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Human Immunodeficiency Virus (HIV) Infection in Infants and Children

By Geoffrey A. Weinberg, MD, Professor of Pediatrics; Director, Clinical Pediatric Infectious Diseases and Pediatric HIV Program, University of Rochester School of Medicine and Dentistry; Golisano Children’s Hospital

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Human immunodeficiency virus (HIV) infection is caused by the retrovirus HIV-1 (and less commonly by the related retrovirus HIV-2). Infection leads to progressive immunologic deterioration and opportunistic infections and cancers. The end stage is acquired immunodeficiency syndrome (AIDS). Diagnosis is by viral antibodies in children > 18 mo and virologic nucleic acid amplification tests (such as PCR) in children < 18 mo. Treatment is with combinations of antiretroviral drugs.

The general natural history and pathophysiology of pediatric HIV infection is similar to that in adults; however, the method of infection, clinical presentations, and treatments often differ. HIV-infected children also have unique social integration issues (see Integration of HIV-Infected Children).

Epidemiology

In the US, HIV probably occurred in children almost as early as in adults but was not clinically recognized for several years. Thus far, about 10,000 cases have been reported in children and young adolescents, representing only 1% of total cases. In 2013, < 100 new cases were diagnosed in children < 13 yr (1).

More than 95% of HIV-infected US children acquired the infection from their mother, either before or around the time of birth (vertical transmission). Most of the remainder (including children with hemophilia or other coagulation disorders) received contaminated blood or blood products. A few cases were the result of sexual abuse. Vertical transmission has declined significantly in the US from about 25% in 1991 (resulting in > 1600 infected children annually) to 1% in 2013 (resulting in only about 70 to 100 infected children annually). Vertical transmission has been reduced by using comprehensive serologic screening and treating of infected pregnant women during both pregnancy and delivery and by providing short-term antiretroviral prophylaxis to exposed newborns.

However, the total number of HIV-infected US adolescents continues to increase despite the marked success in decreasing perinatal HIV infection. This paradoxical increase is a result of both greater survival among perinatally infected children and new cases of HIV infection acquired via sexual transmission among other adolescents (in particular, among young men who have sex with men). Reducing transmission of HIV among young men who have sex with men continues to be an important focus of domestic HIV control efforts as is continuing the reduction of vertical transmission.

Worldwide, about 2 million children have HIV infection (5% of the total caseload worldwide). Each year, about 150,000 more children are infected (7 to 10% of all new infections), and about 110,000 children die. Although these numbers represent a daunting amount of illness, new programs created to deliver antiretroviral therapy (ART) to pregnant women and children have reduced the annual number of new childhood infections and childhood deaths by 33% in the past few years (1). However, infected children still do not receive ART nearly as often as adults, and interrupting vertical transmission and providing treatment to HIV-infected children remain the two most important goals of global pediatric HIV medicine.

Transmission of HIV

The infection risk for an infant born to an HIV-positive mother who did not receive ART during pregnancy is estimated at 25% (range 13 to 39%). Risk factors for vertical transmission include

  • Seroconversion during pregnancy or breastfeeding (major risk)

  • High plasma viral RNA concentrations (major risk)

  • Advanced maternal disease

  • Low maternal peripheral CD4+ T-cell counts

Prolonged rupture of membranes is no longer thought to be an important risk factor.

Cesarean delivery before onset of active labor reduces the risk of mother-to-child transmission (MTCT). However, it is clear that MTCT is reduced most significantly by giving combination ART, usually including zidovudine (ZDV), to the mother and neonate (see Human Immunodeficiency Virus (HIV) Infection in Infants and Children : Prevention). ZDV monotherapy reduces MTCT from 25% to about 8%, and current combination ART reduces it to ≤ 1%.

HIV has been detected in both the cellular and cell-free fractions of human breast milk. The incidence of transmission by breastfeeding is about 6/100 breastfed children/yr. Estimates of the overall risk of transmission through breastfeeding are 12 to 14%, reflecting varying durations of breastfeeding. Transmission by breastfeeding is greatest in mothers with high plasma viral RNA concentrations (eg, women who become infected during pregnancy or during the period of breastfeeding).

Classification

HIV infection causes a broad spectrum of disease, of which AIDS is the most severe. Past classification schemes established by the CDC defined the progression of clinical and immunologic decline. These clinical and immunologic categories are becoming less relevant in the era of combination ART. When ART is taken as prescribed, it almost invariably decreases symptoms and increases CD4+ T-cell counts. The categories are most useful for clinical research and for describing the severity of illness at the time of diagnosis in children < 13 yr. For adolescents ≥ 13 yr and adults, newer classification systems now simply use CD4+ T-cell count as the major component of staging unless AIDS-defining conditions (eg, opportunistic infections) are present (see Table: Clinical Categories for Children Aged < 13 Yr With HIV Infection).

Clinical categories in children < 13 yr (see Table: Clinical Categories for Children Aged < 13 Yr With HIV Infection) are defined by presence or absence of certain common opportunistic infections or cancers. These categories are

  • N = Not symptomatic

  • A = Mildly symptomatic

  • B = Moderately symptomatic

  • C = Severely symptomatic

Immunologic categories (HIV infection stages) in children < 13 yr (see Table: Immunologic Categories (HIV Infection Stages) for Children < 13 Yr With HIV Infection Based on Age-Specific CD4+ T-Cell Count or Percentage) reflect the degree of immune suppression based on the CD4+ T-cell count (absolute count and as percentage of total lymphocyte count):

  • 1 = No evidence of immune suppression

  • 2 = Moderate suppression

  • 3 = Severe suppression

Thus, a child classified in stage B3 would have moderately advanced clinical symptoms and severe immunocompromise. Clinical and immunologic categories form a unidirectional hierarchy; once classified at a certain level, children cannot be reclassified at a less severe level, regardless of clinical or immunologic improvement.

