Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection

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Nucleoside and Nucleotide Analogue Reverse Transcriptase Inhibitors (NRTIs)

Tenofovir AF

Last Updated: April 27, 2017; Last Reviewed: April 27, 2017

Tenofovir Alafenamide (TAF, Genvoya)
Tenofovir Alafenamide (TAF, Genvoya)
For additional information see Drugs@FDA: http://www.accessdata.fda.gov/scripts/cder/daf/
Formulations
Fixed-Dose Combination Tablets
  • [Descovy] Emtricitabine 200 mg plus tenofovir alafenamide (TAF) 25 mg
  • [Genvoya] Elvitegravir 150 mg plus cobicistat 150 mg plus emtricitabine 200 mg plus TAF 10 mg
  • [Odefsey] Emtricitabine 200 mg plus rilpivirine 25 mg plus TAF 25 mg
Dosing Recommendations Selected Adverse Events
Combination Tablets
[Descovy] Emtricitabine 200 mg plus TAF 25 mg
Pediatric/Adolescent (Weighing ≥35 kg) and Adult Dose:

  • 1 tablet once daily
[Genvoya] Elvitegravir plus Cobicistat plus Emtricitabine plus TAF
Pediatric/Adolescent (Weighing ≥35 kg) and Adult Dose:

  • 1 tablet once daily with food in antiretroviral (ARV) treatment-naive patients or to replace the current ARV regimen in those who are virologically suppressed (i.e., HIV-1 RNA <50 copies/mL) and on a stable ARV regimen for at least 6 months with no history of treatment failure and no known substitutions associated with resistance to the individual components of Genvoya.
[Odefsey] Emtricitabine plus Rilpivirine plus TAF
Pediatric/Adolescent (Weighing ≥35 kg) and Adult Dose:
  • 1 tablet once daily with a meal as initial therapy in those with no ARV treatment history with HIV-1 RNA less than or equal to 100,000 copies per mL; or to replace a stable ARV regimen in those who are virologically-suppressed (HIV-1 RNA less than 50 copies per mL) for at least 6 months with no history of treatment failure and no known substitutions associated with resistance to the individual components of Odefsey. 
  • Asthenia, headache, diarrhea, nausea
  • Increased serum lipids
Special Instructions
  • Measure serum creatinine before starting a TAF-containing regimen.
  • Screen patients for hepatitis B virus (HBV) infection before use of TAF. Severe acute exacerbation of HBV infection can occur when TAF is discontinued; therefore, in patients with HBV infection monitor hepatic function for several months after therapy with TAF is stopped.
  • If using Descovy please see the Emtricitabine section of the drug appendix. 
  • If using Genvoya please see the Elvitegravir, Emtricitabine, and Cobicistat sections of the drug appendix for additional information.
  • Use of Genvoya is not recommended with other ARV drugs. 
  • Do not use Genvoya with elvitegravir, cobicistat, tenofovir disoproxil fumarate, emtricitabine, lamivudine, or protease inhibitors co-formulated with cobicistat. 
  • When using Odefsey, refer to the Emtricitabine and Rilpivirine sections of the drug appendix. Patients must be able to take rilpivirine with a meal of at least 500 calories on a regular schedule (a protein drink alone does not constitute a meal).
Pharmacology
  • TAF undergoes renal excretion.
  • Dosing in patients with renal insufficiency: TAF-containing formulations are not recommended in patients with estimated creatinine clearance below 30 mL per minute.
  • TAF-containing formulations do not require dosage adjustment in patients with mild or moderate hepatic impairment, but should not be used in patients with severe hepatic impairment because they have not been studied in that group.

Drug Interactions (see also the Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents and http://www.hiv-druginteractions.org/)

  • Metabolism: Genvoya contains elvitegravir and cobicistat. Elvitegravir is metabolized predominantly by cytochrome P (CYP) 450 3A4, secondarily by UGT1A1/3, and by oxidative metabolism pathways. Elvitegravir is a modest inducer of CYP2C9. Cobicistat is an inhibitor of CYP3A4 and a weak inhibitor of CYP2D6; in addition, cobicistat inhibits adenosine triphosphate-dependent transporters BCRP and P-glycoprotein and the organic anion-transporting polypeptides OAT1B1 and OAT1B3. Potential exists for multiple drug interactions when using both elvitegravir and cobicistat. 
  • Odefsey contains rilpivirine which is a CYP 3A substrate and requires dosage adjustments when administered with CYP 3A-modulating medications.
  • Before Genvoya or Odefsey 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 could reduce clearance of tenofovir alafenamide (TAF) or emtricitabine. Concomitant use of nephrotoxic drugs should be avoided when using Genvoya.
  • Protease inhibitors: Genvoya should not be administered concurrently with products or regimens containing ritonavir because of similar effects of cobicistat and ritonavir on CYP3A metabolism.

