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

Dolutegravir Cerebrospinal Fluid Diffusion in HIV-1–Infected Patients with Central Nervous System... Downloaded from https://academic.oup.com/ofid/article-abstract/6/6/ofz174/5510470 by Ed 'DeepDyve' Gillespie user on 04 June 2019 Open Forum Infectious Diseases BRIEF REPORT [2]. It also may be the cause of neurocognitive disorders in a Dolutegravir Cerebrospinal Fluid significant proportion of patients [3 ]. The role of the brain as Diffusion in HIV-1–Infected Patients a latent reservoir for HIV must be considered in the devel- opment of therapeutic strategies for eliminating HIV from with Central Nervous System infected subjects [4]. Impairment Dolutegravir (DTG) is increasingly being used in com- 1,2 3 2 4 Thibaut Gelé, Valérie Furlan, Anne-Marie Taburet, Coralie Pallier, bination with nucleoside/nucleotide reverse transcriptase 5 6,7,8 2,6 Pierre-Hadrien Becker, Cécile Goujard, Jacques Gasnault, 1,2,9,* 6,10,* inhibitors. Recently, the World Health Organization (WHO) Aurélie Barrail-Tran, and Antoine Chéret has even issued new antiretroviral (ART) treatment guidelines Department of Clinical Pharmacy, Assistance Publique-Hôpitaux de Paris, Hôpitaux Universitaires Paris-Sud, Hôpital Bicêtre, Le Kremlin-Bicêtre, France; CEA–Paris-Sud recommending DTG-based treatment as the preferred first-line University–INSERM U1184, IDMIT Infrastructure, Fontenay-aux-Roses, France; Department treatment option for all adults, adolescents, and children, in- of Pharmacology, Assistance Publique-Hôpitaux de Paris, Hôpitaux Universitaires Paris-Sud, Hôpital Bicêtre, Le Kremlin-Bicêtre, France; Department of Virology, Assistance Publique- cluding women and adolescent girls who have access to con- Hôpitaux de Paris, Hôpitaux Universitaires Paris-Sud, Hôpital Paul-Brousse, Villejuif, France; sistent and reliable contraception [5]. DTG is well tolerated and 5 6 Department of Biochemistry; Department of Internal Medicine, Assistance Publique- Hôpitaux de Paris, Hôpitaux Universitaires Paris-Sud, Hôpital Bicêtre, Le Kremlin-Bicêtre, rapidly inhibits viral replication [6]. 7 8 France; CESP, Paris-Sud University–INSERM U1018, Villejuif, France; College of Medicine, Following on from the study that has characterized the cere- Paris-Sud University, Le Kremlin-Bicêtre, France; College of Pharmacy, Paris-Sud University, brospinal fluid (CSF) diffusion of DTG in antiretroviral therapy– Châtenay-Malabry, France; Paris-Descartes University–INSERM U1016, CNRS 8104, Institut Cochin, Paris, France. naive, HIV-1–infected adults [7], we aimed to determine if DTG diffusion is also sufficient to reach effective concentrations This study aimed to determine dolutegravir cerebrospinal fluid in the CSF in treatment-experienced patients with HIV-related (CSF) diffusion in 13 patients with HIV-related cerebral impair - CNS (central nervous system) impairment (HCI). ment enrolled in a real-life observational study. Dolutegravir e p Th rimary endpoint is the evaluation of DTG CSF concen- median (range) CSF concentration [9.6 (3.6–22.8) ng/mL] tration in treatment-experienced patients with HCI. Secondary reached CSF therapeutic concentrations whatever the blood- brain barrier status and diffused in correlation with the albumin endpoints are to evaluate the DTG diffusion and its correlation quotient (P = .0186). with the albumin quotient used to evaluate BBB status. Keywords. cerebrospinal fluid; central nervous system diffusion; central nervous system impairment; dolutegravir; METHODS pharmacokinetics. Patients and Study Design All of the patients included in this monocenter, prospective, e m Th ajor obstacle to a functional cure for human immunode- single arm, open label, observational study were admitted to ficiency virus (HIV) infection is the persistence of a latent HIV the Neuro-HIV Rehabilitation Care Unit (Assistance Publique- reservoir. This residual viral replication results partly from the Hôpitaux de Paris, Hôpitaux Uuniversitaires Paris -Sud, Bicêtre existence of pharmacological sanctuaries largely impenetrable to Hospital, Le Kremlin-Bicêtre, France) between September 2015 drugs. A recent study showed that the virus can replicate in these and October 2016. Blood and CSF samples were collected simul- sanctuaries, in which there is less antiviral pressure, contributing taneously during