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

Despite the advent of modern, potent antiretroviral therapy (ART), human immunodeficiency virus (HIV)–associated neurocognitive impairment continues to be clinically significant [1–3]. In HIV-infected patients receiving therapy, HIV has been found in the cerebrospinal fluid (CSF) of individuals who have an undetectable plasma viral load, both for patients with neurologic symptoms [4] and for those who are neurologically asymptomatic [5]. Such discordant findings between plasma and CSF may be influenced by choice of therapy, because treatment with ART that has better estimated distribution into the central nervous system (CNS) has been associated with better viral suppression in CSF [6–8]. Thus, it has become increasingly important to understand to what degree components of ART can exert activity within the brain, a long-considered “sanctuary” site [6, 9–11]. Although the CSF space is not equivalent to the brain extracellular or intracellular environment, drug distribution into the CSF is a practical way to gain some understanding of the potential for CNS tissue distribution. Therefore, CSF provides a valuable surrogate to estimate drug distribution and antiviral effects across the blood-brain barrier and blood-CSF barrier [12–14]. The CSF distribution of many antiretrovirals, including lopinavir, darunavir, efavirenz and raltegravir, has been assessed [15–18]. Dolutegravir (DTG; Tivicay, ViiV Healthcare, Research Triangle Park, North Carolina) is a novel HIV integrase inhibitor (INI) with a pharmacokinetic profile that allows once-daily administration in INI-naive subjects. The efficacy and safety of DTG in large, phase III trials have been reported elsewhere [19, 20]. Dolutegravir is approximately 99% bound to plasma proteins and is primarily metabolized via uridine 5′-diphospho-glucuronosyltransferase 1A1, with cytochrome P450 3A4 as a minor pathway. It is also a substrate of P-glycoprotein and breast cancer resistance protein. These attributes indicate that distribution across the blood-brain barrier and blood-CSF barrier will be limited. However, owing to the potency of DTG, even modest distribution into the CNS may result in concentrations that provide antiviral activity. Study ING116070 was designed to assess the extent of DTG entry into the CSF compartment, and to evaluate virologic responses in CSF and plasma. Results from the planned week 16 primary analysis are presented.