1. Ongoing developments on donor selection from MSM A former regulator’s perspective
Albert Farrugia PhD
School of Surgery
University of Western Australia
And
Kedrion S.p.A Lucca, Italy
Plasma Users Group Meeting
Estoril
14 January 2015

2. Environments and inputs
USA EU
Australia

4. Risk of HIV transmission by blood transfusion before implementation of anti-HIV tests
90 % risk reduction
Busch et al 1991 cited by A Williams at BPAC Dec 2014

5. USA Blood Donor Screening – FDA MSM
March 1983 – Permanent deferral – sexually active homosexual or bi-sexual men with multiple partners
September 1985 – Permanent deferral – Male who had sex with another male since 1977, even one time
February 1990 – Permanent deferral – Men who had sex with another man even one time since 1977
April 1992 – Current DHQ – From 1977 to the present, have you
Male donors: had sexual contact with another male, even once?
A. Williams BPAC December 2014

6. (FDA’s guidance documents, including this guidance, do not establish legally enforceable responsibilities. Instead, guidances describe the FDA’s current thinking on a topic and should be viewed only as recommendations, unless specific regulatory or statutory requirements are cited. The use of the word should in FDA’s guidances means that something is suggested or recommended, but not required)

7. REDS-II – Adjusted Odds Ratios from multivariable logistic regression analysis of factors associated with HIV infection
Risk factor
AOR
95% CI
p value
Black, NH
10.7
<0.001
MSM or sex with MSM, ever (Ref. never)
Males
62.3
<0.001
Multiple partners, last year (Ref. monogamous)
2.3
<0.01
Sex with HIV positive partner, ever
131.7
<0.001
Tattoo, body piercing, or at least three ear piercings
2.8
<0.001
Custer et al Transfusion May;55(5):

8. Blood DROPS - sexual history among donors complying and noncomplying with MSM77
Characteristic
Comply with policy (n = 3100)
Do not comply (n = 83)
p value
Gay/homosexual/queer
4 (0.1)
20 (24.1)
<0.001
Last sex with a woman <6 months
2304 (74.5)
46 (55.4)
0.001
Last sex with a man 6 months
5 (0.2)
21 (25.3)
<0.001
Custer et al TRANSFUSION 2015;55;2826–2834

9. US Blood Donors reporting MSM
MSM as % of US blood donors
FDA MSM Guidance Dec 2015

10. Blood DROPS - Opinions about blood donation, current rules, and possible MSM policies
Survey question/content
Complying male blood donors (%)
Noncomplying male blood donors (%)
p value
Agree
Disagree
Don't know
Policy should be amended so that a man who has had sex with only one other man in the past year and is in a truly monogamous relationship should be allowed to become a blood donor
49.0
41.8
9.2
81.9
12.0
6.9
<0.001
Men who have, or have had, oral or anal sex with other men should donate blood despite the current rule that does not allow it.
57.6
12.4
30.0
45.8
49.4
4.8
<0.001
Would follow a policy placing a temporary ban on blood donations if had sexual contact with another man in a 1-year period before donating blood
Only asked of those donors reporting MSM
50.6
31.3
18.1
Custer et al TRANSFUSION 2015;55;2826–2834

11. Transfusion of blood components from donors in the HIV window period A case for ID NAT?
Case number: primary author; country, year of transfusion
NAT screening results on transfused unit
Subsequent qualitative NAT result on transfused unit
Clade
Reported viral load in copies/mL (assay used)
Revised estimate of viral load by limiting dilution†
Blood component
Estimated plasma volume (mL)
Estimated viral load transfused (total copies)
Transmission to recipient
Case 1: Ling75; Singapore, 1997 ND
ID positive E
5-39 (NucliSense qualitative and quantitative assays) 50
RBCs
20¶
1000
Yes
MP variable
PLTs
25¶
1250
Case 2: Delwart74; US, 2000
Negative MP of 24, in house B
180 (NGI)
40§
7200
Case 3: Najiouallah80; France, 2001 or 2002
Negative MP of 24
<200 (Amplicor)
20‖
<4000
Case 4: Phelps79; US, 2002
Negative MP of 16
Unknown
FFP
225§
Case 5: Schmidt82; Germany, 2007
Negative MP of 96
146 IU (CAP/CTM HIV-1 test)
1460**
Case 6: Harritshoj81; Denmark, 2007
Negative MP of 96††
246 (Abbott Real time); <40 (CAP/CTM)‡‡
4920
NA§§
6150
Kleinman et al TRANSFUSION Volume 49, November 2009

