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Observational Study
. 2025 Jun 2;231(5):1221-1229.
doi: 10.1093/infdis/jiae585.

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

Sara Gianella  1 , Tingting Yu  2 , Rui Wang  2   3 , Caroline Ignacio  1 , Merle Schanz  4 , Roger D Kouyos  4   5 , Gemma Caballero  1 , Noah C Gaitan  1 , Stephen Rawlings  6 , Herbert Kuster  4   5 , Karin J Metzner  4   5 , Rajesh T Gandhi  7 , Jonathan Z Li  8 , Huldrych F Günthard  4   5 , Davey M Smith  1 , Antoine Chaillon  1
Affiliations
Observational Study

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

Sara Gianella et al. J Infect Dis. .

Abstract

Background: Identifying risk factors for human immunodeficiency virus (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 antiretroviral therapy (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 >1000 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 in plasma, 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. Fewer 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, as indicated by variable selection in multivariable analysis.

Conclusions: 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. Clinical Trials Registration. NCT00537966 and NCT03001128.

Keywords: ART interruption; HIV; predictors.

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Conflict of interest statement

Potential conflicts of interest . H. F. G. reports honoraria for advisory boards and data safety monitoring boards for Gilead, Merck, ViiV, GSK, Johnson and Johnson, and Janssen and Novartis, unrelated to the submitted work; unrestricted research grants from Gilead, ViiV; and is a subcontractor to a Bill and Melinda Gates foundation grant (money paid to the institution). All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.

Figures

Figure 1.
Figure 1.
The first quartile (Q1, bottom line) and third quartile (Q3, top line) The height of the box represents the IQR, calculated as IQR = Q3 − Q1. Middle line is the median. Diamond shows average values. Abbreviations: ACTG, Advancing Clinical Therapeutics Globally for HIV/AIDS and Other Infections; ART, antiretroviral therapy; HIV, human immunodeficiency virus; ZPHI, Zurich HIV Primary Infection cohort.
Figure 2.
Figure 2.
Immunological factors significantly associated with time to viral rebound after FDR adjustment in combined dataset (ZPHI + ACTG study A5345, n = 113). HR is shown on the X-axis: HR <1 indicates positive association, and HR > 1 indicates negative association with time to viral rebound. Y-axis shows P values after FRD adjustment. Gray squares are not significant, darker gray triangle are significant at P < .05 before FDR, and black dots are significant at P < .05 before and after FDR. Abbreviations: ACTG, Advancing Clinical Therapeutics Globally for HIV/AIDS and Other Infections; FDR, false discovery rate; HR, hazard ratio; ZPHI, Zurich HIV Primary Infection cohort.
See this image and copyright information in PMC

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