Issue Summary

Blood Products Advisory Committee

Gaithersburg, Maryland

July 21, 2005

 

 

Topic I: FDAs Current Considerations on the Management of Whole Blood and Source Plasma Donors and Units when a Donor Tests Positive for Hepatitis B Virus (HBV) DNA by a Nucleic Acid Test (NAT)

 

 

Issue

 

The FDA seeks the advice of the Committee on management of donors and units, and on a proposed algorithm to permit reentry of some donors of Whole Blood, blood components and Source Plasma, when a donor tests positive for hepatitis B virus DNA by a nucleic acid test (NAT).

 

Background

 

The FDA has recently approved the COBAS AmpliscreenTM HBV Test. This is the first licensed NAT to screen blood donors for infection with HBV. This NAT can be used to test minipools (MP) of up to 24 plasma samples and can also be used to test individual donations (ID). FDA has decided that the use of the test is optional and that its use cannot replace HBV serologic testing. (The reasons for this are explained in detail in the Appendix.) Therefore, at the present time, blood centers may screen blood donations by using COBAS HBV NAT voluntarily as an additional test to currently recommended serologic testing.

 

Currently, for HBV screening, Whole Blood and components for transfusion are routinely tested for both hepatitis B surface antigen (HBsAg) and antibody to hepatitis B core antigen (anti-HBc) consistent with current regulations and guidance documents (see References). Source Plasma for further manufacture into injectable plasma derivatives is routinely screened for HBsAg, but not for anti-HBc (see Appendix). Therefore, for HBV screening, centers that implement HBV NAT will be using a total of three assays to test Whole Blood and blood components (HBV NAT, HBsAg and anti-HBc), and two assays to test Source Plasma (HBV NAT and HBsAg). Thus, these blood establishments will encounter a number of possible test result combinations, and they will need to make suitable decisions regarding the management of donors and units based on these test result combinations.

Discussion

 

In regard to donor and unit management when the HBV DNA NAT result is negative, FDA has already communicated the following information on our website1:

 

If a unit tests negative or is part of a minipool that tests negative for HBV DNA, donor

and unit management should be consistent with FDA requirements/recommendations in

regard to testing donors for HBsAg and anti-HBc (see References and the following two

paragraphs).

 

Whole Blood units and units of blood components that test HBV DNA negative using the

COBAS AmpliScreen HBV Test in ID format or in MP format and that test

negative for HBsAg and anti-HBc can be used for transfusion, provided that all other

blood screening tests were negative and the units were otherwise suitable for release.

 

Source Plasma units that test HBV DNA negative using the COBAS AmpliScreen HBV

Test in ID or MP format and that test negative for HBsAg can be used for further

manufacture, provided that all other screening tests were negative and the units were

otherwise suitable for release.

 

In regard to donor and unit management when the HBV DNA NAT result is positive, FDA has communicated the following information on our website1:

 

Units that test HBV DNA positive using the COBAS AmpliScreen HBV Test in MP or in

ID format should be discarded and not used for blood transfusion or further

manufacture.

 

Donors whose units test positive for HBV DNA should be indefinitely deferred until

reentry algorithms are formulated, validated, and approved.

 

It is FDAs current consideration that an algorithm can be developed to determine the eligibility of donors whose samples give positive results in HBV NAT for Whole Blood and blood components for transfusion and for Source Plasma for further manufacture into plasma derivatives. The current consideration is that the algorithm, and hence the donor qualification, can be based on negative NAT and serologic test results on follow-up samples.

The algorithm that FDA is considering for management of donors who test HBV DNA positive is as follows, and an explanation for it is in the Appendix:

1. Whole Blood and Blood Components for Transfusion. See Table 1.

 

Whenever a donor tests HBV NAT-positive and HBsAg repeatedly reactive (RR), and the latter result is confirmed by neutralization (irrespective of the anti-HBc test results), or tests HBV NAT-positive and anti-HBc RR (irrespective of the HBsAg test results), that donor should be permanently deferred (Categories 1, 2, 3 and 4, below). Whenever a donor tests positive for HBV DNA and tests non-reactive (NR) for anti-HBc, and either HBsAg NR, or HBsAg RR /not confirmed by neutralization (Category 5 and 6, below), that donor should be indefinitely deferred, but may be reevaluated for possible reentry, as described below. (A unit that tests positive by HBV NAT, or that is RR for HBsAg or anti-HBc should not be used.)

