Human immunodeficiency virus (HIV) has led to a worldwide pandemic that has exacted a dramatic toll on children, especially in resource-limited countries. It is estimated that approximately 1.8 million children younger than 15 years of age were living with HIV in 2015, the vast majority in sub-Saharan Africa.¹ In the same year worldwide, approximately 150,000 children were infected perinatally with HIV and 110,000 children died due to HIV/AIDS (acquired immunodeficiency syndrome).¹ In 2014 in the United States there were approximately 9000 children and youth less than 19 years of age living with diagnosed HIV infection.² In resource-rich countries including the United States, the vertical transmission rate has dropped to less than 2%,^3-6 and combination antiretroviral therapy (ART) has diminished mortality and morbidity associated with HIV disease.^7-9 The pediatric hospitalist must be familiar with the care of HIV-exposed newborns and HIV-infected children, because the initial diagnosis and management of complications often occur in the hospital setting.

Historically, HIV infection and AIDS were differentiated by the 1987 Centers for Disease Control (CDC) case definition for AIDS surveillance—that is, the presence of opportunistic infections or other so-called AIDS-defining conditions.¹⁰ The pediatric classification of the severity of HIV disease was subsequently revised to include infection status, clinical status, and immunologic status (Tables 108-1 and 108-2).^11,12 The absolute CD4⁺ T-cell count and CD4% decline naturally with age until 6 years of age when they stabilize at adult levels (Table 108-2). Thus, a 4 year old HIV-infected child with a prior episode of Pneumocystis jiroveci pneumonia (previously Pneumocystis carinii pneumonia, abbreviated PJP) and a prior CD4 count nadir of 350 cells/mm² would be categorized as C3.¹²

Most infants infected vertically with HIV acquire the infection intrapartum and therefore are asymptomatic as newborns. Rates of prematurity and low birth weight are higher in HIV-infected than in uninfected infants, but there are usually no physical examination findings that would specifically implicate HIV as the cause. Consequently, any newborn whose mother’s HIV status is unknown should be considered at risk.

The natural history of HIV infection in vertically infected children is one of rapid progression when compared to adolescents and adults infected horizontally, likely due to immunologic immaturity at the time of infection. In developed countries, approximately 20% develop profound immunosuppression and AIDS-defining conditions, such as Pneumocystis jiroveci pneumonia, HIV encephalopathy, or repeated invasive bacterial infections during the first year of life.^13-15 Without treatment, these “rapid progressors” typically succumb to the disease by 2 years of age. Of the remaining 80%, onset of disease is more gradual with 4% to 8% progressing to AIDS each year;^13,14 the average age of AIDS diagnosis is between 6 and 9 years of age. In the absence of treatment, only 2% remain completely asymptomatic and have preserved immune function, as measured by CD4 count, at 10 years of age.¹⁶

The most common AIDS-defining conditions in children are Pneumocystis jiroveci pneumonia (PJP), lymphoid interstitial pneumonitis (LIP), multiple or recurrent invasive bacterial infections, HIV wasting syndrome, HIV encephalopathy, esophageal candidiasis, cytomegalovirus (CMV) disease, and disseminated infection with Mycobacterium avium-intracellulare complex.^12,17 However, clues to the diagnosis are evident prior to development of AIDS in most children. Recurrent sinopulmonary infections, prolonged or atypical course of common childhood infections, impaired growth, or delayed attainment of developmental milestones may be evident.¹² Nonspecific findings on physical examination, such as generalized lymphadenopathy, parotitis, or dermatitis and laboratory abnormalities, such as anemia, neutropenia, thrombocytopenia, or hypergammaglobulinemia may be seen. The age of onset of symptoms predicts long-term survival.

In the early years of the HIV epidemic, vertical transmission of HIV (also termed perinatal transmission or mother-to-child transmission) occurred at rates of 15% to 40%.^18-20 Sixty percent to 75% of infections occurred during the process of delivery, while 10% to 20% occurred in utero and 10% to 15% as a consequence of breastfeeding. Rare cases of transmission related to feeding infants pre-masticated food have been observed.²¹ In the United States, the estimated number of vertically transmitted HIV infections peaked in 1992, at approximately 900 cases. Since then, numerous interventions, including prenatal counseling and testing for HIV, use of antenatal ART for pregnant women, elective cesarean delivery, zidovudine (ZDV, also known as AZT) infusion during labor, and ZDV prophylaxis for newborns, have been instituted. These interventions have dramatically reduced the vertical transmission rate to about 1% of infants born in the developed world.^4-6 In 2015, 120 children younger than 13 years of age were diagnosed with HIV infection in the United States, of which 86 (72%) were attributed to vertical transmission.² Ongoing challenges include primary prevention of infection in girls and young women, incomplete testing during pregnancy, and failure to implement preventive interventions once the diagnosis is established. Substance abuse, psychiatric illness, and socioeconomic issues such as poverty, limited access to medical care, and inadequate housing are associated with HIV infection and vertical transmission of HIV.

