Perinatally-acquired HIV infection

Infectious Disorders

Updated 08.04.2025
Released 09.24.1994
Expires For CME 08.04.2028

Perinatally-acquired HIV infection

Authors: Madeleine Goldstein DO MPH, Brian Zanoni MD

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Editor: Christina M Marra MD

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Perinatally-acquired HIV infection

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Introduction

Overview

Perinatally-acquired HIV is the transmission of HIV-1 from birthing parent to child, which occurs during or soon after birth. With the successful implementation of antiretroviral treatment for affected individuals during pregnancy, the current prevalence ranges from 1% to 2% in the United States. This article includes an overview of perinatally-acquired HIV infection, with updated criteria on reducing transmission through pregnancy, the delivery process, and breast- or chestfeeding, as well as newborn diagnosis and treatment and the use of prophylaxis.

Key points

	• Perinatally-acquired HIV infection is the transmission of HIV-1 from a pregnant person to a child through pregnancy, childbirth, or breast- or chestfeeding.
	• Prevalence is 1% to 2% in the United States with timely initiation of antiretroviral treatment for birthing parents during pregnancy.
	• The disease can be mild to severe and can include recurrent infections and neurologic abnormalities.
	• All infants with perinatal HIV exposure should receive antiretroviral prophylaxis within 6 to 12 hours after delivery.
	• Newborn testing guidelines have been updated and are included for review.
	• Infant feeding guidelines and management have been updated and are included for review.

Historical note and terminology

In 1982, soon after the initial descriptions of cases of HIV infection, four children with unexplained immunodeficiency and opportunistic infections were reported by the Centers for Disease Control and Prevention (20). It was not until the following year, however, that the clinical and immunologic features of pediatric HIV infection were described in the literature (55; 66).

Clinical manifestations

Presentation and course

At birth, most neonates with perinatally-acquired HIV-1 are clinically well and are indistinguishable from uninfected newborns. Some neonates with HIV-1, however, may be ill due to comorbid conditions, such as those associated with prematurity, in utero exposure to drugs and alcohol, or other congenital infections, such as cytomegalovirus (10).

Common initial presentations of untreated children living with HIV include cases of Pneumocystis jirovecii pneumonia, mucosal candidiasis infections, recurrent bacterial infections, failure to thrive or wasting, pulmonary tuberculosis, or disseminated herpes zoster infection. Pneumocystis jirovecii pneumonia peaks from 3 to 6 months and is rare within the first month of life. Episodes of oral candidiasis can occur in infants with intact immune systems, but if the infant has severe, recurrent, or persistent infections, HIV or other immunodeficiency needs to be considered. Recurrent bacterial infections can present as pneumonia, sinusitis, or otitis. Individuals living with HIV are more likely to develop tuberculosis disease due to immunologic impairment. Therefore, if a child is diagnosed with tuberculosis, investigation for an underlying HIV infection should be undertaken. In less severe forms without serious infections, the child may present with a constellation of lymphadenopathy, chronic interstitial lung disease, or persistent parotid gland swelling (70). With the widespread use of antiretroviral therapy, many of these symptoms are significantly less common and less severe.

The consequences of CNS infection by HIV-1 are highly variable among children with perinatally-acquired HIV-1 and can be delayed for several years (08). However, neurologic symptoms should not be viewed in isolation from, but associated with, other clinical symptoms and with immunological and virological results; the course of clinical symptoms and biological signs distinguishes a severe infantile mode of evolution from a slowly progressive disease.

Among children living with HIV-1, neurologic disorders are common and may present at any stage of the disease. Twenty percent of children living with HIV-1 not on antiretroviral therapy suffer from a severe disease characterized by a progressive encephalopathy and opportunistic infections, with an onset during the first 3 years of life (16; 08; 75). In a large prospective study of children with HIV-1 not on antiretroviral therapy, the cumulative incidence of encephalopathy was 9.9% at 12 months and 13.1% at 24 months, whereas new cases steadily accumulated to reach a cumulative incidence of 16.3% at 84 months (75). This early onset progressive encephalopathy in children with HIV-1 is associated with other AIDS-defining symptoms (which can also occur in isolation) as well as with an early decrease in the number of circulating CD4 lymphocytes and a high viral load (determined by HIV-1 RNA PCR quantification). Viral load is typically high in infants, reaching a peak in the first weeks of life, and often does not decline to a stable set point for several years (68; 75). Prevalence of HIV encephalopathy has decreased from 40.7% to 18.2% in patients born after 1996, thought to be related to the response of maternal intravenous zidovudine monotherapy (67). In another prospective study, rates of active progressive HIV encephalopathy were as low as 1.6% among children on combination antiretroviral therapy, but rates of arrested HIV encephalopathy were higher at 10% (22). There has been no link between progressive HIV encephalopathy and ADHD or isolated developmental delay (44; 22; 73; 82).

Neurologic manifestations of HIV are heterogeneous and may evolve with time. HIV-associated progressive encephalopathy is the most severe form and was thought to affect up to 50% of children with perinatally-acquired HIV before widespread use of antiretroviral therapy (25). The first abnormal neurologic signs are usually observed between the ages of 3 and 12 months. Motor symptoms are initially noted with both abnormal rigidity of limbs and abnormal postural tone, not unlike those observed in cerebral palsy. Over time, these symptoms result in spastic paraparesis or quadriparesis, sometimes associated with dystonic posturing and a loss of motor milestones. Thirty to 50% of children develop buccolingual dyspraxia: the mouth remains open with abnormal and permanent drooling as well as difficulties with chewing small pieces of food (at an appropriate age). Stagnation of cognitively, behaviorally, and socially adaptive skills usually occurs a few months later; patients initially appear comparatively less affected. The pattern of regression is quite variable between children, although most decline in a stepwise manner with long plateau periods over 2 to 4 years. After 3 years, affected children are significantly delayed, with small head circumference and severe spastic tetraparesis. Interestingly, the group of infants with early HIV encephalopathy had a significantly lower head circumference than other children living with HIV-1 (75). It is not unusual for the children to make some cognitive or even motor acquisitions during the plateau periods. Death usually occurs before the age of 5 years.

