Abstract
CINAMMON is a phase IV, open-label, single-arm, pilot study assessing maraviroc (MVC) in the central nervous system (CNS) when added to darunavir/ritonavir monotherapy (DRV/r) in virologically suppressed HIV-infected subjects. CCR5 tropic participants on DRV/r were recruited. Participants remained on DRV/r for 12 week (w) (control phase). MVC 150 mg qd was added w12–w36 (intervention phase). Lumbar puncture (LP) and neurocognitive function (Cogstate) examinations scheduled at baseline, w12 and w36; MRI before w12, again at w36. Primary endpoint was CSF inflammatory marker changes during intervention phase. Secondary endpoints included changes in NC function and MRI parameters. CSF/plasma DRV/r concentrations measured at w12 and w36, MVC at w36. Nineteen patients recruited, 15 completed (17M, 2F). Dropouts: headache (2), knee problem (could not attend, 1), personal reasons (1). Mean age (range) 45.4 years (27.2–65.1), 13/19 white, 10/19 MSM. No changes in selected CSF markers were seen w12–w36. Overall NC function did not improve w12–w36: total age adjusted z score improved by 0.27 (weighted paired t test; p = 0.11); for executive function only, age adjusted z score improved by 0.54 (p = 0.03). MRI brain parameters unchanged. DRV plasma:CSF concentration ratio unchanged between w12 (132) and w36 (112; p = 0.577, Wilcoxon signed-rank). MVC plasma:CSF concentration ratio was 35 at w36. No changes in neuroinflammatory markers seen. In this small study, addition of 24w MVC 150 mg qd to stable DRV/r monotherapy showed possible improvement in executive function with no global NC effect. Learning effect cannot be excluded. This effect should be further evaluated.
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09 January 2018
Due to a production error the bottom portion of Figure 1 was omitted. The corrected figure is given below.
References
Cogstate (2017) https://cogstate.com/cognitive-tests/. Accessed 27 April 2017
Abdulle (2002) Continuing intrathecal immunoactivation despite two years of effective antiretroviral therapy against HIV-1 infection. AIDS 16:2145–2149
Abdulle S, Mellgren Å, Brew B et al (2007) CSF neurofilament protein (NFL)—a marker of active HIV-related neurodegeneration. J Neurol 254(8):1026–1032. https://doi.org/10.1007/s00415-006-0481-8
Albert SM, Marder K, Dooneief G, Bell K, Sano M, Todak G, Stern Y (1995) Neuropsychologic impairment in early HIV infection: a risk factor for work disability. Arch Neurol 52(5):525–530. https://doi.org/10.1001/archneur.1995.00540290115027
Arenas-Pinto et al (2016) Neurocognitive function and neuroimaging markers in virologically suppressed HIV-positive patients randomised to ritonavir-boosted protease inhibitor monotherapy or standard combination ART: a cross-sectional sub-study from the PIVOT Trial. Clin Infect Dis 63(2):257–264. https://doi.org/10.1093/cid/ciw279
Avison MJ, Nath A, Berger JR (2002) Understanding pathogenesis and treatment of HIV dementia: a role for magnetic resonance? Trends Neurosci 25(9):468–473. https://doi.org/10.1016/S0166-2236(02)02234-8
Baker LM, Paul RH, Heaps-Woodruff JM, Chang JY, Ortega M, Margolin Z, Usher C, Basco B, Cooley S, Ances BM (2015) The effect of central nervous system penetration effectiveness of highly active antiretroviral therapy on neuropsychological performance and neuroimaging in HIV infected individuals. J NeuroImmune Pharmacol 10(3):487–492. https://doi.org/10.1007/s11481-015-9610-4
