Donor Derived Infectious Disease Risk Can we Learn Anything from the Blood Experience? Dr Patrick Coghlan National Transplantation Services Australian.

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