Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection

The information in the brief version is excerpted directly from the full-text guidelines. The brief version is a compilation of the tables and boxed recommendations.

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Regimens Recommended for Initial Therapy of Antiretroviral-Naive Children

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

Panel's Recommendations Regarding Regimens Recommended for Initial Therapy of Antiretroviral-Naive Children
Panel's Recommendations
  • The selection of an initial regimen should be individualized based on several factors, including the characteristics of the proposed regimen, the patient’s characteristics, drug efficacy, potential adverse effects, patient and family preferences, and the results of viral resistance testing (AIII).
  • For treatment-naive children, the Panel on Antiretroviral Therapy and Medical Management of Children Living with HIV (the Panel) recommends initiating antiretroviral therapy with three drugs: a dual-nucleoside/nucleotide reverse transcriptase inhibitor backbone plus an integrase strand transfer inhibitor, a non-nucleoside reverse transcriptase inhibitor, or a boosted protease inhibitor (AI*).
  • Table 7 provides a list of Panel-recommended regimens that are designated as Preferred or Alternative; recommendations vary by a patient’s 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 childrenwith 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 childrenfrom 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

Figure 1. Preferred and Alternative Regimens by Age and Drug Class

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a If treatment is scheduled to begin before a patient is aged 14 days, NVP or RAL are the Preferred agents because they are the only options with dosing information available for this age group. However, available clinical trial data does not suggest that initiating treatment within the first 14 days of life is more beneficial than starting treatment after 14 days of age. Additional considerations regarding the use of NVP or RAL in infants aged <14 days can be found in Antiretroviral Management of Newborns with Perinatal HIV Exposure or Perinatal HIV. Switching from NVP to LPV/r should be considered when the infant is aged ≥14 days with a postmenstrual age (the span of time between the first day of the mother’s last menstrual period and birth, plus the time elapsed after birth) of 42 weeks; LPV/r has produced better clinical outcomes in studies of children aged <3 years than NVP. Data are limited on the clinical outcomes of using RAL in infants and children aged <2 years.

b LPV/r should not be administered to neonates before a postmenstrual age of 42 weeks and a postnatal age ≥14 days.

c RAL can be used in infants weighing ≥2 kg. RAL pills or chewable tablets can be used in children aged ≥2 years. Granules can be administered to infants and children from birth to age 2 years.

d BIC is available only as part of an FDC tablet that contains BIC/FTC/TAF and is recommended as a Preferred regimen for adolescents aged ≥12 years and weighing ≥25 kg. It is recommended as an Alternative regimen for children aged ≥6 years and weighing ≥25 kg.

e DTG is recommended as a Preferred regimen only for children and adolescents aged ≥3 years and weighing ≥25 kg. It is recommended as an Alternative regimen in children aged ≥3 years and weighing 20 kg to <25 kg. For children weighing <20 kg, the use of RAL can be considered when an INSTI-based regimen is desired.

f EVG is currently recommended only as a component of FDC tablets. Tablets containing EVG/COBI/FTC/TAF are recommended as a Preferred regimen for children and adolescents weighing ≥35 kg, and as an Alternative regimen for children and adolescents weighing ≥25 kg.

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

h Once-daily DRV should not be used in children aged <12 years or weighing <40 kg. Once-daily DRV should also not be used 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 recommended as an Alternative drug combination for children aged ≥6 years to <12 years, because there are other drugs that can be administered once daily. This combination is considered a Preferred option for adolescents aged ≥12 years with SMR 1–3 when once-daily administration is possible.

Key to Acronyms: ATV/r = atazanavir/ritonavir; BIC = bictegravir; CD4 = CD4 T lymphocyte; COBI = cobicistat; DRV = darunavir; DRV/r = darunavir/ritonavir; DTG = dolutegravir; EVG = elvitegravir; EVG/c = elvitegravir/cobicistat; 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; NVP = nevirapine; PI = protease inhibitor; RAL = raltegravir; SMR = sexual maturity rating; TAF = tenofovir alafenamide

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

An ART regimen for treatment-naive children is generally made up of a two-NRTI backbone and either one NNRTI or one INSTI or one PI boosted with RTV or COBI. Preferred regimens are designated based on efficacy, ease of administration, and acceptable toxicity. Alternative regimens have also demonstrated efficacy, but clinical experience with these regimens is limited or these regimens are more difficult to administer than Preferred regimens. Regimens should be tailored to the individual patient by weighing the advantages and disadvantages of each combination. Many agents have multiple formulations and age and weight recommendations. Please consult Appendix A: Pediatric Antiretroviral Drug Information for additional information and recommended dosages and formulations (see Table 8 below).

