Acute and Early HIV Infection - Clinical Manifestations and Diagnosis - UpToDate

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Acute and early HIV infection: Clinical manifestations and

diagnosis
Author: Paul E Sax, MD
Section Editor: Rajesh T Gandhi, MD, FIDSA
Deputy Editor: Jennifer Mitty, MD, MPH
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Mar 2023. | This topic last updated: Apr 18, 2022.
INTRODUCTION
Acute human immunodeficiency virus (HIV) infection may present as a mononucleosis type of
syndrome with a constellation of nonspecific symptoms. Without a high degree of suspicion,
the diagnosis can frequently be missed by clinicians. In some cases, early HIV infection may be
asymptomatic.
The clinical manifestations and diagnosis of acute and early HIV will be reviewed here. The
pathogenesis, epidemiology, and treatment of early HIV infection are discussed separately. (See
"Acute and early HIV infection: Pathogenesis and epidemiology" and "Acute and early HIV
infection: Treatment".)
DEFINITIONS
Different terms, including acute, recent, primary, and early HIV infection, have been used in the
literature to refer to variable intervals following initial infection with the virus. In this topic, we
use the term "early HIV infection" to refer to the approximate six-month period following HIV
acquisition. We use the term "acute HIV infection" to refer to symptomatic early infection, as
this reflects common usage in clinical care.
CLINICAL FEATURES
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Asymptomatic infection — An estimated 10 to 60 percent of individuals with early HIV

infection will not experience symptoms, although the exact proportion is difficult to estimate
since patients generally come to attention because of symptoms, and thus asymptomatic
infections often remain undetected. In a study of 50 acutely infected individuals who had been
identified by prospective viral testing of high-risk individuals and then were followed twice
weekly, almost all had at least one reported symptom or sign during the first four weeks of
infection, but these were mainly short-lived, nonspecific, and unlikely to have brought the
individual to clinical attention outside of a study setting [1]. Subjects complained of symptoms
at only 29 percent of the biweekly study visits during this period.
Time course — In patients who have acute symptomatic infection, the usual time from HIV
exposure to the development of symptoms is two to four weeks, although incubation periods
as long as ten months have been observed [2]. In one study that evaluated viral dynamics
following HIV infection, the highest frequency of symptoms and signs were observed just
before peak viremia occurred, approximately two weeks after the initial detection of viral RNA
[1]. It is possible that the route of acquisition and quantity of virus inoculum influence the time
to peak viremia and the length of the incubation period.
Most symptoms associated with acute HIV infection are self-resolving; however, the severity and
duration of symptoms vary widely from patient to patient.
Signs and symptoms — A variety of symptoms and signs may be seen in association with acute
symptomatic HIV infection. This constellation of symptoms is also known as the acute retroviral
syndrome. Published series consistently report that the most common findings are fever,
lymphadenopathy, sore throat, rash, myalgia/arthralgia, diarrhea, weight loss, and headache
( table 1) [1,3-7]. None of these findings is specific for acute HIV infection, but certain
features, especially prolonged duration of symptoms and the presence of mucocutaneous
ulcers, are suggestive of the diagnosis.
Beyond these more common symptoms, a wide range of other symptoms have been described
in patients with acute or early HIV infection. In one prospective study of 290 such patients, 17
percent were ill enough to require hospitalization [6]. In addition, 26 percent of patients were
considered to have atypical symptomatic presentations, including opportunistic infections and
central nervous system manifestations.
The presence and increased severity and duration of symptoms appear to be poor prognostic
factors [8-10]. As an example, in a study of 218 female sex workers with well-documented dates
of HIV seroconversion based on longitudinal screening, each additional symptom present at the
time of acute infection was associated with an increasing risk of overall mortality after a median
follow-up of 4.6 years [10]. Importantly, these data were collected on patients who did not have
access to HIV therapy.
Constitutional symptoms — Fever, fatigue, and myalgias are the most common symptoms
reported by patients with acute HIV infection [1,8,11]. Fever in the range of 38 to 40ºC is present
in the vast majority of patients with symptomatic acute HIV infection [4,9,12-14]. In one study of
41 patients, the mean maximum reported temperature was 38.9ºC [15].
Adenopathy — Nontender lymphadenopathy primarily involving the axillary, cervical, and

