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Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection

Integrase Inhibitors

Elvitegravir

(Last updated: March 1, 2016; last reviewed: March 1, 2016)

Elvitegravir (EVG, VITEKTA)
Elvitegravir (EVG, VITEKTA)
For additional information see Drugs@FDA: http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm
Formulations
Tablet: 85 mg and 150 mg
Fixed-Dose Combination Tablets:
  • [Stribild] Elvitegravir 150 mg plus cobicistat 150 mg plus emtricitabine 200 mg plus tenofovir disoproxil (TDF) 300 mg
  • [Genvoya] Elvitegravir 150 mg plus cobicistat 150 mg plus emtricitabine 200 mg plus tenofovir alafenamide (TAF) 10 mg
Dosing Recommendations Selected Adverse Events
Note: Elvitegravir should only be used with a pharmacokinetic (PK) enhancer (boosting agent) such as ritonavir as part of a boosted protease inhibitor (PI)-containing regimen, or in combination with cobicistat in Stribild or Genvoya.

Pediatric Dose (Weighing <35 kg):
  • No data on appropriate dose of elvitegravir as Vitekta or in Stribild or Genvoya in children with body weight <35 kg.
Adolescent (Weighing >35 kg) and Adult Dose:
Genvoya (Any Sexual Maturity Rating; Tanner Stage):a
  • One tablet once daily
Stribild (SMR 4 or 5)a:
  • One tablet once daily
  • Elvitegravir (as Vitekta) in combination with an HIV PI co-administered with ritonavir and another antiretroviral (ARV) drug.b

Recommended Elvitegravir Dose Taken Once Daily with Food (All Drugs Administered Orally)
Dosage of EVG Dosage of Concomitant PI Dosage of Concomitant Ritonavir
85 mg once daily Atazanavir 300 mg once daily 100 mg once daily
Lopinavir 400 mg twice daily 100 mg twice daily
150 mg once daily
Darunavir 600 mg twice daily 100 mg twice daily
Fosamprenavir 700 mg twice daily 100 mg twice daily
Tipranavir 500 mg twice daily 200 mg twice daily

  • Diarrhea (elvitegravir)
  • Stribild-associated adverse events: Nausea, diarrhea, fatigue, headache. TDF—renal insufficiency, decreased bone mineral density, flatulence; cobicistat—alteration in tubular secretion of creatinine.
  • Genvoya-associated adverse events: Nausea, diarrhea, fatigue, headache.
  • TAF-associated adverse events: Increased low-density lipoprotein-cholesterol and total cholesterol.
  • Cobicistat-associated adverse events: Alteration in tubular secretion of creatinine.
Special Instructions
  • Administer with food.
  • When used in combination with TDF, monitor estimated creatinine clearance (CrCl), urine glucose, and urine protein at baseline and every 3 to 6 months while on therapy; in patients at risk of renal impairment, also monitor serum phosphate. Patients with increase in serum creatinine >0.4 mg/dL should be closely monitored for renal safety.
  • Screen patients for hepatitis B virus (HBV) infection before use of emtricitabine, TDF, or TAF. Severe acute exacerbation of HBV can occur when emtricitabine, TDF, or TAF is discontinued; therefore, monitor hepatic function for several months after therapy with emtricitabine, TDF, or TAF is stopped.
  • Do not use elvitegravir with PIs co-administered with cobicistat (not yet studied), or with other elvitegravir-containing drugs including Stribild or Genvoya. Neither Stribild nor Genvoya is recommended for use with other ARV drugs.
Metabolism/Elimination
  • Elvitegravir is metabolized by cytochrome P (CYP) 450 3A4 and is a modest inducer of CYP2C9.
  • Elvitegravir should only be used with a PK enhancer (boosting agent) such as ritonavir as part of a boosted PI-containing regimen or in combination with cobicistat (in Stribild or Genvoya). Refer to those sections for further details.
  • Stribild should not be initiated in patients with estimated creatinine clearance <70 mL/min and should be discontinued in patients with estimated CrCl <50 mL/min because dose adjustments required for FTC and TDF cannot be achieved with a fixed-dose combination tablet.
  • Genvoya should not be initiated in patients with estimated CrCl <30 mL/min.
  • Neither Stribild nor Genvoya should be used in patients with severe hepatic impairment.
a Stribild and Genvoya are Food and Drug Association (FDA)-approved for use in ARV treatment-naive adults or to replace the current ARV regimen in adults who are virologically suppressed (HIV-1 RNA <50 copies/mL) 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 Stribild or Genvoya.
b Elvitegravir as Vitekta is not FDA-approved for use in children aged <18 years. The PK profile is similar to that in adults when given with either atazanavir/ritonavir or lopinavir/ritonavir, or darunavir/ritonavir. Vitekta was well tolerated in adolescents, but the use of a multi-pill regimen was associated with poor adherence and a high percentage of virologic failures, leading to the recommendation for use in adolescents only when elvitegravir is part of a coformulated regimen like Stribild or Genvoya.

