Acute HIV and the North Carolina STAT Project Past, Present and Future Peter Leone, MD Associate...

Acute HIV and the North Acute HIV and the North Carolina STAT ProjectCarolina STAT Project

Past, Present and FuturePast, Present and Future

Peter Leone, MDPeter Leone, MD

Associate Professor of MedicineAssociate Professor of Medicine

University of North CarolinaUniversity of North Carolina

Medical DirectorMedical Director

North Carolina HIV/STD Prevention and North Carolina HIV/STD Prevention and CareCare

A

C

B

D

7/28/05Develops HA, FeverWent to ER, LP, labsDX: RMSF, doxycycline givenSymptoms worsen 2 Days later admittedHIV Ab negDischarge Aseptic meningitisPossible RMSF

8/15/05-8/30/05 A&B: Sex 3-4x

8/30/05A,B,C: 3-way

9/10/05Develops fever, ST, fatigueLocal PMD gives Z-pack

Partners B&C “steady”Sex 1-2x/wk

10/15/05B,C,D have 3-way

9/30/05Develops fever, LAD,STLocal PMD gives Z-pack

10/28/05Develops fever, ST, oral ulcers, thrushAntibiotics givenRequests HIV test

A

C

B

D 11/15/05HIV+(ELISA +WB: I)

A

C

B


12/1/05HIV+

12/1/05HIV+

A

C

B


12/1/05HIV+

12/1/05HIV+

12/20/05HIV+

A

C

B


12/1/05HIV+

12/1/05HIV+

12/20/05HIV+

5 infections could have been avoided if acute HIV infection 5 infections could have been avoided if acute HIV infection considered at first presentationconsidered at first presentation

Definition of Acute HIV Definition of Acute HIV InfectionInfection

Time period following infection with HIV Time period following infection with HIV during which HIV virus can be detected in during which HIV virus can be detected in blood but antibodies to HIV are notblood but antibodies to HIV are not

OROR

Window periodWindow period when routine HIV antibody when routine HIV antibody tests (EIAs) are negative but HIV virus can tests (EIAs) are negative but HIV virus can be detected in bloodbe detected in blood

Primary HIV InfectionPrimary HIV Infection

Definition: Acute HIV infection + recent Definition: Acute HIV infection + recent infection with HIV. infection with HIV.

Recent Infection: patients who are positive Recent Infection: patients who are positive on HIV antibody testing (EIA), but have on HIV antibody testing (EIA), but have one of the following:one of the following:– A recent prior negative HIV test or A recent prior negative HIV test or – Results of detuned antibody test suggesting Results of detuned antibody test suggesting

recent infection. recent infection.

Couthino et al., Bulletin of Mathematical Biology 2001

Detecting Acute HIV Detecting Acute HIV InfectionsInfections

0 1 2 3 4 5 6 7 8 9 10

Symptoms

p24 Antigen

HIV RNA

HIV Ab Tests

Weeks Since Infection

PCR Testing of Pooled Sera to Identify Acute HIV Infection

(seronegative, PCR positive)Pooled HIV RNA Testing: Yields

15%NYC 3 STD ClinicsNew York City

10%6/1553 (0.39%)STD clinicWashington DC

5%4/2128 (0.19%)STD clinics, community testing and drug treatment

Atlanta

00/15000STD clinicsMaryland (not Baltimore)

7.1%1/1698 (0.06%)Men tested in 3 STD ClinicsLos Angeles

10.5%11/2722 (0.40%)SF STD Clinic PatientsSan Francisco

13.5%21/5995 (0.35%)Men who have sex with men tested through PHSKC

Public-Health Seattle & King County

4%23/109,250 (0.02%)All persons tested for HIV via North Carolina DOH

North Carolina

Increase in Testing Yield

Prevalence HIV RNA+/EIA-

PopulationProgram

Source: ISSTDR, 2007

How do we pick-up How do we pick-up Acute HIV infection if Acute HIV infection if routine antibody tests routine antibody tests

are negative?are negative?

