Abstract Background Most individuals on combination antiretroviral therapy (ART) have HIV plasma viral loads below the limit of detection. However, episodes of low-level viremia (LLV) are observed in subsets of individuals, 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 &amp;lt;200 copies/ml six months post 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, segmented into categories undetectable, and based on AUC tertiles into low, intermediate, and high. Results We included 8’132 participants with a total of 49’579 person-years of follow-up. Median follow-up time was 4.7 years, and median number of HIV RNA measurements was 16. Participants had a median age of 38 years, 75.9% were male, 74.4% had white ethnicity, and 45.9% had HIV-1 subtype B. LLV was associated with an increased risk for subsequent viral failure, with the highest LLV category showing the strongest association (hazard ratio = 3.3 compared to undetectable viral load) among all included variables including ethnicity, age, and ART. Conclusions LLV was strongly associated with the risk for subsequent viral failure, even after adjusting 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.

HIV-1 low-level viremia predicts viral failure in participants on antiretroviral therapy in the Swiss HIV Cohort Study