Plasma concentration of neurofilament light chain protein decreases after switching from tenofovir disoproxil fumarate to tenofovir alafenamide fumarate


Autoři: Linn Hermansson aff001;  Aylin Yilmaz aff001;  Richard W. Price aff003;  Staffan Nilsson aff004;  Scott McCallister aff005;  Tariro Makadzange aff005;  Moupali Das aff005;  Henrik Zetterberg aff006;  Kaj Blennow aff005;  Magnus Gisslen aff001
Působiště autorů: Department of Infectious Diseases, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden aff001;  Region Västra Götaland, Sahlgrenska University Hospital, Department of Infectious Diseases, Gothenburg, Sweden aff002;  Department of Neurology, University of California, San Francisco, United States of America aff003;  Mathematical Sciences, Chalmers University of Technology, Gothenburg, Sweden aff004;  Gilead Sciences Inc, Institute of Neuroscience and Physiology, Foster City, California, United States of America aff005;  Department of Psychiatry and Neurochemistry, University of Gothenburg, Gothenburg, Sweden aff006;  Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden aff007;  Department of Neurodegenerative Disease, UCL Institute of Neurology, Queen Square, London, United Kingdom aff008;  UK Dementia Research Institute, UCL, London, United Kingdom aff009
Vyšlo v časopise: PLoS ONE 14(12)
Kategorie: Research Article
doi: 10.1371/journal.pone.0226276

Souhrn

Background

Because tenofovir alafenamide (TAF) leads to significantly lower plasma tenofovir concentrations than tenofovir disoproxil fumarate (TDF) and is a stronger substrate for P-glycoprotein (P-gp) than TDF, TAF could lead to decreased central nervous system (CNS) tenofovir exposure than TDF. We aimed to determine if switching from TDF to TAF increases the risk of neuronal injury, by quantifying plasma levels of neurofilament light protein (NfL), a sensitive marker of neuronal injury in HIV CNS infection.

Methods

Plasma NfL concentration was measured at baseline, week 24, and week 84 in stored plasma samples from 416 participants (272 switching to elvitegravir (E)/cobicistat (C)/emtricitabine (F)/TAF and 144 continuing E/C/F/TDF) enrolled in the randomized, active-controlled, multicenter, open-label, noninferiority Gilead GS-US-292-0109 trial.

Results

While plasma NfL levels in both groups were within the normal range, we found a small but significant decrease in the E/C/F/TAF arm after 84 weeks from a geometric mean of 9.3 to 8.8 pg/mL (5.4% decline, 95% CI 2.0–8.4, p = 0.002). This change was significantly different (p = 0.001) from that of the E/C/F/TDF arm, in which plasma NfL concentration changed from 9.7 pg/mL at baseline to 10.2 pg/mL at week 84 (5.8% increase, 95% CI -0.8–12.9, p = 0.085). This increase is in line with what could be expected in normal ageing. Plasma NfL concentrations significantly correlated with age. No correlation was found between plasma NfL and serum creatinine.

Conclusions

We found no biomarker evidence of CNS injury when switching from TDF to TAF. It is unclear whether the small decrease in plasma NfL found after switch to TAF is of any clinical relevance, particularly with plasma NfL levels in both arms remaining within the limits found in HIV-negative controls. These results indicate that switching from TDF to TAF appears safe with regard to neuronal injury.

Klíčová slova:

Blood plasma – Central nervous system – Cerebrospinal fluid – Creatinine – HIV infections – Immune activation – Macrophages – Plasma proteins


Zdroje

1. Burdo TH, Lackner A, Williams KC. Monocyte/macrophages and their role in HIV neuropathogenesis. Immunol Rev. 2013;254(1):102–13. doi: 10.1111/imr.12068 23772617

2. Gisslen M, Chiodi F, Fuchs D, Norkrans G, Svennerholm B, Wachter H, et al. Markers of immune stimulation in the cerebrospinal fluid during HIV infection: a longitudinal study. Scand J Infect Dis. 1994;26(5):523–33. doi: 10.3109/00365549409011810 7855550

3. Kaul M, Garden GA, Lipton SA. Pathways to neuronal injury and apoptosis in HIV-associated dementia. Nature. 2001;410(6831):988–94. doi: 10.1038/35073667 11309629