occipital nodes is also common. Adenopathy often develops during the second week of the
illness, concomitant with the emergence of a specific immune response to HIV. The nodes
decrease in size following the acute presentation, but a modest degree of adenopathy tends to
persist [14]. Mild hepatosplenomegaly also can occur [16].
Oropharyngeal findings — Sore throat is a frequent manifestation of acute HIV infection. The
physical examination reveals pharyngeal edema and hyperemia, usually without tonsillar
enlargement or exudate [17,18]. However, unilateral or bilateral tonsillitis has also been
described [6].
Painful mucocutaneous ulceration is one of the most distinctive manifestations of acute HIV
infection. Shallow, sharply demarcated ulcers with white bases surrounded by a thin area of
erythema may be found on the oral mucosa, anus, penis, or esophagus [19]. These ulcerative
lesions may reflect mucocutaneous disease associated with acute HIV infection [14] or
coincident sexually transmitted infections, such as herpes simplex virus, syphilis, or chancroid
[20]. In one study of 10 men who have sex with men (MSM) with acute HIV infection and
mucocutaneous ulceration limited to one location, the lesions occurred at a site involved in
sexual activity at the time of probable transmission. (See "Prevention of sexually transmitted
infections".)
In another study of 16 men with acute HIV infection and odynophagia, endoscopy
demonstrated esophageal ulcers 0.3 to 1.5 cm in diameter in all of the patients [21]. Tissue
obtained from these ulcers in eight of the subjects revealed virus particles by electron
microscopy that were morphologically consistent with HIV; in one patient HIV was cultured
from the lesion.
Rash — A generalized rash is also a common finding in symptomatic acute HIV infection. The
eruption typically occurs 48 to 72 hours after the onset of fever and persists for five to eight
days. The upper thorax, collar region, and face are most often involved, although the scalp and
extremities, including the palms and soles, may be affected. The lesions are characteristically
small (5 to 10 mm), well-circumscribed, oval or round, pink to deeply red colored macules or
maculopapules [19]. Vesicular, pustular, and urticarial eruptions have also been reported
[18,22] but are not nearly as common as a maculopapular rash. Pruritus is unusual and only
mild when present.
Histopathologic findings are nonspecific in the skin lesions, and biopsy of a skin lesion usually
does not assist in the diagnosis of acute HIV infection. The epidermis is normal and the dermis
contains a sparse lymphocytic infiltrate, mainly around vessels of the superficial plexus [16].
Gastrointestinal symptoms — Since the gastrointestinal tract is a primary target during

acute infection, patients with acute HIV infection often complain of nausea, diarrhea, anorexia,
and weight loss, averaging 5 kg. More serious gastrointestinal manifestations are rare and
include pancreatitis and hepatitis [23,24].
Neurologic findings — Headache, often described as retroorbital pain exacerbated by eye

movement, frequently accompanies acute HIV infection. More serious neurologic
manifestations of acute HIV infection have also been reported but are unusual [6,25].
The first severe neurologic syndrome to be recognized was aseptic meningitis, with severe
headache, meningismus, photophobia, and a lymphocytic pleocytosis on cerebrospinal fluid
(CSF) analysis [26,27]. In a study of 41 patients with symptomatic acute HIV infection, 10 (24
percent) had symptoms and signs suggestive of aseptic meningitis [15]. HIV was cultured from
the CSF in 12 of the 24 patients who agreed to undergo lumbar puncture (a median of 51 days
after HIV seroconversion). Meningoencephalitis can also occur during acute HIV infection
[28,29].
Rarely, a self-limited encephalopathy may accompany acute HIV infection. One report described
two patients with fever, pronounced personality changes, confusion, and, in one case,
tonic/clonic seizures, associated with seroconversion to HIV [30]. Another report described an
acutely infected patient with signs of both encephalopathy and myelopathy, including lower
extremity spasticity, bilateral extensor plantar reflexes, and urinary retention, which progressed
to upper extremity spasticity and weakness [31].
The peripheral nervous system also may be affected by acute HIV infection. As an example, one
report described two cases of Guillain-Barré syndrome occurring 1 and 20 weeks after
symptomatic acute HIV [32]. Facial nerve and brachial palsies have also been noted [22,33,34].
Other — Apart from complaints of a dry cough, pulmonary manifestations are uncommon
during acute HIV infection. There have been rare reports of pneumonitis in this setting,
manifesting as cough, dyspnea, and hypoxia without evidence for other infectious etiologies
[35,36]. Two of these patients had increased interstitial markings on chest radiograph.
Bronchoalveolar lavage was performed in one patient and revealed a predominance of CD8+
lymphocytes.
Acute rhabdomyolysis and vasculitis are other unusual manifestations [37,38]. (See "Overview
of viral myositis".)
Opportunistic infections — Although usually associated with later stage HIV disease,
opportunistic infections can rarely occur during the transient CD4 lymphopenia of early HIV
infection [39]. In a study of 290 patients who were diagnosed with acute or early HIV infection
at a single center over 10 years, 21 presented with an opportunistic illness [6].
Oral and esophageal candidiasis is the opportunistic infection most often seen in these patients
[6,40,41]. The factors responsible for the frequency of esophageal candidiasis during the
immunosuppression of acute HIV infection are not well understood [42]. Two possibilities are
that esophageal ulceration provides a local environment that promotes the growth of Candida
species, and that the administration of antibiotics to empirically treat the symptoms of acute
HIV may alter normal oropharyngeal flora.
Other opportunistic infections that have been reported during acute HIV infection include
cytomegalovirus (CMV) infection (proctitis, colitis, and hepatitis) [6,24], Pneumocystis jirovecii
pneumonia [43], and prolonged, severe cryptosporidiosis [44].
Laboratory features — In early HIV infection, which is a period of rapid viral replication and
infection of CD4 T cells, the viral RNA level is typically very high (eg, >100,000 copies/mL) and
the CD4 cell count can drop transiently. (See 'HIV RNA detection' below and 'Opportunistic
infections' above.)
As an example, in a study of 50 acutely infected individuals, the median peak viral level was
approximately 5 million copies/mL and occurred at a median of 13 days (range 6 to 18)
following initial detection of viral RNA [1]. Subsequently, the viral load dropped to a median of
30,000 copies/mL between 18 and 42 days following RNA detection and remained generally
stable within one log over the following year.
The leukocyte count and lymphocyte subset counts vary during the acute illness. Initially, there
is a fall in the total white blood cell count. In one study, for example, the leukocyte count
dropped to a low of 960/microL nine days after the onset of symptoms [45]. CD4 cell counts
drop in relation to the increase in viral load, and CD8 cell counts increase. Following peak
viremia, CD4 cell counts rebound and CD8 cell counts decline, but do not generally return to
baseline levels. CD8 cell levels remain higher than CD4 cell levels, resulting in a persistent
inversion of the normal CD4:CD8 ratio to less than 1 [45]. Atypical lymphocytes may be seen
during this latter phase although at a frequency and intensity significantly less than in the
classic mononucleosis syndrome caused by Epstein-Barr virus (EBV) (<50 percent versus 90
percent of cases).
A positive heterophile antibody test has also been reported uncommonly during acute HIV
[14,16,18]; whether this represents a false positive test or reactivation of EBV during acute HIV
is not clear [46]. Regardless of the cause, the importance of this finding is that a positive
heterophile antibody test does not exclude the diagnosis of acute HIV infection.
Additionally, elevations of liver enzymes, mild anemia, and thrombocytopenia have all been
reported in association with early HIV infection.
DIFFERENTIAL DIAGNOSIS
The differential diagnosis of acute HIV infection includes mononucleosis due to Epstein-Barr
virus (EBV) or cytomegalovirus (CMV), toxoplasmosis, rubella, syphilis, disseminated gonococcal
infection, viral hepatitis, and other viral infections. Certain features of new onset autoimmune
diseases may also resemble the acute retroviral syndrome. A number of clinical findings help
distinguish these disorders from acute HIV:
● Mucocutaneous ulceration is unusual in these other infections with the exception of