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: Stribild and Genvoya contain 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 (ATP)-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.
  • Renal elimination: Drugs that decrease renal function or compete for active tubular secretion could reduce clearance of tenofovir disoproxil fumarate (TDF) or emtricitabine. Concomitant use of nephrotoxic drugs should be avoided when using Stribild.
  • Protease inhibitors: Neither Stribild nor Genvoya should be administered concurrent with products or regimens containing ritonavir because of similar effects of cobicistat and ritonavir on CYP3A metabolism. Cobicistat and ritonavir are not interchangeable, and when administered with either atazanavir or darunavir, may result in different drug interactions when used with other concomitant medications.
  • Neither Stribild nor Genvoya is recommended for use with other antiretroviral (ARV) drugs.

Major Toxicities

  • More common: Nausea, diarrhea, and flatulence
  • Less common (more severe): Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with nucleoside reverse transcriptase inhibitors (NRTIs) including TDF and emtricitabine. TDF caused bone toxicity (osteomalacia and reduced bone mineral density [BMD]) in animals when given in high doses. Decreases in BMD have been reported in both adults and children taking TDF; the clinical significance of these changes is not yet known. Evidence of renal toxicity, including increases in serum creatinine, blood urea nitrogen, glycosuria, proteinuria, phosphaturia, and/or calciuria and decreases in serum phosphate, has been observed with TDF. Numerous case reports of renal tubular dysfunction have been reported in patients receiving TDF; patients at increased risk of renal dysfunction should be closely monitored if treated with Stribild.

Resistance

The International Antiviral Society-USA (IAS-USA) maintains a list of updated resistance mutations (see http://iasusa.org/sites/default/files/tam/october_november_2015.pdf#page=10) and the Stanford University HIV Drug Resistance Database offers a discussion of each mutation (see http://hivdb.stanford.edu/DR/). There is phenotypic cross-resistance between elvitegravir and raltegravir.1

Pediatric Use

Approval
Elvitegravir was Food and Drug Administration (FDA)-approved in 2014 as a tablet for use in adults in combination with a protease inhibitor (PI) plus ritonavir and was FDA-approved in 2012 for use in adults as the fixed-dose combination product Stribild, which contains elvitegravir, cobicistat, emtricitabine, and TDF. Neither elvitegravir nor Stribild is FDA-approved for use in children aged <18 years.2,3 In November 2015, Genvoya was FDA-approved for use in youth aged ≥12 years and body weight ≥35 kg.4

Formulations
Elvitegravir is an integrase strand transfer inhibitor that is metabolized rapidly by CYP3A4. Elvitegravir must be used in combination with a PI co-administered with ritonavir and another ARV drug, in the fixed-dose combination product Stribild,3 or Genvoya,4 which contain cobicistat (see below). Cobicistat itself does not have ARV activity, but is a CYP3A4 inhibitor that acts as a pharmacokinetic (PK) enhancer, similar to ritonavir.5 Both ritonavir and cobicistat slow elvitegravir metabolism and allow once-daily administration of elvitegravir when used in approved doses and combinations. Note that the dose of elvitegravir is different when used with atazanavir/ritonavir (ATV/r) or lopinavir compared to its use with different PIs plus ritonavir, or compared to its use with cobicistat as a component of Stribild or Genvoya. Complex or unknown mechanisms of drug interactions between cobicistat or ritonavir with elvitegravir and PIs may result in different drug interactions when used with other medications.5

Stribild is FDA-approved as a complete ARV regimen in HIV-1-infected ARV-naive adults aged ≥18 years or to replace the current ARV regimen in those who are virologically suppressed (HIV-1 RNA <50 copies/mL) 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 Stribild.3 Trials have shown non-inferiority of Stribild to regimens of emtricitabine combined with TDF plus ATV/r,6,7 or emtricitabine plus TDF plus efavirenz.8,9 Cobicistat inhibits renal tubular secretion of creatinine, and serum creatinine will often increase soon after initiation of treatment with Stribild. Therefore, creatinine-based calculations of estimated glomerular filtration rate (GFR) will be altered, even though the actual GFR might be only minimally changed.10 Adults who experience a confirmed increase in serum creatinine greater than 0.4 mg/dL from baseline should be closely monitored for renal toxicity by following creatinine for further increases and urinalysis for evidence of proteinuria or glycosuria.3 Because TDF is included in Stribild and can be associated with renal toxicity, careful periodic evaluation of renal function is warranted. This nephrotoxicity may be more pronounced in patients with pre-existing renal disease.3

