Introduction
This guideline, developed by the New York State Department of Health AIDS Institute (NYSDOH AI), is designed to assist clinicians in New York State who are providing medical care to adult patients (aged 18 years and older) presenting with potential acute HIV infection. It addresses patients in ambulatory, inpatient, and emergency settings who exhibit signs or symptoms suggestive of recent HIV infection or report a possible exposure within the past four weeks. Early and accurate clinical diagnosis is paramount in managing HIV, and these guidelines, regularly updated to reflect the latest evidence-based practices and aligned with resources available through platforms like NCBI for in-depth research (ncbi.nlm.nih.gov), aim to ensure optimal patient care and public health outcomes.
The primary goal of this guideline is to equip New York State clinicians with the knowledge and recommendations necessary for the effective clinical diagnosis and subsequent care of acute HIV infection. Specifically, upon review of these guidelines, clinicians will be able to:
- Maintain a heightened awareness of the risks, signs, and symptoms associated with acute HIV infection. This includes considering HIV as a differential diagnosis for patients presenting with symptoms resembling influenza, mononucleosis, or other common viral syndromes, including COVID-19.
- Conduct appropriate initial and follow-up diagnostic testing when acute HIV infection is suspected.
- Effectively manage the treatment of acute HIV infection, adhering to best practices in clinical care.
- Comply with New York State regulations regarding HIV reporting and partner notification, crucial steps in public health management.
- Confidently recommend or initiate immediate antiretroviral therapy (ART) to improve individual patient health and significantly reduce the risk of onward HIV transmission. Facilitate access to comprehensive and ongoing HIV care and prevention services.
Terminology in HIV Infection Stages
To ensure clarity in understanding the progression of HIV infection, it is important to define key terms used throughout this guideline:
- Acute HIV infection: This term refers to the initial phase following HIV acquisition, characterized by viremia and the presence of detectable p24 antigen or HIV RNA. During this stage, diagnostic HIV antibodies are not yet detectable. This phase is sometimes referred to as “primary HIV infection” in medical literature.
- Recent infection: This generally describes the period within the first 6 months after HIV infection.
- Early infection: This is a broader term that can encompass both acute and recent infection, preceding the chronic stage of HIV infection.
The Importance of Early Diagnosis for Effective HIV Care
There is increasing evidence supporting the initiation of HIV treatment as soon as possible after diagnosis. Numerous studies have demonstrated the clinical benefits of early antiretroviral therapy (ART) initiation, including:
- Improved preservation of the patient’s immune system function.
- Significantly faster achievement of viral suppression.
- Reduction in the viral reservoir, which is a critical factor in ongoing research towards HIV cure strategies.
Starting ART during acute HIV infection can lead to these positive outcomes and is a critical component of modern HIV clinical care. Furthermore, the risk of sexual HIV transmission is substantially higher during the acute and recent phases of infection compared to chronic infection. This increased transmissibility is directly linked to the high levels of viremia present during early infection. Early initiation of ART provides a significant public health benefit by dramatically reducing HIV transmission rates, particularly when individuals achieve and maintain viral suppression. New York State, aligning with the Prevention Access Campaign’s consensus, recognizes that Undetectable = Untransmittable (U=U), meaning individuals with a sustained undetectable viral load (for ≥6 months) will not sexually transmit HIV.
Identifying and diagnosing acute HIV infection is therefore a crucial step in linking individuals to early care and offers a significant opportunity to reduce HIV transmission within the community. Prompt diagnosis and intervention are essential for both individual and public health. Studies have shown that patients diagnosed with HIV early are more likely to adopt risk-reduction behaviors when provided with counseling at the time of diagnosis and are effectively linked to ongoing HIV primary care. For those who choose to start ART, the risk of transmission is significantly reduced, further highlighting the importance of early clinical diagnosis and care in HIV management.
