INTRODUCTION — Considerable progress has been made towards eliminating 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 .
The 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. The epidemiology of pediatric HIV, prophylactic treatment of infants born to HIV-infected mothers, diagnostic testing for HIV in young children, approach to febrile HIV-infected infants and children, and issues related to HIV infection in adolescents are discussed separately:
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 acquired immune deficiency syndrome (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 the developing world (WHO) and are described briefly below.
Centers for Disease Control and Prevention classification system — In 2014, the CDC revised the surveillance case definition for HIV infection to incorporate diagnostic testing algorithms that do not rely on Western blot or immunofluorescence HIV antibodies (table 2) . The 2014 surveillance case definition applies to persons of all ages; the previous version had separate case definitions for adults and adolescents ≥13 years and children younger than 13 years . 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 based upon the absolute CD4 count (table 3), unless the individual has had a stage 3 (ie, AIDS-defining) opportunistic illness (table 1). 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 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  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 living with HIV, regardless of WHO clinical stage and/or CD4 count . HIV-infected children 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
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, failure to thrive, and developmental delay are other common presenting features of HIV infection. The most common acquired immune deficiency syndrome (AIDS)-defining conditions observed among American children with vertically acquired HIV infection include:
●Pneumocystis jirovecii pneumonia (PCP)
●Recurrent bacterial infections
●Cytomegalovirus (CMV) pneumonia, colitis, encephalitis, or retinitis
Effect of combination antiretroviral therapy — The use of highly effective combination antiretroviral therapy (ART) has led to a decline in the incidence of OI in children with vertically acquired HIV infection [6-9]. In a study that evaluated data from 364 HIV-infected children 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 . The incidence rates of specific infections before and after combination ART were as follows:
●PCP (5.8 versus 0.3 cases per 100 person-years)
●Recurrent bacterial infection (4.7 versus 0.2 cases per 100 person-years)
●Extraocular CMV (1.4 versus 0.1 cases per 100 person-years)
●Disseminated nontuberculous mycobacterium (1.3 versus 0.2 cases per 100 person-years)
●Esophageal candidiasis (0.9 versus 0.4 cases per 100 person-years)
●Herpes simplex virus (0.2 versus 0 cases per 100 person-years)
Selected AIDS-defining conditions
Pneumocystis jirovecii pneumonia — PCP accounts for approximately one-half of all AIDS-defining conditions diagnosed during the first year of life. The median age at diagnosis of PCP in children in one series was five months . In adults and older children, PCP develops in individuals with CD4 counts <200 cells/microL or CD4 percent <15 as well as in patients with poor virologic control. In infants, however, PCP can develop with CD4 counts >200 cells/microL.
PCP 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 HIV-infected children with PCP, four clinical variables are independently associated with PCP: age <6 months, respiratory rate ≥60 breaths per minute, arterial hemoglobin saturation ≤92 percent, and absence of vomiting . 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 may reveal extensive ground-glass opacities, with a patchy distribution affecting the central lung, sparing the lung periphery . (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. Specific stains and fluorescently conjugated monoclonal antibody allow visualization of the cyst capsule of the organism. Pulmonary fluid or tissue may be obtained from bronchoalveolar lavage, induced sputum, intubation with deep endotracheal aspiration, or lung biopsy in settings where these procedures are available. In resource-limited settings, appropriate specimens have been obtained through sputum induction or nasogastric aspirates . Polymerase chain reaction has been used to diagnose PCP in children and has been found to be more sensitive but less specific compared with microscopic methods [14,15]. Polymerase chain reaction has the advantage that testing can be performed on oral washes and nasopharyngeal aspirates; however, these tests are not standardized and are not available in many centers . (See "Epidemiology, clinical presentation, and diagnosis of Pneumocystis pulmonary infection in patients with HIV", section on 'Evaluation and diagnosis'.)
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 PCP 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 PCP-related deaths.
Chemoprophylaxis and treatment of PCP in individuals with HIV infection are discussed in a separate topic review. (See "Treatment and prevention of Pneumocystis infection in patients with HIV".)
Recurrent bacterial infections — Bacterial infections occur commonly in children with HIV infection. Before the era of combination ART, pneumonia and bacteremia were the two bacterial infections observed most commonly . Streptococcus pneumoniae, Salmonella species, Staphylococcus aureus, and Haemophilus influenzae type b are the bacteria isolated most frequently. Pseudomonas is associated with late-stage disease and severe immunosuppression . Risk factors for bacterial infection in HIV-infected children have not been defined precisely, but young children with vertically acquired HIV appear to be at particular risk [18,19].
