Switching to bictegravir/emtricitabine/tenofovir alafenamide maintained HIV-1 RNA suppression in participants with archived antiretroviral resistance including M184V/I

Kristen Andreatta, Madeleine Willkom, Ross Martin, Silvia Chang, Lilian Wei, Hui Liu, Ya-Pei Liu, Hiba Graham, Erin Quirk, Hal Martin, Kirsten L White, Kristen Andreatta, Madeleine Willkom, Ross Martin, Silvia Chang, Lilian Wei, Hui Liu, Ya-Pei Liu, Hiba Graham, Erin Quirk, Hal Martin, Kirsten L White

Abstract

Objectives: Studies 1878 and 1844 demonstrated non-inferior efficacy of switching suppressed HIV-1-infected adults to bictegravir/emtricitabine/tenofovir alafenamide (BIC/FTC/TAF) versus continuing boosted PI-based triple regimens or dolutegravir/abacavir/lamivudine (DTG/ABC/3TC). Here, detailed analyses of pre-existing resistance in the two BIC/FTC/TAF switch studies and efficacy at week 48 are described.

Methods: Pre-existing resistance was assessed from historical genotypes (documented resistance to study drugs was excluded) and by retrospective baseline proviral archive DNA genotyping from whole blood. Outcomes were based on HIV-1 RNA at week 48 with missing values imputed using the last on-treatment observation carried forward method.

Results: Cumulative pre-existing resistance data from historical and proviral genotypes were obtained for 95% (543/570) of participants who switched to BIC/FTC/TAF. Altogether, 40% (217/543) had one or more pre-existing primary resistance substitutions in protease, reverse transcriptase and/or integrase. Pre-switch NRTI resistance was detected in 16% (89/543) of BIC/FTC/TAF-treated participants, with M184V or M184I detected by proviral genotyping in 10% (54/543). At week 48, 98% (561/570) of all BIC/FTC/TAF-treated participants versus 98% (213/217) with pre-existing resistance and 96% (52/54) with archived M184V/I had HIV-1 RNA <50 copies/mL. No BIC/FTC/TAF-treated participants developed treatment-emergent resistance to study drugs.

Conclusions: Pre-existing resistance substitutions, notably M184V/I, were unexpectedly common among suppressed participants who switched to BIC/FTC/TAF. High rates of virological suppression were maintained in the overall study population and in those with pre-existing resistance, including M184V/I, for up to 48 weeks of BIC/FTC/TAF treatment with no resistance development. These results indicate that BIC/FTC/TAF is an effective treatment option for suppressed patients, including those with evidence of archived NRTI resistance.

© The Author(s) 2019. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy.