The initial evaluation of an HIV-exposed neonate begins with a detailed prenatal history. In addition to the typical elements (e.g. prenatal laboratory studies, medical complications of pregnancy, alcohol or illicit drug use, mode of delivery), the nursery clinician should determine the following aspects of the prenatal history: when the mother was diagnosed with HIV; the prenatal antiviral regimen, if any; and the most recent maternal viral load and CD4 count. The clinician must also verify that the mother received intrapartum intravenous ZDV at the onset of labor. Although elective cesarean section is often performed to decrease the risk of vertical transmission, vaginal delivery may be performed when the maternal viral load is less than 1000 copies/mL.

Immediately following birth, a complete blood count (CBC) with differential should be performed on the newborn as a baseline before initiating postpartum antiretroviral prophylaxis. The standard postpartum antiretroviral prophylaxis regimen for the infant is ZDV for 4 weeks.²² The addition of 3 doses of nevirapine during the first week of life to 6 weeks of zidovudine is currently recommended for infants of mothers who received no antepartum antiretroviral medications.²² Some experts recommend the use of triple combination ART for infants perceived to be at high risk of HIV infection, though there are limited clinical trial data to support this practice.²³ Such “high-risk” scenarios include women diagnosed with HIV infection at the time of delivery (and therefore previously untreated) and women who are either not receiving therapy or are poorly adherent to therapy and known to have a high viral load.

Diagnosis of HIV infection during early infancy relies on detection of the virus in serum using DNA or RNA polymerase chain reaction (PCR); serology is of little utility due to transplacental passage of maternal antibodies. Cord blood samples should not be used for testing because maternal blood may contaminate the sample. PCR should be performed within 48 hours of birth, at 1 to 2 months, and at 4 to 6 months of age.¹² A positive result from the birth to 48 hour sample is indicative of in utero transmission. A reactive PCR at or beyond 1 month of age, subsequent to a negative birth to 48 hour test, reflects infection acquired during the birthing process or via breast milk. The overall sensitivity of PCR for diagnosing HIV infection at 1 month is about 95% (i.e. 95% of infected infants will have a positive HIV PCR by 1 month of age).¹² Exclusion of HIV infection in non-breastfed infants requires either¹²: (1) two negative HIV DNA or RNA virologic test results from separate specimens obtained at 1 month of age or later, one of which was obtained at 4 months of age or later; or (2) two or more negative HIV antibody tests taken at 6 months of age or later. In children 18 months or older, HIV infection is confirmed by a reactive enzyme-linked immunosorbent assay (ELISA) and confirmatory Western blot for anti-HIV-1 and anti-HIV-2 IgG. It should be noted that children born in Africa may be infected with HIV-2, which may be missed by HIV-1 PCR primers.

HIV INFECTION

Combination ART has dramatically improved the health and life expectancy of HIV-infected children.^7-9 In the United States, the 10-year survival for children born between 1997 and 2004 who were initiated on ART during the first 6 months of life was 94%.⁷ As in adults, ART is now recommended for all HIV infected children regardless of clinical status, immunologic status (CD4 count) or viral load. Urgent initiation of ART is warranted for all infants <12 months of age and for those with AIDS defining conditions or severe immunodeficiency as defined by absolute CD4 count. The immediate goals of therapy are to maintain an undetectable viral load and to restore normal CD4 count while minimizing adverse effects of the medications.

A unique aspect of pediatric HIV care is the choice of antiretroviral medications to be used.²⁴ In general, treatment options are more limited for young children because of a lack of availability of liquid formulations or pediatric size tablets and capsules.²⁵ In addition, the pharmacokinetic properties of antiretroviral medications differ significantly in children compared with adults, and for some medications the toxicity profile is particularly problematic in young children (e.g. tenofovir).²⁵ Up-to-date guidelines for the use of antiretroviral medications, published by the US Department of Health and Human Services, are available online.²⁴

Five classes of antiretroviral agents are available for treatment of HIV infection:^24,25 (1) entry inhibitors (including CCR5 antagonists and fusion inhibitors); (2) nucleoside reverse transcriptase inhibitors (NRTIs); (3) non-nucleoside reverse transcriptase inhibitors (NNRTIs); integrase strand transfer inhibitors (INSTIs); and (5) protease inhibitors (PIs). Combination ART comprises at least three agents from at least two classes of medication. Currently, the recommended first-line ART regimens consist of a dual-NRTI “backbone” in combination with either an NNRTI, a PI on an INSTI.²⁴

Adjunctive therapies, used for children with poorly controlled or advanced HIV, include intravenous immunoglobulin infusions every 3 to 4 weeks and antimicrobial prophylaxis. Commonly used prophylactic agents include trimethoprim-sulfamethoxazole and azithromycin for the prevention of P. jiroveci pneumonia and disseminated Mycobacterium avium-intracellulare complex infection, respectively. Specific recommendations for the prevention of opportunistic infections and use of prophylactic medications are available.¹⁷

INFECTIONS IN AN HIV-INFECTED CHILD

When evaluating an HIV-infected child for infection, it is crucial to determine the child’s CD4 count (and CD4%), most recent viral load, and ART regimen.²⁴ CD4 count must be interpreted according to age-specific ranges (see Table 108-2).

