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Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection

What to Start

Regimens Recommended for Initial Therapy of Antiretroviral-Naive Children

(Last updated: April 27, 2015; last reviewed: April 27, 2015)

Panel's Recommendations

Panel's Recommendations

  • Selection of an initial regimen should be individualized based on a number of factors including characteristics of the proposed regimen, patient characteristics, and results of viral resistance testing (AIII).
  • The Panel recommends initiating combination antiretroviral therapy (cART) in treatment-naive children using one of the following preferred agents plus a dual-nucleoside/nucleotide reverse transcriptase inhibitor backbone combination:
    • For neonates/infants aged ≥42 weeks postmenstrual and ≥14 days postnatal and children <3 years: lopinavir/ritonavir (AI);
    • For children aged 3 years to <6 years: efavirenz or lopinavir/ritonavir (AI*);
    • For children aged ≥6 years: atazanavir/ritonavir or efavirenz or lopinavir/ritonavir (AI*).
  • The Panel recommends the following preferred dual-nucleoside reverse transcriptase inhibitor backbone combinations:
    • For infants <3 months: zidovudine plus (lamivudine or emtricitabine) (AI*);
    • For children aged ≥3 months: abacavir plus (lamivudine or emtricitabine) (AI) or zidovudine plus (lamivudine or emtricitabine) (AI*);
      • HLA-B*5701 genetic testing should be performed before initiating abacavir-based therapy, and abacavir should not be given to a child who tests positive for HLA-B*5701 (AII*);
    • For children aged ≥12 years: abacavir plus lamivudine or plus emtricitabine (AI).
    • For adolescents at Tanner Stage 4 or 5: abacavir plus lamivudine or plus emtricitabine (AI) or tenofovir disoproxil fumarate plus lamivudine or plus emtricitabine (AI*).
  • Table 8 provides a list of Panel-recommended alternative and acceptable regimens.
  • For infants aged <42 weeks postmenstrual or <14 days postnatal, data are currently inadequate to provide recommended dosing to allow the formulation of an effective, complete cART regimen (see Specific Issues in Antiretroviral Therapy in Newborn Infants with HIV Infection).
  • Both emtricitabine and lamivudine, and tenofovir disoproxil fumarate have antiviral activity and efficacy against hepatitis B. For a comprehensive review of this topic, and hepatitis C and tuberculosis during HIV coinfection, the reader should access the Pediatric Opportunistic Infections Guidelines.

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 HIV-Infected Children (the Panel)’s recommendations are based on reviews of pediatric and adult clinical trial data published in peer-reviewed journals (the Panel may also review 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 combination antiretroviral therapy (cART) 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 studies in adults, 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 demonstrate that safety and efficacy are suggested using surrogate markers; additional considerations are listed above.
  • Alternative: Drugs or drug combinations are designated as alternatives 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.
  • Use in 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

A cART regimen for children should generally consist of two nucleoside reverse transcriptase inhibitors (NRTIs) plus one active drug from the following classes: non-nucleoside reverse transcriptase inhibitor (NNRTI) or protease inhibitor (PI), generally boosted with low-dose ritonavir. Although integrase strand transfer inhibitors (INSTIs) or CCR5 antagonists may be considered for first-line treatment of adults, there are insufficient data to recommend these agents as preferred agents for initial therapy in children and adolescents at this time. Choice of a regimen should be individualized based on a number of factors including characteristics of the proposed regimen, patient characteristics, and results of viral resistance testing. Advantages and disadvantages of each class-based regimen are delineated in detail in the sections that follow and in Table 9. In addition, because cART 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.

Choice of Non-Nucleoside Reverse Transcriptase Inhibitor-Based versus Protease Inhibitor-Based Initial Regimens

Preferred regimens for initial therapy include both NNRTI- and PI-based regimens. The selection of a NNRTI- or PI-based regimen should be based on patient characteristics, especially age, and preferences, results of viral drug resistance testing, and information cited below.

Clinical trial data in children provide some guidance for choosing between a NNRTI-based regimen and a PI-based regimen for initial therapy. The P1060 study compared a nevirapine-based regimen to a lopinavir-based regimen in HIV-infected infants and children (in 6 African countries and India) aged 2 months to 35 months. Infants and children in this study were stratified at entry based on prior maternal or infant exposure to peripartum single-dose nevirapine prophylaxis or no exposure, and randomized to receive either zidovudine, lamivudine, and nevirapine or zidovudine, lamivudine, and lopinavir/ritonavir (lopinavir boosted with low-dose ritonavir). Median age was 0.7 years in the single-dose nevirapine-exposed and 1.7 years in the nevirapine-unexposed children. Among infants and children with prior exposure to nevirapine, 39.6% of children in the nevirapine group reached a study endpoint of death, virologic failure, or toxicity by Week 24 compared with 21.7% of children in the lopinavir/ritonavir group.1 Among infants and children with no prior nevirapine exposure, 40.1% of children treated with nevirapine met a study endpoint after 24 weeks in the study compared with 18.4% of children who received lopinavir/ritonavir.2 Based on these data, a PI-based regimen containing lopinavir/ritonavir is the preferred initial regimen for HIV-infected children aged <3 years.

A comparison of a PI-based regimen and a NNRTI-based regimen was also undertaken in HIV-infected treatment-naive children aged 30 days to <18 years in PENPACT-1 (PENTA 9/PACTG 390) (the study did not dictate the specific NNRTI or PI drug initiated). In the PI-based group, 49% of children received lopinavir/ritonavir and 48% received nelfinavir; in the NNRTI-based group, 61% of children received efavirenz and 38% received nevirapine. Efavirenz was recommended only for children aged >3 years. 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 cART regimen. In both groups, 82% of children had viral loads <400 copies/mL, suggesting that selection of a NNRTI or a PI did not influence outcome. Although the age of participants overlapped somewhat between P1060 and PENPACT-1 (in PENPACT-1, the lowest quartile was aged <2.8 years), PENPACT-1 generally enrolled older children.3

Data from PROMOTE-pediatrics trial also demonstrated comparable virologic efficacy among children randomized to receive either a NNRTI or lopinavir/ritonavir-based cART.4 Children were aged 2 months to <6 years, with a median of 3.1 years (intermediate between P1060 and PENPACT 1). Children had no perinatal exposure to nevirapine and could be cART-naive or currently receiving cART with HIV RNA level <400 copies/mL at enrollment. In the NNRTI arm, children aged <3 years received nevirapine and those aged >3 years primarily received efavirenz. Among 185 children randomized to lopinavir/ritonavir- (n = 91) or NNRTI- (n = 92) based cART, the proportion with HIV RNA level <400 copies/mL at 48 weeks was 80% in the lopinavir/ritonavir arm versus 76% in the NNRTI-arm, a difference of 4% (95% CI: -9% to +17%).

