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Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection

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Regimens Recommended for Initial Therapy of Antiretroviral-Naive Children

Last Updated: April 27, 2017; Last Reviewed: April 27, 2017

Panel's Recommendations Regarding Regimens Recommended for Initial Therapy of Antiretroviral-Naive Children
Panel's Recommendations
  • Selection of an initial regimen should be individualized based on several factors, including characteristics of the proposed regimen, patient characteristics, and results of viral resistance testing (AIII)
  • For treatment-naive children, the Panel recommends initiating antiretroviral therapy with 3 drugs, including either a boosted protease inhibitor, non-nucleoside reverse transcriptase inhibitor, or integrase strand transfer inhibitor plus a dual-nucleoside/nucleotide reverse transcriptase inhibitor backbone (AI*).
  • Table 7 provides a list of Panel-recommended regimens that are designated as Preferred, Alternative, or for use in Special Circumstances; recommendations vary by age, weight, and sexual maturity rating.
     
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

Criteria Used for Recommendations

In general, the Panel on Antiretroviral Therapy and Medical Management of Children Living with HIV (the Panel)’s recommendations are based on reviews of pediatric and adult clinical trial data published in peer-reviewed journals, data prepared by manufacturers for Food and Drug Administration (FDA) review, and data presented in abstract format at major scientific meetings. Few randomized, Phase III clinical trials of antiretroviral therapy (ART) in pediatric patients exist that provide direct comparison of different treatment regimens. Most pediatric drug data come from Phase I/II safety and pharmacokinetic (PK) trials and non-randomized, open-label studies. In general, even in adult studies, assessment of drug efficacy and potency is primarily based on surrogate marker endpoints, such as CD4 T lymphocyte (CD4) cell count and HIV RNA levels. The Panel continually modifies recommendations on optimal initial therapy for children as new data become available, new therapies or drug formulations are developed, and additional toxicities are recognized. 

Information considered by the Panel for recommending specific drugs or regimens includes:

  • Data demonstrating durable viral suppression, immunologic improvement, and clinical improvement (when such data are available) with the regimen, preferably in children as well as adults;
  • The extent of pediatric experience with the particular drug or regimen;
  • Incidence and types of short- and long-term drug toxicity with the regimen, with special attention to toxicity reported in children;
  • Availability and acceptability of formulations appropriate for pediatric use, including palatability, ease of preparation (e.g., powders), volume of syrups, and pill size/number of pills;
  • Dosing frequency and food and fluid requirements; and
  • Potential for drug interactions with other medications.
The Panel classifies recommended drugs or drug combinations into one of several categories as follows:
  • Preferred: Drugs or drug combinations are designated as Preferred for use in treatment-naive children when clinical trial data in children or, more often, in adults have demonstrated optimal and durable efficacy with acceptable toxicity and ease of use, and pediatric studies using surrogate markers demonstrate safety and efficacy; additional considerations are listed above.
  • Alternative: Drugs or drug combinations are designated as Alternative for initial therapy when clinical trial data in children or adults show efficacy but there are disadvantages compared with preferred regimens in terms of more limited experience in children: the extent of antiviral efficacy or durability is less well defined in children or less than a preferred regimen in adults; there are specific toxicity concerns; or there are dosing, formulation, administration, or interaction issues for that drug or regimen.
  • Special Circumstances: Some drugs or drug combinations are recommended for use as initial therapy only in Special Circumstances when preferred or alternative drugs cannot be used.

Factors to Consider When Selecting an Initial Regimen

An ART regimen for children should generally consist of 2 nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs) plus 1 active drug from the following classes: integrase strand transfer inhibitor (INSTI), non-nucleoside reverse transcriptase inhibitor (NNRTI), or a boosted protease inhibitor (PI). Choice of a regimen should be individualized based on several factors, including characteristics of the proposed regimen, patient characteristics, and results of viral resistance testing. Drug recommendations often include both age and weight limitations. Although age can be used as a rough guide, body weight—when available—is the preferred determinant of the recommendation for selecting a specific drug (except for infants aged <14 days). When FDA approvals are based solely on weight, the Panel has suggested an approximate age for administration. Advantages and disadvantages of each class-based regimen are delineated in detail in the sections that follow and in Table 8. Additional information regarding advantages and disadvantages of drug combinations can be found in the Adult and Adolescent Guidelines.  Specific information about clinical efficacy, adverse events (AEs) and dosing recommendations for each drug can be found in Appendix A: Pediatric Antiretroviral Drug Information. In addition, because ART will most likely need to be administered lifelong, considerations related to the choice of initial antiretroviral (ARV) regimen should also include an understanding of barriers to adherence, including the complexity of schedules and food requirements for different regimens, differing formulations, palatability problems, and potential limitations in subsequent treatment options, should resistance develop. Treatment should only be initiated after assessment and counseling of caregivers about adherence to therapy. 

Emtricitabine, lamivudine, tenofovir disoproxil fumarate, (TDF) and tenofovir alafenamide (TAF) have antiviral activity and efficacy against hepatitis B and should be considered children with coinfection. For a comprehensive review of this topic, as well as hepatitis C and tuberculosis during HIV coinfection, see the Tuberculosis section of Pediatric OI Guidelines.

Choosing Between an Integrase Strand Transfer Inhibitor-, a Non-Nucleoside Reverse Transcriptase Inhibitor-, or a Boosted Protease Inhibitor-Based Initial Regimen

Preferred regimens for initial therapy include INSTI-, NNRTI-, or boosted PI-based regimens. The choice of regimen should be based on patient characteristics, especially age, results of viral drug resistance testing, drug efficacy and AEs, patient and family preference, pill size, and dosing frequency. 

Clinical trial data in children provide some guidance for choosing between an NNRTI-based regimen and a PI-based regimen for initial therapy. Three pediatric studies have compared an NNRTI-based regimen to a PI-based regimen and results varied based on age of the population studied and specific drug within the class. 