routine care and at any time during the dosing to the continual replenishment of viral reservoirs [1]. interval. Plasma and CSF HIV-RNA levels were determined HIV is known to aeff ct the blood-brain barrier (BBB) by reverse transcriptase-polymerase chain reaction (RT-PCR) leading to intrathecal immunoactivation and neuronal injury (Abbott RealTime  M2000, detection threshold  =  40 copies/ mL [Abbott Laboratories, Abbott Park, IL]). For this research, monitoring was conducted on a bank comprising routine blood Received 16 November 2018; editorial decision 27 March 2019; accepted 17 May 2019. and CSF samples. Therefore, patient care did not differ from *A.B.-T. and A.C. contributed equally to this work. Correspondence: A.  Barrail-Tran, Doctor, Department of Clinical Pharmacy, Assistance usual care, thus the non-interventional nature of this research. Publique-Hôpitaux de Paris, Hôpitaux Universitaires Paris Sud, Hôpital Bicêtre, 78 Rue du French regulation did not require an ethic committee’s agree- Général Leclerc, Le Kremlin-Bicêtre, Ile-de-France 94270, France (aurelie.barrail-tran@aphp.fr). ® ment for use of health data or biobank, nor a written consent. Open Forum Infectious Diseases © The Author(s) 2019. Published by Oxford University Press on behalf of Infectious Diseases However, each patient admitted to the hospital received written Society of America. This is an Open Access article distributed under the terms of the Creative information stating that medical records and biological samples 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 drawn for care might be used for medical research. Each patient medium, provided the original work is not altered or transformed in any way, and that the had the right to express opposition; none of the patients who work is properly cited. For commercial re-use, please contact journals.permissions@oup.com participated in this study expressed opposition. DOI: 10.1093/ofid/ofz174 BRIEF REPORT • ofid • 1 Downloaded from https://academic.oup.com/ofid/article-abstract/6/6/ofz174/5510470 by Ed 'DeepDyve' Gillespie user on 04 June 2019 DTG Concentration and Diffusion undetectable HIV CSF viral load (<40 copies/mL). Only one pa- Bound and unbound plasma DTG were separated by ul- tient had an undetectable HIV CSF viral load associated with a trafiltration (Centrifree devices, cutoff, 30  kDa; Millipore, detectable HIV plasma viral load. For the patients with a detect- Molsheim, France). Total plasma, unbound plasma, and CSF able viral load, median plasma and CSF viral loads were 2.3 log DTG concentrations were determined with a quality control- copies/mL (range: 1.8–3.0 log copies/mL) and 2.8 log copies/ 10 10 validated method based on liquid chromatography-tandem mL (range: 1.7–4.8 log copies/mL), respectively. mass spectrometry (LC-MS/MS) (Acquity TQD-UPLC system, DTG Concentrations Waters Corp., Milford, MA ). Lower limits of quantification for Total plasma, unbound plasma, and total CSF DTG total plasma concentration was 2  ng/mL or unbound or CSF concentrations are shown in Table 1. Median plasma DTG con- DTG concentration was 0.5 ng/mL each. centration was 1,675  ng/mL (range: 137–5,091  ng/mL). The e un Th bound fraction (Fu ) was determined as the ratio of DTG median unbound DTG concentration was 9.2  ng/mL (range: unbound to total plasma DTG concentrations. DTG diffusion 0.8–34.5  ng/mL) and was correlated with total plasma DTG was assessed by calculating the ratio of total CSF to total plasma concentration (Pearson’s correlation coefficient, r  =  0.9677, DTG concentrations (Q ), and BBB permeability was assessed DTG P < .0001). Consequently, the median plasma Fu was 0.66% by calculating the albumin quotient, as the ratio of CSF albumin DTG (range: 0.44%–0.94%), and Fu remained stable and was inde- (mg/L) to plasma albumin (g/L) concentrations [8]. A BBB was DTG pendent of total plasma DTG concentration. defined as damaged if Q was over 6.8 for patients younger than DTG concentration was lower in the CSF than in plasma, but 45 years and over 10.2 for patients over 45 years of age. in the same range as the unbound plasma DTG concentration. e m Th edian CSF DTG concentration was 9.6  ng/mL (range: Pharmacokinetic and Statistical Analysis 3.6–22.8  ng/mL). Q was 0.65% (range: 0.19%–5.11%). All The correlations between total plasma DTG concentrations, DTG