Highlights of the

IPFA/PEI 17th Workshop on Surveillance and Screening of

Blood Borne Pathogens

Cees L. van der Poel, MD, PhD

Transfusion Technology Assessment Group (TTA) Julius Centre Health Sciences & Primary Care

Session 1 Welcome address

•  Dr. Perry (IPFA) –  “Not that blood is not safe, but how do we keep it safe”

•  Dr. Sindik-Milolevic (Croatia) –  Institute of Immunology, 117 years -> Inc –  Vaccins and plasma products –  Priority on self sufficiency (IVIG) –  New facilities and new products

•  Ms. Mihaljevic (Croatia) –  Institute of Transfusion Medicine and Blood Safety –  Screening tests used in BTC (n=5) from 2 -> 8 –  Residual Risk for HBV and HCV down since 1995 –  0,2-0,5% pregnant women HBV pos, vaccination programme 1999 –  HIV and Syph trends up, MSM

Session 2 Malaria and Babesiosis

•  Prof. Chiodini (UK) –  Immigration renders “London as the window to the Globe” –  Malaria 50% underreported, trends down in reporting countries –  Case mix more dangerous -> Falc. and Vivax –  Pathogenicity Vivax underestimated –  Knowlesi, tourism and ARDS, not Duffy dependent –  two major types detected, but plea for broader sensitivity of Ab test –  cross reactions <-> mixed infections common –  Donors who transmitted had high Ab titers

•  Dr. Kumar (FDA, USA) –  150.000 donors / yr deferred –  Limited detection of PCR –  Recombinant antigens for broader tests –  Risk assessment model donor deferral: 60% travel to a Mexican region 1 case

per 61 years –  60% deferral reduced by Ab testing

Session 2 Malaria and Babesiosis

•  Dr. Owusu-Ofori (Ghana) –  Costs of newer treatments -> testing options –  Better and cheaper tests needed –  TTM study !!! -> PTM 3.1% attack rate,

•  but where did it come from? 5/6 PTM donor no parasitaemia •  7 parasitaemic donations -> 1 parasitaemic recipient

–  Consider patient characteristics, semi-immune protected against clinical M

•  Dr. Leiby (ARC, USA) –  Distribution of B. spp changing and more complex (EU) –  Babesiosis significant transfusion risk (Microti, US), –  80-100 Txm cases, 12 fatal outcomes –  Tick deferral no solution –  TEST NEEDED

Session 3 Emerging infections

•  Dr. Dodd (ARC, USA) –  Of mice and men: “XMRV a virus searching for disease” and “CFS a

disease searching for a virus” –  Association with PC and CFS not established –  Donor prevalence up to 3,7 % (NAT) –  Blood Txm a “theoretical risk” (where did we hear that before?) –  “A causal role of XMRV in CFS is an intriguing possibility….”

–  (Mikovitz and Ruscetti, Science, 14 May, 2010) •  Ms Lam (Singapore)

–  Malaysia, 2 mosquito’s and 2 infections, CHIKV and DHF –  Testing or PR or “beware of the mozzies” –  Few reported Txm cases: immunity, clinicians do not associate

•  Dr. Velati (Italy) –  WNV in NE Italy, regional 0,7% donors Ab pos –  WNV NAT in outbreak, 2009: 1:25.000 donors NAT pos –  Region is essential for blood supply –  Rest of Italy: 28 day deferral –  Mozzies largely extinguished, WNV (low) endemic but CHIKV imported

(2007)

Session 3 Emerging infections

•  Prof. Zaaijer (Netherlands) –  Q fever in NLD, largest outbreak ever

•  Coutinho: “We don’t need terrorists, we can produce it ourselves” –  One Txm case in Lit in 1977 –  3/1000 donors (second half outbreak 2009) PCR confirmed pos,

seroprev 13%, incidence 3% –  2 possible Txm cases

•  IgG in 2 recipients: 1x PCR positive donor (study), 1x PCR negative donor (look-back) who reported Q fever after donation

–  Screening since march 15th, 2010 •  Round table

–  Look for Coxiella partitioning in blood –  Coming next in this theatre: Does EU have XMRV?

•  MSM no risk group for XMRV (in Amsterdam) –  XMRV disease after blood Txm? –  Will companies make smaller scale tests or can we do it ourselves?

(EU)

With every breath you take …..

•  “See your GP in case

of coughing, headache or

fever…..”

