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Review

The clinical pharmacology of integrase inhibitors

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Pages 31-44 | Received 03 Oct 2018, Accepted 26 Nov 2018, Published online: 21 Dec 2018

References

  • Aronson JK. A manifesto for clinical pharmacology from principles to practice. Br J Clin Pharmacol. 2010 Jul;70(1):3–13.
  • Sc M, Wolters P, Calabrese S, et al. The Antiretroviral Regimen Complexity Index. A novel method of quantifying regimen complexity. J Acquir Immune Defic Syndr. 2007;45(5):535–544.
  • Tseng A, Seet J, Phillips EJ. The evolution of three decades of antiretroviral therapy: challenges, triumphs and the promise of the future. Br J Clin Pharmacol. 2015 Feb;79(2):182–194.
  • Arts EJ, Hazuda DJ. HIV-1 Antiretroviral Drug Therapy. Cold Spring Harb Perspect Med. 2012 Apr;2(4):a007161.
  • Zdanowicz MM. The pharmacology of HIV drug resistance. Am J Pharm Educ. 2006 Oct 15;70(5):100.
  • Rosenbloom DI, Hill AL, Alireza Rabi SA, et al. Antiretroviral dynamics determines HIV evolution and predicts therapy outcome. Nat Med. 2012 Sep;18(9):1378–1385.
  • Bezabhe WM, Chalmers L, Luke R, et al. Adherence to antiretroviral therapy and virologic failure. Medicine. 2016 Apr;95(15):e3361.
  • Bednasz CJ, Venuto CS, Ma Q, et al. Pharmacokinetic considerations for combining antiretroviral therapy, direct-acting antiviral agents for hepatitis C virus, and addiction treatment medications. Clin Pharmacol Drug Dev. 2017 Mar;6(2):135–139.
  • Hicks C, Gulick RM. Raltegravir: the first HIV type 1 integrase inhibitor. Clinl Infect Dis. 2009;48:931–939.
  • Zuo X, Huo Z, Kang D, et al. Current insights into anti-HIV drug discovery and development: a review of recent patent literature (2014–2017). Expert Opin Ther Pat. 2018;28(4):299–316.
  • Cited 2018 Aug 25. Available from: https://www.hiv-druginteractions.org
  • At P, Kk S, Cv F. Comparative clinical pharmacokinetics and pharmacodynamics of HIV-1 integrase strand transfer inhibitors. Clin Pharmacokinet. 2017;56(1):25–40.
  • Calcagno A, Di Perri G, Bonora S. Pharmacokinetics and pharmacodynamics of antiretrovirals in the central nervous system. Clin Pharmacokinet. 2014 Oct;53(10):891–906.
  • Gallant JE, Thompson M, DeJesus E, et al. Antiviral activity, safety, and pharmacokinetics of bictegravir as 10-day monotherapy in HIV-1-infected adults. J Acquir Immune Defic Syndr. 2017 May 1;75(1):61–66.
  • Cahn P, Sax PE, Squires K, et al. Raltegravir 1200 mg once daily vs 400 mg twice daily, with emtricitabine and tenofovir disoproxil fumarate, for previously untreated HIV-1 infection: week 96 results from ONCEMRK, a randomized, double-blind, noninferiority trial. J Acquir Immune Defic Syndr. 2018 Aug 15;78(5):589–598.
  • Cited 2018 Sep. Available from: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR-Product_Information/human/04449/WC500250892.pdf
  • Rizk MLKR, Schulz BBJ, Larson P, et al., editor. A multiple dose study of raltegravir formulations (Abstract 523). 21st CROI; 2014 March 3–6; Boston,MA. CROI Foundation/IAS–USA.
  • Krishna RRM, Schulz V, Ingelse B, et al., editor. A single dose food effect study of raltegravir formulations. 14th European AIDS Conference; October 16–19, 2013; Brussels. (Abstract PE10/17). European AIDS Clinical Society.
  • Eisfeld C, Reichelt D, Evers S, et al. CSF penetration by antiretroviral drugs. CNS Drugs. 2013 Jan;27(1):31–55.
  • Letendre S, Marquie-Beck J, Capparelli E, et al. Validation of the CNS penetration-effectiveness rank for quantifying antiretroviral penetration into the central nervous system. Arch Neurol. 2008 Jan;65(1):65–70.