patients had CSF DTG concentrations above the wild-type 50% unbound plasma DTG concentrations, and total CSF DTG inhibitory concentration in vitro (IC50  = 0.2 ng/mL) [9] and concentrations were analyzed with Pearson’s correlation anal- CNS above the CSF therapeutic concentration (estimated at 2.4 ng/ ysis. Similar analyses were performed to assess the correla- mL) [10]. e Th median CSF inhibitory quotient (IQ ) (ratio of tion between the diffusion of DTG into the CSF and albumin CSF CSF DTG concentration to IC50 ) was 48 (range: 18–114). quotient. CNS CSF DTG concentration was not correlated with total Wilcoxon rank sum tests were used to analyze CSF DTG plasma DTG concentration (Pearson’s correlation coefficient, concentrations as a function of CSF HIV-RNA levels (detect- r  =  0.5102, P  =  .0748) and there was no correlation between able versus undetectable). CSF DTG concentration and unbound DTG concentration All numerical variables are expressed as medians and ranges (Pearson’s correlation coefficient, r = 0.4748, P = .1011). unless otherwise indicated. The data were analyzed with GraphPad Prism (version 6.00 for MacOS, GraphPad Sowa ft re, DTG Diffusion into the CSF San Diego, CA). Differences were considered significant if P < .05. The median albumin quotient was 5.3 (range: 0.8–10.4). The RESULTS CSF diffusion of DTG (Q ) was significantly correlated with DTG albumin quotient (Pearson’s correlation coefficient, r = 0.6396, Characteristics of the Population P  =  .0186; Figure 1). Patients with damaged BBB (n = 3, 23%) Thirteen patients (5 women and 8 men) were enrolled in the have the higher CSF DTG concentrations. study. The median age of the patients was 46  years (range: CSF DTG concentrations did not differ significantly be- 39–56 years). All patients had at least 1 HCI: HIV encephalitis tween patients with and without a detectable CSF viral load (n  =  6), progressive multifocal leukoencephalopathy (PML) (P = .8835). (n = 4), cerebral toxoplasmosis (n = 2), or herpes simplex virus-2 encephalitis associated with PML (n = 1). The duration of the current ART regimen was 41  days (8–343  days) and median Table 1. Dolutegravir Concentrations in Plasma and Cerebrospinal Fluid CD4 cell count was 258/µL (range: 52–646/µL). The other anti- retroviral drugs administered together with DTG were the fol- Dolutegravir concentration Median (range) lowing: abacavir (ABC) + lamivudine (3TC) (n = 5); tenofovir Total plasma – ng/mL 1675 (137–5091) DF (TDF) + emtricitabine (FTC) + darunavir/ritonavir (DRV/r) Unbound plasma – ng/mL 9.2 (0.8–34.5) Fu – % 0.66 (0.44–0.94) (n = 4); ABC + 3TC + DRV/r (n = 2); ABC + 3TC + maraviroc DTG Total CSF – ng/mL 9.6 (3.6–22.8) (MVC) (n = 1); or TDF + FTC + DRV/r + MVC (n = 1). Twelve Q – % 0.65 (0.19–5.11) DTG patients received DTG once daily (50  mg/day); 1 patient re- IQ 48 (18–114) CSF ceived this drug twice daily (100 mg/day). Seven (54%) patients Abbreviations: CSF, cerebrospinal fluid; Fu , unbound fraction; IQ , CSF inhibitory quo- DTG CSF had an undetectable HIV plasma viral load and 8 (62%) had an tient; Q , total CSF to total plasma dolutegravir concentrations ratio. DTG 2 • ofid • BRIEF REPORT Downloaded from https://academic.oup.com/ofid/article-abstract/6/6/ofz174/5510470 by Ed 'DeepDyve' Gillespie user on 04 June 2019 6 drug administration. This good ability to diffuse also is con- sistent with the good placental transfer [12], which gives rise to questions in light of the last WHO statement on potential safety issue related to neural tube defects in infants born to women who were taking DTG at the time of conception and during early pregnancy [13]. This study has 2 main limitations due to real-life study. The number of patients included is small, but this is an obvious con- sequence of the need for lumbar puncture samples collected during routine care. Furthermore, heterogeneous ART back- bone regimens could influence the viral load level. Taken together, our findings indicate that DTG is present at therapeutic concentrations over the dosing interval in the CSF of all treatment-experienced patients with HCI, even if r = .6396 the BBB is intact and despite high levels of binding to plasma P = .0186 proteins. Therefore, DTG may have a real benefit in the control 0369 12 of HIV replication in the CNS. This control should help to limit CSF-to-Plasma albumin