Update on Neurologic Complications in Persons With HIV Infection: 2017

Transcription

1 Update on Neurologic Complications in Persons With HIV Infection: 2017 FORMATTED: MM/DD/YY Chicago, Illinois: May 10, 2017 Dennis Kolson, MD, PhD Professor of Neurology University of Pennsylvania Philadelphia, Pennsylvania Slide 3 of 34 Learning Objectives After attending this presentation, learners will be able to: Recognize and list the early neurologic manifestations of acute HIV infection Describe the chronic neurologic manifestations and potential management options for neurologic complications of HIV infection in individuals on suppressive antiretroviral therapy To describe the rationale for adjunctive neuroprotective strategies for cognitive impairment in individuals on suppressive antiretroviral therapy Neurological complications of chronic HIV infection are less severe with use of antiretroviral therapy/art Pre-ART era neuropathy HIV encephalitis HAND ~ 40% severe HAND: HIV encephalitis & dementia ~20% Post-ART era HAND prevalence remains ~ 40% BUT neuropathy Slide 4a of 34 less severe HAND: encephalitis & dementia now ~2% neuropathy prevalence ~ 30% neuropathy prevalence < 30% with newer ARTs HIV-encephalitis (HIVE) HAND

2 Neurological complications of chronic HIV infection are less severe with use of antiretroviral therapy/art Pre-ART era neuropathy HIV encephalitis HAND ~ 40% severe HAND: HIV encephalitis & dementia ~20% Post-ART era HAND prevalence remains ~ 40% BUT neuropathy Slide 4b of 34 less severe HAND: encephalitis & dementia now ~2% neuropathy prevalence ~ 30% neuropathy prevalence < 30% with newer ARTs HIV-encephalitis (HIVE) HAND HIV infiltrates the CNS early (days-week) after systemic HIV Infection meningitis symptoms ACTIVATED MACROPHAGE/ MICROGLIA proinflammatory cytokines/chemokines viral replication HIV CD4+ T lymphocyte MACROPHAGE NMDA Receptor Excitotoxins Glutamate QUIN, ROS,Ntox, PAF, TNF-, & gp120, Tat Glutamate Regulation HIV HIV ASTROCYTE MONOCYTE NEURON Neuronal Injury (loss of synapses and dendrites and cell death) Blood Brain Barrier Endothelial Lumen Slide 5 of 34 Adapted from Gill & Kolson, Crit. Rev. Immunol. (2013). Slide 6 of 34 Acute neurological complications of HIV infection: meningitis Acute Inflammatory Demyelinating Neuropathy (AIDP)

3 Early neurological complications of HIV infection prior to initiation of antiretroviral therapy/art meningitis Acute IDP Chronic IDP HAND (less severe) DSPN PML Slide 7 of 34 Early HIV infection (days 10-20) is associated with symptoms of meningitis in ~25% of individuals* *Typically HIV antibody ELISA negative at this time Meningitis (~25%) Slide 8 of 34 McMichael AJ, Nat. Rev. Immunol. (2010) Early neurologic complications of HIV-1 infection: meningitis HIV meningitis (acute HIV-1 infection): 25-50% of patients with clinical/subclinical meningitis duration ~ 2 weeks/self-limited occasional cranial nerve sx: facial droop or diplopia CSF: lymphocytes (5-70/mm 3 ) in ~ 30% of acute infections Protein (<70 mg/dl) IgG index PATIENT WILL BE SERONEGATIVE!!! Slide 9 of 34

