Approach
Diagnosis and prevention of HIV are the responsibility of all healthcare practitioners. Providers should be sufficiently trained to diagnose HIV and to manage the stage of positive living. Awareness of primary infection (the first days to 6 months after HIV acquisition) in high-risk patient groups is critical to avoid missed diagnoses. Early recognition and prompt therapy can improve individual patient care and prevent further transmission.
While timely diagnosis is critical to prevent transmission, the overall pooled mean time from infection to diagnosis was approximately 3 years (shorter for men who have sex with men, and longer for heterosexuals and people who inject drugs) in one meta-analysis of studies conducted in countries outside of Africa including the US and UK.[86]
Establishing the diagnosis
A person who feels they are at risk for being HIV positive or those who are getting routine HIV screening should receive pre-test counselling. This should include determining actual risk factors and working through the process to follow with both a negative (risk-reduction counselling) and positive results. It may be prudent in cases where HIV is suspected to present the HIV test as an opt-out option among other diagnostics. Combined HIV antigen/antibody tests, either enzyme-linked immunosorbent assay (ELISA) or rapid tests, are the most frequently used tests to diagnose HIV.[87] A positive (reactive) result from an initial antibody/antigen test is confirmed by a subsequent positive result from a HIV-1/HIV-2 antibody differentiation immunoassay (multispot) or molecular HIV test.[88] A quantitative HIV RNA polymerase chain reaction (PCR) must be used to diagnose acute retroviral syndrome along with signs and symptoms typical of this clinical syndrome. See HIV testing (below).
Initial assessment
Initial assessment of a person newly diagnosed with HIV should be thorough and include a comprehensive and focused medical history and clinical examination, as well as appropriate laboratory tests, in order to assess the stage of HIV in the individual. Baseline laboratory investigations depend on available resources, and are used to define management goals and plans.
At the end of the session a comprehensive management plan for future care should be made, including a plan for initiation of antiretroviral therapy (ART) and risk reduction counselling.[4][78]
The patient may present at 1 of 4 stages:
During the acute seroconversion illness
During an asymptomatic period of clinical latency
During a symptomatic period of immune dysregulation and milder immune deficiency before the development of AIDS
With severe immunodeficiency and AIDS
History
The clinician should elicit a history of common symptoms likely to be related to HIV, paying particular attention to those symptoms that would assist in staging the HIV by US Centers for Disease Control and Prevention (CDC) or World Health Organization (WHO) classifications.[88][89] These include fevers and night sweats, loss of weight, skin rashes, oral thrush or ulceration, diarrhoea, headaches, and changes in mental status or neuropsychiatric function. Symptoms such as fever, sore throat, night sweats, fatigue, malaise, myalgia, diarrhoea, and rash may all be associated with acute or primary infection.[1] All recent hospital admissions should be detailed as they may be related to HIV. Risk of tuberculosis (TB) and sexually transmitted infections (STIs) should be assessed (symptoms and any known contact) and a vaccination history taken (particularly hepatitis A and B, pneumococcal, and tetanus). A note should be made of current drug history and known allergies. All women should be asked about current and prior pregnancies and whether they have been pregnant since knowing their HIV status. The date of their latest Papanicolaou test should be confirmed.
Attention should be paid to risk factors for contracting HIV, such as intravenous drug use and sexual history, including sexual orientation and risks of further HIV transmission, number of partners, whether partners are aware of HIV status, use of condoms and previous STIs (including viral hepatitis).[4]
Social background and lifestyle issues should be discussed, including:[4]
Home environment: type of housing, how many people live there, water and electricity supply
Children: ages and HIV status if known
Disclosure of HIV status: to sexual partner, family, and/or friends
Support structures: people who can provide emotional support for the patient
Employment
Smoking history
Exercise
Current and prior use of alcohol or other substance use (especially during sexual encounters)
In previously-treated patients who present to a new physician for an initial evaluation, a detailed history of previous ART, including resistance test results, should be obtained.
Partner notification services should be offered regularly. Disclosure to sexual partner(s) is important as that person will need to be assessed for risk of HIV and tested. Non-disclosure may indicate a reluctance to accept the diagnosis of HIV and can result in poor adherence to ART later.[90]
Clinical examination
In starting with the physician's general impression of the patient, it should be established if the patient is well or unwell. The examination should be tailored to the extent of the patient's symptoms. Specific factors for evaluation include:
Weight and height measurement
Examination for generalised lymphadenopathy, noting site, size, and mobility of nodes
Skin inspection for HIV-associated rashes and scars (including herpes zoster), papular pruritic eruptions, fungal infections, or Kaposi's sarcoma
Examination of the mouth for oral thrush or ulcers, oral hairy leukoplakia, Kaposi's sarcoma, and periodontal disease
Chest and cardiovascular examination for signs of, for example, pulmonic infection
Abdominal examination to evaluate for hepatomegaly or splenomegaly
Examination of the genitalia for signs of STIs (in all patients)
Neurological examination, including an assessment of mental status, meningismus, and peripheral neuropathy, and fundoscopy looking for retinal lesions[4][88]
Psychiatric assessment should include noting the patient's affect and orientation
Laboratory testing at entry into care
The following tests are recommended at entry into care:[78]
HIV antigen/antibody test
HIV viral load
CD4 count
Genotypic resistance testing
Hepatitis A, B, and C screening
Basic metabolic profile
Liver function tests
FBC with differential
Lipid profile
Random or fasting glucose
Urinalysis
Pregnancy testing
Also screen for STIs regardless of risk (e.g., gonorrhoea, chlamydia, syphilis, mpox), as well as coinfections including toxoplasmosis, cryptococcosis, and tuberculosis. A chest x-ray should be ordered if there are symptoms of tuberculosis or pneumonia.[4][91]
Frequency and timing of testing may vary for each test and local guidance should be consulted. Testing recommendations usually may differ in developing nations.