concentration ratio the local inflammatory response and HIV-induced neurotox- icity, thereby protecting individuals against HCI and favoring Figure 1. Evaluation of dolutegravir cerebrospinal fluid (CSF) diffusion. The CSF neurocognitive recovery. diffusion of dolutegravir was significantly correlated with albumin quotient. Acknowledgments DISCUSSION We gratefully acknowledge all of the patients participating in this study. Also, we are grateful for the active cooperation of the teams within the in- In this study, we evaluated if the diffusion of DTG is suffi- volved departments of Bicêtre Hospital. cient to obtain therapeutic concentrations in the CSF of HIV-1 Financial support. J.G. reports grants from Janssen and ViiV as well as per- sonal fees from Gilead. A.B.T. reports personal fees from Gilead, ViiV, Janssen, patients. Not only is this a real-life study, but, moreover, it in- Roche, Abbvie, and MSD. A.C. reports grants from Merck, Janssen, ViiV, and cluded patients who were treatment-experienced and presented personal fees from Gilead and Janssen. All other authors: none to declare. at least 1 HIV-related CNS impairment. Potential conifl cts of interest. All authors: No reported conflicts of in- terest. All authors have submitted the ICMJE Form for Disclosure of IQ were consistent with those reported in another pre- CSF Potential Conflicts of Interest. Conflicts that the editors consider relevant to vious study (median [range]), 48 (18–114) versus 66 (19–92) the content of the manuscript have been disclosed. [7], suggesting high levels of antiretroviral activity. Whatever the BBB status, DTG seems to have a sufficient capacity of dif- References fusion and, therefore, to have a benefit in medical management 1. Lorenzo-Redondo  R, Fryer  HR, Bedford  T, et  al. Persistent HIV-1 replication maintains the tissue reservoir during therapy. Nature 2016; 530:51–6. of HCI. 2. Anesten  B, Yilmaz  A, Hagberg  L, et  al. Blood-brain barrier integrity, intra- e CS Th F-to-plasma DTG concentration ratio (median, thecal immunoactivation, and neuronal injury in HIV. Neurol Neuroimmunol Neuroinflamm 2016; 3:e300. 0.65%) is highly consistent with the size of the Fu in plasma DTG 3. Simioni S, Cavassini M, Annoni JM, et al. Cognitive dysfunction in HIV patients (median, 0.66%). CSF diffusion of DTG was strongly correlated despite long-standing suppression of viremia. AIDS 2010; 24:1243–50. with albumin quotient (r  =  0.6396, P  =  .0186) suggesting that 4. González-Scarano F, Martín-García J. The neuropathogenesis of AIDS. Nat Rev Immunol 2005; 5:69–81. the CSF diffusion of DTG depends at least partly on the physical 5. World Health Organization. Updated Recommendations on First-Line and Second- integrity of the BBB, with greater damage to the BBB associated Line Antiretroviral Regimens and Post-Exposure Prophylaxis and Recommendations on Early Infant Diagnosis of HIV: Interim Guidance. (WHO/CDS/HIV/18.51). with higher levels of DTG in the CSF. This good diffusion prob- Geneva, Switzerland: World Health Organization; 2018. ably may explain part of the neuropsychiatric adverse effects 6. Molina  JM, Clotet  B, van  Lunzen  J, et  al.; FLAMINGO study team. Once-daily dolutegravir versus darunavir plus ritonavir for treatment-naive adults with observed in some patients with DTG [11]. HIV-1 infection (FLAMINGO): 96 week results from a randomised, open-label, e n Th ovelty of this study is our finding that increasing the phase 3b study. Lancet HIV 2015; 2:e127–36. 7. Letendre  SL, Mills  AM, Tashima  KT, et  al.; extended ING116070 study team. BBB permeability is associated to an increase of CSF diffusion ING116070: a study of the pharmacokinetics and antiviral activity of dolutegravir of DTG in treatment-experienced patients with HCI. Given in cerebrospinal fluid in HIV-1-infected, antiretroviral therapy-naive subjects. the observational nature of this study, ART regimens and sam- Clin Infect Dis 2014; 59:1032–7. 8. Link  H, Tibbling  G. Principles of albumin and IgG analyses in neurological pling times were heterogeneous, leading to the wide range of disorders. II. Relation of the concentration of the proteins in serum and cerebro- plasma DTG concentrations. However, this allows to be con- spinal fluid. Scand J Clin Lab Invest 1977; 37:391–6. 