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

TitleING116070: a study of the pharmacokinetics and antiviral activity of dolutegravir in cerebrospinal fluid in HIV-1-infected, antiretroviral therapy-naive subjects.
Publication TypeJournal Article
Year of Publication2014
AuthorsLetendre, S, Mills, AM, Tashima, KT, Thomas, DA, Min, SS, Chen, S, Song, IH, Piscitelli, SC
Corporate Authorsextended ING116070 study team
JournalClin Infect Dis
Volume59
Issue7
Pagination1032-7
Date Published2014 Oct
ISSN1537-6591
KeywordsAdult, Anti-HIV Agents, Cerebrospinal Fluid, CHARTER, Dideoxynucleosides, Drug Combinations, Heterocyclic Compounds, 3-Ring, HIV Infections, HIV-1, Humans, Internal, Lamivudine, Male, Middle Aged, Plasma, RNA, Viral, Treatment Outcome, Viral Load
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.

DOI10.1093/cid/ciu477
Alternate JournalClin. Infect. Dis.
PubMed ID24944232
PubMed Central IDPMC4166983
Grant ListHHSN271201000036C / MH / NIMH NIH HHS / United States
K24 MH097673 / MH / NIMH NIH HHS / United States
P30 MH062512 / MH / NIMH NIH HHS / United States