Pediatric HIV Infection Treatment & Management

ART is the mainstay in human immunodeficiency virus (HIV) treatment. Appropriate antiretroviral therapy (ART) and treatment of specific infections and malignancies are critical in treating patients who are HIV positive. Intervening early may prevent damage to the immune system and potentially retard dissemination of infection. Combination ART is recommended for all infants, children, and adolescents who meet treatment criteria.

Reduction in the mortality rate associated with perinatally acquired HIV-1 over the past 10 years is a result of improved ART. However, only triple combination ART appears to significantly reduce the relative hazard ratio of death, as compared with no treatment.

The inadequacy of merely reducing the viral load has been realized in recent years. Quick suppression of the viral load with highly active ART (HAART) substantially slows viral replication and prevents resistant mutations.

Panel on Antiretroviral Therapy and Medical Management of HIV-Infected Children

The following are the 2010 goals for treating pediatric patients with HIV infection, from the Panel on Antiretroviral Therapy and Medical Management of HIV-Infected Children^[29] :

• Reducing HIV-related mortality and morbidity
• Restoring and/or preserving immune function
• Maximally and durably suppressing viral replication
• Minimizing drug-related toxicity
• Maintaining normal physical growth and neurocognitive development
• Improving quality of life

The following are several important factors to consider in making treatment decisions about when to initiate antiretroviral therapy:

• Severity of HIV disease
• Risk of disease progression
• Laboratory assessments (eg, CD4⁺ count, plasma HIV RNA levels)
• Availability of appropriate and palatable drug formulations
• Adverse effects of the antiretroviral medications
• Effect of initial treatment regimen choice on later therapeutic options
• Presence of comorbidities that may affect drug choices
• Potential antiretroviral drug interactions with required concomitant medications
• Ability of the child and caregiver to adhere to treatment regimen

A high prevalence of infections, such as candidiasis and varicella-zoster virus infection, must be anticipated, and appropriate prevention and treatment strategies must be initiated.

As the disease progresses, wasting is noted, with weight loss and growth retardation in children. Low protein stores can be countered by increasing the intake of amino acids, specifically threonine and methionine.

Address abnormalities in psychological and neurologic development, due, in part, to the tropism of the virus for CNS tissue in children who are HIV positive.

Social, economic, and psychological factors impair the ability of many HIV-infected children and their parents to attend regular clinic appointments. This problem can be challenging and may require substantial use of social and child protective services on a regular basis.

Psychosocial support is extremely important. Failure to provide such services can result in a lack of compliance with medications and appointments.

Treatment guidelines for HIV disease change constantly. The most current guidelines may be viewed at the AIDS Info Web site, a service of the US Department of Health and Human Services.

Although current HAART regimens have substantially and dramatically decreased AIDS-related opportunistic infections (OIs) and deaths, prevention and management of OIs remain critical components of care for HIV-infected children.^[31] In 2009, the Centers for Disease Control and Prevention (CDC), the National Institutes of Health, the HIV Medicine Association of the Infectious Diseases Society of America, the Pediatric Infectious Diseases Society, and the American Academy of Pediatrics released Guidelines for the Prevention and Treatment of Opportunistic Infections Among HIV-Exposed and HIV-Infected Children.

As of June 2011, 26 antiretroviral drugs have been approved for use in adults and adolescents with HIV; 17 of these have an approved pediatric treatment indication, and 15 are available as a pediatric formulation or capsule size. Classes of antiretroviral agents include the following:

• Nucleoside reverse transcriptase inhibitors (NRTIs)
• Protease inhibitors (PIs)
• Nonnucleoside reverse transcriptase inhibitors (NNRTIs)
• Fusion inhibitors
• CCR5 co-receptor antagonists (entry inhibitors)
• HIV integrase strand transfer inhibitors
• Nucleoside reverse transcriptase inhibitors (NRTIs)

The reverse transcriptase inhibitors (NRTIs, NNRTIs) suppress HIV replication by competitive inhibition of viral reverse transcriptase. PIs prevent the late stages of viral replication by interfering with the formation of structural proteins of the virion core.

Treatment Guidelines

Most patients with vertically acquired HIV are treated regardless of their immune status. Most infants younger than 1 year should be aggressively treated. Pediatric HIV experts agree that infected infants who have clinical symptoms of HIV disease or evidence of immune compromise should be treated.^[29] Patients aged 1 year or older with AIDS or significant symptoms should be aggressively treated regardless of CD4 percentage and count or plasma HIV RNA level.

The importance of early treatment of HIV in children younger than 12 months was illustrated in the Children with HIV Early Antiretroviral Therapy trial, which showed a 76% reduction in infant mortality and a 75% reduction in HIV progression with the early initiation of treatment.^[32]

For patients aged 1 year or older, the age-related CD4 thresholds for initiating treatment are less than 25% for children aged 1-4 years and less than 350 cells/μL for children aged 5 years or older, regardless of symptoms or plasma HIV RNA level.

Initiate treatment in children aged 1 year or older who are asymptomatic or have mild symptoms and have a CD4 of 25% or more in children aged 1-4 years or 350 cells/μL or more in children aged 5 years or older who have plasma HIV RNA of 100,000 copies/mL or more.

ART may be considered or deferred in children aged 1 year or older who are asymptomatic or have mild symptoms and who have a CD4 of 25% or more in children aged 1-4 years and 350 cell/μL or more for children aged 5 years or older who have plasma HIV RNA or less than 100,000 copies/mL.

