High HIV-1 viremia and low anti-Env antibody responses are associated with delayed treatment response to fostemsavir in highly treatment-experienced individuals

Fostemsavir (FTR) is an approved first-in-class small molecule Env antagonist for treating multi-drug resistant (MDR) HIV-1 infection. In the BRIGHTE study, viral suppression rates in heavily treatment-experienced people with HIV (PWH) increased from week 48 through week 96. Factors that contribute to this late response are not well understood. Given FTR's ability to stabilize a native HIV-1 envelope trimer conformational state, we examined anti-HIV humoral immune responses in the BRIGHTE study to explore how evolving antibody responses in the presence of drug correlate with delayed viral suppression. 16 BRIGHTE study participants (ppt) were selected based on their time to first viremic suppression: eight early (EVS) and eight late viral suppressors (LVS). Immune responses were also analyzed in eight ppt from the SAILING study that evaluated dolutegravir. Anti-HIV Env IgG titer, cell-free and cell-to-cell neutralization activity, FcγRIIa- and FcγRIIIa-signaling, and plasma cytokines at weeks 0, 4 and 108 were examined and correlated with clinical variables associated with treatment response. FTR treatment did not significantly enhance antibody responses against reference strain of HIV in LVS compared to EVS. However, at baseline, LVS had significantly lower anti-HIV IgG titers, higher VL, lower CD4⁺ T-cell counts and experienced greater increases in CD4⁺ T-cell counts than EVS. Additionally, IL-8 levels were increased in LVS vs. EVS at treatment initiation. In comparison, SAILING ppt showed increased FcγRIIa signaling during drug treatment compared to the FTR groups. Further studies will determine if pre-treatment characteristics influence timing to viral suppression in FTR-treated individuals with MDR-HIV.