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Pediatric HIV infection: Epidemiology, clinical manifestations, and outcome

Pediatric HIV infection: Epidemiology, clinical manifestations, and outcome
Authors:
Susan L Gillespie, MD, PhD
Gayatri Mirani, MD, MAS
Section Editor:
Mary E Paul, MD
Deputy Editor:
Milana Bogorodskaya, MD
Literature review current through: Apr 2025. | This topic last updated: Nov 11, 2024.

INTRODUCTION — 

Considerable progress has been made towards eliminating human immunodeficiency virus (HIV) among children; however, the global burden of pediatric HIV and acquired immune deficiency syndrome (AIDS) remains a challenge for health care workers around the world, particularly in resource-limited settings [1].

The epidemiology, case definition, and classification of pediatric HIV infection, clinical manifestations of some of the AIDS-defining conditions (table 1), and outcomes of HIV infection in children are reviewed here. Prophylactic treatment of infants born to mothers with HIV, diagnostic testing for HIV in young children, and issues related to HIV infection in adolescents are discussed separately:

●(See "Intrapartum and postpartum management of pregnant women with HIV in resource-abundant settings", section on 'Introduction'.)

●(See "Pediatric HIV infection: Diagnostic testing in children younger than 18 months".)

●(See "The adolescent with HIV infection".)

The details of antiretroviral therapy (ART) for pediatric HIV infection are beyond the scope of these topic reviews. Guidelines on the treatment of pediatric HIV infection are available through the HIV.gov Clinical Info website.

CASE DEFINITIONS — 

The Centers for Disease Control and Prevention (CDC) and World Health Organization (WHO) each have established case definitions for HIV infection and AIDS in children and adults to standardize the description of HIV infection cases for public health surveillance and research purposes. These classification systems are useful for characterizing HIV infection in the United States (CDC) and in resource-limited settings (WHO) and are described briefly below.

●Centers for Disease Control and Prevention classification system — The CDC surveillance case definitions are used primarily for monitoring the HIV infection burden and planning for prevention and care in populations, not as the basis for clinical decisions in individual patients.

The 2014 revised case definition classifies HIV infection in all age groups as stage 1, 2, or 3 (table 2) based upon the absolute CD4 count (table 3), unless the individual has had a stage 3 (ie, AIDS-defining) opportunistic illness (table 1) [2]. The CD4 percentage is used only when the corresponding CD4 count is unknown, even for young children. Specific criteria are provided for different age groups (<1 year, 1 through 5 years, and ≥6 years). If no CD4 count or percentage is known, the stage is classified as unknown. If a stage 3 opportunistic illness has been diagnosed, then the stage is 3 regardless of the CD4 absolute count or percentage. The CDC staging system indicates the most severe stage in the individual's lifetime and does not provide guidance for assigning a revised, less severe stage after antiretroviral therapy (ART)-mediated improvement in HIV-related symptom severity.

Stage 0 indicates early HIV infection and allows routine monitoring of cases diagnosed within several months after infection. Stage 0 includes the most highly infectious period when viral loads are extremely high and intervention may be most effective in preventing secondary transmission of infection to others. The criteria for stage 0 supersede and are independent of the criteria used for other stages.

●World Health Organization classification system — The WHO classification system for pediatric HIV/AIDS [3] uses clinical or immunologic criteria for patients with laboratory-confirmed HIV infection (table 4 and table 5).

This four-stage system (ie, WHO clinical stage 1 to WHO clinical stage 4) classifies an individual's clinical status from asymptomatic to severely symptomatic. The WHO classification also includes criteria for the presumptive diagnosis of advanced HIV infection in HIV-exposed infants based on clinical criteria, allowing practitioners in resource-limited areas to initiate lifesaving ART before definitive laboratory diagnosis is completed.

To track improvement or worsening, staging continues after commencing ART using the same clinical criteria (table 4) and denoting the stage as "T1," "T2," "T3," or "T4" to indicate that the assessment was made on ART.

The WHO recommends initiating ART for all infants, children, and adolescents with HIV, regardless of WHO clinical stage and/or CD4 count [4]. Children with HIV in the following categories are considered to be at the highest priority for initiating ART:

•WHO stage 3 or 4

•Age <2 years

•Age 2 to 5 years with CD4 count ≤750 cells/mm3 or CD4 percentage <25 percent

•Age ≥5 years with CD4 count ≤350 cells/mm3

EPIDEMIOLOGY

Global HIV/AIDS statistics — Significant progress is being made in the quest to eliminate HIV among children. In 2023, 120,000 children <15 years old were newly infected with HIV, bringing the total number of children worldwide with HIV or AIDS to 1.4 million [5,6]. Most reside in resource-limited areas, with approximately 90 percent living in sub-Saharan Africa. Most HIV infections in children are acquired via perinatal transmission during pregnancy, labor, delivery, or breastfeeding. Therefore, the epidemiology of pediatric HIV is inextricably related to the efforts and success of preventing perinatal HIV transmission. (See "Prevention of vertical HIV transmission in resource-limited settings".)

Resource-rich settings — In the United States and other resource-abundant settings, the number of children younger than 13 years of age newly diagnosed with HIV has decreased dramatically due to successful perinatal HIV transmission prevention interventions. The Centers for Disease Control and Prevention (CDC) estimates that the number of children diagnosed with perinatally acquired HIV in the United States dropped from a peak of 1650 in 1991 to 65 in 2018 [7,8]. In the United States, perinatal transmission prevention efforts began in 1985 with the recommendation for HIV testing in high-risk pregnant women and the avoidance of breastfeeding for women with HIV and continued with development of a framework in 2012 for the elimination of HIV perinatal transmission [9]. The following interventions are crucial to the elimination of HIV perinatal transmission:

●Prevention of HIV infection in women and girls of childbearing potential

●Identification of HIV infection among women and girls of childbearing potential

●Assurance of adequate preconception antiretroviral therapy (ART) and family planning services for women with HIV infection

●Early identification of HIV infection of pregnant women through universal prenatal screening (first and third trimester opt out HIV testing)

●Provision of adequate prenatal care for women with HIV infection

●Maximal reduction of maternal viral load through appropriate use of ART

●Cesarean delivery when maternal viral load is >1,000 copies/mL

●Provision of neonatal antiretroviral (ARV) prophylaxis

●Maternal support, monitoring, and discussion of the risks and benefits of neonatal replacement feeding versus breastfeeding [10,11]

Prenatal and intrapartum management of women with HIV is discussed in detail separately. (See "Prenatal evaluation of women with HIV in resource-abundant settings".)

