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Posted: Dec. 20, 2001

Addenda: May 23, 2008

Link Updated: Apr. 28, 2011

 

Hepatitis B core testing and donor deferral

A frustrated blood banker wrote that he is tired of losing donors because of Hepatitis B core testing. He realizes the FDA allows for two positive anti-HBc test results, after which a donor is excluded, even if the positive tests for anti-HBc are separated by years. He has had a case where the positive tests were 10 years apart with many negative anti-HBc test results in the interim. He is wondering if some one can shed logic on why he should indefinitely defer this particular donor. He wants to know if it is still necessary to indefinitely defer such donors? He is aware of a guideline issued by the DEPARTMENT OF HEALTH & HUMAN SERVICES, Food and Drug Administration, DATED: September 10, 1991, FROM: Acting Director, Center for Biologics Evaluation and Research entitled: SUBJECT: FDA Recommendations Concerning Testing for Antibody to Hepatitis B Core Antigen (Anti-HBc).


The following replies were submitted in response to the above:

  1. A Southern California donor center medical director believes that the above-cited FDA memo is the most current on this topic as he does not know of any other FDA pronouncements that nullify or amend the memo. Based on that memo, his center would follow the FDA memo and defer the donor. The responding blood banker did say that the inquiring member could submit a 640.120 request for exemption for the individual donor, since that is always a possibility that could be pursued, but he doubts the FDA would approve the request. As for the logic behind the FDA memo, the memo has a list of references. But for the 2X Anti-HBc positive ever (even with intervening negatives) provision of the memo, you might want to inquire directly from the FDA on that one.

  2. A Northern California donor center medical expert is unaware of any alteration in the anti-HBc guidance. While she may agree that in light of current testing it may be an unnecessarily restrictive deferral until there is either 1) a reentry algorithm for core or 2) NAT testing on blood donors for HBV, she would be surprised if the FDA will change it.

  3. A Central California donor center director commented that he can understand the frustration of the blood banker who is losing a donor because of two reactive hepatitis B core antibody results, despite their being 10 years apart, with many negative tests in the interim. However, as per the above-cited 1991 FDA document there is little choice, if the establishment has accepted these recommendations and incorporated them into their SOP’s. The wording is quite clear in that "donors should be deferred indefinitely…whenever they test repeated reactive for anti-HBc on more than one occasion, regardless of the time interval between the two repeated reactive tests." It further goes on to note that there is no donor re-entry protocol, as there is not an available confirmatory test. As further noted in the recommendation, the FDA does permit the use of anti-HBc reactive plasma for further manufacture as recovered plasma; it does not impose this requirement on Source Plasma for further manufacturing. Therefore, according to the Central Californian, the inquiring blood banker has several choices:
    • "The individual could continue to draw the donor as a Source Plasma donor, assuming they have the appropriate license and procedures in place, or draw them solely for the preparation of recovered plasma and then tossing the rest of the transfusable components away. The blood banker could not adopt the "recommendations" of the FDA, or only adopt those parts that he/she feels are appropriate for his/her institution. Recommendations are not requirements, and unless a recommendation is taken in toto, the individual blood bank could not be held responsible for the entire document if only limited parts were accepted and put into practice (i.e., into their own SOP). The risk here is that most people are doing this, as most have adopted the recommendations in toto; therefore, the individual would not be meeting the prevailing "standard of practice." Thus, if something goes wrong with one of these units, i.e., the unit is implicated in a resultant case of hepatitis, especially hepatitis B, it would be difficult to defend in court, with most experts, including myself, saying that we had adopted these recommendations and did not modify them in any consequential way. Please note we did not adopt the item that states, "iii. Blood establishments should include in their donor history questionnaire a question regarding any previous anti-HBc test results which were repeated reactive." I don’t believe this is on the uniform donor history, let alone most people’s history form. Most of us rely on our computer to tell us this."
    • Another option would be to develop a donor re-entry protocol and submit it to the FDA for approval. While there is no "available confirmatory test," we tried to develop one using the Hepatitis B vaccine and the resultant response of these anti-HBc only individuals as a potential one, and published our study (Aoki et al. Transfusion 1993;33:362-367). The FDA didn’t like our approach, so we are unable to use it; but it is a viable way to differentiate (in most cases) those individuals who have a false positive anti-HBc test from those who have a true positive one, primarily when they do not have concomitant anti-HBs, the protective antibody.
    • Another approach would be to develop a reentry algorithm, utilizing a nucleic acid test for hepatitis B virus DNA. The protocol could state that if an individual were non-reactive for hepatitis B DNA, despite being reactive for anti-HBc, and/or if they have concomitant anti-HBs of a certain level that they should be considered, by definition, not to be a hepatitis B carrier."

