Abstract
Bictegravir, cabotegravir, dolutegravir, elvitegravir, and raltegravir are members of the latest class of antiretrovirals available to treat human immunodeficiency virus (HIV) infection, the integrase strand transfer inhibitors. Integrase strand transfer inhibitors are potent inhibitors of the HIV integrase enzyme with IC90/95 values in the low nanogram per milliliter range and they retain antiviral activity against strains of HIV with acquired resistance to other classes of antiretrovirals. Each of the integrase strand transfer inhibitors have unique pharmacokinetic/pharmacodynamic properties, influencing their role in clinical use in specific subsets of patients. Cabotegravir, approved for use in Canada but not yet by the US Food and Drug Administration, is formulated in both oral and intramuscular formulations; the latter of which has shown efficacy as a long-acting extended-release formulation. Cabotegravir, raltegravir, and dolutegravir have minimal drug–drug interaction profiles, as their metabolism has minimal cytochrome P450 involvement. Conversely, elvitegravir metabolism occurs primarily via cytochrome P450 3A4 and requires pharmacokinetic boosting to achieve systemic exposures amenable to once-daily dosing. Bictegravir metabolism has similar contributions from both cytochrome P450 3A4 and uridine 5ʹ-diphospho-glucuronosyltransferase 1A1. Bictegravir, dolutegravir, and raltegravir are recommended components of initial regimens for most people with HIV in the US adult and adolescent HIV treatment guidelines. This review summarizes and compares the pharmacokinetics and pharmacodynamics of the integrase strand transfer inhibitor agents, and describes specific pharmacokinetic considerations for persons with hepatic impairment, renal dysfunction, pregnancy, and co-infections.
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References
Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. Department of Health and Human Services. http://aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf. Accessed 30 Jan 2020.
World Health Organization. Update of recommendations on first- and second-line antiretroviral regimens. WHO/CDS/HIV/19.15; Licence: CC BY-NC-SA 3.0 IGO. Geneva: World Health Organization; 2019.
Podany AT, Scarsi KK, Fletcher CV. Comparative clinical pharmacokinetics and pharmacodynamics of HIV-1 integrase strand transfer inhibitors. Clin Pharmacokinet. 2017;56(1):25–40.
Bictarvey® [package insert]. Foster City (CA): Gilead Sciences; Feb 2018.
Zhang HCJ, Wei X, Wang H, Vu A, Ling J, Martin H, et al. Clinical pharmacology of the HIV integrase strand transfer inhibitor bictegravir. Conference on Retroviruses and Opportunistic Infections; Seattle, WA. Feb 13–16, 2017.
Gallant JE, Thompson M, DeJesus E, Voskuhl GW, Wei X, Zhang H, et al. Antiviral activity, safety, and pharmacokinetics of bictegravir as 10-day monotherapy in HIV-1-infected adults. J Acquir Immune Defic Syndr. 2017;75(1):61–6.
Orkin C, Arasteh K, Hernández-Mora MG, Pokrovsky V, Overton ET, Girard P-M, et al. Long-acting cabotegravir and rilpivirine after oral induction for HIV-1 Infection. New England J Med. 2020;382(12):1124–35.
Swindells S, Andrade-Villanueva J, Richmond G, Rizzardini G, Baumgarten A, et al. Long-acting cabotegravir and rilpivirine for maintenance of HIV-1 suppression. New England J Med. 2020;382(12):1112–23.
Spreen W, Min S, Ford S, Chen S, Lou Y, Bomar M, et al. Pharmacokinetics, safety, and monotherapy antiviral activity of GSK1265744, an HIV integrase strand transfer inhibitor. HIV Clin Trials. 2013;14(5):192–203.
Patel P, Ford SL, Lou Y, Bakshi K, Tenorio AR, Zhang Z, et al. Effect of a high-fat meal on the pharmacokinetics of the HIV integrase inhibitor cabotegravir. Clin Pharmacol Drug Dev. 2019;8(4):443–8.
Bowers GD, Culp A, Reese MJ, Tabolt G, Moss L, Piscitelli S, et al. Disposition and metabolism of cabotegravir: a comparison of biotransformation and excretion between different species and routes of administration in humans. Xenobiotica. 2016;46(2):147–62.
