bounds of the 95% confidence intervals for HBsAg specificity in blood donors are 99.77 and 99.89% for the two assays in use in the United States according to their Food and Drug Administration (FDA)-accepted instructions for use.12, 13 This study confirms this specificity. So with false positives unusual, the resulting burdens of donors deferred unnecessarily are small.

As to precedent, there are two apposite examples. The first, based on considerably less data, accrued over less time, is HIV p24 antigen screening. Despite a prior negative recommendation from the FDA's Blood Products Advisory Committee that included the authors of this commentary, the test was introduced in a 1995 memorandum from FDA.14 The agency's justification was largely the identification of infectious p24-positive donations using archived samples from HIV antibody–seroconverting donors. Residual risk estimates were in the 1 in 440,000 to 1 in 640,000 range. Screening was required (before the availability of HIV NAT) despite large donor screening studies with no yield,15, 16 but the blood community was subsequently permitted to stop p24 testing simultaneously with the implementation of licensed donor MP-NAT as an alternative direct viral detection test. Further, this suspension occurred even as the HIV epidemic expanded, in contrast to the current epidemiology of HBV and without contemporaneous real-world donor testing data analogous to that provided in the current paper. Rather, it was based on comparatively small validation studies by the NAT manufacturers demonstrating that NAT could detect infection at the time of or before p24 antigen testing.17

The second example is rescission of the requirement for universal screening for antibody to Trypanosoma cruzi,18 the hemoparasite that causes Chagas disease. It was replaced with one-time testing based on real-world evidence that identified no incident infections among 4.2 million donors subjected to repeat testing during 4 years of screening.19

It is axiomatic that good clinical and laboratory practices should eschew the provision of services, including diagnostic testing, that do not add value to care. When the authors trained, every patient admitted to the hospital was subjected to a standard battery of tests that might include a serologic test for syphilis, urine analysis, and a chest x-ray. Subsequent analyses have demonstrated that such screening approaches not only waste resources, but also lead to chains of unneeded, potentially harmful, evaluation unrelated to the complaints of the patient. The Choosing Wisely campaign of the American Board of Internal Medicine promotes dialog between providers and patients aiming to assure that care is appropriate. Its mission is to promote conversations between clinicians and patients to help patients choose care that is “supported by evidence, not duplicative of other tests or procedures already received, free from harm, truly necessary.”20 Transfusion medicine is not exempted from these value-based tenets. In terms of other precepts that influence policy, transfusion medicine is also not exempt from application of the precautionary principle and it would not be surprising if some advocates urged retention of HBsAg testing as a precautionary measure. Their enthusiasm should be blunted, however, by this new evidence that quantifies the minimal additional risk that would be incurred if the test is dropped. Revision will also not sit well with those whose opinions reflect the anchoring bias that results when greater importance than is due is awarded to HBsAg testing, based on its unquestionable value when originally introduced, to the exclusion of consideration of the contemporary corpus of data.

Pathogen evolution can allow false-negative assay results, due to genome sequence changes that affect NAT, or to epitope changes that alter the performance of serologic tests.21-24 Current donor molecular screening assays, while relevant details are proprietary, can reduce this risk using several strategies. Their targets are highly conserved nucleic acid sequences. Amplification and detection of multiple sequences within the genome or a gene using multiple probes and primers reduces the probability that a diverging pathogen strain would be missed. Employment of orthogonal assays, that is, HBV NAT and anti-HBc, is further insurance, and anti-HBc assays remain positive when HBV DNA and HBsAg have decreased to undetectable levels with current donor tests. Finally, having robust surveillance sources to monitor sequence and antigenic changes in appropriate populations and geographies is important to anticipate and prevent these false negatives. The pathway to clearance of assay changes that assure maintenance of acceptable clinical sensitivity in the face of sequence or antigenic evolution, namely, the biologics license application, is a time-consuming, expensive regulatory hurdle. Fortunately, these events affecting donor testing have been rare, especially with current screening algorithms. Still, they bear close consideration during any decision to remove a test.