4. Ulfhammer G, Eden A, Mellgren A, Fuchs D, Zetterberg H, Hagberg L, et al. Persistent central nervous system immune activation following more than 10 years of effective HIV antiretroviral treatment. AIDS. 2018;32(15):2171–8. doi: 10.1097/QAD.0000000000001950 30005007

5. Yilmaz A, Yiannoutsos CT, Fuchs D, Price RW, Crozier K, Hagberg L, et al. Cerebrospinal fluid neopterin decay characteristics after initiation of antiretroviral therapy. J Neuroinflammation. 2013;10:62. doi: 10.1186/1742-2094-10-62

6. Petzold A. Neurofilament phosphoforms: surrogate markers for axonal injury, degeneration and loss. J Neurol Sci. 2005;233(1–2):183–98. doi: 10.1016/j.jns.2005.03.015 15896809

7. Hjalmarsson C, Bjerke M, Andersson B, Blennow K, Zetterberg H, Aberg ND, et al. Neuronal and glia-related biomarkers in cerebrospinal fluid of patients with acute ischemic stroke. J Cent Nerv Syst Dis. 2014;6:51–8. doi: 10.4137/JCNSD.S13821 24932109

8. Lu CH, Macdonald-Wallis C, Gray E, Pearce N, Petzold A, Norgren N, et al. Neurofilament light chain: A prognostic biomarker in amyotrophic lateral sclerosis. Neurology. 2015;84(22):2247–57. doi: 10.1212/WNL.0000000000001642 25934855

9. Rojas JC, Karydas A, Bang J, Tsai RM, Blennow K, Liman V, et al. Plasma neurofilament light chain predicts progression in progressive supranuclear palsy. Annals of clinical and translational neurology. 2016;3(3):216–25. doi: 10.1002/acn3.290 27042681

10. Bergman J, Dring A, Zetterberg H, Blennow K, Norgren N, Gilthorpe J, et al. Neurofilament light in CSF and serum is a sensitive marker for axonal white matter injury in MS. Neurology(R) neuroimmunology & neuroinflammation. 2016;3(5):e271.

11. Hakansson I, Tisell A, Cassel P, Blennow K, Zetterberg H, Lundberg P, et al. Neurofilament light chain in cerebrospinal fluid and prediction of disease activity in clinically isolated syndrome and relapsing-remitting multiple sclerosis. Eur J Neurol. 2017;24(5):703–12. doi: 10.1111/ene.13274 28261960

12. Khalil M, Teunissen CE, Otto M, Piehl F, Sormani MP, Gattringer T, et al. Neurofilaments as biomarkers in neurological disorders. Nat Rev Neurol. 2018;14(10):577–89. doi: 10.1038/s41582-018-0058-z 30171200

13. Yilmaz A, Blennow K, Hagberg L, Nilsson S, Price RW, Schouten J, et al. Neurofilament light chain protein as a marker of neuronal injury: review of its use in HIV-1 infection and reference values for HIV-negative controls. Expert Rev Mol Diagn. 2017;17(8):761–70. doi: 10.1080/14737159.2017.1341313 28598205

14. Abdulle S, Mellgren A, Brew BJ, Cinque P, Hagberg L, Price RW, et al. CSF neurofilament protein (NfL)—a marker of active HIV-related neurodegeneration. J Neurol. 2007;254(8):1026–32. doi: 10.1007/s00415-006-0481-8 17420923

15. Jessen Krut J, Mellberg T, Price RW, Hagberg L, Fuchs D, Rosengren L, et al. Biomarker evidence of axonal injury in neuroasymptomatic HIV-1 patients. PLoS One. 2014;9(2):e88591. doi: 10.1371/journal.pone.0088591 24523921

16. Mellgren A, Price RW, Hagberg L, Rosengren L, Brew BJ, Gisslen M. Antiretroviral treatment reduces increased CSF neurofilament protein (NfL) in HIV-1 infection. Neurology. 2007;69(15):1536–41. doi: 10.1212/01.wnl.0000277635.05973.55 17923616

17. van Zoest RA, Underwood J, De Francesco D, Sabin CA, Cole JH, Wit FW, et al. Structural Brain Abnormalities in Successfully Treated HIV Infection: Associations With Disease and Cerebrospinal Fluid Biomarkers. J Infect Dis. 2017;217(1):69–81. doi: 10.1093/infdis/jix553 29069436

