title: Unexpected finding of delayed-onset seizures in HIV-positive, treatment-experienced subjects in the Phase IIb evaluation of fosdevirine (GSK2248761).
abstract: BACKGROUND
  Fosdevirine (GSK2248761) is a non-nucleoside reverse transcriptase inhibitor with HIV-1 activity against common efavirenz-resistant strains. Two partially blind, randomized, Phase IIb studies were initiated (1 in treatment-naive and 1 in treatment-experienced subjects with HIV) to select a once-daily dose of fosdevirine for Phase III trials.
  
  
  METHODS
  In the SIGNET study, treatment-naive subjects were randomized 1:1:1 to receive once-daily fosdevirine 100 or 200 mg or efavirenz 600 mg, each along with tenofovir disoproxil fumarate/emtricitabine 300 mg/200 mg or abacavir/lamivudine 600 mg/300 mg. In the SONNET study, treatment-experienced subjects with non-nucleoside reverse transcriptase inhibitor-resistant HIV-1 were randomized 1:1:1 to treatment with fosdevirine 100 or 200 mg once daily or etravirine 200 mg twice daily, each along with twice-daily darunavir/ritonavir 600/100 mg and raltegravir 400 mg. The primary efficacy end point was the proportion of subjects with HIV-1 RNA<50 copies/ml. Safety and pharmacokinetics were also addressed.
  
  
  RESULTS
  A total of 35 subjects were exposed to fosdevirine 100 or 200 mg. Trials were halted when 5 treatment-experienced subjects (1 receiving fosdevirine 100 mg, 4 receiving fosdevirine 200 mg) developed new-onset seizures after ≥4 weeks of exposure to fosdevirine. There was no clear association between seizures and fosdevirine plasma drug levels. Time to seizure onset ranged from 28 to 81 days, and all 5 subjects experienced ≥1 seizure after drug discontinuation.
  
  
  CONCLUSIONS
  The delayed onset of seizures after fosdevirine exposure and persistence after discontinuation is without precedent in antiretroviral drug development, leading to additional investigation and underscoring the need for careful subject monitoring.
authors.affiliation: GlaxoSmithKline, Research Triangle Park, NC, USA. david.a.margolis@gsk.com.
authors.forename: David A
authors.initials: DA
authors.lastname: Margolis
authors.forename: Joseph J
authors.initials: JJ
authors.lastname: Eron
authors.forename: Edwin
authors.initials: E
authors.lastname: DeJesus
authors.forename: Scott
authors.initials: S
authors.lastname: White
authors.forename: Paul
authors.initials: P
authors.lastname: Wannamaker
authors.forename: Britt
authors.initials: B
authors.lastname: Stancil
authors.forename: Mark
authors.initials: M
authors.lastname: Johnson
mesh_terms: D019380:Anti-HIV Agents / Q000494:pharmacology / Q000627:therapeutic use*; D057915:Drug Substitution; D005260:Female; D015658:HIV Infections / Q000150:complications* / Q000188:drug therapy*; D015497:HIV-1; D006801:Humans; D007211:Indoles / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use*; D008297:Male; D010721:Phosphinic Acids / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use*; D018894:Reverse Transcriptase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D012640:Seizures / Q000150:complications*; D013997:Time Factors; D016896:Treatment Outcome; D028761:Withholding Treatment
chemical_list: D019380:Anti-HIV Agents; C534138:IDX 899; D007211:Indoles; D010721:Phosphinic Acids; D018894:Reverse Transcriptase Inhibitors