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: September 12, 2019; Last Reviewed: September 12, 2019

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 or barrier to resistance, and decreases the risk of drug-associated toxicity (AII).
  • Before making changes to a patient’s regimen, clinicians must carefully consider the patient’s previous regimens, past episodes of ARV therapy failure, prior drug resistance test results, and the patient’s ability to tolerate the new drug regimen (AIII). Archived drug resistance can limit the antiviral activity of a new drug regimen.
  • Children should be carefully monitored after a change in treatment. Viral load measurement is recommended 2 weeks 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

Clinicians choose initial antiretroviral (ARV) regimens for children with HIV by evaluating the pharmacokinetic, safety, and efficacy data for the drugs that are available in formulations that are suitable for the child’s age and weight at the 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 achieved sustained virologic suppression (e.g., suppression for 6 months–12 months) on their current regimen, clinicians should consider switching patients to new ARV regimens in order to permit the use of pills instead of liquids, reduce pill burden, allow the use of once-daily medications, reduce the risk of adverse events, 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

Treatment Simplification

Many children with HIV must initiate treatment with twice-daily dosing, and regimens may include a variety of drug formulations, depending on which formulations are available for a child’s age and weight. Clinicians should regularly review treatment options as children grow, because it may be possible to simplify dosing using coformulated drugs and/or once-daily regimens (see Table 16 below). Clinicians should also consider a child’s antiretroviral therapy (ART) history and resistance test results. Small studies have shown that children who achieve virologic suppression using twice-daily dosing for certain ARV drugs (i.e., abacavir, nevirapine) maintain virologic suppression when they switch from twice-daily regimens to once-daily regimens (see the abacavir and nevirapine drug sections and fixed-dose combinations [FDCs] in Table 1 and Table 2). However, these studies reported mixed results when switching the dosing for lopinavir/ritonavir (LPV/r) from twice daily to once daily; therefore, once-daily dosing of LPV/r is not recommended.3-7

Treatment Optimization

Several studies have addressed switching ARV regimen components in children with sustained virologic suppression. Treatment optimization may include improving the potency of regimen, improving a child’s growth or other health outcomes, or maximizing palatability. Despite concerns for drug class resistance, the results of the NEVEREST 2 study demonstrated that young children (i.e., those aged <2 years) with virologic suppression who switch from LPV/r to a nevirapine-based regimen can maintain virologic suppression as well as those who continue taking LPV/r, provided that they have good adherence and no baseline resistance to nevirapine.8,9 In the NEVEREST 3 study, children aged ≥3 years who had a history of exposure to nevirapine and who achieved virologic suppression on a LPV/r-based regimen maintained virologic suppression when switched from LPV/r to an efavirenz-based regimen.10-12 Similarly, in the NEVEREST 2 study, children who switched to a nevirapine-based regimen showed better immune and growth responses than those who stayed on a LPV/r regimen.8 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.

Toxicity Management

Several studies in small cohorts of children have demonstrated sustained virologic suppression and reassuring safety outcomes when drugs that have greater long-term toxicity risks are replaced with drugs that are thought to have lower toxicity risks (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.13-17

Regimens That Are Not Recommended for Use in Children

Dual-therapy and monotherapy PI regimens (darunavir/ritonavir, LPV/r, atazanavir/ritonavir)18,19 and monotherapy INSTI regimens (dolutegravir)20,21 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 they are not currently recommended as management strategies in children due to the lack of data.19,22-25 The FDC of dolutegravir/rilpivirine (Juluca), a nucleoside-sparing, dual-therapy regimen, was recently approved by the Food and Drug Administration as a complete regimen to replace the current ARV regimen in patients who have been virologically suppressed (HIV 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-drug 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 rates of virologic suppression in both groups (noninferiority) through 48 weeks.26 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 the use of adult formulations in adolescents, and this product may be appropriate for certain 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 dolutegravir/rilpivirine (Juluca) in adolescents and children until more data are available.