Ford SL, Gould E, Chen S, Lou Y, Dumont E, Spreen W, et al. Effects of etravirine on the pharmacokinetics of the integrase inhibitor S/GSK1265744. Antimicrob Agents Chemother. 2013;57(1):277–80.
Song I, Borland J, Min S, Lou Y, Chen S, Patel P, et al. Effects of etravirine alone and with ritonavir-boosted protease inhibitors on the pharmacokinetics of dolutegravir. Antimicrob Agents Chemother. 2011;55(7):3517–21.
Spreen W, Ford SL, Chen S, Wilfret D, Margolis D, Gould E, et al. GSK1265744 pharmacokinetics in plasma and tissue after single-dose long-acting injectable administration in healthy subjects. J Acquir Immune Defic Synd. 2014;67(5):481–6.
Spreen W, Williams P, Margolis D, Ford SL, Crauwels H, Lou Y, et al. Pharmacokinetics, safety, and tolerability with repeat doses of GSK1265744 and rilpivirine (TMC278) long-acting nanosuspensions in healthy adults. J Acquir Immune Defic Synd. 2014;67(5):487–92.
Tivicay® [package insert]. Research Triangle Park (NC): Viiv Healthcare; Aug 2015.
Song I, Borland J, Chen S, Patel P, Wajima T, Peppercorn A, et al. Effect of food on the pharmacokinetics of the integrase inhibitor dolutegravir. Antimicrob Agents Chemother. 2012;56(3):1627–9.
Weller S, Chen S, Borland J, Savina P, Wynne B, Piscitelli SC. Bioequivalence of a dolutegravir, abacavir, and lamivudine fixed-dose combination tablet and the effect of food. J Acquir Immune Defic Synd. 2014;66(4):393–8.
Min S, Song I, Borland J, Chen S, Lou Y, Fujiwara T, et al. Pharmacokinetics and safety of S/GSK1349572, a next-generation HIV integrase inhibitor, in healthy volunteers. Antimicrob Agents Chemother. 2010;54(1):254–8.
Min S, Sloan L, DeJesus E, Hawkins T, McCurdy L, Song I, et al. Antiviral activity, safety, and pharmacokinetics/pharmacodynamics of dolutegravir as 10-day monotherapy in HIV-1-infected adults. AIDS. 2011;25(14):1737–45.
Reese MJ, Savina PM, Generaux GT, Tracey H, Humphreys JE, Kanaoka E, et al. In vitro investigations into the roles of drug transporters and metabolizing enzymes in the disposition and drug interactions of dolutegravir, a HIV integrase inhibitor. Drug Metab Dispos. 2013;41(2):353–61.
Castellino S, Moss L, Wagner D, Borland J, Song I, Chen S, et al. Metabolism, excretion, and mass balance of the HIV-1 integrase inhibitor dolutegravir in humans. Antimicrob Agents Chemother. 2013;57(8):3536–46.
van Lunzen J, Maggiolo F, Arribas JR, Rakhmanova A, Yeni P, Young B, et al. Once daily dolutegravir (S/GSK1349572) in combination therapy in antiretroviral-naive adults with HIV: planned interim 48 week results from SPRING-1, a dose-ranging, randomised, phase 2b trial. Lancet Infect Dis. 2012;12(2):111–8. https://doi.org/10.1016/S1473-3099(11)70290-0.
Raffi F, Jaeger H, Quiros-Roldan E, Albrecht H, Belonosova E, Gatell JM, et al. Once-daily dolutegravir versus twice-daily raltegravir in antiretroviral-naive adults with HIV-1 infection (SPRING-2 study): 96 week results from a randomised, double-blind, non-inferiority trial. Lancet Infect Dis. 2013;13(11):927–35. https://doi.org/10.1016/S1473-3099(13)70257-3.
Zhang J, Hayes S, Sadler BM, Minto I, Brandt J, Piscitelli S, et al. Population pharmacokinetics of dolutegravir in HIV-infected treatment-naive patients. Br J Clin Pharmacol. 2015;80(3):502–14.
Vitekta® [package insert]. Foster City (CA): Gilead Sciences, Inc.; Jul 2015.
Stribild® [package insert]. Foster City (CA): Gilead Sciences, Inc.; Jul 2015.
