2. HISTORY
• In 1985, the first description of acute
human immunodeficiency virus (HIV)
infection, a "mononucleosis-like" illness,
was published based upon the clinical
records of 12 men with documented
seroconversion to HIV during the
preceding six months; 11 of these
individuals experienced a remarkably
similar illness.
• Since that time, larger studies have
described the clinical and laboratory
features of acute and early HIV infection.
4. • Increased awareness of the clinical spectrum of acute HIV infection
and better diagnostic tests (in particular HIV RNA and the combined
HIV antigen/antibody test) have led to more accurate identification of
recently acquired infection.
• In addition, several studies now provide support for initiating
antiretroviral therapy during early HIV for both individual and public
health benefits.
5. 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.
6. PATHOGENESIS
• HIV has several targets including dendritic cells, macrophages, and CD4+ T cells.
• Target cells — HIV-1 most often enters the host through the anogenital mucosa.
• The viral envelope protein, glycoprotein (GP)-120, binds to the CD4 molecule on
dendritic cells.
• Interstitial dendritic cells are found in cervicovaginal epithelium as well as
tonsillar and adenoidal tissue, which may serve as initial target cells in infection
transmitted via genital-oral sex .
• Newly acquired HIV infection is more commonly due to transmission of
macrophage tropic rather than T cell tropic viruses .
• Viral entry into these cells is mediated by different coreceptors. In order to enter
macrophages, GP-120 must bind to the chemokine receptor CCR5 as well as CD4 .
• Macrophage tropic viruses are designated as R5 in comparison to T cell tropic
viruses, which are called X4, based upon the CXCR4 receptor on these cells .
7.
8. • HIV infected cells fuse with CD4+ T cells, leading to spread of the virus.
• HIV is detectable in regional lymph nodes within two days of mucosal exposure
and in plasma within another three days.
• Once virus enters the blood, there is widespread dissemination to organs such as
the brain, spleen, and lymph nodes.
• The intestinal mucosa is also a primary target during initial infection .
• Massive CD4 T-cell depletion during acute infection has been demonstrated with
simian immunodeficiency virus (SIV) in rhesus macaques .
• Both studies documented that destruction occurred preferentially in CD4+
memory T cells, which may result from direct infection as well as through
apoptosis.
• This can lead to an. early and disproportionate loss of CD4+ T cells in the
gastrointestinal compartment, compared to peripheral blood.
• It has also been proposed that microbial translocation, due to changes in the gut
mucosal barrier, may be the etiology of chronic immune activation in HIV
infection
9.
10. Viremia
• Studies in primates suggest viral penetration of mucosal epithelium,
followed by infection of submucosal CD4+ T cells, dendritic cells, and
macrophages with subsequent spread to lymph nodes and ultimately,
plasma.
• Viremia was documented between 5 to 30 days after experimental
intravaginal simian immunodeficiency virus (SIV) exposure.
• In humans, HIV RNA levels rapidly increase from the earliest quantifiable
measure to a peak level that usually coincides with seroconversion .
• However, a period of low-level viremia preceding ramp-up viremia, may be
more common than originally thought.
• The HIV DNA level in peripheral blood mononuclear cells provides an
estimate of the cellular HIV reservoir, which is established soon after
infection.
11. Cellular immune response
• At the time of initial infection with HIV, patients have a large number of susceptible CD4+ T cells
and no HIV-specific immune response.
• Viral replication is therefore rapid; plasma HIV RNA levels may climb to more than 10(7)
copies/mL and p24 antigen levels may exceed 100 pg/mL.
• Concomitant with the evolution of HIV specific immunity, primarily due to the emergence of
virus-specific CD8+ cytotoxic T lymphocytes, plasma RNA levels fall precipitously by 2 to 3 logs,
and symptoms of the acute retroviral syndrome resolve.
• In the absence of antiretroviral therapy, plasma HIV RNA levels will stabilize at an individual's
given "set-point" within six months of infection .
• The host factors, virus factors, and pharmacologic interventions, which determine this set point,
are active issues for ongoing investigations
12. • Genetic susceptibility — Cohorts of individuals who are highly exposed (people who inject drugs or
commercial sex workers) but who remain HIV-seronegative have been described
• A nested case-control study of 266 HIV-seropositive patients and 532 seronegative controls was conducted
to examine whether any of nine candidate host genes may play a role in susceptibility to HIV infection
• Self-reported risk behaviors were analyzed from data collected at semi-annual visits
• Four single-nucleotide polymorphisms (CCR-2, CCR5, MIP1A, and IL2) were significantly associated with HIV
infection susceptibility in different genetic models.
• The most extensively studied of these genetic factors is the C-C chemokine receptor 5 (CCR5), a major
coreceptor for HIV .
• CCR5 (delta) 32 is an allele that contains a 32-base pair deletion and codes for a nonfunctional coreceptor.
• CCR5 (delta) 32 homozygotes (people who inherited the allele from both parents) are highly resistant to HIV
infection.
• Patients who are heterozygous for the 32-base pair deletion can acquire HIV infection, but have a slower rate
of progression.
13. EPIDEMIOLOGY
• Risk factors — Symptomatic acute HIV infection has been reported in
all major risk categories including men who have sex with men
(MSM), people who inject drugs, blood product recipients, and health
care workers with a needle-stick exposure .
