HIV transmission dynamics and population-wide drug resistance in rural South Africa.

Despite expanded antiretroviral therapy (ART) in South Africa, HIV-1 transmission persists. Integrase strand transfer inhibitors (INSTI) and long-acting injectables offer potential for superior viral suppression, but pre-existing drug resistance could threaten their effectiveness. In a community-based study in rural KwaZulu-Natal, prior to widespread INSTI usage, we enroled 18,025 individuals to characterise HIV-1 drug resistance and transmission networks to inform public health strategies. HIV testing and reflex viral load quantification were performed, with deep sequencing (20% variant threshold) used to detect resistance mutations. Phylogenetic and geospatial analyses characterised transmission clusters. One-third of participants were HIV-positive, with 21.7% having detectable viral loads; 62.1% of those with detectable viral loads were ART-naïve. Resistance to older reverse transcriptase (RT)-targeting drugs was found, but INSTI resistance remained low (<1%). Non-nucleoside reverse transcriptase inhibitor (NNRTI) resistance, particularly to rilpivirine (RPV) even in ART-naïve individuals, was concerning. Twenty percent of sequenced individuals belonged to transmission clusters, with geographic analysis highlighting higher clustering in peripheral and rural areas. Our findings suggest promise for INSTI-based strategies in this setting but underscore the need for RPV resistance screening before implementing long-acting cabotegravir (CAB) + RPV. The significant clustering emphasises the importance of geographically targeted interventions to effectively curb HIV-1 transmission.