With regard to virologic suppression, the results of the P1060 study suggest that a PI-based regimen containing lopinavir/ritonavir should be the preferred initial regimen for children aged <3 years. However, in both single-dose nevirapine-exposed and nevirapine-unexposed children in the P1060 study, participants receiving the nevirapine-based regimen demonstrated better immunologic response and growth than those receiving a lopinavir/ritonavir-based regimen, although these differences did not achieve statistical significance. Similarly, in the NEVEREST study, children switched to a nevirapine regimen showed better immune and growth responses than those continuing a lopinavir/ritonavir regimen.5 Based on these findings, the potential for improved lipid profiles with nevirapine use,5,6 and the poor palatability of liquid lopinavir/ritonavir, liquid nevirapine remains an acceptable alternative for infants who were not exposed to peripartum single-dose nevirapine or infant nevirapine prophylaxis and who cannot tolerate lopinavir/ritonavir. In children aged ≥3 years, either a NNRTI-based or a PI-based regimen is acceptable.

Non-Nucleoside Reverse Transcriptase Inhibitor-Based Regimens (One Non-Nucleoside Reverse Transcriptase Inhibitor plus Two-Nucleoside Reverse Transcriptase Inhibitor Backbone)

Summary: Non-Nucleoside Reverse Transcriptase Inhibitor-Based Regimens

Efavirenz (aged ≥3 months), etravirine (aged ≥6 years) and nevirapine (aged ≥15 days) have an FDA-approved pediatric indication for treatment of HIV infection. In the United States, nevirapine is the only NNRTI available in a liquid formulation. Efavirenz capsules can be opened and sprinkled on age-appropriate food. This administration procedure has been approved by the FDA for use in children as young as age 3 months who weigh at least 3.5 kg. However, at this time, there are concerns regarding variable PK of the drug in the very young and the committee does not currently endorse its use for infants and children aged 3 months to 3 years at this time. Additional data about the PK in children in this age group are awaited. Advantages and disadvantages of different NNRTI drugs are delineated in Table 9. Use of NNRTIs as initial therapy preserves the PI class for future use and confers lower risk of dyslipidemia and fat maldistribution than use of some agents in the PI class. In addition, for children taking solid formulations, NNRTI-based regimens generally have a lower pill burden than PI-based regimens. The major disadvantages of the current NNRTI drugs FDA-approved for use in children are that a single viral mutation can confer high-level drug resistance to nevirapine and efavirenz, 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 HIV-infected adults. Like PIs, 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.

Efavirenz, in combination with two NRTIs, is the preferred NNRTI for initial therapy of children aged ≥3 years based on clinical trial experience in adults and children. Nevirapine is considered as a component of an alternative NNRTI-based regimen because of its association with the rare occurrence of significant hypersensitivity reactions (HSRs), including Stevens-Johnson syndrome, rare but potentially life-threatening hepatitis,7,8 and conflicting data about virologic efficacy compared to preferred regimens.

Currently, data are insufficient to recommend etravirine or rilpivirine-based regimens as initial therapy in children. Etravirine is licensed for management of treatment-experienced adults and children aged ≥6 years and rilpivirine is licensed only for adults.

Preferred Non-Nucleoside Reverse Transcriptase Inhibitors

Efavirenz as Preferred Non-Nucleoside Reverse Transcriptase Inhibitor (For Children Aged ≥3 Years) (AI*)

In clinical trials in HIV-infected adults, efavirenz in combination with two NRTIs has been associated with excellent virologic response. Efavirenz-based regimens have proven virologically superior or non-inferior to a variety of regimens including those containing lopinavir/ritonavir, nevirapine, rilpivirine, atazanavir, elvitegravir, raltegravir, and maraviroc.9-16

Efavirenz in combination with two NRTIs or with a NRTI and a PI has been studied in HIV-infected children17-23 with results comparable to those seen in adults. For children aged ≥3 years who are unable to swallow pills, efavirenz capsules can be opened and sprinkled on age-appropriate food. Bioequivalence data based on bioavailability and PK support this option.24

The major limitations of efavirenz are central nervous system (CNS) side effects in both children and adults; reported adverse effects include fatigue, poor sleeping patterns, vivid dreams, poor concentration, agitation, depression, and suicidal ideation. Although in most patients this toxicity is transient, in some, the symptoms may persist or occur months after initiating efavirenz. In several studies, the incidence of such adverse effects was correlated with efavirenz plasma concentrations and the occurrence was more frequent in adults with higher levels of drug.25-28 The ENCORE1 study in adults has demonstrated that a dose of 400 mg of efavirenz is associated with fewer adverse events but non-inferior virologic response when compared with the recommended 600-mg dose of efavirenz in adults.29 In patients with pre-existing psychiatric conditions, efavirenz should be used cautiously for initial therapy. Rash may also occur with efavirenz treatment; it is generally mild and transient but appears to be more common in children than adults.21,23 In addition, first-trimester exposure to efavirenz is potentially teratogenic (see Appendix A: Pediatric Antiretroviral Drug Information for detailed information). Although emerging information about the use of efavirenz in pregnancy is reassuring,30-33 alternative regimens that do not include efavirenz should be strongly considered in adolescent females who are trying to conceive or who are not using effective and consistent contraception, because of the potential for teratogenicity with first-trimester efavirenz exposure, assuming these alternative regimens are acceptable to the provider and will not compromise the woman’s health (BIII).

