Standard versus double dose dolutegravir in patients with HIV-associated tuberculosis: a phase 2 non-comparative randomised controlled (RADIANT-TB) trial

Rulan Griesel, Andrew Hill, Graeme Meintjes, Gary Maartens, Rulan Griesel, Andrew Hill, Graeme Meintjes, Gary Maartens

Abstract

Dolutegravir, a second-generation integrase strand transfer inhibitor (InSTI), is replacing efavirenz as first-line antiretroviral therapy (ART) in low middle-income countries (LMICs). Tuberculosis remains the leading cause of HIV-related morbidity and mortality in LMICs. Rifampicin is a key agent in the treatment of tuberculosis but induces genes involved in dolutegravir metabolism and efflux. The resulting drug-drug interaction (DDI) reduces the exposure of dolutegravir. However, this can be overcome by supplying a supplemental dose of 50 mg dolutegravir 12 hours after the standard daily dose, which is difficult to implement in LMICs. Four lines of evidence suggest that the supplemental dose may not be necessary: 1) a phase 2 study showed 10 mg of dolutegravir as effective as 50 mg; 2) the prolonged dissociative half-life of dolutegravir after binding to its receptor; 3) a DDI study reported dolutegravir trough concentrations were maintained above its minimum effective concentration when using 50 mg dolutegravir with rifampicin; and 4) virologic outcomes were similar between standard and double dose of raltegravir (a first-generation InSTI) in participants with HIV-associated tuberculosis treated with rifampicin. We hypothesise that virologic outcomes with standard dose dolutegravir-based ART will be acceptable in patients on rifampicin-based antituberculosis therapy. Here we outline the protocol for a phase 2, non-comparative, randomised, double-blind, placebo-controlled trial of standard versus double dose dolutegravir among adults living with HIV (ART naïve or first-line interrupted) on rifampicin-based antituberculosis therapy. A total of 108 participants will be enrolled from Khayelitsha in Cape Town, South Africa. Follow up will occur over 48 weeks. The primary objective is to assess proportion virological suppression at 24 weeks between groups analysed by modified intention to treat. Participant safety and the emergence of antiretroviral resistance mutations among those with virologic failure will be assessed throughout. Trial registrations: clinicaltrials.gov NCT03851588 (22/02/2019), SANCTR DOH-27-072020-8159 (03/07/2020).

Keywords: Dolutegravir; drug-drug interaction; rifampicin; tuberculosis.

Conflict of interest statement

No competing interests were disclosed.

Copyright: © 2021 Griesel R et al.

