Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.
ADVANCED SEARCH
Log in
Top
Neurotoxicity Research
Published in: Neurotoxicity Research 4/2016

01-11-2016 | Review

Neurotoxicity in the Post-HAART Era: Caution for the Antiretroviral Therapeutics

Authors: Ankit Shah, Mohitkumar R. Gangwani, Nitish S. Chaudhari, Alexy Glazyrin, Hari K. Bhat, Anil Kumar

Published in: Neurotoxicity Research | Issue 4/2016

Login to get access

Abstract

Despite the advent of highly active antiretroviral therapy (HAART), HIV-associated neurological disorders (HAND) remain a major challenge in human immunodeficiency virus (HIV) treatment. The early implementation of HAART in the infected individuals helps suppress the viral replication in the plasma and other compartments. Several studies also report the beneficial effect of drugs that successfully penetrate central nervous system (CNS). However, recent data in both clinical setup and in in vitro studies indicate CNS toxicity of the antiretrovirals (ARVs). Although the evidence is limited, correlation between prolonged use of ARVs and neurotoxicity strongly suggests that it is essential to study the underlying mechanisms responsible for such toxicity. Furthermore, closer attention toward clinical outcomes is required to screen various ARV regimens for their association with HAND and other comorbidities. A growing body of literature also indicates a possible role of accelerated aging in the antiretroviral therapy-associated neurotoxicity. Lastly, owing to high pill burden, multiple drugs in the HIV treatment also invite a possible role of drug–drug interaction via various cytochrome P450 enzymes. The particular emphasis of this review is to highlight the need to identify alternative approaches in reducing the CNS toxicity of the ARV drugs in HIV-infected individuals.
Literature
Abbott NJ, Patabendige AA, Dolman DE, Yusof SR, Begley DJ (2010) Structure and function of the blood–brain barrier. Neurobiol Dis 37:13–25PubMedCrossRef
Akay C, Cooper M, Odeleye A, Jensen BK, White MG, Vassoler F, Gannon PJ, Mankowski J, Dorsey JL, Buch AM, Cross SA, Cook DR, Pena MM, Andersen ES, Christofidou-Solomidou M, Lindl KA, Zink MC, Clements J, Pierce RC, Kolson DL, Jordan-Sciutto KL (2014) Antiretroviral drugs induce oxidative stress and neuronal damage in the central nervous system. J Neurovirol 20:39–53. doi:10.​1007/​s13365-013-0227-1 PubMedPubMedCentralCrossRef
András IE, Pu H, Deli MA, Nath A, Hennig B, Toborek M (2003) HIV-1 Tat protein alters tight junction protein expression and distribution in cultured brain endothelial cells. J Neurosci Res 74:255–265PubMedCrossRef
András IE, Pu H, Tian J, Deli MA, Nath A, Hennig B, Toborek M (2005) Signaling mechanisms of HIV-1 Tat-induced alterations of claudin-5 expression in brain endothelial cells. J Cereb Blood Flow Metab 25:1159–1170PubMedCrossRef
Anthony IC, Ramage SN, Carnie FW, Simmonds P, Bell JE (2006) Accelerated Tau deposition in the brains of individuals infected with human immunodeficiency virus-1 before and after the advent of highly active anti-retroviral therapy. Acta Neuropathol 111:529–538. doi:10.​1007/​s00401-006-0037-0 PubMedCrossRef
Antinori A, Arendt G, Becker JT, Brew BJ, Byrd DA, Cherner M, Clifford DB, Cinque P, Epstein LG, Goodkin K, Gisslen M, Grant I, Heaton RK, Joseph J, Marder K, Marra CM, McArthur JC, Nunn M, Price RW, Pulliam L, Robertson KR, Sacktor N, Valcour V, Wojna VE (2007) Updated research nosology for HIV-associated neurocognitive disorders. Neurology 69:1789–1799. doi:10.​1212/​01.​WNL.​0000287431.​88658.​8b PubMedPubMedCentralCrossRef
Antiretroviral Therapy Cohort C (2008) Life expectancy of individuals on combination antiretroviral therapy in high-income countries: a collaborative analysis of 14 cohort studies. Lancet 372:293–299. doi:10.​1016/​S0140-6736(08)61113-7 CrossRef
Apostolova N, Funes HA, Blas-Garcia A, Alegre F, Polo M, Esplugues JV (2015) Involvement of nitric oxide in the mitochondrial action of efavirenz: a differential effect on neurons and glial cells. J Infect Dis 211:1953–1958. doi:10.​1093/​infdis/​jiu825 PubMedCrossRef
Atluri VSR, Hidalgo M, Samikkannu T, Kurapati KRV, Jayant RD, Sagar V, Nair MP (2015) Effect of human immunodeficiency virus on blood–brain barrier integrity and function: an update. Front Cell Neurosci 9:212PubMedPubMedCentralCrossRef
