Date Published:
2014 Oct

Publication Type:
Journal Article

Authors:

S.L. Letendre
A.M. Mills
K.T. Tashima
D.A. Thomas
S.S. Min
S. Chen
I.H. Song
S.C. Piscitelli

Secondary:
Clin Infect Dis

Volume:
59

Pagination:
1032-7

Issue:
7

PMID:
24944232

URL:
https://pubmed.ncbi.nlm.nih.gov/24944232

DOI:
10.1093/cid/ciu477

Keywords:
Adult;Anti-HIV Agents;Cerebrospinal Fluid;CHARTER;Dideoxynucleosides;Drug Combinations;Heterocyclic Compounds, 3-Ring;HIV Infections;HIV-1;Humans;Internal;Lamivudine;Male;Middle Aged;Oxazines;Piperazines;Plasma;Pyridones;RNA, Viral;Treatment Outcome;Viral Load

Abstract:
<p>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.</p>