title: HIV-1 replication in central nervous system increases over time on only protease inhibitor therapy.
abstract: There are concerns about central nervous system (CNS)-replication of HIV-1 in patients on boosted protease inhibitors. Purpose of this study was to compare HIV-1 viral loads (VLs) from patients treated with only boosted dual protease inhibitor (bdPI), versus combination antiretroviral therapy (cART group), containing two nucleoside analogue reverse transcriptase inhibitors (NRTI) and a third partner. All patients from a large German HIV-treatment cohort with available medication, clinical and demographic data, including results from simultaneous HIV-1 viral load (VL) assessments in cerebrospinal fluid (CSF) and blood plasma, were retrospectively evaluated as controlled cross-sectional study. CSF had been obtained from patients with variable neurological symptoms during 2005-2014. Statistical analysis comprised nonparametric tests, regression and correlation techniques accounting for undetectable quantifications. Statistical analysis comprised nonparametric tests, regression and correlation techniques accounting for undetectable quantifications. Overall, 155 patients were evaluable (bdPI: 24; cART: 131). At time of CSF-collection, both groups were comparable in age, gender, CD4-cell counts, or primary HIV-transmission risks, though bdPI patients were clinically more advanced. The proportion of patients with undetectable HIV-1 (<50 copies/ml) in CSF was lower for bdPI group (25 vs 49.6 %; p = 0.026), but similar in plasma (46 vs 41 %). Median CSF-VL was higher in bdPI group (600 vs 50 copies/ml; p = 0.027) and similar in plasma. Mean VL CSF/plasma ratio was 342.91 for bdPI- and 54.48 for cART patients (p < 0.001). Pearson's regression analysis revealed a trend for an elevated VL-ratio over time within bdPI group. HIV-1 replication was higher and more frequently detectable in CSF from bdPI patients, indicating a worse CNS penetration effectiveness of used boosted PI. Within bdPI group, measured CNS-viral replication was increasing over time, suggesting an over time impaired HIV-1 suppression in CSF.
authors.affiliation: Infectious diseases Unit, Medical Department, University Hospital Frankfurt, Goethe-University, Theodor Stern Kai 7, 60590, Frankfurt, Germany.
authors.forename: Maximilian
authors.initials: M
authors.lastname: Donath
authors.affiliation: Infectious diseases Unit, Medical Department, University Hospital Frankfurt, Goethe-University, Theodor Stern Kai 7, 60590, Frankfurt, Germany.
authors.forename: Timo
authors.initials: T
authors.lastname: Wolf
authors.affiliation: Institute for Medical Virology, University-Hospital Frankfurt, Goethe-University, Paul Ehrlich Straße 40, 60596, Frankfurt, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Stürmer
authors.affiliation: Institute of Biostatistics and Mathematical Modeling, Johann Wolfgang Goethe-University, Theodor Stern Kai 7, 60590, Frankfurt, Germany.
authors.forename: Eva
authors.initials: E
authors.lastname: Herrmann
authors.affiliation: Infektiologikum Frankfurt, Stresemannallee 3, 60596, Frankfurt, Germany.
authors.forename: Markus
authors.initials: M
authors.lastname: Bickel
authors.affiliation: Infectious diseases Unit, Medical Department, University Hospital Frankfurt, Goethe-University, Theodor Stern Kai 7, 60590, Frankfurt, Germany.
authors.forename: Pavel
authors.initials: P
authors.lastname: Khaykin
authors.affiliation: Infectious diseases Unit, Medical Department, University Hospital Frankfurt, Goethe-University, Theodor Stern Kai 7, 60590, Frankfurt, Germany.
authors.forename: Siri
authors.initials: S
authors.lastname: Göpel
authors.affiliation: Infektiologikum Frankfurt, Stresemannallee 3, 60596, Frankfurt, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Gute
authors.affiliation: Infectious diseases Unit, Medical Department, University Hospital Frankfurt, Goethe-University, Theodor Stern Kai 7, 60590, Frankfurt, Germany.
authors.forename: Annette
authors.initials: A
authors.lastname: Haberl
authors.affiliation: Infectious diseases Unit, Medical Department, University Hospital Frankfurt, Goethe-University, Theodor Stern Kai 7, 60590, Frankfurt, Germany.
authors.forename: Philipp
authors.initials: P
authors.lastname: de Leuw
authors.affiliation: Infectious diseases Unit, Medical Department, University Hospital Frankfurt, Goethe-University, Theodor Stern Kai 7, 60590, Frankfurt, Germany.
authors.forename: Gundolf
authors.initials: G
authors.lastname: Schüttfort
authors.affiliation: Institute for Medical Virology, University-Hospital Frankfurt, Goethe-University, Paul Ehrlich Straße 40, 60596, Frankfurt, Germany.
authors.forename: Annemarie
authors.initials: A
authors.lastname: Berger
authors.affiliation: Infectious diseases Unit, Medical Department, University Hospital Frankfurt, Goethe-University, Theodor Stern Kai 7, 60590, Frankfurt, Germany. c.stephan@em.uni-frankfurt.de.
authors.forename: Christoph
authors.identifier: http://orcid.org/0000-0003-3777-9006
authors.initials: C
authors.lastname: Stephan
mesh_terms: D000328:Adult; D000368:Aged; D023241:Antiretroviral Therapy, Highly Active; D018791:CD4 Lymphocyte Count; D020805:Central Nervous System Viral Diseases / Q000188:drug therapy* / Q000821:virology*; D005260:Female; D015658:HIV Infections / Q000188:drug therapy* / Q000821:virology*; D017320:HIV Protease Inhibitors / Q000627:therapeutic use*; D015497:HIV-1 / Q000502:physiology*; D006801:Humans; D008297:Male; D008875:Middle Aged; D012189:Retrospective Studies; D013997:Time Factors; D016896:Treatment Outcome; D019562:Viral Load; D014779:Virus Replication; D055815:Young Adult
chemical_list: D017320:HIV Protease Inhibitors
keywords: Blood–brain barrier; HIV persistence; HIV reservoir; Low-level replication; Protease inhibitor therapy; Viral escape