When treating older children, some advocate considering a child's Tanner stage when determining dosing regimens. Adolescents in early puberty (Tanner stages I and II) should be treated according to pediatric dosing guidelines. Adolescents in late puberty (Tanner stage IV) and postpubertal adolescents should follow adult dosing guidelines.

Initial combination therapy for ART-naive children

Combination ART with at least 3 drugs from at least 2 classes of drugs is recommended for initial treatment of infected infants, children, and adolescents because it provides the best opportunity to preserve immune function and delay disease progression.

The use of zidovudine as a single agent is appropriate only when used in infants of indeterminate HIV status during the first 6 weeks of life to prevent perinatal HIV transmission. Infants confirmed as HIV infected while receiving chemoprophylaxis should have prophylactic antiretroviral drugs discontinued and treatment initiated, with a combination regimen of at least 3 drugs.

The only preferred regimens for children younger than 3 years are coformulated lopinavir/ritonavir-based therapy and nevirapine-based therapy. Infants exposed to nevirapine in the peripartum period as part of a preventing-mother-to-child-transmission (PMTCT) strategy should not be treated with nevirapine-based combination therapy because of the established higher risk of treatment failure due to nevirapine resistance. Lopinavir/ritonavir-based combination therapy would be the only recommended, preferred initial regimen.

One study evaluated the use of lopinavir/ritonavir combination therapy in children younger than 6 years with HIV type 1 infection who have not undergone highly active antiretroviral therapy (HAART). Seventy percent of the 43 children in the study realized a virologic success at month 12. Overall, 20 children experienced virologic failure; risk factors for virologic failure were determined to be young age and low socioeconomic status.^[33]

Drug combinations for initial therapy include a backbone of 2 NRTIs plus 1 NNRTI or a PI.

NNRTI-based regimens

The preferred NNRTI-based regimen (1 NNRTI plus 2 NRTIs) is as follows:

• Nevirapine plus 2 NRTIs for children younger than 3 years who have not been exposed to nevirapine as part of maternal-infant prophylaxis or who require a liquid formulation
• Efavirenz in combination with 2 NRTIs for children aged 3 years or older

An alternative regimen is nevirapine in combination with 2 NRTIs for children aged 3 years or older.

Etravirine is not recommended due to lack of pediatric formulation, pediatric pharmacokinetic data, efficacy or safety data in children, and lack of data in antiretroviral-naïve patients.

Nevirapine is not recommended for infants exposed to nevirapine as part of maternal-infant prophylaxis.

Nevirapine is not recommended for postpubertal girls with CD4 counts more than 250/μL.

Efavirenz is not recommended for sexually active female adolescents when reliable contraception cannot be assured.

Efavirenz is not recommended for children younger than 3 years.

PI-based regimens

In PI-based regimens, the PI may be given with ritonavir, a PI that boosts blood levels of other PIs, permitting a reduced dosage of the coadministered drug. The preferred PI-based regimen (ie, a boosted or unboosted PI plus 2 NRTIs ) is lopinavir/ritonavir plus 2 NRTIs.

Alternative regimens are as follows:

• Atazanavir (plus low-dose ritonavir) and 2 NRTIs for children older than 6 years
• Darunavir (plus low-dose ritonavir) and 2 NRTIs for children aged 6 years or older
• Fosamprenavir (plus low-dose ritonavir) and 2 NRTIs for children aged older than 6 years

Alternative regimens for special circumstances are as follows:

• Atazanavir unboosted (for treatment-naïve adolescents >13 y and >39 kg who are unable to tolerate ritonavir) in combination with 2 NRTIs (unboosted atazanavir should not be used with tenofovir)
• Fosamprenavir unboosted (for children >2 y) in combination with 2 NRTIs
• Nelfinavir in combination with 2 NRTIs (for children >2 y)

PIs that are not recommended include the following:

• Indinavir, saquinavir, or tipranavir
• Dual (full-dose) PIs
• Full-dose ritonavir or use of ritonavir as the sole PI
• Unboosted atazanavir in children age < 13 years and/or < 39 kg
• Nelfinavir in children age < 2 years
• Unboosted darunavir
• Once-daily dosing of lopinavir/ritonavir, boosted darunavir, or boosted or unboosted fosamprenavir

Selection of dual NRTIs for initial combination therapy

Preferred dual NRTIs include the following:

• Abacavir plus lamivudine or emtricitabine (HLA-B*5701 genetic testing should be performed prior to initiating abacavir-based therapy, and abacavir should not be given to a child who tests positive for HLA-B*5701, due to increased risk of hypersensitivity reaction)
• Didanosine plus lamivudine or emtricitabine
• Zidovudine plus lamivudine or emtricitabine
• For postpubertal or Tanner stage 4 adolescents only, tenofovir plus lamivudine or emtricitabine

Zidovudine plus abacavir or didanosine is an alternative. Stavudine plus lamivudine or emtricitabine is indicated in special circumstances.

Dual NRTIs NOT recommended include the following:

• Stavudine plus didanosine (due to increased toxicity)
• Abacavir plus didanosine, abacavir plus tenofovir, and didanosine plus tenofovir (due to insufficient data)
• Tenofovir as part of any dual-NRTI backbone in children in Tanner stages 1–3 due to lack of pediatric dosing data and formulation and concerns related to bone toxicity

Monitoring therapy

Close monitoring to determine whether the child is tolerating ART and to answer any questions the caregiver may have are essential to the success of these therapies. At 4-8 weeks after the start of therapy, the CD4⁺ count and/or percentage and HIV RNA levels should be reassessed, and laboratory evaluations for toxicity should be done.