Auclair M, Afonso P, Capel E, Caron-Debarle M, Capeau J (2014) Impact of darunavir, atazanavir and lopinavir boosted with ritonavir on cultured human endothelial cells: beneficial effect of pravastatin. Antivir Ther 19:773–782PubMedCrossRef
Azzam R, Lal L, Goh SL, Kedzierska K, Jaworowski A, Naim E, Cherry CL, Wesselingh SL, Mills J, Crowe SM (2006) Adverse effects of antiretroviral drugs on HIV-1-infected and -uninfected human monocyte-derived macrophages. J Acquir Immune Defic Syndr 42:19–28. doi:10.​1097/​01.​qai.​0000214809.​83218.​88 PubMed
Baliga RS, Liu C, Hoyt DG, Chaves AA, Bauer JA (2004) Vascular endothelial toxicity induced by HIV protease inhibitor. Cardiovasc Toxicol 4:199–206PubMedCrossRef
Ballabh P, Braun A, Nedergaard M (2004) The blood–brain barrier: an overview: structure, regulation, and clinical implications. Neurobiol Dis 16:1–13PubMedCrossRef
Banks WA, Erickson MA (2010) The blood–brain barrier and immune function and dysfunction. Neurobiol Dis 37:26–32PubMedCrossRef
Bazzoni G, Dejana E (2004) Endothelial cell-to-cell junctions: molecular organization and role in vascular homeostasis. Physiol Rev 84:869–901PubMedCrossRef
Becker JT, Lopez OL, Dew MA, Aizenstein HJ (2004) Prevalence of cognitive disorders differs as a function of age in HIV virus infection. AIDS 18(Suppl 1):S11–S18PubMedCrossRef
Blas-Garcia A, Polo M, Alegre F, Funes HA, Martinez E, Apostolova N, Esplugues JV (2014) Lack of mitochondrial toxicity of darunavir, raltegravir and rilpivirine in neurons and hepatocytes: a comparison with efavirenz. J Antimicrob Chemother 69:2995–3000. doi:10.​1093/​jac/​dku262 PubMedCrossRef
Bonfanti P, Valsecchi L, Parazzini F, Carradori S, Pusterla L, Fortuna P, Timillero L, Alessi F, Ghiselli G, Gabbuti A, Di Cintio E, Martinelli C, Faggion I, Landonio S, Quirino T (2000) Incidence of adverse reactions in HIV patients treated with protease inhibitors: a cohort study. Coordinamento Italiano Studio Allergia e Infezione da HIV (CISAI) Group. J Acquir Immune Defic Syndr 23:236–245PubMedCrossRef
Brown LA, Jin J, Ferrell D, Sadic E, Obregon D, Smith AJ, Tan J, Giunta B (2014) Efavirenz promotes beta-secretase expression and increased Abeta1-40,42 via oxidative stress and reduced microglial phagocytosis: implications for HIV associated neurocognitive disorders (HAND). PLoS One 9:e95500. doi:10.​1371/​journal.​pone.​0095500 PubMedPubMedCentralCrossRef
Caniglia EC, Cain LE, Justice A, Tate J, Logan R, Sabin C, Winston A, van Sighem A, Miro JM, Podzamczer D, Olson A, Arribas JR, Moreno S, Meyer L, del Romero J, Dabis F, Bucher HC, Wandeler G, Vourli G, Skoutelis A, Lanoy E, Gasnault J, Costagliola D, Hernan MA, Collaboration H-C (2014) Antiretroviral penetration into the CNS and incidence of AIDS-defining neurologic conditions. Neurology 83:134–141. doi:10.​1212/​WNL.​0000000000000564​ PubMedPubMedCentralCrossRef
Carvalhal A, Gill MJ, Letendre SL, Rachlis A, Bekele T, Raboud J, Burchell A, Rourke SB, the Centre for Brain Health in HA (2015) Central nervous system penetration effectiveness of antiretroviral drugs and neuropsychological impairment in the Ontario HIV Treatment Network Cohort Study. J Neurovirol. doi:10.​1007/​s13365-015-0404-5 PubMed
Cespedes MS, Aberg JA (2006) Neuropsychiatric complications of antiretroviral therapy. Drug Saf 29:865–874PubMedCrossRef
Chaudhuri A, Yang B, Gendelman HE, Persidsky Y, Kanmogne GD (2008) STAT1 signaling modulates HIV-1-induced inflammatory responses and leukocyte transmigration across the blood–brain barrier. Blood 111:2062–2072PubMedPubMedCentralCrossRef
Chen C, Lu X-H, Yan S, Chai H, Yao Q (2005) HIV protease inhibitor ritonavir increases endothelial monolayer permeability. Biochem Biophys Res Commun 335:874–882PubMedCrossRef
Cherry CL, Mobarok M, Wesselingh SL, Fain R, Weinstock S, Tachedjian G, Srivastava S, Tyssen DP, Glass JD, Hooker DJ (2010) Ubisol-AquaTM: coenzyme Q10 prevents antiretroviral toxic neuropathy in an in vitro model. CHR 8:232–239. doi:10.​2174/​1570162107911111​06 CrossRef
Cohen C, Elion R, Ruane P, Shamblaw D, DeJesus E, Rashbaum B, Chuck SL, Yale K, Liu HC, Warren DR, Ramanathan S, Kearney BP (2011) Randomized, phase 2 evaluation of two single-tablet regimens elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate versus efavirenz/emtricitabine/tenofovir disoproxil fumarate for the initial treatment of HIV infection. AIDS 25:F7–12. doi:10.​1097/​QAD.​0b013e328345766f​ PubMedCrossRef
