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(See also Human Immunodeficiency Virus (HIV).)
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 viral PCR assay 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 Sidebar 1: Human Immunodeficiency Virus (HIV) Infection in Infants and Children: Integration of HIV-Infected Children ).
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Sidebar 1
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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, > 9300 cases have been reported in children and adolescents, representing only 1% of total cases.
More than 90% of 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 are the result of sexual abuse. Fewer than 5% of cases have no clear source. Vertical transmission now accounts for almost all new cases in US preadolescents. Cases in adolescents represent survivors of vertically transmitted infection and newly acquired infection (typically from sexual contact, particularly by young men who have sex with men).
Worldwide, about 2 million children have HIV infection (6% of the total caseload worldwide), and about 370,000 more children are infected each year (14% of all new infections). In sub-Saharan Africa, where the epidemic has been present longest, some prenatal clinics report that 25 to 40% of all women of childbearing age are seropositive for HIV. HIV infection is rapidly increasing in India, China, Southeast Asia, and some areas of Eastern Europe and Russia. About 270,000 children die of HIV infection worldwide each year.
Transmission:
Infection risk for an infant born to an HIV-positive mother who did not receive antiretroviral (ARV) therapy during pregnancy is estimated at 13 to 39%. Risk is greatest for infants born to mothers who seroconvert during pregnancy and for those with advanced disease, low peripheral CD4+ T-cell counts, prolonged rupture of membranes, and high plasma viral RNA concentrations. In vaginal deliveries, a 1st-born twin is at greater risk than a 2nd-born twin, although this relationship may not hold true in developing countries
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 ARV therapy (including zidovudine [ZDV, AZT]) 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 highly active antiretroviral therapy (HAART) reduces it to < 2%.
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 concentrations (eg, women who become infected during pregnancy or during the period of breastfeeding).
The total number of HIV-infected US adolescents continues to increase despite the marked success in decreasing perinatal HIV infection through comprehensive diagnosis and treatment of infected pregnant women. This paradoxical increase is a result of both greater survival among perinatally infected children and the additional acquisition of new cases of HIV infection by sexual transmission among other adolescents.
Classification:
HIV infection causes a broad spectrum of disease, of which AIDS is the most severe. Classification schemes established by the Centers for Disease Control and Prevention (CDC) define the progression of clinical and immunologic decline.
Clinical categories in children < 13 yr (see Table 1: Human Immunodeficiency Virus (HIV) Infection in Infants and Children: 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
Immunologic categories in children < 13 yr (see Table 2: Human Immunodeficiency Virus (HIV) Infection in Infants and Children: Immunologic Categories for Children < 13 Yr With HIV Infection Based on Age-Specific CD4+ T-Cell Counts and Percentages of Total Lymphocyte Counts) reflect the degree of immune suppression based on the CD4+ T-cell count (absolute count and as percentage of total lymphocyte count):
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.
These clinical and immunologic categories are becoming less clinically relevant in the era of HAART, which (when taken as prescribed) almost invariably leads to a decrease in symptoms and an increase in CD4+ T-cell counts. The categories are most useful for clinical research and for describing the severity of illness at the time of diagnosis.
