Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection

Nucleoside and Nucleotide Analogue Reverse Transcriptase Inhibitors (NRTIs)

Drug Interactions

Additional information about drug interactions is available in the Adult and Adolescent Antiretroviral Guidelines and the HIV Drug Interaction Checker.

• Metabolism: Tenofovir alafenamide (TAF) is a substrate of the adenosine triphosphate-dependent transporters P-glycoprotein (P-gp) and the breast cancer resistance protein (BCRP). Drugs that strongly affect P-gp and BCRP activity may lead to changes in TAF absorption. P-gp inducers are expected to decrease TAF exposure, and P-gp inhibitors are expected to increase absorption and plasma concentrations of TAF.² A study of 98 healthy participants without HIV measured plasma TAF and tenofovir (TFV) exposures when TAF was administered with other antiretroviral (ARV) drugs. Coadministration of TAF with rilpivirine (RPV) and dolutegravir (DTG) did not change either TAF or TFV exposure. Coadministration of TAF with the P-gp and BCRP inhibitor cobicistat (COBI), or coadministration with atazanavir/ritonavir (ATV/r) or lopinavir/ritonavir (LPV/r), increased both TAF and TFV exposures. Coadministration of TAF with darunavir/ritonavir (DRV/r) resulted in unchanged TAF area under the curve (AUC) and doubled TFV AUC. Coadministration of TAF with the P-gp and BCRP inducer efavirenz decreased TAF and TFV exposures.⁴
• Coadministration of TAF with rifamycins (rifabutin, rifampin, or rifapentine) is not recommended.^3,5
• Genvoya contains elvitegravir (EVG) and COBI, in addition to TAF (see the Elvitegravir and Cobicistat sections for details). EVG is metabolized predominantly by cytochrome P450 (CYP) 3A4, secondarily by uridine diphosphate glucuronosyltransferase 1A1/3, and by oxidative metabolism pathways. EVG is a modest inducer of CYP2C9. COBI is an inhibitor of CYP3A4 and a weak inhibitor of CYP2D6; in addition, COBI inhibits the adenosine triphosphate-dependent transporters BCRP and P-gp and the organic anion-transporting polypeptides OAT1B1 and OAT1B3. Potential exists for multiple drug interactions when using both EVG and COBI.
• Absorption: Administering EVG and bictegravir (BIC) concurrently with antacids or supplements that contain iron, calcium, aluminum and/or magnesium lowers plasma concentrations of these ARV drugs (see the Elvitegravir and Bictegravir sections for details).
• Odefsey contains RPV, which is a CYP3A substrate, and requires dose adjustments when administered with CYP3A-modulating medications.
• Before Genvoya, Odefsey, Descovy, Biktarvy, or Symtuza is administered, a patient’s medication profile should be carefully reviewed for potential drug interactions.
• Renal elimination: Drugs that decrease renal function or compete for active tubular secretion (e.g., acyclovir, ganciclovir, high-dose nonsteroidal anti-inflammatory drugs) could reduce clearance of the TAF metabolite TFV or emtricitabine (FTC). Concomitant use of nephrotoxic drugs should be avoided when using Genvoya.
• Protease inhibitors: Genvoya should not be administered concurrently with products or regimens that contain ritonavir (RTV), because COBI and RTV have similar effects on CYP3A metabolism.

Major Toxicities

• More common: Nausea, diarrhea, headache. Greater weight gain has been reported with the use of TAF than with tenofovir disoproxil fumarate (TDF) in adults and children⁶ (see Table 17h. Lipodystrophies and Weight Gain for details).
• Less common (more severe): Cases of lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside reverse transcriptase inhibitors (NRTIs).

Resistance

The International Antiviral Society–USA maintains a list of updated HIV drug resistance mutations, and the Stanford University HIV Drug Resistance Database offers a discussion of each mutation.

Pediatric Use

Approval

TAF is available as a component of several fixed-dose combination (FDC) tablets. These FDC tablets are listed in Appendix A, Table 1. Antiretrovirals Available in Fixed-Dose Combination Tablets or as a Co-packaged Formulation, by Drug Class and Appendix A, Table 2. Antiretroviral Fixed-Dose Combination Tablets and Co-packaged Formulations: Minimum Body Weights and Considerations for Use in Children and Adolescents.

