HIV/AIDS
Recognition and Diagnosis of the
Acute Retroviral Syndrome
Andrew Urban MD
University of Wisconsin-Madison
HIV Care Program
Objectives
• Understand the challenges and importance associated
with establishing the diagnosis of the Acute Retroviral
Syndrome
• Discuss the role of acutely infected individuals in the
epidemiology of HIV
• Discuss the initial viral and immunologic events in the
pathogenesis of Acute HIV infection
• Understand the limitations and proper use of laboratory
tests in making the diagnosis of the Acute Retroviral
Syndrome
KM-1
• 26 year old female presents to an Emergency Dept in
Southern California with the following 2 week history:
– Abrupt onset severe fatigue
– Nausea
– Fever up to 103.8° daily for the first week, 100° since
– Rash on chest and arms, now fading
– Sore throat and enlarged neck glands, now improving
• Recently married, unemployed. Lives in south-
central Wisconsin. Remote hx of substance abuse.
HIV negative 3 months ago (tested just before
getting married).
KM-2
• On exam: VSS, afebrile, faint macular rash on chest
and back, palpable tender cervical and axillary LN.
No oral or genital sores.
• Labs: Monospot (negative), CBC (normal), HIV test
done in E.R. (negative), urine pregnancy (positive).
• Diagnosis from E.R. : Pregnant and has the flu.
KM-3
• Her and her husband return to Wisconsin.
• She is feeling better, but still tired.
• You see her in clinic and review her workup.
• Are you satisfied with what you see?
• Her HIV test is NEGATIVE. What should you do next?
A. Nothing, this is really bad morning sickness.
B. Order HIV-RNA (viral load) to confirm the diagnosis of HIV – her risk
factors make her a high pre-test probability.
C. Order HIV-RNA (viral load) to make the presumptive diagnosis of
Acute HIV.
D. Order standard HIV ELISA/Western Blot because the test done in the
E.R. was probably a rapid test and has poor sensitivity.
E. Order CD4 T-lymphocyte count for confirmation of HIV infection.
F. Order VDRL to diagnose secondary syphilis.
HIV: Making the Diagnosis
• Identifying risks and screening for HIV are important roles for non-HIV
specialists
• 4 out of 10 HIV infected individuals get a “late diagnosis”
– Diagnosis of HIV and AIDS made within 12 months
• Average CD4 count, new patient, UAB
– 104!
• Opportunities are often missed
– “Red flag” conditions (e.g. zoster, aseptic meningitis)
– Acute retroviral syndrome
HIV Testing - Routine Serology
Routine screening HIV Antibody testing has two parts, and
clinical labs follow standard algorithms.
• 1. ELISA (EIA) Antibody
– Highly sensitive
– When ELISA is repeatedly positive a HIV-1 Western Blot is
automatically performed
– Most algorithms incorporate HIV-2 specific EIA testing
• 2. Western Blot Antibody
– Highly specific
– A Western Blot is never ordered by itself
– Reported as positive, negative, or indeterminate
WB
Diagnosis of HIV established
Positive
Evolving antibody
ELISA WB response in early
Positive Indeterminate infection OR false +
ELISA
WB
Early infection OR false + ELISA
Negative
HIV Testing - Routine Serology
• It takes time to evolve the antibody response
– Serology usually first become positive 3-4 weeks post-exposure, and
nearly all (95%) individuals are positive by 8 weeks
– Rare cases of HIV seroconversion window periods lasting > 6 months
involving occupational exposure to HIV as well as co-transmission of HIV
and HCV
• Accuracy of combined tests
– sensitivity >99.9% specificity >99.9%
NEJM 1997;337;1485
KM-2
• On exam: VSS, afebrile, faint macular rash on chest
and back, palpable tender cervical and axillary LN.
No oral or genital sores.
• Labs: Monospot (negative), CBC (normal), HIV test
done in E.R. (negative), urine pregnancy (positive)
• Diagnosis from E.R. : Pregnant and has the flu.
Alternative Testing Methods for
Diagnosing Chronic HIV Infection
• Home Kits (Confide™)
– Finger stick, put blood on filter strip
– Mail in : 3d (FedEx) or 7d turnaround
• Saliva Testing (OraSure™)
– Pad placed between cheek and gum (saliva IgG)
– Mail in : 3d turnaround
• Rapid Tests (OraQuick™)
– Fingerstick blood test, performed in local labs
– 20 minute turnaround
– If negative no further testing
– If positive always need standard testing to confirm
The Acute Retroviral Syndrome
• Acute HIV infection = Primary HIV infection; the clinical
syndrome associated with this phase of the illness is the
Acute Retroviral Syndrome
• Transient symptomatic viral syndrome occurring soon
after initial exposure to HIV, and associated with high
levels of HIV replication
Acute Retroviral Syndrome
• First clinical manifestation of HIV infection
– 2-6 weeks after exposure
– Self-limited illness lasts one to several weeks
• Most (50-90%) individuals are symptomatic
– 15% are hospitalized
– Can sometimes have opportunistic infections
• Commonly misdiagnosed
– Risk factors are not asked
– Called a “viral syndrome” as presentation usually nonspecific
– Mimics acute mononucleosis or acute influenza
Acute Retroviral Syndrome
• Public Health Risk
– extremely infectious: high titer HIV-RNA
– 40-60% of all new infections are transmitted by acutely
infected individuals
– drug-resistant HIV transmission rapidly increasing
• Early treatment with HAART during Acute HIV may
augment HIV-specific immune function
Am J Public Health 1997;87:1928 Nature 2000;407:523
Drug-Resistant HIV
• Newly diagnosed individuals
– Significant increases in multiclass drug-resistant HIV in recently
infected individuals have been reported worldwide
• Time trends in Primary HIV-1 drug resistance among 225
recently infected persons, San Francisco (JAMA 2002;288:181)
Mutations Associated With Drug Resistance (%)
NRTI NNRTI PI > 2 classes
1996-97 25 0 2.5 2.5
2000-01 20.9 13.2 7.7 13.2
“Mono- or flu-like” illness.
