Approach

Diagnosis and prevention of HIV are the responsibility of all healthcare practitioners. Providers should be sufficiently trained to diagnose infection and to manage the stage of positive living. Awareness of primary HIV 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.

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. Antibody tests, either enzyme-linked immunosorbent assay (ELISA) or rapid tests, are the most frequently used tests to diagnose HIV, but there has been a switch towards newer-generation HIV antibody/antigen-based assays.[63] A positive (reactive) result from an initial HIV antibody or combination antibody/antigen test is confirmed by a subsequent positive result from a supplemental molecular HIV test (typically HIV RNA or viral load) that differs from the initial test.[64] A quantitative HIV RNA polymerase chain reaction (PCR) must be used to diagnose acute retroviral syndrome.

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 disease in the individual. Baseline laboratory investigations depend on available resources, and are used to define management goals and plans.

All patients should have: HIV antibody testing; a lymphocyte subset panel, including CD4 count; a hepatitis screen; a venereal disease research laboratory test; tuberculin skin test; and, ideally, full blood count (FBC), chemistry profile, creatinine, liver function tests (LFTs), fasting blood glucose, serum lipids, and urinalysis. HIV viral load should also be performed at baseline in most developed countries. Drug resistance testing (genotype/phenotype) is recommended in settings where there are high levels of circulating resistant virus (e.g., the US).[52] Frequency and timing of testing vary for each investigation, and local guidance should be consulted.

At the end of the session a comprehensive management plan for future care should be made, including a plan for initiation of potent combination antiretroviral therapy (ART) and risk reduction counselling.[4][52]

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 disease by US Centers for Disease Control and Prevention (CDC) or World Health Organization (WHO) classifications.[64][65] 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 HIV infection.[9] All recent hospital admissions should be detailed as they may be related to HIV. Risk of tuberculosis (TB) and 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 medicine 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][66]

Social background and lifestyle issues should be discussed, including:[4][66]

  • 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.

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.

Disclosure to sexual partner(s) is important as that person will need to be assessed for risk of HIV infection and tested. Non-disclosure may indicate a reluctance to accept the diagnosis of HIV and can result in poor adherence to ART later.[66] 

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, 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][64]

  • Psychiatric assessment should include noting the patient's affect and orientation.

Anorexia and lymphadenopathy may be associated with acute or primary HIV infection.[9]

HIV testing

Several laboratory tests are available and have various benefits and limitations:

  • ELISA: the most established tests for detecting HIV infection rely on ELISA as an initial screening test. 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 to 4 weeks, with almost all newly infected people 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 ELISA tests reduce the window period to about 2 to 4 weeks, thereby reducing the number of false-negative results, especially in areas where incident infections are common. The ELISA is the preferred screening method in the developing world since it lends itself to high throughput, rapid testing, and automation.

  • Fourth-generation antibody (ELISA) and antigen (p24): the latest fourth-generation HIV tests incorporate the p24 antigen, meaning that obtaining a diagnosis of HIV during the window period is more likely, as the test examines both antibodies and the p24 antigen. This reduces the window period from 3 months to an average of 10 days; these tests may therefore be recommended for HIV confirmation.[63]

  • Western blot: despite high specificity, the use of ELISA in populations where the prevalence of disease is low will lead to a high proportion of positive results being false. Thus, in the developed world, the protocol is to confirm positive or indeterminate ELISA results with a second test, the Western blot. Western blots require significant time and resources and so are not suited to many high-prevalence areas.

  • Rapid test: this has worked well in resource-poor settings. Several have been endorsed by the US Food and Drug Administration and the WHO. These tests have higher than 99% sensitivity and specificity when combined with a confirmatory Western blot in the developed world and a second rapid test in the developing world

  • Other HIV screening tests: tests are available which 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

  • Nucleic acid testing (RNA or DNA): this provides the most sensitive test for HIV infection in the newborn, and can be used at 4 to 6 weeks of age. Placentally transferred maternal antibodies can persist in the neonate for up to 18 months, so antibody tests cannot be used to establish the diagnosis.

  • Reverse-transcriptase PCR of viral RNA (viral load): this test measures active replication of HIV in blood and other body fluids, and is primarily used to assess activity of HIV and monitor the response to ART. There is an ultra-sensitive version of this test that can reliably measure viral RNA levels as low as 20 RNA copies/mL of plasma. This is also the most sensitive test for adults with acute HIV infection who might be in a window period without detectable antibody or antigen (p24).

  • p24 antigen: this is a core HIV protein and is present during high viral replication and so is detectable in the blood during acute infection and again during late stages of infection. Its use, therefore, is as a supplementary test during the window period. This test becomes positive later than HIV RNA (viral load) during acute HIV infection, and this is why it is less sensitive during this stage of infection.

CD4 count

The CD4 cell count indicates the health of the host's immune system and assists in the initial assessment and on-going 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.

Drug resistance testing

Baseline antiretroviral drug resistance testing is important in settings where it is available to ensure the success of initial ART.[20] Estimates in the US are that the frequency of new infection with a virus with at least one major resistance mutation is around 10% to 25%.[20] The WHO reports ≥10% of adults starting antiretroviral therapy had a strain of HIV that was resistant to efavirenz or nevirapine in 12 of the 18 countries it surveyed between 2014 and 2018.[67]

Genotypic testing is cheaper and easier than phenotypic testing and is more commonly performed at baseline in the US due to increased transmission rates of genotype resistant virus.[68] 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 in the US.[69]

Genotypic testing is recommended at diagnosis to guide selection of initial ART. Treatment should not be delayed while awaiting results, as the regimen can be modified once results are received. Testing is also recommended when changing ART regimens in the following patient groups: patients with virologic failure and HIV RNA levels >1000 copies/mL, patients with HIV RNA levels >500 copies/mL and <1000 copies/mL, and patients with suboptimal viral load reduction.[52]

A 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 resistance testing provides any benefit for treatment-naive patients.[70] [ Cochrane Clinical Answers logo ]

Other tests

Pregnancy testing (urine beta human chorionic gonadotrophin [beta-hCG]) should be done on all women of childbearing potential prior to starting ART, as some drugs are not recommended in pregnancy.

Hepatitis A, B, and C, STIs (gonorrhoea, chlamydia, and syphilis), toxoplasma IgG, and human leukocyte antigen (HLA)-B*5701 testing should be performed in all individuals at their first clinic visit and prior to initiation of ART.

Tuberculin skin test should be performed, if deemed clinically necessary. A reaction of >5 mm may require TB prophylaxis.

A chest x-ray should be requested if there are symptoms of TB or pneumonia.[4]

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.[64][65] 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 infection. See Criteria section for detailed staging categories.

Baseline investigations prior to initiating ART

Before patients commence ART, the following tests should be done and monitored during the course of therapy:

  • LFTs

  • FBC with differential

  • Electrolytes

  • Serum creatinine (and calculated glomerular filtration rate) and urinalysis for proteinuria

  • Random or fasting lipid profile

  • Random or fasting plasma glucose

  • Hepatitis B surface antigen

  • STI (gonorrhoea, chlamydia, syphilis) and hepatitis C screening

  • HLA-B*5701 testing

  • HIV RNA (viral load)

  • Lymphocyte subset panel, including CD4 count

  • HIV genotype resistance assay.


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