HIV in the peripheral nervous system

1
HIV in the peripheral nervous system

• Kate Cherry, Burnet Institute
• NeuroAIDS in the Asia Pacific region
• July 2007

2
Peripheral neuropathies seen in HIV

• HIV-associated sensory neuropathies
• Distal sensory polyneuropathy (due to HIV)
• Antiretroviral toxic neuropathy
• Inflammatory polyneuropathies
• Acute inflammatory demyelinating polyneuropathy
• Chronic inflammatory demyelinating polyneuropathy
• Mononeuritis multiplex
• Autonomic neuropathy
• Neuropathies due to opportunistic infections (eg
  CMV)
• Neuropathy in diffuse infiltrative lymphomatosis
  syndrome

From Cornblath and Hoke, 2006
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Peripheral neuropathies seen in HIV

• HIV-associated sensory neuropathies
• Distal sensory polyneuropathy (due to HIV)
• Antiretroviral toxic neuropathy
• Inflammatory polyneuropathies
• Acute inflammatory demyelinating polyneuropathy
• Chronic inflammatory demyelinating polyneuropathy
• Mononeuritis multiplex
• Autonomic neuropathy
• Neuropathies due to opportunistic infections (eg
  CMV)
• Neuropathy in diffuse infiltrative lymphomatosis
  syndrome

From Cornblath and Hoke, 2006
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HIV-SN outline

• Clinical features
• Pathogenesis, rates and risk factors
• Of neuropathy due to HIV
• Of neuropathies seen in the era of HAART
• Management options
• Recommendations
• Some of the evidence
• Whats new on the horizon?

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Not so happy feet

• Symptoms (extremities)
• Pain
• Spontaneous
• Evoked
• Paresthesias
• Numbness
• Signs
• Absent / reduced ankle jerks
• Impaired sensation
• Weakness / wasting NOT common
• DSP and ATN clinically identical

From Positive Living 2007
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Neuropathy due to HIV itself
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Neuropathy rates in untreated HIV
? Increasing peripheral nerve damage with
advancing HIV disease
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Peripheral nerve pathology in HIV

• Distally predominant neuronal pathology in HIV,
  more marked in those with HIV-SN
• Loss of nerve fibers / axonal degeneration
• Preferential loss of small, unmyelinated fibers
• in vitro HIV gp120 causes dose dependent
  apoptosis of sensory neurons (Keswani 2003)
• Inflammation throughout the PNS

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Epidermal nerve fiber quantification( small,
unmyelinated nerve fibers)
Normal skin plentiful epidermal nerve fibers
SN reduced epidermal nerve fibers
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Loss of cutaneous nerve fibers in HIV
rho0.9 p0.04
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HIV infection in the peripheral nervous system

• Productive HIV infection of macrophages
• CCR5-using HIV strains (Jones et al 2005)
• Isolates similar from those with and without SN
• In vitro neurotoxicity also not different
• HOST RESPONSE likely critical in HIV-SN
  disordered inflammation throughout the PNS
• ? macrophage numbers and activation in DRGs and
  nerves
• Cytokine dysregulation ? TNFa and ?IL4

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Neuropathy occurring since the introduction of
HAART
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Neurotoxicity from NRTIs

• Inhibit DNA polymerase ?
• Mitochondrial toxicity
• ddC gt ddI gt d4T gtgt others
• in vitro ddC, d4T and ddI cause necrosis of
  sensory neurons dose-dependent (Keswani 2003)

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Recent SN incidence data(SN based mainly on
symptoms)
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Recent SN incidence data(SN based mainly on
symptoms)
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Recent SN prevalence data (SN definition
included neuropathic signs)
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Recent SN prevalence data (SN definition
included neuropathic signs)
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Recent SN prevalence data (SN definition
included neuropathic signs)
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A role for protease inhibitors?
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A role for protease inhibitors?
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Indinavir and HIV are associated with reduced
neurite growth in vitro
CD4 and CCR5 expressing DRGs from transgenic
rats (Pettersen et al 2006)
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A role for protease inhibitors?
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A role for protease inhibitors?
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A role for protease inhibitors?
Direct drug toxicity, or an indirect effect?
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Host factors determining ATN risk?

• Polymorphisms affecting polymerase ??
• Case report of novel mutation (Yamanaka 2007)
• No association with CAG repeats (Chen 2002)
• Mitochondrial haplotype T increased in Caucasians
  with ATN (Hulgan 2005)
• HFE gene polymorphisms (Kallianpur 2006)
• Identical phenotype to DSP ? is the host
  inflammatory response important in ATN?

