ING116070: a study of the pharmacokinetics and antiviral activity of dolutegravir in cerebrospinal fluid in HIV-1-infected, antiretroviral therapy-naive subjects.
Title | ING116070: a study of the pharmacokinetics and antiviral activity of dolutegravir in cerebrospinal fluid in HIV-1-infected, antiretroviral therapy-naive subjects. |
Publication Type | Journal Article |
Year of Publication | 2014 |
Authors | Letendre, SL, Mills, AM, Tashima, KT, Thomas, DA, Min, SS, Chen, S, Song, IH, Piscitelli, SC |
Corporate Authors | extended ING116070 study team |
Journal | Clin Infect Dis |
Volume | 59 |
Issue | 7 |
Pagination | 1032-7 |
Date Published | 2014 Oct |
ISSN | 1537-6591 |
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 | 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. |
DOI | 10.1093/cid/ciu477 |
Alternate Journal | Clin Infect Dis |
PubMed ID | 24944232 |
PubMed Central ID | PMC4166983 |
Grant List | HHSN271201000036C / MH / NIMH NIH HHS / United States K24 MH097673 / MH / NIMH NIH HHS / United States P30 MH062512 / MH / NIMH NIH HHS / United States |