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Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection

What to Start

What Not to Start: Regimens Not Recommended for Initial Therapy of Antiretroviral-Naive Children

(Last updated:2/12/2014; last reviewed:2/12/2014)

Many additional antiretroviral agents (ARVs) and combinations are available; some are not recommended for initial therapy, although they may be used in treatment-experienced children. This section describes ARV drugs and drug combinations that are not recommended or for which data are insufficient to recommend use for initial therapy in ARV-naive children.

Not Recommended 

These include drugs and drug combinations that are not recommended for initial therapy in ARV-naive children because of inferior virologic response, potential serious safety concerns (including potentially overlapping toxicities), or pharmacologic antagonism. These drugs and drug combinations are listed in Table 8. 

Insufficient Data to Recommend 

Drugs and drug combinations approved for use in adults that have insufficient, limited, and/or no pharmacokinetic (PK) or safety data in children cannot be recommended as initial therapy in children. However, these drugs and drug combinations may be appropriate for consideration in management of treatment-experienced children (see Management of Children Receiving Antiretroviral Therapy). These drugs are also listed in Table 8.

Antiretroviral Drugs and Combinations Not Recommended for Initial Therapy 

In addition to the regimens listed below, several ARVs—including unboosted atazanavir in adolescents aged <13 years, nelfinavir and tenofovir disoproxil fumarate (tenofovir) in children aged <2 years, unboosted darunavir, once-daily dosing of lopinavir/ritonavir, and full-dose ritonavir—are not recommended for use as initial therapy. 

Enfuvirtide-Based Regimens 

Enfuvirtide, a fusion inhibitor, is Food and Drug Administration (FDA)-approved for use in combination with other ARV drugs to treat children aged ≥6 years who have evidence of HIV replication despite ongoing antiretroviral therapy (i.e., treatment-experienced children on non-suppressive regimens). Enfuvirtide is not recommended as initial therapy because the drug must be administered subcutaneously twice daily and is associated with a high incidence of local injection site reactions (98%). 

Fosamprenavir without Ritonavir Boosting 

Fosamprenavir without ritonavir boosting has been studied in children aged ≥2 years but is not recommended because the volume of fosamprenavir oral suspension necessary to administer in the absence of ritonavir boosting is prohibitive. In addition, low levels of exposure may result in selection of resistance mutations that are associated with darunavir resistance.

Indinavir-Based Regimens

Although adequate virologic and immunologic responses have been observed with indinavir-based regimens in adults, the drug is not available in a liquid formulation and high rates of hematuria, sterile leukocyturia, and nephrolithiasis have been reported in pediatric patients using indinavir.1-4 The incidence of hematuria and nephrolithiasis with indinavir therapy may be higher in children than adults.1,4 Therefore, indinavir alone or with ritonavir boosting is not recommended as initial therapy in children. 

Regimens Containing Only NRTIs 

In adult trials, regimens containing only nucleoside reverse transcriptase inhibitors (NRTIs) have shown less potent virologic activity when compared with more potent non-nucleoside reverse transcriptase inhibitor (NNRTI)- or protease inhibitor (PI)-based regimens. These include studies of zidovudine plus abacavir plus lamivudine, stavudine plus didanosine plus lamivudine, stavudine plus lamivudine plus abacavir, didanosine plus stavudine plus abacavir, tenofovir plus abacavir plus lamivudine, and tenofovir plus didanosine plus lamivudine.5,6 Data on the efficacy of triple-NRTI regimens for treatment of ARV-naive children are limited; in small observational studies, response rates of 47% to 50% have been reported.7,8 In a study of the triple-NRTI regimen abacavir, lamivudine, and zidovudine in previously treated children, the combination showed evidence of only modest viral suppression, with only 10% of 102 children maintaining a viral load of <400 copies/mL at 48 weeks of treatment.9 Therefore, regimens containing only NRTIs are not recommended. A possible exception to this recommendation is the treatment of young children (aged <3 years) with concomitant HIV infection and tuberculosis in whom a nevirapine based regimen is not acceptable. For these children where treatment choices are limited, the World Health Organization recommends the use of a triple-NRTI regimen.10 

