Curr Infect Dis Rep (2013) 15:564–568 DOI 10.1007/s11908-013-0375-8
CENTRAL NERVOUS SYSTEM (J LYONS, SECTION EDITOR)
Neurological Complications in Controlled HIV Infection Kate M. Crossley & Bruce J. Brew
Published online: 22 October 2013 # Springer Science+Business Media New York 2013
Abstract In recent years, there have been great advances in therapies for human immunodeficiency virus (HIV) that have allowed suppression of the virus and its effects on the body. Despite this progress, neurological complications persist in HIV-infected individuals. In this review we consider the possible ways that HIV might cause neurotoxicity and neuroinflammation. We discuss the spectrum of neurological disorders caused by HIV and its treatment, with a particular focus on both HIV-associated neurocognitive disorders and peripheral neuropathies. Since there has been a shift to HIV being a chronic illness, we also review the increasing prevalence of cerebrovascular disease and neurodegenerative disorders. Keywords Human Immunodeficiency Virus . Neurotoxicity . HIV-Associated Neurocognitive Disorders . Peripheral Neuropathy
neurocognitive disorders and, perhaps, neurodegenerative conditions. In particular, there has been a persistence of the milder forms of the HIV-associated neurocognitive disorders (HANDs) and a high prevalence of peripheral neuropathies, both of which have a significant impact on quality of life. This review will highlight recent additions to our understanding of the neurological complications of controlled HIV infection. It is important to understand the neuropathogenesis of HIV, and hence, we will cover the concept of the CNS as a reservoir for HIV and how this provides a possible mechanism for the persisting neurocognitive dysfunction seen since the introduction of HAART. We will also discuss the spectrum of neurological disorders caused by HIV, with particular focus on HAND, peripheral neuropathies, cerebrovascular disease, and neurodegenerative disorders, with the intention of providing an update on the most commonly encountered neurological disorders seen in the virally suppressed HIV patient.
Introduction The CNS as a Viral Reservoir Human immunodeficiency virus (HIV) infected individuals are affected by the full spectrum of neurological disorders. However, the introduction of highly active antiretroviral therapy (HAART) has shifted this spectrum from the opportunistic infections, severe neurocognitive disorders, and central nervous system (CNS) tumors seen in advanced disease to less severe K. M. Crossley : B. J. Brew (*) Department of Neurology, St. Vincent’s Hospital, Level 4 Xavier Building, 390 Victoria St Darlinghurst, Sydney, Australia e-mail: [email protected] B. J. Brew Peter Duncan Neurosciences Unit and Applied Neurosciences Programme, St Vincent’s Centre for Applied Medical Research, Sydney, Australia
The CNS is invaded early in the course of acute HIV infection. HAART has been shown to decrease the CSF viral load, and generally, CSF HIV-1 viral load levels correspond to plasma levels [1, 2••]. However, the blood brain barrier’s structure, efflux pumps, and metabolizing enzymes limit the penetration of HAART to the CNS. The protein binding of antiretroviral drugs (ARVs) in plasma compounds this [1, 3]. Thus, the CNS acts as a sanctuary site for HIV, where it infects infiltrating monocytes and resting CD4+ lymphocytes, which act as a viral reservoir [4•]. This enables the virus to evade HAART and provides a potential source for persisting viral replication [5, 6]. The virus can mutate and evolve in the CNS separately from the virus in the plasma, even in those with suppressed plasma viral load [2••, 7•, 8].
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This chronic low-grade viral replication is thought to contribute to persisting neuroinflammation and impaired neurocognition, even in HAART-treated patients [1, 5, 9]. This hypothesis is supported by a 2013 study that showed that patients with latent HIV (defined as having high levels of HIV-1 DNA and no detectable RNA or significant p24 in the CNS) had moderate cognitive deficits and changes of neuroinflammation [10•]. HIV also produces viral proteins that are neurotoxic, such as the transcription factor Tat [11]. Since none of the current ARVs work at the transcription level, they do not suppress the ongoing production of Tat [12].
Spectrum of Neurological Disorders Caused by HIV Only 1 %–4 % of patients develop acute neurological disease at seroconversion [13]. The most common of these is aseptic meningitis, which in most cases will respond to supportive care [14]. A few patients go on to have recurrent bouts of aseptic meningitis [3, 13]. HIV may also cause more chronic, slowly progressive processes [13]. These include HAND and peripheral neuropathies, as previously mentioned, but also psychiatric conditions, chronic headaches, motor weakness, spasticity, and incoordination [2••, 3]. In addition, other factors, such as chronic substance abuse, antiretroviral neurotoxicity, and malnutrition, may cloud the picture. This is further compounded by the fact that many individuals with HIV infection are now aging [5].