In the United States, when women with HIV and their infants receive all applicable perinatal transmission prevention interventions, perinatal HIV transmission rates can be reduced to less than 1 percent [8,12,13]. However, cases of perinatal HIV transmission still occur, typically in the setting of delayed entry to prenatal care, discovery of HIV diagnosis during pregnancy rather than preconception, and delays in ART initiation [14].  

In the United States and other resource-abundant settings, outcomes for children with HIV have improved, in large part due to early initiation of antiretroviral therapy. (See 'Improved outcomes with ART' below.)

Resource-limited settings — In 2023, approximately 120,000 infants and children aged zero to 15 years were newly infected with HIV worldwide, bringing the total number of children with HIV worldwide to 1.4 million [5,6]. Additionally, about 140,000 adolescents aged 10 to 19 years were newly infected with HIV worldwide.  

More than 90 percent of children with HIV in resource-limited settings acquire infection from their mothers during pregnancy, labor/delivery, or through breastfeeding. Just as in the United States and other resource-abundant settings, increasing emphasis has been placed on efforts to prevent perinatal transmission with the use of antiretroviral therapy throughout pregnancy, at delivery, and in the exposed infant starting immediately after birth. It is hoped that with continued expansion of perinatal prevention programs, perinatal transmission of HIV may become rare in the future. (See "Prevention of vertical HIV transmission in resource-limited settings".)

Risk factors for HIV acquisition — The majority of children acquire HIV vertically: during pregnancy, delivery, or during breastfeeding. However, children can also become infected through other routes of transmission, such as through sexual contact, exposure of blood products, or contaminated needles.

●Exposure through pregnancy, birth, and breastfeeding – Vertical transmission of HIV can occur at any time during gestation and delivery and postnatally through breast milk. More than 90 percent of children with HIV worldwide have acquired the virus via vertical transmission. In the absence of antiretroviral therapy (ART), the rate of vertical transmission (in absence of breastfeeding) of HIV is approximately 25 percent [15]. The use of ART in pregnant women with HIV and their infants has dramatically reduced perinatal transmission. Although it is known that HIV can be transmitted early in gestation in utero, most transmissions (50 to 80 percent) are believed to occur during the time period of labor and delivery [16]. (See "Prevention of vertical HIV transmission in resource-limited settings", section on 'Risk of vertical HIV transmission' and "Antiretroviral selection and management in pregnant individuals with HIV in resource-abundant settings".)

In the postpartum period, HIV transmission can occur through breastfeeding. Among chronically infected women, without maternal ART or infant ARV prophylaxis, the risk of an infant acquiring HIV through breastfeeding is 15 percent to 20 percent over two years. The risk of vertical transmission among mothers who acquire HIV while breastfeeding is even higher due to high maternal plasma viral loads associated with acute HIV infection [17]. Risk factors for HIV transmission through breastfeeding are discussed separately. (See "Prevention of HIV transmission during breastfeeding in resource-limited settings", section on 'Epidemiology of HIV transmission through breastfeeding'.)

●Exposure through sexual contact – Outside of perinatal transmission, sexual exposure is the major route of transmission of HIV to children. A diagnosis of HIV in a child whose mother does not have HIV should prompt suspicion and evaluation for sexual activity and sexual abuse. The precise risk of HIV transmission from one act of sexual intercourse with an infected person is not known; some people have had multiple sexual contacts with an infected person without acquiring HIV infection while others have become infected after one sexual encounter. Females are at higher risk of acquiring HIV from heterosexual intercourse compared with males.

Globally, adolescent girls and young women are disproportionately affected by HIV. They are at higher risk for gender-based violence, leading to increased risk of HIV acquisition. In 2018, 3 out of 5 new diagnoses in 15 to 24-year-olds worldwide were among young women [18]. In contrast, in the United States and in other settings with concentrated epidemics, males who have sex with males (including adolescent boys) account for the highest number of new infections. As an example, in the United States, 13 to 24 year olds accounted for 20 percent of new infections in the United States in 2021, with most being gay and bisexual males [19]. In general, the risk of acquiring a sexually transmitted infection is proportional to the number of different sexual partners. However, for some girls and young women, a steady male partner who has sexual contact outside the primary relationship is the only source of HIV exposure [20].

Male circumcision can reduce the risk of heterosexually acquired HIV infection in men [21]. The World Health Organization (WHO) recommends male circumcision as part of a comprehensive HIV prevention package in settings with high HIV burden. The effect of male circumcision on HIV transmission is discussed separately. (See "Neonatal circumcision: Risks and benefits", section on 'Reduction in HIV and other sexually transmitted infections'.)

Pre-exposure prophylaxis against HIV infection is discussed separately. (See "HIV pre-exposure prophylaxis", section on 'Summary and recommendations'.)

●Exposure through blood or blood products – HIV transmission to children via contaminated blood and/or blood products is rare, but can and does occur. Exposure to HIV-infected blood may occur in the healthcare setting through a contaminated blood product transfusion or use of non-sterile needles or in the community with nonsterile razor blades for ritual scarring or traditional healing.

Nosocomial non-perinatal transmission of HIV in children has been reported in outbreak situations with reuse of needles and syringes [22-25]. In a large outbreak in Pakistan, out of 930 patients infected, 763 were children less than 15 years old. In another study reported from Nigeria that looked at 597 children who acquired HIV from 2004 to 2011, 14 of the cases were associated with transfusion [26].

Compared with industrialized nations, some countries in sub-Saharan Africa experience more transfusion-associated HIV transmission because of a higher prevalence of HIV infection in donor populations, a lack of HIV antibody screening in some areas, and a higher residual risk of contamination in blood supplies, despite antibody screening.

