Sections

Workup

Approach Considerations

Screening for human immunodeficiency virus (HIV) infection is paramount, since infected individuals may remain asymptomatic for years while the infection progresses. Serologic tests are the most important studies in the evaluation for HIV infection.

Secondary testing that may be performed to assist with diagnosis or staging includes the following:

Viral culture
Lymph node biopsy
Proviral DNA polymerase chain reaction (PCR)
Genotyping of viral DNA/RNA

In June 2014, the Centers for Disease Control and Prevention (CDC) issued new recommendations for HIV testing in laboratories that are aimed at reducing the time needed to diagnose HIV infection by as much as 3-4 weeks over previous testing approaches. The new testing algorithm is performed as follows^{[96, 97]}:

Diagnosis starts with a fourth-generation test that detects HIV in the blood earlier than antibody tests can; it identifies the viral protein HIV-1 p24 antigen, which appears in the blood before antibodies do
If this test is positive, an immunoassay that differentiates HIV-1 from HIV-2 antibodies should be performed; results from such assays can be obtained faster than they can from the Western blot test
In patients with positive results on the initial antigen test but with negative or indeterminate results on the antibody differentiation assay, HIV-1 nucleic acid testing should be performed to determine whether infection is present

In August 2013, the FDA approved the Alere Determine HIV-1/2 Ag/Ab Combo test (Orgenics, Ltd), the first rapid HIV test for the simultaneous detection of HIV-1 p24 antigen as well as antibodies to both HIV-1 and HIV-2 in human serum, plasma, and venous or fingerstick whole blood specimens. Detection of HIV-1 antigen permits earlier detection of HIV-1 infection than is possible by testing for HIV-1 antibodies alone.^{[10, 11]}

This rapid test can be used in outreach settings to identify HIV-infected individuals who might not be able to be tested in traditional health care settings. The test does not distinguish between antibodies to HIV-1 and HIV-2, and is not intended to be used for screening of blood donors.^{[10, 11]}

Staging of HIV disease is based partially on clinical presentation, but other laboratory tests can help in deciding whether to initiate or modify treatment.

Baseline laboratory studies for other infections (eg, tuberculosis) are important in the initial workup of a patient with newly diagnosed HIV infection. In addition, baseline levels of factors that may be affected by antiretroviral therapy (eg, lipids) should be measured.

Screening for HIV Infection

The US Preventive Services Task Force (USPSTF) strongly recommends that clinicians screen for HIV in all adolescents and adults at increased risk for HIV infection, and all pregnant women.^[3]

The American College of Obstetricians and Gynecologists recommends that all females aged 13-64 years be tested for HIV at least once during their lifetime.^{[98, 99]}Retesting annually or more often is recommended for those at high risk because of injection drug use, sex with an injection drug user, sex for money or drugs, sex since their most recent HIV test with men who have sex with men, or sex since their most recent HIV test with more than 1 person.

Guidelines issued in 2015 on HIV testing during pregnancy by the American College of Obstetricians and Gynecologists are as follows^{[100, 101]}:

Women should be tested for HIV during routine prenatal testing, on an opt-out basis when possible.
Women at high risk for HIV infection, including injection drug users and women with multiple sex partners during their pregnancy, should be retested in their third trimester.
Women who have not been tested should be offered rapid screening when in labor; if the rapid test result is positive, antiretroviral therapy should be initiated while awaiting results of a confirmatory test.
All pregnant women should be screened for HIV infection as early as possible during each pregnancy using the opt-out approach when allowed.
Repeat HIV testing in the third trimester is recommended among women in areas with high HIV incidence or prevalence and among women known to be at risk for acquiring HIV infection.
Women who were not tested earlier in pregnancy or whose HIV status otherwise is undocumented should be offered rapid screening upon labor and delivery using the opt-out approach when allowed.
If a rapid HIV test result in labor is reactive, antiretroviral prophylaxis should be immediately initiated while awaiting supplemental test results.
If the diagnosis of HIV infection is established, the woman should be linked into ongoing care with a specialist in HIV care for comanagement.