Eighty percent of children with perinatally-acquired HIV-1infection who are not on antiretroviral therapy have a slowly progressive disease during which, for several years, they remain either asymptomatic or have reversible symptoms. Similarly, there is no severe immune deficiency, and viral load in the blood is relatively low. At school age, these children usually have normal school results and cognitive levels, except for visuospatial and temporal orientation tests, which are more frequently abnormal than in the general population (42; 76; 09). When compared to healthy controls, pediatric patients living with HIV-1 did not show worsening of memory or executive function over several years, although a history of AIDS-defining illness and higher viral load were associated with worse cognitive functioning overall (46).

Prognosis and complications

The risk of development of an early and severe form of HIV-1 is highly linked to the viral load in the birthing parent’s peripheral blood at the time of birth, as well as that of the baby during the first weeks of life (15; 38). Viral load influences the time of transmission from birthing parent to fetus as well (most likely) as the time of penetration of the virus into the central nervous system. Severe symptoms (including encephalopathy) occur more frequently in infants, with a high viral load in the blood at birth that is tightly linked to maternal viral load at delivery (74; 68). Early treatment with combination antiretroviral medication and prevention of opportunistic infections improves the quality of life of children living with HIV-1 and shows a positive impact on neurodevelopmental outcomes, including cognitive and motor impairments (43; 40). In a prospective, longitudinal observational study, children with HIV-1 on early antiretroviral therapy had similar neurodevelopmental outcomes as uninfected children, apart from visual perception (in which children with HIV-1 scored lower) (40). More long-term studies are needed to assess the role of antiretroviral therapy and neurodevelopmental function.

Significant inequalities persist worldwide, with more than 90% of the 3 million children with HIV living in low- and middle-income countries (19). The survival rate of children living with HIV-1 in the United States and Europe was close to 60% at 7 years of age (16; 79; 80; 76) but has been further improved by antiretroviral therapy and efficient preventive treatment of opportunistic infections. A multicenter, prospective birth cohort study in the U.S. from 1985 to 2004 showed statistically significant 10-year survival rates of 94% in children who received antiretroviral therapy compared to 45% in children who did not receive antiretroviral therapy (35).

During the course of HIV-1 infection, several secondary lesions of the CNS can be clinically observed (Table 1). In most cases, all of them occurred after the onset of severe immune deficiency (eg, when CD4 lymphocyte counts are less than 200). Although their description is beyond the scope of this short annotation, four clinical situations can be distinguished: (1) acute retinitis and encephalitis, the most frequent etiologic agent being cytomegalovirus; (2) tumor-like lesions (toxoplasmosis, lymphoma, and sarcoma); (3) brain infarcts due to aneurysmal lesions of large vessels and multiple areas of vascular obstruction of small cortical vessels; and (4) progressive encephalopathy with abnormal appearance of white matter on MRI. This might be due to a secondary infection with a human polyomavirus, JC virus, leading to a progressive multifocal leukoencephalopathy, subsequently resulting in a progressive encephalopathy, but also to infections with mycobacteria, mycoplasma, and viruses such as cytomegalovirus and varicella zoster virus. A firm diagnosis is always difficult to establish, but amplification of genetic material by polymerase chain reaction may be diagnostic.

Development of vascular lesions has been associated with HIV-1 infection, and is thought to result from endothelial dysfunction secondary to chronic inflammation and cytokine imbalances from the infection. This has sometimes been referred to as HIV-associated vasculopathy. Moyamoya syndrome has been described in association with pediatric HIV-1 infection, with evidence of worse outcomes associated with poor HIV control (89).

Cardiovascular problems associated with HIV-1 infection, including left ventricular dysfunction and increased left ventricular mass, are common and clinically important indicators of survival for children living with HIV (36).

Table 1. Secondary CNS Complications

CNS infections
	• Common childhood bacterial pathogens • Viral encephalitis and retinitis (CMV, varicella, JC virus) • Tuberculosis • Parasitic encephalitis (toxoplasmosis)
CNS neoplasms
	• Primary B-cell lymphoma • Other kymphoma • Sarcoma
Vascular complications
	• Intracerebral hemorrhage, including subarachnoid hemorrhage • Infarctions
		- Hemorrhagic - Ischemic, large vessel and cortical

Other complications
	• Basal ganglia abnormalities
	• Leukoencephalopathy other than progressive multifocal leukoencephalopathy

Clinical vignette

A 17-month-old female patient, accompanied by her mother, presented to a medical mission clinic in Port-au-Prince, Haiti, with a 2-month duration of muscle rigidity and general failure to thrive. Although the child had these symptoms for months, the mother brought her in due to altered mental status, or more specifically described by her mother as “my daughter just isn’t herself today.” On examination, the child had microcephaly and generalized muscle rigidity. On further questioning, the mother had an unknown HIV status but had two previous children with cerebral palsy who died from opportunistic infections.

(I) What would be your DDX? Symptoms: muscle rigidity, failure to thrive, altered mental status, microcephaly
	(A) Infant or child
		• Toxoplasmosis, HIV-1, rubella, cytomegalovirus, herpes, syphilis, Epstein-Barr virus.
		• Each of these infections is usually associated with an increased serum concentration of specific immunoglobulin. Cytomegalovirus can be identified in blood or urine by progressive multifocal leukoencephalopathy. Syphilis serological tests can identify syphilis.
	(B) Late infancy and childhood
		• Severe combined immunodeficiency or variants such as adenosine deaminase or nucleoside phosphorylase deficiency, Omenn syndrome, Bare lymphocyte syndrome, DiGeorge syndrome, HIV encephalopathy.
(II) What is your next step in diagnosing and treating this child?
	(A) Maternal HIV-1 antibodies acquired transplacentally in the infant can persist for up to 18 to 24 months after birth and complicate the use of conventional IgG antibody tests in diagnosing HIV-1 infection in infants and young children. HIV-1 DNA or HIV-1 RNA PCR assays are recommended and preferred in children younger than 18 months.
		• Updated information on the most current guidelines for treating children and adolescents with HIV can be obtained at ClinicalInfo.hiv.gov.
(III) After testing and diagnosing the mother with HIV-1, what is your advice if she has plans for more children?
	(A) Treatment
		• The goal is to reduce perinatal transmission of HIV. Early (prenatal) identification of infants at risk for HIV-1 infection is critically important. HIV-1 screening and counseling should be a routine part of pregnancy care. It is recommended that all pregnant individuals living with HIV receive antiretroviral therapy, regardless of CD4 cell count or plasma HIV RNA copy number, to prevent perinatal transmission and for the benefit of maternal health. Achieving and maintaining an undetectable viral load is essential for preventing perinatal transmission of HIV.
	(B) If she becomes pregnant again:
		• She should visit her healthcare provider regularly. Her doctor should monitor CD4 cell counts and plasma viral load routinely during pregnancy. Plasma viral load should also be assessed at 34 to 36 weeks of gestation to aid in the decision regarding mode and timing of delivery. If the viral load is greater than 1,000 copies/ml near term gestation, the patient should be counseled regarding the benefits of scheduled cesarean section at 38 weeks of gestation for prevention of perinatal transmission.
		• Patient-centered counseling should be provided as early as possible during pregnancy to support shared decision-making regarding infant feeding plans. Although infant formula or pasteurized donor human milk eliminates the risk of postnatal transmission of HIV, achieving and maintaining viral suppression with antiretroviral therapy during pregnancy and postpartum decreases the risk of transmission through breast- or chestfeeding to less than 1%.
		• After delivery, it is important to follow up with a pediatric infectious disease specialist for HIV testing and management of infant prophylaxis with antiretroviral therapy.
	(C) Other screening tools
		• Drug resistance testing should be done before modifying antiretroviral therapy medications in all pregnant women.
		• Monitor antiretroviral therapy toxicity by checking CBC, BUN, creatinine, and LFTs.
		• Screening for gestational diabetes is usually done at 24 to 28 weeks but should be done earlier if the patient is on protease inhibitors. Protease inhibitors have been shown to be associated with glucose intolerance.
		• Testing should be done for viral hepatitis (both B and C).
		• Consider tuberculosis testing and toxoplasma serology if indicated.