Genvoya® [package insert]. Foster City (CA): Gilead Sciences, Inc.; Nov 2015.
Kawaguchi I, Ishikawa T, Ishibashi M, Irie S, Kakee A, editors. Safety and pharmacokinetics of single oral dose of JTK-303/GS-9137, a novel HIV integrase inhibitor, in healthy volunteers. 13th Conference on Retroviruses and Opportunistic Infections; Denver, CO. Feb 5–8, 2006.
Kearney B, Mathias A, Zhong L, editors. Pharmacokinetics/pharmacodynamics of GS-9137 an HIV integrase inhibitor in treatment-naive and experienced patients. International Workshop on Clinical Pharmacology of HIV Therapy; 2006.
German P, Warren D, West S, Hui J, Kearney BP. Pharmacokinetics and bioavailability of an integrase and novel pharmacoenhancer-containing single-tablet fixed-dose combination regimen for the treatment of HIV. J Acquir Immune Defic Synd. 2010;55(3):323–9.
DeJesus E, Berger D, Markowitz M, Cohen C, Hawkins T, Ruane P, et al. Antiviral activity, pharmacokinetics, and dose response of the HIV-1 integrase inhibitor GS-9137 (JTK-303) in treatment-naive and treatment-experienced patients. J Acquir Immune Defic Synd. 2006;43(1):1–5.
German P, Warren D, Wei L, Zhong L, Hui J, Kearney B, editors. Effect of food on pharmacokinetics of elvitegravir, emtricitabine, tenofovir DF and the pharmacoenhancer GS-9350 as a fixed-dose combination tablet. 49th Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC); 2009; San Francisco (CA). Sep 12-15, 2009
Shiomi M, Matsuki S, Ikeda A, Ishikawa T, Nishino N, Kimura M, et al. Effects of a protein-rich drink or a standard meal on the pharmacokinetics of elvitegravir, cobicistat, emtricitabine and tenofovir in healthy Japanese male subjects: a randomized, three-way crossover study. J Clin Pharmacol. 2014;54(6):640–8.
Patel P, Song I, Borland J, Patel A, Lou Y, Chen S, et al. Pharmacokinetics of the HIV integrase inhibitor S/GSK1349572 co-administered with acid-reducing agents and multivitamins in healthy volunteers. J Antimicrob Chemother. 2011;66(7):1567–72.
Ramanathan S, Shen G, Hinkle J, Enejosa J, Kearney B, editors. Pharmacokinetic evaluation of drug interactions with ritonavir-boosted HIV integrase inhibitor GS-9137 (elvitegravir) and acid-reducing agents. 8th International Workshop on Clinical Pharmacology of HIV Therapy; April 16–18, 2007. Budapest, Hungary.
Ramanathan S, Wright M, West S, Kearney B, editors. Pharmacokinetics, metabolism, and excretion of ritonavir-boosted GS-9137 (elvitegravir). 8th International Workshop on Clinical Pharmacology of HIV Therapy; April 16–18, 2007. Budapest, Hungary.
Isentress® [package insert]. Whitehouse Station (NJ): Merck & Co., Inc.; May 2017.
Siccardi M, D’Avolio A, Rodriguez-Novoa S, Cuenca L, Simiele M, Baietto L, et al. Intrapatient and interpatient pharmacokinetic variability of raltegravir in the clinical setting. Ther Drug Monit. 2012;34(2):232–5.
Kiser JJ, Bumpass JB, Meditz AL, Anderson PL, Bushman L, Ray M, et al. Effect of antacids on the pharmacokinetics of raltegravir in human immunodeficiency virus-seronegative volunteers. Antimicrob Agents Chemother. 2010;54(12):4999–5003.
Arab-Alameddine M, Fayet-Mello A, Lubomirov R, Neely M, di Iulio J, Owen A, et al. Population pharmacokinetic analysis and pharmacogenetics of raltegravir in HIV-positive and healthy individuals. Antimicrob Agents Chemother. 2012;56(6):2959–66.
Brainard DM, Friedman EJ, Jin B, Breidinger SA, Tillan MD, Wenning LA, et al. Effect of low-, moderate-, and high-fat meals on raltegravir pharmacokinetics. J Clin Pharmacol. 2011;51(3):422–7.
