Infectivity based risk modeling

1
Infectivity based risk modeling
Nico Lelie
Chiron, France
2
1133 dilution iatrogen serum (CF titre 11280)
in 130L plasma pool (CF titre110)
LF Barker and R Murray AJMS, 1972 26327-33
10 geq?
2/5(40)
3/5(60)
2/5(40)
104 geq?
1/5(20)
3/5(60)
2/5(20)
3/5(60)
22/37(59)
25/37(68)
3
HBV Analytical Standards
Analytical standards Relation IU to genome
equivalents and infectious dose
HBV (NAT)
HBsAg
1 IU 7,5 geq1 5 cps2
1VQC standard, 2 Bayer Versant bDNA3.0
1 CID50 10 geq3
3Yoshizawa et al
1 IU 0,5 ng (PEI) 1,9 ng
(AFSSAPS)
Pictures Prof. Gerlich
4
Increase of virus concentration (C) in early ramp
up phase of window
Early viral dynamics
geq/ml
CCo 2t/l
l 0.45 days
.
.
.
l 0.85 days
l 2.56 days
days
doubling times Glynn et al, Transfusion,
200545994, Fiebig et al, AIDS 2003171871
Biswas et al,
Transfusion 2003,43788
5
HIV window phase
Probability of HIV-RNA detection during onset
viraemia
4 days
MP-TMA (116)
ID-TMA
delta days
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Mathematical model
Probability non RNA/DNA detection during window
phase (Weusten et al, Transfusion 2002, 42, 537)
100 copies
1 copy
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Viral load and infectivity
Relation between viral nucleic acid concentration
and infectivity titre

• Virus plasma source immune genomes per
  ref.
• complex infectious dosea
• HBV chronic carrier -
  10-100 1,2,8
• HCV acute phase,H-strain -
  10-100 3,4,7
• chronic phase gt1000 3
• F-strain gt10000 4
• HIV window - 1000-100000
  5,6
• infectious dose HBV CID50 , HCV CID50,, HIV
  1 CID50 1-10 TCID50
• References
• Berninger et al, J. Med. Virol. (1982) 957-68
• Ulrich et al J Infect Dis. (1989) 160 37-43
• Hijikata et al. J. Virol. (1993) 671953
• Alter et al. J. Viral Hep. (1995) 2121-132
• Piatak et al, Science (1993) 2591749-1754
• Prince et al. PNAS (1988) 856944-6948
• Katayma K. Intervirology 20044757-64
• Yoshizawa et al, to be published

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HIV transmission cases by transfusion after
introduction mini-pool NAT
HIV MP NAT breakthrough
Study Country Blood product load cps/ml geq transfused1 Trans mission
Delwart et al, Vox Sang 2004, 86,171-177 USA RC 180 5000 yes
Ling et al, JAMA 2000 284210-214 Singapore RC 5-391 3000 yes
SANBS, to be published South Africa RC/PC 145 5000 no/yes
Zanetti, personal communication Italy RC 80 2500 no

• Assuming 30 ml plasma in red cell concentrate
• 120 geq/ml in limiting dilution analysis with VQC
  genotype E standard.

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Proportion of HIV-RNA positives in dilutions of
differential infectious window phase plasma
(South Africa)
borderline infectious HIV
Window plasma2 Ampliscreen pos (n 3) Ultrio pos (n 24)
neat 100 100
12 100
14 100 100
16 67
18 66,7
116 0 33,3
124 33
132 20,8
164 16,7
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HIV production of defective virus?
HIV infectivity
cell
capsid
virus
RNA
11
Probability of infection in window
HIV infection risk
risk
HBV
100
HIV
HCV
50

geq/ml
10
100
1000
Probability of infection HCV / HBV
Probability of infection HIV
12
Residual HIV window phase risk days
15 days
7 days
9 days
5,6 days
1 copy/20 ml day 0
ID-NAT day 5,6
MP-NAT day 9
p24 Ag day 15
Anti-HIV day 22
Busch et al, Transfusion 200545254
3,2 risk days

6,5 risk days
0,2 risk days
7 days
Anti-HIV day 22
p24 Ag day 15
MP-NAT day 9
ID-NAT day 5,6
1 copy/20 ml day 0
Weusten et al, Transfusion 200242537
13
Residual window phase risk days of viral
transmission by NAT screened red cell
transfusions based on mathematical model
Weusten et al (Transfusion 2002, 42, 537) on
PeliCheck analytical sensitivity data in geq/ml
published by Koppelman et al, Transfusion
2005451258-66 and Vox Sang 200589 193-200
20 ml plasma in red cell concentrate
ID-NAT risk reduction
Pool Size HBV HCV HIV
500 ul Ultio neat 15,3 1,4 0,2
1 ml Ampliprep Ampliscreen minipools 124 23,1 4,5 3,2
No NAT, only serology 30,51 58,33 16,7 (6,5)2
40 x
2 x
80 x
1) based on HBsAg sensitivity of 2000 geg/ml 2)
based on anti-HIV screening 22 days, based on
HIV-Ag testing with 10.000 geq/ml sensitivity 6,5
days 3) Based on anti-HCV screening
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Infectivity of blood
serology
antigen
antibody
NAT
infectivity
T 0
high
medium
low
neutralized
low
eclipse
relative concentration
antibody
virus
antigen detection limit
infectivity threshold
NAT detection limit
infectivity threshold
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Diagnostic Sensitivity Tigris and PRISM in
312,033 donations in RSA
HIV yield in RSA
Ultrio/dHIV reactive
non specific? non infectious?
infectious window phase
PRISM anti-HIV reactive
311,702
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Infectivity based risk modeling with ID-NAT(red
cell transfusions)
ID-NAT risk reduction

• rest infectious window period
• HIV 0-0,5 days
• HCV 1-2 days
• HBV 1-2 weeks
• window phase risk reduction factor to serology
• HBV 2 x
• HCV 40 x
• HIV 80 x
• significant risk reduction occult HBV
  transmission
• infectivity ID-NAT negative serology yield
  questionable
• ID-NAT negative low infectious transfusions may
  not have clinical consequences