( See also Human Immunodeficiency Virus (HIV) Infection Human Immunodeficiency Virus (HIV) Infection Human immunodeficiency virus (HIV) infection results from 1 of 2 similar retroviruses (HIV-1 and HIV-2) that destroy CD4+ lymphocytes and impair cell-mediated immunity, increasing risk of certain... read more in adults.)
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 Integration of HIV-Infected Children 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... read more .
Epidemiology of HIV Infection in Infants and Children
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 2018, < 100 new cases were diagnosed in children < 13 years of age ( 1 Epidemiology reference 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... read more ).
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 2018 (resulting in only about 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 and young adults (13 to 24 years of age) 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 and young adults (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 1.7 million children have HIV infection (4% of the total caseload worldwide). Each year, about 160,000 more children are infected (9% of all new infections), and about 100,000 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 to 50% in the past few years ( 1 Epidemiology reference 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... read more ). However, infected children still do not receive ART nearly as often as adults, and interrupting vertical transmission Prevention of perinatal transmission 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... read more 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 Prevention Prevention 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... read more ). 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/year. 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 of HIV Infection in Infants and Children
HIV infection causes a broad spectrum of disease, of which AIDS is the most severe. Past classification schemes established by the Centers for Disease Control and Prevention (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 years. For adolescents ≥ 13 years 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 Years With HIV Infection Clinical Categories for Children Aged < 13 Years With HIV Infection ).
Clinical categories in children < 13 years ( see Table: Clinical Categories for Children Aged < 13 Years With HIV Infection Clinical Categories for Children Aged < 13 Years 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 years ( see Table: Immunologic Categories (HIV Infection Stages) for Children < 13 Years With HIV Infection Based on Age-Specific CD4+ T-Cell Count or Percentage Immunologic Categories (HIV Infection Stages) for Children < 13 Years 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.
Symptoms and Signs of HIV Infection in Infants and Children
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 years, some children remain asymptomatic for > 5 years 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 months; 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 years 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, central nervous system (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 Pneumocystis jirovecii Pneumonia Pneumocystis jirovecii is a common cause of pneumonia in immunosuppressed patients, especially in those infected with human immunodeficiency virus (HIV) and in those receiving systemic... read more is the most common and serious and has high mortality. Pneumocystis pneumonia can occur as early as age 4 to 6 weeks but occurs mostly in infants aged 3 to 6 months 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 Candida esophagitis Esophageal infection occurs mainly in patients with impaired host defenses. Primary agents include Candida albicans, herpes simplex virus, and cytomegalovirus. Symptoms are odynophagia and chest... read more , disseminated cytomegalovirus infection Cytomegalovirus (CMV) Infection Cytomegalovirus (CMV, human herpesvirus type 5) can cause infections that have a wide range of severity. A syndrome of infectious mononucleosis that lacks severe pharyngitis is common. Severe... read more , chronic or disseminated herpes simplex virus infection Neonatal Herpes Simplex Virus (HSV) Infection Neonatal herpes simplex virus infection is usually transmitted during delivery. A typical sign is vesicular eruption, which may be accompanied by or progress to disseminated disease. Diagnosis... read more and varicella-zoster virus infection Chickenpox Chickenpox is an acute, systemic, usually childhood infection caused by the varicella-zoster virus (human herpesvirus type 3). It usually begins with mild constitutional symptoms that are followed... read more , and, less commonly, Mycobacterium tuberculosis Perinatal Tuberculosis (TB) Tuberculosis can be acquired during the perinatal period. Symptoms and signs are nonspecific. Diagnosis is by culture and sometimes x-ray and biopsy. Treatment is with isoniazid and other antituberculous... read more and M. avium complex infections, chronic enteritis caused by Cryptosporidium Cryptosporidiosis Cryptosporidiosis is infection with the protozoan Cryptosporidium. The primary symptom is watery diarrhea, often with other signs of gastrointestinal distress. Illness is typically self-limited... read more or other organisms, and disseminated or CNS cryptococcal or Toxoplasma gondii infection Toxoplasmosis Toxoplasmosis is infection with Toxoplasma gondii. Symptoms range from none to benign lymphadenopathy, a mononucleosis-like illness, to life-threatening central nervous system (CNS) disease... read more .