12. More DROPS……and the FDA
(Donors non-complying with MSM77)
Agree
Disagree
Don’t know
Because blood donations are screened, I believe it's safe for me to give blood and I would do so regardless of the rules.
63.9
31.3
4.8
Custer et al TRANSFUSION 2015;55;2826–2834
“….it has been suggested that no donor deferral is necessary, given the relatively low likelihood that a recently infected individual would give blood. However, in the setting of the approximately 50,000 new HIV infections per year in the United States, conservative calculations performed by FDA estimate that this approach could potentially be associated with an approximately four-fold increase in HIV transmissions resulting from blood transfusions each year. Such a policy, increasing the potential for the transmission of HIV infection, is not aligned with maintaining or improving the safety of the blood supply in the U.S…..”
FDA MSM Guidance Dec 2015

13. FDA’s risk assessment of the effect of changing MSM deferral policy on risk from test failure/handling errors Anderson, SA et. al.,; Transfusion, 2009; 49:
General test failure or handling errors (~ HIV prevalence)
Considered
Adherence with deferral policies
Unknown, but unchanged
Predicted increase in residual risk over permanent deferral
No deferral
Not Considered
One-year deferral (more than 1 sex partner)
One-year deferral (any sex)
3% increase in risk
Five-year deferral (any sex)
0·5% increase in risk

14. Factors contributing to Quarantine Release Errors Licensed Blood Establishments FDA Public Workshop: Quarantine Release Errors September 13, 2011
Contributing Factors
#QREs
Computer
Equip
Human
Process Controls
Collection
379 0% 2%
83% 9%
Comp. Prep.
490 1%
77%
14%
Donor Screening
4,548
81%
17%
Donor Deferral
550
29%
69%
Testing
158 6% 8%
61%
20%
QC & Distribution
2,618
75%
13%

15. FDA MSM Guidance December 2015 Operational Assessment
The operational assessment examined quarantine release errors. Such errors occur when a blood establishment accidentally releases a unit of blood that should not have been released due to issues with donor qualification or testing. It became clear at an FDA workshop held in September 2011 that HIV risk from quarantine release errors has been minimized effectively by increased use of computerized inventory management, with a remaining small risk of human errors. Following the workshop, a White Paper was produced by AABB on this topic which describes a number of measures that could be taken to characterize and prevent such errors . Quarantine release errors currently appear to contribute minimally to the risk of HIV transmission through the blood supply .

17. Principle of HIV Recency Assays
. Principle of assays that discriminate recent from long-standing HIV infections, based on maturation of HIV-specific antibody responses, for use in cross-sectional incidence estimation. LS-EIA, less-sensitive-enzyme immunoassay. 2
Busch et al AIDS. 24(18): , November 27, 2010.

18. HIV Recency Tests and their limitations
. Summary of tests for recent infection and their limitations 3
NB – None are licensed for blood screening
Busch et al AIDS. 24(18): , November 27, 2010.

19. Principle of Limiting antigen Avidity Assay M Owen, CDC – FDA BOAC December 2015
Proportion of samples classified as assay positive using the LAg-Avidity assay alone
High
Low Ag
Low antigen concentration of a single multi-subtype Ag (special kit)
Monovalent binding of antibodies
Low avidity antibodies, if present, are easilly dissociated with low pH
PLoS ONE 8(12): e doi: /journal.pone

20. Optimized multi-assay algorithms (MAAs).
Proportion of samples classified as assay positive using two avidity assays alone or with HIV viral load, as a function of the duration of HIV infection
Optimized multi-assay algorithms (MAAs).
PLoS ONE 8(12): e doi: /journal.pone

21. Statistical challenges in estimation of incidence and changes to incidence
Statistical power for difference in incidence
Consider 2 year study to compare incidence in 2 groups (e.g. pre and post policy change)
Sample size for 80% power
Assume estimated incidence is 100/100,000 PY
Follow subjects for 1 year
For calculations, assume events occur at 6 months
Subjects
Cases I
SE (I)
95% Confidence limits
10,000 10
100.1
31.6
100+62
100,000
100
10.0
1,000,000
1,000
3.16
Increase in I
Cases per 105 PY
N per group
50%
10 vs 15
392,344
40%
10 vs 14
30%
10 vs 13
1,002,679
20%
10 vs 12
2,157,961
10%
10 vs 11
8,239,572
Brambilla D, FDA BPAC Dec 2014

23. Commission directive 2004/33/EC Annex III: Eligibility criteria for donors
Permanent deferral, such as for • Persons whose sexual behaviour puts them at high risk of acquiring severe infectious diseases that can be transmitted by blood Temporary deferral, such as for • Persons whose behaviour or activity places them at risk of acquiring infectious disease that may be transmitted by blood. Defer after cessation of risk behaviour for a period determined by the disease in question and availability of appropriate tests

