Tenofovir-lamivudine-dolutegravir Combination as Second-line ART: a Randomised Controlled Trial

Summary

The strategy to support virological suppression on second-line antiretroviral treatment (ART) includes the provision of ART that has a low pill burden, good tolerability, low toxicity, is easily monitored, has a high barrier to resistance, and that is low cost. The fixed-dose combination of tenofovir-lamivudine-dolutegravir offers significant advantage as a potential second-line regimen compared to the World Health Organization standard of care second-line regimen of zidovudine-lamivudine-dolutegravir, in terms of cost, tolerability and monitoring requirements. The ARTIST study is a phase 2, randomised, double-blind, placebo-controlled trial aiming to determine the proportion of patients achieving virological suppression when recycling the tenofovir-emtricitabine/lamivudine backbone with dolutegravir (tenofovir-lamivudine-dolutegravir fixed-dose combination) as a second-line with and without a lead-in supplementary dose of dolutegravir, in patients failing a tenofovir-emtricitabine/lamivudine-efavirenz first-line regimen. There is evidence to suggest that even in the presence of resistance mutations to tenofovir and lamivudine (K65R or M184V/I), using this backbone with dolutegravir will provide an effective second-line regimen in patients who have failed a first-line regimen of tenofovir-emtricitabine/lamivudine-efavirenz. The strategy of giving a lead-in supplementary dose of dolutegravir is in view of the inducing effect of efavirenz on dolutegravir metabolism and transport that persists for 2 weeks after efavirenz is stopped; the inducing effect decreases with time after efavirenz is stopped. Given that these patients will have elevated viral loads, a high baseline risk of nucleoside reverse transcriptase inhibitor (NRTI) resistance and efavirenz resistance, and the inducing effect of efavirenz on dolutegravir metabolism and transport that persists for 2 weeks, this study will comprise two stages. The first stage will evaluate virological suppression in 62 participants initiated on the fixed-dose combination of tenofovir-lamivudine-dolutegravir with a lead-in supplementary dose of dolutegravir for the first 14 days. The study will progress to the second stage if this strategy proves effective, and 130 participants will then be randomised to receive the fixed-dose combination of tenofovir-lamivudine-dolutegravir with and without this lead-in dose. The primary endpoint is virological suppression (viral load \<50 copies/mL) at 24 weeks. A pharmacokinetic sub-study will be conducted on 12 participants in stage 1 and 24 participants in stage 2, to assess the trough concentrations of dolutegravir and off-treatment concentrations of efavirenz at day 3, 7, 14, and 28. This is to evaluate the need for the lead-in supplementary dose of dolutegravir.

Timeline

Start

2019-08-08

Primary completion

2022-04-26

Completion

2022-10-27

Publications

• Griesel R, Banda CG, Zhao Y, Omar Z, Wiesner L, Meintjes G, Sinxadi P, Maartens G. Pharmacokinetics of Single-Dose Versus Double-Dose Dolutegravir After Switching From a Failing Efavirenz-Based Regimen. J Acquir Immune Defic Syndr. 2024 May 1;96(1):85-91. doi: 10.1097/QAI.0000000000003402.
• Keene CM, Cassidy T, Zhao Y, Griesel R, Jackson A, Sayed K, Omar Z, Hill A, Ngwenya O, Van Zyl G, Flowers T, Goemaere E, Maartens G, Meintjes G. Recycling Tenofovir in Second-line Antiretroviral Treatment With Dolutegravir: Outcomes and Viral Load Trajectories to 72 weeks. J Acquir Immune Defic Syndr. 2023 Apr 15;92(5):422-429. doi: 10.1097/QAI.0000000000003157.
• Zhao Y, Griesel R, Omar Z, Simmons B, Hill A, van Zyl G, Keene C, Maartens G, Meintjes G. Initial Supplementary Dose of Dolutegravir in Second-Line Antiretroviral Therapy: A Noncomparative, Double-Blind, Randomized Placebo-Controlled Trial. Clin Infect Dis. 2023 May 24;76(10):1832-1840. doi: 10.1093/cid/ciad023.
• Zhao Y, Keene C, Griesel R, Sayed K, Gcwabe Z, Jackson A, Ngwenya O, Schutz C, Goliath R, Cassidy T, Goemaere E, Hill A, Maartens G, Meintjes G. AntiRetroviral Therapy In Second-line: investigating Tenofovir-lamivudine-dolutegravir (ARTIST): protocol for a randomised controlled trial. Wellcome Open Res. 2021 Feb 17;6:33. doi: 10.12688/wellcomeopenres.16597.1. eCollection 2021.

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Indications