The Centers for Disease Control and Prevention (CDC) recommends HIV screening for patients in all health-care settings, after the patient is notified that testing will be performed unless the patient declines (opt-out screening); the CDC recommends that persons at high risk for HIV infection be screened for HIV at least annually.^[4]

Citing the benefits of early diagnosis and treatment and the failure of risk-based screening to identify a substantial proportion of HIV-infected patients early in the disease, the American College of Physicians recommends that clinicians adopt routine screening for HIV and encourage all patients to be tested.^[5]

Screening assays

A high-sensitivity enzyme-linked immunobsorbent assay (ELISA) should be used for screening. Most ELISAs can be used to detect HIV-1 types M, N, and O and HIV-2.

A positive ELISA result should be followed with confirmatory testing in the form of one or more Western blot assays or similar specific assay. Specific diagnostic criteria vary by test. Results typically are reported as positive, negative, or indeterminate.

Testing for HIV-2 should be ensured for patients from an HIV-2 endemic area or those who have indeterminate results on HIV-1 Western blot testing. Not all HIV tests include detection of HIV-2 or Group O. In New York City, 62 cases of HIV-2 were detected over an 8-year period, of which 40 were initially misdiagnosed as HIV-1.^[102]

Early detection using combination screens may be more effective than simply using serology. The additional detection of p24 antigen or viral RNA may detect a greater number of very recent infections before seroconversion occurs. This likely would result in significant reductions in transmission as well as overall health costs and healthcare burden.^[103]

To address the problem of confirmatory supplemental tests giving false-negative results early in the course of HIV infection, the CDC conducted two prospective evaluations of a new HIV diagnostic algorithm. The new diagnostic algorithm replaces the Western blot (WB) with an HIV-1/HIV-2 antibody differentiation assay as the supplemental test and includes an RNA test to resolve reactive immunoassay (IA) with negative supplemental test results.^[104]

CD4+ T-cell Count

The CD4 T-cell count is a reliable indicator of the current risk of acquiring opportunistic infections. CD4 counts vary, and serial counts generally are a better measure of any significant changes. The reference range for CD4 counts is 500-2000 cells/μL. After seroconversion, CD4 counts tend to decrease (around 700/μL on average) and continue to decline over time. For surveillance purposes, a CD4 count under 200/μL is considered AIDS-defining in the United States owing to the increased risk for opportunistic infections at this level. The magnitude of discordance between absolute CD4 T-cell numbers and CD4 T-cell percentages is greatest in those with active hepatitis C virus and more advanced liver disease.^[105]

In children under 5 years of age, the CD4 T-cell percentage is considered more important than the absolute count. (Less than 25% is considered worthy of starting therapy, regardless of the total CD4 count). In adults with chronic hepatitis C and low absolute CD4 T-cells, the CD4 percentage may also be more useful, due to probable T-cell sequestration in the liver.^[8]

Viral Load

Viral load in peripheral blood is used as a surrogate marker of viral replication rate. This is a surrogate because most of the viral replication occurs in the lymph nodes rather than in the peripheral blood.

The test is a quantitative amplification of the viral RNA using nucleic acid sequence-based amplification (NASBA), reverse-transcription polymerase chain reaction (RT-PCR), or similar technologies. Quantitative viral-load assays should not be used as a diagnostic tool because several false-positive misdiagnoses have been reported in the literature.

The rate of progression to AIDS and death is related to the viral load, although, on an individual level, it is poorly predictive of the absolute rate of CD4 T-cell loss. Patients with viral loads greater than 30,000/mL are 18.5 times more likely to die of AIDS than those with undetectable viral loads.

With therapy, viral loads often can be suppressed to an undetectable level (ie, < 20-75 copies/mL, depending on the assay used); this is considered optimal viral suppression. At the same time, the CD4 count rises and the risk of opportunistic infections and death is reduced. Complete inhibition of viral replication appears impossible and may be unnecessary.

