Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection

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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

Modifying Antiretroviral Regimens in Children with Sustained Virologic Suppression on Antiretroviral Therapy

Last Updated: May 22, 2018; Last Reviewed: May 22, 2018

Panel's Recommendations for Modifying Antiretroviral Regimens in Children with Sustained Virologic Suppression on Antiretroviral Therapy
Panel's Recommendations
  • Children who have sustained virologic suppression on their current antiretroviral (ARV) regimen should be regularly evaluated for opportunities to change to a new regimen that facilitates adherence, simplifies administration, increases ARV potency, and decreases the risk of drug-associated toxicity (AII).
  • All past regimens and past episodes of ARV therapy failure, tolerability, and all prior drug resistance testing results should be considered in order to avoid choosing new ARV drugs for which archived drug resistance would limit antiviral activity (AIII).
  • Children should be carefully monitored after a change in treatment. Viral load measurement is recommended 2 to 4 weeks after a change in a child’s ARV regimen (BIII).
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

Initial antiretroviral (ARV) regimens are chosen based on the safety, pharmacokinetic, and efficacy data available regarding formulations suitable for the child’s age at start of treatment. New ARV options may become available as children grow and learn to swallow pills, and as new drugs, drug formulations, and data become available. Even in cases where patients have experienced sustained virologic suppression (e.g., 6–12 months) on their current regimen, changing to a new ARV regimen should be considered in order to permit use of pills instead of liquids, reduce pill burden, allow use of once-daily medications, reduce risk of adverse events (AEs), minimize drug interactions, and align a child’s regimen with widely used, efficacious adult regimens.1 Often the changes enhance adherence and improve quality of life.2

Several studies have addressed switching ARV regimen components in children with sustained virologic suppression. According to the results of the NEVEREST 2 study, young children (i.e., those aged <2 years) with virologic suppression who switch from lopinavir/ritonavir (LPV/r) to nevirapine can maintain virologic suppression as well as those who continue taking LPV/r, provided that there is good adherence and no baseline resistance to nevirapine.3,4 In the NEVEREST 3 study, children aged ≥3 years with a history of exposure to nevirapine and with virologic suppression on LPV/r continued to maintain virologic suppression when switched from LPV/r to efavirenz.5-7 Similarly, in the NEVEREST 2 study, children who switched to a nevirapine regimen showed better immune and growth responses than those who stayed on a LPV/r regimen.3 By extrapolation, replacing LPV/r with an equally potent protease inhibitor (PI) (e.g., darunavir, atazanavir) or an integrase strand transfer inhibitor (INSTI) (e.g., elvitegravir, raltegravir, dolutegravir) would likely be effective, but these substitutions have not been directly studied in children. Several studies in small cohorts of children have demonstrated sustained virologic suppression and reassuring safety outcomes when drugs that have greater long-term toxicity risk are replaced with drugs that are thought to have less toxicity risk (e.g., replacing stavudine with tenofovir disoproxil fumarate, tenofovir alafenamide, zidovudine, or abacavir; replacing PIs with non-nucleoside reverse transcriptase inhibitors), including improved lipid profiles.8-12 Small studies have shown that children who achieve virologic suppression on certain twice-daily regimens (i.e., abacavir, nevirapine) maintain virologic suppression if changed from twice-daily to once-daily regimens (see the Abacavir and Nevirapine drug sections). However, these studies show mixed results when switching LPV/r dosing from twice daily to once daily; therefore, once-daily LPV/r is not recommended in children aged <12 years or weighing <30 kg.13-16

Dual and monotherapy PI (darunavir/ritonavir, LPV/r, atazanavir/ritonavir)17,18 and monotherapy INSTI (dolutegravir) strategies19,20 have been used to simplify or reduce the toxicity of regimens in adult patients who have sustained virologic suppression, with varying success. These strategies are still being explored, but are not currently recommended as management strategies. Limited studies on these strategies have been done in children, and these strategies cannot be endorsed at this time.18,21-24 The fixed-dose combination (FDC) of dolutegravir/rilpivirine (Juluca), a nucleoside-sparing dual-therapy regimen, was recently approved by the Food and Drug Administration (FDA) as a complete regimen to replace the current ARV regimen in patients who have been virologically suppressed (HIV-1 RNA <50 copies/mL) on a stable ARV regimen for at least 6 months with no history of treatment failure. This approval was based on two Phase 3 clinical trials, SWORD-1 and SWORD-2, in which treatment-experienced adults who were virologically suppressed on three- or four-drug regimens were randomized to either switch to dolutegravir/rilpivirine or to stay on their original regimens. Results from these trials showed similar virologic suppression rates in both groups (noninferiority) through 48 weeks.25 There are no equivalent data for this drug combination in pediatric patients. The Panel on Antiretroviral Therapy and Medical Management of Children Living with HIV (the Panel) usually endorses adult formulations for use in adolescents, and this product may be appropriate for selected adolescents. However, because this treatment simplification strategy has not been evaluated in adolescents, who may have difficulties adhering to therapy, the Panel does not recommend use of the FDC Juluca for adolescents and children until more data are available.