Clinical Categories for Children Aged < 13 Yr With HIV Infection

Category N: Not symptomatic

Children who have no symptoms or signs considered to result from HIV infection or who have only 1 of the conditions listed in category A

Category A: Mildly symptomatic

Children with ≥ 2 of the conditions listed below but none of the conditions listed in category B or C:

Dermatitis

Hepatomegaly

Lymphadenopathy ( 0.5 cm at > 2 sites; bilateral = 1 site)

Parotitis

Recurrent or persistent upper respiratory tract infection, sinusitis, or otitis media

Splenomegaly

Category B: Moderately symptomatic

Children with symptomatic conditions attributed to HIV infection beyond those listed in category A but not among those listed in category C; conditions in category B include but are not limited to the following:

Anemia (Hb < 8 g/dL), neutropenia (<1,000/μL), or thrombocytopenia (< 100,000/μL) persisting 30 days

Bacterial meningitis, pneumonia, or sepsis (single episode)

Candidiasis, oropharyngeal (thrush), persisting (> 2 mo) in children > 6 mo of age

Cardiomyopathy

Cytomegalovirus infection with onset before 1 mo of age

Diarrhea, recurrent or chronic

Hepatitis

Herpes zoster (shingles) involving 2 distinct episodes or > 1 dermatome

HSV stomatitis, recurrent (> 2 episodes within 1 yr)

HSV bronchitis, pneumonitis, or esophagitis with onset before 1 mo of age

Leiomyosarcoma

Lymphoid interstitial pneumonitis or pulmonary lymphoid hyperplasia complex

Nephropathy

Nocardiosis

Persistent fever (lasting > 1 mo)

Toxoplasmosis with onset before 1 mo of age

Varicella, disseminated (complicated chickenpox)

Category C: Severely symptomatic (stage 3–defining opportunistic infections)

Children with ≥ 1 of the following conditions:

Serious bacterial infections, multiple or recurrent (ie, any combination of 2 culture-confirmed infections within a 2-yr period), of the following types: septicemia, pneumonia, meningitis, bone or joint infection, or abscess of an internal organ or body cavity (excluding otitis media, superficial skin or mucosal abscesses, and indwelling catheter-related infections) in a child < 6 yr of age

Candidiasis, esophageal or pulmonary (bronchi, trachea, lungs)

Cervical cancer, invasive, in a child or adolescent ≥ 6 yr of age

Coccidioidomycosis, disseminated (at a site other than or in addition to the lungs or cervical or hilar lymph nodes)

Cryptococcosis, extrapulmonary

Cryptosporidiosis (chronic intestinal) or isosporiasis (chronic intestinal) with diarrhea persisting > 1 mo

Cytomegalovirus disease with onset of symptoms at age > 1 mo (at a site other than the liver, spleen, or lymph nodes)

Cytomegalovirus retinitis (with loss of vision)

Encephalopathy (1 of the following progressive findings present for 2 mo in the absence of a concurrent illness other than HIV infection that could explain the findings):

  • Failure to attain or loss of developmental milestones or loss of intellectual ability, verified by standard developmental scale or neuropsychologic tests

  • Impaired brain growth or acquired microcephaly shown by head circumference measurements or presence of brain atrophy on CT or MRI (serial imaging is required for children < 2 yr)

  • Acquired symmetric motor deficit manifested by 2 of the following: paresis, pathologic reflexes, ataxia, or gait disturbance

Histoplasmosis, disseminated (at a site other than or in addition to the lungs or cervical or hilar lymph nodes)

HSV infection causing a mucocutaneous ulcer persisting for > 1 mo or HSV bronchitis, pneumonitis, or esophagitis for any duration affecting a child > 1 mo of age

Kaposi sarcoma

Lymphoma, primary, in the brain

Lymphoma: Small, noncleaved cell lymphoma (Burkitt), or immunoblastic or large-cell lymphoma of B-cell or unknown immunologic phenotype

Mycobacterium tuberculosis, pulmonary, disseminated, or extrapulmonary (at any site)

Mycobacterium avium complex, Mycobacterium kansasii, or other species or unidentified species, disseminated or extrapulmonary

Pneumocystis jirovecii pneumonia

Pneumonia, recurrent, in children or adolescents ≥ 6 yr of age

Progressive multifocal leukoencephalopathy

Salmonella (nontyphoid) septicemia, recurrent

Toxoplasmosis of the brain with onset at > 1 mo of age

Wasting syndrome in the absence of a concurrent illness (other than HIV infection) that could explain any one of the following 3 findings:

  • Persistent weight loss > 10% of baseline

  • Downward crossing of 2 of the following percentile lines on the weight-for-age chart (eg, 95th, 75th, 50th, 25th, 5th) in a child 1 yr

  • < 5th percentile on weight-for-height chart on 2 consecutive measurements 30 days apart

plus 1 of the following:

  • Chronic diarrhea (ie, 2 loose stools/day for 30 days)

  • Documented fever (for 30 days, intermittent or constant)

HSV = herpes simplex virus.

Adapted from Centers for Disease Control and Prevention: Revised surveillance case definitions for HIV infection among adults, adolescents, and children aged <18 months and for HIV infection and AIDS among children aged 18 months to < 13 years of age—United States, 2008. Morbidity and Mortality Weekly Report 57(RR-10):1–13, 2008; and Centers for Disease Control and Prevention: Revised surveillance case definition for HIV infection–United States, 2014. Morbidity and Mortality Weekly Report 63(RR-3):1–10, 2014.

Immunologic Categories (HIV Infection Stages) for Children < 13 Yr With HIV Infection Based on Age-Specific CD4+ T-Cell Count or Percentage

Immunologic Categories (Stages)*

< 1 yr

1 to < 6 yr

≥ 6 yr

Cells/µL

%

Cells/µL

%

Cells/µL

%

1

1500

34

1000

30

500

26

2

750–1499

26–33

500–999

22–29

200–499

14–25

3

< 750

< 26

< 500

< 22

< 200

< 14

*The stage is based primarily on the CD4 cell count; the CD4 cell count takes precedence over the CD4 percentage; the percentage is considered only if the count is missing. If a stage 3–defining opportunistic infection has been diagnosed, the stage is 3 regardless of CD4 test results.

Adapted from Centers for Disease Control and Prevention: Revised surveillance case definitions for HIV infection —United States, 2014. Morbidity and Mortality Weekly Report 63(RR–3):1–10, 2014.