Potential Antiretroviral Drug Switches in Children with Virologic Suppression

Table 16 contains examples of potential ARV changes in children with sustained virologic suppression on their current regimen for the purposes of treatment simplification, optimization, or reduced toxicity. When considering such a change, a clinician should first ensure that a recent viral load test indicates that the child is not experiencing virologic failure and that the child has a reliable history of good adherence. It is also critical to consider ART history, tolerability, and all prior drug resistance test results in order to avoid choosing new ARV drugs for which archived drug resistance would re-emerge and limit the activity of the regimen.27-31 The evidence that supports 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 weeks–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 for Children with Sustained Virologic Suppression

Note: This list is not exhaustive and does not necessarily contain all potential treatment options. Instead, it provides examples of changes that could be made. The table only includes information about switching between ARV drugs; it does not include all the information that clinicians should consider before prescribing these drugs. Please refer to individual drug sections, Table 1, and Table 2 in Appendix A: Pediatric Antiretroviral Drug Information for further information about the use of specific ARV drugs and FDC formulations.

Table 16. Examples of Changes in Antiretroviral Regimen Components for Children with Sustained Virologic Suppression
Current ARV Drug(s) Age, Weight, and SMR Requirements Potential ARV Drug Switch Comments
NRTIs
ABC or 3TC Twice Daily Aged ≥1 year ABC once daily See abacavira and lamivudine sections.
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.

Aged ≥2 years

Weighing 17 kg to <25 kg

TDF TDF is a reasonable, once-daily option for HLA-B*5701–positive children for whom ABC is not recommended. TDF is available in low-strength tablets alone or in combination with FTC.

Aged ≥2 years 

Weighing ≥25 kg

TAFc Less long-term mitochondrial toxicity. Once-daily dosing. Coformulation with other ARV drugs can further reduce pill burden. TAF preferred over TDF for lower bone and renal toxicity.
NNRTIs
 NVP Any age (starting at full-term birth and weighing ≥2 kg RALd RAL has potentially greater barrier to resistance than NVP. Both are dosed twice daily in children.
EFV Aged ≥3 months

Weighing ≥5 kg
ATV/r ATV/r has a potentially greater barrier to resistance; however, taking ATV/r may be difficult for some patients, as ATV oral powder must be mixed with food or a beverage before administration, and the palatability of the RTV oral solution is poor.
Aged ≥3 years

Weighing ≥10 kg
DRV/r DRV/r has a potentially greater barrier to resistance. DRV/r is administered twice daily to patients aged <12 years, but may be administered once daily in children aged ≥12 years who do not have DRV resistance mutations.
Weighing ≥25 kg BIC as Biktarvy Once-daily dosing. BIC is available as a component of the FDC BIC/FTC/TAF (Biktarvy), which is a complete ARV regimen that can be taken with or without food.
Weighing ≥25 kg EVG as Genvoya EVG is available as a component of the FDC EVG/COBI/FTC/TAF (Genvoya), which is a complete ARV regimen that must be taken with food.
Weighing ≥20 kg DTG DTG is available as a smaller single-drug tablet or as an FDC, both of which can be dosed once daily if there are no concerns about INSTI resistance. DTG plus the weight-appropriate dose of FTC/TDF (Truvada) can be used in children weighing 20 kg to <25 kg. Higher barrier to resistance, which makes it a good choice for patients who have trouble with adherence. See the dolutegravir section for information regarding safety concerns when using DTG in adolescent females of childbearing potential and pregnant adolescents.e
Aged ≥12 years

Weighing ≥35 kg
RPV RPV may improve lipid levels.
PIs
LPV/r Twice Daily Any age (starting at full-term birth) and weighing ≥2 kg RALd Better palatability. RAL HD can only be given once daily in children weighing >50 kg. Unlike LPV/r, the use of RAL is not restricted to infants with a corrected gestational age of >42 weeks. RAL granules may be difficult to dose for some caregivers.
Aged ≥3 years

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

Weighing ≥5 kg
ATV/r Once-daily dosing. ATV/r may improve lipid levels; however, taking ATV/r may be difficult for some patients, as ATV oral powder must be mixed with food or a beverage before administration, and the palatability of the RTV oral solution is poor.
Aged ≥3 years

