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Pathogenesis and treatment of HIV-associated peripheral neuropathies

Pathogenesis and treatment of HIV-associated peripheral neuropathies. Justin C. McArthur HIV Neurosciences Program Johns Hopkins University February 7 th , 2006. No disclosures. Objectives Clinical features of sensory neuropathies Changing epidemiology and risk factors

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Pathogenesis and treatment of HIV-associated peripheral neuropathies

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  1. Pathogenesis and treatment of HIV-associated peripheral neuropathies Justin C. McArthur HIV Neurosciences Program Johns Hopkins University February 7th, 2006 No disclosures

  2. Objectives Clinical features of sensory neuropathies Changing epidemiology and risk factors Pathology and pathophysiology Animal and in vitro models Treatment strategies HIV sensory neuropathies

  3. Diagnosis and HIV stage Sensory neuropathies (DSP, ATN): Variable Mononeuropathy multiplex: Early (limited); Late (progressive), Hep C Progressive polyradiculopathy: Late, CMV Inflammatory demyelinating polyneuropathy: Early Myopathy: Any (AZT); Early (polymyositis) ALS-type disorder: Late, rare HIV-associated neuromuscular weakness syndrome: D4T Major Neuromuscular Syndromes in HIV Disease Distal sensory polyneuropathy DSP Antiretroviral toxic neuropaty ATN Modified from David Simpson

  4. Clinical features of HIV sensory neuropathies Common length-dependent symptoms: • Spontaneous pain in feet, paresthesias, • Evoked pain ~ touch, rubbing (not cold) • Numbness ~ unusual in fingers • Lancinating pains Examination: •  sens. thresholds 85% • Absent/reduced AJ’s 96% • Distal weakness 33% • Atrophy or wasting 30% • Fasciculations 0% Features of HIV distal sensory polyneuropathy and antiretroviral toxic neuropathy are identical. Neuropathic sx. are correlated with plasma HIV RNA …."springtime in nerveland”…. Cornblath, 1988; Tagliati M, 1999

  5. ACTG 5117 Neuropathy cohort: 83 HIV+ subjects followed over 48 weeks: infrequent transitions Simpson DM, in press 7-10% of subjects showed transition in either direction: predictors included baseline severity, epidermal nerve fiber densities, and white race.

  6. Epidemiology of HIV sensory neuropathies

  7. ddC neuro-toxicity was noted early • Phase I/II trials: • A reversible painful peripheral neuropathy developed in 10 patients after 6-14 weeks' treatment with 2',3'-dideoxycytidine. • Lancet. 1988 Jan 16;1(8577):76-81

  8. abbreviation : ddC preferred name : zalcitabine trade name : Hivid 2',3'-dideoxycytidine abbreviation : d4T preferred name : stavudine trade name : Zerit 2',3'-didehydro-2',3'-dideoxythymidine abbreviation : ddI preferred name : didanosine trade name : Videx 2',3'-dideoxyinosine Neurotoxic Nucleoside RT inhibitors

  9. Changing incidence of HIV-associated Neurological ConditionsJohns Hopkins HIV Clinical Cohortper 100 person years HAART Richard Moore & Kelly Gebo

  10. Rising prevalence of HIV-associated sensory neuropathiesJohns Hopkins HIV Clinical Cohort per 100 persons • Identified risk factors: • age (2-3 fold) or DM • nadir CD4 count • plasma HIV RNA • APOE4/mtDNA haplogroup • d4T or ddI exposure • ?? HCV Richard Moore & Kelly Gebo

  11. Neuropathy is frequent in advanced HIV/AIDS, and may be asymptomatic • Of 187 patients, 99 (53%) had DSP. • Patients with neuropathy were older, and more commonly male • Twenty-six of 99 patients with DSP were asymptomatic. • Asymptomatic neuropathy was correlated with opiate and sedative abuse and dependence • DSP was not correlated with plasma viral load, decreased CD4 cell counts, or neurotoxic antiretroviral therapy Morgello S. et al Arch Neurol. 2004 Apr;61(4):546-51

  12. Risk Factors and Determinants for HIV-associated Sensory Neuropathies: The role of dideoxynucleoside exposure The Nerve Project (NS44807) Cherry C, et al Neurology, 2006

