Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection

The information in the brief version is excerpted directly from the full-text guidelines. The brief version is a compilation of the tables and boxed recommendations.

  •   Table of Contents

Download Guidelines

Management of Children Receiving Antiretroviral Therapy

Recognizing and Managing Antiretroviral Treatment Failure

Last Updated: April 14, 2020; Last Reviewed: April 14, 2020

Panel's Recommendations for Recognizing and Managing Antiretroviral Treatment Failure
Panel's Recommendations
  • The causes of antiretroviral (ARV) treatment failure—which include poor adherence, drug resistance, poor absorption of medications, inadequate dosing, and drug-drug interactions—should be assessed and addressed (AII).
  • Perform ARV drug-resistance testing when virologic failure occurs, while the patient is still taking the failing regimen (AI*) (see Drug-Resistance Testing in the Adult and Adolescent Antiretroviral Guidelines for more information).
  • ARV regimens should be chosen based on treatment history and drug-resistance testing, including both past and current resistance test results (AI*).
  • The new regimen should include at least two, but preferably three, fully active ARV medications; the assessment of anticipated ARV activity should be based on treatment history and past resistance test results (AII*).
  • The goal of therapy following treatment failure is to achieve and maintain virologic suppression, which is defined as a plasma viral load that is below the limits of detection as measured by highly sensitive assays with lower limits of quantification of 20 copies/mL to 75 copies/mL (AI*).
  • When complete virologic suppression cannot be achieved, the goals of therapy are to preserve or restore immunologic function (as measured by CD4 T lymphocyte values), prevent clinical disease progression, and prevent the development of additional drug resistance that could further limit future ARV drug options (AII).
  • Children who require evaluation and management of treatment failure should be managed by or in collaboration with a pediatric HIV specialist (AI*).
Rating of Recommendations: A = Strong; B = Moderate; C = Optional

Rating of Evidence: I = One or more randomized trials in children with clinical outcomes and/or validated endpoints; I* = One or more randomized trials in adults with clinical outcomes and/or validated laboratory endpoints with accompanying data in children† from one or more well-designed, nonrandomized trials or observational cohort studies with long-term clinical outcomes; II = One or more well-designed, nonrandomized trials or observational cohort studies in children with long-term outcomes; II* = One or more well-designed, nonrandomized trials or observational studies in adults with long-term clinical outcomes with accompanying data in children from one or more similar nonrandomized trials or cohort studies with clinical outcome data; III = Expert opinion

Studies that include children or children/adolescents, but not studies limited to post-pubertal adolescents

Table 17. Discordance Among Virologic, Immunologic, and Clinical Responses
Differential Diagnosis of Poor Immunologic Response Despite Virologic Suppression
Poor Immunologic Response Despite Virologic Suppression and Good Clinical Response:
  • Lab error (in CD4 value or viral load measurement)
  • Misinterpretation of normal, age-related CD4 count decline (i.e., the immunologic response is not actually poor)
  • Low pretreatment CD4 count or percentage
  • AEs that are associated with the use of certain drugs (e.g., ZDV, TMP-SMX, systemic corticosteroids)
  • Use of systemic corticosteroids or chemotherapeutic agents
  • Conditions that can cause low CD4 values (e.g., HCV, acute viral infections, TB, malnutrition, Sjogren’s syndrome, sarcoidosis, syphilis)
Poor Immunologic and Clinical Responses Despite Virologic Suppression:
  • Lab error
  • Falsely low viral load result for an HIV strain/type that is not detected by viral load assay (i.e., HIV-1 non-M groups, HIV-1 non-B subtypes, HIV-2)
  • Persistent immunodeficiency that occurs soon after initiating ART but before ART-related reconstitution
  • Primary protein-calorie malnutrition
  • Untreated TB
  • Malignancy
Differential Diagnosis of Poor Clinical Response Despite Adequate Virologic and Immunologic Responses
  • IRIS
  • A previously unrecognized, pre-existing infection or condition (e.g., TB, malignancy)
  • Malnutrition
  • Clinical manifestations of previous organ damage: brain (e.g., strokes, vasculopathy, worsening neurodevelopmental delay), lungs (e.g., bronchiectasis), cardiac (i.e., cardiomyopathy), renal (i.e., HIV-related kidney disease)
  • A new clinical event due to a non-HIV illness or condition
  • A new, otherwise unexplained HIV-related clinical event (e.g., treatment failure)
Key: AE = adverse effects; ART = antiretroviral therapy; CD4 = CD4 T lymphocyte; HCV = hepatitis C virus; IRIS = immune reconstitution inflammatory syndrome; TB = tuberculosis; TMP-SMX = trimethoprim-sulfamethoxazole; ZDV = zidovudine