HIV-Associated Neurocognitive Disorders HAND consists of three clinically diagnosed subdisorders: asymptomatic neurocognitive impairment (ANI), mild neurocognitive disorder (MND), and HIV-associated dementia (HAD) [15]. ANI is a subclinical cognitive dysfunction that does not interfere with daily function. MND is a mild cognitive dysfunction that does interfere with activities of daily living to a limited extent. HAD is a subcortical dementia that causes a combination of significant cognitive and functional decline with marked impact on daily activities. HAND is common even in those with suppressed HIV plasma viraemia [2••, 16]. The CHARTER study identified confounding conditions that may interfere with a HAND diagnosis (i.e., substance abuse, major depression, brain trauma, etc.). The overall prevalence of HAND in all recruited patients was 52 %. Excluding severely confounded cases, the level of ANI in patients who were virally suppressed remained relatively high at 33 %, with an estimated 12 % prevalence of MND and 2 % for HAD [17]. Ciccarelli et al. also reported a high prevalence of minor cognitive disorders, with ANI found in 35.6 % of a population of apparently asymptomatic HIVinfected patients [18•].
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While the incidence of HAD has significantly fallen since the introduction of HAART, its prevalence is increasing as patients live longer [19]. Approximately 7 % of treated HIVpositive patients develop HAD, as compared with 25 % of untreated HIV-infected patients [20]. There is also emerging evidence of metabolic abnormalities and volume loss in the virally suppressed brain. While persisting peripheral blood viraemia is associated with regional brain atrophy [21•], it has also been shown that virally suppressed HIV-positive patients have faster brain volume loss than do HIV-negative patients [22]. Anderson, Law, et al. used fluorine-18-flourodeoxyglucose positron emission tomography (FDG-PET) scanning to examine the prevalence of cerebral metabolic abnormalities in virally suppressed patients. They found that more than half (55 %) of the patients exhibited varying severities of mesial frontal reduction in the relative metabolic rate of glucose [22]. Several possible explanations have been proposed for this persisting prevalence of HAND. One theory is that with the increased survival and later age of infections, the aging brain is at increased vulnerability for cognitive impairment. There is insufficient evidence to support this currently [23, 24]. Another theory is that in the context of the poor CNS penetration of some antiretroviral agents, there is a persistence of HIV replication in brain macrophages, with subsequent evolution of highly neurovirulent CNS HIV strains [18•, 23]. Pharmacokinetic data have enabled the ranking of antiretroviral CNS penetration effectiveness (CPE). Antiretroviral drugs with higher CPE scores (neuroHAART) have been observed to decrease CSF viral load and improve neurocognitive function [4•, 23]. Similarly, the CHIC group in the United Kingdom observed an independent association between lower CPE scores and higher all-cause mortality. They raised the possibility that this was the result of patients with advanced disease being prescribed regimens with lower scores but also suggested that low CPE scoring regimens are related to cognitive impairment [16]. Further research is needed to clarify the benefits and risks of neuroHAART. A third theory is that the HAART medications are themselves neurotoxic; however, the evidence is limited [18•, 23, 24]. There is also a possibility that in a minority of cases, HAND may be secondary to an immune reconstitution inflammatory syndrome (IRIS) induced by the commencement of antiretrovirals [8]. IRIS can develop in the presence of an opportunistic infection such as progressive multifocal leukoencephalopathy (PML), but the immune response might also directly target the reservoirs of human immunodeficiency virus in the brain [25]. The resultant CNS inflammation can cause persisting damage that may contribute to the patient’s future risk of HAND [1]. The risk factors for HAND in the virally suppressed patient appear to be a low nadir CD4 cell count [26] and possibly
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other factors such as disease duration, clade type, and CSF viraemia [1, 17, 27, 28]. It is unclear whether patients with both HIV and hepatitis C have higher rates of neurocognitive impairment than do patients with HIV infection alone, since there is conflicting evidence [29, 30]. The ALLRT study showed that active hepatitis C in the setting of virally suppressed HIV infection does not exacerbate neurocognitive dyfsunction [31]. The impact of neurocognitive impairment is significant, leading to difficulty with activities of daily living (including reduced adherence to treatment), increased morbidity and mortality, and decreased quality of life [16, 24, 27, 32].