syphilis and, if present, should heighten suspicion for acute HIV.
● Rash is uncommon in EBV mononucleosis (unless antibiotics have been administered),

CMV mononucleosis, and toxoplasmosis and tends to spare the palms and soles in rubella.
The rash of acute HIV infection may resemble pityriasis rosea, but marked constitutional
symptoms are unusual in pityriasis [18].
● The abrupt onset of symptoms, pharyngeal edema with little associated tonsillar exudate
or hypertrophy, and diarrhea, which can be seen in acute HIV, are features that help to
distinguish it from EBV mononucleosis. Both atypical lymphocytosis and a positive
heterophile antibody test can occur in the setting of acute HIV; thus, these findings do not
exclude the possibility of HIV. However, the number of atypical lymphocytes present is
generally higher in EBV than HIV.
● New onset systemic lupus erythematosus (SLE) can closely resemble acute HIV infection.
However, SLE is distinguished by the presence of antinuclear antibodies.
Symptoms associated with the acute retroviral syndrome have also been observed in patients
with established HIV infection who discontinued suppressive antiretroviral therapy (ART)
[47,48]. In these case reports, symptoms including fever, lymphadenopathy, and rash
developed in four patients 10 days to four weeks after discontinuing all antiretroviral drugs. HIV
viral levels, which had been <50 copies/mL in all of the patients, rose dramatically to as high as
1,000,000 copies/mL, and CD4 counts dropped appreciably. Cases of recrudescent symptomatic
acute HIV have also been reported in patients treated during acute infection who have stopped
treatment [49]. These situations are easily distinguished from the acute retroviral syndrome of
acute HIV infection by history.
DIAGNOSIS
The diagnosis of acute or early HIV infection is established by the detection of HIV viremia in the
setting of a particular HIV testing pattern (ie, negative screening immunoassay OR a positive
combination antibody/antigen immunoassay with a negative antibody-only immunoassay).
However, because of the increasing sensitivity of available immunoassays, an individual with
acute or early HIV infection (ie, infected within the prior six months) may already have
completely reactive immunoassays (eg, both the combination antibody/antigen immunoassay
and the antibody-only immunoassay) in addition to detectable viremia. In such cases, the
timing of infection, and thus the diagnosis of acute or early versus established infection, must
be inferred from clinical presentation (eg, symptoms consistent with acute retroviral syndrome
at presentation or recognized in hindsight or a very high viral RNA level), exposure history, and
any available past serological testing.
When the possibility of acute or early HIV infection is being considered based on clinical
suspicion (see 'Clinical suspicion' below), we perform the most sensitive immunoassay available
(ideally, a combination antigen/antibody immunoassay) in addition to an HIV virologic (viral
load) test. (See 'Diagnostic algorithm' below.)
Because of the increasing availability of HIV screening tests that significantly shorten the time
from HIV acquisition to a positive test and recommendations to use specific screening
algorithms that are more sensitive for early infection [50], more patients with acute or early HIV
are being diagnosed on routine screening. (See 'Detection of early infection through routine
screening' below and "Screening and diagnostic testing for HIV infection", section on 'Testing
algorithm'.)
Given the increasing data supporting individual and public health benefits for antiretroviral
therapy (ART) during acute and early infection instead of later in the course of the disease,
newly-diagnosed patients should be referred promptly to an appropriate specialist to review
treatment options. (See "Acute and early HIV infection: Treatment", section on 'Rationale for
initiation of ART in early infection'.)
Clinical suspicion — Given the wide range of symptoms associated with acute HIV infection,
clinicians should have a low threshold to suspect it. In particular, the possibility of acute HIV
infection should be considered in patients who present with the more typical signs and
symptoms, including an ill-defined febrile illness, heterophile-negative mononucleosis-like
syndrome, heterophile positive mononucleosis in an unusual host (for example, an older adult
patient), and/or aseptic meningitis. Certain clinical features, such as a rash, mucocutaneous
ulcers, diarrhea, or lymphadenopathy, should heighten the suspicion for HIV infection. (See
'Clinical features' above.)
Although all patients should be questioned about HIV risk behaviors, including sexual activity
and injection drug use, patients may be reluctant to disclose this information or may not
perceive their behavior as high risk. As an example, we have seen several men who acquired
HIV through receptive oral sex and expressed surprise that this was a mode of HIV transmission
(see "Management of nonoccupational exposures to HIV and hepatitis B and C in adults",
section on 'Exposure to HIV'). Thus, the absence of elicited risk factors should not preclude the
possibility of HIV infection.
Early HIV infection should also be considered in patients who have had a recent high-risk
exposure or those who have had a recent sexually transmitted infection (particularly syphilis),
regardless of the presence of symptoms or signs. Certain patients who have had a very recent
high-risk exposure (ie, within 72 hours) may be candidates for post-exposure prophylaxis (PEP)
against HIV. The evaluation and management of such patients are discussed in detail
elsewhere. (See "Management of nonoccupational exposures to HIV and hepatitis B and C in
adults" and "Management of health care personnel exposed to HIV".)
Diagnostic algorithm — When the possibility of acute or early HIV infection is being
considered, we perform the most sensitive diagnostic tests available, such as an HIV virologic
(viral load) test. We favor using an RT-PCR-based viral load test, if available. We also send a
combination antigen/antibody test in addition to an HIV virologic (viral load) test, as these tests,
if negative in the context of a detectable HIV viral load, strongly suggest early HIV infection.
Note that with current assays, a positive HIV virologic test is generally diagnostic of HIV
infection, as false positive results on these tests have become quite rare. Special considerations
for patients with a recent exposure and for those taking pre-exposure prophylaxis (PrEP) are
discussed below. (See 'Considerations for specific populations' below.)
● Negative antigen/antibody test and negative virologic test – A negative HIV

