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Infección aguda y temprana por VIH: manifestaciones

clínicas y diagnóstico.
Autor: Paul E Sax, MD
Editor de la sección: John G. Bartlett, MD
Editor Adjunto: Meg Sullivan, MD

Todos los temas se actualizan a medida que se dispone de nueva evidencia y se completa nuestro proceso de revisión
por pares .

Revisión de literatura vigente hasta mayo de 2019. | Este tema fue actualizado por última vez el 16 de mayo de
2019.

INTRODUCCIÓN

La infección aguda por VIH puede presentarse como un tipo de síndrome de mononucleosis con una
constelación de síntomas inespecíficos. Sin un alto grado de sospecha, los médicos pueden pasar
por alto con frecuencia el diagnóstico. En algunos casos, la infección temprana por VIH puede ser
asintomática.

Las manifestaciones clínicas y el diagnóstico de VIH agudo y precoz se revisarán aquí. La patogenia,
la epidemiología y el tratamiento de la infección temprana por VIH se discuten por separado.
(Consulte "Infección por VIH aguda y temprana: patogénesis y epidemiología" y "Infección por VIH
aguda y temprana: Tratamiento" .)

DEFINICIONES

En la literatura se han utilizado diferentes términos, incluida la infección por VIH aguda, reciente,
primaria y temprana, para referirse a intervalos variables después de la infección inicial con el virus.
En este tema, usamos el término "infección temprana por VIH" para referirnos al período aproximado
de seis meses después de la adquisición del VIH. Utilizamos el término "infección aguda por VIH"
para referirnos a una infección temprana sintomática, ya que esto refleja el uso común en la atención
clínica.

CARACTERÍSTICAS CLÍNICAS

Infección asintomática : se estima que entre el 10 y el 60 por ciento de las personas con infección
temprana por VIH no experimentarán síntomas [ 1 ], aunque la proporción exacta es difícil de
estimar, ya que los pacientes generalmente reciben atención debido a los síntomas y, por lo tanto,
las infecciones asintomáticas a menudo no se detectan. En un estudio de 50 individuos con infección
aguda que se identificaron mediante pruebas virales prospectivas de individuos de alto riesgo y luego
fueron seguidos dos veces por semana, casi todos presentaron al menos un síntoma o signo
informado durante las primeras cuatro semanas de infección, pero estos fueron principalmente de
corta duración, inespecíficos, y es poco probable que hayan llevado a la persona a la atención clínica
fuera del entorno del estudio [ 2]. Los sujetos se quejaron de síntomas en solo el 29 por ciento de las
visitas de estudio quincenales durante este período.

Curso temporal : en pacientes con infección sintomática aguda, el tiempo habitual desde la
exposición al VIH hasta el desarrollo de los síntomas es de dos a cuatro semanas, aunque se han
observado periodos de incubación de hasta 10 meses [ 3 ]. En un estudio que evaluó la dinámica
viral después de la infección por VIH, se observó la mayor frecuencia de síntomas y signos justo
antes de que se produjera el pico de viremia, aproximadamente dos semanas después de la
detección inicial del ARN viral [ 2 ]. Es posible que la ruta de adquisición y la cantidad de inóculo del
virus influyan en el tiempo de pico de la viremia y en la duración del período de incubación.

La mayoría de los síntomas asociados con la infección aguda por VIH se resuelven por sí solos; sin
embargo, la gravedad y la duración de los síntomas varían ampliamente de un paciente a otro.

Signos y síntomas : se puede observar una variedad de síntomas y signos en asociación con una
infección sintomática aguda por VIH. Esta constelación de síntomas también se conoce como el
síndrome retroviral agudo. Las series publicadas informan sistemáticamente que los hallazgos más
comunes son fiebre, linfadenopatía, dolor de garganta, erupción cutánea, mialgia / artralgia, diarrea,
pérdida de peso y dolor de cabeza ( tabla 1 ) [ 2,4-8 ]. Ninguno de estos hallazgos es específico para
la infección aguda por VIH, pero ciertas características, especialmente la duración prolongada de los
síntomas y la presencia de úlceras mucocutáneas, sugieren el diagnóstico.

Más allá de estos síntomas más comunes, se ha descrito una amplia gama de otros síntomas en
pacientes con infección aguda o temprana por VIH. En un estudio prospectivo de 290 de estos
pacientes, se consideró que 74 (26 por ciento) de los pacientes tenían presentaciones sintomáticas
atípicas, incluidas las infecciones oportunistas y las manifestaciones del sistema nervioso central [ 7
].