●Exposure through premastication – Although rare, there have been reports of children acquiring HIV after eating foods premasticated by individuals with HIV [27,28].

●Exposure through injection drug use – Injection of illicit drugs is increasingly associated with transmission of HIV worldwide. Although it may be a cause of HIV transmission among adolescents, there are limited data on the incidence or prevalence of HIV among adolescents who inject drugs [29]. (See "Global epidemiology of HIV infection", section on 'Injection drug use' and "The adolescent with HIV infection", section on 'Risk factors'.)

Progress in providing pediatric treatment — It is critical to continue supporting and placing emphasis on programs aimed at preventing vertical HIV transmission and expanding care and treatment services to children with HIV. Globally, there are numerous barriers to implementing pediatric ART on a wide scale. These include:

●Lack of infrastructure

●Lack and loss of health professional capacity

●The relatively high cost of some pediatric formulations of antiretroviral medications

●The perceived complexity of treating children

The percent of people with HIV worldwide who were receiving ART has increased from around 24 percent in 2010 to around 76 percent in 2022. Of the estimated 1.2 million pregnant women with HIV in 2022, an estimated 82 percent received ART [30]. However, the number of children accessing ART was reported to be only 57 percent in 2022. While this is a substantial increase from UNAIDS report in 2009, at which time only 15 percent of children with HIV received ART, this is still a very low percentage. This gap must be addressed urgently since without treatment, approximately one-half of infants with HIV die by the age of two years and approximately 100,000 children <15 years old die from HIV and AIDS each year [31,32].

CLINICAL MANIFESTATIONS — 

Clinical manifestations of HIV infection in infants and children are varied and often nonspecific. Lymphadenopathy, frequently in association with hepatosplenomegaly, can be an early sign of infection. During the first year of life, oral candidiasis, pneumonia, failure to thrive, and developmental delay are common presenting features of HIV infection. As HIV infection persists without effective treatment, children experience progressive immunosuppression and develop acquired immune deficiency syndrome (AIDS). The most common AIDS-defining conditions observed among American children with vertically acquired HIV infection include:

●Pneumocystis jirovecii pneumonia (PJP)

●Esophageal candidiasis

●Recurrent bacterial infections

●Wasting syndrome

●Cytomegalovirus (CMV) pneumonia, colitis, encephalitis, or retinitis

●HIV encephalopathy

Guidelines for the prevention and treatment of opportunistic infections (OIs) in children with HIV are available through the HIV.gov Clinical Info website.

SELECTED AIDS-DEFINING CONDITIONS — 

Opportunistic infections are much less common now that more children are starting antiretroviral therapy (ART) earlier in their infection. However, in children who are not on ART, opportunistic infections are common and can often be the first presenting sign of HIV infection. In a cohort study of over 2700 children with HIV (majority perinatally infected and on ART) enrolled from 2000 to 2004, the most commonly reported infections were bacterial infections, herpes zoster virus, dermatophyte infections, and oral candidiasis [33]. Incidence rates of bacteremia, Pneumocystis jirovecii pneumonia, disseminated Mycobacterium avium complex, lymphoid interstitial pneumonitis, systemic fungal infection, cytomegalovirus retinitis, and tuberculosis were all less than 0.50 per 100 person-years.

Pneumocystis jirovecii pneumonia — (PJP) — PJP accounts for approximately one-half of all AIDS-defining conditions diagnosed during the first year of life. The median age at diagnosis of PJP in children in one series was five months [34]. In infants, PJP can develop with CD4 counts >200 cells/microL. In adults and older children, PJP develops in individuals with CD4 counts <200 cells/microL or CD4 <15 percent and poor virologic control.

PJP should be suspected in patients with low-grade fever, tachypnea, nonproductive cough, and progressive shortness of breath. The onset of symptoms may be insidious, with nonspecific symptoms of mild cough, dyspnea, poor feeding, diarrhea, and weight loss. On physical examination, lung auscultation may be normal even in the presence of severe clinical disease and hypoxemia; rales and rhonchi may not become apparent until late in the clinical course. In children with HIV and PJP, four clinical variables are independently associated with Pneumocystis pneumonia (PCP): age <6 months, respiratory rate ≥60 breaths per minute, arterial hemoglobin saturation ≤92 percent, and absence of vomiting [35]. A typical chest radiograph may show bilateral perihilar interstitial infiltrates that become more homogeneous and diffuse as the disease progresses (image 1). When chest radiographic findings are normal, high-resolution computed tomography (CT) may reveal extensive ground-glass opacities, with a patchy distribution affecting the central lung, sparing the lung periphery (image 2) [36]. (See "Epidemiology, clinical presentation, and diagnosis of Pneumocystis pulmonary infection in patients with HIV", section on 'Radiographic manifestations'.)

P. jirovecii cannot be cultured in the laboratory, and definitive diagnosis relies on microscopic demonstration of the organism in pulmonary fluids or tissues in the presence of clinical disease. In resource-limited settings, appropriate specimens have been obtained through sputum induction or nasogastric aspirates [37]. Polymerase chain reaction (PCR) has been used to diagnose PJP in children and has been found to be more sensitive but less specific compared with microscopic methods [38,39].

The mortality rate in immunocompromised patients ranges from 5 to 40 percent if treated and approaches 100 percent if untreated. Because one-half of all cases of PJP in children with perinatally acquired HIV occur in infants three to six months of age, early identification of HIV-exposed infants and timely initiation of prophylaxis is essential to prevent PJP-related deaths. Indications for initiating Pneumocystis prophylaxis and treatment of Pneumocystis pneumonia in children are discussed in detail elsewhere. (See "Treatment and prevention of Pneumocystis infection in patients with HIV", section on 'Regimens for prophylaxis' and "Pediatric HIV infection: Management of infants born to mothers with HIV in resource-abundant settings", section on 'Limited role for pneumocystis prophylaxis'.)