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Cytokine genotype predicts ATN in Australian
patients(36 d4T treated patients 16 ATN and 20
ATN-free)
Overall model p0.001 Cherry et al 2007
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Cytokine expression in painful and painless
neuropathies
Uceyler et al, Neurology 2007
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Macrophage activation in DRG / nerve
HIV-SN
Neuronal /- mitochondrial injury
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HIV
Macrophage activation in DRG / nerve
HIV-SN
Neuronal /- mitochondrial injury
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HIV
Macrophage activation in DRG / nerve
HIV-SN
Neuronal /- mitochondrial injury
d4T / ddI
? PIs
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HIV
Cytokine genotype
Macrophage activation in DRG / nerve

• Host vulnerabilities
• Nutritional
• Age
• Height
• Genetic
• Metabolic
• Other?

HIV-SN
Neuronal /- mitochondrial injury
d4T / ddI
? PIs
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Management of HIV neuropathies
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Typical HIV-SN management guidelines

• Exclude other causes (B12 etc)
• Remove the underlying cause
• Provide analgesia
• Simple or compound (mild pain)
• Narcotic (severe pain)
• Pain modification if analgesia incomplete
• Antidepressant agents
• Anticonvulsant agents
• Treat co-existing depression
• Possible role of complimentary / alternative
  therapies

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Controlled analgesic trials in HIV-SN
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Controlled analgesic trials in HIV-SN
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Cochrane review of Lamotrigine for chronic
neuropathic pain

• Reviewed as at April 2007
• 7 studies, 502 subjects
• 6 studies showed NO BENEFIT from lamotrigine
• HIV-SN study showed a statistically significant
  benefit in a sub-group of 42 patients on
  anti-retroviral therapy
• this result is unlikely to be clinically
  significant The limited evidence currently
  available suggests that lamotrigine is unlikely
  to be of benefit in the treatment of neuropathic
  pain.

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Smoked cannabis vs placeboD Abrams et al 2007

• 50 patients
• Painful HIV-SN
• Cannabis vs placebo 3 x daily for 5 days
• SIGNIFICANT FINDINGS
• 34 (vs 17) ? pain
• gt30 ? pain in 52 (vs 24)
• No serious adverse events

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Controlled analgesic trials in HIV-SN
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SN management strategies under investigation
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High dose topical capsaicin (NeurogesX)

• 8 by weight capsaicin patches
• Functional inactivation of cutaneous nociceptors
• Controlled trial (n 307) pain reduction for up
  to 12 weeks
• Capsaicin patch 5.9 ? 4.7 (23 ?)
• Placebo patch 5.9 ? 5.3 (11 ?)
• Difference in pain scores p0.0025 (Simpson et
  al 2006)
• Larger, international trial currently underway in
  HIV-SN
• Some concerns / limitations
• Modest ? in pain scores only (1.2 out of 10)
• Regular re-application likely
• Palliation of symptoms only
• 0.1 capsaicin causes epidermal denervation in 48
  hours

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Oral flupirtine (CNS Bio)

• Centrally acting potassium channel opener
• Modest analgesic for musculoskeletal pain
  (Germany)
• Synergy with opioids in rodent models of
  neuropathic pain
• Neuro-protective effects in vitro
• Pilot study in terminal cancer patients (n10)
• Neuropathic pain inadequately controlled by
  opioids
• Flupirtine added ? TOTAL relief of neuropathic
  pain in 8/10
• Planned study in HIV-SN with pain despite opioids
• Currently before Ethics at the Alfred (Melbourne)

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Summary

• HIV-SN remains common.
• New risks are emerging
• Host factors contribute
• ? may be useful in preventative strategies
• Management is difficult
• Pain relief often inadequate
• New strategies under investigation

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Acknowledgements
Burnet Institute Kate Cherry Steve
Wesselingh David Hooker Masqura Moborok Luxshimi
Lal Kaarin Smyth The Alfred Hospital Patient
volunteers Chris Bowtell-Harris Anne Mijch Kerrie
Watson Ian Woolley
University of Western Australia Patricia
Price Jacquita Affandi The Asia-Pacific
neuroAIDS consortium Patient volunteers Darma
Imran Evy Yuhaningsik Adeeba Kamarulzaman Johns
Hopkins University Justin McArthur Pete Hauer