  13. The likelihood of having symptomatic neuropathy at baseline: •  strong association with use of ddI ever (OR=3.21, CI: 1.56, 6.60) •  strong association with use of d4T ever (OR=7.66, CI: 2.89, 20.33) • No association between months of exposure, time off a particular d-drug, hepatitis C, and presence of metabolic syndrome (Thomas D. AAN 2006)

  14. Pathology of HIV sensory neuropathies

  15. HIV-associated sensory neuropathy: Pathology • HIV infection is confined to macrophages • Prominent macrophage activation both in DRG and multifocally in proximal nerve • Ultra-structural: decrease in density of dermal Remak bundles; abnormal and bizarrely shaped mitochondria in ATN.  Length-dependent loss of cutaneous and centrally-directed nerve fibers: both small and large fibers are affected

  16. Distal sensory polyneuropathy: axonal degeneration Control HIV-SN Axonal degeneration is universal at autopsy. Griffin JW, 1994

  17. epidermis HIV sensory neuropathies Skin biopsy assesses unmyelinated nerve fibers Thigh: normal density Distal leg: reduced density and nerve fiber swellings

  18. Segmented dermal fibers Morphological abnormalities on skin biopsies nerve fiber swellings

  19. Degenerating axons surrounded by flattened Schwann cell processes. Large abnormal mitochondria ATN neuropathy A healthy Remak bundle at the papillary dermis containing 3 axons surrounded by collagen. (x25K) Control Remak bundle with dilated unmyelinated axons showing watery axoplasm and granular debris. DSP neuropathy Courtesy of Dr Gigi Ebenezer

  20. Mike Polydefkis Nerve fiber repair is as impaired in HIV infection as in diabetes HIV neg controls HIV+ controls HIV+ neuropathy Diabetics 30 20 ENFD Regeneration gap 10 0 0 25 50 75 100 Days

  21. Pathogenesis of distal sensory polyneuropathy • associated with advanced HIV disease (Childs E., 1999) • some response in thermal thresholds to HAART (Martin 2000) • HIV proteins are toxic to cortical and DRG cultures (Nath 2001; Keswani, 2002) • gp120 can bind to chemokine receptors in DRG neurons and induce calcium fluxes(Miller R, 2002) • DRG macrophage activation prominent (Pardo C, 2001)

  22. Carlos Pardo HIV infection is confined to macrophages within the DRG: p24 and GFAP do not colocalize within in the perineuronal nest

  23. 45% ↑ 45%↓ Macrophage activation and neuronal reduction in DRG correlates with HIV-SN (Pardo C, 2003)

  24. Ahmet Hoke Gp120 + DEVD Gp120 [100pg/ml] Control Gp120 causes a dose-dependent axonal degeneration in sensory neurons in DRG cultures, mediated thru’ apoptosis Keswani et al Ann of Neurol, 9/2003 Gp120 neuronal effect requires Schwann cells, but the axonal effect is mediated thru’ chemokine receptors Hoke A and Melli G. 2005

  25. CD68 immunostaining for activated/infiltrating macrophages in DRG of SIV-infected macaques (squares) showing significant increase in macrophage staining in DRG Epidermal nerve fiber density (% volume immunopositive for nerve fiber marker PGP 9.5) decreases with severity of DRG ganglionitis. SIV macaque model of HIV DSP(Mankowski J, Laast V, Zink MC, Clements J)

  26. Pathophysiology of antiretroviral toxic neuropathy: arole for mitochondrial toxicity ? • elevated serum lactate is a marker of ATN (Brew B., 2001) • mitochondrial gamma DNA polymerase is inhibited by specific NRTI’s (Martin JL, 1994) • acute ‘neuromyopathy’ with LAS (Marcus, 2001; Simpson 2004) • mitochondrial DNA levels are reduced with prolonged exposure to d4T or ddI, and mtDNA haplogroups are risk factors (Cherry K, 2002; Hulgan T, 2005)

  27. Control ddC 1µM Total Neuritic Length/Neuron ddC 10µM ddC 20µM NRTI concentration NRTI’s cause dose-dependent axonal degeneration in sensory neurons. Mediated thru’ necrosis Keswani et al Ann of Neurol, 1/2003

