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

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 characteristics of the proposed regimen, patient characteristics, drug efficacy, potential adverse effects, patient and family preferences, and 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, including either an integrase strand transfer inhibitor, a non-nucleoside reverse transcriptase inhibitor, or a boosted protease 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 or Alternative; 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

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

An ART regimen for treatment-naive children generally contains one NNRTI or one PI boosted with RTV or COBI or one INSTI plus a two-NRTI backbone. Preferred regimens are designated based on efficacy, ease of administration, and acceptable toxicity. Alternative regimens have also demonstrated efficacy, but have more limited experience in children or less favorable ease of administration than Preferred regimens. Regimens should be individualized based on the advantages and disadvantages of each combination (see Table 8).

Children who are receiving effective and tolerable ART regimens can continue with 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 Fixed-Dose Combination Available
Infants, Birth to Age <14 Daysa,b 2 NRTIs plus NVP No
2 NRTIs plus RAL No
Children Aged ≥14 Days to <3 Years 2 NRTIs plus LPV/r No
2 NRTIs plus RALc No
Children Aged ≥3 Years to <6 Years 2 NRTIs plus ATV/r No
2 NRTIs plus twice-daily DRV/rd No
2 NRTIs plus RALc No
Children Aged ≥6 Years to <12 Years 2 NRTIs plus ATV/r No
2 NRTIs plus DTGe No
Adolescents Aged ≥12 Years and SMR 1–3 2 NRTIs plus ATV/r No
2 NRTIs plus DTGe FDC available
2 NRTIs plus once-daily DRV/rd No
2 NRTIs plus EVG/COBIf FDCs available
Adolescents Aged ≥12 Years and SMR 4 or 5 Refer to the Adult and Adolescent Guidelines No
Alternative Regimens
Age Regimens Fixed-Dose Combination Available
Children Aged >14 Days to <3 Years 2 NRTIs plus NVPg No
Children Aged ≥3 Months to <3 Years and Weighing ≥10 kg 2 NRTIs plus ATV/r No
Children Aged ≥3 Years to <6 Years 2 NRTIs plus EFVh No
2 NRTIs plus LPV/r No
Children Aged ≥6 Years to <12 Years 2 NRTIs plus twice-daily DRV/rd No
2 NRTIs plus EFVh No
2 NRTIs plus EVG/COBIf FDCs available
2 NRTIs plus LPV/r No
2 NRTIs plus RALc No
Adolescents Aged ≥12 Years and SMR 1–3 2 NRTIs plus EFVh FDC available
2 NRTIs plus RALc No
2 NRTIs plus RPVi FDC available
Preferred 2-NRTI Backbone Options for Use in Combination with Additional Drugs
Age 2-NRTI Backbone Options Fixed-Dose Combination Available
Children, Birth to Age <3 Months ZDV plus (3TC or FTC)j No
Children Aged ≥3 Months to <6 Years ABC plus (3TC or FTC)k FDC available
ZDV plus (3TC or FTC)j FDC available
Children and Adolescents Aged ≥6 Years and SMR 1–3 ABC plus (3TC or FTC)k FDC available
FTC/TAFl FDC available
Adolescents Aged ≥12 Years and SMR 4 or 5 Refer to the Adult and Adolescent Guidelines No
Alternative 2-NRTI Backbone Options for Use in Combination with Additional Drugs
Age 2-NRTI Backbone Options Fixed-Dose Combination Available
Children Aged ≥3 Months ZDV plus ABC No
Children Aged ≥2 Years to 12 Years TDF plus (3TC or FTC)m FDC available
Children and Adolescents Aged ≥6 Years and SMR 1–3 ZDV plus (3TC or FTC)j FDC available
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. 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). Clinicians should consult an expert in pediatric HIV infection. Additional considerations regarding the use of NVP or RAL in infants aged <14 days can be found in Antiretroviral Management of Newborns. A change from NVP to LPV/r should be considered when the infant is aged ≥14 days and 42 weeks 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), based on infant genotype and better outcomes of LPV/r than NVP in children aged <3 years. Data are very 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.
d DRV once daily should not be used in children aged <12 years or weighing <40 kg. DRV once daily 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 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 who are not sexually mature (SMR 1–3) where once-daily administration is possible.
e DTG is recommended only for children and adolescents weighing ≥30 kg. An FDC tablet containing ABC/DTG/3TC (Triumeq) is available.
f EVG is currently recommended only in FDC tablets. Tablets containing EVG/COBI/FTC/TAF are recommended as Preferred for children and adolescents weighing ≥35 kg and as Alternative for children aged ≥6 years and weighing ≥25 kg.
g NVP should not be used in postpubertal girls with CD4 cell counts >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 and weighing ≥3.5 kg, but it is not recommended by the Panel as initial therapy in children aged ≥3 months to 3 years. An FDC tablet containing EFV/FTC/TDF (Atripla) is available.
i RPV should be administered to adolescents aged ≥12 years and weighing ≥35 kg who have an initial viral load ≤100,000 copies/mL. FDC tablets containing FTC/RPV/TAF (Odefsey) and FTC/RPV/TDF (Complera) are available.
j An FDC containing 3TC/ZDV (Combivir and generic) is available.
k An FDC containing ABC/3TC (Epzicom and generic) is available.
l An FDC containing FTC/TAF is available. FTC/TAF is FDA-approved 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. There is insufficient data to recommend use of FTC/TAF in combination with a boosted PI in children weighing <35 kg. For children and adolescents weighing ≥35 kg, TAF can be used in the single-tablet regimen EVG/COBI/FTC/TAF, or as FTC/TAF in combination with an NNRTI, an INSTI, or a boosted PI.
m An FDC containing FTC/TDF (Truvada) is available.