Acute Retroviral SyndromeAcute Retroviral Syndrome 40-90% of new HIV infections are 40-90% of new HIV infections are

symptomaticsymptomatic

Signs and symptoms typically begin Signs and symptoms typically begin 1-4 weeks following the exposure1-4 weeks following the exposure

Symptoms can last from days to Symptoms can last from days to several weeks, but usually <14 daysseveral weeks, but usually <14 days

Pilcher C et al. N Engl J Med 2005;352:1873-1883Kahn JO, Walker BD. N Engl J Med. 1998;339:33-39Schacker T, et al. Ann Intern Med. 1996;125:257-264

Acute HIV Incubation Acute HIV Incubation PeriodsPeriods

Days from Sexual Exposure to Onset of Symptoms2821147

Fre

quen

cy

10

8

6

4

2

0

31 Patients Average = 14 days

Range: 5-30 days

Sources: Pilcher, JAMA 2001; Borrow, Nat Med 1997; Schacker AIM 1996; Lindback, AIDS 2001

Non-specific Mononucleosis-Non-specific Mononucleosis-like Signs and Symptomslike Signs and Symptoms

FeverFever RashRash Oral ulcerOral ulcer Weight lossWeight loss Loss of Loss of

appetiteappetite HeadacheHeadache FatigueFatigue

AdenopathyAdenopathy Sore throat/ Sore throat/

pharyngitispharyngitis Muscle and/or joint Muscle and/or joint

painpain DiarrheaDiarrhea GI upset/nausea/GI upset/nausea/ vomitingvomiting

Common Signs & SymptomsCommon Signs & Symptoms

44

52

55

57

59

74

86

0 10 20 30 40 50 60 70 80 90 100

adenopathy

pharyngitis

headache

rash

myalgias

lethargy

fever

Vanhems P et al. AIDS 2000; 14:0375-0381.

% of patients

Study of 160 patients with primary HIV infection in 3 countries

Acute HIV and SymptomsAcute HIV and Symptoms

Schacker Schacker Kinloch-de Loes Kinloch-de Loes NC NC STDSTD

FeverFever 93%93% 87% 48%87% 48%

FatigueFatigue 9393 26 37 26 37

PharyngitisPharyngitis 7070 48 3048 30

HeadacheHeadache 5555 39 2639 26

Rash 15Rash 15

GI Symptoms 37GI Symptoms 37

Schacker TW, et al., AIM 1996 125:257-64

Common Mis-diagnosesCommon Mis-diagnoses

MononucleosisMononucleosis Rocky Mountain Spotted FeverRocky Mountain Spotted Fever Strep throat Strep throat InfluenzaInfluenza ““Viral illness”Viral illness” Secondary syphilisSecondary syphilis

Primary HIV Infection: Primary HIV Infection: PathogenesisPathogenesis

1

10

100

1,000

10,000

100,000

1,000,000

10,000,000

Pla

sma

HIV

RN

A (

copi

es/m

L)

Plasma HIV RNA

CD4 Cell Count

4-8 Weeks Up to 12 Years 2-3 Years

CD

4 Cell C

ount (cells/m

m³)

Symptoms

Primary HIV Progression AIDS

How do we pick-up How do we pick-up Acute HIV infection if Acute HIV infection if patients don’t have patients don’t have

symptoms?symptoms?

Our approach to Screening for Our approach to Screening for AHI Specimen poolingAHI Specimen pooling

• AdvantagesAdvantages Seamless (almost) incorporation into HIV Seamless (almost) incorporation into HIV

testingtestingReduced cost Reduced cost No real change in specificityNo real change in specificityUniversal applicationUniversal application

• DisadvantagesDisadvantagesRequires large testing volumeRequires large testing volumeSmall loss in sensitivitySmall loss in sensitivityLogisticsLogisticsTime to Dx and locating patientTime to Dx and locating patient

STAT Testing ProtocolSTAT Testing Protocol

Acute HIVHIV Negative

HIV Positive

EIA/ Western Blot

HIV RNA testing

F/U Testing(Ab + HIV RNA)

+

+

-

-

- +

Pooling and HIV RNA testingPooling and HIV RNA testing

A B C D E F G H I

1 2 3 4 5 6 7 8 9 10

A B C D E F G H I

A B C D E F G H I A B C D E F G H I

90 individual HIV antibody negative specimens

9 intermediate pools (10 specimens)

1 master pool (90 specimens)

Distribution of Viral Loads in Ab Negative VCT Specimens

NC Testing Data 2002-2005 (n=58)

0

2

4

6

8

10

12

14

16

2 3 4 5 6 7 8

n

log HIV RNA cp/ml

Low viral load specimens

0

2

4

6

8

10

12

14

16

2 3 4 5 6 7 8

n

log HIV RNA cp/ml

STAT Case

Possible acute HIV Infection

STAT Case

Possible acute HIV Infection

ConfirmatoryTest

HIV Antibody and RNA Testing

ConfirmatoryTest

HIV Antibody and RNA Testing

•DIS Interview•Referral to Care•DIS Interview•Referral to Care

Contact < 72 hrs

Contact < 8 weeks

Contact > 8 weeks

STAT Post-Exposure

Protocol

STAT Contact Protocol

STAT Contact Protocol

Routine PartnerNotification

Protocol

Routine PartnerNotification

Protocol

EIA or Ab(-)