HAND Therapy Several authors have advocated the early initiation of HAART, given the association between nadir CD4 count and HAND risk [5, 33•]. Reductions in the viral load in the CSF have been shown to correlate with improvements in cognition [28]. Some patients are able to achieve complete CSF viral suppression even with persisting detectable CNS virus, and these patients demonstrate similar neurocognitive improvement to those who achieve suppression in both plasma and CSF [27]. However, it is worth noting that CNS HIV suppression does not guarantee full cognitive recovery [34]. Patients should routinely be monitored for cognitive impairment to enable early diagnosis and treatment of HAND [24, 35••].
Peripheral Neuropathy The true prevalence of HIV-associated sensory neuropathies (HIV-SNs) is not well characterized, with most estimates falling between 30 % and 60 % worldwide in patients with HIV-1 infection [36••, 37]. However, there is autopsy evidence that all HIV-positive patients have pathological evidence of neuropathy [37]. The most common HIV-SN is distal sensory polyneuropathy (DSP). This is thought to be indirectly due to HIV via the chronic immune system activation [37]. DSP may be asymptomatic or, conversely, can result in a “stocking and glove” distribution of numbness, paraesthesia, and pain [38]. Using standard neurophysiological techniques, it is indistinguishable from antiretroviral toxic neuropathy (ATN), the incidence of which peaks within 3 months of commencing an antiretroviral [36••]. There is some evidence that neurophysiological excitability studies can distinguish between DSP and ATN [39]. In particular, the nucleoside reverse transcriptase inhibitors, such as stavudine and didanosine, have been associated with ATN [36••, 40]. Risk factors for peripheral neuropathy include prior neuropathy, older age, nutritional deficiencies, taller height,
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comorbidities (such as diabetes, alcohol abuse, or isoniazid exposure), and more advanced HIV infection, although it can occur at any stage [36••, 37, 38, 40].
Cerebrovascular Disease HIV-positive patients have an increased risk of stroke because of opportunistic infections, vasculopathy, and mass lesions, in addition to the metabolic effects of HIV and its treatment [13, 41]. There also tends to be a higher prevalence of traditional cardiovascular risk factors, such as smoking in patients with HIV, predisposing to vascular disease. Additionally, the prolonged lifespan of HIV patients since the introduction of HAART increases the proportion of older patients at increased stroke risk [42]. Although overall hospital admissions as a result of stroke decreased from 1997 to 2006 in the United States, the proportion of those in HIV-infected patients increased [43].
Neurodegenerative Disorders It has also been suggested that neurodegenerative diseases such as Alzheimer’s disease, Parkinson’s disease. and vascular cognitive impairment may be facilitated by the presence of HIV, although this is not yet certain [2••]. There is some neuropathological evidence, such as the finding of low concentrations of amyloid beta (AB) 1-42 and elevated tau in the CSF of HIV patients, which is akin to the pattern found in patients with Alzheimer’s disease [44]. Additionally, some, but not all, studies have found AB deposition in the brains of HIV-infected patients at autopsy [19].
Other Neurological Disorders Seizure disorders are common in HIV-positive patients, with a reported incidence as high as 11 %. Their management is complicated by the interactions of antiretrovirals and antiepileptic medication [45]. Vestibular symptoms are also common, irrespective of disease stage and may be due to direct effects of HIV on the peripheral and central vestibular system [46•]. Acute inflammatory demyelinating polyneuropathy, or Guillain-Barré syndrome, is seen as an HIV seroconversion illness, particularly in the context of a normal CD4 count, although it has been described in AIDS patients. Chronic inflammatory demyelinating polyneuropathy more frequently occurs in more advanced disease [3, 36••]. Other described peripheral neuropathies in HIV-positive patients with suppressed virus or during seroconversion include multifocal mononeuropathy,
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vasculitic neuropathies, brachial plexitis, and Bell’s palsy. The latter may be bilateral in HIV [47].
Conclusion Despite the dramatic improvement in HIV prognosis and morbidity that was the result of the introduction of HAART, neurological disorders continue to have a significant impact on the quality of life of individuals living with HIV. In particular, HAND and peripheral neuropathies both have a high prevalence in the virally suppressed patient, and neither can yet be adequately prevented, although, in HAND at least, trials are underway. Compliance with Ethics Guidelines Conflict of Interest Bruce Brew has been a board member for GlaxoSmithKline, Biogenldec, ViiV Healthcare, Merck Serono, International Journal for Tryptophan Research, Faculty of 1000 Medicine, Journal of Neurovirology, and Neurobehavioral HIV Medicine, is an employee of University of New South Wales, has received grants from National Health and Medical Research Council of Australia and MSRA, and has received honoraria from ViiV Healthcare, Boehringer Ingelheim, Abbott, Abbvie, and Biogen Idec. He has also received royalties from HIV Neurology and Palliative Neurology. Kate Crossley declares no conflicts 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.
References Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance 1. del Palacio M, Álvarez S, Muñoz-Fernández MA. HIV-1 infection and neurocognitive impairment in the current era. Rev Med Virol. 2012;22:33–45. 2. •• Cysique LA, Brew BJ. Prevalence of non-confounded HIV-associated neurocognitive impairment in the context of plasma HIV RNA suppression. J Neurovirol. 2011;17:176–83. A study of a cohort of advanced HIV+ individuals on cART that found that despite suppression of systemic viral load, HIV-related neuropsychological impairment prevalence reached 18.1%. 3. Singer EJ et al. Neurologic presentations of AIDS. Neurol Clin. 2010;28:253–75. 4. • Cysique LA, Waters EK, Brew BJ. Central nervous system antiretroviral efficacy in HIV infection: a qualitative and quantitative review and implications for future research. BMC Neurol. 2011;11:148. A meta-review that found that neuroHAART improves neurocognitive function and suppresses CSF HIV RNA.
567 5. Mirza A, Rathore MH. Human immunodeficiency virus and the central nervous system. Semin Pediatr Neurol. 2012;19:119–23. 6. Kraft-Terry SD et al. HIV-1 neuroimmunity in the era of antiretroviral therapy. Neurobiol Dis. 2010;37:542–8. 7. • Peluso MJ 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. Retrospective case series of 10 HIV-infected patients who presented with neurological symptoms and were shown to have CSF "escape" of virus. 8. Brew BJ. Benefit or toxicity from neurologically targeted antiretroviral therapy? Clin Infect Dis. 2010;50:930–2. 9. Liner KJ, Ro MJ, Robertson KR. HIV, antiretroviral therapies, and the brain. Curr HIV/AIDS Rep. 2010;7:85–91. 10. • Desplats P et al. Molecular and pathologic insights from latent HIV1 infection in the human brain. Neurology. 2013;80:1415–23. A case–control study of the neuropathologic and molecular findings in patients with latent CNS HIV-1 infection that found an association with increased levels of chromatin modifiers, including BCL11B. 11. Mocchetti I, Bachis A, Avdoshina V. Neurotoxicity of human immunodeficiency virus-1: viral proteins and axonal transport. Neurotox Res. 2012;21:79–89. 12. Jaeger LB, Nath A. Modeling HIV-associated neurocognitive disorders in mice: new approaches in the changing face of HIV neuropathogenesis. Dis Models Mech. 2012;5:313–22. 13. Hogan C, Wilkins E. Neurological complications in HIV. Clin Med. 2011;11(6):571–5. 14. Brew BJ et al. The neurological features of early and 'latent' human immunodeficiency virus infection. Aust NZ J Med. 1989;19:700–5. 15. Antinori A, Arendt G, Becker JT. Updated research nosology for HIVassociated neurocognitive disorders. Neurology. 2007;69:1789–99. 16. Garvey L et al. Antiretroviral therapy CNS penetration and HIV-1– associated CNS disease. Neurology. 2011;76:693–700. 17. Heaton RK et al. HIV-associated neurocognitive disorders persist in the era of potent antiretroviral therapy CHARTER study. Neurology. 2010;75:2087–96. 18. • Ciccarelli N et al. Efavirenz associated with cognitive disorders in otherwise asymptomatic HIV infected patients. Neurology. 2011;76: 1403–9. A cross-sectional single-cohort study that found an association between HAND and efavirenz use. 19. Brew BJ, et al. Neurodegeneration and ageing in the HAART Era. J Neuroimmune Pharm. 2009;4(2):163–74 20. Yao H et al. HIV neuropathogenesis: a tight rope walk of innate immunity. J Neuroimmune Pharm. 2010;5:489–95. 21. • Kallianpur KJ et al. Peripheral blood HIV DNA is associated with atrophy of cerebellar and subcortical gray matter. Neurology. 2013;80: 1792–9. A cross-sectional study that used MRI and MR spectroscopy to demonstrate an association between regional brain atrophy and persistance of HIV DNA in the peripheral blood. 22. Andersen ÅB et al. Cerebral FDG-PET scanning abnormalities in optimally treated HIV patients. J Neuroinflammation. 2010;7:13. 23. Gannon P, Khana MZ, Kolsona DL. Current understanding of HIVassociated neurocognitive disorders pathogenesis. Curr Opin Neurol. 2011;24:275–83. 24. Mothobia NZ, Brew BJ. Neurocognitive dysfunction in the highly active antiretroviral therapy era. Curr Opin Infect Dis. 2012;25:4–9. 25. Johnson T, Nath A. Immune reconstitution inflammatory system and the central nervous system. Curr Opin Neurol. 2011;24:284–90. 26. Cysique LAJ, Maruff P, Brew BJ. Variable benefit in neuropsychological function in HIV-infected HAART-treated patients. Neurology. 2006;66:1447–50. 27. Tan IL, McArthur JC. HIV-associated neurological disorders a guide to pharmacotherapy. CNS Drugs. 2012;26(2):123–34. 28. Rackstraw S. HIV-related neurocognitive impairment – a review. Psychol, Health Med. 2011;16(5):548–63. 29. Thien H et al. Improved cognitive function as a consequence of hepatitis C virus treatment. HIV Med. 2007;8:520–8.
