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      Dolutegravir Cerebrospinal Fluid Diffusion in HIV-1–Infected Patients with Central Nervous System Impairment

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          Abstract

          This study aimed to determine dolutegravir cerebrospinal fluid (CSF) diffusion in 13 patients with HIV-related cerebral impairment enrolled in a real-life observational study. Dolutegravir median (range) CSF concentration [9.6 (3.6–22.8) ng/mL] reached CSF therapeutic concentrations whatever the blood-brain barrier status and diffused in correlation with the albumin quotient ( P = .0186).

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          Most cited references6

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          Once-daily dolutegravir versus darunavir plus ritonavir for treatment-naive adults with HIV-1 infection (FLAMINGO): 96 week results from a randomised, open-label, phase 3b study.

          The primary analysis of the FLAMINGO study at 48 weeks showed that patients taking dolutegravir once daily had a significantly higher virological response rate than did those taking ritonavir-boosted darunavir once daily, with similar tolerability. We present secondary efficacy and safety results analysed at 96 weeks.
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            Antiviral activity, safety, and pharmacokinetics/pharmacodynamics of dolutegravir as 10-day monotherapy in HIV-1-infected adults.

            To evaluate the antiviral activity, safety, pharmacokinetics, and pharmacokinetics/pharmacodynamics of dolutegravir (DTG), a next-generation HIV integrase inhibitor (INI), as short-term monotherapy. A phase IIa, randomized, double-blind, dose-ranging study. In this study, INI-naive, HIV-1-infected adults currently off antiretroviral therapy were randomized to receive DTG (2, 10, or 50 mg) or placebo once daily for 10 days in an eight active and two placebo randomization scheme per DTG dose. Placebo patients were pooled for the purpose of analysis. Thirty-five patients (n = 9 for DTG 2 and 10 mg, n = 10 for DTG 50 mg, and n = 7 for placebo) were enrolled. Baseline characteristics were similar across dose groups. Significant reductions in plasma HIV-1 RNA from baseline to day 11 were observed for all DTG dose groups compared with placebo (P < 0.001), with a mean decrease of 1.51-2.46 log(10) copies/ml. In addition, a well characterized dose-response relationship was observed for viral load decrease. Most patients (seven of 10, 70%) receiving DTG 50 mg achieved plasma HIV-1 RNA less than 50 copies/ml. The pharmacokinetic variability was low (coefficient of variation, range 25-50%). Plasma HIV-1 RNA reduction was best predicted by Cτ using an E(max) model. The most common adverse events were diarrhea, fatigue, and headache; the majority of adverse events were mild or moderate in severity. Dolutegravir demonstrated potent antiviral activity, good short-term tolerability, low pharmacokinetic variability, and a predictable pharmacokinetics/pharmacodynamics relationship, which support once-daily dosing without a pharmacokinetic booster in integrase-naive patients in future studies.
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              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. METHODS Design and Study Population ING116070 is an ongoing, 96-week, phase IIIb, single-arm, open-label, multicenter (3 US sites) study in ART-naive (≤10 days of prior therapy), HIV-1–infected adults (≥18 years old). Eligible participants had a screening plasma HIV-1 RNA level ≥5000 copies/mL and a CD4+ cell count ≥200 cells/mm3 and were negative for the HLA-B*5701 allele. Exclusions included contraindication to lumbar puncture, moderate or severe cognitive impairment, evidence of primary viral resistance, active US Centers for Disease Control and Prevention category C disease (except Kaposi sarcoma), defined laboratory values, pregnancy, breastfeeding, moderate or severe hepatic impairment, hepatitis B virus infection, anticipated need for hepatitis C virus therapy during the study period, malignancy, or recent treatment with HIV-1 vaccines or immunomodulators. Ethics committee approval was obtained at all participating centers in accordance with the principles of the 2008 Declaration of Helsinki. Each patient provided written informed consent before undergoing study procedures. This study is registered at ClinicalTrials.gov (NCT01499199). Eligible subjects received (DTG 50 mg) along with the dual nucleoside reverse-transcriptase inhibitor (NRTI) combination tablet abacavir/lamivudine (ABC/3TC [Kivexa/Epzicom, ViiV Healthcare]; 600/300 mg), all taken once daily. The intention-to-treat exposed and safety populations both comprised all randomized subjects who received ≥1 dose of study medication. Study End Points The primary study analyses occurred at week 16; additional analyses were preplanned for weeks 2 and 96. The primary end point was the DTG concentration in CSF at week 16. Secondary end points included DTG concentrations in plasma (total and unbound) and CSF (total), the relationship between DTG concentrations in plasma and CSF, the proportion of subjects with plasma HIV-1 RNA 200 copies/mL on or after week 16, with cases triggering virologic resistance testing. Resistance testing was performed by Monogram Biosciences. Statistical Analyses ING116070 was a single-arm study to assess the distribution of DTG into the CSF compartment. As such, it included no formal hypothesis test. Pearson correlations between DTG concentrations in plasma (total and unbound) and CSF at weeks 2 and 16 were calculated. Efficacy analyses were based on the intention-to-treat exposed population. Subjects' responses (eg, 100 000 copies/mL, No. (%) 5 (38)  Mean (SD), log10 copies/mL 4.93 (0.86)  Median (range), log10 copies/mL) 4.73 (3.60, 6.57) Baseline CSF HIV-1 RNA  Mean (SD), log10 copies/mL 3.59 (1.21)  Median (range), log10 copies/mL 3.64 (1.46, 5.60) Baseline CD4+ cell count   2 subjects (7 of 13 [54%]), with 2 headaches reported as being related to the study drug. Headache