The main goal of therapy is to lower HIV RNA to undetectable levels, although not all infants achieve this. Some have a 10-fold or 5-fold decrease in the viral load.

Treatment failure

Treatment failure is defined as virologic, immunologic, or clinical.^[29]

Virologic failure includes incomplete response and viral rebound. Incomplete virologic response to therapy is defined for all children any of the following:

• A less than 1.0¹⁰ decrease in HIV RNA copy number from baseline after 8–12 weeks of therapy,
• HIV RNA of greater than 400 copies/µL after 6 months of therapy
• Repeated HIV RNA levels above the level of detection after 12 months of therapy (However, children with very high viral load levels may take longer to go to undetectable levels.)

Viral rebound is repeated detection of HIV RNA despite previously achieved undetectable viral load levels

Immunologic failure includes incomplete response and immunologic decline. Incomplete response is defined as a failure by a child younger than 5 years with severe immune suppression (CD4⁺ < 15%) to improve CD4⁺ values by 5 or more percentage points, or as a failure by a child aged 5 years or older with severe immunosuppression (CD4⁺ < 200 cells/µL) to improve CD4⁺ values by 50 cells/µL or greater above baseline within the first year of therapy

Immunologic decline includes a sustained decline of 5 percentage points in CD4⁺ percentage below pretherapy baseline at any age, or decline to below pretherapy baseline in absolute CD4⁺ cell count in children who are aged 5 years and older.

Clinical failure includes all of the following:

• Growth failure
• Progressive neurodevelopmental deterioration
• Serious or recurrent infection and illness

Breastfeeding

In the United States and other parts of the world where replacement feeding is affordable, feasible, acceptable, sustainable, and safe, breastfeeding by HIV-infected women (including those receiving antiretroviral drugs) is not recommended.^[29]

Observational data and randomized clinical trials have demonstrated that infant prophylaxis (primarily using daily infant nevirapine) during breastfeeding significantly decreases the risk of postnatal transmission in breast milk and that maternal triple-drug prophylaxis during breastfeeding may likewise decrease postnatal infection.^{[15, 34]} The results from a randomized, double-blind, placebo-controlled trial confirm that nevirapine prophylaxis via breastfeeding infants up to age 6 months provides protection from transmission of HIV-1 from mother to child.^[35]

Both infant nevirapine prophylaxis and maternal triple-drug prophylaxis during breastfeeding may be associated with the development of antiretroviral drug resistance in infants who become infected despite prophylaxis.^[29]

Drug interactions with antiretroviral drugs

Antiretroviral drug (ARD) regimens often contain 3 or more agents. In addition, other drugs are typically required to manage the numerous infectious and systemic consequences of AIDS.

Therefore, the likelihood of drug interactions increases. The outcome of the drug interactions may reduce or eliminate the efficacy or increase the toxicity of 1 or both drugs. A thorough understanding of the mechanisms of interactions is essential to minimize or prevent adverse effects and to prevent inadequate treatment.

Regarding the mechanisms, drug interactions are classified as pharmacokinetic or pharmacodynamic. Pharmacokinetic interactions alter drug absorption, distribution, or elimination (metabolism, excretion). Pharmacodynamic alterations manifest as additive, synergistic, or antagonistic drug effects.

Several ARDs may affect or be affected by absorption kinetics. Didanosine contains an aluminum and magnesium buffer that may affect the absorption of other drugs (eg, ciprofloxacin). Delavirdine is poorly absorbed when the pH of the GI tract increases.

Many ARD pharmacokinetic interactions alter the cytochrome P450 (CYP) metabolic enzyme system. Cytochromes are metabolic enzymes in the liver, and CYP denotes the specific enzyme.

The CYP system is classified into families, 3 of which are important in humans: CYP1, CYP2, and CYP3. Further delineation into subfamilies is denoted with a capital letter (eg, CYP3A). The nomenclature is completed with the description of individual proteins called isoenzymes, which are delineated with a second number (eg, CYP3A4).

Drugs may be substrates, inhibitors, and/or inducers of particular isoenzymes. Substrates are metabolized by means of the CYP system. They may also be classified as inhibitors (ie, those with reversible and competitive action that decreases metabolism) and/or inducers (ie, those with reversible and competitive action that increases metabolism). Inhibitors decrease hepatic metabolism of isoenzyme substrates (ie, increase serum concentrations), whereas inducers increase this metabolism (ie, decrease serum levels).

All currently approved protease inhibitors and NNRTIs are metabolized in the CYP system, principally by the 3A4 isoenzyme. Some also induce or inhibit CYP3A4, respectively decreasing or increasing serum levels of the 3A4 substrate. Strong inhibitors (eg, ritonavir) have been used in small doses to increase drug levels (eg, of the lopinavir-ritonavir combination), enhancing the efficacy of those drugs with a low enough dose to limit the risk of adverse effects.

Drug interactions among antiretroviral agents may be used to increase and sustain serum levels of one another, enhancing efficacy and decreasing adverse effects (eg, Kaletra, which is a fixed-dose combination product of lopinavir and ritonavir). Other interactions may decrease levels, causing concern about sufficient efficacy. Discussion of drug interactions can be found in Antiretroviral Therapy for HIV Infection.

Treatment for patients at risk for vertical acquisition

Within 6-12 hours of the delivery of a neonate at risk, zidovudine therapy should be started after a baseline CBC count is obtained. Zidovudine should be continued until the infant is 6 weeks of age, when it may be discontinued if all DNA HIV polymerase chain reaction (PCR) results are negative. If HIV infection is confirmed in the infant, zidovudine must be stopped immediately to abort monotherapy.