antigen/antibody test and negative virologic test strongly suggest that HIV infection has
not been acquired. In the case of very recent high-risk exposures when HIV transmission
remains a concern, repeat testing in one to two weeks (especially if symptoms of acute
HIV develop) is warranted. (See 'Very recent exposure' below.)
● Negative antigen/antibody test and detectable viral load – A negative HIV

antigen/antibody test and a detectable viral load suggest early HIV infection. In most
patients, HIV RNA levels are markedly elevated; however, in some cases the viral load may
be low. As an example, this may occur in patients receiving PrEP since they may have
partial suppression due to the antiretroviral agents they are receiving. (See 'Patients taking
pre-exposure prophylaxis' below.)
On rare occasion, a low RNA level (eg, <100 copies/mL) may represent a false positive viral
test. In this setting, the viral load test should be repeated on a new blood specimen; a
second positive virologic test suggests HIV infection. Some experts use a higher threshold
when considering a false positive viral load [51], but we favor being more conservative,
especially in patients with risk factors for HIV infection, given the specificity of current
assays. (See 'HIV RNA detection' below.)
● Positive antigen/antibody test and detectable viral load – A positive antigen/antibody

test and positive virologic test can be seen in either early or established HIV infection. A
positive antigen/antibody test should prompt a second, antibody-only immunoassay
(preferably the HIV-1/HIV-2 differentiation immunoassay) if not already performed. A
negative result on this second test with a positive virologic test supports the diagnosis of
early HIV infection. However, a positive result on the second immunoassay does not
exclude the possibility of recent infection and seroconversion. In such cases, the
distinction between early and established infection must be inferred from clinical
presentation (eg, symptoms consistent with acute retroviral syndrome at presentation or
recognized in hindsight or a very high viral RNA level), exposure history, and any available
past serological testing (eg, a negative serological test within the prior six months).
This diagnostic algorithm for suspected acute HIV infection is distinct from general screening
algorithms that include an immunoassay followed by a confirmatory immunoassay of a second
type if the first is positive, with HIV RNA testing reserved for discrepant results between the two
immunoassays. The major difference is the use of the virologic test at the same time as the
screening immunoassay. (See 'Detection of early infection through routine screening' below
and "Screening and diagnostic testing for HIV infection".)
Detection of early infection through routine screening — Since many guidelines now
recommend universal screening for HIV infection, new HIV diagnoses, including those of early
infection, may be made among patients in whom HIV infection was not initially suspected.
In the United States, the recommended algorithm for screening involves an initial fourth
generation combined antigen/antibody immunoassay with a confirmatory antibody-only HIV-
1/HIV-2 differentiation immunoassay followed by HIV viral testing if there is a discrepancy
( algorithm 1) [50]. In this algorithm, acute or early HIV is diagnosed when the initial
immunoassay is reactive, the second immunoassay is nonreactive, and the viral test detects HIV
RNA repeatedly or at a high level. (See "Screening and diagnostic testing for HIV infection",
section on 'Testing algorithm'.)
This algorithm is more sensitive for detecting acute and early HIV infection than the previous
algorithm, which involved following a reactive screening immunoassay with a Western blot test.
As an example, in a study of 99 patients who had a reactive combination antibody and antigen
immunoassay on screening followed by a nonreactive second immunoassay, RNA testing was
positive in 55 individuals, thus making the diagnosis of early infection [52]. Of these patients
with early infection, 27 also underwent Western blot testing, of whom 15 (56 percent) had a
negative test and thus may have otherwise had missed diagnoses.
Of note, while this algorithm is more likely to detect some cases of early HIV infection during
routine screening, if acute or early HIV infection is suspected (eg, based on the presence of
symptoms or recent exposures), we continue to favor performing a sensitive immunoassay and
virologic test at the same time. (See 'Diagnostic algorithm' above.)
Some laboratories may still employ Western blot testing to confirm an initial reactive
immunoassay. Detecting early HIV with this algorithm requires checking a viral RNA test if the