is a known AE associated with lumbar punctures, with the majority of such headaches reported following the lumbar puncture. Table 3 summarizes drug-related AEs reported in >1 subject; all were considered grade 1 in intensity with the exception of a single grade 2 worsening of depression that the investigator thought might be related to the investigational product. The subject had an extensive personal and family history of depression and was maintained in the study. No deaths occurred. One subject prematurely withdrew from the study before week 2; this was because of a grade 4, non–drug-related SAE of pharyngitis and a grade 2 AE of syphilis. The only other SAE reported during the study, in a different subject, was a non–drug-related SAE of cholecystitis. No clinically significant trends in postdose laboratory abnormalities were observed. Table 3. Most Common Drug-Related Adverse Eventsa Type of Event Adverse Events, No. (%) Any event 8 (62) Fatigue 2 (15) Headache 2 (15) Nausea 2 (15) a Adverse events reported for >1 subject in the safety population (N = 13). DISCUSSION Many consider that distribution of antiretroviral drugs into “sanctuary” sites in therapeutic concentrations favors suppression of HIV replication there. One such site, the CNS, may be especially important because drug-resistant viruses that are not present in blood have been found there (ie, the viruses can have a different fold change in IC50 compared with those found in the plasma [24]). In this study, DTG was measurable in all CSF samples collected 2–6 hours after dosing and exceeded the IC50 against wild-type virus (0.51 nmol/L = 0.2 ng/mL) [25]. Median DTG CSF concentrations were 90-fold and 66-fold above the IC50 at weeks 2 and 16, respectively, suggesting that DTG achieves therapeutic concentrations in the CSF. The planned narrow sampling window does not allow us to demonstrate persistence of drug in the CSF over the entire dosing interval, especially at the end of the interval when CSF concentrations might be lowest. However, DTG likely has slow clearance of drug and flat concentration-time profiles in the CSF, similar to what has been observed with other antiretrovirals [26–28]. In addition, ABC and 3TC both distribute well into the CNS [29, 30], indicating that a combination regimen of ABC/3TC with DTG might be effective in rapidly clearing HIV from the CSF. In parallel with these pharmacokinetic data, HIV-1 RNA rapidly declined in both plasma and CSF, and was undetectable (<50 copies/mL) at week 16 in the CSF in all evaluable subjects and in plasma in 10 of 12 evaluable subjects (83%), demonstrating the potent antiviral activity of this regimen in multiple compartments. Dolutegravir is highly protein bound in plasma, and only total DTG was measured in the CSF owing to assay limits. However, the impact of protein binding for unbound DTG concentration in the CSF is probably small because the concentration of binding proteins (eg, albumin and α-1 acid glycoprotein) in CSF is much lower than in plasma (100- to 1000-fold lower) [31, 32]. This is supported by findings of other studies with other highly bound antiretrovirals demonstrating that nearly all the drug in the CSF was unbound [33]. The similarity of the concentration of DTG in CSF and the unbound concentration in plasma implies that the distribution of DTG into CSF is probably governed mainly by passive diffusion with a low possibility of active transporter involvement. The more rapid decline in plasma HIV-1 RNA for an INI-based versus an efavirenz-based regimen [34] makes the INI class attractive for patients with high viral loads or with significant issues, such as neurocognitive impairment. The distribution of raltegravir into CSF was evaluated in HIV-infected patients [28]. Although raltegravir has a higher CSF-to-plasma ratio of approximately 6% versus 0.5% for DTG, the greater potency of DTG results in a much higher CSF inhibitory quotient (ratio of drug concentration to IC50). The raltegravir concentrations in CSF exceeded the IC50 for wild-type HIV (3.2 ng/mL) in all specimens by a median of 4.5-fold, whereas in this study DTG exceeded the IC50 by 66–90-fold. Although the clinical relevance of these values is unknown, they suggest the potential for a greater effect, especially if INI resistance is present. Furthermore, DTG has demonstrated wild-type activity against most INI single-mutant HIV-1 and thus provides a greater barrier to the development of resistance in the CNS [25]. A previous phase IIa study (ING111521) has demonstrated good correlation between DTG plasma concentration and reduction in HIV-1 RNA in plasma after 10-day monotherapy [35]. In this current study, no correlation was identified between DTG concentration in CSF and HIV-1 RNA reduction in CSF, primarily because CSF concentrations were well in excess of the IC50 and most subjects in the study had good responses to therapy in both plasma and CSF. The uniformity of response did not allow for the description of a concentration-effect relationship. In general, DTG was well tolerated in the ART-naive, HIV-1–infected subjects in this study. The most common AE was headache, which was often temporally related to lumbar puncture and not deemed related to study drug by the investigator in most cases. Overall, the safety profile of DTG plus ABC/3TC in this limited number of patients is consistent with findings of larger phase III studies administering the same regimen [19, 20]. In 1 subject with PDVF, integrase genotypic or phenotypic results did not show development of resistance to INIs or NRTIs. Other studies of DTG (50 mg once daily) in ART-naive patients have demonstrated a lack of NRTI or INI resistance in participants with PDVF for up to 96 weeks of study, despite the development of resistance in the comparator treatment arm [19, 20]. Given the pharmacokinetic and efficacy data in this study, the combination of DTG, ABC, and 3TC may be an effective regimen in subjects with neurocognitive complications of HIV disease.
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                Author and article information