  • The P1060 study demonstrated superiority of a lopinavir/ritonavir (LPV/r)-based regimen compared to a nevirapine-based regimen in infants and children aged 2 months to 35 months, regardless of prior maternal or infant exposure to peripartum single-dose nevirapine prophylaxis (21.7% vs. 39.6% death, virologic failure, or toxicity by Week 24 with prior nevirapine exposure and 18.4% vs. 40.1% with no prior exposure).
  • Those in the nevirapine group demonstrated greater, but not statistically significant, improvements in immunologic status and growth. Similar improved immune and growth parameters were also demonstrated in the NEVEREST study where children switched to a nevirapine regimen versus those who continued on a LPV/r regimen after achieving virologic control.2
  • PENPACT-1 (PENTA 9/PACTG 390) compared a PI-based regimen and a NNRTI-based regimen in treatment-naive children aged 30 days to <18 years (the study did not dictate the specific NNRTI or PI initiated). In the PI-based group, 49% of children received LPV/r and 48% received nelfinavir; in the NNRTI-based group, 61% of children received efavirenz and 38% received nevirapine. After 4 years of follow-up, 73% of children randomized to PI-based therapy and 70% randomized to NNRTI-based therapy remained on their initial ART regimen. In both groups, 82% of children had viral loads <400 copies/mL.3
  • The PROMOTE-pediatrics trial demonstrated comparable virologic efficacy among children randomized to receive either an NNRTI or LPV/r-based ART.4 Children were aged 2 months to <6 years and had no perinatal exposure to nevirapine. Selection of NNRTI was based on age (children aged <3 years received nevirapine and those aged >3 years primarily received efavirenz). At 48 weeks, the proportion with HIV RNA level <400 copies/mL at 48 weeks was 80% in the LPV/r arm versus 76% in the NNRTI arm, a difference of 4% and not statistically significant (95% CI: -9% to +17%). 
Clinical investigation of INSTI-based regimens in children has been limited to non-comparative studies demonstrating safety, tolerability, and PKs. The recommendation for an INSTI as part of an initial regimen is based largely on extrapolation of efficacy from adult comparative trials showing superior efficacy of INSTI-containing compared to PI-containing and NNRTI-containing regimens5,6 and small studies in ART-naive adolescents.7
 
 Based on the above data, the Panel considers the following as Preferred for children when used in combination with 2 NRTIs:
  • Aged <14 days: Nevirapine
  • Aged ≥14 days to <2 years: LPV/r 
  • Aged ≥2 years to <3 years: LPV/r or raltegravir
  • Aged ≥3 to <6 years: Raltegravir, boosted atazanavir, or twice-daily boosted darunavir
  • Aged ≥6 to <12 years: Dolutegravir (body weight ≥30 kg) or boosted atazanavir
  • Aged ≥12 years or body weight as noted for children who have not reached sexual maturity:
  • Weighing ≥30 kg: Dolutegravir 
  • Weighing ≥35 kg: Elvitegravir/cobicistat (only the elvitegravir/cobicistat-containing fixed-drug combination elvitegravir/cobicistat/emtricitabine/TAF is recommended at this time) 
  • Weighing ≥40 kg: Boosted atazanavir or once-daily boosted darunavir 

Alternative and Special Circumstances regimens are shown in Table 7.

Integrase Strand Transfer Inhibitor-Based Regimens 

Three INSTIs—dolutegravir, elvitegravir, and raltegravir—are licensed for the treatment of ARV-naive adults with HIV. These agents have quickly become the preferred regimen in adults because of their virologic efficacy, lack of drug-drug interactions, and favorable toxicity profile. Raltegravir is licensed for treatment of children as young as age 4 weeks. Dolutegravir is approved for use in children weighing ≥30 kg. Elvitegravir has been studied in adolescents in 2 fixed-dose combination regimens and in combination with 2 NRTIs and ritonavir boosting. (Table 8 lists the advantages and disadvantages of INSTIs. See Appendix A: Pediatric Antiretroviral Drug Information for detailed pediatric information on each drug).

Dolutegravir

The FDA has approved dolutegravir for use in children weighing ≥30 kg. The approval was supported by data from a study of 46 treatment-experienced—but INSTI-naive—adolescents7,8 and 11 treatment-experienced (but INSTI-naive) children aged ≥6 years.9 The drug has a very favorable safety profile and can be given once daily in treatment of INSTI-naive patients. 

Recommendation:

  • Based on virologic potency and safety profile in adult and pediatric studies,5,7,10 the Panel recommends dolutegravir in combination with a 2-NRTI backbone as a Preferred INSTI regimen for children and adolescents weighing ≥30 kg (AI*).

Elvitegravir

Elvitegravir is an INSTI available as a tablet, as a fixed-dose combination tablet containing elvitegravir/cobicistat/emtricitabine/TDF and as a fixed-dose combination tablet containing elvitegravir/cobicistat/emtricitabine/TAF. Both are FDA-approved for use in ART-naive adults with HIV. Elvitegravir/cobicistat/emtricitabine/TAF is FDA-approved for use in ART-naive adolescents aged ≥12 years and weighing ≥35 kg. Cobicistat is a specific, potent cytochrome P3A (CYP3A) inhibitor that has no activity against HIV and is used as a PK enhancer, which allows for once-daily dosing of elvitegravir.

Recommendation:

  • Based on virologic potency and safety profile in adult and adolescent studies,11-15 the Panel recommends elvitegravir only in the fixed-dose combination elvitegravir/cobicistat/emtricitabine/TAF as a Preferred INSTI regimen for children and adolescents aged ≥12 years and weighing ≥35 kg (AI*).

Raltegravir

Raltegravir is FDA-approved for treatment of children aged ≥4 weeks and weighing ≥3 kg. It is available in film-coated tablets, chewable tablets, and single packets of granules for oral suspension.