Although current HAART regimens have substantially and dramatically decreased AIDS-related OIs and deaths, prevention and management of OIs remain critical components of care for HIV-infected children.^[31]

OIs are typically an indication of severe immune suppression. However, an increased capacity to mount inflammatory reactions as a result of successful HAART may result in the development of immune reconstitution inflammatory syndrome (IRIS), which manifests as worsening of an existing active, latent, or occult OI. Although IRIS has primarily been reported in adults after initiation of HAART, it also has been reported in children .

IRIS may unmask viable pathogens. Alternatively, in so-called paradoxical IRIS, symptomatic relapse reflects reconstitution of specific T-cell–mediated immunity against persisting antigens from dead organisms; cultures in these cases are sterile.^[31]

Selected opportunistic pathogens and common sources are as follows:

• Cytomegalovirus (CMV) infection from CMV-positive blood products
• Cryptosporidium infection from unprocessed ground water or exposure to a young or stray animal
• Pneumocystis jiroveci pneumonia (PCP) from exposure to other individuals with PCP
• Toxoplasma gondii infection from cats or ingesting undercooked red meat
• Tuberculosis (TB) from exposure to high-risk individuals

Antibiotic therapy

Tables 2 and 3 below summarize the antibiotics used for primary and secondary prophylaxis of opportunistic infections and their appropriate dosages.

Antibiotic prophylaxis does not guarantee protection, and opportunistic organisms should be appropriately included in the differential diagnosis for all HIV-infected patients.

Several antibiotics used for prophylaxis have clinically significant adverse interactions with antiretroviral agents. For example, rifampin and rifabutin reduce the effectiveness and increase the toxicity of protease inhibitors and nonnucleoside reverse transcriptase inhibitors (NNRTIs). Also, isoniazid is hepatotoxic and may interact poorly with protease inhibitors that are hepatotoxic.

Table 2. Antibiotics for Primary and Secondary Prophylaxis of Opportunistic Infections (Open Table in a new window)

Table 3. Drugs and Doses for Prophylaxis of Opportunistic Infections (Open Table in a new window)

Pneumocystis pneumonia

Prophylaxis is the most important measure for decreasing the incidence of PCP, it but does not guarantee protection. Table 4 below delineates the CD4⁺ indications for starting prophylaxis with regard to the patient's age or status.

Table 4. CD4⁺ -Based Indications for Starting PCP Prophylaxis (Open Table in a new window)

PCP prophylaxis should be started in all infants aged 6 weeks who were born to HIV-infected mothers. It should be continued until HIV infection has been ruled out.

Viral infection

Previous CMV infection or CMV retinitis requires prophylaxis with ganciclovir 5 mg/kg/day IV, foscarnet 90-120 mg/kg/day IV, or an implant delivering sustained-release ganciclovir.

Severe or frequent recurrences of herpes simplex require prophylaxis with acyclovir 80 mg/kg/d given by mouth 2 or 4 times day.

Varicella or herpes zoster should be treated with IV acyclovir 500 mg/m²/dose 3 times a day for 7 days.

Fungal infection

Candida

Thrush occurs in a third of patients with non–category C disease and in one half of patients with category C disease. Candidal esophagitis is an AIDS-defining condition and can result in severe dysphagia and anorexia; the diagnosis can be confirmed with endoscopy. Disseminated systemic fungemia is rare, but indwelling catheters and neutropenia increase a patient's susceptibility.

Primary prophylaxis is not generally recommended, but prophylaxis after repeated infections may be helpful. Prophylactic treatment is used in severe recurrent cases, but prolonged prophylaxis can lead to resistance.

Nystatin may not be helpful in managing repeated thrush or cutaneous infections, and topical clotrimazole or miconazole may be needed. Fluconazole, itraconazole, or ketoconazole may be needed if topical treatments fail or if candidal esophagitis develops. Candidal esophagitis recalcitrant to treatment with azole compounds and disseminated disease should be treated with amphotericin.

Cryptosporidium

Cryptosporidium infections cause chronic, secretory, watery diarrhea that may be large in volume. Maintaining an adequate fluid balance is most important and may be challenging.

A unique parasitophorous vacuole in the host cell shelters the parasite from antimicrobial drugs. Control of the infection can be difficult because no curative therapy exists. The best treatment is prevention and good immunity. Avoidance of tap water may have some value in prevention.

Cryptococcus

Cryptococcal meningitis is uncommon in children, though it should be ruled out when signs of meningeal are observed or when fever without a clear source causes severe headache. CSF samples should be examined with India ink stain, and the presence of cryptococcal antigen should be determined. Treatment with amphotericin and flucytosine is necessary, followed by maintenance therapy with fluconazole or itraconazole.

Mycobacterial infection

M tuberculosis causes primary pulmonary disease in children and is most likely to affect children with existing lung disease. Extrapulmonary disease can occur, especially when immune function is decreased, and it may be present with or without pulmonary disease. Fever, cough, and tachypnea are common presenting symptoms.

PPD testing is useful only if the findings are positive, and it should not be used as a diagnostic method. Gastric aspirates, induced sputum samples, and bronchoalveolar lavage specimens are necessary, and susceptibility testing should be performed.

Initial therapy should involve 4 drugs: isoniazid, rifampin or rifabutin, pyrazinamide, and ethambutol or streptomycin. Therapy should continue for 1 year if the isolate is drug susceptible or more than 1 year if the isolate is multidrug resistant. Rifampin and rifabutin interact with protease inhibitors, requiring an alteration in HAART. Children younger than 4 years should not be treated with ethambutol because of possible optic neuritis.

