ING116070: a study of the pharmacokinetics and antiviral activity of dolutegravir in cerebrospinal fluid in HIV-1-infected, antiretroviral therapy-naive subjects

Clin Infect Dis. 2014 Oct;59(7):1032-7. doi: 10.1093/cid/ciu477. Epub 2014 Jun 18.

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.

Keywords: HIV; cerebrospinal fluid; dolutegravir.

Publication types

  • Clinical Trial, Phase III
  • Multicenter Study
  • Research Support, N.I.H., Extramural

MeSH terms

  • Adult
  • Anti-HIV Agents / pharmacokinetics*
  • Anti-HIV Agents / therapeutic use*
  • Cerebrospinal Fluid / chemistry*
  • Dideoxynucleosides / therapeutic use
  • Drug Combinations
  • HIV Infections / drug therapy*
  • HIV Infections / virology
  • HIV-1 / isolation & purification
  • Heterocyclic Compounds, 3-Ring / pharmacokinetics*
  • Heterocyclic Compounds, 3-Ring / therapeutic use*
  • Humans
  • Lamivudine / therapeutic use
  • Male
  • Middle Aged
  • Oxazines
  • Piperazines
  • Plasma / chemistry
  • Pyridones
  • RNA, Viral / blood
  • RNA, Viral / cerebrospinal fluid
  • Treatment Outcome
  • Viral Load

Substances

  • Anti-HIV Agents
  • Dideoxynucleosides
  • Drug Combinations
  • Heterocyclic Compounds, 3-Ring
  • Oxazines
  • Piperazines
  • Pyridones
  • RNA, Viral
  • abacavir, lamivudine drug combination
  • Lamivudine
  • dolutegravir

Associated data

  • ClinicalTrials.gov/NCT01499199