Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection

Integrase Inhibitors

Drug Interactions

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

Absorption: Elvitegravir (EVG) plasma concentrations are lower with concurrent administration of divalent cations due to the formation of complexes in the gastrointestinal tract and not due to changes in gastric pH. Therefore, Stribild and Genvoya should be administered at least 4 hours before or after administering antacids and supplements or multivitamins that contain iron, calcium, aluminum, and/or magnesium.¹

• Metabolism: Stribild and Genvoya contain EVG and cobicistat (COBI). EVG is metabolized predominantly by cytochrome P450 (CYP) 3A4, secondarily by uridine diphosphate glucuronyl transferase 1A1/3, and by oxidative metabolism pathways. EVG is a moderate inducer of CYP2C9. COBI is a strong inhibitor of CYP3A4 and a weak inhibitor of CYP2D6. In addition, COBI inhibits the adenosine triphosphate-dependent transporters, P-glycoprotein and the breast cancer resistance protein, and the organic anion-transporting polypeptides OATP1B1 and OATP1B3. See the Cobicistat section for a more detailed summary of drug interactions. Multiple drug interactions are possible when using both EVG and COBI. Neither Stribild nor Genvoya should be administered concurrently with products or regimens that contain ritonavir (RTV), because of the similar effects of COBI and RTV on CYP3A4 metabolism. Coadministration of medications that induce or inhibit CYP3A4 may respectively decrease or increase exposures of EVG and COBI. Coadministration of medications that are CYP3A4 substrates may result in clinically significant adverse reactions that are severe, life-threatening, or fatal, or may result in loss of therapeutic effect if dependent on conversion to an active metabolite due to CYP3A4 inhibition by COBI.
• Renal elimination: Drugs that decrease renal function or compete for active tubular secretion could reduce clearance of tenofovir, in the form of tenofovir disoproxil fumarate (TDF), or emtricitabine (FTC). Concomitant use of nephrotoxic drugs should be avoided when using Genvoya or Stribild. COBI inhibits MATE1, which increases serum creatinine levels up to 0.4 mg/dL from baseline in adults. Creatinine-based calculations of estimated glomerular filtration rate (GFR) will be altered, but the actual GFR might be only minimally changed.² Significant increases in serum creatinine levels >0.4 mg/dL from baseline may represent renal toxicity and should be evaluated. People who experience a confirmed increase in serum creatinine levels should be closely monitored for renal toxicity; clinicians should monitor creatinine levels for further increases and perform a urinalysis to look for evidence of proteinuria or glycosuria.³

Major Toxicities

More common: Nausea, diarrhea, fatigue, headache, flatulence

Less common (more severe): Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported in patients receiving nucleoside reverse transcriptase inhibitors, including TDF and FTC. 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 who were taking TDF; the clinical significance of these changes is not yet known. Evidence of renal toxicity has been observed in patients taking TAF or TDF, including a higher incidence of glycosuria, proteinuria, phosphaturia, and/or calciuria; increases in the levels of serum creatinine and blood urea nitrogen; and decreases in serum phosphate levels. Numerous case reports of renal tubular dysfunction have been reported in patients receiving TAF or TDF; patients at increased risk of renal dysfunction should be closely monitored if they are being treated with Genvoya or Stribild. This nephrotoxicity may be more pronounced in patients with preexisting renal disease.³ Although postmarketing cases of renal impairment have been reported with TAF, Genvoya, which contains tenofovir alafenamide (TAF), has an improved bone and renal safety profile when compared to Stribild, which contains TDF, in children and adults.^4,5 However, Genvoya is associated with greater increases in lipid levels than Stribild, according to findings from large-scale clinical trials in adults.⁶

Resistance

The International Antiviral Society–USA maintains a list of updated resistance mutations and the Stanford University HIV Drug Resistance Database offers a discussion of each mutation. There is phenotypic cross-resistance between EVG and raltegravir.⁷

