Long-term safety and impact of immune recovery in heavily treatment-experienced adults receiving fostemsavir for up to 5 years in the phase 3 BRIGHTE study

Abstract

Introduction: Fostemsavir is a gp120-directed attachment inhibitor approved for heavily treatment-experienced (HTE) adults with multidrug-resistant HIV-1. We provide detailed week 240 safety results from the BRIGHTE study and evaluate the impact of immune recovery on safety outcomes.

Methods: The phase 3 BRIGHTE trial is ongoing; data for this analysis were collected from the first participant's first visit (February 23, 2015) through the last participant's last visit for week 240 (March 22, 2021). Safety endpoints were assessed in participants who received fostemsavir + optimized background therapy. In participants with baseline CD4+ T-cell count <200 cells/mm³, exposure-adjusted adverse event (AE) rates were assessed among subgroups with or without CD4+ T-cell count ≥200 cells/mm³ at any time during 48-week analysis periods through week 192.

Results: Through a median of 258 weeks (range, 0.14-319) of treatment, discontinuations due to AEs occurred in 30/371 (8%) participants. Serious AEs were reported in 177/371 (48%) participants, including 16 drug-related events in 13 (4%) participants. Thirty-five (9%) deaths occurred, primarily related to AIDS or acute infections. COVID-19-related events occurred in 25 (7%) participants; all resolved without sequelae. Among participants with baseline CD4+ T-cell count <200 cells/mm³, 122/162 (75%) achieved CD4+ T-cell count ≥200 cells/mm³ at week 192. Exposure-adjusted AE rates were markedly lower among participants achieving CD4+ T-cell count ≥200 cells/mm³ at any time vs those sustaining <200 cells/mm³. No new AIDS-defining events were reported after week 48 in participants with CD4+ T-cell count ≥200 cells/mm³.

Conclusions: Cumulative safety findings through the BRIGHTE 240-week interim analysis are consistent with other trials in HTE participants with advanced HIV-1 and comorbid disease. Reduced rates of AIDS-defining events and AEs were observed in participants with immunologic recovery on fostemsavir-based treatment.

Clinical trial number: NCT02362503, https://clinicaltrials.gov/study/NCT02362503.

Keywords: ARV; clinical trials; drug resistance; intervention; treatment.

Figure 1

Exposure-adjusted rates of (A, D, G) all-cause AEs, (B, E, H) infection and infestation PTSIs, and (C, F, I) AIDS-defining events through week 192^† by CD4+ T-cell count during the analysis period for participants with baseline CD4+ T-cell count <200 cells/mm³. In participants randomized to placebo, only data from start of open-label fostemsavir are included. For each panel, AE rates are based on the number of reported AEs for the specified category (y-axis) with a start date within the specified analysis period (legend). AE, adverse event; OBT, optimized background therapy; PTSI, preferred term of special interest. ^†Week 192 was used as the data cutoff for these analyses because subsequent results were impacted by study completion and the COVID-19 pandemic. ^‡Infectious disorders and ectoparasitic infestations. Infections and infestations included PTSIs from the Medical Dictionary for Regulatory Activities infections and infestations system organ class, which were selected to exclude terms associated with non-specific infections and infections that were non-serious and/or typically not related to immunosuppression. ^§Number of participants who received fostemsavir, had ≥1 CD4+ T-cell count during the specified analysis period, and had CD4+ T-cell count <200 cells/mm³ for all measures throughout the specified analysis period (<200 subgroup) or had at least 1 measure of ≥200 cells/mm³ at any time during the specified analysis period (≥200 subgroup). ^¶Total number of participant-years of treatment with fostemsavir for subgroup participants over the specified analysis period.