References

    1. Saag MS, Benson CA, Gandhi RT. et al. Antiretroviral drugs for treatment and prevention of HIV infection in adults - 2018 recommendations of the International Antiviral Society–USA Panel. JAMA 2018; 320: 379–96.
    1. The Department of Health and Human Services (DHHS) Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents Living with HIV .
    1. 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; 75: 61–6.
    1. 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: 7086–97.
    1. Mulato A, Acosta R, Yant SR. et al. Forgiveness of antiretroviral regimens: in vitro HIV-1 viral breakthrough with 2-drug versus 3-drug regimens simulating variable adherence to treatment [Poster 50]. In: 17th European Meeting on HIV & Hepatitis - Treatment Strategies & Antiviral Drug Resistance, Rome, Italy.
    1. Gallant J, Lazzarin A, Mills A. et al. 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. Lancet 2017; 390: 2063–72.
    1. Sax PE, Pozniak A, Montes ML. 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: 2073–82.
    1. Wohl D, Yazdanpanah Y, Baumgarten A. et al. Bictegravir Combined with Emtricitabine and Tenofovir Alafenamide Versus Dolutegravir, Abacavir, and Lamivudine for Initial Treatment of HIV-1 Infection: Week 96 Results from a Randomised, Double-Blind, Multicentre, Phase 3, Non-Inferiority Trial. Lancet HIV. 2019; 6: e355–63.
    1. Stellbrink HJ, Arribas J, Stephens JL. et al. Co-Formulated Bictegravir, Emtricitabine, and Tenofovir Alafenamide Versus Dolutegravir with Emtricitabine and Tenofovir Alafenamide for Initial Treatment of HIV-1 Infection: Week 96 Results from a Randomised, Double-Blind, Multicentre, Phase 3, Non-Inferiority Trial. Lancet HIV; 6: e364–72.
    1. Daar ES, DeJesus E, Ruane P. 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, multicentre, phase 3, non-inferiority trial. Lancet HIV 2018; 5: e347–56.
    1. Molina JM, Ward D, Brar I. 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, multicentre, active-controlled, phase 3, non-inferiority trial. Lancet HIV 2018; 5: e357–65.
    1. Wensing AM, Calvez V, Gunthard HF. et al. Special contribution: 2017 update of the drug resistance mutations in HIV-1 . Topics Antivir Med 2017; 24: 132–41.
    1. Miller MD, Margot N, Lu B. et al. Genotypic and phenotypic predictors of the magnitude of response to tenofovir disoproxil fumarate treatment in antiretroviral-experienced patients. J Infect Dis 2004; 189: 837–46.
    1. Margot NA, Wong P, Kulkarni R. et al. Commonly transmitted HIV-1 drug resistance mutations in reverse-transcriptase and protease in antiretroviral treatment-naive patients and response to regimens containing tenofovir disoproxil fumarate or tenofovir alafenamide. J Infect Dis 2017; 215: 920–7.
    1. Wittkop L, Gunthard HF, de Wolf F. et al. Effect of transmitted drug resistance on virological and immunological response to initial combination antiretroviral therapy for HIV (EuroCoord-CHAIN joint project): a European multicohort study. Lancet Infect Dis 2011; 11: 363–71.
    1. Aldous AM, Castel AD, Parenti DM. et al. Prevalence and trends in transmitted and acquired antiretroviral drug resistance, Washington, DC, 1999-2014. BMC Res Notes 2017; 10: 474..
    1. Rhee SY, Clutter D, Fessel WJ. et al. Trends in the molecular epidemiology and genetic mechanisms of transmitted human immunodeficiency virus type 1 drug resistance in a large US clinic population. Clin Infect Dis 2018; 68: 213–21.
    1. Miller MD, Haddad M, Su C. et al. Trends in HIV-1 reverse transcriptase resistance-associated mutations and antiretroviral prescription data from 2003-2010. Antivir Ther 2012; 17: 993–9.
    1. Marconi VC, Sunpath H, Lu Z. et al. Prevalence of HIV-1 drug resistance after failure of a first highly active antiretroviral therapy regimen in KwaZulu Natal, South Africa. Clin Infect Dis 2008; 46: 1589–97.
    1. Karkashadze E, Dvali N, Bolokadze N. et al. Epidemiology of HIV drug resistance in HIV patients with virologic failure of first-line therapy in the country of Georgia. J Med Virol 2018; 91: 235–40.
    1. Cheng CY, Tsai MS, Yang CJ. et al. Patterns of emergent resistance-associated mutations after initiation of non-nucleoside reverse-transcriptase inhibitor-containing antiretroviral regimens in Taiwan: a multicenter cohort study. IDR 2018; 11: 849–59.
    1. BIKTARVY®, Gilead Sciences Inc. BIKTARVY® (Bictegravir, Emtricitabine, and Tenofovir Alafenamide) Tablets, for Oral Use US Prescribing Information (USPI), Foster City, CA, Revised: February 2018.
    1. Genvoya, Gilead Science Inc. GENVOYA® (Elvitegravir, Cobicistat, Emtricitabine, and Tenofovir Alafenamide) Tablets, for Oral Use US Prescribing Information. Foster City, CA, Revised: August 2018.
    1. Healthcare V. TRIUMEQ Full Prescribing Information (US), Revised: May 2018; 46.