9. Kobayashi  M, Yoshinaga  T, Seki  T, et  al. In Vitro antiretroviral properties of S/ fident about the DTG diffusion whatever the treatment back- GSK1349572, a next-generation HIV integrase inhibitor. Antimicrob Agents bone and over a wide range of time delay between sampling and Chemother 2011; 55:813–21. BRIEF REPORT • ofid • 3 CSF-to-Plasma dolutegravir concentration ratio (%) Downloaded from https://academic.oup.com/ofid/article-abstract/6/6/ofz174/5510470 by Ed 'DeepDyve' Gillespie user on 04 June 2019 10. Min S, Sloan L, DeJesus E, et al. Antiviral activity, safety, and pharmacokinetics/ 12. Rimawi  BH, Johnson  E, Rajakumar  A, et  al. Pharmacokinetics and placental pharmacodynamics of dolutegravir as 10-day monotherapy in HIV-1-infected transfer of elvitegravir, dolutegravir, and other antiretrovirals during pregnancy. adults. AIDS 2011; 25:1737–45. Antimicrob Agents Chemother 2017; 61: pii:e02213–16. 11. Hill  AM, Mitchell  N, Hughes  S, Pozniak  AL. Risks of cardiovascular or central 13. W orld Health Organization. Statement on Dolutegravir: Potential Safety Issue Affecting nervous system adverse events and immune reconstitution inflammatory syn- Women Living With HIV Using Dolutegravir at the Time of Conception. Geneva, drome, for dolutegravir versus other antiretrovirals: meta-analysis of randomized Switzerland: World Health Organization; 2018. Available at: https://www.who.int/ trials. Curr Opin HIV AIDS 2018; 13:102–11. medicines/publications/drugalerts/Statement_on_DTG_18May_2018final.pdf. 4 • ofid • BRIEF REPORT http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Open Forum Infectious Diseases Oxford University Press

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

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Oxford University Press
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© The Author(s) 2019. Published by Oxford University Press on behalf of Infectious Diseases Society of America.
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DOI
10.1093/ofid/ofz174
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Abstract

Downloaded from https://academic.oup.com/ofid/article-abstract/6/6/ofz174/5510470 by Ed 'DeepDyve' Gillespie user on 04 June 2019 Open Forum Infectious Diseases BRIEF REPORT [2]. It also may be the cause of neurocognitive disorders in a Dolutegravir Cerebrospinal Fluid significant proportion of patients [3 ]. The role of the brain as Diffusion in HIV-1–Infected Patients a latent reservoir for HIV must be considered in the devel- opment of therapeutic strategies for eliminating HIV from with Central Nervous System infected subjects [4]. Impairment Dolutegravir (DTG) is increasingly being used in com- 1,2 3 2 4 Thibaut Gelé, Valérie Furlan, Anne-Marie Taburet, Coralie Pallier, bination with nucleoside/nucleotide reverse transcriptase 5 6,7,8 2,6 Pierre-Hadrien Becker, Cécile Goujard, Jacques Gasnault, 1,2,9,* 6,10,* inhibitors. Recently, the World Health Organization (WHO) Aurélie Barrail-Tran, and Antoine Chéret has even issued new antiretroviral (ART) treatment guidelines Department of Clinical Pharmacy, Assistance Publique-Hôpitaux de Paris, Hôpitaux Universitaires Paris-Sud, Hôpital Bicêtre, Le Kremlin-Bicêtre, France; CEA–Paris-Sud recommending DTG-based treatment as the preferred first-line University–INSERM U1184, IDMIT Infrastructure, Fontenay-aux-Roses, France; Department treatment option for all adults, adolescents, and children, in- of Pharmacology, Assistance Publique-Hôpitaux de Paris, Hôpitaux Universitaires Paris-Sud, Hôpital Bicêtre, Le Kremlin-Bicêtre, France; Department of Virology, Assistance Publique- cluding women and adolescent girls who have access to con- Hôpitaux de Paris, Hôpitaux Universitaires Paris-Sud, Hôpital Paul-Brousse, Villejuif, France; sistent and reliable contraception [5]. DTG is well tolerated and 5 6 Department of Biochemistry; Department of Internal Medicine, Assistance Publique- Hôpitaux de Paris, Hôpitaux Universitaires Paris-Sud, Hôpital Bicêtre, Le Kremlin-Bicêtre, rapidly inhibits viral replication [6]. 