  • Calcagno A, Barco A, Trunfio M, et al. CNS-targeted antiretroviral strategies: when are they needed and what to choose. Curr HIV/AIDS Rep. 2018 Feb;15(1):84–91.
  • Calcagno A, Simiele M, Alberione MC, et al. Cerebrospinal fluid inhibitory quotients of antiretroviral drugs in HIV-infected patients are associated with compartmental viral control. Clin Infect Dis. 2015;60(2):311–317.
  • Calcagno A, Simiele M, Motta I, et al. Elvitegravir/cobicistat/tenofovir/emtricitabine penetration in the cerebrospinal fluid of three HIV-positive patients. AIDS Res Hum Retroviruses. 2016 May;32(5):409–411.
  • Letendre SL, Mills AM, Tashima KT, et al. NG116070: a study of the pharmacokinetics and antiviral activity of dolutegravir in cerebrospinal fluid in HIV-1-infected, antiretroviral therapy-naive subjects. Clin Infect Dis. 2014 Oct;59(7):1032–1037.
  • Fletcher CV, Thorkelson A, Winchester L, et al. Comparative lymphoid tissue pharmacokinetics (PKs) of integrase inhibitors (INSTI). 24h Conference on Retroviruses and Opportunistic Infections (CROI). March 4-7, 2018. Boston. Abstract 27. CROI Foundation/IAS–USA.
  • Custodio JM Clinical pharmacology of the HIV integrase strand transfer inhibitor bictegravir. Webcast presented at: conference on Retroviruses and Opportunistic Infections (CROI); February 13–16, 2017; Seattle, WA. CROI Foundation/IAS–USA.
  • Chen S, St Jean P, Borland J, et al. Evaluation of the effect of UGT1A1 polymorphisms on dolutegravir pharmacokinetics. Pharmacogenomics. 2014 Jan;15(1):9–16.
  • Belkhir L, Seguin-Devaux C, Elens L, et al. Impact of UGT1A1 polymorphisms on Raltegravir and its glucuronide plasma concentrations in a cohort of HIV-1 infected patients. Sci Rep. 2018 May 9;8(1):7359.
  • Williams JA, Hyland R, Jones BC, et al. Drug-drug interactions for UDP-glucuronosyltransferase substrates: a pharmacokinetic explanation for typically observed low exposure (AUCi/AUC) ratios. Drug Metab Dispos. 2004 Nov;32(11):1201–1208.
  • Wenning LA, Hanley WD, Brainard DM, et al. Effect of rifampin, a potent inducer of drug-metabolizing enzymes, on the pharmacokinetics of raltegravir. Antimicrob Agent Chemoter. 2009;53:2852–2856.
  • Dooley K, Sayre P, Borland J, et al. Safety, tolerability, and pharmacokinetics of the HIV integrase inhibitor dolutegravir given twice daily with rifampin or once daily with rifabutin: results of a phase 1 study among healthy subjects. J Acquir Immune Defic Syndr. 2013 Jan 1;62(1):21–27.
  • Grinsztejn B, De Castro N, Arnold V, et al. Raltegravir for the treatment of patients co-infected with HIV and tuberculosis (ANRS 12 180 Reflate TB): a multicentre,phase 2, non-comparative, open-label, randomised trial. Lancet Infect Dis. 2014;14:459–467.
  • Custodio JM, Sk W, Collins S, et al. Pharmacokinetics of Bictegravir administered twice daily in combination with Rifampicin. 25th Conference on Retroviruses and Opportunistic Infections (CROI). Boston, March 4-7 2018, abstr. n. 34. CROI Foundation/IAS–USA.
  • Custodio JM, West S, Lutz J, et al. Twice daily administration of tenofovir alafenamide in combination with rifampin: potential for tenofovir alafenamide use in HIV-TB coinfection. 16th European AIDS Conference (EACS). October 25 –27 2017. Milan. Oral abstract PS13/4. European AIDS Clinical Society.
  • Cerrone M, Alfarisi O, Neary M, et al. Rifampin effect on tenofovir alafenamide (TAF) plasma/intracellular pharmacokinetics. 25th CROI. Boston. 4–7 March 2018. Oral abstract 28LB. 2018 CROI Foundation/IAS–USA.