Multidrug-resistant TB is highly prevalent among HIV-infected individuals. It is associated with a poor prognosis.

Disseminated M avium-intracellulare complex (MAC) infection is not uncommon in children with clinically significant disease progression, and a low CD4⁺ count is a major risk factor for MAC disease. MAC infection is second only to PCP among the most common opportunistic infections in children with AIDS, occurring in 6-15% of children with HIV infection. This percentage increases to 24% in children with CD4⁺ counts of less than 100 cells/mL. In the United States, MAC infection may be more common in the South than elsewhere.

MAC is ubiquitous, commonly existing in water, soil, and household environments. In some individuals, colonization may occur before infection. Person-to-person transmission has not been documented.

Although localized pulmonary disease is the common form of infection in hosts not infected with HIV, localized disease is uncommon in HIV-infected individuals, and disseminated disease is typical. Disseminated MAC infections commonly cause fever, night sweats, malaise, anorexia, and weight loss. Anemia and elevated alkaline phosphatase levels are also common. Involvement of the bone marrow may produce neutropenia.

GI symptoms are common in some presentations. Abdominal pain, hepatosplenomegaly, and diarrhea with associated malabsorption may be common, but elevated transaminase levels are not common. CT or MRI may reveal general intestinal lymphadenopathy.

Sputum, stool, and blood acid-fast cultures should be obtained when the presence of MAC is suspected. The reticuloendothelial system is a common reservoir for mycobacteria, though the bone marrow, GI tract, lungs, adrenals, and kidneys may also be affected.

Control of a MAC infection requires at least 2 or 3 antibiotics, but more may be necessary if clinical symptoms do not resolve. Early detection and treatment is most effective.

Exposure to antibiotics before treatment suggests that other agents may be more effective than those previously used. In addition, a lack of a response to a regimen may indicate the need to empirically change antibiotics instead of simply adding antibiotics, as drug resistance can develop rapidly. Although polyantimicrobial therapy may be useful, toxicity is more common with this approach.

Initial regimens may include macrolides, rifabutin, and ethambutol. Rifabutin interacts with several protease inhibitors, and ethambutol is not generally used in children younger than 4 years because of the possible development of optic neuritis. However, ethambutol is the only choice in many situations, and it is used when indicated. Amikacin, cefoxitin, ciprofloxacin, ofloxacin, doxycycline, rifampin, and streptomycin may also be used for treatment. The best treatment is effective HAART with immune reconstitution, which increases the CD4⁺ count.

Blood cultures should be obtained at regular intervals until the results are negative and the susceptibilities of identified organisms are determined. Treatment must be continued indefinitely.

Prophylaxis is extremely important. Table 5 indicates the CD4⁺ count at which prophylaxis should be started with regard to the patient's age.

Table 5. CD4⁺ -Based Indications for MAC Prophylaxis (Open Table in a new window)

Clarithromycin administered for MAC prophylaxis may also protect the patient against Cryptosporidium infection. Nitazoxanide is being investigated for treatment. Other drugs, such as paromomycin, azithromycin, and hyperimmune bovine colostrum have been used with suboptimal results. Octreotide must be used with caution because it can slow diarrhea but not clear the infection.

Pancreatitis and/or bowel infarction may develop.

Toxoplasmosis

Toxoplasmosis is a rare CNS infection in children. When it occurs, it is usually acquired congenitally.

Specific immunoglobulin G and immunoglobulin M titers, as well as head ultrasonography to detect CNS lesions, should be performed in neonates with risk of congenital infection or in whom it is suspected. Treatment with pyrimethamine, folinic acid, and sulfadiazine or clindamycin is required when infection occurs.

Screening for opportunistic infections

All HIV-infected children should be screened for certain opportunistic infections. The patient and all family members should undergo yearly TB screening. Immune function should be tested by means of a candidal or mumps control. Anergy to the control is an indication for yearly chest radiography instead of the use of a PPD.

CMV infection accelerates HIV progression in infants. At birth, positive findings on urine culture can help guide later management. Cultures not obtained immediately after birth may imply colonization and not congenital infection. CMV infection should be treated only if it is symptomatic.

Toxoplasmosis, other infections, rubella, CMV, and herpes simplex (TORCH syndrome) are not common during gestation in women with well-controlled HIV infection. However, women with poorly controlled HIV infection or neonates who have growth retardation at birth should be screened for TORCH infections. Patients with AIDS not uncommonly carry toxoplasmosis, and this infection may be transmitted in utero if the mother is severely immunosuppressed during pregnancy.

Assessment of immunologic function

Immunologic function should be assessed in high-risk patients. Immunoglobulin levels should be checked every 3-6 months. Hypogammaglobulinemia is defined as an immunoglobulin G level of less than 2.5 g/L.

Humoral immune function can be checked by measuring specific antibody titers after immunization. Cellular immune function is checked by using a subcutaneous candidal control.

Children with hypogammaglobulinemia, humoral immune dysfunction, or more than 2 serious bacterial infections in a year should be given intravenous immunoglobulin (IVIG) 400 mg/kg every 4 weeks.

Thrombocytopenia is common in HIV infection, and platelet production generally decreases regardless of the platelet count. Anemia can result from HIV infection or its treatment. Neutropenia is relatively common in advanced disease and creates a clinically significant risk for infection.

Thrombocytopenia

Immune-mediated platelet destruction develops in approximately 20% of children with HIV infection. In children with advanced disease, severe thrombocytopenia may need to be managed.