Clinical Presentation, Testing, and Diagnosis of Acute HIV Infection
Recommendations for Clinical Practice
The following recommendations are provided to guide clinicians in the presentation, testing, and diagnosis of acute HIV infection:
Presentation of Acute HIV Infection:
- Clinicians should consider acute HIV infection in the differential diagnosis for any patient presenting with symptoms consistent with influenza, mononucleosis, or other viral syndromes, especially if the patient reports sexual or parenteral exposure to an individual known to have or be at risk for HIV within the preceding month. (A2)
- Acute HIV infection should also be considered in the differential diagnosis for any patient, regardless of reported risk factors, who presents with flu-like or mono-like symptoms, or other viral syndrome symptoms (A3), and particularly when the patient exhibits any of the following:
- Rash (A2)
- Requests HIV testing (A3)
- Newly diagnosed sexually transmitted infection (STI) (A2)
- Aseptic meningitis (A2)
- Pregnancy or breastfeeding status (A3)
- Current use of antiretroviral medications for PrEP or PEP (A3)
Testing for Acute HIV Infection:
- When acute HIV is suspected, clinicians should always perform a plasma HIV RNA assay in conjunction with an Ag/Ab combination immunoassay. [a] (A2)
Diagnosis of Acute HIV Infection:
- A presumptive diagnosis of acute HIV infection can be made when plasma HIV RNA levels are ≥200 copies/mL, as detected by a sensitive nucleic acid test (NAT), and the HIV screening or type-differentiation test result is negative or indeterminate. (A2)
- In cases of a low-level quantitative HIV RNA viral load result (
- Expert consultation is recommended when an ambiguous HIV result is obtained for a patient taking PrEP or PEP, as diagnosing acute HIV in these individuals can be particularly complex. (A3)
Note:
[a] When point-of-care screening is utilized, even with a rapid Ag/Ab combination immunoassay, laboratory-based Ag/Ab combination immunoassay is recommended for confirmatory diagnostic HIV testing.
[b] A serologic test result not meeting HIV infection criteria includes a nonreactive screening result (antibody or Ag/Ab combination) or a reactive screening result with a nonreactive or indeterminate antibody differentiation confirmatory result.
Understanding HIV Test Detection Windows
The time between HIV infection and detectable viral markers varies depending on the type of test used. Figure 1 (above) illustrates the window of detection for different HIV tests, including antibody (Ab), antigen/antibody combination (Ag/Ab), and HIV RNA tests.
Variable Clinical Presentations of Acute HIV Infection
The clinical presentation of acute HIV infection is highly diverse. While fever and symptoms resembling influenza or mononucleosis are common, they are nonspecific. Patients may also present with more distinctive signs and symptoms of acute retroviral syndrome (ARS), such as rash, mucocutaneous ulcers, oral candidiasis, lymphadenopathy, and meningismus. These more specific symptoms should raise clinical suspicion for acute HIV infection. The typical timeframe from HIV exposure to the onset of symptoms is generally 2 to 4 weeks, with a range from 5 to 29 days. However, in some instances, symptoms may appear up to 3 months post-exposure. It’s important to note that this timeline can be extended and atypical in individuals who acquire HIV while using PEP or PrEP.
Box 1: Acute Retroviral Syndrome
Signs and symptoms of ARS and their expected frequency in symptomatic patients are listed below [a]. Oral ulcers and weight loss are noted as highly specific symptoms in studies, while fever and rash are identified as strong predictors. A high index of suspicion is warranted when these symptoms are present.
- Fever (80%)
- Tiredness or fatigue (78%)
- Malaise (68%)
- Joint pain (Arthralgias) (54%)
- Headache (54%)
- Loss of appetite (54%)
- Rash (51%)
- Night sweats (51%)
- Muscle pain (Myalgias) (49%)
- Nausea (49%)
- Diarrhea (46%)
- Fever and rash (46%)
- Sore throat (Pharyngitis) (44%)
- Lymphadenopathy (39%)
- Oral ulcers (mouth sores) (37%)
- Stiff neck (34%)
- Weight loss (>5 lb; 2.5 kg) (32%)
- Confusion (25%)
- Photophobia (24%)
- Vomiting (12%)
- Infected gums (10%)
- Sores on anus (5%)
- Sores on genitals (2%)
Note:
[a] Data adapted from Suanzes, et al. 2023 and Hecht, et al. 2002.