How to take a venous blood sample from the antecubital fossa using a vacuum needle.
Laboratory testing prior to ART initiation/modification
Before ART initiation/modification, the following tests are recommended:[78]
HIV viral load
CD4 count
Genotypic resistance testing
Tropism testing (if considering a CCR5 antagonist)
HLAB*5701 testing (if considering abacavir)
Hepatitis B serology (if switching to a regimen that does not contain tenofovir)
Basic metabolic profile
Liver function tests
FBC with differential
Random or fasting glucose
Pregnancy test
If ART is initiated soon after diagnosis and entry into care, repeat baseline laboratory testing is not necessary.
Frequency and timing of testing may vary for each test and local guidance should be consulted. Testing recommendations usually may differ in developing nations. For monitoring recommendations during treatment, see Monitoring.
HIV testing
HIV testing is recommended at entry into care, if an HIV diagnosis has not been previously confirmed.[78]
There are three types of HIV tests available:[93]
Combination antigen/antibody immunoassays
Antibody immunoassays
Nucleic acid tests
The US Centers for Disease Control and Prevention (CDC) recommends the following testing algorithm for people with potential HIV exposure or acquisition.[93]
A fourth-generation combination antigen/antibody immunoassay that detects HIV-1 and HIV-2 antibodies and the HIV-1 p24 antigen is recommended as the initial test. Options include ELISA or rapid tests. No further testing is required for specimens that are negative (non-reactive).
An HIV-1/HIV-2 antibody differentiation immunoassay (multispot) is recommended if the initial antigen/antibody test is positive (reactive).
An HIV nucleic acid test should be considered if there is a possibility of early infection (e.g., when recent HIV exposure is suspected or reported), or if the HIV-1/HIV-2 antibody differentiation immunoassay is non-reactive, indeterminate, or discordant.
Diagnostic testing algorithms vary, and you should consult your local guidance. The World Health Organization (WHO) recommends a standard three-test strategy in order to minimise false-positive results and prevent misdiagnosis.[69]
ELISA is the most established test for detecting HIV.
During or shortly after infection, IgM antibodies to HIV first appear. This is followed weeks to months later by IgG antibodies to Gag and Env, and then to viral enzymes and regulatory proteins. The time to first detectable IgG by ELISA takes a median of 3-4 weeks, with almost all people with HIV having detectable IgG levels by 6 months. During this time an ELISA test may be falsely negative, a period known as the window period.
Fourth-generation combination antigen/antibody ELISA tests incorporate the p24 antigen, meaning that obtaining a diagnosis of HIV during the window period is more likely, as the test detects both HIV antibodies and the p24 antigen. The p24 protein is present during high viral replication and so is detectable in the blood during acute infection and again during late stages of infection. This reduces the number of false-negative results, especially in areas where incident infections are common, and reduces the window period to an average of 10 days.[87]
ELISA is the preferred screening method in resource-limited settings since it lends itself to high throughput, rapid testing, high sensitivity, and automation.
Rapid tests may be used for initial testing in some clinical settings, and several tests are available.
Most of the rapid tests detect HIV antibodies in blood (fingerstick) with high sensitivity and specificity when combined with confirmatory testing.
False-negatives may occur during the window period immediately after infection before antibodies to HIV have occurred.
Other HIV screening tests are available that detect the presence of HIV antibodies in fluids other than blood. Saliva has higher concentrations of IgA and IgG, and both ELISA and rapid tests exist for saliva. However, these tests are most often used for surveillance. Historically, Western blot was done to confirm ELISA testing. However, easier and less expensive testing such as the HIV-1/HIV-2 antibody differentiation immunoassay (multispot) has largely replaced Western blot for confirmatory testing.[94] A quantitative HIV RNA PCR must be used to diagnose acute retroviral syndrome.
Testing people on pre-exposure prophylaxis (PrEP)
People who acquire HIV while taking PrEP may sometimes have ambiguous test results.