  • Iwamoto M, Wenning LA, Petry AS, et al. Minimal effects of ritonavir and efavirenz on the pharmacokinetics of raltegravir. Antimicrob Agents Chemother. 2008;52(12):4338–4343.
  • Song I, Borland J, Lou Y et al. Effects of enzyme inducers, tipranavir and efavirenz, on the pharmacokinetics of the integrase inhibitor, Dolutegravir (S/GSK1349572). 12th International Workshop on Clinical Pharmacology of HIV Therapy, Miami 2011; abstract O_02. Virology Education.
  • Tivicay US Prescribing Information, Viiv Healthcare, June 2016.
  • Zhang H, West S, Vu A, et al. Lack of clinically relevant effect of bictegravir on metformin pharmacokinetics and pharmacodynamics. 18th International Workshop on Clinical Pharmacology of Antiviral Therapy, Chicago, June 2017, abstract P_50. Virology Education.
  • Biktarvy Prescribing Information, Gilead Sciences Inc, February 2018.
  • Harea S, Vosb AM, Claytonb RF, et al. Molecular mechanisms of retroviral integrase inhibition and the evolution of viral resistance. PNAS. 2010;107:20057–20062.
  • Thierry S, Munir S, Thierry E, et al. Integrase inhibitor reversal dynamics indicate unintegrated HIV-1 dna initiate de novo integration. Retrovirology. 2015 Mar 12;12:24.
  • White KL, Niedziela-Majka A, Nikolai Novikov N, et al. Bictegravir dissociation half-life from HIV-1 G140S + Q148H integrase/DNA complexes. 24th Conference on Retroviruses and Opportunistic Infections. Seattle, Feb 13-17, 2017. Abstr. n. 497. CROI Foundation/IAS–USA.
  • Ke H, Wang R, Felix DeAnda F, et al. Dolutegravir (S/GSK1349572) exhibits significantly slower dissociation than raltegravir and elvitegravir from wild-type and integrase inhibitor-resistant HIV-1 integrase-DNA complexes. Antimicrob Agent Chemoter. 2011;55:4552–4559.
  • Hurt CB, Sebastian J, Hicks CB, et al. Resistance to HIV integrase strand transfer inhibitors among clinical specimens in the United States, 2009–2012. Clin Infect Dis. 2014;58(3):423–431.
  • Mata-Marín JA, Smeke AE, Rodriguez MR, et al. Effectiveness and risk factors for virological outcome of raltegravir-based therapy for treatment-experienced HIV-infected patients. Drugs R D. 2017;17(1):225–231.
  • Grobler JA, Dj H. Resistance to HIV integrase strand transfer inhibitors: in vitro findings and clinical consequences. Curr Opin Virol. 2014 Oct;8:98–103.
  • Llibre JM, Pulido F, García F, et al. Genetic barrier to resistance for dolutegravir. AIDS Rev. 2015;17(1):56–64.
  • Castagna A, Maggiolo F, Penco G, 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;210:354–362.
  • Tsiang M, Jones GS, Goldsmith J, et al. Antiviral activity of bictegravir (GS-9883), a novel potent HIV-1 integrase strand transfer inhibitor with an improved resistance profile. Antimicrob Agents Chemother. 2016;60(12):7086–7097.
  • Darcis G, Berkhout B. Human immunodeficiency virus resistance to dolutegravir: are we looking in the wrong place? J Infect Dis. 2018;218:2020.
  • Deeks ED, Raltegravir once-daily tablet: a review in HIV-1 infection. Drugs. 2017 Oct; 77(16):1789–1795
  • Siccardi M, DʼAvolio A, Rodriguez-Novoa S, et al. Intrapatient and interpatient pharmacokinetic variability of raltegravir in the clinical setting. Ther Drug Monit. 2012 Apr;34(2):232–235.
  • Kassahun K, McIntosh I, Cui D, et al. Metabolism and disposition in humans of raltegravir (MK-0518), an anti-AIDS drug targeting the human immunodeficiency virus 1 integrase enzyme. Drug Met Disp. 2007;35:1657–1663.
  • Kiser JJ, Bumpass JB, Meditz AL, et al. Effects of antacids on the pharmacokinetics of raltegravir in human immunodeficiency virus-seronegative volunteers. Antimicrob Agent Chemoter. 2010;54:4999–5003.