Recurrent bacterial infections — Bacterial infections occur commonly in children with HIV infection. Before the era of combination ART, pneumonia and bacteremia were the two serious bacterial infections observed most commonly [40]. Streptococcus pneumoniae, Salmonella species, Staphylococcus aureus, and Haemophilus influenzae are the bacteria isolated most frequently, although mortality due to H. influenzae and S. pneumoniae are declining worldwide [41]. Pseudomonas spp is associated with late-stage disease and severe immunosuppression [42]. Risk factors for bacterial infection in children with HIV have not been defined precisely, but young children with perinatally acquired HIV appear to be at particular risk [43,44].

Wasting syndrome — Wasting refers to loss of lean body mass and is defined by meeting at least one of the following criteria in the absence of a concurrent illness other than HIV:

●Persistent weight loss greater than 10 percent of baseline

●Downward crossing of two or more major percentile lines on the pediatric weight-for-age chart (eg, 95th, 75th, 50th, 25th, 5th)

●Less than 5th percentile on weight-for-height chart on two consecutive measurements 30 or more days apart, plus chronic diarrhea or documented fever

Wasting is a well-recognized AIDS-defining condition for children and adults. HIV infection, opportunistic infections from immunocompromise, and increased metabolic demands all can lead to loss of weight and lean body mass. In children, wasting can severely impact normal growth and development. Wasting also is associated with a high risk for HIV disease progression and short-term mortality [45].

Esophageal candidiasis — Clinical features and risk factors for the development of esophageal candidiasis have not been widely addressed in children with HIV. In a retrospective study of 448 children with HIV followed at the National Cancer Institute between 1987 and 1995 (prior to use of combination ART), 8 percent had at least one episode of esophageal candidiasis and several children had multiple episodes [46].

Risk factors for esophageal candidiasis included [46]:

●Prior oral candidiasis (present in nearly all affected children)

●Low CD4 count (which was an independent predictor)

●Receipt of antibiotics

Clinical manifestations included [47]:

●Oral thrush (72 percent)

●Odynophagia (50 percent)

●Fever (55 percent)

●Nausea and/or vomiting (39 percent)

Evaluation and treatment of suspected esophageal candidiasis are discussed separately. (See "Candida infections in children", section on 'Esophagitis' and "Evaluation of the patient with HIV, odynophagia, and dysphagia".)

HIV encephalopathy — Neurodevelopmental and neurocognitive disorders are well-recognized complications of HIV infection. Most children with untreated HIV infection have central nervous system (CNS) abnormalities. (See "HIV-associated neurocognitive disorders: Epidemiology, clinical manifestations, and diagnosis".)

●Definition – HIV encephalopathy is defined by one or more of the following:

•Failure to attain developmental milestones, loss of milestones, or loss of cognitive ability.

•Impaired brain growth or acquired microcephaly, as determined by head circumference measurements, or brain atrophy demonstrated by CT or magnetic resonance imaging (MRI).

•Acquired symmetric motor deficits manifested by two or more of the following: paresis, pathologic reflexes, ataxia, or gait disturbances.

●Associated findings – HIV encephalopathy may be associated with spastic weakness of the extremities, microcephaly, seizures, and abnormalities on brain imaging (particularly cerebral atrophy and basal ganglia calcification (image 3)). The encephalopathy may be static or progressive. Static HIV encephalopathy is more common and involves global cognitive and motor deficits with a normal range of learning [48]. Progressive HIV encephalopathy, the most severe form of HIV encephalopathy, occurs almost exclusively in untreated HIV and involves severe developmental delay or regression of developmental milestones.

●Pathogenesis – Manifestations of HIV encephalopathy may be due to the direct effects of HIV infection in the CNS, effects of immune mediators, or other unidentified agents. CNS infection by HIV is generally restricted to monocytes, macrophages, and their derivatives. Activation of these cells by HIV results in overproduction of inflammatory mediators. These inflammatory mediators and/or HIV viral proteins may serve as neurotoxins, eventually causing neuronal dysfunction and death. Inflammatory lesions, reactive gliosis, and white-matter degenerative changes are some of the neuropathologic findings noted in the brains of children with HIV [49-51].

●Risk factors – HIV encephalopathy is associated with the severity of clinical disease and is a common AIDS-defining condition in both resource-abundant and resource-limited settings, particularly in the era before widespread use of combination ART or in settings where access to ART is limited [52-55].

Risk factors for the development of HIV encephalopathy include [56-58]:

•Lack of ART

•Advanced HIV disease

•Low CD4 count

•High viral load

●Impact of ART – The use of highly active combination ART has greatly reduced the incidence of severe neurocognitive impairment in children. In addition, combination ART is effective in treating children with HIV encephalopathy and improves cognitive functioning, particularly when started early in the course of their disease or at a young age [52,53,59-61]. In a large prospective cohort study in the United States, there was a 50 percent reduction in the incidence of HIV encephalopathy after introduction of combination ART regimens [62]. However, HIV-related neurocognitive deficits can occur even in children on suppressive combination ART [63-67].

The age and timing of ART initiation are important determinants in the development of HIV encephalopathy. The greatest risk for developing HIV encephalopathy is in the first 12 months of life in the absence of ART; more than one-half of children who develop HIV encephalopathy are symptomatic by one year of age [57]. Compared with older children, young children with HIV have more severe delay in mental and motor development [52].

In a randomized controlled trial evaluating the effects of early (before three months of age) or deferred (until clinical or immunologic progression) ART in 90 infants with HIV in South Africa, the early treatment group had lower mortality and had better neurodevelopmental functioning at median age of 11 months compared with infants with HIV whose treatment was deferred [68]. The fact that differences in infant neurodevelopmental functioning can be detected as early as one year of age based on ART treatment suggests that HIV damages the CNS very early in the course of infection and may explain in part why results of studies of children with HIV initiating ART later in childhood less definitively demonstrate improvement in neurocognitive function after ART [67].

Adult patients who attain cerebrospinal fluid (CSF) virologic suppression with ART therapy have greater improvement in neurocognitive functioning than those who do not [69]. Antiretroviral medications variably cross the blood-brain barrier, and, in some adult patients, there may be discordance between CSF and plasma HIV replication and potential for the development of CSF HIV resistance [70,71]. ART regimens including drugs with greater CNS penetration reduce virus load in CSF better compared with regimens with poorer CNS penetration but have not been definitively shown to improve cognitive performance [62,69,72,73]. Given these results, routine evaluation of CSF for viral suppression is not recommended.