Epidemiology reference

  • 1. Taylor AW, Nesheim SR, Zhang X, et al: Estimated perinatal HIV infection among infants born in the United States, 2002–2013. JAMA Pediatrics 171:435–442, 2017. doi: 10.1001/jamapediatrics.2016.5053.

Symptoms and Signs

Natural history in untreated children

Infants infected perinatally usually are asymptomatic during the first few months of life, even if no combination ART is begun. Although the median age at symptom onset is about 3 yr, some children remain asymptomatic for > 5 yr and, with appropriate ART, are expected to survive to adulthood. In the pre-ART era, about 10 to 15% of children had rapid disease progression, with symptoms occurring in the first year of life and death occurring by 18 to 36 mo; these children were thought to have acquired HIV infection earlier in utero. However, most children probably acquire infection at or near birth and have slower disease progression (surviving beyond 5 yr even before ART was used routinely).

The most common manifestations of HIV infection in children not receiving ART include generalized lymphadenopathy, hepatomegaly, splenomegaly, failure to thrive, oral candidiasis, CNS disease (including developmental delay, which can be progressive), lymphoid interstitial pneumonitis, recurrent bacteremia, opportunistic infections, recurrent diarrhea, parotitis, cardiomyopathy, hepatitis, nephropathy, and cancers.

Complications of HIV in children

When complications occur, they typically involve opportunistic infections (and rarely cancer). Combination ART has made such infections uncommon, and they now occur mainly in undiagnosed children who have not yet received ART or in children who are not adherent to ART.

When opportunistic infections occur, Pneumocystis jirovecii pneumonia is the most common and serious and has high mortality. Pneumocystis pneumonia can occur as early as age 4 to 6 wk but occurs mostly in infants aged 3 to 6 mo who acquired infection before or at birth. Infants and older children with Pneumocystis pneumonia characteristically develop a subacute, diffuse pneumonitis with dyspnea at rest, tachypnea, oxygen desaturation, nonproductive cough, and fever (in contrast to non–HIV-infected immunocompromised children and adults, in whom onset is often more acute and fulminant).

Other opportunistic infections in immunosuppressed children include Candida esophagitis, disseminated cytomegalovirus infection, chronic or disseminated herpes simplex virus infection and varicella-zoster virus infection, and, less commonly, Mycobacterium tuberculosis and M. avium complex infections, chronic enteritis caused by Cryptosporidium or other organisms, and disseminated or CNS cryptococcal or Toxoplasma gondii infection.

Cancers in immunocompromised children with HIV infection are relatively uncommon, but leiomyosarcomas and certain lymphomas, including CNS lymphomas and non-Hodgkin B-cell lymphomas (Burkitt type), occur much more often than in immunocompetent children. Kaposi sarcoma is very rare in HIV-infected children. (See Cancers Common in HIV-Infected Patients.)

Children receiving combination antiretroviral therapy

Combination ART has significantly changed the clinical manifestations of pediatric HIV infection. Although bacterial pneumonia and other bacterial infections (eg, bacteremia, recurrent otitis media) still occur more often in HIV-infected children, opportunistic infections and growth failure are much less frequent than in the pre-ART era. New problems, such as alterations in serum lipids, hyperglycemia, fat maldistribution (lipodystrophy and lipoatrophy), nephropathy, and osteonecrosis, are reported; however, the incidence is lower in children than in HIV-infected adults.

Although combination ART clearly improves neurodevelopmental outcome, there seems to be an increased rate of behavioral, developmental, and cognitive problems in treated HIV-infected children. It is unclear whether these problems are caused by HIV infection itself, therapeutic drugs, or other biopsychosocial factors among HIV-infected children. It is unknown whether any additional effects of HIV infection or ART during critical periods of growth and development will manifest later in life because the first wave of perinatally infected children is just now reaching adulthood. To detect such adverse effects, providers will need to monitor HIV-infected children over time.

Diagnosis

  • Serum antibody tests

  • Virologic nucleic acid tests (NATs; includes HIV DNA PCR or HIV RNA assays)

HIV-specific tests

In children > 18 mo, the diagnosis of HIV infection is made using a serum 4th-generation HIV-1/2 antigen/antibody combination immunoassay followed by a 2nd-generation HIV-1/2 antibody differentiation assay and, if required, an HIV-1 qualitative RNA assay. This diagnostic testing algorithm has supplanted the previous sequential testing by serum immunoassay and Western blot confirmation. Only very rarely does an older HIV-infected child lack HIV antibody because of significant hypogammaglobulinemia.

Children < 18 mo retain maternal antibody, causing false-positive results even with the 4th-generation HIV-1/2 antigen/antibody combination immunoassay, so diagnosis is made by HIV virologic assays such as qualitative RNA assays (eg, transcription-mediated amplification of RNA) or DNA PCR assays (known collectively as NATs), which can diagnose about 30 to 50% of cases at birth and nearly 100% of cases by 4 to 6 mo of age. HIV viral culture has acceptable sensitivity and specificity but is technically more demanding and hazardous and has been replaced by NATs.

Another type of NAT, the quantitative HIV RNA assay (ie, the viral load assay used for monitoring efficacy of treatment) is becoming more widely used for diagnostic testing of infants. Quantitative RNA assays are as sensitive as DNA PCR in infants not given ART, are less expensive, and are more widely available than are the other NATs. However, care must be taken when using RNA assays for infant diagnosis because test specificity is uncertain at very low RNA concentrations (< 5,000 copies/mL) and sensitivity is unknown in infants of mothers with complete treatment-mediated viral suppression at the time of delivery.

Three serial virologic tests (a NAT) should be done initially within the first 2 wk of life, at about 1 mo of age, and between 4 mo and 6 mo for all infants with perinatal HIV exposure. A positive test should be confirmed immediately by using the same or another virologic test. If the serial HIV virologic tests are negative at ≥ 2 wk and ≥ 4 wk, the infant is considered uninfected with > 95% accuracy (in the absence of any AIDS-defining illness). If HIV virologic tests are also negative at ≥ 4 wk and ≥ 4 mo, the infant is considered uninfected with about 100% accuracy (in the absence of any AIDS-defining illness). Nevertheless, many experts continue to recommend follow-up antibody tests (1 antigen/antibody combination assay at > 18 mo or, alternatively, 2 such assays done between 6 mo and 18 mo) to definitively exclude HIV infection and confirm seroreversion (loss of passively acquired HIV antibodies). If an infant <18 mo with a positive antibody test but negative virologic tests develops an AIDS-defining illness (category C—see Table: Clinical Categories for Children Aged < 13 Yr With HIV Infection), HIV infection is diagnosed.