Recommendation:

  • Based on randomized clinical trials in adults and pediatric studies, largely in ARV-experienced children and adolescents,5,16-22 the Panel recommends raltegravir as a Preferred INSTI in children aged ≥2 years to <6 years who are able to take either the chewable or film-coated tablets. 
  • Raltegravir is an Alternative INSTI for children and adolescents aged ≥6 years, because of the availability of once-daily regimens with other drugs.
  • At this time, there is limited information about the use of single packets of granules for oral suspension in children aged <2 years. Because of the limited data, the Panel recommends raltegravir granules as an Alternative INSTI in children aged ≥4 weeks to <2 years. 

Non-Nucleoside Reverse Transcriptase Inhibitor-Based Regimens

Efavirenz (aged ≥3 months), etravirine (aged ≥6 years), nevirapine (aged ≥15 days), and rilpivirine (aged ≥12 years) have an FDA-approved pediatric indication for treatment of HIV infection. Advantages of NNRTIs as initial therapy include long half-life allowing for less frequent drug administration, lower risk of dyslipidemia and fat maldistribution compared to some agents in the PI class, and generally, compared to PIs, a lower pill burden. The major disadvantages of NNRTI drugs FDA-approved for use in children are that a single viral mutation can confer high-level drug resistance (except etravirine) and cross-resistance to other NNRTIs is common. Rare, but serious and potentially life-threatening, skin and hepatic toxicity can occur with all NNRTI drugs, but is most frequent with nevirapine, at least in adults with HIV. NNRTIs have the potential to interact with other drugs also metabolized via hepatic enzymes; however, these drug interactions are less frequent with NNRTIs than with boosted PI regimens (Table 8  lists the advantages and disadvantages of NNRTIs. See Appendix A: Pediatric Antiretroviral Drug Information for detailed pediatric information on each drug).

Efavirenz

Efavirenz in combination with 2 NRTIs is the Preferred NNRTI for initial therapy of children aged ≥3 to 12 years based on clinical trial experience in adults and children. Efavirenz capsules can be opened and sprinkled on age-appropriate food for use in children aged 3 months weighing ≥3.5 kg.23 However, because of concerns regarding variable PK of the drug in the very young, the Panel does not currently endorse its use for infants and children aged 3 months to 3 years. 

Recommendation:

  • Based on efficacy and tolerability,10,16,23-41 the Panel recommends efavirenz in combination with a 2-NRTI backbone as the Alternative NNRTI regimen for initial treatment of HIV in children aged ≥3 (AI*).

Nevirapine 

Nevirapine has extensive clinical and safety experience in children with HIV and has shown ARV efficacy in a variety of combination regimens.1,3,4,42-46 Nevirapine has also been used extensively as prophylaxis for the prevention of HIV transmission in young infants in the peripartum period and during breastfeeding. Although there is information about the safety and pharmacokinetics of nevirapine used at prophylaxis doses that target lower nevirapine drug levels, there is less information regarding higher doses necessary for treatment. Early testing of infants allows identification of confirmed HIV infection before 14 days of age. In these cases, the Panel recommends the use of nevirapine as a Preferred NNRTI if treatment initiation is planned prior to age 14 days. However, there are currently no clinical trial data suggesting that initiating treatment within the first 14 days of life improves outcome compared to starting after age 14 days. Consultation with an expert in Pediatric HIV infection should be sought. Additional considerations regarding the use of nevirapine in infants aged <14 days of can be located in Specific Issues in Antiretroviral Therapy in Newborn Infants with HIV Infection.
Recommendation:
  • Based on the rare occurrence of significant hypersensitivity reactions (HSRs), including Stevens-Johnson syndrome, rare (but potentially life-threatening) hepatitis,47,48 and conflicting data about virologic efficacy compared to preferred regimens,1,3,4,44-46,49-57 the Panel recommends nevirapine in combination with a 2-NRTI backbone as a Preferred NNRTI regimen in infants aged <14 days and an Alternative NNRTI regimen for children aged ≥14 days to <3 years (AI). A change from nevirapine to LPV/r should be considered after 14 days of life and 42 weeks post-gestational age based on infant genotype and the better outcomes of LPV/r in children aged <3 years.

Rilpivirine

Rilpivirine is currently available both as a single-agent formulation and a once-daily, fixed-dose combination tablet containing emtricitabine and TDF. The single-agent formulation is approved for use in adolescents aged ≥12 years. 

Recommendation:
  • Based on the limited experience in adolescents and larger body of evidence in adults,31,58-62 the Panel recommends rilpivirine in combination with a 2-NRTI backbone as an Alternative NNRTI regimen for children and adolescents aged ≥12 years and weighing ≥35 kg and with HIV viral load ≤100,000 copies/mL (AI*).

Protease Inhibitor-Based Regimens

Advantages of PI-based regimens include excellent virologic potency and high barrier for development of drug resistance (requires multiple mutations). However, because PIs are metabolized via hepatic enzymes, the drugs have potential for multiple drug interactions. They may also be associated with metabolic complications such as dyslipidemia, fat maldistribution, and insulin resistance. Factors to consider in selecting a PI-based regimen for treatment-naive children include virologic potency, dosing frequency, pill burden, food or fluid requirements, availability of palatable pediatric formulations, drug interaction profile, toxicity profile (particularly related to metabolic complications), age of the child, and availability of data in children. Table 8 lists the advantages and disadvantages of PIs. See Appendix A: Pediatric Antiretroviral Drug Information for detailed pediatric information on each drug.

Ritonavir is a potent inhibitor of the cytochrome P450 3A4 isoenzyme and can be used in low doses as a PK booster when co-administered with some PIs, increasing drug exposure by prolonging the half-life of the boosted PI. Currently only LPV/r is available as a coformulated product. When ritonavir is used as a PI booster with other PIs, 2 agents must be administered. In addition, the use of ritonavir boosting increases the potential for hyperlipidemia63 and drug-drug interactions.
 