Dalakas MC, Semino-Mora C, Leon-Monzon M (2001) Mitochondrial alterations with mitochondrial DNA depletion in the nerves of AIDS patients with peripheral neuropathy induced by 2′3′-dideoxycytidine (ddC). Lab Investig 81:1537–1544PubMedCrossRef
Divi RL, Einem TL, Fletcher SL, Shockley ME, Kuo MM, St Claire MC, Cook A, Nagashima K, Harbaugh SW, Harbaugh JW, Poirier MC (2010) Progressive mitochondrial compromise in brains and livers of primates exposed in utero to nucleoside reverse transcriptase inhibitors (NRTIs). Toxicol Sci 118:191–201. doi:10.​1093/​toxsci/​kfq235 PubMedPubMedCentralCrossRef
Dragovic G, Jevtovic D (2003) Nucleoside reverse transcriptase inhibitor usage and the incidence of peripheral neuropathy in HIV/AIDS patients. Antivir Chem Chemother 14:281–284PubMedCrossRef
Du Pasquier RA, Jilek S, Kalubi M, Yerly S, Fux CA, Gutmann C, Cusini A, Gunthard HF, Cavassini M, Vernazza PL, Swiss HIVCS (2013) Marked increase of the astrocytic marker S100B in the cerebrospinal fluid of HIV-infected patients on LPV/r-monotherapy. AIDS 27:203–210. doi:10.​1097/​QAD.​0b013e32835a9a4a​ PubMedCrossRef
Eagling VA, Back DJ, Barry MG (1997) Differential inhibition of cytochrome P450 isoforms by the protease inhibitors, ritonavir, saquinavir and indinavir. Br J Clin Pharmacol 44:190–194PubMedPubMedCentralCrossRef
Eagling VA, Wiltshire H, Whitcombe IW, Back DJ (2002) CYP3A4-mediated hepatic metabolism of the HIV-1 protease inhibitor saquinavir in vitro. Xenobiotica 32:1–17PubMedCrossRef
Ellis RJ, Marquie-Beck J, Delaney P, Alexander T, Clifford DB, McArthur JC, Simpson DM, Ake C, Collier AC, Gelman BB, McCutchan JA, Morgello S, Grant I, Group C (2008) Human immunodeficiency virus protease inhibitors and risk for peripheral neuropathy. Ann Neurol 64:566–572. doi:10.​1002/​ana.​21484 PubMedPubMedCentralCrossRef
Fiala M, Murphy T, MacDougall J, Yang W, Luque A, Iruela-Arispe L, Cashman J, Buga G, Byrns RE, Barbaro G (2004) HAART drugs induce mitochondrial damage and intercellular gaps and gp 120 causes apoptosis. Cardiovasc Toxicol 4:327–337PubMedCrossRef
Fu W, Chai H, Yao Q, Chen C (2005) Effects of HIV protease inhibitor ritonavir on vasomotor function and endothelial nitric oxide synthase expression JAIDS. J Acquir Immune Defic Syndr 39:152–158PubMed
Fumaz CR, Gonzalez-Garcia M, Borras X, Munoz-Moreno JA, Perez-Alvarez N, Mothe B, Brander C, Ferrer MJ, Puig J, Llano A, Fernandez-Castro J, Clotet B (2012) Psychological stress is associated with high levels of IL-6 in HIV-1 infected individuals on effective combined antiretroviral treatment. Brain Behav Immun 26:568–572. doi:10.​1016/​j.​bbi.​2012.​01.​001 PubMedCrossRef
Funes HA, Blas-Garcia A, Esplugues JV, Apostolova N (2015) Efavirenz alters mitochondrial respiratory function in cultured neuron and glial cell lines. J Antimicrob Chemother 70:2249–2254. doi:10.​1093/​jac/​dkv098 PubMedCrossRef
Fung HB, Guo Y (2004) Enfuvirtide: a fusion inhibitor for the treatment of HIV infection. Clin Ther 26:352–378PubMedCrossRef
Galluzzi L, Pinti M, Troiano L, Prada N, Nasi M, Ferraresi R, Salomoni P, Mussini C, Cossarizza A (2005) Changes in mitochondrial RNA production in cells treated with nucleoside analogues. Antivir Ther 10:191–195PubMed
Garvey L, Winston A, Walsh J, Post F, Porter K, Gazzard B, Fisher M, Leen C, Pillay D, Hill T, Johnson M, Gilson R, Anderson J, Easterbrook P, Bansi L, Orkin C, Ainsworth J, Palfreeman A, Gompels M, Phillips AN, Sabin CA, study UKCHC (2011) Antiretroviral therapy CNS penetration and HIV-1-associated CNS disease. Neurology 76:693–700. doi:10.​1212/​WNL.​0b013e31820d8b0b​ PubMedPubMedCentralCrossRef
Gatanaga H, Hayashida T, Tsuchiya K, Yoshino M, Kuwahara T, Tsukada H, Fujimoto K, Sato I, Ueda M, Horiba M, Hamaguchi M, Yamamoto M, Takata N, Kimura A, Koike T, Gejyo F, Matsushita S, Shirasaka T, Kimura S, Oka S (2007) Successful efavirenz dose reduction in HIV type 1-infected individuals with cytochrome P450 2B6*6 and *26. Clin Infect Dis 45:1230–1237. doi:10.​1086/​522175 PubMedCrossRef
Gervot L, Rochat B, Gautier JC, Bohnenstengel F, Kroemer H, de Berardinis V, Martin H, Beaune P, de Waziers I (1999) Human CYP2B6: expression, inducibility and catalytic activities. Pharmacogenetics 9:295–306PubMedCrossRef
