Viral and Immune Risk Factors of HIV Rebound after Interruption of Antiretroviral Therapy

BACKGROUND Identifying risk factors for HIV rebound after treatment interruption is crucial for designing effective remission strategies. METHODS Peripheral blood mononuclear cells from participants in the Zurich HIV Primary Infection Cohort (ZPHI, N=73) and ACTG study A5345 (N=44) were analyzed before ART interruption. We measured cell-associated HIV RNA, total HIV DNA, and proviral diversity (env gene). Immune phenotyping was conducted by flow cytometry. Cox proportional hazards (PH) models and penalized Cox PH models with an adaptive LASSO penalty identified risk factors for time to rebound (HIV RNA >1,000 copies/mL). RESULTS Late ART initiation was associated with higher rebound risk (shorter time to rebound), as compared to early ART. Higher pre-ART HIV RNA, total HIV DNA, and increased cellular HIV transcription at the time of ART interruption were associated with higher rebound risk. Higher proviral diversity was associated with higher rebound risk but only among male participants and those enrolled in the ZPHI cohort. Less CD4+ T cells at ART interruption, higher proportions of effector and terminally differentiated T cells, and more activated and exhausted T cells were associated with higher rebound risk, primarily in early treated participants. No significant immunological risk factors were found in participants treated during chronic HIV. In the combined cohort, total HIV DNA and terminally differentiated CD8+ T Cells appeared to be the most relevant risk factors for time to rebound. CONCLUSION These findings underscore the importance of early ART initiation and suggest that tailored interventions based on virologic, immunologic, and demographic factors may help achieve sustained viral suppression.