Regimens Containing Three Drug Classes

Data are insufficient to recommend initial regimens containing agents from three drug classes (e.g., NRTI plus NNRTI plus PI). Although efavirenz plus nelfinavir plus one or two NRTIs was shown to be safe and effective in HIV-infected children with prior NRTI therapy, this regimen was not studied as initial therapy in treatment-naive children and has the potential for inducing resistance to three drug classes, which could severely limit future treatment options.11-13

Regimens Containing Three NRTIs and a NNRTI 

Data are currently insufficient to recommend a regimen of three NRTIs plus a NNRTI in young infants. A recent review of 9 cohorts from 13 European countries suggested superior responses to this 4-drug regimen when compared to boosted PI or 3-drug NRTI regimens.14 There has been speculation that poor tolerance and adherence to a PI-based regimen may account for differences. The ARROW trial conducted in Uganda and Zimbabwe randomized 1,206 children (median age 6 years) to a standard NNRTI-based 3-drug regimen versus 4-drug regimen (3 NRTIs and a NNRTI). After a 36-week induction period, the children on the four-drug regimen were continued on a dual NRTI plus NNRTI or an all NRTI-based regimen. Although early benefits in CD4 T lymphocyte (CD4) improvement and virologic control were observed in the four-drug arm, these benefits were not sustained after de-intensification to the three-NRTI arm.15 Furthermore, after a median of 3.7 years on therapy, children in the initial 4-drug arm that changed to an all NRTI-based regimen had significantly poorer virologic control.16 Based on demonstrated benefits of recommended three-drug regimens and lack of additional efficacy data on the four-drug regimen, the Panel does not currently recommend this regimen. 

Saquinavir with Low-Dose Ritonavir 

A saquinavir/ritonavir-based regimen compared with a lopinavir/ritonavir-based regimen demonstrated comparable virologic and immunologic outcomes when used as initial therapy in treatment-naive adults.17 However, saquinavir is not recommended for initial therapy in children because the agent is not available in a pediatric formulation and dosing and outcome data on saquinavir use in children are limited. 

Stavudine in Combination with Didanosine 

The dual-NRTI combination of stavudine/didanosine is not recommended for use as initial therapy because of greater toxicity when used in combination. In small pediatric studies, stavudine/didanosine demonstrated virologic efficacy and was well tolerated.18-20 However, in studies in adults, stavudine plus didanosine-based combination regimens were associated with greater rates of neurotoxicity, pancreatitis, hyperlactatemia and lactic acidosis, and lipodystrophy than therapies based on zidovudine plus lamivudine.21,22 In addition, cases of fatal and non-fatal lactic acidosis with pancreatitis/hepatic steatosis have been reported in women receiving this combination during pregnancy.23,24 

Tipranavir-Based Regimens 

This agent has been studied in treatment-experienced children and adults. Tipranavir is a PI licensed for use in children age ≥2 years. Tipranavir-based regimens are not recommended because higher doses of ritonavir to boost tipranavir must be used and rare, but serious, cases of intracranial hemorrhage have been reported. 

Not Recommended for Initial Therapy for Children Because of Insufficient Data 

A number of ARV drugs and drug regimens are not recommended for initial therapy of ARV-naive children or for specific age groups because of insufficient pediatric data. These include the dual-NRTI backbone combinations abacavir/didanosine, abacavir/tenofovir, and didanosine/tenofovir. In addition, several new agents appear promising for use in adults but do not have sufficient pediatric PK and safety data to recommend their use as components of an initial therapeutic regimen in children. These agents include maraviroc (CCR5 antagonist), elvitegravir (ISTI), and etravirine and rilpivirine (both NNRTIs). Additionally, there are dosing schedules that may not be recommended in certain age groups based on insufficient data. As new data become available, these agents may be considered as recommended agents or regimens. These are summarized below and also listed in Table 8.

Darunavir with Low-Dose Ritonavir when Administered Once Daily (for Children Aged ≥3 to 12 Years)

Data are limited on PK of once-daily ritonavir-boosted darunavir in young children. While modeling studies identified a once-daily dosing regimen now approved by the FDA, the Panel is concerned about the lack of efficacy data for persons aged ≥3 to <12 years treated with once-daily ritonavir-boosted darunavir. Therefore once-daily dosing for initial therapy is not recommended in this age group. For children age ≥3 to <12 years, twice-daily darunavir boosted with ritonavir is an alternate PI regimen. For patients who have undetectable viral load on twice-daily therapy with darunavir boosted with ritonavir, practitioners can consider changing to once-daily treatment to enhance ease of use and support adherence. 

