Pretreatment Resistance to Integrase Inhibitors in the Swiss HIV Cohort Study From 1995 to 2025.

Background: Studies in Switzerland and other settings have reported minimal pretreatment integrase strand transfer inhibitor (INSTI) resistance, but many were conducted before widespread use of INSTIs or are limited regarding data availability and representativeness. Consequently, many questions remain regarding the transmissibility of INSTI drug resistance mutations (DRMs). Methods: In sequences predating antiretroviral therapy (ART) initiation collected in the Swiss HIV Cohort Study (SHCS) resistance database, we assessed INSTI DRMs using the Stanford HIV database algorithm. We use bayesian regression models to assess INSTI DRM trends, as well as epidemiological clustering. Models are adjusted for age, sex, HIV subtype, and time as a spline, with random effects for the SHCS center of registration and the sequencing laboratory. Results: In total, 3704 SHCS participants had an integrase sequence before ART initiation; 213 (5.8%) had INSTI DRMs, including 11 (0.3%) with major INSTI DRMs. The most common DRMs were the polymorphic accessory INSTI DRMs E157Q, T97A, and L74M. There was no change in the probability of detecting INSTI DRM(s) over the past 3 decades. Epidemiological clustering was similar between individuals with or without pre-ART INSTI DRMs; however, the clusters they formed were smaller, particularly before 2010. Conclusions: This study demonstrates that in Switzerland pre-ART INSTI DRMs are very rare, despite INSTIs being used for more than 10 years. In cases where pre-ART INSTI DRMs are detected, information on the context in which they emerged is rarely available, highlighting the need for continued genetic surveillance, particularly in the face of increasing numbers of individuals with INSTI resistance globally.