Major Toxicities

  • More common: Nausea, diarrhea, headache.
  • Less common (more severe): Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with use of nucleoside reverse transcriptase inhibitors.

Resistance

The International Antiviral Society-USA (IAS-USA) maintains a list of updated resistance mutations (see https://www.iasusa.org/sites/default/files/tam/22-3-642.pdf) and the Stanford University HIV Drug Resistance Database offers a discussion of each mutation (see http://hivdb.stanford.edu/DR/).

Pediatric Use 

Approval
TAF is Food and Drug Administration (FDA)-approved for use in children aged at least 12 years and weighing at least 35 kg when used as part of the single-tablet regimen of elvitegravir/cobicistat/emtricitabine/TAF (EVG/COBI/FTC/TAF), or when used as the co-formulated TAF/FTC as part of an antiretroviral therapy regimen. While TAF/FTC/rilpivirine (RPV) is not FDA-approved for use in persons aged <18 years, each componenet of the regimen is approved for use in children aged at least 12 years and weighing at least 35 kg. TAF has antiviral activity and efficacy against hepatitis B virus (HBV). Testing for HBV should be performed prior to starting TAF treatment. If HBV is found, there could be rebound of clinical hepatitis when TAF is stopped (reviewed in Guidelines for Prevention and Treatment of Opportunistic Infections in HIV-Infected Children). 

Tenofovir Alafenamide versus Tenofovir Disoproxil Fumarate

Both tenofovir disoproxil fumarate (TDF) and TAF are prodrugs of the nucleotide reverse transcriptase inhibitor tenofovir (TFV). After oral administration TDF is well absorbed,1,2 and is so rapidly metabolized to TFVthat TDF itself cannot be measured in blood (even when plasma is sampled within 5 minutes of administration).3 TFV is the main compound measurable in plasma after TDF administration. From the bloodstream TFV enters cells and is phosphorylated to the active agent tenofovir diphosphate (TFV-DP).

TAF4 also has good oral bioavailability.5 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 compared to TDF, and the main component in plasma is the prodrug itself, TAF.6 Once inside the cell, TAF is hydrolyzed to TFV,7,8 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.4 Therefore a lower dose of TAF results in equivalent or higher concentrations of TFV-DP inside cells compared to the much higher doses of TDF needed to attain a similar intracellular TFV-DP concentration.
 
The key pharmacokinetic difference between TDF and TAF is that TDF results in higher plasma TFV concentration compared to TAF, but when administered at FDA-approved doses, both result in equivalent intracellular TFV-DP concentrations.6 Because it is intracellular TFV-DP that suppresses viral replication, TAF should have antiviral efficacy equivalent to TDF, but should avoid the toxicities that are specifically related to plasma TFV. High plasma TFV concentration has been associated with TDF-related endocrine disruption that is associated with low bone mineral density (BMD)9 and with both glomerular9,10 and proximal tubular11 toxicity. If some of the TDF-associated nephrotoxicity is from intracellular damage to mitochondria,12 studies of longer duration may be needed to confirm the renal tubular safety of TAF.

Table 1. Multiple-Dose Pharmacokinetics at Day 10 of Once-Daily Oral Administration in Adults with HIV Infectiona: TAF vs. TDF6
Parameter TAF 8 mg
(N = 9)
TDF 300 mg
(N = 6)
Plasma TFV AUCtau (ng h/mL) 65.5 (23.5)
1,918.0 (39.4)
Plasma TFV Cmax (ng/mL) 4.2 (24.7)
252.1 (36.6)
Plasma TFV Ctau (ng/mL)
2.1 (33.8)
38.7 (44.7)
PBMC TFV-DP AUCtau (microM h) 3.5 (77.1)
3.0 (119.6)
aMean age 38 years; range 20–57 years

Note: Data are mean (% coefficient of variation); tau is the dosing interval (i.e., 24 hours), Cmax is the maximum concentration.