Clues to HIV
NEJM 1998;339:33-39
More Severe Clinical Findings Can Be
Associated with Acute Retroviral Syndrome
• Neurologic
– Aseptic meningitis
– Acute encephalitis
– Guillain-Barre’
– Bell’s palsy
• Opportunistic infections
– Thrush
– PCP
– Reactivation of TB, cryptococcus, toxoplasmosis, CMV, etc
• Others
– Vasculitis, myocarditis, hepatitis, hemophagocytic syndrome, etc
Early Events During Sexual
Transmission of HIV
• Virus contacts mucosal surface and is transported to regional lymph
nodes by mucosal dendritic cells (time ~ 48 hours)
• CD4 T-lymphocyte rich lymph node environment supports intense viral
replication and initial viremia (time ~ 4 days)
• Increase in plasma HIV-RNA with widespread dissemination to CNS,
spleen, and gut-associated lymphatic tissue (time ~ 4-11 days)
• Onset of clinical symptoms (time ~ days to weeks)
• HIV-specific CD4 and CD8 T-cell mediated immune responses vigorously
lower viral load until the “setpoint” is reached (time ~ 6-12 months)
Viral Load
CD4 Count
CD4 and CD8 HIV Specific Immune Responses
~ 6-12 months
Viral Load Set Point
Diagnosis of Acute HIV
• What to Order: tests to look directly for the virus as well as
routine HIV antibody testing
• Why: routine antibody testing is usually negative at the time of
Acute HIV presentation so we must look for direct evidence of
the virus, in addition full seroconversion must be documented in
all cases from start to finish.
• Tests to look directly for the virus
– Plasma HIV-RNA (not FDA approved for diagnosis) or
– Plasma p24 Antigen (FDA approved for diagnosis)
• Routine HIV Antibody testing
– Expect NEGATIVE or WEAKLY POSITIVE result
– Repeat immediately and in 6 weeks, document full seroconversion
Serology and Virology in Acute HIV
HIV-EIA WB P24 HIV-RNA
− − + +
+ − + +
+ Ind + +
+ + + +
The hallmark of Acute HIV Infection is a high level of
Plasma HIV-RNA or HIV p24 Ag in the setting of a negative
ELISA, a negative or evolving Western Blot, and subsequent
Demonstration of complete seroconversion
The Use of Plasma HIV-RNA (viral load)
in the Diagnosis of Acute HIV
• Not FDA approved
• Positive 5 days before the p24 Ag assay, and 1-3 weeks
before the detection of antibodies
• Be aware of potential for false-positives
– Average plasma HIV-RNA during symptomatic acute infection is
greater than 10 million copies/ml
– As person recovers, viral load comes down towards set point
– Low values (especially < 5000 copies/ml) should raise the
question of a false-positive test, and prompt additional testing
• Always get follow-up serology to document complete
seroconversion
Am J Med 1997;102:117
Diagnosis of Primary HIV-1 Infection
436 patients with symptoms consistent with primary HIV
54 (12.4%) diagnosed with primary HIV
Positive Positive
HIV RNA p24 Ag
Primary HIV 54/54 (100) 47/53 (88.7)
Uninfected 8/303 (2.6) 0/303 (0)
mean HIV-RNA = 269 copies/ml (52-1950)
Ann Int Med 2001;134:25-29
Acute HIV: To Treat or Not To Treat
• Optimal management of Acute HIV with HAART remains
controversial
• Potential benefits tempered by drug-associated toxicites
and need for long-term high level adherence
• Small studies have found that acutely infected
individuals treated with HAART using structured
treatment interruptions can lead to augmented HIV-
specific immune responses, and a lower viral set point
when HAART is stopped
Nature 2000;407:523
Management of the
Acute Retroviral Syndrome
• Symptomatic care, vigilance for OIs
• Evaluate for other potential exposures as appropriate
– VDRL, GC, Chlamydia, HSV, HPV, HAV, HBV, HCV, CMV
• Counsel on transmission risks
• Refer to HIV specialist ASAP
When to Refer to HIV Specialist
• Urgently
– acute HIV infection
– recently acquired infection (< 6 months)
– pregnancy
– active OI
• All antiretroviral and resistance testing decision making
• Interpretation of serologic testing
– indeterminate western blot or positive HIV-RNA
• Post-exposure prophylaxis
– drug choices/intolerance or concerns about resistance