Diagnosis and Clinical Manifestations of HIV Infection


Acknowledgements

The authors acknowledge the use of substantial material from this chapter in the previous edition.

Most cases of HIV infection in infants and young children result from perinatal transmission, which can occur in utero, during labor and delivery, or postnatally during breastfeeding. HIV acquired by sexual contact and injectable drug use contributes to the growing number of cases in adolescents and young adults. The early clinical manifestations of HIV infection are varied and sometimes are indistinct, particularly in infants and young children. Early diagnosis is a prerequisite to the timely provision of effective antiretroviral therapy and prevention of HIV transmission from those who are unaware that they are living with HIV. This chapter outlines approaches for diagnosing HIV in infants, children, adolescents, and young adults and provides an overview of the pathologic effects of HIV on various organ systems in these age groups. Infectious complications and management of HIV are discussed in Chapter 112, Chapter 113 , respectively.

Diagnosis

Who Should be Screened for HIV

In 2006, the Center for Disease Control and Prevention (CDC) published recommendations for universal HIV screening in all persons aged 13–64 years at least once in their lifetime. Individuals at high risk for HIV acquisition should be screened at least annually. Women should be screened during each pregnancy, including while in labor if not performed previously. Offering HIV screening as part of routine clinical care, rather than using a risk-based approach, destigmatizes the testing process and increases acceptance of testing. An opt-out approach should be used, in which oral or written information about the test is provided and assent is inferred unless the patient declines; written consent is not required. Universal screening allows for the early identification of asymptomatic people living with HIV (PLHIV), linkage of PLHIV to care, initiation of antiretroviral treatment (ART) that can reduce clinical progression and mortality, and prevention of ongoing transmission through viral load reduction and risk behavior modification.

Available HIV Tests

Rapid Tests

Several rapid tests are available to detect HIV antibodies (sometimes in combination with HIV antigen) in saliva or blood specimens collected by fingerstick or venipuncture. These tests are useful for point-of-care testing, including in non-healthcare venues, because testing is minimally invasive and the results are available promptly. Table 111.1 compares the features of the FDA-approved rapid tests available as of 2019. Individuals with positive (reactive) rapid tests require confirmation with an FDA-approved antigen-antibody test.

TABLE 111.1
US Food and Drug Administration-Cleared Point-of-Care HIV Tests
US Food and Drug Administration. Complete List of Donor Screening Assays for Infectious Agents and HIV Diagnostic Assays. https://www.fda.gov/vaccines-blood-biologics/complete-list-donor-screening-assays-infectious-agents-and-hiv-diagnostic-assays . Published 2019. Updated September 18, 2019. Accessed October 21, 2019.
Brand Name Manufacturer Component Detected Format Acceptable Sample Types
Home Access HIV-1 Test System Home Access Health Corporation Antibodies to HIV-1 Immunoassay Dried blood spot
OraQuick In-Home HIV Test OraSure Technologies Antibodies to HIV-1 and HIV-2 Immunoassay Oral fluid
Sure Check HIV 1/2 Assay Chembio Diagnostic Systems, Inc. Antibodies to HIV-1 and HIV-2 Immunoassay Serum, plasma, whole blood (venipuncture or fingerstick)
HIV 1/2 STAT-PAK Assay Chembio Diagnostic Systems, Inc. Antibodies to HIV-1 and HIV-2 Immunoassay Serum, plasma, whole blood (venipuncture or fingerstick)
OraQuick ADVANCE Rapid HIV-1/2 Antibody Test OraSure Technologies Antibodies to HIV-1 and HIV-2 Immunoassay Saliva, plasma, whole blood (venipuncture or fingerstick)
Chembio DPP HIV {1/2} Assay Chembio Diagnostic Systems, Inc. Antibodies to HIV-1 and HIV-2 Immuno-chromatographic assay Saliva, serum, plasma, whole blood (venipuncture or fingerstick)
Uni-Gold Recombigen
HIV-1/2
Trinity Biotech Antibodies to HIV-1 and HIV-2 Immunoassay Serum, plasma, whole blood (venipuncture or fingerstick)
Determine HIV-1/2 Ag/Ab combo Alere Scarbourough, Inc. p24 Antigen and antibodies to HIV-1 and HIV-2 Immunoassay Serum, plasma, whole blood (venipuncture or fingerstick)

Antigen-Antibody Tests

In healthcare settings, the recommended approach for the diagnostic evaluation of patients ≥24 months of age should follow the schema outlined in Fig. 111.1 . In brief, testing should begin with a combination immunoassay that detects HIV-1 and HIV-2 antibodies and HIV-1 p24 antigen. All specimens reactive on this initial assay should then undergo supplemental testing with an immunoassay that differentiates HIV-1 from HIV-2 antibodies. Specimens that are reactive on the initial immunoassay and nonreactive or indeterminate on the antibody differentiation assay proceed to HIV-1 nucleic acid testing (NAT) to resolve the diagnostic ambiguity. Additional testing, including HIV viral load measurement, CD4 + T-lymphocyte quantification, and an antiretroviral resistance assay, are then recommended to confirm the diagnosis of HIV infection, determine the need for prophylactic therapy against opportunistic infections and prepare for initiation of antiretroviral therapy.

FIGURE 111.1, Schema for diagnosis of HIV infection in children >24 months, adolescents, and adults. NAT, nuclear acid test.