Giunta B, Ehrhart J, Obregon DF, Lam L, Le L, Jin J, Fernandez F, Tan J, Shytle RD (2011) Antiretroviral medications disrupt microglial phagocytosis of beta-amyloid and increase its production by neurons: implications for HIV-associated neurocognitive disorders. Mol Brain 4:23. doi:10.​1186/​1756-6606-4-23 PubMedPubMedCentralCrossRef
Glover M, Hebert VY, Nichols K, Xue SY, Thibeaux TM, Zavecz JA, Dugas TR (2014) Overexpression of mitochondrial antioxidant manganese superoxide dismutase (MnSOD) provides protection against AZT-or 3TC-induced endothelial dysfunction. Antivir Res 111:136–142PubMedPubMedCentralCrossRef
Gomes MJ, Neves J, Sarmento B (2014) Nanoparticle-based drug delivery to improve the efficacy of antiretroviral therapy in the central nervous system. Int J Nanomed 9:1757–1769
Gongvatana A, Harezlak J, Buchthal S, Daar E, Schifitto G, Campbell T, Taylor M, Singer E, Algers J, Zhong J, Brown M, McMahon D, So YT, Mi D, Heaton R, Robertson K, Yiannoutsos C, Cohen RA, Navia B, Consortium HIVN (2013) Progressive cerebral injury in the setting of chronic HIV infection and antiretroviral therapy. J Neurovirol 19:209–218. doi:10.​1007/​s13365-013-0162-1 PubMedPubMedCentralCrossRef
Govindarajan R, Leung GP, Zhou M, Tse C-M, Wang J, Unadkat JD (2009) Facilitated mitochondrial import of antiviral and anticancer nucleoside drugs by human equilibrative nucleoside transporter-3. Am J Physiol Gastrointest Liver Physiol 296:G910–G922PubMedPubMedCentralCrossRef
Green DA, Masliah E, Vinters HV, Beizai P, Moore DJ, Achim CL (2005) Brain deposition of beta-amyloid is a common pathologic feature in HIV positive patients. AIDS 19:407–411PubMedCrossRef
Grigorian A, Hurford R, Chao Y, Patrick C, Langford TD (2008) Alterations in the Notch4 pathway in cerebral endothelial cells by the HIV aspartyl protease inhibitor, nelfinavir. BMC Neurosci 9:27PubMedPubMedCentralCrossRef
Hashiguchi Y, Hamada A, Shinohara T, Tsuchiya K, Jono H, Saito H (2013) Role of P-glycoprotein in the efflux of raltegravir from human intestinal cells and CD4+ T-cells as an interaction target for anti-HIV agents. Biochem Biophys Res Commun 439:221–227PubMedCrossRef
Heaton RK, Clifford DB, Franklin DR Jr, Woods SP, Ake C, Vaida F, Ellis RJ, Letendre SL, Marcotte TD, Atkinson JH, Rivera-Mindt M, Vigil OR, Taylor MJ, Collier AC, Marra CM, Gelman BB, McArthur JC, Morgello S, Simpson DM, McCutchan JA, Abramson I, Gamst A, Fennema-Notestine C, Jernigan TL, Wong J, Grant I, Group C (2010) HIV-associated neurocognitive disorders persist in the era of potent antiretroviral therapy: CHARTER Study. Neurology 75:2087–2096. doi:10.​1212/​WNL.​0b013e318200d727​ PubMedPubMedCentralCrossRef
Heaton RK, Franklin DR Jr, Deutsch R, Letendre S, Ellis RJ, Casaletto K, Marquine MJ, Woods SP, Vaida F, Atkinson JH, Marcotte TD, McCutchan JA, Collier AC, Marra CM, Clifford DB, Gelman BB, Sacktor N, Morgello S, Simpson DM, Abramson I, Gamst AC, Fennema-Notestine C, Smith DM, Grant I, Group C (2015) Neurocognitive change in the era of HIV combination antiretroviral therapy: the longitudinal CHARTER study. Clin Infect Dis 60:473–480. doi:10.​1093/​cid/​ciu862 PubMedCrossRef
Huang W, Eum SY, András IE, Hennig B, Toborek M (2009) PPARα and PPARγ attenuate HIV-induced dysregulation of tight junction proteins by modulations of matrix metalloproteinase and proteasome activities. FASEB J 23:1596–1606PubMedPubMedCentralCrossRef
Jamaluddin MS, Lin PH, Yao Q, Chen C (2010) Non-nucleoside reverse transcriptase inhibitor efavirenz increases monolayer permeability of human coronary artery endothelial cells. Atherosclerosis 208:104–111PubMedCrossRef
James CW, McNelis KC, Matalia MD, Cohen DM, Szabo S (2002) Central nervous system toxicity and amprenavir oral solution. Ann Pharmacother 36:174PubMedCrossRef
Jensen BK, Monnerie H, Mannell MV, Gannon PJ, Espinoza CA, Erickson MA, Bruce-Keller AJ, Gelman BB, Briand LA, Pierce RC, Jordan-Sciutto KL, Grinspan JB (2015) Altered oligodendrocyte maturation and myelin maintenance: the role of antiretrovirals in HIV-associated neurocognitive disorders. J Neuropathol Exp Neurol 74:1093–1118. doi:10.​1097/​NEN.​0000000000000255​ PubMedCrossRef
Jin J, Grimmig B, Izzo J, Brown LA, Hudson C, Smith AJ, Tan J, Bickford PC, Giunta B (2016) HIV non-nucleoside reverse transcriptase inhibitor efavirenz reduces neural stem cell proliferation in vitro and in vivo. Cell Transplant. doi:10.​3727/​096368916X691457​ PubMed