Iwamoto M, Wenning L, Petry A, Laethem M, De Smet M, Kost J, et al. Safety, tolerability, and pharmacokinetics of raltegravir after single and multiple doses in healthy subjects. Clin Pharmacol Ther. 2008;83(2):293–9.
Markowitz M, Morales-Ramirez JO, Nguyen B-Y, Kovacs CM, Steigbigel RT, Cooper DA, et al. Antiretroviral activity, pharmacokinetics, and tolerability of MK-0518, a novel inhibitor of HIV-1 integrase, dosed as monotherapy for 10 days in treatment-naive HIV-1-infected individuals. J Acquir Immune Defic Synd. 2006;43(5):509–15.
Petry A, Wenning L, Laethem M, De Smet M, Kost J, Merschman S et al., editors. Safety, tolerability, and pharmacokinetics after single and multiple doses of MK-0518 in healthy subjects. 46th Interscience Conference on Antimicrobial Agents and Chemotherapy; Sep 27–30 2006. San Francisco, CA.
Kassahun K, McIntosh I, Cui D, Hreniuk D, Merschman S, Lasseter K, et al. Metabolism and disposition in humans of raltegravir (MK-0518), an anti-AIDS drug targeting the human immunodeficiency virus 1 integrase enzyme. Drug Metab Dispos. 2007;35(9):1657–63.
Wenning L, Petry A, Kost J, Jin B, Breidinger S, DeLepeleire I, et al. Pharmacokinetics of raltegravir in individuals with UGT1A1 polymorphisms. Clin Pharmacol Ther. 2009;85(6):623–7.
Eron JJ Jr, Rockstroh JK, Reynes J, Andrade-Villanueva J, Ramalho-Madruga JV, Bekker LG, et al. Raltegravir once daily or twice daily in previously untreated patients with HIV-1: a randomised, active-controlled, phase 3 non-inferiority trial. Lancet Infect Dis. 2011;11(12):907–15. https://doi.org/10.1016/S1473-3099(11)70196-7.
Rizk ML, Hang Y, Luo W-L, Su J, Zhao J, Campbell H, et al. Pharmacokinetics and pharmacodynamics of once-daily versus twice-daily raltegravir in treatment-naive HIV-infected patients. Antimicrob Agents Chemother. 2012;56(6):3101–6.
Cahn P, Kaplan R, Sax PE, Squires K, Molina J-M, Avihingsanon A, et al. Raltegravir 1200 mg once daily versus raltegravir 400 mg twice daily, with tenofovir disoproxil fumarate and emtricitabine, for previously untreated HIV-1 infection: a randomised, double-blind, parallel-group, phase 3, non-inferiority trial. Lancet HIV. 2017;4(11):e486–94.
Debinski HS, Lee CS, Danks JA, Mackenzie PI, Desmond PV. Localization of uridine 5ʹ-diphosphate-glucuronosyltransferase in human liver injury. Gastroenterology. 1995;108(5):1464–9.
Furlan V, Demirdjian S, Bourdon O, Magdalou J, Taburet AM. Glucuronidation of drugs by hepatic microsomes derived from healthy and cirrhotic human livers. J Pharmacol Exp Ther. 1999;289(2):1169–75.
George J, Murray M, Byth K, Farrell GC. Differential alterations of cytochrome P450 proteins in livers from patients with severe chronic liver disease. Hepatology. 1995;21(1):120–8.
Cabenuva® [prescribing information]. Toronto (ON): Janssen; Mar 2020.
Zhang H, Shao Y, Garner W, et al. The effect of hepatic or renal impairment on bictegravir pharmacokinetics. Presented at the 18th International Workshop on Clinical Pharmacology of Antiviral Therapy; June 14–16, 2017. Chicago, IL.
Shaik JSB, Ford SL, Lou Y, Zhang Z, Bakshi KK, Tenorio AR, et al. A phase 1 study to evaluate the pharmacokinetics and safety of cabotegravir in patients with hepatic impairment and healthy matched controls. Clin Pharmacol Drug Dev. 2019;8(5):664–73.
Song IH, Borland J, Savina PM, Chen S, Patel P, Wajima T, et al. Pharmacokinetics of single-dose dolutegravir in HIV-seronegative subjects with moderate hepatic impairment compared to healthy matched controls. Clin Pharmacol Drug Dev. 2013;2(4):342–8. https://doi.org/10.1002/cpdd.55.