Western blot is negative or indeterminate. In such cases, a reactive immunoassay followed by a
negative or indeterminate Western blot followed by a positive viral RNA test is most likely
indicative of early HIV infection. Thus, a reactive immunoassay followed by a negative or
indeterminate Western blot should not be erroneously interpreted as a negative screening
pattern for HIV without further testing.
Clinical relevance of early detection — Diagnosis of acute HIV is important, since prompt
initiation of ART reduces the likelihood of HIV transmission to others and can reduce the size of
the latent HIV reservoir, potentially making patients eligible for future investigative HIV
eradication strategies. Early ART also can improve symptoms related to acute HIV infection. This
is discussed in detail elsewhere. (See "Acute and early HIV infection: Treatment", section on
'Rationale for initiation of ART in early infection'.)
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Considerations for specific populations
Very recent exposure — Detectable viremia does not develop until approximately 10 to 15
days after infection, and even the most sensitive immunoassays do not become positive until
five days after that ( table 2). Thus, if exposure occurred during this window, the diagnosis of
HIV infection may be missed. If initial immunoassay and virologic tests are negative and clinical
suspicion for recent HIV exposure is high, we repeat testing one to two weeks later.
Patients taking pre-exposure prophylaxis — Some patients who are taking pre-exposure
prophylaxis (PrEP) will acquire HIV. Such patients may have ambiguous HIV test results. As an
example, patients with acute HIV typically have high viral loads, but those on PrEP may have low
viral loads because of the antiviral activity of the PrEP regimen.
In general, any detectable viral load is suggestive of new HIV infection (particularly in
populations with risk factors for HIV transmission), since current assays are unlikely to have
false positives. However, in persons with a very low HIV RNA (eg, <100 copies/mL), the diagnosis
should be confirmed before initiating ART [51]. By contrast, in those with a higher, yet still low
HIV RNA level (eg, 100 to 3000 copies/mL), it is reasonable to repeat the viral load for
confirmation but initiate a three-drug ART regimen pending the results. If ART was initiated
before confirmatory testing is performed, DNA testing may be helpful. (See "Screening and
diagnostic testing for HIV infection", section on 'Viral detection'.)
A more detailed discussion of how to evaluate HIV test results in patients receiving PrEP is
presented elsewhere. (See "HIV pre-exposure prophylaxis", section on 'Persons with a positive
HIV test'.)
Diagnostic test performance in early HIV infection
HIV RNA detection — Early HIV infection is characterized by markedly elevated HIV RNA
levels, easily detectable with the HIV RNA (viral load) assays commonly used for monitoring of
HIV disease. Our preferred test for HIV RNA detection in the evaluation for early HIV infection is
the reverse transcriptase-polymerase chain reaction (RT-PCR) test because of its superior
performance to the branch DNA (bDNA) technique. Although not approved by the US Food and
Drug Administration (FDA) for this indication, the RT-PCR test is widely available for HIV disease
monitoring and is highly sensitive and specific. A false positive test should be ruled out if the
viral load is low (eg, <100 copies/mL) in the setting of suspected early HIV infection [53,54]. A
repeat sample should be drawn in this setting since a second positive viral load (especially if
higher) suggests a true positive result [55], as would subsequent seroconversion. (See
'Diagnostic algorithm' above.)
In a study of 436 patients with symptoms consistent with acute HIV infection, all of the 54
patients diagnosed with acute HIV had RNA levels >100,000 copies/mL [5]. Although false-
positive detection of HIV RNA occurred in 8 of 303 (2.6 percent) patients without HIV infection,
all of the false-positives had HIV RNA levels <2000 copies/mL, making them easily
distinguishable from the true positives whose values were much higher. Furthermore, all of the
false positives occurred with bDNA rather than RT-PCR viral load testing; bDNA testing has
subsequently become less widely used. In a separate study of 258 symptomatic patients
evaluated for acute HIV infection, RT-PCR based testing also had a lower false positive rate than
bDNA tests (3 versus 5 percent) [56]. (See "Techniques and interpretation of HIV-1 RNA
quantitation", section on 'Laboratory methods for quantitation of HIV-1 RNA'.)
A qualitative nucleic acid test (NAT) based on transcription mediated amplification is an