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Table 1
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| Clinical Categories for Children Aged < 13 Yr With HIV Infection |
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Category N: Not symptomatic
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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
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Category A: Mildly symptomatic
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Children with ≥ 2 of the conditions listed below but none of the conditions listed in category B or C:
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Dermatitis
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Hepatomegaly
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Lymphadenopathy (≥ 0.5 cm at > 2 sites; bilateral = 1 site)
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Parotitis
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Recurrent or persistent upper respiratory tract infection, sinusitis, or otitis media
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Splenomegaly
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Category B: Moderately symptomatic
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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:
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Anemia (< 8 g/dL), neutropenia (< 1,000/μL), or thrombocytopenia (< 100,000/μL) persisting ≥ 30 days
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Bacterial meningitis, pneumonia, or sepsis (single episode)
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Candidiasis, oropharyngeal (thrush), persisting (> 2 mo) in children > 6 mo of age
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Cardiomyopathy
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Cytomegalovirus infection with onset before 1 mo of age
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Diarrhea, recurrent or chronic
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Hepatitis
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Herpes zoster (shingles) involving ≥ 2 distinct episodes or > 1 dermatome
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HSV stomatitis, recurrent (> 2 episodes within 1 yr)
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HSV bronchitis, pneumonitis, or esophagitis with onset before 1 mo of age
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Leiomyosarcoma
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Lymphoid interstitial pneumonitis or pulmonary lymphoid hyperplasia complex
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Nephropathy
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Nocardiosis
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Persistent fever (lasting > 1 mo)
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Toxoplasmosis with onset before 1 mo of age
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Varicella, disseminated (complicated chickenpox)
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Category C: Severely symptomatic
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Children with ≥ 1 of the following conditions:
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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)
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Candidiasis, esophageal or pulmonary (bronchi, trachea, lungs)
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Coccidioidomycosis, disseminated (at a site other than or in addition to the lungs or cervical or hilar lymph nodes)
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Cryptococcosis, extrapulmonary
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Cryptosporidiosis or isosporiasis with diarrhea persisting > 1 mo
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Cytomegalovirus disease with onset of symptoms at age > 1 mo (at a site other than the liver, spleen, or lymph nodes)
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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):
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Failure to attain or loss of developmental milestones or loss of intellectual ability, verified by standard developmental scale or neuropsychologic tests
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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)
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Acquired symmetric motor deficit manifested by ≥ 2 of the following: paresis, pathologic reflexes, ataxia, or gait disturbance
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Histoplasmosis, disseminated (at a site other than or in addition to the lungs or cervical or hilar lymph nodes)
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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
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Kaposi's sarcoma
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Lymphoma, primary, in the brain
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Lymphoma: Small, noncleaved cell lymphoma (Burkitt's), or immunoblastic or large-cell lymphoma of B-cell or unknown immunologic phenotype
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Mycobacterium tuberculosis, disseminated or extrapulmonary
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Mycobacterium, other species or unidentified species, disseminated (at a site other than or in addition to the lungs, skin, or cervical or hilar lymph nodes)
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Pneumocystis jirovecii pneumonia
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Progressive multifocal leukoencephalopathy
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Salmonella (nontyphoid) septicemia, recurrent
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Toxoplasmosis of the brain with onset at > 1 mo of age
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Wasting syndrome in the absence of a concurrent illness (other than HIV infection) that could explain any one of the following 3 findings:
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Persistent weight loss > 10% of baseline
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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
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< 5th percentile on weight-for-height chart on 2 consecutive measurements ≥ 30 days apart
plus 1 of the following:
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Chronic diarrhea (ie, ≥ 2 loose stools/day for ≥ 30 days)
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Documented fever (for ≥ 30 days, intermittent or constant)
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HSV = herpes simplex virus.
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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.
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Table 2
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| Immunologic Categories for Children < 13 Yr With HIV Infection Based on Age-Specific CD4+ T-Cell Counts and Percentages of Total Lymphocyte Counts |
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Immunologic Categories
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< 12 mo
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1–5 yr
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6–12 yr
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Cells/µL
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%
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Cells/µL
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%
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Cells/µL
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%
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1: No evidence of suppression
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≥ 1500
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≥ 25
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≥ 1000
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≥ 25
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≥ 500
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≥ 25
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2: Evidence of moderate suppression
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750–1499
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15–24
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500–999
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15–24
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200–499
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15–24
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3: Severe suppression
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< 750
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< 15
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< 500
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< 15
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< 200
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< 15
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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.
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Symptoms and Signs
Natural history in untreated children:
Infants infected perinatally usually are asymptomatic during the first few months of life. Although the median age at symptom onset is about 3 yr, some children remain asymptomatic for > 5 yr and, with appropriate ARV therapy, are expected to survive to adulthood. In the pre-ARV therapy 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 ARV therapy was used routinely).
The most common manifestations of HIV infection in children 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:
Pneumocystis jirovecii pneumonia is the most common, serious, opportunistic infection among HIV-infected children 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 children with Pneumocystis pneumonia characteristically develop a subacute, diffuse pneumonitis with dyspnea at rest, tachypnea, O2 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 common opportunistic infections include Candida esophagitis, disseminated cytomegalovirus infection, and chronic or disseminated herpes simplex and varicella-zoster virus infections, 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's type), occur much more often than in immunocompetent children. Kaposi's sarcoma is very rare in HIV-infected children.