Kakuda TN, Scholler-Gyure M, Hoetelmans RM (2010) Clinical perspective on antiretroviral drug–drug interactions with the non-nucleoside reverse transcriptase inhibitor etravirine. Antivir Ther 15:817–829. doi:10.​3851/​IMP1652 PubMedCrossRef
Kanmogne GD, Schall K, Leibhart J, Knipe B, Gendelman HE, Persidsky Y (2007) HIV-1 gp120 compromises blood–brain barrier integrity and enhance monocyte migration across blood–brain barrier: implication for viral neuropathogenesis. J Cereb Blood Flow Metab 27:123–134PubMedCrossRef
Kempf DJ, Marsh KC, Kumar G, Rodrigues AD, Denissen JF, McDonald E, Kukulka MJ, Hsu A, Granneman GR, Baroldi PA, Sun E, Pizzuti D, Plattner JJ, Norbeck DW, Leonard JM (1997) Pharmacokinetic enhancement of inhibitors of the human immunodeficiency virus protease by coadministration with ritonavir. Antimicrob Agents Chemother 41:654–660PubMedPubMedCentral
Kis O, Robillard K, Chan GN, Bendayan R (2010) The complexities of antiretroviral drug–drug interactions: role of ABC and SLC transporters. Trends Pharmacol Sci 31:22–35PubMedCrossRef
Kline ER, Sutliff RL (2008) The roles of HIV-1 proteins and antiretroviral drug therapy in HIV-1-associated endothelial dysfunction. J Investig Med 56:752–769PubMedPubMedCentralCrossRef
Kline ER, Bassit L, Hernandez-Santiago BI, Detorio MA, Liang B, Kleinhenz DJ, Walp ER, Dikalov S, Jones DP, Schinazi RF (2009) Long-term exposure to AZT, but not d4T, increases endothelial cell oxidative stress and mitochondrial dysfunction. Cardiovasc Toxicol 9:1–12PubMedCrossRef
Kumar GN, Rodrigues AD, Buko AM, Denissen JF (1996) Cytochrome P450-mediated metabolism of the HIV-1 protease inhibitor ritonavir (ABT-538) in human liver microsomes. J Pharmacol Exp Ther 277:423–431PubMed
Kumar GN, Dykstra J, Roberts EM, Jayanti VK, Hickman D, Uchic J, Yao Y, Surber B, Thomas S, Granneman GR (1999) Potent inhibition of the cytochrome P-450 3A-mediated human liver microsomal metabolism of a novel HIV protease inhibitor by ritonavir: a positive drug–drug interaction. Drug Metab Dispos 27:902–908PubMed
Lai Y, Tse CM, Unadkat JD (2004) Mitochondrial expression of the human equilibrative nucleoside transporter 1 (hENT1) results in enhanced mitochondrial toxicity of antiviral drugs. J Biol Chem 279:4490–4497. doi:10.​1074/​jbc.​M307938200 PubMedCrossRef
Lalezari JP, Henry K, O’Hearn M, Montaner JS, Piliero PJ, Trottier B, Walmsley S, Cohen C, Kuritzkes DR, Eron JJ Jr, Chung J, DeMasi R, Donatacci L, Drobnes C, Delehanty J, Salgo M, Group TS (2003) Enfuvirtide, an HIV-1 fusion inhibitor, for drug-resistant HIV infection in North and South America. N Engl J Med 348:2175–2185. doi:10.​1056/​NEJMoa035026 PubMedCrossRef
Lazzarin A, Clotet B, Cooper D, Reynes J, Arasteh K, Nelson M, Katlama C, Stellbrink HJ, Delfraissy JF, Lange J, Huson L, DeMasi R, Wat C, Delehanty J, Drobnes C, Salgo M, Group TS (2003) Efficacy of enfuvirtide in patients infected with drug-resistant HIV-1 in Europe and Australia. N Engl J Med 348:2186–2195. doi:10.​1056/​NEJMoa035211 PubMedCrossRef
Lee H, Hanes J, Johnson KA (2003) Toxicity of nucleoside analogues used to treat AIDS and the selectivity of the mitochondrial DNA polymerase. Biochemistry 42:14711–14719. doi:10.​1021/​bi035596s PubMedCrossRef
Letendre S (2011) Central nervous system complications in HIV disease: HIV-associated neurocognitive disorder. Top Antivir Med 19:137–142PubMedPubMedCentral
Letendre SL, Ellis RJ, Ances BM, McCutchan JA (2010) Neurologic complications of HIV disease and their treatment. Top HIV Med 18:45–55PubMed
Lewis W (2003) Mitochondrial dysfunction and nucleoside reverse transcriptase inhibitor therapy: experimental clarifications and persistent clinical questions. Antivir Res 58:189–197PubMedCrossRef
Lillibridge JH, Liang BH, Kerr BM, Webber S, Quart B, Shetty BV, Lee CA (1998) Characterization of the selectivity and mechanism of human cytochrome P450 inhibition by the human immunodeficiency virus-protease inhibitor nelfinavir mesylate. Drug Metab Dispos 26:609–616PubMed
Liu Z-J, Shirakawa T, Li Y, Soma A, Oka M, Dotto GP, Fairman RM, Velazquez OC, Herlyn M (2003) Regulation of Notch1 and Dll4 by vascular endothelial growth factor in arterial endothelial cells: implications for modulating arteriogenesis and angiogenesis. Mol Cell Biol 23:14–25PubMedPubMedCentralCrossRef
Ma Q, Vaida F, Wong J, Sanders CA, Kao YT, Croteau D, Clifford DB, Collier AC, Gelman BB, Marra CM, McArthur JC, Morgello S, Simpson DM, Heaton RK, Grant I, Letendre SL, Group C (2016) Long-term efavirenz use is associated with worse neurocognitive functioning in HIV-infected patients. J Neurovirol 22:170–178. doi:10.​1007/​s13365-015-0382-7 PubMedCrossRef