The presence and increased severity and duration of symptoms appear to be poor prognostic factors
[9-11]. 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 [11]. 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 [2,9,12]. Fever in the range of 38 to 40ºC is present in
the vast majority of patients with symptomatic acute HIV infection [5,10,13-15]. In one study of 41
patients, the mean maximum reported temperature was 38.9ºC [16].

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 [15]. Mild
hepatosplenomegaly also can occur [17].

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 [18,19]. However, unilateral or bilateral tonsillitis has also been described [7].

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 [20]. These ulcerative lesions may reflect
mucocutaneous disease associated with acute HIV infection [15] or coincident sexually transmitted
infections, such as herpes simplex virus, syphilis, or chancroid [21]. 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 [22]. 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 [20].
Vesicular, pustular, and urticarial eruptions have also been reported [19,23] 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 [17].

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 [24,25].

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 [7,26].

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
[27,28]. In a study of 41 patients with symptomatic acute HIV infection, 10 (24 percent) had symptoms
and signs suggestive of aseptic meningitis [16]. 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).

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 [29]. 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 [30].

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 [31]. Facial nerve and brachial palsies have also been noted [23,32,33].

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 [34,35]. 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 [36,37]. (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 [38]. 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 [7].

Oral and esophageal candidiasis is the opportunistic infection most often seen in these patients
[7,39,40]. The factors responsible for the frequency of esophageal candidiasis during the
immunosuppression of acute HIV infection are not well understood [41]. 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 CMV
infection (proctitis, colitis, and hepatitis) [7,25], Pneumocystis jirovecii pneumonia [42], and prolonged,
severe cryptosporidiosis [43].

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 [2]. 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 [44]. 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 [44]. 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 [15,17,19];
whether this represents a false positive test or reactivation of EBV during acute HIV is not clear [45].
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 [19].

● 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 [46,47]. 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 [48]. 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 [49], 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
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 screening immunoassay available (ideally, a combination antigen/antibody
immunoassay) in addition to an HIV virologic (viral load) test. We favor using an RT-PCR based viral
load test, if available. A positive HIV virologic test is generally indicative of HIV infection. The
approximate timing of infection (ie, early versus established) can be assessed by the pattern of
immunoassay reactivity and the clinical presentation (table 2):

● A negative HIV screening immunoassay and negative virologic test strongly suggests 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.)

● A negative HIV screening immunoassay and a positive virologic test suggest early HIV infection.
In this situation, however, an RNA level <1000 copies/mL may rarely represent a false positive
viral test and the viral load test should be immediately repeated on a new blood specimen. A
second positive virologic test suggests HIV infection, which a repeat serologic test several weeks
later to evaluate for seroconversion can confirm. (See 'HIV RNA detection' below.)

● A positive HIV screening immunoassay and positive virologic test can be seen in either early or
established HIV infection. A positive screening immunoassay 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 acute 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).

If the diagnosis of acute or early HIV infection was based on a single positive virologic test in the
setting of a negative HIV immunoassay, it is appropriate to confirm the diagnosis of acute or early HIV
with a second test. This may be a repeat HIV RNA or serologic test in several weeks to document
seroconversion. If treatment is started, it need not await the confirmatory testing unless the initial
diagnosis is uncertain.

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) [49].
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 [50]. 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 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'.)

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.

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 (<1000
copies/mL) in the setting of suspected early HIV infection [51,52]. A repeat sample should be drawn
in this setting since a second positive viral load (especially if higher) suggests a true positive result
[53], as would subsequent seroconversion.
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 [6]. 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) [54]. (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 [55,56]. 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 [57,58]. 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 [59,60].
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 [61-63].

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 [64,65]. 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) [65]. 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 [66]. (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 [67,68].
As an example, in a study of 150 patients with acute HIV infection treated with antiretroviral therapy
(ART), three patients did not develop a fully evolved antibody response and/or demonstrated
evidence of seroreversion after successful HIV RNA suppression [67]. It has been postulated that
maturation of the antibody response can be thwarted by rapid HIV RNA suppression early in the
course of disease [69]. It is critical that clinicians and patients understand that seroreversion does not
indicate viral eradication [68,70].

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 [1,71]. 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 [72-74]. 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 'HIV-infected patients'.)