US Food and Drug Administratio. Dolutegravir. 2013. http://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/204790Orig1s000ClinPharmR.pdf. Accessed 18 Feb 2016.
Custodio JM, Rhee M, Shen G, Ling KH, Kearney BP, Ramanathan S. Pharmacokinetics and safety of boosted elvitegravir in subjects with hepatic impairment. Antimicrob Agents Chemother. 2014;58(5):2564–9. https://doi.org/10.1128/aac.02180-13.
US Food and Drug Administration. Elvitegravir. 2011. http://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/203100Orig1s000ClinPharmR.pdf. Accessed 18 Feb 2016.
Iwamoto M, Hanley WD, Petry AS, Friedman EJ, Kost JT, Breidinger SA, et al. Lack of a clinically important effect of moderate hepatic insufficiency and severe renal insufficiency on raltegravir pharmacokinetics. Antimicrob Agents Chemother. 2009;53(5):1747–52. https://doi.org/10.1128/aac.01194-08.
Calza L, Danese I, Colangeli V, Manfredi R, Magistrelli E, Verucchi G, et al. Plasma concentrations of efavirenz, darunavir/ritonavir and raltegravir in HIV-HCV-coinfected patients without liver cirrhosis in comparison with HIV-monoinfected patients. Infect Dis (Lond). 2015;47(9):625–36. https://doi.org/10.3109/23744235.2015.1034169.
Hernandez-Novoa B, Moreno A, Perez-Elias MJ, Quereda C, Dronda F, Casado JL, et al. Raltegravir pharmacokinetics in HIV/HCV-coinfected patients with advanced liver cirrhosis (Child-Pugh C). J Antimicrob Chemother. 2014;69(2):471–5. https://doi.org/10.1093/jac/dkt386.
Barau C, Braun J, Vincent C, Haim-Boukobza S, Molina JM, Miailhes P, et al. Pharmacokinetic study of raltegravir in HIV-infected patients with end-stage liver disease: the LIVERAL-ANRS 148 study. Clin Infect Dis. 2014;59(8):1177–84. https://doi.org/10.1093/cid/ciu515.
Parasrampuria R, Ford SL, Lou Y, Fu C, Bakshi KK, Tenorio AR, et al. A phase I study to evaluate the pharmacokinetics and safety of cabotegravir in adults with severe renal impairment and healthy matched control participants. Clin Pharmacol Drug Dev. 2019;8(5):674–81.
Weller S, Borland J, Chen S, Johnson M, Savina P, Wynne B, et al. Pharmacokinetics of dolutegravir in HIV-seronegative subjects with severe renal impairment. Eur J Clin Pharmacol. 2014;70(1):29–35. https://doi.org/10.1007/s00228-013-1590-9.
German P, Wei X, Mizuno V, Cheng A, Kearney B, Mathias A, editors. Pharmacokinetics of elvitegravir and cobicistat in subjects with severe renal impairment. 13th International Workshop on Clinical Pharmacology of HIV Therapy; April 16–18, 2012. Barcelona, Spain.
Pozniak A, Arribas JR, Gathe J, Gupta SK, Post FA, Bloch M, 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, multi-center, open-label, phase 3 study. J Acquir Immune Defic Syndr. 2016;71(5):530–7. https://doi.org/10.1097/qai.0000000000000908.
Eron JJ Jr, Lelievre J-D, Kalayjian R, Slim J, Wurapa AK, Stephens JL, et al. Safety of elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide in HIV-1-infected adults with end-stage renal disease on chronic haemodialysis: an open-label, single-arm, multicentre, phase 3b trial. Lancet HIV. 2019;6(1):e15–24.
Eron JJ, Lelievre J-D, Kalayjian R, Slim J, Wurapa AK, Stephens JL, et al., editors. Longer-term safety and efficacy of elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide in virologically suppressed adults living with HIV and end-stage renal disease on chronic hemodialysis. Open Forum Infectious Diseases. New York (NY): Oxford University Press; 2019.