Mahajan SD, Roy I, Xu G, Yong KT, Ding H, Aalinkeel R, Reynolds J, Sykes D, Nair BB, Lin EY, Prasad PN, Schwartz SA (2010) Enhancing the delivery of anti retroviral drug “Saquinavir” across the blood brain barrier using nanoparticles. Curr HIV Res 8:396–404PubMedPubMedCentralCrossRef
Manda VK, Mittapalli RK, Geldenhuys WJ, Lockman PR (2010) Chronic exposure to nicotine and saquinavir decreases endothelial Notch-4 expression and disrupts blood–brain barrier integrity. J Neurochem 115:515–525PubMedCrossRef
Manda KR, Banerjee A, Banks WA, Ercal N (2011) Highly active antiretroviral therapy drug combination induces oxidative stress and mitochondrial dysfunction in immortalized human blood–brain barrier endothelial cells. Free Radic Biol Med 50:801–810PubMedCrossRef
Maxwell S, Scheftner WA, Kessler HA, Busch K (1988) Manic syndrome associated with zidovudine treatment. JAMA 259:3406–3407PubMedCrossRef
Meyer RP, Gehlhaus M, Knoth R, Volk B (2007) Expression and function of cytochrome p450 in brain drug metabolism. Curr Drug Metab 8:297–306PubMedCrossRef
Michaud V, Bar-Magen T, Turgeon J, Flockhart D, Desta Z, Wainberg MA (2012) The dual role of pharmacogenetics in HIV treatment: mutations and polymorphisms regulating antiretroviral drug resistance and disposition. Pharmacol Rev 64:803–833. doi:10.​1124/​pr.​111.​005553 PubMedCrossRef
Mondal D, Pradhan L, Ali M, Agrawal KC (2004) HAART drugs induce oxidative stress in human endothelial cells and increase endothelial recruitment of mononuclear cells. Cardiovasc Toxicol 4:287–302PubMedCrossRef
Morlese JF, Qazi NA, Gazzard BG, Nelson MR (2002) Nevirapine-induced neuropsychiatric complications, a class effect of non-nucleoside reverse transcriptase inhibitors? AIDS 16:1840–1841PubMedCrossRef
Nag S, Kapadia A, Stewart D (2011) Review: molecular pathogenesis of blood–brain barrier breakdown in acute brain injury. Neuropathol Appl Neurobiol 37:3–23PubMedCrossRef
Noseda M, Chang L, McLean G, Grim JE, Clurman BE, Smith LL, Karsan A (2004) Notch activation induces endothelial cell cycle arrest and participates in contact inhibition: role of p21Cip1 repression. Mol Cell Biol 24:8813–8822PubMedPubMedCentralCrossRef
O’Mahony SM, Myint AM, Steinbusch H, Leonard BE (2005) Efavirenz induces depressive-like behaviour, increased stress response and changes in the immune response in rats. NeuroImmunoModulation 12:293–298. doi:10.​1159/​000087107 PubMedCrossRef
Palmer S, Maldarelli F, Wiegand A, Bernstein B, Hanna GJ, Brun SC, Kempf DJ, Mellors JW, Coffin JM, King MS (2008) Low-level viremia persists for at least 7 years in patients on suppressive antiretroviral therapy. Proc Natl Acad Sci USA 105:3879–3884. doi:10.​1073/​pnas.​0800050105 PubMedPubMedCentralCrossRef
Pedrol E, Llibre JM, Tasias M, Curran A, Guardiola JM, Deig E, Guelar A, Martinez-Madrid O, Tikhomirova L, Ramirez R, Group RS (2015) Outcome of neuropsychiatric symptoms related to an antiretroviral drug following its substitution by nevirapine: the RELAX study. HIV Med 16:628–634. doi:10.​1111/​hiv.​12298 PubMedCrossRef
Persidsky Y, Ramirez SH, Haorah J, Kanmogne GD (2006) Blood–brain barrier: structural components and function under physiologic and pathologic conditions. J Neuroimmune Pharmacol 1:223–236PubMedCrossRef
Persson A, Sim SC, Virding S, Onishchenko N, Schulte G, Ingelman-Sundberg M (2014) Decreased hippocampal volume and increased anxiety in a transgenic mouse model expressing the human CYP2C19 gene. Mol Psychiatry 19:733–741. doi:10.​1038/​mp.​2013.​89 PubMedCrossRef
Pettersen JA, Jones G, Worthington C, Krentz HB, Keppler OT, Hoke A, Gill MJ, Power C (2006) Sensory neuropathy in human immunodeficiency virus/acquired immunodeficiency syndrome patients: protease inhibitor-mediated neurotoxicity. Ann Neurol 59:816–824. doi:10.​1002/​ana.​20816 PubMedCrossRef
Price JL, Davis PB, Morris JC, White DL (1991) The distribution of tangles, plaques and related immunohistochemical markers in healthy aging and Alzheimer’s disease. Neurobiol Aging 12:295–312PubMedCrossRef
Ragin AB, Storey P, Cohen BA, Epstein LG, Edelman RR (2004) Whole brain diffusion tensor imaging in HIV-associated cognitive impairment. AJNR Am J Neuroradiol 25:195–200PubMedPubMedCentral