Children receiving combination antiretroviral therapy:
Combination ARV therapy 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 pretreatment era. New problems, such as alterations in serum lipids, hyperglycemia, fat maldistribution (lipodystrophy and lipoatrophy), nephropathy, and osteonecrosis, are reported, although with lower incidence than in HIV-infected adults. Although combination therapy 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.
Diagnosis
HIV-specific tests:
In children > 18 mo, diagnosis is made using serum antibody tests (enzyme immunoassay [EIA] and confirmatory Western blot) as in adults. 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 on EIA, so diagnosis is made by HIV virologic assays such as DNA PCR, which can diagnose about 30% of cases at birth and nearly 100% 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 DNA PCR in most laboratories.
HIV RNA assays (the viral load assays used for monitoring efficacy of treatment) are becoming more widely used for diagnostic testing of infants. RNA assays are probably as sensitive as DNA PCR in infants not given ARV therapy, are less expensive, and are more widely available than is DNA PCR. However, care must be taken when using RNA assays for infant diagnosis because test specificity is uncertain at very low RNA concentrations (< 10,000 copies/mL) and sensitivity is unknown in infants of mothers with complete treatment-mediated viral suppression at the time of delivery. The modified p24 antigen assay is less sensitive than either HIV DNA PCR or RNA assays and should be used only if the latter are unavailable.
An initial virologic test should be done within the first 2 wk of life, at about 1 mo of age, and between 4 mo and 6 mo. A positive test should be confirmed immediately by using the same or another virologic test. If the serial HIV virologic tests are all negative, the infant is considered uninfected with > 95% accuracy (in the absence of any AIDS-defining illness). Follow-up antibody tests (1 EIA at > 18 mo or, alternatively, 2 EIAs done between 6 mo and 18 mo) are done to 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 1: Human Immunodeficiency Virus (HIV) Infection in Infants and Children: Clinical Categories for Children Aged < 13 Yr With HIV Infection), HIV infection is diagnosed.
Rapid tests for HIV antibody are derivatives of EIAs that provide results within minutes to hours. They can be done as point-of-care tests on oral secretions, whole blood, or serum. In the US, these tests are perhaps most useful in labor and delivery suites to test women of unknown HIV serostatus, thus allowing counseling, commencement of ARV therapy 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. In the US, rapid assays require confirmatory tests, such as Western blot testing. These confirmatory tests are especially important because in areas where the expected HIV prevalence is low, even a specific rapid assay yields mostly false positives (low positive predictive value by Bayes' theorem—see Clinical Decision Making: Bayes' Theorem). However, if the expected probability of HIV (or seroprevalence) is high, the positive predictive value increases.
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. Written or oral 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 AIDS must be reported to the appropriate public health department. In many states, HIV infection (before the development of AIDS) also must be reported.
Other tests:
Once infection is diagnosed, other tests are done:
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 2: Human Immunodeficiency Virus (HIV) Infection in Infants and Children: Immunologic Categories for Children < 13 Yr With HIV Infection Based on Age-Specific CD4+ T-Cell Counts and Percentages of Total Lymphocyte Counts) 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 pretherapy 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 HAART regimens, most perinatally infected children survive well beyond 5 yr. Many children are surviving into young adulthood; increasing numbers have given birth to or fathered their own children.
Nevertheless, opportunistic infections, particularly Pneumocystis pneumonia, progressive neurologic disease, and severe wasting, are associated with a poor prognosis. 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.
Treatment
Because of the success of ARV therapy, 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 specialists who have experience in the management of pediatric HIV infection.
ARV drugs:
There are > 2 dozen ARV drugs (see Table 3: Human Immunodeficiency Virus (HIV) Infection in Infants and Children: Dosage and Administration of Antiretroviral Drugs for Childrena), including multidrug combination products, available in the US, each of which may have adverse effects and drug interactions with other ARV drugs or commonly used antibiotics, anticonvulsants, and sedatives. New ARV drugs, immunomodulators, and vaccines are under evaluation. For current information on dosing, adverse effects, and drug interactions, see guidelines for the use of antiretroviral agents in pediatric HIV infection and guidelines for adults and adolescents available at www.aidsinfo.nih.gov. Useful treatment information is also available at www.hivguidelines.org and www.unaids.org/en/.