• Transmission of HIV during early infection is correlated with
unprotected anal intercourse, the number of sexual contacts, and
high rates of acute sexually transmitted diseases in MSM
14. Infectivity
• Patients with early HIV infection are highly contagious to others, given
the typical transiently high viral loads seen in early HIV infection.
• Blood HIV viral load correlates with the risk of transmission of HIV.
• In men with acute HIV infection, the viral load in semen appears to
follow a similar pattern to that seen in blood, with the highest levels
occurring at approximately 20 days after infection or six days after the
onset of symptoms for those with an acute retroviral syndrome
15. • 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.
16. • 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
• 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.
17.
18. • Constitutional symptoms — Fever, fatigue, and myalgias are the most
common symptoms reported by patients with acute HIV infection
• Fever in the range of 38 to 40ºC is present in the vast majority of
patients with symptomatic acute HIV infection.
19. 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.
• Mild hepatosplenomegaly also can occur
20. 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 .
• However, unilateral or bilateral tonsillitis has also been described .
• 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 .
• These ulcerative lesions may reflect mucocutaneous disease associated
with acute HIV infection or coincident sexually transmitted infections, such
as herpes simplex virus, syphilis, or chancroid .
21. 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 .
• Vesicular, pustular, and urticarial eruptions have also been reported 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
22. 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. 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 .
• 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 .
• Meningoencephalitis can also occur during acute HIV infection
25. 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.
26. • When the possibility of acute or early HIV infection is being
considered based on clinical suspicion we perform the most sensitive
immunoassay available (ideally, a combination antigen/antibody
immunoassay) in addition to an HIV virologic (viral load)
27.
28.
29.
30. • 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, more patients with acute or early
HIV are being diagnosed on routine screening
31. 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.
32. • 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.
• Thus, the absence of elicited risk factors should not preclude the
possibility of HIV infection.
33. • 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.
34. 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 .
• 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.
35. 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
• A repeat sample should be drawn in this setting since a second positive viral load
(especially if higher) suggests a true positive result as would subsequent
seroconversion
36. 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
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 .
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 .
• 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 . This highlights the importance of HIV
viral level testing when acute or early infection is suspected
37. 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 .
• 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 .
• 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 (NNRTI) are more common than protease
inhibitor (PI)and integrase inhibitor (II)resistance mutations.
38. • 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.
39.
40.
41.
42. • The CDC classifies HIV infection into 3 categories, according to the
presence of certain infections or diseases.
• These conditions may be exacerbated by the HIV infection or
represent true opportunistic infections.
• Category A is asymptomatic HIV infection without a history of
symptoms or AIDS-defining conditions.
43. • Category B is HIV infection with symptoms that are directly attributable to HIV infection (or a
defect in T-cell–mediated immunity) or that are complicated by HIV infection. These include, but
are not limited to, the following:
• Bacillary angiomatosis
• Oropharyngeal candidiasis (thrush)
• Vulvovaginal candidiasis, persistent or resistant
• Pelvic inflammatory disease (PID)
• Cervical dysplasia (moderate or severe)/cervical carcinoma in situ
• Oral hairy leukoplakia
• Idiopathic thrombocytopenic purpura
• Constitutional symptoms, such as fever (>38.5°C) or diarrhea lasting more than 1 month
• Peripheral neuropathy
• Herpes zoster (shingles), involving 2 or more episodes or 1 or more dermatomes
44. Category C is HIV infection with AIDS-defining
opportunistic infections
45. • These 3 categories are further subdivided based on the CD4+ T-cell
count. Categories A1, B1, and C1 are characterized by CD4+ T-cell
counts greater than 500/µL.
• Categories A2, B2, and C2 are characterized by CD4+ T-cell counts
between 200/µL and 400/µL
• HIV infections in patient with CD4+ T-cell counts under 200/µL are
designated as A3, B3, or C3.
46. MANAGEMENT OF EARLY HIV INFECTION
• Prompt treatment — We agree with the United States Department of
Health and Human Services guidelines that recommend initiation of
antiretroviral therapy (ART) as soon as possible following the
diagnosis of acute and early HIV infection .
• If resources allow, initiation of ART on the same day of diagnosis,
even in the setting of acute or early HIV infection, can be a safe and
effective treatment strategy.
47. • Selection of antiretroviral regimen — Although the ultimate choice of
antiretroviral regimen should be informed by the results of drug resistance
testing, we initiate treatment as soon as feasible, even if results of baseline
resistance testing are not yet known.
• In such cases, we agree with the United States Department of Health and
Human Services recommendations to initiate one of the following
regimens
â—ŹDolutegravir plus tenofovir and either emtricitabine or lamivudine
â—ŹBictegravir-tenofovir alafenamide-emtricitabine
â—ŹRitonavir-boosted darunavir plus tenofovir and
either emtricitabine or lamivudine
48. HOW LONG ??
• Duration – Once initiated, ART is continued indefinitely.
• Studies evaluating the effects of a discrete course of ART early in HIV
infection suggest an improvement in surrogate markers of HIV disease
with earlier versus delayed therapy, but the durability of these
benefits following ART discontinuation is unclear.
• In contrast, substantial evidence from clinical trials in chronic
infection demonstrate increased AIDS- and non-AIDS-related
morbidity and mortality with treatment discontinuation.
• Thus, we recommend not using a treatment interruption strategy in
patients with acute or early HIV infection