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Micha Nübling Paul-Ehrlich-Institut

Yield obtained by mandatory HCV- and HIV1-NAT in Germany and break through infections – 1999 - 2007. Micha Nübling Paul-Ehrlich-Institut. NAT Background. All blood collection centers were contacted in regard to their testing experience 1999-2007 (questionnaire, 2008) 4,5 mio RBCs / year

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Micha Nübling Paul-Ehrlich-Institut

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  1. Yield obtained by mandatory HCV- and HIV1-NAT in Germany and break through infections – 1999 - 2007 Micha Nübling Paul-Ehrlich-Institut

  2. NAT Background • All blood collection centers were contacted in regard to their testing experience 1999-2007 (questionnaire, 2008) • 4,5 mio RBCs / year • German Red Cross 7 centers 75% • Hospital assoc. 75 centers 20% • Private 5 centers 5% • NAT-assays • CE marked screening NATs • CE marked diagnostic NATs validated for sensitivity etc • Validated in-house NATs

  3. NAT Background • Mandatory NATs for all blood / plasma donations • Definition of minimal NAT sensitivity limit (ID) • 01.04.1999 HCV-NAT 5.000 IU / ml ( = 20.000 cps / ml) • 01.05.2004 HIV1-NAT 10.000 IU / ml ( = 5.000 cps / ml)

  4. HCV-RNA doubling time 10,8 h 1,0E+10 1,0E+09 1,0E+08 1,0E+07 1,0E+06 HCV-RNA (copies / ml) 1,0E+05 1,0E+04 5.000 IU / ml 1,0E+03 1,0E+02 1,0E+01 1,0E+00 0 10 20 30 40 50 60 70 80 90 Days after infection HCV-infection antiHCV pos antiHCV negative phase Viremia during the "diagnostic window"HCV

  5. HCV

  6. NAT onlies: HCV 92 HCV-NAT onlies among 40.8 million donations (76 centers; 1999-2007) = 1 / 440 000 donations Nübling et al. (2009) Transfusion (in press)

  7. NAT onlies: HCV 92 HCV-NAT onlies = 1 / 440.000 donations „Higher incidence“ centers #47 6 / 202.435 donations = 1 / 33.700 #15 16 / 587.000 donations = 1 / 36.700 #08 9 / 427.000 donations = 1 / 47.400 „Lower incidence“ centers #30 4 / 4.415.033 donations = 1 / 1.100.000 #52 6 / 6.713.709 donations = 1 / 1.120.000 #23 0 / 903.948 donations= 0 / 903.948

  8. HCV genotypes in NAT Yield Cases 26 yield cases with HCV genotype data

  9. 5.000 IU / ml Viral Loads in HCV NAT Yield Cases 40 yield cases with viral load data 39 (99%) >> 5.000 IU/ml Nübling et al. (2009) Transfusion (in press)

  10. Transfusion-associated HCV transmissionsCases reported to PEI Introduction of NAT missed by AmpliScreen HCV / 24

  11. HCV transmission 01-2005 repeat donor: seroconversion (antiHCV, HCV-RNA) HCV genotype 2b look-back recipient(erythrocytes) HCV-pos HCV genotype 2b plasmastill available replicate testing (n=5) in all available NAT systems 10-2004 previous donation antiHCV (Ortho 3.0) neg HCV-RNA (AmpliScreen/24) neg

  12. HCV transmission HCV window phase, genotype 2b 95% LOD (WHO IS, gt1) pos results (ID)Screening CE-NATsCobas AmpliScreen HCV Test v 2.0 29 IU/ml1 / 5CAP Cobas TaqScreen 11 IU/ml5 / 5Procleix HIV-1/HCV Assay 2 IU/ml0 / 5Procleix Ultrio Assay 3 IU/ml 2 / 5Diagnostic CE-NATsCobas Amplicor HCV Test v 2.0 43 IU/ml 1 / 5HPS Cobas TaqMan HCV Test 15 IU/ml 3 / 5CAP Cobas Amplicor HCV Test v 2.0 11 IU/ml 3 / 5CAP Cobas TaqMan HCV Test 13 IU/ml 3 / 5Versant HCV RNA Qual 10 IU/ml 0 / 5Abbott RealTime HCV 11 IU/ml 4 / 5