Alternative Non-Nucleoside Reverse Transcriptase Inhibitors

Nevirapine as Alternative Non-Nucleoside Reverse Transcriptase Inhibitor (AI)

Nevirapine has extensive clinical and safety experience in HIV-infected children and has shown ARV efficacy in a variety of combination regimens (see Appendix A: Pediatric Antiretroviral Drug Information for detailed information).34 Nevirapine in combination with two NRTIs or with a NRTI and a PI has been studied in HIV-infected children.1-4,35-37

Randomized clinical trials in adults have not demonstrated virologic inferiority for a nevirapine-based regimen compared to either efavirenz or atazanavir-based regimens.38,39

Randomized clinical trials in children have demonstrated conflicting results. In the P1060 trial of children aged <3 years, a nevirapine-based regimen was less effective compared to a lopinavir/ritonavir regimen, regardless of prior history of maternal nevirapine exposure.1,2 In PENPACT-1 and PROMOTE-pediatrics, there was no difference in virologic suppression between NNRTI-based and PI-based regimens (see Choice of NNRTI- Versus PI- Based Initial Regimens). However, interpretation of these studies is complicated by the fact that the children in P1060 were younger than those in PROMOTE-pediatrics and PENPACT-1. Furthermore, efavirenz was allowed in PROMOTE-pediatrics and PENPACT-1 and was preferentially prescribed to older children. Comparisons of a nevirapine-based regimen and an efavirenz-based regimen in children in non-randomized studies have suggested that efavirenz is more effective but it is usually used in older children.40-42

In addition to concerns about virologic efficacy, adult randomized clinical trials have demonstrated higher rates of toxicity and drug discontinuation in the nevirapine arms.38,39 Data in adults indicate that symptomatic hepatic toxicity is more frequent in individuals with higher CD4 cell counts and in women, particularly women with CD4 cell counts >250 cells/mm3 and men with CD4 cell counts >400 cells/mm3. In the published literature, hepatic toxicity appears to be less frequent in children receiving chronic nevirapine therapy than in adults.36,37,43,44 Although there is limited evidence in children of hepatic toxicity associated with CD4 cell count, overall toxicity has been reported to be more frequent among children with CD4 percentage ≥15% at therapy initiation.45 The safety of substituting efavirenz for nevirapine in patients who have experienced nevirapine-associated hepatic toxicity is unknown. Efavirenz use in this situation has been well tolerated in the very limited number of patients in whom it has been reported, but this substitution should be attempted with caution.46

Nevirapine-based regimens are considered an alternative rather than the preferred NNRTI in children aged ≥3 years because of the greater potential for toxicity and possibly increased risk of virologic failure. In children aged <3 years, nevirapine is considered an alternative because of increased risk of virologic failure compared to a PI lopinavir/ritonavir regimen.

Nevirapine should not be used as part of an initial therapy regimen in postpubertal adolescent girls with CD4 cell counts >250/mm3 because of the increased risk of symptomatic hepatic toxicity, unless the benefit clearly outweighs the risk.8 Nevirapine also should be used with caution in children with elevated pretreatment liver function tests.

Protease Inhibitor-Based Regimens (Protease Inhibitors [Boosted or Unboosted] plus Two-Nucleoside Reverse Transcriptase Inhibitor Backbone)

Summary: Protease Inhibitor-Based Regimens

Advantages of PI-based regimens include excellent virologic potency, high barrier for development of drug resistance (requires multiple mutations), and sparing of the NNRTI drug class. 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 9 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 (CYP3A4) 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 lopinavir/ritonavir is available as a co-formulated product. When ritonavir is used as a PI booster with other PIs, two agents must be administered. In addition, the use of low-dose ritonavir increases the potential for hyperlipidemia47 and drug-drug interactions.

The Panel recommends either atazanavir with low-dose ritonavir or co-formulated lopinavir/ritonavir as the preferred PI for initial therapy in children based on virologic potency in adult and pediatric studies, high barrier to development of drug resistance, excellent toxicity profile in adults and children, availability of appropriate dosing information, and experience as initial therapy in both resource-rich and resource-limited areas. Darunavir/ritonavir is considered an alternative PI regimen. Several regimens including unboosted atazanavir in adolescents aged ≥13 years, fosamprenavir/ritonavir in children aged ≥6 months, and nelfinavir are considered appropriate for use in special circumstances when preferred and alternative drugs are not available or are not tolerated.

Preferred Protease Inhibitors

Atazanavir with Low-Dose Ritonavir as Preferred Protease Inhibitor (for Children ≥6 Years) (AI*)

Atazanavir is a once-daily PI that was approved by the FDA in March 2008 for use in children aged ≥6 years. Approval was extended in 2014 for use in infants and children aged ≥3 months and weighing ≥10 kg. It has efficacy equivalent to efavirenz-based and lopinavir/ritonavir-based combination therapy when given in combination with two NRTIs in treatment-naive adults.9,48-50 Seventy-three percent of 48 treatment-naive South African children achieved viral load <400 copies/mL by 48 weeks when given atazanavir with or without low-dose ritonavir in combination with 2 NRTIs.51 Among 43 treatment-naive children aged 6 to 18 years in IMPAACT/PACTG P1020A who received the capsule formulation of atazanavir with or without ritonavir, 51% and 47% achieved viral load <400 copies/mL and <50 copies/mL, respectively, by 96 weeks.52,53 When given with low-dose ritonavir boosting, atazanavir achieves enhanced concentrations compared with the unboosted drug in adults and children aged ≥6 years54-56 and in ARV-naive adults, appears to be associated with fewer PI-resistance mutations at virologic failure compared with atazanavir given without ritonavir boosting.57,58 The main adverse effect associated with atazanavir/ritonavir is indirect hyperbilirubinemia, with or without jaundice or scleral icterus, but without concomitant hepatic transaminase elevations. Although atazanavir is associated with fewer lipid abnormalities than other PIs, lipid levels are higher with low-dose ritonavir boosting than with atazanavir alone.47 Although atazanavir with low-dose ritonavir is approved for use in infants as young as 3 months, the Panel does not endorse usage as a preferred regimen in infants and children younger than 6 years due to lack of experience and concern about efficacy. Efficacy studies of atazanavir are ongoing in infants and children aged <6 years.

