HIV Diagnosis, Acute Infection and Superinfection Don Kurtyka, ARNP, MS, MBA University of South Florida College of Medicine Tampa General Hospital Hillsborough County Health Department.
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Transcript HIV Diagnosis, Acute Infection and Superinfection Don Kurtyka, ARNP, MS, MBA University of South Florida College of Medicine Tampa General Hospital Hillsborough County Health Department.
HIV Diagnosis,
Acute Infection and
Superinfection
Don Kurtyka, ARNP, MS, MBA
University of South Florida College of Medicine
Tampa General Hospital
Hillsborough County Health Department
Objectives
Discuss the diagnosis of HIV and available
tests
Describe the approach to the diagnosis of
acute retroviral syndrome
Debate the advantages and disadvantages
of early treatment of acute HIV infection
Discuss the evidence for the possibility of
superinfection / reinfection and the
implications for patient education and
management
Anonymous vs Confidential
Anonymous
Identifying information not provided
Results not linked to identifying information
Allows reporting of HIV infection without breaching
confidentiality
Disadvantage: may not be able to locate clients for test
results
Confidential
Clients linked to test result by identifying information
Results remain confidential
Informed consent
Pre-Test Counseling
Goal: reduce HIV acquisition and transmission
Accurate and current information about HIV
Obtain informed consent
Transmission and acquisition
HIV test info: risk, benefits, meaning of potential
test results
Assessment of individuals risks and appropriate
risk reduction activities
Capacity to comprehend HIV testing and consent
Post-Test Counseling
Accurate and current information about HIV
Local resources
Risk reduction education
Referrals for ongoing care and support
Healthy living strategies
Meaning of test results and state reporting
guidelines
Mental health support / counseling
Diagnosis of HIV Infection
Viral antibodies
Viral antigens
Viral RNA/DNA
Culture
Lancet, 1996; 348: 176.
Enzyme Immunoassay
Enzyme-Linked Immunosorbent Assay
(EIA, ELISA)
Primary HIV antibody screening test
Serum plasma, dried blood spots, oral fluids,
urine
HIV-1/2, HIV-1, HIV-2
High degree sensitivity and specificity
Repeatedly reactive: confirmatory testing
Negative Antibody Test Results
HIV negative
Recent infection: too early for seroconversion
CDC: follow-up testing at 6 weeks, 12 weeks,
6 months
Confirmation Process
Non-negative screenings should be
confirmed
Western Blot (WB)
Immunofluorescent Antibody Assay (IFA)
Higher specificity than EIA
Interpretation can be subjective
Predictive Value: HIV Ab Tests
Depends on the prevalence of HIV infection
in the population
Low HIV prevalence: predictive value of a
positive test is low
HIV Ab testing of low prevalence populations
likely to produce more false-positive than
true-positive results
Window Period
Time delay from infection to positive EIA
Average: 10-22 days
Most seroconvert within six months
Am J Med 2000; 109
HIV-1 vs HIV-2
HIV-1: Most cases
Group M: predominant strain world-wide
Subtypes (clades): A to K, N, O
Clade B
US and Europe
98% of HIV-1 in US
Most non-B subtypes were acquired outside US
Clade C: Southeast Asia
N (“new”): 1998
Group O: West Africa
Recombination between viruses of different clades
becoming more common
Predominant HIV-1 Subtypes
A: West/East/Central Africa, East Europe,
Mideast
B: North America, Europe, Mideast, East
Asia, Latin America
C: South Africa, South Asia, Ethiopia
D: East Africa
E: Southeast Asia
JAIDS 2002; 29:184
HIV-2
Primarily found in West Africa
Causes immune deficiency due to depletion of CD4
cells
5-8 fold less efficient transmission compared to
HIV-1
Associated with lower viral load
Slower rate of CD4 decline and clinical progression
Negative Ab tests in 20-30% depending on EIA
assay
WB: not well standardized nor FDA approved
Bartlett, JG 2003: Medical Management of HIV Infection, p5.