additional sensitive method to detect acute HIV viremia in patients who are antibody-negative
[57,58]. The main utility of NAT is for large population screening (such as blood donor
screening), which is generally performed on pooled specimens because of the cost of the test.
HIV antigen detection — The p24 antigen is a viral core protein that appears in the blood as
the viral RNA level rises following HIV infection [59,60]. Although earlier assays to detect p24
antigen were considerably less sensitive than viral RNA testing, subsequent assays have better
diagnostic performance, with a sensitivity range of 89 to nearly 100 percent compared to RNA
detection [61,62]. This assay detects a level of antigen that approximately corresponds to an
HIV RNA level of 30,000 to 50,000 copies/mL and becomes positive approximately five to seven
days following the detection of viral RNA [63-65].
The p24 antigen test is also available as combination HIV antibody/p24 antigen tests that turn
positive with detection of either the antigen or the antibody and shortens the window period
between HIV acquisition and a positive test compared with antibody only tests. Nevertheless,
combination immunoassays remain less sensitive than nucleic acid based tests for acute HIV
infection in clinical settings [66,67]. As an example, in a study comparing a fourth generation
combination test (Architect) with pooled HIV RNA testing among 134 patients with acute HIV
infection, both were highly specific and the combination test was less costly, but it was also less
sensitive (80 versus 98 percent with pooled RNA testing) [67]. This highlights the importance of
HIV viral level testing when acute or early infection is suspected. (See 'Diagnostic algorithm'
above.)
Rapid combination antigen/antibody tests do not appear to be quite as sensitive as the

standard combination test used in laboratories [68]. (See "Screening and diagnostic testing for
HIV infection", section on 'Combination HIV antigen and antibody tests'.)
Serologic studies — After infection with HIV, the time at which antibodies against HIV
antigens can be detected in the serum depends upon the sensitivity of the serologic test
( table 2). Thus, depending on the time since infection and the sensitivity of the immunoassay
test used, patients with acute or early HIV infection may have either a negative or reactive
immunoassay. (See "Screening and diagnostic testing for HIV infection".)
Very early treatment for acute HIV infection can lead to abrogation of HIV antibody responses
[69,70]. As an example, in a study of 150 patients with acute HIV infection treated with ART,
three patients did not develop a fully evolved antibody response and/or demonstrated evidence
of seroreversion after successful HIV RNA suppression [69]. It has been postulated that
maturation of the antibody response can be thwarted by rapid HIV RNA suppression early in the
course of disease [71]. It is critical that clinicians and patients understand that seroreversion
does not indicate viral eradication [70,72].
ADDITIONAL EVALUATION
Drug resistance testing — For all patients with newly diagnosed HIV infection (including those
with early HIV), drug resistance testing should be performed after the initial diagnosis has been
established [51,73]. In studies of patients with acute and early HIV infection, about 15 to 20
percent of patients were infected with an isolate harboring at least one drug resistance
mutation [74-76]. The presence of mutations in transmitted strains is strongly influenced by
antiretroviral drug use patterns in the source. Mutations conferring resistance to non-
nucleoside reverse transcriptase inhibitors are more common than protease inhibitor and
integrase inhibitor resistance mutations. (See "Acute and early HIV infection: Pathogenesis and
epidemiology".)
In this setting, genotype resistance testing is preferred over phenotype testing because of its
lower cost, faster turnaround time (approximately one versus three to four weeks), and its
greater sensitivity for mixtures of resistant and wild-type virus. The interpretation of results of
resistance testing is discussed in detail elsewhere. (See "Overview of HIV drug resistance testing
assays" and "Interpretation of HIV drug resistance testing".)
Screening for coinfections and prior exposures — All patients with newly diagnosed HIV
infection should also undergo testing for other sexually transmitted infections. (See "Screening
for sexually transmitted infections", section on 'Patients with HIV infection'.)
Evaluation for exposure to other chronic infections, as performed in patients diagnosed with
chronic HIV infection, is also indicated to establish the risk of possible future reactivation or
need for vaccination. (See "Initial evaluation of adults with HIV", section on 'Screening for
coinfections' and "Initial evaluation of adults with HIV", section on 'Sexually transmitted
infections'.)
PUBLIC HEALTH IMPLICATIONS
Establishing the diagnosis of early HIV infection is clearly important from the public health
perspective. Patients are typically highly infectious during early HIV due to an enormous viral
burden in blood and genital secretions (with a general range of serum RNA levels 100,000 to
greater than one million copies/mL compared with 30,000 to 50,000 copies/mL in chronic
infection without treatment) [77-79]. Moreover, such patients may be unaware that they are
infected and continue to engage in risky sexual activity and needle sharing, putting others at
risk. In one analysis of recently infected men who have sex with men (MSM), the rate of
transmission during early infection was 9 to 15-fold greater than the transmission risk during
chronic infection [80]. Similarly, in some settings, transmission from acutely infected individuals
is estimated to account for the majority of new HIV infections [81-83]. Pregnant women who are
unaware of their acute infection can transmit HIV perinatally unless a timely diagnosis is made
and antiretroviral therapy (ART) is initiated [84].
Nevertheless, the diagnosis of acute or early HIV infection is infrequently made in clinical
practice. In a case series from Seattle, for example, the diagnosis of HIV infection was
considered in only 5 of 19 patients (26 percent) with acute retroviral syndrome who sought care
from their primary care clinicians, emergency departments, and walk-in clinics [15]. This finding
was especially surprising since these patients were enrolled in a surveillance program for HIV.
There are several reasons why acute and early HIV infection is so infrequently diagnosed:
● The symptoms, especially in mild cases, are nonspecific and resolve spontaneously
without treatment. Also, many patients may be asymptomatic. (See 'Clinical features'
above.)
● Clinicians may be uncomfortable asking questions about sexual exposure or intravenous

