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Simplifying ARV Therapy in the Setting of Resistance

  • Neha Sheth PanditEmail author
  • Daniel B. Chastain
  • Andrea M. Pallotta
  • Melissa E. Badowski
  • Emily C. Huesgen
  • Sarah M. Michienzi
Antimicrobial Development and Drug Resistance (K Claeys and A Vega, Section Editors)
  • 82 Downloads
Part of the following topical collections:
  1. Topical Collection on Antimicrobial Development and Drug Resistance

Abstract

Purpose of Review

HIV treatment simplification is typically indicated for virologically suppressed patients with no baseline resistance-associated mutations (RAMs) or prior virologic failure (VF) to the simplification regimen. Simplification can occur to minimize pill burden, toxicities, drug-drug interactions, or costs. As most studies for treatment simplification excluded patients with baseline RAMs or prior VF, this review is aimed to critically analyze data regarding treatment simplification in treatment-experienced patients.

Recent Findings

Antiretroviral (ARV) regimens containing three-, two-, and one-drug(s) have been scarcely studied to assess virologic efficacy in treatment-experienced patients. Three-drug regimens with the most data and highest efficacy are with integrase strand transfer inhibitors (INSTIs). Regimens including dolutegravir (DTG) and bictegravir have been shown to maintain efficacy in patients with certain baseline RAMs. Dual therapy regimens include the use of DTG plus either lamivudine (3TC), rilpivirine (RPV), or other ARVs. None of these studies evaluated patients with baseline DTG resistance. Baseline RAMs to 3TC were not a predictor of VF in patients on DTG/3TC. Efficacy was seen with DTG/RPV; however, studies showed high rates of discontinuation. DTG plus boosted-protease inhibitors were studied in smaller but promising studies. Two small studies assessed the use of monotherapy with boosted darunavir or DTG, both showing virologic efficacy.

Summary

Currently, three- and two-drug ARV regimens may be considered in this population with most studies evaluating the use of DTG and bictegravir without baseline INSTI RAMs. Future studies should include heavily treatment-experienced patients with a variety of baseline RAMs and a larger sample size.

Keywords

HIV Simplification Antiretroviral 

Notes

Compliance with Ethical Standards

Conflict of Interest

Neha Sheth Pandit, Daniel B. Chastain, Andrea M. Pallotta, Melissa E. Badowski, Emily C. Huesgen, and Sarah M. Michienzi declare that they have no conflict of interest.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

References

Papers of particular interest, published recently, have been highlighted as: • Of importance