7 8 France; CESP, Paris-Sud University–INSERM U1018, Villejuif, France; College of Medicine, Following on from the study that has characterized the cere- Paris-Sud University, Le Kremlin-Bicêtre, France; College of Pharmacy, Paris-Sud University, brospinal fluid (CSF) diffusion of DTG in antiretroviral therapy– Châtenay-Malabry, France; Paris-Descartes University–INSERM U1016, CNRS 8104, Institut Cochin, Paris, France. naive, HIV-1–infected adults [7], we aimed to determine if DTG diffusion is also sufficient to reach effective concentrations This study aimed to determine dolutegravir cerebrospinal fluid in the CSF in treatment-experienced patients with HIV-related (CSF) diffusion in 13 patients with HIV-related cerebral impair - CNS (central nervous system) impairment (HCI). ment enrolled in a real-life observational study. Dolutegravir e p Th rimary endpoint is the evaluation of DTG CSF concen- median (range) CSF concentration [9.6 (3.6–22.8) ng/mL] tration in treatment-experienced patients with HCI. Secondary reached CSF therapeutic concentrations whatever the blood- brain barrier status and diffused in correlation with the albumin endpoints are to evaluate the DTG diffusion and its correlation quotient (P = .0186). with the albumin quotient used to evaluate BBB status. Keywords. cerebrospinal fluid; central nervous system diffusion; central nervous system impairment; dolutegravir; METHODS pharmacokinetics. Patients and Study Design All of the patients included in this monocenter, prospective, e m Th ajor obstacle to a functional cure for human immunode- single arm, open label, observational study were admitted to ficiency virus (HIV) infection is the persistence of a latent HIV the Neuro-HIV Rehabilitation Care Unit (Assistance Publique- reservoir. This residual viral replication results partly from the Hôpitaux de Paris, Hôpitaux Uuniversitaires Paris -Sud, Bicêtre existence of pharmacological sanctuaries largely impenetrable to Hospital, Le Kremlin-Bicêtre, France) between September 2015 drugs. A recent study showed that the virus can replicate in these and October 2016. Blood and CSF samples were collected simul- sanctuaries, in which there is less antiviral pressure, contributing taneously during routine care and at any time during the dosing to the continual replenishment of viral reservoirs [1]. interval. Plasma and CSF HIV-RNA levels were determined HIV is known to aeff ct the blood-brain barrier (BBB) by reverse transcriptase-polymerase chain reaction (RT-PCR) leading to intrathecal immunoactivation and neuronal injury (Abbott RealTime  M2000, detection threshold  =  40 copies/ mL [Abbott Laboratories, Abbott Park, IL]). For this research, monitoring was conducted on a bank comprising routine blood Received 16 November 2018; editorial decision 27 March 2019; accepted 17 May 2019. and CSF samples. Therefore, patient care did not differ from *A.B.-T. and A.C. contributed equally to this work. Correspondence: A.  Barrail-Tran, Doctor, Department of Clinical Pharmacy, Assistance usual care, thus the non-interventional nature of this research. Publique-Hôpitaux de Paris, Hôpitaux Universitaires Paris Sud, Hôpital Bicêtre, 78 Rue du French regulation did not require an ethic committee’s agree- Général Leclerc, Le Kremlin-Bicêtre, Ile-de-France 94270, France (aurelie.barrail-tran@aphp.fr). ® ment for use of health data or biobank, nor a written consent. Open Forum Infectious Diseases © The Author(s) 2019. Published by Oxford University Press on behalf of Infectious Diseases However, each patient admitted to the hospital received written Society of America. This is an Open Access article distributed under the terms of the Creative information stating that medical records and biological samples 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 drawn for care might be used for medical research. Each patient medium, provided the original work is not altered or transformed in any way, and that the had the right to express opposition; none of the patients who work is properly cited. For commercial re-use, please contact journals.permissions@oup.com participated in this study expressed opposition. DOI: 10.1093/ofid/ofz174 BRIEF REPORT • ofid • 1 Downloaded from https://academic.oup.com/ofid/article-abstract/6/6/ofz174/5510470 by Ed 'DeepDyve' Gillespie user on 04 June 2019 DTG Concentration and Diffusion undetectable HIV CSF viral load (<40 copies/mL). Only one pa- Bound and unbound plasma DTG were separated by ul- tient had an undetectable HIV CSF viral load associated with a trafiltration (Centrifree devices, cutoff, 30  kDa; Millipore, detectable HIV plasma viral load. For the patients with a detect- Molsheim, France). Total plasma, unbound