Not uncommonly, successfully treated patients will demonstrate intermittent viremia, with viral loads transiently detectable at low levels (typically, < 400 copies/mL); this appears to occur more commonly with some viral load assays than others. Such “blips” are not thought to represent viral replication or to predict virologic failure.^[9]Virologic failure is defined as a confirmed viral load of more than 200 copies/mL; although this is a research definition, it may be useful in clinical practice.^[9]

Secondary HIV Testing

Viral culture is expensive and time-consuming and is less sensitive in patients with low viral loads. Viral culture may be performed as part of phenotypic drug-resistance testing.

Lymph node architecture is disrupted during HIV infection. HIV DNA, RNA, and proteins may be detected with molecular techniques, and electron microscopy may reveal virions.

Proviral DNA PCR usually is performed only in newborns because conventional serologic testing is useless in these patients (maternal antibodies may persist for 9 months or longer). Two or more negative results separated by at least 1 month is considered a negative result.

Genotyping of viral DNA/RNA can guide therapy. Because patterns of mutations that lead to resistance to specific drugs or drug classes are now well-recognized, sequencing of the viral genome allows for the selection of specific antivirals that are more likely to elicit a response.

Baseline Studies

Baseline studies for other infections that are important in the initial workup of a patient with newly diagnosed HIV infection include the following:

Purified protein derivative (PPD) skin testing for tuberculosis
Cytomegalovirus (CMV) testing
Syphilis testing
Rapid amplification testing for gonococcal and chlamydial infection
Hepatitis A, B, and C serology
Anti-Toxoplasma antibody
Ophthalmologic examination

A purified protein derivative skin test is placed to evaluate for tuberculosis infection. Chest radiography should be performed in patients with a positive PPD test result.

Serology should be performed to test for CMV infection. The presence of anti-CMV IgG indicates previous exposure to CMV. Ophthalmologic examination is used to evaluate for CMV retinitis in people with very low CD4 T-cell counts.

For syphilis screening, rapid plasma reagent (RPR) testing can be used initially, but more specific testing should be used for follow-up, as RPR can yield false-positive results. Lumbar puncture is used to evaluate neurologic symptoms.

Rapid amplification testing is used to evaluate for gonococcal infection and chlamydia in cases of sexual HIV transmission. Pelvic examination is performed in females (with wet mount for trichomoniasis).

Hepatitis A, B, and C serology is performed to determine the need for vaccination or treatment and to evaluate for chronic infection. Patients infected with hepatitis C may be candidates for treatment. Genotyping and baseline liver function tests are crucial.

Anti-Toxoplasma antibody is measured to determine whether patients have had toxoplasmosis, and thus are at risk for reactivation of infection in the event of immunocompromise. Patients with prior Toxoplasma infection require prophylaxis if their CD4⁺ T-cell counts drop below 100/µL.

Tests to establish baseline values of factors that may be affected by antiretroviral therapy include the following:

Liver function tests
Serum chemistries
Blood urea nitrogen (BUN)/serum creatinine
Fasting lipid panel
Vitamin B12 and folate levels
Thyroid function studies^[106]

Other tests include urinalysis to evaluate for HIV-associated nephropathy and a drug screen to effectively exclude other metabolic and infectious etiologies.^[107]

Histologic Findings

Certain histologic findings are characteristic of various features of HIV infection and AIDS. The lymph node architecture is progressively disrupted; this can be reversed with effective antiviral therapy. Findings include hyperplasia, multinucleated syncytia of T cells, and loss of the normal follicular dendritic network. Nucleic acid or immunohistochemical stains for viral antigens shows virus localizing to macrophages, T cells, and dendritic cells. Electron microscopy may reveal virions or intracellular virus within phagosomes in macrophages.

Multinucleated giant cells are a characteristic finding in patients with HIV encephalopathy. Myelin pallor and microgliosis also may be observed.