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 Cancers Common in HIV-Infected Patients AIDS-defining cancers in HIV-infected patients are Kaposi sarcoma Lymphoma, Burkitt (or equivalent term) Lymphoma, immunoblastic (or equivalent term) Lymphoma, primary, of central nervous system read more .)
Children receiving combination antiretroviral therapy (ART)
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. However, no such effects have been noted in perinatally infected children who were treated with ART and are now young adults. To detect such adverse effects, providers will need to monitor HIV-infected children over time.
Diagnosis of HIV Infection in Infants and Children
Serum antibody tests
Virologic nucleic acid tests (NATs; includes HIV DNA polymerase chain reaction or HIV RNA assays)
In children > 18 months, 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 months retain maternal antibody, causing false-positive results even with the 4th-generation HIV-1/2 antigen/antibody combination immunoassay, so diagnosis must be made by HIV virologic assays such as qualitative RNA assays (eg, transcription-mediated amplification of RNA) or DNA polymerase chain reaction (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 months of age. HIV viral culture has acceptable sensitivity and specificity but has been replaced by NATs because it is technically more demanding and hazardous.
The quantitative HIV RNA assay (ie, the HIV plasma viral load assay used for monitoring efficacy of treatment) is a type of NAT, that 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 (< 5000 copies/mL) and sensitivity is unknown in infants of mothers with complete treatment-mediated viral suppression at the time of delivery.
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 Bayes Theorem Test results may help make a diagnosis in symptomatic patients (diagnostic testing) or identify occult disease in asymptomatic patients (screening). If the tests were appropriately ordered on... read more ). 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].)
HIV testing schedules for perinatal exposure
(See also the 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 14, 2020. Available at AIDSinfo.)
Testing schedules vary depending on whether an infant perinatally exposed to HIV by a mother living with HIV infection is considered at low or higher risk of transmission; higher-risk infants are tested more frequently.
Low risk of perinatal HIV transmission is defined by the following:
The mother received antiretroviral therapy (ART) during pregnancy.
The mother had good virologic control as shown by plasma HIV viral RNA of < 50 copies/mL near delivery.
There were no concerns about the mother's adherence to ART.
Testing of infants at low risk is recommended at ages:
14 to 21 days
4 to 6 months
Higher risk of perinatal HIV transmission is defined as a mother living with HIV infection who has one or more of the following factors:
Did not receive prenatal care
Did not receive ART during pregnancy
Did not receive antepartum or intrapartum antiretroviral drugs
Received only intrapartum drugs
Initiated ART late in pregnancy (during the late 2nd or 3rd trimester)
Diagnosed with acute HIV infection during pregnancy
Had an unknown or a detectable (≥ 50 copies/mL) HIV plasma viral load near delivery (particularly when delivery was vaginal)
Has acute or primary HIV infection during pregnancy or breastfeeding (in which case breastfeeding should be stopped)
Testing of infants at higher risk is recommended at ages:
14 to 21 days
1 to 2 months
4 to 6 months
A positive test should be confirmed immediately using the same or another virologic test; two positive tests confirm HIV infection.
If the serial HIV virologic tests are negative at ≥ 2 weeks and at ≥ 4 weeks and in the absence of any AIDS-defining illness, the infant is considered presumptively uninfected (ie, with > 95% accuracy). If HIV virologic tests are also negative at ≥ 4 weeks and at ≥ 4 months, and again in the absence of any AIDS-defining illness, the infant is considered definitively uninfected (ie, with about 100% accuracy). Nevertheless, many experts continue to recommend follow-up antibody tests (1 antigen/antibody combination assay at > 18 months or, alternatively, 2 such assays done between 6 months and 18 months) to definitively exclude HIV infection and confirm seroreversion (loss of passively acquired HIV antibodies). If an infant < 18 months with a positive antibody test but negative virologic tests develops an AIDS-defining illness (category C— see Table: Clinical Categories for Children Aged < 13 Years With HIV Infection Clinical Categories for Children Aged < 13 Years With HIV Infection ), HIV infection is diagnosed.