EIA/Ab (+) and WB (+)or EIA/Ab (-) RNA (+) Confirmed Acute HIV +

STAT NotificationConfirmed Acute HIV +

STAT Notification

Immediate contactDr. Leone

UNC ID – on call

Immediate contactDr. Leone

UNC ID – on call

Repeat Testing

EIA or Ab (+)

FalseRNA

Positive

FalseRNA

PositiveAb -

STAT Index Case ProtocolSTAT Index Case Protocol

Notification of AHI in STAT 02-05

0

10

20

30

40

50

60

70

80

90

100

Notification and interviews successful for 41 (93%) index cases•80% index cases were successfully entered into care. •PCRS successful for 102 (78%) of 130 named partners

Time to notification improved to ~11 days from the time of testing (est. ~39D into 80D hyper-infectious period)

The STAT SystemState Laboratory

Laboratory Identification

Disease Intervention Specialist Team

Notification, Interviews, Confirmatory Testing,

Transportation to Clinic

UNC Weekly Case-Conference

(Surveillance, Lab, DIS, UNC Evaluation Teams)

Data collection

UNC/Duke Collaborative

Free Urgent clinical evaluation

Recruitment to studies

UNC Acute HIV Program

Research Database

UNC Specimen Repository

-surveillance/research testing

Screening and Tracing Active Transmission (STAT) Program

• From 2003-2006, 79 cases identified– 3 not located– 1 refusal for PCRS

• 269 partners (from 75 AHI patients) identified within an 8-week exposure window– 174 (65%) named 132 (76%) located – 95 (35%) anonymous

STAT PCRS Outcomes (2003-2006)

Not Located 24% (42)

Found and refused 4% (7)

Previosly positive 26%

(45)

Negative 86% (69)

Newly Identified Chronic

Infection 9% (7)

Recent Infection 1% (1)

Acute Infection 4% (3)

46% (80) Counseled & Tested

Why focus on Acute Why focus on Acute HIV Infection?HIV Infection?

HIV Epidemic in NCHIV Epidemic in NC 7th leading cause of death for men and 7th leading cause of death for men and

women ages 25-44 in 2004women ages 25-44 in 2004

Approximately 10,600 HIV-infected NC Approximately 10,600 HIV-infected NC residents were unaware of their status in residents were unaware of their status in 2005 2005

HIV incidence in the US and NC is stable or HIV incidence in the US and NC is stable or increasing increasing

NC ranked 2nd in the US for the number of NC ranked 2nd in the US for the number of AIDS cases from non-metropolitan areasAIDS cases from non-metropolitan areas

New Patients in the UNC ID New Patients in the UNC ID ClinicClinic

The median CD4 count was 202 The median CD4 count was 202 cells/mm3 for patients initiating HIV cells/mm3 for patients initiating HIV care.care.

Majority (68%) initiated HIV care within 1 Majority (68%) initiated HIV care within 1 year of their first positive HIV test.year of their first positive HIV test.

75% met guidelines for starting HIV 75% met guidelines for starting HIV treatment at their first visit.treatment at their first visit.

NC DHHS- HIV/STD Prevention & Care Branch

HIV viremia during early infection

HIV RNA (plasma)HIV Antibody

11

0 10 20 30 40 50 60 70 80 90 100

HIV p24 Ag

16 22

Ramp-up viremia

DT = 21.5 hrs

1st gen2nd gen

3rd gen

p24 Ag EIA -

HIV MP-NAT -

HIV ID-NAT -

Peak viremia: 106-108 gEq/mL

“blip” viremia

Viral set-point: 102 -105 gEq/mL

Primary HIV-1 InfectionPrimary HIV-1 Infection

Time in YearsInfection

CD4Cells

1000

800

600

400

200

0

Early Opportunistic Infections

Late Opportunistic Infections

+

1 2 3 4 5 6 7 8 9 10 11 12 13 14

Earlier HIV DiagnosisEarlier HIV Diagnosis

Allows prompt entry into careAllows prompt entry into care Initiation of ART prior to CD4 decline Initiation of ART prior to CD4 decline

<200 improves mortality and morbidity<200 improves mortality and morbidity Management of STIs and other illnessManagement of STIs and other illness Short-term behavioral changes can Short-term behavioral changes can

have a large impact on HIV spreadhave a large impact on HIV spread Improve natural history of disease with Improve natural history of disease with

treatment during acute HIV infection?treatment during acute HIV infection?