Colbers A, Greupink R, Burger D. Pharmacological considerations on the use of antiretrovirals in pregnancy. Curr Opin Infect Dis. 2013;26(6):575–88. https://doi.org/10.1097/QCO.0000000000000017.
Jeong H, Choi S, Song JW, Chen H, Fischer JH. Regulation of UDP-glucuronosyltransferase (UGT) 1A1 by progesterone and its impact on labetalol elimination. Xenobiotica. 2008;38(1):62–75. https://doi.org/10.1080/00498250701744633.
van der Galiën R, ter Heine R, Greupink R, Schalkwijk SJ, van Herwaarden AE, Colbers A, et al. Pharmacokinetics of HIV-integrase inhibitors during pregnancy: mechanisms, clinical implications and knowledge gaps. Clin Pharmacokinet. 2019;58(3):309–23.
McCormack SA, Best BM. Protecting the fetus against HIV infection: a systematic review of placental transfer of antiretrovirals. Clin Pharmacokinet. 2014;53(11):989–1004. https://doi.org/10.1007/s40262-014-0185-7.
Panel on Treatment of HIV-Infected Pregnant Women and Prevention of Perinatal Transmission. Recommendations for use of antiretroviral drugs in pregnant HIV-1-infected women for maternal health and interventions to reduce perinatal HIV transmission in the United States. Available from http://aidsinfo.nih.gov/contentfiles/lvguidelines/PerinatalGL.pdf. Accessed 30 Jan 2020.
Patel P TS, Ford S, Margolis DA, Romach BH, Baker M, Sutton K, et al. Cabotegravir pharmacokinetic tail in pregnancy and neonatal outcomes. Conference on Retroviruses and Opportunistic Infections; 8–11 March, 2020; Boston (MA): abstract no. 775.
Colbers A BP, Freriksen J, Konopnicki D, Weizsäcker K, Hidalgo Tenorio C, Moltó J, et al. Dolutegravir pharmacokinetics during pregnancy and postpartum. Conference on Retroviruses and Opportunistic Infections; 2019; Seattle (WA): poster 0758, Mar 4–7, 2019
Waitt C, Orrell C, Walimbwa S, Singh Y, Kintu K, Simmons B, et al. Safety and pharmacokinetics of dolutegravir in pregnant mothers with HIV infection and their neonates: a randomised trial (DolPHIN-1 study). PLoS Med. 2019;16(9):e1002895.
Mulligan N, Brookie M, Jiajia W, Capparelli EV, Alice S, Emily B, et al. Dolutegravir pharmacokinetics in pregnant and postpartum women living with HIV. AIDS (Lond). 2018;32(6):729.
Momper JD, Brookie M, Jiajia W, Capparelli EV, Alice S, Emily B, et al. Elvitegravir/cobicistat pharmacokinetics in pregnant and postpartum women with HIV. AIDS (Lond). 2018;32(17):2507.
Colbers A SS, Konopnicki D, Rockstroh J, Burger D. Elvitegravir pharmacokinetics during pregnancy and postpartum. International Workshop on Clinical Pharmacology of Antiviral Therapy; 2018; Baltimore (MD): abstract no. 17, May 22, 2018.
Watts DH, Stek A, Best BM, Wang J, Capparelli EV, Cressey TR, et al. Raltegravir pharmacokinetics during pregnancy. J Acquir Immune Defic Syndr. 2014;67(4):375–81. https://doi.org/10.1097/qai.0000000000000318.
Blonk MI, Colbers AP, Hidalgo-Tenorio C, Kabeya K, Weizsacker K, Haberl AE, et al. Raltegravir in HIV-1-infected pregnant women: pharmacokinetics, safety, and efficacy. Clin Infect Dis. 2015;61(5):809–16. https://doi.org/10.1093/cid/civ366.
Sax PE, DeJesus E, Crofoot G, Ward D, Benson P, Dretler R, et al. Bictegravir versus dolutegravir, each with emtricitabine and tenofovir alafenamide, for initial treatment of HIV-1 infection: a randomised, double-blind, phase 2 trial. Lancet HIV. 2017;4(4):e154–60.
Sax PE, Pozniak A, Montes ML, Koenig E, DeJesus E, Stellbrink H-J, et al. Coformulated bictegravir, emtricitabine, and tenofovir alafenamide versus dolutegravir with emtricitabine and tenofovir alafenamide, for initial treatment of HIV-1 infection (GS-US-380–1490): a randomised, double-blind, multicentre, phase 3, non-inferiority trial. Lancet. 2017;390(10107):2073–82.
