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Real-time, Universal Screening for Acute HIV Infection in a Routine HIV Counseling and Testing Population
Christopher D. Pilcher, MD;
J. Todd McPherson, MS;
Peter A. Leone, MD;
Marlene Smurzynski, MSPH;
Judy Owen-O'Dowd, BS;
Amy L. Peace-Brewer, PhD;
Juanita Harris, BS;
Charles B. Hicks, MD;
Joseph J. Eron, Jr, MD;
Susan A. Fiscus, PhD
JAMA. 2002;288:216-221.
ABSTRACT
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Context Acute human immunodeficiency virus (HIV) infection cannot be diagnosed
by routine antibody tests and is rarely diagnosed in clinical practice. However,
HIV nucleic acid–based testing is widely used to screen for antibody-negative
acute infection among low-risk blood donors.
Objective To assess the feasibility of screening in high-volume laboratories for
acute and long-term HIV infection in a routine HIV testing population, in
which HIV infection prevalence is low, using specimen pooling and HIV RNA
reverse transcriptase-polymerase chain reaction (RT-PCR) tests.
Design and Setting Clinical diagnostic performance evaluation at a state-funded public
health virology and serology laboratory.
Participants A total of 8505 consecutive individuals presenting for routine HIV counseling
and testing during a total of 20 business days to simulate a month of testing
in August and December 2001 at 110 publicly funded testing sites in North
Carolina.
Main Outcome Measures Prevalence of acute and long-term HIV infection. Serum specimens negative
by HIV enzyme immunoassay (EIA) were screened in pools by an ultrasensitive
HIV RNA RT-PCR test. Results for individual HIV RNA–positive specimens
were reclassified as true or false according to results of confirmatory testing.
Results Of the 8505 individuals screened, 8194 had not previously tested HIV
positive and had sufficient serum to complete the testing protocol. Of those,
39 had long-term HIV infection (prevalence, 47.6 per 10 000 at-risk persons
[95% confidence interval, 33.8-65.0 per 10 000]). Of the 8155 at-risk
individuals whose antibody tests were negative, 5 were HIV RNA positive. Four
of those had true-positive acute infection (prevalence, 4.9 per 10 000
[95% confidence interval, 1.3-12.5 per 10 000]). All 4 were women; 2
developed symptoms consistent with an acute retroviral syndrome in the week
after testing. Screening all specimens required 147 HIV RNA tests. Overall
specificity of the strategy was 0.9999.
Conclusions These findings suggest the widespread diagnosis of acute HIV infections
in a routine testing population is not only possible but feasible using specimen
pooling and nucleic acid testing. These additional procedures may increase
diagnostic yield by approximately 10% compared with conventional HIV antibody
testing.
INTRODUCTION
An estimated 40 000 persons are infected with human immunodeficiency
virus (HIV) each year in the United States.1
Although the potential individual2-3
and public health4-8
benefits of recognizing acute HIV infection have been discussed, the diagnosis
is rarely made in practice.9-10
There are no public health systems in place to facilitate acute HIV infection
diagnosis. Proposed sensitive/less sensitive antibody testing algorithms11-12 distinguish recent from more long-standing
infections but only after seroconversion. Real-time diagnosis of acute HIV
infection requires a positive HIV p24 antigen or HIV nucleic acid test result,
together with a negative, equivocal, or evolving HIV antibody test result.13 Because specimen pooling and nucleic acid amplification
of HIV antibody–negative specimens can permit accurate, low-cost blood
product HIV and hepatitis screening14 and can
be used for estimation of HIV incidence,8 we
hypothesized that a nucleic acid–based screening strategy incorporating
multistage pooling could make screening for acute infection feasible in settings
with presumably low disease prevalence but high testing volume, such as large
commercial and state public health laboratories.
METHODS
Study Design
We conducted a clinical diagnostic performance evaluation, comparing
standard of care HIV antibody testing with a protocol including both HIV antibody
testing and HIV RNA reverse transcriptase-polymerase chain reaction (RT-PCR)
on pooled HIV-seronegative specimens. Specimens positive for HIV RNA by RT-PCR
testing were confirmed by HIV seroconversion. The protocol was approved by
the University of North Carolina at Chapel Hill Committee on the Protection
of the Rights of Human Subjects. Because of the nature of the study, a waiver
for requirement of informed consent was approved by the committee. Individuals
had previously provided written consent for HIV testing and a confidentiality
policy was already in place for HIV testing in the health departments.
