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Donor Derived Infectious Disease Risk Can we Learn Anything from the Blood Experience?

Donor Derived Infectious Disease Risk Can we Learn Anything from the Blood Experience?. We come in Peace! And It’s 25 years since we commenced HIV Ab screening of Blood!. Dr Patrick Coghlan National Transplantation Services Australian Red Cross Blood Services Melbourne

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Donor Derived Infectious Disease Risk Can we Learn Anything from the Blood Experience?

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  1. Donor Derived Infectious Disease Risk Can we Learn Anything from the Blood Experience? We come in Peace! And It’s 25 years since we commenced HIV Ab screening of Blood! Dr Patrick Coghlan National Transplantation Services Australian Red Cross Blood Services Melbourne Transplant Workshop POW Hospital 8 March 2010

  2. All volunteer donors HBsAg test 25 20 15 AIDS high-risk exclusions % Recipients Infected Anti-HIV test 10 ALT/HBcAb tests Anti-HCV test Improved HCV tests 5 NAT Implementation 0 1965 1970 1975 1980 1985 1990 1995 2000 Year of Transfusion TGA Blood is much safer now, but is it safe enough? Clinically significant viral infections by blood transfusion have been virtually eliminated by: Paradigm Shift ALARA ----- Precautionary principle principle “Zero Risk” • Increasingly stringent donor eligibility criteria • Increasingly sensitive/additional serological screening tests • Nucleic acid amplification testing (NAT) Tobler and Busch, Clin Chem 1997.

  3. (B/O/T) Donor Derived Viral Infections • HBV, HCV hepatitis, cirrhosis, HCC • HIV AIDS • HTLV Adult T-Cell Leukaemia, TSP/HAM • CMV CMV disease • EBV Inf. Mononucleosis, Lymphoma PTLPD • HHV8 Kaposi Sarcoma (immunocompromised) • Erythrovirus (Parvo) RBC aplasia • Dengue Dengue Fever • CHIKV Chikungunya Fever • WNV WNME • Lyssavirus Rabies • Arenavirus Lymphocytic Chorio-Meningitis Plasmodium Malaria Babesia Babesiosis Trypanosoma Chaga’s disease Leishmania Leishmaniasis Toxoplasma Toxoplasmosis Treponema Syphilis Borrelia Lyme Disease Mycobacteria TB TSEs CJD, vCJD,

  4. Safety Paradigms: Organs and Tissues vs Blood

  5. Sources of Residual Risk • Assay performance • Window period (>90% of risk) • time between exposure to an agent and detection with screening tests • Viral variants (strains, subtypes) not detected by current tests • Infectious chronic antibody negative carriers • Testing errors • (haemodilution) • (Feral organs & tissues) Busch MP. HIV and Blood Transfusions: Focus on Seroconversion. Vox Sang 67(S3):13-18, 1994.

  6. ID NAT EP MP NAT EP Anti-HIV WP (PRISM) Infection HIV 0 5.4 9 22 Days ID NAT EP Anti-HCV WP (PRISM) MP NAT EP Infection HCV 0 4.9 5.4 66 Days HBsAg WP (PRISM) ID NAT EP MP NAT EP Infection HBV 0 23.9 34.2 38.3 Days Infectious disease testing of blood donations Every blood donation is screened for the presence of markers for infection with HIV, HCV, HBV and HTLV • NAT assay yield over 10 years: • HIV-1: 3 HIV-1 yield cases (1 in 3.6 million donations) • HCV: 24 HCV yield cases (1 in 446,000 donations) • [HBV: 33 HBV yield cases (1 in 327,000 donations)]

  7. Hepatitis B NAT virus-positive blood donors in the early and late stages of HBV infection: analyses of the window period and kinetics of HBV DNA Yoshikawa et al Vox Sanguinis88 (2), 77-86 .

  8. Acute and chronic HBV infection • Most HBV infections in adults are acute infections which are “cleared”: HBsAg negative anti-HBc positive HBV DNA negative anti-HBs positive • HBV infections may become chronic (particularly in neonates): HBsAg positive anti-HBc positive HBV DNA positive anti-HBs negative • Occult HBV infection: HBsAg negative anti-HBc positive HBV DNA positive (low) anti-HBs negative or low

  9. Ab & Ag ChLIA (HIV & HCV Antigen) (US$20m/QALY) Selection NAT (US$~2M/QALY) Viral Inactivation* Screening Fractionation Donors------Donation Patients The transient increase in initial reactive rate (IR) and repeat reactive rate (RR) of a problematic HIV antibody assay. M J Nightingale et al. Transfusion Medicine, 17,404-412, 2007 haemovigilance Initial reactive rate (IR) and repeat reactive rate (RR) during the ‘settling in’ of an HIV Ab assay M J Nightingale et al. Transfusion Medicine, 17,404-412, 2007 Blood Safety Strategies CMV Neg Leucodepletion Appropriate Use • Test System Optimisation • Registration • Supplier accreditation • Supplier audit • Assay evaluation/specification • Batch release certification • Pre-acceptance testing • Automation • Monitoring SPC • EQAS * VI = Solvent Detergent/Inactine Methylene Blue UV/Psoralens Riboflavin Viral filtration