568 30. McPhail ME, Robertson KR. Neurocognitive impact of antiretroviral treatment: thinking long-term. Curr HIV/AIDS Rep. 2011;8:249–56. 31. Clifford DB et al. Effects of active HCV replication on neurologic status in HIV RNA virally suppressed patients. Neurology. 2009;73:309–14. 32. Lindl KA et al. HIV-associated neurocognitive disorder: pathogenesis and therapeutic opportunities. J Neuroimmune Pharm. 2010;5:294–309. 33. • Ellisa RJ et al. CD4 nadir is a predictor of HIV neurocognitive impairment in the era of combination antiretroviral therapy. AIDS. 2011;25:1747–51. A large observational study that showed the risk of neuropsychological impairment was lowest in patients without a low CD4 nadir pre-CART initiation. 34. Letendre SL. Central nervous system complications in HIV disease: HIV-associated neurocognitive disorder. Top Antivir Med. 2011;19(4): 137–42. 35. •• The Mind Exchange Working Group. Assessment, diagnosis, and treatment of HIV-associated neurocognitive disorder: a consensus report of the mind exchange program. Clin Infect Dis. 2013;56(7): 1004–17. Evidence-based consensus statement from international experts to guide the diagnosis, monitoring, and treatment of HAND. 36. •• Centner CM, Bateman KJ, Heckmann JM. Manifestations of HIV infection in the peripheral nervous system. Lancet Neurol. 2013;12: 295–309. A review of the clinical presentation, causes, and management of peripheral neuropathies in HIV-infected patients. 37. Ghosh S, Chandran A, Jansen JP. Epidemiology of HIV-related neuropathy: a systematic literature review. AIDS Res Hum Retrovir. 2012;28(1):36–48.
Curr Infect Dis Rep (2013) 15:564–568 38. Kamerman PR, Wadley AL, Cherry CL. HIV-associated sensory neuropathy: risk factors and genetics. Curr Pain Headache Rep. 2012;16:226–36. 39. Ng K et al. Axonal excitability in viral polyneuropathy and nucleoside neuropathy in HIV patients. J Neurol Neurosurg Psychiatry. 2011;82:978–80. 40. Cherry CL et al. Antiretroviral use and other risks for HIV-associated neuropathies in an international cohort. Neurology. 2006;66:867–73. 41. Cruse B et al. Cerebrovascular disease in HIV-infected individuals in the era of highly active antiretroviral therapy. J Neurovirol. 2012;18: 264–76. 42. Benjamin LA et al. HIV infection and stroke: current perspectives and future directions. Lancet Neurol. 2012;11:878–90. 43. Sen S et al. Recent developments regarding human immunodeficiency virus infection and stroke. Cerebrovasc Dis. 2012;33:209–18. 44. Brew BJ et al. CSF amyloid beta42 and tau levels correlate with AIDS dementia complex. Neurology. 2005;65:1490–2. 45. Birbeck GL et al. Evidence-based guideline: antiepileptic drug selection for people with HIV/AIDS. Neurology. 2012;78:139– 45. 46. • Heinze B, Swanepoel DW, Hofmeyr LM. Systematic review of vestibular disorders related to human immunodeficiency virus and acquired immunodeficiency syndrome. J Laryngol Otol. 2011;125: 881–90. Guidelines for the selection of antiepileptic drugs among people with HIV/AIDS. 47. Brew BJ. HIV neurology. Oxford University Press; 2001.