Dolutegravir for Children Aged <12 Years 

Dolutegravir is an integrase strand transfer inhibitor (INSTI) that has recently been approved by the FDA for use in children aged 12 years and older and weighing at least 40 kg. At this time there is no information about its use in children aged < 12 years but a clinical trial in treatment-experienced children aged <12 years is under way. 

Efavirenz for Children Aged ≥3 Months to 3 Years 

Efavirenz is FDA-approved for use in children as young as age 3 months who weigh at least 3.5 kg. Concerns regarding variable PK of the drug in the very young have resulted in a recommendation to not use efavirenz in children under age 3 years at this time (see Efavirenz in Appendix A: Pediatric Antiretroviral Drug Information). However, should efavirenz be considered, CYP2B6 genotyping that predicts efavirenz metabolic rate should be performed, if available. Therapeutic drug monitoring can also be considered. 

Elvitegravir-Based Regimens

Elvitegravir is an INSTI only available as a fixed-dose combination tablet containing elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate, and is FDA-approved for use as combination antiretroviral therapy (cART) in HIV-1-infected cART-naive adults. It is not FDA-approved for use in children aged <18 years. There are no data on its use in individuals younger than age 18 years, and it cannot be considered for use as initial therapy for children at this time (see http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/203100s000lbl.pdf).

Etravirine-Based Regimens 

Etravirine is an NNRTI that has been studied in treatment-experienced children 6 years of age and older. It is associated with multiple interactions with other ARVs, including ritonavir-boosted tipranavir, ritonavir-boosted fosamprenavir, ritonavir-boosted atazanavir, and unboosted PIs, and must be administered twice daily. Studies in treatment-experienced younger children are under way. It is unlikely that etravirine will be studied in treatment-naive children.

Rilpivirine-Based Regimens 

Rilpivirine is currently available both as a single-agent formulation and a once-daily, fixed-dose combination tablet containing emtricitabine and tenofovir. An ongoing study is assessing the safety and efficacy in adolescents aged 12 to 18 years. In adult studies, reduced viral suppression was observed in patients with initial HIV RNA >100,000 copies/mL. 

Maraviroc-Based Regimens 

Maraviroc is an entry inhibitor that has been used infrequently in children. A dose finding study in children aged 2 to 18 years is currently under way. The drug has multiple drug interactions and must be administered twice daily. In addition, tropism assays must be performed prior to use to ensure the presence of only CCR5-tropic virus. 

Antiretroviral Drug Regimens that Should Never be Recommended

Several ARV drugs and drug regimens should never be recommended for use in therapy of children or adults. These are summarized in Table 9. Clinicians should be aware of the components of fixed-drug combinations so that patients do not inadvertently receive a double dose of a drug contained in such a combination. 