Biological basis

Etiology and pathogenesis

Human immunodeficiency virus type-1 is an RNA retrovirus that belongs to the lentivirus subfamily of nononcogenic cytopathic retroviruses.

HIV-1 works by integrating the DNA version of its genome into the host cell chromosomal DNA. Principal targets of HIV-1 are the human peripheral blood CD4+ T lymphocytes and monocytes. Activated CD4+ T lymphocytes expressing the cytokine receptors CCR5 or CXCR4 serve as preferred targets for HIV-1 infection, as these receptors function as viral co-receptors. The loss of CD4+ T lymphocytes occurs due to the direct cytopathic effects of the virus and the indirect effects on uninfected cells, causing cell death. Similarly, HIV causes a cytopathic infection in monocytes; the infection is of a lesser degree, as compared to that seen in CD4+ T lymphocytes, but it causes monocytes to collapse with one another, forming multinucleated giant cells, most prominent in the brain parenchyma. It also leads to prominent macrophage activation in various tissues, including brain, peripheral nerve, kidney, and heart. It is postulated that this massive macrophage activation leads to a release of cytokines that are injurious to neurons in the brain and other cell types in tissues. The pathogenesis of HIV infection has been studied in CNS tissues, where HIV infects astrocytes in addition to cells of monocytic lineage. These infected cells also release viral proteins that have toxic properties and, hence, have been termed “virotoxins.” A number of subcellular mechanisms have been proposed with regard to end-organ damage caused by these virotoxins. The virotoxins also lead to the release of chemoattractant molecules, or chemokines, which attract mononuclear cells into endorgans, thus setting up a positive feedback loop. In the brain, HIV-1 is found mostly within cells of the basal ganglia, subthalamic nucleus, substantia nigra, dentate nucleus, and white matter (09).

In untreated children living with HIV-1, one of the first immunologic abnormalities is impairment of B-cell function, manifested by polyclonal hypergammaglobulinemia and spontaneous B-cell proliferation. Although the quantity of immunoglobulins is elevated, there are diminished in vivo vaccine responses to both T-cell dependent and independent antigens as well as decreased responses to B-cell mitogens (13; 37). The decreased antibody responses predispose these infants and children living with HIV to serious bacterial infections. The B-cell activation may also result in polyclonal polymorphic B-cell lymphoproliferative disorders, such as lymphoid interstitial pneumonitis, parotitis, and unusual B-cell-related complications, such as B-cell lymphomas.

An increased production of autoantibodies may also result from B-cell dysfunction. Circulating immune complexes, antinuclear antibodies, antibody to double-stranded DNA, red cell antibodies, and antiplatelet antibodies have been reported (37). Hypogammaglobulinemia, another manifestation of B-cell dysfunction, has also been noted in some infants with severe advanced disease.

Thymic abnormalities in some fetuses of HIV-1-infected women suggest that an interaction between the virus and the developing fetal immune system may account for the early and severe immune deficiency observed in 15% to 25% of infants with perinatally-acquired HIV-1 infection. The pathophysiologic mechanism is as yet unclear; both an induction of an immune deficiency in utero and a state of immune tolerance have been proposed (16; 57).

Resting CD4+ T cells and glial cells (including microglia and astrocytes) remain key cellular reservoirs for latent HIV-1, allowing the virus to persist despite antiretroviral therapy (17; 04). Although peripheral blood is commonly used to assess viral burden, it may not accurately reflect the extent of HIV-1 compartmentalization in lymphoid tissues, the central nervous system, and other sanctuary sites.. Tissue-specific viral reservoirs contribute to clinical variability, and the long-term course of infection may be influenced by the distribution and differentiation state of infected immune cells, including CD4⁺ T cell subsets and monocyte/macrophage-lineage cells, particularly in pediatric and perinatally infected populations (65; 50; 23). Additional factors, including the role of clonal expansion of infected cells, immune exhaustion, and the establishment of tissue-resident memory T cells, contribute to maintaining viral persistence (72; 90). High sequence variability and mutation rates may also increase the pathogenicity of the virus (65).

Epidemiology

Improved access to antiretroviral therapy, international guidelines supporting early treatment initiation, and the introduction of simple, effective, and well-tolerated treatment regimens have contributed to the increased survival of children with perinatally-acquired HIV into adolescence and adulthood. However, vulnerable populations continue to bear a disproportionate burden of the HIV epidemic. Approximately 3 million children are living with HIV globally, with more than 90% living in low- and middle-income countries (Joint United Nations Programme on HIV/AIDS 2023). Notably, the most significant decrease in new infections worldwide in recent years was among children and adolescents. However, there were about 130,000 new infections among children younger than 10 years of age in 2022, with the majority occurring in low- and middle-income countries (Joint United Nations Programme on HIV/AIDS 2023). In the same year, approximately 100,000 children and adolescents died from HIV-related illnesses (Joint United Nations Programme on HIV/AIDS 2023). Rates of perinatal transmission of HIV continue to decrease, especially within the United States, due in part to improved access to antiretroviral therapy and routine testing during pregnancy. Fewer than 1% of the approximately 37,000 new HIV infections in the U.S. in 2019 were due to perinatal transmission (21). Ongoing transmission is often due to the acquisition of HIV during pregnancy, undiagnosed HIV during pregnancy, or untreated HIV during pregnancy and, in part, may be due to a birthing parent having one or more sexually transmitted infections or with CMV alone (01; 02).