Key to Acronyms: 3TC = lamivudine; ABC = abacavir; ATV/r = atazanavir/ritonavir; ART = antiretroviral therapy; 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

Figure 2. 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, 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). Clinicians should consult an expert in pediatric HIV infection. Additional considerations regarding the use of NVP or RAL in infants aged <14 days can be found in Antiretroviral Management of Newborns. A change from NVP to LPV/r should be considered when the infant is aged ≥14 days and 42 weeks 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), based on infant genotype and better outcomes of LPV/r than NVP in children aged <3 years. Data are very 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.
d DRV once daily should not be used in children aged <12 years or weighing <40 kg. DRV once daily 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 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 SMR 1–3 where once-daily administration is possible.
e DTG is recommended only for children and adolescents weighing ≥30 kg. For those children weighing <30 kg, RAL can be considered if an INSTI-based regimen is desired.
f EVG is currently recommended only in FDC tablets. Tablets containing EVG/COBI/FTC/TAF are recommended as Preferred for children and adolescents weighing ≥35 kg and Alternative 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 FDA-approved for treatment of infants aged ≥15 days.
h EFV is licensed for use in children aged ≥3 months and weighing ≥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; 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; RAL = raltegravir; RPV = rilpivirine; TAF = tenofovir alafenamide

Table 8. Advantages and Disadvantages of Antiretroviral Components Recommended for Initial Therapy in Childrena
ARV Class ARV Agent(s) Advantages Disadvantages
INSTIs
In Alphabetical Order
All INSTIs INSTI Class Advantages:
  • Susceptibility of HIV to a new class of ARV drugs
  • Few drug-drug interactions
  • Well-tolerated
INSTI Class Disadvantages:
  • Limited data on pediatric dosing or safety
DTG
  • Once-daily administration
  • Can give with food
  • Available in an FDC tablet containing ABC/DTG/3TC (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
  • CNS side effects, particularly sleep disturbances
EVG
  • Once-daily administration
  • Available in the following FDC tablets: EVG/COBI/FTC/TDF (Stribild) and 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 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
  • Powder formulation requires a multistep preparation before administration.
NNRTIs
In Alphabetical Order
All NNRTIs 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 in the FDC 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
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 the following 1-pill-daily, FDC tablets: FTC/RPV/TDF (Complera) and FTC/RPV/TAF (Odefsey)
  • Should not use in patients with HIV viral load >100,000 copies/mL
  • 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 2 steps of viral replication by inhibiting the activity of 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 RTV boosting, resulting in associated drug interactions.
Boosted ATV
  • 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).
  • ATV requires a boosting agent. ATV/COBI is available as an FDC tablet (Evotaz), which can reduce the pill burden associated with a boosted-PI regimen. However, the use of ATV/COBI in pediatric patients is still being investigated. RTV is currently the only boosting agent for ATV that is FDA-approved for use in children.
  • 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 a large number of drug interactions
Boosted DRV
  • Can be used once daily in children aged ≥12 years
  • Liquid formulation available
  • DRV requires a boosting agent. DRV/COBI is available as an FDC tablet (Prezcobix), which can reduce the pill burden associated with a boosted-PI regimen. However, the use of DRV/COBI in pediatric patients is still being investigated. RTV is currently the only boosting agent for DRV that is FDA-approved for use in children.
  • Pediatric pill burden high with current tablet dose formulations
  • Food effect (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 component 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 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 is better than RTV alone
  • Food effect (liquid formulation should be administered with food)
  • RTV component is associated with 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.
  • ABC and 3TC are available in the following FDC tablets: ABC/3TC (Epzicom and generic; for older/larger patients) and ABC/DTG/3TC (Triumeq; a single, large tablet).
  • 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
  • Less TFV-associated renal and bone toxicity with TAF compared to TDF in adults
  • FTC and TAF are available in the following FDC tablets: FTC/TAF (Descovy), EVG/COBI/FTC/TAF (Genvoya), and FTC/RPV/TAF (Odefsey)
  • Limited data in children
  • Increased lipids
TDF plus (3TC or FTC) for adolescents with SMR 4 or 5
  • 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
  • FTC and TDF are available in the following FDC tablets: FTC/TDF (Truvada; available in multiple dosages), EFV/FTC/TDF (Atripla), EVG/COBI/FTC/TDF (Stribild), and FTC/RPV/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 (Combivir and generic) 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
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 and Adolescent Guidelines for more information.

Key to Acronyms: 3TC = lamivudine; ABC = abacavir; AE = adverse event; ARV = antiretroviral; ATV = atazanavir; BSA = body surface area; CNS = central nervous system; COBI = cobicistat; CYP = cytochrome P; 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; PK = pharmacokinetic; 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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