Less critically, the test manufacturers, for whom reduced sales can reduce margins, may balk at continuing to play in this space if they speculate about eroding return on investments that discourage test development through the expensive regulatory gauntlet. No such issue has been observed as West Nile virus, Chagas, Zika, and Babesia infections have entered our calculus. What is more, they have amply demonstrated the capacity to make compensatory price adjustments given that current reagent contracts are generally bundled across the menu of required tests and structured per donation tested, not strictly on a price per assay. Pricing for Chagas tests is an example where testing all donors was converted to one-time testing and realized no cost reductions for purchasers, despite markedly reduced testing volume. We speculate that the same will be true when Zika ID-NAT moves to the MP-NAT format and HBsAg is no longer required.

When one has objective data like that from this study and an articulated threshold for tolerable risk, it becomes a straightforward exercise to apply risk-based decision making (RBDM).25 This framework has most frequently been applied to decisions about whether to undertake an affirmative intervention or not, for example, the implementation of testing for donor Babesia infection or the need to intervene to reduce donor iron depletion. When, however, new data are generated about an “old topic,” there is no a priori argument that RBDM is less suitable for considering stopping an intervention. The RBDM process starts with a problem formulation, in this case, estimating the continued value of HBsAg. Then there is the development of participation and communication strategies—critically stakeholder identification and engagement—with an eye to assuring that all material points of view are attended to. Experts then execute clinical/scientific, health economic, and contextual assessments, for and with the participation of the assembled stakeholders and subject to their critiques. These inputs are evaluated and decision making undertaken within the boundaries of an organization's, and in this case a regulator's, risk tolerance. Finally, the process is expressly iterative. A mandatory evaluation of the impact of whatever decision is taken and implemented and new evidence can provoke further RBDM cycles to revisit a decision. For HBsAg testing, the discussion seems to us to reduce to the definition of acceptable risk and accepting a nonzero incremental risk as we consider dropping a measure that is long integrated into our processes. In this instance that increment seems to be around one in 4 million donations. Tolerable or acceptable risk is contingent on many factors: the outcome being discussed, any number of contextual factors (e.g., ethical and legal), and the identity and opinions of those bearing the risk. By way of example, in the United Kingdom, an explicit HIV tolerable risk threshold of an additional one case per million was used during the deliberations leading to their decision to reduce their donor deferral for men who have sex to 3 months and reconsideration of other HIV risk behaviors.26

The question in the title of the paper by Dodd and coworkers, “Is there a case for continuation of HBsAg detection,?” deserves an answer. A compelling argument can be made for responding with an RBDM initiative. When the Alliance of Blood Operators RBDM project to develop a framework to guide “major policy and operational change” by the blood community was reviewed in TRANSFUSION, the process was lauded for a number of reasons, specifically including its demand for “subsequent review and revised decisions in light of new information and technology.”27 Revisiting the historical decision to use HBsAg seems paradigmatic of this approach considering these extensive new data.

US blood collectors have likely already seen enough data to have formed a position on a continued regulatory requirement to test donors for HBsAg and will advocate for stopping. For us, it remains to solicit and understand other stakeholder points of view, including transfusing clinicians, representatives of transfused patients, and the regulator now presented with high-quality data from Dodd and colleagues. The Achilles' heel of RBDM may be revealed in such an undertaking—that the group with the lowest risk tolerance dominates the outcome—but it is worth making the case. Other risks of similar magnitude are already tolerated, albeit not in the context of stopping an intervention so “traditional” as testing for HBsAg.

The article by Dodd and colleagues supplies sufficient new information to warrant review of the justification for persisting with HBsAg donor testing. RBDM, which AABB has recently invoked for considering donor screening for infection with Babesia sp. and mitigation of donor iron depletion, offers a framework for such a review. Multiple international applications have also been undertaken.28-30 Solomon, then AABB President, provided an enduring aphorism in 1994, that “the future of the relationship between blood banks and the FDA is in the hands of blood bank professionals.”31 This new opportunity should be embraced by AABB. Questions from these professionals about whether some of the tests we use are still useful must not fall on deaf ears. The Association should capitalize on an opportunity to bring the regulators, the regulated, and others with interest to the table to find answers within this framework.