Skip to main content

Advertisement

SpringerLink
Log in

Neurologic Complications in Treated HIV-1 Infection

  • Infection (J Halperin, Section Editor)
  • Published:
Current Neurology and Neuroscience Reports Aims and scope Submit manuscript

Abstract

Effective combination antiretroviral therapy has transformed HIV infection into a chronic disease, with HIV-infected individuals living longer and reaching older age. Neurological disease remains common in treated HIV, however, due in part to ongoing inflammation and immune activation that persist in chronic infection. In this review, we highlight recent developments in our understanding of several clinically relevant neurologic complications that can occur in HIV infection despite treatment, including HIV-associated neurocognitive disorders, symptomatic CSF escape, cerebrovascular disease, and peripheral neuropathy.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

Papers of particular interest, published recently, have been highlighted as: • Of importance

  1. Zaidi J, Grapsa E, Tanser F, Newell ML, Barnighausen T. Dramatic increase in HIV prevalence after scale-up of antiretroviral treatment. AIDS. 2013;27:2301–5.

    Article  PubMed  PubMed Central  Google Scholar 

  2. Ortblad KF, Lozano R, Murray CJ. The burden of HIV: insights from the Global Burden of Disease Study 2010. AIDS. 2013;27:2003–17.

    Article  PubMed  PubMed Central  Google Scholar 

  3. Spudich S, Gisslen M, Hagberg L, Lee E, Liegler T, Brew B, 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;204:753–60.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Valcour V, Chalermchai T, Sailasuta N, Marovich M, Lerdlum S, Suttichom D, et al. Central nervous system viral invasion and inflammation during acute HIV infection. J Infect Dis. 2012;206:275–82.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Yilmaz A, Price RW, Spudich S, Fuchs D, Hagberg L, Gisslen M. Persistent intrathecal immune activation in HIV-1-infected individuals on antiretroviral therapy. J Acquir Immune Defic Syndr. 2008;47:168–73.

    Article  PubMed  PubMed Central  Google Scholar 

  6. Price RW, Peterson J, Fuchs D, Angel TE, Zetterberg H, Hagberg L, et al. Approach to cerebrospinal fluid (CSF) biomarker discovery and evaluation in HIV infection. J Neuroimmune Pharmacol. 2013;8:1147–58. A detailed summary of the utility of CSF biomarkers as a window into the pathobiology, diagnosis and assessment of response to treatment in CNS involvement of HIV infection.

    Article  PubMed  PubMed Central  Google Scholar 

  7. Gonzalez-Scarano F, Martin-Garcia J. The neuropathogenesis of AIDS. Nat Rev Immunol. 2005;5:69–81.

    Article  CAS  PubMed  Google Scholar 

  8. Price RW. Neurological complications of HIV infection. Lancet. 1996;348:445–52.

    Article  CAS  PubMed  Google Scholar 

  9. Heaton RK, Clifford DB, Franklin Jr DR, Woods SP, Ake C, Vaida F, et al. HIV-associated neurocognitive disorders persist in the era of potent antiretroviral therapy: CHARTER Study. Neurology. 2010;75:2087–96.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Robertson KR, Smurzynski M, Parsons TD, Wu K, Bosch RJ, Wu J, et al. The prevalence and incidence of neurocognitive impairment in the HAART era. AIDS. 2007;21:1915–21.

    Article  PubMed  Google Scholar 

  11. Simioni S, Cavassini M, Annoni JM, Rimbault Abraham A, Bourquin I, Schiffer V, et al. Cognitive dysfunction in HIV patients despite long-standing suppression of viremia. AIDS. 2010;24:1243–50.

    PubMed  Google Scholar 

  12. Meyer AC, Boscardin WJ, Kwasa JK, Price RW. Is it time to rethink how neuropsychological tests are used to diagnose mild forms of HIV-associated neurocognitive disorders? Impact of false-positive rates on prevalence and power. Neuroepidemiology. 2013;41:208–16. A thought-provoking perspective on the potential misclassifcation of milder forms of HIV-associated neurocognitive disorders using currently accepted definitions and the impact of high false positive frequencies on prevalence estimates.

    Article  PubMed  PubMed Central  Google Scholar 

  13. Gorman AA, Foley JM, Ettenhofer ML, Hinkin CH, van Gorp WG. Functional consequences of HIV-associated neuropsychological impairment. Neuropsychol Rev. 2009;19:186–203.