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 Years With HIV Infection Based on Age-Specific CD4+ T-Cell Count or Percentage Immunologic Categories (HIV Infection Stages) for Children < 13 Years 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 months are typically very high (mean of about 200,000 RNA copies/mL). By 24 months, 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 for HIV Infection in Infants and Children
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 years; however, with appropriate combination ART regimens, most perinatally infected children survive well into adulthood. Increasing numbers of these perinatally infected 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 years). 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 also contributed to this person's cure. Other HIV-infected transplant recipients have not experienced cure; however, -a few well-documented cases of infants with transient eradication of replication-competent HIV have been reported. One such 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 weeks of life. The ART was given for about 15 months, after which time it was inadvertently interrupted. Nevertheless, at 24 months 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. At present, interruption of ART is not recommended.
Treatment of HIV Infection in Infants and Children
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
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 Antiretroviral Drug Therapy in Children There are > 30 antiretroviral (ARV) drugs ( see Table: Dosage and Administration of Selected Antiretroviral Drugs for Children*), including multidrug combination products, available in the US... read more .)
Initiation of ART for children is similar to that in adults; essentially, all children with HIV infection should be given ART as soon as possible (rapid initiation, within 1 to 2 weeks of diagnosis). The goal of therapy is similar to that in adults: suppress HIV replication (as measured by HIV plasma 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.
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 Transition to Adult Care 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... read more ). 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.
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, complete blood count, serum chemistry values including electrolytes, liver and kidney tests, HIV plasma viral load, CD4+ lymphocyte counts, and, for adolescent girls, a pregnancy test
Every 3 to 4 months: Physical examination, adherence evaluation, complete blood count, serum chemistry values, including electrolytes, liver and kidney tests, HIV plasma viral load, and CD4+ lymphocyte counts
Every 6 to 12 months: 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. This testing is often done at entry into care so that safety of possible future use of abacavir will be known.
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 months, and a stable family support system, many clinicians will extend the interval of laboratory evaluations to every 6 months. However, clinical care visits every 3 months 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.
Integration of HIV-Infected Children
HIV infection in a child affects the entire family. Serologic testing of siblings and parents is recommended. The physician must provide education and ongoing counseling.
The infected child should be taught good hygiene and behavior to reduce risk to others. How much and when the child is told about the illness depends on age and maturity. Older children and adolescents should be made aware of their diagnosis and the possibility of sexual transmission and should be counseled appropriately. Families may be unwilling to share the diagnosis with people outside the immediate family because it can create social isolation. Feelings of guilt are common. Family members, including children, can become clinically depressed and require counseling.
Because HIV infection is not acquired through the typical types of contact that occur among children (eg, through saliva or tears), HIV-infected children should be allowed to attend school without restrictions. Similarly, there are no inherent reasons to restrict foster care, adoptive placement, or child care of HIV-infected children. Conditions that may pose an increased risk to others (eg, aggressive biting or the presence of exudative, weeping skin lesions that cannot be covered) may require special precautions.
The number of school personnel aware of the child’s condition should be kept to the minimum needed to ensure proper care. The family has the right to inform the school, but people involved in the care and education of an infected child must respect the child’s right to privacy. Disclosures of information should be made only with the informed consent of the parents or legal guardians and age-appropriate assent of the child.
Routine pediatric vaccination protocols ( see Table: Childhood Vaccination Schedule Childhood Vaccination Schedule Vaccination follows a schedule recommended by the Centers for Disease Control and Prevention (CDC), the American Academy of Pediatrics, the American Academy of Family Physicians, and the American... read more ) are recommended for children with HIV infection, with several exceptions. The main exception is that live-virus vaccines and live-bacteria vaccines (eg, bacille Calmette–Guérin [BCG]) should be avoided or used only in certain circumstances ( see Table: Considerations for Use of Live Vaccines in Children With HIV Infection Considerations for Use of Live Vaccines in Children With HIV Infection ). In addition, 1 to 2 months after the last dose of the hepatitis B vaccine Hepatitis B (HepB) Vaccine The hepatitis B vaccine is 80 to 100% effective in preventing infection or clinical hepatitis B in people who complete the vaccine series. For more information, see Hepatitis B Advisory Committee... read more 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 years of age should be immunized with 13-valent pneumococcal conjugate vaccine (PCV-13) Pneumococcal Vaccine Pneumococcal disease (eg, otitis media, pneumonia, sepsis, meningitis) is caused by some of the > 90 serotypes of Streptococcus pneumoniae (pneumococci). Vaccines are directed against... read more as well as pneumococcal polysaccharide vaccine (PPSV) Pneumococcal Vaccine Pneumococcal disease (eg, otitis media, pneumonia, sepsis, meningitis) is caused by some of the > 90 serotypes of Streptococcus pneumoniae (pneumococci). Vaccines are directed against... read more . Certain postexposure treatment recommendations also differ. Recently, quadrivalent meningococcal conjugate immunization Meningococcal Vaccine The meningococcal serogroups that most often cause meningococcal disease in the US are serogroups B, C, and Y. Serogroups A and W cause disease outside the US. Current vaccines are directed... read more 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 polio vaccine should be given according to the routine schedule, and inactivated influenza vaccination Influenza Vaccine Based on recommendations by the World Health Organization and the Centers for Disease Control and Prevention (CDC), vaccines for influenza are modified annually to include the most prevalent... read more should be given yearly.