CENTRAL NERVOUS SYSTEM (J LYONS, SECTION EDITOR)
Neurological Complications in Controlled HIV Infection Kate M. Crossley & Bruce J. Brew
Published online: 22 October 2013 # Springer Science+Business Media New York 2013
Abstract In recent years, there have been great advances in therapies for human immunodeficiency virus (HIV) that have allowed suppression of the virus and its effects on the body. Despite this progress, neurological complications persist in HIV-infected individuals. In this review we consider the possible ways that HIV might cause neurotoxicity and neuroinflammation. We discuss the spectrum of neurological disorders caused by HIV and its treatment, with a particular focus on both HIV-associated neurocognitive disorders and peripheral neuropathies. Since there has been a shift to HIV being a chronic illness, we also review the increasing prevalence of cerebrovascular disease and neurodegenerative disorders. Keywords Human Immunodeficiency Virus . Neurotoxicity . HIV-Associated Neurocognitive Disorders . Peripheral Neuropathy
neurocognitive disorders and, perhaps, neurodegenerative conditions. In particular, there has been a persistence of the milder forms of the HIV-associated neurocognitive disorders (HANDs) and a high prevalence of peripheral neuropathies, both of which have a significant impact on quality of life. This review will highlight recent additions to our understanding of the neurological complications of controlled HIV infection. It is important to understand the neuropathogenesis of HIV, and hence, we will cover the concept of the CNS as a reservoir for HIV and how this provides a possible mechanism for the persisting neurocognitive dysfunction seen since the introduction of HAART. We will also discuss the spectrum of neurological disorders caused by HIV, with particular focus on HAND, peripheral neuropathies, cerebrovascular disease, and neurodegenerative disorders, with the intention of providing an update on the most commonly encountered neurological disorders seen in the virally suppressed HIV patient.
Introduction The CNS as a Viral Reservoir Human immunodeficiency virus (HIV) infected individuals are affected by the full spectrum of neurological disorders. However, the introduction of highly active antiretroviral therapy (HAART) has shifted this spectrum from the opportunistic infections, severe neurocognitive disorders, and central nervous system (CNS) tumors seen in advanced disease to less severe K. M. Crossley : B. J. Brew (*) Department of Neurology, St. Vincent’s Hospital, Level 4 Xavier Building, 390 Victoria St Darlinghurst, Sydney, Australia e-mail: [email protected] B. J. Brew Peter Duncan Neurosciences Unit and Applied Neurosciences Programme, St Vincent’s Centre for Applied Medical Research, Sydney, Australia
The CNS is invaded early in the course of acute HIV infection. HAART has been shown to decrease the CSF viral load, and generally, CSF HIV-1 viral load levels correspond to plasma levels [1, 2••]. However, the blood brain barrier’s structure, efflux pumps, and metabolizing enzymes limit the penetration of HAART to the CNS. The protein binding of antiretroviral drugs (ARVs) in plasma compounds this [1, 3]. Thus, the CNS acts as a sanctuary site for HIV, where it infects infiltrating monocytes and resting CD4+ lymphocytes, which act as a viral reservoir [4•]. This enables the virus to evade HAART and provides a potential source for persisting viral replication [5, 6]. The virus can mutate and evolve in the CNS separately from the virus in the plasma, even in those with suppressed plasma viral load [2••, 7•, 8].
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This chronic low-grade viral replication is thought to contribute to persisting neuroinflammation and impaired neurocognition, even in HAART-treated patients [1, 5, 9]. This hypothesis is supported by a 2013 study that showed that patients with latent HIV (defined as having high levels of HIV-1 DNA and no detectable RNA or significant p24 in the CNS) had moderate cognitive deficits and changes of neuroinflammation [10•]. HIV also produces viral proteins that are neurotoxic, such as the transcription factor Tat [11]. Since none of the current ARVs work at the transcription level, they do not suppress the ongoing production of Tat [12].
Spectrum of Neurological Disorders Caused by HIV Only 1 %–4 % of patients develop acute neurological disease at seroconversion [13]. The most common of these is aseptic meningitis, which in most cases will respond to supportive care [14]. A few patients go on to have recurrent bouts of aseptic meningitis [3, 13]. HIV may also cause more chronic, slowly progressive processes [13]. These include HAND and peripheral neuropathies, as previously mentioned, but also psychiatric conditions, chronic headaches, motor weakness, spasticity, and incoordination [2••, 3]. In addition, other factors, such as chronic substance abuse, antiretroviral neurotoxicity, and malnutrition, may cloud the picture. This is further compounded by the fact that many individuals with HIV infection are now aging [5].