plasma, and CSF able viral load, median plasma and CSF viral loads were 2.3 log DTG concentrations were determined with a quality control- copies/mL (range: 1.8–3.0 log copies/mL) and 2.8 log copies/ 10 10 validated method based on liquid chromatography-tandem mL (range: 1.7–4.8 log copies/mL), respectively. mass spectrometry (LC-MS/MS) (Acquity TQD-UPLC system, DTG Concentrations Waters Corp., Milford, MA ). Lower limits of quantification for Total plasma, unbound plasma, and total CSF DTG total plasma concentration was 2  ng/mL or unbound or CSF concentrations are shown in Table 1. Median plasma DTG con- DTG concentration was 0.5 ng/mL each. centration was 1,675  ng/mL (range: 137–5,091  ng/mL). The e un Th bound fraction (Fu ) was determined as the ratio of DTG median unbound DTG concentration was 9.2  ng/mL (range: unbound to total plasma DTG concentrations. DTG diffusion 0.8–34.5  ng/mL) and was correlated with total plasma DTG was assessed by calculating the ratio of total CSF to total plasma concentration (Pearson’s correlation coefficient, r  =  0.9677, DTG concentrations (Q ), and BBB permeability was assessed DTG P < .0001). Consequently, the median plasma Fu was 0.66% by calculating the albumin quotient, as the ratio of CSF albumin DTG (range: 0.44%–0.94%), and Fu remained stable and was inde- (mg/L) to plasma albumin (g/L) concentrations [8]. A BBB was DTG pendent of total plasma DTG concentration. defined as damaged if Q was over 6.8 for patients younger than DTG concentration was lower in the CSF than in plasma, but 45 years and over 10.2 for patients over 45 years of age. in the same range as the unbound plasma DTG concentration. e m Th edian CSF DTG concentration was 9.6  ng/mL (range: Pharmacokinetic and Statistical Analysis 3.6–22.8  ng/mL). Q was 0.65% (range: 0.19%–5.11%). All The correlations between total plasma DTG concentrations, DTG patients had CSF DTG concentrations above the wild-type 50% unbound plasma DTG concentrations, and total CSF DTG inhibitory concentration in vitro (IC50  = 0.2 ng/mL) [9] and concentrations were analyzed with Pearson’s correlation anal- CNS above the CSF therapeutic concentration (estimated at 2.4 ng/ ysis. Similar analyses were performed to assess the correla- mL) [10]. e Th median CSF inhibitory quotient (IQ ) (ratio of tion between the diffusion of DTG into the CSF and albumin CSF CSF DTG concentration to IC50 ) was 48 (range: 18–114). quotient. CNS CSF DTG concentration was not correlated with total Wilcoxon rank sum tests were used to analyze CSF DTG plasma DTG concentration (Pearson’s correlation coefficient, concentrations as a function of CSF HIV-RNA levels (detect- r  =  0.5102, P  =  .0748) and there was no correlation between able versus undetectable). CSF DTG concentration and unbound DTG concentration All numerical variables are expressed as medians and ranges (Pearson’s correlation coefficient, r = 0.4748, P = .1011). unless otherwise indicated. The data were analyzed with GraphPad Prism (version 6.00 for MacOS, GraphPad Sowa ft re, DTG Diffusion into the CSF San Diego, CA). Differences were considered significant if P < .05. The median albumin quotient was 5.3 (range: 0.8–10.4). The RESULTS CSF diffusion of DTG (Q ) was significantly correlated with DTG albumin quotient (Pearson’s correlation coefficient, r = 0.6396, Characteristics of the Population P  =  .0186; Figure 1). Patients with damaged BBB (n = 3, 23%) Thirteen patients (5 women and 8 men) were enrolled in the have the higher CSF DTG concentrations. study. The median age of the patients was 46  years (range: CSF DTG concentrations did not differ significantly be- 39–56 years). All patients had at least 1 HCI: HIV encephalitis tween patients with and without a detectable CSF viral load (n  =  6), progressive multifocal leukoencephalopathy (PML) (P = .8835). (n = 4), cerebral toxoplasmosis (n = 2), or herpes simplex virus-2 encephalitis associated with PML (n = 1). The duration of the current ART regimen was 41  days (8–343  days) and median Table 1. Dolutegravir Concentrations in Plasma and Cerebrospinal Fluid CD4 cell count was 258/µL (range: 52–646/µL). The other anti- retroviral drugs administered together with DTG were the fol- Dolutegravir concentration Median (range) lowing: abacavir (ABC) + lamivudine (3TC) (n = 5); tenofovir Total plasma – ng/mL 1675 (137–5091) DF (TDF) + emtricitabine (FTC) + darunavir/ritonavir (DRV/r) Unbound plasma – ng/mL 9.2 (0.8–34.5) Fu – % 0.66 (0.44–0.94) (n = 4); ABC + 3TC + DRV/r (n = 2); ABC + 3TC + maraviroc DTG Total CSF – ng/mL 9.6 (3.6–22.8) (MVC) (n = 1); or TDF + FTC + DRV/r + MVC (n = 1). Twelve Q – % 0.65 (0.19–5.11) DTG patients received DTG once daily (50  mg/day); 1 patient re- IQ 48 (18–114) CSF ceived this drug twice daily (100 mg/day). Seven (54%) patients Abbreviations: CSF, cerebrospinal fluid; Fu , unbound fraction; IQ , CSF inhibitory quo- DTG CSF had an undetectable HIV plasma viral load and 8 (62%) had an tient; Q , total CSF to total plasma dolutegravir concentrations ratio. DTG 2 • ofid • BRIEF REPORT Downloaded from https://academic.oup.com/ofid/article-abstract/6/6/ofz174/5510470 by Ed 'DeepDyve' Gillespie user on 04 June 2019 6 drug administration. This good ability to diffuse also is con- sistent with the good placental transfer [12], which gives rise to questions in light of the last WHO statement on potential safety issue related to neural tube defects in infants born to women who were taking DTG at the time of conception and during early pregnancy [13]. This study has 2 main limitations due to real-life study. The number of patients included is small, but this is an obvious con- sequence of the need for lumbar puncture samples collected during routine care. Furthermore, heterogeneous ART back- bone regimens could influence the viral load level. Taken together, our findings indicate that DTG is present at therapeutic concentrations over the dosing interval in the CSF of all treatment-experienced patients with HCI, even if r = .6396 the BBB is intact and despite high levels of binding to plasma P = .0186 proteins. Therefore, DTG may have a real benefit in the control 0369 12 of HIV replication in the CNS. This control should help to limit CSF-to-Plasma albumin concentration ratio the local inflammatory response and HIV-induced neurotox- icity, thereby protecting individuals against HCI and favoring Figure 1. Evaluation of dolutegravir cerebrospinal fluid (CSF) diffusion. The CSF neurocognitive recovery. diffusion of dolutegravir was significantly correlated with albumin quotient. Acknowledgments DISCUSSION We gratefully acknowledge all of the patients participating in this study. Also, we are grateful for the active cooperation of the teams within the in- In this study, we evaluated if the diffusion of DTG is suffi- volved departments of Bicêtre Hospital. cient to obtain therapeutic concentrations in the CSF of HIV-1 Financial support. J.G. reports grants from Janssen and ViiV as well as per- sonal fees from Gilead. A.B.T. reports personal fees from Gilead, ViiV, Janssen, patients. Not only is this a real-life study, but, moreover, it in- Roche, Abbvie, and MSD. A.C. reports grants from Merck, Janssen, ViiV, and cluded patients who were treatment-experienced and presented personal fees from Gilead and Janssen. All other authors: none to declare. at least 1 HIV-related CNS impairment. Potential conifl cts of interest. All authors: No reported conflicts of in- terest. All authors have submitted the ICMJE Form for Disclosure of IQ were consistent with those reported in another pre- CSF Potential Conflicts of Interest. Conflicts that the editors consider relevant to vious study (median [range]), 48 (18–114) versus 66 (19–92) the content of the manuscript have been disclosed. [7], suggesting high levels of antiretroviral activity. Whatever the BBB status, DTG seems to have a sufficient capacity of dif- References fusion and, therefore, to have a benefit in medical management 1. Lorenzo-Redondo  R, Fryer  HR, Bedford  T, et  al. Persistent HIV-1 replication maintains the tissue reservoir during therapy. Nature 2016; 530:51–6. of HCI. 2. Anesten  B, Yilmaz  A, Hagberg  L, et  al. Blood-brain barrier integrity, intra- e CS Th F-to-plasma DTG concentration ratio (median, thecal immunoactivation, and neuronal injury in HIV. Neurol Neuroimmunol Neuroinflamm 2016; 3:e300. 0.65%) is highly consistent with the size of the Fu in plasma DTG 3. Simioni S, Cavassini M, Annoni JM, et al. Cognitive dysfunction in HIV patients (median, 0.66%). 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Open Forum Infectious DiseasesOxford University Press

Published: Jun 1, 2019

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