Click here to view this table as an image

Table 8. ART Regimens or Components Not Recommended for Initial Treatment of HIV Infection in Children
Regimen or ARV Component
Rationale for Being Not Recommended
Unboosted ATV-containing regimens in children aged <13 years and/or weight <39 kg
Reduced exposure
DRV-based regimens once-daily in children ≥3 to 12 years
Insufficient data to recommend
Unboosted DRV 
Use without ritonavir has not been studied
Dual (full-dose) PI regimens
Insufficient data to recommend
Dual NRTI combination of ABC plus ddI
Insufficient data to recommend
Dual NRTI combination of ABC plus TDF
Insufficient data to recommend
Dual NRTI combination of d4T plus ddI
Significant toxicities
Dual NRTI combination of TDF plus ddI
Increase in concentrations; high rate of virologic failure
EFV-based regimens for children aged <3 years
Appropriate dose not determined
ENF-containing regimens
Insufficient data to recommend
Injectable preparation
ETV-based regimens
Insufficient data to recommend
EVG-based regimens
Insufficient data to recommend
FPV without RTV boosting
Reduced exposure
Medication burden
IDV-based regimens
Renal toxicities
LPV/r dosed once daily
Reduced drug exposure
MVC-based regimens
Insufficient data to recommend
NFV-containing regimens for children aged <2 years
Appropriate dose not determined
Regimens containing only NRTIs
Inferior virologic efficacy
Regimens containing three drug classes
Insufficient data to recommend
Full-dose RTV or use of RTV as the sole PI
GI intolerance
Metabolic toxicity
Regimens containing three NRTIs and an NNRTI
Insufficient data to recommend
RPV-based regimens
Insufficient data to recommend
SQV-based regimens
Limited dosing and outcome data burden
TDF-containing regimens in children aged <2 years
Potential bone toxicity
Appropriate dose has yet to be determined
TPV-based regimens
Increased dose of RTV for boosting
Reported cases of intracranial hemorrhage 
Key to Abbreviations: ABC = abacavir, ATV = atazanavir, d4T=stavudine, ddI = didanosine, DRV = darunavir, EFV = efavirenz, ETV = etravirine, EVG = elvitegravir, FPV = fosamprenavir, IDV = indinavir, LPV/r = ritonavir-boosted lopinavir, MVC = maraviroc, NFV = nelfinavir, NNRTI = non-nucleoside reverse transcriptase inhibitor, NRTI = nucleoside reverse transcriptase inhibitor, PI = protease inhibitor, RAL = raltegravir, RTV = ritonavir, SQV = saquinavir, T-20 = enfuvirtide, TDF = tenofovir disoproxil fumarate, RPV = rilpivirine, TPV = tipranavir

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Table 9. ART Regimens or Components that Should Never Be Recommended for Treatment of HIV Infection in Children
Regimen/Component Rationale Exceptions
ART Regimens Never Recommended for Children
One ARV drug alone (monotherapy)
  • Rapid development of resistance
  • Inferior antiviral activity compared with combination including ≥3 ARV drugs
  • HIV-exposed infants (with negative viral testing) during 6-week period of prophylaxis to prevent perinatal transmission of HIV
  • 3TC or FTC interim “bridging regimen” in special circumstances of children with treatment failure associated with drug resistance and persistent nonadherence
Two NRTIs alone
  • Rapid development of resistance
  • Inferior antiviral activity compared with combination including ≥3 ARV drugs
  • Not recommended for initial therapy.
  • For patients currently on 2 NRTIs alone who achieve virologic goals, some clinicians may opt to continue this treatment. 
TDF plus ABC plus (3TC or FTC) as a triple-NRTI regimen
  • High rate of early viral failure when this triple-NRTI regimen used as initial therapy in treatment-naive adults.
  • No exceptions
TDF plus ddI plus (3TC or FTC) as a triple-NRTI regimen
  • High rate of early viral failure when this triple-NRTI regimen used as initial therapy in treatment-naive adults.
  • No exceptions
ARV Components Never Recommended as Part of an ARV Regimen for Children
ATV plus IDV
  • Potential additive hyperbilirubinemia
  • No exceptions
Dual-NNRTI combinations
  • Enhanced toxicity
  • No exceptions
Dual-NRTI combinations:
  • 3TC plus FTC
  • Similar resistance profile and no additive benefit
  • No exceptions
  • d4T plus ZDV
  • Antagonistic effect on HIV
  • No exceptions
EFV in first trimester of pregnancy or for sexually active adolescent girls of childbearing potential when reliable contraception cannot be ensured
  • Potential for teratogenicity
  • When no other ARV option is available and potential benefits outweigh risks 
NVP in adolescent girls with CD4 count >250 cells/mm3 or adolescent boys with CD4 count >400 cells/mm3
  • Increased incidence of symptomatic (including serious and potentially fatal) hepatic events in these patient groups
  • Only if benefit clearly outweighs risk
Unboosted SQV, DRV, or TPV
  • Poor oral bioavailablity
  • Inferior virologic activity compared with other PIs
  • No exceptions
Key to Abbreviations: 3TC = lamivudine, ABC = abacavir, ARV = antiretroviral, ATV = atazanavir, d4T = stavudine, ddI = didanosine, DRV = darunavir, EFV = efavirenz, FTC = emtricitabine, IDV = indinavir, NNRTI = non-nucleoside reverse transcriptase inhibitor, NRTI = nucleoside reverse transcriptase inhibitor, NVP = nevirapine, PI = protease inhibitor, SQV = saquinavir, TDF = tenofovir, TPV = tipranavir, ZDV = zidovudine

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