Preferred and alternative PIs are presented in alphabetical order below.

Atazanavir/Ritonavir 

Atazanavir is a once-daily PI that was approved by the FDA in March 2008 for use in combination with a 2-NRTI backbone in children aged ≥6 years. Atazanavir is most often boosted with ritonavir. Approval was extended in 2014 for use in infants and children aged ≥3 months and weighing ≥5 kg. Atazanavir in combination with cobicistat has been approved by the FDA for use in adults. Its use in children and adolescents is under investigation but no data are currently available. 

Recommendation:

  • Based on virologic potency in adult and pediatric studies and tolerability in pediatric studies,19,27,60,63-69 the Panel recommends atazanavir/ritonavir (ATV/r) in combination with a 2-NRTI backbone as a Preferred PI regimen for children aged ≥3 years (AI*).
  • Because of the limited experience with ATV/r in younger children, the Panel recommends ATV/r as Alternative PI therapy in infants and children aged >3 months to <3 years and weighing between 5 and 25 kg (AI*).
  • The Panel does not recommend unboosted atazanavir. 

Darunavir/Ritonavir 

Darunavir/ritonavir (DRV/r) is FDA-approved for ARV-naive and ARV-experienced adults and for ARV-naive and ARV-experienced children aged ≥3 years. DRV/r is approved for once-daily use in adults and children without darunavir resistance-associated mutations. Once-daily dosing of DRV/r was conducted as a sub-study of a twice-daily dosing trial in children aged 3 to <12 years. This PK evaluation lasted only 2 weeks, after which the participants switched back to the twice-daily regimen.70 FDA dosing recommendations are based on PK models from this study, but this dose has never undergone trials for clinical efficacy in this age group. Because of the lack of efficacy data on once-daily DRV/r in treatment-naive or treatment-experienced children aged <12 years, the Panel recommends dosing darunavir with ritonavir twice daily in children aged >3 years to <12 years.71

Recommendation:

  • Based on its virologic potency in adult and pediatric studies, high barrier to development of drug resistance, and excellent toxicity profile in adults and children,19,71-78 the Panel recommends DRV/r in combination with a 2-NRTI backbone as a Preferred PI regimen for children aged ≥3 years to <6 years and children and adolescents aged ≥12 years (AI*).
  • Based on findings from the DIONE study, once-daily dosing of DRV/r is part of a Preferred PI regimen in treatment-naive children and adolescents weighing ≥40 kg (AI*).
  • Twice-daily dosing of DRV/r is part of a Preferred PI regimen in children aged ≥3 to <6 years and weighing ≥10 kg  and an Alternative PI regimen in children aged ≥6 years to <12 years (AI*).
  • Twice-daily dosing of DRV/r if the following darunavir resistance-associated substitutions are present in the HIV protease: V11I, V32I, L33F, I47V, I50V, I54L, I54M, T74P, L76V, I84V, and L89V. 

Lopinavir/Ritonavir 

Lopinavir/ritonavir (LPV/r) is approved for treatment of HIV infection in adults and in infants and children with a postmenstrual age ≥42 weeks and postnatal age ≥14 days. Once-daily LPV/r is FDA-approved for initial therapy in adults,79 but PK data in children do not support a recommendation for once-daily dosing.80-82

Recommendation:
  • Based on virologic potency in adult and pediatric studies and tolerability in pediatric studies,10,29,64,65,72,79-81,83-87 the Panel recommends LPV/r in combination with a 2-NRTI backbone as a Preferred PI regimen for infants with a postmenstrual age ≥42 weeks and postnatal age ≥14 days to <3 years (AI).

Selection of Dual-Nucleoside Reverse Transcriptase Inhibitor Backbone as Part of Initial Combination Therapy

Dual-NRTI combinations form the backbone of combination regimens for both adults and children. Currently, 8 NRTIs (zidovudine, didanosine, lamivudine, stavudine, abacavir, emtricitabine, TDF, and TAF) are FDA-approved for use in children aged <13 years. Dual-NRTI combinations that have been studied in children include zidovudine in combination with abacavir, didanosine, or lamivudine; abacavir in combination with lamivudine, stavudine, or didanosine; emtricitabine in combination with stavudine or didanosine; TDF in combination with lamivudine or emtricitabine; and TAF in combination with emtricitabine.15,37,66,88-92 Advantages and disadvantages of different dual-NRTI backbone options are delineated in Table 8. Also, see Appendix A: Pediatric Antiretroviral Drug Information for detailed pediatric information on each drug.

In the dual-NRTI regimens listed below, lamivudine and emtricitabine are interchangeable. Both lamivudine and emtricitabine are well tolerated with few AEs. Although there is less experience in children with emtricitabine than with lamivudine, it is similar to lamivudine and can be substituted for lamivudine as one component of a preferred dual-NRTI backbone (i.e., emtricitabine in combination with abacavir or TDF or zidovudine). The main advantage of emtricitabine over lamivudine is that it can be administered once-daily as part of an initial regimen. Both lamivudine and emtricitabine select for the M184V resistance mutation, which is associated with high-level resistance to both drugs; a modest decrease in susceptibility to abacavir and didanosine, and improved susceptibility to zidovudine, stavudine, and TDF based on decreased viral fitness.93,94

Dual-Nucleoside Reverse Transcriptase Inhibitor Backbone Regimens (in Alphabetical Order)

Abacavir in Combination with Lamivudine or Emtricitabine 

Abacavir is approved for use in children aged ≥3 months when administered as part of an ART regimen.