    Article  PubMed  PubMed Central  Google Scholar 

  14. Heaton RK, Marcotte TD, Mindt MR, Sadek J, Moore DJ, Bentley H, et al. The impact of HIV-associated neuropsychological impairment on everyday functioning. J Int Neuropsychol Soc. 2004;10:317–31.

    Article  PubMed  Google Scholar 

  15. Tozzi V, Balestra P, Murri R, Galgani S, Bellagamba R, Narciso P, et al. Neurocognitive impairment influences quality of life in HIV-infected patients receiving HAART. Int J STD AIDS. 2004;15:254–9.

    Article  CAS  PubMed  Google Scholar 

  16. Hinkin CH, Castellon SA, Durvasula RS, Hardy DJ, Lam MN, Mason KI, et al. Medication adherence among HIV+ adults: effects of cognitive dysfunction and regimen complexity. Neurology. 2002;59:1944–50.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Birbeck GL, Kvalsund MP, Byers PA, Bradbury R, Mang’ombe C, Organek N, et al. Neuropsychiatric and socioeconomic status impact antiretroviral adherence and mortality in rural Zambia. Am J Trop Med Hyg. 2011;85:782–9.

    Article  PubMed  PubMed Central  Google Scholar 

  18. Andrade AS, Deutsch R, Celano SA, Duarte NA, Marcotte TD, Umlauf A, et al. Relationships among neurocognitive status, medication adherence measured by pharmacy refill records, and virologic suppression in HIV-infected persons. J Acquir Immune Defic Syndr. 2013;62:282–92.

    Article  PubMed  PubMed Central  Google Scholar 

  19. Vivithanaporn P, Heo G, Gamble J, Krentz HB, Hoke A, Gill MJ, et al. Neurologic disease burden in treated HIV/AIDS predicts survival: a population-based study. Neurology. 2010;75:1150–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Heaton RK, Franklin DR, Ellis RJ, McCutchan JA, Letendre SL, Leblanc S, et al. HIV-associated neurocognitive disorders before and during the era of combination antiretroviral therapy: differences in rates, nature, and predictors. J Neurovirol. 2011;17:3–16.

    Article  CAS  PubMed  Google Scholar 

  21. Peluso MJ, Spudich S. Treatment of HIV in the CNS: effects of antiretroviral therapy and the promise of non-antiretroviral therapeutics. Curr HIV/AIDS Rep. 2014;11(3):353–62.

    Article  PubMed  Google Scholar 

  22. Burdo TH, Lackner A, Williams KC. Monocyte/macrophages and their role in HIV neuropathogenesis. Immunol Rev. 2013;254:102–13. This review outlines evidence in support of the widely accepted hypotheis that monocyte/macrophage activation in the CNS is a primary mechanism underlying neurological deficits in treated HIV infection.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  23. Ellis RJ, Badiee J, Vaida F, Letendre S, Heaton RK, Clifford D, et al. CD4 nadir is a predictor of HIV neurocognitive impairment in the era of combination antiretroviral therapy. AIDS. 2011;25:1747–51.

    Article  CAS  PubMed  Google Scholar 

  24. Hellmuth J, Milanini B, Valcour V. Interactions between ageing and NeuroAIDS. Curr Opin HIV AIDS. 2014;9:527–32.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Masters MC, Ances BM. Role of neuroimaging in HIV-associated neurocognitive disorders. Semin Neurol. 2014;34:089–102. This review highlights several of the key imaging techniques used to evaluate HIV-associated neurocognitive disorders.

    Article  Google Scholar 

  26. Becker JT, Cuesta P, Fabrizio M, Sudre G, Vergis EN, Douaihy A, et al. Brain structural and functional recovery following initiation of combination antiretroviral therapy. J Neurovirol. 2012;18:423–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Harezlak J, Buchthal S, Taylor M, Schifitto G, Zhong J, Daar E, et al. Persistence of HIV-associated cognitive impairment, inflammation, and neuronal injury in era of highly active antiretroviral treatment. AIDS. 2011;25:625–33.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Mohamed MA, Barker PB, Skolasky RL, Selnes OA, Moxley RT, Pomper MG, et al. Brain metabolism and cognitive impairment in HIV infection: a 3-T magnetic resonance spectroscopy study. Magn Reson Imaging. 2010;28:1251–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Plessis SD, Vink M, Joska JA, Koutsilieri E, Stein DJ, Emsley R. HIV infection and the fronto-striatal system: a systematic review and meta-analysis of fMRI studies. AIDS. 2014;28:803–11. This meta-analysis of functional imaging studies evaluating the impact of HIV on the brain identified consistent differences in the left inferior frontal gyrus and caudate nucleus between HIV-infected participants and uninfected controls across studies.

