RESULTS
death, human immunodeficiency virus type 1, psychosis, virologic failure, SAEs, acute kidney injury, insomnia, Insomnia, headache, coronavirus disease 2019
PULMONARY TUBERCULOSIS, CORONAVIRUS DISEASE 2019, ADVERSE EVENTS, SENSITIVITY, ADVERSE EVENT, HUMAN IMMUNODEFICIENCY VIRUS TYPE
Participants were recruited between 28 August 2020 and 10 November 2021. Of 178 adults screened, 130 participants were randomly assigned to receive lead-in supplementary dolutegravir (n = 65) or placebo (n = 65) (Eligibility assessment, randomization, treatment, and follow-up. *Eight patients had CD4 count <100 cells/µL and 3 had CD4 count <50 cells/µL. The protocol was amended to broaden the CD4 inclusion criterion from ≥100 to ≥50 cells/µL on 14 July 2021. Baseline CharacteristicsAbbreviations: ART, antiretroviral therapy; BMI, body mass index; DTG, dolutegravir; HIV-1, human immunodeficiency virus type 1; IQR, interquartile range; NRTI, nucleoside reverse transcriptase inhibitor; TFV-DP, tenofovir diphosphate; TLD, tenofovir-lamivudine-dolutegravir; XTC, lamivudine or emtricitabine.Resistance was classified with the Stanford algorithm, with a score of ≥15 indicating at least low-level resistance.Denominators indicate the numbers of participants with available viral sequences.Both NRTIs had a Stanford score <15 indicating susceptibility or only potential of low-level resistance.Virologic outcomes by study arm at weeks 12 and 24 are shown in Summary of Plasma Human Immunodeficiency Virus Type 1 RNA OutcomesAbbreviations: CI, confidence interval; DTG, dolutegravir; HIV-1, human immunodeficiency virus type 1; mITT, modified intention-to-treat; TLD, tenofovir-lamivudine-dolutegravir.mITT analysis excludes those switching study drug for reasons of stopping contraception or desire to become pregnant, becoming pregnant, transfer out for nonclinical reasons, and death from non-HIV and nondrug causes.Sensitivity analysis excludes those excluded from mITT analysis, as well as loss to follow-up, missing viral load within the window, switching study drug for reasons other than treatment failure, and evidence of poor adherence (tenofovir diphosphate <350 fmol/punch).One-sided 97.5% CI when 0 or 100% were successful.In the subgroup with resistance to both tenofovir and lamivudine at baseline, virologic suppression at week 24 was achieved by 39 of 45 (87% [95% CI: 73%–95%]) participants in the supplementary dolutegravir arm and 36 of 45 (80% [95% CI: 65%–90%]) participants in the placebo arm. Time to virologic suppression by arm is shown in Kaplan-Meier for time to virological suppression (human immunodeficiency virus type 1 RNA <50 copies/mL). Abbreviations: DTG, dolutegravir; HIV-1, human immunodeficiency virus type 1; TLD, tenofovir-lamivudine-dolutegravir.Six participants (3 in each arm) met protocol-defined criteria for GART by week 24; no participants developed dolutegravir resistance or acquired new resistance mutations to tenofovir or lamivudine. One participant in the supplementary dolutegravir arm developed virologic failure at week 16; GART detected no integrase resistance mutations and the participant reported poor adherence (corroborated by TFV-DP concentration <350 fmol/punch at week 12). There were 19 participants with HIV-1 RNA ≥50 copies/mL at week 24; 15 of 19 (79%) later resuppressed HIV-1 RNA <50 copies/mL with enhanced adherence counseling.Median increase in CD4Tenofovir diphosphate (TFV-DP) concentrations at baseline, 12 weeks, and 24 weeks (boxes indicate interquartile range, horizontal solid lines are medians, vertical lines are ranges, and solid circles are outliers). Dotted lines refer to TFV-DP concentrations categorized using the threshold defined by Anderson et al [Grade 3 or 4 adverse events and serious adverse events were uncommon (Proportion of participants with a ≥1-unit increase in the Insomnia Severity Index (ISI) and reported insomnia as an adverse event. Sleep was evaluated using the ISI, a 7-item tool with a total score ranging from 0 to 28. A higher score indicates a worse performance. Numerator is the number of individuals who reported insomnia with at least a 1-unit increase in ISI score from baseline (week 0). Denominator is the number of individuals with an ISI score at each week for all individuals with a baseline result. Abbreviations: DTG, dolutegravir; TLD, tenofovir-lamivudine-dolutegravir.Number (%) of Participants With Adverse EventsAbbreviations: AE, adverse event; DTG, dolutegravir; SAE, serious adverse event; TLD, tenofovir-lamivudine-dolutegravir.The death in the DTG arm was caused by severe coronavirus disease 2019 (COVID-19).The SAEs in the DTG arm were severe COVID-19 leading to death, and acute psychosis, which was considered unrelated to the study drug and resolved without discontinuation of the study drug.The grade 3 AEs in the DTG arm were acute psychosis and incident pulmonary tuberculosis. The grade 3 AEs in the placebo arm were raised random glucose (experienced by 2 participants), acute kidney injury (experienced by 2 participants), and headache.One participant in the placebo arm switched from tenofovir to zidovudine after developing a creatinine elevation.