In children with normal immunologic function, as determined by CD4 count, the infectious agents are usually similar to those seen in children without HIV. However, they are at higher risk of invasive bacterial infection and therefore, a lower threshold for obtaining blood culture, urinalysis, urine culture, stool culture, chest radiograph, and lumbar puncture may be appropriate, on a case-by-case basis. The need for antimicrobial therapy should be determined in a manner similar to children without HIV. Children with neutropenia from HIV infection should have empirical antimicrobial therapy similar to that given to children with neutropenia from other causes.

In children with CD4 counts in the severe immunodeficiency range (category 3; Table 108-2), the risk of opportunistic infection increases dramatically. Multiple concurrent infections are not uncommon. Such children should be admitted for investigation. Broad-spectrum empirical antimicrobial therapy may be warranted and should be chosen in consultation with an infectious disease specialist. Treatment guidelines for opportunistic infections in HIV-infected children are available.¹⁷ Key management aspects for HIV-infected children presenting with fever and symptoms indicative of central nervous system, respiratory tract, and gastrointestinal tract are provided below.

Fever

Acute onset of fever is a common reason for an HIV-infected child to be brought to medical attention. The child may be admitted for fever without localizing signs or for fever of unknown origin. As with all children, the majority of fevers are due to common, self-limited infections, such as a viral upper respiratory infection. HIV infection necessitates a more thorough investigation for a focus of infection, however. Children with HIV have a higher incidence of bacteremia and invasive bacterial disease than does the general population, regardless of CD4 count. Streptococcus pneumoniae is the most common cause of invasive bacterial infection, but rates of disease due to other pathogens, including Haemophilus influenzae type B, Staphylococcus aureus, Escherichia coli, and non-typhi Salmonella species are also higher than in HIV-negative children.^26,27

The absence of localizing signs in a child with a fever and a low CD4 count dictates a broader, more intensive diagnostic evaluation because of the breadth of potential infectious causes. The compromised immunity caused by advanced HIV disease may obscure the focus of infection, including infection within the central nervous system (CNS). A child whose CD4 count is in the severe immunodeficiency range (category 3; see Table 108-2) may have an infection caused by either typical pathogens (e.g. S. pneumoniae, Staphylococcus aureus) or opportunistic pathogens (e.g. mycobacteria, fungi). Fever without localizing signs may also be caused by disseminated herpesvirus infections, such as herpes simplex virus (HSV), varicella-zoster virus (VZV), Epstein-Barr virus, or CMV. The scope and tempo of the evaluation are dictated by the child’s immunologic status and the acuity of presentation. A partial list of causes of undifferentiated fever in HIV-infected children is provided in Table 108-3.

Central Nervous System

HIV encephalopathy is the most common CNS complication of HIV infection, typically presenting during the first 2 years of life. It is characterized by impaired brain growth, developmental delay or regression, and symmetric motor deficits.²⁶ Cerebral atrophy and basal ganglia calcifications are classic neuroimaging findings. Cerebral vasculopathy leading to ischemic stroke or intracranial hemorrhage secondary to profound thrombocytopenia are a rare complication of HIV infection in children.^28,29

In HIV-infected children whose CD4 count is normal, central nervous system infections are usually caused by the same pathogens as in HIV-uninfected children. However, such children are at slightly increased risk for bacterial meningitis compared with children without HIV. Their cerebrospinal fluid findings are similar to those in children without HIV. For those with meningitis, empiric antibiotic therapy should target S. pneumoniae and Neisseria meningitidis, and in the unimmunized, Haemophilus influenzae type B.

In children with a CD4 count is in the severe immunodeficiency range (category 3; see Table 108-2), opportunistic pathogens such as CMV and other herpes group viruses, Cryptococcus neoformans, Toxoplasma gondii, and JC virus must be considered, in addition to typical CNS pathogens.^28,30 CMV is the most common opportunistic infection of the CNS in children, typically presenting as subacute or chronic meningoencephalitis. Cryptococcal meningitis, the most common opportunistic fungal infection of the CNS, presents insidiously with a gradual onset of fever, headache, malaise, and emesis.³¹ Frank signs of meningismus are often absent; a lymphocytic pleocytosis is characteristic, but the cerebrospinal fluid findings may be completely normal. Progressive multifocal leukoencephalopathy, due to reactivation of latent JC virus, is a rare complication seen in children with advanced HIV infection.³² Slowly progressive confusion, personality changes, and focal neurologic findings are characteristic. In the absence of ART, progressive multifocal leukoencephalopathy is uniformly fatal within months of diagnosis.