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

This study investigates factors associated with delayed viral suppression in HIV-1 patients receiving fostemsavir (FTR), a first-in-class HIV-1 attachment inhibitor. It focuses on how high HIV-1 viremia and low anti-Env antibody responses are linked to delayed treatment response in heavily treatment-experienced individuals. The analysis was conducted on samples from the BRIGHTE study, comparing participants who achieved early viral suppression (EVS) to those with late viral suppression (LVS).

Key findings:

1. High Viral Load and Low Antibody Responses: LVS participants exhibited significantly higher baseline viral loads and lower anti-HIV-1 IgG titers compared to EVS participants. This suggests that immune factors, particularly humoral responses, may influence the time to viral suppression.

   
   

2. Cytokine Response: LVS participants had elevated IL-8 levels at the start of treatment, indicating higher inflammatory status, which could impair immune response and delay suppression. Cytokines such as CXCL10 and IL-10 decreased over time in both EVS and LVS groups.

   
   

3. Neutralization and Fc Receptor Activation: There were no significant differences in the ability of IgG from LVS and EVS groups to neutralize HIV-1, either in cell-free or cell-to-cell assays. However, the FTR-treated group did not show a notable increase in FcγRIIa or FcγRIIIa signaling over time, suggesting that the Fc-mediated immune response did not improve significantly during treatment.

   
   

4. Delayed Immune Response: Despite high viral loads, LVS individuals exhibited immune reconstitution with increasing CD4+ T-cell counts, but this was not accompanied by an enhanced antibody response. This could explain the delayed viral suppression observed in these individuals.

   
   

In conclusion, the study suggests that delayed viral suppression in FTR-treated individuals with high HIV-1 viremia and weak anti-Env responses may result from a combination of immune dysfunction and slower immune recovery. The findings underline the importance of antibody responses in determining the timing of virologic control and suggest potential pathways to improve outcomes in such patients.

https://www.sciencedirect.com/science/article/abs/pii/S0166354225000221