Standard treatment is with combination ARV therapy to maximize viral suppression and minimize selection of drug-resistant strains. Most commonly, ARV therapy consists of a backbone of 2 nucleoside analog reverse transcriptase inhibitors (ZDV plus lamivudine or emtricitabine, abacavir plus lamivudine or emtricitabine, didanosine plus lamivudine or emtricitabine, or, for postpubertal adolescents, tenofovir plus emtricitabine) given in combination with either a ritonavir-boosted protease inhibitor (lopinavir/ritonavir, ritonavir-boosted atazanavir, ritonavir-boosted fosamprenavir, or ritonavir-boosted darunavir) or a nonnucleoside reverse transcriptase inhibitor (efavirenz or, in some situations, nevirapine). Other combinations sometimes are used, but fewer data are available to support their use as first-line regimens. Monotherapy or dual nucleoside reverse transcriptase inhibitor therapy alone (except for ZDV chemoprophylaxis in HIV-exposed infants) is strongly discouraged. Because expert opinions on therapeutic strategies change rapidly, consultation with specialists is strongly advised.
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Table 3
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| Dosage and Administration of Antiretroviral Drugs for Childrena
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Drug
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Recommended Dosage (Oral)
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Selected Adverse Effects
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Nucleoside reverse transcriptase inhibitors (NRTIs)
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Abacavir (ABC)b
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< 13 yr: 8 mg/kg q 12 h
≥ 13 yr: 300 mg q 12 h or 600 mg q 24 h
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More common: Nausea, vomiting, fever, headache, rash, anorexia
Less common: Hypersensitivity syndrome (∼ 5%), which may cause fever, fatigue, malaise, nausea, vomiting, abdominal pain, lymphadenopathy, or rash mostly during the first 6 wk of use and primarily among patients with HLA-B*5701 genotype (before prescribing abacavir, clinicians should test for this allele); risk of hypotension or death with rechallenge
Rare: Increased hepatic aminotransferases, elevated serum glucose and triglycerides, possibly increased risk of MI in adults
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Didanosine (ddI)c
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< 13 yr, pediatric solution:
4 mo–13 yr: 120 mg/m2 q 12 h
≥ 13 yr, extended-release capsules q 24 h:
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More common: Diarrhea, nausea, vomiting
Less common: Peripheral neuropathy, lactic acidosis, hepatomegaly with steatosis
Rare: Pancreatitis, retinitis
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Emtricitabine (FTC)
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< 18 yr, weight-based dosing:
≥ 18 yr: 200 mg q 24 h
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More common: Headache, diarrhea, nausea, rash, hyperpigmentation
Less common: Lactic acidosis, hepatomegaly with steatosis
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Lamivudine (3TC)
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0–3 mo: 2 mg/kg q 12 h
4 mo–12 yr: 4 mg/kg q 12 h
≥ 13 yr: 150 mg q 12 h or 300 mg q 24 h
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More common: Headache, fatigue, nausea, diarrhea, rash
Less common: Pancreatitis, neutropenia, peripheral neuropathy, lactic acidosis, hepatomegaly with steatosis
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Stavudine (d4T)
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0–1 mo: 0.5 mg/kg q 12 h
2 mo–12 yr: 1 mg/kg q 12 h
≥ 13 yr, weight-based dosing:
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More common: Headache, GI disturbances, rash, lipoatrophy
Less common: Peripheral neuropathy, pancreatitis, lactic acidosis, hepatomegaly with steatosis, lipodystrophy
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Tenofovir (TDF)d
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< 18 yr: Unknown; in clinical trials, 8 mg/kg q 24 h up to 300 mg q 24 h
≥ 18 yr: 300 mg q 24 h
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More common: Nausea, diarrhea, vomiting
Less common: Lactic acidosis, hepatomegaly with steatosis, reduced bone mineral density, renal tubular dysfunction
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Zidovudine (ZDV, AZT)e
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0–6 wk: 2 mg/kg q 6 h
3 mo–12 yr: 240 mg/m2 q 12 h or weight-based dosing:
≥ 13 yr: 300 mg q 12 h
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More common: Anemia, granulocytopenia, macrocytosis, headache, malaise, nausea, vomiting, anorexia
Less common: Hepatotoxicity, myositis, myopathy (associated with prolonged use), lactic acidosis, hepatomegaly with steatosis
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NRTI combination products
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ZDV/3TC