Descovy, an FDC tablet that contains FTC and TAF (FTC/TAF), is approved by the U.S. Food and Drug Administration (FDA) for use in children who weigh ≥14 kg to <25 kg at a dose of FTC 120 mg/TAF 15 mg and for children who weigh ≥25 kg to <35 kg at a dose of FTC 200 mg/TAF 25 mg when used as part of an ARV regimen that does not include a boosted protease inhibitor (PI). Descovy is approved by the FDA for use in children who weigh ≥35 kg at a dose of FTC 200 mg/TAF 25 mg when used in combination with any ARV drugs, including RTV-boosted or COBI-boosted PIs. Odefsey, an FDC tablet that contains FTC, RPV, and TAF (FTC/RPV/TAF), is approved by the FDA⁷ for use in children who weigh ≥35 kg. Genvoya, an FDC tablet that contains EVG, COBI, FTC, and TAF (EVG/c/FTC/TAF), is approved by the FDA for use in children who weigh ≥25 kg when used without other ARV drugs⁸ (see Table A below). BIC is available only as part of the FDC tablet Biktarvy, which contains BIC, FTC, and TAF (BIC/FTC/TAF). Biktarvy is approved by the FDA^9,10 for use in children or adolescents with body weight ≥14 kg to <25 kg at a dose of BIC 30 mg/FTC 120 mg/TAF 15 mg and for children, adolescents, and adults with body weight ≥25 kg at a dose of BIC 50 mg/FTC 200 mg/TAF 25 mg.^10,11 Symtuza, an FDC tablet that contains DRV, COBI, FTC, and TAF (DRV/c/FTC/TAF) is approved by the FDA¹² for use in children and adolescents who weigh ≥40 kg.

TAF has antiviral activity and efficacy against hepatitis B virus (HBV). Testing for HBV should be performed prior to starting treatment with TAF. If HBV is found, rebound of clinical hepatitis could occur when TAF is stopped. For more information about hepatitis rebound in patients with HBV/HIV coinfection, see the Hepatitis B Virus section of the Pediatric Opportunistic Infection Guidelines. TAF alone (as Vemlidy) is approved by the FDA for use in persons aged ≥8 years, but it is approved only for treating HBV, not HIV.

Formulations

TAF-containing pills are smaller than their TDF-containing counterparts, a significant advantage for some pediatric patients who may have trouble swallowing larger pills (see Appendix A, Table 2. Antiretroviral Fixed-Dose Combination Tablets and Co-packaged Formulations: Minimum Body Weights and Considerations for Use in Children and Adolescents). EVG/c/FTC/TAF contains TAF 10 mg, whereas FTC/TAF and FTC/RPV/TAF contain TAF 25 mg. BIC/FTC/TAF is available in two strengths: one containing TAF 15 mg for children aged ≥2 years and weighing <25 kg and the other containing TAF 25 mg for persons weighing ≥25 kg. COBI boosts TAF blood concentrations and tenofovir diphosphate (TFV-DP) intracellular exposure after TAF administration. Therefore, in persons weighing ≥25 kg, administration of EVG/c/FTC/TAF, which contains TAF 10 mg and COBI, achieves TFV-DP systemic exposure that is similar to the exposure achieved by FTC/RPV/TAF or BIC/FTC/TAF containing TAF 25 mg but no COBI.

Tenofovir Alafenamide Versus Tenofovir Disoproxil Fumarate

Both TDF and TAF are prodrugs of the NRTI TFV. After oral administration, TDF is well absorbed^13,14 and is so rapidly metabolized to TFV that TDF itself cannot be measured in blood (even when plasma is sampled within 5 minutes of administration).¹⁵ TFV is the main compound that is measurable in plasma after TDF administration. From the bloodstream, TFV enters cells and is phosphorylated to the active agent TFV-DP.

TAF also has good oral bioavailability.^16,17 Within the enterocyte and liver, TAF is not metabolized to TFV as quickly as TDF, so the plasma TFV concentration is much lower with administration of TAF than with TDF, and the main component in plasma is the prodrug itself, TAF.¹⁸ Once inside the cell, TAF is hydrolyzed to TFV,^19,20 and then TFV-DP is produced by the same mechanism as for TDF. Relative to TDF, TAF more effectively delivers TFV to cells throughout the body.¹⁶ Therefore, a much lower dose of TAF results in intracellular concentrations of TFV-DP that are higher than the concentrations seen after TDF administration (see Table B below). Additionally, the half-life of TFV-DP in peripheral blood mononuclear cells is longer for TAF (2.9 days, 95% confidence interval [CI], 1.5–5.5) than for TDF (2.1 days, 95% CI, 1.5–2.9).²¹

The key pharmacokinetic (PK) difference between TDF and TAF is that TDF results in higher plasma TFV concentrations than TAF, but when administered at FDA-approved doses, both drugs produce high, therapeutically effective intracellular TFV-DP concentrations.^18,22 Because it is intracellular TFV-DP that suppresses viral replication, TAF should have antiviral efficacy that is equivalent to the antiviral efficacy of TDF. However, the toxicities that are specifically related to high plasma TFV concentrations should not occur when using TAF. High plasma TFV concentration has been linked to TDF-related endocrine disruption that is associated with low bone mineral density (BMD).²³ High plasma TFV concentration also has been closely associated with both glomerular^23-25 and proximal tubular²⁶ renal toxicity.