18. Gisslen M, Price RW, Andreasson U, Norgren N, Nilsson S, Hagberg L, et al. Plasma Concentration of the Neurofilament Light Protein (NfL) is a Biomarker of CNS Injury in HIV Infection: A Cross-Sectional Study. EBioMedicine. 2016;3:135–40. doi: 10.1016/j.ebiom.2015.11.036 26870824

19. Piehl F, Kockum I, Khademi M, Blennow K, Lycke J, Zetterberg H, et al. Plasma neurofilament light chain levels in patients with MS switching from injectable therapies to fingolimod. Mult Scler. 2018;24(8):1046–54. doi: 10.1177/1352458517715132 28627962

20. Hansson O, Janelidze S, Hall S, Magdalinou N, Lees AJ, Andreasson U, et al. Blood-based NfL: A biomarker for differential diagnosis of parkinsonian disorder. Neurology. 2017;88(10):930–7. doi: 10.1212/WNL.0000000000003680 28179466

21. Byrne LM, Rodrigues FB, Blennow K, Durr A, Leavitt BR, Roos RAC, et al. Neurofilament light protein in blood as a potential biomarker of neurodegeneration in Huntington's disease: a retrospective cohort analysis. Lancet Neurol. 2017;16(8):601–9. doi: 10.1016/S1474-4422(17)30124-2 28601473

22. Mattsson N, Andreasson U, Zetterberg H, Blennow K, Alzheimer's Disease Neuroimaging I. Association of Plasma Neurofilament Light With Neurodegeneration in Patients With Alzheimer Disease. JAMA Neurol. 2017;74(5):557–66. doi: 10.1001/jamaneurol.2016.6117 28346578

23. Ruane PJ, Dejesus E, Berger D, Markowitz M, Bredeek UF, Callebaut C, et al. Antiviral activity, safety, and pharmacokinetics/pharmacodynamics of tenofovir alafenamide as 10-day monotherapy in HIV-1-positive adults. J Acquir Immune Defic Syndr. 2013;63(4):449–55. doi: 10.1097/QAI.0b013e3182965d45 23807155

24. Lee WA, He G-X, Eisenberg E, Cihlar T, Swaminathan S, Mulato A, et al. Selective Intracellular Activation of a Novel Prodrug of the Human Immunodeficiency Virus Reverse Transcriptase Inhibitor Tenofovir Leads to Preferential Distribution and Accumulation in Lymphatic Tissue. Antimicrob Agents Chemother. 2005;49(5):1898. doi: 10.1128/AAC.49.5.1898-1906.2005 15855512

25. Mills A, Arribas JR, Andrade-Villanueva J, DiPerri G, Van Lunzen J, Koenig E, et al. Switching from tenofovir disoproxil fumarate to tenofovir alafenamide in antiretroviral regimens for virologically suppressed adults with HIV-1 infection: a randomised, active-controlled, multicentre, open-label, phase 3, non-inferiority study. The Lancet Infectious Diseases. 2016;16(1):43–52. doi: 10.1016/S1473-3099(15)00348-5 26538525

26. DeJesus E, Haas B, Segal-Maurer S, Ramgopal MN, Mills A, Margot N, et al. Superior Efficacy and Improved Renal and Bone Safety After Switching from a Tenofovir Disoproxil Fumarate- to a Tenofovir Alafenamide-Based Regimen Through 96 Weeks of Treatment. AIDS Res Hum Retroviruses. 2018;34(4):337–42. doi: 10.1089/AID.2017.0203 29368537

27. Begley R, Das M, Zhong L, Ling J, Kearney BP, Custodio JM. Pharmacokinetics of Tenofovir Alafenamide When Coadministered With Other HIV Antiretrovirals. J Acquir Immune Defic Syndr. 2018;78(4):465–72. doi: 10.1097/QAI.0000000000001699 29649076

28. van Gelder J, Deferme S, Naesens L, De Clercq E, van den Mooter G, Kinget R, et al. Intestinal absorption enhancement of the ester prodrug tenofovir disoproxil fumarate through modulation of the biochemical barrier by defined ester mixtures. Drug Metab Dispos. 2002;30(8):924–30. doi: 10.1124/dmd.30.8.924 12124311