24. Proportion of MSM among HIV-positive blood donors and in public health studies in EU member states (MS) MS
Proportion of MSM among newly diagnosed HIV-positive individuals
Blood donor population
General population
MS with permanent deferral of MSM
France
50% (2007)–53% (2008)
47% (2008)
Germany
51% (2001–2005)–43% (2006–2010)
67% (2009)
Greece
53% (2003–2008)
61% (2009) NL
31% (1995–2003)–45% (2004–2008)
68% (2008)
MS without permanent deferral of MSM
Italy
22% (2009–2010)
26% (2008)
Spain
70% (2008–2009)
57% (2008)
Offergeld et al Vox Sanguinis (2014) 107, 420–427

25. Deferral from donating blood of men who have sex with men: impact on the risk of HIV transmission by transfusion in France
Estimates
Residual risk per million donations (CI 95%)
% of current RR estimate
Current – Permanent deferral
0·41 (0·0–1·39)
100
Policy change to deferral only if > 1MSM/year
Best-case scenario
0·33 (0·0–1·17) 81
Worst-case scenario
1·53 (0·0–4·31)
371
 Trend in HIV incidence among men who have sex with men and other blood donors – France, 1994–2008.
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Vox Sanguinis Volume 102, Issue 1, pages 13-21, 21 JUN 2011

26. Effect of change from permanent MSM deferral to individual assessment on HIV prevalence in Italian donors
MSM
Heterosexuals
Year
Total donors
HIV ab +ve/105 donors
RR∘ (95% CI) P
1999 (reference)
775,357 1
1.7
2009
1,425,791
1.9
2.9 (1.0–8.4)
0.06
2.6
1.5 (0.8–2.7)
0.23
2010
1,441,350
1.8
2.7 (0.9–7.8)
0.09
0.20
1999 – Permanent deferral, – introduction of individual assessment
Blood Transfus Jul; 11(3): 441–448

27. BUT……Characteristics of RTD and FTD among 113 HIV-positive Italian blood donors reporting a risk behaviour <4 months before donation
RTD
FTD
Total donors
No. %
HET 46
63·9 31
75·6 77
68·1
MSM 24
33·3 9
22·0 33
29·2
Reason for not having reported risk behaviour during pre-donation interview
Thinking that behaviour yielded a negligible risk of infection 15
20·8 10
24·4 25
22·1
Donating blood only to be tested for HIV 6
8·3
5·3
Not knowing the HIV positivity of the partner 4
5·6 1
2·4 5
4·4
Raimondo Vox Sang Sep 28.

29. Developments in Australia – MSM deferral
Over , the Australian Red Cross Blood Service switched from a five year to a one year MSM deferral.
A comparision of the five years prior and the five years post the change revealed no significance increase in HIV+ve donors (24/4,025,571 vs 24/4,964,628; p=0.47 [Seed et al TRANSFUSION 2010;50: ]
Compliance to this policy is high - >99.7% [Seed et al Vox Sanguinis (2014) 106, 14–22] (NB – Non-compliance in Australia is a criminal offence)
ARCBS proposed a six month deferral to the TGA in 2014; this was not granted
National data show a 10% increase in newly-diagnosed HIV in Australia in 2012
This was the largest increase in 20 years and was predominantly in MSM

30. The inescapable reality Relationship of plasma pool size to infectivity risk
TRANSFUSION 1996;36:77&775

31. Prevalence of blood borne infections in haemophilic birth cohorts in the USA.
Based on the results of laboratory testing for HBV (▪), HCV (▴), and HIV-1 (◯).The proportion was zero for HIV after 1984, for HCV after 1992, and for HBV after 1993.
Soucie et al Transfusion 2001 Mar;41(3):338–43

32. Transfusion-transmitted HIV in the USA in the testing era
MMWR Oct 22, 2010

33. Effect of PRT on Viruses in Whole Blood
Model virus used
Log/ml reduction
Type
HIV, latent
intracellular human HIV
4.5
enveloped
HIV, active
cell-associated human HIV
5.9
West Nile virus
≥5.1
Hepatitis C virus
sindbis virus
3.2
Hepatitis B virus
pseudorabies virus
2.5
Rabies virus
vesicular stomatitis virus
≥6.3
Influenza virus, avian flu virus
influenza A virus
≥5.0
Cytomegalovirus
infectious bovine rhinotracheitis virus
2.1
Human B19 virus
porcine parvovirus
non-enveloped
Hepatitis A virus
human hepatitis A
1.8
encephalomyocarditis virus
Chikungunya virus
La Reunion clinical isolate
Transfus Med Hemother Feb; 38(1): 8–18.

34. MSM and Regulatory Effort Conclusions
The deferral policies wordlwide have steadily decreased in effectiveness
Recent policy changes imposed by societal pressure are unlikely to improve this
Continuous attempts to reconfigure the blood safety paradigm through reliance on enhanced testing ignore the basis of precautionism
The rapid introduction of PRT for the transfusion sector is the only measure which can decrease the already low risk of blood transfusion
For this, regulators have to be more proactive, and ignore cost imposts