Presentation on theme: "Donor Derived Infectious Disease Risk Can we Learn Anything from the Blood Experience? Dr Patrick Coghlan National Transplantation Services Australian."— Presentation transcript:
Donor Derived Infectious Disease Risk Can we Learn Anything from the Blood Experience? Dr Patrick Coghlan National Transplantation Services Australian Red Cross Blood Services Melbourne Transplant Workshop POW Hospital 8 March 2010 We come in Peace! And It’s 25 years since we commenced HIV Ab screening of Blood!
All volunteer donors HBsAg test AIDS high-risk exclusions Anti-HIV test ALT/HBcAb tests Anti-HCV test Improved HCV tests 19651970197519801985199019952000 Year of Transfusion % Recipients Infected 25 20 15 10 5 0 NAT Implementation Tobler and Busch, Clin Chem 1997. Blood is much safer now, but is it safe enough? TGA Paradigm Shift ALARA ----- Precautionary principle principle “Zero Risk” Clinically significant viral infections by blood transfusion have been virtually eliminated by: Increasingly stringent donor eligibility criteria Increasingly sensitive/additional serological screening tests Nucleic acid amplification testing (NAT)
Safety Paradigms: Organs and Tissues vs Blood ParameterO&T DonorsBlood Donors TimelineRestrictive <12 -18 hrs24 – 48 hrs Medical & Social History 2 nd & 3 rd hand Poorly standardised Statutory declaration Standardised Screening paradigmSerology basedSerology + NAT NAT practice & capacity VariableStandard Policies & RegulationsIncomplete Immature GMP based Mature, Prescribed Biovigilance systemVoluntary, Jurisdictional No standardisation Jurisdictional Haemovigilance Public expectationRisk-benefit tradeoffs“Zero Risk” ProtectionsRisk ManagementLegislative
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.
Infectious disease testing of blood donations 0 5.4 9 22 Days HIV Infection ID NAT EP MP NAT EP Anti-HIV WP (PRISM) 0 4.9 5.4 66 Days HCV Infection Anti-HCV WP (PRISM) MP NAT EP ID NAT EP HBV 0 23.9 34.2 38.3 Days Infection ID NAT EP MP NAT EP HBsAg WP (PRISM) 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)] Every blood donation is screened for the presence of markers for infection with HIV, HCV, HBV and HTLV
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 Sanguinis 88 (2), 77-86.
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
Blood Safety Strategies Ab & Ag ChLIA (HIV & HCV Antigen) (US$20m/QALY) NAT (US$~2M/QALY) PatientsDonors------Donation Screening Selection * VI = Solvent Detergent/Inactine Methylene Blue UV/Psoralens Riboflavin Viral filtration haemovigilance Test System Optimisation Registration Supplier accreditation Supplier audit Assay evaluation/specification Batch release certification Pre-acceptance testing Automation Monitoring SPC EQAS Viral Inactivation* Fractionation 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 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 CMV Neg Leucodepletion Appropriate Use
Safety Strategies: Organ & Tissue Donation EIA Screening: Anti-HIV, anti-HCV, HBsAg, anti-HBc, anti-HTLV, anti-CMV, Syphilis Ab NAT (urgent - high risk) PatientsDonors------Donation History Physical exam Selection biovigilance Test System Optimisation Supplier accreditation Supplier audit Assay evaluation/specification Batch release certification Pre-acceptance testing Automation Monitoring SPC EQAS CMV neg; leucodepletion How can we calculate the risk if we don’t know the incidence of acute post-transplantation infection? 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
HIV prevalence in the population aged 15 – 49 years in selected countries * * * National Centre in HIV Epidemiology and Clinical Research: 2008 Prevalence High prevalence increases impact of test failure (or absence!) High prevalence leads to high testing loss
Diagnoses of HIV infection and AIDS in Australia Source: State and Territory health authorities - NCHECR
Newly acquired hepatitis B infection by year and age group Source: National Notifiable Diseases Surveillance System
Hepatitis C infection by year and age group Source: National Notifiable Diseases Surveillance System
Source: Collaboration of Australian Needle and Syringe Programs HIV and hepatitis C prevalence in needle and syringe programs by year and sex
HIV and hepatitis C prevalence 1 in blood donors by year 1 Prevalence per 100 000 donations Source: Australian Red Cross Blood Service
Characterising Assays Assay Result + - Presence of Disease + - True Positive (TP) False Negative (FN) False Positive (FP) True Negative (TN) + Predictive value TP/(TP+FP) - Predictive value TN/(TN+FN) Sensitivity TP/(TP+FN) Specificity TN/(TN+FP) Probability that test is negative in the absence of disease PJC 2000 Probability of a reactive sample being confirmed as positive.