Recommendations:
  • Based on virologic efficacy and favorable toxicity profile,17,95-102 the Panel recommends abacavir plus lamivudine or emtricitabine as the Preferred dual-NRTI combination for children aged ≥3 months (AI)
  • Once-daily doing of abacavir is recommended when using the pill formulation. Twice-daily dosing of liquid abacavir is recommended for initial therapy; a change to once-daily dosing can be considered in clinically stable patients with undetectable viral load and stable CD4 cell count after approximately 6 months (24 weeks) of twice-daily dosing.103-106

Tenofovir Alafenamide in Combination with Emtricitabine 

TAF is an oral prodrug of tenofovir. It is approved by the FDA as a component of the fixed-drug combination tablet also containing elvitegravir, cobicistat, and emtricitabine for the treatment of HIV in ARV-naive individuals aged ≥12 years with estimated creatinine clearance ≥30 mL/min. 

Recommendation:

  • Based on the potential for less renal and bone AEs,13,107 the Panel recommends TAF plus emtricitabine (combined with elvitegravir and cobicistat) as a Preferred dual-NRTI combination in children and adolescents weighing ≥35 kg with estimated creatinine clearance ≥30 mL/min. 

Tenofovir Disoproxil Fumarate in Combination with Lamivudine or Emtricitabine 

TDF is FDA-approved for use in children and adolescents aged ≥2 years when administered as part of an ART regimen.

Recommendation:

  • Based on virologic efficacy and ease of dosing,89-92,96-99,108-113 the Panel recommends TDF in combination with lamivudine or emtricitabine as an Alternative dual-NRTI combination for use in children and adolescents at Sexual Maturity Rating (SMR) III (AI*)
  • Because of decreases in bone mineral density (BMD) observed in adults and children receiving TDF and its unknown clinical significance,89-92,114,115 the Panel recommends TDF use in children aged ≥2 years and SMR I or II in Special Circumstances after weighing potential risks of decreased BMD versus benefits of therapy.

Zidovudine in Combination with Lamivudine or Emtricitabine 

Zidovudine is available as a syrup, capsule, tablet, and injectable/intravenous preparations. It is licensed for treatment in infants as young as 4 weeks and prophylaxis in newborns. 

Recommendation:

  • Because of the extensive experience and favorable safety profile,100,116-118 the Panel recommends zidovudine in combination with lamivudine or emtricitabine as a Preferred NRTI for infants and children from birth to ≤12 years (AI*).
  • In adolescents, the Panel recommends zidovudine in combination with lamivudine or emtricitabine as an Alternative NRTI because zidovudine must be administered twice daily.

Alternative Dual-Nucleoside Reverse Transcriptase Inhibitor Regimens

Other dual-NRTI regimens have been studied in children and the Panel recommends as alternative dual-NRTI combinations: 

Zidovudine in Combination with Abacavir or Didanosine (BII)

  • In a large pediatric study, the combination of zidovudine and didanosine had the lowest rate of toxicities.116
  • Zidovudine plus abacavir and zidovudine plus lamivudine had lower rates of viral suppression and more toxicity leading to drug modification than did abacavir plus lamivudine in a European pediatric study.88,95

Didanosine in Combination with Lamivudine or Emtricitabine (BI*)

  • The combination of didanosine and emtricitabine allows for once-daily dosing.37 
  • Didanosine is recommended to be administered on an empty stomach but that is impractical for infants who must be fed frequently and it may decrease medication adherence in older children because of the complexity of the regimen. 
  • To improve adherence, some practitioners recommend administration of didanosine to young children without regard to timing of meals. However, data are inadequate to allow a strong recommendation at this time, and it is preferable to administer didanosine under fasting conditions when possible.

Table 7. Antiretroviral Regimens Recommended for Initial Therapy for HIV Infection in Children

An ART regimen in treatment-naive children generally contains 1 NNRTI or 1 PI boosted with ritonavir or cobicistat or 1 INSTI plus a 2-NRTI backbone. Preferred regimens are so designated based on efficacy, ease of administration and acceptable toxicity. Alternative regimens have also demonstrated efficacy, but have disadvantages compared with preferred regimens in terms of more limited experience in children or less favorable ease of administration. Regimens should be individualized based on advantages and disadvantages of each combination (see Table 8).

For children who are receiving an effective and tolerable ART regimen, that regimen can be continued as they age even if the combination they are receiving is no longer a preferred regimen.

Table 7. Antiretroviral Regimens Recommended for Initial Therapy for HIV Infection in Children
Preferred Regimens
Infants, Birth to <14 Daysa,b
2 NRTIs plus NVP
Children Aged ≥14 Days to <3 Years 2 NRTIs plus LPV/r
Children Aged ≥2 Years to <3 Years 2 NRTIs plus LPV/r
2 NRTIs plus RALc
Children Aged ≥3 Years to <6 Years
2 NRTIs plus ATV/r
2 NRTIs plus twice-daily DRV/rd
2 NRTIs plus RALc
Children aged ≥6 Years to <12 Years 2 NRTIs plus ATV/r
2 NRTIs plus DTGe
Adolescents Aged ≥12 Years and Not Sexually Mature (SMR I–III) 2 NRTIs plus ATV/r
2 NRTIs plus DTGe
2 NRTIs plus once daily DRV/rd
2 NRTIs plus EVG/COBIf
Adolescents Aged ≥12 Years and Sexually Mature (SMR IV or V) Refer to Adult and Adolescent Guidelines
Alternative Regimens
Children Aged >14 Days to <3 Years 2 NRTIs plus NVPg
Children Aged ≥4 Weeks and <2 Years and Weighing ≥3 kg 2 NRTIs plus RALc
Children Aged ≥3 Months to <3 Years and Weighing ≥10 kg
2 NRTIs plus ATV/r
Children Aged ≥3 Years to <6 Years 2 NRTIs plus EFVh
2 NRTIs plus LPV/r
Children Aged ≥6 Years to <12 Years
2 NRTIs plus twice-daily DRV/rd
2 NRTIs plus EFVh
2 NRTIs plus LPV/r
2 NRTIs plus RALc
Adolescents Aged ≥12 Years and Not Sexually Mature (SMR I–III) 2 NRTIs plus EFVh
2 NRTIs plus RALc
2 NRTIs plus RPVi
Preferred 2-NRTI Backbone Options for Use in Combination with Additional Drugs
Children, Birth to 3 Months ZDV plus (3TC or FTC)
Children Aged ≥3 Months and <12 Years ABC plus (3TC or FTC)
ZDV plus (3TC or FTC)
Adolescents Aged ≥12 Years and Not Sexually Mature (SMR I–III) ABC plus (3TC or FTC)
TAF plus FTC
Adolescents Aged ≥12 Years and Sexually Mature (SMR IV or V) Refer to the Adult and Adolescent Guidelines
Alternative 2-NRTI Backbone Options for Use in Combination with Additional Drugs
Children Aged ≥2 Weeks ZDV plus ddI
Children ≥3 Months ZDV plus ABC
Adolescents at SMR III
TDF plus (3TC or FTC)
Adolescents Aged ≥12 Years at SMR III
ZDV plus (3TC or FTC)
2-NRTI Regimens for Use in Special Circumstances in Combination with Additional Drugs
Children Aged ≥2 Years and Adolescents, SMR I or II
ddI plus (3TC or FTC)
TDF plus (3TC or FTC)
a If treatment initiation is planned prior to 14 days of age, NVP is the Preferred agent. However, there are currently no clinical trial data suggesting that initiating treatment within the first 14 days of life improves outcome (compared with starting after 14 days of age). Consultation with an expert in pediatric HIV infection should be sought. Additional considerations regarding the use of NVP in infants aged <14 days can be located in Specific Issues in Antiretroviral Therapy in Newborn Infants with HIV Infection. A change from NVP to LPV/r should be considered when the infant is aged ≥14 days and 42 weeks post-gestational age, based on infant genotype and the better outcomes of LPV/r in children aged <3 years.