Infants at high risk of HIV transmission are recommended to have two additional NATs at birth and at 8 to 10 wk of age along with the 3 tests recommended above. Transmission risk is increased with the following:

  • Increased or unknown maternal viral load at delivery

  • Infants born to women not taking antiretroviral therapy

  • Known highly antiretroviral drug-resistant virus in mother

Rapid immunoassay tests for HIV antibody may be done as point-of-care tests on oral secretions, whole blood, or serum and provide results in minutes to hours. In the US, these tests are most useful in labor and delivery suites to test women of unknown HIV serostatus, thus allowing counseling, commencement of ART to prevent MTCT, and testing of the infant to be arranged during the birth visit. Similar advantages accrue in other episodic care settings (eg, emergency departments, adolescent medicine clinics, sexually transmitted disease clinics) and in the developing world. However, rapid assays typically require confirmatory tests, such as a second antigen/antibody assay, an HIV-1/2 antibody differentiation assay, or a NAT. These confirmatory tests are especially important because in areas where the expected HIV prevalence is low, even a specific rapid assay yields mostly false-positive results (low positive predictive value by Bayes theorem). The higher the pre-test probability of HIV (ie, seroprevalence), the higher the positive predictive value of the test. As more laboratories are able to do same-day testing using 4th-generation HIV-1/2 antigen/antibody combination immunoassays, there will be less need for the comparatively less sensitive and less specific rapid immunoassays.

Before HIV testing of a child is done, the mother or primary caregiver (and the child, if old enough) should be counseled about the possible psychosocial risks and benefits of testing. Oral (or written) consent should be obtained and recorded in the patient’s chart, consistent with state, local, and hospital laws and regulations. Counseling and consent requirements should not deter testing if it is medically indicated; refusal of a patient or guardian to give consent does not relieve physicians of their professional and legal responsibilities, and sometimes authorization for testing must be obtained by other means (eg, court order). Test results should be discussed in person with the family, the primary caregiver, and, if old enough, the child. If the child is HIV-positive, appropriate counseling and subsequent follow-up care must be provided. In all cases, maintaining confidentiality is essential.

Children and adolescents meeting the criteria for HIV infection or AIDS must be reported to the appropriate public health department.

(For questions regarding neonatal diagnosis, clinicians can call the Perinatal HIV Consultation and Referral Services Hotline: 1-888-HIV-8765 [1-888-448-8765].)

Other tests

Once infection is diagnosed, other tests are done:

  • CD4+ T-cell count

  • CD8+ T-cell count

  • Plasma viral RNA concentration

Infected children require measurement of CD4+ and CD8+ T-cell counts and plasma viral RNA concentration (viral load) to help determine their degree of illness, prognosis, and the effects of therapy. CD4+ counts may be normal (eg, above the age-specific cutoffs of category 1 in Table Immunologic Categories (HIV Infection Stages) for Children < 13 Yr With HIV Infection Based on Age-Specific CD4+ T-Cell Count or Percentage) initially but fall eventually. CD8+ counts usually increase initially and do not fall until late in the infection. These changes in cell populations result in a decrease in the CD4+:CD8+ cell ratio, a characteristic of HIV infection (although sometimes occurring in other infections). Plasma viral RNA concentrations in untreated children < 12 mo are typically very high (mean of about 200,000 RNA copies/mL). By 24 mo, viral concentrations in untreated children decrease (to a mean of about 40,000 RNA copies/mL). Although the wide range of HIV RNA concentrations in children make the data less predictive of morbidity and mortality than in adults, determining plasma viral concentrations in conjunction with CD4+ counts still yields more accurate prognostic information than does determining either marker alone. Less expensive alternative surrogate markers such as total lymphocyte counts and serum albumin levels may also predict AIDS mortality in children, which may be useful in developing nations.

Although not routinely measured, serum immunoglobulin concentrations, particularly IgG and IgA, often are markedly elevated, but occasionally some children develop panhypogammaglobulinemia. Patients may be anergic to skin test antigens.

Prognosis

In the pre-ART era, 10 to 15% of children from industrialized countries and perhaps 50 to 80% of children from developing countries died before age 4 yr; however, with appropriate combination ART regimens, most perinatally infected children survive well into adolescence. The majority of vertically infected children born during the past decade in the US are surviving into young adulthood; increasing numbers of these young adults have given birth to or fathered their own children.

Nevertheless, if opportunistic infections occur, particularly Pneumocystis pneumonia, progressive neurologic disease, or severe wasting, the prognosis is poor unless virologic and immunologic control is regained with combination ART. Mortality due to Pneumocystis pneumonia ranges from 5 to 40% if treated and is almost 100% if untreated. Prognosis is also poor for children in whom virus is detected early (ie, by 7 days of life) or who develop symptoms in the first year of life.

There has been only one well-documented case of an adult in whom replication-competent HIV was eradicated (ie, the person has been "cured" for > 5 yr). This HIV-infected adult required a hematopoietic stem cell transplant for leukemia. The donor cells were homozygous for the CCR5-delta 32 mutation, which made the engrafted lymphocytes resistant to infection with CCR5-tropic HIV; subsequently, HIV has remained undetectable. It is likely that ART, bone marrow ablation, and graft-vs-host disease contributed to this person's cure. Other HIV-infected transplant recipients have not experienced cure; however, one well-documented case of an infant with transient eradication of replication-competent HIV has been reported. The infant was born to an HIV-infected mother who had not received prenatal care or prenatal (or intrapartum) ART. Beginning on the second day of life, the infant was given combination ART at high doses not yet known to be safe and effective for use in the first 2 wk of life. The ART was given for about 15 mo, after which time it was inadvertently interrupted. Nevertheless, at 24 mo of age the infant had no detectable replicating virus RNA (a "functional cure") but did have detectable proviral DNA. Subsequently, however, HIV replication ensued. Several similar cases of infants with temporary interruption of HIV replication have been reported; none have been "cured" of their HIV infection, and it is not yet known if cure is possible. What is known, however, is that HIV infection is a treatable infection that is already compatible with long-term survival if effective ART is given. Future research will undoubtedly uncover ways to improve ART tolerance and efficacy and perhaps help achieve the goal of curative therapy.