  • Arab-Alameddine M, Fayet-Mello A, Lubomirov R, et al. Population pharmacokinetic analysis and pharmacogenetics of raltegravir in HIV-positive and healthy individuals. Antimicrob Agent Chemoter. 2012;56:2959–2966.
  • Brainard DM, Friedman EJ, Jin B, et al. Effect of low-moderate- and high fat meals on raltegravir pharmacokinetics. J Clin Pharmacol. 2011;51:422–427.
  • Markowitz M, Morales-Ramirez JO, Nguyen BY, et al. Antiretrovral activity, pharmacokinetics and tolerability of MK-0518, a novel inhibitor of HIV-1 integrase, dosed as monotherapy for 10 days in treatment-naïve HIV-1-infected individuals. JAIDS. 2006;43:509–515.
  • Iwamoto M, Wenning L, Petry A, et al. Safety, tolerability and pharmacokinetics of raltegravir after single and multiple doses in healthy subjects. Clin Pharm Ther. 2008;83:293–299.
  • Petry A, Wenning L, Laethem M, et al. Safety, tolerability, and pharmacokinetics after single and multiple doses of MK-0518 in healthy subjects; 46th Interscience Conference on Antimicrobial Agents and Chemotherapy, 2006 Sep 27-30, 2006; San Francisco, CA. American Society for Microbiology.
  • Eron JJ Jr, Rockstroh JK, Reynes J, 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 Dec;11(12):907–915.
  • Rizk ML, Hang Y, Luo WL, et al. Pharmacokinetics and pharmacodynamics of once-daily versus twice-daily raltegravir in treatment-naïve HIV-infected patients. Antimicrob Agents Chemother. 2012 Jun;56(6):3101–3106.
  • Krishna R, Rizk ML, Larson P, et al. Single- and multiple-dose pharmacokinetics of once-daily formulations of raltegravir. Clin Pharmacol Drug Dev. 2018 Feb;7(2):196–206.
  • Iwamoto M, Hanley WD, Petry AS, et al. Lack of clinically important effect of moderate hepatic insufficiency and severe renal insufficiency on raltegravir pharmacokinetics. Antimicrob Agent Chemoter. 2009;53:1747–1752.
  • Molto J, Sanz-Moreno J, Valle M, et al. Minimal removal of raltegravir by hemodyalisis in HIB-infected patients with end-stage disease. Antimicrob Agent Chemoter. 2010;54:3047–3048.
  • Giguere P, La Porte C, Zhang G, et al. Pharmacokinetics of darunavir, etravirine and raltegravir in an HIV-infected patient on hemodialysis. Aids. 2009;23:740–742.
  • 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. [cited 2018 Sep]. Available from: http://aidsinfo.nih.gov/contentfiles/lvguidelines/PerinatalGL.pdf
  • IsentressR. Merck & Co. Inc. February: Whitehouse Station, NJ, 2015.
  • Kearney B, Mathias A, Zhong L Pharmacokinetics/pharmacodynamics of GS-9137 an HIV integrase inhibitor in treatment-naive and experienced patients. International Workshop on Clinical Pharmacology of HIV Therapy, 2006 Apr 20-22; Lisbon. Virology Education.
  • German P, Warren D, West S, et al. 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 Syndr. 2010 Nov;55(3):323–329.
  • DeJesus E, Berger D, Markowitz M, 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 Sep;43(1):1–5.
  • German P, Warren D, Wei L, et al. 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 Sep 12-15; San Francisco, CA. American Society for Microbiology.
  • Patel P, Song I, Borland J, 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 Jul;66(7):1567–72.
  • Ramanathan S, Shen G, Hinkle J, et al. 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; 2007 Apr 16-18;  Budapest, Hungary. Virology Education
  • Pozniak A, Arribas JR, Gathe J, 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. 2015. DOI:10.1097/qai
  • Food and Drug Administration (FDA). Elvitegravir. 2011. [cited 2018 Sep]. Available from: http://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/203100Orig1s000ClinPharmR.pdf.
  • Custodio JM, Rhee M, Shen G, et al. Pharmacokinetics and safety of boosted elvitegravir in subjects with hepatic impairment. Antimicrob Agents Chemother. 2014 May;58(5):2564.
