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Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection

Integrase Inhibitors

Elvitegravir

(Last updated: March 5, 2015; last reviewed: March 5, 2015)

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 Tablet:
Elvitegravir (EVG) + cobicistat (COBI) + emtricitabine (FTC) + tenofovir disoproxil fumarate (TDF) (Stribild):
EVG 150 mg + COBI 150 mg + FTC 200 mg + TDF 300 mg
Dosing Recommendations

Note: EVG 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.

Pediatric Dose (Aged <18 Years):
  • Not Food and Drug Administration-approved for use in children aged <18 years. EVG (as Vitekta) should not be used in a multi-pill regimen with a boosted PI in this age group (see text). Preliminary data from an ongoing clinical trial suggest the adult formulation of EVG in Stribild may be appropriate for use in youth aged ≥12 years and body weight ≥35 kg.
Adult Dose (Aged ≥18 Years):
  • EVG (as Vitekta) must be used in combination with an HIV PI co-administered with ritonavir and another antiretroviral (ARV) drug.
Recommended EVG dosage taken once daily with food (all drugs administered orally)
Dosage of EVG Dosage of Concomitant Protease Inhibitor 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

Fixed-Dose Combination Tablets

Stribild (EVG + COBI + FTC + TDF):
  • Adult dose (aged ≥18 years): 1 tablet once daily in ARV treatment-naive adults
Selected Adverse Events
  • Diarrhea (EVG)
  • Stribild-associated adverse events: TDF—renal insufficiency, decreased bone mineral density, flatulence; cobicistat—alteration in tubular secretion of creatinine.
Special Instructions
  • Administer with food.
  • When used in combination with TDF, monitor estimated creatinine clearance, 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 FTC or TDF. Severe acute exacerbation of HBV can occur when FTC or TDF is discontinued; therefore, monitor hepatic function for several months after therapy with FTC or TDF is stopped.
  • Do not use EVG with PIs co-administered with cobicistat (not yet studied), or with other EVG-containing drugs including Stribild. Stribild is not recommended for use with other ARV drugs.
Metabolism
  • EVG is metabolized by cytochrome P (CYP) 450 3A4 and is a modest inducer of CYP2C9.
  • EVG 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).
  • Stribild should not be initiated in patients with estimated creatinine clearance (CrCl) <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.
  • Stribild should not be used in patients with severe hepatic impairment.

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 contains elvitegravir and cobicistat. Elvitegravir is metabolized by cytochrome P (CYP) 450 3A4 and is a modest inducer of CYP2C9. Cobicistat is an inhibitor of CYP3A4 and a weak inhibitor of CYP2D6; in addition, cobicistat inhibits ATP-dependent transporters BCRP and P-glycoprotein and the organic anion transporting polypeptides OAT1B1 and OAT1B3. Potential exists for multiple drug interactions when using cobicistat.
  • Renal elimination: Drugs that decrease renal function or compete for active tubular secretion could reduce clearance of tenofovir disoproxil fumarate (tenofovir) or emtricitabine. Concomitant use of nephrotoxic drugs should be avoided when using Stribild.
  • Protease inhibitors: Stribild should not 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.
  • Stribild is not 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 tenofovir and emtricitabine. Tenofovir caused bone toxicity (osteomalacia and reduced bone density) in animals when given in high doses. Decreases in bone mineral density have been reported in both adults and children taking tenofovir; 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 tenofovir. Numerous case reports of renal tubular dysfunction have been reported in patients receiving tenofovir; 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 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/). 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 adults in combination with an HIV 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 tenofovir. Neither elvitegravir nor Stribild is FDA-approved for use in children aged <18 years.2

Formulations
Elvitegravir is an integrase strand transfer inhibitor that is metabolized rapidly by CYP3A4. Elvitegravir must be used in combination with an HIV PI co-administered with ritonavir and another ARV drug, or in the fixed-dose combination product Stribild,3 which contains 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.4 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 ritonavir plus atazanavir or lopinavir compared to its use with different PIs plus ritonavir, or compared to its use with cobicistat as a component of Stribild. 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.4

Stribild is FDA-approved as a complete ARV regimen in HIV-1-infected ARV-naive adults aged ≥18 years.3 Trials have shown non-inferiority of Stribild to regimens of emtricitabine combined with tenofovir plus ritonavir-boosted atazanavir,5,6 or emtricitabine plus tenofovir plus efavirenz.7,8 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 (eGFR) will be altered, even though the actual GFR might be only minimally changed.9 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 tenofovir 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

Use 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 darunavir/ritonavir, fosamprenavir/ritonavir, or atazanavir/ritonavir in addition to NRTIs. However, 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, and is not generally recommended by the Panel.

A PK study of the adult dosage formulation of EVG/COBI/FTC/TDF in 14 HIV-infected youth median age 16 years (range 13–17 years) and weight 57 kg (range 35–80 kg) suggested that elvitegravir drug exposures in adolescents were similar to those in adults.10 Preliminary week 24 results in 20 patients from a safety and efficacy study in South Africa, the United States, and Thailand, median age 16 years (range 12–17 years) and weight 55 kg (range 35–82 kg) suggested safety and efficacy similar to that seen in adult trials.11 This study is ongoing, with a planned enrollment of 36 participants and duration of 48 weeks to more fully characterize use of EVG/COBI/FTC/TDF in youth aged 12 to 18 years (https://clinicaltrials.gov/ct2/show/NCT01721109).

Use in Children Younger Than 12
Early bioequivalence data of pediatric formulations of both elvitegravir12 and cobicistat13 support progression to Phase II/III studies in children, which are underway.

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. VITEKTA [package insert]. Food and Drug Administration. 2014. Available at http://www.accessdata.fda.gov/drugsatfda_docs/label/2014/203093s000lbl.pdf. Accessed January 30, 2015.
  3. Stribild [package insert]. Food and Drug Administration. 2014. Available at http://www.accessdata.fda.gov/drugsatfda_docs/label/2014/203100s011lbl.pdf. Accessed January 30, 2015.
  4. TYBOST [package insert]. Gilead Sciences. 2014. Available at http://www.gilead.com/~/media/Files/pdfs/medicines/hiv/tybost/tybost_pi.pdf. Accessed January 30, 2015.
  5. 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.
  6. 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.
  7. 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.
  8. 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.
  9. 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.
  10. 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.
  11. Chokephaibulkit C, Gaur A, et al. Safety, efficacy and pharmakokinetics of the integrase inhibitor-based Stribild single-tablet regimen in HIV-infected treatment naive adolescents through 24 weeks. Presented at: 6th International Workshop on HIV Pediatrics. 2014. Melbourne, Australia.
  12. 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.
  13. 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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