Version October 2024
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
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".)
Altered presentation in patients receiving PrEP — In patients receiving cabotegravir for pre-exposure prophylaxis (PrEP), the clinical manifestations of acute HIV may be different from those typically observed in people not on PrEP. In a clinical trial of cabotegravir for PrEP, fever and rash were notably absent in those with acute HIV; similarly, other localized symptoms such as pharyngitis and diarrhea were not observed [39]. The combination of pauci-symptomatic acute HIV and the unreliable results on routine HIV screening with the antigen/antibody test has prompted experts to recommend HIV RNA as the screening tool for assessing HIV acquisition among those on cabotegravir PrEP. (See "HIV pre-exposure prophylaxis", section on 'Patient monitoring'.)
Opportunistic infections — Although usually associated with later stage HIV disease, opportunistic infections can rarely occur during the transient CD4 lymphopenia of early HIV infection [40]. 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 [6,41,42]. The factors responsible for the frequency of esophageal candidiasis during the immunosuppression of acute HIV infection are not well understood [43]. 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 [44], and prolonged, severe cryptosporidiosis [45].
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 [46]. 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 [46]. 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 [47]. 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) [48,49]. 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 [50]. 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 [51], 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 in adults", 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. 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, <200 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 repeat positive virologic test suggests HIV infection [52]. (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 in adults".)
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) [51]. 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 in adults", 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 [53]. 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'.)
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, <200 copies/mL), the diagnosis should be confirmed before initiating ART [52]. By contrast, in those with a higher, yet still low HIV RNA level (eg, 200 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 in adults", section on 'Nucleic acid tests'.)
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, <200 copies/mL) in the setting of suspected early HIV infection [54,55]. A repeat sample should be drawn in this setting since a second positive viral load (especially if higher) suggests a true positive result [56], 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) [57]. (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 [58,59]. 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 [60,61]. 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 [62,63]. 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 [64-66].
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 [67,68]. 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) [68]. 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 [69]. (See "Screening and diagnostic testing for HIV infection in adults", 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 in adults".)
Very early treatment for acute HIV infection can lead to abrogation of HIV antibody responses [70,71]. 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 [70]. It has been postulated that maturation of the antibody response can be thwarted by rapid HIV RNA suppression early in the course of disease [72]. It is critical that clinicians and patients understand that seroreversion does not indicate viral eradication [71,73].
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 [52,74]. Genotype resistance testing is preferred over other types of resistance tests (eg, phenotype). (See "Overview of HIV drug resistance testing assays" and "Interpretation of HIV drug resistance testing".)
In some laboratories, genotype tests do not routinely test for integrase resistance. Additional testing for integrase resistance should be requested if there is concern for resistance to integrase inhibitors (eg, use of cabotegravir for PreP or exposure to a source with integrase resistance).
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 [75-77]. 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".)
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) [78-80]. 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 [81]. Similarly, in some settings, transmission from acutely infected individuals is estimated to account for the majority of new HIV infections [82-84]. 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 [85].
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, <200 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, who contributed as Section Editor on earlier versions of this topic and was a founding Editor-in-Chief for UpToDate in Infectious Diseases.
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