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.
What to Start
What Not to Start: Regimens Not Recommended for Initial Therapy of Antiretroviral-Naive Children
Last Updated: April 14, 2020; Last Reviewed: April 14, 2020
Many antiretroviral (ARV) agents and combinations are available; some are not recommended for use as part of an initial regimen in ARV-naive children, although they may be used in ARV-experienced children. This section describes ARV drugs and drug combinations that either are not recommended for use in ARV-naive children or that lack sufficient data to recommend their use in ARV-naive children. Several ARV drugs that are no longer available or that have not been recommended for use in children for several years have been removed from this chapter, including the nucleoside reverse transcriptase inhibitors (NRTIs) stavudine and didanosine; the protease inhibitors (PIs) indinavir, nelfinavir, saquinavir, tipranavir (TPV), and fosamprenavir; and the fusion inhibitor enfuvirtide. Information about these agents is available in Archived Drugs.
The Panel on Antiretroviral Therapy and Medical Management of Children Living with HIV (the Panel) classifies ARV drugs and drug combinations that are not recommended for use in ARV-naive children into one of three categories:
- Not Recommended for Initial Therapy: These include ARV drugs and drug combinations that are not recommended for initial therapy in ARV-naive children because they produce an inferior virologic response, they pose potential serious safety concerns (including potentially overlapping toxicities), they are associated with pharmacologic antagonism, or there are better options within a drug class. These drugs and drug combinations are listed in Table 9, and selected drugs or drug combinations are discussed below.
- Insufficient Data to Recommend for Initial Therapy: ARV drugs and drug combinations that are approved for use in adults but that have insufficient, limited, and/or no pharmacokinetic (PK) or safety data for children cannot be recommended for initial therapy in children. However, these drugs and drug combinations may be appropriate to consider when managing treatment-experienced children (see Management of Children Receiving Antiretroviral Therapy). These drugs are also listed in Table 9, and selected drugs or drug combinations are discussed below.
- Antiretroviral Drug Regimens That Are Never Recommended: Several ARV drug and drug combinations should never be used in children or adults. These are summarized in Table 10. Clinicians should also be aware of the components of fixed-dose combination (FDC) tablets so that patients do not inadvertently receive a double dose of a drug contained in such a combination.
Antiretroviral Drugs and Drug Combinations Not Recommended for Initial Therapy in Children
Atazanavir without Ritonavir or Cobicistat Boosting
Although unboosted atazanavir (ATV) is approved by the Food and Drug Administration (FDA) for use in treatment-naive adolescents aged ≥13 years and weighing ≥40 kg who are unable to tolerate ritonavir (RTV), data from the IMPAACT/PACTG 1020A study indicate that adolescents require higher doses of unboosted ATV (as measured by mg/m2 of body surface area) than adults in order to achieve adequate drug concentrations.1 The Panel does not recommend using ATV without RTV boosting because of these findings.
Regimens that Contain Only Nucleoside Reverse Transcriptase Inhibitors
In adult trials, regimens that contain only NRTIs have shown less potent virologic activity than non-nucleoside reverse transcriptase inhibitor (NNRTI)-based or PI-based regimens.2,3 Data on the efficacy of triple-NRTI regimens for treatment of ARV-naive children are limited to small observational studies.4,5 In a study on the use of the triple-NRTI regimen abacavir plus lamivudine (3TC) plus zidovudine in ARV-experienced children, this combination showed evidence of only modest viral suppression; only 10 of the 102 children had viral loads of <400 copies/mL at Week 48 of treatment.6 Therefore, regimens that contain only NRTIs are not recommended for treatment-naive or treatment-experienced children.
Regimens that Contain Three Drug Classes
The Panel does not recommend using regimens that contain agents from three drug classes as initial regimens (e.g., an NRTI plus an NNRTI plus a PI or an integrase strand transfer inhibitor plus an NRTI plus a PI or NNRTI). Although studies of regimens that contain three classes of drugs have demonstrated that these regimens are safe and effective in ARV-experienced children and adolescents, these regimens have not been studied as initial regimens in treatment-naive children and adolescents. These regimens also have the potential to induce resistance to three drug classes, which could severely limit future treatment options.7-11 Ongoing studies are investigating the use of drugs from three drug classes to treat neonates.