PPV & NPV for test with 90% Sensitivity and Specificity Source: Alison Kesson 2009
How good are current tests? Current serological tests for HIV, HCV, HBV, HTLV, CMV are capable of detecting >99.9 % of infectious donations.
Prevalence Reduction 2000 – 2006 (ARCBS)* NumberDonor Prevalence Population Prevalence * Reduction Hepatitis C 81813 in 1x10 5 1-2 in 10 2 75-150 Hepatitis B 6059.6 in 1x10 5 5-10 in 10 3 50-100 HIV 182.9 in 1x10 6 1 in 10 3 350 HTLV 203.2 in 1x10 6 –– Reflects combined impact of education and selection Sourced from National Surveillance of Notifiable Infectious Diseases Reporting (Source: Polizzotto et al) *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
Organ Allocation Risk Management & Biovigilance Risk assessment and organ allocation RECIPIENT Pre-transplant diagnostic testing Pre-transplant sampling storage for later testing required Post-transplant diagnostic testing TRANS- PLANTATION Risk assessment and risk management Surveillance DONOR Prospective diagnostic testing Retrospective diagnostic testing Organ procurement Biobank Storage Serum Tissue DNA Prospective screening Source: W Rawlinson 2009
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
Universal Viral Screening Markers 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 Donors with identified risk factors MSM IV Drug Users Incarceration in previous 12 months Sexual partners of above Unexplained F o /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
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
HIV HBV HCV 1996199419921990198819861984 1:100 1:1000 1:10 000 1:100 000 1:1 000 000 1998 2000 Risk per unit 2002 Evolution of Approaches to Estimate Transfusion RisksJA-Jan03 Measured Risk: Prescreening donor prevalence PCR/culture studies Recipient SC studies Modeled Risk: I – WP Model < 1984 < 1984 Retrospective Cohorts: TTVS NIH TSS Source: Mike Busch
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
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 Incidence-Window Period Model Source: Seed et al ARCBS 2005
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 Incidence-Window Period Model Source: Seed et al ARCBS 2005 NAT (US$~2M/QALY)
Residual risk estimates for TTIs Agent & testWP d 2005-20062006-20072007-2008 HIV (NAT) 9 1 in 69,560,0001 in 35,256,0001 in 5,400,000 HCV (NAT) 5.4 1 in 12,215,0001 in 3,211,0001 in 2,700,000 HBV (HBsAg) 38 1 in 669,000 1 in 1,927,0001 in 739,000 HTLVI/II (Ab) 51 1 in 10,549,0001 in 14,728,0001 in 17,500,000 Source: ARCBS June 2009
Prevalence & Incidence of HIV, HCV, HBV and HTLV among Musculoskeletal Tissue Donors and First Time Blood Donors Yao et al. Annals Int Med 148,10; 793-5 NAT: Residual Risk* Reduction Sero.NATHIVWP RR 22 1:161,000 9 1:400,000 (1:5,400,000) HCVWP RR 66 1:55,000 7 1:500,000 (1:2,700,000) HBVWP RR 44 1:172,000 22 1:345,000 (1:739,000) * Estimated probability of viraemia in donor DDI Risk: Reg BD << FTBD << O&TD
Source: ANZOD Calman 1995 Minuscule Risk Massive Risk Neg Min VL One in 1 Million = Effective Zero HCV HIV HBV HTLV ? O&T General Anaesthesia Mistransfusion TRALI TA-GVHD Cardiac Metabolic risk in Neonates Under-transfusion Dzik 2003 CMV vCJD
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
Biovigilance (Donors – Processes – Recipients) 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 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 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