Treatment

  • Antiretroviral (ARV) drugs: Combination ART most commonly includes 2 nucleoside reverse transcriptase inhibitors (NRTIs) plus either a protease inhibitor (PI) or an integrase strand transfer inhibitor (INSTI); sometimes a nonnucleoside reverse transcriptase inhibitor (NNRTI)is given with 2 NRTIs

  • Supportive care

Because of the success of combination ART, much of the current focus is on the management of HIV infection as a chronic disease, addressing both medical and social issues. Important long-term medical issues include the need to manage HIV-related and drug-related metabolic complications and to account for age-related changes in drug pharmacokinetics and pharmacodynamics. Social issues include the need to cope with peer pressure from noninfected adolescents, ensure school success and appropriate career choice, and educate children about transmission risk. Adolescents often have difficulty seeking and following health care advice and need particular help with treatment adherence. Children and adolescents should be managed in collaboration with experts who have experience in the management of pediatric HIV infection.

Indications for ART in children

(For a discussion of specific ARV drugs and dosages, see Antiretroviral Drug Therapy in Children.)

Initiation of ART for children is similar to that in adults; essentially, all children with HIV infection should be given ART. The urgency of initiating ART depends primarily on the child's age, immunologic and clinical criteria, and readiness of the caregivers to give the drugs (see Table Indications for Initiation of Antiretroviral Therapy (ART) in HIV-Infected Children and Adolescents). The goal of therapy is similar to that in adults: suppress HIV replication (as measured by plasma HIV RNA PCR viral load) and maintain or achieve age-normal CD4+ counts and percentages with the least amount of drug toxicity. Before making the decision to initiate therapy, the practitioner should fully assess the readiness of the caregiver and child to adhere with ARV drug administration and discuss the potential benefits and risks of therapy. Because expert opinions on therapeutic strategies change rapidly, consultation with experts is strongly advised.

Indications for Initiation of Antiretroviral Therapy (ART) in HIV-Infected Children and Adolescents

Age

Criteria

Recommendation*

< 12 mo

Regardless of clinical symptoms, immune status, or viral load

Urgent treatment (within 1–2 wk, including expedited discussion on adherence)

1 to < 6 yr

Severe symptoms (CDC clinical category C [stage 3–defining opportunistic infections]) or CD4 count < 500 cells/μL—see Table: Clinical Categories for Children Aged < 13 Yr With HIV Infection)

Urgent treatment (within 1–2 wk, including expedited discussion on adherence)

Moderate symptoms (CDC clinical category B) or CD4 cell count 500–999 cells/μL

Treat

Asymptomatic or mild symptoms (CDC clinical category A or N) and CD4 cell count ≥ 1000 cells/μL

Treat but on a case-by-case basis while fully assessing adherence and clinical/ psychosocial factors; may temporarily defer with close monitoring

≥ 6 yr

Severe symptoms (CDC clinical category C [stage 3–defining opportunistic infections]) or CD4 count < 200 cells/μL (see Table: Clinical Categories for Children Aged < 13 Yr With HIV Infection)

Urgent treatment (within 1–2 wk, including expedited discussion on adherence)

Moderate symptoms (CDC clinical category B) or CD4 cell count 200–499 cells/μL

Treat

Asymptomatic or mild symptoms (CDC clinical category A or N) and CD4 cell count ≥ 500 cells/μL

Treat

For adolescents aged ≥ 13 yr with sexual maturity ratings 4 or 5, many alternative fixed-dose ARV combinations are available; consultation with an HIV expert is advised

*Adherence should be assessed and discussed with children and adolescents with HIV infection and their caregivers before initiation of therapy.

ARV = antiretroviral.

For information on adverse effects, other doses (especially for information on fixed-dose combination products), and drug interactions, see the continually updated Department of Health and Human Services Panel on Antiretroviral Therapy and Medical Management of HIV-Infected Children, a Working Group of the Office of AIDS Research Council. Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection, April 27, 2017.

Adherence

Antiretroviral drug therapy will be successful only if the family and child are able to adhere to a possibly complex medical regimen. Nonadherence not only leads to failure to control HIV but also selects drug-resistant HIV strains, which reduces future therapeutic choices. Barriers to adherence should be addressed before starting treatment. Barriers include availability and palatability of pills or suspensions, adverse effects (including those due to drug interactions with current therapy), pharmacokinetic factors such as the need to take some drugs with food or in a fasted state, and a child’s dependence on others to give drugs (and HIV-infected parents may have problems with remembering to take their own drugs). Newer once- or twice-daily combination regimens and more palatable pediatric formulations may help improve adherence.

Adherence may be especially problematic in adolescents regardless of whether they have been infected perinatally or have acquired HIV infection later on through sexual activity or injection drug use. Adolescents have complex biopsychosocial issues, such as low self-esteem, chaotic and unstructured lifestyles, fear of being singled out because of illness, and sometimes a lack of family support, all of which may reduce drug adherence. In addition, adolescents may not be developmentally able to understand why drugs are necessary during periods of asymptomatic infection and they may worry greatly about adverse effects. Despite frequent contact with the medical system, perinatally infected adolescents may fear or deny their HIV infection, distrust information provided by the health care team, and poorly make the transition to the adult health care system (see Transition to Adult Care). Treatment regimens for adolescents must balance these issues. Although the goal is to have the adolescent adhere to a maximally potent regimen of ARV drugs, a realistic assessment of the adolescent's maturity and support systems may suggest that the treatment plan begin by focusing on avoidance of opportunistic illness and provide information about reproductive health services, housing, and how to succeed in school. Once care team members are confident the adolescent is receiving proper support, they can decide exactly which ARV drugs are best.

Monitoring

Clinical and laboratory monitoring are important for identifying drug toxicity and therapeutic failure.