Session 4 Updates

•  Dr. Alter (NIH, USA) –  PR is good if we can do it, the question is whether we can

•  For plasma doable •  For cells more difficult…

– HOVON study more bleeding, is there DNA in platelets?

–  “The precautionary principle asserts that measures need to be taken to face potential serious risks (in absence of conclusive evidence)”

•  ……but the measures need to be proportional…… –  “Soft PR” (low viral loads, OBI’s) plus multiplex testing

(100-10 c/ml) would yield 100% safety

J-L Kerkhoffs et al, British Journal of Haematology, April 6th, 2010

Session 4 Updates

•  Prof. Busch (BSRI, USA) –  (57 slides in 20 minutes….) –  Global screening with NAT …..in 22 countries –  Global NAT yield 2/M for HIV and HCV, but 7/M for HBV –  50% of HCV NAT yield tackled by HCV Ag testing

•  NLD 1 HCV yield case in 9 million donations –  10-100 copies needed for HIV Txm

•  but 1-10 for HBV / HCV –  Nat yields better data on seroconversion time frames –  IL28B polymorphism and HCV clearance –  Future in multiplex testing

Virus titre modeling: HIV

* Viral doubling time: 0.85 days * NAT pool size: 48 donations * Test characteristics: X95 = 25 gEq/ml

X99.9 = 75 gEq/ml

Session 4 Updates

•  Prof. Allain (Cambridge, UK) –  In type D OBI more often (escape) mutations, may escape serological detection –  HBsAg assays vary in ability to detect OBI variants –  HBsAg assays may benefit to use OBI mutants to reach broader sensitivity –  Before diagnose OBI use other HBsAg tests

•  Dr. Coste (EFS, France) –  New screening technologies incl. vCJD –  Sample size and prep: tennis court preferred –  Bio-receptors and transducers, quantum dots, bio barcodes –  micro arrays: limited options for use –  Micro / nano arrays (2nd gen): not before 2020 –  One realistic candidate vCJD screening test, ELISA format

•  good specificity •  good anlytical sensitivity •  dissappointing in-vovo sens (0/3 human vCJD cases) •  PMCA possible as confirmation test (cell lines)

Session 5 Manufacturers

•  mr. Schochetman (Abbott) –  Mol tools for pathogen discovery:

•  virochip DeRisi 2003 (SARS) 60 K oligonucleotides, all 2500 viruses, including plants and animals

•  Solexa™ sequencing tool, 80 Million reads / run –  XMRV

•  Macaques can have it in their reproductve tract •  Dr. Petti (Novartis)

–  Concern for the patient…..future public heath threats……Wilson&Jungner?

–  Clinical relevance? Global tolerable risk? •  Dr. Linnen (Gen-Probe)

–  B19/HAV ready, XMRV prototype, Dengue in Brazil studies planned……

–  Panther ™ instrument –  XMRV 0/1435 ARC donors, no XMRV in HIV+ samples –  HIV viral load in WB similar to plasma

•  so HIV is in the plasma and not in the RBC

Session 5 Manufacturers

•  Dr. Saldanha (Roche) –  Multi-dye technology RT PCR Cobas s201

•  Rapid development of CHIKV etc “if the need is shown to us”

–  HAV/B19, SD and pools, B19 types 1,2,3 •  High titer of one may mask the other

–  HBV, HCV, HIV-1+O and HIV-2 •  Detection of combined infections at different titers

•  Prof Roth (GFE Blut mbH) –  “in-house testing” GFE Blut RT PCR’s licensed by Roche for

GFEB associates, CE marked, 2,5 M donations/yr –  One tube process HCV, HIV-1+O, HIV-2, HBV, HAV, B19 –  HCV, HIV, HBV sens 500-600 c/ml –  HBV sens balanced by anti-HBc

Session 6 Plasma screening

•  Mr. Matsubayashi (Hokkaido, Japan) –  HEV world wide spread, Japan mostly type 3 &4, type 4 more

pathogenic –  in Japan 2% of cases BTx related (3/5 from Hokkaido) –  In-house HEV NAT in pools@20 pos in 1 : 8,000 donations

•  57% ALT up, RNA pos up to 2 months •  12% long term IgG neg (?) •  Eating history of viscera

–  Lookback 4/8 transmissions, –  More heat stable than expected, 20nm nanofiltration is OK

•  Dr. Baylis (PEI, Germany) –  EDQM Proficiency testing B19 NAT: type 3a dissapointing –  0/109 ALT elevated samples SD NAT neg for HEV (HCV and HBV) –  10% plasma pools HEV NAT pos, Type 3 EU and US, type 4 Asia –  Labs 2-3 log difference in sensitivity, international standard? –  Include PARV4 DNA? Present in 4% of plasma pools, IVDU related, no

pathology yet

Session 6 Plasma screening

•  Dr. Ayob (Malaysia) –  Global market changes: mergers, dramatic rise in IVIG use –  Concentrates safe, (life long) Rx cryo is not –  Fractionated products costly for developing world – not affordable –  Strengthen National Blood Programs, regulate imported products,

contract fractionation local plant/joint venture –  Centralize hemophilia treatment –  Change cultures and not tests !!

