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.

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Management of Children Receiving Antiretroviral Therapy

Recognizing and Managing Antiretroviral Treatment Failure

Last Updated: April 16, 2019; Last Reviewed: April 16, 2019

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, and before changing to a new regimen (AI*).
  • 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, with assessment of anticipated ARV activity based on treatment history and past resistance test results (AII*).
  • The goal of therapy following treatment failure is to achieve and maintain virologic suppression, as measured by a plasma viral load below the limits of detection using the most sensitive assay (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 or viral load measurement)
  • Misinterpretation of normal, age-related CD4 decline (i.e., the immunologic response is not actually poor)
  • Low pretreatment CD4 cell count or percentage
  • Adverse effects of using ZDV
  • Use of systemic corticosteroids or chemotherapeutic agents
  • Conditions that can cause low CD4 values, such as HCV, acute viral infections, TB, malnutrition, Sjogren’s syndrome, sarcoidosis, and 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 (HIV-1 non-M groups, non-B subtypes; HIV-2)
  • Persistent immunodeficiency soon after initiation of 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), lungs (e.g., bronchiectasis), cardiac (cardiomyopathy), renal (HIV-related kidney disease)
  • A new clinical event due to a non-HIV illness or condition
  • A new, otherwise unexplained HIV-related clinical event (treatment failure)
Key to Acronyms: ART = antiretroviral therapy; CD4 = CD4 T lymphocyte; HCV = hepatitis C virus; IRIS = immune reconstitution inflammatory syndrome; TB = tuberculosis; ZDV = zidovudine

Table 18. Options for Regimens with at Least Two Fully Active Agents with Goal of Virologic Suppression in Patients with Failed Antiretroviral Therapy and Evidence of Viral Resistancea
Prior Regimen New Regimen Optionsa
Two NRTIs plus NNRTI

Two NRTIs plus PI

Two NRTIs plus INSTI

Two NRTIs plus PI

Two NRTIs plus INSTI

Two NRTIs plus a different RTV-boosted PI

INSTI plus different RTV-boosted PI plus or minus an NNRTI and plus or minus NRTI(s)

Two NRTIs plus INSTI

Two NRTIs plus RTV-boosted PI

DTGb (if not used in the prior regimen) plus RTV-boosted PI plus or minus 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)

INSTI plus two NRTIs (if NRTIs are fully active)

INSTI plus two NRTIs plus or minus RTV-boosted PI (if NRTIs are not fully active)

INSTI plus or minus RTV-boosted PI plus or minus (ETR or RPV) plus or minus NRTI(s) (if minimal NRTI activity). Consider adding T-20 and/or MVC if additional active drug(s) are needed.

a 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 in 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 as 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.
b Because of recent concerns about the potential for neural tube defects in infants born to women who conceived while taking regimens that contained dolutegravir, this drug should be prescribed with caution in female adolescents. Specific recommendations about the initiation and use of dolutegravir in women of childbearing potential and in pregnant women 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 and Recommendations for Use of Antiretroviral Drugs During Pregnancy).

Key to Acronyms: 3TC = lamivudine; ART = antiretroviral therapy; ARV = antiretroviral; 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; PI = protease inhibitor; RPV = rilpivirine; RTV = ritonavir; T-20 = enfuvirtide; TAF = tenofovir alafenamide; TDF = tenofovir disoproxil fumarate; ZDV = zidovudine  

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