The most important recent change in pediatric HIV has been the dramatic reduction of perinatal transmission of HIV, which can occur in utero, at the time of delivery, or postnatally via breast- or chestfeeding. During the early part of the epidemic, the transmission rate in large prospective studies ranged from 25% to 30% in the absence of antiretroviral treatment and non-breast- or chestfeeding parents but could be as high as 50% with prolonged breast- or chestfeeding, depending on the maternal viral load, genetic factors, and, likely, other factors such as sanitary conditions (74; 51; 70). Achieving and maintaining viral suppression with antiretroviral therapy throughout pregnancy, postexposure prophylaxis offered as soon as possible to all infants after birth, as well as simplified and better-tolerated treatment regimens, have helped to decrease the transmission rate to less than 1% within the United States. Additionally, although infant feeding with prepared formula or pasteurized donor human milk from a milk bank eliminates the risk of postnatal HIV transmission to the infant, the PROMISE Study showed that maintaining an undetectable viral load throughout pregnancy, labor and delivery, and breast- or chestfeeding decreases the risk of transmission of HIV through breast- or chestfeeding to less than 1% (28; 29).

Prevention

Perinatal transmission of HIV may occur during pregnancy, childbirth, or, rarely, via transmission by breast milk postnatally. The most effective strategy for preventing perinatally-acquired HIV is to prevent HIV-1 infection in people who can become pregnant. Individuals who are trying to conceive, or are pregnant, postpartum, or breast- or chestfeeding should be counseled on the use of pre-exposure prophylaxis (PrEP) to prevent HIV acquisition. HIV PrEP is the use of specific antiretroviral medications, including tenofovir disoproxil fumarate (TDF)/emtricitabine (FTC) or cabotegravir (CAB) to prevent HIV acquisition. TDF/FTC is the only FDA-approved option for PrEP for people with receptive vaginal exposure, with demonstrated safety in pregnancy and during breast- or chestfeeding. Additionally, a phase 3 randomized controlled trial, PURPOSE 1, evaluating HIV prevention among cisgender adolescent girls and young women in South Africa and Uganda, found that there were zero HIV infections among participants receiving twice-yearly lenacapavir injections (06). CDC guidelines recommend the use of TDF/FTC as PrEP during periconception, antepartum, and postpartum periods, though lenacapavir is a promising consideration for the future. PrEP is indicated for those who request it, as well as individuals who have a history of a bacterial sexually transmitted infection (eg, gonorrhea, syphilis, or chlamydia) in the past 6 months, those who are taking nonoccupational postexposure prophylaxis (nPEP) and anticipate ongoing indications for prevention or have used multiple courses of nPEP, those who have infrequent condom usage with one or more partners of unknown HIV status, those who engage in transactional sex, those who have substance use disorder or substance use associated with sex, those who have a partner with HIV with unknown or inconsistent virologic suppression, those who have a history of experiencing intimate partner violence, or those who have a partner with any of these factors.

Guidelines from the CDC and the American College of Obstetricians and Gynecologists recommend HIV screening and counseling as a routine part of pregnancy care, including testing in the first trimester (or first visit if later than the first trimester). Pregnant individuals who were seronegative on initial testing should consider retesting during the third trimester. Pregnant people are considered at increased risk if they have a history of a partner living with HIV, history of substance use, history of a sexually transmitted infection, signs or symptoms of acute HIV infection, live in areas with increased incidence of HIV infections in women of childbearing age (17 or more HIV cases per 100,000 person-year), or receive care in facilities with at least one diagnosed HIV case per 1000 person-years. If testing was not completed during pregnancy or a person presents during labor with an unknown HIV status or ongoing high risk of infection, a rapid HIV antibody test should be completed. A confirmatory HIV test should be drawn as soon as possible if rapid HIV antibody testing is positive (70).

Prevention of perinatally-acquired HIV includes maternal or birth parent antiretroviral therapy in addition to universal screening of pregnant individuals. The rate of perinatal transmission of HIV-1 ranges from 5% to 10% during pregnancy, 20% to 30% during delivery, and 10% to 20% through breast- or chestfeeding in the absence of antiretroviral therapy, whereas it is reduced to less than 1% with the use of antiretroviral therapy (54). The selection of which antiretroviral medications to use should be individualized for people with HIV who are pregnant or are trying to conceive, including possible risk of teratogenicity, preterm birth, effects on growth and development; pharmacokinetic changes in pregnancy; potential drug interactions with other medications; the patient’s prior exposure to antiretroviral therapy and resistance testing; comorbidities; and a patient’s ability to tolerate and adhere to a regimen. Although a study in Botswana in 2019 found that dolutegravir (an integrase strand transfer inhibitor) exposure at time of conception was associated with a slightly higher rate of neural tube defects compared to other types of antiretroviral medication exposure (0.30% vs. 0.10%), expanded and ongoing surveillance of birth outcomes among pregnant women receiving antiretroviral therapy in both Botswana and Eswatini showed that the neural tube defect prevalence in women receiving dolutegravir at conception is not significantly different from the rates in women receiving other antiretroviral medications at conception or women without HIV in these countries (91; 92; 30).

Additionally, although not routinely recommended in the antiretroviral therapy era, cesarean section can help reduce peripartum transmission of HIV-1 infection in certain clinical scenarios. Recommendations from the American College of Obstetricians and Gynecologists and the Department of Health and Human Services are as follows: (1) pregnant people with HIV with plasma viral loads greater than 1,000 copies/mL should be informed of the benefits of elective cesarean sections; (2) elective cesarean delivery should be after 38 weeks gestation; (3) pregnant people with HIV should receive antiretroviral therapy during pregnancy, which should not be discontinued before cesarean delivery; and (4) pregnant people should receive intravenous zidovudine in addition to their background antiretroviral therapy regimen 3 hours before elective cesarean delivery (41).