  1. 1.
    • Panel of Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents with HIV. Department of Health and Human Services. Available at http://aidsinfo.nih.gov/contentfiles/lvguidelines/AdultsandAdolescentGL.pdf. Access on July 12, 2019. Standard of care guidelines that discuss the role of ART in treatment experienced patients.
  2. 2.
    Lee S, Kim S, Chang H, Jung H, Kim Y, Hwang S, et al. Effectiveness, safety, and tolerability of a switch to dual therapy with dolutegravir plus cobicistat-boosted darunavir in treatment-experienced patients with human immunodeficiency virus. Infect Chemother. 2018;50:252–62.  https://doi.org/10.3947/ic.2018.50.3.252.CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Tsiang M, Jones GS, Goldsmith J, Mulato A, Hansen D, Kan E, 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;60:7086–97.PubMedPubMedCentralGoogle Scholar
  4. 4.
    Daar ES, DeJesus E, Ruane P, Crofoot G, Oguchi G, Creticos C, et al. Efficacy and safety of switching to fixed-dose bictegravir, emtricitabine, and tenofovir alafenamide from boosted protease inhibitor-based regimens in virologically suppressed adults with HIV-1: 48 week results of a randomised, open-label, multicentere, phase 3, non-inferiority trial. Lancet HIV. 2018;5:e347–56.  https://doi.org/10.1016/S2352-3018(18)30091-2.CrossRefPubMedGoogle Scholar
  5. 5.
    Molina JM, Ward D, Brar I, Mills A, Stellbrink HJ, Lopez-Cortes L, et al. Switching to fixed-dose bictegravir, emtricitabine, and tenofovir alafenamide from dolutegravir plus abacavir and lamivudine in virologically suppressed adults with HIV-1: 48 week results of a randomised, double-blind, multicentere, active-controlled, phase 3, non-inferiority trial. Lancet HIV. 2018;5:e357–65.  https://doi.org/10.1016/S2352-3018(18)30092-4.CrossRefPubMedGoogle Scholar
  6. 6.
    • Andreatta K, Willkom M, Martin R, Chang S, Liu YP, Graham H, et al. Long-term B/F/TAF switch efficacy in patients with archived pre-existing resistance. Abstract 552. Conference on Retroviruses and Opportunistic Infections 2019; Seattle, WA. Reviews the role of INSTIs in patients with baseline RAMs. Google Scholar
  7. 7.
    Acosta R, Willkom M, Andreatta K, Liu H, Martin R, Chang S, et al. High level of preexisting NRTI resistance prior to switching to B/F/TAF: Study 4030. Abstract 551. Conference on Retroviruses and Opportunistic Infections 2019; Seattle, WA.Google Scholar
  8. 8.
    Santoro MM, Fornabaio C, Malena M, Galli L, Poli A, Marcotullio S, et al. Susceptibility to bictegravir in highly ARV experienced patients after INSTI failure. Abstract 550. Conference on Retroviruses and Opportunistic Infections 2019; Seattle, WA.Google Scholar
  9. 9.
    Chen G, Sun H, Chang S, Cheng A, Huang Y, Lin K, et al. Effectiveness of switching from protease inhibitors to dolutegravir in combination with nucleoside reverse-transcriptase inhibitors as maintenance antiretroviral therapy among HIV-positive patients. Int J Antimicrob Agents. 2019.  https://doi.org/10.1016/j.ijantimicag.2019.03.016.CrossRefGoogle Scholar
  10. 10.
    Charpentier C, Peytavin G, Le MP, Joly V, Cabras O, Perrier M, et al. High virological suppression regardless of the genotypic susceptibility score after switching to a dolutegravir-based regimen: week 48 results in an observational cohort. J Antimicrob Chemother. 2018;73:1665–71.  https://doi.org/10.1093/jac/dky062.CrossRefPubMedGoogle Scholar
  11. 11.
    Baldin G, Ciccullo A, Capetti A, Rusconi S, Sterrantino G, Cossu MV, et al. Efficacy and safety of switching to dolutegravir plus emtricitabine/tenofovir disoproxil fumarate (TDF) or elvitegravir/cobicistat/emtricitabine/TDF in virologically suppressed HIV-infected patients in clinical practice: results from a multicentere, observational study. HIV Med. 2019;20:164–8.  https://doi.org/10.1111/hiv.12688.CrossRefPubMedGoogle Scholar
  12. 12.
    Perez-Valero I, Libre J, Lazzarin A, di Perri G, Pulido F, Molina JM, et al. A phase 3b open-label pilot study to evaluate switching to elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide (E/C/F/TAF) single-tablet regimen in virologically-suppressed HIV-1 infected adults harboring the NRTI resistance mutation M184V and/or M184I (GS-US-292-1824): week 24 results. HIV/Hep Americas 2019; Bogota, Colombia.Google Scholar
  13. 13.
    Perrier M, Charpentier C, Peytavin G, Le M, Blondel L, Visseauz B, et al. Switch as a maintenance to elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate: week 48 results in a clinical cohort. J Antimicrob Chemother. 2017;72:1745–51.  https://doi.org/10.1093/jac/dkx018.CrossRefPubMedGoogle Scholar
  14. 14.
