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

Environments and inputs USA EU Australia

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

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

(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)

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 5.9-19.4 <0.001 MSM or sex with MSM, ever (Ref. never)   Males 62.3 27.6-140.4 <0.001 Multiple partners, last year (Ref. monogamous) 2.3 1.4-3.8 <0.01 Sex with HIV positive partner, ever 131.7 26.7-650.1 <0.001 Tattoo, body piercing, or at least three ear piercings 2.8 1.6-4.8 <0.001 Custer et al Transfusion. 2015 May;55(5):1098-107.

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

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

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

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

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

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; 49:1102-1114 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

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%

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 .

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):2763-2771, November 27, 2010.

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):2763-2771, November 27, 2010.

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): e82772. doi:10.1371/journal.pone.0082772

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): e82772. doi:10.1371/journal.pone.0082772

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 10.0 100+19.6 1,000,000 1,000 3.16 100+6.3 Increase in I Cases per 105 PY N per group 50% 10 vs 15 392,344 40% 10 vs 14 588.523 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

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

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

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. © IF THIS IMAGE HAS BEEN PROVIDED BY OR IS OWNED BY A THIRD PARTY, AS INDICATED IN THE CAPTION LINE, THEN FURTHER PERMISSION MAY BE NEEDED BEFORE ANY FURTHER USE. PLEASE CONTACT WILEY'S PERMISSIONS DEPARTMENT ON PERMISSIONS@WILEY.COM OR USE THE RIGHTSLINK SERVICE BY CLICKING ON THE 'REQUEST PERMISSION' LINK ACCOMPANYING THIS ARTICLE. WILEY OR AUTHOR OWNED IMAGES MAY BE USED FOR NON-COMMERCIAL PURPOSES, SUBJECT TO PROPER CITATION OF THE ARTICLE, AUTHOR, AND PUBLISHER. Vox Sanguinis Volume 102, Issue 1, pages 13-21, 21 JUN 2011

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, 2009-10 – introduction of individual assessment Blood Transfus. 2013 Jul; 11(3): 441–448

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. 2015 Sep 28.

Developments in Australia – MSM deferral Over 1996-2000, 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;50:2722-2730] 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

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

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

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

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. 2011 Feb; 38(1): 8–18.

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