Pediatric Use

Approval

Genvoya (elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide [EVG/c/FTC/TAF]) is approved by the U.S. Food and Drug Administration (FDA) for use in antiretroviral (ARV)-naive children and adolescents with HIV weighing ≥25 kg with any sexual maturity rating (SMR). It also can be used to replace the current ARV regimen in those who have been virologically suppressed (HIV RNA <50 copies/mL) on a stable ARV regimen for at least 6 months with no history of treatment failure and no known mutations associated with resistance to the individual components of Genvoya.⁶

Stribild (elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate [EVG/c/FTC/TDF]) is approved by the FDA as a complete regimen for use in children and adolescents aged ≥12 years and weighing ≥35 kg. However, the Panel on Antiretroviral Therapy and Medical Management of Children Living with HIV recommends limiting the use of Stribild to adolescents with SMRs of 4 or 5 due to concerns about decreased BMD in pre-pubertal patients. It can also be used to replace the current ARV regimen in those who have been virologically suppressed (HIV RNA <50 copies/mL) on a stable ARV regimen for at least 6 months with no history of treatment failure and no known mutations associated with resistance to the individual components of Stribild.³

Efficacy in Clinical Trials in Adults

EVG/c/FTC/TDF was found to be noninferior to a regimen of efavirenz/emtricitabine/TDF (EFV/FTC/TDF)^8-10 and noninferior to a regimen of atazanavir/ritonavir (ATV/r) plus FTC/TDF in adults through 144 weeks of treatment.^11-13 In two studies, 1,733 adults were randomly assigned to receive either EVG/c/FTC/TDF or EVG/c/FTC/TAF.⁵ After 48 weeks, those receiving EVG/c/FTC/TAF had significantly smaller mean serum creatinine increases (0.08 vs. 0.12 mg/dL; P < 0.0001), significantly less proteinuria (median percent change in protein −3% vs. +20%; P < 0.0001), and a significantly smaller decrease in BMD at the spine (mean percent change −1.30% vs. −2.86%; P < 0.0001) and hip (−0.66% vs. −2.95%; P < 0.0001). Larger increases in fasting lipid levels were observed with EVG/c/FTC/TAF than with EVG/c/FTC/TDF; the median increases in levels of total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, and triglycerides were all higher in patients who received EVG/c/FTC/TAF.

Use of Elvitegravir in Children and Adolescents Weighing ≥25 kg

Studies of EVG/c/FTC/TDF and EVG/c/FTC/TAF in children with HIV aged ≥12 years and weighing ≥35 kg have demonstrated safety and efficacy similar to that seen in adults through 24 weeks and 48 weeks of study, respectively; these formulations are approved by the FDA for use in this age/weight group.¹⁵ EVG/c/FTC/TDF is not approved to treat children weighing <35 kg. EVG/c/FTC/TAF is preferred over EVG/c/FTC/TDF when treating children with SMRs 1 to 3 because EVG/c/FTC/TAF carries a lower risk of renal and bone toxicity than EVG/c/FTC/TDF.⁶ Long-term bone safety data through 96 weeks with EVG/c/FTC/TAF in adolescents weighing ≥35 kg revealed no concerns for toxicity in this age group on the basis of BMD (median change from baseline spine BMD height-age [HA] z-score +0.14 and total body less head [TBLH] HA z score of −0.07) and serum biomarkers of bone formation and resorption.¹⁶