  13. HIV

  14. HIV1-RNA doubling time 21,5 h 1,0E+10 1,0E+09 p24-positive 1,0E+08 1,0E+07 1,0E+06 HIV-RNA (copies / ml) 1,0E+05 1,0E+04 10.000 IU / ml 1,0E+03 1,0E+02 p24-negative 1,0E+01 1,0E+00 30 36 27 33 24 0 3 6 9 12 15 18 21 Days after infection HIV-infection antiHIV-negative phase antiHIV pos Viremia during the "diagnostic window"HIV-1

  15. NAT onlies: HIV 11 HIV-NAT onlies among 19 million donations (2004-2007) = 1 / 1 700 000 donations (17 HIV-NAT onlies from 1999 to 2007 = 1 / 2 400 000 donations) Introduction of HIV NAT Nübling et al. (2009) Transfusion (in press)

  16. 10,000 IU/ml Viral Loads in HIV NAT Yield Cases 11 yield cases with viral load data10 > 10 000 IU/ml Nübling et al. (2009) Transfusion (in press)

  17. Transfusion-associated HIV transmissionsCases reported to PEI Introduction of HIV NAT

  18. HIV transmission 04 - 2007 repeat donor: seroconversion (antiHIV1/2) HIV1 subtype B look-back recipient(erythrocytes) HIV1-seroconversion HIV1 subtype B, variant as in donor back-up sample 147 IU/ml ID CAP CTM HIV Ag/Ab test negative (Abbott) 01-2007 previous donation antiHIV1/2 neg HIV1-RNA (CAP CTM/96) neg

  19. HIV transmission 04 - 2007 repeat donor: seroconversion (antiHIV1/2) • quantitative HIV-NATs • screening HIV-NATs CAP CTM HIV (IU/ml) HPS CTM HIV (IU/ml) CAM HIV (IU/ml) Abbott RealTime HIV-1 (IU/ml) Procleix Ultrio Cobas AmpliScreen HIV (MP) Cobas TaqScreen neg neg <LLQ 924 pos (5/5) pos (2/2) pos 01 - 2007back-up sample 147 IU/ml ID (CAP CTM HIV) HIV Ag/Ab test negative (Abbott) recovered plasma into manufacturing pool: HIV1-RNA neg

  20. Sense primer CAP CTM HIV-1 Test (nt 1788 – nt 1819) CTM Primer:5´ AGT GGG GGG ACA TCA AGC AGC CAT GCA AA 3´ Donor:5´ AGT GGG GGG ACA TCA AGC AGC CAT GCA AA 3´ Probe CAP CTM HIV-1 Test(nt 1821 – nt 1856) CTM Probe:5´ TCT GCA GCT TCC TCA TTG ATG GT A TCT TTT AAC 3´ Donor:5´ TCT GCA GCT TCC TCA TTG ATG GT T TCT TTT AAC 3´ Antisense primer CAP CTM HIV-1 Test (nt 1921 – nt 1950) CTM Primer: 5´ G G T ACT AGT AGT TCC TGC TAT GTC ACT T CC 3´ Donor:5´ G T T ACT AGT AGT TCC TGC TAT GTC ACT A CC 3´ HIV-1 subtype B Transmission≈ 100 fold underdetection in routine NAT Schmidt et al. (2009) Transfusion (in press) Nübling et al. (2009) Transfusion (in press)

  21. Conclusions Challenges for Pathogen Testing Virus safety with routine measures high safety margins achieved testing experience limitations low virus level may be NAT neg vulnerability mismatches unpredictable sensitivity levels (HCV, HIV) appear asreasonable compromise for low incidence population

  22. NAT minimal sensitivity (D) IU HIV1-RNA/ml sample/cut-off HIV-NAT and HIV-Combo assay • Preseroconversion (antiHIV1/2 negative) follow-ups • Quantitative NAT (IU/ml) • Architect HIV Ag/Ab Combo (Abbott) (s/co)

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