Lopinavir with Low-Dose Ritonavir as Preferred Protease Inhibitor (for Infants with a Postmenstrual Aged ≥42 Weeks and Postnatal Age ≥14 Days) (AI)

In clinical trials of treatment-naive adults, regimens containing lopinavir/ritonavir plus 2 NRTIs have been demonstrated to be comparable to a variety of other regimens including atazanavir, darunavir (at 48 weeks), fosamprenavir, saquinavir/ritonavir, and efavirenz. Lopinavir/ritonavir was demonstrated to have superior virologic activity when compared to nelfinavir.11,48,50,59-64 Lopinavir/ritonavir has been studied in both ARV-naive and ARV-experienced children and has demonstrated durable virologic activity and low toxicity (see Appendix A: Pediatric Antiretroviral Drug Information for detailed information).1,65-71 In addition, dosing and efficacy data in infants as young as age 25 days are available.68,72 Post-marketing reports of lopinavir/ritonavir-associated cardiac toxicity (including complete atrioventricular block, bradycardia, and cardiomyopathy), lactic acidosis, acute renal failure, CNS depression, and respiratory complications leading to death have been reported, predominantly in preterm neonates. These reports have resulted in a change in lopinavir/ritonavir labeling including a recommendation to not administer the combination to neonates until they reach 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 of at least 14 days. In addition, although once-daily lopinavir/ritonavir is FDA-approved for initial therapy in adults,73 PK data in children do not support a recommendation for once-daily dosing in children.74,75 A recent study of 173 virologically suppressed children (median age 11 years) on twice-daily lopinavir/ritonavir were randomized to continue twice daily dosing or change to once-daily dosing. At 48 weeks, non-inferiority for viral load suppression was not demonstrated and lopinavir drug exposure was lower among participants with once-daily dosing. These results suggest that lopinavir/ritonavir should only be administered twice daily in children.76

Alternative Protease Inhibitors

Atazanavir with Low-Dose Ritonavir as Alternative Protease Inhibitor (for Children ≥3 Months and <6 Years Who Weigh >10 kg) (AI*)

Atazanavir in a powder formulation to be administered once daily with liquid low-dose ritonavir was approved by the FDA in 2014 for use in infants and children aged ≥3 months and weighing ≥10 kg based on findings of two open-label clinical trials, PRINCE I and PRINCE II.58 Sixty-five infants and children weighing between 10 and 25 kg were studied. Using a weight band approach for determining dose, PK targets were met. The drug was well tolerated and among 41 naive infants and children, 27 (66%) achieved HIV RNA levels <50 copies at week 48. Because of the limited experience with this agent in younger children, the Panel recommends atazanavir with low-dose ritonavir as alternative PI therapy in infants and children aged >3 months and weighing between 10 and 25 kg.

Darunavir with Low-Dose Ritonavir Administered Once Daily as Alternative Protease Inhibitor (for Children Aged ≥12 Years) or Twice Daily (for Children Aged ≥3 to 12 Years) (AI*)

Darunavir combined with low-dose ritonavir is FDA-approved for ARV-naive and -experienced adults and for ARV-naive and -experienced children aged ≥3 years. In a randomized, open-label trial in adults, darunavir/ritonavir (800/100 mg once daily) was found to be non-inferior to lopinavir/ritonavir (once or twice daily) when both boosted PIs were administered in combination with tenofovir disoproxil fumarate (tenofovir)/emtricitabine. Adverse events were also less common in the darunavir/ritonavir group (P < 0.01).59,77 Unfortunately, there is limited information about the use of darunavir combined with low-dose ritonavir as part of an initial therapy regimen for HIV-infected children. To date the only clinical trial of darunavir with low-dose ritonavir as initial therapy is a study of once-daily darunavir/ritonavir in treatment-naive adolescents aged 12 to 18 years (mean age, 14.6 years). After 24 weeks of treatment, 11 of 12 subjects had HIV-1 RNA <50 copies/mL and the agents were well tolerated.78,79

Data in treatment-experienced children have also demonstrated that the regimen is effective and well-tolerated. In a study of treatment-experienced children (aged 6–17 years), DELPHI, twice-daily darunavir/ritonavir-based therapy was well tolerated and 48% of the children achieved HIV-1 RNA <50 copies/mL by 48 weeks.80 In another study of treatment-experienced pediatric participants (aged 3 to <6 years and weight ≥10 kg to <20 kg), ARIEL, 57% of subjects had HIV-1 RNA <50 copies/mL and 81% were less than 400 copies/mL after 24 weeks of treatment.81 Twenty children completed the trial; 1 stopped prematurely because of vomiting. Based on data from these studies and the findings of high potency and low toxicity in adults, darunavir/ritonavir is recommended as an alternative agent for initial therapy in HIV-infected children. Some experts, however, would only recommend darunavir/ritonavir for treatment-experienced children and reserve its use for patients with resistant mutations to other PIs.

As noted above, darunavir/ritonavir is approved for once-daily use in adults and children. In addition to the DELPHI study noted above, a PK study of 24 patients, aged 14 to 23 years receiving once-daily darunavir, demonstrated darunavir exposure similar to that in adults receiving once-daily therapy—although there was a trend toward lower exposures in those aged <18 years.82 Also, in the ARIEL study, 10 treatment-experienced children were switched from twice-daily dosing to once-daily dosing after 24 weeks of therapy. PK studies were performed after 2 weeks of once-daily dosing and demonstrated darunavir mean area under the curve 24-hour equivalent to 128% of the adult AUC 24 hour.83 Based on these findings, the FDA has approved use of once-daily darunavir in children. At this time, the Panel recommends that once-daily dosing of darunavir/ritonavir as alternative initial therapy be considered only in treatment-naive adolescents aged >12 years. Additional experience with once-daily dosing of darunavir/ritonavir in children aged ≥3 years through age 12 years is awaited. Also, if darunavir resistance-associated substitutions are present (V11I, V32I, L33F, I47V, I50V, I54L, I54M, T74P, L76V, I84V, and L89V), once-daily administration should not be used. If darunavir/ritonavir is used as alternative therapy in children aged <12 years or if any of these resistance-associated substitutions are present, the Panel recommends twice-daily dosing.

PIs for Use in Special Circumstances

Atazanavir without Ritonavir Boosting in Children Aged ≥13 Years (BII*)

Although unboosted atazanavir is FDA-approved for treatment-naive adolescents aged ≥13 years who weigh >39 kg and are unable to tolerate ritonavir, data from the IMPAACT/PACTG 1020A study indicate that higher doses of unboosted atazanavir (on a mg/m2 basis) are required in adolescents than in adults to achieve adequate drug concentrations56 (see Appendix A: Pediatric Antiretroviral Drug Information for detailed information on dosing used in IMPAACT/PACTG P1020A). If using unboosted atazanavir in treatment-naive patients, clinicians should consider using a dual-NRTI combination other than didanosine/emtricitabine because this combination demonstrated inferior virologic response in adults in ACTG 5175.84 Also, unboosted atazanavir should not be used in combination with tenofovir because concomitant administration results in lower atazanavir exposure. If didanosine, emtricitabine, and atazanavir are used in combination, patients should be instructed to take didanosine and atazanavir at least 2 hours apart, to take atazanavir with food, and to take didanosine on an empty stomach. The complexity of this regimen argues against its use.

