1. Disease staging—The Centers for Disease Control and Prevention (CDC) published revised disease staging for HIV-infected adults, adolescents, and children in 2014 (http://www.cdc.gov/mmwr/preview/mmwrhtml/rr6303a1.htm). (Tables 41–1 and 41–3). Stage 1, 2, and 3 are determined by categories of age-adjusted absolute CD4 T-lymphocyte counts and percentages that indicate progressively severe immune suppression; Stage 3 is defined as AIDS (Table 41–3). Acquired immunodeficiency syndrome is also diagnosed in individuals having one or more of the severe opportunistic illnesses or other serious conditions listed in Table 41–1. Stage 0 is applied to adults or adolescents who had a negative HIV diagnostic test in the 180 days preceding their positive HIV test, indicating recent acquisition of infection, irrespective of their CD4 count and/or clinical conditions. An individual’s staging may vary with time, improving or worsening depending on the outcome of the patient’s treatment course. The WHO has established a clinical staging system that is used widely outside the United States (Table 41–4). Disease stage as well as level of plasma viremia and clinical symptoms are used in determining the urgency with which to initiate ARV therapy in children.
Table 41–3.HIV infection stage based on age-specific CD4 T-lymphocyte counts and percentages of total lymphocytes. |Favorite Table|Download (.pdf) Table 41–3.HIV infection stage based on age-specific CD4 T-lymphocyte counts and percentages of total lymphocytes.
| ||Age of Child |
| ||< 1 y ||1–5 y ||≥ 6 y |
|Stage ||Cells/μL ||% ||Cells/μL ||% ||Cells/μL ||% |
|1. ||≥ 1500 ||≥ 34 ||≥ 1000 ||≥ 30 ||≥ 500 ||≥ 26 |
|2. ||750–1499 ||26–33 ||500–999 ||22–29 ||200–499 ||14–25 |
|3. ||< 750 ||< 26 ||< 500 ||< 22 ||< 200 ||< 14 |
Table 41–4.World Health Organization clinical staging of HIV for infants and children with established HIV infection. |Favorite Table|Download (.pdf) Table 41–4.World Health Organization clinical staging of HIV for infants and children with established HIV infection.
Clinical stage 1: Asymptomatic
Persistent generalized lymphadenopathy
Clinical stage 2: Mild symptoms
Unexplained persistent hepatosplenomegaly
Papular pruritic eruptions
Fungal nail infection
Lineal gingival erythema
Extensive wart virus infection
Extensive molluscum contagiosum
Recurrent oral ulcerations
Unexplained persistent parotid enlargement
Recurrent or chronic upper respiratory tract infections (otitis media, otorrhea, sinusitis, or tonsillitis)
Clinical stage 3: Advanced symptoms
Unexplained moderate malnutrition or wasting not adequately responding to standard therapy
Unexplained persistent diarrhea
Unexplained persistent fever
Persistent oral candidiasis (after first 6–8 wk of life)
Oral hairy leukoplakia
Acute necrotizing ulcerative gingivitis or periodontitis
Lymph node tuberculosis
Severe recurrent bacterial pneumonia
Symptomatic lymphoid interstitial pneumonitis
Chronic HIV-associated lung disease including bronchiectasis
Unexplained anemia, neutropenia, thrombocytopenia
Clinical stage 4: Severe symptoms
Unexplained severe wasting, stunting, or severe malnutrition not responding to standard therapy
Recurrent severe bacterial infections (such as empyema, pyomyositis, bone or joint infection, or meningitis but excluding pneumonia)
Chronic herpes simplex infection
Esophageal candidiasis (or candidiasis of trachea, bronchi, or lungs)
Cytomegalovirus infection: retinitis or cytomegalovirus infection affecting another organ, with onset at age older than 1 mo
Central nervous system toxoplasmosis (after 1 mo of life)
Disseminated endemic mycosis (coccidiomycosis or histoplasmosis)
Disseminated nontuberculous mycobacterial infection
Chronic cryptosporidiosis (with diarrhea)
Cerebral or B-cell non-Hodgkin lymphoma
Progressive multifocal leukoencephalopathy
Symptomatic HIV-associated nephropathy or HIV-associated -cardiomyopathy
2. Infections related to immunodeficiency—Progressive immune dysfunction of both humoral and cell-mediated responses results in susceptibility to infections. Bacteremia, especially due to Streptococcus pneumoniae, occurs at rates of 3 per 100 child-years without cART and decreases to 0.36 per 100 child-years with cART, but this remains at least three times higher than in HIV-uninfected children. Infections with Mycobacterium tuberculosis are a major cause of morbidity in countries with high rates of endemic tuberculosis (TB). Given the frequency of coinfection, diagnosis of M tuberculosis in a child is an indication for HIV testing. Likewise, children with HIV infection and their family members should have regular evaluation for M tuberculosis exposure and testing if appropriate. Herpes zoster (shingles) occurs 10 times more frequently among untreated HIV-infected children compared with age-matched healthy children.
