Initial supplementary dose of dolutegravir in second-line antiretroviral therapy: a non-comparative, double-blind, randomised placebo-controlled trial

Initial supplementary dose of dolutegravir in second-line antiretroviral therapy: a non-comparative, double-blind, randomised placebo-controlled trial. Zhao, Y., Griesel, R., Omar, Z., Simmons, B., Hill, A., van Zyl, G., Keene, C., Maartens, G., & Meintjes, G. A Clinical Infectious Diseases, 76(10):1832–1840, jan, 2023.

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Background: Dolutegravir concentrations are reduced by efavirenz induction effect necessitating twice daily dolutegravir dosing when co-administered. Efavirenz induction persists for several weeks after stopping, which could potentially select for dolutegravir resistance if switching occurred with unsuppressed HIV-1 RNA levels and standard dolutegravir dosing. We evaluated the need for a lead-in supplementary dolutegravir dose in adults failing first-line tenofovir-emtricitabine-efavirenz (TEE). Methods: We conducted a randomised, double-blind, placebo-controlled, phase 2 trial in Khayelitsha, South Africa. Eligible patients had virologic failure (two consecutive HIV-1 RNA≥1000 copies/mL) on first-line TEE. Participants were randomly assigned (1:1) to switch to 2 tenofovir-lamivudine-dolutegravir (TLD) with a supplementary 50 mg dolutegravir dose or placebo taken 12 hours later for 14 days. Primary outcome was proportion with HIV-1 RNA\textless50 copies/mL at week 24. This study was not powered to compare arms. Results: 130 participants were randomised (65 to each arm). Median baseline HIV-1 RNA was 4.0 log 10 copies/mL and 76% had baseline resistance to both tenofovir and lamivudine. One participant died and two were lost to follow-up. At week 24, 55/64 (86%, 95% confidence interval [CI], 75-93%) in the supplementary dolutegravir arm and 53/65 (82%, 95% CI, 70-90%) in the placebo arm had HIV-1 RNA\textless50 copies/mL. Grade 3 or 4 adverse events were similar in frequency between arms. None of six participants (3 in each arm) eligible for resistance testing by 24 weeks developed dolutegravir resistance. Conclusions: Our findings do not support the need for initial dolutegravir dose adjustment in patients switching to TLD who failed first-line TEE. Clinical Trials Registration: NCT03991013

@article{Zhao2023,
abstract = {Background: Dolutegravir concentrations are reduced by efavirenz induction effect necessitating twice daily dolutegravir dosing when co-administered. Efavirenz induction persists for several weeks after stopping, which could potentially select for dolutegravir resistance if switching occurred with unsuppressed HIV-1 RNA levels and standard dolutegravir dosing. We evaluated the need for a lead-in supplementary dolutegravir dose in adults failing first-line tenofovir-emtricitabine-efavirenz (TEE). Methods: We conducted a randomised, double-blind, placebo-controlled, phase 2 trial in Khayelitsha, South Africa. Eligible patients had virologic failure (two consecutive HIV-1 RNA≥1000 copies/mL) on first-line TEE. Participants were randomly assigned (1:1) to switch to 2 tenofovir-lamivudine-dolutegravir (TLD) with a supplementary 50 mg dolutegravir dose or placebo taken 12 hours later for 14 days. Primary outcome was proportion with HIV-1 RNA{\textless}50 copies/mL at week 24. This study was not powered to compare arms. Results: 130 participants were randomised (65 to each arm). Median baseline HIV-1 RNA was 4.0 log 10 copies/mL and 76{\%} had baseline resistance to both tenofovir and lamivudine. One participant died and two were lost to follow-up. At week 24, 55/64 (86{\%}, 95{\%} confidence interval [CI], 75-93{\%}) in the supplementary dolutegravir arm and 53/65 (82{\%}, 95{\%} CI, 70-90{\%}) in the placebo arm had HIV-1 RNA{\textless}50 copies/mL. Grade 3 or 4 adverse events were similar in frequency between arms. None of six participants (3 in each arm) eligible for resistance testing by 24 weeks developed dolutegravir resistance. Conclusions: Our findings do not support the need for initial dolutegravir dose adjustment in patients switching to TLD who failed first-line TEE. Clinical Trials Registration: NCT03991013},
author = {Zhao, Ying and Griesel, Rulan and Omar, Zaayid and Simmons, Bryony and Hill, Andrew and van Zyl, Gert and Keene, Claire and Maartens, Gary and Meintjes, Graeme A},
doi = {10.1093/CID/CIAD023},
file = {:C$\backslash$:/Users/01462563/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Zhao et al. - 2023 - Initial supplementary dose of dolutegravir in second-line antiretroviral therapy a non-comparative, double-blind, r.pdf:pdf},
issn = {1058-4838},
journal = {Clinical Infectious Diseases},
keywords = {Antiretroviral therapy,HIV,OA,dolutegravir,efavirenz,fund{\_}ack,original,second-line},
mendeley-tags = {OA,fund{\_}ack,original},
month = {jan},
number = {10},
pages = {1832--1840},
pmid = {36645792},
title = {{Initial supplementary dose of dolutegravir in second-line antiretroviral therapy: a non-comparative, double-blind, randomised placebo-controlled trial}},
url = {https://academic.oup.com/cid/advance-article/doi/10.1093/cid/ciad023/6988111},
volume = {76},
year = {2023}
}

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Methods: We conducted a randomised, double-blind, placebo-controlled, phase 2 trial in Khayelitsha, South Africa. Eligible patients had virologic failure (two consecutive HIV-1 RNA≥1000 copies/mL) on first-line TEE. Participants were randomly assigned (1:1) to switch to 2 tenofovir-lamivudine-dolutegravir (TLD) with a supplementary 50 mg dolutegravir dose or placebo taken 12 hours later for 14 days. Primary outcome was proportion with HIV-1 RNA\\textless50 copies/mL at week 24. This study was not powered to compare arms. Results: 130 participants were randomised (65 to each arm). Median baseline HIV-1 RNA was 4.0 log 10 copies/mL and 76% had baseline resistance to both tenofovir and lamivudine. One participant died and two were lost to follow-up. At week 24, 55/64 (86%, 95% confidence interval [CI], 75-93%) in the supplementary dolutegravir arm and 53/65 (82%, 95% CI, 70-90%) in the placebo arm had HIV-1 RNA\\textless50 copies/mL. Grade 3 or 4 adverse events were similar in frequency between arms. None of six participants (3 in each arm) eligible for resistance testing by 24 weeks developed dolutegravir resistance. Conclusions: Our findings do not support the need for initial dolutegravir dose adjustment in patients switching to TLD who failed first-line TEE. 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