title: A phase IV, double-blind, multicentre, randomized, placebo-controlled, pilot study to assess the feasibility of switching individuals receiving efavirenz with continuing central nervous system adverse events to etravirine.
abstract: BACKGROUND
  Two nucleoside reverse transcriptase inhibitors (NRTIs) and efavirenz (EFV) is a recommended initial regimen for HIV-1. Most EFV-related central nervous system (CNS) toxicity resolves early though symptoms may persist; we studied switching to etravirine (ETR) in these individuals.
  
  
  METHODS
  A randomized, double-blind trial in patients with viral suppression but ongoing CNS adverse events after more than 12 weeks EFV. Patients received 2NRTI/EFV/ETR-placebo (delayed switch) or 2NRTI/ETR/EFV-placebo (immediate switch) for 12 weeks followed by 12-week open-label phase (2NRTI/ETR). Primary end-point was percentage with G2-4 CNS adverse events at 12 weeks.
  
  
  RESULTS
  Thirty-eight men; 20/18 were randomized to immediate switch/delayed switch; median CD4 was 444/498 cells/μl, respectively. Baseline CNS adverse events were similar. Nineteen immediate switch patients completed follow-up (one lost to follow-up) and 13 on delayed switch (two lost to follow-up, two withdrawn consent, one adverse event). Immediate switch G2-4 CNS adverse event: 90% at baseline, 60% at week 12 (P = 0.041). Delayed switch G2-4 CNS adverse event: 88.9% at baseline, 81.3% at week 12 (P = ns). Combined (both arms) percentage decline in G2-4 CNS adverse event after 12 weeks of ETR was significant for overall adverse events, insomnia, abnormal dreams and nervousness (P = 0.009, 0.016, 0.001, and 0.046, respectively). All participants on study maintained HIV-RNA below 50 and median week 24 CD4 was 593 and 607 cells/μl on immediate switch and delayed switch. Two participants experienced new G3-4 adverse events [delayed switch: G3 flatulence on EFV); immediate switch: G4 viral URTI on ETR (SAE)].
  
  
  CONCLUSIONS
  Switching EFV to ETR led to a significant reduction in overall G2-4 CNS adverse events, including insomnia, abnormal dreams and nervousness as individual adverse event. Lack of improvement for some events suggests other causative factors.
authors.affiliation: Chelsea & Westminster Hospital, London, UK. lwaters@nhs.net
authors.forename: Laura
authors.initials: L
authors.lastname: Waters
authors.forename: Martin
authors.initials: M
authors.lastname: Fisher
authors.forename: Alan
authors.initials: A
authors.lastname: Winston
authors.forename: Chris
authors.initials: C
authors.lastname: Higgs
authors.forename: Wendy
authors.initials: W
authors.lastname: Hadley
authors.forename: Lucy
authors.initials: L
authors.lastname: Garvey
authors.forename: Sundhiya
authors.initials: S
authors.lastname: Mandalia
authors.forename: Nicky
authors.initials: N
authors.lastname: Perry
authors.forename: Mackie
authors.initials: M
authors.lastname: Nicola
authors.forename: Mark
authors.initials: M
authors.lastname: Nelson
mesh_terms: D000328:Adult; D000480:Alkynes; D048588:Benzoxazines / Q000009:adverse effects*; D018791:CD4 Lymphocyte Count; D002493:Central Nervous System Diseases / Q000139:chemically induced* / Q000523:psychology; D003521:Cyclopropanes; D005240:Feasibility Studies; D015658:HIV Infections / Q000150:complications / Q000188:drug therapy* / Q000523:psychology; D017320:HIV Protease Inhibitors / Q000008:administration & dosage / Q000009:adverse effects; D015497:HIV-1; D006801:Humans; D008297:Male; D008875:Middle Aged; D009570:Nitriles; D010865:Pilot Projects; D011724:Pyridazines / Q000008:administration & dosage / Q000627:therapeutic use*; D011743:Pyrimidines; D012367:RNA, Viral; D018894:Reverse Transcriptase Inhibitors / Q000008:administration & dosage / Q000009:adverse effects*; D007319:Sleep Initiation and Maintenance Disorders / Q000139:chemically induced* / Q000523:psychology; D016896:Treatment Outcome; D019562:Viral Load
chemical_list: D000480:Alkynes; D048588:Benzoxazines; D003521:Cyclopropanes; D017320:HIV Protease Inhibitors; D009570:Nitriles; D011724:Pyridazines; D011743:Pyrimidines; D012367:RNA, Viral; D018894:Reverse Transcriptase Inhibitors; C451734:etravirine; C098320:efavirenz