1. Acute HIV Infection: New Frontiers for HIV Prevention
Antonio E. Urbina, MD
Medical Director HIV Education and Training
St. Vincent Catholic Medical Center-Manhattan
May 17, 2006
St. Vincent Catholic Medical Center is a
Local Performance Site of the NY/NJ AETC

2. Lifetime Cost of HIV Care in the US in the Current Treatment Era
$500,000
B R Schackman, et al Abstract, 3rd IAS Conference

3. Since 1999, HIV infections have remained steady at 40-45,000/year
HIV Incidence
Since 1999, HIV infections have remained steady at 40-45,000/year
CDC HIV/AIDS Surveillance Report

4. 12% of US population
CDC HIV/AIDS Surveillance Report 2003

7. Prevention vs. Treatment
Structure of US health system favors treatment over prevention
Access to healthcare is tied to labor market and not citizenship
Our for-profit health system favors treatment over prevention
More profits are generated when people are ill as opposed to when they are well

8. Improve HIV Detection Normalize HIV Testing
outpatient and inpatient settings
Increase detection of persons in acute HIV infection (AHI)
Use pooled plasma viral load testing (PPLVT) in high risk settings, i.e. STD clinics

9. The arrows indicate the path of the virus
The arrows indicate the path of the virus. The viral-envelope protein binds to the CD4 molecule on dendritic cells. Entry into
the cells requires the presence of CCR5, a surface chemokine receptor. Dendritic cells, which express the viral coreceptors
CD4 and CCR5, are selectively infected by R5 (macrophagetropic) strains. 8
Within two days after mucosal exposure, virus
can be detected in lymph nodes. Within another three days, it
Leone P UNC

10. Primary HIV-1 Infection Acute + Recent (4-6 months)
1000
800
600
400
200
Early Opportunistic Infections
CD4 Cells +
Late Opportunistic Infections 1 2 3 4 5 6 7 8 9 10 11 12 13 14
Infection
Time in Years
Leone P UNC

11. Schacker, T. et. al. Ann Intern Med 1996;125:257-264
Days from sexual exposure to onset of symptoms in 12 patients who could identify the exact date and time of the sexual exposure that led to acquisition of human immunodeficiency virus
Schacker, T. et. al. Ann Intern Med 1996;125:

12. Detection of HIV by Diagnostic Tests
Symptoms
p24 Antigen
HIV RNA
HIV EIA*
Western blot
The presence of HIV can be detected using tests that detect HIV directly in the blood, as early as 1-2 weeks after infection. Antibody tests take one to five weeks longer.
The big question is: do people show up for HIV tests during the first few weeks after infection? If not, the question of when different tests detect HIV would be moot. BUT IF THEY DO, we could be missing a lot of HIV infections depending on which test is used.
Although Western blot is considered by many to be the “standard” confirmatory test, it turns positive considerably later than many of the accurate screening tests.
Weeks Since Infection
*3rd generation, IgM-sensitive EIA
*2nd generation EIA
*viral lysate EIA
After Fiebig et al, AIDS 2003; 17(13):1871-9

13. Acute HIV Infection (www.hivguidelines.org)

15. How effective are we at capturing AHI?

16. Acute HIV Infection (AHI)
Nearly 60 million individuals diagnosed with HIV, fewer than 1,000 cases have been diagnosed in AHI [1]
1/60,000 detection rate
In NYC, fewer than 20 cases of AHI have been diagnosed [2]
[1] Pilcher, et al AIDS 2004
[2] NYC DOH STARHS Program

19. Why so lax in diagnosing AHI?
1. Treatment and diagnosis of HIV infection has been relegated to specialists
Lack of education of how to diagnose AHI
Discomfort related to difficult issues surrounding HIV
2. Clinicians inability to spend the additional time
Flanigan T, et al Annals of Int Med 2001

20. AHI 1% of patients with negative tests for EBV had AHI [1]
1% of patients with “any viral syndrome” in a Boston urgent care center had AHI [2]
In a Malawi STD clinic, 2.8% of all male clients with acute STD had AHI [3]
[1] Rosenberg, et al N Engl J Med 1999
[2] Pincus, et al Clin Infect Dis 2003
[3] Pilcher, et al AIDS 2004

21. Clinical Presentation of HIV Seroconversion*
Schacker, T. et. al. Ann Intern Med 1996;125:

23. How do you diagnose?

24. ICD-9 Code for AHI (exposure to HIV)
VO1.7

26. AHI and Hyperinfectiousness
Growing evidence that persons in AHI are very infectious
High-titer viremia in plasma and genital fluids [1,2]
Absence of immune factors that may neutralize infectivity [2]
Kahn JO, et al N Engl J Med 1998
Quinn TC, et al N Engl J Med 2000

27. AHI and Sexual Risk Behavior
MSM seroconverters from HIVNet Vaccine Trial
Colfax, G et al AIDS 2002

28. Role of AHI in Secondary Transmissions
Koopman [1] and Jacquez [2] used population modeling to argue that the spread of HIV from patients in AHI could contribute disproportionately to the epidemic
suggested that patients in AHI could be up to 1,000 x more infectious than those in chronic infection
Koopman JS, et al J Acquir Immune Defic Synd Hum Retrovirol 1997
Jacquez JA, et al J Acquir Immune Defic Syndr 1994