    Article  PubMed  Google Scholar 

  30. Caniglia EC, Cain LE, Justice A, Tate J, Logan R, Sabin C, et al. Antiretroviral penetration into the CNS and incidence of AIDS-defining neurologic conditions. Neurology. 2014;83:134–41. This large multinational observational cohort study found an association between intiation of an ART regimen with a high CNS penetration effectiveness (CPE) score and risk of HIV dementia. While these unexpected results may have been due to various limitations of the study, including channeling bias, they also underscore the ongoing controversy regarding the impact of treatment with an ART regimen with higher CPE score on cognitive function.

    Article  PubMed  PubMed Central  Google Scholar 

  31. Ma Q, Vaida F, Wong J, Sanders CA, Kao YT, Croteau D, et al. Long-term efavirenz use is associated with worse neurocognitive functioning in HIV-infected patients. J Neurovirol. 2016;22:170–8.

    Article  CAS  PubMed  Google Scholar 

  32. Robertson KR, Su Z, Margolis DM, Krambrink A, Havlir DV, Evans S, et al. Neurocognitive effects of treatment interruption in stable HIV-positive patients in an observational cohort. Neurology. 2010;74:1260–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Dufour CA, Marquine MJ, Fazeli PL, Henry BL, Ellis RJ, Grant I, et al. Physical exercise is associated with less neurocognitive impairment among HIV-infected adults. J Neurovirol. 2013;19:410–7.

    Article  PubMed  PubMed Central  Google Scholar 

  34. Evering TH, Applebaum A, La Mar M, Garmon D, Dorfman D, Markowitz M. Rates of non-confounded HIV-associated neurocognitive disorders in men initiating combination antiretroviral therapy during primary infection. AIDS. 2016;30:203–10. Although limited by its small sample size, the exclusion of individuals with comorbid conditions that could confound or negatively impact cognitive function was a major strength of this cross-sectional study that demonstrated low rates of HIV-associated neurocognitive disorders in individuals who initiated ART during primary infection.

    Article  CAS  PubMed  Google Scholar 

  35. Crum-Cianflone NF, Moore DJ, Letendre S, Poehlman Roediger M, Eberly L, Weintrob A, et al. Low prevalence of neurocognitive impairment in early diagnosed and managed HIV-infected persons. Neurology. 2013;80:371–9.

    Article  PubMed  PubMed Central  Google Scholar 

  36. Kore I, Ananworanich J, Valcour V, Fletcher JL, Chalermchai T, Paul R, et al. Neuropsychological impairment in acute HIV and the effect of immediate antiretroviral therapy. J Acquir Immune Defic Syndr. 2015;70:393–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Wright E, Grund B, Robertson K, Cysique L, Collins G, Brew B, et al. No difference between the effects of immediate versus deferred ART on neuropsychological test performance in HIV-positive adults with CD4+ cell counts > 500 cells/μL. Barcelona: Presented at the 15th European AIDS Conference; 2015.

    Google Scholar 

  38. Ndhlovu LC, Umaki T, Chew GM, Chow DC, Agsalda M, Kallianpur KJ, et al. 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 Neurovirol. 2014;20:571–82.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Gates TM, Cysique LA, Chaganti J, Siefried KJ, Brew BJ. Maraviroc-enhanced CART improves cognition in virally suppressed HAND: a pilot study. Seattle: Presented at the 22nd Conference on Retroviruses and Opportunistic Infections; 2015.

    Google Scholar 

  40. Letendre S, Marquie-Beck J, Capparelli E, Best B, Clifford D, Collier AC, et al. Validation of the CNS penetration-effectiveness rank for quantifying antiretroviral penetration into the central nervous system. Arch Neurol. 2008;65:65–70.

    Article  PubMed  PubMed Central  Google Scholar 

  41. Baker LM, Paul RH, Heaps-Woodruff JM, Chang JY, Ortega M, Margolin Z, et al. 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. 2015;10(3):487–92.