Table 16 displays examples of changes in ARV regimen components that are made for reasons of simplification, convenience, and safety profile in children who have sustained virologic suppression on their current regimen. When considering such a change, a clinician should first ensure that a recent viral load test indicates that the child does not have virologic treatment failure and that the child has a reliable history of good adherence. It is also critical to consider antiretroviral therapy (ART) history, tolerability, and all prior drug resistance testing results in order to avoid choosing new ARV drugs for which archived drug resistance would reemerge and limit activity.26-30 The evidence supporting many of these ARV changes is indirect, extrapolated from data about drug performance during initial therapy or follow-up therapy after treatment failure. When such changes are made, careful monitoring (e.g., taking a viral load measurement 2–4 weeks after making the switch to the new regimen) is important to ensure that virologic suppression is maintained.

Table 16. Examples of Changes in Antiretroviral Regimen Components that Are Made for Reasons of Simplification, Convenience, and Safety Profile in Children Who Have Sustained Virologic Suppression on Their Current Regimen

Note: This list is not exhaustive and does not necessarily contain all potential treatment options. Instead, it shows examples of what kinds of changes can be made. The comments provided in the table are relevant only to the potential ARV change are listed and do not include all relevant information. Please refer to the individual drug sections in Appendix A: Pediatric Antiretroviral Drug Information for further information.

Table 16. Examples of Changes in Antiretroviral Regimen Components that Are Made for Reasons of Simplification, Convenience, and Safety Profile in Children Who Have Sustained Virologic Suppression on Their Current Regimen
Current ARV Drug(s) Age, Weight, and SMR Requirements Potential ARV Switch Comments
NRTIs
ABC or 3TC Twice Daily Aged ≥1 year ABC once daily See Abacavira and Lamivudine sections in Appendix A: Pediatric Antiretroviral Drug Information for full discussion of once-daily dosing.
Aged ≥3 years 3TC once daily
ZDV, ddI, or d4Tb Aged ≥3 months ABC Less long-term mitochondrial toxicity.

Children aged ≥1 year can take ABC once daily (see Abacavira in Appendix A: Pediatric Antiretroviral Drug Information).
Aged ≥2 years TDF TDF is a reasonable, once-daily option for HLA-B*5701–positive children who are unable to take ABC. TDF is available in low-strength combination tablets with FTC for use in children weighing ≥17 kg. TAF is preferred for children weighing ≥25 kg.
Weighing ≥25 kg TAFc Less long-term mitochondrial toxicity. Once-daily dosing. Co-formulation with other ARV drugs can further reduce pill burden. TAF preferred over TDF for lower bone and renal toxicity. See TAF in Appendix A: Pediatric Antiretroviral Drug Information for full discussion.
NNRTIs
EFV N/A RALd None
Aged ≥3 months

Weighing ≥5 kg
ATV/r None
Aged ≥3 years

Weighing ≥10 kg
DRV/r DRV/r may be administered once daily in children aged ≥12 years who do not have DRV resistance mutations.
Weighing ≥25 kg EVG as Genvoya EVG is available as a component of the FDC EVG/COBI/FTC/TAF (Genvoya). Genvoya is a complete ARV regimen.
Weighing ≥30 kg DTG Smaller pill, higher barrier to resistance given concern for adherence challenges developing in adolescents.
Aged ≥ 12 years

Weighing ≥35 kg
RPV None
PIs
LPV/r Twice Daily N/A RALd None
Aged ≥3 years

Weighing ≥10 kg
EFV Once-daily dosing. Better palatability. Lower incidence of adverse lipid effects. See Efavirenz in Appendix A: Pediatric Antiretroviral Drug Information regarding concerns about dosing for children aged <3 years.
Aged ≥3 months

