Impact of the evolution of national ART guidelines and Initiation criteria on low–level viremia trends and predictors in Anhui Province: a sequential period analysis

Over the past two decades, China’s National Free Antiretroviral Treatment Program has undergone significant paradigm shifts. However, how evolving national ART guidelines and initiation criteria have shaped the long-term incidence of persistent low-level viremia (LLV) remains poorly understood. This study evaluated 22–year trends and modern predictors of LLV across six distinct treatment eras (2003–2025), aligned with the latest clinical frameworks. We conducted a retrospective cohort study of 25,087 people living with HIV (PLWH) initiating ART in Anhui Province, categorized into six sequential periods by initiation date. The primary outcome was persistent LLV, defined per the 2025 Chinese Expert Consensus. Multivariable Cox proportional hazards models were utilized to identify independent risk factors in the overall cohort. Of the 25,087 participants, 5,106 (20.4%) experienced persistent LLV. The population–level incidence of LLV exhibited a dramatic decline from 53.5% (95% CI: 48.3%–58.6%) in Period 1 (2003–2006) to 10.1% (95% CI: 9.5%–10.8%) in Period 6 (2021–2025) ( P for trend < 0.001). In the overall cohort (2003–2025), advanced age (≥ 60 years: aHR = 1.36, 95% CI: 1.20–1.54) and severe baseline immunosuppression (CD4 + count < 200 cells/µL vs. ≥500 cells/µL: aHR = 1.40, 95% CI: 1.27–1.55) emerged as robust independent predictors. Notably, within the modern treatment era (Period 6, 2021–2025), the hazard conferred by severe baseline immunosuppression was significantly amplified (CD4 + count < 200 cells/µL vs. ≥500 cells/µL: aHR = 2.05, 95% CI: 1.61–2.60, P < 0.001) compared to the overall cohort. Furthermore, in this contemporary era, initial regimen choices showed distinct hazard profiles after adjusting for baseline characteristics. Compared to traditional NNRTI-based options, patients starting INSTI-based ( aHR = 1.30, 95% CI: 1.05–1.60) or PI-based regimens ( aHR = 1.61, 95% CI: 1.27–2.05) faced significantly higher LLV hazards. While China’s optimized ART strategies have achieved a five–fold reduction in LLV incidence over two decades, the relative impact of severe baseline immunosuppression has intensified in the modern era. Aging populations and late presenters remain critical biological bottlenecks for universal viral suppression. Tailored clinical management is therefore essential to reach the UNAIDS ‘third 95’ target. This requires intensified monitoring and strategic deployment of high-genetic-barrier regimens for these high-risk subgroups.