Nucleic Acid Tests

Nucleic acid tests use polymerase chain reaction (PCR) or transcription-mediated amplification (TMA) to identify cell-free HIV RNA or cell-associated HIV DNA. Quantitative RNA PCR results are reported as the number of copies of the viral genome per mL of plasma and are equivalent to the “viral load.” HIV DNA PCR is available as a qualitative assay, sometimes in combination with qualitative RNA PCR. In PLHIV who are receiving ART, cell-associated HIV DNA should still be detectable by PCR even when the plasma RNA PCR is below the threshold of quantification (known as an “undetectable viral load”). Antiretroviral resistance assays (also known as a “genotype”), further discussed in Chapter 113 , also depends on NAT to sequence mutations in the virus that confer resistance to ART.

Interpretation of HIV Test Results

The sensitivity and specificity of available HIV tests depend on the timing of infection in relation to the date of the HIV test ( Fig. 111.2 ). During acute HIV infection, there is initially an eclipse period in which no laboratory markers of infection are consistently detectable. HIV RNA is the first marker to become detectable, approximately 10 days after infection. HIV p24 antigen becomes detectable 4–10 days after the appearance of RNA, followed by immunoglobulin M (IgM) and then IgG antibodies, which appear 10–13 and 18–38 days after the appearance of RNA, respectively. Because seroconversion can take several weeks, tests that measure only IgG antibodies are not sensitive to detect acute HIV infection.

FIGURE 111.2, Sequence of appearance of laboratory markers for HIV-1 infection.

Besides acute HIV infection, other special circumstances can lead to false-positive or false-negative HIV antibody test results. False-positive results have been attributed to participation in HIV vaccine trials, autoimmune disorders, , and technical or clerical errors. The prolonged half-life of maternal antibodies can lead to false-positive results in perinatally HIV-exposed infants, as discussed in the following sections. Delayed seroconversion can lead to false-negative results in persons taking ART for pre-exposure or post-exposure prophylaxis at the time of HIV infection as well as in infants and adults who initiated ART very soon after infection.

The worldwide genetic variability of HIV affects the sensitivity of HIV NAT. Subtype B of HIV-1 is the predominant variant found in North America, South America, and Western Europe. HIV-2 and other subtypes of HIV-1 are found in Africa, India, and Southeast Asia. There is no FDA-cleared nucleic acid test that detects HIV-2, but CLIA approved tests are performed in selected specialty laboratories. HIV-1 DNA tests used in the US do not detect all non-B subtypes of HIV-1. HIV-1 RNA assays are more sensitive for detecting non-subtype B HIV-1 and should be preferentially used when infection is thought to have originated in Asia or Africa.

HIV Testing in Perinatally HIV-Exposed Infants

Accurate detection of HIV infection in children <18 months of age relies on NAT, owing to the confounding effects of transplacentally acquired maternal antibodies. Seroreversion (loss of maternal anti-HIV antibodies) usually does not occur until 12–18 months of age and may not occur until 24 months of age. The sensitivity of PCR for detection of perinatally acquired HIV is 55%–58% at birth, 89% at 1 month, and approaches 100% by 3 months of age. HIV PCR also has excellent specificity, with the exception that low-level positive results (<4 log 10 copies/mL), especially in the immediate newborn period, may represent a false-positive result and should be repeated. , Cord blood specimens should not be used for HIV PCR testing because contamination of specimens with maternal blood can cause false-positive results. The use of ART, and particularly multiple-drug ART, for postnatal prophylaxis may restrict HIV replication sufficiently to prevent detection by PCR testing, , resulting in false-negative results in infants with perinatally acquired HIV. In theory, DNA PCR may be more sensitive than RNA PCR for infants receiving multiple-drug ART for postnatal prophylaxis ; however, a single study showed that both types of testing appear to be equally sensitive in this scenario, and the US Public Health Service has no preference for PCR test used.

Perinatally HIV-exposed infants should have NAT testing performed at regular intervals as defined in Fig. 111.3 . It is necessary to perform at least one nucleic acid test after the cessation of antiretroviral prophylaxis. Confirmation of HIV infection is based on the results of two positive virologic tests from separate blood samples. HIV infection is presumptively excluded in nonbreastfed infants who have had ≥2 negative PCR tests, with one test obtained at ≥14 days of age and the other obtained at ≥4 weeks of age, or 1 negative PCR test at ≥8 weeks of age, or one negative HIV antibody test at age ≥6 months of age. Definitive exclusion of HIV infection in a nonbreastfed infant requires ≥2 negative PCR tests, with one obtained at ≥1 month of age and the other at ≥4 months of age, or 2 negative HIV antibody tests from separate specimens obtained at age ≥6 months. Some experts confirm the absence of HIV infection after ≥12 months of age in children with prior negative PCR tests by performing an antibody test to document seroreversion.

FIGURE 111.3, Recommended nucleic acid testing (NAT) schedule for HIV-exposed infants. Low-risk infants include those whose mothers received antiretroviral therapy (ART) during pregnancy and had sustained viral suppression. Higher risk infants include those whose mothers did not receive prenatal care, did not receive antepartum or intrapartum ART, received intrapartum ART only, initiated ART late in pregnancy, received a diagnosis of acute HIV infection during pregnancy, or had detectable viral loads close to the time of delivery. ∗For higher risk infants, additional nucleic acid testing is recommended at birth and 2–4 weeks after cessation of postnatal antiretroviral prophylaxis.

In the US, women living with HIV (WLHIV) are counseled to avoid breastfeeding. However, some women may choose to breastfeed despite intensive counseling. Initial monitoring of infants born to WLHIV who choose to breastfeed should include PCR testing at the standard time points as per Fig. 111.3 . Many experts then recommend testing at least every 3 months throughout breastfeeding, followed by 4–6 weeks, 3 months, and 6 months after cessation of breastfeeding.

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