Weighing ≥5 kg
ATV/r Once-daily dosing.
Aged ≥3 years

Weighing ≥10 kg
DRV/r DRV/r is administered twice daily to patients aged <12 years, but may be administered once daily only in children aged ≥12 years who do not have DRV resistance mutations.
Weighing ≥25 kg EVG as Genvoya EVG is available as a component of the FDC EVG/COBI/FTC/TAF (Genvoya). Genvoya is a complete ARV regimen.
Weighing ≥30 kg DTG None
Aged ≥12 years

Weighing ≥35 kg
RPV None
BIC as Biktarvy Once-daily dosing. BIC is available as a component of the FDC BIC/FTC/TAF (Biktarvy). Biktarvy is a complete ARV regimen; pediatric use is investigational.
Other
Any Multi-Pill and/or Twice-Daily Regimen Weighing ≥25 kg EVG/COBI/FTC/TAF (Genvoya) Once-daily dosing. Single pill. Alignment with adult regimens.
Weighing ≥30 kg FTC/TAFc (Descovy) plus DTG Once-daily dosing. May be more desirable because of small pill sizes, even though it increases pill burden to 2 pills instead of 1.
Weighing ≥35 kg

SMR 4 or 5
EVG/COBI/FTC/TDF (Stribild) Once-daily dosing. Single pill. Alignment with adult regimens.
Aged ≥12 years

Weighing ≥35 kg
FTC/RPV/TAF (Odefsey) Once-daily dosing. Single pill. Alignment with adult regimens.
Aged ≥12 years

Weighing ≥35 kg
BIC/FTC/TAFe (Biktarvy) Once-daily dosing. Single pill. Pediatric use is investigational.
Aged ≥12 years

Weighing ≥35 kg

SMR 4 or 5
FTC/RPV/TDF (Complera) Once-daily dosing. Single pill. Alignment with adult regimens.
Weighing ≥40 kg ABC/DTG/3TC (Triumeq) Once-daily dosing. Single pill. Alignment with adult regimens. Large pill size may be a deterrent.
Weighing ≥40 kg

SMR 4 or 5
EFV/FTC/TDF (Atripla) Once-daily dosing. Single pill. Alignment with adult regimens.
a For infants and young children being treated with liquid formulations of ABC, initiation with once-daily ABC is not generally recommended. In clinically stable patients with undetectable viral loads who have had stable CD4 T lymphocyte cell counts for more than 6 months (24 weeks) on twice-daily ABC, the dose can be changed from twice daily to once daily.
b d4T and ddI should be replaced with a safer drug as soon as possible because of concerns about long-term adverse events (see Stavudine and Didanosine in Appendix A: Pediatric Antiretroviral Drug Information).
c For children and adolescents weighing 25 kg to <35 kg, TAF can be used in combination with an INSTI or an NNRTI, but not a boosted PI. For children and adolescents weighing ≥35 kg, TAF can be used in combination with an INSTI, NNRTI, or a boosted PI.
d RAL HD once daily is only recommended for virologically suppressed children weighing ≥50 kg.
e Biktarvy has not been FDA-approved for use in patients aged <18 years but is being studied in children and adolescents aged ≥12 years to 18 years and weighing ≥35 kg.

Key to Acronyms: 3TC = lamivudine; ABC = abacavir; ARV = antiretroviral; ATV/r = atazanavir/ritonavir; BIC = bictegravir, COBI = cobicistat; d4T = stavudine; ddI = didanosine; DRV/r = darunavir/ritonavir; DTG = dolutegravir; EFV = efavirenz; EVG = elvitegravir; FDA = Food and Drug Administration; FDC = fixed-dose combination; FTC = emtricitabine; INSTI = integrase strand transfer inhibitor; LPV/r = lopinavir/ritonavir; NNRTI = non-nucleoside reverse transcriptase inhibitor; NRTI = nucleoside reverse transcriptase inhibitor; PI = protease inhibitor; RAL = raltegravir; RPV = rilpivirine; SMR = sexual maturity rating (previously Tanner stages); TAF = tenofovir alafenamide; TDF = tenofovir disoproxil fumarate; TFV= tenofovir; ZDV = zidovudine

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