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.