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≥ 13 yr: 300/150 mg q 12 h
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See individual drugs
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ZDV/3TC/ABC
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≥ 13 yr: 300/150/300 mg q 12 h
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See individual drugs
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3TC/ABC
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≥ 13 yr: 300/600 mg q 24 h
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See individual drugs
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FTC/TDF
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≥ 13 yr: 200/300 mg q 24 h
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See individual drugs
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FTC/TDF/EFV
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≥ 13 yr: 200/300/600 mg q 24 h
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See individual drugs
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Nonnucleoside reverse transcriptase inhibitors (NNRTIs)
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Efavirenz (EFV)f
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3–12 yr, weight-based dosing:
≥ 13 yr: 600 mg q 24 h
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More common: Rash, CNS disturbances (eg, somnolence, insomnia, abnormal dreams, confusion) mostly in adults, increased hepatic aminotransferases
Teratogenic in primates
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Etravirine (ETR)g
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< 18 yr: Unknown
≥ 18 yr: 200 mg q 12 h, taken with food
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More common: Mild rash (appears to be less cross-reactive with other NNRTIs)
Less common: More severe rash (including Stevens-Johnson syndrome), hypersensitivity
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Nevirapine (NVP)h
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2 wk–12 yr: 150 mg/m2 q 12 h
≥ 13 yr: 200 mg q 12 h
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More common: Rash (including Stevens-Johnson syndrome), fever, nausea, headache
Less common: Hepatic inflammation (rarely, life threatening, less common among children than adults and more likely when active hepatitis B, hepatitis C, or pregnancy is present); hypersensitivity reactions
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Protease inhibitors (PIs)
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Atazanavir (ATV) with low-dose RTV as a pharmacokinetic booster
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6–17 yr, weight-based dosing:
15–24 kg: ATV 150 mg + RTV 80 mg q 24 h
25–31 kg: ATV 200 mg + RTV 100 mg q 24 h
32–38 kg: ATV 250 mg + RTV 100 mg q 24 h
≥39 kg: ATV 300 mg + RTV 100 mg q 24 h
≥ 18 yr: ATV 300 mg + RTV 100 mg q 24 h
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More common: Asymptomatic indirect hyperbilirubinemia (30%), jaundice (10%), headache, arthralgia, nausea, vomiting, diarrhea, insomnia
Less common: Prolongation of PR interval on ECG
Rare: Hepatitis (especially in patients with hepatitis B or C co-infection), hyperglycemia, diabetes mellitus, nephrolithiasis
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Darunavir (DRV)i with low-dose RTV as a pharmacokinetic booster
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6–17 yr, weight-based dosing:
20–29 kg: DRV 375 mg + RTV 50 mg q 12 h
30–39 kg: DRV 450 mg + RTV 60 mg q 12 h
≥ 40 kg: DRV 600 mg + RTV 100 mg q 12 h
≥ 18 yr: DRV 600 mg + RTV 100 mg q 12 h
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More common: Diarrhea, nausea, vomiting
Less common: Rash (including Stevens-Johnson syndrome)
Rare: Hepatitis (especially in patients with hepatitis B or C coinfection), hyperglycemia, diabetes mellitus
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Fosamprenavir (f-APV)j with low-dose RTV as a pharmacokinetic booster
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6–12 yr: f-APV 18 mg/kg + RTV 3 mg/kg q 12 h (up to f-APV 700 mg + RTV 100 mg q 12 h)
≥ 13 yr: f-APV 700 mg + RTV 100 mg q 12 h
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More common: Diarrhea, nausea, vomiting, rash, lipid abnormalities
Less common: Rash (including Stevens-Johnson syndrome), fat redistribution, elevated serum creatinine kinase
Rare: Hyperglycemia, diabetes mellitus
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Indinavir (IDV) with RTV as a pharmacokinetic booster
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< 13 yr: Unknown
≥ 13 yr: IDV 800 mg + RTV 200 mg q 12 h
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More common: Nausea, abdominal pain, headache, asymptomatic indirect hyperbilirubinemia (10%), lipid abnormalities, rash, crystalluria and nephrolithiasis (more common among children [29%] than adults [12%], especially if patients are not adequately hydrated)
Less common: Fat redistribution
Rare: Diabetes mellitus, hemolytic anemia