Public Health BenefitPublic Health Benefit

Acute HIV is Acute HIV is the mostthe most infectious period infectious period

HIV RNA levels in the genital tract HIV RNA levels in the genital tract correspond to HIV RNA levels in the correspond to HIV RNA levels in the bloodblood

Diagnosis is often missed even when Diagnosis is often missed even when patients are symptomatic with acute HIV patients are symptomatic with acute HIV infectioninfection

Plasma Viral Load and HIV Transmission Risk

• Rakai (Uganda) • 453 HIV-disc.

couples• 11.6 % TR / year

0

10

20

30

<400 400-3500

3500-10'000

10'000-50'000

>50000

HIV-RNA load (cp/ml)

% p

art

ne

rs in

fec

ted

Quinn 2000, NEJM 342:921

Wawer, et al, JID 2005, 191:1403

Viral Loads at Initial DetectionViral Loads at Initial Detection

Pilcher C et al. N Engl J Med 2005;352:1873-1883Pilcher C et al. N Engl J Med 2005;352:1873-1883

0123456789

10

Established HIV+ (n=66)

Lo

g H

IV R

NA

cp

/ml

Median Viral Loads

29,347

209,183

Acute HIV+ (n=21)

HIV transmission prob. per male-female act: fold-change relative to wk 16

(calculated after Chakraborty H, et al AIDS 2003)

Weeks from Testing Positive for AHI

Fo

ld-c

han

ge

vs

. wk

16

0

2

4

6

8

10

12

14

16

1 2 4 8 12 16

Risk of TransmissionRisk of Transmission

HIV RNA in Semen(Log 10

copies/ml)

Risk of TransmissionReflects Genital Viral Burden

(1/30-1/200)

(1/1000 - 1/10,000)

(1/500 - 1/2000)

(1/100-1/1000)

55

44

33

22

Acute Infection

Asymptomatic Infection

HIV Progression

AIDS

Further Evidence That Primary HIV Infection Accounts for a Large Proportion of HIV Transmission

Contribution of Primary HIV to Ongoing HIV Transmission

30%Phylogeneticanalysis

Swiss cohort pop. –mostly MSM

Yerly (2004)


Sussex,UK cohort pop. – mostly MSM

Pao (2005)


Lab-based pop. in Quebec with recently

acquired HIV (<6 months)- mostly MSM

Brenner (2007)

MethodPopulation Percentage New Infections

Attributable to PHI

Author (year)

Source: ISSTDR, 2007

Public Health BenefitPublic Health Benefit

Identify HIV transmission networks Identify HIV transmission networks

Allows real time prevention with Allows real time prevention with index case and partnersindex case and partners

Awareness of HIV status has been Awareness of HIV status has been associated with decreased sexual associated with decreased sexual risk behaviors risk behaviors

Lessons for Public HealthLessons for Public Health

Acute HIV infection may be unexpectedly Acute HIV infection may be unexpectedly prevalent in common clinical scenariosprevalent in common clinical scenarios

Immediate rather than deferred testing is Immediate rather than deferred testing is keykey– HIV ELISA and HIV RNAHIV ELISA and HIV RNA

Sexual partners of acutely HIV infected Sexual partners of acutely HIV infected individuals are at a markedly increased individuals are at a markedly increased per-act risk of acquiring HIVper-act risk of acquiring HIV

Lessons for Public HealthLessons for Public Health

Linkage of acute HIV diagnosis with Emergent Linkage of acute HIV diagnosis with Emergent ID Consultation is paramountID Consultation is paramount– Interpretation and counseling on test resultsInterpretation and counseling on test results– Extensive counseling of newly diagnosed patientExtensive counseling of newly diagnosed patient– Facilitate linkage to care and servicesFacilitate linkage to care and services– Consideration of ART for interested patientsConsideration of ART for interested patients

Acutely infected individuals provide public Acutely infected individuals provide public health officials with a unique opportunity to health officials with a unique opportunity to understand complex sexual networksunderstand complex sexual networks

Screening and Tracing Active Transmission (STAT) Program

2003 2004 2005 2006

Total Tests (publicly-funded clinics)

107,733 118,998 128,708 140,100

Antibody positive 581 552 571 592

Antibody negative, RNA+ (acute)

22 21 21 15

November 1, 2002 – May 28, 2008

TOTAL 2002 2003 2004 2005 2006 2007 2008

Number of True RNA Positives

108 2 22 21 21 15 16 11

Number of Community Index Cases(acute and recent)

