ING116070: A Study of the Pharmacokinetics and Antiviral Activity of Dolutegravir in Cerebrospinal Fluid in HIV-1–Infected, Antiretroviral Therapy–Naive Subjects

• Published in: Clinical infectious diseases Vol. 59; no. 7; pp. 1032 - 1037
• Main Authors: Letendre, Scott L., Mills, Anthony M., Tashima, Karen T., Thomas, Deborah A., Min, Sherene S., Chen, Shuguang, Song, Ivy H., Piscitelli, Stephen C.
• Format: Journal Article
• Language: English
• Published: United States OXFORD UNIVERSITY PRESS 01.10.2014; Oxford University Press
• Subjects: Adult; AIDS; Anti-HIV Agents - pharmacokinetics; Anti-HIV Agents - therapeutic use; Antiretroviral drugs; Antiretrovirals; Antivirals; Blood plasma; Central nervous system; Cerebrospinal fluid; Cerebrospinal Fluid - chemistry; Dideoxynucleosides - therapeutic use; Drug Combinations; Heterocyclic Compounds, 3-Ring - pharmacokinetics; Heterocyclic Compounds, 3-Ring - therapeutic use; HIV; HIV 1; HIV Infections - drug therapy; HIV Infections - virology; HIV-1 - isolation & purification; HIV/AIDS; Human immunodeficiency virus; Human immunodeficiency virus 1; Humans; Lamivudine - therapeutic use; Male; Medical treatment; Middle Aged; Pharmacokinetics; Plasma; Plasma - chemistry; Ribonucleic acid; RNA; RNA, Viral - blood; RNA, Viral - cerebrospinal fluid; Treatment Outcome; Viral Load; HIV; cerebrospinal fluid; dolutegravir
• ISSN: 1058-4838; 1537-6591; 1537-6591
• DOI: 10.1093/cid/ciu477

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.