  • At entry into care and at initiation of ART (and if changing ART regimen): Physical examination, adherence evaluation, CBC, serum chemistry values including electrolytes, liver and kidney function tests, HIV RNA viral load, and CD4+ lymphocyte counts

  • Every 3 to 4 mo: Physical examination, adherence evaluation, CBC, serum chemistry values, including electrolytes, liver and kidney function tests, HIV RNA viral load, and CD4+ lymphocyte counts

  • Every 6 to 12 mo: Lipid profiles and urinalysis

HIV genotypic resistance testing should be done at entry into care and upon ART changes due to presumed virologic failure.

If abacavir is to be given, HLA-B*5701 status must be tested; abacavir should be given only to patients who are HLA-B*5701–negative.

If children have a stable treatment status, ie, nondetectable HIV RNA and normal age-adjusted CD4+ lymphocyte counts without clinical signs of toxicity for at least 12 mo, and a stable family support system, many clinicians will extend the interval of laboratory evaluations to every 6 mo. However, clinical care visits every 3 mo are valuable because clinicians have the opportunity to review adherence, monitor growth and clinical symptoms, and update weight-based dosing of ARV drugs as needed.

Vaccination

Routine pediatric vaccination protocols (see Table: Childhood Vaccination Schedule) are recommended for children with HIV infection, with several exceptions. The main exception is that live-virus vaccines and live-bacteria vaccines (eg, BCG) should be avoided or used only in certain circumstances (see Table: Considerations for Use of Live Vaccines in Children With HIV Infection). In addition, 1 to 2 mo after the last dose of the hepatitis B vaccine series, HIV-infected children should be tested to determine whether the level of antibodies to hepatitis B surface antigen (anti-HBs) is protective ( 10 mIU/mL). HIV-infected children and adolescents < 18 yr of age should be immunized with 13-valent pneumococcal conjugate vaccine (PCV-13) as well as pneumococcal polysaccharide vaccine (PPSV). Certain postexposure treatment recommendations also differ. Recently, quadrivalent meningococcal conjugate immunization has been recommended for routine and catch-up use in HIV-infected children, adolescents, and adults (see the Advisory Committee for Immunization Practices' [ACIP] recommendations for the use of meningococcal conjugate vaccines in people who have HIV).

Live oral poliovirus vaccine and live-attenuated influenza vaccine are not recommended; however, inactivated influenza vaccination should be given yearly.

The live measles-mumps-rubella (MMR) vaccine and varicella vaccine should not be given to children with manifestations of severe immunosuppression. However, the MMR and varicella-zoster virus (VZV) vaccines (separately; not combined as MMRV vaccine, which has a higher titer of attenuated varicella virus, the safety of which has not been shown in this population) can be given to asymptomatic patients following the routine schedule and to patients who have had HIV symptoms but who are not severely immunocompromised (ie, not in category 3 [see Table: Immunologic Categories (HIV Infection Stages) for Children < 13 Yr With HIV Infection Based on Age-Specific CD4+ T-Cell Count or Percentage], including having a CD4+ T-cell percentage of 15%). If possible, the MMR and VZV vaccines should be given starting at age 12 mo in symptomatic patients to enhance the likelihood of an immune response, ie, before the immune system deteriorates. The 2nd dose of each may be given as soon as 4 wk later in an attempt to induce seroconversion as early as possible, although typically a 3-mo interval between varicella vaccine doses is preferred in noninfected children < 13 yr. If the risk of exposure to measles is increased, such as during an outbreak, the measles vaccine should be given at an earlier age, such as 6 to 9 mo.

The live oral rotavirus vaccine may be given to HIV-exposed or HIV-infected infants according to the routine schedule. Safety and efficacy data are limited in symptomatic infants but there very likely is overall benefit to immunization, particularly in areas where rotavirus causes significant mortality.

The BCG vaccine is not recommended in the US because it is an area of low TB prevalence. However, elsewhere in the world, especially in developing countries where TB prevalence is high, BCG is routinely used; many of these countries also have high HIV prevalence among childbearing women. BCG as a live bacterial vaccine has caused some harm in HIV-infected children but likely protects non–HIV-infected and even some HIV-infected children from acquiring TB. Thus, the WHO now recommends that children who are known to be HIV-infected, even if asymptomatic, should no longer be immunized with BCG vaccine. However, BCG may be given to asymptomatic infants of unknown HIV infection status born to HIV-infected women, depending on the relative incidence of TB and HIV in the particular area. BCG also may be given to asymptomatic infants born to women of unknown HIV infection status.

In some areas of the world, children are routinely given the yellow fever vaccine; it should be given only to those without severe immunosuppression.

Because children with symptomatic HIV infection generally have poor immunologic responses to vaccines, they should be considered susceptible when they are exposed to a vaccine-preventable disease (eg, measles, tetanus, varicella) regardless of their vaccination history. Such children should receive passive immunization with IV immune globulin. IV immune globulin also should be given to any nonimmunized household member who is exposed to measles.

Seronegative children living with a person with symptomatic HIV infection should receive inactivated poliovirus vaccine rather than oral polio vaccine. Influenza (inactivated or live), MMR, varicella, and rotavirus vaccines may be given normally because these vaccine viruses are not commonly transmitted by the vaccinee. Adult household contacts should receive annual influenza vaccination (inactivated or live) to reduce the risk of transmitting influenza to the HIV-infected person.

Considerations for Use of Live Vaccines in Children With HIV Infection

Live Vaccine

Comments

BCG

Not recommended in US; internationally, may be given to HIV-exposed neonates of unknown HIV infection status (see Human Immunodeficiency Virus (HIV) Infection in Infants and Children : Vaccination)

Not recommended in US; inactivated polio vaccine given instead according to routine schedule*

Not recommended; inactivated vaccine given instead according to routine schedule*

Can be given to children whose CD4+ T-cell percentage is 15%

Administration at 12 mo of age followed by 2nd dose within 1–3 mo enhances likelihood of response before HIV-induced immunologic decline occurs

MMR plus separate varicella-zoster virus (VZV) vaccine preferred over MMRV to minimize adverse effects

If risk of exposure to measles is increased (eg, during an outbreak), given at a younger age (eg, 6–9 mo); however, this dose not considered part of routine schedule (ie, restart at 12 mo)

Rotavirus, live-attenuated

Limited evidence to date suggests that benefits of vaccine very likely outweigh its risks

Can be given to children whose CD4+ T-cell percentage is 15%

Administration at 12 mo of age followed by 2nd dose within 1–3 mo enhances likelihood of response before HIV-induced immunologic decline occurs

MMR plus separate VZV vaccine preferred over MMRV to minimize adverse effects

*Given according to the usual pediatric immunization schedule (see Table: Recommended Immunization Schedule for Ages 0–6 yr and see Table: Recommended Immunization Schedule for Ages 7–18 yr).