Infant feeding with prepared formula or pasteurized donor human milk from a milk bank eliminates the risk of postnatal HIV transmission to the infant. Historically, individuals were advised against breast- or chestfeeding regardless of whether the birth parent or infant were on antiretroviral therapy in the United States and other high-income countries, given the access to formula and potential risk of transmission via breast milk. Outside of the United States, where formula is not as readily accessible, additional antiretroviral therapies are given during the breast- or chestfeeding period to help reduce the risk of transmission while allowing the infant to maintain nutrition (70). Breastfeeding guidance has changed within the U.S. as a result of community advocacy, considerations of equity and cultural norms, and increasing evidence of the low risk of transmission via breast milk among individuals with sustained viral suppression (77; 28; 31; 29). In 2023, the Department of Health and Human Services Perinatal HIV Guidelines were revised to support shared decision-making between pregnant individuals and their care providers about infant feeding (56). If a parent decides to breast- or chestfeed, care of the parent and infant should be coordinated before delivery with the obstetrician, HIV provider, infant provider, lactation consultant, and social worker. Breast- or chestfeeding parents and their infants should be followed closely postnatally to monitor maternal antiretroviral therapy and viral load, as well as infant antiretroviral prophylaxis and HIV testing.

Differential diagnosis

The infant or child with perinatally-acquired HIV may present with several clinical manifestations. Differential diagnosis, therefore, depends on the presenting signs and symptoms as well as the age of the child. In infancy, lymphadenopathy, hepatosplenomegaly, thrombocytopenia, anemia, or leukopenia may occur with other congenital or perinatal infections (toxoplasmosis, rubella, cytomegalovirus, herpes, syphilis, Epstein-Barr virus). Moreover, these infections are often associated with immunologic abnormalities. However, each of these infections is usually associated with an increased concentration of specific immunoglobulin or through detection via specific nucleic acid amplification tests.

Later in infancy and childhood, if the presenting symptoms are chronic, recurrent, or opportunistic infections, the most important and likely diagnosis is an underlying immunodeficiency disorder. Primary, congenital, and secondary immunodeficiency disorders are included in the differential diagnosis. Inherited forms of cellular congenital immunodeficiency diseases that may be considered include severe combined immunodeficiency or variants such as Nezelof syndrome, adenosine deaminase or nucleoside phosphorylase deficiency, Omenn syndrome, Bare lymphocyte syndrome, severe combined immune deficiency with graft-versus-host disease, and DiGeorge syndrome. Other congenital immunodeficiencies include Wiskott-Aldrich syndrome, ataxia-telangiectasia, X-linked lymphoproliferative syndrome, chronic mucocutaneous candidiasis, agammaglobulinemia, and dysgammaglobulinemia. An appropriate history, examination, and immunologic analysis, including HIV-1 antigen/antibody testing, can usually rule out these conditions. Hematological disorders that should be considered in the differential diagnosis include neutrophil disorders, reticuloendotheliosis, lymphoma, and idiopathic thrombocytopenic purpura. Secondary immunodeficiencies, including malignancy, malnutrition, nephrotic syndrome, protein-losing enteropathy, and severe diarrhea, should also be considered (37).

The differential diagnosis in the infant or child who presents with progressive neurologic dysfunction includes other neurodegenerative diseases (particularly the progressive genetic metabolic diseases, especially if the child has hepatosplenomegaly) and other CNS infections. A thorough history (including family history and potential exposures), physical and neurologic examination, and laboratory studies, including neuroimaging and HIV testing (either nucleic acid test or antigen/antibody testing for a child greater than 18 months of age), help to make the diagnosis.

Diagnostic workup

The goal of the diagnostic workup is to establish the presence or absence of HIV-1 infection and, if present, to determine the stage of the disease, extent of immune dysfunction, and presence or absence of neurologic involvement. Table 2 demonstrates the guidelines for diagnosing HIV-1 infection in infants and children.

Newborns and young children (up to 18 to 24 months of age) present special diagnostic challenges. Although the detection of anti-HIV-1-specific IgG antibody in peripheral blood in older children and adults is taken as proof of HIV-1 infection, a positive antibody test in a well infant or young child is uninterpretable, as maternal IgG crosses the placenta and may persist for up to 18 to 24 months. Thus, a positive IgG antibody test only confirms the seropositivity of the birthing parent. Direct evidence for HIV-1 infection may be sought by virologic testing (eg, nucleic acid tests), including either HIV RNA or HIV DNA polymerase chain reaction assays in infants younger than 18 to 24 months of age. Plasma HIV RNA and HIV DNA nucleic acid tests can both be used to diagnose HIV infection in infants; however, both tests can be affected by maternal antiretroviral therapy through transplacental transfer of antiretroviral therapy from the pregnant person to the fetus or by antiretroviral therapy medications administered as prophylaxis or presumptive HIV therapy to the infant. HIV DNA qualitative PCR assays from whole blood detecting cell-associated virus are thought to be less affected by antiretroviral therapy. Infants with known exposure to HIV-1, either by positive maternal testing or positive rapid antibody test of the infant after birth, are recommended to have HIV-1 DNA PCR or RNA PCR assays within the first 14 days of life, between 1 to 2 months of age, and between 4 to 6 months of age. Additional testing at birth should be considered for newborns who are considered at a high risk of perinatal HIV transmission, including infants born to individuals with HIV who: (1) did not receive prenatal care, (2) received no antepartum antiretroviral therapy or only intrapartum antiretroviral medications or initiated antiretroviral medications late in pregnancy (during the late second or third trimester), (3) received a diagnosis of acute HIV infection during pregnancy or labor, or (4) had detectable HIV viral loads of 50 or more copies/mL close to the time of delivery.

HIV infection is considered presumptively excluded in non-breast- or chestfed infants with either: (1) two or more negative virologic tests (including one at age 2 weeks or older and one at age 4 weeks or older), or (2) one negative virologic test at age 8 weeks or older or at least 2 weeks after discontinuing antiretroviral therapy, or (3) one negative HIV antibody test at 6 months of age or older. HIV infection is definitively excluded in non-breast- or chestfed infants with either: (1) two or more negative virologic tests, with one obtained at 1 month of age or older (and at least 2 weeks after discontinuation of antiretroviral therapy) and one at 4 months of age or older; or (2) two negative HIV antibody tests from separate specimens that were obtained at 6 months of age or older. Current guidelines no longer routinely recommend additional HIV testing (including nucleic acid, antibody, or antigen/antibody tests) for non-breast- or chestfed infants who meet the criteria for definitive exclusion of HIV and who have had no known or suspected HIV exposure postnatally. Two positive HIV-1 DNA PCR or RNA PCR assays are required to make the diagnosis. Therefore, if testing reveals a positive result, a repeat test to confirm the diagnosis is recommended (11; 63; 88; 56).