Population
Consecutive serum samples submitted to the North Carolina State Laboratory
of Public Health for routine HIV testing from 110 publicly funded testing
centers were tested according to the study protocol. Testing centers include
sexually transmitted disease (STD), antenatal, and other publicly funded clinics,
as well as nontraditional (eg, mobile) HIV counseling and testing sites. A
pilot phase examined 2013 specimens submitted over 4 days in August 2001.
When follow-up was complete for individuals in the pilot phase, including
evaluation of pilot protocols, additional specimens (n = 6492) were collected
on 16 consecutive business days in December 2001 to simulate 1 month of continuous
testing.
Clinical Information
Self-reported testing history and demographic and lifetime risk information
were obtained at the time of specimen collection. Linked data, such as risk,
demographic, and testing site information, were abstracted for all individuals
from the Counseling and Testing Services Database created by the US Centers
for Disease Control and Prevention and maintained for the North Carolina HIV/STD
Prevention and Care Branch by the State Laboratory of Public Health. Contact
information was maintained separately by the state laboratory of public health
for confidentiality protection. Where multiple risk factors existed for individuals,
risk categories were resolved by a standard hierarchical structure proposed
by the US Department of Health and Human Services.15
Definitions
Individuals were considered at risk for HIV infection if they had no
prior positive HIV test result by self-report or on record with the North
Carolina Department of Health and Human Services. Infection with HIV was defined
by a repeatedly reactive HIV enzyme immunoassay (EIA) result at either initial
or confirmatory testing together with a positive HIV Western blot result.
Specimens were considered HIV antibody negative on initial testing that were
EIA negative (no repeat EIA or testing by Western blot), EIA reactive once
but not repeatedly reactive (no testing by Western blot), or EIA repeatedly
reactive but with a negative or indeterminate Western blot result. Following
pooling and RT-PCR testing on antibody-negative specimens, patients with an
antibody-negative specimen who were HIV RNA positive and were subsequently
confirmed to be HIV infected (with the confirmatory protocol described below),
were classified as having acute HIV infection.
Initial Testing Protocol
All specimens were identified by testing number only and all laboratories
were blinded to clinical information. Initial HIV-EIA antibody testing was
done on all specimens using the Vironostika HIV-1 Microelisa System (viral
lysate) (Biomerieux, Durham, NC). Repeatedly EIA-reactive specimens were confirmed
by BioRad Western blot (BioRad, Hercules, Calif). Specimens that were HIV
antibody negative were then manually pooled according to a pyramid-type pooling
scheme modified from a protocol described by Quinn et al8
and were screened for the presence of HIV RNA using RT-PCR tests. Pooling
and HIV RNA screening procedures are illustrated in Figure 1. The pooling procedure relied on 1 full-time technician
to process about 500 specimens daily. A 4-stage 100:1, 50:1, and 10:1 pooling
scheme was used for the pilot phase; for the continuation phase, the 3-stage
90:1, 10:1, and 1:1 scheme shown in Figure
1 was substituted for more rapid diagnosis. Master pool screening
used Roche Ultrasensitive (Roche Diagnostics, Branchburg, NJ; an absolute
lower limit of detection of 20 copies/mL permits detection of individual specimens
with >1800 copies/mL in a master pool with 1:90 dilution). Resolution testing
of HIV RNA–positive master pools used the standard Roche Monitor kit
(absolute lower limit of detection, 200 copies/mL), with the exception of
the 50-specimen intermediate pools tested by Ultrasensitive in the project's
pilot phase. Confirmatory RT-PCR was performed on all HIV RNA–positive
specimens before they were reported as being HIV positive.
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Figure 1. Schema for Pooling HIV-Seronegative
Specimens and for Resolution Testing of HIV RNA–Positive Master Pools
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Initial Confirmatory Testing Protocol
Following initial EIA testing, pooling, and initial RT-PCR and confirmatory
RT-PCR testing, antibody-negative, HIV RNA–positive specimens were submitted
to confirmatory antibody testing. To account for differing sensitivities of
EIA kits in the setting of acute HIV infection,16
these specimens were retested using the viral lysate EIA and tested using
HIVAB HIV-1/2 ELISA (enyzme-linked immunosorbent assay), a more sensitive
recombinant peptide-based third-generation EIA (Abbott Diagnostics, Abbott
Park, Ill). A Western blot was run on each confirmed HIV RNA–positive
specimen.