  10. EIA Screening: Anti-HIV, anti-HCV, HBsAg, anti-HBc, anti-HTLV, anti-CMV, Syphilis Ab Selection NAT (urgent - high risk) History Physical exam CMV neg; leucodepletion biovigilance Safety Strategies: Organ & Tissue Donation Epidemiology of Agents: • Prevalence • High prevalence increases impact of test failure (or absence!) • High prevalence leads to high testing loss • Incidence • High incidence impacts window period risk • Transmission routes • May permit risk-based intervention • Recipient status • Susceptibility, impact of infection Donors------Donation Patients • Test System Optimisation • Supplier accreditation • Supplier audit • Assay evaluation/specification • Batch release certification • Pre-acceptance testing • Automation • Monitoring SPC • EQAS How can we calculate the risk if we don’t know the incidence of acute post-transplantation infection?

  11. HIV prevalence in the population aged 15 – 49 years in selected countries • Prevalence • High prevalence increases impact of test failure (or absence!) • High prevalence leads to high testing loss * * * National Centre in HIV Epidemiology and Clinical Research: 2008

  12. Diagnoses of HIV infection and AIDS in Australia Source: State and Territory health authorities - NCHECR

  13. Newly acquired hepatitis B infection by year and age group Source: National Notifiable Diseases Surveillance System

  14. Hepatitis C infection by year and age group Source: National Notifiable Diseases Surveillance System

  15. HIV and hepatitis C prevalence in needle and syringe programs by year and sex Source: Collaboration of Australian Needle and Syringe Programs

  16. HIV and hepatitis C prevalence1in blood donors by year 1 Prevalence per 100 000 donations Source: Australian Red Cross Blood Service

  17. Presence of Disease - + + True Positive (TP) False Positive (FP) + Predictive value TP/(TP+FP) Assay Result - False Negative (FN) True Negative (TN) - Predictive value TN/(TN+FN) Specificity TN/(TN+FP) Sensitivity TP/(TP+FN) Characterising Assays Probability of a reactive sample being confirmed as positive. Probability that test is negative in the absence of disease PJC 2000

  18. Predictive Values

  19. PPV & NPV for test with 90% Sensitivity and Specificity Source: Alison Kesson 2009

  20. How good are current tests? • Current serological tests for HIV, HCV , HBV, HTLV, CMV are capable of detecting >99.9 % of infectious donations.

  21. Prevalence Reduction 2000 – 2006 (ARCBS)* *6.2 million allogeneic blood donations between July 2000 and June 2006 Tested for hepatitis C, hepatitis B, HIV, and HTLV I/II Donors with positive test results contacted for reassessment of risk factors and repeat testing (Source: Polizzotto et al)

  22. DONOR Organ procurement Prospective diagnostic testing Prospective screening Retrospective diagnostic testing • Biobank Storage • Serum • Tissue • DNA Risk assessment and risk management Risk assessment and organ allocation RECIPIENT Pre-transplant diagnostic testing Pre-transplant sampling storage for later testing required TRANS-PLANTATION Post-transplant diagnostic testing Surveillance Organ Allocation Risk Management & Biovigilance Source: W Rawlinson 2009

  23. NSW Health Policy – Organ Donation and Transplantation Managing Risks of transmission of HIV, HCV and HBV The objectives of this policy directive are to: • provide a process by which clinicians can identify organ donors who are at increased risk of HIV, HBV or HCV infection, • conduct appropriate and timely diagnostic testing, • provide a guide on consultation, where necessary, to identify circumstances where an organ that may be infectious may be transplanted and circumstances where transplantation is contraindicated and • provide guidance with respect to informed consent from recipients regarding the risk of HIV, HBV or HCV transmission from solid organ transplantation

  24. Serology: Anti-HIV-1/2 Anti-HCV Anti-HTLV-I/II HBsAg Anti- HBc Anti-HBs anti-EBV anti-CMV Syphilis antibody (TPHA ) NAT: HIV-1 RNA HCV RNA (HBV DNA) Prospective in “increased risk” Retrospective Universal Viral Screening Markers • Donors with identified risk factors • MSM • IV Drug Users • Incarceration in previous 12 months • Sexual partners of above • Unexplained Fo /weight loss/ LAD/cough etc • Partner with HIV/HBV/HCV • Prostitution • STD in past 12 months • Cosmetic body piercing/tattooing • (cocaine snorting) • “Physician concern” Source: NSW Health Policy – Organ Donation and Transplantation - Managing Risks of transmission of HIV, HCV and HBV

