Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection

The Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection (Pediatric Guidelines) address the diagnosis of HIV infection in infants and children and the use of antiretroviral therapy (ART) in children with HIV, including adolescents with sexual maturity ratings (SMRs; formerly Tanner Staging) 1 to 3. Note that the Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents with HIV, developed by the Panel on Antiretroviral Guidelines for Adults and Adolescents, are suitable for the care and management of adolescents in late puberty (SMRs 4–‍5).

The Pediatric Guidelines also include recommendations for managing adverse events that are associated with the use of antiretroviral (ARV) drugs in children and a detailed review of information about the safety, efficacy, and pharmacokinetics (PK) of ARV agents in children. The U.S. Department of Health and Human Services (HHS) Panel on Antiretroviral Therapy and Medical Management of Children Living with HIV (the Panel), a working group of the Office of AIDS Research Advisory Council (OARAC), reviews new data on an ongoing basis and regularly updates the guidelines. The guidelines are available on the Clinicalinfo website. These guidelines are developed for the United States and may not be applicable in other countries. The World Health Organization provides guidelines for resource-limited settings.

The Pediatric Guidelines and the Perinatal Guidelines contain some closely related content that can overlap. To ensure that information is consistent across the guidelines and that users can easily find the information they need, the Panels that publish these two sets of guidelines have developed a process to jointly produce sections for shared content areas. The development of these sections is led by a group composed of members from both Panels; the sections are discussed separately and voted on by each full Panel. Jointly produced sections include—

• Pregnancy and Postpartum HIV Testing and Identification of Perinatal and Postnatal HIV Exposure
• Diagnosis of HIV Infection in Infants and Children
• Antiretroviral Management of Newborns with Perinatal HIV Exposure or HIV Infection
• Infant Feeding for Individuals with HIV in the United States

Since the guidelines were first developed in 1993 (with the support of the François-Xavier Bagnoud Center, Rutgers School of Nursing, The State University of New Jersey), advances in medical management have dramatically reduced both the number of new pediatric HIV infections and the morbidity and mortality in children with HIV in the United States. The widespread use of ARV drugs in people with HIV during pregnancy and the use of ARV prophylaxis in infants who have been exposed to HIV have reduced the annual rate of perinatally acquired HIV infection^1,2 from a peak of 43.1 per 100,000 births in 1992 to 1.0 per 100,000 births in 2020. Racial and ethnic disparities are evident in annual rates of new perinatal infection; in 2020, perinatal infections occurred in Black or African American infants (3.8 per 100,000 births) at annual rates of 4 and 13 times those of Hispanic/Latinx (0.9 per 100,000 births) and White infants (0.3 per 100,000 births), respectively.¹ Since the introduction of ART, mortality in children with perinatal HIV infection has decreased by about 90%, and the incidence of opportunistic infections and other infections in these children has significantly declined.^3,4 ARV drug-resistance testing has made it easier for clinicians to choose effective initial and subsequent regimens. Treatment strategies focus on early initiation of potent ARV regimens that are capable of maximally suppressing viral replication, which can prevent disease progression, preserve or restore immunologic function, reduce the size of viral reservoirs, and prevent the development of drug resistance.^5,6 In addition, the availability of new drugs and drug formulations has led to more potent regimens with lower toxicity, lower pill burden, and less frequent medication administration—all factors that can improve adherence and outcomes. However, delays in the development and testing of pediatric formulations continue to limit the availability of optimal ARV regimens for children, especially infants.⁷

Children with HIV in the United States are increasingly born outside the United States⁸; they may be members of immigrant families or they may have been adopted by U.S. residents. These children may have non-B subtypes of HIV, incomplete medical and treatment histories, an increased risk of tuberculosis and other infections that are endemic in their countries of origin, and legal and psychosocial needs related to immigration.^9,10

Finally, as children with HIV grow older, new challenges arise related to adherence, drug resistance, reproductive health planning, transition to adult medical care, and the potential for long-term complications from HIV and its treatments.^11-13

The pathogenesis of HIV infection and the virologic and immunologic principles underlying the use of ART are generally similar for all individuals with HIV. However, unique considerations exist for infants, children, and adolescents with HIV, including—

• Acquisition of infection through perinatal exposure for most children with HIV;
• In utero and neonatal exposure to ARV drugs in most children with perinatal HIV infection¹⁴;
• The need to use HIV virologic tests to diagnose perinatal HIV infection in infants younger than 18 months;
• Age-specific interpretations of CD4 T lymphocyte (CD4) cell counts;
• Higher plasma viral loads in infants with perinatal HIV infection than in adolescents and adults with non-perinatal HIV infection;
• Age-related changes in PK parameters that are caused by the continuing development and maturation of organ systems involved in drug absorption, distribution, metabolism, and clearance¹⁵;
• Differences in the clinical manifestations and treatment of HIV in growing, immunologically immature individuals; and
• Special considerations associated with adherence to ART in infants, children, and adolescents.

The care of children with HIV is complex and evolves as results of new research are reported, new ARV drugs are approved, and new approaches to treatment are recommended. As new drugs become available, a critical need exists for clinical trials that define appropriate drug doses and identify possible toxicities in infants, children, and adolescents. As additional ARV drugs are approved and optimal strategies for the use of these drugs in children become better understood, the Panel will modify these guidelines.