Children who are receiving effective and tolerable ART regimens can continue using those regimens as they age, even if the combinations they are receiving are no longer Preferred regimens.

Table 7. Antiretroviral Regimens Recommended for Initial Therapy for HIV Infection in Children
Preferred Regimens
Age Regimens FDC Available
(see Fixed-Dose Combinations)
Infants, Birth to Age <14 Daysa,b Two NRTIs plus NVP No
Weight ≥2 kg Two NRTIs plus RALc No
Children Aged ≥14 Days to <3 Years Two NRTIs plus LPV/r No
Weight ≥2 kg Two NRTIs plus RALc No
Children Aged ≥3 Years Weight <25 kg Two NRTIs plus ATV/r No
Two NRTIs plus twice-daily DRV/rd No
Two NRTIs plus RALc No
Weight ≥25 kg Two NRTIs plus DTGe Yes
Two NRTIs plus EVG/COBIf Yes
Adolescents Aged ≥12 Years with SMR 1–3 Weight ≥25 kg Two NRTIs plus BICg Yes
Adolescents Aged ≥12 Years with SMR 4 or 5 Refer to the Adult and Adolescent Antiretroviral Guidelines Yes
Alternative Regimens
Age Regimens FDC Available
Children Aged ≥14 Days to <3 Years Two NRTIs plus NVPh No
Children Aged ≥3 Months to <3 Years Two NRTIs plus ATV/r No
Children Aged ≥3 Years Weight ≥20 kg to <25 kg Two NRTIs plus DTGe No
Children Aged ≥3 Years Weight ≥25 kg Two NRTIs plus ATV/r No
Two NRTIs plus DRV/rd No 
Two NRTIs plus RALc No 
Children Aged ≥3 Years Two NRTIs plus EFVi Noj
Two NRTIs plus LPV/r No
Children Aged ≥6 Years to <12 Years Weight ≥25 kg Two NRTIs plus BICg Yes
Adolescents Aged ≥12 Years with SMR 1–3 Weight ≥35 kg Two NRTIs plus RPVk Yes
Adolescents Aged ≥12 Years with SMR 4 or 5 Refer to the Adult and Adolescent Antiretroviral Guidelines Yes
Preferred Dual-NRTI Backbone Options for Use in Combination with Other Drugs
Age Dual-NRTI Backbone Options FDC Available
Children, Birth to Age <3 Months ZDV plus (3TC or FTC)l Noj
Children Aged ≥3 Months to <6 Years ABC plus (3TC or FTC)m Yes
ZDV plus (3TC or FTC)l Yes
Children and Adolescents Aged ≥6 Years with SMR 1–3 ABC plus (3TC or FTC)m Yes
Weighing ≥25 kg and receiving a regimen that contains an INSTI or an NNRTI FTC/TAFn Yes
Adolescents Aged ≥12 Years with SMR 4 or 5 Refer to the Adult and Adolescent Antiretroviral Guidelines Yes
Alternative Dual-NRTI Backbone Options for Use in Combination with Other Drugs
Age Dual-NRTI Backbone Options FDC Available
Children Aged ≥3 Months ZDV plus ABC No
Children Aged ≥2 Years to 12 Years TDF plus (3TC or FTC)o Yes
Children and Adolescents Aged ≥6 Years and SMR 1–3 ZDV plus (3TC or FTC)l Yes
a If treatment is scheduled to begin before a patient is aged 14 days, NVP or RAL are Preferred agents because they are the only options with dosing information available for this age group. While many pediatric experts favor initiating ART as soon as possible after birth in order to limit the establishment of viral reservoirs, available clinical trial data does not suggest that initiating treatment within the first 14 days of life leads to better clinical outcomes than initiating treatment after 14 days of age. Clinicians should consult an expert in pediatric HIV infection before initiating treatment in infants aged <14 days. Additional considerations regarding the use of NVP or RAL in infants aged <14 days can be found in Antiretroviral Management of Newborns with Perinatal HIV Exposure or Perinatal HIV. Switching from NVP to LPV/r should be considered when the infant is aged ≥14 days with a postmenstrual age of 42 weeks (the span of time between the first day of the mother’s last menstrual period and birth, plus the time elapsed after birth); LPV/r has produced better clinical outcomes in studies of children aged <3 years than NVP. Data are limited on the clinical outcomes of using RAL in infants and children aged <2 years.