b LPV/r should not be administered to neonates before a postmenstrual age (first day of the mother’s last menstrual period to birth plus the time elapsed after birth) of 42 weeks and postnatal age ≥14 days.

c RAL pills or chewable tablets can be used in children aged ≥2 years. Granules can be administered in infants and children aged 4 weeks to 2 years.

d DRV once-daily should not be used in children aged <12 years or weighing <40 kg or if any one of the following resistance-associated substitutions are present: V11I, V32I, L33F, I47V, I50V, I54L, I54M, T74P, L76V, I84V, and L89V. DRV/r is an Alternative recommendation for children aged ≥6 years to <12 years because there are options that can be administered once-daily. It is preferred for adolescents aged ≥12 years and not sexually mature (SMR I–III) where once-daily administration is possible.

e DTG is recommended only for children and adolescents weighing ≥30 kg.

f EVG is currently recommended only in fixed-dose combination tablets. Tablets containing EVG/COBI/FTC/TAF are recommended as Preferred for children and adolescents weighing ≥35 kg. Tablets containing EVG/COBI/FTC/TDF are recommended only for children and adolescents weighing ≥35 kg, and in SMR IV or V.

g NVP should not be used in post-pubertal girls with a CD4 cell count >250/mm3, unless the benefit clearly outweighs the risk. NVP is FDA-approved for treatment of infants aged ≥15 days.

h ERV is licensed for use in children aged ≥3 months who weigh ≥3.5 kg but is not recommended by the Panel as initial therapy in children aged ≥3 months to 3 years. i RPV should be administered to adolescents aged ≥12 years and weighing ≥35 kg who have an initial viral load ≤100,000 copies/mL.

Key to Acronyms: 3TC = lamivudine; ABC = abacavir; ATV = atazanavir; ATV/r = atazanavir/ritonavir; ART = antiretroviral therapy; COBI=cobicistat; ddI = didanosine; DRV = darunavir; DRV/r = darunavir/ritonavir; DTG = dolutegravir; EFV = efavirenz; EVG = elvitegravir; FDA = Food and Drug Administration; FTC = emtricitabine; 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; TAF = tenofovir alafenamide; TDF = tenofovir disoproxil fumarate; ZDV = zidovudine

 Figure 2. Preferred and Alternative Regimens by Age and Drug Class

WhattoStart

a If treatment initiation is planned prior to 14 days of age, NVP is the Preferred agent. However, there are currently no clinical trial data suggesting that initiating treatment within the first 14 days of life improves outcome (compared with starting after 14 days of age). Consultation with an expert in pediatric HIV infection should be sought. Additional considerations regarding the use of NVP in infants aged <14 days can be located in Specific Issues in Antiretroviral Therapy in Newborn Infants with HIV Infection. A change from NVP to LPV/r should be considered after 14 days of life and 42 weeks post-gestational age based on infant genotype and the better outcomes of LPV/r in children aged <3 year.

LPV/r should not be administered to neonates before a postmenstrual age (first day of the mother’s last menstrual period to birth plus the time elapsed after birth) of 42 weeks and postnatal age ≥14 days.

c RAL pills or chewable tablets can be used in children aged ≥2 years. Granules can be administered in infants and children aged 4 weeks to 2 years.

d
DRV once-daily should not be used in children aged <12 years or weighing <40 kg and if any one of the following resistance-associated substitutions are present: V11I, V32I, L33F, I47V, I50V, I54L, I54M, T74P, L76V, I84V, and L89V. DRV/r is an Alternative recommendation for children aged ≥6 years to <12 years because there are options that can be administered once daily. It is preferred for adolescents aged ≥12 years and not sexually mature (SMR I–III) where once-daily administration is possible. 

e DTG is recommended only for children and adolescents weighing ≥30 kg.

f EVG is currently recommended only in fixed-dose combination tablets. Tablets containing elvitegravir plus cobicistat plus emtricitabine plus TAF are recommended as Preferred for children and adolescents weighing ≥35 kg. Tablets containing elvitegravir plus cobicistat plus emtricitabine plus TDF are recommended only for children and adolescents weighing ≥35 kg, and in SMR IV or V.

g NVP should not be used in post-pubertal girls with CD4 cell count >250/mm3, unless the benefit clearly outweighs the risk. NVP is FDA-approved for treatment of infants aged ≥15 days.

h EFV is licensed for use in children aged ≥3 months who weigh ≥3.5 kg but is not recommended by the Panel as initial therapy in children aged ≥3 months to 3 years. 

i RPV should be administered to adolescents aged ≥12 years and weighing ≥35 kg who have an initial viral load ≤100,000 copies/mL.

