PRESTIGIO RING: “Persistent low-level viremia with preserved immunological profile in people with multidrug-resistant HIV: is it time to defer switching?”

Persistent low-level viremia (LLV) in heavily treatment-experienced (HTE) people with HIV (PWH) harboring multidrug-resistant virus remains a challenging clinical scenario. We report two cases from the PRESTIGIO Registry of individuals with longstanding HIV infection, high cumulative genotypic resistance, and sustained LLV despite no current adherence issues. In both cases, a regimen confidently containing ≥2 fully active agents was not achievable without incorporating entry and/or capsid inhibitors. Through these cases, we highlight diagnostic and therapeutic uncertainties in the management of LLV, including: the unfeasibility of RNA-based genotyping, the limited availability of data on resistance assessment by DNA-based genotypic testing, and the possibility that such viremia stems from clonal viral production rather than active replication. Although both individuals maintained a stable immune profile and low transmission risk, these cases underscore the need for tailored guidance in managing LLV in HTE PWH.