  • Momper JD, Bm B, Wang J, et al. Elvitegravir/cobicistat pharmacokinetics in pregnant and postpartum women with HIV. Aids. 2018 Aug 20:1. Epub ahead of print. DOI: 10.1097/QAD.0000000000001992
  • Weller S, Chen S, Borland J, et al. Bioequivalence of a dolutegravir, abacavir, and lamivudine fixed-dose combination tablet and the effect of food. J Acquir Immune Defic Syndr. 2014 Aug 1;66(4):393–398.
  • Min S, Sloan L, DeJesus E, et al. Antiviral activity, safety, and pharmacokinetics/pharmacodynamics of dolutegravir as 10-day monotherapy in HIV-1-infected adults. Aids. 2011;25(14):1737–1745.
  • Min S, Song I, Borland J, et al. Pharmacokinetics and safety of S/GSK1349572, a next-generation HIV integrase inhibitor, in healthy volunteers. Antimicrob Agents Chemother. 2010 Jan;54(1):254–258.
  • TivicayR. ViiV Healthcare: Research Triangle Park. NC: Aug. 2015.
  • Song I, Borland J, Chen S, et al. Effect of food on the pharmacokinetics of the integrase inhibitor dolutegravir. Antimicrob Agents Chemother. 2012 Mar;56(3):1627–1629.
  • Yagura H, Watanabe D, Kushida H, et al. Impact of UGT1A1 gene polymorphisms on plasma dolutegravir trough concentrations and neuropsychiatric adverse events in Japanese individuals infected with HIV-1. BMC Infect Dis. 2017 Sep 16;17(1):622.
  • Borghetti A, Calcagno A, Lombardi F, et al. SLC22A2 genetic variants and dolutegravir trough concentrations correlate with specific psychiatric symptopms in HIV-positive patients on Dolutegravir. 19th International Workshop on Clinical Pharmacology of Antiviral Therapy. 2018 May 22-24; Baltimore, MD. Virology Education
  • Cailhol J, Rouyer C, Alloui C, et al. Dolutegravir and neuropsychiatric adverse events: a continuing debate. Aids. 2017 Sep 10;31(14):2023–2024.
  • Weller S, Borland J, Chen S, et al. Pharmacokinetics of dolutegravir in HIV-seronegative subjects with severe renal impairment. Eur J Clin Pharmacol. 2014 Jan;70(1):29–35.
  • Food and Drug Administration (FDA). Dolutegravir. 2013. [cited 2018 Sep]. Available from: http://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/204790Orig1s000ClinPharmR.pdf.
  • Song IH, Borland J, Savina PM, 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 Oct;2(4):342–348.
  • World Health Organization. Potential safety issue affecting women living with HIV using dolutegravir at the time of conception. Geneva, Switzerland. May 18, 2018.
  • Zash R, Jacobson DL, Diseko M, et al. Comparative safety of dolutegravir-based or efavirenz-based antiretroviral treatment started during pregnancy in Botswana: an observational study. Lancet Glob Health. 2018 Jul;6(7):e804–e810.
  • Cited 2018 Sep. Available from: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/002753/WC500160680.pdf
  • Cited 2018 Sep. Available from: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/004449/WC500250892.pdf
  • Hicks CB, Cahn P, Cooper DA, et al. Durable efficacy of tipranavir-ritonavir in combination with an optimised background regimen of antiretroviral drugs for treatment-experienced HIV-1-infected patients at 48 weeks in the Randomized Evaluation of Strategic Intervention in multi-drug reSistant patients with Tipranavir (RESIST) studies: an analysis of combined data from two randomised open-label trials. Lancet. 2006 Aug 5;368(9534):466–475.
  • Lazzarin A, Clotet B, Cooper D, et al. Efficacy of enfuvirtide in patients infected with drug-resistant HIV-1 in Europe and Australia. N Engl J Med. 2003 May 29;348(22):2186–2195.
  • Clotet B, Bellos N, Molina JM, et al. Efficacy and safety of darunavir-ritonavir at week 48 in treatment-experienced patients with HIV-1 infection in POWER 1 and 2: a pooled subgroup analysis of data from two randomised trials. Lancet. 2007 Apr 7;369(9568):1169–1178.