Follow-up Confirmatory Testing
Patients were notified of their result by North Carolina Department
of Health and Human Services HIV/STD Prevention and Care Branch disease intervention
specialists, interviewed about possible symptoms of acute infection, and encouraged
to return for a repeat blood draw and follow-up confirmatory testing. The
viral lysate EIA and Western blot were run on these confirmatory samples.
Descriptive statistics were generated using STATA software (College
Station, Tex).
RESULTS
In total, 8505 specimens were received during the study period; pilot
and continuation phase populations were similar regarding sex, age, and risk
category (C.D.P., unpublished data, April 2002). The disposition of specimens
is given in Figure 2. Specimens
from 299 patients had insufficient sample volume to complete the testing protocol
and were not analyzed; they were also similar to those of the overall population
(C.D.P., unpublished data, April 2002). Twelve specimens from patients who
were diagnosed previously as having HIV were not eligible for pooling. Of
the 8194 remaining specimens, 39 were HIV antibody positive and were also
not submitted for pooling. We used the 8194 specimens eligible for pooling
as the denominator for estimation of acute infection prevalence to allow for
prevalence of both acute and long-term HIV infection to be assessed and compared
relative to the overall pool of at-risk subjects. The 8155 HIV antibody–negative
specimens were pooled and screened for HIV RNA.
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Figure 2. Disposition of Specimens Screened
for HIV RNA and Antibodies From Publicly Funded Testing Sites During a Total
of 20 Business Days in North Carolina
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A total of 147 HIV RNA determinations were required to complete all
testing, equivalent to 1 HIV RNA determination per 55 specimens initially
submitted. Manual pooling and HIV RNA detection procedures were completed
within 14 days of specimen receipt during the project's continuation phase.
Five specimens were HIV RNA positive. The details of confirmatory testing
are given in Table 1. Patient A
had an initial viral load of 1771 copies/mL. The HIV RNA positivity was confirmed
on repeat testing of the same specimen. However, the patient had no evidence
of seropositivity on either repeat testing of the initial sample or at the
follow-up confirmatory blood draw 2 months later. The HIV RNA RT-PCR test
was performed to validate the negative antibody results at follow-up and results
were also negative. Thus, patient A was classified as false-positive. The
remaining 4 HIV RNA–positive individuals, patients B through E, were
each confirmed to be HIV infected and each were classified as acute. Patients
B and C were initially negative by all antibody testing and later seroconverted.
Patient D was negative by viral lysate EIA, was weakly positive by the more
sensitive EIA, and was negative by Western blot. Patient D had fully seroconverted
by the follow-up confirmatory draw. Patient E was initially positive by the
more sensitive EIA but at an unusually low optical densitometry value consistent
with low titer of antibody. This patient refused a confirmatory draw. Final
classification of patient E as acute was based on the common presumption11-12 that low HIV antibody titers indicate
recent or acute HIV infection.
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Table. Results of Tests Used for Reclassification
of Human Immunodeficiency Virus (HIV) RNA–Positive, HIV Antibody–Negative
Results
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Thus, HIV RNA screening yielded 4 additional true-positive and 1 false-positive
results. The positive predictive value (PPV) of HIV RNA RT-PCR testing for
diagnosing acute infection with antibody-negative specimens in this study
was 0.80 (95% confidence interval [CI], 0.26-1.00) and the estimated specificity,
0.9999 (95% CI, 0.9993-1.000). The overall PPV of the serial antibody and
HIV RNA RT-PCR testing strategy for either acute or long-term HIV infection
was 0.98 (95% CI, 0.88-1.00) with specificity of 0.9994 (95% CI, 0.9986-0.9998).
Because confirmatory testing results are lacking for HIV antibody–negative
patients who tested negative for HIV RNA, the true sensitivity cannot be estimated,
and it is possible that overall specificity may have been slightly overestimated.