    Article  PubMed  Google Scholar 

  42. Fabbiani M, Grima P, Milanini B, Mondi A, Baldonero E, Ciccarelli N, et al. Antiretroviral neuropenetration scores better correlate with cognitive performance of HIV-infected patients after accounting for drug susceptibility. Antivir Ther. 2015;20:441–7.

    Article  CAS  PubMed  Google Scholar 

  43. Vassallo M, Durant J, Biscay V, Lebrun-Frenay C, Dunais B, Laffon M, et al. Can high central nervous system penetrating antiretroviral regimens protect against the onset of HIV-associated neurocognitive disorders? AIDS. 2014;28:493–501.

    Article  CAS  PubMed  Google Scholar 

  44. Marra CM, Zhao Y, Clifford DB, Letendre S, Evans S, Henry K, et al. Impact of combination antiretroviral therapy on cerebrospinal fluid HIV RNA and neurocognitive performance. AIDS. 2009;23:1359–66.

    Article  PubMed  PubMed Central  Google Scholar 

  45. Libertone R, Lorenzini P, Balestra P, Pinnetti C, Ricottini M, Plazzi MM, et al. Central nervous system penetration-effectiveness rank does not reliably predict neurocognitive impairment in HIV-infected individuals. J Int AIDS Soc. 2014;17:19655.

    PubMed  PubMed Central  Google Scholar 

  46. Ellis RJ, Letendre S, Vaida F, Haubrich R, Heaton RK, Sacktor N, et al. Randomized trial of central nervous system-targeted antiretrovirals for HIV-associated neurocognitive disorder. Clin Infect Dis. 2014;58:1015–22. This small randomized controlled trial, which was terminated early, did not find a significant cognitive benefit of CNS-targeted compared with non-CNS-targeted ART regimens.

    Article  CAS  PubMed  Google Scholar 

  47. Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. Department of Health and Human Services. Available at http://aidsinfo.nih.gov/contentfiles/lvguidelines/AdultandAdolescentGL.pdf. Accessed 18 Mar 2016.

  48. Canestri A, Lescure FX, Jaureguiberry S, Moulignier A, Amiel C, Marcelin AG, 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;50:773–8.

    Article  PubMed  Google Scholar 

  49. Peluso MJ, Ferretti F, Peterson J, Lee E, Fuchs D, Boschini A, et al. Cerebrospinal fluid HIV escape associated with progressive neurologic dysfunction in patients on antiretroviral therapy with well controlled plasma viral load. AIDS. 2012;26:1765–74.

    Article  CAS  PubMed  Google Scholar 

  50. Ferretti F, Gisslen M, Cinque P, Price RW. Cerebrospinal fluid HIV escape from antiretroviral therapy. Curr HIV/AIDS Rep. 2015;12:280–8. The authors review the poorly understood but well documented phenomenon of CSF escape in HIV.

    Article  PubMed  Google Scholar 

  51. Lescure FX, Moulignier A, Savatovsky J, Amiel C, Carcelain G, Molina JM, et al. CD8 encephalitis in HIV-infected patients receiving cART: a treatable entity. Clin Infect Dis. 2013;57:101–8.

    Article  CAS  PubMed  Google Scholar 

  52. Fois AF, Brew BJ. The potential of the CNS as a reservoir for HIV-1 infection: implications for HIV eradication. Curr HIV/AIDS Rep. 2015;12:299–303.

    Article  PubMed  Google Scholar 

  53. Chow FC, Regan S, Feske S, Meigs JB, Grinspoon SK, Triant VA. Comparison of ischemic stroke incidence in HIV-infected and non-HIV-infected patients in a US health care system. J Acquir Immune Defic Syndr. 2012;60:351–8.

    Article  PubMed  PubMed Central  Google Scholar 

  54. Marcus JL, Leyden WA, Chao CR, Chow FC, Horberg MA, Hurley LB, et al. HIV infection and incidence of ischemic stroke. AIDS. 2014;28:1911–9.

    Article  CAS  PubMed  Google Scholar 

  55. Rasmussen LD, Engsig FN, Christensen H, Gerstoft J, Kronborg G, Pedersen C, et al. Risk of cerebrovascular events in persons with and without HIV. AIDS. 2011;25:1637–46.