drug use, especially with patients whom they see infrequently, such as young, previously
healthy individuals.
● Primary care clinicians may not be aware of high-risk behavior even in patients they know
well. Such patients often choose to undergo counseling and serial serologic testing at an
anonymous clinic rather than to discuss risk behaviors with their primary care provider.
● Patients may not perceive themselves to be at risk.
● Clinicians and patients may assume continued validity of a previously negative HIV test,
even in high-risk patients.
These issues highlight the importance of maintaining a high degree of suspicion in considering
the possibility of acute HIV infection in patients with ill-defined febrile illnesses regardless of
apparent risk factors. (See 'Clinical suspicion' above.)
All patients with suspected or confirmed acute or early HIV infection should be counseled to
adopt behaviors that guard against HIV transmission, including consistent and correct condom
use and avoidance of sharing injection drug use equipment.
SOCIETY GUIDELINE LINKS
Links to society and government-sponsored guidelines from selected countries and regions
around the world are provided separately. (See "Society guideline links: HIV screening and
diagnostic testing".)
SUMMARY AND RECOMMENDATIONS
● Definitions – In this topic, we use the term "early HIV infection" to refer to the
approximate six-month period following HIV acquisition. We use the term "acute HIV
infection" to refer to symptomatic early infection. (See 'Definitions' above.)
● Clinical features
• Signs and symptoms – A variety of symptoms and signs may be seen in association
with acute HIV infection, known as the acute retroviral syndrome. The most common
findings are fever, lymphadenopathy, sore throat, rash, myalgia/arthralgia, and
headache. When it occurs, painful mucocutaneous ulceration is one of the most
distinctive manifestations of acute HIV infection. Aseptic meningitis and
meningoencephalitis have also been reported. Some patients with early HIV infection
may have no or only very mild symptoms ( table 1). (See 'Clinical features' above.)
• Viral load and CD4 count – In early HIV infection, the viral RNA level is typically very
high (eg, >100,000 copies/mL) and the CD4 cell count can drop transiently.
Opportunistic infections can rarely occur during this transient CD4 lymphopenia. (See
'Laboratory features' above and 'Opportunistic infections' above.)
● Diagnosis
• Clinical suspicion – The diagnosis of acute HIV infection requires a high level of clinical
suspicion and should be considered in patients who present with consistent signs and
symptoms, including an ill-defined febrile illness, and/or aseptic meningitis. Early HIV
infection should also be considered in patients who have had a recent high-risk
exposure or those who have had a recent sexually transmitted infection (particularly
syphilis), regardless of the presence of symptoms or signs. (See 'Clinical suspicion'
above.)
The differential diagnosis of acute HIV infection includes mononucleosis due to

Epstein-Barr virus (EBV) or cytomegalovirus (CMV), toxoplasmosis, rubella,
disseminated gonococcal infection, syphilis, viral hepatitis, and other viral syndromes.
Certain features of new onset autoimmune diseases may also resemble the acute
retroviral syndrome. (See 'Differential diagnosis' above.)
• Diagnostic testing – When the possibility of acute or early HIV infection is being
considered, we perform the most sensitive diagnostic tests available, such as an HIV
virologic (viral load) test. We also send a combination antigen/antibody test in addition
to an HIV viral load test; a negative antigen/antibody test in the context of a detectable
HIV viral load strongly suggests early HIV infection. On rare occasion, a very low viral
RNA (eg, <100 copies/mL) may represent a false positive test and should be repeated.
(See 'Diagnostic algorithm' above.)
Some patients infected with HIV within the previous six months will have already
undergone seroconversion and thus have completely reactive immunoassays (eg, both
the combination antibody/antigen immunoassay and the antibody-only immunoassay)
and a positive virologic test ( table 2). In these situations, the timing of infection and
thus the diagnosis of early HIV infection can be presumptively made on the basis of
clinical presentation (eg, earlier symptoms consistent with acute retroviral syndrome
recognized in hindsight or a very high viral RNA level), exposure history, and any
available past serological testing. (See 'Diagnostic algorithm' above.)
● Role of drug resistance testing – Drug resistance testing should be performed after the
initial diagnosis of HIV infection. Infection with a virus that harbors at least one drug-
resistant mutation is estimated to occur in up to 20 percent of newly infected patients.
(See 'Additional evaluation' above.)
● Management of persons who are newly diagnosed with HIV – Newly-diagnosed

patients should be started on antiretroviral therapy (ART) as soon as possible. In some
cases, ART can be started on the same day as diagnosis. Prompt initiation of ART can
reduce the size of the latent HIV reservoir, improve symptoms related to acute HIV
infection, and reduce the likelihood of transmitting HIV to others. (See "Acute and early
HIV infection: Treatment", section on 'Rationale for initiation of ART in early infection'.)
● Patient counseling – All patients with suspected or confirmed acute or early HIV infection
should be counseled to adopt behaviors that guard against HIV transmission, including
consistent and correct condom use and avoidance of sharing injection drug use
equipment. (See 'Public health implications' above.)
ACKNOWLEDGMENT
UpToDate gratefully acknowledges John G Bartlett, MD (deceased), who contributed as Section