29. Blood viral load in acute HIV (n=171) Average fitted curve, with 95% confidence intervals
log 10 HIV RNA 8 7 6 5 4 3 2 1
8-10 fold increase risk from peak to day 54
300
200
100
Days from Infection
Peak: day 23
Pilcher, et al JID 2004

30. Semen viral load in acute HIV (n=30)
log 10 HIV RNA 7 6 5 4 3 2 1 10 20 30 40 50 60 70 80 90
100
Days from Infection
Pilcher, et al JID 2004

31. Rates of HIV-1 Transmission per Coital Act, by Stage of HIV-1 Infection, in Rakai, Uganda
Retrospectively identified 235 monogamous, HIV-discordant couples in Ugandan population-based cohort from
Estimated rates of HIV transmission per coital act in HIV discordant couples by stage of infection in the index partner
Recent seroconversion vs. chronic vs. late stage
HIV transmission within pairs was confirmed by sequence analysis
Wawer, et al JID, 2005

32. Wawer, et al JID, 2005

33. Transmission Of HIV During AHI: Relationship To Sexual Risk And STI
103 individuals with AHI were followed from
Viruses from 34% were related
Significant associations with clustering were:
Young age
High CD4 count
Number of sexual partners
UAI
STIs
Pao P et al AIDS 2005

34. Clustering: efficient dissemination by core groups and identification of networks
“Efficient disseminator”
Identification via PHI
“Acute Case”

35. Why isn’t individual viral load testing incorporated into HIV Testing?
Direct HIV detection methods (RNA testing) are expensive—5 to10 x more than Ab tests
Cost range from $60-$290
Decreased specificity
False positives
Typically viral loads <5000 are FP
Pooling specimens improves specificity and greatly reduces cost

36. Pooling schema Individual specimens Pools of 10
To pool the antibody negative specimens, a small part of each sample is removed and put into a tube that in the end represents all ten specimens

37. Pooling schema Individual specimens N=100 Pools of 10 A B C D E
F G H I J K
Individual specimens
N=100
Pools of 10
A hundred specimens are pooled this way into 10 pools of 10 each
A B C D E
F G H I J K

38. Pooling schema Individual specimens N=100 Pools of 10 Master pool
A B C D E
F G H I J K
Individual specimens
N=100
Pools of 10
The pools of 10 are then each sampled to create a “master pool” representing 100 specimens
A B C D E
F G H I J K
Master pool

39. Resolution Testing Individual testing on 10 specimens
Only master pools are actually tested for virus. If one is positive for HIV RNA, the lab works backward to determine which pool of 10, and then which individual specimen has the RNA in it. In the example shown here, 2000 patients are screened in the pools, but only 10 individual specimens are tested in the final round. This “resolution testing” procedure virtually eliminates the possibility of false positive results.
Pools of 10 screened
A B C D E
Master pools screened

40. Detection of AHI during HIV Testing in North Carolina
12 month observational study to evaluate this strategy for HIV testing at 110 publicly funded sites in NC
Primary objective was to compare the performance and yield of standard AB testing with algorithm that included both standard AB testing and PPVLT
Pilcher, et al NEngl J Med 2005

41. Performance of Algorithm
Sensitivity for standard AB testing (sAb) was 0.962
Use of PPLVT increased rate of HIV case identification by 3.9% over that sAB
Specificity and positive predictive value (PPV) of combined testing (Ab + PPVLT) with pooling was and 0.997

42. 6% in AHI

43. Interventions Targeting Acute Infection
All subjects (n=23) with AHI were notified (within 72 hours after test results)
No adverse events were reported (e.g., psychological trauma, violence against or from partners, etc)
21/23 subjects with AHI began specialty medical care, including 1 pregnant woman who received ARVS (baby was negative)
Pilcher, et al NEngl J Med 2005

44. Interventions Targeting Acute Infection
48 sexual partners of subjects with AHI received counseling for risk reduction
18 of these (38%) had HIV infection
13 (27%) previously recognized
5 (10 %) newly diagnosed
11 were probably the source of the AHI
10 were aware of their status, but only 3 disclosed to partners
3 of possible transmitters had been named in surveillance records as potential source of infection in 3 other cases suggesting roles as “core transmitters”
Pilcher, et al NEngl J Med 2005

45. Social Networks and Risk Association
Designated case managers collected data on social networks of acutely infected subjects
4 were college students; 2 in one town were identified within 1 month of each other
Revealed a new HIV outbreak among young black MSMs in these colleges
Pilcher, et al NEngl J Med 2005

46. Costs
PPLVT added an additional $3.63 per specimen and $17,515 per additional index case identified
Added only 3.3% increase over annual budget
Pilcher, et al NEngl J Med 2005

48. Thanks Frederick Siegal, MD Barbara Johnston, MD
Paul Galatowitsch, PhD
All staff at the HIV Center