b LPV/r should not be administered to neonates before a postmenstrual age 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 from birth to age 2 years. No dosing information is available for preterm infants or those with a weight of < 2 kg at birth.

d DRV should only be used in children weighing ≥10 kg. Once-daily DRV should not be used in children aged <12 years or weighing <40 kg. Once-daily DRV should also not be used when 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 recommended as an Alternative drug combination for children aged ≥6 years to <12 years and weighing >25 kg, because there are other drugs that can be administered once daily and that are better tolerated. Note that DRV/r can be administered once daily in adolescents aged ≥12 years and weighing ≥40 kg who are not sexually mature (SMR 1–3).

e DTG is recommended as a Preferred agent for children and adolescents aged ≥3 years and weighing ≥25 kg. It is recommended as an Alternative agent in children aged ≥3 years and weighing 20 kg to <25 kg. An FDC tablet containing ABC/DTG/3TC (Triumeq) is available for children weighing ≥25 kg.

f EVG is currently recommended only as a component of FDC tablets. Tablets containing EVG/COBI/FTC/TAF are recommended as a Preferred regimen for children and adolescents weighing ≥35 kg, and as an Alternative regimen for children and adolescents weighing ≥25 kg.

g BIC is available only as part of an FDC tablet that contains BIC/FTC/TAF and is recommended as a Preferred regimen for adolescents aged ≥12 years and weighing ≥25 kg. It is recommended as an Alternative regimen for children aged ≥6 years and weighing ≥25 kg.

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

i EFV is approved by the FDA for use in children aged ≥3 months and weighing ≥3.5 kg, but it is not recommended by the Panel for initial therapy in children aged ≥3 months to 3 years. An FDC tablet containing EFV/FTC/TDF (Atripla) and EFV 600 mg/3TC/TDF (Symfi) is available. See efavirenz section for information about use of the FDC EFV 400 mg/3TC/TDF (Symfi Lo).

j FDA-approved FDCs are not included in this table when they are not approved for use in the specific patient populations being discussed.

k RPV should be administered to adolescents aged ≥12 years and weighing ≥35 kg who have initial viral loads ≤100,000 copies/mL. FDC tablets containing FTC/RPV/TAF (Odefsey) and FTC/RPV/TDF (Complera) are available.

l An FDC containing 3TC/ZDV (Combivir and generic) is available.

m An FDC containing ABC/3TC (Epzicom and generic) is available.

n FTC/TAF is recommended as a Preferred combination for children and adolescents weighing ≥25 kg; an FDC containing FTC/TAF is available. FTC/TAF is approved by the FDA for children weighing ≥25 kg when used in the single-tablet regimen EVG/COBI/FTC/TAF or as TAF/FTC in combination with an NNRTI or INSTI. FTC/TAF plus a boosted PI is only recommended for use in children and adolescents weighing ≥35 kg.

o An FDC containing FTC/TDF (Truvada) is available.

