Study design and participants
This retrospective cross-sectional study included data from adult PWH with available plasma historical genotype resistance testing (HGRT) in RT and PT genes performed prior LP, attending five Italian Clinics (Amedeo di Savoia Hospital, Turin; L. Spallanzani IRCCS, Rome; Spedali Civili General Hospital, Brescia; Santi Paolo e Carlo Hospital, Milan; Umberto I Hospital, Rome) and one Clinic in the UK (University Hospital Sussex NHS Foundation Trust, Brighton) between January 2001 to December 2021.
Eligible participants were age ≥18 years with at least one paired plasma and CSF VL and on ART since at least one year. The temporal criterion of ART duration was chosen to reduce the contribution of CSF slow suppressor (higher CSF VL compared to plasma VL due to slower suppression in CNS after the beginning of ART) to CVE. CVE was defined as a) plasma VL undetectable by clinical diagnostic assay (100% with lower limit of quantification of 50 copies/mL) and CSF VL ≥51 copies/mL; b) detectable plasma VL with concurrent CSF VL of at least 0.5 Log10 cp/mL higher than plasma10. PWH with any active inflammatory and/or infectious CNS disorder that could transiently increase CSF HIV RNA (such as CNS infections, autoimmune diseases or conditions increasing cells trafficking across the blood-brain barrier, as previously associated with secondary CVE23–26) were excluded to focus on etiologic mechanisms underlying primary CVE. In case of availability of multiple CSF/plasma pairs per participant, the first pair only was included unless collected on different ART regimens at least one year apart. In case of multiple episodes of CVE per participant only the first one was included to avoid selection and sampling bias. The institutional review board at each involved site approved the research.