acute hiv and the north carolina stat project past, present and future peter leone, md associate...
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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
D 11/15/05HIV+(ELISA +WB: I)
12/1/05HIV+
12/1/05HIV+
A
C
B
D 11/15/05HIV+(ELISA +WB: I)
12/1/05HIV+
12/1/05HIV+
12/20/05HIV+
A
C
B
D 11/15/05HIV+(ELISA +WB: I)
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)
34%Phylogeneticanalysis
Sussex,UK cohort pop. – mostly MSM
Pao (2005)
49%Phylogeneticanalysis
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
Phylogenetic analysis of D1/R1
1. Blood and semen populations are well-mixed2. However, a subset of duplicated semen amplicons suggests selective outgrowth
*
*
****
Phylogenetic analysis of D1/R1
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
Phylogenetic analysis of D1/R1
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