Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection
The information in the brief version is excerpted directly from the full-text guidelines. The brief version is a compilation of the tables and boxed recommendations.
Nucleoside and Nucleotide Analogue Reverse Transcriptase Inhibitors (NRTIs)
Last Updated: May 22, 2018; Last Reviewed: May 22, 2018
|Tenofovir Alafenamide (TAF, Vemlidy)
For additional information see Drugs@FDA: http://www.accessdata.fda.gov/scripts/cder/daf/
|Tablets: 25 mga
Fixed-Dose Combination Tablets:
|Dosing Recommendations||Selected Adverse Events|
|[Descovy] Emtricitabine plus TAF
Pediatric, Adolescent (Weighing ≥25 kg), and Adult Dose:
[Genvoya] Elvitegravir plus Cobicistat plus Emtricitabine plus TAF
Pediatric, Adolescent (Weighing ≥25 kg), and Adult Dose:
[Odefsey] Emtricitabine plus Rilpivirine plus TAF
Pediatric, Adolescent (Weighing ≥35 kg), and Adult Dose:
[Biktarvy] Bictegravir plus Emtricitabine plus TAF
Pediatric/Adolescent Dose (Aged <18 Years):
|a TAF 25 mg tablets (Vemlidy) are FDA-approved for treatment of HBV. In select circumstances, TAF might be used as one component of a combination ARV regimen, with dosing recommendations similar to those for Descovy.|
- Metabolism: Tenofovir alafenamide (TAF) is a substrate of the adenosine triphosphate-dependent transporters P-glycoprotein (P-gp) and 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 Coadministration of TAF with rifamycins is not recommended.3
- Genvoya contains elvitegravir and cobicistat in addition to TAF. 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-gp and the organic anion-transporting polypeptides OAT1B1 and OAT1B3. Potential exists for multiple drug interactions when using both elvitegravir and cobicistat.
- Absorption: Administering elvitegravir and bictegravir concurrently with antacids lowers plasma concentrations of these antiretroviral (ARV) drugs. This is due to formation of complexes in the gastrointestinal tract, and not because of changes in gastric pH. Administration of Genvoya (which contains elvitegravir) or Biktarvy (which contains bictegravir) should be separated from administration of antacids by at least 2 hours, but preferably 4 hours. Chelation by high concentrations of divalent cations, such as iron, decreases absorption of integrase strand transfer inhibitors (INSTIs), including elvitegravir and bictegravir. Because of this, Genvoya or Biktarvy should be administered at least 4 hours before or after iron supplements or multivitamins containing iron.
- Odefsey contains rilpivirine, which is a CYP3A substrate and requires dose adjustments when administered with CYP3A-modulating medications.
- Before Genvoya, Odefsey, Descovy, or Biktarvy 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 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.
- More common: Nausea, diarrhea, headache.
- Less common (more severe): Cases of lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with use of nucleoside reverse transcriptase inhibitors.
Descovy, a fixed-dose combination (FDC) drug that contains emtricitabine and TAF (FTC/TAF), is Food and Drug Administration (FDA)-approved for use in children aged ≥6 years and weighing ≥25 kg when used as part of an antiretroviral therapy regimen that does not include a ritonavir- or cobicistat-boosted protease inhibitor (PI). Descovy is FDA-approved for use in children aged ≥6 years and weighing ≥35 kg when used in combination with any antiretroviral (ARV) drugs, including ritonavir- or cobicistat-boosted PIs. Odefsey, an FDC containing TAF, emtricitabine, and rilpivirine (TAF/FTC/RPV), is FDA-approved for use in children weighing ≥35 kg. Genvoya, an FDC containing elvitegravir, cobicistat, emtricitabine, and TAF (EVG/COBI/FTC/TAF), is FDA-approved for use in children aged ≥6 years and weighing ≥25 kg when used as the single-tablet regimen without other ARVs (Table A). Bictegravir is only available as part of the FDC Biktarvy, which contains bictegravir, emtricitabine, and TAF (BIC/FTC/TAF). Biktarvy is not FDA-approved for use in children or adolescents, but it was reported to be safe and effective in a small study in adolescents.4
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. For more information about hepatitis rebound in patients with HBV/HIV coinfection, see the Pediatric Opportunistic Infections Guidelines. TAF alone (as Vemlidy) is FDA-approved for use in persons aged ≥8 years, and is only approved for treating HBV, not HIV.