●Prognosis – HIV encephalopathy is associated with increased mortality. Among infants enrolled in the Women and Infants Transmission Study, mortality of children diagnosed with HIV encephalopathy far exceeded that of the entire cohort (41 versus 12.5 percent) [57]. The median survival time after diagnosis of HIV encephalopathy was 22 months, similar to survival after diagnosis of PCP [56]. However, it is important to note that this study was carried out before the widespread use of combination ART, which, as described above, has dramatically reduced the incidence of HIV encephalopathy in the United States.

Cytomegalovirus disease — CMV is ubiquitous and pediatric infection occurs in utero, during birth, and through breastfeeding and, at any age, by direct person-to-person contact with virus-containing secretions. In immunocompetent children, most infections are asymptomatic and symptomatic infections are generally limited to an infectious mononucleosis-like syndrome with prolonged fever and mild hepatitis. However, in patients with severe immunosuppression due to HIV or other causes, CMV can present with fever, pneumonia, colitis, encephalitis, or retinitis. CMV infection in older children with perinatally acquired HIV infection appears to be associated with growth stunting and chronic lung disease [74]. (See "Overview of cytomegalovirus (CMV) infections in children", section on 'CMV infections in immunocompromised hosts'.)

In addition, all infants less than 21 days of age (with or without confirmed HIV infection) born to mothers with HIV should be considered for screening for congenital CMV. This is discussed in detail elsewhere. (See "Pediatric HIV infection: Management of infants born to mothers with HIV in resource-abundant settings", section on 'Congenital CMV testing' and "Congenital cytomegalovirus (cCMV) infection: Clinical features and diagnosis", section on 'Clinical suspicion'.)

CMV retinitis (picture 1) is rare in the combination ART era and occurs principally among children with HIV and severe immunosuppression. CMV retinitis can lead to blindness if untreated, and, therefore, caregivers should be advised to report to the clinic if they notice changes in the child's vision, including blurry vision or "floaters." However, many children are completely asymptomatic and regular funduscopic examinations are necessary to detect changes. Routine fundoscopic examinations are typically performed every six months on children with HIV <5 years of age who are infected with CMV and are severely immunosuppressed. Patients with funduscopic changes should be referred to an ophthalmologist. Management of CMV in children with HIV is discussed in the HIV.gov clinical guidelines. (See "Pathogenesis, clinical manifestations, and diagnosis of AIDS-related cytomegalovirus retinitis", section on 'Clinical manifestations' and "Treatment of AIDS-related cytomegalovirus retinitis".)

Other — A wide variety of other clinical manifestations of pediatric HIV infection have been described. Many of these are used to help with the staging of HIV infection in children [75].

●Other AIDS-defining conditions – Other AIDS-defining conditions include (table 1):

•Pulmonary candidiasis

•Cryptosporidiosis

•Chronic herpes simplex virus

•Kaposi sarcoma

•Mycobacterium avium complex infection

LONG-TERM COMPLICATIONS IN UNTREATED HIV — 

Children with untreated HIV are susceptible to a variety of other non-AIDS-associated complications.

●Lymphoid interstitial pneumonia (LIP) – LIP is a form of interstitial lung disease that may be seen in patients with HIV (image 4). It is characterized histopathologically by infiltration of the interstitium and alveolar spaces of the lung by lymphocytes, plasma cells, and other lymphoreticular elements. Typical clinical features include tachypnea, diffuse crackles on lung auscultation, hypoxia with episodic respiratory exacerbations, generalized lymphadenopathy, parotitis, and clubbing. LIP is far more common in children than in adults; however, in the era of combination ART, the incidence of LIP has declined in both populations. (See "Lymphoid interstitial pneumonia".)

●Hematologic abnormalities – Anemia, thrombocytopenia, and leukopenia are frequently observed in children with untreated HIV [76].

●Dermatologic manifestations – Common dermatologic manifestations include fungal, bacterial, and viral infections of the skin; severe seborrheic dermatitis; vasculitis; and drug eruptions. Oral findings include infections such as oral candidiasis, aphthous ulcers, and parotid gland swelling.

●Renal disease – Renal disease, with proteinuria, nephrotic syndrome, and renal insufficiency, has been reported [49,50]. Children with HIV disease may present with urinary tract infections, acute renal failure, HIV-associated hemolytic uremic syndrome, nephropathy, tubulopathy, and chronic kidney disease. In the era of ART, there has been a major improvement in HIV-associated nephropathy and decrease in progression to end stage renal disease [77]. (See 'Long-term morbidities' below.)

●Cardiac manifestations – Cardiomyopathy, pericardial effusion, myocarditis, and arrhythmia have been described in children with HIV, particularly those who are not receiving ART [78,79]. In one study, infants with HIV had higher heart rates and lower left ventricular fractional shortening compared with infants without HIV [78]. In another study of 68 children with AIDS, 28 percent of patients had serious cardiac events following progression to AIDS [79].

OUTCOMES — 

Outcomes of pediatric HIV infection depend upon whether effective treatment is provided.

High mortality in untreated HIV infection — Without treatment, HIV infection causes progressive immunosuppression due to HIV virus-mediated depletion of CD4+ lymphocytes, leaving patients at risk of developing opportunistic infections (OIs) and other HIV-related disorders. Risk factors for death include CD4 percent <15 percent, having an AIDS-defining condition (table 1), younger age, and delayed antiretroviral therapy (ART) initiation [80]. Most deaths in children with untreated HIV infection were due to HIV-related conditions [69].

Opportunistic infections and deaths are less common among children in the United States in the ART era, but the mortality rate remains elevated, with a standardized mortality rate 31.5 times that of the general United States pediatric population [81]. Those who died were older, not virologically suppressed, and died of HIV-related medical conditions in 86 percent of cases [81].  

Infants and young children with HIV have a particularly high risk for disease progression with up to 50 percent of children born with HIV dying before two years of age without treatment [82,83]. After five years of age, the risk of disease progression and mortality in the absence of treatment is similar to those observed among young adults [84].