 

Table 1

 

Category

HBV NAT Result

HBsAg Result

Anti-HBc Result

Donor and Unit

1

Positive

Repeat Reactive / Neutralized

Non-Reactive

Unit Not Used, Donor Permanently Deferred

2

Positive

Repeat Reactive / Neutralized

Repeat Reactive

3

Positive

Repeat Reactive / Not Neutralized

Repeat Reactive

4

Positive

Non-Reactive

Repeat Reactive

5

Positive

Non-Reactive

Non-Reactive

Unit Not Used, Donor

Indefinitely Deferred

Donor possibly may be
re-entered (see below)

6

Positive

Repeat Reactive /

Not Neutralized

Non-Reactive

2. Source Plasma for Further Manufacture into Plasma Derivatives. See Table 2.

Whenever a donor tests HBV NAT-positive and HBsAg repeatedly reactive, which is confirmed by neutralization, that donor should be permanently deferred (Category 1, below). Whenever a donor tests positive for HBV DNA and tests NR for HBsAg or HBsAg RR /not confirmed by neutralization (Category 2 and 3, below), that donor should be indefinitely deferred, but may be reevaluated for possible reentry, as described below. (A unit that tests positive by HBV NAT, or that is RR for HBsAg should not be used.)

Table 2

Category

HBV NAT Result

HBsAg Result

Donor and Unit

1

 

Positive

Repeat Reactive / Neutralized

Unit Not Used, Donor Permanently Deferred

2

Positive

Non-Reactive

Unit Not Used, Donor Indefinitely Deferred

Donor possibly may be
re-entered (see below)

3

Positive

Repeat Reactive /

Not Neutralized

 

3. Donor Reevaluation. See Table 3.

i. In regard to reevaluation for possible reentry of a donor of Whole Blood or blood components for transfusion, at least 6 months after the original donation, a new sample from the donor should be obtained (no donation is made at this time), and follow-up testing using individual sample HBV NAT, HBsAg, and anti-HBc licensed assays should be performed. a) If a positive individual sample HBV NAT is obtained, then, irrespective of HBsAg and anti-HBc test results, the donor is permanently deferred. b) If a negative individual sample HBV NAT result and a non-reactive HBsAg result and a non-reactive anti-HBc result are obtained on the sample, the donor may be reentered (that is, the donor is eligible to donate in the future, provided the donor meets all donor eligibility criteria). c) If a negative individual sample HBV NAT result is obtained, together with a repeatedly reactive HBsAg result and/or a repeatedly reactive anti-HBc result, the donor should be further evaluated as described in the FDA recommendations.2, 3 (Note: FDAs guidance documents do not yet address reentry of donors of blood and blood components intended for transfusion, who test anti-HBc repeatedly reactive on more than one occasion.)

Follow-up testing on a donor of Whole Blood or blood components for transfusion, who is deferred because of HBV NAT results, may be performed prior to the end of this 6-month waiting period for donor notification purposes or for medical reasons. However, if a positive HBV NAT is obtained, during this 6-month waiting period, irrespective of HBsAg and anti-HBc results, the donor should be permanently deferred. Negative and non-reactive results on the follow-up HBV tests may be used in donor counseling. However, only a negative individual sample HBV NAT result and a non-reactive HBsAg result and a non-reactive anti-HBc obtained from a sample collected at least 6 months after the original donation qualify the donor in category 5 or 6, Table 1, for reentry.