TAF-containing pills are smaller than their tenofovir disoproxil fumarate (TDF)-containing counterparts, a significant advantage for some pediatric patients who may have trouble swallowing larger pills. TAF is available as the coformulated tablets FTC/TAF,2 FTC/RPV/TAF,5 EVG/COBI/FTC/TAF,6 and BIC/FTC/TAF7 (Descovy, Odefsey, Genvoya, and Biktarvy, respectively). EVG/COBI/FTC/TAF (Genvoya) contains TAF 10 mg while FTC/TAF, FTC/RPV/TAF, and BIC/FTC/TAF (Descovy, Odefsey, and Biktarvy, respectively) contain TAF 25 mg. Cobicistat boosts TAF blood concentrations and tenofovir diphosphate (TFV-DP) intracellular exposure after TAF administration. Therefore, administration of EVG/COBI/FTC/TAF (Genvoya), which contains TAF 10 mg and cobicistat, achieves TFV-DP systemic exposure that is similar to the exposure achieved by FTC/RPV/TAF (Odefsey) or BIC/FTC/TAF (Biktarvy), which contain TAF 25 mg but no cobicistat.
|Drug||Contains||Dose of TAF||Minimum Age||Minimum Body Weight||Comment|
|Vemlidy||TAF||25 mg||18 years||N/A||Approved for HBV treatment only.|
||FTC/TAF||25 mg||6 years||25 kg||Use with an INSTI or NNRTI, but not with a boosted PI.|
|FTC/TAF||25 mg||6 years||35 kg||Use with any ARVs, including a boosted PI.|
|Odefsey||FTC/RPV/TAF||25 mg||12 years||35 kg||Not to be used with other ARVs.|
|Genvoya||EVG/COBI/FTC/TAF||10 mg||6 years||25 kg||TAF dose is lower because of the cobicistat boosting.|
|Biktarvya||BIC/FTC/TAF||25 mg||18 years||N/A||Not to be used with other ARVs.|
|a See Bictegravir section for information about investigational use in children and adolescents aged 12–18 years and weighing ≥35 kg.
Key to Acronyms: ARV = antiretroviral; BIC = bictegravir; COBI = cobicistat; EVG = elvitegravir; FTC = emtricitabine; HBV = hepatitis B virus; INSTI = integrase strand transfer inhibitor; NNRTI = non-nucleoside reverse transcriptase inhibitor; PI = protease inhibitor; RPV = rilpivirine; TAF = tenofovir alafenamide
Tenofovir Alafenamide versus Tenofovir Disoproxil Fumarate
Both TDF and TAF are prodrugs of the nucleotide reverse transcriptase inhibitor tenofovir (TFV). After oral administration, TDF is well absorbed8,9 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).10 TFV is the main compound measurable in plasma after TDF administration. From the bloodstream, TFV enters cells and is phosphorylated to the active agent TFV-DP.
TAF11 also has good oral bioavailability.12 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.13 Once inside the cell, TAF is hydrolyzed to TFV,14,15 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.11 Therefore, a much lower dose of TAF results in intracellular concentrations of TFV-DP that are equivalent or higher than the concentrations seen after TDF administration.
The key pharmacokinetic 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 and therapeutically effective intracellular TFV-DP concentrations.13 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 linked to TDF-related endocrine disruption that is associated with low bone mineral density (BMD).16 High plasma TFV has also been closely associated with both glomerular16,17 and proximal tubular18 renal toxicity.
|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 (µM*h)||3.5 (77.1)||3.0 (119.6)|
|a Mean age 38 years; range 20–57 years
Note: Data are mean (% coefficient of variation), tau is the dosing interval (i.e., 24 hours), and 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; TFV-DP = tenofovir diphosphate
Tenofovir Alafenamide Efficacy in Clinical Trials in Adults and Adolescents
In adults, TAF is noninferior to TDF over 48 to 96 weeks in its ability to control viral load when used in combination with elvitegravir, cobicistat, and emtricitabine;19-22 with emtricitabine and rilpivirine;23 with darunavir, cobicistat, and emtricitabine;24 and when TAF and emtricitabine are administered in combination with other ARV drugs.25 The combination of TAF, elvitegravir, cobicistat, and emtricitabine has been shown to have similar efficacy when used in adults and two groups of children: those aged ≥12 years and weighing ≥35 kg26 and those aged ≥6 years and weighing ≥25 kg.27
Drug Exposure and Virologic Response
Virologic suppression is most closely related to intracellular TFV-DP concentrations. At clinically meaningful doses, TAF generates peripheral blood mononuclear cell TFV-DP concentrations in adults that are about seven-fold higher than those generated with TDF.13,19 Higher TFV-DP concentrations result in a stronger antiviral potency13 and a higher barrier to resistance.28,29 Therefore, compared to TDF, TAF may have a potentially enhanced ability to maintain effectiveness with nucleoside reverse transcriptase inhibitor (NRTI)-resistant virus. The mean TFV-DP concentration is higher in youths aged 12 to 18 years than in adults: 221.8 fmol/million cells (with a coefficient of variation [CV] of 94.4%) versus 120.8 fmol/million cells (CV 91.4%), respectively.26
Drug Exposure and Safety: All Age Groups
FTC/TAF (Descovy) can be safely combined with dolutegravir or raltegravir without concern for drug interactions. Emtricitabine and TAF have also safely been combined with bictegravir in the fixed-dose combination Biktarvy.