Key to Acronyms: ATV/r = atazanavir/ritonavir; DRV/r = darunavir/ritonavir; DTG = dolutegravir; EFV = efavirenz; EVG=elvitegravir; FDA = Food and Drug Administration; LPV/r = lopinavir/ritonavir; NRTI = nucleoside reverse transcriptase inhibitor; NVP = nevirapine; RAL = raltegravir; RPV=rilpivirine; TAF = tenofovir alafenamide; TDF = tenofovir disoproxil fumarate

 

Table 8. Advantages and Disadvantages of Antiretroviral Components Recommended for
ARV Class ARV Agent(s) Advantages Disadvantages
INSTIs
In Alphabetical Order
 
 
  Integrase Inhibitor Class Advantages:
  • Susceptibility of HIV to a new class of ARVs
  • Few drug-drug interactions
  • Well-tolerated
Integrase Inhibitor Class Disadvantages:
  • Limited data on pediatric dosing or safety
DTG
  • Once-daily administration
  • Can give with food
  • Available as a fixed-dose combination tablet containing ABC/3TC/DTG (Triumeq) in a single, but large, tablet
  • Single-agent DTG pills are available in several dosages and are small in size
  • Drug interactions with EFV, FPV/r, TPV/r, and rifampin necessitating twice-daily dosing
EVG
  •  Once-daily administration
  • Available as a fixed-dose combination tablet containing EVG/COBI/FTC/TDF (Stribild) and as a fixed-dose combination tablet containing EVG/COBI/FTC/TAF (Genvoya)
  • COBI has the potential for multiple drug interactions because of metabolism via hepatic enzymes (e.g., CYP3A4)
  • COBI inhibits tubular secretion of creatinine and may result in increased serum creatinine but with normal glomerular clearance.
 RAL
  • Can give with food
  • Available in tablet, chewable tablet, and powder formulations

  •  Potential for rare systemic allergic reaction or hepatitis
NNRTIs
In Alphabetical Order
  NNRTI Class Advantages:
  • Long half-life
  • Less dyslipidemia and fat maldistribution than PIs
  • PI-sparing
  • Lower pill burden than PIs for children taking solid formulation; easier to use and adhere to than PI-based regimens.

NNRTI Class Disadvantages:
  •  Single mutation can confer resistance, with cross-resistance between EFV and NVP.
  • Rare but serious and potentially life-threatening cases of skin rash, including SJS, and hepatic toxicity with all NNRTIs (but highest with NVP)
  • Potential for multiple drug interactions due to metabolism via hepatic enzymes (e.g., CYP3A4).
EFV
  • Once-daily administration
  • Available as a fixed-dose combination tablet containing EFV/FTC/TDF (Atripla) 
  • Potent ARV activity
  • Can give with food (but avoid high-fat meals).
  • Capsules can be opened and added to food.
  • Neuropsychiatric AEs (bedtime dosing recommended to reduce CNS effects)
  • Rash (generally mild)
  • No commercially available liquid.
  • Limited data on dosing for children aged <3 years.
  • No data on dosing for children aged <3 months.
  • Use with caution in adolescent females of childbearing age.
NVP
  • Liquid formulation available.
  • Dosing information for young infants available.
  • Can give with food
  • Extended-release formulation is available that allows for once-daily dosing in older children.
    .

  • Reduced virologic efficacy in young infants, regardless of exposure to NVP as part of a peripartum preventive regimen.
  • Higher incidence of rash/HSR than other NNRTIs
  • Higher rates of serious hepatic toxicity than EFV
  • Decreased virologic response compared with EFV
  • Twice-daily dosing necessary in children with BSA <0.58 m2
RPV
  • Once-daily dosing
  • Available in a 1-pill-daily, fixed-dose combination tablet containing RPV/FTC/TDF (Complera) and RPV/FTC/TAF (Odefsey
  • Should not use in patients with HIV viral load >100,000 copies/mL
  • Low barrier for resistance
PIs 
In Alphabetical Order

 
  PI Class Advantages:
  •  NNRTI-sparing
  • Clinical, virologic, and immunologic efficacy are well-documented.
  • Resistance to PIs requires multiple mutations.
  • When combined with dual-NRTI backbone, targets HIV at 2 steps of viral replication (viral reverse transcriptase and protease enzymes).

PI Class Disadvantages:
  • Metabolic complications,including dyslipidemia, fat maldistribution, insulin resistance
  • Potential for multiple drug interactions because of metabolism via hepatic enzymes (e.g., CYP3A4)
  • Higher pill burden than NRTI- or NNRTI-based regimens for patients taking solid formulations
  • Poor palatability of liquid preparations, which may affect adherence to treatment regimen
  • Most PIs require ritonavir boosting resulting in associated drug interactions.
ATV/r
  • Once-daily dosing
  • Powder formulation available
  • ATV has less effect on TG and total cholesterol levels than other PIs (but RTV boosting may be associated with elevations in these parameters).
  • Available in a fixed-dose combination tablet containing ATV/COBI (Evotaz) that reduces pill burden of a boosted PI regimen