Brettschneider PA, Schottle D, Claus A, Riepe M, Tumani H (2006) The neurofilament heavy chain (NfH) in the cerebrospinal fluid diagnosis of Alzheimer’s disease. Dement Geriatr Cogn Disord 21:291–295
Brew BJ (1990) Cerebrospinal fluid neopterin in human immunodeficiency virus type 1 infection. Ann Neurol 28(4):556–560. https://doi.org/10.1002/ana.410280413
Brew BJ (1996) Predictive markers of AIDS dementia complex: CD4 cell count and cerebrospinal fluid concentrations of beta 2-microglobulin and neopterin. J Infect Dis 174(2):294–298. https://doi.org/10.1093/infdis/174.2.294
Burdo T, Weiffenbach A, Woods SP et al (2013 Jun) Elevated sCD163 in plasma but not cerebrospinal fluid is a marker of neurocognitive impairment in HIV infection. AIDS 1(9):27(9)–21395. https://doi.org/10.1097/QAD.0b013e32836010bd
Carroll A, Brew B (2017) HIV-Associated Neurocognitive Disorders: recent advances in pathogenesis, biomarkers, and treatment. F1000 Research 6:312 PMC. Web
Carvalhal A, Gill MJ, Letendre SL et al (2016) Central nervous system penetration effectiveness of antiretroviral drugs and neuropsychological impairment in the Ontario HIV Treatment Network Cohort Study. J Neuro-Oncol 22(3):349–357. https://doi.org/10.1007/s13365-015-0404-5
Cassol E, Misra V, Morgello S, Gabuzda D (2013) Applications and limitations of inflammatory biomarkers for studies on neurocognitive impairment in HIV infection. J NeuroImmune Pharmacol 8(5):1087–1097. https://doi.org/10.1007/s11481-013-9512-2
Cysique LA, Brew BJ (2011) Prevalence of nonconfounded HIV-associated neurocognitive impairment in the context of plasma HIV RNA suppression. J Neuro-Oncol 17:176–183
EACS Guidelines (2017) http://www.eacsociety.org/guidelines/eacs-guidelines/eacs-guidelines.html. Accessed 12 May 2017
Gates TM, Cysique LA, Siefried KJ, Chaganti J, Moffat KJ, Brew BJ (2016) Maraviroc-intensified combined antiretroviral therapy improves cognition in virally suppressed HIV-associated neurocognitive disorder. AIDS 30(4):591–600. https://doi.org/10.1097/QAD.0000000000000951
Gazzard B, Hill A, Anceau A (2011) Cost-efficacy analysis of the MONET trial using UK antiretroviral drug prices. Appl Health Econ Health Policy 9(4):217–223
Gisslén M, Hagberg L, Brew B et al (2007) Elevated cerebrospinal fluid neurofilament light protein concentrations predict the development of AIDS dementia complex. J Infect Dis 195(12):1774–1778. https://doi.org/10.1086/518043
Gray L, Roche M, Churchill MJ, Sterjovski J, Ellett A, Poumbourios P, Sheffief S, Wang B, Saksena N, Purcell DFJ, Wesselingh S, Cunningham A, Brew BJ, Gabuzda D, Gorry PR (2009) Tissue-specific sequence alterations in the human immunodeficiency virus type 1 envelope favoring CCR5 usage contribute to persistence of dual-tropic virus in the brain. J Virol 83(11):5430–5441. https://doi.org/10.1128/JVI.02648-08
Gutmann C, Cusini A, Gunthard HF et al (2010) Randomized controlled study demonstrating failure of LPV/r monotherapy in HIV: the role of compartment and CD4-nadir. AIDS 24(15):2347–2354. https://doi.org/10.1097/QAD.0b013e32833db9a1
Hagberg (2010) Cerebrospinal fluid neopterin: an informative biomarker of central nervous system immune activation in HIV-1 infection. AIDS Res Ther 7(1):15. https://doi.org/10.1186/1742-6405-7-15
