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Susan L. Stramer, PhD American Red Cross BPAC Aug 2, 2011

T. cruzi Incidence Study in Blood Donors and its Implications for Selective Testing: Study Results. Susan L. Stramer, PhD American Red Cross BPAC Aug 2, 2011. Acknowledgements. ARC Rebecca Townsend Ed Notari Roger Dodd Jaye Brodsky Community Blood Centers of FL Bruce Lenes

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Susan L. Stramer, PhD American Red Cross BPAC Aug 2, 2011

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  1. T. cruzi Incidence Study in Blood Donors and its Implications for Selective Testing: Study Results Susan L. Stramer, PhD American Red Cross BPAC Aug 2, 2011

  2. Acknowledgements • ARC • Rebecca Townsend • Ed Notari • Roger Dodd • Jaye Brodsky • Community Blood Centers of FL • Bruce Lenes • Sharon Edie • Angelica Lynn • BSI • Brian Custer • Hany Kamel • Mike Busch

  3. Major Points No observed incidence Observe low level reactivity False positivity Remote prior infections < 1% observed rate of transfusion transmissions Retesting policy adds no value Complex and resource intensive

  4. The Ortho T. cruzi EIA (Ab) is used for donor screening ARC and BSI implemented “universal testing” Jan 29, 2007 Repeat reactive (RR) donations are further tested using a laboratory-derived test (LDT) RIPA (Quest Diagnostics) RIPA-pos donors are considered confirmed whether at index, repeat of independent index sample or at donor follow-up Donors of RR donations are followed and tested by EIA/RIPA RIPA pos donors also tested by parasitologic tests Hemoculture (HC) and PCR RR donors are also asked to respond to a detailed survey regarding demographics and risk factors True pos “cases” and false pos “controls” Background

  5. Retest Algorithm for T. cruzi Ab RR (Ortho EIA) Donors Independent Index or Donor follow-up (F/U) samples PRISM added to algorithm following licensure (April 2010)

  6. Due to low rate of transfusion transmission identified by lookback, and donor risk being remote (22-mo experience), selective T. cruzi Ab testing implemented by all ARC and BSI regions except those included in the “Incidence Study” 8/10/09 ARC 4/1/10 BSI 1X nonreactive test result qualifies the donor for all future donations Regions having the highest prevalence in the Southwestern and South Central portion of the US (5-fold above “system”) remained on universal testing to represent “endemic travel” and “autochthonous” risk Assumption was that the highest prevalence sites would provide the greatest chance of observing donor incidence (if it were to occur) 3 ARC = S CA (Los Angeles; 006), OK/TX (049) and AR (055) Community Blood Centers of FL (S FL) Central Coast UBS (CA) Background

  7. Continue universal testing for 5 years to extend the timeframes for detection of incident infection in repeat donors in regions with presumed increased travel to endemic areas and those with the greatest likelihood of autochthonous infection 5 million person years (pys) total Donor observation period target a mean of 1.9 years (from first to last donation) Incident case = seroconverter Screen RR and RIPA pos with a prior donation having a low signal (S/CO < 0.5) and who has serologic progression on follow-up on EIA (S/CO > 2.0) while remaining RIPA pos; donor may be HC/PCR pos Incidence Study Protocol

  8. Accumulate ~ 5 million pys of observation in high prevalence areas We chose 4 as the number of incident donors that would be acceptable during a 5-year study as comparable to other TTD residual risks ~ 1 incident case per million pys The upper 95% CI for a value of 4 is ~ 10 Upper CI of 10 per 5 million pys translates to 2 per million pys Add 20% for risk in remainder of US (5-fold lower) Criterion established for study: upper limit of acceptable risk = 2.4 cases per million pys Incidence Study Outcome

  9. Study completed after 48 months 1/29/07-1/31/11 54 months in one region, Los Angeles included in the IND prior to test kit licensure No incident/seroconverting donors were identified Incidence Study Completion

  10. Red Cross Biomedical Services 35 Regions collecting in 43 states and Puerto Rico 7 Divisions 5 National Testing Laboratories 10

  11. Blood Systems Collections Areas 3 CTS laboratories 13 main regional areas collecting in UBS/BCP centers located in 18 states