Key to Acronyms: 3TC = lamivudine; ABC = abacavir; ATV/r = atazanavir/ritonavir; ART = antiretroviral therapy; BIC = bictegravir; CD4 = CD4 T lymphocyte; COBI = cobicistat; DRV = darunavir; 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; NVP = nevirapine; PI = protease inhibitor; RAL = raltegravir; RPV = rilpivirine; SMR = sexual maturity rating; TAF = tenofovir alafenamide; TDF = tenofovir disoproxil fumarate; ZDV = zidovudine

Table 8. Advantages and Disadvantages of Antiretroviral Components Recommended for Initial Therapy in Children

See Appendix A: Pediatric Antiretroviral Drug Information and Table 7. Antiretroviral Regimen Considerations for Initial Therapy Based on Specific Clinical Scenarios in the Adult and Adolescent Antiretroviral Guidelines for more information.

Table 8. Advantages and Disadvantages of Antiretroviral Components Recommended for Initial Therapy in Children
ARV Class ARV Agent(s) Advantages Disadvantages
INSTIs
In Alphabetical Order
All INSTIs INSTI Class Advantages:
  • Few drug-drug interactions
  • Well-tolerated
INSTI Class Disadvantages:
  • Limited data on pediatric dosing or safety
BIC Once-daily administration

Can give with or without food

Available in FDC tablets (see Fixed-Dose Combinations)
FDC tablet is not recommended for patients with hepatic impairment or an estimated creatinine clearance <30 mL/min

FDC tablet should not be coadministered with rifampin or dofetilide
DTG Once-daily administration

Can give with food

Available in FDC tablets (see Fixed-Dose Combinations)

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 of DTG

CNS side effects, particularly sleep disturbances and possible increased risk of neural tube defects in infants born to women who were receiving dolutegravir at the time of conception
EVG Once-daily administration

Available in FDC tablets (see Fixed-Dose Combinations)
Among INSTIs, EVG has the lowest barrier to the development of resistance.

If EVG is administered with COBI, there is potential for multiple drug interactions because COBI is metabolized by hepatic enzymes (e.g., CYP3A4).

COBI inhibits tubular secretion of creatinine, and this may result in increased serum creatinine but normal glomerular clearance.
RAL Can give with food

Available in tablet, chewable tablet, and powder formulations

Once-daily administration (with RAL HD) can be used for treatment-naive or virologically suppressed children weighing ≥50 kg.
Potential for rare systemic allergic reaction or hepatitis

Granule formulation requires a multistep preparation before administration; caregiver must be taught how to properly prepare this formulation.
NNRTIs
In Alphabetical Order
All NNRTIs NNRTI Class Advantages:
  • Long half-life
  • Lower risk of dyslipidemia and fat maldistribution than PIs
  • PI-sparing
  • Lower pill burden than PIs for children taking the solid formulation; easier to use and adhere to than PI-based regimens
NNRTI Class Disadvantages:
  • A 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. All NNRTIs pose this risk, but the risk is greatest with NVP.
  • Potential for multiple drug interactions due to metabolism via hepatic enzymes (e.g., CYP3A4)
EFV Once-daily administration

Available in the FDC tablets (see Fixed-Dose Combinations)

Potent ARV activity

Can give with food (but avoid high-fat meals)

Capsules can be opened and added to food.
Neuropsychiatric AEs (bedtime dosing is recommended to reduce CNS effects)

Rash (generally mild)

No commercially available liquid formulation

Limited data on dosing for children aged <3 years

No data on dosing for children aged <3 months
NVP Liquid formulation is available.

Dosing information for young infants is 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

Low barrier for resistance
RPV Once-daily dosing

Available in FDC tablets (see Fixed-Dose Combinations)
Should not use in patients with HIV viral loads >100,000 copies/mL

Must be taken with a ≥500 kcal meal at a consistent time each day; this may affect adherence.

Low barrier for resistance
PIs
In Alphabetical Order
All PIs PI Class Advantages:
  • NNRTI-sparing
  • Clinical, virologic, and immunologic efficacy are well-documented.
  • Resistance to PIs requires multiple mutations.
  • When combined with a dual-NRTI backbone, a regimen containing a PI targets HIV at two steps of viral replication by inhibiting the activity of viral reverse transcriptase and protease enzymes.
PI Class Disadvantages:
  • Metabolic complications, including dyslipidemia, fat maldistribution, and insulin resistance
  • Potential for multiple drug interactions because of metabolism via hepatic enzymes (e.g., CYP3A4)
  • Higher pill burden than NRTI-based or NNRTI-based regimens for patients taking solid formulations
  • Poor palatability of liquid preparations, which may affect adherence
  • Most PIs require RTV boosting, resulting in drug interactions that are associated with RTV.
Boosted ATV Once-daily dosing

Powder formulation is 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).
No liquid formulation

Should be administered with food)

Indirect hyperbilirubinemia is common, but asymptomatic. Scleral icterus may be distressing to the patient, which may affect adherence.