The platelet count may transiently increase with IV immunoglobulin (IVIG), interferon (IFN)-alfa, corticosteroids, or anti-Rh immunoglobulin. IVIG is the treatment of choice. Regimens include IVIG 1-2 g/kg/day for 2-5 days. Three million units of IFN-alfa administered 3 times per week increases the platelet count in 50% of adults after 3 weeks. A 4-week course of prednisone 1-2 mg/kg followed by a 2- to 4-week taper is an alternative, but the immunosuppressive adverse effects must be considered carefully.

Anti-Rh immunoglobulin is useful in Rh-positive patients who have not undergone splenectomy, and it is relatively inexpensive. A 1- to 2-g decrease in the hemoglobin level occurs, which limits use of this therapy in patients with anemia. In most patients, 25 mcg/kg administered IV on 2 consecutive days with repeated doses of IV anti-Rh or intramuscular (IM) anti-D every 2-4 weeks increases the platelet count. As an alternative, 6-13 mcg/kg IM administered every week also produces a reasonable increase in the platelet count.

More long-lasting responses can be achieved with zidovudine or danazol treatment or splenectomy. In most adults, high-dose zidovudine can reverse HIV-related idiopathic thrombocytopenia purpura (HIV-ITP). Treatment of HIV infection, especially with zidovudine, appears to improve the platelet count and platelet production. In adults, danazol 400-800 mg daily increases the platelet count in 1-2 months.

Splenectomy is an effective long-term treatment. Although splenectomy is not associated with an increased mortality rate, the risk of fulminant infections with encapsulated bacteria increases.

Anemia

Iatrogenic anemia is not uncommon, and HIV infection often suppresses bone marrow, serum erythropoietin levels, and responses of the bone marrow to erythropoietin. An infectious or neoplastic agent may cause new-onset anemia. A standard workup for anemia should be performed along with a determination of the erythropoietin level, reticulocyte count, and indirect bilirubin level.

A high reticulocyte count indicates a good bone marrow response. When accompanied by a high indirect bilirubin level, hemolytic anemia should be suspected. In the setting of glucose-6-phosphate dehydrogenase (G6PD) deficiency, the use of sulfonamides, dapsone, or oxidant drugs can cause iatrogenic erythrocyte hemolysis. A low indirect bilirubin level indicates a response to acute blood loss or recent replacement of a necessary cofactor.

Disseminated intravascular coagulation and thrombotic thrombocytopenic purpura can cause hemolytic anemia and are associated with thrombocytopenia and fragmented RBCs on smears.

Although the prevalence of erythrocyte autoantibodies is high in HIV-infected patients, especially those with hypergammaglobulinemia, the rate of hemolysis by this mechanism is low.

Hemophagocytic syndrome occurs when macrophages in the bone marrow phagocytose erythrocytes.

A low reticulocyte count indicates bone marrow suppression or ineffective erythropoiesis. Vitamin B-12 or folic acid deficiency produces a high mean corpuscular volume (MCV) and indirect bilirubin level. Patients with HIV are especially at risk for these deficiencies because of poor nutrition and poor small-bowel function. As many as 33% of patients with HIV have a negative vitamin B-12 balance.

Folic acid deficiency causes the production of large oval erythrocytes, hypersegmented polymorphonucleocytes, and pancytopenia. Vitamin B-12 deficiency causes subacute combined degeneration of the spinal cord with high cortical dysfunction. Before treatment is started with supplemental parenteral vitamin B-12 and oral folic acid, serum folate and vitamin B-12 levels must be measured.

A low or normal indirect bilirubin value suggests secondary myelosuppression.

A high mean corpuscular volume (MCV) indicates iatrogenic pharmaceutical suppression of erythropoiesis. A low MCV suggests iron deficiency anemia. A normal MCV suggests HIV anemia, anemia related to chronic disease, an infectious etiology, or neoplastic marrow invasion.

Parvovirus B19 and many pharmaceutical agents cause neutropenia in addition to anemia.

Ancillary hematologic laboratory tests may help clarify the differential diagnosis, and an investigation of an infectious etiology may be warranted if the CD4⁺ count is low.

Several etiologies may be involved, resulting in laboratory values that may not be correlated with a particular type of anemia. Clinical evaluation and correlation with laboratory values is necessary. Bone marrow biopsy may be necessary if laboratory and clinical findings are inconclusive.

Serum erythropoietin levels of less than 500 IU/L and anemia due to bone marrow suppression as a result of infection, inflammation, or pharmaceutical agents should be managed with erythropoietin. Other causes of anemia must be ruled out and managed before erythropoietin is given.

Erythropoietin should be started at a dosage of 100 U/kg given subcutaneously 3 times per week; this may be increased to 200 U/kg/dose. After the hematocrit returns to normal, dosing should be decreased to once every week or every other week to maintain a stable hematocrit. Adverse effects include pain at the injection site and fever. Supplemental iron should always be given with erythropoietin therapy.

Neutropenia

Neutropenia is relatively common in advanced HIV disease. In 25% of patients with moderate neutropenia, bacterial infections develop, most often within 24 hours of the onset of neutropenia. The following myelosuppressive drugs—especially zidovudine, trimethoprim-sulfamethoxazole, and ganciclovir—can induce neutropenia:

• Zidovudine
• Lamivudine
• Didanosine
• Stavudine
• Ganciclovir
• Valganciclovir
• Foscarnet
• Flucytosine
• Amphotericin
• Sulfonamides
• Trimethoprim, trimethoprim-sulfamethoxazole
• Pyrimethamine
• Pentamidine

Infectious agents such as parvovirus B19 can cause myelosuppression, as can invasive neoplastic processes of the marrow.