When FTC/TAF (Descovy), which contains TAF 25 mg, is combined with cobicistat- or ritonavir-boosted atazanavir, darunavir, or lopinavir, the P-gp inhibitors cobicistat or ritonavir increase the TAF exposure to higher concentrations than those seen with use of EVG/COBI/FTC/TAF (Genvoya) which contains TAF 10 mg. However, the plasma TFV concentrations (the cause of bone and renal toxicity) are still much lower than those seen with the use of Stribild, an FDC that contains elvitegravir, cobicistat, emtricitabine, and TDF (see Table C).
|Regimen||TAF AUCa||TAF AUC Ratio
TAF Containing Regimen/Genvoya (10 mg TAF) Adult Exposure
|TFV AUCa||TFV AUC Ratio
TFV Containing Regimen/Stribild (300 mg TDF) Adult Exposure
|Stribild (EVG/COBI/FTC/TDF 300 mg)||N/A||N/A||4,400||1.00|
|Genvoya (EVG/COBI/FTC/TAF 10 mg)||210||1.0||290||0.07|
|DRV/r plus TAF 25 mgb||196||0.93||259||0.06|
|DRV/c plus TAF 25 mg||239||1.1||935||0.21|
|Stribild for ages 12–18 years||N/A||N/A||6,028||1.37|
|Genvoya for ages 12–18 years||200||0.95||290||0.07|
|Genvoya for ages 6–12 years||330||1.6||440||0.10|
|a AUC: ng*h/mL
b Values for this row do not come from observed data. These values were predicted based on data from studies using TAF 10 mg. The AUC values predicted for TAF 25 mg were obtained by multiplying the TAF 10 mg AUC by 2.5 for both TAF and TFV AUC.
Source: Table modified from FDA Summary Review of tenofovir alafenamide, available at https://www.accessdata.fda.gov/drugsatfda_docs/nda/2016/208215Orig1s000SumR.pdf and from the tenofovir alafenamide clinical pharmacology review, available at https://www.accessdata.fda.gov/drugsatfda_docs/nda/2016/208215Orig1s000ClinPharmR.pdf, using data from the Stribild product label (FDA 2017 August) and Genvoya product label (FDA 2017 September)
Key to Acronyms: AUC = area under curve; COBI = cobicistat; DRV/r = darunavir/ritonavir; DRV/c = darunavir/cobicistat; EVG = elvitegravir; FTC = emtricitabine; TAF = tenofovir alafenamide; TDF = tenofovir disoproxil fumarate; TFV = tenofovir
Clinical trials in adults showing the safety of emtricitabine/TAF administered with ritonavir-boosted atazanavir or ritonavir-boosted darunavir have used emtricitabine/TAF 200 mg/10 mg, a formulation not available in the United States.30 The FDA states that when emtricitabine/TAF 200 mg/25 mg (Descovy) is combined with cobicistat- or ritonavir-boosted atazanavir, darunavir, or lopinavir in adults, “no clinically significant drug interactions have been observed or are expected,” so the combination of emtricitabine/TAF (Descovy) is FDA-approved for adults independent of the accompanying ARVs (which may include a boosted PI or an INSTI).2 Moreover, in Trial 299-0102, a Phase 2b trial in adults comparing a regimen of darunavir/cobicistat (DRV/c) plus emtricitabine/TAF 10 mg to a regimen of DRV/c plus emtricitabine/TDF, there was a concern of worse Week 48 virologic outcome for the TAF 10 mg arm. Hence, emtricitabine/TAF 25 mg was recommended for approval instead of emtricitabine/TAF 10 mg.31 This is not the case in Canada or Europe, where emtricitabine is combined with TAF 10 mg in an FDC and used in combination with boosted PIs.