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 the HIV-infected adult", section on 'Screening for co-infections'
and "Initial evaluation of the HIV-infected adult", 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) [75-77]. 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 [78]. Similarly, in some settings,
transmission from acutely infected individuals is estimated to account for the majority of new HIV
infections [79-81]. Pregnant women who are unaware of their acute infection can transmit HIV
perinatally unless a timely diagnosis is made and antiretroviral therapy is initiated [82].

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 [16]. 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

● 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.)

● 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
has also been reported. Some patients with early HIV infection may have no or only very mild
symptoms (table 1). (See 'Clinical features' above.)

● 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.)

● The differential diagnosis of acute HIV infection includes mononucleosis due to Epstein-Barr
virus (EBV) or cytomegalovirus (CMV), toxoplasmosis, rubella, syphilis, viral hepatitis,
disseminated gonococcal infection, and other viral infections. Certain features of new onset
autoimmune diseases may also resemble the acute retroviral syndrome. (See 'Differential
diagnosis' above.)

● 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, heterophile-negative mononucleosis-like syndrome, 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.)

● Diagnosis of acute HIV is important, since prompt initiation of antiretroviral therapy reduces the
likelihood of HIV transmission to others and can reduce the size of the latent HIV reservoir,
potentially making patients eligible for future HIV eradication strategies. (See "Acute and early
HIV infection: Treatment", section on 'Rationale for initiation of ART in early infection'.)

● When the possibility of acute or early HIV infection is being considered, we perform the most
sensitive immunoassay available (ideally, a combination antigen/antibody immunoassay) in
addition to an HIV virologic (viral load) test. A positive virologic test indicates HIV infection. Acute
or early HIV infection is indicated if the initial immunoassay is negative OR if a combination
antigen/antibody immunoassay is positive but a second antibody-only immunoassay is negative.
(See 'Diagnostic algorithm' above.)

● Because of the increasing sensitivity of immunoassays, 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.)

● A viral RNA level <1000 copies/mL in a patient with a negative serologic test may represent a
false positive viral test, as patients with acute or early HIV infection typically have very high levels
of viremia. The virologic test should be immediately repeated on a new blood specimen. A
second positive virologic test suggests HIV infection, which a repeat serologic test several weeks
later to evaluate for seroconversion can confirm. (See 'Diagnostic algorithm' above.)

● With the widespread availability of HIV screening tests that significantly shorten the time from
HIV acquisition to a positive test, more patients with acute or early HIV infection are being
diagnosed on routine screening. (See 'Detection of early infection through routine screening'
above.)

● Drug-resistant testing should be performed after the initial diagnosis of HIV infection, as infection
with a virus that harbors at least one drug resistance mutation is estimated to occur in up to 20
percent of newly infected patients. (See 'Additional evaluation' 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. (See 'Public health implications'
above.)

● Given the increasing data supporting individual and public health benefits for antiretroviral
therapy 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'.)

Use of UpToDate is subject to the Subscription and License Agreement.

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Topic 86984 Version 22.0

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

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 copies/mL RNA 10 to 15

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.

Graphic 87673 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.

Graphic 91270 Version 2.0

Contributor Disclosures
Paul E Sax, MD Grant/Research/Clinical Trial Support: Gilead Sciences [HIV (tenofovir, emtricitabine,
elvitegravir, cobicistat)]; GlaxoSmithKline [HIV (lamivudine, abacavir, dolutegravir)]. Consultant/Advisory Boards:
Gilead Sciences [HIV (tenofovir, emtricitabine, elvitegravir, cobicistat)]; GlaxoSmithKline [HIV (lamivudine,
abacavir, dolutegravir)]; Janssen Pharmaceuticals [HIV (darunavir, etravirine, rilpivirine)]; Merck [HIV
(raltegravir)]. John G Bartlett, MD Nothing to disclose Meg Sullivan, MD Grant/Research/Clinical Trial Support:
Gilead Sciences [Pre-exposure prophylaxis for contraception (Tenofovir)]. Consultant/Advisory Boards: Gilead
Sciences [Pre-exposure prophylaxis for contraception (Tenofovir)].

Las revelaciones de los contribuyentes son revisadas para los conflictos de interés por el grupo editorial.
Cuando se encuentran, estos se abordan examinando un proceso de revisión multinivel y los requisitos para que
se proporcionen referencias que respalden el contenido. El contenido referenciado adecuadamente es requerido
por todos los autores y debe cumplir con los estándares de evidencia UpToDate.

Política de conflicto de intereses.