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Lopinavir/ritonavir (LPV/r)k
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2 wk–6 mo: 16 mg/kg (as LPV component) q 12 h
7 mo–12 yr, weight-based dosing (as LPV component):
15–40 kg: 10 mg/kg q 12 h
≥ 13 yr: LPV 400 mg q 12 h
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More common: Nausea, vomiting, diarrhea, headache, rash, lipid abnormalities
Less common: Fat redistribution
Rare: Diabetes mellitus, hyperglycemia, ketoacidosis, pancreatitis, hepatitis
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Nelfinavir (NFV)
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2–12 yr: 45–55 mg/kg q 12 h
≥ 13 yr: 1250 mg q 12 h
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More common: Diarrhea, abdominal pain, asthenia, lipid abnormalities, fewer drug interactions
Less common: Fat redistribution
Rare: Diabetes mellitus, hyperglycemia, ketoacidosis, hepatitis
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Ritonavir (RTV)l
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As a pharmacokinetic booster, 100 mg q 12 h (except 200 mg q 12 h with IDV or TPV)
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More common: Nausea, vomiting, diarrhea, anorexia, headache, lipid abnormalities
Less common: Fat redistribution
Rare: Diabetes mellitus, hepatitis, hyperglycemia, ketoacidosis, pancreatitis, prolongation of PR interval
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Saquinavir (SQV) with low-dose RTV as a pharmacokinetic booster
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< 16 yr: Unknown
≥ 16 yr: SQV 1000 mg + RTV 100 mg q 12 h
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More common: Diarrhea, abdominal discomfort, anorexia, headache, nausea, rash, lipid abnormalities
Less common: Fat redistribution
Rare: Diabetes mellitus, hepatitis, hyperglycemia, ketoacidosis, pancreatitis
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Tipranavir (TPV) with RTV as pharmacokinetic booster
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2–12 yr: TPV 14 mg/kg + RTV 6 mg/kg q 12 h (up to TPV 500 mg + RTV 200 mg q 12 h)
≥ 13 yr: TPV 500 mg + RTV 200 mg q 12 h
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More common: Diarrhea, nausea, fatigue, headache, rash, lipid abnormalities, elevated hepatic aminotransferases
Less common: Fat redistribution, clinical hepatitis (especially in patients with chronic hepatitis B or C coinfection), epistaxis
Rare: Diabetes mellitus, hyperglycemia, ketoacidosis, possible association with intracranial hemorrhage
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Entry inhibitor (CCR5 antagonist)
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Maraviroc (MVC)m
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< 16 yr: Unknown
≥ 16 yr: 150, 300, or 600 mg q 12 h depending on coadministered CYP3A inducers or inhibitors
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More common: Cough, fever, rash, musculoskeletal symptoms, dizziness
Less common: Cardiovascular abnormalities (< 2% of adults), liver failure (< 2% of adults), cholestatic jaundice (< 2% of adults)
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Fusion inhibitor
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Enfuvirtide (T20)n
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6–15 yr: 2 mg/kg sc q 12 h (up to 90 mg sc q 12 h)
≥16 yr: 90 mg sc q 12 h
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More common: Local injection site reaction (pain, discomfort, induration, erythema, nodules, ecchymosis) in ∼ 98%
Rare: Hypersensitivity reaction
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Integrase inhibitor
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Raltegravir (RAL)
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< 16 yr: Unknown
≥ 16 yr: 400 mg q 12 h
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More common: Nausea, headache, diarrhea, fatigue
Less common: Abdominal pain, vomiting, elevated hepatic aminotransferases in patients coinfected with hepatitis B or C
Rare: Elevated creatinine kinase, myopathy, rhabdomyolysis
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aFor information on adverse effects, other doses, and drug interactions, see 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, February 23, 2009. Available at www.aidsinfo.nih.gov/ContentFiles/PediatricGuidelines.pdf.
b
Abacavir has a 5% hypersensitivity rate in patients of all ages; patients with possible hypersensitivity must not be rechallenged.
cThe didanosine dose must be adjusted when tenofovir is also used.
d
Tenofovir is functionally grouped within nucleoside reverse transcriptase inhibitors but is actually a nucleotide reverse transcriptase inhibitor by chemical structure.
eThe dosing interval for zidovudine is extended for premature infants.
fProtease inhibitor dosing may be affected by use of efavirenz.
gEtravirine has multiple drug interactions with protease inhibitors and cannot be given with other nonnucleoside reverse transcriptase inhibitors.