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 per se, OI, 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 .
Esophageal candidiasis — Clinical features and risk factors for the development of esophageal candidiasis have not been widely addressed in HIV-infected children. In a retrospective study of 448 HIV-infected children 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 .
Risk factors for esophageal candidiasis included :
●Prior oral candidiasis (present in nearly all affected children)
●Low CD4 count (which was an independent predictor)
●Receipt of antibiotics
Clinical manifestations included :
●Oral thrush (94 percent)
●Odynophagia (80 percent)
●Retrosternal pain (57 percent)
●Fever (29 percent)
●Nausea and/or vomiting (24 percent)
●Drooling or dehydration (12 percent each)
●Hoarseness (6 percent)
●Gastrointestinal bleeding (6 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 computed tomography or magnetic resonance imaging
•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 2)). The encephalopathy may be static or progressive. Static HIV encephalopathy is more common and involves global cognitive and motor deficits with a normal rate of learning . 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 generally is 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 HIV-infected children [23-25].
●Risk factors – HIV encephalopathy is associated with the severity of clinical disease and is a common AIDS-defining condition in both high-income and low/middle-income countries, particularly in the era before widespread use of combination ART or in settings where access to ART is limited [26-29].
Risk factors for the development of HIV encephalopathy include [30-32]:
•Lack of access to 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 [26,27,33-35]. 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 . However, HIV-related neurocognitive deficits can occur even in children on suppressive combination ART [37-41].
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; more than one-half of children who develop HIV encephalopathy are symptomatic by one year of age . Compared with older children, young HIV-infected children have more severe delay in mental and motor development .
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 HIV-infected infants, the early treatment group had better neurodevelopmental functioning at median age of 11 months compared with HIV-infected infants whose treatment was deferred . 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 HIV-infected children initiating combination ART later in childhood less definitively demonstrate improvement in neurocognitive function after effective ART treatment .
Patients who attain cerebrospinal fluid (CSF) virologic suppression with combination ART therapy have greater improvement in neurocognitive functioning than those who do not . Antiretroviral medications variably cross the blood-brain barrier, and, in some patients, there may be discordance between CSF and plasma HIV replication and potential for the development of CSF HIV resistance [44,45]. 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 [36,43,46,47].
●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) . The median survival time after diagnosis of HIV encephalopathy was 22 months, similar to survival after diagnosis of PCP . 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 is transmitted from mother to child (during pregnancy, perinatally, and via breastfeeding) and by direct person-to-person contact with virus-containing secretions. In immunocompetent children, most infections are asymptomatic. An infectious mononucleosis-like syndrome with prolonged fever and mild hepatitis can occur. In patients with HIV/AIDS, CMV can present with fever, pneumonia, colitis, encephalitis, or retinitis. Early CMV infection may accelerate HIV disease progression in infants . CMV infection in older children with perinatally acquired HIV infection appears to be associated with growth stunting and chronic lung disease . (See "Overview of cytomegalovirus infections in children", section on 'Immunocompromised hosts'.)
CMV retinitis (picture 1) is rare in the combination ART era and occurs principally among HIV-infected children with severe immunosuppression. CMV retinitis can lead to blindness if untreated, and, therefore, patients should be advised to report to the clinic if they notice changes in their vision, including blurry vision or "floaters." However, many patients are completely asymptomatic and regular funduscopic examinations are necessary to detect changes. Patients with funduscopic changes should be referred to an ophthalmologist, as indicated. (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.
●Other AIDS-defining conditions – Other AIDS-defining conditions include (table 1):
•Chronic herpes simplex virus
•Mycobacterium avium complex infection
●Lymphoid interstitial pneumonia (LIP) – LIP is a form of interstitial lung disease that may be seen in HIV-infected patients (image 3). It is characterized histopathologically by infiltration of the interstitium and alveolar spaces of the lung by lymphocytes, plasma cells, and other lymphoreticular elements. 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 HIV-infected children .
●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 [23,24].
●Cardiac manifestations – Cardiomyopathy, pericardial effusion, myocarditis, and arrhythmia have been described in HIV-infected children, particularly those who are not receiving ART [51,52]. In one study, HIV-infected infants had higher heart rates and lower left ventricular fractional shortening compared with HIV-uninfected infants . In another study of 68 children with AIDS, 28 percent of patients had serious cardiac events following progression to AIDS .