    Article  PubMed  Google Scholar 

  56. Sico JJ, Chang CC, So-Armah K, Justice AC, Hylek E, Skanderson M, et al. HIV status and the risk of ischemic stroke among men. Neurology. 2015;84:1933–40. This study of the large, racially diverse Veterans Aging Cohort Study-Virtual Cohort confirmed findings from several other cohorts that HIV infection is an independent risk factor for ischemic stroke. Women, however, were excluded from the study.

    Article  PubMed  PubMed Central  Google Scholar 

  57. Chow FC, He W, Bacchetti P, Regan S, Feske SK, Meigs JB, et al. Elevated rates of intracerebral hemorrhage in individuals from a US clinical care HIV cohort. Neurology. 2014;83:1705–11.

    Article  PubMed  PubMed Central  Google Scholar 

  58. Durand M, Sheehy O, Baril J-G, LeLorier J, Tremblay CL. Risk of spontaneous intracranial hemorrhage in HIV-infected individuals: a population-based cohort study. J Stroke Cerebrovasc Dis. 2013;22:e34–41.

    Article  PubMed  Google Scholar 

  59. Hasse B, Ledergerber B, Furrer H, Battegay M, Hirschel B, Cavassini M, et al. Morbidity and aging in HIV-infected persons: the Swiss HIV Cohort Study. Clin Infect Dis. 2011;53:1130–9.

    Article  PubMed  Google Scholar 

  60. Schouten J, Wit FW, Stolte IG, Kootstra NA, van der Valk M, Geerlings SE, et al. Cross-sectional comparison of the prevalence of age-associated comorbidities and their risk factors between HIV-infected and uninfected individuals: the AGEhIV cohort study. Clin Infect Dis. 2014;59:1787–97.

    Article  PubMed  Google Scholar 

  61. Womack JA, Chang CC, So-Armah KA, Alcorn C, Baker JV, Brown ST, et al. HIV infection and cardiovascular disease in women. J Am Heart Assoc. 2014;3, e001035.

    Article  PubMed  PubMed Central  Google Scholar 

  62. Triant VA, Lee H, Hadigan C, Grinspoon SK. Increased acute myocardial infarction rates and cardiovascular risk factors among patients with human immunodeficiency virus disease. J Clin Endocrinol Metab. 2007;92:2506–12.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Lang S, Mary-Krause M, Cotte L, Gilquin J, Partisani M, Simon A, et al. CO4 FHDoH-A: increased risk of myocardial infarction in HIV-infected patients in France, relative to the general population. AIDS. 2010;24:1228–30.

    Article  PubMed  Google Scholar 

  64. Chow FC, Wilson MR, Wu K, Ellis R, Bosch R, Linas B. Stroke incidence highest in women and black HIV-infected participants in ALLRT cohort. Boston: Presented at the 23nd Conference on Retroviruses and Opportunistic Infections; 2016.

    Google Scholar 

  65. Li JZ, Arnold KB, Lo J, Dugast AS, Plants J, Ribaudo HJ, et al. Differential levels of soluble inflammatory markers by human immunodeficiency virus controller status and demographics. Open Forum Infect Dis. 2015;2:117.

    Article  Google Scholar 

  66. Martin GE, Gouillou M, Hearps AC, Angelovich TA, Cheng AC, Lynch F, et al. Age-associated changes in monocyte and innate immune activation markers occur more rapidly in HIV infected women. PLoS One. 2013;8, e55279.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Longenecker CT, Jiang Y, Orringer CE, Gilkeson RC, Debanne S, Funderburg NT, et al. Soluble CD14 is independently associated with coronary calcification and extent of subclinical vascular disease in treated HIV infection. AIDS. 2014;28:969–77.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Fitch KV, Srinivasa S, Abbara S, Burdo TH, Williams KC, Eneh P, et al. Noncalcified coronary atherosclerotic plaque and immune activation in HIV-infected women. J Infect Dis. 2013;208:1737–46. This study demonstrated differences in immune activation between HIV-infected women and men, with greater immune activation in HIV-infected women, which corresponded to a higher burden of noncalcified coronary plaque.

    Article  PubMed  PubMed Central  Google Scholar 

  69. Westhorpe CLV, Maisa A, Spelman T, Hoy JF, Dewar EM, Karapanagiotidis S, et al. Associations between surface markers on blood monocytes and carotid atherosclerosis in HIV-positive individuals. Immunol Cell Biol. 2014;92:133–8.