Regimens that Contain Three Nucleoside Reverse Transcriptase Inhibitors and a Non-Nucleoside Reverse Transcriptase Inhibitor
Data are currently insufficient to recommend using a regimen that contains three NRTIs plus an NNRTI in young infants. A review of nine cohorts from 13 European countries suggested that this four-drug regimen produced responses that were superior to the responses observed in patients receiving boosted-PI regimens or three-drug NRTI regimens.12 There has been speculation that poor tolerance and poor adherence to a PI-based regimen may account for some of the differences. The ARROW trial, conducted in Uganda and Zimbabwe, randomized 1,206 children (with a median age of 6 years) to receive either a standard NNRTI-based, three-drug regimen (two NRTIs and one NNRTI) or a four-drug regimen (three NRTIs and one NNRTI). After a 36-week induction period, the children on the four-drug regimen continued treatment on a regimen that contained two NRTIs plus one NNRTI or a three-NRTI regimen. Although improvements in CD4 T lymphocyte (CD4) cell counts were observed at Week 36 (with a percentage change of approximately 14.4% in the four-drug arm compared to 12.6% in the three-drug arm), these benefits were not sustained after patients switched to the three-drug regimens for the duration of the study. Furthermore, no differences in viral load suppression rates were observed between the two arms at Week 36.13 Because three-drug regimens have been shown to be effective and well tolerated, and because efficacy data is lacking for the four-drug regimen, the Panel does not currently recommend the four-drug regimen.
Antiretroviral Drugs and Combinations with Insufficient Data to Recommend for Initial Therapy in Children
Several ARV drugs and drug regimens are not recommended for use as initial therapy in ARV-naive children or for specific age groups because of insufficient pediatric data. In some cases, new agents have shown promise in adult clinical trials but do not have sufficient pediatric PK and safety data to recommend their use as components of an initial therapeutic regimen in children. In addition, some dosing schedules may not be recommended in certain age groups due to insufficient data. As new data become available, these agents may become recommended agents or regimens. These agents and regimens are summarized below and are also listed in Table 9.
Doravirine (DOR) is an NNRTI that is available as both a single-drug tablet and an FDC tablet that contains DOR 100 mg/3TC 300 mg/tenofovir disoproxil fumarate (TDF) 300 mg and is marketed as Delstrigo. Efficacy studies in adults have demonstrated that DOR/3TC/TDF is noninferior to efavirenz (EFV)-based regimens and darunavir (DRV)-based regimens. DOR compared favorably to the other drugs in these trials in terms of adverse events. Currently, DOR is not approved for use in children or adolescents aged <18 years, but there are ongoing studies of DOR in children and adolescents. At this time, the Panel does not recommend the use of DOR in children or adolescents.
Darunavir with Low-Dose Ritonavir-Based Regimens Administered Once Daily for Children Aged ≥3 Years to <12 Years
While modeling studies identified a once-daily dosing schedule for darunavir/ritonavir (DRV/r) that is now approved by the FDA, the Panel is concerned about the lack of direct PK studies for this approach in individuals aged ≥3 years to <12 years. Therefore, there is insufficient data to recommend once-daily dosing for initial therapy in this age group. For children aged ≥3 years to <12 years, twice-daily DRV/r is a Preferred drug combination. For older children who have undetectable viral loads while receiving a twice-daily DRV/r-based regimen, practitioners can consider switching to once-daily DRV/r dosing if no DRV-associated resistance mutations are present. Once-daily dosing helps support adherence by making this drug combination easier to use.
Efavirenz-Based Regimens for Children Aged ≥3 Months to 3 Years
EFV is approved by the FDA for use in children aged >3 months and weighing ≥3.5 kg. An EFV-based regimen has been shown to have variable PKs in studies of the very young; because of this, the Panel does not recommend using EFV in children aged <3 years at this time (see the Efavirenz section in Appendix A: Pediatric Antiretroviral Drug Information). When use of EFV is being considered for children aged <3 years, cytochrome P450 (CYP) 2B6 genotyping should be performed, if available, in order to predict a patient’s metabolic rate for EFV. Therapeutic drug monitoring can also be considered.
Etravirine (ETR) is an NNRTI that has been studied in treatment-experienced children aged ≥1 years and is now approved by the FDA for use in children aged ≥2 years and weighing ≥10 kg.14-16 It is associated with multiple interactions with other ARV drugs, including TPV/ritonavir, ATV/ritonavir, and unboosted PIs, and must be administered twice daily. It is unlikely that the use of ETR will be studied in treatment-naive children.