Key to Acronyms: AUC = area under the curve; PBMC = peripheral blood mononuclear cell; TAF = tenofovir alafenamide; TDF = tenofovir disoproxil fumarate

Tenofovir Alafenamide Efficacy in Clinical Trials in Adults and Adolescents

In adults, TAF is non-inferior to TDF over 48 weeks in its ability to control viral load in combination with elvitegravir, cobicistat, and emtricitabine,13-15 with darunavir/cobicistat/emtricitabine,16 and when TAF-emtricitabine is administered in combination with other antiretroviral drugs.17 TAF shows similar efficacy in children aged at least 12 years and weighing at least 35 kg.18

Pharmacokinetics

Relationship of Drug Exposure to Virologic Response
Virologic success is most closely related to intracellular TFV-DP concentrations. There are no data available for intracellular TFV-DP in children or adolescents treated with TAF, but the peripheral blood mononuclear cell TFV-DP concentration in adults is similar with TDF and TAF.6,13 In 24 pediatric patients aged 12 to <18 years who received EVG/COBI/FTC/TAF the plasma TAF area under the curve was decreased 23% compared to exposures achieved in treatment-naive adults. The clinical significance of this is unclear.19

Formulations

TAF is available as the co-formulated tablets FTC/TAF,20 EVG/COBI/FTC/TAF,19 and FTC/TAF/RPV.21 The amount of TAF (10 mg) in EVG/COBI/FTC/TAF is lower than the amount of TAF (25 mg) in FTC/TAF or FTC/TAF/RPV because cobicistat boosts TAF blood concentrations. TAF-containing pills are smaller than their TDF-containing counterparts, a significant advantage for some pediatric patients who may have trouble swallowing larger pills.

Toxicity

Bone
TAF less frequently causes bone toxicity compared to TDF.13-17 For example in one study of 1,733 randomized adult participants with HIV, those treated with EVG/COBI/FTC/TAF had a smaller decrease in BMD at spine (mean change –1.30% vs. –2.86%; P < 0.0001) and hip (–0.66% vs. –2.95%; P < 0.0001) at 48 weeks compared to those given EVG/COBI/FTC/TDF.13 These differences were maintained to 96 weeks.22 

Renal
Short-term studies in adolescents age 12 to 17 years18 and 48-week studies in adults13-17 show that TAF less frequently is associated with glomerular and renal tubular damage than is TDF. For example, in one study of 1,733 randomized adult participants with HIV, those treated with EVG/COBI/FTC/TAF had smaller mean increase in serum creatinine (0.08 vs. 0.12 mg/dL; P <0.0001) compared to those given EVG/COBI/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 weeks13, and these differences persisted to 96 weeks of follow-up.22 Safety of EVG/COBI/FTC/TAF has been shown in adults with estimated creatinine clearance between 30 and 69 mL/min.23 For TAF, less intense renal safety monitoring may be needed than with 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 evaluated after 48 weeks of therapy, the initiation of EVG/COBI/FTC/TAF is associated with increases in serum lipids greater than those observed with the initiation of EVG/COBI/FTC/TDF, with mean increase in total cholesterol of 31 mg/dL versus 23 mg/dL and low-density lipoprotein (LDL) cholesterol of 16 mg/dL versus 4 mg/dL, respectively. In 48 adolescents treated with EVG/COBI/FTC/TAF, median changes from baseline to weeks 24 and 36 were the following: fasting total cholesterol increased 26 mg/dL and 36 mg/dL, respectively; fasting direct LDL increased 10 mg/dL and 17 mg/dL, respectively; and fasting triglycerides increased 14 mg/dL and 19 mg/dL, respectively.24 Monitoring serum lipids while the patient is taking EVG/COBI/FTC/TAF seems reasonable given these data.