Granulocyte-macrophage colony-stimulating factor (GM-CSF) and granulocyte colony-stimulating factor (G-CSF) are used to treat neutropenia and to promote granulocyte production and function. GM-CSF has more adverse effects than G-CSF, and it promotes viral replication. However, GM-CSF does not increase the viral load if it is used with ART.

G-CSF is started at a dosage of 5 mcg/kg/day, and it is given until neutropenia resolves. Titration to once or twice per week is typical. Adverse effects of G-CSF are minimal and include bone pain and elevations in lactate dehydrogenase (LDH) and alkaline phosphatase levels. GM-CSF is started at a dosage of 5 mcg/kg/d given subcutaneously for 5 days and then titrated to effect. Adverse effects include flulike symptoms, myalgias, bone pain, fatigue, and fever.

Based on the patient's living arrangements and stage of infection, inpatient care may be warranted at some time during the patient's illness. The extensive testing required to rule out an underlying infection or a malignancy may be easiest performed if the child is admitted to a health care facility.

If an infection or a malignancy is detected, hospital admission may be appropriate. For example, if intravenous antibiotics are given, a child is usually admitted to the hospital. A serious reaction to an antiviral drug may also mandate hospitalization to follow up on the progression of the reaction and to observe the patient if new drugs are begun.

Malnutrition with an accompanying failure to thrive is not uncommon in children infected with HIV. The patient's dietary habits should be reviewed on a regular basis, and a nutritional specialist should be involved in the patient's treatment.

Poor appetite results in poor nutritional intake. Appetite stimulants can be useful.

High-energy, high-protein nutritional supplements are commonly needed. Caretakers must be instructed to avoid giving the child any food or water that has a high risk of being contaminated with any infectious agent. HIV and accompanying opportunistic infections can worsen GI symptoms.

Nasogastric, nasojejunal, and/or gastrostomy tubes may be needed to support the patient's nutritional and fluid status. Gastrostomy tubes are well tolerated, and they are often more comfortable than nasogastric or nasojejunal tubes.

Parenteral hyperalimentation may be necessary when the patient's GI tract cannot support substantial feedings.

Medication compliance is a central issue. This is particularly important with regard to ART because missing even 1 dose can easily lead to subtherapeutic levels of many drugs used in ART. Subtherapeutic levels promote the development of drug resistance.

The treatment regimen may be difficult. Patients must take multiple doses of several ARDs every day, as well as prophylactic antibiotics and supplemental vitamins. Therefore, the risk of missing a dose is high. New ARDs are being developed to simplify the medical regimen. The simplest dosing regimen should be carefully selected to help avoid this pitfall.

Noncompliance with prescribed medications is multifactorial and major in some populations. In general, children do not like to take medications, especially if they taste bad. Several drugs have an unpleasant taste. Adverse effects (eg, GI upset, diarrhea, allergy) may cause the caretaker to discontinue a medication without informing the physician. Many drugs can cause compliance problems, even in the most reliable individuals.

The caretaker or child should bring the medications to each clinic visit. The bottles should be checked against a list of prescribed medications kept in the chart.

The caretaker or patient should be questioned regarding the particular time and method of administration, and he or she should be asked to state the names of the medications without referring to the bottles. Although some caretakers cannot perfectly complete this task, they may still be giving the medications correctly. This assessment method allows the physician to judge the caretaker's familiarity with the medications and to detect any problems with drug administration.

Known adverse effects of drugs should be directly addressed. Some caretakers or patients are frightened or embarrassed to disclose adverse effects that may be preventing them from properly using the medications. For example, though a patient may be taking a medication regularly, it may induce frequent vomiting, which affects drug delivery. Adolescent patients may avoid taking the medications at school to prevent their peers from knowing about their disease.

Partial compliance can be worse than no compliance because resistance occurs when drugs are given at subtherapeutic doses. Drug resistance develops rapidly. If the patient is not taking a medication, the virus does not develop resistance it, and the medication is still useful for future treatment of the virus.

Administering medications with chocolate or peanut butter can help. Some medications can also be mixed in chocolate milk or pudding. If such a technique is used, proper dental hygiene is important to wash out the sugar after a drug is administered.

Placement of gastrostomy tube for drug administration is a feasible option in children who cannot be compliant. Such a device also is useful for nutritional supplementation. This option must be planned in advance because the potentially tenuous condition of children with advanced HIV can make surgical procedures risky.

A home visiting nurse or a family member experienced in healthcare may be able to assist and instruct primary caregivers in giving medications.

Immunizations for most childhood diseases and other preventable pathogens should be given to the child with HIV infection. All typical childhood vaccines should be given, with the exception of live vaccines in selected children.

Inactivated poliovirus vaccine should be given instead of the live oral poliovirus vaccine, though this is a consideration only in developing countries where live oral vaccines are used.

The measles-mumps-rubella (MMR) vaccine should be given to all children whose disease is not in CDC immune category 3. The second dose should be given as soon as 1 month after the first dose to ensure early seroconversion. If a recent measles epidemic has occurred, the measles or mono-measles vaccine should be administered as early as possible to all children, except those whose disease is in CDC immune category 3.

Pneumococcal conjugate heptavalent vaccine (PCV 7) is recommended for all HIV-infected children aged 2–59 months. For children 24-59 months who have already received PPV 23, 2 doses of PCV 7 administered at least 2 months apart are recommended. Administering PCV 7 to older children with high-risk conditions, such as HIV infection, is not contraindicated.

Pneumococcal polysaccharide vaccine (PPV 23) should be given to children at 2 years of age, with 1 revaccination 3-5 years later.