    Article  CAS  PubMed  Google Scholar 

  70. McKibben RA, Margolick JB, Grinspoon S, Li X, Palella FJ, Kingsley LA, et al. Elevated levels of monocyte activation markers are associated with subclinical atherosclerosis in men with and those without HIV infection. J Infect Dis. 2015;211:1219–28.

    PubMed  Google Scholar 

  71. Lo J, Lu MT, Ihenachor EJ, Wei J, Looby SE, Fitch KV, et al. Effects of statin therapy on coronary artery plaque volume and high-risk plaque morphology in HIV-infected patients with subclinical atherosclerosis: a randomised, double-blind, placebo-controlled trial. Lancet HIV. 2015;2:e52–63.

    Article  PubMed  PubMed Central  Google Scholar 

  72. Curno MJ, Rossi S, Hodges-Mameletzis I, Johnston R, Price MA, Heidari S. A systematic review of the inclusion (or exclusion) of women in HIV research: from clinical studies of antiretrovirals and vaccines to cure strategies. J Acquir Immune Defic Syndr. 2016;71:181–8.

    Article  CAS  PubMed  Google Scholar 

  73. Gillis J, Smieja M, Cescon A, Rourke SB, Burchell AN, Cooper C, et al. Risk of cardiovascular disease associated with HCV and HBV coinfection among antiretroviral-treated HIV-infected individuals. Antivir Ther. 2014;19:309–17.

    Article  CAS  PubMed  Google Scholar 

  74. Freiberg MS, Cheng DM, Kraemer KL, Saitz R, Kuller LH, Samet JH. The association between hepatitis C infection and prevalent cardiovascular disease among HIV-infected individuals. AIDS. 2007;21:193–7.

    Article  PubMed  PubMed Central  Google Scholar 

  75. Fernández-Montero JV, Barreiro P, de Mendoza C, Labarga P, Soriano V. Hepatitis C virus coinfection independently increases the risk of cardiovascular disease in HIV-positive patients. J Viral Hepat. 2016;23:47–52.

    Article  PubMed  CAS  Google Scholar 

  76. Bedimo R, Westfall AO, Mugavero M, Drechsler H, Khanna N, Saag M. Hepatitis C virus coinfection and the risk of cardiovascular disease among HIV-infected patients. HIV Med. 2010;11:462–8.

    CAS  PubMed  Google Scholar 

  77. Sabin CA, Worm SW, Weber R, Reiss P, El-Sadr W, Dabis F, et al. Use of nucleoside reverse transcriptase inhibitors and risk of myocardial infarction in HIV-infected patients enrolled in the D:A:D study: a multi-cohort collaboration. Lancet. 2008;371:1417–26.

    Article  CAS  PubMed  Google Scholar 

  78. Choi AI, Vittinghoff E, Deeks SG, Weekley CC, Li Y, Shlipak MG. Cardiovascular risks associated with abacavir and tenofovir exposure in HIV-infected persons. AIDS. 2011;25:1289–98.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Worm SW, Kamara DA, Reiss P, Fontas E, De Wit S, El-Sadr W, et al. Evaluation of HIV protease inhibitor use and the risk of sudden death or nonhemorrhagic stroke. J Infect Dis. 2012;205:535–9.

    Article  CAS  PubMed  Google Scholar 

  80. Gutierrez J, Goldman J, Dwork AJ, Elkind MS, Marshall RS, Morgello S. Brain arterial remodeling contribution to nonembolic brain infarcts in patients with HIV. Neurology. 2015;85:1139–45.

    Article  CAS  PubMed  Google Scholar 

  81. Soontornniyomkij V, Umlauf A, Chung SA, Cochran ML, Soontornniyomkij B, Gouaux B, et al. HIV protease inhibitor exposure predicts cerebral small vessel disease. AIDS. 2014;28:1297–306.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Chow FC, Bacchetti P, Kim AS, Price RW, Hsue PY. Effect of CD4+ cell count and viral suppression on risk of ischemic stroke in HIV infection. AIDS. 2014;28:2573–7.

    Article  PubMed  PubMed Central  Google Scholar 

  83. Vinikoor MJ, Napravnik S, Floris-Moore M, Wilson S, Huang DY, Eron JJ. Incidence and clinical features of cerebrovascular disease among HIV-infected adults in the Southeastern United States. AIDS Res Hum Retroviruses. 2013;29:1068–74.

    Article  PubMed  PubMed Central  Google Scholar 

  84. Sabin CA, Ryom L, De Wit S, Mocroft A, Phillips AN, Worm SW, et al. Associations between immune depression and cardiovascular events in HIV infection. AIDS. 2013;27:2735–48.