The timing and route of HIV infection in children seems to be an important determinant of disease progression. Children infected in utero or within the first one to two months of life have a higher mortality rate at 12 months than those infected at older age through breastfeeding [83,85]. Among a small South African cohort of infants with HIV infection born to mothers with HIV, 35, 70, and 80 percent of infants progressed to severe immunosuppression within 3, 6, and 12 months of life, respectively. Rapid progression was inversely related to maternal CD4 count and more common in infants with intrauterine infection [86]. Other factors, including early onset of HIV-related conditions, failure to thrive, and generalized lymphadenopathy, were all poor prognostic features, whereas lymphoid interstitial pneumonia (LIP) was associated with milder illness [82].

While mortality has decreased significantly around the world, delays in diagnosis and/or starting ART in resource-limited settings are likely a major reason for higher mortality rates seen in some areas.

Improved outcomes with ART — Early diagnosis and treatment of infants, children, and adolescents with HIV dramatically decreases morbidity and mortality [87,88]. Additional benefits of combination ART in children and adolescents with HIV include improved growth and immune function [68,89-91], and marked decrease in the incidence of OIs [33,42,88,92-96]. This benefit of ART led the World Health Organization (WHO) [97,98] and the United States ART guidelines [98] to recommend timely initiation of combination ART for all children with HIV infection regardless of age, CD4 count, or HIV viral load.

Prompt ART reduces mortality — Initiating ART as soon as possible after acquisition of infection results in the best outcomes. The Children with HIV Early Antiretroviral Therapy (CHER) study demonstrated that in perinatally infected infants with normal immune function, initiating ART early (before 12 weeks of age) compared with delaying ART until the child met clinical or immune criteria reduced mortality by 75 percent [99]. Based in part on results from the CHER study, the WHO revised its treatment recommendations to include virologic testing of all infants born to mothers with HIV at four to six weeks of age and treatment of all children with HIV less than 12 months of age, regardless of immunologic or clinical stage [100]. Other risk factors for mortality in the first year of ART treatment include young age, low CD4 percent, advanced clinical disease, anemia, and low weight for age [101-106].

The benefit of ART on morbidity and mortality has been shown in both resource-abundant and resource-limited settings. In the United States between 1994 and 2000, the mortality rate decreased from 7.2 to 0.8 deaths per 100 person-years; mortality rate was inversely associated with ART treatment [80]. In another study that evaluated data from 364 children with HIV born from 1986 to 1998 and monitored until 2004, the overall incidence rate of OI decreased from 14.4 cases per 100 person-years before 1997 (ie, prior to use of combination ART) to 1.1 cases per 100 person-years after 1997 [92]. In resource-limited settings, several studies using pooled data from different cohorts from 15 countries in Asia, Africa, and the Caribbean have found similar improvements in the outcomes of children with HIV treated with combination ART [91,101-103,107].

Higher mortality in resource-limited settings — Despite similar effect of ART on improved outcomes in both resource-abundant and resource-limited settings, absolute mortality rates, particularly among children <5 years, remain higher in resource-limited settings compared with resource-abundant settings. For example, in a study of children with HIV who are receiving ART conducted from 2020 to 2022 in resource-limited settings, mortality rates were 4.9 and 2.5 percent for children aged <1 year and 1 to 4 years, respectively compared to rates of 0.5 percent for children 5 to 14 years [108]. This is partly due to higher early childhood mortality in children under the age of 5 years in these settings, even in children without HIV, as well as delays in infant diagnosis and prompt initiation of ART [103,108].

In pooled analyses, the median age of children treated with ART ranged from 3.5 to 4.9 years [101-103]. Approximately 30 percent of children treated with ART are <18 months of age, and only 12 to 24 percent of patients are <12 months [101-103]. In a study using data from a large international cohort of children with HIV, approximately two-thirds of children in resource-limited settings already had severe immunodeficiency at the time of ART initiation [109]. The small proportion of young children receiving ART and the failure to start ART prior to the onset of severe immunodeficiency highlights the continued need to scale up programs in resource-limited settings to improve the early identification of infants exposed to and infected with HIV and to assure appropriate follow-up and timely initiation of treatment.

Long-term morbidities — In children and young adults treated for HIV infection in childhood, overall prognosis is quite good if diagnosed and treated early. Most ART regimens are well tolerated and most children are able to sustain viral suppression, preserve physical health, and live a healthy and normal life. Their developmental trajectory is similar to the general pediatric population.

The majority of clinical care (outside of ART) is similar to the general pediatric population. The most common roadblocks for these children tend to be medication adherence and the questions and stigma that arise surrounding HIV status disclosure. Special attention should be paid to ensuring adherence to ART and reviewing drug-drug interactions whenever a starting a new medication.

Common long-term morbidities include [110-120]:

●Mental health concerns, including anxiety, mood, and substance use disorders (25 to 60 percent) (see "Pediatric unipolar depression: Epidemiology, clinical features, assessment, and diagnosis" and "Anxiety disorders in children and adolescents: Epidemiology, pathogenesis, clinical manifestations, and course")

●Dyslipidemia (25 to 50 percent) [121] (see "Dyslipidemia in children and adolescents: Definition, screening, and diagnosis")

●Cardiovascular complications, including cardiomyopathy and accelerated atherosclerosis (10 to 20 percent) (see "Definition and classification of the cardiomyopathies" and "Overview of the management of the child or adolescent at risk for premature atherosclerotic cardiovascular disease (ASCVD)")

●Insulin resistance and diabetes mellitus (approximately 15 percent) (see "Epidemiology, presentation, and diagnosis of type 2 diabetes mellitus in children and adolescents")

●Decreased bone mineral density (2 to 7 percent) (see "Vitamin D insufficiency and deficiency in children and adolescents" and "Drugs that affect bone metabolism", section on 'Antiretroviral therapy')

●Renal disease (2 to 7 percent) (see "Chronic kidney disease in children: Epidemiology, etiology, and course" and "Chronic kidney disease in children: Clinical manifestations, evaluation, and diagnosis")

Management of children with HIV is out of the scope of UpToDate topics. Information on the treatment of pediatric HIV infection are available through the HIV.gov Clinical Info website.