Fosamprenavir with Low-Dose Ritonavir as Alternative Protease Inhibitor (for Children Aged ≥6 Months) (AI*)

Fosamprenavir (the prodrug of amprenavir) is available in a pediatric liquid formulation and a tablet formulation. In an adult clinical trial, fosamprenavir with low-dose ritonavir was demonstrated to be noninferior to lopinavir/ritonavir.61 In June 2007, fosamprenavir suspension was FDA-approved for use in pediatric patients aged ≥2 years. The approval was based on two open-label studies in pediatric patients aged 2 to18 years.85,86 PK, safety and efficacy were assessed in an international study of PI-naive and PI-experienced pediatric patients, aged 4 weeks to 2 years.87,88 Overall, fosamprenavir was well tolerated except for vomiting and effective in suppressing viral load and increasing CD4 cell count (see Appendix A: Pediatric Antiretroviral Drug Information for detailed information). These data supported FDA approval for use in PI-naive children as young as 4 weeks who were born at ≥38 weeks’ gestation and had attained a postnatal age of 28 days. Young infants, however, demonstrated low drug exposure. Fosamprenavir should always be used in combination with low-dose ritonavir boosting and only for children aged ≥6 months. Once-daily dosing of fosamprenavir is not recommended for pediatric patients.

Nelfinavir for Children Aged ≥2 Years (BI*)

Nelfinavir in combination with 2 NRTIs is an acceptable PI choice for initial treatment of children aged ≥2 years in special circumstances. The pediatric experience with nelfinavir-based regimens in ARV-naive and ARV-experienced children is extensive, with follow-up in children receiving the regimen for as long as 7 years.89 The drug has been well tolerated; diarrhea is the primary adverse effect. However, in clinical studies the virologic potency of nelfinavir has varied greatly, with reported rates of virologic suppression ranging from 26% to 69% (see Appendix A: Pediatric Antiretroviral Drug Information for detailed information). Several studies have shown a correlation between nelfinavir trough concentrations and virologic response in treatment-naive pediatric patients.90 In one such study, virologic response at Week 48 was observed in 29% of children with subtherapeutic nelfinavir troughs (<0.8 mg/L) versus 80% of children with therapeutic nelfinavir troughs (>0.8 mg/L).90 The interpatient variability in plasma concentrations is great in children, with lower levels in younger children.91-96 The optimal dose of nelfinavir in younger children, particularly in those aged <2 years, has not been well defined. These data, combined with data in adults showing inferior potency of nelfinavir compared with other PIs and efavirenz, balanced against the advantage of a PI that is not coadministered with low-dose ritonavir for boosting,64,97-100 make nelfinavir an agent for use in special circumstances in treatment-naive children aged ≥2 years and not recommended for treatment of children aged <2 years.

Nelfinavir is currently available only as tablets, which can be dissolved in water or other liquids to make a slurry that is then ingested by children unable to swallow whole tablets. Dissolving nelfinavir tablets in water and swallowing whole tablets resulted in comparable PK parameters in a study in adults.101

Integrase Strand Transfer Inhibitor-Based Regimens (Integrase Strand Transfer Inhibitors plus Two-Nucleoside Reverse Transcritase Inhibitor Backbone)

Summary: Integrase Strand Transfer Inhibitor-Based Regimens

Alternative Integrase Strand Transfer Inhibitors

Raltegravir is FDA-approved for treatment of HIV-infected 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. Raltegravir has a favorable safety profile and lacks significant drug interactions. The Panel considers raltegravir an alternative INSTI in children aged ≥2 years who are able to take either the chewable or film-coated tablets. The tablet formulations are not interchangeable (they are not bio-equivalent), and therefore, require different dosing. Safety and efficacy data are promising, but at this time, there are little data on raltegravir use as initial therapy in HIV-infected infants and children.102-104

Dolutegravir has recently been approved by the FDA for use in children aged ≥12 years and weighing ≥40 kg. The approval was supported by data from a study of 23 treatment-experienced but INSTI-naive children and adolescents.105 The drug has a very favorable safety profile and can be dosed once daily in treatment of INSTI-naive patients.

Integrase Strand Transfer Inhibitors for Use in Special Circumstances

Raltegravir can be considered for use in special circumstances in infants and children aged 4 weeks to 2 years. At this time, there is limited information about the use of single packets of granules for oral suspension in children aged <2 years. For this group of children, raltegravir granules may be considered as initial therapy in special circumstances.102-104

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

Summary: Selection of Dual-Nucleoside Reverse Transcriptase Inhibitor Backbone Regimen

Dual-NRTI combinations form the backbone of combination regimens for both adults and children. Currently, 7 NRTIs (zidovudine, didanosine, lamivudine, stavudine, abacavir, emtricitabine, and tenofovir) 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; and tenofovir in combination with lamivudine or emtricitabine.19,54,89,95,106-114 Advantages and disadvantages of different dual-NRTI backbone options are delineated in Table 9.

In the dual-NRTI regimens listed below, lamivudine and emtricitabine are interchangeable. Both lamivudine and emtricitabine are well tolerated with few adverse effects. 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 tenofovir 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 tenofovir based on decreased viral fitness.115,116

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

Abacavir in Combination with Lamivudine or Emtricitabine (for Children ≥ 3 Months) (AI)

Abacavir in combination with lamivudine has been shown to be as potent as or possibly more potent than zidovudine in combination with lamivudine in both children and adults.117,118 In 5 years of follow-up, abacavir plus lamivudine maintained significantly better viral suppression and growth in children than did zidovudine plus lamivudine and zidovudine plus abacavir.118 However, retrospective observational data from African children aged <16 years suggests the possibility of worse virologic outcome with abacavir/lamivudine based first-line cART when compared to the stavudine/lamivudine-based first-line cART.119,120 Multiple confounders could have contributed to these findings and further data collection and evaluation is warranted. Additionally, abacavir/lamivudine or emtricitabine has the potential for abacavir-associated life-threatening HSRs in a small proportion of patients. Abacavir hypersensitivity is more common in individuals with certain HLA genotypes, particularly HLA-B*5701 (see Appendix A: Pediatric Antiretroviral Drug Information); however, in the United States, the prevalence of HLA-B*5701 is much lower in African Americans and Hispanics (2% to 2.5%) than in whites (8%).121 Prevalence in Thai and Cambodian children is approximately 4%.122 Pretreatment screening for HLA-B*5701 before initiation of abacavir treatment resulted in a significant reduction in the rate of abacavir HSRs in HIV-infected adults (from 7.8% to 3.4%).123 Before initiating abacavir-based therapy in HIV-infected children, genetic screening for HLA-B*5701 should be performed and children who test positive for HLA-B*5701 should not receive abacavir (AII*).