Genvoya is FDA-approved as a complete ARV regimen in HIV-1-infected ARV-naive individuals aged ≥12 years and body weight ≥35 kg or to replace the current ARV regimen in those who are virologically suppressed (i.e., HIV-1 RNA <50 copies/mL) 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.3 Because Genvoya contains tenofovir alafenamide (TAF) instead of TDF, Genvoya would be expected to have less bone and renal toxicity compared to Stribild. Diminished renal and bone toxicity of Genvoya has been shown in two studies in adults in which, compared to those treated with Stribild, participants treated with Genvoya had significantly smaller increase in serum creatinine, less proteinuria, and smaller decreases in BMD at the spine and hip after 48 weeks of treatment.11

Use of Elvitegravir as Vitekta in Adolescents Aged 12 to 18 Years
A PK study of the adult dose of elvitegravir as Vitekta in 25 youth aged 12 to 18 years showed plasma concentrations similar to those in adults when given in regimens that included ATV/r or lopinavir/ritonavir (LPV/r) in addition to NRTIs. However, the elvitegravir trough plasma concentration was lower when co-administered with darunavir/ritonavir, tipranavir/ritonavir, or fosamprenavir/ritonavir than when it was co-administered with ATV/r or LPV/r, even though the lower elvitegravir dose was used when given with atazanavir/ritonavir or LPV/r.12 This was a multi-pill regimen and medication adherence was poor during the 48-week treatment phase of the study. Data were insufficient to establish safety and effectiveness of elvitegravir as Vitekta in this age group. Therefore, elvitegravir as Vitekta was not FDA-approved for use in this age group,2 although its use with ATV/r or LPV/r might be considered in patients in whom adherence could be assured.

Use of Elvitegravir as Stribild or Genvoya in Adolescents Aged 12 to 18 years
Studies of the adult dosage formulation of Stribild in HIV-infected youth aged ≥12 years with body weight ≥35 kg have demonstrated PK, safety, and efficacy similar to that in adults through 24 weeks of study.13-16 Studies of the adult dosage formulation of Genvoya in HIV-infected youth aged ≥12 years with body weight ≥35 kg have shown safety comparable to that of adults, and this formulation is FDA-approved for use in this age/weight group. Because of the diminished renal and bone toxicity of Genvoya compared to Stribild, Genvoya might be preferable to Stribild for treatment of youth with sexual maturity rating 1 to 3. Note that in 24 pediatric subjects aged 12 to < 18 years who received Genvoya the TAF area under the curve was decreased 23% compared to exposures achieved in treatment-naive adults.4 The clinical significance of this is unclear.

Use of Elvitegravir as Vitekta in Children Aged Younger Than 12 years
In children aged ≥6 years and body weight ≥30 kg, when elvitegravir 85 mg (the adult dose) was co-administered in regimens containing either LPV/r or ATV/r, elvitegravir exposures were similar to those in adults.17 Pediatric formulations of both elvitegravir18 and cobicistat19 are bioequivalent to adult formulations. Studies are ongoing of pediatric formulations in children aged <6 years and body weight <30 kg.