    Article  PubMed  Google Scholar 

  85. Duprez DA, Neuhaus J, Kuller LH, Tracy R, Belloso W, De Wit S, et al. Inflammation, coagulation and cardiovascular disease in HIV-infected individuals. PLoS One. 2012;7, e44454.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Tenorio AR, Zheng Y, Bosch RJ, Krishnan S, Rodriguez B, Hunt PW, et al. Soluble markers of inflammation and coagulation but not T-cell activation predict non-AIDS-defining morbid events during suppressive antiretroviral treatment. J Infect Dis. 2014;210:1248–59. Several inflammatory markers predicted non-AIDS-defining events in this case–control study, including a composite of myocardial infarction and stroke.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Ghosh S, Chandran A, Jansen JP. Epidemiology of HIV-related neuropathy: a systematic literature review. AIDS Res Hum Retroviruses. 2012;28:36–48.

    Article  PubMed  Google Scholar 

  88. Robinson-Papp J, Sharma S, Simpson DM, Morgello S. Autonomic dysfunction is common in HIV and associated with distal symmetric polyneuropathy. J Neurovirol. 2013;19:172–80. This study of over 100 clinic-based HIV-infected patients investigated the prevalence of autonomic dysfunction in HIV and its association with distal symmetric neuropathy.

    Article  PubMed  PubMed Central  Google Scholar 

  89. Kaku M, Simpson DM. HIV neuropathy. Curr Opin HIV AIDS. 2014;9:521–6. This is a comprehensive review of the clinical presenation and management of HIV associated neuropathy.

    Article  CAS  PubMed  Google Scholar 

  90. Geraci AP, Simpson DM. Neurological manifestations of HIV-1 infection in the HAART era. Compr Ther. 2001;27:232–41.

    Article  CAS  PubMed  Google Scholar 

  91. Lee AJ, Bosch RJ, Evans SR, Wu K, Harrison T, Grant P, et al. Patterns of peripheral neuropathy in ART-naive patients initiating modern ART regimen. J Neurovirol. 2015;21:210–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Simpson DM, Tagliati M. Nucleoside analogue-associated peripheral neuropathy in human immunodeficiency virus infection. J Acquir Immune Defic Syndr Hum Retrovirol. 1995;9:153–61.

    CAS  PubMed  Google Scholar 

  93. Brinkman K, ter Hofstede HJ, Burger DM, Smeitink JA, Koopmans PP. Adverse effects of reverse transcriptase inhibitors: mitochondrial toxicity as common pathway. AIDS. 1998;12:1735–44.

    Article  CAS  PubMed  Google Scholar 

  94. Lehmann HC, Chen W, Borzan J, Mankowski JL, Hoke A. Mitochondrial dysfunction in distal axons contributes to human immunodeficiency virus sensory neuropathy. Ann Neurol. 2011;69:100–10.

    Article  CAS  PubMed  Google Scholar 

  95. Pettersen JA, Jones G, Worthington C, Krentz HB, Keppler OT, Hoke A, et al. Sensory neuropathy in human immunodeficiency virus/acquired immunodeficiency syndrome patients: protease inhibitor-mediated neurotoxicity. Ann Neurol. 2006;59:816–24.

    Article  CAS  PubMed  Google Scholar 

  96. Ellis RJ, Marquie-Beck J, Delaney P, Alexander T, Clifford DB, McArthur JC, et al. Human immunodeficiency virus protease inhibitors and risk for peripheral neuropathy. Ann Neurol. 2008;64:566–72.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Chen H, Clifford DB, Deng L, Wu K, Lee AJ, Bosch RJ, et al. Peripheral neuropathy in ART-experienced patients: prevalence and risk factors. J Neurovirol. 2013;19:557–64.

    Article  PubMed  PubMed Central  Google Scholar 

  98. Keswani SC, Polley M, Pardo CA, Griffin JW, McArthur JC, Hoke A. Schwann cell chemokine receptors mediate HIV-1 gp120 toxicity to sensory neurons. Ann Neurol. 2003;54:287–96.