Acute vs Long-term HIV Infection
The 4 patients with confirmed HIV antibody–negative acute infections
detected by the study protocol represented a 10.3% increase in diagnostic
yield, above the 39 new HIV infections diagnosed with antibody testing alone
during the study period. Overall acute HIV infection prevalence was estimated
at 4 per 8194 or 4.9 per 10 000 persons at risk (95% CI, 1.3-12.5 per
10 000). The overall long-term HIV infection prevalence estimate of 47.6
per 10 000 persons (95% CI, 33.8-65.0 per 10 000) was consistent
with North Carolina's annual prevalence figures.17
All 4 acute infections were in women presenting for testing at STD clinics.
One woman had painful genital ulceration at the time of testing; mucocutaneous
ulceration of the genitals can be a presenting feature of the acute retroviral
syndrome (http://hivatis.org/trtgdlns.html#Adult). A genital ulcer
viral culture was negative for herpes simplex virus. Three women had no symptoms
to suggest acute retroviral syndrome at testing (1 was tested after presenting
for evaluation of chronic vaginitis, and 2 were tested because of concern
with risky sexual exposures.) Two women developed symptoms consistent with
an acute retroviral syndrome in the week following testing; 1 presented to
an emergency department and was diagnosed as having acute urinary tract infection.
COMMENT
This first clinical evaluation of real-time universal acute HIV infection
screening showed that in a routine HIV-testing population, a number of prevalent
HIV infections may be missed by routine antibody testing. The observed prevalence
of acute HIV infection in at-risk persons undergoing routine HIV testing in
North Carolina (4.9 cases per 10 000) was similar to estimates derived
from retrospective studies of routine testing populations in Europe18-20 and is about 1000-fold
higher than that found in low-risk blood donors with similar testing procedures.14
Time, Cost, and Accuracy
All continuation-phase testing was completed within 14 days of specimen
receipt, at an estimated additional cost of US $2.01 per specimen or $4109
per additional case diagnosed. Resolution testing of only positive pools markedly
improves both the approximate overall specificity (0.9999) and PPV (0.80)
of nucleic acid–based testing, which may otherwise be prone to an unacceptable
rate of false-positive results.13 The imperfect
sensitivity of nucleic acid testing for early acute infection can be further
reduced by pooling, and it is imperative that patients with recent exposures
still be counseled to have follow-up testing if all initial testing results
are negative.
Potential Implications for Public Health
The ability to identify patients with acute HIV infection in real time
could potentially provide clinical benefits to the individuals identified
since early initiation of antiretroviral therapy may improve long-term prognosis.2-3 This information could present a unique
public health opportunity to influence the risk of sexual transmission occurring
at a time of particular contagiousness.4-5,7, 12, 21-26
Sexual partners of individuals with acute HIV infection may be candidates
for postexposure prophylaxis. Tracing both source patients and exposed partners
could facilitate direct interventions targeting networks with active HIV transmission.6-7
The strategy presented herein is limited in that the pooling that makes
this strategy medically and economically feasible is possible only in laboratories
that have large testing volume, such as public health and commercial laboratories.
The relative cost advantage of pooling over individual testing may be lost
in settings where acute infection prevalence may be high. Additionally, regulatory
concerns could delay implementation of commercial attempts to adapt blood-screening
procedures to the clinical setting.
However, this study suggests that HIV nucleic acid–based screening
could make early diagnosis, entry into care, and partner screening possible
for persons with acute HIV infection who would otherwise be missed.
AUTHOR INFORMATION
Financial Disclosures: Dr Pilcher has received
research grants or funding, honoraria including for continuing medical education
(CME) programs, lecture sponsorships, assay kits or reagents, or government
grants or research funding from or is a consultant to Beckman-Coulter, Biomerieux,
GlaxoSmithKline, Immunex, and Roche; Dr Hicks has research grants or funding,
honoraria including for CME, or government grants or research funding from
or is a consultant to Abbott, Agouron, Bristol-Myers Squibb, Boehringer Ingelheim,
DuPont, Merck, Roche, Triangle, and ViroLogic; Dr Eron is a principal investigator
for University of North Carolina research contracts from Abbott, Merck, Roche/Trimeris,
and Pharmasett; consultant to, receives research grant funding or honoraria
for ad hoc consulting, sponsored talks, or CME programs from Abbott, Boehringer
Ingelheim, Bristol-Myers Squibb, GlaxoSmithKline, Merck, NIH-NIAID, Substance
Abuse and Mental Health Services Administration, Triangle Pharmaceuticals,
Trimeris, ViroLogic, and Tibotec-Virco; Dr Fiscus has received research grants
or funding, assay kits or reagents, or government grants or research funding
from or is a consultant for BioMerieux, Centers for Disease Control and Prevention,
CONRAD, GlaxoSmithKline, National Institutes of Health, PerkinElmer LifeSciences,
Roche Molecular Systems, and Visible Genetics.
