title: Discordant CSF/plasma HIV-1 RNA in patients with unexplained low-level viraemia.
abstract: The central nervous system has been proposed as a sanctuary site where HIV can escape antiretroviral control and develop drug resistance. HIV-1 RNA can be at higher levels in CSF than plasma, termed CSF/plasma discordance. We aimed to examine whether discordance in CSF is associated with low level viraemia (LLV) in blood. In this MRC-funded multicentre study, we prospectively recruited patients with LLV, defined as one or more episode of unexplained plasma HIV-1 RNA within 12 months, and undertook CSF examination. Separately, we prospectively collected CSF from patients undergoing lumbar puncture for a clinical indication. Patients with durable suppression of viraemia and no evidence of CNS infection were identified as controls from this group. Factors associated with CSF/plasma HIV-1 discordance overall were examined. One hundred fifty-three patients were recruited across 13 sites; 40 with LLV and 113 undergoing clinical lumbar puncture. Seven of the 40 (18 %) patients with LLV had CSF/plasma discordance, which was significantly more than 0/43 (0 %) with durable suppression in blood from the clinical group (p = 0.005). Resistance associated mutations were shown in six CSF samples from discordant patients with LLV (one had insufficient sample for testing), which affected antiretroviral therapy at sampling in five. Overall discordance was present in 20/153 (13 %) and was associated with nadir CD4 but not antiretroviral concentrations in plasma or CSF. CSF/plasma discordance is observed in patients with LLV and is associated with antiretroviral resistance associated mutations in CSF. The implications for clinical practice require further investigation.
authors.affiliation: Institute of Infection and Global Health, University of Liverpool, The Ronald Ross Building, 8 West Derby Street, Liverpool, L69 7BE, UK. s.nightingale@liv.ac.uk.|Department of Molecular and Clinical Pharmacology, University of Liverpool, Liverpool, UK. s.nightingale@liv.ac.uk.|Royal Liverpool and Broadgreen University Hospitals NHS Trust, Liverpool, UK. s.nightingale@liv.ac.uk.
authors.forename: Sam
authors.initials: S
authors.lastname: Nightingale
authors.affiliation: Institute of Infection and Global Health, University of Liverpool, The Ronald Ross Building, 8 West Derby Street, Liverpool, L69 7BE, UK.
authors.forename: Anna Maria
authors.initials: AM
authors.lastname: Geretti
authors.affiliation: Institute of Infection and Global Health, University of Liverpool, The Ronald Ross Building, 8 West Derby Street, Liverpool, L69 7BE, UK.
authors.forename: Apostolos
authors.initials: A
authors.lastname: Beloukas
authors.affiliation: Brighton and Sussex University Hospitals NHS Trust, Brighton, UK.
authors.forename: Martin
authors.initials: M
authors.lastname: Fisher
authors.affiliation: St Marys' Hospital, Imperial College Healthcare NHS Trust, London, UK.
authors.forename: Alan
authors.initials: A
authors.lastname: Winston
authors.affiliation: Department of Molecular and Clinical Pharmacology, University of Liverpool, Liverpool, UK.
authors.forename: Laura
authors.initials: L
authors.lastname: Else
authors.affiliation: St Stephen's AIDS Research Trust and Chelsea and Westminster Hospital NHS Foundation Trust, London, UK.
authors.forename: Mark
authors.initials: M
authors.lastname: Nelson
authors.affiliation: Birmingham Heartlands Hospital, Heart of England NHS Foundation Trust, Birmingham, UK.
authors.forename: Stephen
authors.initials: S
authors.lastname: Taylor
authors.affiliation: North Manchester General Hospital, Pennine Acute Hospitals NHS Trust, Manchester, UK.
authors.forename: Andrew
authors.initials: A
authors.lastname: Ustianowski
authors.affiliation: North Middlesex University Hospital NHS Trust, London, UK.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Ainsworth
authors.affiliation: Research Department of Infection and Population Health, University College London, London, UK.
authors.forename: Richard
authors.initials: R
authors.lastname: Gilson
authors.affiliation: Research Department of Infection and Population Health, University College London, London, UK.
authors.forename: Lewis
authors.initials: L
authors.lastname: Haddow
authors.affiliation: Victoria Royal Infirmary, Newcastle upon Tyne Hospitals NHS Trust, Newcastle, UK.
authors.forename: Edmund
authors.initials: E
authors.lastname: Ong
authors.affiliation: Department of Molecular and Clinical Pharmacology, University of Liverpool, Liverpool, UK.
authors.forename: Victoria
authors.initials: V
authors.lastname: Watson
authors.affiliation: Royal Infirmary of Edinburgh, NHS Lothian, Edinburgh, UK.
authors.forename: Clifford
authors.initials: C
authors.lastname: Leen
authors.affiliation: Leeds General Infirmary, Leeds Teaching Hospitals NHS Trust, Leeds, UK.
authors.forename: Jane
authors.initials: J
authors.lastname: Minton
authors.affiliation: Kings College Hospital NHS Foundation Trust, London, UK.
authors.forename: Frank
authors.initials: F
authors.lastname: Post
authors.affiliation: Department of Molecular and Clinical Pharmacology, University of Liverpool, Liverpool, UK.
authors.forename: Munir
authors.initials: M
authors.lastname: Pirmohamed
authors.affiliation: Institute of Infection and Global Health, University of Liverpool, The Ronald Ross Building, 8 West Derby Street, Liverpool, L69 7BE, UK.|Walton Centre for Neurology and Neurosurgery, Liverpool, UK.
authors.forename: Tom
authors.initials: T
authors.lastname: Solomon
authors.affiliation: Department of Molecular and Clinical Pharmacology, University of Liverpool, Liverpool, UK.|Royal Liverpool and Broadgreen University Hospitals NHS Trust, Liverpool, UK.
authors.forename: Saye
authors.initials: S
authors.lastname: Khoo
mesh_terms: D000328:Adult; D019380:Anti-HIV Agents / Q000627:therapeutic use; D018791:CD4 Lymphocyte Count; D002490:Central Nervous System / Q000187:drug effects / Q000378:metabolism / Q000473:pathology / Q000821:virology; D024882:Drug Resistance, Viral / Q000235:genetics; D005260:Female; D015658:HIV Infections / Q000097:blood / Q000134:cerebrospinal fluid / Q000175:diagnosis* / Q000188:drug therapy; D015497:HIV-1 / Q000187:drug effects / Q000235:genetics / Q000254:growth & development; D006801:Humans; D008297:Male; D008875:Middle Aged; D009483:Neuropsychological Tests; D011446:Prospective Studies; D012367:RNA, Viral / Q000037:antagonists & inhibitors / Q000097:blood* / Q000134:cerebrospinal fluid*; D014766:Viremia / Q000097:blood / Q000134:cerebrospinal fluid / Q000175:diagnosis* / Q000188:drug therapy
chemical_list: D019380:Anti-HIV Agents; D012367:RNA, Viral
keywords: Antiretroviral agents; Central nervous system; Cerebrospinal fluid; Drug resistance; HIV; Viral