188 1 11 23 38 40 53 22

Case Count0

1

2 (Burke, Franklin, Pitt, Henderson, Onslow, Martin)

3 (Buncombe, New Hanover)

4 (Robeson)

8 (Cumberland)

12 (Forsythe, Guilford)

15 (Wake)

15 (Mecklenburg)

STAT Acutes by County (11/1/2002-2/1/2008)

HH

0 50 100 150 20025Miles

Duke University Hospital

UNC Hospitals

H

H

Testing Site November 2002- May 2005

Tests Ab+ AHI (%) % of AHIHIV CTS 18,299 400 12 (2.9) 21STD 117,804 526 27 (4.9) 48FP 47,476 28 -- -- Prenatal/OB 47,598 39 2 (4.9) 3Prison/Jail 7,158 57 4 (6.6) 7Other 37,073 320 13(3.9) 22

The STD/HIV Connection• Susceptibility:

– Genital ulcers provide portal of HIV entry– Non-ulcerative STDs increase target cells

– STD treatment has been shown to slow the spread of HIV infection (individual & community)

• Infectiousness: – Presence of another STD increases amount of HIV in genital secretions – Treating STDs in PWHIV decreases

• the amount of HIV they shed• how often they shed the virus

Potential impact of STI co-infection on detection of AHI

HIV/STI Co-Infection

Event

week 1 week 2 week 3 week 4

GC

Trichomoniasis

Chlamydia

Syphilis

HSV

ARS Symptoms

3rd gen. EIA

HIV RNA +

4th gen. EIA

McCoy 0-014

STI Co-infections

• 23 clients (30%) had a concurrent STI

STD Type N (%)Men

(n=13)Women(n=10)

Gonorrhea 9 (39) 7 (54) 2 (20)

Trichomoniasis 5 (22) 0 (0) 5 (50)

Syphilis 4 (17) 4 (31) 0 (0)

Herpes 3 (13) 2 (15) 1 (10)

Chlamydia 3 (13) 1 (8) 2 (20)

Bacterial vaginosis 3 (13) - - 3 (30)

GUD, unspecified 1 (4) 1 (8) 0 (0)

Other reported STD-related sx 5 (7) 4 (7) 1 (6)

McCoy 0-014

STI Co-infections by Race, Gender, and Risk Category

0

5

10

15

20

25

White Non-White White Non-White White Non-White

MSM Male Hetero Female

No.

of

AH

I ca

ses

p = 0.03

MSM Male Hetero Female

STI Co-infection

McCoy 0-014

Missed Opportunities in STD Clinics

• HIV testing not offered to all• Risk factors for HIV either not obtained or not

recognized• HIV testing not integrated into STD services• Primary HIV Syndrome unrecognized by

patients and clinicians• Diagnostic test for Acute HIV Infections is not

ordered

NC HIV Testing in STD Clinics

• HIV testing to be offered to all STD clients for each new visit regardless of when last HIV test performed

• DHHS policy to offer opt-out HIV testing• 2005 estimate ~52% of NC STD clinic clients tested

for HIV• Wake County ( 2nd largest STD clinic in North

Carolina) with ~80-85% with universal offering of HIV testing.

• Wake County HIV testing increased to ~90% with opt-out approach

Acute HIV and North CarolinaSTAT

Duke-UNC Acute HIV Infection Research Consortium

Research opportunities for patients with Acute and Recent HIV Infection:

1) “Treatment of Acute HIV Infection with Once Daily Atripla” (24 month treatment study which supplies Atripla)

2) “Longitudinal Assessment of Acute/Recent HIV Infection” (Adds to limited scientific knowledge currently available regarding acute/recent infection)

Duke-UNC Acute HIV Infection Research Consortium

3) “CHAVI 001: Acute HIV-1 Infection Prospective Cohort Study”

Acquire information to develop an HIV vaccine

The most relevant information may come from people with acute HIV infection and their partners

CHAVI Index Cases by County of Residence, 6/2007-2/2008n=18

U D

0 50 100 150 20025Miles

2 27

WakeGuilfordForsythe

Key D Duke University HospitalU UNC Hospital

2

Cumberland

Durham

1

1

Halifax

1

Pitt

1

Randolph

1

Martin

Key

CHAVI Partners By County of Residence, 6/2007-2/2008

n=58

UD

0 50 100 150 20025Miles

Duke University Hospital

UNC Hospitals

D

U

17

21

9

3

1Mecklenburg

Forsythe Guilford

Durham Wake

Cumberland

Other Partner Locations

“NC”: 3 SC: 1 GA: 2

WA: 1 Abroad: 2 Unk: 6

Hertford

1

1

Bertie

Martin

1

Scotland

1

Northampton

1

1

CravenHarnett

1

Pasquotank

1

Granville

1

Lee

1

Advatages to Dx and Care of AHI

1.An HIV diagnosis per se results in subsequent risk reduction

2. Initiation of HAART to reduce plasma and hence genital viral load thus reducing transmission potential

3. As we identify more undiagnosed HIV+ and more are successfully placed on HAART, transmission will shift even more to AHI