  • No liquid formulation
  • Food effect (should be administered with food)
  • Indirect hyperbilirubinemia is common but asymptomatic.
  • Must be used with caution in patients with preexisting conduction system defects (can prolong PR interval of ECG).
  • RTV component associated with large number of drug interactions.
DRV/r
  • Can be used once daily in children aged ≥12 years
  • Liquid formulation available
  • Available in a fixed-dose combination tablet containing DRV/COBI (Prezcobix) that reduces pill burden of a boosted PI regimen.
  • Pediatric pill burden high with current tablet dose formulations
  • Food effect (should be administered with food)
  • Must be given with RTV boosting to achieve adequate plasma concentrations.
  • Contains sulfa moiety. The potential for cross sensitivity between DRV and other drugs in sulfonamide class is unknown.
  • RTV component associated with large number of drug interactions.
  • Can only be used once-daily in absence of certain PI-associated resistance mutations.
LPV/r
  • LPV only available coformulated with RTV in liquid and tablet formulations
  • Tablets can be given without regard to food but may be better tolerated when taken with meal or snack.
  • Poor palatability of liquid formulation (bitter taste), although palatability of combination better than RTV alone.
  • Food effect (liquid formulation should be administered with food).
  • RTV component associated with large number of drug interactions.
  • Should not be administered to neonates before a postmenstrual age (first day of the mother’s last menstrual period to birth plus the time elapsed after birth) of 42 weeks and a postnatal age ≥14 days.
  • Must be used with caution in patients with preexisting conduction system defects (can prolong PR and QT interval of ECG).
Dual-NRTI Backbones
In Alphabetical Order
 
 
 
 
 
 
ABC plus (3TC or FTC)
  • Palatable liquid formulations
  • Can give with food.
  • ABC and 3TC are coformulated as a single pill for older/larger patients weighing ≥25 kg 
  • Available as a fixed-dose combination tablet containing ABC/3TC/DTG (Triumeq) in a single, but large, tablet.

  • Risk of ABC HSR; perform HLA-B*5701 screening before initiation of ABC treatment.
ddI plus (3TC or FTC)
  • Delayed-release capsules of ddI may allow once-daily dosing in children aged ≥6 years, weighing ≥20 kg, able to swallow pills, and who can receive adult dosing along with once-daily FTC.
  • FTC available as a palatable liquid formulation administered once daily.
  • Food effect (ddI is recommended to be taken 1 hour before or 2 hours after food). Some experts give ddI without regard to food in infants or when adherence is an issue (ddI can be co-administered with FTC or 3TC).
  • Limited pediatric experience using delayed-release ddI capsules in younger children
  • Pancreatitis, lactic acidosis, neurotoxicity with ddI
TAF plus FTC for adolescents ≥12 years 
  • Once-daily dosing
  • Small tablet size
  • Less tenofovir-associated renal and bone toxicity with TAF compared to TDF in adults
  • TAF and FTC are coformulated as a single tablet (Descovy).
  • Available as fixed-dose combination tablets: EVG/COBI/FTC/TAF (Genvoya) and RPV/FTC/TAF (Odefsey)
N/A
TDF plus (3TC or FTC) for adolescents, SMR IV or V
  • Once-daily dosing for TDF
  • Resistance is slow to develop.
  • Less mitochondrial toxicity than other NRTIs.
  • Can give with food.
  • Available as reduced-strength tablets and oral powder for use in younger children
  • TDF and FTC are coformulated as single tablet (Truvada) and available in multiple strengths.
  • Available as fixed-dose combination tablets: EFV/FTC/TDF (Atripla), EVG/COBI/FTC/TDF (Stribild), and RPV/FTC/TDF (Complera) 
  • Limited pediatric experience
  • Potential bone and renal toxicity, toxicity may be less in post-pubertal children.
  • Appropriate dosing is complicated by numerous drug-drug interactions with other ARV agents including ddI, LPV/r, ATV, and TPV.
ZDV plus (3TC or FTC) 
  • Extensive pediatric experience
  • ZDV and 3TC are coformulated as single pill for older/larger patients.
  • Palatable liquid formulations
  • Can give with food.
  • FTC is available as a palatable liquid formulation administered once daily.
  • Bone marrow suppression with ZDV
  • Lipoatrophy with ZDV
ZDV plus ABC 
  • Palatable liquid formulations
  • Can give with food
  • Risk of ABC HSR; perform HLA-B*5701 screening before initiation of ABC treatment
  • Bone marrow suppression and lipoatrophy with ZDV
ZVD plus ddI 
  • Extensive pediatric experience
    Delayed-release capsules of ddI may allow SMR dosing of ddI in older children able to swallow pills and who can receive adult doses

  • Bone marrow suppression and lipoatrophy with ZDV
  • Pancreatitis, neurotoxicity, lactic acidosis with ddI
  • ddI liquid formulation is less palatable than 3TC or FTC liquid. formulation
  • Food effect (ddI is recommended to be taken 1 hour before or 2 hours after food). Some experts give ddI without regard to food in infants or when adherence is an issue.
a See Appendix A: Pediatric Antiretroviral Drug Information and Table 7. Antiretroviral Regimen Considerations as Initial Therapy based on Specific Clinical Scenarios in the Adult ARV Guidelines for more information.

Key to Acronyms: 3TC = lamivudine; ABC = abacavir; AE =  adverse event; ARV = antiretroviral; ATV/r = atazanavir/ritonavir; BSA = body surface area; CNS = central nervous system; COBI = cobicistat; DRV/r = darunavir/ritonavir; ddI = didanosine; DTG = dolutegravir; ECG = electrocardiogram; EFV = efavirenz; EVG = elvitegravir; FPV/r = fosamprenavir/ritonavir; FTC = emtricitabine; HSR = hypersensitivity reaction; 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; PK = pharmacokinetic; RAL = raltegravir; RPV = rilpivirine; RTV = ritonavir; SJS = Stevens-Johnson Syndrome; SMR = sexual maturity rating; TAF = tenofovir alafenamide; TDF = tenofovir disoproxil fumarate; TG = triglycerides; TPV/r = tipranavir/ritonavir; ZDV = zidovudine

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