Late-stage immunodeficiency is accompanied by susceptibility to a variety of opportunistic pathogens. Pneumonia caused by P jiroveci is a common AIDS-defining diagnosis in children with unrecognized HIV infection who, therefore, are not receiving PCP prophylaxis. The incidence is highest between ages 2 and 6 months and is often fatal during this period. Symptoms are difficult to distinguish from those of viral or atypical pneumonia (see Chapter 43). Persistent candidal mucocutaneous infections (oral, cutaneous, and vaginal) are common. Candidal esophagitis occurs with more advanced disease. Cytomegalovirus (CMV) infections may result in disseminated disease, hepatitis, gastroenteritis, retinitis, and encephalitis. Disseminated infection with Mycobacterium avium complex (MAC), presenting with fever, night sweats, weight loss, diarrhea, fatigue, lymphadenopathy, hepatomegaly, anemia, and granulocytopenia, may occur in those who have CD4 T-lymphocyte counts below 50–100/μL. A variety of diarrheal pathogens that cause mild, self-limited symptoms in healthy persons may result in severe, chronic diarrhea in HIV-infected persons. These include Cryptosporidium parvum, Microsporidia, Cyclospora, Isospora belli, Giardia lamblia, and bacterial pathogens. Chronic parvovirus infection manifested by anemia can occur.
3. Organ system disease—HIV infection may directly affect a variety of organ systems and produce disease manifestations that include encephalopathy, pneumonitis, hepatitis, diarrhea, hematologic suppression, nephropathy, and cardiomyopathy. On average, HIV-infected children have lower than normal neuropsychological functioning. In many children, neuropsychological deficits do not normalize when ARV therapy is started, despite suppression of viremia. Without cART, findings include acquired microcephaly, progressive motor deficit, ataxia, pseudobulbar palsy, and failure to attain (or loss of) developmental milestones.
Lymphoid interstitial pneumonitis, which is common in untreated children with HIV infection, is characterized by a diffuse peribronchial and interstitial infiltrate composed of lymphocytes and plasma cells. It may be asymptomatic or associated with dry cough, hypoxemia, dyspnea or wheezing on exertion, and clubbing of the digits. Children with this disorder frequently have enlargement of the parotid glands and generalized lymphadenopathy.
4. Malignancy—Children with HIV are at increased risk of malignancy. The most commonly occurring tumors are non-Hodgkin lymphomas, which may occur at unusual extranodal sites (central nervous system, bone, gastrointestinal tract, liver, or lungs). Human papillomavirus infection of the cervix is more likely to progress to neoplasia, and the rate of progression is not altered by cART. Carcinoma due to anal human papillomavirus is also a concern. Kaposi sarcoma, a skin and mucous membrane malignancy, common in HIV-infected MSM with advanced disease, is also observed among HIV-infected African children, but it is rare in children in the United States.
Established HIV infection in perinatally-exposed children older than 18–24 months, in children whose mothers were not HIV–infected, and in adolescents may be diagnosed by detecting HIV antibody using a multi-test algorithm typically including an HIV antibody/antigen immunoassay. A confirmatory test on the same sample using an assay that detects antibody using different antigen or test principle (indicated by a different manufacturer) is performed because rare individuals have cross-reacting antibodies which result in a false-positive antibody tests. If the initial test used detects both HIV antigen and anti-HIV antibody and the confirmatory test that detects only antibody is non-reactive, follow-up HIV NAT is indicated if acute HIV infection is a possibility since antigen detection may precede antibody formation. Definitive diagnosis of HIV infection requires a positive result on a second sample obtained on a different occasion.