OUTCOME — Outcomes of pediatric HIV infection depend upon whether effective treatment is provided.
Untreated HIV infection — Without treatment, HIV infection causes progressive immunosuppression5 due to HIV virus-mediated depletion of CD4+ lymphocytes, leaving patients at risk of developing opportunistic infections (OIs) and other HIV-related disorders. Most untreated HIV-infected children show progression of HIV infection to acquired immune deficiency syndrome (AIDS) and die before age five years [53,54].
Among children, especially those who acquired the infection vertically, there is considerable variability in the presenting manifestations of HIV infection, progression of disease, immunosuppression, and mortality. Untreated infection typically follows one of two patterns of progression:
●Slow progression – In most patients, HIV infection progresses slowly, with clinical and immunologic deterioration by 5 to 10 years of life. In these children, the first year of life is characterized by the development of mild and nonspecific signs and symptoms (eg, lymphadenopathy, hepatosplenomegaly, parotitis), followed by clinical and immunologic deterioration. In North American and European cohorts, approximately 75 percent of untreated patients have severe immunosuppression by 10 years of age [55,56]. In resource-limited settings, the rate of progression is faster, with mortality rates of 50 to 62 percent by age five years [53,54].
●Rapid progression – A minority of patients have rapid disease progression, in which there is severe immunologic progression and/or advanced clinical stages (ie, OIs, encephalopathy) within the first year of life. This pattern occurs in 15 to 20 percent of untreated children in North American and European cohorts [55,56]. In resource-limited settings, there is a faster rate of disease progression, with mortality of 26 to 45 percent by age one year and 45 to 53 percent by age two years [53,54]. However, many of these studies were conducted before the widespread availability of cotrimoxazole prophylaxis.
Disease progression and immunosuppression are associated with increased susceptibility to OIs, the most common cause of morbidity and mortality for HIV-infected individuals. In children, the most common OIs are serious bacterial infections, such as pneumonia and bacteremia, followed by herpes zoster, disseminated M. avium complex infections, and invasive candidal infections of the esophagus or tracheobronchial tree .
Timing of HIV transmission from mother to child seems to be an important determinant of disease progression. Children infected within the first one to two months of life have a higher mortality rate at 12 months than those infected later [54,57]. Among a small South African cohort of infected infants born to mothers who received antiretroviral medications to prevent mother-to-child transmission of 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 . 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 .
HIV infection treated with antiretroviral therapy — Two developments have had the greatest impact on the outcome of pediatric HIV infection:
●Availability and use of highly effective, combination antiretroviral therapy (ART), and
●Early initiation of ART in HIV-infected infants 
Treatment of HIV with effective, combination ART has changed the natural history of the infection by preventing or reversing the progressive immunodeficiency that characterizes the infection. Combination ART is associated with improvement in virologic, immunologic, and clinical health for HIV-infected adults and children [60-62]. (See "When to initiate antiretroviral therapy in persons with HIV", section on 'Universal treatment'.)
Among HIV-infected children and adolescents, increasing use of effective combination ART regimens has resulted in a steep decline in mortality [63,64]. Additional benefits of combination ART in children and adolescents with HIV include improved growth, improvement in immune function, and marked decrease in the incidence of OIs [64-67].
Developed settings — In the United States and other developed countries, the mortality rate among HIV-infected children in the era of highly effective combination ART is approximately 0.5 to 0.9 per 100 children per year [68-74].
In a study from the Pediatric AIDS Clinical Trials Group (PACTG), which included HIV-infected children enrolled between April 1993 and December 2006 and followed for a median of 5.3 years, the following observations characterize trends in HIV mortality in a developed setting :
●Among 3553 enrolled children, there were 298 deaths (1.47 deaths per 100 person-years).
●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 combination ART treatment.
●The six-year survival probability increased for each successive birth cohort (from 81 percent for those born before 1985 to 99 percent for those born during 2000 to 2006).
●Combination ART was associated with prolongation of life; among children who died, the mean age at death increased from 8.9 years in 1994 to 18.2 years in 2006.
●Risk factors for death included CD4 percent <15, having an AIDS-defining condition (table 1) at study entry, younger age at entry, and belonging to an early birth cohort.