A positive HIV antigen/antibody test result or a positive HIV RNA test result in the setting of a negative HIV antibody result should prompt immediate confirmation of the diagnosis. In people with an HIV RNA level ≥200 copies/mL who are taking PrEP, immediate initiation of an effective HIV treatment regimen is recommended while awaiting confirmation of the diagnosis. In people who have a negative HIV antibody test result and a very low positive quantitative HIV RNA test result (<200 copies/mL), a confirmatory HIV antibody test and quantitative plasma HIV RNA test should be performed; treatment should not be started until results are available.[78]
HIV self-testing
HIV self-testing may be offered as an additional approach to HIV testing services. Rapid self-tests can be purchased from a pharmacy, can be done at home, and produce results within 20 minutes. Self-testing may also be used to deliver PrEp (e.g., for initiation, reinitiation, and continuation). Evidence shows that self-testing increases the uptake of HIV testing. It is considered to be acceptable and feasible in a range of populations and settings.[95][96]
CD4 count
CD4 count is recommended at entry into care and prior to initiation of ART. If ART is delayed, testing is recommended every 3 to 6 months.[78] The CD4 count indicates the health of the host's immune system and assists in the initial assessment and ongoing monitoring of the patient. This is one of the most important tests to complete at entry into care as it establishes the patient's risk of developing HIV-associated complications, including AIDS-defining infections and malignancies.
An average CD4 count for an HIV-negative adult is 800 cells/microlitre, and the average drop in CD4 count in HIV-positive patients is 75 cells/microlitre/year. People with a CD4 count of >500 cells/microlitre are usually asymptomatic, but still at an increased risk for general infections. A CD4 count of <350 cells/microlitre implies substantial immune suppression. A CD4 count <200 cells/microlitre defines an individual as having AIDS and places the patient at high risk for opportunistic infections (OIs), with Pneumocystis jirovecii pneumonia being the most common OI.[88][97]
HIV viral load
Reverse-transcriptase PCR of HIV RNA (viral load) measures the active replication of HIV in the blood and other body fluids, and is primarily used to assess activity of HIV and monitor the response to ART. Viral load is recommended at entry into care and prior to initiation of ART.[78]
There is an ultrasensitive version of the test that can reliably quantify viral RNA levels as low as 20 copies/mL of plasma. This is also the most sensitive test for adults with acute infection who might be in a window period without detectable HIV antibodies or p24 antigen. There are also point-of-care qualitative HIV RNA viral load assays that require less laboratory expertise with potential applications in under-resourced settings.[98][99]
Drug resistance testing
Genotypic testing is recommended at entry into care and prior to initiation of ART to help guide selection of initial ART. If ART is deferred, repeat testing is optional and may be considered at the time of ART initiation. Treatment should not be delayed while awaiting results, as the regimen can be modified once results are received.[78]
Testing is also recommended to assist the selection of ART when changing regimens in treatment-experienced patients:[78]
With virological failure and HIV RNA levels >200 copies/mL (drug resistance testing may be unsuccessful in patients with HIV RNA levels between 200 to 500 copies/mL, but should still be considered)
With suboptimal viral load reduction.
Standard genotype testing involves testing for mutations in the integrase, reverse transcriptase and protease genes. Testing is recommended while the patient is still taking the ART regimen, or within 4 weeks after discontinuing the regimen, for non-long-acting agents. For patients taking long-acting injectable drugs, testing is recommended regardless of the time since discontinuation.[78]
Baseline antiretroviral drug resistance testing is important in settings where it is available to ensure the success of initial ART.[19] Estimates in the US are that the frequency of a new diagnosis with a virus with at least one major resistance mutation is around 10% to 25%.[19] The WHO reports that ≥10% of adults starting ART had a strain of HIV that was resistant to efavirenz or nevirapine in 26 of the 40 countries it surveyed between 2014 and 2021.[100] Eleven countries reported pre-treatment resistance to dolutegravir; only South Sudan detected an extremely low prevalence (0.2%) of resistance to dolutegravir.[100]
Genotypic testing is preferred over phenotypic testing to guide ART in treatment-naive patients, or guide therapy in people with a suboptimal virological response or virological failure while on first- and second-line regimens.[78] Genotypic testing is cheaper and easier than phenotypic testing and is more commonly performed at baseline due to increased transmission rates of genotype resistant virus.[101] Phenotypic testing may be preferable to assess resistance in patients who have failed several regimens (salvage) as the patient's genotypes may be difficult to interpret. However, with newer, more potent ART, including several regimens with a high genetic barrier to resistance and low failure rates, there is less drug resistance.[102] Combined genotypic and phenotypic resistance testing is recommended for people with known or suspected complex drug-resistance mutation patterns.[78]
One Cochrane review found that drug resistance testing (genotypic or phenotypic) is likely to have little or no impact on mortality, progression to AIDS, or CD4 count. However, it may reduce the risk of virological failure and viral load in patients who are experiencing treatment failure. It is unclear whether the benefits of resistance testing may be greater for treatment-naive patients.[103]
[ 
]
Disease staging
Once the initial assessment and CD4 count is completed, the patient can be staged according to either the CDC or the WHO classification systems.[88][89][97] Timing of follow-up and further management may depend on the classification, including any underlying or concurrent infections/malignancies; however, recommendations for initiation of ART should be advised at all stages of HIV. Staging may be particularly useful in settings where CD4 count testing is not available. See Criteria for detailed staging categories.
Use of this content is subject to our disclaimer