For infants with perinatal HIV exposure who are being breast- or chestfed, virologic testing should be completed at the standard time points, as well as at birth and between the 1- to 2-month and 4- to 6-month ages. Additional virologic testing should be sent every 3 months if breast- or chestfeeding continues after 6 months of age. Regardless of the age of the child at cessation of breast- or chestfeeding, virologic diagnostic testing should be sent at 4 to 6 weeks, 3 months, and 6 months after breast- or chestfeeding is discontinued. Throughout breast- or chestfeeding, viral load monitoring of the birthing parent should be sent every 1 to 2 months. If the birthing parent’s viral load becomes detectable during breast- or chestfeeding, immediate nucleic acid testing of the infant should be sent.

The initial laboratory evaluations of a child over age 18 to 24 months who is suspected of having HIV-1 infection should include HIV-1 serologic testing (Table 2). If initial screening and confirmatory testing return positive, additional diagnostic testing should be completed, including HIV-1 RNA quantitative PCR (if not already sent), lymphocyte subsets (CD4) enumeration, and a complete blood count. Other routine diagnostic tests, such as a urine analysis and a chemistry panel, may also be warranted. Most children will have a normal blood count, a positive antibody test, and variable T-cell abnormalities, dependent on the age of the patient and the stage of disease (56).

Currently, clinical prognostic and therapeutic decisions are based on virologic markers of HIV-1 infection (preferably viral load) and the degree of CD4 lymphopenia relative to normal values for age. Surprisingly enough, the viral load in CSF is usually low in patients with early severe neurologic symptoms (75; 22).

The evaluation of a child living with HIV for neurologic involvement requires the clinical skills and primary diagnostic tools of the neurologist. The approach to the diagnosis of HIV-1-associated CNS disease, including differential diagnosis (secondary complications, confounding comorbid complications), involves a careful medical and developmental history, HIV-1 systemic disease history, current immunologic status, neurologic examination, psychological assessment, and neuroimaging studies (07; 08; 03; 40; 24).

Table 2. Diagnostic Testing for HIV-1 Infection in Infants and Children

Age group	Recommended virologic testing
Infants born to birthing parents with HIV	HIV nucleic acid test^a testing at the following ages: • Birth^b • 14 to 21 days • 1 to 2 months^b,c • 4 to 6 months^d
Children with non-perinatal HIV exposure or children with perinatal HIV exposure aged older than 24 months	• Antigen/antibody combination immunoassay^e• HIV-1/HIV-2 antibody differentiation immunoassay• HIV-1 nucleic acid test^g
^aHIV RNA or HIV DNA nucleic acid tests that directly detect HIV ^bFor high-risk infants, virologic diagnostic testing is recommended at birth. Additional virologic testing is recommended 2 to 6 weeks after antiretroviral drugs are discontinued. ^cFor low-risk infants, testing may be timed to occur at least 2 weeks after cessation of antiretroviral prophylaxis ^dFor infants with perinatal HIV exposure who are being breast- or chestfed, if breast- or chestfeeding continues beyond 6 months of age, nucleic acid testing should be performed every 3 months during breast- or chestfeeding. Regardless of the age of the child when breast- or chestfeeding ends, additional nucleic acid testing should be performed at 4 to 6 weeks, 3 months, and 6 months after cessation of breast- or chestfeeding. Additional nucleic acid testing of the infant is indicated if maternal viral load becomes detectable during breast- or chestfeeding. Consultation with an infectious disease expert is recommended for questions about HIV diagnostic testing for infants with perinatal HIV exposure who are being breast- or chestfed. ^eThese detect HIV-1/2 antibodies and/or HIV-1 p24 antigen. These tests are recommended for initial screening for established infection and for acute HIV-1 infection; however, p24 antigen from HIV-1 non-B strains, HIV-1 non-M strains, and HIV-2 strains may not be detected. ^fHIV-1/HIV-2 antibody differentiation immunoassays differentiate HIV-1 antibodies from HIV-2 antibodies and are recommended for supplemental confirmatory testing after initial antigen/antibody combination immunoassay screening tests. ^gHIV-1 RNA nucleic acid test is indicated as an additional test to diagnose acute HIV infection.

Neuroimaging. CT and MRI findings in infants and children with HIV-1 infection are dependent on the severity of CNS involvement. This can be further complicated by the presence of other opportunistic infections, such as cytomegalovirus and toxoplasmosis, which can also demonstrate intracranial calcifications, microcephaly, hydrocephalus, and atrophy. Table 3 summarizes imaging findings based on neuroanatomical localization. CT and MRI abnormalities are frequent in these patients and can consist of enlargement of the subarachnoid space and ventricles, calcifications of the basal ganglia and subcortical areas, and white matter abnormalities (08). In addition to these findings, some children may also develop cerebral aneurysms, resulting in subarachnoid hemorrhage or cerebral infarcts. The aneurysms are usually fusiform, involving the major blood vessels that can be seen on vascular imaging studies (59).

Table 3. Neuroimaging Findings

	CT	MRI
Cerebral atrophy	• Present in most patients • Serial studies often show progressive atrophy	• Present in most patients • Serial studies often show progressive atrophy
Basal ganglia	• Basal ganglia calcification, ± frontal white matter • Present in a subset of patients • Serial studies may show progressive "calcification"	• May show an abnormal high signal (T2-weighted images at time when CT is "normal") • May show an abnormal low signal (T2-weighted images at the time when CT shows calcification)
White matter	• White matter hypodensities • Serial studies often show progressive changes	• May show an abnormal high signal (T2-weighted images)

Management

Antiretroviral therapy. Medications that treat HIV-1 infection attempt to interfere with the replication of HIV. Targeted points in the growth cycle of the virus include blockage of viral entry or fusion, prevention of transcription of RNA to DNA (reverse transcriptase inhibitors), interference with translation (drugs acting on regulatory genes or their proteins), inhibition of assembly (protease inhibitors), release of virus (interferon), and integrase inhibitors. Newer therapies in development include nucleoside reverse transcriptase translocation inhibitors, broadly neutralizing antibodies, and capsid inhibitors. Updated information on the most current recommendations for treating children with HIV can be obtained by accessing the website of the HIV Treatment Information Service (hivinfo.nih.gov) and in consultation with an expert in pediatric HIV-1 infection.

