Donor Derived Infectious Disease Risk Can we Learn Anything from the Blood Experience?
Dr Patrick CoghlanNational Transplantation ServicesAustralian Red Cross Blood ServicesMelbourne
Transplant WorkshopPOW Hospital8 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 testALT/HBcAb tests
Anti-HCV test
Improved HCV tests
1965 1970 1975 1980 1985 1990 1995 2000
Year of Transfusion
% R
ecip
ien
ts I
nfe
cte
d
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)
(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
PlasmodiumPlasmodium MalariaMalariaBabesiaBabesia BabesiosisBabesiosisTrypanosomaTrypanosoma Chaga’s diseaseChaga’s diseaseLeishmaniaLeishmania LeishmaniasisLeishmaniasisToxoplasmaToxoplasma ToxoplasmosisToxoplasmosisTreponemaTreponema SyphilisSyphilisBorreliaBorrelia Lyme DiseaseLyme DiseaseMycobacteriaMycobacteria TBTBTSEsTSEs CJD, vCJD,CJD, vCJD,
Safety Paradigms: Organs and Tissues vs Blood
Parameter O&T Donors Blood Donors
Timeline Restrictive <12 -18 hrs 24 – 48 hrs
Medical & Social History
2nd & 3rd hand
Poorly standardised
Statutory declaration
Standardised
Screening paradigm Serology based Serology + NAT
NAT practice & capacity
Variable Standard
Policies & Regulations Incomplete
Immature
GMP based
Mature, Prescribed
Biovigilance system Voluntary, Jurisdictional
No standardisation
Jurisdictional Haemovigilance
Public expectation Risk-benefit tradeoffs “Zero Risk”
Protections Risk Management Legislative
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 NATEP
MP NATEP
Anti-HIV WP (PRISM)
0 4.9 5.4 66 Days
HCV
Infection
Anti-HCV WP
(PRISM)
MP NATEP
ID NATEP
HBV 0 23.9 34.2 38.3 Days
InfectionID NAT
EPMP NAT
EPHBsAg 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 StrategiesAb & Ag ChLIA
(HIV & HCV Antigen) (US$20m/QALY)NAT (US$~2M/QALY)
PatientsDonors------Donation
Screening
Selection
* VI = Solvent Detergent/Inactine Methylene Blue UV/Psoralens
RiboflavinViral filtration
haemovigilanceTest 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 assayM J Nightingale et al. Transfusion Medicine, 17,404-412, 2007
CMV NegLeucodepletionAppropriate 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
HistoryPhysical exam
Selection
biovigilanceTest 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 prevalence1 in blood donors by year
1 Prevalence per 100 000 donationsSource: Australian Red Cross Blood Service
Characterising Assays
AssayResult
+
-
Presence of Disease
+ -True Positive
(TP)
False Negative(FN)
False Positive(FP)
True Negative(TN)
+ Predictive valueTP/(TP+FP)
- Predictive valueTN/(TN+FN)
SensitivityTP/(TP+FN)
SpecificityTN/(TN+FP)
Probability that test is negative in the absence
of diseasePJC 2000
Probability of a reactive sample being confirmed as positive.
Predictive Values
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)*
Number Donor PrevalencePopulation Prevalence* Reduction
Hepatitis C 818 13 in 1x105 1-2 in 102 75-150
Hepatitis B 605 9.6 in 1x105 5-10 in 103 50-100
HIV 18 2.9 in 1x106 1 in 103 350
HTLV 20 3.2 in 1x106 – –
Reflects combined impact of education and selectionSourced from National Surveillance of Notifiable Infectious Diseases Reporting
(Source: Polizzotto et al)
*6.2 million allogeneic blood donations between July 2000 and June 2006Tested for hepatitis C, hepatitis B, HIV, and HTLV I/IIDonors 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 StorageSerumTissueDNA
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 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
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
HIVHIV
HBVHBV
HCVHCV
19961996199419941992199219901990198819881986198619841984
1:1001:100
1:10001:1000
1:10 0001:10 000
1:100 0001:100 000
1:1 000 0001:1 000 000
19981998 20002000
Risk Risk per unitper unit
20022002
Evolution of Approaches to Estimate Transfusion Risks
JA-Jan03JA-Jan03
Measured Risk:
•Prescreening donor prevalence
•PCR/culture studies
•Recipient SC studies
Modeled Risk: I – WP Model
< 1984< 1984
RetrospectiveCohorts:TTVSNIHTSS
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 WPwhere 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 WPwhere 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 & test WP
d
2005-2006 2006-2007 2007-2008
HIV
(NAT)
9 1 in 69,560,000 1 in 35,256,000 1 in 5,400,000
HCV
(NAT)
5.4 1 in 12,215,000 1 in 3,211,000 1 in 2,700,000
HBV
(HBsAg)
38 1 in
669,000
1 in 1,927,000 1 in
739,000
HTLVI/II
(Ab)
51 1 in 10,549,000 1 in 14,728,000 1 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. NAT
HIV WP
RR
22
1:161,000
9
1:400,000
(1:5,400,000)
HCV WP
RR
66
1:55,000
7
1:500,000
(1:2,700,000)
HBV WP
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
1 in 11 in 10
1 in 100
1 in 1,000
1 in 10,000
1 in 100,000
1 in 1 million
1 in 10 million
1 in 100 million
1 in 1billion
1 in 1trillion
1 in 10billion
1 in 100billion
-6 -5 -4 -3 -2 -1 0 +1 +2 +3 +4 +5 +6
Pat’s Take Home: Current estimates of risk
The Paling Perspective Scale © John Paling
Blajchman - 2002 Calman 1995
MinusculeRisk
MassiveRisk
Neg Min VL
One in 1 Million = Effective Zero
HCV
HIV
HBV
HTLV
? O&T
? O&T
? O&T
General Anaesthesia
Mistransfusion
TRALI
TA-GVHD
Cardiac
Metabolic risk in NeonatesUnder-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 transplantgrading (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
Annual Reports to SHOT 1996 - 2008
0
200
400
600
800
1000
1200
No
. of
rep
ort
s
Source: SHOT Annual Report 2008
Source: SHOT Annual Report 2008
Decline in Mortality Definitely Related to Transfusion 1996 - 2008
Acknowledgements
ARCBS POWH UNOS
Clive Seed Bill Rawlinson Mike Ison
Angelo Margaritis
Phil Kiely
Tony Keller