Drug Exposure and Safety: Aged 12 Years to 18 Years and Weighing ≥35 kg
Studies of EVG/COBI/FTC/TAF (Genvoya) in children aged 12 to 18 years and weighing ≥35 kg showed that drug exposures were similar to those found in adults (Table C), and that the drug was well tolerated and efficacious over 48 weeks of study.26 Since these drug exposures were similar to those seen in adults, emtricitabine/TAF was also FDA-approved for 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 adult dose formulation of Biktarvy (which contains bictegravir 50 mg, emtricitabine 200 mg, and TAF 25 mg) was administered to youths aged 12 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, and all of the 24 participants had viral loads <50 copies/mL at 24 weeks.4
Drug Exposure and Safety: Aged 6 Years to <12 Years and Weighing 25 kg to <35 kg
Studies of EVG/COBI/FTC/TAF (Genvoya) in children aged 6 to <12 years and weighing ≥25 kg showed that drug exposures were somewhat higher than those found in adults (Table C), but the drug was well tolerated and efficacious over 24 weeks of study.27,32 This led to FDA approval of Genvoya for children aged ≥6 years who weigh ≥25 kg.6
Because integrase inhibitors do not increase TAF concentrations, regimens of FTC/TAF 25 mg (Descovy) plus an INSTI are expected to result in safe drug exposures that are similar to those seen with the single-tablet regimen EVG/COBI/FTC/TAF 10 mg (Genvoya). This led the FDA to approve Descovy for children aged ≥6 years and weighing ≥25 kg when used in combination with other ARVs that do not include a boosted PI.2
Because cobicistat- or ritonavir-boosted atazanavir, darunavir, or lopinavir increase the TAF exposure to higher concentrations than those seen with use of EVG/COBI/FTC/TAF (Genvoya), and because there are no data on this combination in children weighing <35 kg, the safety of FTC/TAF (Descovy) combined with cobicistat- or ritonavir-boosted PIs in children with body weights between 25 kg and <35 kg cannot be assured. That is why the FDA approval for Descovy in combination with boosted PIs is limited to children weighing ≥35 kg (Table A).2
TAF causes bone toxicity less frequently than TDF.19-21,24,25 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 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 EVC/COBI/FTC/TDF.19 These differences were maintained to 96 weeks.22
Studies in adolescents aged 12 to 17 years26 and adults19-21,24,25 show that TAF is less frequently associated with glomerular and renal tubular damage than TDF. For example, in one study of 1,733 randomized adult participants with HIV, those treated with EVG/COBI/FTC/TAF had a smaller mean increase in serum creatinine (0.08 vs. 0.12 mg/dL; P < 0.0001) than those given EVC/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 weeks.19 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.33 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.
In treatment-naive adults evaluated after 48 weeks of therapy, the initiation of elvitegravir/cobicistat/emtricitabine/TAF was associated with increases in serum lipids greater than those observed with the initiation of elvitegravir/cobicistat/emtricitabine/TDF, with a mean increase in total cholesterol of 31 mg/dL versus 23 mg/dL and low-density lipoprotein (LDL) cholesterol levels of 16 mg/dL versus 4 mg/dL, respectively. In 48 adolescents treated with elvitegravir/cobicistat/emtricitabine/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.34 Monitoring serum lipids while the patient is taking TAF-containing FDCs is warranted, given these data. For more information, see the Dyslipidemia section.
- Huhn GD, Tebas P, Gallant J, et al. A randomized, open label trial to evaluate switching to elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide plus darunavir in treatment-experienced HIV-1-infected adults. J Acquir Immune Defic Syndr. 2017;74(2):193-200. Available at: https://www.ncbi.nlm.nih.gov/pubmed/27753684.
- Emtricitabine/tenofovir alafenamide (Descovy) [package insert]. Food and Drug Administration. 2017. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/208215s001lbl.pdf.
- Cerrone M, Alfarisi O, Neary M, et al. Rifampin effect on tenofovir alafenamide (TAF) plasma/intracellular pharmacokinetics. Presented at: Conference on Retroviruses and Opportunistic Infections. 2018. Boston, MA. Available at: http://www.croiconference.org/sessions/rifampin-effect-tenofovir-alafenamide-taf-plasmaintracellular-pharmacokinetics.
- Gaur A, Rodriguez C, McGrath EJ, et al. Bictegravir/FTC/TAF single-tablet regimen in adolescents: week 24 results. Presented at: Conference on Retroviruses and Opportunistic Infections. 2018. Boston, MA. Available at: http://www.croiconference.org/sessions/bictegravirftctaf-single-tablet-regimen-adolescents-week-24-results.
- Emtricitabine/rilpivirine/tenofovir alafenamide (Odefsey) [package insert]. Food and Drug Administration. 2017. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/208351s001lbl.pdf.
- Elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide (Genvoya) [package insert]. Food and Drug Administration. 2017. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/207561s013lbl.pdf.
- Bictegravir/emtricitabine/tenofovir alafenamide (Biktarvy) [product insert]. Food and Drug Administration. 2018. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/210251s000lbl.pdf.
- Barditch-Crovo P, Deeks SG, Collier A, et al. Phase 1/2 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- Orkin C, DeJesus E, Ramgopal M, et al. Switching from tenofovir disoproxil fumarate to tenofovir alafenamide coformulated with rilpivirine and emtricitabine in virally suppressed adults with HIV-1 infection: a randomised, double-blind, multicentre, phase 3b, non-inferiority study. Lancet HIV. 2017;4(5):e195-e204. Available at: https://www.ncbi.nlm.nih.gov/pubmed/28259777.
- 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.
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