An advantage of an abacavir regimen is the potential to switch to once-daily dosing in children with undetectable plasma RNA after approximately 24 weeks of therapy. Three small studies have now demonstrated equivalent drug exposure following a change from a twice-daily to a once-daily dosing regimen in children aged ≥3 months who had undetectable or low, stable plasma RNA after a variable period of twice-daily abacavir dosing. Two of the three demonstrated continued virologic suppression and one did not assess viral suppression.124-127 Recently, the ARROW trial reported findings from 669 HIV-infected children who had been receiving abacavir and lamivudine twice daily for 36 weeks and were randomized to either continue twice-daily dosing or change to once-daily dosing. At 48 weeks, once-daily abacavir was non-inferior to twice-daily dosing in terms of viral suppression;128 therefore, the Panel suggests that in clinically stable patients with undetectable plasma RNA and stable CD4 cell counts for more than 6 months, switching from twice-daily to once-daily dosing of abacavir is recommended as part of a once-daily regimen.

Tenofovir in Combination with Lamivudine or Emtricitabine (for Adolescents, Tanner Stage 4 or 5) (AI*)

Tenofovir is FDA-approved for use in children and adolescents aged ≥2 years. Because of decreases in bone mineral density (BMD) observed in adults and children receiving tenofovir, the Panel has opted to consider use of tenofovir based on Tanner stage. We have reserved our strongest recommendation in support of using tenofovir for adolescents who are in the late stages of or who have completed puberty (Tanner stages 4 and 5). Tenofovir can be used in younger children after weighing potential risks of decreased BMD versus benefits of therapy. In comparative clinical trials in adults, tenofovir when used with lamivudine or emtricitabine as a dual-NRTI backbone was superior to zidovudine used with lamivudine and efavirenz in viral efficacy.129,130 In ACTG 5202, adults who had a screening HIV-1 RNA ≥100,000 copies/mL receiving tenofovir/emtricitabine as part of a cART regimen had a longer time to virologic failure and to first adverse event compared to those assigned to abacavir/lamivudine.131 However, this has not been demonstrated in other comparative trials or in a meta-analysis.132,133 Tenofovir has been studied in HIV-infected children in combination with other NRTIs and as an oral sprinkle/granule formulation.109-112 The use of tenofovir in pediatric patients aged 2 years to <18 years is approved by the FDA based on data from 2 randomized studies. In study 321, 87 treatment-experienced subjects aged 12 to <18 years were randomized to receive tenofovir or placebo plus optimized background regimen for 48 weeks. Although there was no difference in virologic response between the two groups, the safety and PKs of tenofovir in children in the study were similar to those in adults receiving tenofovir.113 In study 352, ninety-two treatment-experienced children aged 2 years to <18 years with virologic suppression on stavudine- or zidovudine-containing regimens were randomized to either replace stavudine or zidovudine with tenofovir or to continue their original regimen. After 48 weeks, 89% of subjects receiving tenofovir and 90% of subjects continuing their original regimen had HIV-1 RNA concentrations <400 copies/mL.114 Tenofovir in combination with lamivudine or emtricitabine is a preferred dual-NRTI combination for use in adolescents Tanner Stage 4 or 5 (AI*). The fixed-dose combination of tenofovir and emtricitabine and the fixed-dose triple combination of tenofovir, emtricitabine, and efavirenz both allow for once-daily dosing, which may help improve adherence in older adolescents.

In some but not all studies, decreases in BMD have been observed in both adults and children taking tenofovir for 48 weeks.109-112,134,135 At this time, data are insufficient to recommend use of tenofovir as part of a preferred regimen for initial therapy in infected children in Tanner Stages 1 through 3, for whom the risk of bone toxicity may be greatest109,112 (see Appendix A: Pediatric Antiretroviral Drug Information for more detailed pediatric information). It is important to note that although decreases in BMD are observed, the clinical significance of these changes is not yet known. Renal toxicity has been reported in children receiving tenofovir.136-139 Given the potential for bone and renal toxicity, tenofovir may be more useful for treatment of children in whom other ARV drugs have failed than for initial therapy of treatment-naive younger children. Numerous drug-drug interactions with tenofovir and other ARV drugs, including didanosine, lopinavir/ritonavir, atazanavir, and tipranavir, complicate appropriate dosing of tenofovir.

Both emtricitabine and lamivudine, and tenofovir have antiviral activity and efficacy against hepatitis B virus (HBV). For a comprehensive review of this topic and interactions of ARV drugs with treatment for hepatitis C virus (HCV) and tuberculosis the reader should access the Pediatric Opportunistic Infections Guidelines.

Zidovudine in Combination with Lamivudine or Emtricitabine (For Children Aged <13 Years) (AI*)

The most extensive experience in children is with zidovudine in combination with lamivudine. Data on the safety of this combination in children are extensive and the combination is generally well tolerated.140 The major toxicities associated with zidovudine/lamivudine are bone marrow suppression, manifested as macrocytic anemia and neutropenia, and an association with lipoatrophy; minor toxicities include gastrointestinal toxicity and fatigue. In addition, the combination of zidovudine and lamivudine is acceptable in infants less than 3 months. Because zidovudine must be administered twice daily, use in adolescents (aged ≥13 years) is an alternative rather than a preferred agent.

