Introduction
Modern combination antiretroviral therapy (ART) is highly effective at suppressing viral replication in plasma compartment with HIV persisting in body reservoirs1. In some cases, cerebrospinal fluid (CSF) viral load (VL) can be significantly above the concentration quantified in plasma. This entity is known as CSF viral escape (CVE) and has been described in 2-20% of patients in several cohorts worldwide2–6. Neurologically symptomatic CVE is a rare clinical syndrome that has been often described in the presence of CSF drug resistance associated mutations (RAMs) in HIV genes7–9. On the contrary, asymptomatic CVE has been more commonly detected in clinical studies of asymptomatic participants undergoing lumbar puncture (LP), where selection bias may exist8,10,11. The long-term implications of CVE remain unclear: longitudinally, patients with detectable CSF HIV RNA may have higher inflammation but no emergence of neurological symptoms11.
Several risk factors for CVE have been reported: the duration of HIV infection, suboptimal adherence, low CD4+ T-cell count nadir, reduced central nervous system (CNS) penetration of antiretrovirals (ARVs), and the use of specific ARVs4,12,13. Regarding the last issue, CVE has been reported more frequently among patients on protease inhibitors (PIs), especially atazanavir-based ART, in Indian and US cohorts12,14,15, and in few more recent cases from Uganda16. Among PIs, atazanavir does do not consistently achieve in vitro 50% inhibitory concentrations for wild-type HIV in the CSF, while better performance has been achieved by boosted darunavir and lopinavir17–21. PI-including regimens are usually recommended as second-line ART in many of the above countries after failure to first-line regimens that included non-nucleos(t)ide reverse transcriptase inhibitors (NNRTIs); in these settings, RAMs have already been selected and patients’ adherence may had been suboptimal. Indeed, PI-based regimens have been associated to a low risk of RAMs selection when given to ART-naïve patients22.
The possible driver of CVE could be the presence of RAMs and the association with PIs use would just be a consequence rather than the cause of worse pharmacological profile generated by prior virological failures. Despite nowadays most patients are on INSTI-based regimens that may show reduced risk of CVE, a better clarification of drivers of this compartmentalized virologic failure, especially in relation to the number of active antiretrovirals within the CNS, is still of current concern as it may elucidate potential limitations of modern dual therapies and of salvage regimens in individuals with archived RAMs. Therefore, the aim of our work was to determine the impact of plasma RAMs in reverse transcriptase (RT) and protease (PT) genes on CVE risk in a multicentric European setting.