    Article  CAS  PubMed  Google Scholar 

  99. Hao S. The molecular and pharmacological mechanisms of HIV-related neuropathic pain. Curr Neuropharmacol. 2013;11:499–512.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Wang SX, Ho EL, Grill M, Lee E, Peterson J, Robertson K, et al. Peripheral neuropathy in primary HIV infection associates with systemic and central nervous system immune activation. J Acquir Immune Defic Syndr. 2014;66:303–10. This study is one of the few that has focused on impairment of the peripheral nevous system in primary HIV infection. Peripheral neuropathy was prevalent in ART-naïve subjects and associated with blood and CSF markers of immune activation.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Pardo CA, McArthur JC, Griffin JW. HIV neuropathy: insights in the pathology of HIV peripheral nerve disease. J Peripher Nerv Syst. 2001;6:21–7.

    Article  CAS  PubMed  Google Scholar 

  102. Evans SR, Ellis RJ, Chen H, Yeh TM, Lee AJ, Schifitto G, et al. Peripheral neuropathy in HIV: prevalence and risk factors. AIDS. 2011;25:919–28.

    Article  PubMed  PubMed Central  Google Scholar 

  103. Cornblath DR, Chaudhry V, Carter K, Lee D, Seysedadr M, Miernicki M, et al. Total neuropathy score: validation and reliability study. Neurology. 1999;53:1660–4.

    Article  CAS  PubMed  Google Scholar 

  104. Stavros K, Simpson DM. Understanding the etiology and management of HIV-associated peripheral neuropathy. Curr HIV/AIDS Rep. 2014;11:195–201.

    Article  PubMed  Google Scholar 

  105. Simpson DM, Brown S, Tobias JK, Vanhove GF. NGX-4010, a capsaicin 8 % dermal patch, for the treatment of painful HIV-associated distal sensory polyneuropathy: results of a 52-week open-label study. Clin J Pain. 2014;30:134–42.

    PubMed  Google Scholar 

  106. Brown S, Simpson DM, Moyle G, Brew BJ, Schifitto G, Larbalestier N, et al. NGX-4010, a capsaicin 8% patch, for the treatment of painful HIV-associated distal sensory polyneuropathy: integrated analysis of two phase III, randomized, controlled trials. AIDS Res Ther. 2013;10:5. Evaluation of two phase III double-blinded clinical trials on the efficacy of a capsaicin 8% dermal patch for the treatment of HIV associated neuropathy found that a single 30 minute application of the patch provided significant pain relief for at least 12 weeks.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Abrams DI, Jay CA, Shade SB, Vizoso H, Reda H, Press S, et al. Cannabis in painful HIV-associated sensory neuropathy: a randomized placebo-controlled trial. Neurology. 2007;68:515–21.

    Article  CAS  PubMed  Google Scholar 

  108. Ellis RJ, Toperoff W, Vaida F, van den Brande G, Gonzales J, Gouaux B, et al. Smoked medicinal cannabis for neuropathic pain in HIV: a randomized, crossover clinical trial. Neuropsychopharmacology. 2009;34:672–80.

    Article  CAS  PubMed  Google Scholar 

  109. Youle M, Osio M. A double-blind, parallel-group, placebo-controlled, multicentre study of acetyl L-carnitine in the symptomatic treatment of antiretroviral toxic neuropathy in patients with HIV-1 infection. HIV Med. 2007;8:241–50.

    Article  CAS  PubMed  Google Scholar 

  110. McArthur JC, Yiannoutsos C, Simpson DM, Adornato BT, Singer EJ, Hollander H, et al. A phase II trial of nerve growth factor for sensory neuropathy associated with HIV infection. AIDS Clinical Trials Group Team 291. Neurology. 2000;54:1080–8.

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Neurology, University of California, San Francisco, CA, USA

    Nisha S. Bhatia

  2. Departments of Neurology and Medicine (Infectious Diseases), University of California, San Francisco, CA, USA

    Felicia C. Chow

Authors
  1. Nisha S. Bhatia
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Felicia C. Chow
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Nisha S. Bhatia.

Ethics declarations

Conflict of Interest

Nisha S. Bhatia and Felicia C. Chow declare that they have no conflict of interest.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

Additional information

This article is part of the Topical Collection on Infection

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Bhatia, N.S., Chow, F.C. Neurologic Complications in Treated HIV-1 Infection. Curr Neurol Neurosci Rep 16, 62 (2016). https://doi.org/10.1007/s11910-016-0666-1

Download citation

  • Published:

  • DOI: https://doi.org/10.1007/s11910-016-0666-1

Keywords

Search

Navigation