Testing Recommendations: HIV-2
Natives of endemic areas
Needle-sharing and sex partners of persons
from endemic areas
Sex or needle-sharing partners of persons
with known HIV-2 infection
Transfusion or non-sterile injection recipients
in endemic areas
Children of HIV-2 infected women
Other
West Africa
HIV-2 Endemic Areas
Benin
Burkina Faso
Cape Verde
Cote d’Ivoire
Gambia
Ghana
Guinea Guinea-Bissau
Liberia
Mali
Mauritania
Niger
Nigeria
Sao Tome
Senegal
Sierrra Leone
Togo
Mozambique
Angola
Confirmation Process: WB
Detects antibodies to HIV-1 proteins
Core: p17, p24, p55
Polymerase: p31, p51, p66
Envelope: gp41, gp120, gp160
Negative: no bands
Positive:
Reactivity to gp41 + gp120/160 or
Reactivity to p24+gp120/160
Indeterminate:
EIA repeatedly reactive
Presence of any band pattern not meeting criteria for
positive results
False Negative Results
High-prevalence population: 0.3%
Low-prevalence: <0.001%
Usually due to testing during window period
Rare patients seroconvert in late-stage
disease
Technical or clerical error
Type N or O
HIV-2
False Positive Test Results
Much less common than in earlier times
Frequency: 0.0004% to 0.0007%
Causes
Autoantibodies (single case, Lupus, ESRD)
HIV vaccines
EIA+: 68%
WB+: 0-44%
Technical / clerical error
NEJM 1988;319:961
Ann Intern Med 1989;110:617
Indeterminate Results
4-20% of WB assays with positive bands
Testing during seroconversion
p24 usually appears first
Late stage HIV: loss of core antibody
HIV vaccine recipients
Technical / clerical error
Infection with O strain or HIV-2
Indeterminate Results (continued)
Cross-reacting nonspecific antibodies
Collagen-vascular disease
Autoimmune disease
Pregnancy
Organ transplantation
Lymphoma, other malignancies
Liver disease
Multiple sclerosis
Recent immunization
Indeterminate Results
Evaluate HIV risk
Low risk: almost never infected with HIV-1 or
HIV-2
Repeat testing: often continued indeterminate
Cause: frequently not established
HIV unlikely
Follow-up serology in 3 months
Seroconversion: usually WB+ in 1 month
Repeat testing at 1, 2, 6 months
Counseling to reduce potential transmission
Frequency of HIV Testing
High risk behavior: every 6-12 months
Annual seroconversion
General population: 0.02%
Military recruits: 0.04%
MSM: 0.5 - 2%
IDU in high prevalence area: 0.7-6%
Alternative Testing
Home test kits
Rapid Testing
Alternative body fluids
Saliva
Urine
Vaginal secretions
Viral detection
Home Testing
Home specimen collection
Self-dried blood spot obtained with lancet
Anonymous coding
Mail/courier to testing facility
Double EIA and confirmatory IFA/WB
Sensitivity/Specificity: ~100%
Results relayed to user by telephone after user
initiates request
Negative: prerecorded message
Positive: live conversation and counseling
Rapid HIV Antibody Detection
Results in 15-20 minutes
Occupational exposure
Women in labor with unknown HIV status
Clients unlikely to return for visits
Outreach
ERs
Rapid HIV Antibody Detection
OraQuick HIV-1 Antibody Test (OraSure)
Results read by provider in 20 minutes
Sensitivity: 99.6% / Specificity: 100%
$20-30
Testing initially delayed due to CLIA requirements
Fingerstick sample of blood
Negative test: definitive
Positive test: needs standard serology confirmation
Not recommended for HIV-2 screening
Rapid HIV Antibody Detection
Single Use Diagnostic System (SUDS) HIV-1
Test
Venipuncture
Results: 15-30 minutes
Confirmatory WB required
Double Check (Organies)
Type N, Type O, HIV-2
EIA may fail to detect O subtype
N group: causes false-negative EIA but may
be WB positive
HIV-2: false negative EIA in 20-30%
Consider specific HIV-2 testing
P24 Antigen
Part of blood bank algorithms since 1996
Uncommon in clinical practice
Detects free, non-complex HIV antigens in
peripheral blood
1 mil
HIV
RNA
100,000
+
_
10,000
Ab
P24 +
1,000
100
Exposure
Symptoms
10
0
20
30
Days
40
50
HIV-1 Antibodies
HIV RNA
Typical Course of Primary
HIV
Rapid Test Results
Reactive (preliminary positive) rapid test
Screening test is positive
Preliminary result
Confirmatory testing required
Precautions to avoid viral transmission
Negative rapid test
No recent exposure: definitive negative
Possible recent exposure:
Recommend re-test
Counseling to prevent transmission
OraQuick: Florida DOH
6 Month Pilot Studies