  12. Cumulative Universal Testing T. cruzi Reactive Donors by State of Residence (01/29/07 – 01/31/11) 48 months 3 1179 1 2 5 5 5 116 1 5 1 5 17 4 DC 6 17 1 5 1 7 22 2 15 69 1 11 488 4 5 22 5 7 4 15 21 3 PR 14 2 5 8 28.8 million donations screened 0.014% RR rate RR from 48 states (-DE, HI) RIPA pos (30%) from 40 states (+PR, DC) 66% from FL and CA (1:5100-1:6800) Overall: 1:24,200 8 48 233

  13. T. cruzi Seroprevalence – Universal + Selective 48 months

  14. Combined Lookback Experience * 1 El Salvadoran recipient rec’d random donor platelets from a Brazilian donor; both donor/recipient PCR/HC (-); likely preexisting Ab in recipient **2 apheresis platelet recipients (no other risk factors) from 2 difft dtns from an Argentine donor; both donor/recipient PCR/HC (+)

  15. Risk of transfusion transmission in the US as determined by tracing prior donations from RIPA-positive donors since the initiation of widespread T. cruzi Ab testing using FDA licensed screening assays and contemporary methods of component manufacture/transfusion practice is < 1% Combined Lookback Experience

  16. When does transfusion transmission occur; US/Canada

  17. 3 2 1 0 0 20 40 60 80 100 120 140 160 Course of Infection in Platelet Recipient Leiby et al, NEJM, 1999; 341(16):1237-1239 Signal/Cutoff (s/co) PCR & HC positive Days Post-transfusion

  18. All donors with > 2 T. cruzi Ab screened donations selected during 48 months (54 months Los Angeles) Time from first => last donation for each donor calculated (observation period); expressed as pys Calculated pys separately for each analysis Mean observation period Total observation period Graphs used person months to show groups of donors within specific observation times Incidence and Exact binary upper and lower 95% confidence limits (UCL, LCL) calculated Person-Time (Donor Observation Period) Calculations

  19. Incidence Study Outcomes

  20. Graph_Chagas_Travel_Both

  21. Graph_Chagas_Autoch_Both

  22. Graph_Chagas_ALL_Both ----Selective testing----

  23. Graph_Chagas_ALL_APH_Both ----Selective testing----

  24. 22 donors identified with nonreactive Ab tests who on subsequent donation at 41-532 days were found to be RR and RIPA pos (index, repeat independent sample or follow-up) 21 based on Ortho EIA testing 1 based on Abbott PRISM clinical trial Reactivity was inconsistent and none of these donors met the definition of an incident/ seroconverting donor Possible Seroconverters Identified During Universal Testing

  25. 3 2 1 0 0 20 40 60 80 100 120 140 160 Course of Infection in Platelet Recipient Leiby et al, NEJM, 1999; 341(16):1237-1239 Signal/Cutoff (s/co) PCR & HC positive Days Post-transfusion

  26. Possible Seroconverters Identified During Universal Testing (to 8/9/09) N=18; 13/13 PCR and 14/14 HC Negative S/CO Days

  27. Possible Seroconverters Identified by Sites Remaining on Universal Testing (from 8/10/09) N=4; 2/2 PCR and HC Negative S/CO Days

  28. Possible Seroconverter Cases N=18 (1/29/07-8/9/09) * Denotes average of 3 S/CO values Yellow highlighted S/CO = 20% elevated negative Chagas Clinical Trial sample with RR PRISM at Index

  29. Possible Seroconverter Cases N=4 (8/10/09-1/31/11)3 regions and CBCF that continued with Universal Testing Of 18+4: 3 “yes” responses on risk questions; all followed with no seroconversion 006LH19583 born and lived in Mexico 39 yrs 006GX87964 Hispanic, born in US W036809203439 born and lived in Venezuela for 10 yrs * Denotes average of 3 S/CO values Yellow highlighted S/CO = 20% elevated negative

  30. T. cruzi antibody reactivityPheresis donor 006KP44769 Follow-up collected 298 days post index RR/RIPA pos donation and retesting of regional retention sample S/CO Assay cutoff 18 prior nonreactive donations Date

  31. US-Derived T. cruzi Study (USTC) 54 eligible RR/RIPA Pos donors (48 ARC and 8 UBS); 37 enrolled 15 Defined as Concordant (CG)/22 Discordant (DG) Vector and reservoir N=28 and N=17 Vector only PR

  32. Possible Seroconverter Cases N=18 (1/29/07-8/9/09) enrolled in USTC Yellow highlighted S/CO = 20% elevated negative Chagas Clinical Trial sample with RR PRISM at Index