To decrease morbidity and mortality associated with HIV, antiretroviral therapy should be initiated in all infants and children with HIV regardless of their clinical symptoms, immune status, or viral load. In clinical trials, children treated with zidovudine had improvement in weight gain and growth, stabilization of CD4 counts, reduction in serum and CSF p24 antigen levels, decrease in immunoglobulin levels, and improvement or stabilization of cognitive function (61; 18; 14). Large randomized controlled trials, START and TEMPRANO, have shown multiple benefits to rapid treatment initiation (defined as therapy that is initiated immediately or within days of diagnosis), including increased antiretroviral therapy uptake and linkage to care, decreased time to viral suppression, and improved rate of virologic suppression (33; 78). Additionally, early treatment initiation in young infants with HIV-1 before 1 year of age is associated with better sustained virologic suppression, reduced size of viral reservoirs, preserved immune function, and prevention of clinical disease progression (85; 69; 49).

Prophylaxis. Antiretroviral prophylaxis for newborns is based on birthing parent and infant risk factors for perinatal HIV acquisition. A national observational study in Italy from 2001 to 2011 examined the effects of antiretroviral exposure on birth defects. The study supported that first trimester exposure to antiretroviral therapy did not increase the risk of congenital abnormalities in infants (27). An analysis of the Quebec Pregnancy Cohort indicated that major congenital malformations were more common in children of birthing parents living with HIV without antiretroviral exposure compared to the general population, but this was not true for children of birthing parents living with HIV with exposure to antiretroviral therapy (12).

Antiretroviral prophylaxis for newborns includes the administration of one or more antiretroviral medications to a newborn without documented HIV infection in order to reduce the risk of perinatal acquisition of HIV. Presumptive HIV therapy involves administration of a three-drug antiretroviral therapy regimen to newborns who are at the highest risk of perinatal HIV infection and were exposed to HIV in utero, during the birthing process, or during breast- or chestfeeding but do not acquire HIV, and is considered preliminary treatment for an infant who is later documented to have HIV.

Low-risk perinatal HIV transmission applies to infants born at 37 weeks of gestation or later to birthing parents who received at least 10 consecutive weeks of antiretroviral therapy during pregnancy. These birthing parents must have maintained viral suppression, defined as at least two consecutive HIV RNA tests showing less than 50 copies/mL, with tests conducted at least 4 weeks apart and within 4 weeks before delivery. Additionally, there should be no concerns regarding adherence to therapy. For HIV-1-exposed infants at low risk of perinatal HIV transmission, the recommended treatment includes a 2-week course of oral zidovudine at 4 mg/kg/dose, administered twice daily and initiated as soon as possible after birth. Zidovudine can be given intravenously if oral medications are not tolerated.

For infants at high risk of perinatal HIV transmission, which includes infants born to birthing parents who did not receive antepartum antiretroviral therapy, did not achieve viral suppression within 4 weeks before delivery, or who had acute or primary HIV infection during pregnancy, presumptive antiretroviral therapy should be initiated. This therapy includes zidovudine (AZT), lamivudine (3TC), and either raltegravir (RAL) or nevirapine (NVP), started as soon as possible after birth and continued for up to 6 weeks. In 2011, a review of 25 trials (22 trials of randomized birthing parents with follow-ups of their infants and three randomized infant trials) assessed the effectiveness of antiretrovirals for reducing the risk of perinatal transmission of HIV infection and concluded that triple antiretroviral therapy is the most effective at preventing transmission of HIV from birthing parent to child (71). Consultation with experts in pediatric HIV care is recommended when managing infants at high risk of perinatal HIV transmission.

Infants who do not meet the criteria for either low or high risk but whose birthing parents were virally suppressed at least 4 weeks before delivery should receive 4 to 6 weeks of oral zidovudine. The antiretrovirals are generally well tolerated, and the most common side effects are anemia and neutropenia related to the zidovudine (70). For the most current recommendations on infant antiretroviral prophylaxis, healthcare providers can refer to the HIV Treatment Information Service website.

Outcomes

The PHACS SMARTT study evaluated the safety of in utero exposure to antiretroviral therapy and found that, overall, the data are generally reassuring, with minimal evidence for serious adverse events. However, they did find an increased rate of premature delivery and selected birth defects with certain antiretroviral exposure. Specifically, atazanavir exposure was associated with lower language achievement at 1 year and a twofold risk of congenital anomalies and was known to increase unconjugated bilirubin levels in the blood. Tenofovir exposure was associated with decreased newborn bone mineral content and reduced growth at 1 year. Some subclinical cardiac abnormalities were also noted, but it is unclear if these will predict a future premature heart disease (81).

A French perinatal multicenter cohort of 13,124 live births from birthing parents living with HIV on antiretroviral therapy found a significant association between first-trimester zidovudine exposure and congenital heart defects, specifically a prevalence of 2.3% (58% ventricular septal defect, 18% atrial septal defect cases). In a U.S. prospective cohort (SMARTT study) of 2580 HIV-exposed but uninfected children, Williams and colleagues looked at first-trimester exposure to antiretrovirals and found that the prevalence of congenital anomalies was 6.8% (87; 84).

The Pediatric AIDS-Defining Cancer Project Working Group found that in a study of 24,991 children in Africa, Europe, and Asia, children living with HIV from sub-Saharan Africa but not those from other geographical regions were at high risk for developing Kaposi sarcoma after antiretroviral therapy initiation. Therefore, they suggest that early antiretroviral therapy initiation in these children may help reduce Kaposi sarcoma risk (60).

Hrapcak and colleagues found that there is an overall 24% prevalence of hearing loss (which is 82% conductive hearing loss) in children aged 4 to 14 years with perinatal HIV in Lilongwe, Malawi (32). Although this amount is lower than previous reports, it is still significant. The authors state that there is an urgent need for improved screening tools, identification, and treatment of hearing to prevent adverse effects on school functioning and quality of life. Suggestions include more frequent ear assessments and hearing evaluations than for children without perinatal HIV infection. Another study found similar rates of hearing loss when tested by objective measures between children living with HIV and healthy controls (53), despite significantly higher numbers of self-reported hearing loss in patients with HIV.