Weighing ≥10 kg
DRV/r DRV/r may improve lipid levels. DRV/r is administered twice daily to patients aged <12 years, but 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), which is a complete ARV regimen that must be taken with food.
Weighing ≥20 kg DTG Once-daily dosing if not concerned about INSTI resistance. May be better tolerated, and can be given as an FDC to children weighing ≥25 kg. DTG plus the weight-appropriate dose of FTC/TDF (Truvada) can be used in children weighing 20 kg to <25 kg. See the dolutegravir section for information regarding safety concerns when using DTG in female adolescents of childbearing potential and pregnant adolescents.e

Aged ≥12  years

Weighing ≥35 kg

RPV  May be better tolerated.
Weighing ≥25 kg BIC as Biktarvy Once-daily dosing. BIC is available as a component of the FDC BIC/FTC/TAF (Biktarvy), which is a complete ARV regimen that can be taken with or without food.
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. Must be taken with food.
Weighing ≥25 kg FTC/TAFc (Descovy) plus DTG Once-daily dosing. This regimen may be more desirable because of smaller pill sizes, but it has a higher pill burden (two pills instead of one). Aligns a child's regimen with an efficacious regimen that is used in adults. See the dolutegravir section for information regarding safety concerns when using DTG in female adolescents of childbearing potential and pregnant adolescents.e
Weighing ≥35 kg

SMR 4 or 5
EVG/COBI/FTC/TDF (Stribild) Once-daily dosing. Single pill. Aligns a child's regimen with an efficacious regimen that is used in adults. Must be taken with food. Renal and bone toxicity limit its use.
Aged ≥12 years

Weighing ≥35 kg
FTC/RPV/TAF (Odefsey) Once-daily dosing. Single pill. Aligns a child's regimen with an efficacious regimen that is used in adults. Must be taken with food at a consistent time daily.
Weighing ≥25 kg BIC/FTC/TAF (Biktarvy) Once-daily dosing. Single pill that can be taken with or without food.
Aged ≥12 years

Weighing ≥35 kg

SMR 4 or 5
FTC/RPV/TDF (Complera) Once-daily dosing. Single pill. Aligns a child's regimen with an efficacious regimen that is used in adults. Must be taken with food at a consistent time daily.
Weighing ≥25 kg ABC/DTG/3TC (Triumeq) Once-daily dosing. Single pill. Aligns a child's regimen with an efficacious regimen that is used in adults. Large pill size may be a deterrent. See the dolutegravir section for information regarding safety concerns when using DTG in female adolescents of childbearing potential and pregnant adolescents.e
Weighing ≥40 kg

SMR 4 or 5
EFV/FTC/TDF (Atripla) Once-daily dosing. Single pill. Aligns a child's regimen with an efficacious regimen that is used in adults.
a For infants and young children who are 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 >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 effects (see Archived Drugs 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 is recommended for twice-daily use in children. Chewable tablets can be used in children weighing ≥11 kg. RAL HD once daily is only recommended for virologically suppressed children weighing ≥50 kg.

e 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 DTG in women of childbearing potential and in pregnant women are available in the Adult and Adolescent Antiretroviral Guidelines (see Table 6b and Adolescents and Young Adults with HIV) and in the Perinatal Guidelines (see Teratogenicity and Recommendations for the Use of Antiretroviral Drugs in Pregnancy).

Key to Acronyms: 3TC = lamivudine; ABC = abacavir; ARV = antiretroviral; ATV = atazanavir; 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; HLA = human leukocyte antigen; INSTI = integrase strand transfer inhibitor; LPV/r = lopinavir/ritonavir; NNRTI = non-nucleoside reverse transcriptase inhibitor; NRTI = nucleoside reverse transcriptase inhibitor; NVP = nevirapine; PI = protease inhibitor; RAL = raltegravir; RPV = rilpivirine; RTV = ritonavir; SMR = sexual maturity rating; TAF = tenofovir alafenamide; TDF = tenofovir disoproxil fumarate; TFV = tenofovir; ZDV = zidovudine

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