Tenofovir Alafenamide Efficacy in Clinical Trials in Adults

In adults, TAF is noninferior to TDF in its ability to control viral load over 48 to 96 weeks when used in combination with EVG, COBI, and FTC^27-30; with FTC and RPV³¹; with DRV, COBI, and FTC^32-34; and when TAF and FTC are administered in combination with other ARV drugs.³⁵ In a switch study of adults who were virologically suppressed on a three-drug regimen that included abacavir (ABC), FTC/TAF was noninferior to a regimen of lamivudine plus ABC plus a third ARV drug over 48 weeks. No differences occurred in BMD or the frequency of renal glomerular toxicities or renal tubular toxicities between these groups, but the TAF group showed a decline in high-density lipoprotein (HDL) cholesterol levels, whereas the ABC group had an increase in HDL cholesterol levels³⁶ (−2 mg/dL vs. +2 mg/dL, respectively; P = 0.0003). Viral load suppression was attained in about 90% of study participants when TAF was given as part of the coformulated BIC/FTC/TAF.^37-39

Tenofovir Alafenamide Efficacy in Clinical Trials in Adolescents and Children

The combination of EVG, COBI, FTC, and TAF has been shown to have similar efficacy when used in adults and two groups of children: those weighing ≥35 kg and aged ≥12 years⁴⁰ and those weighing ≥25 kg and aged ≥6 years⁴¹ (see the Elvitegravir section for details). In a switch study, treatment with BIC/FTC/TAF resulted in viral load suppression at 48 weeks in 49 of 50 (98%) children aged 6 years to <12 years and in 50 of 50 (100%) children aged 12 years to <18 years⁹ (see the Bictegravir section for details).

Pharmacokinetics

Drug Exposure and Virologic Response

Virologic suppression in people who are taking TAF or TDF is most closely related to intracellular TFV‑DP concentrations. In adults, TAF generates peripheral blood mononuclear cell TFV-DP concentrations that are twofold²² to sevenfold higher than those generated with TDF at clinically meaningful doses.^18,21,27 Higher TFV-DP concentrations result in a stronger antiviral potency¹⁸ and a higher barrier to resistance.^42,43 Therefore, because TAF administration leads to higher intracellular TFV-DP concentrations than TDF, TAF may be more effective against NRTI-resistant virus than TDF. The mean TFV-DP concentration is higher in youth aged 12 to 18 years than in adults: 221.8fmol/million cells (with a coefficient of variation [CV] of 94.4%) versus 120.8 fmol/million cells (CV 91.4%), respectively.⁴⁰

Drug Exposure and Safety: All Age Groups

FTC/TAF can be safely combined with DTG or raltegravir without concern for drug interactions. FTC and TAF also have been safely combined with BIC in the FDC tablet Biktarvy.

When FTC/TAF, which contains TAF 25 mg, is combined with boosted ATV, DRV, or LPV, the P‑gp inhibitors COBI or RTV increase the TAF exposure to higher concentrations than those seen with the use of EVG/c/FTC/TAF, which contains TAF 10 mg. However, the plasma TFV concentrations seen with the use of EVG/c/FTC/TAF or TAF plus DRV/r or DRV/c are still much lower than those seen with the use of Stribild, an FDC tablet that contains EVG, COBI, FTC, and TDF (see Table C below).

The clinical trials in adults that have shown the safety of FTC plus TAF administered with ATV/r or DRV/r have used FTC 200 mg/TAF 10 mg, a formulation that is not available in the United States.⁴⁴ The FDA states that when FTC 200 mg/TAF 25 mg is combined with boosted ATV, DRV, or LPV in adults, “no clinically significant drug interactions have been observed or are expected.”² The combination of FTC 200 mg/TAF 25 mg is approved by the FDA for use in adults, independent of the accompanying ARV drugs (which may include a boosted PI or an integrase strand transfer inhibitor [INSTI]).² Moreover, in Trial GS-US-299-0102 (NCT01565850) a Phase 2b trial in adults that compared a regimen of DRV/c plus FTC/TAF 10 mg to a regimen of DRV/c plus FTC/TDF, virologic outcomes at Week 48 were worse for participants in the TAF 10-mg arm than in the TDF arm.⁴⁵ Hence, FTC/TAF 25 mg was recommended for approval instead of FTC/TAF 10 mg.⁴⁵ This is not the case in Canada or Europe where FTC is combined with TAF 10 mg in an FDC for use in combination with boosted PIs.