Sax PE, DeJesus E, Crofoot G, Ward D, Benson P, Dretler R, et al. Coformulated bictegravir, emtricitabine, tenofovir alafenamide after initial treatment with bictegravir or dolutegravir and emtricitabine/tenofovir alafenamide. AIDS. 2018;32(12):1723–5.
Gallant J, Lazzarin A, Mills A, Orkin C, Podzamczer D, Tebas P, Girard PM, Brar I, Daar ES, Wohl D, Rockstroh J, Wei X, Custodio J, White K, Martin H, Cheng A, Quirk E. Bictegravir, emtricitabine, and tenofovir alafenamide versus dolutegravir, abacavir, and lamivudine for initial treatment of HIV-1 infection (GS-US-380-1489): a double-blind, multicentre, phase 3, randomised controlled non-inferiority trial. The Lancet. 2017;390(10107):2063–72.
US Food and Drug Administration. Bictegravir. 2017. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2018/210251Orig1s000MultidisciplineR.pdf.Accessed 30 Jan 2020.
Margolis DA, Brinson CC, Smith GH, de Vente J, Hagins DP, Eron JJ, et al. Cabotegravir plus rilpivirine, once a day, after induction with cabotegravir plus nucleoside reverse transcriptase inhibitors in antiretroviral-naive adults with HIV-1 infection (LATTE): a randomised, phase 2b, dose-ranging trial. Lancet Infect Dis. 2015;15(10):1145–55.
Margolis DA, Gonzalez-Garcia J, Stellbrink H-J, Eron JJ, Yazdanpanah Y, Podzamczer D, et al. Long-acting intramuscular cabotegravir and rilpivirine in adults with HIV-1 infection (LATTE-2): 96-week results of a randomised, open-label, phase 2b, non-inferiority trial. Lancet. 2017;390(10101):1499–510.
Clotet B, Feinberg J, van Lunzen J, Khuong-Josses MA, Antinori A, Dumitru I, et al. Once-daily dolutegravir versus darunavir plus ritonavir in antiretroviral-naive adults with HIV-1 infection (FLAMINGO): 48 week results from the randomised open-label phase 3b study. Lancet. 2014;383(9936):2222–31. https://doi.org/10.1016/S0140-6736(14)60084-2.
Cahn P, Pozniak AL, Mingrone H, Shuldyakov A, Brites C, Andrade-Villanueva JF, et al. Dolutegravir versus raltegravir in antiretroviral-experienced, integrase-inhibitor-naive adults with HIV: week 48 results from the randomised, double-blind, non-inferiority SAILING study. Lancet. 2013;382(9893):700–8. https://doi.org/10.1016/S0140-6736(13)61221-0.
Castagna A, Maggiolo F, Penco G, Wright D, Mills A, Grossberg R, et al. Dolutegravir in antiretroviral-experienced patients with raltegravir- and/or elvitegravir-resistant HIV-1: 24-week results of the phase III VIKING-3 study. J Infect Dis. 2014;210(3):354–62. https://doi.org/10.1093/infdis/jiu051.
Llibre JM, Hung C-C, Brinson C, Castelli F, Girard P-M, Kahl LP, et al. Efficacy, safety, and tolerability of dolutegravir-rilpivirine for the maintenance of virological suppression in adults with HIV-1: phase 3, randomised, non-inferiority SWORD-1 and SWORD-2 studies. Lancet. 2018;391(10123):839–49.
Cahn P, Madero JS, Arribas JR, Antinori A, Ortiz R, Clarke AE, et al. Dolutegravir plus lamivudine versus dolutegravir plus tenofovir disoproxil fumarate and emtricitabine in antiretroviral-naive adults with HIV-1 infection (GEMINI-1 and GEMINI-2): week 48 results from two multicentre, double-blind, randomised, non-inferiority, phase 3 trials. Lancet. 2019;393(10167):143–55.