Renn CL, Leitch CC, Lessans S, Rhee P, McGuire WC, Smith BA, Traub RJ, Dorsey SG (2011) Brain-derived neurotrophic factor modulates antiretroviral-induced mechanical allodynia in the mouse. J Neurosci Res 89:1551–1565. doi:10.​1002/​jnr.​22685 PubMedCrossRef
Robertson K, Su Z, Margolis D, Krambrink A, Havlir D, Evans S, Skiest D, Team AS (2010) Neurocognitive effects of treatment interruption in stable HIV-positive patients in an observational cohort. Neurology 74:1260–1266PubMedPubMedCentralCrossRef
Rotger M, Colombo S, Furrer H, Bleiber G, Buclin T, Lee BL, Keiser O, Biollaz J, Decosterd L, Telenti A, Swiss HIVCS (2005) Influence of CYP2B6 polymorphism on plasma and intracellular concentrations and toxicity of efavirenz and nevirapine in HIV-infected patients. Pharmacogenet Genomics 15:1–5PubMedCrossRef
Sacktor N, McDermott MP, Marder K, Schifitto G, Selnes OA, McArthur JC, Stern Y, Albert S, Palumbo D, Kieburtz K, De Marcaida JA, Cohen B, Epstein L (2002) HIV-associated cognitive impairment before and after the advent of combination therapy. J Neurovirol 8:136–142. doi:10.​1080/​1355028029004961​5 PubMedCrossRef
Saitoh A, Capparelli E, Aweeka F, Sarles E, Singh KK, Kovacs A, Burchett SK, Wiznia A, Nachman S, Fenton T, Spector SA (2010) CYP2C19 genetic variants affect nelfinavir pharmacokinetics and virologic response in HIV-1-infected children receiving highly active antiretroviral therapy. J Acquir Immune Defic Syndr 54:285–289. doi:10.​1097/​QAI.​0b013e3181bf648a​ PubMedPubMedCentralCrossRef
Sanchez Martin A, Cabrera Figueroa S, Cruz Guerrero R, Hurtado LP, Hurle AD, Carracedo Alvarez A (2013) Impact of pharmacogenetics on CNS side effects related to efavirenz. Pharmacogenomics 14:1167–1178. doi:10.​2217/​pgs.​13.​111 PubMedCrossRef
Sanchez AB, Varano GP, de Rozieres CM, Maung R, Catalan IC, Dowling CC, Sejbuk NE, Hoefer MM, Kaul M (2016) Antiretrovirals, methamphetamine, and HIV-1 envelope protein gp120 compromise neuronal energy homeostasis in association with various degrees of synaptic and neuritic damage. Antimicrob Agents Chemother 60:168–179. doi:10.​1128/​AAC.​01632-15 CrossRef
Saracchini S, Vaccher E, Covezzi E, Tortorici G, Carbone A, Tirelli U (1989) Lethal neurotoxicity associated to azidothymidine therapy. J Neurol Neurosurg Psychiatry 52:544–545PubMedPubMedCentralCrossRef
Sharma P, Garg S (2010) Pure drug and polymer based nanotechnologies for the improved solubility, stability, bioavailability and targeting of anti-HIV drugs. Adv Drug Deliv Rev 62:491–502PubMedCrossRef
Simioni S, Cavassini M, Annoni JM, Abraham AR, Bourquin I, Schiffer V, Calmy A, Chave JP, Giacobini E, Hirschel B, Du Pasquier RA (2010) Cognitive dysfunction in HIV patients despite long-standing suppression of viremia. AIDS 24:1243–1250. doi:10.​1097/​QAD.​0b013e3283354a7b​ PubMed
Sutliff RL, Dikalov S, Weiss D, Parker J, Raidel S, Racine AK, Russ R, Haase CP, Taylor WR, Lewis W (2002) Nucleoside reverse transcriptase inhibitors impair endothelium-dependent relaxation by increasing superoxide. Am J Physiol Heart Circu Physiol 283:H2363–H2370CrossRef
Teppler H, Brown DD, Leavitt RY, Sklar P, Wan H, Xu X, Lievano F, Lehman HP, Mast TC, Nguyen BY (2011) Long-term safety from the raltegravir clinical development program. Curr HIV Res 9:40–53PubMedPubMedCentralCrossRef
Toborek M, Lee YW, Flora G, Pu H, András IE, Wylegala E, Hennig B, Nath A (2005) Mechanisms of the blood–brain barrier disruption in HIV-1 infection. Cell Mol Neurobiol 25:181–199PubMedCrossRef
Tsuchiya K, Gatanaga H, Tachikawa N, Teruya K, Kikuchi Y, Yoshino M, Kuwahara T, Shirasaka T, Kimura S, Oka S (2004) Homozygous CYP2B6*6 (Q172H and K262R) correlates with high plasma efavirenz concentrations in HIV-1 patients treated with standard efavirenz-containing regimens. Biochem Biophys Res Commun 319:1322–1326. doi:10.​1016/​j.​bbrc.​2004.​05.​116 PubMedCrossRef
van Heeswijk RP, Veldkamp A, Mulder JW, Meenhorst PL, Lange JM, Beijnen JH, Hoetelmans RM (2001) Combination of protease inhibitors for the treatment of HIV-1-infected patients: a review of pharmacokinetics and clinical experience. Antivir Ther 6:201–229PubMed
van Praag RM, Weverling GJ, Portegies P, Jurriaans S, Zhou X-J, Turner-Foisy ML, Sommadossi J-P, Burger DM, Lange JM, Hoetelmans RM (2000) Enhanced penetration of indinavir in cerebrospinal fluid and semen after the addition of low-dose ritonavir. Aids 14:1187–1194PubMedCrossRef