The hallmark of HIV disease progression is decline in the absolute number and percentage of CD4 T lymphocytes and an increasing percentage of CD8 T lymphocytes. The CD4 T-lymphocyte values are predictive of the child’s risk of opportunistic infections. Healthy infants and children have CD4 T-lymphocyte numbers that are much higher than in adults; these gradually decline to adult levels by age 5–6 years. Hence, age-adjusted values must be used when assessing a child’s absolute CD4 T-lymphocyte count (see Table 41–3). CD4 T-lymphocyte percentage is used when CD4 T cell count is not available.
Hypergammaglobulinemia of IgG, IgA, and IgM is characteristic in untreated HIV. Late in the disease, some individuals may become hypogammaglobulinemic. Hematologic abnormalities (anemia, neutropenia, and thrombocytopenia) may occur due to effects of HIV disease or cART. Cerebrospinal fluid (CSF) may either be normal or may be associated with elevated protein and a mononuclear pleocytosis; HIV nucleic acid testing may be positive in CSF.
C. Differential Diagnosis
HIV infection should be in the differential diagnosis for children being evaluated for immunodeficiency. Depending on the degree of immunosuppression, the presentation in HIV infection may be similar to that of B-cell (eg, hypogammaglobinemia), T-cell, or combined immunodeficiencies (eg, severe combined immunodeficiency) (see Chapter 33). HIV infection should also be considered in the evaluation of children with failure to thrive, developmental delay, chronic lung disease, and M tuberculosis infection. Chronic HIV infection presenting with generalized lymphadenopathy or hepatosplenomegaly may resemble infections with viruses such as EBV or CMV in children or adolescents. Because blood tests are definitive for the diagnosis of HIV infection, the diagnosis can be readily established or excluded. In rare cases, HIV-infected children with hypogammaglobulinemia have falsely negative antibody tests but may be diagnosed with a nucleic acid–based test. Absence of maternal risk factors or history of negative test results during pregnancy should not dissuade from testing for HIV if the patient has signs consistent with HIV-associated disease since maternal acquisition of HIV late in pregnancy can result in transmission to the infant and may be missed by maternal prenatal HIV testing.
et al; HIV Research Network: Trends in hospitalizations among children and young adults with perinatally acquired HIV. Pediatr Infect Dis J 2014;33(5):488–494 PMID:
M, Van Rie
A: Neurodevelopment in perinatally HIV-infected children: a concern for adolescence. J Int AIDS Soc 2013;16:18603 PMID:
. doi: http://dx.doi.org/10.7448/IAS.16.1.18603.
HIV infection calls for specific cART to prevent progressive deterioration of the immune system as well as prophylactic measures at late stages of HIV infection to prevent opportunistic infections. Guidelines for the treatment of HIV and prevention of opportunistic infections developed by US national working groups of pediatric HIV specialists are published by the U.S. Public Health System at: http://www.aidsinfo.nih.gov. The treatment paradigm changes frequently; therefore, prior to initiating treatment, expert consultation should be obtained.
1. Principles of HIV treatment—Combination ART reduces HIV replication and thereby results in an increase in CD4 T-lymphocyte count and reconstitution of immune function. HIV has a high spontaneous mutation rate that leads to emergence of drug resistance if viral suppression is incomplete. Prevention of resistance mutations requires that virus is not replicating and thus has no opportunity to generate new mutations. Regimens that fully suppress viral replication (plasma HIV RNA < 75 copies/mL) are key to long-term treatment success.
The current standard regimens are combinations of three drugs, including two drugs with different mechanisms of action. Optimally, children on cART will have laboratory monitoring every 3–4 months to confirm viral suppression. If plasma virus becomes consistently detectable (> 200 copies/mL), the underlying cause must be determined (eg, poor adherence or viral resistance), and, if necessary, a change in the medication combination is made.
Within 3–6 months of successful cART, circulating HIV declines to below the limit of detection and CD4 T-lymphocyte counts improve and may normalize. However, HIV persists in long-lived resting cells, and cessation of ARV treatment results in resumption of viremia and decline in CD4 T lymphocytes. Therefore, treatment for HIV with currently available modalities must be lifelong.