ii. In regard to reevaluation for possible reentry of a donor of Source Plasma, at least 6 months after the original donation, a new sample from the donor should be obtained (no donation is made at this time), and follow-up testing using individual sample HBV NAT and HBsAg licensed assays should be performed. a) If a positive individual sample HBV NAT is obtained, then, irrespective of the HBsAg test result, the donor is permanently deferred. b) If a negative individual sample HBV NAT result and a non-reactive HBsAg result are obtained on the sample, the donor may be reentered (that is, the donor is eligible to donate in the future, provided the donor meets all donor eligibility criteria). c) If a negative individual sample HBV NAT result is obtained, together with a repeatedly reactive HBsAg result, the donor should be further evaluated as described in the FDA recommendations.2

Follow-up testing on a donor of Source Plasma, who is deferred because of HBV NAT results, may be performed prior to the end of this 6-month waiting period for donor notification purposes or for medical reasons. However, if a positive HBV NAT is obtained during this 6-month waiting period, irrespective of the HBsAg result, the donor should be permanently deferred. Negative and non-reactive results on the follow-up HBV tests may be used in donor counseling. However, only a negative individual sample HBV NAT result and a non-reactive HBsAg result obtained from a sample collected at least 6 months after the original donation qualify the donor in category 5 or 6 for reentry.

Table 3

 

HBV NAT Result

HBsAg and/or Anti-HBc Result

Donor

a

Positive

Any test result

Permanently Deferred

b

Negative

Negative

Reenter

c

Negative

Repeat Reactive

Further evaluation (see references 2 and 3, as applicable)

 

Questions for the Committee

 

  1. Based on the scientific data, does the Committee agree with FDAs proposal that

 

a)      A donor of Whole Blood and blood components for transfusion who tests HBV NAT positive, anti-HBc non-reactive and HBsAg non-reactive or HBsAg repeatedly reactive/not confirmed by neutralization, may be reentered, if after a minimum period of 6 months a sample from the donor tests negative for HBV

DNA by individual donation NAT, non-reactive for anti-HBc and non-reactive for

HBsAg, and that

b)     A donor of Source Plasma for further manufacture into plasma derivatives who tests HBV NAT positive and HBsAg non-reactive or HBsAg repeatedly

reactive/not confirmed by neutralization, may be reentered, if after a minimum

period of 6 months a sample from the donor tests negative for HBV DNA by

individual donation NAT and non-reactive for HBsAg?

  1. Please discuss any alternative approaches FDA should consider.

References

 

1.        Frequently asked questions regarding implementation of Roche Molecular Systems

COBAS Ampliscreen HBV Test - 4/21/05

http://www.fda.gov/cber/products/hbvroc042105qa.htm

 

2. Recommendations for the Management of Donor and Units that are Initially Reactive for

Hepatitis B Surface Antigen (HBsAg) - 12/2/87

(PDF) (No text version available) http://www.fda.gov/cber/memo.htm

3.       FDA Recommendations Concerning Testing for Antibody to Hepatitis B Core Antigen (Anti-HBc) - 9/10/91
(PDF), (Text) http://www.fda.gov/cber/memo.htm

Additional References

4.       Recommendations for the Quarantine and Disposition of Units from Prior Collections from Donors with Repeatedly Reactive Screening Tests for Hepatitis B Virus, Hepatitis C Virus (HCV) and Human T-Lymphotropic Virus Type I (HTLV-I) - 7/19/96
(PDF), (Text) http://www.fda.gov/cber/memo.htm

5. 21 CFR 610.40 Test Requirements

http://frwebgate.access.gpo.gov/cgi-bin/get-

cfr.cgi?TITLE=21&PART=610&SECTION=40&TYPE=TEXT

http://www.gpoaccess.gov/cfr/index.html

 

 

6. 21 CFR 610.41 Donor Deferral

http://frwebgate.access.gpo.gov/cgi-bin/get-cfr.cgi?TITLE=21&PART=610&SECTION=41&TYPE=TEXT&YEAR=2004

http://www.gpoaccess.gov/cfr/index.html

 

7. 21 CFR 630.6 Donor Notification

http://frwebgate.access.gpo.gov/cgi-bin/get- cfr.cgi?TITLE=21&PART=630&SECTION=6&TYPE=TEXT&YEAR=2004 http://www.gpoaccess.gov/cfr/index.html

8.      Ganem D, Prince AM. Hepatitis B virus infection Natural history and clinical consequences. N. Engl. J. Med. 2004; 350:1118-1129.