4. As frequency of HIV testing increases, we will idenitfy more AHI

5.Opportunity for short term behavior change (period of high infectivity of weeks)

Conclusion

• Make HIV testing routine

• Opt-out HIV Testing for all STD clients

• Screen all STD clients for AHI

• Include AHI in the Differential Dx of Acute Viral Syndrome in all Sexually Active Adults

Conclusion

• AHI is a true Public Health Emergency!

• AHI detection and case investigation puts identification of HIV at leading edge of transmission

• Opportunity for both early diagnosis and prevention

• Report all AHI cases within 24 hrs

laboratory

Given this VL distribution:Analytical vs. Clinical Sensitivity

LL, cp/ml Ab- HIV

N=58

Se (Ab-) All HIV

N=1437

Se (all)

1000 56 96.5 1435 99.9

3000 54 93.1 1433 99.7

5000 52 89.6 1431 99.6

10000 49 84.5 1428 99.4

Ab only 0 0 1379 95.9

Requirement for Analytical Sensitivity is Less Stringent than for VL Monitoring

• To be recommended as part of (all) general HIV testing, a NAAT would likely need ~95% detection at viral loads the equivalent of 5,000 to 10,000 HIV RNA copies per mL

• Better sensitivity required for effective analysis of pooled specimens

• Acute HIV infections (first 2-3 months) are estimated to account for as much as half of all HIV transmission (Wawer at al JID 2005)

• They represent 0-10% of detectable infections presenting for HIV testing

• Real-time recognition of acute infections creates opportunities for highly targeted treatment, prevention and surveillance activities

Detection of Acute HIV

• “Detuned” assays can identify recent seroconversion, but with a 1-2 month delay from infection. These also do not identify additional cases over routine antibody tests.

• Real-time diagnosis of acute HIV depends on the identification of HIV antigens (e.g., p24) or nucleic acids (NAAT) in the absence of HIV antibodies.

Detection of Acute HIV

HIV NegativeEstablishedHIV Positive

Ab screen

NAATscreen

+

-+

Possible Acute HIV

-

The Gold Standard for Acute Screening is RNA Group Testing of Ab - Specimens

Ab confirm+

-

Pilcher, CD et al. JAMA 2002;288:216-221

• NAAT is highly sensitive and with pooling, may be made specific.

• However, even pooled NAAT may be inefficient in high prevalence areas (>5%) and is technically demanding.

• ‘Fourth generation’ HIV ELISAs detect both antigen and antibody simultaneously– Easy to perform – Equipment available in most HIV laboratories

Testing to Identify Acute HIV

Window Periods for HIV Tests

Stekler J. et al CID 2007

Ricardo da Silva de Souza – August 2006

Commercial Assays Comparative Timing of Detection of Acute HIV Infection

= combined antigen-antibody = immunometric = Class specific antibody capture = antiglobulin / indirect

Source HPA -UK

Reducing time to case identification

Summary: Pooling vs. Individual NAAT

• Pooled screening (even with ‘minipools’) makes testing possible by reducing costs and improving predictive value

• More complex but more efficient for through put and cost

• Single specimen NAAT screening should be reserved for situations where the pre-test likelihood of acute HIV infection is >/= 1% (e.g., suspected AHI, ?ED/urgent care screening)

Opportunities for

New Technologies and Approaches

• Need to reduce time to identification of AHI

• NC median time to identification is ~9D

• Fast Track can reduce time to 2-4 days

• Current POC HIV tests only test for Ab

• 4th generation EIA can reduce time to Dx and reduce cost

• Strategy may need to combine individual NAAT or discrepant POC 3rd generation EIA to identify AHI

Rapid Antibody TestingThe Good• Makes testing feasible in non-traditional settings

– Highly effective for outreach situations (needle exchange, bathhouse testing, “street-corner” outreach)

• Increases receipt of positive HIV test results– Where HIV results notification (PCRS) not in place

• May increase requests for HIV testing

The Not So Good• Confidentiality

• Cost 2-3x ELISA Ab tests

• May defer resource allocation/personal to HIV negatives

• May miss AHI

• Requires Confirmation

Alternative Approaches

• North Carolina AHI referral network

• Educate community providers about AHI

• Educate high risk community about AHI

• Linkage of ED testing to ID clinic and local health departments…… strongly encourage partnerships . EDs will test if burden for referral to care is met.