Drug Exposure and Safety: Aged 12 to 18 Years and Weighing ≥35 kg

A study of FTC/TAF in 18 children and adolescents (aged 12 years to 18 years and weighing ≥35 kg) was performed using FTC 200 mg/TAF 10 mg plus a boosted third ARV drug or FTC 200 mg/TAF 25 mg with an unboosted third ARV drug. The results of this study showed TAF exposures in children and adolescents that were like those seen in adults. TAF was well tolerated and efficacious during the 24 weeks of study. Asymptomatic Grade 3 or 4 elevations in amylase levels were noted in 5 of 28 participants (18%), and Grade 3 or 4 elevations in fasting low-density-lipoprotein (LDL) levels were noted in 2 of 28 participants (7%).⁴⁶

Studies of EVG/c/FTC/TAF in children aged 12 years to 18 years and weighing ≥35 kg showed that TAF and TFV exposures were like those found in adults (see Table C above), and that the drug combination was well tolerated and efficacious over 48 weeks of study.⁴⁰ Because these TAF and TFV exposures were similar to those seen in adults, FTC 200 mg/TAF 25 mg was also approved by the FDA for use in this age and weight group, independent of the accompanying ARV drugs in the regimen (which may include a boosted PI or an INSTI).²

The formulation of Biktarvy, which contains BIC 50 mg/FTC 200 mg/TAF 25 mg, was administered to 50 children aged 6 years to <12 years and weighing ≥25 kg and 50 children and adolescents aged 12 years to <18 years and weighing ≥35 kg who had had viral loads <50 copies/mL for at least 6 months. The drug was well tolerated. All 50 participants in the study⁹ had viral loads <50 copies/mL at Week 24, and 49 participants had viral loads <50 copies/mL at Week 48 (see the Bictegravir section for details).

Drug Exposure and Safety: Aged 6 Years to <12 Years and Weighing 25 kg to <35 kg

Studies of EVG/c/FTC/TAF in children aged 6 years to <12 years who weighed ≥25 kg showed that TAF and TFV exposures were somewhat higher than those found in adults (see Table C above), but the drug combination was well tolerated and efficacious over 24 weeks of study.^41,47 This led to FDA approval of EVG/c/FTC/TAF for use in children aged ≥6 years and weighing ≥25 kg.⁸ Follow-up to 96 weeks in a small number of participants showed no change from baseline in the median spine BMD z-score, but there was a decline in the median total body BMD z-score, and a possible decline in the median estimated glomerular filtration rate.⁴⁸

Because INSTIs do not increase TAF concentrations, regimens that include FTC/TAF 25 mg plus an INSTI are expected to result in safe drug exposures that are like those seen with coformulated EVG/c/FTC/TAF 10 mg. This led the FDA to approve FTC/TAF 25 mg for use in children aged ≥6 years and weighing ≥25 kg when used in combination with other ARV drugs that do not include a boosted PI.²

Because boosted ATV, DRV, or LPV increase TAF exposure to concentrations that are higher than those seen with use of EVG/c/FTC/TAF, and because no data exist on the use of this combination in children weighing <35 kg, the safety of FTC/TAF combined with COBI-boosted or RTV-boosted PIs in children weighing between 25 kg and <35 kg cannot be assured. Therefore, FDA approval for FTC/TAF used in combination with boosted PIs is limited to children weighing ≥35 kg (see Table A above).²

Drug Exposure and Safety: Aged ≥2 Years and Weighing ≥14 kg to <25 kg

Biktarvy tablets consisting of BIC 30 mg/FTC 120 mg/TAF 15 mg were administered to children aged ≥2 years weighing 14 kg to <25 kg and who had viral loads <50 copies/mL on stable ART. At 24 weeks, the median change in CD4 T lymphocyte (CD4) cell count was −100 cells/mm³, and the change in CD4 percentage was +0.5%. HIV RNA at <50 copies/mL was maintained in 20 of the 22 participants at 24 weeks⁴⁹ (see the Bictegravir section for details).