  25. Donor Risk Classification • HIV infection is an absolute contra-indication to organ donation • Potential donors known to have HBV and/or HCV infection • Exclude HIV/HBV/HCV co-infections with NAT • Potential donors with identified risk factors/behaviours • Normally require both serology and prospective NAT for assessment • If risk behaviours reliably determined > 6 months prior – serology alone • Potential donors whose infectious status cannot be reliably determined • Risk behaviours occurred in previous 2 months • Irrespective of negative serology or NAT suitable only for recipients requiring urgent heart, lung or liver transplantation • [Consider High Risk behaviour in last 2 weeks] • Should this be an absolute exclusion? • NAT results less reliable

  26. Evolution of Approaches to Estimate Transfusion Risks • Measured Risk: • Prescreening donor prevalence • PCR/culture studies • Recipient SC studies Retrospective Cohorts: TTVS NIH TSS Risk per unit 1:100 Modeled Risk: I – WP Model HIV 1:1000 HCV 1:10 000 HBV 1:100 000 1:1 000 000 2000 1998 1984 1986 1988 1990 1992 1994 1996 2002 < 1984 Source: Mike Busch JA-Jan03

  27. Viral transmission: Measuring risk • Classical approaches to measure risk (i.e. follow-up studies/missed infections in screened donors) - too few events • Risk estimates now use mathematical modelling yielding theoretical risk levels based on: • Frequency of marker-negative, window period donations • Rare transmission events (variants) • Antibody negative carriers • Procedural testing errors

  28. Incidence-Window Period Model • Assumes that Window Period transmissions represent the major component of the residual risk • Probably holds true for HIV and HCV, but less so for HBV where chronic infection can be marked by transient HBsAg detection • P =  x WP where P = probability donor gave infectious unit during window period,  = the incidence and WP = window period Source: Seed et al ARCBS 2005

  29. Incidence-Window Period Model P =  x WP where P = probability donor gave infectious unit during window period,  = the incidence and WP = window period For HIV NAT [ = 6 x 10-7 ; WP = 9 days (9/365) = 0.02465] P = 6 x 10-7 x 0.02465 = 1.479 x 10-7 or 1 in 6,759,259 NAT (US$~2M/QALY) Source: Seed et al ARCBS 2005

  30. Residual risk estimates for TTIs Source: ARCBS June 2009

  31. Prevalence & Incidence of HIV, HCV, HBV and HTLV among Musculoskeletal Tissue Donors and First Time Blood Donors DDI Risk: Reg BD << FTBD << O&TD Yao et al . Annals Int Med 148,10; 793-5 * Estimated probability of viraemia in donor

  32. Neg Min VL Massive Risk Minuscule Risk ? O&T HBV HIV ? O&T HCV ? O&T HTLV General Anaesthesia Mistransfusion TRALI TA-GVHD Cardiac Metabolic risk in Neonates Under-transfusion CMV vCJD One in 1 Million = Effective Zero Source: ANZOD Calman 1995 Dzik 2003

  33. Biovigilance: definition based on EU Blood Directive: 2002/98/EC “A set of organised surveillance procedures relating to serious adverse or unexpected events or reactions in donors or recipients, and the epidemiological follow-up of donors … intended to collect and assess information on the different activities in relation to the transplant, in order to continuously improve quality and safety of the processes, the organs/tissues/cells and the related services” Source: European Haemovigilance Network (EHN) Council of Europe Rec. No. R (95) 15

  34. Biovigilance (Donors – Processes – Recipients) The Challenge: - Political will to be “vigilant” - Appropriate legal framework(s) - National coverage - Operational framework defined (to all levels) - Comprehensive mandate (whole of sector) - Respective responsibilities defined - Centralised evaluation / analysis site established - Nationally coordinated action (corrective, preventive) - Adequate funding guaranteed Wide Spectrum of Biovigilance Systems • Haemovigilance to Tissue vigilance to Biovigilance (not Pharmacovigilance) • Mandatory or Voluntary or Mixed • Strictly centralised (national) to decentralised (jurisdictional or hospital) • All abnormal events to more restrictive serious events only • Run by National Authority, Public Health bureaucracy, Regulator, Professional Societies • Clinical and biological signs • immediate / acute reaction • delayed reaction • infectious transmission • allo-immmunisation • Others • Imputability– (possible) relationship between event / reaction and transplant grading (according to the following scale): 0 = none or excluded 1 = possible 2 = likely 3 = sure or certain (proven) • Severity – degree of the reaction / event grading (according to the following scale): 0 = no sign 1 = immediate signs without vital risk / resolution 2 = immediate signs with vital risk 3 = long term morbidity 4 = death Source: European Haemovigilance Network (EHN) Council of Europe Rec. No. R (95) 15

  35. Source: SHOT Annual Report 2008

  36. Decline in Mortality Definitely Related to Transfusion 1996 - 2008 Source: SHOT Annual Report 2008

  37. Acknowledgements ARCBS POWH UNOS • Clive Seed Bill Rawlinson Mike Ison • Angelo Margaritis • Phil Kiely • Tony Keller

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