The responding Central Californian's donor center has been faced with this problem even more acutely of late because they are now using Abbott’s anti-HBc test, which he reports has more false positives than their previous one from Ortho. He says they made the switch because they, in part, believed the PRISM would soon be licensed, and they could then go to the anti-HBc test that is part of this system; they believe it to be not only more sensitive but much more specific. For the last year, all of their donors, who have a single reactive result for anti-HBc, have been put on hold until their PRISM is in place with its anti-HBc test and they can have them come back and, hopefully, be negative, i.e., not to have a second reactive anti-HBc result. In order to keep these donors’ interest, they have communicated with them approximately a year after their initial result to remind them that "we still hope to get back to them when we have a better test to be sure their anti-HBc is a false reactive result". For some, they involve them in research studies, so that they still have a connection with the donor center and do not completely lose hope.

  1. Another California blood bank physician wrote that he did not see an "out" on this issue. His facility also defers indefinitely whenever they observe that a donor has two repeatedly reactive results for anti-HBc in their system, regardless of the intervening duration (and number of donations) that might separate the two results. The responding blood banker does not think it is logical, nor does he believe this deferral adds significantly to the safety of the blood supply. He only hopes that, as we appear to be moving toward HBV NAT, the FDA eventually will consider implementing a re-entry algorithm.
  2. Another Californian wrote "The science fiction scenario I've sometimes painted for donors deferred for core runs like this:
    • 2003: FDA licenses HIV/HCV NAT
    • 2005: blood banks implement HBV NAT under IND
    • 2008: FDA licenses HBV NAT
    • 2010: FDA revises core deferral"
    He calls to the e-network's attention the article by Yotsuyanagi et al., which appeared in the September issue of TRANSFUSION entitled "Frequent presence of HBV in the sera of HbsAg negative, anti-HBc-positive blood donors". The responding blood banker believes the conclusions of this article are significant that "replication of HBV is ongoing in a substantial proportion of healthy blood donors who have anti-HBc."

  3. A blood bank physician from Pennsylvania wrote that the issue of anti-HBc testing has frustrated blood bankers, and donors,for over 10 years. He thinks part of the frustration stems from the lack of a validated confirmatory test to separate out those donors who are truly positive from those who are false-positive. This issue has also been a source of frustration for solid organ transplant programs and organ procurement organizations, and has caused the publication of a number of papers dealing with this issue. HBV-DNA testing may, or may not, prove to be a reliable "confirmatory" test for anti-HBc-positive donors. Two recent papers have dealt with the use of HBV-DNA testing in HBc-positive donors (see, Transfusion 2001;41:1093-1099 (Sept. 2001) (same links as above); and, Progress in Transplantation 2000;10:42-46 (March 2000). As bad as the anti-HBc antibody test is, the fact remains that a certain percentage (albeit probably small) of anti-HBc-positive only donors are found to be HBV-DNA-positive and thus are "low grade" chronic carriers of HBV. What we do not know are: 1) the transmission rate of HBV from anti-HBc-positive only donors to transfusion recipients; 2) the sensitivity and specificity of HBV-DNA (i.e., validation) testing in the blood donor population as a confirmatory test for anti-HBc-positivity and/or as a test in lieu of anti-HBc testing; and, 3) if there is a difference between the donor who tests anti-HBc-positive twice in a period of two months, for example, versus the one whose two positive tests are separated by 10 years. The responding blood banker would like to see HBV-DNA testing validated for use in blood donor screening, but this will require a multi-institutional, multi-year project. He echoes the fact that all of us are frustrated and disappointed that many perfectly good blood donors are being deferred. In the case of the donor presented, he would not perform a recall of the blood components collected over the ten-year interval (and he knows of no regulation mandating such). He might be tempted, however, to have HBV-DNA testing performed by a reliable laboratory and, if negative, submit an exemption to the FDA.

ADDENDA May 23, 2008

  1. The Editors believe that the following Draft Guidance for Industry "Requalification Method for Reentry of Blood Donors Deferred Because of Reactive Test Results for Antibody to Hepatitis B Core Antigen (Anti-HBc)" is germane to this discussion.

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