29. Lepist EI, Phan TK, Roy A, Tong L, MacLennan K, Murray B, et al. Cobicistat boosts the intestinal absorption of transport substrates, including HIV protease inhibitors and GS-7340, in vitro. Antimicrob Agents Chemother. 2012;56(10):5409–13. doi: 10.1128/AAC.01089-12 22850510

30. Storch CH, Theile D, Lindenmaier H, Haefeli WE, Weiss J. Comparison of the inhibitory activity of anti-HIV drugs on P-glycoprotein. Biochem Pharmacol. 2007;73(10):1573–81. doi: 10.1016/j.bcp.2007.01.027 17328866

31. Ocque AJ, Hagler CE, Morse GD, Letendre SL, Ma Q. Development and validation of an LC-MS/MS assay for tenofovir and tenofovir alafenamide in human plasma and cerebrospinal fluid. J Pharm Biomed Anal. 2018;156:163–9. doi: 10.1016/j.jpba.2018.04.035 29709783

32. Best BM, Letendre SL, Koopmans P, Rossi SS, Clifford DB, Collier AC, et al. Low cerebrospinal fluid concentrations of the nucleotide HIV reverse transcriptase inhibitor, tenofovir. J Acquir Immune Defic Syndr. 2012;59(4):376–81. doi: 10.1097/QAI.0b013e318247ec54 22217676

33. Anthonypillai C, Gibbs JE, Thomas SA. The distribution of the anti-HIV drug, tenofovir (PMPA), into the brain, CSF and choroid plexuses. Cerebrospinal fluid research. 2006;3:1. doi: 10.1186/1743-8454-3-1 16390539

34. Takasawa K, Terasaki T, Suzuki H, Ooie T, Sugiyama Y. Distributed model analysis of 3'-azido-3'-deoxythymidine and 2',3'-dideoxyinosine distribution in brain tissue and cerebrospinal fluid. J Pharmacol Exp Ther. 1997;282(3):1509–17. 9316866

35. Bam RA, Birkus G, Babusis D, Cihlar T, Yant SR. Metabolism and antiretroviral activity of tenofovir alafenamide in CD4+ T-cells and macrophages from demographically diverse donors. Antivir Ther. 2014;19(7):669–77. doi: 10.3851/IMP2767 24625459

36. Yilmaz A, Verhofstede C, D'Avolio A, Watson V, Hagberg L, Fuchs D, et al. Treatment intensification has no effect on the HIV-1 central nervous system infection in patients on suppressive antiretroviral therapy. J Acquir Immune Defic Syndr. 2010;55(5):590–6. doi: 10.1097/QAI.0b013e3181f5b3d1 20847699

37. Dahl V, Lee E, Peterson J, Spudich SS, Leppla I, Sinclair E, et al. Raltegravir treatment intensification does not alter cerebrospinal fluid HIV-1 infection or immunoactivation in subjects on suppressive therapy. J Infect Dis. 2011;204(12):1936–45. doi: 10.1093/infdis/jir667 22021620

38. Robertson K, Liner J, Meeker RB. Antiretroviral neurotoxicity. J Neurovirol. 2012;18(5):388–99. doi: 10.1007/s13365-012-0120-3 22811264

39. Kurella M, Chertow GM, Fried LF, Cummings SR, Harris T, Simonsick E, et al. Chronic kidney disease and cognitive impairment in the elderly: the health, aging, and body composition study. J Am Soc Nephrol. 2005;16(7):2127–33. doi: 10.1681/ASN.2005010005 15888561

40. Seliger SL, Wendell CR, Waldstein SR, Ferrucci L, Zonderman AB. Renal function and long-term decline in cognitive function: the Baltimore Longitudinal Study of Aging. Am J Nephrol. 2015;41(4–5):305–12. doi: 10.1159/000430922 26201453

41. Anderson AM, Easley KA, Kasher N, Franklin D, Heaton RK, Zetterberg H, et al. Neurofilament light chain in blood is negatively associated with neuropsychological performance in HIV-infected adults and declines with initiation of antiretroviral therapy. J Neurovirol. 2018;24(6):695–701. doi: 10.1007/s13365-018-0664-y 30105502


Článek vyšel v časopise

PLOS One


2019 Číslo 12