• Raise awareness of 3rd generation EIA +/ WB I as possible AHI

Cost-effectiveness of the STAT Program: Decision Tree Analysis

• The expected savings from averting new HIV cases offset 22% of the testing costs

• Overall cost per QALY of $4,345

• Conclusion: the program appears to be well below the cost effectiveness threshold of $50,000 which is often used as an indicator of good public health investment opportunities in the US.

• Still, cost a barrier for new programs

Targeting NAAT Screening by Site

• Over 2 years, at 135 public testing sites in NC, 325 acute and recent infections were identified among 224,124 testing clients (66% females, 4% MSM)

• Only 1/3 acute clients had HIV symptoms at testing

• There were no cases in 48 of 100 counties

Targeted Screening:

• If NAAT used only in HIV C&T, STD, prison, and field visit sites in counties with 1 case, 95.4% of acute cases identified testing only 54.0% of the population with NAAT

• Testing only in STD clinics identified 40.1% of cases while testing 41.4% of the population.

Targeting is necessary; but be wary of preconceptions

• It is possible to construct a targeting algorithm for NAAT testing based on knowledge of local incidence, prevalence and individual risk factors associated with having recent infection

• “Detuned” test results can be used to develop NAAT targeting criteria

• A priori assumptions about who to test with NAAT are likely to be incorrect (i.e., limiting testing to only “high risk” clinics, or to symptomatic clients would be counterproductive)

Opportunities for New Approaches

• Need to reduce time to identification of AHI

• NC median time to identification is ~9D

• Fast Track can reduce time to 2-4 days

• We are implementing Fast track to all STD clinics based on symptoms and requiring STAT clinician approval

Fast Track Targeted AHI Testing :

1. Screen all clients for HIV Ab

2. Target

Problem: Which symptoms (fever?)

What time period (2-4 wks)?

What duration ( >2 days)?

Symptoms at best will detect 40%

- Targeted testing

Risk based ( i.e. MSM, anal/vaginal sex in past 2 weeks,etc )

Symptoms based (Fever + for >2 days within past 4 weeks)

Site based ( prevalence 0.5% or type STD,CTS, etc.)

3. Need for further research to define symptom screen and develop predictive models for targeted AHI testing

Opportunities for New Technology

• Current POC HIV tests only test for Ab

• 4th generation EIA can reduce time to Dx and reduce cost

• Plan to do real time side by side comparison of NAAT pooling with 4th generation assay

• May need to combine individual NAAT or discrepant POC 3rd generation EIA to identify AHI

Biology

Determining the Genetic Linkage of HIV-1 Subtype B Transmission Pairs: Analyses of

Viral env Sequences From Donor and Recipient

Jeffrey A. Anderson, MD-PhD

University of North Carolina

Background

• A genetic bottleneck occurs during mucosal transmission, resulting in a subset of viruses responsible for transmission of HIV.

DONOR RECIPIENT

Background

• Determining the genetic composition of the transmitted virus is critical to developing insight into disease progression, HIV pathogenesis, and candidate vaccines.

• Key questions:– From the donor quasispecies, what are the properties of the specific

variant(s) being transmitted?– Are genital tract secretions a separate compartment from blood plasma?

135 D3

81 R3

ELISA WB

# of env amplicons

blood

148 D2

40 R2

174 D1

150 R1

3 MSM Transmission pairs from CHAVI 001: Donor vs. Recipient

Sampling Time

Weeks

Post-infection

9

11

+

+

+

+

Chronic

Chronic

14

22

0

36

2

5

6-7

-

+

+

-

+

+

Fiebig 1/2

Fiebig 5/6

Fiebig 5/6

1

28

0

0

0

17

# of env amplicons

semenStage

22 + + Chronic 36 0

2

4

-

+

NA

+

Fiebig 1/2

Fiebig 5/6

43

29

0

0

9

11

+

+

+

+

Chronic

Chronic

20

22

0

32

2

5

-

+

-

+

Fiebig 1/2

Fiebig 5/6

29

25

0

1

269 86

Experimental design

Identify patients with acute HIV-1 infection, and sexual partners through contact tracing