9. Schreiber GB, Busch MP, Kleinman SH, Korelitz JJ. The risk of transfusion-transmitted

viral infections. N. Engl. J. Med. 1996; 334:1685-1690.

 

10.  Roth WK et al. NAT for HBV and anti-HBc testing increase blood safety. Transfusion 2002; 42:869-875.

 

11.  Public Health Impact of Implementing HBV Minipool NAT. Advisory Committee on Blood Safety and Availability; Transcript, August 27, 2004.

PDF http://www.hhs.gov/bloodsafety/pastmeetings.html#o

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

APPENDIX

 

Explanation of the Proposed Algorithm for Management of Donors who Test HBV DNA Positive

 

I. According to the proposed algorithm, whenever a donor tests HBV NAT positive and HBsAg repeatedly reactive, with the latter result confirmed by neutralization, the donor is permanently deferred. (Table 1, categories 1 and 2; Table 2, category 1.) This is consistent with current FDA recommendations, whereby a donor who has an HBsAg positive test of record is permanently deferred.

II. According to the proposed algorithm, whenever a donor tests HBV NAT positive and anti-HBc repeatedly reactive, the donor is permanently deferred. (Table 1, categories 3 and 4.)

 

Table 1, category 3. In the case where the donors HBV NAT is positive and the HBsAg test is repeatedly reactive, but not confirmed by neutralization, whereas the anti-HBc result is repeatedly reactive, the donor is indefinitely deferred. This is consistent with current FDA recommendations, whereby a donor who tests both anti-HBc repeatedly reactive and HBsAg repeatedly reactive (even if the latter is not confirmed by neutralization) is permanently deferred.

 

Table 1, category 4. In the case where the donors HBV NAT is positive and the HBsAg test is non-reactive, but the anti-HBc result is repeatedly reactive, the donor is permanently deferred. At the present time, FDA believes that permanent deferral is a reasonable precautionary stance, because two very different types of HBV tests are signaling possible HBV infection.

 

III. Clinical seroconversion studies with COBAS Ampliscreen HBV NAT showed that the maximum period of time that HBV DNA preceded HBsAg detection was slightly more than 3 months (108 days). The reason that FDA is recommending at least a 6-month waiting period after a positive HBV positive result prior to retesting is to ensure that, if a true infection exists, seroconversion to anti-HBc occurs and is detected.

Clinical Significance of Hepatitis B Virus Infection

Hepatitis B virus (HBV) is a major human pathogen that causes acute and chronic

hepatitis, cirrhosis and hepatocellular carcinoma (for a review, see Ganem and Prince,

2004). HBV is an enveloped virus with a partially duplex circular DNA genome of

approximately 3,200 bases. Most primary infections in adults are self-limited, the virus

is cleared from blood and liver, and individuals develop a lasting immunity. Fewer than 5

percent of infected adults develop persistent infections that can be asymptomatic (i.e. a

carrier state). About twenty percent of chronically infected individuals can develop cirrhosis.

Chronically infected subjects have 100 times higher risk of developing hepatocellular carcinoma than noncarriers.

Donor Screening for HBV Infection

 

HBsAg becomes detectable in blood 30 to 60 days after infection followed by emergence of anti-HBc. Viremia develops by the time HBsAg is detected, and can reach 109-1010 virions/ml in acute infections. Upon clearance of the HBV infection by the immune response, the HBsAg antigen disappears from the circulation and anti-HBc usually remains indefinitely. In chronically infected individuals, HBsAg and anti-HBc usually remain for life, and lower viral titers can be detected in blood for a long period, but tend to decline over time.

