(Last updated: April 27, 2015; last reviewed: April 27, 2015)
Many additional antiretroviral (ARV) agents 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.
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 10.
Insufficient Data to RecommendDrugs and drug combinations approved for use in adults that have insufficient, limited, and/or no pharmacokinetic (PK) or safety data for 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 10.
Antiretroviral Drugs and Combinations Not Recommended for Initial TherapyIn 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 RegimensEnfuvirtide, 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 combination antiretroviral therapy (cART) (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 BoostingFosamprenavir without ritonavir boosting has been studied in children aged ≥2 years but is not recommended because the large 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 RegimensAlthough 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 Nucleoside Reverse Transcriptase InhibitorsIn 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 for 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 ClassesData are insufficient to recommend initial regimens containing agents from three drug classes (e.g., NRTI plus NNRTI plus PI). Although studies containing three classes of drugs have demonstrated these regimens to be safe and effective in previously treated HIV-infected children and adolescents, these regimens have not been studied as initial therapy in treatment-naive children and adolescents and have the potential for inducing resistance to three drug classes, which could severely limit future treatment options.11-15 Ongoing studies, however, are investigating three drug classes as treatment in HIV-infected neonates.
Regimens Containing Three NRTIs and an NNRTIData are currently insufficient to recommend a regimen of three NRTIs plus an NNRTI in young infants. A recent review of nine cohorts from 13 European countries suggested superior responses to this four-drug regimen when compared to boosted PI or three-drug NRTI regimens.16 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 three-drug regimen versus a four-drug regimen (three NRTIs and an 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 improvement and virologic control were observed in the four-drug arm, these benefits were not sustained after de-intensification to the three-NRTI arm.17 Furthermore, after a median of 3.7 years on therapy, children in the initial four-drug arm who changed to an all NRTI-based regimen had significantly poorer virologic control.18 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 RitonavirA 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.19 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 DidanosineThe 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.20-22 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.23,24 In addition, cases of fatal and non-fatal lactic acidosis with pancreatitis/hepatic steatosis have been reported in women receiving this combination during pregnancy.25,26
Tipranavir-Based RegimensThis agent has been studied in treatment-experienced children and adults. Tipranavir is a PI licensed for use in children aged ≥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.
Antiretroviral Drugs and Combinations with Data Insufficient to Recommend for Initial Therapy in ChildrenA number of ARV drugs and drug regimens are not recommended for initial therapy in 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 (integrase strand transfer inhibitor [INSTI]), and etravirine and rilpivirine (both NNRTIs). In addition, some dosing schedules 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 10.
Darunavir with Low-Dose Ritonavir when Administered Once Daily (for Children Aged ≥3 to 12 Years)Data are limited on PK of once-daily darunavir/ritonavir in young children. While modeling studies identified a once-daily dosing regimen now approved by FDA, the Panel is concerned about the lack of efficacy data for individuals aged ≥3 to <12 years treated with once-daily darunavir/ritonavir. Therefore once-daily dosing for initial therapy is not recommended in this age group. For children aged ≥3 to <12 years, twice-daily darunavir boosted with ritonavir is an alternate PI regimen. For older children who have undetectable viral load on twice-daily therapy with darunavir/ritonavir, practitioners can consider changing to once-daily treatment to enhance ease of use and support adherence if no darunavir-associated resistance mutations are present.
Dolutegravir for Children Aged <12 YearsDolutegravir is an INSTI that has recently been approved by FDA for use in children 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 YearsEfavirenz is FDA-approved for use in children as young as 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 younger than 3 years at this time (see Efavirenz in Appendix A: Pediatric Antiretroviral Drug Information). Based on the recommended efavirenz dosage for children younger than 3 years, the IMPAACT P1070 study estimated the variability in area under the curve (AUC) for efavirenz based on polymorphisms in cytochrome P (CYP) 2B6 516. The findings suggest that 38% of extensive metabolizers would have subtherapeutic AUCs and 67% of poor metabolizers would have excessive AUCs based on recommended dosing.27 Thus, 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 RegimensElvitegravir is an INSTI available as a tablet and as a fixed-dose combination tablet containing elvitegravir/cobicistat/emtricitabine/tenofovir. It is FDA-approved for use as cART in HIV-1-infected cART-naive adults. Elvitegravir tablets must be taken in combination with a low-dose, ritonavir-boosted PI. Neither formulation is FDA-approved for use in children aged <18 years. A small study (14 participants) of the fixed-dose combination tablet containing elvitegravir/cobicistat/emtricitabine/tenofovir in treatment-naive children and adolescents, aged 12 to 17 years, has reported PK, tolerability, and virologic efficacy at 24 weeks. The therapy was well tolerated and all subjects taking the cART at 24 weeks had viral loads less than 400 copies/mL; 11 had viral loads less than 50 copies/mL. Steady state exposure was similar to that observed in adults, as were small increases in serum creatinine without evidence of nephrotoxicity. These data suggest that elvitegravir/cobicistat/emtricitabine/tenofovir is efficacious in children and adolescents aged 12 to 18 years, but evidence is insufficient for this regimen to be recommended as initial therapy for treatment-naive children and adolescents in this age group.