  33. USTC Testing Results for the Discordant Group (DG); N=22

  34. Rate of Possible Seroconverters: Universal Testing ARC + CBCF * NS; p = 0.10 Chi square and Exact measures mid-P (2-tail)

  35. Donor follow-up of 3 donor populations derived from 246 RR/RIPA Pos ARC donors enrolled in follow-up during 48 months (651 total RIPA pos) N=174 Consistent RR/RIPA Pos N=57 Inconsistent RR/RIPA Pos Index Ortho EIA RR; RIPA pos index or follow up N=22 Possible Seroconverters with 16 donors followed (15 Ortho EIA/1 Abbott PRISM triggered) Demographic analysis of 3 populations Analysis of Ortho EIA cutoff values for 3 populations Relationship of Ab S/CO values with PCR positivity Higher S/CO values correlate with PCR positivity Assay VariabilityBiologic (test component or other agent, remote prior infection)/Analytic (cutoff)

  36. Distribution of T. cruzi RIPA-Positive Donation S/CO Values ARC Donors Participating in Follow-up (n=246)Mean Ortho EIA Test-of-Record Results Mean follow-up 76 days (2 - 1083) Number of Donors Mean follow-up 94 days (23 - 347) Mean follow-up 77 days (18 - 277) S/CO Value

  37. Distribution of T. cruzi RIPA-Positive Donation S/CO Values ARC Donors Participating in Follow-upMean Ortho EIA Test-of-Record Results 4.79 Jaye’s Box and Whisker graph 1.39 1.17 *p < 0.0001 Wilcoxon Rank Sums N = 174* N = 15 N = 57 % PCR + 30 4 0 HC + 8 0 0

  38. Risk Factors/Demographics: RIPA-Pos Donors – 48 months Chi-square with Yates correction; *p<0.01;***p < 0.0001;3 “yes” no seroconversion

  39. Ortho Assay Variability as defined by the Cutoff Cutoff = PC mean [0.425]; PC range = OD ≥ 0.300, ≤ 1.800 Acceptable Cutoff Range: 0.1275 – 0.705

  40. T. cruzi Ab reactivity (EIA) correlates with PCR positivity among seroreactive donors in Brazil, Honduras, USSabino et al., accepted 2011 AABB Annual Mtg p<0.005 p<0.001 p<0.0001 6.57 6.33 5.78 5.50 4.27 3.56 N= 45 40 9 19 16 81

  41. 2005 donor cohort (~2.7 million donors) followed from first to last donation 9-year donation data to model retest volume (~60 million donations) for a 2- or 5-year retest policy Impact of Retesting after 2 or 5 Years

  42. All donors with an initial donation in CY2005 who had subsequent donations through CY2010 included Time from first => last donation calculated Plotted the number of donors within the 2005 cohort (2,678,057) who continued to donate (i.e., not yet had their last donation within the study period) Determination of Repeat Donation Patterns for ARC Donors in CY2005

  43. 36,688,648 Untested donations 15,850,682 1st Test donations 7,135,528 Retest donations

  44. 41,773,568 Untested donations 15,850,682 1st Test donations 2,050,608 Retest donations

  45. Ongoing 1-time testing to qualify a donor for repeat donation is “safe” as evidenced by: Zero observed incidence in the 4-year “Incidence Study” 6 million plus pys of observation 4.22 million donors (mean obs time = 1.435 pys) Upper 95% confidence value (0.61/million pys) yielded risk of incidence lower than that of other current infectious diseases < 1% obs’d occurrence of transfusion transmission Risk greatest in donors with high S/CO values, consistently RIPA pos and PCR/HC pos Low frequency of donors identified during universal testing from ARC + CBCF with inconsistent reactivity who were not seroconverters 22/~19 million donations or 1/900,000 Biologic and analytic false positives, remote prior infection? Summary

  46. Retesting test-negative donors after 2 or 5 years adds no value relative to the low (no) risk of incidence and infrequent occurrence of transfusion transmission Implementation of such systems would be a burden to blood centers requiring significant resources Anywhere from 500,000 to 1 million additional tests per year for the ARC; 2x for the US Competes/may prevent the implementation of other other safety initiatives e.g., Babesia Summary

  47. A selective testing strategy based on qualifying a donor by a single negative donation has high sensitivity and has significantly reduced the amount of testing required without compromising recipient safety Conclusion

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