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.
BackgroundDolutegravir 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).MethodsWe 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 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<50 copies/mL at week 24. This study was not powered to compare arms.Results130 participants were randomised (65 to each arm). Median baseline HIV-1 RNA was 4.0 log10 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<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.ConclusionsOur findings do not support the need for initial dolutegravir dose adjustment in patients switching to TLD who failed first-line TEE.