HIV-Associated Neurocognitive Disorders HAND consists of three clinically diagnosed subdisorders: asymptomatic neurocognitive impairment (ANI), mild neurocognitive disorder (MND), and HIV-associated dementia (HAD) [15]. ANI is a subclinical cognitive dysfunction that does not interfere with daily function. MND is a mild cognitive dysfunction that does interfere with activities of daily living to a limited extent. HAD is a subcortical dementia that causes a combination of significant cognitive and functional decline with marked impact on daily activities. HAND is common even in those with suppressed HIV plasma viraemia [2••, 16]. The CHARTER study identified confounding conditions that may interfere with a HAND diagnosis (i.e., substance abuse, major depression, brain trauma, etc.). The overall prevalence of HAND in all recruited patients was 52 %. Excluding severely confounded cases, the level of ANI in patients who were virally suppressed remained relatively high at 33 %, with an estimated 12 % prevalence of MND and 2 % for HAD [17]. Ciccarelli et al. also reported a high prevalence of minor cognitive disorders, with ANI found in 35.6 % of a population of apparently asymptomatic HIVinfected patients [18•].
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While the incidence of HAD has significantly fallen since the introduction of HAART, its prevalence is increasing as patients live longer [19]. Approximately 7 % of treated HIVpositive patients develop HAD, as compared with 25 % of untreated HIV-infected patients [20]. There is also emerging evidence of metabolic abnormalities and volume loss in the virally suppressed brain. While persisting peripheral blood viraemia is associated with regional brain atrophy [21•], it has also been shown that virally suppressed HIV-positive patients have faster brain volume loss than do HIV-negative patients [22]. Anderson, Law, et al. used fluorine-18-flourodeoxyglucose positron emission tomography (FDG-PET) scanning to examine the prevalence of cerebral metabolic abnormalities in virally suppressed patients. They found that more than half (55 %) of the patients exhibited varying severities of mesial frontal reduction in the relative metabolic rate of glucose [22]. Several possible explanations have been proposed for this persisting prevalence of HAND. One theory is that with the increased survival and later age of infections, the aging brain is at increased vulnerability for cognitive impairment. There is insufficient evidence to support this currently [23, 24]. Another theory is that in the context of the poor CNS penetration of some antiretroviral agents, there is a persistence of HIV replication in brain macrophages, with subsequent evolution of highly neurovirulent CNS HIV strains [18•, 23]. Pharmacokinetic data have enabled the ranking of antiretroviral CNS penetration effectiveness (CPE). Antiretroviral drugs with higher CPE scores (neuroHAART) have been observed to decrease CSF viral load and improve neurocognitive function [4•, 23]. Similarly, the CHIC group in the United Kingdom observed an independent association between lower CPE scores and higher all-cause mortality. They raised the possibility that this was the result of patients with advanced disease being prescribed regimens with lower scores but also suggested that low CPE scoring regimens are related to cognitive impairment [16]. Further research is needed to clarify the benefits and risks of neuroHAART. A third theory is that the HAART medications are themselves neurotoxic; however, the evidence is limited [18•, 23, 24]. There is also a possibility that in a minority of cases, HAND may be secondary to an immune reconstitution inflammatory syndrome (IRIS) induced by the commencement of antiretrovirals [8]. IRIS can develop in the presence of an opportunistic infection such as progressive multifocal leukoencephalopathy (PML), but the immune response might also directly target the reservoirs of human immunodeficiency virus in the brain [25]. The resultant CNS inflammation can cause persisting damage that may contribute to the patient’s future risk of HAND [1]. The risk factors for HAND in the virally suppressed patient appear to be a low nadir CD4 cell count [26] and possibly
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other factors such as disease duration, clade type, and CSF viraemia [1, 17, 27, 28]. It is unclear whether patients with both HIV and hepatitis C have higher rates of neurocognitive impairment than do patients with HIV infection alone, since there is conflicting evidence [29, 30]. The ALLRT study showed that active hepatitis C in the setting of virally suppressed HIV infection does not exacerbate neurocognitive dyfsunction [31]. The impact of neurocognitive impairment is significant, leading to difficulty with activities of daily living (including reduced adherence to treatment), increased morbidity and mortality, and decreased quality of life [16, 24, 27, 32].
HAND Therapy Several authors have advocated the early initiation of HAART, given the association between nadir CD4 count and HAND risk [5, 33•]. Reductions in the viral load in the CSF have been shown to correlate with improvements in cognition [28]. Some patients are able to achieve complete CSF viral suppression even with persisting detectable CNS virus, and these patients demonstrate similar neurocognitive improvement to those who achieve suppression in both plasma and CSF [27]. However, it is worth noting that CNS HIV suppression does not guarantee full cognitive recovery [34]. Patients should routinely be monitored for cognitive impairment to enable early diagnosis and treatment of HAND [24, 35••].