AAP = American Academy of Pediatrics; ACIP = Advisory Committee on Immunization Practices; MMRV = measles-mumps-rubella-varicella.

Transition to Adult Care

Transition of HIV-infected youth from the pediatric health care model to the adult health care model takes time and advance planning. This process is active and ongoing and does not simply involve a one-time referral to an adult care clinic or office. The pediatric health care model tends to be family-centered, and the care team includes a multidisciplinary team of physicians, nurses, social workers, and mental health professionals; perinatally infected youth may have been cared for by such a team for their entire life.

In contrast, the typical adult health care model tends to be individual-centered, and the health care practitioners involved may be located in separate offices requiring multiple visits. Health care practitioners at adult care clinics and offices are often managing high patient volumes, and the consequences of lateness or missed appointments (which may be more common among adolescents) are stricter. Finally, changes in insurance coverage in adolescence or young adulthood can complicate transition of medical care as well. Planning transition over several months and having adolescents have discussions or joint visits with the pediatric and adult health care practitioners can lead to a smoother and more successful transition. Several resources for transition of HIV-infected youth into adult health care are now available from the American Academy of Pediatrics (see Policy Statement: Transitioning HIV-Infected Youth Into Adult Health Care) and the New York State Department of Health AIDS Institute (see Transitioning HIV-Infected Adolescents Into Adult Care).

Prevention

Prevention of perinatal transmission

Appropriate prenatal ART attempts to optimize maternal health, interrupt MTCT, and minimize in utero drug toxicity. In the US and other countries where ARV drugs and HIV testing are readily available, treatment with ARV drugs is standard for all HIV-infected pregnant women (see treatment of HIV infection in adults). Rapid HIV testing of pregnant women who present in labor without documentation of their HIV serostatus may allow immediate institution of such measures.

All HIV-infected pregnant women should initiate combination ART to prevent MTCT, as well as for their own health, as soon as the diagnosis of HIV infection is made and they are ready to adhere to ART. Pregnancy is not a contraindication to combination ARV regimens; the use of the ARV agent efavirenz is no longer contraindicated during the 1st trimester. Most experts believe that HIV-infected women already receiving combination ART who become pregnant should continue that therapy, even during the 1st trimester. An alternative is to stop all therapy until the beginning of the 2nd trimester and resume at that time.

Combination ARV oral therapy is continued throughout the pregnancy, and IV ZDV is given during labor, at 2 mg/kg IV for the first hour and then 1 mg/kg/h IV until delivery. Some experts now believe that IV ZDV is not required for women receiving combination ART who have achieved HIV plasma RNA viral loads < 400 copies/mL near delivery; others recommend its use regardless of the degree of virologic control. Ideally, combination ART is continued for all women postpartum, even for those not previously receiving ART before pregnancy.

The full-term neonate born to a woman who has had good virologic control with her ART (as shown by a plasma HIV viral RNA of < 400 copies/mL) is considered at low risk of HIV acquisition (< 0.5 to 1%) and should be given ZDV 4 mg/kg po q 12 h for the first 4 to 6 wk of life. This regimen is the backbone of infant prophylaxis, utilized for all infants born to HIV-infected women regardless of the woman's degree of virologic control. If virologic control is poor, however, additional interventions are considered (see below).

Infants born to women who are not receiving ART, who have either unknown plasma viral loads or viral loads ≥ 400 copies/mL at the time of labor and delivery, or who are known to be infected with highly ARV-resistant HIV are considered at high risk of HIV acquisition (1 to 25%). In these situations, elective cesarean delivery before onset of labor is recommended if the maternal viral load is > 1000 copies/mL. If labor has already begun, it is less certain whether cesarean delivery will contribute to further reduction of MTCT. Women and their high-risk infants are given ZDV as described previously (ie, the women receive drugs IV during labor and delivery; the infants receive drugs by mouth). In addition, additional ARV drugs should be given to the infant. Unfortunately, very few ARV drugs (notably ZDV, nevirapine, and lamivudine) are known to be safe and effective for infants < 14 days postnatal age, and fewer still have dosing data available for premature infants. Recent clinical trial data and expert opinion suggest that either a regimen of oral ZDV given for 6 wk and supplemented with 3 separate doses of nevirapine given over the first several days of life or a combination regimen of ZDV, lamivudine, and nevirapine given for 6 wk can significantly reduce MTCT in infants at high risk of HIV acquisition born to women who did not receive any antepartum therapy. An expert in pediatric or maternal HIV infection should be immediately consulted (see information at www.aidsinfo.nih.gov or www.nccc.ucsf.edu). Clinicians also can call the Perinatal HIV Consultation and Referral Services Hotline: 1-888-HIV-8765 (1-888-448-8765) for questions regarding interventions to decrease vertical HIV transmission and neonatal diagnosis.

Although the final decision to accept ART remains with the pregnant woman, it should be stressed that the proven benefits of therapy in preventing MTCT far outweigh the theoretical risks of any ARV fetal toxicity.

Breastfeeding (or donating to milk banks) is contraindicated for HIV-infected women in the US and other countries where safe and affordable alternative sources of feeding are readily available. Premastication of food for infants by HIV-infected mothers is also contraindicated. However, in countries where infectious diseases and undernutrition are major causes of early childhood mortality and safe, affordable infant formula is not available, the protection breastfeeding offers against the mortality risks of respiratory and GI infections may counterbalance the risk of HIV transmission. In these developing countries, the WHO recommends that HIV-infected mothers continue to breastfeed for the first 6 mo of the infant's life and then rapidly wean the infant to food.