DeJesus E, Berger D, Markowitz M, Cohen C, Hawkins T, Ruane P, et al. Antiviral activity, pharmacokinetics, and dose response of the HIV-1 integrase inhibitor GS-9137 (JTK-303) in treatment-naive and treatment-experienced patients. J Acquir Immune Defic Syndr. 2006;43(1):1–5. https://doi.org/10.1097/01.qai.0000233308.82860.2f.
Zolopa AR, Berger DS, Lampiris H, Zhong L, Chuck SL, Enejosa JV, et al. Activity of elvitegravir, a once-daily integrase inhibitor, against resistant HIV type 1: results of a phase 2, randomized, controlled, dose-ranging clinical trial. J Infect Dis. 2010;201(6):814–22. https://doi.org/10.1086/650698.
DeJesus E, Rockstroh JK, Henry K, Molina JM, Gathe J, Ramanathan S, 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):2429–38. https://doi.org/10.1016/S0140-6736(12)60918-0.
Sax PE, DeJesus E, Mills A, Zolopa A, Cohen C, Wohl D, 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):2439–48. https://doi.org/10.1016/S0140-6736(12)60917-9.
Fletcher CV. Drug interactions should be evaluated in patients. Clin Pharmacol Ther. 2010;88(5):585–7. https://doi.org/10.1038/clpt.2010.213.
Fletcher CV. Editorial commentary: cerebrospinal fluid inhibitory quotients of antiretroviral drugs. Clin Infect Dis. 2015;60(2):318–20. https://doi.org/10.1093/cid/ciu775.
US Food and Drug Administration. Guidance for industry, antiviral product development, conducting and submitting virology studies to the agency. 2006. Available from: http://www.fda.gov/OHRMS/DOCKETS/98fr/05d-0183-gdl0002-01.pdf. Accessed 18 Feb 2016.
Lennox JL, DeJesus E, Lazzarin A, Pollard RB, Madruga JV, Berger DS, et al. Safety and efficacy of raltegravir-based versus efavirenz-based combination therapy in treatment-naive patients with HIV-1 infection: a multicentre, double-blind randomised controlled trial. Lancet. 2009;374(9692):796–806. https://doi.org/10.1016/S0140-6736(09)60918-1.
Walmsley SL, Antela A, Clumeck N, Duiculescu D, Eberhard A, Gutierrez F, et al. Dolutegravir plus abacavir-lamivudine for the treatment of HIV-1 infection. N Engl J Med. 2013;369(19):1807–18. https://doi.org/10.1056/NEJMoa1215541.
Raffi F, Rachlis A, Stellbrink HJ, Hardy WD, Torti C, Orkin C, et al. Once-daily dolutegravir versus raltegravir in antiretroviral-naive adults with HIV-1 infection: 48 week results from the randomised, double-blind, non-inferiority SPRING-2 study. Lancet. 2013;381(9868):735–43. https://doi.org/10.1016/S0140-6736(12)61853-4.
Department of Health and Human Services (DHHS). Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. http://aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf. Accessed 9 Feb 2016.
Simoni JM, Nance RM, Delaney JAC, Wilson I, Aunon F, Safren SA, et al. HIV viral load in US clinics over time: trends and predictions from CNICS. Conference on Retroviruses and Opportunistic Infections (CROI); 22 February 2016; Boston (MA).
Nance RM, Delaney JC, Simoni JM, Wilson IB, Mayer KH, Whitney BM, et al. HIV viral suppression trends over time among HIV-infected patients receiving care in the United States, 1997 to 2015: a cohort study. Ann Intern Med. 2018;169(6):376–84.
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We acknowledge support from the following grants from the National Institutes of Health: 1R01HD085887-01A1 (to KS), 1K23AI134307 (to ATP), and RO1 AI124965-01 and UM1AI06701 (to CVF).
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Anthony T. Podany, Michelle Pham, Kimberly K. Scarsi, and Courtney V. Fletcher have no conflicts of interest that are directly relevant to the content of this review.
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Podany, A.T., Scarsi, K.K., Pham, M.M. et al. Comparative Clinical Pharmacokinetics and Pharmacodynamics of HIV-1 Integrase Strand Transfer Inhibitors: An Updated Review. Clin Pharmacokinet 59, 1085–1107 (2020). https://doi.org/10.1007/s40262-020-00898-8
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DOI: https://doi.org/10.1007/s40262-020-00898-8