Alternative Dual-Nucleoside Reverse Transcriptase Inhibitor Regimens

Alternative dual-NRTI combinations include zidovudine in combination with abacavir or didanosine (BII), didanosine in combination with lamivudine or emtricitabine (BI*), zidovudine with lamivudine or emtricitabine in adolescents (aged ≥13 years) (AI*), and tenofovir in combination with lamivudine or emtricitabine in children and adolescents who are Tanner Stage 3 (as opposed to Tanner Stages 4 and 5, where this is a preferred dual-NRTI regimen) (BI*). There is considerable experience with use of these dual-NRTI regimens in children, and in a large pediatric study, the combination of zidovudine and didanosine had the lowest rate of toxicities.140 However, zidovudine/abacavir and zidovudine/lamivudine had lower rates of viral suppression and more toxicity leading to drug modification than did abacavir/lamivudine in a European pediatric study.95,118 The combination of didanosine and emtricitabine allows for once-daily dosing. In a study of 37 treatment-naive children aged 3 to 21 years, long-term virologic suppression was achieved with a once-daily regimen of didanosine, emtricitabine, and efavirenz; 72% of subjects maintained HIV RNA suppression to <50 copies/mL through 96 weeks of therapy.19 Prescribing information for didanosine recommends administration on an empty stomach. However, this 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. A comparison of didanosine given with or without food in children found that systemic exposure was similar but with slower and more prolonged absorption with food.141 To improve adherence, some practitioners recommend administration of didanosine without regard to timing of meals for young children. However, data are inadequate to allow a strong recommendation at this time, and it is preferable to administer didanosine under fasting conditions when possible.

Dual-Nucleoside Reverse Transcriptase Inhibitor Backbone Regimens for Use in Special Circumstances

The dual-NRTI combinations of stavudine with lamivudine or emtricitabine in children of any age are recommended for use in special circumstances. Stavudine is recommended for use only in special circumstances because the ARV is associated with a higher risk of lipoatrophy and hyperlactatemia than other NRTI drugs.142-147 Children receiving dual-NRTI combinations containing stavudine had higher rates of clinical and laboratory toxicities than children receiving zidovudine-containing combinations.140 However, in a prospective study, 365 treatment-naive children were randomized to stavudine, zidovudine, or abacavir as part of a cART regimen. After 96 weeks, there were no differences in overall tolerability, CD4 change, or virologic response among the groups. There was no difference in skinfold z-scores among the groups, however, 2 children randomized to stavudine underwent a drug substitution due to lipodystrophy.148 In children with anemia in whom there are concerns related to abacavir hypersensitivity or who are too young to receive abacavir or tenofovir, stavudine may be preferable to zidovudine for initial therapy because of its lower incidence of hematologic toxicity.

In children aged ≥2 years and those who are prepubertal or in the early stages of puberty (Tanner Stages 1 and 2), tenofovir in combination with lamivudine or emtricitabine is also recommended for use in special circumstances. As discussed above, the use of tenofovir during puberty when bone toxicity may be greatest may require caution. However, tenofovir may be a reasonable choice for initial therapy in children with demonstrated resistance to other NRTIs, coinfection with hepatitis B virus, or in those desiring a once-daily NRTI where abacavir is not an option. The Panel awaits additional safety data, especially with the recently licensed powder formulation, before providing a broader recommendation in younger children.

Both emtricitabine and lamivudine, and tenofovir have antiviral activity and efficacy against hepatitis B. For a comprehensive review of this topic, and hepatitis C virus and tuberculosis during HIV coinfection the reader should access the Pediatric Opportunistic Infections Guidelines.

Table 8. Antiretroviral Regimens Recommended for Initial Therapy for HIV Infection in Children
 
A cART regimen in treatment-naive children generally contains one NNRTI plus a two-NRTI backbone or one PI (generally with low-dose ritonavir boosting) plus a two-NRTI backbone. Regimens should be individualized based on advantages and disadvantages of each combination (see Table 9).
Preferred Regimens
Children aged ≥14 days to <3 yearsa Two NRTIs plus LPV/r
Children aged ≥3 years to <6 years Two NRTIs plus EFVb
Two NRTIs plus LPV/r
Children aged ≥6 years Two NRTIs plus ATV plus low-dose RTV
Two NRTIs plus EFVb
Two NRTIs plus LPV/r
Alternative Regimens
Children aged >14 days Two NRTIs plus NVPc
Children ≥3 months to <6 years and weighing ≥10 kg Two NRTIs plus ATV plus low-dose RTV
Children ≥2 years Two NRTIs plus RALd
Children aged ≥3 years to <12 years Two NRTIs plus twice-daily DRV plus low-dose RTV
Children aged ≥12 years Two NRTIs plus once-daily DRV plus low-dose RTVe
 Children aged ≥12 years and weighing ≥ 40kg Two NRTIs plus DTG
Regimens for Use in Special Circumstances
Children aged ≥4 weeks and <2 years and weighing ≥3 kg Two NRTIs plus RALd
Children aged ≥6 months Two NRTIs plus FPVf plus low-dose RTV
Children aged ≥2 years Two NRTIs plus NFV
Children aged ≥12 years and weighing ≥40kg Two NRTIs plus DTG
Treatment-naive adolescents aged ≥13 years and weighing >39 kg Two NRTIs plus ATV unboosted
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 ≥13 years at Tanner Stage 3 ABC plus (3TC or FTC)
Adolescents at Tanner Stage 4 or 5 ABC plus (3TC or FTC)
TDF plus (3TC or FTC)
Alternative 2-NRTI Backbone Options for Use in Combination with Additional Drugs
Children aged ≥2 weeks ddI plus (3TC or FTC)
ZDV plus ddI
Children ≥3 months ZDV plus ABC
Children and adolescents at Tanner Stage 3 TDF plus (3TC or FTC)
Adolescents ≥13 years ZDV plus (3TC or FTC)
2-NRTI Regimens for Use in Special Circumstances in Combination with Additional Drugs
  • d4T plus (3TC or FTC)
  • TDF plus (3TC or FTC) (prepubertal children aged ≥2 years and adolescents, Tanner Stage 1 or 2)
a 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.
b 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. Unless adequate contraception can be ensured, EFV-based therapy is not recommended for adolescent females who are sexually active and may become pregnant.
c NVP should not be used in postpubertal 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.
d RAL pills or chewable tablets can be used in children aged ≥2 years as an alternate INSTI. Use of granules or chewable tablets in infants and children aged 4 weeks to 2 years can be considered in special circumstances.
e DRV once daily should 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).
f FPV with low-dose RTV should only be administered to infants born at ≥38 weeks’ gestation who have attained a postnatal age of 28 days and to infants born before 38 weeks’ gestation who have reached a postmenstrual age of 42 weeks.
Key to Acronyms: 3TC = lamivudine; ABC = abacavir; ARV = antirretroviral; ATV = atazanavir; cART = combination antiretroviral therapy; d4T = stavudine; ddI = didanosine; DRV = darunavir; DTG = dolutegravir; EFV = efavirenz; FPV = fosamprenavir; FTC = emtricitabine; INSTI = integrase strand transfer inhibitor; LPV/r = fixed dose formulation lopinavir/ritonavir; NFV = nelfinavir; NNRTI = non-nucleoside reverse transcriptase inhibitor; NRTI = nucleoside reverse transcriptase inhibitor; NVP = nevirapine; PI = protease inhibitor; RAL = raltegravir;  RTV = ritonavir; TDF = tenofovir; ZDV = zidovudine

