INSTIs for the management of HIV-associated TB (INSIGHT study): a phase 2b study to evaluate the efficacy, safety and pharmacokinetics of a combination of bictegravir, emtricitabine and tenofovir alafenamide fumarate for the treatment of HIV-1 infection in patients with drug-susceptible tuberculosis on a rifampicin-based treatment regimen: a phase 2b open-label randomised controlled trial
Anushka Naidoo, Kelly E Dooley, Kogieleum Naidoo, Nesri Padayatchi, Nonhlanhla Yende-Zuma, Rubeshan Perumal, Gillian Dorse, Resha Boodhram, Emmanuella Chinonso Osuala, Anushka Naidoo, Kelly E Dooley, Kogieleum Naidoo, Nesri Padayatchi, Nonhlanhla Yende-Zuma, Rubeshan Perumal, Gillian Dorse, Resha Boodhram, Emmanuella Chinonso Osuala
Abstract
Introduction: Cotreatment of HIV and tuberculosis (TB) reduces morbidity and mortality in coinfected patients. Availability of antiretroviral treatment (ART) drug options, including within drug classes, is important, particularly in high HIV/TB burden low and middle-income countries.
Methods and analysis: This is a phase 2b, open-label, non-comparative randomised controlled trial to assess the antiretroviral activity of a fixed-drug, single tablet, combination of bictegravir (BIC) 50 mg/emtricitabine (FTC) 200 mg/tenofovir alafenamide (TAF) 25 mg (Biktarvy). The primary objective is to determine the efficacy, safety and pharmacokinetics of two times per day, coformulated BIC 50 mg/FTC 200 mg/TAF 25 mg in HIV-positive ART-naïve patients with TB who are receiving a rifampicin-based treatment regimen and to characterise viral suppression rates at week 24 through to week 48 in the BIC/FTC/TAF arm. We will enrol 120 patients randomised in a 2:1 ratio to the intervention or control arm of the study. A non-comparative contemporaneous control arm in which participants receive a dolutegravir-based regimen (standard of care) will also be enrolled.
Ethics and dissemination: The University of KwaZulu-Natal Biomedical Research Ethics Committee (BREC) and the South African Health Products Regulatory Authority (SAHPRA) have granted regulatory approval (trial reference numbers: BREC/00001300/2020 and SAHPRA 20200810). Trial results will be disseminated through conference presentations, peer-reviewed publications and the clinical trial registry.
Trial registration number: Clinicaltrials.gov; Trial registration number: NCT04734652; South African National Clinical Trials Register (SANCTR DOH-27-012021-6789).
Keywords: Clinical trials; HIV & AIDS; Tuberculosis.
Conflict of interest statement
Competing interests: None declared.
© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.
References
- UNAIDS . Unaids data 2018. Geneva, Switzerland: Joint United Nations Program on HIV AIDS, 2018.
- WHO . Policy brief: updated recommendations on first-line and second-line antiretroviral regimens and post-exposure prophylaxis and recommendations on early infant diagnosis of HIV. Geneva, Switzerland: World Health Organization, 2018.
- Dorward J, Lessells R, Drain PK, et al. . Dolutegravir for first-line antiretroviral therapy in low-income and middle-income countries: uncertainties and opportunities for implementation and research. Lancet HIV 2018;5:e400–4. 10.1016/S2352-3018(18)30093-6
- Acosta RK, Willkom M, Martin R, et al. . Resistance analysis of Bictegravir-Emtricitabine-Tenofovir Alafenamide in HIV-1 treatment-naive patients through 48 weeks. Antimicrob Agents Chemother 2019;63. 10.1128/AAC.02533-18. [Epub ahead of print: 25 04 2019].
- Deeks ED. Bictegravir/Emtricitabine/Tenofovir Alafenamide: a review in HIV-1 infection. Drugs 2018;78:1817–28. 10.1007/s40265-018-1010-7
- 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. 10.1097/QAI.0000000000001306
- Stellbrink H-J, Arribas JR, 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 2019;6:e364–72. 10.1016/S2352-3018(19)30080-3
- Wohl DA, 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. 10.1016/S2352-3018(19)30077-3
- WHO . Global tuberculosis report 2018. Geneva, Switzerland: World Health Organization, 2018.