Strict adherence to the prescribed treatment is critical. A wide range of issues may impact adherence, including pill burden, dosing frequency, and tolerability as well as psychosocial factors such as developmental stage, mental health of child and caregiver, HIV knowledge, and beliefs about treatment. Programs and services that enhance adherence are essential adjuncts of any HIV treatment regimen.
2. Criteria for initiation of antiretroviral medications—Even without treatment, many individuals with HIV will have slow disease progression and are asymptomatic for several years. This has led to debate about the optimal timing for initiation of cART. The current paradigm has shifted toward earlier initiation. Early treatment has advantages of more complete immune reconstitution and reduced risk of disease complications but presents potential risks of increased medication toxicity and development of viral resistance. Country-specific treatment guidelines are published and updated when new evidence is available. The criteria for initiation may differ among countries, particularly for resource-rich versus resource-limited settings. WHO recommendations are found at: http://www.who.int/hiv/pub/guidelines/en/.
The United States guidelines recommend clinicians consider treatment for all HIV-infected children and adolescents even at early stages of the disease. Infants with perinatally acquired HIV have a 30%–50% risk of progression to AIDS or death by age 12–24 months, and there are no tests that reliably identify these rapid progressors. A randomized trial that compared early versus deferred treatment for infants demonstrated a survival benefit with early treatment. Therefore, infants younger than 12 months per US guidelines, and younger than 2 years per WHO guidelines, irrespective of clinical or immunologic progression, or those at Stage 3 should begin treatment as soon as possible after diagnosis. For children who have survived longer prior to diagnosis, the risk of rapid progression is less. However, those with evidence of clinical progression (moderate symptoms and WHO Stages 3 and 4) or with low CD4 T-lymphocyte counts (stage 2) are recommended to start treatment. High plasma viral load (> 100,000 copies/mL) is independently associated with near-term disease progression and is another indicator for initiating treatment. For children lacking evidence of disease progression and with low viral loads, deferred treatment may be considered, but most clinicians recommend treatment to reduce the effects of HIV on growth, development, and organ systems.
3. Antiretroviral medications—There are 24 ARV medications approved by the U.S. Food and Drug Administration (FDA) categorized into five different drug classes for the treatment of HIV. An additional category, pharmacokinetic enhancers, includes two drugs with drug-drug interactions which increase the area under the curve and minimum concentrations of other ARV agents, particularly the protease inhibitor class. Many of the drugs have pediatric indications for older children, but pharmacokinetic data and administration forms appropriate for infants and toddlers are not available for many. Specific drugs in each class and the mechanism of action of each class are described briefly in Table 41–5.
Table 41–5.U.S. Food and Drug Administration–approved antiretroviral drug class (mechanism of action) and specific drugs in class. |Favorite Table|Download (.pdf) Table 41–5.U.S. Food and Drug Administration–approved antiretroviral drug class (mechanism of action) and specific drugs in class.
