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Alternatives for acute HIV testing: RNA, p24, heat dissociated p24

Alternatives for acute HIV testing: RNA, p24, heat dissociated p24. Christopher D. Pilcher, MD University of North Carolina at Chapel Hill Center for AIDS Research. Acknowledgements. NC DHHS Evelyn Foust J. Todd McPherson Rhonda Ashby Del Williams UNC-Chapel Hill Myron S. Cohen

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Alternatives for acute HIV testing: RNA, p24, heat dissociated p24

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  1. Alternatives for acute HIV testing: RNA, p24, heat dissociated p24 Christopher D. Pilcher, MD University of North Carolina at Chapel Hill Center for AIDS Research

  2. Acknowledgements NC DHHS Evelyn Foust J. Todd McPherson Rhonda Ashby Del Williams UNC-Chapel Hill Myron S. Cohen Peter A. Leone Irving F. Hoffman Susan A. Fiscus JoAnn Kuruc Lisa Hightow Matthew A. Price Joseph J. Eron, Jr William C. Miller Melissa Kerkau Priya Joshi Trang Q. Nguyen Kristen Hampton Marc Serre Paul Alabanza Amy James Brant Stalzer CIPRASUL-University of Caxias do Sul (UCS), Porto Alegre, Brazil Ricardo deSouza Emory University Frances Priddy Carlos del Rio The UNC Project- Lilongwe, Malawi Francis E.A. Martinson Peter N. Kazembe David Chilongozi Clement Mapanje Phyllita Kumwera Syze Gama Dave Namakwa NIMH , NIDDK, HPTN, UNC Fogarty Center, UNC STD CRC, UNC CFAR

  3. Testing to Identify Acute HIV • Acute HIV infections (first 2-3 months) are estimated to account for as much as half of all HIV transmission (Wawer JID in press) • They represent 0-10% of detectable infections presenting for HIV testing, depending on the population • Recognition of the acutely infected population creates opportunities for highly targeted treatment, prevention and surveillance activities • Diagnosis requires modification of “standard” treatment algorithms

  4. Ab testing up front—reflexed to NAAT if negative Ab screen + - Ab confirm - + NAAT screen + - Established HIV Positive HIV Indeterminate, Possible Acute HIV HIV Negative

  5. 2. Simultaneous acute and Ab screening—reflexed to Ab confirmation if positive NAAT or Ag and Ab screen - + Ab confirm - + Established HIV Positive HIV Indeterminate, Possible Acute HIV HIV Negative

  6. Testing to Identify Acute HIV Algorithms must include: • A screening assay for acute HIV infection • EARLY sensitivity for viral nucleic acid or proteins • High specificity to reduce “false alarms” • Screening and confirmatory testing for established HIV • LATER sensitivity will allow one to discern more acute infections from established infections

  7. The gold standard for acute screening: RNA group testing of Ab- specimensPilcher, CD et al. JAMA 2002;288:216-221 Individual specimens Pools of 10

  8. Pooling schema A B C D E F G H I J Individual specimens N=100 10 Pools of 10 A B C D E F G H I J

  9. 2-Stage Pooling A B C D E F G H I J Individual specimens N=100 10 Pools of 10 A B C D E F G H I J 1 Screening Pool

  10. Resolution Testing A Individual testing on 10 specimens 10 pools of 10 screened 20 Screening Pools Tested N=2000

  11. Vironostika 1st gen EIA WB NucliSens NAAT NC DHHS STAT Program:all publicly funded VCT in NC (N~120,000 per yr) 90:10:1 pooling + - Established HIV Positive + - HIV Indeterminate, Possible Acute HIV HIV Negative

  12. Vironostika 1st gen EIA WB STAT Confirmatory Testing + - NAAT Established HIV Positive + - F/U Testing (Ab+NAAT) + - HIV Negative Acute HIV

  13. Specimen Pooling/RNA Testing: NC’s STAT Program • Of 109,250 previously negative clients tested 11/02-10/03, 23/606 (4%) of HIV infections were acute • 16/23 (67%) acutes were identified in STD clinic testing sites • 1 pregnant female was identified • NAAT PPV 90%; Specificity >99.99%

  14. Pooling and NAAT:Logistical and Cost Issues • Ideally suited to high throughput, centralized testing • Most efficient at low prevalences of acute HIV • Turnaround time: 10-14 d • Cost reasonable • $3.63 per HIV test performed • $17,000 per acute index case identified

  15. Evaluating Alternative Algorithms • 3 studies conducted in high HIV incidence testing populations • RNA group testing as the gold standard • Evaluate different algorithms

  16. Vironostika 1st gen EIA WB STAT Testing + - NAAT Established HIV Positive + - F/U Testing (Ab+NAAT) + - HIV Negative Acute HIV