References

    1. World Health Organisation: Updated recommendations on first-line and second-line antiretroviral regimens and post-exposure prophylaxis and recommendations on early infant diagnosis of HIV: interim guidelines. Supplement to the 2016 consolidated guidelines on the use of antiretroviral drugs for treating and preventing HIV infection. Geneva: World Health Organization; (WHO/CDS/HIV/18.51).2018.
    1. Lawn SD, Wood R, De Cock KM, et al. : Antiretrovirals and isoniazid preventive therapy in the prevention of HIV-associated tuberculosis in settings with limited health-care resources. Lancet Infect Dis. 2010;10(7):489–98. 10.1016/S1473-3099(10)70078-5
    1. Dooley KE, Sayre P, Borland J: 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;62(1):21–7. 10.1097/QAI.0b013e318276cda9
    1. Dooley KE, Kaplan R, Mwelase N, et al. : Dolutegravir-based Antiretroviral Therapy for Patients Coinfected With Tuberculosis and Human Immunodeficiency Virus: A Multicenter, Noncomparative, Open-label, Randomized Trial. Clin Infect Dis. 2020;70(4):549–56. 10.1093/cid/ciz256
    1. 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):1737–45. 10.1097/QAD.0b013e32834a1dd9
    1. Van Lunzen J, Maggiolo F, Arribas JR, 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. 10.1016/S1473-3099(11)70290-0
    1. Hightower KE, Wang R, 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 Agents Chemother. 2011;55(10):4552–9. 10.1128/AAC.00157-11
    1. Wang X, Cerrone M, Ferretti F, et al. : Pharmacokinetics of dolutegravir 100 mg once daily with rifampicin. Presented at: 19th International Workshop on Clinical Pharmacology, Baltimore,2018.
    1. Wenning LA, Hanley WD, Brainard DM, et al. : Effect of rifampin, a potent inducer of drug-metabolizing enzymes, on the pharmacokinetics of raltegravir. Antimicrob Agents Chemother. 2009;53(7):2852–6. 10.1128/AAC.01468-08
    1. 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(6):459–67. 10.1016/S1473-3099(14)70711-X
    1. Griesel R: RADIANT-TB Informed Consent Form. figshare.Figure.2020. 10.6084/m9.figshare.13431266.v1
    1. Griesel R: RADIANT-TB Mental health assessment questionnaire. figshare.Figure.2020. 10.6084/m9.figshare.13431305.v1
    1. Alexander MJ, Haugland G, Lin SP, et al. : Mental health screening in addiction, corrections and social service settings: Validating the MMS. Int J Ment Health Addict. 2008;6(1):105–19. 10.1007/s11469-007-9100-x
    1. Bastien CH, Vallieres A, Morin CM: Validation of the Insomnia Severity Index as an outcome measure for insomnia research. Sleep Med. 2001;2(4):297–307. 10.1016/s1389-9457(00)00065-4
    1. Griesel R: RADIANT-TB Sleep assessment questionnaire. figshare.Figure.2020. 10.6084/m9.figshare.13431380.v1
    1. Phillips TK, Sinxadi P, Abrams EJ, et al. : A Comparison of Plasma Efavirenz and Tenofovir, Dried Blood Spot Tenofovir-Diphosphate, and Self-Reported Adherence to Predict Virologic Suppression Among South African Women. J Acquir Immune Defic Syndr. 2019;81(3):311–8. 10.1097/QAI.0000000000002032
    1. Anderson PL, Liu AY, Castillo-Mancilla JR, et al. : Intracellular Tenofovir-Diphosphate and Emtricitabine-Triphosphate in Dried Blood Spots following Directly Observed Therapy. Antimicrob Agents Chemother. 2017;62(1):e01710–17. 10.1128/AAC.01710-17
    1. Zash R, Holmes L, Diseko M, et al. : Neural-Tube Defects and Antiretroviral Treatment Regimens in Botswana. N Engl J Med. 2019;381(9):827–40. 10.1056/NEJMoa1905230
    1. Division of AIDS, National institute of allergy and infectious diseases, National Institute of Health: Division of AIDS table for grading the severity of adult and pediatric adverse events. Version 2.1.2017.
    1. Bonnet M, Bhatt N, Baudin E, et al. : Nevirapine versus efavirenz for patients co-infected with HIV and tuberculosis: a randomised non-inferiority trial. Lancet Infect Dis. 2013;13(4):303–12. 10.1016/S1473-3099(13)70007-0
    1. Havlir DV, Kendall MA, Ive P, et al. : Timing of antiretroviral therapy for HIV-1 infection and tuberculosis. N Engl J Med. 2011;365(16):1482–91. 10.1056/NEJMoa1013607
    1. Griesel R: RADIANT-TB_SPIRIT checklist_27Nov2020.docx. figshare.Dataset.2020. 10.6084/m9.figshare.13431137.v1
    1. Modongo C, Wang Q, Dima M, et al. : Clinical and Virological Outcomes of TB/HIV Coinfected Patients Treated With Dolutegravir-Based HIV Antiretroviral Regimens: Programmatic Experience From Botswana. J Acquir Immune Defic Syndr. 2019;82(2):111–5. 10.1097/QAI.0000000000002126

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