4 Slide 10 of 34 Early neurologic complications of HIV-1 infection: Acute Inflammatory Demyelinating Polyneuropathy (AIDP) meningitis Acute IDP Chronic IDP HAND (less severe) DSPN PML Early neurologic complications of HIV-1 infection: Acute inflammatory Demyelinating Polyneuropathy (AIDP) Natural history CSF: < 50 cells/ul elevated protein indistinguishable from GBS Symptoms & signs Treatment AIDP: (rare) weakness plasmapheresis most often at mild sensory sx. IVIG seroconversion (20-30d) pain corticosteroids progresses rapidly respiratory over days to < 4 weeks autonomic ankle reflexes absent Slide 11a of 34 response rates probably similar to HIV-negative patients Robinson-Papp, Muscle & Nerve. (2009) Kaku M, Curr Opin HIV AIDS. (2014) Early neurologic complications of HIV-1 infection: Acute inflammatory Demyelinating Polyneuropathy (AIDP) Natural history CSF: < 50 cells/ul elevated protein indistinguishable from GBS Symptoms & signs Treatment AIDP: (rare) weakness plasmapheresis most often at mild sensory sx. IVIG seroconversion (20-30d) pain corticosteroids progresses rapidly respiratory over days to < 4 weeks autonomic ankle reflexes absent Slide 11b of 34 response rates probably similar to HIV-negative patients Robinson-Papp, Muscle & Nerve. (2009) Kaku M, Curr Opin HIV AIDS. (2014)

5 Slide 12 of 34 Chronic neurological complications of HIV infection: Chronic Inflammatory Demyelinating Neuropathy (CIDP) Later neurological complications of HIV infection after initiation of antiretroviral therapy/art meningitis Acute IDP Chronic IDP HAND (less severe) DSPN PML Slide 13 of 34 Chronic inflammatory demyelinating polyneuropathy (CIDP) CSF: < 50 cells/ul elevated protein indistinguishable from idiopathic CIDP Peripheral nerve onion-bulb in CIDP Symptoms & Natural history signs Treatment CIDP: >1 year- later weakness plasmapheresis stages of HIV infection up to 30%of CIDP patients are HIV+* progresses over > 8 weeks relapses and remissions mild sensory sx. pain * respiratory autonomic ankle reflexes absent IVIG Slide 14 of 34 response rates probably similar to HIV-negative patients Robinson-Papp, Muscle & Nerve. (2009) Kaku M, Curr Opin HIV AIDS. (2014)

6 Chronic inflammatory demyelinating polyneuropathy (CIDP) CSF: < 50 cells/ul elevated protein indistinguishable from idiopathic CIDP Peripheral nerve onion-bulb in CIDP Symptoms & Natural history signs Treatment CIDP: >1 year- later weakness plasmapheresis stages of HIV infection up to 30%of CIDP patients are HIV+* progresses over > 8 weeks relapses and remissions mild sensory pain * respiratory autonomic ankle reflexes absent IVIG Slide 14b of 34 response rates probably similar to HIV-negative patients Robinson-Papp, Muscle & Nerve. (2009) Kaku M, Curr Opin HIV AIDS. (2014) Distal symmetric polyneuropathy (DSPN) meningitis Chronic IDP HAND (less severe) Acute IDP DSPN PML Slide 15 of 34 Distal symmetric polyneuropathy (DSPN) Natural history prevalence ~ 30% occurs with or without ART use ART associated (d-drugs): d4t (Stavudine) ddi (didanosine) ddc (zalcitabine) Symptoms & signs Symmetric, distal, sensory (axonal +/- demyelinating) Pain predominates burning hyperalgesia tightness numbness preserved proprioception Treatment Slide 16a of 34 Capsaicin (8% top.) proved effective Neurontin Lamictal (weak evidence) modify ART regimen Simpson, Neurol. (2008), Robinson-Papp, Muscle & Nerve. (2009) Kaku M, Curr Opin HIV AIDS. (2014)