●Ninety-seven percent of deaths were directly attributable to HIV infection. Between 1994 to 1996 and 2001 to 2006, the proportion of deaths caused by OI declined from 36 to 24 percent; the proportion of deaths due to P. jirovecii pneumonia (PCP) and cytomegalovirus (CMV) remained unchanged; and the proportion of deaths due to end-stage AIDS, sepsis, and renal failure increased.
In a subsequent study from the International Maternal Pediatric Adolescent AIDS Clinical Trials (IMPAACT) network including patients enrolled between 2009 to 2013 and followed for a median of 3.7 years, the mortality rate declined even further to approximately 0.6 per 100 patients per year . Combination ART was used in 85 percent of patients (compared with 75 percent of patients in the PACTG study between 2004 and 2007). Most deaths (86 percent) were directly linked to infection or other HIV-associated medical conditions. The most common primary causes of death included pneumonia, advanced AIDS, progressive multifocal leukoencephalopathy, and sepsis.
Resource-limited settings — In resource-limited settings, several studies using pooled data from different cohorts have found similar improvements in the outcomes of HIV-infected children treated with combination ART [62,75-78]. However, delays in starting ART in resource-limited settings are likely a major reason for high mortality rates seen in some studies.
In the available studies, mortality rates at one, two, and three years were 4.5, 6.9, and 7.7 percent, respectively [75-77]. These rates are similar to those observed among children in developed settings. The effectiveness of ART in resource-limited settings has also been demonstrated in an analysis of data pooled from cohorts from 15 countries in Asia, Africa, and the Caribbean .
Despite these encouraging results and increasing access to ART, mortality remains high for HIV-infected children in low- and middle-income countries. 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 [75-77,79-81].
Early diagnosis and treatment of HIV-infected infants dramatically decreases morbidity and mortality. 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 . Based in part on results from the CHER study, the World Health Organization (WHO) revised its treatment recommendations to include virologic testing of all HIV-exposed infants at four to six weeks of age and treatment of all HIV-infected children less than 12 months of age, regardless of immunologic or clinical stage .
Early infant diagnosis and prompt initiation of ART remains a challenge in resource-limited settings, and delays in starting ART are likely a major reason for the high mortality rates seen in resource-limited settings. Treatment of young children in resource-limited settings lags behind that of older children and adults. In pooled analyses, the median age of children treated with ART ranged from 3.5 to 4.9 years [75-77]. Approximately 30 percent of children treated with ART are <18 months of age, and only 12 to 24 percent of patients are <12 months [75-77]. In a study using data from a large international cohort of HIV-infected children, approximately two-thirds of children in low- and middle-income countries already had severe immunodeficiency at the initiation of ART . 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 HIV-exposed and infected infants 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, common long-term morbidities include [69,85-94]:
●Mental health concerns, including anxiety, mood, and substance abuse 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) (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 atherosclerosis")
●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: Definition, epidemiology, etiology, and course" and "Chronic kidney disease in children: Clinical manifestations and evaluation")
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".)
●The Centers for Disease Control and Prevention (CDC) and World Health Organization (WHO) have developed differing classification systems for pediatric HIV/acquired immunodeficiency syndrome (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.)
●The clinical manifestations of pediatric HIV infection are varied and often nonspecific (eg, lymphadenopathy, oral candidiasis, failure to thrive). The most common AIDS-defining conditions in children in the United States include Pneumocystis jirovecii pneumonia (PCP), recurrent bacterial infections, wasting syndrome, candida esophagitis, HIV encephalopathy, and cytomegalovirus (CMV) (table 1). (See 'Clinical manifestations' above.)
●Outcomes of HIV infection depend upon whether effective treatment is provided. Highly effective, combination antiretroviral therapy (ART) has radically reduced mortality and morbidity, particularly the incidence of opportunistic infections (OIs). (See 'Outcome' above.)
●Without treatment, HIV infection causes progressive immunosuppression, leaving patients at risk of developing OI and other HIV-related disorders. Most untreated HIV-infected children die before age five years. However, there is considerable variability, particularly for those with vertically acquired infection. (See 'Untreated HIV infection' above.)
●Combination ART is associated with improvement in virologic, immunologic, and clinical health for HIV-infected adults and children. The use of combination ART in children has reduced the morbidity and mortality associated with HIV infection in the developed world. However, limited access to adequate health care to sustain widespread HIV diagnosis and treatment has hampered progress in controlling HIV in resource-limited settings. (See 'HIV infection treated with antiretroviral therapy' above.)
●Long-term morbidities in children and young adults treated for HIV infection in childhood 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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