Influenza vaccine should be given yearly to all children older than 6 months and to family members of the patient.

Administer 2 doses of single-antigen varicella vaccine at a minimum interval of 3 months to HIV-infected children 12 months of age or older in CDC clinical class N, A, or B with CD4⁺ T-lymphocyte counts 15% or higher and without evidence of varicella. Varicella vaccine was previously recommended for asymptomatic or mildly symptomatic HIV-infected children (CDC clinical class N or A) with age-specific CD4⁺ T-lymphocyte counts of 25% or higher. Otherwise, varicella vaccination is strictly forbidden, and exposure to varicella should be treated with intramuscular (IM) varicella-zoster immunoglobulin within 72 hours of exposure.

Measles, mumps, rubella and varicella (MMRV) vaccine should not be administered as a substitute for the component vaccines when HIV-infected children are being vaccinated. No data are available regarding the safety, immunogenicity, or efficacy of this combination vaccine in HIV-infected children.

All children should receive hepatitis A vaccine at age 12-23 months. Vaccination should be completed according to the approved schedules and integrated into the routine childhood vaccination schedule. Children who are not vaccinated by the age of 2 years can be vaccinated at subsequent visits.

The potential risks and benefits of administering rotavirus vaccine to infected infants must be considered because immunocompromised hosts sometimes have severe, prolonged, and even fatal rotavirus gastroenteritis. However, safety or efficacy data are not available for the administration of rotavirus vaccine to infants with HIV/AIDS and other clinical manifestations of HIV infection. Data clinical trials are insufficient to support the administration of rotavirus vaccine to infants with indeterminate HIV status who were born to mothers with HIV/AIDS.

Use of the combined tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis vaccines (Tdap) is not contraindicated in HIV-infected children. The immunogenicity of Tdap in persons with immunosuppression has not been studied and could be suboptimal. Tdap can be administered to children and adolescents aged 11-18 years at an interval of less than 5 years after Td vaccination, as the benefit of providing protection against pertussis is likely to be increased. Data from a Canadian study of children and adolescents support the safety of an interval as short as about 2 years between Td and Tdap vaccinations.

An infectious disease specialist usually provides primary care and coordinates the care of the other specialists. In general, assembling a team of specialists is the best approach for managing the medical care of a child with HIV infection. A human development specialist, a nutritionist, a psychologist, and a case manager should be involved in the treatment of every child with HIV infection.

Examinations by specialists should occur routinely. Obtain a neurodevelopmental evaluation every 3-6 months.

The patient should follow up with an ophthalmologist every 6-12 months. Obtain an ophthalmologic evaluation for CMV, tuberculosis, and toxoplasmosis infections, as well as for corneal ulceration, which is often secondary to underlying nutritional deficits.

Obtain dental examinations at age 1-2 years, with follow-up every 3-6 months. Obtain an audiologic evaluation at age 2 years or sooner if concern exists.

Surgical consultation may be indicated in patients requiring central venous access for long-term parenteral medication or hyperalimentation. Placement of subcutaneous ports is common in children requiring long-term parenteral therapy, but the risks of placing such a line should be weighed against the possible need for recurrent replacement because of repeated line infections.

A cardiologist, endocrinologist, gastroenterologist, nephrologist, neurologist, pulmonologist, and mental health specialist should be consulted when necessary.

Children with HIV infection require regular monitoring, with intervals determined by age and clinical status (eg, every 2 wk initially in infancy, with an increase in intervals as the child ages and the immune status stabilizes). In younger children, evaluations should occur every 1-6 months. In older children, a review of systems is advised every 3 months and a physical evaluation should be performed every year. CD4⁺ counts must be checked every 3-6 months.

Accurate height and weight documentation at each visit is important because HIV infection is known to adversely affect growth rates in children. Children with improved height growth velocity may be less likely to exhibit virologic or immunologic failure and less likely to have clinical disease progression.^[38] A decrease in the growth velocity should alert the clinician to worsening of the underlying disease or inadequate nutrition.

Dietary habits should be reviewed at each clinical visit. Aggressive nutritional management prevents growth failure and improves immune function.

Most children with HIV infection have some developmental delay. Developmental assessment and therapy (including physical, occupational, and speech therapies) should be available.

Social support staff should continually reevaluate the child's support system. Children with HIV infection have many issues and need extra support from inside and outside the family. Every attempt should be made to support the efforts of a caring family and child.

Monitor CD4⁺ levels or percentages in infants or patients newly diagnosed with HIV at 3- to 4-month intervals to assess patients' immune status. In children younger than 5 years, the 2010 Panel on Antiretroviral Therapy and Medical Management of HIV-Infected Children recommends using CD4 percentages over absolute CD4 counts for monitoring disease progression because of inherent age-related changes in absolute CD4 counts.^[29]

Other laboratory values should be monitored as follows:

• Every 3 months: Evaluate the HIV viral load and complete blood count; additional laboratory tests may be needed depending on the ART regimen
• Every 3-6 months: Check liver function and amylase, lipase, and lactate dehydrogenase levels
• Every 6 months: Perform quantitative immunoglobulin tests and urinalysis and evaluate the fasting lipid profile
• Every year: Perform chest radiography and cytomegalovirus (CMV) and Toxoplasma serologic tests if baseline values are negative

Maintain an established vaccination schedule in children who are HIV positive to protect them against vaccine-preventable illnesses (see Immunizations).

Obtain a cerebrospinal fluid analysis in patients with neurologic disease (based on risk factors of the area and the clinical presentation of the child).