Table 9. Advantages and Disadvantages of Antiretroviral Components Recommended for Initial Therapy in Children
ARV Class ARV Agent(s) Advantages Disadvantages 
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 nevirapine)
  • Potential for multiple drug interactions due to metabolism via hepatic enzymes (e.g., CYP3A4)
EFV
  • Potent ARV activity
  • Once-daily administration
  • Can give with food (but avoid high-fat meals).
  • Capsules can be opened and added to food.
  • Neuropsychiatric adverse effects (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
PIs
In Alphabetical Order

 
 
 
 
 
 
 

PI Class Advantages:

  • NNRTI-sparing
  • Clinical, virologic, and immunologic efficacy well documented.
  • Resistance to PIs requires multiple mutations.
  • When combined with dual NRTI backbone, targets HIV at two 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 low-dose 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).
  • No liquid formulation
  • Food effect (should be administered with food).
  • Indirect hyperbilirubinemia common but asymptomatic.
  • Must be used with caution in patients with pre-existing conduction system defects (can prolong PR interval of ECG).
  • RTV component associated with large number of drug interactions (see RTV).
ATV
  • Once-daily dosing
  • Powder formulation available
  • Less effect on TG and total cholesterol levels than other PIs.
  •  No liquid formulation
  • Food effect (should be administered with food)
  • Indirect hyperbilirubinemia common but asymptomatic
  • Must be used with caution in patients with pre-existing conduction system defects (can prolong PR interval of ECG).
  • May require RTV boosting in treatment-naive adolescents to achieve adequate plasma concentrations.
  • Unboosted ATV cannot be used with TDF.
DRV/r
  • Effective in PI-experienced children when given with low-dose RTV boosting.
  • Can be used once daily in children aged ≥12 years.
  • Liquid formulation available
  • Pediatric pill burden high with current tablet dose formulations.
  • Food effect (should be given 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 (see RTV).
  • Can only be used once daily in absence of certain PI-associated resistance mutations.
FPV/r
  • Oral prodrug of APV with lower pill burden
  • Pediatric formulation available, which should be given to children with food.
  • Skin rash
  • More limited pediatric experience than preferred PI
  • Must be given with food to children.
  • RTV component associated with large number of drug interactions (see RTV).
  • Contains sulfa moiety. Potential for cross-sensitivity between FPV and other drugs in sulfonamide class is unknown.
  • Should only be administered to infants born at ≥38 weeks’ gestation and who have attained a postnatal age of 28 days.
LPV/r
  • LPV only available co-formulated 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 (see RTV).
  • 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 pre-existing conduction system defects (can prolong PR and QT interval of ECG).
NFV
  • Can give with food.
  • Simplified 2-tablet (625 mg) twice-daily regimen has a reduced pill burden compared with other PI-containing regimens in older patients where the adult dose is appropriate.
  • Diarrhea
  • Food effect (should be administered with food).
  • Appropriate dosage for younger children not well defined.
  • Adolescents may require higher doses than adults.
  • Less potent than boosted PIs.
INSTI
 
 
 

Integrase Inhibitor Class Advantages:

  • Susceptibility of HIV to a new class of ARVs

Integrase Inhibitor Class Disadvantages:

  • Limited data on pediatric dosing or safety
DTG
  • Once-daily administration
  • Can give with food.
  • Limited data on pediatric dosing or safety.
  • Drug interactions with EFV, FPV/r, TPV/r, and rifampin necessitating twice daily dosing.
RAL
  • Susceptibility of HIV to a new class of ARVs.
  • Can give with food.
  • Available in a chewable tablet and powder formulation
  • Limited data on pediatric dosing or safety.
  • Potential for rare systemic allergic reaction or hepatitis
Dual-NRTI Backbones
In Alphabetical Order

 
 
 
 
 
 
ABC plus (3TC or FTC)
  • Palatable liquid formulations
  • Can give with food.
  • ABC and 3TC are co-formulated as a single pill for older/larger patients; ABC, 3TC are also co-formulated with DTG for use in adults.
  • Risk of ABC HSR; perform HLA-B*5701 screening before initiation of ABC treatment.
d4T plus (3TC or FTC)
  • Extensive pediatric experience
  • Palatable liquid formulations
  • Can give with food.
  • FTC is available as a palatable liquid formulation administered once daily.
  • d4T associated with higher incidence of hyperlactatemia/lactic acidosis, lipoatrophy, peripheral neuropathy, hyperlipidemia.
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.
TDF plus (3TC or FTC) for adolescents, Tanner Stage 4 or 5
  • Resistance slow to develop.
  • Once-daily dosing for TDF
  • Less mitochondrial toxicity than other NRTIs
  • Can give with food.
  • TDF and FTC are co-formulated as single pill for older/larger patients.
  • Available as reduced-strength tablets and oral powder for use in younger children.
  • Limited pediatric experience
  • Potential bone and renal toxicity, may be less in postpubertal 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 co-formulated 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.
ZDV plus ddI
  • Extensive pediatric experience
  • Delayed-release capsules of ddI may allow once-daily 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 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 for more information.
Key to Acronyms: 3TC = lamivudine; ABC = abacavir; ARV = antiretroviral; ATV = atazanavir; ATV/r = atazanavir/ritonavir; BSA = body surface area; CNS = central nervous system; d4T = stavudine; DRV/r = darunavir/ritonavir; ddI = didanosine; DTG = dolutegravir; ECG = electrocardiogram; EFV = efavirenz; FPV/r = fosamprenavir/ritonavir; FTC = emtricitabine; HSR = hypersensitivity reaction; INSTI = integrase strand transfer inhibitor; LPV/r = lopinavir/ritonavir; NFV=nelfinavir; NNRTI = non-nucleoside reverse transcriptase inhibitor; NRTI = nucleoside reverse transcriptase inhibitor; NVP = nevirapine; PI = protease inhibitor; PK = pharmacokinetic; RAL = raltegravir; RTV = ritonavir; SJS = Stevens-Johnson Syndrome; TDF = tenofovir; TG = triglycerides; ZDV = zidovudine

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