                Journal
                Open Forum Infect Dis
                Open Forum Infect Dis
                ofid
                Open Forum Infectious Diseases
                Oxford University Press (US )
                2328-8957
                June 2019
                03 June 2019
                03 June 2019
                : 6
                : 6
                : ofz174
                Affiliations
                [1 ]Department of Clinical Pharmacy, Assistance Publique-Hôpitaux de Paris, Hôpitaux Universitaires Paris-Sud, Hôpital Bicêtre, Le Kremlin-Bicêtre, France
                [2 ]CEA–Paris-Sud University–INSERM U1184, IDMIT Infrastructure, Fontenay-aux-Roses, France
                [3 ]Department of Pharmacology, Assistance Publique-Hôpitaux de Paris, Hôpitaux Universitaires Paris-Sud, Hôpital Bicêtre, Le Kremlin-Bicêtre, France
                [4 ]Department of Virology, Assistance Publique-Hôpitaux de Paris, Hôpitaux Universitaires Paris-Sud, Hôpital Paul-Brousse, Villejuif, France
                [5 ]Department of Biochemistry, Hôpitaux Universitaires Paris-Sud, Hôpital Bicêtre, Le Kremlin-Bicêtre, France
                [6 ]Department of Internal Medicine, Assistance Publique-Hôpitaux de Paris, Hôpitaux Universitaires Paris-Sud, Hôpital Bicêtre, Le Kremlin-Bicêtre, France
                [7 ]CESP, Paris-Sud University–INSERM U1018, Villejuif, France
                [8 ]College of Medicine, Paris-Sud University, Le Kremlin-Bicêtre, France
                [9 ]College of Pharmacy, Paris-Sud University, Châtenay-Malabry, France
                [10 ]Paris-Descartes University–INSERM U1016, CNRS 8104, Institut Cochin, Paris, France
                Author notes

                A.B.-T. and A.C. contributed equally to this work.

                Correspondence: A. Barrail-Tran, Doctor, Department of Clinical Pharmacy, Assistance Publique-Hôpitaux de Paris, Hôpitaux Universitaires Paris Sud, Hôpital Bicêtre, 78 Rue du Général Leclerc, Le Kremlin-Bicêtre, Ile-de-France 94270, France ( aurelie.barrail-tran@ 123456aphp.fr ).
                Article
                ofz174
                10.1093/ofid/ofz174
                6546201
                31198814
                fdcae5da-1e31-47d2-8f44-0423a55483aa
                © The Author(s) 2019. Published by Oxford University Press on behalf of Infectious Diseases Society of America.

                This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs licence ( http://creativecommons.org/licenses/by-nc-nd/4.0/), which permits non-commercial reproduction and distribution of the work, in any medium, provided the original work is not altered or transformed in any way, and that the work is properly cited. For commercial re-use, please contact journals.permissions@oup.com

                History
                : 16 November 2018
                : 17 May 2019
                Page count
                Pages: 4
                Categories
                Brief Reports

                cerebrospinal fluid,central nervous system diffusion,central nervous system impairment,dolutegravir,pharmacokinetics

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