Staging

The CDC classifies HIV infection into 3 categories, according to the presence of certain infections or diseases.^[12]These conditions may be exacerbated by the HIV infection or represent true opportunistic infections.

Category A is asymptomatic HIV infection without a history of symptoms or AIDS-defining conditions.

Category B is HIV infection with symptoms that are directly attributable to HIV infection (or a defect in T-cell–mediated immunity) or that are complicated by HIV infection. These include, but are not limited to, the following:

Bacillary angiomatosis
Oropharyngeal candidiasis (thrush)
Vulvovaginal candidiasis, persistent or resistant
Pelvic inflammatory disease (PID)
Cervical dysplasia (moderate or severe)/cervical carcinoma in situ
Oral hairy leukoplakia
Idiopathic thrombocytopenic purpura
Constitutional symptoms, such as fever (>38.5°C) or diarrhea lasting more than 1 month
Peripheral neuropathy
Herpes zoster (shingles), involving 2 or more episodes or 1 or more dermatomes

Category C is HIV infection with AIDS-defining opportunistic infections, as outlined in Pathophysiology.

These 3 categories are further subdivided based on the CD4⁺ T-cell count. Categories A1, B1, and C1 are characterized by CD4⁺ T-cell counts greater than 500/µL. Categories A2, B2, and C2 are characterized by CD4⁺ T-cell counts between 200/µL and 400/µL. HIV infections in patient with CD4⁺ T-cell counts under 200/µL are designated as A3, B3, or C3.

Importantly, once an HIV infection has been staged into a higher clinical category, it remains in that category permanently. In addition, the infection is classified based on the lowest CD4⁺ T-cell count in that patient.

For example, if a given HIV-positive patient recovers from a bout of Pneumocystis pneumonia (PCP) and the CD4⁺ T-cell count improves from 50/µL to 250/µL, that patient’s HIV infection remains classified as C3. Persons with A3, B3, and C1-3 HIV infection are considered to have AIDS. This is important to recognize, as this designation is not based solely on the previous occurrence of opportunistic infections but rather on the current risk for infection based on a reduced CD4⁺ T-cell count.

Treatment & Management

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Media Gallery

Electron microscopy of human immunodeficiency virus (HIV)–1 virions. Courtesy of CDC (Dr Edwin P Ewing, Jr).
Genome layout of human immunodeficiency virus (HIV)–1 and HIV-2.
Timeline of CD4 T-cell and viral-load changes over time in untreated human immunodeficiency virus (HIV) infection. Courtesy of Wikipedia (based on an original from Pantaleo et al (1993)).
Incidence of HIV infection by risk group. Courtesy of CDC (derived from the revised 2006 estimated figures).
Changes in survival of people infected with HIV. As therapies have become more aggressive, they have been more effective, although survival with HIV infection is not yet equivalent to that in uninfected people. Modified from Lohse N et al. Survival of persons with and without HIV infection in Denmark, 1995-2005. Ann Intern Med. 2007;146(2):87-95.

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Table 1. Antiretroviral Drug Classes and Agents

