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

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

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

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

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

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

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

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

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;125:257-264

Detection of HIV by Diagnostic Tests Symptoms p24 Antigen HIV RNA HIV EIA* Western blot 0 1 2 3 4 5 6 7 8 9 10 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

Acute HIV Infection (www.hivguidelines.org)

How effective are we at capturing AHI?

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

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

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

Clinical Presentation of HIV Seroconversion* Schacker, T. et. al. Ann Intern Med 1996;125:257-264

How do you diagnose?

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

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

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

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

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

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

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 1994-1999 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

Wawer, et al JID, 2005

Transmission Of HIV During AHI: Relationship To Sexual Risk And STI 103 individuals with AHI were followed from 1999-2003 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

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

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

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

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

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

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

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

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 0.999 and 0.997

6% in AHI

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

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

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

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

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