EVG/c/FTC/TAF is FDA-approved to treat children with any SMR weighing ≥25 kg; this approval was based on 24 weeks of data in 23 children.¹⁷ In this study, children who had been virologically suppressed (HIV RNA <50 copies/mL) for at least 6 months were switched from their current regimens to EVG/c/FTC/TAF. No study discontinuations occurred due to medication toxicity, but a concerning decline in CD4 T lymphocyte (CD4) cell counts was observed in all 23 children over the first 24 weeks of EVG/c/FTC/TAF treatment. CD4 counts declined by a median of 130 cells/mm³ (with a range of −472 cells/mm³ to 266 cells/mm³) from baseline. However, after enrolling additional children (for a total of 52 participants), the median CD4 count decline at 48 weeks was 25 cells/mm³ and at 96 weeks was 45 cells/mm³.¹⁸ Additionally, the CD4 percentage did not significantly change across Weeks 24, 48, and 96.¹⁹ The mechanism for the reduction in CD4 count is unclear, and this reduction has only been reported in this study. Plasma exposures of all four drugs were higher in these children than the plasma exposures seen in historical data from adults, but no association was identified between plasma exposures of the four components of EVG/c/FTC/TAF and CD4 counts.²⁰ Long-term bone safety data with EVG/c/FTC/TAF through 96 weeks revealed no concerns for toxicity in this cohort on the basis of BMD (median change from baseline spine BMD HA z-score of −0.2 and TBLH HA z-score of −0.32) and serum biomarkers of bone formation and resorption.¹⁹

A retrospective analysis of integrase strand transfer inhibitor (INSTI) use in children and adolescents showed that 83.7% (61/73) of patients on an EVG/c-containing therapy continued their prescribed regimen through the end of the study follow-up period (median [interquartile range] 2.0 [1.4–2.7] years of exposure). Treatment interruption due to virologic occurred in 4.1% (3/73) of those on EVG/c, which was comparable to that of dolutegravir (DTG)-based regimens (3.7% [5 of 134 participants]) and lower than RAL-based regimens (17.3% [19 of 110 participants]). Two of the participants who experienced virologic failures with EVG had major INSTI drug resistance mutations, but both attained virologic suppression after switching to regimens containing darunavir (DRV) or DRV with DTG.²¹

Use of Elvitegravir in Children Weighing 14 to < 25 kg

EVG/c/FTC/TAF is not approved to treat children weighing <25 kg.^3,6 A pharmacokinetic (PK), safety, and efficacy study with a low-dose tablet in children aged ≥2 years and weighing ≥14 kg to <25 kg is ongoing.²¹ In this study, children had to be virologically suppressed (HIV RNA <50 copies/mL) for at least 6 months prior to entry. Virologic suppression was maintained¹⁹ in 27 (100%) of 27 children at Week 16, 26 (96%) of 27 children at Week 24, and 26 (96%) of 27 children at Week 48. No participant discontinued the study drug because of adverse events or met criteria for resistance analyses through Week 48. CD4 counts decreased¹⁹ by a mean of 187 cells/mm³ between baseline and Week 48, although the CD4 percentage did not differ (mean [standard deviation (SD)] change of 0.0 [<5.0]). At least 90% of children reported that swallowing the low-dose tablet was “easy” or “super easy” and perceived the tablet size when swallowing as “okay” at baseline, Week 4, and Week 24.²¹ Long-term bone safety data with the low-dose formulation through 48 weeks revealed no concerns for bone safety in this cohort¹⁶ on the basis of BMD (median change from baseline in spine BMD HA z-score +0.14 and TBLH HA z-score of −0.06) and serum biomarkers of bone formation and resorption.

Pharmacokinetics

EVG/c/FTC/TDF (Stribild)

The PKs of EVG 150 mg, COBI 150 mg, FTC 200 mg, and TDF 300 mg as a fixed-dose combination (FDC) tablet were evaluated in 14 treatment-naive adolescents with HIV between 12 and <18 years of age and weighing ≥35 kg.¹⁴ EVG area under the plasma concentration versus time curve over the dosing interval (AUC_tau) and peak concentrations (C_max) were 30% higher (90% confidence interval [CI], 105-162%) and 42% higher (90% CI, 116-173%), respectively, in comparison to historical data in adults. EVG concentrations at the end of the dosing interval (C_tau) were 6% higher (90% CI, 70-160%) than in adults, and approximately ninefold higher than the protein-adjusted 95% inhibitory concentration (PA-IC₉₅) of 44.5 ng/mL for EVG. COBI, FTC, and TFV exposures were comparable to those measured in adults.

