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Despite the scale-up of antiretroviral therapy (ART) in South Africa, HIV-1 incidence remains high. The anticipated use of potent integrase strand transfer inhibitors and long-acting injectables aims to enhance viral suppression at the population level and diminish transmission. Nevertheless, pre-existing drug resistance could impede the efficacy of long-acting injectable ART combinations, such as rilpivirine (an NNRTI) and cabotegravir (an INSTI). Consequently, a thorough understanding of transmission networks and geospatial distributions is vital for tailored interventions, including pre-exposure prophylaxis with long-acting injectables. However, empirical data on background resistance and transmission networks remain limited. In a community-based study in rural KwaZulu-Natal (2018-2019), prior to the widespread use of integrase inhibitor-based first-line ART, we performed HIV testing with reflex HIV-1 RNA viral load quantification on 18,025 participants. From this cohort, 6,096 (33.9%) tested positive for HIV via ELISA, with 1,323 (21.7%) exhibiting detectable viral loads (> 40 copies/mL). Of those with detectable viral loads, 62.1% were ART-naïve, and the majority of the treated were on an efavirenz + cytosine analogue + tenofovir regimen. Deep sequencing analysis, with a variant abundance threshold of 20%, revealed NRTI resistance mutations such as M184V in 2% of ART-naïve and 32% of treated individuals. Tenofovir resistance mutations K65R and K70E were found in 12% and 5% of ART-experienced individuals, respectively, and in less than 1% of ART-naïve individuals. Integrase inhibitor resistance mutations were notably infrequent (

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