Must be used with caution in patients with preexisting conduction system defects (can prolong PR interval of ECG).

RTV is associated with a large number of drug interactions.
Boosted DRV Can be used once daily in children aged ≥12 years

Liquid formulation is available.

DRV requires a boosting agent.

Available in FDC tablets (see Fixed-Dose Combinations)
Pediatric pill burden high with current tablet dose formulations

Should be administered with food

Must be boosted to achieve adequate plasma concentrations

Contains sulfa moiety. The potential for cross-sensitivity between DRV and other drugs in sulfonamide class is unknown.

RTV is associated with a large number of drug interactions.

Can only be used once daily in the absence of certain PI-associated resistance mutations
LPV/r LPV is only available coformulated with RTV in liquid and tablet formulations.

Tablets can be given without regard to food, but they may be better tolerated when taken with meal or snack.
Poor palatability of liquid formulation (bitter taste), although the palatability of the FDC is better than RTV alone

Liquid formulation should be administered with food.

RTV is associated with a large number of drug interactions.

Should not be administered to neonates before a postmenstrual age (the span of time between the first day of the mother’s last menstrual period and birth, plus the time elapsed after birth) of 42 weeks and a postnatal age ≥14 days

Must be used with caution in patients with pre-existing 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

Available in FDC tablets (see Fixed-Dose Combinations)
Risk of ABC HSR; perform HLA-B*5701 screening before initiation of ABC treatment.
FTC/TAF for children aged ≥6 years Once-daily dosing

Small tablet size

Lower risk of TFV-associated renal and bone toxicity with TAF than with TDF in adults

Available in FDC tablets (see Fixed-Dose Combinations)
Limited data on the safety and efficacy of this combination in children

Increased lipid levels
TDF plus (3TC or FTC) for adolescents with SMR 4 or 5 Once-daily dosing for TDF

Resistance is slow to develop.

Lower risk of mitochondrial toxicity than other NRTIs

Can give with food

Available as reduced-strength tablets and oral powder for use in younger children

Available in FDC tablets (see Fixed-Dose Combinations)
Limited pediatric experience

Potential bone and renal toxicity

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

Coformulations of ZDV and 3TC are available (Combivir and generic) for children weighing ≥30 kg.

Palatable liquid formulations

Can give with food

FTC is available as a palatable liquid formulation that can be administered once daily.
Bone marrow suppression with ZDV

Lipoatrophy with ZDV
ZDV plus ABC Palatable liquid formulations

Can give with food
Risk of ABC HSRs; perform HLA-B*5701 screening before initiation of ABC treatment.

Bone marrow suppression and lipoatrophy with ZDV
Key to Acronyms: 3TC = lamivudine; ABC = abacavir; AE = adverse event; ARV = antiretroviral; ATV = atazanavir; BIC = bictegravir; BSA = body surface area; CNS = central nervous system; COBI = cobicistat; CYP = cytochrome P450; ddI = didanosine; DRV = darunavir; DTG = dolutegravir; ECG = electrocardiogram; EFV = efavirenz; EVG = elvitegravir; FDC = fixed-dose combination; FPV/r = fosamprenavir/ritonavir; FTC = emtricitabine; HSR = hypersensitivity reaction; INSTI = integrase strand transfer inhibitor; LPV = lopinavir; 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; SJS = Stevens-Johnson Syndrome; SMR = sexual maturity rating; TAF = tenofovir alafenamide; TDF = tenofovir disoproxil fumarate; TFV= tenofovir; TG = triglycerides; TPV = tipranavir; TPV/r = tipranavir/ritonavir; ZDV = zidovudine

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