HIV AIDS infection in infants

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor-in-Chief: Ujjwal Rastogi, M.B.B.S. [2] ; Alejandro Lemor, M.D. [3]

Overview

The use of antiretroviral therapy (ART) during pregnancy in HIV-infected women has resulted in a dramatic decrease in the transmission rate to infants, which is currently less than 2% in the United States, and the number of infants with AIDS in the United States continues to decline. For infants born to mothers with unknown HIV status, rapid HIV antibody testing of the mother and/or infant is recommended as soon as possible after birth, with immediate initiation of infant antiretroviral prophylaxis if the rapid test is positive. Virologic assays that directly detect HIV must be used to diagnose HIV infection in infants younger than 18 months. HIV antibody testing cannot establish HIV infection in this age group because maternal HIV antibodies may persist and interfere with the interpretation of a positive HIV antibody test. Children living with HIV infection bring new challenges of adherence, drug resistance, reproductive health planning, management of multiple drugs, and long-term complications from HIV and its treatments.

HIV/AIDS in the Pediatric Age Group

HIV infection in the pediatric has unique features which include:

• Acquisition of infection through perinatal exposure
• In utero, intrapartum, and/or postpartum neonatal exposure to zidovudine and other ART drugs in perinatally infected children
• Requirement for HIV virologic testing to diagnose perinatal HIV infection in infants younger than 18 months
• Age-specific differences in CD4 cell counts
• Changes in pharmacokinetic parameters with age caused by the continuing development and maturation of organ systems involved in drug metabolism and clearance
• Differences in the clinical and virologic manifestations of perinatal HIV infection secondary to the occurrence of primary infection in growing, immunologically immature persons
• Special considerations associated with adherence to ART treatment for infants, children, and adolescents

Diagnosis

Pediatric Classification System

To read more about the HIV pediatric classification system, click here

Treatment

General Considerations

• A number of factors need to be considered in making decisions about initiating and changing antiretroviral therapy (ART) in children, including:
  • Severity of HIV disease and risk of disease progression, as determined by age, presence or history of HIV-related or AIDS-defining illnesses, level of CD4 cell immunosuppression, and magnitude of HIV plasma viremia.
  • Availability of appropriate (and palatable) drug formulations and pharmacokinetic (PK) information on appropriate dosing in the child’s age group.
  • Potency, complexity (e.g., dosing frequency, food and fluid requirements), and potential short- and long-term adverse effects of the ARV regimen.
  • Effect of initial regimen choice on later therapeutic options.
  • the child’s ARV treatment history.
  • Presence of ARV drug-resistant virus.
  • Presence of comorbidity, such as tuberculosis (TB), hepatitis B virus (HBV) or hepatitis C virus (HCV) infection, or chronic renal or liver disease, that could affect drug choice.
  • Potential ARV drug interactions with other prescribed, over-the-counter, or complementary/alternative medications taken by the child.
  • The ability of the caregiver and child to adhere to the regimen.

Goals of Antiretroviral Treatment

The goals of ART for HIV-infected children include:

• Reducing HIV-related mortality and morbidity.
• Restoring and/or preserving immune function as reflected by CD4 cell measures.
• Maximally and durably suppressing viral replication.
• Preventing emergence of viral drug-resistance mutations.
• Minimizing drug-related toxicity.
• Maintaining normal physical growth and neurocognitive development.
• Improving quality of life.

Recommendations

Grading of Recommendations and Levels of Evidence

Strength of recommendation	Level of evidence
A. Strong	I. One or more randomized trials with clinical outcomes and/or validated laboratory endpoint
B. Moderate	II. One or more well-designed, nonrandomized trials or observational cohort studies with long-term clinical outcomes
C. Optional	III. Expert opinion based on evaluation of other evidence

Infants Born To Mothers with Unknown HIV Infection

• For infants born to mothers with unknown HIV status, rapid HIV antibody testing of the mother and/or infant is recommended as soon as possible after birth, with immediate initiation of infant antiretroviral (ARV) prophylaxis if the rapid test is positive (AII). In the setting of a positive test, standard antibody confirmatory testing such as a Western blot also should be performed on mothers (or their infants) as soon as possible. If the confirmatory test is negative, ARV prophylaxis can be discontinued (AIII).
• If the HIV antibody confirmatory test is positive, a newborn HIV DNA polymerase chain reaction (PCR) should be obtained (AIII).
• If the newborn HIV DNA PCR is positive, ARV prophylaxis should be discontinued and the infant promptly referred to a pediatric HIV specialist for confirmation of the diagnosis and treatment of HIV infection with standard combination antiretroviral therapy (ART) (AI).