Peripheral Neuropathy The true prevalence of HIV-associated sensory neuropathies (HIV-SNs) is not well characterized, with most estimates falling between 30 % and 60 % worldwide in patients with HIV-1 infection [36••, 37]. However, there is autopsy evidence that all HIV-positive patients have pathological evidence of neuropathy [37]. The most common HIV-SN is distal sensory polyneuropathy (DSP). This is thought to be indirectly due to HIV via the chronic immune system activation [37]. DSP may be asymptomatic or, conversely, can result in a “stocking and glove” distribution of numbness, paraesthesia, and pain [38]. Using standard neurophysiological techniques, it is indistinguishable from antiretroviral toxic neuropathy (ATN), the incidence of which peaks within 3 months of commencing an antiretroviral [36••]. There is some evidence that neurophysiological excitability studies can distinguish between DSP and ATN [39]. In particular, the nucleoside reverse transcriptase inhibitors, such as stavudine and didanosine, have been associated with ATN [36••, 40]. Risk factors for peripheral neuropathy include prior neuropathy, older age, nutritional deficiencies, taller height,
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comorbidities (such as diabetes, alcohol abuse, or isoniazid exposure), and more advanced HIV infection, although it can occur at any stage [36••, 37, 38, 40].
Cerebrovascular Disease HIV-positive patients have an increased risk of stroke because of opportunistic infections, vasculopathy, and mass lesions, in addition to the metabolic effects of HIV and its treatment [13, 41]. There also tends to be a higher prevalence of traditional cardiovascular risk factors, such as smoking in patients with HIV, predisposing to vascular disease. Additionally, the prolonged lifespan of HIV patients since the introduction of HAART increases the proportion of older patients at increased stroke risk [42]. Although overall hospital admissions as a result of stroke decreased from 1997 to 2006 in the United States, the proportion of those in HIV-infected patients increased [43].
Neurodegenerative Disorders It has also been suggested that neurodegenerative diseases such as Alzheimer’s disease, Parkinson’s disease. and vascular cognitive impairment may be facilitated by the presence of HIV, although this is not yet certain [2••]. There is some neuropathological evidence, such as the finding of low concentrations of amyloid beta (AB) 1-42 and elevated tau in the CSF of HIV patients, which is akin to the pattern found in patients with Alzheimer’s disease [44]. Additionally, some, but not all, studies have found AB deposition in the brains of HIV-infected patients at autopsy [19].
Other Neurological Disorders Seizure disorders are common in HIV-positive patients, with a reported incidence as high as 11 %. Their management is complicated by the interactions of antiretrovirals and antiepileptic medication [45]. Vestibular symptoms are also common, irrespective of disease stage and may be due to direct effects of HIV on the peripheral and central vestibular system [46•]. Acute inflammatory demyelinating polyneuropathy, or Guillain-Barré syndrome, is seen as an HIV seroconversion illness, particularly in the context of a normal CD4 count, although it has been described in AIDS patients. Chronic inflammatory demyelinating polyneuropathy more frequently occurs in more advanced disease [3, 36••]. Other described peripheral neuropathies in HIV-positive patients with suppressed virus or during seroconversion include multifocal mononeuropathy,
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vasculitic neuropathies, brachial plexitis, and Bell’s palsy. The latter may be bilateral in HIV [47].
Conclusion Despite the dramatic improvement in HIV prognosis and morbidity that was the result of the introduction of HAART, neurological disorders continue to have a significant impact on the quality of life of individuals living with HIV. In particular, HAND and peripheral neuropathies both have a high prevalence in the virally suppressed patient, and neither can yet be adequately prevented, although, in HAND at least, trials are underway. Compliance with Ethics Guidelines Conflict of Interest Bruce Brew has been a board member for GlaxoSmithKline, Biogenldec, ViiV Healthcare, Merck Serono, International Journal for Tryptophan Research, Faculty of 1000 Medicine, Journal of Neurovirology, and Neurobehavioral HIV Medicine, is an employee of University of New South Wales, has received grants from National Health and Medical Research Council of Australia and MSRA, and has received honoraria from ViiV Healthcare, Boehringer Ingelheim, Abbott, Abbvie, and Biogen Idec. He has also received royalties from HIV Neurology and Palliative Neurology. Kate Crossley declares no conflicts 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.
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