Premastication (prechewing) of food, practiced by some mothers of young infants, is also contraindicated for HIV-infected women.

Prevention of adolescent transmission

Because adolescents are at special risk of HIV infection, they should receive education, have access to HIV testing, and know their serostatus. Education should include information about transmission, implications of infection, and strategies for prevention, including abstaining from high-risk behaviors and engaging in safe sex practices (eg, correct and consistent use of condoms) for those who are sexually active. Efforts should especially target adolescents at high risk of HIV infection, in particular, black and Hispanic adolescent men who have sex with other men because this is the fastest-growing US demographic of new HIV infections among youth; however, all adolescents should receive risk-reduction education.

In most US states, informed consent is necessary for testing and the release of information regarding HIV serostatus. Decisions regarding disclosure of HIV status to a sex partner without the patient’s consent should be based on the possibility of domestic violence to the patient after disclosure to the partner, likelihood that the partner is at risk, whether the partner has reasonable cause to suspect the risk and to take precautions, and presence of a legal requirement to withhold or disclose such information. Preexposure prophylaxis (PrEP—see also Prevention of transmission) with a fixed-dose combination of tenofovir disoproxil fumarate plus emtricitabine (TDF/FTC) is being used more frequently for the HIV-negative partner of an HIV-infected adult. Older adolescents may also receive PrEP, although issues of confidentiality and cost (with possible lack of insurance reimbursement) are more complex than with adult PrEP. For further discussion, see www.hivguidelines.org or www.aidsinfo.nih.gov.

Prevention of opportunistic infections

Prophylactic drug treatment is recommended in certain HIV-infected children for prevention of Pneumocystis pneumonia and M. avium complex infections. Data are limited on the use of prophylaxis for opportunistic infection by other organisms, such as cytomegalovirus, fungi, and toxoplasma. Guidance on prophylaxis of these and other opportunistic infections is also available at www.aidsinfo.nih.gov.

Prophylaxis against Pneumocystis pneumonia is indicated for

  • HIV-infected children 6 yr of age with CD4+ count < 200 cells/mL or CD4+ percentage < 14%

  • HIV-infected children 1 to <6 yr of age with CD4+ count < 500 cells/mL or CD4+ percentage < 22%

  • HIV-infected infants < 12 mo of age regardless of CD4+ count or percentage

  • Infants born to HIV-infected women (beginning at 4 to 6 wk of age), until HIV infection is either presumptively excluded (by documentation of 2 negative virologic test results, 1 at 2 wk of age and 1 at 4 wk of age) or definitively excluded (by documentation of 2 negative virologic test results, 1 at 1 mo of age and 1 at 4 mo of age) (Note: For these definitions of HIV exclusion to be valid, the infant must not be breastfeeding.)

Once immune reconstitution with combination ART occurs, discontinuation of Pneumocystis pneumonia prophylaxis may be considered for HIV-infected children who have received combination ART for > 6 mo and whose CD4+ percentage and CD4+ count have remained higher than the previously described treatment thresholds for > 3 consecutive mo. Subsequently, the CD4+ percentage and count should be reevaluated at least every 3 mo, and prophylaxis should be reinstituted if the original criteria are reached.

The drug of choice for Pneumocystis prophylaxis at any age is trimethoprim/sulfamethoxazole (TMP/SMX) TMP 75 mg/SMX 375 mg/m2 po bid on 3 consecutive days/wk (eg, Monday-Tuesday-Wednesday); alternative schedules include the same dose 2 times/day every day, the same dose 2 times/day on alternate days, or twice the dose (TMP 150 mg/SMX 750 mg/m2) po once/day for 3 consecutive days/wk. Some experts find it easier to use weight-based dosing (TMP 2.5 to 5 mg/SMX 12.5 to 25 mg/kg po bid).

For patients who cannot tolerate TMP/SMX, dapsone 2 mg/kg (not to exceed 100 mg) po once/day is an alternative, especially for those < 5 yr of age. Oral atovaquone given daily or aerosolized pentamidine (300 mg via specially designed inhaler for children ≥ 5 yr) given once/mo is an additional alternative. IV pentamidine has also been used but is both less effective and more toxic.

Prophylaxis against Mycobacterium avium complex infection is indicated in

  • Children 6 yr with CD4+ count < 50/mL

  • Children 2 to 6 yr with CD4+ count < 75/mL

  • Children 1 to 2 yr with CD4+ count <500/mL

  • Children < 1 yr with CD4+ count < 750/mL

Weekly azithromycin or daily clarithromycin is the drug of choice, and daily rifabutin is an alternative.

Key Points

  • Most HIV cases in infants and children result from MTCT before or during birth, or from breastfeeding in countries where safe and affordable infant formula is not available.

  • Maternal antiretroviral treatment can reduce incidence of MTCT from about 25% to < 1%.

  • Diagnose children < 18 mo using qualitative RNA assays (eg, transcription-mediated amplification of RNA) or DNA PCR assays.

  • Diagnose children > 18 mo using a 4th-generation HIV-1/2 antigen/antibody combination immunoassay followed by a 2nd-generation HIV-1/2 antibody differentiation assay and, if required, an HIV-1 qualitative RNA assay.

  • Urgently treat all HIV-infected infants < 12 mo of age; those 1 to < 6 yr of age who have stage 3–defining opportunistic infections or CD4 counts < 500 cells/μL; and those ≥ 6 yr of age who have stage 3–defining opportunistic infections or CD4 counts < 200 μL.

  • Treat all other HIV-infected children and adolescents as soon as issues of adherence are more fully assessed and addressed with the children and their caretakers.

  • Combination ART is given, preferably using a fixed-dose combination product if feasible, for increased adherence.

  • Give prophylaxis for opportunistic infections based on age and CD4+ count.

More Information

Resources In This Article

Drugs Mentioned In This Article

  • Drug Name
    Select Trade
  • MYCOBUTIN
  • RETROVIR
  • VIREAD
  • No US brand name
  • SUSTIVA
  • BIAXIN
  • ZITHROMAX
  • ZIAGEN
  • MEPRON
  • EMTRIVA
  • ACZONE
  • EPIVIR
  • VIRAMUNE
  • NEBUPENT