Use of Tenofovir Alafenamide in Genvoya in Children Aged 6 to <12 years
Studies are ongoing of Genvoya in children aged 6 to <12 years and body weight ≥25 kg.25

References

  1. Barditch-Crovo P, Deeks SG, Collier A, et al. Phase I/II trial of the pharmacokinetics, safety, and antiretroviral activity of tenofovir disoproxil fumarate in human immunodeficiency virus-infected adults. Antimicrob Agents Chemother. 2001;45(10):2733-2739. Available at http://www.ncbi.nlm.nih.gov/pubmed/11557462.
  2. Tong L, Phan TK, Robinson KL, et al. Effects of human immunodeficiency virus protease inhibitors on the intestinal absorption of tenofovir disoproxil fumarate in vitro. Antimicrob Agents Chemother. 2007;51(10):3498-3504. Available at http://www.ncbi.nlm.nih.gov/pubmed/17664327.
  3. Lee WA, Martin JC. Perspectives on the development of acyclic nucleotide analogs as antiviral drugs. Antiviral Res. 2006;71(2-3):254-259. Available at http://www.ncbi.nlm.nih.gov/pubmed/16837073.
  4. Lee WA, He GX, Eisenberg E, et al. Selective intracellular activation of a novel prodrug of the human immunodeficiency virus reverse transcriptase inhibitor tenofovir leads to preferential distribution and accumulation in lymphatic tissue. Antimicrob Agents Chemother. 2005;49(5):1898-1906. Available at http://www.ncbi.nlm.nih.gov/pubmed/15855512.
  5. Babusis D, Phan TK, Lee WA, Watkins WJ, Ray AS. Mechanism for effective lymphoid cell and tissue loading following oral administration of nucleotide prodrug GS-7340. Mol Pharm. 2013;10(2):459-466. Available at http://www.ncbi.nlm.nih.gov/pubmed/22738467.
  6. Ruane PJ, DeJesus E, Berger D, et al. Antiviral activity, safety, and pharmacokinetics/pharmacodynamics of tenofovir alafenamide as 10-day monotherapy in HIV-1-positive adults. J Acquir Immune Defic Syndr. 2013;63(4):449-455. Available at http://www.ncbi.nlm.nih.gov/pubmed/23807155.
  7. Birkus G, Kutty N, He GX, et al. Activation of 9-[(R)-2-[[(S)-[[(S)-1-(Isopropoxycarbonyl)ethyl]amino] phenoxyphosphinyl]-methoxy]propyl]adenine (GS-7340) and other tenofovir phosphonoamidate prodrugs by human proteases. Mol Pharmacol. 2008;74(1):92-100. Available at http://www.ncbi.nlm.nih.gov/pubmed/18430788.
  8. Birkus G, Wang R, Liu X, et al. Cathepsin A is the major hydrolase catalyzing the intracellular hydrolysis of the antiretroviral nucleotide phosphonoamidate prodrugs GS-7340 and GS-9131. Antimicrob Agents Chemother. 2007;51(2):543-550. Available at http://www.ncbi.nlm.nih.gov/pubmed/17145787.
  9. Havens PL, Kiser JJ, Stephensen CB, et al. Association of higher plasma vitamin D binding protein and lower free calcitriol levels with tenofovir disoproxil fumarate use and plasma and intracellular tenofovir pharmacokinetics: cause of a functional vitamin D deficiency? Antimicrob Agents Chemother. 2013;57(11):5619-5628. Available at http://www.ncbi.nlm.nih.gov/pubmed/24002093.
  10. Poizot-Martin I, Solas C, Allemand J, et al. Renal impairment in patients receiving a tenofovir-cART regimen: impact of tenofovir trough concentration. J Acquir Immune Defic Syndr. 2013;62(4):375-380. Available at http://www.ncbi.nlm.nih.gov/pubmed/23196828.
  11. Rodriguez-Novoa S, Labarga P, D'Avolio A, et al. Impairment in kidney tubular function in patients receiving tenofovir is associated with higher tenofovir plasma concentrations. AIDS. 2010;24(7):1064-1066. Available at http://www.ncbi.nlm.nih.gov/pubmed/20299966.
  12. Herlitz LC, Mohan S, Stokes MB, Radhakrishnan J, D'Agati VD, Markowitz GS. Tenofovir nephrotoxicity: acute tubular necrosis with distinctive clinical, pathological, and mitochondrial abnormalities. Kidney International. 2010;78(11):1171-1177. Available at http://www.ncbi.nlm.nih.gov/pubmed/20811330.