Venhoff N, Lebrecht D, Deveaud C, Beauvoit B, Bonnet J, Muller K, Kirschner J, Venhoff AC, Walker UA (2010) Oral uridine supplementation antagonizes the peripheral neuropathy and encephalopathy induced by antiretroviral nucleoside analogues. AIDS 24:345–352. doi:10.​1097/​QAD.​0b013e328335cdea​ PubMedCrossRef
Villa G, Solida A, Moro E, Tavolozza M, Antinori A, De Luca A, Murri R, Tamburrini E (1996) Cognitive impairment in asymptomatic stages of HIV infection. A longitudinal study. Eur Neurol 36:125–133PubMedCrossRef
Vishnuvardhan D, Moltke LL, Richert C, Greenblatt DJ (2003) Lopinavir: acute exposure inhibits P-glycoprotein; extended exposure induces P-glycoprotein. Aids 17:1092–1094PubMedCrossRef
Wang X, Chai H, Yao Q, Chen C (2007) Molecular mechanisms of HIV protease inhibitor-induced endothelial dysfunction JAIDS. J Acquir Immune Defic Syndr 44:493–499PubMedCrossRef
Wang X, Chai H, Lin PH, Yao Q, Chen C (2009) Roles and mechanisms of human immunodeficiency virus protease inhibitor ritonavir and other anti-human immunodeficiency virus drugs in endothelial dysfunction of porcine pulmonary arteries and human pulmonary artery endothelial cells. Am J Pathol 174:771–781PubMedPubMedCentralCrossRef
Ward BA, Gorski JC, Jones DR, Hall SD, Flockhart DA, Desta Z (2003) The cytochrome P450 2B6 (CYP2B6) is the main catalyst of efavirenz primary and secondary metabolism: implication for HIV/AIDS therapy and utility of efavirenz as a substrate marker of CYP2B6 catalytic activity. J Pharmacol Exp Ther 306:287–300. doi:10.​1124/​jpet.​103.​049601 PubMedCrossRef
Watkins CC, Treisman GJ (2015) Cognitive impairment in patients with AIDS—prevalence and severity. HIV AIDS (Auckl) 7:35–47. doi:10.​2147/​HIV.​S39665
Wright EJ, Grund B, Robertson K, Brew BJ, Roediger M, Bain MP, Drummond F, Vjecha MJ, Hoy J, Miller C, de Oliveira AP, Pumpradit W, Shlay JC, El-Sadr W, Price RW, Group ISS (2010) Cardiovascular risk factors associated with lower baseline cognitive performance in HIV-positive persons. Neurology 75:864–873. doi:10.​1212/​WNL.​0b013e3181f11bd8​ PubMedPubMedCentralCrossRef
Xu C, Desta Z (2013) In vitro analysis and quantitative prediction of efavirenz inhibition of eight cytochrome P450 (CYP) enzymes: major effects on CYPs 2B6, 2C8, 2C9 and 2C19. Drug Metab Pharmacokinet 28:362–371PubMedPubMedCentralCrossRef
Yeh RF, Gaver VE, Patterson KB, Rezk NL, Baxter-Meheux F, Blake MJ, Eron JJ Jr, Klein CE, Rublein JC, Kashuba AD (2006) Lopinavir/ritonavir induces the hepatic activity of cytochrome P450 enzymes CYP2C9, CYP2C19, and CYP1A2 but inhibits the hepatic and intestinal activity of CYP3A as measured by a phenotyping drug cocktail in healthy volunteers. J Acquir Immune Defic Syndr 42:52–60. doi:10.​1097/​01.​qai.​0000219774.​20174.​64 PubMed
Zhong D, Lu H, Conklin BS, Lin PH, Lumsden AB, Yao Q, Chen C (2002) HIV protease inhibitor ritonavir induces cytotoxicity of human endothelial cells. Arterioscler Thromb Vasc Biol 22:1560–1566PubMedCrossRef
Zlokovic BV (2008) The blood–brain barrier in health and chronic neurodegenerative disorders. Neuron 57:178–201PubMedCrossRef
Metadata
Title
Neurotoxicity in the Post-HAART Era: Caution for the Antiretroviral Therapeutics
Authors
Ankit Shah
Mohitkumar R. Gangwani
Nitish S. Chaudhari
Alexy Glazyrin
Hari K. Bhat
Anil Kumar
Publication date
01-11-2016
Publisher
Springer US
Published in
Neurotoxicity Research / Issue 4/2016
Print ISSN: 1029-8428
Electronic ISSN: 1476-3524
DOI
https://doi.org/10.1007/s12640-016-9646-0

Other articles of this Issue 4/2016

Neurotoxicity Research 4/2016 Go to the issue

Original Article

Nanocapsules with Polyelectrolyte Shell as a Platform for 1,25-dihydroxyvitamin D3 Neuroprotection: Study in Organotypic Hippocampal Slices

Original Article

Protective Effects of Pituitary Adenylate Cyclase-Activating Polypeptide (PACAP) Against Oxidative Stress in Zebrafish Hair Cells

Original Article

Neurotoxic Effects of 5-MeO-DIPT: A Psychoactive Tryptamine Derivative in Rats

Original Article

Comparison of the Effects of Acute and Chronic Administration of Tetrahydroisoquinoline Amines on the In Vivo Dopamine Release: A Microdialysis Study in the Rat Striatum

Original Article

Characterization of the Kynurenine Pathway in CD8+ Human Primary Monocyte-Derived Dendritic Cells

Original Article

The Influence of the CB1 Receptor Ligands on the Schizophrenia-Like Effects in Mice Induced by MK-801