7 Distal symmetric polyneuropathy (DSPN) Natural history prevalence ~ 30% occurs with or without ART use ART associated (d-drugs): d4t (Stavudine) ddi (didanosine) ddc (zalcitabine) Stocking/glove distribution of pain in DSPN Symptoms & signs Symmetric, distal, sensory (axonal +/- demyelinating) Pain predominates burning hyperalgesia tightness numbness preserved proprioception Treatment Slide 16b of 34 Capsaicin (8% top.) proved effective Neurontin Lamictal (weak evidence) modify ART regimen Simpson, Neurol. (2008), Robinson-Papp, Muscle & Nerve. (2009) Kaku M, Curr Opin HIV AIDS. (2014) Immune Reconstitution Inflammatory Syndrome (IRIS) meningitis Chronic IDP HAND (less severe) Acute IDP DSPN PML Slide 17 of 34 Slide 18a of 34 Immune Reconstitution Inflammatory Syndrome (IRIS) Initiation of cart (1-6 months): CNS syndrome (mild or severe) resulting from heightened immunologic and/or inflammatory response against opportunistic pathogen (or other antigen associated with HIV suppression by cart) robust inflammatory CNS infiltration (MRI detection) CNS IRIS in ~1-30% of pts. initiating cart rapid decline of viral load - greatest risk with CD4 <50 and VL >100K most commonly associated with crypto meningitis, TB, PML Johnson, Ann NY Acad Sci (2010) Johnson, Curr Opin HIV AIDS (2014)

8 Slide 18b of 34 Immune Reconstitution Inflammatory Syndrome (IRIS) Initiation of cart (1-6 months): CNS syndrome (mild or severe) resulting from heightened immunologic and/or inflammatory response against opportunistic pathogen (or other antigen associated with HIV suppression by cart) robust inflammatory CNS infiltration (MRI detection) CNS IRIS in ~1-30% of pts. initiating cart rapid decline of viral load - greatest risk with CD4 <50 and VL >100K most commonly associated with crypto meningitis, TB, PML Johnson, Ann NY Acad Sci (2010) Johnson, Curr Opin HIV AIDS (2014) Admission: stroke HIV-associated CNS IRIS 24 days post-art: IRIS 31 days post-art: IRIS Slide 19 of yo HIV+ man, off ART x 3 years, then re-start: 3 weeks right hemiparesis, slurred speech CD4 T cells 24 99/mm 3 CSF: 56 cells/ul 64 mg/dl prot. Zafiri et al. New Microbiologica. (2013) HIV-associated CNS IRIS in PML patient Slide 20 of 34 Before ART 1 mo. post-art 52 yo HIV+ man, ART naïve x 16 years, admitted for sub-acute cognitive decline cart started: CD4 T cells /mm 3 JC virus confirmed at autopsy Vendrely A, Acta Neuropathol. (2005)

9 Progressive Multifocal Leukoencephalopathy (PML) meningitis Chronic IDP HAND (less severe) Acute IDP DSPN PML Slide 22 of 34

10 Progressive Multifocal Leukoencephalopathy (PML) Natural history Symptoms & signs Treatment papovavirus (JC virus) activation in the brain white matter (myelin) damage, early in occipital areas ~4% of all untreated patients ~1% in ART-treated patients Death within ~1 year in 90% hemiparesis memory loss slurred speech ~20-40% seizures visual sxs., blind spots sensory disturbances up to 60% ~30-60% ~15-30% ~25% ~20% Slide 23 of 34 None effective?inhibit JC virus?reconstitute immune system Progressive Multifocal Leukoencephalopathy (PML) Natural history Symptoms & signs Treatment papovavirus (JC virus) activation in the brain white matter (myelin) damage, early in occipital areas ~4% of all untreated patients ~1% in ART-treated patients Death within ~1 year in 90% hemiparesis memory loss slurred speech ~20-40% seizures visual sxs., blind spots sensory disturbances up to 60% ~30-60% ~15-30% ~25% ~20% Slide 23b of 34 None effective?inhibit JC virus?reconstitute immune system Progressive Multifocal Leukoencephalopathy (PML) Note lesions restricted to white matter Slide 24 of 34