EVG/c/FTC/TAF (Genvoya)

The PK of EVG 150 mg, COBI 150 mg, FTC 200 mg, and TAF 10 mg as an FDC tablet have been evaluated in adolescents 12 to <18 years of age weighing ≥35 kg¹⁴ and children 6 to <12 years of age weighing ≥25 kg.¹⁷ AUC_tau, C_max, and C_tau for EVG, COBI, FTC, TAF, and TFV were comparable to or higher than those measured in adults with HIV in both cohorts (see Tables B and C below).

The PK of a low-dose FDC tablet containing EVG 90 mg, COBI 90 mg, FTC 120 mg, and TAF 6 mg were evaluated in 27 children with HIV weighing ≥14 kg and <25 kg.²¹ EVG and TAF AUC_tau were higher in comparison to historical data in adults receiving full-strength Genvoya (see Tables B and C below). EVG C_tau was 21% lower (90% CI [53.1-117%]) in children versus adults but was approximately 4.4‑fold higher and ninefold higher than the PA-IC₉₅ and PA-IC₅₀ for wild-type virus, respectively. However, EVG C_tau measured in this cohort was lower than those previously measured in children and adolescents weighing ≥25 kg with EVG at the 150‑mg dose. COBI, FTC, and TFV exposures were all comparable to or higher than historical data in adults.

Formulations

EVG is an INSTI that is metabolized by CYP3A4. EVG is only available in the FDC products Stribild³ or Genvoya,⁶ both of which contain COBI (see below). COBI itself does not have ARV activity, but it is a CYP3A4 inhibitor that acts as a PK enhancer, similar to RTV.²²

Coadministration of Elvitegravir, Cobicistat, and Darunavir

The combination of Stribild or Genvoya plus darunavir (DRV) may provide a low pill-burden regimen for antiretroviral therapy-experienced individuals. However, an unfavorable drug interaction between EVG/c and DRV is possible, and the available data on the magnitude of the interaction are conflicting. Data on the efficacy of the combination in adults also are conflicting.^23-29

The most rigorous drug interaction study, performed in HIV-seronegative adults, found 21% lower DRV trough concentrations (C_trough) and 52% lower EVG C_trough with DRV 800 mg plus EVG/c 150 mg/150 mg once daily compared to the administration of either darunavir/cobicistat 800 mg/150 mg once daily or EVG/c 150 mg/150 mg once daily alone.²³ The actual C_trough were 1,050 ng/mL for DRV and 243 ng/mL for EVG.

Despite the findings of the aforementioned drug interaction study in HIV-seronegative adults, the most rigorous efficacy evaluation found that among 89 treatment-experienced adults who were receiving five-tablet ARV regimens, 96.6% achieved virologic suppression (HIV RNA <50 copies/mL) 24 weeks after simplifying their regimens to a two-tablet regimen of Genvoya plus DRV 800 mg once daily.²⁷ Intensive PK sampling was performed in 15 of these patients (17%). Mean DRV and EVG C_trough were 1,250 ng/mL and 464 ng/mL, respectively.

Given the uncertainty around the true magnitude of the drug interaction and the absence of data in children, this combination should be used with caution in children.