    1. STRIBILD®, Gilead Sciences Inc. STRIBILD® (Elvitegravir, Cobicistat, Emtricitabine, Tenofovir Disoproxil Fumarate) Tablets, for Oral Use. U.S. Prescribing Information, Foster City, CA, Revised January 2017.
    1. COMPLERA®, Gilead Sciences Inc. COMPLERA® (Emtricitabine, Rilpivirine, Tenofovir Disoproxil Fumarate) Tablets, for Oral Use US Prescribing Information, Foster City, CA, Revised April 2017.
    1. ODEFSEY®, Gilead Sciences Inc. ODEFSEY® (Emtricitabine, Rilpivirine, and Tenofovir Alafenamide) Tablets, for Oral Use US Prescribing Information, Foster City, CA. Revised April 2017.
    1. Wolf K, Walter H, Beerenwinkel N. et al. Tenofovir resistance and resensitization. Antimicrob Agents Chemother 2003; 47: 3478–84.
    1. Whitcomb JM, Parkin NT, Chappey C. et al. Broad nucleoside reverse-transcriptase inhibitor cross-resistance in human immunodeficiency virus type 1 clinical isolates. J Infect Dis 2003; 188: 992–1000.
    1. Ross L, Parkin N, Chappey C. et al. Phenotypic impact of HIV reverse transcriptase M184I/V mutations in combination with single thymidine analog mutations on nucleoside reverse transcriptase inhibitor resistance. AIDS 2004; 18: 1691–6.
    1. Armitage AE, Deforche K, Chang CH. et al. APOBEC3G-induced hypermutation of human immunodeficiency virus type-1 is typically a discrete “all or nothing” phenomenon. PLoS Genet 2012; 8: e1002550..
    1. Dauwe K, Staelens D, Vancoillie L. et al. Deep sequencing of HIV-1 RNA and DNA in newly diagnosed patients with baseline drug resistance showed no indications for hidden resistance and is biased by strong interference of hypermutation. J Clin Microbiol 2016; 54: 1605–15.
    1. Ho YC, Shan L, Hosmane NN. et al. Replication-competent non-induced proviruses in the latent reservoir increase barrier to HIV-1 cure. Cell 2013; 155: 540–51.
    1. Noguera-Julian M, Cozzi-Lepri A, Di Giallonardo F. et al. Contribution of APOBEC3G/F activity to the development of low-abundance drug-resistant human immunodeficiency virus type 1 variants. Clin Microbiol Infect 2016; 22: 191–200.
    1. Perez-Valero I, Llibre JM, Lazzarin A. 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 [Presentation TUAB0104]. In: International AIDS Conference (IAC), Amsterdam, The Netherlands. 2018.
    1. Delaugerre C, Braun J, Charreau I. et al. Comparison of resistance mutation patterns in historical plasma HIV RNA genotypes with those in current proviral HIV DNA genotypes among extensively treated patients with suppressed replication. HIV Med 2012; 13: 517–25.
    1. Wirden M, Soulie C, Valantin MA. et al. Historical HIV-RNA resistance test results are more informative than proviral DNA genotyping in cases of suppressed or residual viraemia. J Antimicrob Chemother 2011; 66: 709–12.
    1. Thielen A, Daumer M, Wolf E. et al. Dynamics of therapy options for hiv-1 infected patients with historical multi-drug resistance (MDR), based on deep-sequencing of proviral DNA-first results from the LOWER study [Presentation]. In: 16th European Meeting on HIV & Hepatitis, Rome, Italy.
    1. Blanco JL, Oldenbuettel C, Thomas R. et al. Pathways of resistance in subjects failing dolutegravir monotherapy [Abstract 42]. In: Conference on Retroviruses and Opportunistic Infections (CROI), Seattle, WA, USA. 2017.
    1. Katlama C, Soulie C, Caby F. et al. Dolutegravir as monotherapy in HIV-1-infected individuals with suppressed HIV viraemia. J Antimicrob Chemother 2016; 71: 2646–50.
    1. Wijting I, Rokx C, Boucher C. et al. Dolutegravir as maintenance monotherapy for HIV (DOMONO): a phase 2, randomised non-inferiority trial. Lancet HIV 2017; 4: e547–54.
    1. Blanco JL, Rojas J, Paredes R. et al. Dolutegravir-based maintenance monotherapy versus dual therapy with lamivudine: a planned 24 week analysis of the DOLAM randomized clinical trial. J Antimicrob Chemother 2018; 73: 1965–71.
    1. Taiwo BO, Zheng L, Stefanescu A. et al. ACTG A5353: a pilot study of dolutegravir plus lamivudine for initial treatment of human immunodeficiency virus-1 (HIV-1)-infected participants with HIV-1 RNA <500000 copies/mL. Clin Infect Dis 2018; 66: 1689–97.
    1. Andreatta KN, Goodman DD, Miller MD. et al. Reduced viral fitness and lack of cross-class resistance with integrase strand transfer inhibitor and nucleoside reverse transcriptase inhibitor resistance mutations. Antimicrob Agents Chemother 2015; 59: 3441–9.
    1. Andreatta KN, Miller MD, White KL.. Drug susceptibility and viral fitness of HIV-1 with integrase strand transfer inhibitor resistance substitution Q148R or N155H in combination with nucleoside/nucleotide reverse transcriptase inhibitor resistance substitutions. Antimicrob Agents Chemother 2016; 60: 757–65.

Source: PubMed

Sponsorzy i współpracownicy

Warunki medyczne

Interwencje lekowe

3
Subskrybuj