SOCIETY GUIDELINE LINKS — 

Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: HIV infection in adolescents" and "Society guideline links: HIV infection in infants and children".)

SUMMARY

●Case definitions – The Centers for Disease Control and Prevention (CDC) and World Health Organization (WHO) have developed differing classification systems for pediatric HIV/AIDS to standardize the description of HIV infection cases for public health surveillance and research purposes (table 2 and table 3 and table 4 and table 5). (See 'Case definitions' above.)

●Epidemiology

•More than 90 percent of children with HIV worldwide have acquired the virus via vertical transmission (either in utero, during labor and delivery, or via breastfeeding). Vertical HIV transmission can be prevented by treating pregnant women with antiretroviral therapy (ART) and providing ART prophylaxis to their infants. (See 'Global HIV/AIDS statistics' above.)

•In the United States and other resource-abundant countries, the incidence of HIV through vertical transmission has decreased to less than 1 percent due to successful programs that provide HIV counseling and testing services for pregnant women, antiretroviral (ARV) therapy, and educational resources. (See 'Resource-rich settings' above.)  

•Although the number of new cases of HIV and HIV deaths among children has decreased in resource-limited settings with wider availability of HIV testing and antiretroviral therapy, cases still continue to occur, particularly in sub-Saharan Africa, where access to care and treatment services for HIV and programs to prevent vertical HIV transmission are limited. (See 'Resource-limited settings' above.)

●Clinical manifestations – The clinical manifestations of pediatric HIV infection are varied and often nonspecific (eg, lymphadenopathy, oral candidiasis, failure to thrive). Opportunistic infections are much less seen now that more children are starting ART earlier in their infection. However, in children who are not on ART, opportunistic infections are common and can often be the first presenting sign of HIV infection. The most common AIDS-defining conditions in children in the United States include Pneumocystis jirovecii pneumonia (PJP), recurrent bacterial infections, wasting syndrome, candida esophagitis, HIV encephalopathy, and cytomegalovirus (CMV) (table 1). (See 'Clinical manifestations' above and 'Selected AIDS-defining conditions' above.)

●Outcomes – Outcomes of HIV infection depend upon whether effective treatment is provided. ART has radically reduced mortality and morbidity, particularly the incidence of opportunistic infections (OIs). (See 'Outcomes' above.)

•Untreated HIV infection – Without treatment, HIV infection causes progressive immunosuppression, leaving patients at risk of developing OI and other HIV-related disorders. Approximately one-half of children with vertically acquired HIV infection die by the age of two years. Continued emphasis on prevention of new pediatric infections through expansion of programs that prevent vertical transmission of HIV and provide treatment services for children with HIV is critical. (See 'High mortality in untreated HIV infection' above.)

•Improved outcomes with ART – ART is associated with improvement in virologic, immunologic, and clinical health for children with HIV. The use of ART in children has reduced the morbidity and mortality associated with HIV infection in resource-abundant settings. However, limited access to adequate health care has hampered progress in controlling HIV in resource-limited settings. (See 'Improved outcomes with ART' above.)

•Long-term morbidities – Children who are diagnosed and treated early for HIV can lead normal and healthy lives. The most common issues that arise surround medication adherence and disclosure of HIV status. When long-term morbidities do occur, the most common ones include mental health concerns, dyslipidemia, insulin resistance and diabetes mellitus, cardiovascular complications, decreased bone mineral density, and renal disease. (See 'Long-term morbidities' above.)

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  112. Shahinian V, Rajaraman S, Borucki M, et al. Prevalence of HIV-associated nephropathy in autopsies of HIV-infected patients. Am J Kidney Dis 2000; 35:884.
  113. Papi L, Menezes AC, Rocha H, et al. Prevalence of lipodystrophy and risk factors for dyslipidemia in HIV-infected children in Brazil. Braz J Infect Dis 2014; 18:394.
  114. Miller TI, Borkowsky W, DiMeglio LA, et al. Metabolic abnormalities and viral replication are associated with biomarkers of vascular dysfunction in HIV-infected children. HIV Med 2012; 13:264.
  115. Lipshultz SE, Williams PL, Wilkinson JD, et al. Cardiac status of children infected with human immunodeficiency virus who are receiving long-term combination antiretroviral therapy: results from the Adolescent Master Protocol of the Multicenter Pediatric HIV/AIDS Cohort Study. JAMA Pediatr 2013; 167:520.
  116. Lipshultz SE, Miller TL, Wilkinson JD, et al. Cardiac effects in perinatally HIV-infected and HIV-exposed but uninfected children and adolescents: a view from the United States of America. J Int AIDS Soc 2013; 16:18597.
  117. DiMeglio LA, Wang J, Siberry GK, et al. Bone mineral density in children and adolescents with perinatal HIV infection. AIDS 2013; 27:211.
  118. Chernoff M, Nachman S, Williams P, et al. Mental health treatment patterns in perinatally HIV-infected youth and controls. Pediatrics 2009; 124:627.
  119. Gadow KD, Angelidou K, Chernoff M, et al. Longitudinal study of emerging mental health concerns in youth perinatally infected with HIV and peer comparisons. J Dev Behav Pediatr 2012; 33:456.
  120. Mellins CA, Elkington KS, Leu CS, et al. Prevalence and change in psychiatric disorders among perinatally HIV-infected and HIV-exposed youth. AIDS Care 2012; 24:953.
  121. The RESPOND Study Group. Incidence of dyslipidemia in people with HIV who are treated with integrase inhibitors versus other antiretroviral agents. AIDS 2021; 35:869.
Topic 5963 Version 41.0

References

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61 : Comparison of developmental milestone attainment in early treated HIV-infected infants versus HIV-unexposed infants: a prospective cohort study.

62 : Impact of HAART and CNS-penetrating antiretroviral regimens on HIV encephalopathy among perinatally infected children and adolescents.

63 : High rates of asymptomatic neurocognitive impairment in vertically acquired HIV-1-infected adolescents surviving to adulthood.

64 : Neurologic disease in HIV-infected children and the impact of combination antiretroviral therapy.

