Persistent low-level HIV viremia: a narrative review of diagnostic predicaments, virological pathomechanisms, and clinical outcomes

Despite major strides made with combination antiretroviral therapy (cART), people living with HIV (PLHIV) continue to face higher mortality rates compared to the general population. A significant part of this gap stems from non-communicable diseases arising from chronic immune activation. While the primary goal of treatment is to suppress the virus to undetectable levels, typically below <20 to <75 copies/mL depending on the assay used, many patients still show low-level viremia (LLV), where HIV RNA persists below the threshold for virologic failure (<1,000 copies/mL). LLV is important in clinical care, yet its definition varies widely across guidelines, and its real-world impact largely depends on the magnitude and persistence of viremia. Studies show that viral blips and persistent low-level viremia (pLLV) should be distinguished. Transient blips are generally not associated with adverse outcomes, whereas pLLV, particularly at levels >200 copies/mL, has been linked to increased risks of virologic failure and drug resistance across different cohorts. However, the findings are heterogeneous, particularly among those with LLV ranging from 50 to 199 copies/mL. Recent evidence suggests that much of the persistent viremia during suppressive ART results from clonally expanded infected CD4+ T cells rather than from ongoing, complete cycles of viral replication. Current guidelines do not recommend routine ART modification for LLV <200 copies/mL; instead, they prioritize adherence assessment, repeat viral load monitoring, and resistance testing when feasible. There is limited evidence supporting regimen modification, which remains restricted to patients with persistent viremia >200 copies/mL, particularly when resistance mutations are detected. This review critically synthesizes current evidence on the definitions, epidemiology, clinical impact, mechanisms, diagnostic approaches and practical management of LLV with a focus on differences in data, challenges, and outcomes between low- and middle-income countries (LMICs) and high-income countries (HICs). It also highlights controversial areas and research priorities.