Editor on earlier versions of this topic and was a founding Editor-in-Chief for UpToDate in
Infectious Diseases.
Use of UpToDate is subject to the Terms of Use.
Topic 86984 Version 32.0
GRAPHICS
Clinical manifestations of acute HIV infection
Features Overall Male Female Sexual* IVDU ¶

(percent) (n = 378) (n = 355) (n = 23) (n = 324) (n = 34)
Fever 75 74 83 77 50
Fatigue 68 67 78 71 50
Myalgia 49 50 26 52 29
Skin rash 48 48 48 51 21
Headache 45 45 44 47 30
Pharyngitis 40 40 48 43 18
Cervical 39 39 39 41 27
adenopathy
Arthralgia 30 30 26 28 26
Night sweats 28 28 22 30 27
Diarrhea 27 27 21 28 23
This table lists the most frequent clinical findings reported among patients with acute HIV infection
from five prospective cohorts.
* Homosexual or heterosexual route of transmission.
¶ IVDU, intravenous drug use as route of transmission.
Reproduced with permission from: Daar ES, Pilcher CD, Hecht FM. Clinical presentation and diagnosis of primary HIV-1
infection. Curr Opin HIV AIDS 2008; 3:10. Copyright © 2008 Lippincott Williams & Wilkins.
Graphic 87682 Version 3.0
Recommended algorithm for HIV diagnosis
HIV: human immunodeficiency virus.
Modified from: CDC and Prevention and Association of Public Health Laboratories. Laboratory Testing
for the Diagnosis of HIV Infection: Updated Recommendations. Available at
http://stacks.cdc.gov/view/cdc/23447. Published June 27, 2014.
Time to positivity of HIV diagnostic tests
Approximate time to
Test Target of detection
positivity (days)
Enzyme-linked immunoassay
First generation IgG antibody 35 to 45
Second generation IgG antibody 25 to 35
Third generation IgM and IgG antibody 20 to 30
Fourth generation IgM and IgG antibody and p24 15 to 20

antigen
Western blot
IgM and IgG antibody 35 to 50 (indeterminate)
45 to 60 (positive)
HIV viral load test
Sensitivity cutoff 50 RNA 10 to 15

copies/mL
Ultrasensitive cutoff 1 to 5 RNA 5

copies/mL
This table demonstrates the approximate time to positivity following infection for various diagnostic
tests for HIV.
IgG: immunoglobulin G; IgM: immunoglobulin M.
References:
1. Branson BM, Stekler JD. Detection of acute HIV infection: We can't close the window. J Infect Dis 2012; 205:521.
2. Owen SM. Testing for acute HIV infection: implications for treatment as prevention. Curr Opin HIV AIDS 2012; 7:125.
3. Cohen MS, Gay CL, Busch MP, et al. The detection of acute HIV infection. J Infect Dis 2010; 202:S270.

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19/4/23, 09:36 Acute and early HIV infection: Clinical manifestations and diagnosis - UpToDate

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Acute and early HIV infection: Clinical manifestations and

Asymptomatic infection — An estimated 10 to 60 percent of individuals with early HIV

Adenopathy — Nontender lymphadenopathy primarily involving the axillary, cervical, and

Gastrointestinal symptoms — Since the gastrointestinal tract is a primary target during

Neurologic findings — Headache, often described as retroorbital pain exacerbated by eye

● Mucocutaneous ulceration is unusual in these other infections with the exception of

● Rash is uncommon in EBV mononucleosis (unless antibiotics have been administered),

● Negative antigen/antibody test and negative virologic test – A negative HIV

● Negative antigen/antibody test and detectable viral load – A negative HIV

● Positive antigen/antibody test and detectable viral load – A positive antigen/antibody

Considerations for specific populations

Diagnostic test performance in early HIV infection

A qualitative nucleic acid test (NAT) based on transcription mediated amplification is an

Rapid combination antigen/antibody tests do not appear to be quite as sensitive as the

PUBLIC HEALTH IMPLICATIONS

● Clinicians may be uncomfortable asking questions about sexual exposure or intravenous

● Patients may not perceive themselves to be at risk.

SOCIETY GUIDELINE LINKS

SUMMARY AND RECOMMENDATIONS

The differential diagnosis of acute HIV infection includes mononucleosis due to

● Management of persons who are newly diagnosed with HIV – Newly-diagnosed

UpToDate gratefully acknowledges John G Bartlett, MD (deceased), who contributed as Section

Use of UpToDate is subject to the Terms of Use.

Topic 86984 Version 32.0

Clinical manifestations of acute HIV infection

Features Overall Male Female Sexual* IVDU ¶

* Homosexual or heterosexual route of transmission.

¶ IVDU, intravenous drug use as route of transmission.

Graphic 87682 Version 3.0

Recommended algorithm for HIV diagnosis

HIV: human immunodeficiency virus.

Graphic 91270 Version 2.0

Time to positivity of HIV diagnostic tests

First generation IgG antibody 35 to 45

Second generation IgG antibody 25 to 35

Third generation IgM and IgG antibody 20 to 30

Fourth generation IgM and IgG antibody and p24 15 to 20

IgM and IgG antibody 35 to 50 (indeterminate)

HIV viral load test

Sensitivity cutoff 50 RNA 10 to 15

Ultrasensitive cutoff 1 to 5 RNA 5

IgG: immunoglobulin G; IgM: immunoglobulin M.

Graphic 87673 Version 3.0

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