The recommendations in these guidelines are based on the current state of knowledge regarding the use of ARV drugs in children. Evidence is drawn primarily from published data regarding the treatment of HIV in infants, children, adolescents, and adults; however, when no such data are available, unpublished data and the clinical expertise of Panel members are also considered. These guidelines are only a starting point for medical decision-making and are not meant to supersede the judgment of clinicians who are experienced in the care of children with HIV. Because of the complexity of caring for children with HIV, health care providers with limited experience in the care of these patients should consult a pediatric HIV specialist. The HIV/AIDS Management Clinician Consultation Center is an excellent resource for telephone consultation. The Center can be contacted at 1-800-933-3413, 9 a.m. to 8 p.m. ET, Monday through Friday.

Basis for Recommendations

Recommendations in these guidelines are based on scientific evidence and expert opinion. Each recommendation includes a letter (A, B, or C) that represents the strength of the recommendation and a Roman numeral (I, II, or III) that represents the quality of the evidence that supports the recommendation.

When approving drugs for use in children, the U.S. Food and Drug Administration (FDA) often extrapolates efficacy data from adult trials, in addition to using safety and PK data from studies in children.¹⁶ Because of this, recommendations for use of ARV drugs in children often rely, in part, on data from clinical trials or studies in adults. Because the course of HIV disease and the effects of ARV drugs in pediatric and adult populations are expected to be similar enough to permit extrapolation of adult efficacy data to pediatric patients, it is appropriate to base approval of ARV drugs for children on evidence from adequate and well-controlled investigations in adults if—

• Supplemental data exist on the PK of the drug in children, indicating that systemic exposure in adults and children is similar; and
• Studies are provided that support the safety of using the drug in pediatric patients.^17-19

If a concern exists that concentration–response relationships might be different in children than in adults, then pediatric drug approval should include evidence from studies that relate drug activity to drug levels (pharmacodynamic data) in children. In many cases, the evidence from studies on the use of ARV drugs in adults (especially from randomized clinical trials) is much more substantial and higher in quality than the available evidence from studies in children. Therefore, for pediatric recommendations, the following rationale has been used when the evidence from studies in children is limited or of lower quality:

Quality of Evidence Rating I - Randomized Clinical Trial Data

• Quality of Evidence Rating I will be used if there are data from large, randomized trials in children with clinical and/or validated laboratory endpoints.
• Quality of Evidence Rating I* will be used if there are high-quality randomized clinical trial data in adults with clinical and/or validated laboratory endpoints and pediatric data from well-designed, nonrandomized trials or observational cohort studies with clinical outcomes that are consistent with the adult studies. A rating of I* may be used for quality of evidence if, for example, a randomized Phase 3 clinical trial in adults demonstrates that a drug is effective in ARV-naive patients, and data from a nonrandomized pediatric trial demonstrate adequate and consistent safety and PK data in the pediatric population.

Quality of Evidence Rating II - Nonrandomized Clinical Trials or Observational Cohort Data

• Quality of Evidence Rating II will be used if there are data from well-designed, nonrandomized trials or observational cohorts in children.
• Quality of Evidence Rating II* will be used if there are well-designed, nonrandomized trials or observational cohort studies in adults with supporting and consistent information from smaller, nonrandomized trials or cohort studies with clinical outcome data in children. A rating of II* may be used for quality of evidence if, for example, a large observational study in adults demonstrates a clinical benefit to initiating treatment at a certain CD4 cell count, and data from smaller observational studies in children indicate that treatment initiation at a similar CD4 cell count is associated with clinical benefit.

Quality of Evidence Rating III - Expert Opinion

• The criteria do not differ for adults and children.

In an effort to improve the quality of evidence available to guide the management of HIV infection in children, clinicians are encouraged to discuss participation in trials with children and their caregivers. Information about clinical trials for adults and children with HIV can be obtained from the Clinicalinfo website or by telephone at 1-800-448-0440.

References

1. Centers for Disease Control and Prevention. Monitoring selected national HIV prevention and care objectives by using HIV surveillance data united states and 6 dependent areas, 2018. 2020. Available at: https://www.cdc.gov/hiv/library/reports/hiv-surveillance/vol-26-no-2/index.html.
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8. Nesheim SR, Linley L, Gray KM, et al. Country of birth of children with diagnosed HIV infection in the United States, 2008-2014. J Acquir Immune Defic Syndr. 2018;77(1):23-30. Available at: https://pubmed.ncbi.nlm.nih.gov/29040167.
9. Fair CD, Alger S. Prepared but unprepared: a qualitative study of provider perspectives on the preparation and adjustment of U.S. families who internationally adopt children with HIV. AIDS Care. 2021;33(10):1363-1367. Available at: https://pubmed.ncbi.nlm.nih.gov/32741214.
10. Shetty AK. Infectious Diseases among Refugee Children. Children (Basel). 2019;6(12). Available at: https://pubmed.ncbi.nlm.nih.gov/31783605.
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16. FDA-ICH Harmonized Guidelines. The International Council of Harmonisation of Technical Requirements of Pharmaceuticals for Human Use; Overview.: 2022.Available at: https://www.fda.gov/media/165161/download. Accessed.
17. Dunne J, Rodriguez WJ, Murphy MD, et al. Extrapolation of adult data and other data in pediatric drug-development programs. Pediatrics. 2011;128(5):e1242-1249. Available at: https://pubmed.ncbi.nlm.nih.gov/22025597.
18. E11(R1) addendum: clinical investigation of medicinal products in the pediatric population guidance for industry [package insert]. Food and Drug Administration. 2018. Available at: https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM530012.pdf.
19. ICH Harmonized Guidelines: Pediatric Extrapoloation E11A [package insert]. Food and Drug Administration. 2022. Available at: https://www.fda.gov/regulatory-information/search-fda-guidance-documents/e11a-pediatric-extrapolation.