The live measles-mumps-rubella (MMR) vaccine Measles, Mumps, and Rubella (MMR) Vaccine The measles, mumps, and rubella (MMR) vaccine effectively protects against all 3 infections. People who are given the MMR vaccine according to the US vaccination schedule are considered protected... read more and varicella vaccine Varicella Vaccine Varicella vaccination provides effective protection against varicella (chickenpox). It is not known how long protection against varicella lasts. But, live-virus vaccines, like the varicella... read more 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 Years With HIV Infection Based on Age-Specific CD4+ T-Cell Count or Percentage Immunologic Categories (HIV Infection Stages) for Children < 13 Years 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 months 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 weeks later in an attempt to induce seroconversion as early as possible, although typically a 3-month interval between varicella vaccine doses is preferred in noninfected children < 13 years. 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 months.
The live oral rotavirus vaccine may be given to HIV-exposed or HIV-infected infants according to the routine schedule Childhood Vaccination Schedule Vaccination follows a schedule recommended by the Centers for Disease Control and Prevention (CDC), the American Academy of Pediatrics, the American Academy of Family Physicians, and the American... read more . 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 tuberculosis (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. The World Health Organization (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 Prevention Yellow fever is a mosquito-borne flavivirus infection endemic in tropical South America and sub-Saharan Africa. Symptoms may include sudden onset of fever, relative bradycardia, headache, and... read more ; 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 Poliomyelitis Vaccine Extensive vaccination has almost eradicated polio worldwide. But cases still occur in areas with incomplete immunization, such as sub-Saharan Africa and southern Asia. There are 3 serotypes... read more 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.
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. A resource for transition of HIV-infected youth into adult health care is available from the American Academy of Pediatrics (see Transitioning HIV-Infected Youth Into Adult Health Care).
Prevention of HIV Infection in Infants and Children
For postexposure prevention, see Postexposure prophylaxis (PEP) Postexposure prophylaxis (PEP) Human immunodeficiency virus (HIV) infection results from 1 of 2 similar retroviruses (HIV-1 and HIV-2) that destroy CD4+ lymphocytes and impair cell-mediated immunity, increasing risk of certain... read more .
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 Treatment Human immunodeficiency virus (HIV) infection results from 1 of 2 similar retroviruses (HIV-1 and HIV-2) that destroy CD4+ lymphocytes and impair cell-mediated immunity, increasing risk of certain... read more ). 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. Combination ART is continued throughout pregnancy. Pregnancy is not a contraindication to combination ART regimens; specifically, neither dolutegravir nor efavirenz is contraindicated during the 1st trimester. Although a clinical trial in Botswana showed a link between periconceptional exposure to dolutegravir and a small increase in infant neural tube defects, it is unknown whether this increase was truly due to dolutegravir or to another factor, such as folate deficiency. The majority of experts believe that HIV-infected women already receiving combination ART who become pregnant should continue that therapy, even early during the 1st trimester.
Elective cesarean delivery before onset of labor is recommended if the maternal HIV plasma viral load is > 1000 copies/mL. If labor has already begun, it is less certain whether cesarean delivery will reduce MTCT.