  17. Determine RT Unigold RT p24 vs. Up24 vs. NAAT:n=1440 STD clients in Lilongwe, Malawi + - or discordant NAAT p24 Up24 Established HIV Positive + - F/U Testing EIA/WB + - HIV Negative Acute HIV

  18. Lilongwe, Malawi; N=1,440 • Overall, 575 cases of HIV detected • 20 (3.5%) were WB-/indeterminate and seroconverted • 12/16 (75%) detected by standard p24 Ag • 16/19 (84%) detected by Up24 Ag • 20/20 (100%) detected by NAAT

  19. Performance of p24 and Up24?Fiscus, et al 12th CROI

  20. p24 and post-test probability: Malawi STD clinic 1 p24 Up24 0.9 Negative 0.8 0.7 0.6 Post-test Probability Expected post-test prob for p24+ (prev .023): 0.79 0.5 0.4 0.3 0.2 0.1 0 0.0226 0 0.005 0.01 0.015 0.03 0.035 0.04 Prevalence

  21. p24 and post-test probability: Urban US STD Clinic 1 p24 Up24 0.9 Negative 0.8 0.7 0.6 Post-test Probability 0.5 Expected post-test prob for p24+ (prev 0.001): 0.15 0.4 0.3 0.2 0.1 0 0.001 0.0226 0 0.01 0.015 0.03 0.035 0.04 Prevalence

  22. The 4th generation EIA vs. NAATN=933 VCT clients in Porto Alegre, Brazil Genscreen Biorad HIV Ag/Ab EIA + - Biomanguinhos IF Abbott MEIA - + NAAT + - + 183 ESTABLISHED HIV 97.3% all HIV+ 5 ACUTE HIV 2.7 % all HIV+ HIV Negative

  23. 4th generation EIA performance: preliminary observations • 5/5 (100%) acutes detected consistent with previous observations of p24 sensitivity • Specificity for acute HIV needs further evaluation

  24. Summary: p24 performance • Algorithms based on p24-based screening (std p24, Up24, 4th generation EIA) have adequate sensitivity and specificity for acute HIV screening in settings with ~1% or greater prevalence of acute HIV infection (e.g., African STD clinics) • However, the risk of false positives and costs of individual re-testing all Ab negative specimens may be unacceptable in most US routine testing populations

  25. Laboratory Detection of HIVfrom Pilcher CD, et al. JCI 2004 Symptoms (~60%) p24 Antigen HIV RNA HIV Ab Tests 1st generation (viral lysate) EIAs 01 2 3 4 5 6 7 8 9 10 Weeks Since Infection

  26. Laboratory Detection of HIVfrom Pilcher CD, et al. JCI 2004 3rd generation EIA, MEIA, rapid tests Symptoms (~60%) p24 Antigen HIV RNA HIV Ab Tests 1st generation (viral lysate) EIAs 01 2 3 4 5 6 7 8 9 10 Weeks Since Infection

  27. deSouza, et al unpublished N=933 VCT clients in Porto Alegre, Brazil Genscreen Biorad HIV Ag/Ab EIA + - Biomanguinhos IF Abbott MEIA - + NAAT + - + 183 ESTABLISHED HIV 97.3% all HIV+ 5 ACUTE HIV 2.7 % all HIV+ HIV Negative

  28. Priddy, et al. 12th CROIn=2,202 VCT and STD clients in Atlanta, GA Gen Systems HIV ½+O EIA WB + - or indeterm. NAAT + - F/U Testing EIA/WB + - HIV negative 68 ESTABLISHED HIV (1 false- rLAV assay) 95.8% all HIV+ 3 ACUTE HIV 4.2 % all HIV+

  29. Determine RT Unigold RT Fiscus, et al. 12th CROIn=1440 STD clients in Lilongwe, Malawi + - or discordant (n=22) NAAT + - F/U Testing EIA/WB + - 555 ESTABLISHED HIV (2 false – on RTs) 96.5% all HIV+ 20 ACUTE HIV 3.5% all HIV+ HIV Negative

  30. Rapid Test Sensitivity • In a Malawi STD clinic with a high ratio of incidence-to-prevalence, the sensitivity of rapid tests for HIV infection varied with their sensitivity for acute HIV • Determine: detected 559 of 575 (97.2%) • Unigold: detected 554 of 575 (96.3%) • Performance should be similar in a US STD clinic or MSM testing population • 6 (30%) of 20 WB -/indeterminate acute HIV infections were Determine+ but Unigold – • Choice of the rapid test, or series of rapid tests used, can significantly affect the ability to detect early infections

  31. Summary: Ab Screening Choices • Even maximum-sensitivity antibody tests will miss between 2-5% of detectable HIV infections in high risk testing populations • If acute screening is to be done, maximum early-sensitivity Ab tests are neither necessary nor desirable • If acute screening is not to be done, choice of Ab assay can significantly affect HIV detection in testing populations with high proportion of incident cases

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