Dosing: Crushing Emtricitabine/Tenofovir Alafenamide Tablets

Viral load suppression was reported in one adult patient with HIV who received crushed FTC/TAF tablets plus crushed DTG tablets. The crushed tablets were mixed with water and administered via a gastrostomy tube. Each dose was followed by a can of a nutritional supplement. No PK parameters were measured.⁵⁰ In adults without HIV, the PKs of crushed DRV/c/FTC/TAF tablets showed decreased TAF bioavailability compared to whole tablets. The clinical implications of these findings are unclear.⁵¹ Case reports in adults with HIV who are receiving crushed BIC/FTC/TAF, a film-coated FDC tablet, lacked PK measurements and described inconsistent virological outcomes.⁵² Based on an adult bioequivalence study, crushed BIC/FTC/TAF may lead to suboptimal FTC and TAF exposures.⁵³ Thus, crushed BIC/FTC/TAF is not recommended (see Bictegravir for details).

Toxicity

Bone

TAF causes bone toxicity less frequently than TDF.^{27-29,32-35,54,55} For example, in one study of 1,733 randomized adult participants with HIV, those treated with EVG/c/FTC/TAF had a smaller decrease in BMD at the spine (mean change −1.30% vs. −2.86%; P < 0.0001) and hip (−0.66% vs. −2.95%; P < 0.0001) at 48 weeks than those given EVG/c/FTC/TDF.²⁷ These differences were maintained until 96 weeks.³⁰ The clinical importance of these changes in BMD is unclear.

Renal

Studies in adolescents aged 12 to 17 years⁴⁰ and adults^{27-29,32,33,35} show that TAF is less frequently associated with glomerular and renal tubular damage than TDF.⁵⁶ For example, in one study of 1,733 randomized adult participants with HIV, those treated with EVG/c/FTC/TAF had a smaller mean increase in serum creatinine (0.08 mg/dL vs. 0.12 mg/dL; P < 0.0001) than those given EVC/c/FTC/TDF, and a smaller percent change from baseline in urine protein to creatinine ratio (median % change −3% vs. +20%; P < 0.0001) at 48 weeks.²⁷ These differences persisted until 96 weeks of follow-up.³⁰ Safety of EVG/c/FTC/TAF has been demonstrated in adults with estimated creatinine clearances between 30 mL/min and 69 mL/min.⁵⁷ Postmarketing cases of renal impairment—including acute renal failure, proximal renal tubulopathy, and Fanconi syndrome—have been reported with TAF-containing products.^2,3 TAF may require less intense renal safety monitoring than TDF, but more experience with the drug in broad clinical practice will be needed before a specific recommendation can be made.

Lipids

In treatment-naive adults who were evaluated after 48 weeks of therapy, initiation of EVG/c/FTC/TAF was associated with increases in serum lipids that were greater than those observed with the initiation of EVG/c/FTC/TDF, with a mean increase in total cholesterol levels of 31 mg/dL versus 23 mg/dL, and a mean increase in LDL cholesterol levels of 16 mg/dL versus 4 mg/dL, respectively. In 48 adolescents who were treated with EVG/c/FTC/TAF, the following median changes from baseline occurred at Weeks 24 and 36: Fasting total cholesterol levels increased 26 mg/dL and 36 mg/dL, respectively; fasting direct LDL levels increased 10 mg/dL and 17 mg/dL, respectively; and fasting triglycerides increased 14 mg/dL and 19 mg/dL, respectively.⁵⁸ Similar TAF-related increases in total cholesterol levels and LDL cholesterol levels have been found when TAF is administered with other combinations of ARV drugs.³³ Monitoring serum lipids while the patient is taking TAF-containing FDC tablets is warranted, given these data (see Table 17b. Dyslipidemia for details).

Weight Gain

Observational data are limited, and no randomized controlled trials have examined TAF-associated weight gain in children. In adults, greater weight gain has been reported with the use of TAF than with the use of TDF^59-65 (see Table 17h. Lipodystrophies and Weight Gain for details). Although weight gain at ART initiation might represent a “return to health,”⁶³ patients initiating treatment with TAF had larger increases in weight than those initiating treatment with TDF^60,61; increases in weight and BMI have been observed in ARV switch studies, as well.^62,65,66 In adults, the effect may be greatest in Black females,^61,65 especially if administered in combination with INSTIs.^61,63 A study in adult women showed increased BMI with the switch to either an INSTI or TAF, but these BMI increases were only seen in persons with BMI <30 kg/m² at baseline.⁵⁹

References

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