During labor, IV ZDV is given at 2 mg/kg IV for the first hour and then 1 mg/kg/hour IV until delivery to women who have ≥ 1 of the following:
Recent HIV plasma viral load > 1000 copies/mL
Unknown HIV plasma viral load near delivery
Are thought to have had incomplete adherence to ART
Many experts now believe that IV ZDV is not required during labor for women receiving combination ART who have achieved HIV plasma viral loads < 50 copies/mL near delivery. However, IV ZDV should be considered for women with a viral load of 50 to 999 copies/mL at or near delivery; it may provide additional protection against perinatal transmission.
After delivery, combination ART is continued for all women, even those who had not previously received ART.
All HIV-exposed newborns should receive a postpartum ARV regimen to reduce the risk of HIV infection. Treatment should begin as soon as possible, preferably within 6 to 12 hours of delivery. The ARV regimen is determined by maternal and infant risk factors for perinatal HIV transmission (see the guidelines for antiretroviral management of neonates with perinatal HIV exposure or HIV infection).
Preventive regimens are categorized as
ARV prophylaxis: One or more ARV drugs are given to neonates at low risk (< 0.5 to 1%).
Empiric HIV therapy: A two- or three-drug regimen is given to neonates at higher risk (1 to 25%) as prophylaxis, also serving as preliminary treatment for those later confirmed to have HIV.
Low-risk infants are candidates for ARV prophylaxis. They include full-term neonates born to women who have had good virologic control with ART (as shown by an HIV plasma viral load < 50 copies/mL) near delivery and in whom there are no concerns related to adherence to ART. Low-risk infants should be given ARV prophylaxis with ZDV 4 mg/kg orally twice daily for the first 4 weeks of life. ZDV is the backbone of infant prophylaxis and is used for all infants born to HIV-infected women regardless of the risk factors.
Higher-risk infants are given empiric HIV therapy (see table Neonatal Antiretroviral Management According to Risk of HIV Infection Neonatal Antiretroviral Management According to Risk of HIV Infection ), either with a two-drug regimen of ZDV for 6 weeks and nevirapine for 3 doses, or with a three-drug regimen. Some experts choose a two-drug prophylaxis regimen if maternal HIV plasma viral load is < 200 to 400 copies/mL. Three-drug regimens include 6 weeks of zidovudine, lamivudine, and either nevirapine (treatment dose) or raltegravir (for dosing, see table Antiretroviral Dosing for Neonates with Perinatal HIV Exposure ). Very few ARV drugs (notably ZDV, nevirapine, lamivudine, and raltegravir) are considered to be safe and effective for infants < 14 days postnatal age, and fewer still (only zidovudine, lamivudine, and nevirapine) have dosing data available for premature infants. The optimal ARV regimen for neonates born to women with ARV drug-resistant virus is unknown.
Infants who subsequently have a positive HIV virologic test are given ART with three drugs. An expert in pediatric or maternal HIV infection should be immediately consulted (see information at AIDSinfo or at the National Clinician Consultation Center). Clinicians also can call the Perinatal HIV Consultation and Referral Services Hotline at 1-888-HIV-8765 (1-888-448-8765) for questions regarding interventions to decrease vertical HIV transmission and neonatal diagnosis.
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. 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 gastrointestinal 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 months 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 Condoms Barrier contraceptives include vaginal spermicides (foams, creams, gels, suppositories), contraceptive gel, condoms, diaphragms, cervical caps, and contraceptive sponges. Vaginal foams, creams... read more ) 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 Prevention of transmission Human immunodeficiency virus (HIV) infection results from 1 of 2 similar retroviruses (HIV-1 and HIV-2) that destroy CD4+ lymphocytes and impair cell-mediated immunity, increasing risk of certain... read more ) 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 PrEP to prevent HIV and promote sexual health from the New York State Department of Health AIDS Institute and Pre-Exposure Prophylaxis (PrEP) from AIDSinfo.
Prevention of opportunistic infections
Prophylactic drug treatment is recommended in certain HIV-infected children for prevention of Pneumocystis pneumonia Pneumocystis jirovecii Pneumonia Pneumocystis jirovecii is a common cause of pneumonia in immunosuppressed patients, especially in those infected with human immunodeficiency virus (HIV) and in those receiving systemic... read more 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 AIDSinfo.