Identification of Perinatal HIV Exposure

• HIV testing early in pregnancy is recommended as standard of care for all pregnant women in the United States (AII).
• Repeat HIV testing in the third trimester is recommended for women who have negative HIV antibody tests earlier in pregnancy if they are at high risk of HIV infection because of behavior or residence in a high-prevalence area (AII).
• Women seen at labor with undocumented HIV status should undergo rapid HIV antibody testing, and women with a positive antibody test should initiate intrapartum antiretroviral (ARV) prophylaxis (AII).
• If acute HIV infection is suspected in a pregnant woman, a virologic test (e.g., plasma HIV RNA assay) should be performed because serologic testing may be negative at this early stage of infection (AII).
• Women who have not been tested for HIV before to or during labor should undergo rapid HIV antibody testing during the immediate postpartum period or their newborns should undergo rapid HIV antibody testing. If the mother or infant is HIV antibody positive, infant ARV prophylaxis should be initiated as soon as possible and the mother advised not to breastfeed pending results of confirmatory HIV antibody testing (AII).

Diagnosis of HIV Infection in Infants

• Virologic assays that directly detect HIV must be used to diagnose HIV infection in infants younger than 18 months (AII). HIV antibody testing cannot establish HIV infection in this age group because maternal HIV antibodies may persist and interfere with the interpretation of a positive HIV antibody test.
• Virologic diagnostic testing is recommended in infants with known perinatal HIV exposure at ages 14–21 days, 1–2 months, and 4–6 months ( AII ).
• Virologic diagnostic testing at birth should be considered for infants at high risk of HIV infection (BIII).
• HIV DNA polymerase chain reaction (PCR) and HIV RNA assays are recommended as preferred virologic assays (AII).
• Confirmation of HIV infection should be based on two positive virologic tests obtained from separate blood samples (AI).
• Definitive exclusion of HIV infection (in the absence of breastfeeding) should be based on at least two negative virologic tests (one at >1 month and one at ≥4 months of age) (AII).
• Some experts confirm the absence of HIV infection at 12–18 months of age in infants with prior negative virologic tests by performing an antibody test to document loss of maternal HIV antibodies (BIII).
• In children ≥18 months of age, HIV antibody assays alone can be used for diagnosis (AII)

Infant Antiretroviral Prophylaxis

• The 6-week neonatal component of the zidovudine chemoprophylaxis regimen is recommended for all HIV-exposed neonates to reduce perinatal transmission of HIV (AI).
• Zidovudine should be initiated as close to the time of birth as possible, preferably within 6–12 hours of delivery (AII).
• The 6-week zidovudine prophylaxis regimen is recommended at gestational age-appropriate doses; zidovudine should be dosed differently for premature infants less than 35 weeks than for infants at least 35 weeks of age (AII).

• In the United States, the use of antiretroviral (ARV) drugs other than zidovudine cannot be recommended in premature infants because of lack of dosing and safety data (BIII).
• The use of intrapartum/neonatal zidovudine is recommended regardless of maternal history of zidovudine resistance (BIII).
• Infants born to HIV-infected women who have not received antepartum ARV drugs should receive prophylaxis with a combination ARV drug regimen, begun as soon after birth as possible (AI). A randomized, controlled trial has shown that a 2 drug regimen of zidovudine given for 6 weeks combined with three doses of nevirapine in the first week of life (at birth, 48 hours later, and 96 hours after the second dose) is as effective as but less toxic than a 3 drug regimen of zidovudine, nelfinavir and lamivudine.
• The 2-drug regimen is preferred due to lower toxicity and because nelfinavir powder is no longer available in the United States. (AI).
• In other scenarios, the decision to combine other drugs with the 6-week zidovudine regimen should be made in consultation with a pediatric HIV specialist, preferably before delivery, and should be accompanied by counseling of the mother on the potential risks and benefits of this approach (BIII).
• The National Perinatal HIV Hotline (1-888-448-8765) provides free clinical consultation on all aspects of perinatal HIV, including infant care.

Laboratory Monitoring of Pediatric HIV Infection Before Initiation of Therapy

• The age of the child must be considered when interpreting the risk of disease progression based on CD4 percentage or count and plasma HIV RNA level (AII). For any given CD4 percentage or count, younger children, especially those in the first year of life, face higher risk of progression than do older children.
• In children younger than 5 years of age, CD4 percentage is preferred for monitoring immune status because of age-related changes in absolute CD4 count in this age group (AII).
• CD4 percentage or count should be measured at the time of diagnosis of HIV infection and at least every 3-4 months thereafter (AIII).
• Plasma HIV RNA should be measured to assess viral load at the time of diagnosis of HIV infection and at least every 3-4 months thereafter (AIII).
• More frequent CD4 cell and plasma HIV RNA monitoring should be considered in children with suspected clinical, immunologic, or virologic deterioration or to confirm an abnormal value (AIII).