|Nucleoside/Nucleotide Reverse Transcriptase Inhibitors (NRTIs) ||Non-nucleoside Reverse Transcriptase Inhibitors (NNRTIs) ||Protease Inhibitors (PIs) |
|(Chain termination of HIV DNA) ||(Synthesis of HIV DNA inhibited) ||(Production of noninfectious virions) |
|Abacavir (ABC; Ziagen)a ||Efavirenz (EFV, Sustiva)a ||Atazanavir (ATV, Reyataz)a |
|Didanosine (ddI; Videx)a ||Etravirine (ETR, Intelence) ||Darunavir (DRV, Prezista)a |
|Emtricitabine (FTC; Emtriva)a ||Nevirapine (NVP, Viramune)a ||Fosamprenavir (FPV, Lexiva)a |
|Lamivudine (3TC; Epivir)a ||Rilpivirine (RPV, Edurant) ||Indinavir (IDV, Crixivan) |
|Stavudine (d4T; Zerit)a || ||Lopinavir/ritonavir (LPV/r, Kaletra)a |
|Tenofovir (TDF; Viread)a || ||Nelfinavir (NFV, Viracept)a |
|Zidovudine (ZDV, AZT; Retrovir)a || ||Ritonavir (RTV, Norvir)a |
| || ||Saquinavir (SQV, Invirase) |
| || ||Tipranavir (TPV, Aptivus)a |
|Integrase Inhibitor ||Entry Inhibitors ||Pharmacokinetic Enhancers |
|(Integration of viral nucleic acid in host genome prevented) ||(Viral entry prevented by inhibition of virus-cell membrane fusion or blocking co-receptor) ||(Interacts with P450 cytochrome enzymes to increase levels of selected ARV) |
Dolutegravir (DTG, Tivicay)a
Elvitegravir (EVG, Vitekta)
Raltegravir (RAL, Isentress)a
Enfuvirtide (T-20, Fuzeon)a
Maraviroc (MVC, Selzentry)
Cobisitat (Cobi, Tybost)
Ritonavir (RTV, r, Norvir)a
DM: Immediate antiretroviral therapy in young HIV-infected children: benefits and risks. Curr Opin HIV AIDS 2014;9(1):87–94 PMID:
4. Complications of antiretroviral medications—ART may result in a range of adverse effects. Each medication has specific toxicities which are described in detail at http://aidsinfo.nih.gov/guidelines/html/2/pediatric-arv-guidelines/113/appendix-a–pediatric-antiretroviral-drug-information. Common adverse events are gastrointestinal distress, hematologic toxicity (anemia, neutropenia), elevated liver enzymes, dyslipidemia (elevated LDL-cholesterol and triglycerides), glucose intolerance, and abnormal fat distribution (lipodystrophy). Reduced bone mineral content and renal dysfunction may result from drug effects as well as from direct effects of HIV. Several drugs (eg, nevirapine, abacavir) have been associated with severe hepatitis, sometimes associated with a systemic hypersensitivity reaction which may be life-threatening if not identified early or upon rechallenge with the same medication. The nucleoside and nucleotide analogues have low-level affinity for the human mitochondrial DNA polymerase. Therefore, these analogues may be incorporated into mitochondrial DNA, which is one mechanism that may lead to adverse effects. Mitochondrial toxicity can result in lactic acidosis, a rare, but potentially fatal, complication. During the initial weeks of treatment, immune restoration may lead to worsening or unmasking of symptoms due to underlying infection with other organisms such as M tuberculosis, an event termed immune reconstitution inflammatory syndrome (IRIS).
E: Update on metabolic issues in HIV patients. Curr Opin HIV AIDS 2014;9(4):332–339 PMID:
D, Van Rie
A: Tuberculosis immune reconstitution inflammatory syndrome in children initiating antiretroviral therapy for HIV infection: a systematic literature review. Pediatr Infect Dis J 2014;33(5):499–503
A: A review of the toxicity of HIV medications. J Med Toxicol 2014;10(1):26–39 PMID:
1. Immunizations—Although vaccines are immunogenic in HIV-infected children, the magnitude and durability of the antibody responses to vaccines are often diminished even when administered to a child on effective cART. Additional doses to boost responses are recommended for some vaccines. More vigorous vaccine responses are found in children with suppressed plasma virus and restored CD4 T-lymphocyte counts. Therefore, for children who were immunized prior to establishment of effective cART, reimmunization should be considered and is recommended for some vaccines (eg, measles-mumps-rubella vaccine).
All inactivated vaccines are safe to administer to HIV-infected children. Annual immunization with inactive influenza vaccine after age 6 months is recommended for HIV-infected children and their close contacts. For live attenuated viral vaccines, the immune status of the child must be considered. Varicella and mumps-measles-rubella vaccines (but not the combined measles-mumps-rubella-varicella vaccine) are recommended for HIV-infected children, provided they are Stage 1 or 2 (see Table 41–3) and only mildly symptomatic (see Table 41–1). Current studies are investigating rotavirus vaccine in HIV-exposed and HIV-infected infants. The majority of infants born to HIV-infected women in the United States will be HIV-uninfected, so rotavirus vaccine is recommended even though it will be initiated before HIV infection is definitively excluded by early testing. Live attenuated influenza vaccine (LAIV) is not recommended for HIV-infected individuals, although initial studies have not identified safety concerns; close contacts may receive LAIV. Yellow fever vaccine is contraindicated in symptomatic HIV infection or with Stage 3 CD4 T-lymphocyte count, but has been well tolerated in asymptomatic, Stage 1 individuals and may also be considered for children in Stage 2. Bacille Calmette-Guérin (BCG), oral polio, smallpox, and live typhoid vaccines should not be given to HIV-infected people.