hWith nevirapine, a 14-day dose escalation lead-in period reduces complications in patients of all ages.
iDarunavir contains a sulfa moiety; the drug's potential for cross-reaction is unknown.
j
Fosamprenavir is a sulfonamide, but its potential for cross-reaction is unknown.
kLopinavir is coformulated with a small amount of ritonavir as a pharmacokinetic booster.
l
Ritonavir is rarely used as a therapeutic protease inhibitor, but if it is, the dose for adolescents and adults is 600 mg q 12 h.
mMaraviroc is given only to patients with CCR5-tropic HIV type 1 infection.
nAn oral preparation of enfuvirtide is not available.
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Indications:
Initiation of ARV therapy depends on virologic, immunologic, and clinical criteria; authorities differ on these criteria. The goal is to 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.
For children ≥ 12 mo, ARV therapy is recommended for all children with significant clinical or immunologic disease (clinical category B or C [Table 1: Human Immunodeficiency Virus (HIV) Infection in Infants and Children: Clinical Categories for Children Aged < 13 Yr With HIV Infection] or CD4+ percentage < 25% for children < 5 yr or CD4+ cell count < 350/μL for children ≥ 5 yr), regardless of the plasma HIV RNA viral load. Therapy is considered for other children who have plasma HIV RNA concentrations ≥ 100,000 copies/mL. Children who do not meet these criteria may be monitored closely without ARV therapy, but their clinical and laboratory data should be reevaluated every 3 to 4 mo.
For children < 12 mo, ARV therapy should be given to all regardless of clinical symptoms, CD4+ T-cell percentages or counts, or plasma HIV RNA viral load; clinical trials have shown that early therapy of infected infants decreases mortality.
Adherence:
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 need to take some drugs with food or in the fasted state, a child's dependence on others to give drugs (and HIV-infected parents may have problems with remembering to take their own drugs), and adolescents' denial or fear of their infection, distrust of the medical establishment, and lack of family support.
Monitoring:
Clinical and laboratory monitoring are important for identifying drug toxicity and therapeutic failure.
Vaccination:
Routine pediatric vaccination protocols (see Approach to the Care of Normal Infants and Children: Recommended Immunization Schedule for Ages 0–6 yr) 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 4: Human Immunodeficiency Virus (HIV) Infection in Infants and Children: 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), and children aged ≥ 2 yr should be given pneumococcal polysaccharide vaccine (PPSV) ≥ 2 mo after their last pneumococcal conjugate vaccine (PCV) dose, and a single revaccination should be given after 5 yr. Certain postexposure treatment recommendations also differ.
Live oral poliovirus vaccine and live-attenuated influenza vaccine are not recommended.
The live measles-mumps-rubella (MMR) and varicella vaccines should not be given to children with AIDS or other manifestations of severe immunosuppression. However, the MMR and varicella 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 symptomatic patients who are not severely immunocompromised (ie, not in category 3 [see Table 2: Human Immunodeficiency Virus (HIV) Infection in Infants and Children: Immunologic Categories for Children < 13 Yr With HIV Infection Based on Age-Specific CD4+ T-Cell Counts and Percentages of Total Lymphocyte Counts], including having a CD4+ T-cell percentage of ≥ 15%); if possible, these 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 generally a 3-mo interval between varicella vaccine doses is preferred in noninfected children < 13 yr. If the risk of exposure to measles is increased, 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 experts feel that there is overall benefit to immunization, particularly in areas where rotavirus causes significant mortality.
The BCG vaccine is not recommended in the US, an area of low TB prevalence. However, elsewhere in the world, especially in developing countries where TB prevalence is high, the WHO recommends that BCG be given to all infants shortly after birth, unless they have symptoms of HIV infection or already have been confirmed to have HIV infection (eg, positive virologic assay). Some cases of disseminated BCG infection in severely immunocompromised AIDS patients have been reported.
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 immune globulin. 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.