Nucleoside reverse transcriptase inhibitors (NRTIs)	Abacavir (Ziagen, ABC) Didanosine (Videx, Videx EC, ddI) Emtricitabine (Emtriva, FTC) Lamivudine (Epivir, 3TC) Stavudine (Zerit, Zerit XR, d4T) Tenofovir DF (Viread, TDF) Tenofovir AF (TAF) Zalcitabine (Hivid, ddC)* Zidovudine (Retrovir, ZDV, AZT)
Protease inhibitors (PIs)	Amprenavir (Agenerase, AVP)* Atazanavir (Reyataz , ATV) Darunavir (Prezista, DRV) Fosamprenavir (Lexiva, f-APV) Indinavir (Crixivan, IDV) Lopinavir and ritonavir (Kaletra, LPV/r) Nelfinavir (Viracept, NFV) Ritonavir (Norvir, RTV) Saquinavir (Invirase [hard gel] capsule, SQV) Tipranavir (Aptivus, TPV)
Non-nucleoside reverse transcriptase inhibitors (NNRTIs)	Delavirdine (Rescriptor, DLV) Efavirenz (Sustiva, EFV) Etravirine (Intelence, ETR) Nevirapine (Viramune, NVP) Rilpivirine (Edurant) Doravirine (Pifeltro, DOR) Cabotegravir (CAB)
Fusion inhibitors	Enfuvirtide (Fuzeon, T-20)
Cellular chemokine receptor (CCR5) antagonists	Maraviroc (Selzentry, MVC)
Integrase inhibitors	Raltegravir (Isentress, RAL) Dolutegravir (Tivicay, DTG) Elvitegravir (Vitekta, EVG)
Entry inhibitors (CD4 post-attachment inhibitors)	Ibalizumab (Trogarzo, IBA)
gp120 Attachment inhibitors	Fostemsavir (Rukobia, FTR)
Capsid inhibitors	Lenacapavir (Sunlenca, LEN)
*No longer available on market

Table 2. Antiretroviral Combination Products

Drug Content per Tablet/Capsule*	Brand Name	Adult Dose (≥40 kg)
Darunavir 800 mg Cobicistat 150 mg Emtricitabine 200 mg Tenofovir AF 10 mg	Symtuza^#	1 tab PO qd with food
Bictegravir 50 mg Emtricitabine 200 mg Tenofovir AF 25 mg	Biktarvy^#	1 tab PO qd
Efavirenz 400 mg Lamivudine 300 mg Tenofovir DF 300 mg	Symfi Lo^#	1 tab PO qHS on an empty stomach
Efavirenz 600 mg Lamivudine 300 mg Tenofovir DF 300 mg	Symfi^#	1 tab PO qHS on an empty stomach
Dolutegravir 50 mg Rilpivirine 25 mg	Juluca^#	1 tab PO qd with a meal Note: This is a complete once-daily regimen in adults who are virologically suppressed (HIV-1 RNA < 50 copies/mL) on a stable ART regimen for ≥6 months with no history of treatment failure and no known substitutions associated with resistance
Dolutegravir 50 mg Lamivudine 300 mg	Dovato^#	1 tab PO qd with or without food Note: This a complete once-daily regimen in treatment-naïve adults with no known substitutions associated with resistance to dolutegravir or lamivudine
Elvitegravir 150 mg Cobicistat 150 mg Emtricitabine 200 mg Tenofovir AF 10 mg	Genvoya^#	1 tab PO qd
Elvitegravir 150 mg Cobicistat 150 mg Emtricitabine 200 mg Tenofovir DF 300 mg	Stribild^#	1 tab PO qd
Cabotegravir IM copackaged with Rilpivirine IM	Cabenuva^#	One-time initiating injection (on last day of oral lead-in dosing): Cabotegravir 600 mg IM plus rilpivirine 900 mg IM, THEN Once-monthly continuation injections: Cabotegravir 400 mg IM plus rilpivirine 600 mg IM
Abacavir 600 mg Lamivudine 300 mg	Epzicom	1 tab PO qd
Abacavir 600 mg Dolutegravir 50 mg Lamivudine 300 mg	Triumeq	1 tab PO qd
Abacavir 300 mg Lamivudine 150 mg Zidovudine 300 mg	Trizivir	1 tab PO bid
Efavirenz 600 mg Emtricitabine 200 mg Tenofovir DF 300 mg	Atripla^#	1 tab PO qd on empty stomach Note: May be used alone as a complete regimen or in combination with other ARTs
Emtricitabine 200 mg Rilpivirine 25 mg Tenofovir DF 300 mg	Complera^#	1 tab PO qd with a meal
Emtricitabine 200 mg Rilpivirine 25 mg Tenofovir AF 25 mg	Odefsey^#	1 tab PO qd with a meal
Emtricitabine 200 mg Tenofovir DF 300 mg	Truvada	1 tab PO qd CrCl 30-49 mL/min: 1 tab PO q48h CrCl < 30 mL/min: Do not administer
Emtricitabine 200 mg Tenofovir AF 300 mg	Descovy	1 tab PO qd CrCl < 30 mL/min: Do not administer
Lamivudine 150 mg Zidovudine 300 mg	Combivir	1 tab PO bid
Lamivudine 300 mg Tenofovir DF 300 mg	Cimduo	1 tab PO qd
Doravirine 100 mg Lamivudine 300 mg Tenofovir DF 300 mg	Delstrigo^#	1 tab PO qd with or without food
*Not indicated for patients requiring dosage adjustments (eg, weight < 40 kg, renal impairment, hepatic impairment, dose-limiting adverse effects) unless otherwise stated. ^#Complete once-daily regimen