Since the advancement of antiretroviral therapy and the implementation of effective strategies to prevent perinatal HIV transmission, the incidence of neurologic complications in children with HIV has declined significantly. Shanbhag and colleagues reported that the prevalence of static or progressive encephalopathy decreased from 40.7% in children born before 1996 to 18.2% in those born after (67). This trend has continued with the widespread use of antiretroviral therapy, with more recent studies showing that the cumulative incidence of progressive encephalopathy has dropped to less than 2% (83). Additional multicenter studies have demonstrated a sustained decline in the incidence of HIV-associated encephalopathy and microcephaly among children receiving antiretroviral therapy (52; 58). Beyond prevention, antiretroviral therapy has also been shown to slow the progression of neurologic impairment, reduce the severity of neurologic sequelae, and, in some cases, contribute to partial reversal of HIV-related encephalopathy (58). Furthermore, early initiation of antiretroviral therapy, particularly before 3 months of age, has been associated with significantly improved neurodevelopmental outcomes in children living with HIV (39). However, despite these improvements, school-aged children with HIV may continue to experience subtle deficits in higher-order cognitive functions (eg, memory, language development, and behavior) with only limited gains following antiretroviral therapy initiation (62).

Future directions of therapeutics include antilatency drugs, which work by activating viral production from latently infected cells to purge and clear HIV-1 reservoirs. Martinez-Bonet and colleagues discuss the possibility of the role of antilatency drugs in children with HIV (48).

In a review article discussing the challenges of eliminating pediatric HIV infection, Luzuriaga and Mofenson also commented that additional research needs to be done to improve methods of early diagnosis in resource-limited settings and methods to define the size and distribution of the latent HIV-1 reservoir in children more actively (45).

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Contributors

All contributors' financial relationships have been reviewed and mitigated to ensure that this and every other article is free from commercial bias.

Authors

Madeleine Goldstein DO MPH

Dr. Goldstein of Emory University School of Medicine has no relevant financial relationships to disclose.
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Brian Zanoni MD

Dr. Zanoni of Emory University School of Medicine received consulting fees from Accordant.
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Editor

Christina M Marra MD

Dr. Marra of the University of Washington School of Medicine has no relevant financial relationships to disclose.
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Former Authors

Anita L Belman MD
Avindra Nath MD
Marc Tardieu MD
Meihui Ma MD
Allyson Bazarsky DO
Dana Vanino MD
Lucie Henry MS
John Herbst
Kelly J Baldwin MD
Karen L Roos MD FAAN

Patient Profile

Age range of presentation: 0 month to 18 years
Sex preponderance: male=female
Heredity: none
Population groups selectively affected: none selectively affected
Occupation groups selectively affected: none selectively affected

ICD & OMIM codes

ICD-10: Psychosis: F29

Acquired immunodeficiency virus, AIDS: B24

Demyelinating disease of central nervous system unspecified: G37.9

Encephalopathy not elsewhere classified: G93.4

Lack of expected normal physiological development in childhood: R62.9

Unspecified disorders of nervous system: G96.9
ICD-11: Human immunodeficiency virus type 1: XN8LD

Contact with or exposure to human immunodeficiency virus: QC90.6

Encephalopathy, not elsewhere classified: 8E47

Lack of expected normal physiological development: MG44.1

Other specified disorders of the nervous system: 8E4Y

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Perinatally-acquired HIV infection

Associated Disorders

Bacterial infections
Candidiasis of the trachea, bronchi, lungs, esophagus
Coccidioidomycosis
Cryptococcosis
Cryptosporidiosis
- Cytomegalovirus disease
- Cytomegalovirus retinitis
- HIV encephalopathy
- HIV-associated progressive encephalopathy
- Chronic herpes simplex ulcer or pneumonitis or esophagitis
- Isosporiasis
- Kaposi sarcoma
- Lymphoid interstitial pneumonitis
- Lymphoma
- Mycobacterium avium complex
- Mycobacterium tuberculosis or acid-fast infection
- Pneumonia
- Pneumocystis carinii pneumoniae
- Progressive multifocal leukoencephalopathy
- Toxoplasmosis of brain
- Wasting syndrome caused by HIV

Differential Diagnosis

toxoplasmosis
rubella
cytomegalovirus
herpes
syphilis
- Epstein-Barr virus
- primary immunodeficiency virus
- congenital immunodeficiency virus
- secondary immunodeficiency virus
- cellular congenital immunodeficiency virus
- Nezlof syndrome
- adenosine deaminase deficiency
- nucleoside phosphorylase deficiency
- Omenn syndrome
- bone lymphocyte syndrome
- severe combined immunodeficiency with graft-versus-host disease
- DiGeorge syndrome
- Wiskott-Aldrich syndrome
- ataxia-telangiectasia
- x-linked lymphoproliferative syndrome
- mucocutaneous candidiasis
- agammaglobulinemia
- dysgammaglobulinemia
- neutrophil disorder
- reticuloendotheliosis
- lymphoma
- idiopathic thrombocytopenia
- purpura
- malignancy
- malnutrition
- nephrotic syndrome
- protein-losing enteropathy
- severe diarrhea
- other neurodegenerative disorders
- other CNS infections

Also Relevant

Acquired human cytomegalovirus
AIDS and HIV: neurologic manifestations and complications
Congenital cytomegalovirus
Congenital syphilis
HIV-associated dementia
- Peripheral nerve complications of HIV-1 infection
- Tuberculosis of the CNS

Perinatally-acquired HIV infection

Cite this article

Introduction

Overview

Key points

Historical note and terminology

Clinical manifestations

Presentation and course

Prognosis and complications

Table 1. Secondary CNS Complications

Clinical vignette

Biological basis

Etiology and pathogenesis

Epidemiology

Prevention

Differential diagnosis

Diagnostic workup

Table 2. Diagnostic Testing for HIV-1 Infection in Infants and Children

Table 3. Neuroimaging Findings

Management

Outcomes

Special considerations

Pregnancy

References

Contributors

Authors

Editor

Former Authors

Patient Profile

ICD & OMIM codes

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Questions or Comment?

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