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Table 4
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| Considerations for Use of Live Vaccines in Children With HIV Infection |
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Live Vaccine
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Symptomatic Infection
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Asymptomatic Infection
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Age
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Comments
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Age
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Comments
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BCG
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Birth
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Not recommended
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Birth
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Not recommended (may give to HIV-exposed neonates with unconfirmed HIV infection status)
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Oral poliovirus
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N/A
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Not recommended
Inactivated vaccine given according to routine schedule*
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N/A
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Not recommended
Inactivated vaccine given according to routine schedule*
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Live-attenuated influenza (LAIV)
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N/A
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Not recommended
Inactivated vaccine given according to routine schedule*
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N/A
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Not recommended
Inactivated vaccine given according to routine schedule*
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Measles-mumps-rubella (MMR)
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At 12 mo followed by the 2nd dose in as soon as 4 wk
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Can be given to children whose CD4+ T-cell percentage is ≥ 15%
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)
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Routine*
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Can be given to children whose CD4+ T-cell percentage is ≥ 15%
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Rotavirus, live- attenuated
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Routine*
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Limited evidence, but benefits of vaccine likely outweigh its risks
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Routine*
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Recommended by AAP, ACIP, and WHO
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Varicella
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At 12 mo followed by the 2nd dose in 3 mo (although may give 2nd dose in as soon as 4 wk)
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Can be given to children whose CD4+ T-cell percentage is ≥ 15%
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At 12 mo followed by the 2nd dose in 3 mo (although may give 2nd dose in as soon as 4 wk)
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Can be given to children whose CD4+ T-cell percentage is ≥ 15%
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*Given according to the usual pediatric immunization schedule (see Table 12: Approach to the Care of Normal Infants and Children: Recommended Immunization Schedule for Ages 0–6 yr and Table 13: Approach to the Care of Normal Infants and Children: Recommended Immunization Schedule for Ages 7–18 yr).
AAP = American Academy of Pediatrics; ACIP = Advisory Committee on Immunization Practices.
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Prevention
For postexposure prevention, see Human Immunodeficiency Virus (HIV): Postexposure prophylaxis (PEP).
Prevention of perinatal transmission:
Appropriate prenatal ARV therapy 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 Human Immunodeficiency Virus (HIV): Treatment). Rapid HIV testing of pregnant women who present in labor without documentation of their HIV serostatus may allow immediate institution of such measures.
HIV-infected pregnant women who have not received ARV drugs previously and who do not meet adult criteria (see Human Immunodeficiency Virus (HIV): Treatment) for HAART are nevertheless recommended to initiate HAART, preferably including ZDV 300 mg po bid, beginning at 14 to 34 wk gestation. Pregnancy is not a contraindication to HAART regimens, although the use of efavirenz is generally contraindicated during the 1st trimester. This regimen is continued throughout the pregnancy. ZDV is given during labor 2 mg/kg IV for the first hour and then 1 mg/kg/h IV until delivery. ZDV 2 mg/kg po qid is given to the neonate for the first 6 wk of life. In the immediate postpartum period, a decision can be made whether to continue maternal therapy.
Most experts believe that HIV-infected women already receiving combination ARV therapy 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.
For HIV-infected pregnant women who present in labor and have had no prior therapy, clinicians have used ARV combinations, cesarean delivery, or both; the woman and her infant are given ZDV as described previously (ie, the woman receives drugs IV during labor and delivery; the infant receives drugs by mouth). Some authorities give additional antiretrovirals in this situation; an expert in pediatric or maternal HIV infection should be immediately consulted (see information at www.aidsinfo.nih.gov or www.nccc.ucsf.edu).
Although the final decision to accept ARV therapy remains with the pregnant woman, it should be stressed that the proven benefits of therapy far outweigh the theoretical risks of 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. 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 mothers continue to breastfeed.
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 [see Family Planning: Condoms]) for those who are sexually active. Efforts should especially target adolescents at high risk of HIV infection, although 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. 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
Once immune reconstitution with HAART occurs, discontinuation of Pneumocystis pneumonia prophylaxis may be considered for HIV-infected children who have received HAART 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 bid every day, the same dose bid on alternate days, or twice the dose (TMP 150 mg/SMX 750 mg/m2) po once/day for 3 consecutive days/wk.
For patients ≥ 5 yr 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) given once/mo is an additional alternative. IV pentamidine has also been used but is less effective and potentially more toxic.
Prophylaxis against Mycobacterium avium complex infection is indicated in
Weekly azithromycin or daily clarithromycin is the drug of choice, and daily rifabutin is an alternative.
Last full review/revision March 2010 by Geoffrey A. Weinberg, MD
Content last modified November 2012
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