Diagnostic Approach to Acute HIV Infection
Due to the nonspecific nature of early symptoms, acute HIV infection is frequently missed in primary care settings, often mimicking common illnesses like influenza or mononucleosis. Additionally, patients may not always recognize or report recent potential HIV exposures. Therefore, clinicians must maintain a high level of suspicion for acute HIV infection in patients presenting with febrile, flu-like, or mono-like illnesses, particularly if they report recent behaviors associated with sexual or parenteral exposure to another person’s blood or bodily fluids. Identifying acute HIV infection during pregnancy is of particular importance as timely intervention can effectively prevent mother-to-child transmission.
The presumptive diagnosis of acute HIV infection is supported by high levels of HIV RNA detected in plasma via sensitive NAT, combined with negative or indeterminate HIV screening or type-differentiation test results. Reflex testing to HIV RNA in cases of discordant results (Ag/Ab combination immunoassay followed by a negative or indeterminate antibody differentiation immunoassay) can aid in identifying acute HIV infection and reduce the need for repeat patient visits for confirmatory testing. While both quantitative and qualitative HIV-1 RNA assays are sensitive for detecting HIV-1 at low thresholds, quantitative assays are more widely available and generally preferred for clinical diagnosis and care. An elevated signal-to-cutoff ratio (≥10) in laboratory-performed Ag/Ab combination immunoassays may help distinguish between acute HIV infection and false-positive results.
Low-level viremia reported in HIV RNA testing (
HIV RNA levels are typically very high during acute infection. However, a low value might indicate various points in the viremia course or potentially represent chronic infection. Furthermore, HIV RNA can be suppressed during acute infection in individuals taking PrEP. In patients using long-acting injectable cabotegravir (CAB-LA) for PrEP, diagnosing acute HIV infection can be challenging due to long-acting early viral inhibition (LEVI syndrome). In these situations, close observation, repeated testing, and consultation with an experienced HIV care provider are recommended to determine if HIV infection has occurred.
Plasma HIV RNA levels in acute infection do not appear to differ significantly between symptomatic and asymptomatic patients. Viremia precedes the detection of a specific immune response by approximately 1 to 2 weeks. Patients diagnosed with acute infection based on HIV RNA testing should always undergo follow-up diagnostic testing 3 weeks later to confirm the infection, following standard HIV laboratory testing algorithms. Figure 2 (above) illustrates a diagnostic algorithm for acute HIV infection.
Key Considerations in Diagnosis:
- Diagnosing acute HIV infection requires a strong clinical awareness due to the nonspecific nature of its signs and symptoms, which can easily be attributed to other viral illnesses.
- Clinical laboratories have specific internal protocols for reporting preliminary HIV test results. Terms such as indeterminate, inconclusive, nondiagnostic, and pending validation may be used for results that cannot be definitively classified. Clinicians should contact their laboratory to understand the meaning of nondefinitive results and the recommended next steps, particularly when acute HIV infection is suspected. Familiarity with institutional test-reporting policies is advised for all clinicians involved in HIV clinical diagnosis and care.
Management of Acute HIV Infection, Including Patients on PEP or PrEP
Recommendations for Managing Acute HIV Infection
The following recommendations guide the clinical care and management of patients diagnosed with acute HIV infection:
Managing Acute HIV Infection:
- Clinicians should recommend immediate ART initiation for all patients diagnosed with acute HIV infection. (A1)
- Patients should be informed about the heightened risk of HIV transmission during acute infection and in the 6 months following infection, as well as the ongoing risk beyond 6 months. [a] (A2)
- As part of the initial management for patients diagnosed with acute HIV infection, clinicians should:
- Consult with a care provider experienced in the treatment of acute HIV infection. (A3)
- Obtain HIV genotypic resistance testing for the protease (A2), reverse transcriptase (A2), and integrase (B2) genes at the time of diagnosis.
Specific Considerations for Patients on PEP or PrEP:
- Patients taking PEP: If acute HIV infection is diagnosed in a patient receiving PEP, ART should be continued while awaiting consultation with an experienced HIV care provider. (A3)
- Patients taking PrEP: Given the increased risk of drug-resistant mutations in patients who acquire HIV while on PrEP, clinicians should consult with an experienced HIV care provider and recommend a fully active ART regimen. (A3)
- Clinicians without access to experienced HIV care providers can contact the Clinical Education Initiative (CEI) Line at 866-637-2342 for expert guidance.