When to Initiate Therapy in Antiretroviral-Naive Children

• Age ≤ 12 months
  • Antiretroviral therapy (ART) should be initiated in HIV-infected infants <12 months of age, regardless of clinical status, CD4 percentage, or viral load (AII).
  • Issues associated with adherence must be fully assessed and discussed with the HIV-infected infant’s caregivers before therapy is initiated (AIII)

• Age > 1 year
  • Antiretroviral therapy (ART) should be initiated in children age ≥1 year with AIDS or significant symptoms (Clinical Category C or most Clinical Category B conditions), regardless of CD4 percentage/count or plasma HIV RNA level (AI*).
  • Initiation of ART is also recommended for children age ≥1 year regardless of symptoms or plasma HIV RNA level if:
    • Age 1 to <5 years and CD4 percentage <25% (AII); or
    • Age ≥5 years and CD4 count ≤500 cells/mm3 (AI* for CD4 percentage <25% or CD4 count <350 cells/mm3 and BII* for CD4 count 350–500 cells/mm3).
  • Initiation of ART is also recommended for children age ≥1 year who are asymptomatic or have mild symptoms (Clinical Categories N and A or a single episode of serious bacterial infection) with a plasma RNA ≥100,000 copies/mL regardless of CD4 percentage/count (BII*).
  • Initiation of ART may be considered for children age ≥1 year who are asymptomatic or have mild symptoms with a plasma RNA RNA <100,000 copies/mL and CD4 percentage >25% if age 1–5 years or CD4 count >500 cells/mm3 if age ≥5 years (CIII).

Initial Combination Therapy for Antiretroviral-Naive Children

• Combination therapy, including either a non-nucleoside reverse transcriptase inhibitor (NNRTI) or a protease inhibitor (PI) plus a dual-nucleoside/nucleotide reverse transcriptase inhibitor (NRTI) backbone, is recommended for initial treatment of HIV-infected children (AI).
• The goal of therapy in treatment-naive children is to reduce plasma HIV RNA levels to below the limits of quantitation of ultrasensitive assays and to preserve or normalize immune status (AI).
• Antiretroviral (ARV) drugs initiated for chemoprophylaxis of mother-to-child-transmission (MTCT) of HIV should be discontinued in infants who are identified as HIV infected (AI).
• ARV drug-resistance testing is recommended before initiation of therapy in all treatment-naive children (AII infants; AIII children).

Recommended Regimens for Initial Therapy of Antiretroviral-Naive Children

• The Panel recommends initiating antiretroviral therapy (ART) in treatment-naive children using one of the following agents (in alphabetical order) plus a dual-nucleoside reverse transcriptase inhibitor (NRTI) backbone combination:
  • For children ≥42 weeks of postmenstrual age and postnatal ≥14 days of age: lopinavir/ritonavir (AI)
  • For children age ≥3 years: efavirenz (AI*)
  • For children age ≥6 years: atazanavir/ritonavir (AI*)
• The Panel recommends the following preferred dual-NRTI backbone combinations:
  • Abacavir + (lamivudine or emtricitabine) (AI)
• HLA-B*5701 genetic testing should be performed before initiating abacavir-based therapy, and abacavir should not be given to a child who tests positive for HLA-B*5701 (AII*).
  • Zidovudine + (lamivudine or emtricitabine) (AI*)
  • For adolescents ≥12 years of age and Tanner Stage 4 or 5: tenofovir + (lamivudine or emtricitabine) (AI*).

Monitoring of Children on Antiretroviral Therapy

• Within 1 to 2 weeks of starting a new antiretroviral (ARV) regimen, children should be evaluated to screen for clinical side effects and to ensure patient/caretaker adherence to the regimen (AIII). Evaluations can be conducted in person or over the phone.
• Following initiation or change in therapy, more frequent evaluation may be needed to support adherence to the regimen (AIII).
• At least every 3 to 4 months thereafter, children should have a monitoring evaluation to assess both effectiveness and potential toxicity of their ARV regimens (AII*)

Specific Adherence Issues in Children

• Adherence is a complex health behavior that is influenced by the regimen prescribed, patient and family factors, and characteristics of health care providers.
• Limited availability of palatable formulations for young children is especially problematic.
• Furthermore, infants and children are dependent on others for administration of medication; thus, assessment of the capacity for adherence to a complex multidrug regimen requires evaluation of the caregivers and their environments as well as the ability and willingness of the child to take the drug.
• Some caregivers may place too much responsibility for managing medications on older children before the children are developmentally able to take on such tasks.
• Many other barriers to adherence exist for children with HIV infection. For example, caregivers’ unwillingness to disclose the child’s HIV infection status to others may create specific problems, including reluctance of caregivers to fill prescriptions locally, hiding or relabeling of medications to maintain secrecy within the household, avoidance of social support, and a tendency for doses to be missed if the parent is unavailable.