    Huhn GD, Tebas P, Gallant J, Wilkin T, Cheng A, Yan M, et al. A randomized, open-label trial to evaluate switching to elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide plus darunavir in treatment-experienced HIV-infected adults. J Acquir Immune Defic Syndr. 2017;74:193–200.  https://doi.org/10.1097/QAI.0000000000001193.CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Eron JJ, Young B, Cooper DA, Youle M, Dejesus E, Andrade-Villanueva J, et al. Switch to a raltegravir-based regimen versus continuation of a lopinavir-ritonavir-based regimen in stable HIV-infected patients with suppressed viraemia (SWITCHMRK 1 and 2): two multicentere, double-blind, randomized controlled trials. Lancet. 2010;375:396–407.  https://doi.org/10.1016/S0140-6736(09)62041-9.CrossRefPubMedGoogle Scholar
  16. 16.
    Porter DP, Toma J, Tan Y, Solberg O, Cai S, Kulkarni R, et al. Clinical outcomes of virologically-suppressed patients with pre-existing HIV-1 drug resistance mutations switching to rilpivirine/emtricitabine/tenofovir disoproxil fumarate in the SPIRIT study. HIV Clin Trials. 2016;17:29–37.  https://doi.org/10.1080/15284336.2015.1115585.CrossRefPubMedGoogle Scholar
  17. 17.
    Gantner P, Reinhart S, Partisani M, Baldeyrou M, Batard ML, Bernard-Henry C, et al. Switching to emtricitabine, tenofovir and rilpivirine as single tablet regimen in virologically suppressed HIV-1-infected patients: a cohort study. HIV Med. 2015;16:132–6.  https://doi.org/10.1111/hiv.12183.CrossRefPubMedGoogle Scholar
  18. 18.
    Cazanave C, Reigadas S, Mazubert C, Bellecave P, Hessamfar M, Le Marec F, et al. Switch to rilpivirine/emtricitabine/tenofovir single-tablet regimen of human immunodeficiency virus-1 RNA-suppressed patients, Agence Nationale de Recherches sur le SIDA et les Hépatites Virales CO3 Aquitaine Cohort, 2012–2014. Open Forum Infect Dis. 2015;2:ofv018.  https://doi.org/10.1093/ofid/ofv018.CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Gazaignes S, Resche-Rigon M, Gatey C, Yang C, Denis B, Fonsart J, et al. Efficacy and safety of a switch to rilpivirine-based regimens in treatment-experienced HIV-1-infected patients: a cohort study. Antivir Ther. 2016;21:329–36.  https://doi.org/10.3851/IMP3010.CrossRefPubMedGoogle Scholar
  20. 20.
    Armenia D, Di Carlo D, Calcagno A, Vendemiati G, Forbici F, Bertoli A, et al. Pre-existent NRTI and NNRTI resistance impacts on maintenance of virological suppression in HIV-1-infected patients who switch to a tenofovir/emtricitabine/rilpivirine single-tablet regimen. J Antimicrob Chemother. 2017;72:855–65.  https://doi.org/10.1093/jac/dkw512.CrossRefPubMedGoogle Scholar
  21. 21.
    Sahloff EG, Duggan JM. Clinical outcomes associated with once-daily ritonavir-boosted darunavir plus tenofovir/emtricitabine in HIV-infected patients harboring at minimum a M184V/I resistance mutation. Ann Pharmacother. 2019;53:50–5.CrossRefGoogle Scholar
  22. 22.
    Lathouwers E, Wong EY, Brown K, Baugh B, Ghys A, Jezorwski J, et al. Week 48 resistance analyses of the once-daily, single-tablet regimen darunavir/cobicistat/ emtricitabine/tenofovir alafenamide (D/C/F/TAF) in adults living with HIV-1 from the AMBER and EMERALD phase 3 trials. Poster presented at: HIV Glasgow Drug Therapy Meeting 2018; Glasgow, UK.Google Scholar
  23. 23.
    Llibre JM, Hung CC, Brinson C, Castelli F, Girard PM, 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;391:839–49.CrossRefGoogle Scholar
  24. 24.
    Reynes J, Meftah N, Tuaillon E, Charpentier C, Montes B. Dual regimen with dolutegravir and lamivudine maintains virologic suppression even in heavily treatment experienced HIV-infected patients: 96 weeks results from maintenance DOLULAM study. Presented at: 9th IAS Conference on HIV Science 2017; Paris France.Google Scholar
  25. 25.
    Charpentier C, Montes B, Perrier M, Meftah N, Reynes J. HIV-1 DNA ultra-deep sequencing analysis at initiation of the dual therapy dolutegravir + lamivudine in the maintenance DOLULAM pilot study. J Antimicrob Chemother. 2017;72:2831–6.  https://doi.org/10.1093/jac/dkx233.CrossRefPubMedGoogle Scholar
  26. 26.
    Ciccullo A, Baldin G, Capetti A, Rusconi S, Sterrantino G, d'Ettorre G, et al. A comparison between two dolutegravir-based two-drug regimens as switch strategies in a multicentre cohort of HIV-1-infected patients. Antivir Ther. 2019;24:63–7.  https://doi.org/10.3851/IMP3270.CrossRefPubMedGoogle Scholar
  27. 27.
    Baldin G, Ciccullo A, Borghetti A, Di Giambenedetto S. Virological efficacy of dual therapy with lamivudine and dolutegravir in HIV-1-infected virologically suppressed patients: long-term data from clinical practice. J Antimicrob Chemother. 2019 Feb 5;74:1461–3.  https://doi.org/10.1093/jac/dkz009.CrossRefGoogle Scholar