Table 18. Options for Regimens with at Least Two Fully Active Agents to Achieve Virologic Suppression in Patients with Virologic Failure and Evidence of Viral Resistance

Clinicians should evaluate a patient’s treatment history and drug-resistance test results when choosing an ART regimen in order to optimize ARV drug effectiveness. This is particularly important when selecting the NRTI components of an NNRTI-based regimen, where drug resistance to the NNRTI can occur rapidly if the virus is not sufficiently sensitive to the NRTIs. Regimens should contain at least two, but preferably three, fully active drugs for durable and potent virologic suppression. If the M184V/I mutation associated with FTC and 3TC is present, these medications should be continued if the new regimen contains TDF, TAF, or ZDV. The presence of this mutation may increase susceptibility to these NRTIs.

Please see individual drug profiles for information about age limitations (e.g., do not use DRV in children aged <3 years), drug interactions, and dose adjustments when devising a regimen for children with multiclass drug resistance. Collaboration with a pediatric HIV specialist is especially important when choosing regimens for children with multiclass drug resistance. Regimens in this table are provided as examples, but the list is not exhaustive.

Table 18. Options for Regimens with at Least Two Fully Active Agents to Achieve Virologic Suppression in Patients with Virologic Failure and Evidence of Viral Resistance
Prior Regimen New Regimen Optionsa
Two NRTIs plus an NNRTI Two NRTIs plus a boosted PI

Two NRTIs plus an INSTIb
Two NRTIs plus a PI Two NRTIs plus an INSTI

Two NRTIs plus a different boosted PI

INSTI plus a different boosted PI with or without an NNRTI and with or without NRTI(s)
Two NRTIs plus an INSTI Two NRTIs plus a boosted PI

DTGa,b or BICb (if not used in the prior regimen) with a boosted PI with or without one or two NRTIs. DTG must be given twice daily if a patient has certain documented INSTI mutations, or if there is concern about certain mutations (see the Dolutegravir section).
Failed Regimen(s) That Included NRTI(s), NNRTI(s), and PI(s) If NRTIs Are Fully Active:
  • INSTI plus two NRTIs
If NRTIs Are Not Fully Active:
  • INSTI plus two NRTIs with or without an RTV-boosted PI
If There is Minimal NRTI Activity:
  • INSTI with or without an RTV-boosted PI with or without ETR or RPV with or without NRTI(s)
  • Consider adding T-20 and/or MVC if additional active drug(s) are needed.
a Exposure to DTG around the time of conception has been associated with a small but significant increase in the risk of infant NTDs. Additional information and specific recommendations about the use of DTG in women and adolescents of childbearing potential and in those who are pregnant or who are trying to conceive are available in the Adult and Adolescent Antiretroviral Guidelines (see Adolescents and Young Adults with HIV and Management of the Treatment-Experienced Patient) and in the Perinatal Guidelines (see Teratogenicity, Recommendations for Use of Antiretroviral Drugs During Pregnancy, and Appendix D. Dolutegravir Counseling Guide for Health Care Providers).

b RAL has a low barrier to resistance and requires twice-daily dosing in children and adolescents; BIC and DTG have a higher barrier to resistance and only require once-daily dosing.

Key: 3TC = lamivudine; ART = antiretroviral therapy; ARV = antiretroviral; BIC = bictegravir; DRV = darunavir; DTG = dolutegravir; ETR = etravirine; FTC = emtricitabine; INSTI = integrase strand transfer inhibitor; MVC = maraviroc; NNRTI = non-nucleoside reverse transcriptase inhibitor; NRTI = nucleoside reverse transcriptase inhibitor; NTD = neural tube defect; PI = protease inhibitor; RAL = raltegravir; RPV = rilpivirine; RTV = ritonavir; T-20 = enfuvirtide; TAF = tenofovir alafenamide; TDF = tenofovir disoproxil fumarate; ZDV = zidovudine

Download Guidelines