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The biology of window period infections: implications for donor screening and inventory hold. Dr. Steven Kleinman FDA BPAC meeting September 21, 2001 . Sources of residual risk. Infectious, window period donations

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the biology of window period infections implications for donor screening and inventory hold

The biology of window period infections: implications for donor screening and inventory hold

Dr. Steven Kleinman

FDA BPAC meeting

September 21, 2001

sources of residual risk
Sources of residual risk
  • Infectious, window period donations
    • time between infectivity and detection with screening tests (may be different from time of exposure to an agent)
  • Viral variants (strains, subtypes) not detected by current tests
  • Infectious chronic antibody neg carriers
  • Errors (testing or product release)
events in early viral infection
Events in early viral infection

WP1

WP

2

Serological

Exposure

Infectivity

Detection

Eclipse

Viremia

stages of infectivity
Stages of Infectivity
  • Surrogate for infectivity is viremia detectable by NAT (PCR)
  • Can define four stages of viremia
    • Pre-ramp up
    • Ramp-up (exponential increase)
    • Plateau phase
    • Post-seroconversion phase
pre ramp up viremia
Pre-ramp-up Viremia
  • Low-level, intermittent “blips” detected prior to quantifiable ramp-up phase
  • Significance not yet understood
    • Inoculum vs focal replication that seeds dissemination vs abortive replication (transient w/o subsequent ramp-up/SC)
    • Is this viremia infectious?
immunosilent carriers chronic antibody negative carriers
Immunosilent carriers: chronic antibody negative carriers
  • Persistent viremia in absence of detectable seroconversion
    • Case reports for HIV, HCV, and HBV
    • Recipient infection via transfusion has been documented for HCV
    • Appears to be rare
estimates of false negative test error rates in routine donor screening
Estimates of false negative test error rates in routine donor screening
  • 1 of 2,015 (0.05%) confirmed seropositive donors tested negative (due to technical testing error) on a subsequent donation (Busch et al. Trans. 2000)
  • 3 of 2,307 (0.13%) HCV seropositive donations to ARC were originally missed and identified by retesting due to positive NAT results (none have subsequently been reported)
sources of window period data
Sources of window period data
  • Defined parenteral exposures (needlestick injury, transfusion)
  • Plasma seroconversion panels
    • Source of infection and date of exposure is unknown
    • Source is inferred to be IVD, sexual, or another (uncommon) mode
hiv needlestick exposure
HIV needlestick exposure
  • 95% of cases seroconverted within 6 months of exposure
  • The delayed seroconverters were viremic for only a short time prior to seroconversion
    • Infectivity may be confined to this short time interval
hiv markers during early infection

0

10

20

30

40

50

60

70

80

90

100

HIV markers during early infection

HCV RNA (plasma)

DT = 21.5 hrs

HIV Antibody

HIV p24 Ag

11

16

22

Theoretical Infectivity Day 0HIV RNA Day 11

HIV p24 Ag Day 16

HIV Antibody Day 22

5 Days

6 Days

time to detection of transfusion transmitted hcv infection n 28
Time to Detection of Transfusion-Transmitted HCV Infection (n=28)

Time toMean95% CI

RNA 12.6 1.5-23.7

ALT 51.5 18.5-84.5

EIA3.0 70.7 32.8-128.6

hcv markers during early infection
HCV markers during early infection

Plateau phase = 57 days

DT= 17.7 hrs

HCV RNA

Anti-HCV

12

0

10

20

30

40

50

60

70

80

90

100

Infection Day 0

HCV RNA Day 12

HCV Antibody Day 70

duration of viremic wps prior to sc detectable by md and id nat
Duration of Viremic WPs Prior to SC Detectable by MD and ID-NAT *

* Assumes sensitivity of ID NAT = 50 gEq / mL, and MP NAT = 1000 gEq / mL

** Does not include detection of intermittent, low-level viremic episodes

preceding ramp-up viremia

slide15

Testing Algorithm for HCV NAT-conversion Panels

Alpha Therapeutic / NGI screening

(Antibody & 512 Pool PCR)

63 HCV NAT-conversion Panels ( 774 Donations )

5 Control Panels ( 54 Donations )

dHCV TMA Testing

Intermittent Pre-Ramp-Up Viremia * in 25/41 (61%) panels >3 pre-r/u units

Ramp-Up & Plateau Phase

Quantitative Viral Load

( Roche Monitor )

Replicate dTMA ( x 3 ) &

NGI UltraQual PCR Testing

* Ramp-Up = consistent RNA detection with progressive increase in viral load.

low level intermittent hcv viremia preceding ramp up phase

NGI

512 PCR

x108

Neat PCR

x107

HCV Monitor PCR (gEq/mL)

% dTMA Positive (4 replicates)

100

x106

75

x105

50

x104

x103

25

x102

-60 -40 -20 0 10 20

Days Pre/Post 1st Quantitative RNA+ Donation

Low-Level Intermittent HCV ViremiaPreceding Ramp-Up Phase

Assay sensitivity (6 x 102)

(BCP ID 10083)

hcv pre ramp up viremia
HCV: Pre-ramp up viremia
  • Intermittent, low-level viremia preceded ramp-up phase viremia by up to 60 days
  • Statistical analysis of the duration of pre-ramp up viremia has not yet been performed
  • Significance for transmission by sexual route has not been determined
hbv markers during early infection

0

10

20

30

40

50

60

70

80

90

100

110

HBV markers during early infection

HBV DNA (PCR)

Anti-HBc

HBsAg

ALT

Infection

59

120

Infection Day 0

HBV DNA Variable, up to 31 days prior to HBsAg by ID NAT( 9-11 days by MP NAT)

HBsAg Day 59; disappears Day 120

window period viremia parameters derived from nat analysis of plasma donor panels
Window Period Viremia Parameters Derived from NAT Analysis of Plasma Donor Panels

* Based on follow-up of 30 plasma donors detected as MP-NAT-pos by Alpha and Bayer (95% CI 29-85 days)

hcv immunosilent carriers
HCV: immunosilent carriers
  • In over 2 years of NAT testing, ARC has identified 2 donors who were HCV RNA positive and did not develope HCV antibody in the subsequent 6 months
  • The denominator is over 12 million donations and an estimated 12,000 HCV antibody positive donations
slide21

ARC HCV NAT Reactive Donations Confirmed with Follow up Sample(s) N = 25

Seroreactive

Seronegative

Seroreactive, NAT Negative

Seronegative, NAT Negative

Number of Days

risk and risk reduction calculations
Risk and risk reduction calculations
  • Risk = Number of donors in infectious window period (Annual Incidence x WP as fraction of year) + Rate of silent carriers + Prevalence x Error rate
    • WP < 0.2 year for all viruses
  • Risk reduction = Annual Incidence x (reduction in WP) + Rate of silent carriers x (reduction factor) + Prevalence x (Reduction in error rate)
interventions to decrease risk compared to single sample serologic screening
Interventions to decrease risk compared to single sample serologic screening

Quarantine/ retestNAT

Window  

Silent carrier no effect 

Testing error  to 0  to 0

Quarantine risk reduction = Incidence x (95% to 100% reduction) + Silent carrier rate + Prevalence x (almost 100% reduction in error rate)