References

1. Ramanathan S, Mathias A, Wei X, et al. Pharmacokinetics of once-daily boosted elvitegravir when administered in combination with acid-reducing agents. J Acquir Immune Defic Syndr. 2013;64(1):45-50. Available at: https://journals.lww.com/jaids/Fulltext/2013/09010/Pharmacokinetics_of_Once_Daily_Boosted.8.aspx.
2. 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: https://www.ncbi.nlm.nih.gov/pubmed/22732469.
3. Stribild (elvitegravir, cobicitstat, emtricitabine, tenofovir disoproxil fumarate) [package insert]. Food and Drug Administration. 2020. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/203100s035lbl.pdf.
4. Sharma S, Gupta S, Majeed S, et al. Exposure-safety of tenofovir in pediatic HIV-infected participants: comparison of tenofovir alafenamide & tenofovir disoproxil fumarate. Abstract 23. Presented at: 10th International Workshop on HIV Pediatrics 2018. Amsterdam, The Netherlands. Available at: https://academicmedicaleducation.com/meeting/international-workshop-hiv-pediatrics-2018/slide-set/32wsharma?check_logged_in=1.
5. 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: https://www.ncbi.nlm.nih.gov/pubmed/25890673.
6. Genvoya (elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide) [package insert]. Food and Drug Administration. 2022. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/207561s029lbl.pdf.
7. 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: https://www.ncbi.nlm.nih.gov/pubmed/22450969.
8. Stribild (elvitegravir, cobicistat, emtricitabine, tenofovir disoproxil fumarate) [package insert]. Food and Drug Administration. 2021. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/203100s036lblet.pdf.
9. 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: https://www.ncbi.nlm.nih.gov/pubmed/22748591.
10. 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: https://www.ncbi.nlm.nih.gov/pubmed/23392460.
11. Wohl DA, Cohen C, Gallant JE, et al. A randomized, double-blind comparison of single-tablet regimen elvitegravir/cobicistat/emtricitabine/tenofovir DF versus single-tablet regimen efavirenz/emtricitabine/tenofovir DF for initial treatment of HIV-1 infection: analysis of week 144 results. J Acquir Immune Defic Syndr. 2014;65(3):e118-120. Available at: https://www.ncbi.nlm.nih.gov/pubmed/24256630.
12. 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;62(5):483-486. Available at: https://www.ncbi.nlm.nih.gov/pubmed/23337366.
13. 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: https://www.ncbi.nlm.nih.gov/pubmed/22748590.
14. Clumeck N, Molina JM, Henry K, et al. A randomized, double-blind comparison of single-tablet regimen elvitegravir/cobicistat/emtricitabine/tenofovir DF vs ritonavir-boosted atazanavir plus emtricitabine/tenofovir DF for initial treatment of HIV-1 infection: analysis of week 144 results. J Acquir Immune Defic Syndr. 2014;65(3):e121-124. Available at: https://www.ncbi.nlm.nih.gov/pubmed/24346640.
15. Gaur AH, Kizito H, Prasitsueubsai W, et al. Safety, efficacy, and pharmacokinetics of a single-tablet regimen containing elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide in treatment-naive, HIV-infected adolescents: a single-arm, open-label trial. Lancet HIV. 2016;3(12):e561-e568. Available at: https://www.ncbi.nlm.nih.gov/pubmed/27765666.
16. Rakhmanina N GC, Natukunda E, Kosalaraksa P, Anugulruengkitt S, Shao Y, Maxwell H, O’Connor C, et al. Effects of long-term treatment with elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide fumarate (E/C/F/TAF) on bone safety parameters in children and adolescents living with HIV [Abstract 64]. Presented at: International Workshop on HIV Pediatrics 2021. Virtual Meeting. Available at: https://academicmedicaleducation.com/meeting/international-workshop-hiv-pediatrics-2021/abstract.
17. Natukunda E, Gaur A, Kosalaraksa P, et al. Safety, efficacy, and pharmacokinetics of single-tablet elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide in virologically suppressed, HIV-infected children: a single-arm, open-label trial. Lancet Child Adolescent Health. 2017;1(1):27-34. Available at: https://www.sciencedirect.com/science/article/pii/S2352464217300093?via%3Dihub.