•  Dr. Smeds (Sweden) –  New EMA guideline on EPI –  BE and PMF holder responsibilities on

•  Monitoring, reporting, setting alert limits and acceptability risk •  Trends and residual risk analysis •  Common alert limits so far not feasible

–  Harmonization with CoE !!!

Session 6 Plasma screening

•  Dr. Over (Netherlands) –  Probabilistic risk models of plasma products major advantages

•  comprehensive, fewer assumptions •  scientifically sound, avoids unrealistic outcomes •  insight in levels of uncertainty •  reveals most influential factors (sens analysis) •  predicts effect of additional measures (cost-effectiveness)

–  Donor incidence and process reduction factor highest impact –  Not all criteria defined yet (e.g. acceptable safety margin) –  Harmonization highly desirable –  A (generic) simplification of the probabilistic model is feasible –  Consensus on remaining assumptions needed –  Communications on simple stats to be developed

Session 7 Cost-effectiveness

•  Dr. Kleinman (Univ. British Columbia, Canada) –  Selective testing: example MP-> SD NAT, based on risk –  Frequent-infrequent donor

•  (harmonize with EU? repeat donor, regular donor) –  Will it reduce cost? (CEA?), it may increase safety? –  Large multi-centre study on SD NAT: standardization !! –  Many options to be analyzed, including CEA –  HBV difficult to model –  How to handle false negatives in the model

•  Dr. Custer (BSRI, USA) –  CEA means value for money ( € or $ ) –  HCV and HIV Ab screening = cost saving –  For children may interventions are cost-effective –  CEA or total cost / benefits? –  Multiplex NAT reduces cost and combines benefits –  ICER may not be appropriate model for blood safety –  But: what else?

Session 7 Cost-effectiveness

•  Mr. Hardiman (Ortho-Clinical Diagnostics, USA) –  Where and why do we invest? –  Heart break hotel or Babes’s bug? –  Emotions maybe more important than science –  The Chagas event –  Additional 20-30 $ per donation for selective testing?

•  (Sanquin estimate: deferred donor + 75 € ) –  There is emotion in the companies vision to Btx –  But ROI is leading

Of mice and men (and cheese) 1

•  Ideally pathogens are reduced (get the Golden Star if we can), •  In real life we see pathogen discovery….

–  potential interest No 1 = blood Txm agents –  Patient concern in the banner –  but priority order seems: B19/HAV > XMRV > Dengue in Brazil…..

•  Soft pathogen reduction + simple tests? Around 100 c/ml •  XMRV in 3,7% of donors, but not at ARC…. •  Macaques have it in their genito-urinary tract but MSM not…..

–  (screening diseases with a new test @ alpha = 0,05, will yield one in 20 chance of “associated” disease)

•  We need a (better) Malaria Ab test, –  so London can remain the Window to the Globe –  in high endemic countries consider recipient characteristics

•  We need a Babesiosis test •  We need tests also on small scale, if Germany can have in-house NAT why

can’t we? •  Mozzies need to be extinguished •  NLD Q fever transmissions @ every breath you take…..

Of mice and men (and cheese) 2

•  Now we use 3 screening tests for HBV but JPA says HBsAg is a good test •  Can we skip some serology? Beware of elite controllers…. •  Non-env viruses and plasma products: use a test or PR or both?

–  If important they will use both…. •  Nano tech not before 2020, No test for vCJD •  Regional self sufficiency – contract fractionation •  Beware of the EPI thing….(free after Dodd in 1996) •  Risk assessments to valuate testing strategies •  Over’s sight model, to Schreiber or to Weusten? •  For blood safety we do not look at the West but the North-East

–  Companies look at the South-West •  If they make it will we use it?

•  Emerging threat of retirement in

the USA

•  Emerging threat of retirement in

Bilthoven

•  (Q-area)