References

  1. Garrido C, Villacian J, Zahonero N, et al. Broad phenotypic cross-resistance to elvitegravir in HIV-infected patients failing on raltegravir-containing regimens. Antimicrob Agents Chemother. 2012;56(6):2873-2878. Available at http://www.ncbi.nlm.nih.gov/pubmed/22450969.
  2. Elvitegravir (Viteka) [package insert]. Food and Drug Administration. 2015. Available at http://www.gilead.com/~/media/files/pdfs/medicines/hiv/vitekta/vitekta_pi.pdf?la=en. Accessed February 10, 2016.
  3. Elvitegravir, cobicistat, emtricitabine, tenofovir disporoxil fumarate (Stribald) [package insert]. Food and Drug Administration. 2015. Available at http://www.gilead.com/~/media/files/pdfs/medicines/hiv/stribild/stribild_pi.pdf?la=en. Accessed February 10, 2016.
  4. Elvitegravir, cobicistat, emtricitabine, tenofovir alafenamide (Genvoya) package insert. Food and Drug Administration. 2015. Available at http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/207561s000lbl.pdf. Accessed February 10, 2016.
  5. Cobicistat (Tybost) [package insert]. Food and Drug Administration. 2014. Available at http://www.gilead.com/~/media/Files/pdfs/medicines/hiv/tybost/tybost_pi.pdf. Accessed February 10, 2016.
  6. DeJesus E, Rockstroh JK, Henry K, et al. Co-formulated elvitegravir, cobicistat, emtricitabine, and tenofovir disoproxil fumarate versus ritonavir-boosted atazanavir plus co-formulated emtricitabine and tenofovir disoproxil fumarate for initial treatment of HIV-1 infection: a randomised, double-blind, phase 3, non-inferiority trial. Lancet. 2012;379(9835):2429-2438. Available at http://www.ncbi.nlm.nih.gov/pubmed/22748590.
  7. Rockstroh JK, Dejesus E, Henry K, et al. A randomized, double-blind comparison of co-formulated elvitegravir/cobicistat/emtricitabine/tenofovir versus ritonavir-boosted atazanavir plus co-formulated emtricitabine and tenofovir DF for initial treatment of HIV-1 infection: analysis of week 96 results. J Acquir Immune Defic Syndr. 2013. Available at http://www.ncbi.nlm.nih.gov/pubmed/23337366.
  8. Sax PE, DeJesus E, Mills A, et al. Co-formulated elvitegravir, cobicistat, emtricitabine, and tenofovir versus co-formulated efavirenz, emtricitabine, and tenofovir for initial treatment of HIV-1 infection: a randomised, double-blind, phase 3 trial, analysis of results after 48 weeks. Lancet. 2012;379(9835):2439-2448. Available at http://www.ncbi.nlm.nih.gov/pubmed/22748591.
  9. Zolopa A, Sax PE, DeJesus E, et al. A randomized double-blind comparison of coformulated elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate versus efavirenz/emtricitabine/tenofovir disoproxil fumarate for initial treatment of HIV-1 infection: analysis of week 96 results. J Acquir Immune Defic Syndr. 2013;63(1):96-100. Available at http://www.ncbi.nlm.nih.gov/pubmed/23392460.
  10. German P, Liu HC, Szwarcberg J, et al. Effect of cobicistat on glomerular filtration rate in subjects with normal and impaired renal function. J Acquir Immune Defic Syndr. 2012;61(1):32-40. Available at http://www.ncbi.nlm.nih.gov/pubmed/22732469.
  11. 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.
  12. Ramanathan S, Mathias AA, German P, Kearney BP. Clinical pharmacokinetic and pharmacodynamic profile of the HIV integrase inhibitor elvitegravir. Clin Pharmacokinet. 2011;50(4):229-244. Available at http://www.ncbi.nlm.nih.gov/pubmed/21348537.
  13. Gaur A, Fourle J, et al. Pharmacokinetics, efficacy and safety of an integrase inhibitor STR in HIV-infected adoelscents. Presented at: 21st Conference on Retroviruses and Opportunistic Infections. 2014. Boston, MA.
  14. Chokephaibulkit C, Gaur A, et al. Safety, efficacy and pharmakokinetics of the integrase inhibitor-based Stribild single-tablet regimen in HIV-infected tratment naive adolescents through 24 weeks. Presented at: 6th International Workshop on HIV Pediatrics. 2014. Melbourne, Australia.
  15. Kizito H, Gaur A, Prasitsuebsai W, et al. Week-24 data from a phase 3 clinical trial of E/C/F/TAF in HIV-infected adolescents. Presented at: 22nd Conference on Retroviruses and Opportunistic Infections. 2015. Seattle, WA.
  16. Kizito H, Gaur A, Prasitsuebsai W, et al. MOAB0104 Changes in renal laboratory parameters and bone mineral density in treatment-naïve HIV-1-infected adolescents initiating therapy with INSTI-based single-tablet regimens containing tenofovir alafenamide (TAF) or tenofovir disoproxil fumarate (TDF). Presented at: 8th International AIDS Society. 2015. Vancouver, BC.
  17. Custodio J, Musiime V, Gaur A, et al. Safety and pharmacokinetics of elvitegravir in HIV-1 infected pediatric subjects. Presented at: 22nd Conference on Retroviruses and Opportunistic Infections. 2015. Seattle, WA.
  18. Custodio J, Yin X, Graham H., et al. Bioequivalence of two pediatric formulations vs adult tablet formulation of elvitegravir. Presented at: Conference on Retroviruses and Opportunistic Infections. 2014. Boston, MA.
  19. Custodio J, Yin, X., Graham, H. Bioequivalence of two pediatric formulations vs adult tablet formulation of cobicistat. Presented at: Conference on Retrovirues and Opportunistic Infections. 2014. Boston MA.

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