title: ING116070: a study of the pharmacokinetics and antiviral activity of dolutegravir in cerebrospinal fluid in HIV-1-infected, antiretroviral therapy-naive subjects.
abstract: BACKGROUND
  Dolutegravir (DTG), a once-daily, human immunodeficiency virus type 1 (HIV-1) integrase inhibitor, was evaluated for distribution and antiviral activity in cerebrospinal fluid (CSF).
  
  
  METHODS
  ING116070 is an ongoing, single-arm, open-label, multicenter study in antiretroviral therapy-naive, HIV-1-infected adults. Subjects received DTG (50 mg) plus abacavir/lamivudine (600/300 mg) once daily. The CSF and plasma (total and unbound) DTG concentrations were measured at weeks 2 and 16. The HIV-1 RNA levels were measured in CSF at baseline and weeks 2 and 16 and in plasma at baseline and weeks 2, 4, 8, 12, and 16.
  
  
  RESULTS
  Thirteen white men enrolled in the study; 2 withdrew prematurely, 1 because of a non-drug-related serious adverse event (pharyngitis) and 1 because of lack of treatment efficacy. The median DTG concentrations in CSF were 18 ng/mL (range, 4-23 ng/mL) at week 2 and 13 ng/mL (4-18 ng/mL) at week 16. Ratios of DTG CSF to total plasma concentration were similar to the unbound fraction of DTG in plasma. Median changes from baseline in CSF (n = 11) and plasma (n = 12) HIV-1 RNA were -3.42 and -3.04 log10 copies/mL, respectively. Nine of 11 subjects (82%) had plasma and CSF HIV-1 RNA levels <50 copies/mL and 10 of 11 (91%) had CSF HIV-1 RNA levels <2 copies/mL at week 16.
  
  
  CONCLUSIONS
  The DTG concentrations in CSF were similar to unbound plasma concentrations and exceeded the in vitro 50% inhibitory concentration for wild-type HIV (0.2 ng/mL), suggesting that DTG achieves therapeutic concentrations in the central nervous system. The HIV-1 RNA reductions were similar in CSF and plasma. Clinical Trials Registration. NCT01499199.
authors.affiliation: University of California, San Diego.
authors.forename: Scott L
authors.initials: SL
authors.lastname: Letendre
authors.affiliation: Anthony Mills, MD, Inc, Los Angeles, California.
authors.forename: Anthony M
authors.initials: AM
authors.lastname: Mills
authors.affiliation: The Miriam Hospital, Providence, Rhode Island.
authors.forename: Karen T
authors.initials: KT
authors.lastname: Tashima
authors.affiliation: GlaxoSmithKline, Durham, North Carolina.
authors.forename: Deborah A
authors.initials: DA
authors.lastname: Thomas
authors.affiliation: GlaxoSmithKline, Durham, North Carolina.
authors.forename: Sherene S
authors.initials: SS
authors.lastname: Min
authors.affiliation: GlaxoSmithKline, Durham, North Carolina.
authors.forename: Shuguang
authors.initials: S
authors.lastname: Chen
authors.affiliation: GlaxoSmithKline, Durham, North Carolina.
authors.forename: Ivy H
authors.initials: IH
authors.lastname: Song
authors.affiliation: GlaxoSmithKline, Durham, North Carolina.
authors.forename: Stephen C
authors.initials: SC
authors.lastname: Piscitelli
mesh_terms: D000328:Adult; D019380:Anti-HIV Agents / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D002555:Cerebrospinal Fluid / Q000737:chemistry*; D015224:Dideoxynucleosides / Q000627:therapeutic use; D004338:Drug Combinations; D015658:HIV Infections / Q000188:drug therapy* / Q000821:virology; D015497:HIV-1 / Q000302:isolation & purification; D006575:Heterocyclic Compounds, 3-Ring / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D006801:Humans; D019259:Lamivudine / Q000627:therapeutic use; D008297:Male; D008875:Middle Aged; D010078:Oxazines; D010879:Piperazines; D010949:Plasma / Q000737:chemistry; D011728:Pyridones; D012367:RNA, Viral / Q000097:blood / Q000134:cerebrospinal fluid; D016896:Treatment Outcome; D019562:Viral Load; D000099226:Dolutegravir; D000099227:Abacavir
chemical_list: D019380:Anti-HIV Agents; D015224:Dideoxynucleosides; D004338:Drug Combinations; D006575:Heterocyclic Compounds, 3-Ring; D019259:Lamivudine; D010078:Oxazines; D010879:Piperazines; D011728:Pyridones; D012367:RNA, Viral; D000099226:Dolutegravir; C492871:abacavir, lamivudine drug combination; D000099227:Abacavir
keywords: HIV; cerebrospinal fluid; dolutegravir