Hillsborough CHD
Duval County Jail
Orlando CBO for substance abuse
Miami: 2 sites
Key West: only anonymous site
Saliva Testing: OraSure
EIA and WB to detect IgG
Specimen collection device, antibody screen, WB
confirmation
Cost: ~$25
Specially treated pad placed between lower cheek
and gum for 2 minutes
Vial sent to lab for processing
Sensitivity and specificity comparable to standard
serologic testing (~99.5%)
Advantages: ease of collection; low cost; improved
patient acceptance
Disadvantage: client must return for results
Urine Testing
Calypte HIV-1 Urine EIA
Positive results require standard serologic
confirmation
Sensitivity: 99%; Specificity: 94%
Cost: ~$4
Vaginal Secretions
IgG EIA
CDC: recommended for rape victims
Semen contains HIV IgG Ab
Indications for HIV Viral
Detection
Confusing / indeterminate serologic test
results
Acute retroviral infection
Neonatal infection
Window period following exposure
Not FDA approved for diagnosis of HIV
Expensive
Viral Detection
p24 Antigen
HIV-1 DNA PCR
Most sensitive: able to detect 1-10 copies of
proviral DNA
S/S: 99% / 98%
HIV-1 RNA (RT-PCR, bDNA)
S/S: 95-98%
Viral culture of PBMC: expensive, labor
intensive, reliability variable
Viral Detection: HIV-2
bDNA proficient at quantitation of many nonclade B viruses
Amplicor version 1.5 designed to detect other
clades
National Recommendations
For HIV Testing of
Pregnant Women
USPHS Recommendations for HIV Screening of
Pregnant Women (4-22-03)
Universal testing for all pregnant women as a routine
part of prenatal care using an “opt out” approach
Labor and Delivery: routine rapid testing if HIV status
unknown
Postnatal: rapid testing for all infants whose mother’s
status is unknown
Regulations, laws, and policies about HIV
screening of pregnant women vary from state to
state
Acute HIV Infection
Acute HIV Infection
Transient symptomatic illness in 40-90%
Usually mild but can be severe
2-6 weeks after infection
Often not recognized by primary care clinicians
Symptoms non-specific
Often resembles influenza, mononucleosis
“Cold symptoms” absent
Can be asymptomatic
Duration: 14 days
DHHS Guidelines July 14, 2003
HIV testing
• CDC statistics – illness is still the most common reason for testing
• ER study (inner-city Baltimore)
– Prevalence 11.3%, with majority being AA males, followed by AA women3
• Think HIV – urgent care sites in high-prevalence regions of MA4
– HIV prevalence was 2.2%, higher than state-funded testing programs
– Testing offered to all, not just those perceived as high-risk
– Intense focus on linkage to care: 88% return rate for those HIV+
• Failure to return for results:
– 508 subjects, 55% failed to return for results2
• Opt-out (actively refusing testing) leads to greater acceptance than opt-in
(actively agreeing to testing): 85-98% vs 25-83%1
1. Mbori-Ngacha D. 10th CROI, Boston 2003; #47; 2. Hightow LB, et al. ibid; #918; 3. Henson C, et al. ibid; #38;
4. Walensky RP, et al. ibid; #39
14
Acute HIV Infection
Fever
LAD
Pharyngitis
Rash
96%
74%
70%
70%
Headache
N/V
HSM
Wt loss
32%
27%
14%
13%
Myalgia/arthralgia
Diarrhea
54%
32%
Thrush
Neuro Sx
12%
12%
Neuro: meningoencepalitis or aseptic meningitis; peripheral neuropathy or radiculopathy;
facial palsy, Guillain-Barre syndrome; brachial neuritis; cognitive impairment or
psychosis
CDC 2002
Rash in Acute HIV Infection
Trunk, face, extremities
Palms and soles rarely involved
5-10 mm diameter
Erythematous, nonpruritic, painless
Laboratory Findings
Acute HIV Infection
Lymphopenia lymphocytosis
Atypical lymphocytes
Transient CD4 decline
VL: 100,000 – 1,000,000
Diagnosis of Acute HIV Infection
Recognition of clinical symptoms
No true constellation of signs/sympoms
Presence of any symptom(s)
History of activity associated with HIV risk
Detectable plasma HIV RNA
Highly sensitive
False positive possible
Detectable p24 Antigen
Less sensitive
False positive rare
Acute HIV Infection
High virus levels (105-106 copies/mL)
2-9% of HIV-negative have false positive
results
Usually associated with low RNA titers <10,000
VL in new infections
Correlates with rate of CD4 decline
Prognostic indicator in early disease
Potential Benefits: Early Intervention
Decrease the severity of acute disease
Alter initial viral set point alter disease