  • Katlama C, Clotet B, Mills A, et al. Efficacy and safety of etravirine at week 96 in treatment-experienced HIV type-1-infected patients in the DUET-1 and DUET-2 trials. Antivir Ther. 2010;15(7):1045–1052.
  • Gulick RM, Lalezari J, Goodrich J, et al. Maraviroc for previously treated patients with R5 HIV-1 infection. N Engl J Med. 2008 Oct 2;359(14):1429–1441.
  • Akil B, Blick G, Hagins DP, et al. Dolutegravir versus placebo in subjects harbouring HIV-1 with integrase inhibitor resistance associated substitutions: 48-week results from VIKING-4, a randomized study. Antivir Ther. 2015;20(3):343–348.
  • Rockstroh JK, DeJesus E, Lennox JL, et al. Durable efficacy and safety of raltegravir versus efavirenz when combined with tenofovir/emtricitabine in treatment-naive HIV-1-infected patients: final 5-year results from STARTMRK. J Acquir Immune Defic Syndr. 2013 May 1;63(1):77–85.
  • Polis MA, Sidorov IA, Yoder C, et al. Correlation between reduction in plasma HIV-1 RNA concentration 1 week after start of antiretroviral treatment and longer-term efficacy. Lancet. 2001 Nov 24;358(9295):1760–1765.
  • Parienti JJ, Renaud Verdon R, Véronique Massari V. Methodological standards in non-inferiority AIDS trials: moving from adherence to compliance. BMC Med Res Methodol. 2006;6:46.
  • Walmsley S, Bernstein B, King M, et al. Lopinavir-ritonavir versus nelfinavir for the initial treatment of HIV infection. N Engl J Med. 2002 Jun 27;346(26):2039–2046.
  • Riddler SA, Haubrich R, DiRienzo AG, et al. Class-sparing regimens for initial treatment of HIV-1 infection. N Engl J Med. 2008 May 15;358(20):2095–2106.
  • Mills AM, Nelson M, Jayaweera D, et al. Once-daily darunavir/ritonavir vs. lopinavir/ritonavir in treatment-naive, HIV-1-infected patients: 96-week analysis. Aids. 2009 Aug 24;23(13):1679–1688.
  • Molina JM, Andrade-Villanueva J, Echevarria J, et al. Once-daily atazanavir/ritonavir compared with twice-daily lopinavir/ritonavir, each in combination with tenofovir and emtricitabine, for management of antiretroviral-naive HIV-1-infected patients: 96-week efficacy and safety results of the CASTLE study. J Acquir Immune Defic Syndr. 2010 Mar;53(3):323–332.
  • Soriano V, Arastéh K, Migrone H, et al. Nevirapine versus atazanavir/ritonavir, each combined with tenofovir disoproxil fumarate/emtricitabine, in antiretroviral-naive HIV-1 patients: the ARTEN trial. Antivir Ther. 2011;16(3):339–348.
  • Sax PE, Tierney C, Collier AC, et al. Abacavir‐lamivudine versus tenofovir‐emtricitabine for initial HIV‐1 therapy. N Engl J Med. 2009;361:2230–2240.
  • Shuter J. Forgiveness of non-adherence to HIV-1 antiretroviral therapy. J Antimicrob Chemother. 2008;61:769–773.
  • Sl W, Antela A, Clumeck N, et al. Dolutegravir plus abacavir-lamivudine for the treatment of HIV-1 infection. N Engl J Med. 2013 Nov 7;369(19):1807–1818.
  • Clotet B, Feinberg J, van Lunzen J, 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 Jun 28;383(9936):2222–2231.
  • Arribas JR, Pialoux G, Gathe J, et al. Simplification to coformulated elvitegravir, cobicistat, emtricitabine, and tenofovir versus continuation of ritonavir-boosted protease inhibitor with emtricitabine and tenofovir in adults with virologically suppressed HIV (STRATEGY-PI): 48 week results of a randomised, open-label, phase 3b, non-inferiority trial. Lancet Infect Dis. 2014 Jul;14(7):581–589.
  • Pozniak A, Markowitz M, Mills A, et al. Switching to coformulated elvitegravir, cobicistat, emtricitabine, and tenofovir versus continuation of non-nucleoside reverse transcriptase inhibitor with emtricitabine and tenofovir in virologically suppressed adults with HIV (STRATEGY-NNRTI): 48 week results of a randomised, open-label, phase 3b non-inferiority trial. Lancet Infect Dis. 2014 Jul;14(7):590–599.