  28. 28.
    Borghetti A, Lombardi F, Gagliardini R, Baldin G, Ciccullo A, Moschese D, et al. Efficacy and tolerability of lamivudine plus dolutegravir compared with lamivudine plus boosted PIs in HIV-1 positive individuals with virologic suppression: a retrospective study from the clinical practice. BMC Infect Dis. 2019;19:59.  https://doi.org/10.1186/s12879-018-3666-8.CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Gagliardini R, Ciccullo A, Borghetti A, Maggiolo F, Bartolozzi D, Borghi V, et al. Impact of the M184V resistance mutation on virological efficacy and durability of lamivudine-based dual antiretroviral regimens as maintenance therapy in individuals with suppressed HIV-1 RNA: a cohort study. Open Forum Infect Dis. 2018;5:ofy113.  https://doi.org/10.1093/ofid/ofy113.CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Borghetti A, Baldin G, Lombardi F, Ciccullo A, Capetti A, Rusconi S, et al. Effcacy and tolerability of lamivudine plus dolutegravir as a switch strategy in a multicentre cohort of patients with suppressed HIV-1 replication. HIV Med. 2018;19:452–4.  https://doi.org/10.1111/hiv.12611.CrossRefGoogle Scholar
  31. 31.
    • Allavena C, Deschanvres C, Peytavin G, Rey D, Valantin MA, Bani-Sadr F, et al. Factors associated with therapeutic failure of 2 drug regimens (DAT’AIDS Cohort). Poster 0493. Conference on Retroviruses and Opportunistic Infections. March 4–7 2019. Seattle, WA. Largest study evaluating patients with baseline RAMs. Google Scholar
  32. 32.
    Capetti AF, Cossu MV, Sterrantino G, Barbarini G, Di Giambenedetto S, De Socio GV, et al. Dolutegravir plus rilpivirine as a switch option in cART-experienced patients: 96-week data. Ann Pharmacother. 2018;52:740–6.  https://doi.org/10.1177/1060028018761600.CrossRefPubMedGoogle Scholar
  33. 33.
    Riccardi N, Del Puente F, Taramasso L, Di Biagio A. Maintenance of viral suppression after optimization therapy from etravirine plus raltegravir to rilpivirine plus dolutegravir in HIV-1-infected patients. J Int Assoc Provid AIDS Care. 2019;18:1–3.  https://doi.org/10.1177/2325958218821657.CrossRefGoogle Scholar
  34. 34.
    Capetti AF, De Socio GV, Cossu MV, Sterrantino G, Cenderello G, Cattelan AM, et al. Durability of dolutegravir plus boosted darunavir as salvage or simplification of salvage regimens in HIV-1 infected, highly treatment-experienced subjects. HIV Clin Trials. 2018;19(6):242–8.  https://doi.org/10.1080/15284336.2018.1550290.CrossRefPubMedGoogle Scholar
  35. 35.
    Jablonowska E, Siwak E, Bociaga-Jasik M, Gasiorowski J, Kalinowska A, Burkacka EF, et al. Real-life study of dual therapy based on dolutegravir and ritonavir-boosted darunavir in HIV-1-infected treatment-experienced patients. PLoS One. 2019;14:e0210476.  https://doi.org/10.1371/journal.pone.0210476.CrossRefPubMedPubMedCentralGoogle Scholar
  36. 36.
    Navarro J, Santos JR, Silva A, Burgos J, Falco V, Ribera E, et al. Effectiveness of once/day dolutegravir plus boosted darunavir as a switch strategy in heavily treated patients with human immunodeficiency virus. Pharmacotherapy. 2019;39:501–7.  https://doi.org/10.1002/phar.2227.CrossRefPubMedGoogle Scholar
  37. 37.
    Gubavu C, Prazuck T, Niang M, Buret J, Mille C, Guinard J, et al. Dolutegravir-based monotherapy or dual therapy maintains a high proportion of viral suppression even in highly experienced HIV-1-infected patients. J Antimicrob Chemother. 2016;71:1046–50.  https://doi.org/10.1093/jac/dkv430.CrossRefPubMedGoogle Scholar
  38. 38.
    Serrano-Villar S, Jarrin I, Viciana P, Pulido F, Vidal F, Bernal E, et al. Effects of ART simplification in the cohort of the Spanish AIDS Research Network (CoRIS). Abstract 494. Conference on Retroviruses and Opportunistic Infections. March 4–7 2019. Seattle, WA.Google Scholar
  39. 39.
    Seang S, Schneider L, Nguyen T, Le MP, Soulie C, Calin R, et al. Darunavir/ritonavir monotherapy at a low dose (600/100 mg/day) in HIV-1-infected individuals with suppressed HIV viraemia. J Antimicrob Chemother. 2018;73:490–3.  https://doi.org/10.1093/jac/dkx417.CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  • Neha Sheth Pandit
    • 1
    Email author
  • Daniel B. Chastain
    • 2
  • Andrea M. Pallotta
    • 3
  • Melissa E. Badowski
    • 4
  • Emily C. Huesgen
    • 5
  • Sarah M. Michienzi
    • 4
  1. 1.University of Maryland Baltimore School of PharmacyBaltimoreUSA
  2. 2.University of Georgia College of PharmacyAlbanyUSA
  3. 3.Department of PharmacyCleveland ClinicClevelandUSA
  4. 4.College of PharmacyUniversity of Illinois at ChicagoChicagoUSA
  5. 5.Indiana University HealthIndianapolisUSA

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