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Author

Shelley A Gilroy, MD, FACP, FIDSA Associate Professor of Medicine, Infectious Disease and HIV Medicine, Albany Medical College; Associate Chief of Staff for Education/DEO, Lead Physician for HIV Medicine, Division of Infectious Diseases, Albany Stratton VA Medical Center

Shelley A Gilroy, MD, FACP, FIDSA is a member of the following medical societies: American College of Physicians, American Medical Association, Infectious Diseases Society of America

Disclosure: Nothing to disclose.

Coauthor(s)

John J Faragon, PharmD, BCPS, AAHIVP Pharmacist, HIV/HCV Medicine, Division of HIV Medicine and Department of Pharmacy, Albany Medical Center; Regional Pharmacy Director, Northeast Caribbean AIDS Education and Training Center; HIV and HCV Education Consultant, VirologyEd Consultants

Disclosure: Serve(d) as a speaker or a member of a speakers bureau for: Gilead; Janssen; Merck.

Chief Editor

Michael Stuart Bronze, MD David Ross Boyd Professor and Chairman, Department of Medicine, Stewart G Wolf Endowed Chair in Internal Medicine, Department of Medicine, University of Oklahoma Health Science Center; Master of the American College of Physicians; Fellow, Infectious Diseases Society of America; Fellow of the Royal College of Physicians, London

Michael Stuart Bronze, MD is a member of the following medical societies: Alpha Omega Alpha, American College of Physicians, American Medical Association, Association of Professors of Medicine, Infectious Diseases Society of America, Oklahoma State Medical Association, Southern Society for Clinical Investigation

Disclosure: Nothing to disclose.

Additional Contributors

Nicholas John Bennett, MBBCh, PhD, FAAP, MA(Cantab) Assistant Professor of Pediatrics, Co-Director of Antimicrobial Stewardship, Medical Director, Division of Pediatric Infectious Diseases and Immunology, Connecticut Children's Medical Center

Nicholas John Bennett, MBBCh, PhD, FAAP, MA(Cantab) is a member of the following medical societies: Alpha Omega Alpha, American Academy of Pediatrics

Disclosure: Received research grant from: Cubist<br/>Received income in an amount equal to or greater than $250 from: Horizon Pharmaceuticals, Shire<br/>Medico legal consulting for: Various.

Acknowledgements

Aaron Glatt, MD Professor of Clinical Medicine, New York Medical College; President and CEO, Former Chief Medical Officer, Departments of Medicine and Infectious Diseases, St Joseph Hospital (formerly New Island Hospital)

Aaron Glatt, MD is a member of the following medical societies: American College of Chest Physicians, American College of Physician Executives, American College of Physicians, American College of Physicians-American Society of Internal Medicine, American Medical Association, American Society for Microbiology, American Thoracic Society, American Venereal Disease Association, Infectious Diseases Society of America, International AIDS Society, and Society forHealthcare Epidemiology of America

Disclosure: Nothing to disclose.

Mary L Windle, PharmD Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Nothing to disclose.