 

All blood and components intended for transfusion are currently tested by both HBsAg and anti-HBc assays. (FDA recommends testing for HBsAg and anti-HBc, consistent with 21 CFR 610.140.) Still, the major cause of HBV transmission by blood is from asymptomatic donors who have not yet developed HBsAg, or chronic cases where serological markers are not detected (occult hepatitis B). During the serologically negative window period (WP), blood from infected individuals can transmit hepatitis B. Look-back studies using polymerase chain reaction (PCR) showed that HBV DNA can be traced to the donors blood (Roth, 2002).

 

The risk of transfusion-transmitted HBV infection was dramatically reduced after FDA established a requirement to label paid donations, which resulted in the near cessation of using paid donors to make blood components for transfusion. Hepatitis B transmission was reduced further after the implementation of HBsAg tests to screen blood donations in the late 1960s and early 1970s. Currently, HBV is transmitted by blood transfusions more frequently than HCV or HIV. The residual risk of posttransfusion HBV infection when donors are screened by HBsAg and anti-HBc screening tests has been estimated as 1: 63,000 (Schreiber et al., 1996) to 1: 180,000 (Busch, December 2001, FDA Workshop) donations. The recent implementation of NAT to screen blood for HIV and HCV significantly reduced the risk for HCV and HIV infections from blood transfusions to 1: 1.6 x l06 and 1: 1.9 x l06 donations, respectively (Busch, December 2001, FDA Workshop). Depending on the sensitivity of the test, implementation of HBV NAT has the potential to reduce the risk of posttransfussion HBV infection to levels similar to those of HIV and HCV.

The FDA does not currently recommend that Source Plasma donors be tested for anti-HBc. If

anti-HBc reactive units were excluded from pools used for the manufacture of plasma derivatives, titers of anti-HBs in those pools would be expected to diminish, as both these

antibodies usually occur together. The presence of anti-HBs is believed to contribute to the safety of certain plasma products such as the immunoglobulins (September 10, 1991, Memorandum). Plasma units that are untested, nonreactive, or repeatedly reactive for anti-HBc are currently acceptable for the manufacture of plasma derivatives (September 10, 1991, Memorandum).

 

 

Use of the COBAS Ampliscreen HBV Assay to Screen Donors

The reasons that the implementation of the COBAS Ampliscreen HBV NAT is optional and that its use cannot replace by serologic assays are explained below:

Following the recommendations of the FDAs Blood Products Advisory Committee (BPAC) and the DHHS Advisory Committee on Blood Safety and Availability (ACBSA), and with the concurrence of the DHHS Blood Safety Committee, FDA decided to regard the use of this test in ID format and in MP format as optional and has not recommended its routine use to reduce the risk of HBV from transfusion. The advice given, and the decision made, regarding optional implementation was based on the fact that large-scale use of this test in ID format is not feasible at the present time, and because, although this assay can detect HBV during the serologically negative window period, its implementation in MP format would only result in a marginal increase in the safety of the blood supply. In a large clinical trial, the MP HBV NAT detected two window period cases in approximately 600,000 volunteer blood donations that were not detected by the currently recommended serological screening tests (HBsAg and anti-HBc). It is estimated that use of this test in addition to current testing could additionally detect approximately 50 infectious donations/year that most likely would infect an estimated 85 blood component recipients. A small proportion of such recipients will develop acute or chronic HBV disease with morbid sequelae (estimated 0.16 QALYs saved per infection prevented, and approximately one case per year of liver failure or hepatocellular carcinoma.11

Data on the use of COBAS Ampliscreen HBV Test in either MP or ID format is insufficient at the present time to allow the replacement of either the HBsAg assay for Whole Blood and Source Plasma donors or the replacement of the HBsAg and the anti-HBc assays for Whole Blood donors. In addition to the data above, the clinical trials indicated that the HBV NAT test was negative in some cases where the HBsAg test was positive or the anti-HBc test was repeat reactive, or both. Although some positive serological results were shown to be false positive by additional testing, other positive serological results could not be resolved because of lack of data. Thus, the COBAS AmpliScreen HBV Test, when implemented, is used together with HBsAg and anti-HBc tests for screening Whole Blood donors and with an HBsAg test for screening Source Plasma donors.