11 Progressive Multifocal Leukoencephalopathy (PML) typical PML: no enhancement atypical PML: patchy enhancement in HIV+, 30 y.o. man atypical PML: ring enhancement HIV+, 25 y.o. man Slide 25 of 34 meningitis Chronic IDP HAND Acute IDP DSPN PML Slide 26 of 34 HIV associated neurocognitive disorders (HAND) have similar prevalence but decreased severity post-art HAND sub-groups ANI: Asymptomatic neurocognitive impairment MND: Mild neurocognitive disorder HAD: HIV-associated dementia functional impairment in certain ADLs affects ~20% of virally suppressed patients Slide 27 of 34 Saylor, Nature Reviews Neurology (2016)

12 1/3 have MRI evidence of white matter abnormality, with or without brain atrophy Slide 28 of year old man, HIV+ for ~20 years, CD4 nadir 50+ cells/ul began ART after severe immunosuppresion; white matter lesions + brain atrophy How to reduce residual HAND impairment in ART- treated individuals? Using ART regimens with higher CNS penetration? multiple (conflicting) reports suggest no benefit ART drugs may directly induce oxidative stress and neuronal damage Intensification of ART regimens with additional classes of antivirals? recent studies of Maraviroc (CCR5 blocker) suggest possible benefit additional studies underway Adjunctive therapies in addition to ART? focus on controlling neuroinflammation & oxidative stress Slide 29a of 34 How to reduce residual HAND impairment in ART- treated individuals? Using ART regimens with higher CNS penetration? multiple (conflicting) reports suggest no benefit ART drugs may directly induce oxidative stress and neuronal damage Intensification of ART regimens with additional classes of antivirals? recent studies of Maraviroc (CCR5 blocker) suggest possible benefit additional studies underway Adjunctive therapies in addition to ART? focus on controlling neuroinflammation & oxidative stress Slide 29b of 34

13 Slide 30 of 34 Neurological complications of HIV can persist in ART-treated individuals and require adjunctive therapies to limit morbidity meningitis Chronic IDP HAND (less severe) Acute IDP DSPN PML HAND Neuropathy (less severe) Slide 33 of 34 Thank you! Kolson Lab: Univ. of Pennsylvania Alexander Gill, MD, PhD student Colleen Kovacsics, PhD student Yoelvis Garcia-Mesa, PhD Rolando Garza, BS Patricia Vance, BS Penn Center for AIDS Research Ron Collman, MD (Director) Acknowledgements University of Texas Medical Branch Ben Gelman, MD, PhD University of North Carolina, Chapel Hill Kevin Robertson, PhD Slide 32 of 34

14 SUGGESTED READINGS Dr Kolson Suggested Readings Activity #: HIV 17 CHI (F) Page: 1 1. Hellmuth J, Fletcher JL, Valcour V, et al. Neurologic signs and symptoms frequently manifest in acute HIV infection. Neurology. 2016;87(2): Ref ID: Johnson T, Nath A. Neurological complications of immune reconstitution in HIV-infected populations. Ann N Y Acad Sci. 2010;1184: Ref ID: Johnson TP, Nath A. New insights into immune reconstitution inflammatory syndrome of the central nervous system. Curr Opin HIV AIDS. 2014;9(6): Ref ID: Kaku M, Simpson DM. HIV neuropathy. Curr Opin HIV AIDS. 2014;9(6): Ref ID: Pavlovic D, Patera AC, Nyberg F, Gerber M, Liu M. Progressive multifocal leukoencephalopathy: current treatment options and future perspectives. Ther Adv Neurol Disord. 2015;8(6): Ref ID: Robinson-Papp J, Simpson DM. Neuromuscular diseases associated with HIV-1 infection. Muscle Nerve. 2009;40(6): Ref ID: Saylor D, Dickens AM, Sacktor N, et al. HIV-associated neurocognitive disorder - pathogenesis and prospects for treatment. Nat Rev Neurol. 2016;12(5):309. Ref ID: Schutz SG, Robinson-Papp J. HIV-related neuropathy: current perspectives. HIV AIDS (Auckl ). 2013;5: Ref ID: Simpson DM, Brown S, Tobias J. Controlled trial of highconcentration capsaicin patch for treatment of painful HIV neuropathy. Neurology. 2008;70(24): Ref ID: 10401