65 : Poor cognitive functioning of school-aged children in thailand with perinatally acquired HIV infection taking antiretroviral therapy.

66 : Early versus deferred antiretroviral therapy for children older than 1 year infected with HIV (PREDICT): a multicentre, randomised, open-label trial.

67 : Cognitive function and neurodevelopmental outcomes in HIV-infected Children older than 1 year of age randomized to early versus deferred antiretroviral therapy: the PREDICT neurodevelopmental study.

68 : Early antiretroviral therapy improves neurodevelopmental outcomes in infants.

69 : Enhancing antiretroviral therapy for human immunodeficiency virus cognitive disorders.

70 : Delayed central nervous system virus suppression during highly active antiretroviral therapy is associated with HIV encephalopathy, but not with viral drug resistance or poor central nervous system drug penetration.

71 : Discordance between cerebral spinal fluid and plasma HIV replication in patients with neurological symptoms who are receiving suppressive antiretroviral therapy.

72 : Impact of combination antiretroviral therapy on cerebrospinal fluid HIV RNA and neurocognitive performance.

73 : Changes in cognition during antiretroviral therapy: comparison of 2 different ranking systems to measure antiretroviral drug efficacy on HIV-associated neurocognitive disorders.

74 : Unexpectedly High Prevalence of Cytomegalovirus DNAemia in Older Children and Adolescents With Perinatally Acquired Human Immunodeficiency Virus Infection.

75 : Unexpectedly High Prevalence of Cytomegalovirus DNAemia in Older Children and Adolescents With Perinatally Acquired Human Immunodeficiency Virus Infection.

76 : The influence of human immunodeficiency virus-1 on hematopoiesis.

77 : Kidney disease in HIV-positive children.

78 : Cardiovascular status of infants and children of women infected with HIV-1 (P(2)C(2) HIV): a cohort study.

79 : Predictors of cardiac morbidity and related mortality in children with acquired immunodeficiency syndrome.

80 : Declines in mortality rates and changes in causes of death in HIV-1-infected children during the HAART era.

81 : Changing Trends in Complications and Mortality Rates Among US Youth and Young Adults With HIV Infection in the Era of Combination Antiretroviral Therapy.

82 : Natural history of human immunodeficiency virus type 1 infection in children: a five-year prospective study in Rwanda. Mother-to-Child HIV-1 Transmission Study Group.

83 : Mortality of infected and uninfected infants born to HIV-infected mothers in Africa: a pooled analysis.

84 : Current CD4 cell count and the short-term risk of AIDS and death before the availability of effective antiretroviral therapy in HIV-infected children and adults.

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88 : Effect of combination therapy including protease inhibitors on mortality among children and adolescents infected with HIV-1.

89 : Five-year follow-up of children with perinatal HIV-1 infection receiving early highly active antiretroviral therapy.

90 : Opportunistic infections and organ-specific diseases in HIV-1-infected children: a cohort study (1990-2006).

91 : Neurodevelopment in children born to HIV-infected mothers by infection and treatment status.

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93 : Impact of highly active antiretroviral therapy (HAART) on the incidence of opportunistic infections, hospitalizations and mortality among children and adolescents living with HIV/AIDS in Belo Horizonte, Minas Gerais State, Brazil.

94 : Trends in hospitalizations of HIV-infected children and adolescents in the United States: analysis of data from the 1994-2003 Nationwide Inpatient Sample.

95 : Antiretroviral therapy outcomes in resource-limited settings for HIV-infected children<5 years of age.

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97 : Post-HAART outcomes in pediatric populations: comparison of resource-limited and developed countries.

98 : Post-HAART outcomes in pediatric populations: comparison of resource-limited and developed countries.

99 : Early antiretroviral therapy and mortality among HIV-infected infants.

100 : Early antiretroviral therapy and mortality among HIV-infected infants.

101 : Early mortality and loss to follow-up in HIV-infected children starting antiretroviral therapy in Southern Africa.

102 : Low risk of death, but substantial program attrition, in pediatric HIV treatment cohorts in Sub-Saharan Africa.

103 : Outcomes of the South African National Antiretroviral Treatment Programme for children: the IeDEA Southern Africa collaboration.

104 : Clinical outcomes and CD4 cell response in children receiving antiretroviral therapy at primary health care facilities in Zambia.

105 : Mortality in the year following antiretroviral therapy initiation in HIV-infected adults and children in Uganda and Zimbabwe.

106 : Prognosis of children with HIV-1 infection starting antiretroviral therapy in Southern Africa: a collaborative analysis of treatment programs.

107 : Effectiveness of pediatric antiretroviral therapy in resource-limited settings: a systematic review and meta-analysis.

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109 : Immunodeficiency in children starting antiretroviral therapy in low-, middle-, and high-income countries.

110 : The new face of the pediatric HIV epidemic in Western countries: demographic characteristics, morbidity and mortality of the pediatric HIV-infected population.

111 : Metabolic and renal adverse effects of antiretroviral therapy in HIV-infected children and adolescents.

112 : Prevalence of HIV-associated nephropathy in autopsies of HIV-infected patients.

113 : Prevalence of lipodystrophy and risk factors for dyslipidemia in HIV-infected children in Brazil.

114 : Metabolic abnormalities and viral replication are associated with biomarkers of vascular dysfunction in HIV-infected children.

115 : Cardiac status of children infected with human immunodeficiency virus who are receiving long-term combination antiretroviral therapy: results from the Adolescent Master Protocol of the Multicenter Pediatric HIV/AIDS Cohort Study.

116 : Cardiac effects in perinatally HIV-infected and HIV-exposed but uninfected children and adolescents: a view from the United States of America.

117 : Bone mineral density in children and adolescents with perinatal HIV infection.

118 : Mental health treatment patterns in perinatally HIV-infected youth and controls.

119 : Longitudinal study of emerging mental health concerns in youth perinatally infected with HIV and peer comparisons.

120 : Prevalence and change in psychiatric disorders among perinatally HIV-infected and HIV-exposed youth.

121 : Incidence of dyslipidemia in people with HIV who are treated with integrase inhibitors versus other antiretroviral agents.