  28. Animal models have not been clarifying.Absence of ddC effect on epidermal innervation in S-D rats: no denervation after 50-100mg/kg ddC daily IP for 8 months McArthur JC unpubl. • Other animal studies: • axonal damage and ‘pain’ in chickens (Tatum A. unpubl.) • ‘demyelinating’ neuropathy in NZW rabbits (Anderson TD, 1992) • until now, few data in HIV transgenic animals • FIV model ~ epidermal denervation (Kennedy JM, 2004 ) • mixed pathology in primates • (Tsai, 1989; Kaul S, 1995 )

  29. HIV-associated Sensory Neuropathies - a mouse model of antiretroviral toxicityHoke A et al • Transgenic mice expressing gp120 under GFAP promoter (developed by L. Mucke) • Gp120 protein is present in the brain, spinal cord and peripheral nerves • Animals are fed ddI (5 mg/ml) orally in their drinking water for 8 weeks

  30. Intraepidermal nerve fiber density is reduced • Number of Remak axons in distal foot nerves is reduced Hoke A, Melli G

  31. Treatment of HIV sensory neuropathies: what have we learned ?

  32. Sampling of controlled trials for HIV-sensory neuropathies

  33. New (unlicensed) treatments for HIV sensory neuropathies Lamotrigine: Na channel Glucuronidation, rash Topiramate: Glutamate Renal excretion, wt loss, kidney stones Gabapentin/pregabalin: A2delta calcium Renal excretion, edema, sedation Duloxetine: serotonin/norepinephrine RRI Nausea, hepatotoxicity Combination therapies: eg NEJM study of gabapentin + morphine

  34. Potential role for erythopoietin as a neuroprotective therapy for HIV-SN • EPO and its cognate receptor, EPOR are functionally expressed thru’ neuraxis • EPO may serve as an endogenous neuroprotective factor. • Schwann cells secrete EPO in response to injury to neighboring axons (NO is the signal), and may partially prevent axonal degeneration (Hoke & Keswani). • NARC-funded clinical trial planned to start Q2-2006 (Clifford & Thomas). Primary outcome ~ skin biopsy

  35. Voltage-gated sodium channels are potential therapeutic target for HIV-SN • 9 structurally related alpha sub-units • Injury to peripheral nerves leads to functional changes in channel subtypes: eg NaV1.8 is ‘essential’ for persistent pain states (Porreca F.) • New agents are in development, eg GSK CDA54 which blocks the inactivated states of NaV1.7 and NaV1.8 • NaV changes are reversible by application of GDNF, with reductions in ectopic activity and pain behavior (Boucher, 2000) • GDNF-based therapeutics are in development, gene therapy/stem cells/artemin (GFRa3-RET ligand)

  36. New trials for HIV-sensory neuropathies 2006-2008:

  37. Summary: HIV-associated sensory neuropathies ~ 2006 • rising global prevalence with the • cumulative use of neurotoxic ARTs • pathology involves length-dependent axonal loss, macrophage activation, and impaired regeneration. Skin biopsy is useful to define the degree of distal axonal degeneration • animal models are now available (transgenic mice, SIV macaques) and may be useful to test therapies • current therapies are only symptomatic, and new neuroprotective strategies are needed, as well as improved outcome measures

  38. Patients, volunteers, other investigators ~ NARC, NEAD Clinical research/imaging: K Carter, D Esposito, M Pomper, N Sacktor, A Venkataramana, R Skolasky, A King, R Benjamin, C Odol, M Fitchett, M Greene, J Creighton Neuropathology/Cutaneous Nerve studies: C Pardo, M Polydefkis, D Thomas, P Hauer, JW Griffin, B Freeman, B Dearman, G Ebenezer Neuroimmunology and Models: K Conant, S Gartner, N Haughey, A Hoke, A Nath SIV macaque: J Clements, C Zink, J Mankowski, Laast V JHU AIDS Service/CFAR: J Bartlett, R Moore, J Gallant $$ ~ NINDS, NIAID, NIMH, NARC, ACTG Johns Hopkins University: HIV Neurosciences Program:

  39. Thank you ….if your feet hurt, your whole body hurts…”

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