Maraviroc (MVC) is an entry inhibitor that is approved by the FDA for use in children aged ≥2 years and weighing ≥10 kg who have CCR5-tropic HIV-1. It has been used infrequently in children. A recent dose-finding study administered both the liquid and tablet formulations of MVC to treatment-experienced children aged 2 to 18 years who were divided into four age cohorts.17 The initial dose was based on body surface area and scaled from the recommended adult dose. Dose adjustments were required in patients who were not receiving a potent CYP3A4 inhibitor or inducer.18 MVC has multiple drug interactions and must be administered twice daily. In addition, tropism assays must be performed prior to use to ensure the presence of only CCR5-tropic virus.
|ARV Regimen or Component||Rationale|
|Unboosted ATV-containing regimens in children||Reduced exposure|
|Regimens containing only NRTIs||Inferior virologic efficacy|
|Regimens containing three drug classes||Potential to induce multiclass resistance
Use as an initial regimen in children has not been studied
|Regimens containing three NRTIs and one NNRTI||Added cost and complexity outweighs any benefit|
|Full-dose RTV or use of RTV as the sole PI||GI intolerance
|LPV/r dosed once daily||Reduced drug exposure|
|DOR-based regimens||Insufficient data to recommend|
|Once-daily DRV-based regimens in children aged ≥3 years to <12 years||Insufficient data to recommend|
|EFV-based regimens for children aged <3 years||Appropriate dose not determined|
|ETR-based regimens||Insufficient data to recommend|
|MVC-based regimens||Insufficient data to recommend|
|Unboosted DRV||Use without RTV has not been studied|
|Full-dose, dual-PI regimens||Insufficient data to recommend
Potential for added toxicities
|TDF-containing regimens in children aged <2 years||Potential bone toxicity
Appropriate dose has yet to be determined
|Key: ABC = abacavir; ARV = antiretroviral; ATV = atazanavir; DOR = doravirine; DRV = darunavir; EFV = efavirenz; ETR = etravirine; GI = gastrointestinal; LPV/r = lopinavir/ritonavir; MVC = maraviroc; NNRTI = non-nucleoside reverse transcriptase inhibitor; NRTI = nucleoside reverse transcriptase inhibitor; PI = protease inhibitor; RTV = ritonavir; TDF = tenofovir disoproxil fumarate|
|ARV Regimens That Are Never Recommended for Use in Children|
|One ARV Drug Alone (Monotherapy)||Rapid development of resistance
Inferior antiviral activity compared to regimens that include ≥3 ARV drugs
Monotherapy “holding” regimens are associated with more rapid CD4 count declines than nonsuppressive ART.
|Infants with perinatal HIV exposure and negative virologic tests who are receiving 4–6 weeks of ZDV prophylaxis to prevent perinatal transmission of HIV|
|Two NRTIs Alone||Rapid development of resistance
Inferior antiviral activity compared to regimens that include ≥3 ARV drugs
|Not recommended for initial therapy
Some clinicians may opt to continue using two NRTIs alone in patients who achieve virologic goals with this regimen.
|TDF plus ABC plus (3TC or FTC) as a Triple-NRTI Regimen||High rate of early viral failure when this triple-NRTI regimen was used as initial therapy in treatment-naive adults||No exceptions|
|ARV Components That Are Never Recommended for Use as Part of an ARV Regimen for Children|
|Dual-NNRTI Combinations||Enhanced toxicity||No exceptions|
|Dual-NRTI Combination of 3TC plus FTC||Similar resistance profile and no additive benefit||No exceptions|
|NVP as Initial Therapy in Adolescent Girls with CD4 Counts >250 cells/mm3 or Adolescent Boys with CD4 Counts >400 cells/mm3||Increased incidence of symptomatic (including serious and potentially fatal) hepatic events in these patient groups||Only if benefit clearly outweighs risk|
|Key: 3TC = lamivudine; ABC = abacavir; ART = antiretroviral therapy; ARV = antiretroviral; CD4 = CD4 T lymphocyte; FTC = emtricitabine; NNRTI = non-nucleoside reverse transcriptase inhibitor; NRTI = nucleoside reverse transcriptase inhibitor; NVP = nevirapine; TDF = tenofovir disoproxil fumarate; ZDV = zidovudine|
- Kiser JJ, Rutstein RM, Samson P, et al. Atazanavir and atazanavir/ritonavir pharmacokinetics in HIV-infected infants, children, and adolescents. AIDS. 2011;25(12):1489-1496. Available at: http://www.ncbi.nlm.nih.gov/pubmed/21610486.
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