Etravirine-Based RegimensEtravirine is an NNRTI that has been studied in treatment-experienced children 6 years and older.28,29 It is associated with multiple interactions with other ARVs, including tipranavir/ritonavir, fosamprenavir/ritonavir, atazanavir/ritonavir, 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 RegimensRilpivirine is currently available both as a single-agent formulation and a once-daily, fixed-dose combination tablet containing emtricitabine and tenofovir. A recent study of rilpivirine, 25 mg daily in combination with two NRTIs in treatment-naive adolescents aged 12 to 18 years, demonstrated that the regimen was well-tolerated over 24 weeks. Among adolescents with baseline viral loads ≤100,000 copies/mL, 86% had a virologic response.30 In adult studies, reduced viral suppression was observed in patients with initial HIV RNA >100,000 copies/mL; similar reduced response was also observed in the pediatric study. In adults, rilpivirine is recommended only if HIV RNA is ≤100,000 copies/mL; it is not recommended as initial therapy for treatment-naive children and adolescents, and if used in older children and adolescents (aged >12 years) it should only be used if HIV RNA is <100,000 copies/mL.
Maraviroc-Based RegimensMaraviroc is an entry inhibitor that has been used infrequently in children. A dose-finding study in treatment-experienced children aged 2 to 18 years is enrolling patients in four age cohorts using both liquid and tablet formulations. Initial dose is based on body surface area and scaled from recommended adult dosage. Dose adjustments were required in patients not receiving a potent CYP450 3A4 inhibitor or inducer.31 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 RecommendedSeveral ARV drugs and drug regimens should never be recommended for use in therapy of children or adults. These are summarized in Table 11. 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.
|Regimen or ARV Component
||Rationale for Being Not Recommended|
|Unboosted ATV-containing regimens in children aged <13 years and/or weight <39 kg
|DRV-based regimens once daily in children ≥3 to 12 years||Insufficient data to recommend|
||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
|Dual NRTI combination of TDF plus ddI||Increase in concentrations; high rate of virologic failure|
|DTG-based regimens for children <12 years or body weight <40 kg||Insufficient data to recommend|
|EFV-based regimens for children aged <3 years||Appropriate dose not determined|
|T20-containing regimens||Insufficient data to recommend
||Insufficient data to recommend|
|EVG-based regimens||Insufficient data to recommend|
|FPV without RTV boosting
|IDV-based regimens||Renal toxicities|
|LPV/r dosed once daily||Reduced drug exposure|
||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
|Regimens containing three NRTIs and an NNRTI
||Insufficient data to recommend|
|RPV-based regimens||Insufficient data to recommend|
||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; ARV = antiretroviral; ATV = atazanavir; d4T = stavudine; ddI = didanosine; DRV = darunavir; EFV = efavirenz; ETR = etravirine; EVG = elvitegravir; FPV = fosamprenavir; GI = gastrointestinal; 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; RPV = rilpivirine; RTV = ritonavir; SQV = saquinavir; T20 = enfuvirtide; TDF = tenofovir disoproxil fumarate; TPV = tipranavir|
|ART Regimens Never Recommended for Children|
|One ARV drug alone (monotherapy)
|Two NRTIs alone||
|TDF plus ABC plus (3TC or FTC) as a triple-NRTI regimen||
|TDF plus ddI plus (3TC or FTC) as a triple-NRTI regimen||
|ARV Components Never Recommended as Part of an ARV Regimen for Children|
|ATV plus IDV||
|EFV in first trimester of pregnancy or for sexually active adolescent girls of childbearing potential when reliable contraception cannot be ensured||
|NVP as initial therapy in adolescent girls with CD4 count >250 cells/mm3 or adolescent boys with CD4 count >400 cells/mm3||
|Unboosted SQV, DRV, or TPV||
|Key to Abbreviations: 3TC = lamivudine; ABC = abacavir; ARV =
antiretroviral; ATV = atazanavir; cART = combination antiretroviral
therapy; CD4 = CD4 T lymphocyte; 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 disoproxil fumarate; TPV =
tipranavir; ZDV = zidovudine