Author Contributions: Dr Pilcher had full access
to all the data in the study and takes responsibility for the integrity of
the data and the accuracy of the data analysis.
Study concept and design: Pilcher, Leone, Hicks,
Eron, Fiscus.
Acquisition of data: Pilcher, McPherson, Leone,
Owen-O'Dowd, Peace-Brewer, Harris, Eron, Fiscus.
Analysis and interpretation of data: Pilcher,
Leone, Smurzynski, Hicks, Eron
Drafting of the manuscript: Pilcher, Leone,
Owen-O'Dowd, Harris, Eron.
Critical revision of the manuscript for important
intellectual content: McPherson, Leone, Smurzynski, Peace-Brewer, Hicks,
Eron, Fiscus
Statistical expertise: Smurzynski.
Obtained funding: Pilcher, Hicks, Eron.
Administrative, technical, or material support:
Pilcher, McPherson, Leone, Owen-O'Dowd, Peace-Brewer, Harris, Hicks, Eron,
Fiscus.
Study supervision: Pilcher, Leone, Eron, Fiscus.
Funding/Support: This work was funded in part
by UNC Center for AIDS Research grants NICHD/NIAID 9-P30-AI50410-04 from the
National Institute of Child Health and Human Development and National Institute
of Allergy and Infectious Diseases, grants NIDDK-R0149381, AI-07001, K23AI01781-01,
and K24 AI01608-01 from the National Institutes of Health. Boehringer Ingelheim
supported a poster presentation but had no input into its content.
Previous Presentation: This work was presented
in part at the 9th Conference on Retroviruses and Opportunistic Infections,
Seattle, Wash, February 2002. Abstract 359-M.
Acknowledgment: We thank Lou Turner, PhD, and
the staff of the Laboratory of Public Health Serology/Virology who did the
antibody testing and pooling. Regina Lee, BS, provided assistance with data
collection and management. Ada Cachafeiro, BS, Mark Turner, BS, Amy James,
BS, Paul Alabanza, BS, and Priya Joshi, BS, of the UNC Center for AIDS Research
Retrovirology Core Laboratory pooled specimens for the pilot phase; Melissa
Kerkau, BS, performed the virologic testing throughout. Confirmatory antibody
testing was done by the staff of the McLendon Clinical Laboratories at UNC-Chapel
Hill. We especially thank the Disease Intervention Specialists of the HIV/STD
Prevention and Care Branch of the NC Department of Health and Human Services
for contacting and interviewing patients, and Del Williams, PhD, for assistance
with the HIV Prevention and Care Database. Sonia Napravnik, MPH, and William
Miller, MD, PhD, and Myron Cohen, MD, MPH, provided critical review of the
manuscript.
Corresponding Author and Reprints: Christopher
D. Pilcher, MD, CB No. 7030, 547 Burnett-Womack Bldg, University of North
Carolina at Chapel Hill, Chapel Hill, NC 27599-7030 (e-mail: cpilcher{at}med.unc.edu).
Author Affiliations: Departments of Medicine
(Drs Pilcher, Leone, and Eron), Epidemiology (Ms Smurzynski), and Microbiology
and Immunology (Drs Peace-Brewer and Fiscus), University of North Carolina
at Chapel Hill; North Carolina State Laboratory of Public Health, Serology/Virology
Laboratory, Raleigh (Mr McPherson and Ms Harris); HIV/STD Prevention and Care
Branch, North Carolina Department of Health and Human Services, Raleigh (Dr
Leone and Ms Owen-O'Dowd); and Department of Medicine, Duke University, Durham,
NC (Dr Hicks).
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Toward Optimal Laboratory Use Section Editor:
David H. Mark, MD, MPH, Contributing Editor.
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