Background: Most individuals receiving combination antiretroviral therapy (ART) have human immunodeficiency virus (HIV) plasma viral loads below the limit of detection. However, episodes of low-level viremia (LLV) are observed in subsets of individuals, the risk factors and clinical significance of which remain debated.

Methods: We included participants enrolled in the Swiss HIV Cohort Study, starting ART between July 1999 and April 2023, with HIV RNA values <200 copies/mL 6 months after ART initiation. Using longitudinally collected data, we applied a time-updated Cox proportional hazards model to determine the association of LLV with the risk of subsequent viral failure, defined as ≥200 copies/mL. LLV was quantified by the time-updated area under the curve (AUC) of HIV RNA values, categorized as undetectable or, based on AUC tertiles, low, intermediate, or high.

Results: We included 8132 participants with a total of 49 579 person-years of follow-up. The median follow-up time was 4.7 years, and the median number of HIV RNA measurements was 16. Participants had a median age of 38 years, 75.9% were male, 74.4% were white, and 45.9% had HIV-1 subtype B. LLV was associated with an increased risk of subsequent viral failure, with the highest LLV category showing the strongest association (hazard ratio, 3.3 [for comparison with undetectable viral load]) among all included variables, including race/ethnicity, age, and ART.

Conclusions: LLV was strongly associated with risk of subsequent viral failure, even after adjustment for demographic and clinical characteristics, including adherence and treatment regimen. The detection of LLV should prompt appropriate measures to decrease the risk of subsequent viral failure.