HIV-1 Low-Level Viremia Predicts Viral Failure in Participants on Antiretroviral Therapy in the Swiss HIV Cohort Study

Abstract

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.

Keywords: antiretroviral therapy; longitudinal study; low-level viremia; treatment guidelines; viral failure.

Figure 1.

Flow chart of the study population on which the current analyses were based. Abbreviations: ART, antiretroviral therapy; SHCS, Swiss HIV Cohort Study.

Figure 2.

A, Schematic depiction of the low-level viremia (LLV) definition showing examples of how the area under the curve (AUC) was calculated. Black dots represent human immunodeficiency virus (HIV) viral RNA measurements. We used a fixed window size of 90 days, starting our analysis at the first HIV RNA measurement ≥180 days after the start of antiretroviral therapy (ART) (see window 1, 180 days after start). To calculate the AUC per window, we interpolated the viral RNA measurements, the last value of each window was carried forward to the end of the corresponding window (see teal area for each window). The first window where viral failure was observed (ie, with interpolated value of ≥200 copies/mL; see window 6) was omitted; viral failure was thus assigned to the end of the last window with values <200 copies/mL (see window 5). Abbreviations: VL, viral load. B, Fraction of LLV categories for measured RNA values, depending on the previous RNA measurement.

Figure 3.

Low-level viremia (LLV) over time. All 90-day observation windows (see Statistical Analysis) with an area under the curve under the human immunodeficiency virus RNA trajectory were divided into tertiles, classified as low, intermediate, and high LLV. A, Fraction of LLV over time, with the highest LLV category per year and participant taken into account. B, Number of participants experiencing viral failure, by year and LLV category, where the highest LLV category during the whole observation time until failure is taken into account.

Figure 4.

Forest plot showing variables and their uni- (upper line) and multivariable (lower line) association with virologic failure in a time-updated analysis. Abbreviations: 3TC/ABC/AZT, lamivudine/abacavir/zidovudine; aHR, adjusted hazard ratio; ART, antiretroviral therapy; BMI, body mass index (calculated as weight in kilograms divided by height in meters squared); HCV, hepatitis C virus; HIV, human immunodeficiency virus; HR, hazard ratio; INSTI, integrase inhibitor; LLV, low-level viremia; MSM, men who have sex with men; NNRTI, nonnucleoside reverse-transcriptase inhibitor; NRTI, nucleoside/nucleotide inhibitor; PI, protease inhibitor; PWID, persons who inject drugs.

Figure 5.

Association of low-level viremia (LLV) with viral failure in various sensitivity analyses. Models were further adjusted for antiretroviral therapy (ART) start year, sex and transmission group, race/ethnicity, age, body mass index, ART regimen, previous AIDS, pre-ART human immunodeficiency virus (HIV) RNA, CD4 cell count nadir, CD4/CD8 ratio, self-reported adherence, replicating hepatitis C virus RNA, and HIV subtype. See Sensitivity Analysis sections for further details. Abbreviations: aHR, adjusted hazard ratio; CI, confidence interval; HR, hazard ratio.