Download HIV Diagnosis,Acute Infection and Superinfection

D-HIV Diagnosis,
Acute Infection and Superinfection
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
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
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
HIV-2
Primarily found in West Africa
Causes immune deficiency due to depletion of CD4
cells
5-8 fold less efficient transmission compared to HIV1
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
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
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
Acute HIV Infection
Fever
96%
Headache
32%
LAD
74%
N/V
27%
Pharyngitis
70%
HSM
14%
Rash
70%
Wt loss
13%
Myalgia/arthralgia
54%
Thrush
12%
Diarrhea
32%
Neuro Sx
12%
Neuro: meningoencepalitis or aseptic meningitis; peripheral neuropathy or radiculopathy;
facial palsy, Guillain-Barre syndrome; brachial neuritis; cognitive impairment or psychosis
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
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
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
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”
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”
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
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
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
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
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
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