Heaton RK, Clifford DB, Franklin DR Jr, Woods SP, Ake C, Vaida F et al (2010) HIV-associated neurocognitive disorders persist in the era of potent antiretroviral therapy: CHARTER study. Neurology 75(23):2087–2096. https://doi.org/10.1212/WNL.0b013e318200d727
Hileman CO, Funderburg NT (2017) Inflammation, immune activation, and antiretroviral therapy in HIV. Curr HIV/AIDS Rep 14(3):93–100. https://doi.org/10.1007/s11904-017-0356-x
Hinkin CH, Castellon SA, Durvasula RS, Hardy DJ, Lam MN, Mason KI, Thrasher D, Goetz MB, Stefaniak M (2002) Medication adherence among HIV+ adults: effects of cognitive dysfunction and regimen complexity. Neurology 59(12):1944–1950. https://doi.org/10.1212/01.WNL.0000038347.48137.67
Hu (1997) S100beta induces neuronal cell death through nitric oxide release from astrocytes. J Neurochem 69:2294–2301
Kelly KM, Beck SE, Metcalf Pate KA et al (2013) Neuroprotective maraviroc monotherapy in simian immunodeficiency virus-infected macaques: reduced replicating and latent SIV in the brain. AIDS 27(18):F21–F28. https://doi.org/10.1097/QAD.0000000000000074
Laubenberger J, Haussinger D, Bayer S, Thielemann S, Schneider B, Mundinger A et al (1996) HIV-related metabolic abnormalities in the brain: depiction with proton MR spectroscopy with short echo times. Radiology 199(3):805–810. https://doi.org/10.1148/radiology.199.3.8638009
Letendre S, Marquie-Beck J, Capparelli E, Best B, Clifford D, Collier AC, Gelman BB, McArthur JC, McCutchan JA, Morgello S, Simpson D, Grant I, Ellis RJ, CHARTER Group (2008) Validation of the CNS penetration-effectiveness rank for quantifying antiretroviral penetration into the central nervous system. Arch Neurol 65(1):65–70. https://doi.org/10.1001/archneurol.2007.31
Martin-Blondel G, Brassat D, Bauer J, Lassmann H, Liblau RS (2016) CCR5 blockade for neuroinflammatory diseases--beyond control of HIV. Nat Rev Neurol 12(2):95–105. https://doi.org/10.1038/nrneurol.2015.248
Mellgren Å, Price RW, Hagberg L et al (2007) Antiretroviral treatment reduces increased CSF neurofilament protein (NFL) in HIV-1 infection. J Neurol 254(8):1026–1032
Mora-Peris B, Croucher A, Else L et al (2013) Pharmacokinetic profile and safety of 150 mg of maraviroc dosed with 800/100 mg of darunavir/ritonavir all once daily, with and without nucleoside analogues, in HIV-infected subjects. J Antimicrob Chemother 68(6):1348–1353. https://doi.org/10.1093/jac/dkt006
Ndhlovu LC, Umaki T, Chew GM, Chow DC, Agsalda M, Kallianpur KJ, Paul R, Zhang G, Ho E, Hanks N, Nakamoto B, Shiramizu BT, Shikuma CM (2014) Treatment intensification with maraviroc (CCR5 antagonist) leads to declines in CD16-expressing monocytes in cART-suppressed chronic HIV-infected subjects and is associated with improvements in neurocognitive test performance: implications for HIV-associated neurocognitive disease (HAND). J Neuro-Oncol 20(6):571–582. https://doi.org/10.1007/s13365-014-0279-x
Okoli C, Siccardi M, Thomas-William S, Dufty N, Khonyongwa K, Ainsworth J, Watson J, Cook R, Gandhi K, Hickinbottom G, Owen A, Taylor S (2012) Once daily maraviroc 300 mg or 150 mg in combination with ritonavir-boosted darunavir 800/100 mg. J Antimicrob Chemother 67(3):671–674. https://doi.org/10.1093/jac/dkr493
Paton NI, Meynard JL, Pulido F, Arenas-Pinto A, Girard PM, Arribas J (2011) Inappropriate claim of ‘failure of ritonavir-boosted lopinavir monotherapy in HIV’ in the monotherapy Switzerland/ Thailand (MOST) trial. AIDS 25(3):393–394. https://doi.org/10.1097/QAD.0b013e328342fb7b
Paton NI, Stöhr W, Arenas-Pinto A, Fisher M, Williams I, Johnson M, Orkin C, Chen F, Lee V, Winston A, Gompels M, Fox J, Scott K, Dunn DT, Protease Inhibitor Monotherapy Versus Ongoing Triple Therapy (PIVOT) Trial Team (2015) Protease inhibitor monotherapy for long-term management of HIV infection: a randomised, controlled, open-label, non-inferiority trial. The Lancet HIV 2(10):e417–e426. https://doi.org/10.1016/S2352-3018(15)00176-9
Pemberton (2001) Cerebrospinal fluid S-100beta and its relationship with AIDS dementia complex. J Clin Virol 22:249–253
Pérez-Valero I, González-Baeza A, Estébanez M et al (2014) A prospective cohort study of neurocognitive function in aviremic HIV-infected patients treated with 1 or 3 antiretrovirals. Clin Infect Dis 59(11):1627–1634. https://doi.org/10.1093/cid/ciu640
Petzold et al (May 2003) Quantification of neurodegeneration by measurement of brain-specific proteins. J Neuroimmunol 138(1):45–48. https://doi.org/10.1016/S0165-5728(03)00092-4
Robertson KR, Smurzynski M, Parsons TD, Wu K, Bosch RJ, Wu J, McArthur JC, Collier AC, Evans SR, Ellis RJ (2007) The prevalence and incidence of neurocognitive impairment in the HAART era. AIDS 21(14):1915–1921. https://doi.org/10.1097/QAD.0b013e32828e4e27
Roche M, Salimi H, Duncan R, Wilkinson BL, Chikere K, Moore MS, Webb NE, Zappi H, Sterjovski J, Flynn JK, Ellett A, Gray LR, Lee B, Jubb B, Westby M, Ramsland PA, Lewin SR, Payne RJ, Churchill MJ, Gorry PR (2013) A common mechanism of clinical HIV-1 resistance to the CCR5 antagonist maraviroc despite divergent resistance levels and lack of common gp120 resistance mutations. Retro- virology 10(1):43. https://doi.org/10.1186/1742-4690-10-43
Salvan AM, Vion-Dury J, Confort-Gouny S, Nicoli F, Lamoureux S, Cozzone PJ (1997a) Cerebral metabolic alterations in human immunodeficiency virus-related encephalopathy detected by proton magnetic resonance spectroscopy. Comparison between sequences using short and long echo times. Investig Radiol 32(8):485–495. https://doi.org/10.1097/00004424-199708000-00008
Salvan AM, Vion-Dury J, Confort-Gouny S, Nicoli F, Lamoureux S, Cozzone PJ (1997b) Brain proton magnetic resonance spectroscopy in HIV-related encephalopathy: identification of evolving metabolic patterns in relation to dementia and therapy. AIDS Res Hum Retrovir 13(12):1055–1066. https://doi.org/10.1089/aid.1997.13.1055
Saylor D, Dickens A, Sacktor N et al (2016) HIV-associated neurocognitive disorder—pathogenesis and prospects for treatment. Nat Rev Neurol 12(4):234–248. https://doi.org/10.1038/nrneurol.2016.27
Schweinsburg BC, Taylor MJ, Alhassoon OM, Gonzalez R, Brown GG, Ellis RJ et al (2005) Brain mitochondrial injury in human immunodeficiency virus-seropositive (HIV+) individuals taking nucleoside reverse transcriptase inhibitors. J Neuro-Oncol 11:356–364
Stanley (1994) Glial cytokines as neuropathogenic factors in HIV infection: pathogenic similarities to Alzheimer’s disease. Neuropathol Exp Neurol 53(3):231–238. https://doi.org/10.1097/00005072-199405000-00003
Tiraboschi JM, Niubo J, Curto J, Podzamczer D (2010) Maraviroc concentrations in cerebrospinal fluid in HIV-infected subjects. J Acquir Immune Defic Syndr 55(5):606–609. https://doi.org/10.1097/QAI.0b013e3181ef70fe
Tiraboschi JM, Muñoz-Moreno JA, Puertas MC, Alonso-Villaverde C, Prats A, Ferrer E, Rozas N, Maso M, Ouchi D, Martinez-Picado J, Podzamczer D (2015) Viral and inflammatory markers in cerebrospinal fluid of patients with HIV-1-associated neurocognitive impairment during antiretroviral treatment switch. HIV Med 16(6):388–392. https://doi.org/10.1111/hiv.12243
Towgood KJ, Pitkanen M, Kulasegaram R, Fradera A, Kumar A, Soni S, Sibtain NA, Reed L, Bradbeer C, Barker GJ, Kopelman MD (2011) Mapping the brain in younger and older asymptomatic HIV-1 men: frontal volume changes in the absence of other cortical or diffusion tensor abnormalities. Cortex 48(2):230–241. https://doi.org/10.1016/j.cortex.2011.03.006
Urenjak J, Williams SR, Gadian DG, Noble M (1992) Specific expression of N-acetylaspartate in neurons, oligodendrocyte-type-2 astrocyte progenitors, and immature oligodendrocytes in vitro. J Neurochem 59(1):55–61. https://doi.org/10.1111/j.1471-4159.1992.tb08875.x
Wilkie FL, Goodkin K, Eisdorfer C, Feaster D, Morgan R, Fletcher MA, Blaney N, Baum M, Szapocznik J (1998) Mild cognitive impairment and risk of mortality in HIV-1 infection. J Neuropsychiatry Clin Neurosci 10(2):125–132. https://doi.org/10.1176/jnp.10.2.125
Woods SP, Moore DJ, Weber E, Grant I et al (2009) Cognitive neuropsychology of HIV-associated neurocognitive disorders. Neuropsychol Rev 19(2):152–168. https://doi.org/10.1007/s11065-009-9102-5
Yilmaz A, Watson V, Else L, Gisslèn M (2009) Cerebrospinal fluid maraviroc concentrations in HIV-1 infected patients. AIDS 23(18):2537–2540. https://doi.org/10.1097/QAD.0b013e328333ae0e
Yilmaz A, Verhofstede C, Davolio A, Watson V, Hagberg L, Fuchs D, Svennerholm B, Gisslén M (2010) Treatment intensification has no effect on the HIV-1 central nervous system infection in patients on suppressive antiretroviral therapy. J Acquir Immune Defic Syndr 55(5):590–596. https://doi.org/10.1097/QAI.0b013e3181f5b3d1
Yoshioka (1992) Simultaneous detection of ferritin and HIV-1 in reactive microglia. Acta Neuropathol 84(3):297–306
Acknowledgements
Many thanks to all of the participants and staff in this study in both London and Barcelona. CINAMMON (SSAT046) was funded by ViiV Healthcare and supported by Pfizer. The study sponsor was the St Stephen’s AIDS Trust (www.ssat.org.uk).
Thanks also to the following people for their help and support, including analyses of the neuroinflammatory markers and imaging: David Back, Miles Chapman, Roger Chinn, Dietmar Fuchs, Chris Higgs, Paul Holmes, Lesley Honeyfield, Zeenat Karolia, Gary Lo, Michael Lunn, Michael Rayment, Alex Rovira and Adam Waldmann.
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A correction to this article is available online at https://doi.org/10.1007/s13365-017-0613-1.
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Barber, T.J., Imaz, A., Boffito, M. et al. CSF inflammatory markers and neurocognitive function after addition of maraviroc to monotherapy darunavir/ritonavir in stable HIV patients: the CINAMMON study. J. Neurovirol. 24, 98–105 (2018). https://doi.org/10.1007/s13365-017-0600-6
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DOI: https://doi.org/10.1007/s13365-017-0600-6