Gianella Sara, Yu Tingting, Wang Rui, Ignacio Caroline, Schanz Merle, Kouyos Roger D, Caballero Gemma, Gaitan Noah C, Rawlings Stephen, Kuster Herbert, Metzner Karin J, Gandhi Rajesh T, Li Jonathan Z, Günthard Huldrych F, Smith Davey M, Chaillon Antoine
Division of Infectious Diseases and Global Public Health, University of California San Diego, La Jolla, California, USA.
Department of Population Medicine, Harvard Pilgrim Health Care Institute and Harvard Medical School, Boston, Massachusetts.
J Infect Dis. 2025 Jun 2;231(5):1221-1229. doi: 10.1093/infdis/jiae585.
Identifying risk factors for human immunodeficiency virus (HIV) rebound after treatment interruption is crucial for designing effective remission strategies.
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).
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.
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.
确定治疗中断后人类免疫缺陷病毒（HIV）反弹的风险因素对于设计有效的缓解策略至关重要。
在抗逆转录病毒疗法（ART）中断前，对苏黎世HIV初发感染队列（ZPHI，n = 73）和ACTG研究A5345（n = 44）参与者的外周血单个核细胞进行分析。我们测量了细胞相关的HIV RNA、总HIV DNA和前病毒多样性（env基因）。通过流式细胞术进行免疫表型分析。Cox比例风险（PH）模型和采用自适应LASSO惩罚的惩罚Cox PH模型确定了反弹时间（HIV RNA>1000拷贝/毫升）的风险因素。
与早期ART相比，ART启动延迟与更高的反弹风险（更短的反弹时间）相关。ART中断时血浆中更高的ART前HIV RNA、总HIV DNA以及细胞HIV转录增加与更高的反弹风险相关。更高的前病毒多样性与更高的反弹风险相关，但仅在男性参与者和ZPHI队列参与者中如此。ART中断时CD4 + T细胞数量较少、效应性和终末分化T细胞比例较高以及活化和耗竭T细胞较多与更高的反弹风险相关，主要见于早期治疗的参与者。在慢性HIV感染期间接受治疗的参与者中未发现显著的免疫风险因素。在合并队列中，多变量分析中的变量选择表明，总HIV DNA和终末分化的CD8 + T细胞似乎是反弹时间最相关的风险因素。
这些发现强调了早期启动ART的重要性，并表明基于病毒学、免疫学和人口统计学因素的针对性干预可能有助于实现持续的病毒抑制。临床试验注册。NCT00537966和NCT03001128。