Prophylaxis against Pneumocystis pneumonia is indicated for
HIV-infected children ≥ 6 years of age with CD4+ count < 200 cells/mcL or CD4+ percentage < 14%
HIV-infected children 1 to < 6 years of age with CD4+ count < 500 cells/mcL or CD4+ percentage < 22%
HIV-infected infants < 12 months of age regardless of CD4+ count or percentage
Infants born to HIV-infected women (beginning at 4 to 6 weeks of age), until HIV infection is either presumptively excluded by documentation of 2 negative virologic test results (1 at ≥ 2 weeks of age and 1 at ≥ 4 weeks of age) or definitively excluded by documentation of 2 negative virologic test results (1 at ≥ 1 month of age and 1 at ≥ 4 months 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 months and whose CD4+ percentage and CD4+ count have remained higher than the previously described treatment thresholds for > 3 consecutive months. Subsequently, the CD4+ percentage and count should be reevaluated at least every 3 months, 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 orally 2 times a day on 3 consecutive days/week (eg, Monday-Tuesday-Wednesday); alternative schedules include the same dose 2 times a day every day, the same dose 2 times a day on alternate days, or twice the dose (TMP 150 mg/SMX 750 mg/m2) once a day for 3 consecutive days/week. Some experts find it easier to use weight-based dosing (TMP 2.5 to 5 mg/SMX 12.5 to 25 mg/kg orally 2 times a day).
For patients who cannot tolerate TMP/SMX, dapsone 2 mg/kg (not to exceed 100 mg) orally once a day is an alternative, especially for those < 5 years of age. Oral atovaquone given daily or aerosolized pentamidine (300 mg via specially designed inhaler for children ≥ 5 years) given once a month 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 years with CD4+ count < 50 cells/mcL
Children 2 to 6 years with CD4+ count < 75 cells/mcL
Children 1 to 2 years with CD4+ count < 500 cells/mcL
Children < 1 year with CD4+ count < 750 cells/mcL
Weekly azithromycin or daily clarithromycin is the drug of choice, and daily rifabutin is an alternative.
Most HIV cases in infants and children result from mother-to-child transmission (MTCT) before or during birth, or from breastfeeding in countries where safe and affordable infant formula is not available.
Maternal antiretroviral therapy (ART) can reduce incidence of MTCT from about 25% to < 1%.
Diagnose children < 18 months using qualitative RNA assays (eg, transcription-mediated amplification of RNA) or DNA polymerase chain reaction (PCR) assays.
Diagnose children > 18 months 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 (using rapid initiation) all HIV-infected infants < 12 months of age; those 1 to < 6 years of age who have stage 3–defining opportunistic infections or CD4 counts < 500 cells/mcL; and those ≥ 6 years of age who have stage 3–defining opportunistic infections or CD4 counts < 200 cells/mcL.
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.
The following are some English-language resources that may be useful. Please note that THE MANUAL is not responsible for the content of these resources.
See the following continually updated government site for information on drug treatment, including adverse effects, dosing (especially for information on fixed-dose combination products), and drug interactions, educational materials, and quick links to related topics:
AIDSinfo.gov: Pre-Exposure Prophylaxis (PrEP)
The following resources provide information about various other prevention, treatment, and education aspects of HIV/AIDS:
New York State Department of Health AIDS Institute HIV Clinical Guidelines Program: Disseminates practical, evidence-based clinical guidelines that promote quality medical care for people in New York who are living with and/or are at risk of acquiring HIV and certain other illnesses
New York State Department of Health AIDS Institute: Pre-exposure prophylaxis (PrEP) guidelines, education, and training for HIV prevention
New York State Department of Health AIDS Institute: Comprehensive information regarding all aspects of HIV/AIDS, including treatment, social awareness, resources for consumers, and training for professionals
UNAIDS: Comprehensive information on how the organization directs, advocates, coordinates, and provides technical support needed to connect leadership from governments, the private sector, and communities to deliver life-saving HIV services
National Clinician Consultation Center: Up-to-date HIV/AIDS guidelines and key treatment protocols for HIV/AIDS treatment, prevention, and exposure
Perinatal HIV Consultation and Referral Services Hotline 1-888-HIV-8765 (1-888-448-8765): Free 24-hour clinical consultation and advice on treating HIV-infected pregnant women and their infants