After informed consent, obtain blood plasma and semen/cervicovaginal lavage

Isolate HIV-1 viral RNA from blood/semen/CVL fluid

Generate a copy of the viral DNA and amplify by PCR

Direct DNA sequence analysis to determine characteristics of HIV

Chromatograms from a single DNA sequence

Donor env blood plasma populations are heterogeneous

D1 D2 D3

Recipient env blood plasma populations are homogeneous

R1 R2 R3

22 identical sequences

2

3

33 identical sequences

10

2

3

3

Phylogenetic analysis of D1/R1

1. Blood and semen populations are well-mixed


1. Blood and semen populations are well-mixed2. However, a subset of duplicated semen amplicons suggests selective outgrowth

*

*

****


1. Blood and semen populations are well-mixed2. However, a subset of duplicated semen amplicons suggests selective outgrowth3. No blood amplicons were duplicated

*

*

**** 42 0

21 11

Blood

Semen

Unique Duplicate

P < 0.0001


1. Blood and semen populations are well-mixed2. However, a subset of duplicated semen amplicons suggests selective outgrowth3. No blood amplicons were duplicated

*

*

**** 42 0

21 11

Blood

Semen

Unique Duplicate

P < 0.0001

4. R1 is clearly genetically linked to D1 semen (99% nt identity), and did not arise from a duplicated semen sequence

Summary• Genetic linkage of 3 subtype B transmission pairs was confirmed

by SGA and DNA sequence analysis.• All donor (D1-D3) populations had heterogeneous env populations,

although D1 had low heterogeneity.• A single variant was transmitted to each recipient (R1-R3).• Semen populations were well-dispersed among blood populations.• Clusters of duplicated sequences in semen of D1 and D3 suggest

outgrowth of specific variants. • These data suggest that semen sequences, in general, represent

sequences present in blood; however, semen populations can be disrupted by selective outgrowth.

• Analyses of additional transmission pairs are ongoing and will lead to a greater knowledge of:– compartmentalization of viral sequences within semen vs. blood– the specific viral variant(s) transmitted from donor to recipient– viral sequences important for HIV-1 vaccine design

Acknowledgments

• Ron Swanstrom and lab members

• Beatrice Hahn

• Brandon Keele

• Jesus Salazar

• Susan Fiscus and lab

• Julie Nelson

• Myron Cohen

• Lihua Ping

• Kristen Dang and Christina Burch

• CHAVI 001 Clinical Core

• NC Dept. of Health and Human Services

• DIS Training Program and Officers

27 individuals (12%) were in closely related (<1% divergence) clusters

Still, a 4-6 week period accounts for 10-15% of Transmission

Frost s et al. CROI 2007

North Carolina may have lower attribution of

AHI on Transmission

Network Analysis: Project SNAP

• Acutely/Recently infected MSM and high risk HIV-negative men recruited for in-depth ACASI interview and qualitative interview

• Respondent driven sampling to derive sexual and social network (2 generations)

• Better understanding of network formation, HIV/STD transmission, sex partner selection and Internet use among NC MSM

If you have an STD, Get Tested for HIV.

Early Detection is Best!

Learn to Recognize IT. Tell a Friend.

Acute HIV is Easily Misdiagnosed.

IT CAN BE MISTAKEN FOR COMMON ILLNESSES

Common Symptoms of Acute HIV:High Fever RashFatigue Swollen GlandsSore Throat Nausea/Vomiting Night Sweats

Symptoms usually appear about2 weeks after exposureWhat Puts You At Risk?Unprotected SexSharing Needles

The Acute HIV Program 919-966-8533

If you suspect you may have Acute HIV, get tested at your Local Health Department or at your doctor’s office.FREE Screening for acute HIV is done on all HIV tests done through the NC Health DepartmentsScreening for acute HIV can be done at your doctor’s office – ask for an HIV RNA test in addition to the standard HIV antibody test.

Conclusions

• HIV antibody screening is a necessary first step in targeting prevention activities

• Assays able to detect antibody-negative infections should be incorporated into current HIV screening/testing

• NAAT may not be reasonable for low-risk ‘routine’ screening in well patients and low prevalence populations

• Models for establishing criteria for targeting NAAT are need

• 4th generation EIAs may present an alternative for diagnosis of acute HIV infection and merit urgent large-scale clinical evaluations

Window Periods for HIV Tests

Stekler J. et al CID 2007

Tests to DX HIV

• Antibody ELISA $47

• Western Blot $212

• p24 Antigen $38

• Individual HIV RNA PCR $218

Acute HIV and the North Carolina STAT Project Past, Present and Future Peter Leone, MD Associate...

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Transcript of Acute HIV and the North Carolina STAT Project Past, Present and Future Peter Leone, MD Associate...