For some vaccines, additional doses or changes to the routine schedule are recommended. Children who have not received Haemophilus influenzae type b (Hib) vaccine and pneumococcal conjugate vaccine (PCV13) series as infants (eg, immigrants) may benefit from Hib vaccine (two doses between 12 and 59 months of age; one dose after 59 months of age) and two doses of PCV13 (separated by 8 weeks) which may be given after the usual cutoff age of 60 months. The 23-valent pneumococcal polysaccharide vaccine (PPSV) should also be given after age 2 years (and after a PCV13 series), with a second dose given 5 years later. Meningococcal conjugate vaccine (MCV) may be given at the routine ages, but because antibody responses to the vaccine may be suboptimal, HIV-infected children should receive a two-dose primary series. The response to hepatitis B vaccine is particularly unreliable in people with HIV infection. Therefore, a test for hepatitis B surface antibody should be obtained after the three-dose series. If the titer is less than 10 mIU/mL, a second series of three vaccinations is recommended.
2. Prophylaxis for infections—Children with suppressed CD4 T-lymphocyte numbers benefit from primary and secondary prophylactic treatment to prevent opportunistic infections. Children who have had their CD4 T-lymphocyte counts restored with ARV therapy to category 1 or 2 for over 3 months can be taken off prophylactic treatments.
Antibiotic prophylaxis for P jiroveci pneumonia has been extremely effective. HIV-infected infants should receive Pneumocystis prophylaxis until age 12 months, after which prophylaxis is based on assessment of symptoms and age-adjusted CD4 T-lymphocyte counts every 3 months. Children with low CD4 T-lymphocyte parameters (Stage 3; see Table 41–3) should continue/begin PCP prophylaxis. Published guidelines from the CDC for P jiroveci pneumonia prophylaxis are summarized in Table 41–6.
Table 41–6.Drug regimens for Pneumocystis jiroveci prophylaxis for children older than 4 wk. |Favorite Table|Download (.pdf) Table 41–6.Drug regimens for Pneumocystis jiroveci prophylaxis for children older than 4 wk.
|Recommended regimen |
| Trimethoprim-sulfamethoxazole, 150 mg TMP/m2/d plus 750 mg SMX/m2/d, administered orally, divided into two doses per d/3 d a week on consecutive days |
| Alternative (same total daily dosages): |
| Single-daily dose 3 d a week on consecutive days |
| Divided twice-daily doses 7 d a week |
| Divided twice-daily doses 3 d a week on alternate days |
|Alternative if trimethoprim-sulfamethoxazole is not tolerated |
| Dapsone, 2 mg/kg/d (not to exceed 100 mg) orally once daily or 4 mg/kg (not to exceed 200 mg) orally once weekly |
| Atovaquone, age 1–3 mo and > 24 mo, 30 mg/kg orally once daily; age 4–24 mo, 45 mg/kg orally once daily |
| Aerosolized pentamidine (children > age 5 y), 300 mg via inhaler monthly |
3. Psychosocial support and mental health—Evaluation and support for psychosocial needs of HIV-affected families is imperative. As with other chronic illnesses, HIV infection affects all family members and also carries additional social stigma. Emotional concerns and financial needs, which are more prominent than medical needs at many stages of the disease process, influence the family’s ability to comply with a medical treatment regimen. HIV-infected children often have comorbid mental health conditions. Rates of attention-deficit/hyperactivity disorder range from 20% to 50% in various studies. Hospital admissions for mental health disorders are more frequent among HIV-infected children. In one study, dual diagnosis of HIV and a mental health disorder occurred in 85% of adolescents who acquired HIV infection through high-risk behaviors. Ideally, care should be coordinated by a team of caregivers that is familiar with HIV disease and its comorbidities, newest therapies, and community resources.
R; American Academy of Pediatrics Committee on Pediatric AIDS: Psychosocial support for youth living with HIV. Pediatrics 2014;133(3):558–562 PMID: