Treatment of HIV in the Central Nervous System

Abstract

Central nervous system (CNS) infection is an important part of systemic human immunodeficiency disease (HIV) infection. It is most often asymptomatic, but can sometimes lead to severe neurologic disease, particularly in advanced stages of immunosuppression. CNS HIV infection usually responds well to antiretroviral treatment, but there are concerns that treatment may not always be fully effective in treating or preventing milder CNS disease and that it, under certain circumstances, might be important to consider antiretroviral drug distribution and effects within the CNS.

Keywords

human immunodeficiency disease - antiretroviral treatment - central nervous system

• References

• 1 Davis LE, Hjelle BL, Miller VE , et al. Early viral brain invasion in iatrogenic human immunodeficiency virus infection. Neurology 1992; 42 (9) 1736-1739
• 2 Spudich S, Gisslen M, Hagberg L , et al. Central nervous system immune activation characterizes primary human immunodeficiency virus 1 infection even in participants with minimal cerebrospinal fluid viral burden. J Infect Dis 2011; 204 (5) 753-760
• 3 Valcour V, Chalermchai T, Sailasuta N , et al; RV254/SEARCH 010 Study Group. Central nervous system viral invasion and inflammation during acute HIV infection. J Infect Dis 2012; 206 (2) 275-282
• 4 Conrad AJ, Schmid P, Syndulko K , et al. Quantifying HIV-1 RNA using the polymerase chain reaction on cerebrospinal fluid and serum of seropositive individuals with and without neurologic abnormalities. J Acquir Immune Defic Syndr Hum Retrovirol 1995; 10 (4) 425-435
• 5 Gisslén M, Fuchs D, Svennerholm B, Hagberg L. Cerebrospinal fluid viral load, intrathecal immunoactivation, and cerebrospinal fluid monocytic cell count in HIV-1 infection. J Acquir Immune Defic Syndr 1999; 21 (4) 271-276
• 6 Spudich SS, Nilsson AC, Lollo ND , et al. Cerebrospinal fluid HIV infection and pleocytosis: relation to systemic infection and antiretroviral treatment. BMC Infect Dis 2005; 5: 98
• 7 Price RW, Brew BJ. The AIDS dementia complex. J Infect Dis 1988; 158 (5) 1079-1083
• 8 Portegies P, de Gans J, Lange JM , et al. Declining incidence of AIDS dementia complex after introduction of zidovudine treatment. BMJ 1989; 299 (6703) 819-821
• 9 Brew BJ, Rosenblum M, Price RW. AIDS dementia complex and primary HIV brain infection. J Neuroimmunol 1988; 20 (2-3) 133-140
• 10 Heaton RK, Clifford DB, Franklin Jr DR , et al; CHARTER Group. HIV-associated neurocognitive disorders persist in the era of potent antiretroviral therapy: CHARTER Study. Neurology 2010; 75 (23) 2087-2096
• 11 Heaton RK, Franklin DR, Ellis RJ , et al; CHARTER Group; HNRC Group. HIV-associated neurocognitive disorders before and during the era of combination antiretroviral therapy: differences in rates, nature, and predictors. J Neurovirol 2011; 17 (1) 3-16
• 12 Sinclair E, Ronquillo R, Lollo N , et al. Antiretroviral treatment effect on immune activation reduces cerebrospinal fluid HIV-1 infection. J Acquir Immune Defic Syndr 2008; 47 (5) 544-552
• 13 Yilmaz A, Price RW, Gisslén M. Antiretroviral drug treatment of CNS HIV-1 infection. J Antimicrob Chemother 2012; 67 (2) 299-311
• 14 Engelhardt B, Sorokin L. The blood-brain and the blood-cerebrospinal fluid barriers: function and dysfunction. Semin Immunopathol 2009; 31 (4) 497-511
• 15 Chiodi F, Keys B, Albert J , et al. Human immunodeficiency virus type 1 is present in the cerebrospinal fluid of a majority of infected individuals. J Clin Microbiol 1992; 30 (7) 1768-1771
• 16 Schnell G, Spudich S, Harrington P, Price RW, Swanstrom R. Compartmentalized human immunodeficiency virus type 1 originates from long-lived cells in some subjects with HIV-1-associated dementia. PLoS Pathog 2009; 5 (4) e1000395
• 17 Schnell G, Price RW, Swanstrom R, Spudich S. Compartmentalization and clonal amplification of HIV-1 variants in the cerebrospinal fluid during primary infection. J Virol 2010; 84 (5) 2395-2407
• 18 Hazenberg MD, Otto SA, Wit FW, Lange JM, Hamann D, Miedema F. Discordant responses during antiretroviral therapy: role of immune activation and T cell redistribution rather than true CD4 T cell loss. AIDS 2002; 16 (9) 1287-1289
• 19 Ransohoff RM, Kivisäkk P, Kidd G. Three or more routes for leukocyte migration into the central nervous system. Nat Rev Immunol 2003; 3 (7) 569-581
• 20 Smit TK, Brew BJ, Tourtellotte W, Morgello S, Gelman BB, Saksena NK. Independent evolution of human immunodeficiency virus (HIV) drug resistance mutations in diverse areas of the brain in HIV-infected patients, with and without dementia, on antiretroviral treatment. J Virol 2004; 78 (18) 10133-10148
• 21 Cysique LA, Maruff P, Brew BJ. Variable benefit in neuropsychological function in HIV-infected HAART-treated patients. Neurology 2006; 66 (9) 1447-1450
• 22 Ellis RJ, Badiee J, Vaida F , et al; CHARTER Group. CD4 nadir is a predictor of HIV neurocognitive impairment in the era of combination antiretroviral therapy. AIDS 2011; 25 (14) 1747-1751
• 23 Abdulle S, Mellgren A, Brew BJ , et al. CSF neurofilament protein (NFL) — a marker of active HIV-related neurodegeneration. J Neurol 2007; 254 (8) 1026-1032
• 24 Crum-Cianflone NF, Moore DJ, Letendre S , et al. Low prevalence of neurocognitive impairment in early diagnosed and managed HIV-infected persons. Neurology 2013; 80 (4) 371-379
• 25 Sailasuta N, Ross W, Ananworanich J , et al; RV254/SEARCH 010 protocol teams. Change in brain magnetic resonance spectroscopy after treatment during acute HIV infection. PLoS ONE 2012; 7 (11) e49272
• 26 Anthony IC, Ramage SN, Carnie FW, Simmonds P, Bell JE. Influence of HAART on HIV-related CNS disease and neuroinflammation. J Neuropathol Exp Neurol 2005; 64 (6) 529-536
• 27 Edén A, Price RW, Spudich S, Fuchs D, Hagberg L, Gisslén M. Immune activation of the central nervous system is still present after >4 years of effective highly active antiretroviral therapy. J Infect Dis 2007; 196 (12) 1779-1783
• 28 Harezlak J, Buchthal S, Taylor M , et al; HIV Neuroimaging Consortium. Persistence of HIV-associated cognitive impairment, inflammation, and neuronal injury in era of highly active antiretroviral treatment. AIDS 2011; 25 (5) 625-633
• 29 Yilmaz A, Yiannoutsos CT, Fuchs D , et al. Cerebrospinal fluid neopterin decay characteristics after initiation of antiretroviral therapy. J Neuroinflammation 2013; 10: 62
• 30 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) 1509-1517
• 31 Best BM, Letendre SL, Koopmans P , et al; CHARTER Study Group. Low cerebrospinal fluid concentrations of the nucleotide HIV reverse transcriptase inhibitor, tenofovir. J Acquir Immune Defic Syndr 2012; 59 (4) 376-381
• 32 Foudraine NA, Hoetelmans RM, Lange JM , et al. Cerebrospinal-fluid HIV-1 RNA and drug concentrations after treatment with lamivudine plus zidovudine or stavudine. Lancet 1998; 351 (9115) 1547-1551
• 33 Best BM, Koopmans PP, Letendre SL , et al; CHARTER Group. Efavirenz concentrations in CSF exceed IC50 for wild-type HIV. J Antimicrob Chemother 2011; 66 (2) 354-357
• 34 van Praag RM, van Weert EC, van Heeswijk RP , et al. Stable concentrations of zidovudine, stavudine, lamivudine, abacavir, and nevirapine in serum and cerebrospinal fluid during 2 years of therapy. Antimicrob Agents Chemother 2002; 46 (3) 896-899
• 35 Nguyen A, Rossi S, Croteau D , et al; CHARTER Group. Etravirine in CSF is highly protein bound. J Antimicrob Chemother 2013; 68 (5) 1161-1168
• 36 Mora-Peris B, Watson V, Vera J , et al. Rilpivirine concentrations in plasma and cerebrospinal fluid after switching from nevirapine-containing cART. Paper presented at: 14th International Workshop on Clinical Pharmacology of HIV Therapy; April 22–24, 2013; Amsterdam, the Netherlands
• 37 Kim RB, Fromm MF, Wandel C , et al. The drug transporter P-glycoprotein limits oral absorption and brain entry of HIV-1 protease inhibitors. J Clin Invest 1998; 101 (2) 289-294
• 38 Vernazza P, Daneel S, Schiffer V , et al. The role of compartment penetration in PI-monotherapy: the Atazanavir-Ritonavir Monomaintenance (ATARITMO) Trial. AIDS 2007; 21 (10) 1309-1315
• 39 Katlama C, Valantin MA, Algarte-Genin M , et al. Efficacy of darunavir/ritonavir maintenance monotherapy in patients with HIV-1 viral suppression: a randomized open-label, noninferiority trial, MONOI-ANRS 136. AIDS 2010; 24 (15) 2365-2374
• 40 Meynard JL, Bouteloup V, Landman R , et al; KALESOLO Study Group. Lopinavir/ritonavir monotherapy versus current treatment continuation for maintenance therapy of HIV-1 infection: the KALESOLO trial. J Antimicrob Chemother 2010; 65 (11) 2436-2444
• 41 Lafeuillade A, Solas C, Halfon P, Chadapaud S, Hittinger G, Lacarelle B. Differences in the detection of three HIV-1 protease inhibitors in non-blood compartments: clinical correlations. HIV Clin Trials 2002; 3 (1) 27-35
• 42 Gutmann C, Cusini A, Günthard HF , et al; Swiss HIV Cohort Study (SHCS). Randomized controlled study demonstrating failure of LPV/r monotherapy in HIV: the role of compartment and CD4-nadir. AIDS 2010; 24 (15) 2347-2354
• 43 Haas DW, Clough LA, Johnson BW , et al. Evidence of a source of HIV type 1 within the central nervous system by ultraintensive sampling of cerebrospinal fluid and plasma. AIDS Res Hum Retroviruses 2000; 16 (15) 1491-1502
• 44 Yilmaz A, Fuchs D, Hagberg L , et al. Cerebrospinal fluid HIV-1 RNA, intrathecal immunoactivation, and drug concentrations after treatment with a combination of saquinavir, nelfinavir, and two nucleoside analogues: the M61022 study. BMC Infect Dis 2006; 6: 63
• 45 Karlström O, Ståhle L, Perrin L, Tegude H, Sönnerborg A. Efficacy of nelfinavir-based treatment in the central nervous system of HIV-1 infected patients. Scand J Infect Dis 2006; 38 (5) 371-374
• 46 Moyle GJ, Sadler M, Buss N. Plasma and cerebrospinal fluid saquinavir concentrations in patients receiving combination antiretroviral therapy. Clin Infect Dis 1999; 28 (2) 403-404
• 47 Saumoy M, Tiraboschi J, Gutierrez M , et al. Viral response in stable patients switching to fosamprenavir/ritonavir monotherapy (the FONT Study). HIV Med 2011; 12 (7) 438-441
• 48 Letendre S, Mills A, Tashima K , et al. Distribution and antiviral activity in cerebrospinal fluid of the integrase inhibitor, dolutegravir: ING116070 Week 16 results. Paper presented at: 20th Conference on Retroviruses and Opportunistic Infections, March–6, 2013; Atlanta, GA
• 49 Yilmaz A, Gisslén M, Spudich S , et al. Raltegravir cerebrospinal fluid concentrations in HIV-1 infection. PLoS ONE 2009; 4 (9) e6877
• 50 Calcagno A, Bonora S, Bertucci R, Lucchini A, D'Avolio A, Di Perri G. Raltegravir penetration in the cerebrospinal fluid of HIV-positive patients. AIDS 2010; 24 (6) 931-932
• 51 Moore JP, Doms RW. The entry of entry inhibitors: a fusion of science and medicine. Proc Natl Acad Sci U S A 2003; 100 (19) 10598-10602
• 52 Price RW, Parham R, Kroll JL , et al. Enfuvirtide cerebrospinal fluid (CSF) pharmacokinetics and potential use in defining CSF HIV-1 origin. Antivir Ther 2008; 13 (3) 369-374
• 53 Thomas SA. Drug transporters relevant to HIV therapy. J HIV Ther 2004; 9 (4) 92-96
• 54 Yilmaz A, Watson V, Else L, Gisslèn M. Cerebrospinal fluid maraviroc concentrations in HIV-1 infected patients. AIDS 2009; 23 (18) 2537-2540
• 55 Tiraboschi JM, Niubo J, Curto J, Podzamczer D. Maraviroc concentrations in cerebrospinal fluid in HIV-infected patients. J Acquir Immune Defic Syndr 2010; 55 (5) 606-609
• 56 Letendre S, Marquie-Beck J, Capparelli E , et al; CHARTER Group. Validation of the CNS penetration-effectiveness rank for quantifying antiretroviral penetration into the central nervous system. Arch Neurol 2008; 65 (1) 65-70
• 57 Gisslén M, Hagberg L, Svennerholm B, Norkrans G. HIV-1 RNA is not detectable in the cerebrospinal fluid during antiretroviral combination therapy. AIDS 1997; 11 (9) 1194
• 58 Mellgren A, Antinori A, Cinque P , et al. Cerebrospinal fluid HIV-1 infection usually responds well to antiretroviral treatment. Antivir Ther 2005; 10 (6) 701-707
• 59 Eggers C, Hertogs K, Stürenburg HJ, van Lunzen J, Stellbrink HJ. Delayed central nervous system virus suppression during highly active antiretroviral therapy is associated with HIV encephalopathy, but not with viral drug resistance or poor central nervous system drug penetration. AIDS 2003; 17 (13) 1897-1906
• 60 Staprans S, Marlowe N, Glidden D , et al. Time course of cerebrospinal fluid responses to antiretroviral therapy: evidence for variable compartmentalization of infection. AIDS 1999; 13 (9) 1051-1061
• 61 Ellis RJ, Gamst AC, Capparelli E , et al. Cerebrospinal fluid HIV RNA originates from both local CNS and systemic sources. Neurology 2000; 54 (4) 927-936
• 62 Gisslén M, Svennerholm B, Norkrans G , et al. Cerebrospinal fluid and plasma viral load in HIV-1-infected patients with various anti-retroviral treatment regimens. Scand J Infect Dis 2000; 32 (4) 365-369
• 63 Yilmaz A, Price RW, Spudich S, Fuchs D, Hagberg L, Gisslén M. Persistent intrathecal immune activation in HIV-1-infected individuals on antiretroviral therapy. J Acquir Immune Defic Syndr 2008; 47 (2) 168-173
• 64 Spudich S, Lollo N, Liegler T, Deeks SG, Price RW. Treatment benefit on cerebrospinal fluid HIV-1 levels in the setting of systemic virological suppression and failure. J Infect Dis 2006; 194 (12) 1686-1696
• 65 Dinoso JB, Kim SY, Wiegand AM , et al. Treatment intensification does not reduce residual HIV-1 viremia in patients on highly active antiretroviral therapy. Proc Natl Acad Sci U S A 2009; 106 (23) 9403-9408
• 66 Dahl V, Lee E, Peterson J , 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) 1936-1945
• 67 Yilmaz A, Verhofstede C, D'Avolio A , 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) 590-596
• 68 Mellgren A, Price RW, Hagberg L, Rosengren L, Brew BJ, Gisslén M. Antiretroviral treatment reduces increased CSF neurofilament protein (NFL) in HIV-1 infection. Neurology 2007; 69 (15) 1536-1541
• 69 Hagberg L, Cinque P, Gisslen M , et al. Cerebrospinal fluid neopterin: an informative biomarker of central nervous system immune activation in HIV-1 infection. AIDS Res Ther 2010; 7: 15
• 70 Abdulle S, Hagberg L, Svennerholm B, Fuchs D, Gisslén M. Continuing intrathecal immunoactivation despite two years of effective antiretroviral therapy against HIV-1 infection. AIDS 2002; 16 (16) 2145-2149
• 71 Abdulle S, Hagberg L, Gisslén M. Effects of antiretroviral treatment on blood-brain barrier integrity and intrathecal immunoglobulin production in neuroasymptomatic HIV-1-infected patients. HIV Med 2005; 6 (3) 164-169
• 72 McArthur JC, Steiner J, Sacktor N, Nath A. Human immunodeficiency virus-associated neurocognitive disorders: Mind the gap. Ann Neurol 2010; 67 (6) 699-714
• 73 Hunt PW. HIV and inflammation: mechanisms and consequences. Curr HIV/AIDS Rep 2012; 9 (2) 139-147
• 74 Canestri A, Lescure FX, Jaureguiberry S , et al. Discordance between cerebral spinal fluid and plasma HIV replication in patients with neurological symptoms who are receiving suppressive antiretroviral therapy. Clin Infect Dis 2010; 50 (5) 773-778
• 75 Peluso MJ, Ferretti F, Peterson J , et al. Cerebrospinal fluid HIV escape associated with progressive neurologic dysfunction in patients on antiretroviral therapy with well controlled plasma viral load. AIDS 2012; 26 (14) 1765-1774
• 76 Lescure FX, Moulignier A, Savatovsky J , et al. CD8 encephalitis in HIV-infected patients receiving cART: a treatable entity. Clin Infect Dis 2013; 57 (1) 101-108
• 77 Gray F, Lescure FX, Adle-Biassette H , et al. Encephalitis with infiltration by CD8+ lymphocytes in HIV patients receiving combination antiretroviral treatment. Brain Pathol 2013; 23 (5) 525-533
• 78 Edén A, Fuchs D, Hagberg L , et al. HIV-1 viral escape in cerebrospinal fluid of subjects on suppressive antiretroviral treatment. J Infect Dis 2010; 202 (12) 1819-1825
• 79 Lescure FX, Omland LH, Engsig FN , et al. Incidence and impact on mortality of severe neurocognitive disorders in persons with and without HIV infection: a Danish nationwide cohort study. Clin Infect Dis 2011; 52 (2) 235-243
• 80 Andersson LM, Hagberg L, Rosengren L, Fuchs D, Blennow K, Gisslén M. Normalisation of cerebrospinal fluid biomarkers parallels improvement of neurological symptoms following HAART in HIV dementia—case report. BMC Infect Dis 2006; 6: 141
• 81 d'Arminio Monforte A, Cinque P, Mocroft A , et al; EuroSIDA Study Group. Changing incidence of central nervous system diseases in the EuroSIDA cohort. Ann Neurol 2004; 55 (3) 320-328
• 82 Robertson KR, Smurzynski M, Parsons TD , et al. The prevalence and incidence of neurocognitive impairment in the HAART era. AIDS 2007; 21 (14) 1915-1921
• 83 Simioni S, Cavassini M, Annoni JM , et al. Cognitive dysfunction in HIV patients despite long-standing suppression of viremia. AIDS 2010; 24 (9) 1243-1250
• 84 Pumpradit W, Ananworanich J, Lolak S , et al; Southeast Asia Research Collaboration with Hawaii (SEARCH) 005 Protocol Team. Neurocognitive impairment and psychiatric comorbidity in well-controlled human immunodeficiency virus-infected Thais from the 2NN Cohort Study. J Neurovirol 2010; 16 (1) 76-82
• 85 Bonnet F, Amieva H, Marquant F , et al; S CO3 Aquitaine Cohort. Cognitive disorders in HIV-infected patients: are they HIV-related?. AIDS 2013; 27 (3) 391-400
• 86 Cysique LA, Brew BJ. Prevalence of non-confounded HIV-associated neurocognitive impairment in the context of plasma HIV RNA suppression. J Neurovirol 2011; 17 (2) 176-183
• 87 Muñoz-Moreno JA, Fumaz CR, Ferrer MJ , et al. Nadir CD4 cell count predicts neurocognitive impairment in HIV-infected patients. AIDS Res Hum Retroviruses 2008; 24 (10) 1301-1307
• 88 Gisslen M, Hagberg L, Rosengren L , et al. Defining and evaluating HIV-related neurodegenerative disease and its treatment targets: a combinatorial approach to use of cerebrospinal fluid molecular biomarkers. J Neuroimmune Pharmacol 2007; 2 (1) 112-119
• 89 Adkins JC, Noble S. Efavirenz. Drugs 1998; 56 (6) 1055-1064 , discussion 1065–1066
• 90 Lochet P, Peyrière H, Lotthé A, Mauboussin JM, Delmas B, Reynes J. Long-term assessment of neuropsychiatric adverse reactions associated with efavirenz. HIV Med 2003; 4 (1) 62-66
• 91 Clifford DB, Evans S, Yang Y, Acosta EP, Ribaudo H, Gulick RM ; A5097s Study Team. Long-term impact of efavirenz on neuropsychological performance and symptoms in HIV-infected individuals (ACTG 5097s). HIV Clin Trials 2009; 10 (6) 343-355
• 92 Robertson KR, Su Z, Margolis DM , et al; A5170 Study Team. Neurocognitive effects of treatment interruption in stable HIV-positive patients in an observational cohort. Neurology 2010; 74 (16) 1260-1266
• 93 Marra CM, Zhao Y, Clifford DB , et al; AIDS Clinical Trials Group 736 Study Team. Impact of combination antiretroviral therapy on cerebrospinal fluid HIV RNA and neurocognitive performance. AIDS 2009; 23 (11) 1359-1366
• 94 Alton EW, Stern M, Farley R , et al. Cationic lipid-mediated CFTR gene transfer to the lungs and nose of patients with cystic fibrosis: a double-blind placebo-controlled trial. Lancet 1999; 353 (9157) 947-954
• 95 Tovar-y-Romo LB, Bumpus NN, Pomerantz D , et al. Dendritic spine injury induced by the 8-hydroxy metabolite of efavirenz. J Pharmacol Exp Ther 2012; 343 (3) 696-703
• 96 Robertson K, Liner J, Meeker RB. Antiretroviral neurotoxicity. J Neurovirol 2012; 18 (5) 388-399