  • Hodder S, Squires K, Kityo C, et al. Brief report: efficacy and safety of switching to coformulated elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide (E/C/F/TAF) in virologically suppressed women. J Acquir Immune Defic Syndr. 2018 Jun 1;78(2):209–213.
  • Shime N, Saito N, Bokui M, et al. Clinical outcomes after initial treatment of methicillin-resistant Staphylococcus aureus infections. Infect Drug Resist. 2018 Aug;6(11):1073–1081.
  • Lewis PO, Heil EL, Covert KL, et al. Treatment strategies for persistent methicillin-resistant Staphylococcus aureus bacteraemia. J Clin Pharm Ther. 2018 Jul 12;43:614–625.
  • Steigbigel RT, Cooper DA, Teppler H, et al. Long-term efficacy and safety of Raltegravir combined with optimized background therapy in treatment-experienced patients with drug-resistant HIV infection: week 96 results of the BENCHMRK 1 and 2 phase III trials. Clin Infect Dis. 2010 Feb 15;50(4):605–612.
  • Raffi F, Rachlis A, Stellbrink HJ, et al. 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 Mar 2;381(9868):735–743.
  • Spivey JM. The postantibiotic effect. Clin Pharm. 1992 Oct;11(10):865–875.
  • la Porte C. Inhibitory quotient in HIV pharmacology. Curr Opin HIV AIDS. 2008 May;3(3):283–287.
  • Cozzi-Lepri A, Phillips AN, Clotet B, et al. Detection of HIV drug resistance during antiretroviral treatment and clinical progression in a large European cohort study. Aids. 2008 Oct 18;22(16):2187–2198.
  • Brenner BG, Wainberg MA. Clinical benefit of dolutegravir in HIV-1 management related to the high genetic barrier to drug resistance. Virus Res. 2017 Jul 15;239:1–9.
  • Cahn P, Sierra Madero J, Arribas J, et al. Non-inferior efficacy of dolutegravir (DTG) plus lamivudine (3TC) versus DTG plus tenofovir/emtricitabine (TDF/FTC) fixed-dose combination in antiretroviral treatment-naïve adults with HIV-1 infection - 48-week results from the GEMINI studies. Program and abstracts of the 22nd International AIDS Conference; July 23-27, 2018; Amsterdam, the Netherlands. ( Abstract TUAB0106LB). IAS (International AIDS Society).
  • Valantin MAS, Lambert-Niclot P, Flandre L, et al. Long-term efficacy of darunavir/ritonavir monotherapy in patients with HIV-1 viral suppression: week 96 results from the MONOI ANRS 136 study. J Antimicrob Chemother. 2012;67:691–695.
  • Cahn P, Andrade-Villanueva J, Arribas JR, et al. Dual therapy with lopinavir and ritonavir plus lamivudine versus triple therapy with lopinavir and ritonavir plus two nucleoside reverse transcriptase inhibitors in antiretroviral-therapy-naive adults with HIV-1 infection: 48 week results of the randomised, open label, non-inferiority GARDEL trial. Lancet Infect Dis. 2014;14:572–580.
  • Di Giambenedetto S, Fabbiani M, Quiros Roldan E, et al. Treatment simplification to atazanavir/ritonavir + lamivudine versus maintenance of atazanavir/ritonavir + two NRTIs in virologically suppressed HIV-1-infected patients: 48 week results from a randomized trial (ATLAS-M). J Antimicrob Chemother. 2017;72:1163–1171.
  • Sued O, Figueroa MI, Gun A, et al. Dual therapy with darunavir/ritonavir plus lamivudine for HIV-1 treatment initiation: week 24 results of the randomized ANDES study. 9th IAS Conference on HIV Science (IAS 2017), July 23-26, 2017, Paris. Abstract MOAB0106LB. IAS (International AIDS Society).
  • Llibre JM, Hung CC, Brinson C, 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 Mar 3;391(10123):839–849.
  • Margolis DA, Brinson CC, Smith GHR, 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;15:1145–1155.
  • Margolis DA, Gonzalez-Garcia J, Stellbrink HJ, 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;390:1499–1510.

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