- Abdool Karim SS, Naidoo K, Grobler A, et al. . Timing of initiation of antiretroviral drugs during tuberculosis therapy. N Engl J Med 2010;362:697–706. 10.1056/NEJMoa0905848
- WHO . Treatment of tuberculosis guidelines. 4th edition. Geneva, Switzerland: World Health Organisation, 2010.
- Reitman ML, Chu X, Cai X, et al. . Rifampin's acute inhibitory and chronic inductive drug interactions: experimental and model-based approaches to drug-drug interaction trial design. Clin Pharmacol Ther 2011;89:234–42. 10.1038/clpt.2010.271
- Joseph Custodio M M, Collins S, Vu A. Pharmacokinetics of bictegravir administered administered twice daily in combination with rifampin. Program and abstracts of the 2018 Conference on Retroviruses and Opportunistic Infections, Boston, 2018.
- 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. 10.1016/S0140-6736(17)32340-1
- White KL, Osman N, Cuadra-Foy E, et al. . Long dissociation of bictegravir from HIV-1 integrase-DNA complexes. Antimicrob Agents Chemother 2021;65:e02406–20. 10.1128/AAC.02406-20
- Gilead Sciences . Biktarvy 50 mg/200 mg/25 Mg film-coated tablets: EU summary of product characteristics, 2018. Available: [Accessed 3 Jun 2019].
- Gilead Sciences . Biktarvy® (bictegravir, emtricitabine, and tenofovir alafenamide): US prescribing information, 2018. Available: [Accessed 3 Jun 2019].
- Maddalena Cerrone OA, Neary M, Marzinke MA, et al. . Rifampin effect on tenofovir alafenamide (TAF) plasma/ intracellular pharmacokinetics. 25th CROI. Boston. 4–7 March 2018. oral Abstract 28LB. 2018.
- Gish RG, Leung NWY, Wright TL, et al. . Dose range study of pharmacokinetics, safety, and preliminary antiviral activity of emtricitabine in adults with hepatitis B virus infection. Antimicrob Agents Chemother 2002;46:1734–40. 10.1128/AAC.46.6.1734-1740.2002
- Rousseau FS, Kahn JO, Thompson M, et al. . Prototype trial design for rapid dose selection of antiretroviral drugs: an example using emtricitabine (Coviracil). J Antimicrob Chemother 2001;48:507–13. 10.1093/jac/48.4.507
- Valade E, Tréluyer J-M, Bouazza N, et al. . Population pharmacokinetics of emtricitabine in HIV-1-infected adult patients. Antimicrob Agents Chemother 2014;58:2256–61. 10.1128/AAC.02058-13
- Natukunda E, Gaur AH, Kosalaraksa P, et al. . Safety, efficacy, and pharmacokinetics of single-tablet elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide in virologically suppressed, HIV-infected children: a single-arm, open-label trial. Lancet Child Adolesc Health 2017;1:27–34. 10.1016/S2352-4642(17)30009-3
- Lelievre J-D, Lelievre J-D, Kalayjian R, 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 2018. 10.1016/S2352-3018(18)30296-0. [Epub ahead of print: 13 Dec 2018].
- Brooks KM, George JM, Pau AK, et al. . Cytokine-Mediated systemic adverse drug reactions in a drug-drug interaction study of dolutegravir with once-weekly isoniazid and rifapentine. Clin Infect Dis 2018;67:193–201. 10.1093/cid/ciy082
- 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 2019;365. 10.1093/cid/ciz256
- Dooley KE, 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;62:21–7. 10.1097/QAI.0b013e318276cda9
- Gengiah TN, Botha JH, Yende-Zuma N, et al. . Efavirenz dosing: influence of drug metabolizing enzyme polymorphisms and concurrent tuberculosis treatment. Antivir Ther 2015;20:297–306. 10.3851/IMP2877
- 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;14:459–67. 10.1016/S1473-3099(14)70711-X
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