progression rate
Suppress viral replication reduce rate of viral
mutation
Preserve HIV-specific immune responses
May permit future discontinuation of therapy with
sustained viral control
Reduce risk for viral transmission
May minimize viral evolution and development of
viral diversity
DHHS Guidelines July 14, 2003
Potential Risks: Early Intervention
Decreased QOL
Medication side effects
Drug toxicities
Dosing constraints
Drug resistance if viral suppression
inadequate
Need for indefinite continuing therapy
Expensive
Potential for transmission of resistant virus
DHHS Guidelines July 14, 2003
Potential Risks: Early Intervention
Long term clinical outcome benefit has not
been documented
Additional studies are needed to delineate
the role of ARV therapy during the primary
infection period
DHHS Guidelines July 14, 2003
Treatment: Acute HIV Infection
Weigh potential benefits against potential
risks
“Certain authorities endorse treatment of
acute HIV infection on the basis of the
theoretical rationale and limited but
supportive clinical trial data”
DHHS Guidelines July 14, 2003
Treatment: Acute HIV Infection
Experienced clinicians recommend consideration of
therapy for patients among whom seroconversion
has occurred within the previous 6 months
“Although the initial burst of viremia among infected
adults usually resolves in 2 months, treatment
during the 2 to 6-month period after infection is
based on the probability that virus replication in
lymphoid tissue is still not maximally contained by
the immune system during this time”
DHHS Guidelines July 14, 2003
Detuned Antibody Testing
Less sensitive ELISA test
May help distinguish between recent seroconverters and
those with long-standing HIV infection
Current ELISAs can detect relatively low levels of Ab
HIV Ab levels increase over first few months
Recent infection: standard ELISA positive
Detuned assay: negative
Able to diagnose individuals who have already
seroconverted on a standard ELISA but are still early in
infection
HIV Superinfection
HIV Super-Infection
Coinfection with a second strain of HIV
during the course of established HIV-1
infection (Jost, NEJM 347:10, 2002)
Known to be theoretically possible
Little direct evidence to support concept
HIV Superinfection
2000: LTNP (patient A) – unprotected
intercourse with ARV-experienced male with
progressive HIV disease (patient B)
Patient A experienced rapid disease
progression
Virus harbored original strain and drugresistant strain from patient B
Angel, J. CROI 2000, Abs LB2
HIV Superinfection
Established infection with HIV-1, subtype AE
Well-controlled viremia on HAART; unable to
remain on ART due to liver toxicity
Sexual exposure to type B in Brazil
Unprecedented rise in viral load and rapid
CD4 depletion
Mixture of B and AE identified
Rapid emergence of type AE
Jost, S. NEJM 347:10, 2002
HIV Superinfection
Evidence supports clades from different
geographic areas have combined
Likely due to superinfection of an individual
harboring a virus of one clade with a second
virus of another clade
McCutchan et al, 1996:N AIDS 10: supp
Robertson et al, 1995: J Mol Evol: 40
SIV Superinfection
SIV superinfection in monkeys may occur, probably
rare
Difficult to superinfect a monkey with established
SIV even with
High infectious dose
IV administration
Possible when challenged with second SIV strain
during or soon after initial infection with first strain
Possible “window of opportunity” for superinfection
Sharpe et al, 1997: J Gen Virol: 78
SIV Superinfection
Development of virus-specific immunity over
time
Primary infection: immunity absent or too
immature to effectively prevent infection
Strengthening of virus-specific immune
responses superinfection less likely
Sharpe et al, 1997: J Gen Virol: 78
Superinfection
Implications for HC Providers
Consider the possibility of superinfection
Counsel patients regarding sexual practices
and safer sex
Summary
Significant advances in assays to detect HIV
infection
Alternatives to standard EIA/WB testing may
facilitate improved, ongoing HIV screening
Detection of acute HIV infection needs to enhanced
Early intervention in acute HIV infection may have
clinical benefits
Superinfection needs to be considered
Risk reduction counseling must be ongoing