18. Rakhmanina N, Natukunda E, Kosalaraksa P, Batra J, Gaur A, et al. Safety and efficacy of E/C/F/TAF in virologically suppressed, HIV-infected children through 96 weeks. Abstract 22. Presented at: 11th International Workshop on HIV Pediatrics; 2019. Mexico City, Mexico.
19. Anugulruengkitt S, A. Gaur, P. Kosalaraksa, A. Liberty, Y. Shao, et al. . Long-term safety & efficacy of elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide fumarate (E/C/F/TAF) single-tablet regimen in children and adolescents living with HIV [abstract 4]. Presented at: International Workshop on HIV Pediatrics 2021. Virtual Meeting. Available at: https://www.natap.org/2021/IAS/IAS_79.htm.
20. Bell T, Baylor M, Rhee S, et al. FDA analysis of CD4+ cell count declines observed in HIV-infected children treated with elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide. Open Forum Infect Dis. 2018;5. Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6253452/
21. Torres-Fernandez D, Jimenez de Ory S, Fortuny C, et al. Integrase inhibitors in children and adolescents: clinical use and resistance. J Antimicrob Chemother. 2022;77(10):2784-2792. Available at: https://www.ncbi.nlm.nih.gov/pubmed/35971971.
22. Natukunda E, Liberty A, Strehlau R, et al. Safety, pharmacokinetics and efficacy of low-dose E/C/F/TAF in virologically suppressed children ≥2 years old living with HIV. Abstract OALB0101. Presented at: International AIDS Conference; 2020. Virtual Meeting. Available at: https://academicmedicaleducation.com/meeting/international-workshop-hiv-pediatrics-2020/abstract/safety-pharmacokinetics-and-efficacy.
23. Stribild (elvitegravir, cobicitstat, emtricitabine, tenofovir disoproxil fumarate) [package insert]. Food and Drug Administration. 2021. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/203100s036lblet.pdf.
24. Tybost (cobicistat) [package insert]. Food and Drug Administration. 2020. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/203094s015lbl.pdf.
25. Ramanathan S, Wang H, Szwarcberg J, Kearney BP. Safety/tolerability, pharmacokinetics, and boosting of twice-daily cobicistat administered alone or in combination with darunavir or tipranavir. Abstract P-08. Presented at: 13th International Workshop on Clinical Pharmacology of HIV Therapy. 2012. Barcelona, Spain. Available at: https://www.natap.org/2012/pharm/Pharm_28.htm.
26. Diaz A, Moreno A, Gomez-Ayerbe C, et al. Role of EVG/COBI/FTC/TDF (Quad) plus darunavir regimen in clinical practice Presented at: 21st International AIDS Conference (AIDS 2016). 2016. Durban, South Africa.
27. Gutierrez-Valencia A, Benmarzouk-Hidalgo OJ, Llaves S, et al. Pharmacokinetic interactions between cobicistat-boosted elvitegravir and darunavir in HIV-infected patients. J Antimicrob Chemother. 2017;72(3):816-819. Available at: https://www.ncbi.nlm.nih.gov/pubmed/27999051.
28. Harris M, Ganase B, Watson B, Harrigan PR, Montaner JSG, Hull MW. HIV treatment simplification to elvitegravir/cobicistat/emtricitabine/tenofovir disproxil fumarate (E/C/F/TDF) plus darunavir: a pharmacokinetic study. AIDS Res Ther. 2017;14(1):59. Available at: https://www.ncbi.nlm.nih.gov/pubmed/29096670.
29. 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.
30. Naccarato MJ, Yoong DM, Fong IW, Gough KA, Ostrowski MA, Tan DHS. Combination therapy with tenofovir disoproxil fumarate/emtricitabine/elvitegravir/cobicistat plus darunavir once daily in antiretroviral-naive and treatment-experienced patients: a retrospective review. J Int Assoc Provid AIDS Care. 2018;17:2325957417752260. Available at: https://www.ncbi.nlm.nih.gov/pubmed/29385867.
31. Ricard F, Wong A, Lebouche B, et al. Low darunavir concentrations in patients receiving Stribild (elvitegravir/cobicistat/emtricitabine/tenofovir disproxil fumarate) and darunavir once daily. Abstract 50. Presented at: 16th International Workshop on Clinical Pharmacology of HIV and Hepatitis Therapy; 2015. Washington, DC. Available at: https://www.natap.org/2015/Pharm/Pharm_04.htm.