  13. Sax PE, Wohl D, Yin MT, et al. Tenofovir alafenamide versus tenofovir disoproxil fumarate, coformulated with elvitegravir, cobicistat, and emtricitabine, for initial treatment of HIV-1 infection: two randomised, double-blind, phase 3, non-inferiority trials. Lancet. 2015;385(9987):2606-2615. Available at http://www.ncbi.nlm.nih.gov/pubmed/25890673.
  14. Sax PE, Zolopa A, Brar I, et al. Tenofovir alafenamide vs. tenofovir disoproxil fumarate in single tablet regimens for initial HIV-1 therapy: a randomized phase 2 study. J Acquir Immune Defic Syndr. 2014;67(1):52-58. Available at http://www.ncbi.nlm.nih.gov/pubmed/24872136.
  15. Mills A, Garner W, Pozniak A, et al. Patient-reported symptoms over 48 weeks in a randomized, open-label, Phase IIIb non-inferiority trial of adults with HIV switching to co-formulated elvitegravir, cobicistat, emtricitabine, and tenofovir DF versus continuation of non-nucleoside reverse transcriptase inhibitor with emtricitabine and tenofovir DF. Patient. 2015;8(4):359-371. Available at http://www.ncbi.nlm.nih.gov/pubmed/26045359.
  16. Mills A, Crofoot G, Jr., McDonald C, et al. Tenofovir alafenamide versus tenofovir disoproxil fumarate in the first protease inhibitor-based single-tablet regimen for initial HIV-1 therapy: a randomized Phase 2 Study. J Acquir Immune Defic Syndr. 2015;69(4):439-445. Available at http://www.ncbi.nlm.nih.gov/pubmed/25867913.
  17. Gallant JE, Daar ES, Raffi F, et al. Efficacy and safety of tenofovir alafenamide versus tenofovir disoproxil fumarate given as fixed-dose combinations containing emtricitabine as backbones for treatment of HIV-1 infection in virologically suppressed adults: a randomised, double-blind, active-controlled phase 3 trial. Lancet HIV. 2016;3(4):e158-165. Available at http://www.ncbi.nlm.nih.gov/pubmed/27036991.
  18. Kizito H, Gaur A, Prasithsirikul W, et al. Safety, efficacy, and pharmacokinetics of integrase inhibitor-based E/C/F/TAF single-tablet regimen in treatment-naive HIV-infected adolescents through 24 weeks of treatment. Abstract 953. 22nd Conference on Retroviruses and Opportunistic Infections; 2015; Seattle, WA.
  19. Elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide (Genvoya) [package insert]. Food and Drug Administration. 2016. Available at http://www.accessdata.fda.gov/drugsatfda_docs/label/2016/207561s002lbl.pdf.
  20. Emtricitabine/tenofovir alafenamide (Descovy) [package insert]. 2016. Food and Drug Administration. Available at http://www.accessdata.fda.gov/drugsatfda_docs/label/2016/208215s000lbl.pdf.
  21. Emtricitabine/rilpivirine/and tenofovir alafenamide (Odefsey) [package insert]. Food and Drug Administration. 2016. Available at http://www.accessdata.fda.gov/drugsatfda_docs/label/2016/208351s000lbl.pdf.
  22. Wohl D, Oka S, Clumeck N, et al. Brief report: a randomized, double-blind comparison of tenofovir alafenamide versus tenofovir disoproxil fumarate, each coformulated with elvitegravir, cobicistat, and emtricitabine for initial HIV-1 treatment: Week 96 results. J Acquir Immune Defic Syndr. 2016;72(1):58-64. Available at http://www.ncbi.nlm.nih.gov/pubmed/26829661.
  23. Pozniak A, Arribas JR, Gathe J, et al. Switching to tenofovir alafenamide, coformulated with elvitegravir, cobicistat, and emtricitabine, in HIV-infected patients with renal impairment: 48-week results from a single-arm, multicenter, open-label Phase 3 Study. J Acquir Immune Defic Syndr. 2016;71(5):530-537. Available at http://www.ncbi.nlm.nih.gov/pubmed/26627107.
  24. Tauber WB, Lewis LL. Clinical Review of elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide (Genvoya). Food and Drug Administration. 2015. Available at http://www.fda.gov/downloads/drugs/developmentapprovalprocess/developmentresources/ucm478088.pdf.
  25. Gaur A, Natukunda E, Kosalaraksa P, et al. Pharmacokinetics, Safety, and Efficacy of E/C/F/TAF in HIV-Infected Children (6-12 yrs). Conference on Retroviruses and Opportunistic Infections; 2017; Seattle, WA.

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