Note:
[a] Only individuals with a sustained (≥6 months) undetectable viral load will not sexually transmit HIV. Refer to the NYSDOH AI U=U Guidance for Implementation in Clinical Settings for further information (https://www.hivguidelines.org/guideline/u-equals-u/?mycollection=hiv-treatment&nlm=false).
Key Aspects of Acute HIV Infection Management
Patients are most infectious during the early stages of HIV infection due to high viremia. Clinicians must counsel patients with acute HIV about this increased transmission risk, particularly in the first 6 months after infection, and the ongoing risk thereafter. Partner notification, safer sex counseling, and screening for other STIs are crucial components of managing any new HIV diagnosis, especially acute infection.
Consultation with Experienced Providers: When selecting an ART regimen for a patient with acute HIV infection, consultation with a care provider experienced in treating acute HIV infection is highly recommended.
- Currently, there is no specific ART regimen specifically recommended for acute HIV infection. Regimen selection should be guided by general recommendations for initial ART regimens.
- The potential for transmitted drug resistance should be considered when prescribing ART, especially while awaiting HIV resistance testing results.
- The risk of acquired mutations is a particular concern for individuals who acquire HIV while taking PrEP.
- Clinicians who need expert guidance and do not have immediate access to experienced HIV care providers should utilize the CEI Line at 866-637-2342.
Summary of Recommendations for Clinical Diagnosis and Care of Acute HIV Infection
Presentation of Acute HIV Infection
- Include acute HIV infection in the differential diagnosis for any patient presenting with flu-like or mono-like symptoms who reports recent sexual or parenteral exposure to someone with or at risk for HIV. (A2)
- Consider acute HIV infection in the differential for any patient with flu-like or mono-like symptoms, regardless of reported risk, especially with rash, request for HIV testing, new STI diagnosis, aseptic meningitis, pregnancy/breastfeeding, or current PrEP/PEP use. (A3)
Testing for Acute HIV Infection
- Always perform a plasma HIV RNA assay with an Ag/Ab combination immunoassay when acute HIV is suspected. [a] (A2)
Diagnosis of Acute HIV Infection
- Presume acute HIV diagnosis with HIV RNA levels ≥200 copies/mL by sensitive NAT and negative or indeterminate HIV screening/differentiation test. (A2)
- Investigate low-level quantitative HIV RNA results with repeat testing and Ag/Ab combination immunoassay to rule out false positives. [b] (A2)
- Seek expert consultation for ambiguous HIV results in patients on PrEP/PEP due to diagnostic challenges. (A3)
Management of Acute HIV Infection
- Recommend immediate ART initiation for all patients with acute HIV infection. (A1)
- Inform patients about increased HIV transmission risk during acute and recent infection (up to 6 months), and ongoing risk beyond. [c] (A2)
- For initial management:
- Consult with an experienced HIV care provider. (A3)
- Obtain HIV genotypic resistance testing (protease, reverse transcriptase, integrase genes). (A2/B2)
- Patients on PEP: Continue ART if acute HIV diagnosed during PEP, pending expert consultation. (A3)
- Patients on PrEP: Consult expert and recommend fully active ART regimen due to higher risk of drug resistance if HIV acquired on PrEP. (A3)
- Utilize CEI Line (866-637-2342) for expert consultation if needed.
Note:
[a] For point-of-care screening, follow up with laboratory-based Ag/Ab combination immunoassay for definitive diagnosis.
[b] Non-definitive serologic result: nonreactive screening (Ab or Ag/Ab) or reactive screening with nonreactive/indeterminate Ab differentiation.
[c] Undetectable = Untransmittable (U=U) applies to individuals with sustained (≥6 months) undetectable viral load.
References
[References from original document would be listed here]
Supplementary Material
[Link to Supplement: Guideline Development and Recommendation Ratings from original document]
Footnotes
Conflict of Interest: No author or writing group conflicts of interest reported.
Created: August 2018; Last Updated: December 2024.
