HIV in the peripheral nervous
system
Kate Cherry, Burnet Institute
NeuroAIDS in the Asia Pacific region
July 2007
Peripheral neuropathies seen in HIV
1.
HIV-associated sensory neuropathies
a.
b.
2.
Inflammatory polyneuropathies
a.
b.
3.
4.
5.
6.
Distal sensory polyneuropathy (due to HIV)
Antiretroviral toxic neuropathy
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
Peripheral neuropathies seen in HIV
1.
HIV-associated sensory neuropathies
a.
b.
2.
Inflammatory polyneuropathies
a.
b.
3.
4.
5.
6.
Distal sensory polyneuropathy (due to HIV)
Antiretroviral toxic neuropathy
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
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
– What’s new on the horizon?
“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
Neuropathy due to HIV itself
Neuropathy rates in untreated HIV
Cohort
SN rate
Source
Air-force recruits found
to be HIV+ (n=798)
1.5%
Barohn 1993
Patients attending an
HIV clinic (n=93)
Hospital inpatients with
AIDS (n=37)
14%
Woolley 1997
35%
So 1988
Axonal degeneration on
autopsy of PNS
100%
Griffin 1994
(unpublished)
 Increasing peripheral nerve damage with advancing HIV disease
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
Epidermal nerve fiber quantification
( small, unmyelinated nerve fibers)
Normal skin – plentiful
epidermal nerve fibers
SN – reduced epidermal
nerve fibers
Loss of cutaneous nerve fibers in HIV
Log Viral Load
5.6
5.4
rho=0.9
5.2
p=0.04
5
4.8
4.6
4.4
4.2
4
3.8
0
2
4
6
8
10
distal calf IENFD
12
14
16
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: ↑ TNFα and IL4
Neuropathy occurring since
the introduction of HAART
Neurotoxicity from NRTIs
• Inhibit DNA polymerase 
• Mitochondrial toxicity
– ddC > ddI > d4T >> others
• in vitro ddC, d4T and ddI
cause necrosis of sensory
neurons: dose-dependent
(Keswani 2003)
Recent SN incidence data
(SN based mainly on symptoms)
Location
Patients
Incidence Follow up
Risks
Uganda
894 ART
clinic patients
36% in 18 78 weeks
months
Forma
Age
Isonaizid 2007
Stavudine
Mozambique 146 pregnant
women given
HAART
18% in 9
months
Not stated Jamisse
2007
Sydney
0% - AZT 4 weeks
6% - d4T
in 1 month
385 HIV neg
(137 given
stavudine)
39 weeks
(median)
Source
Stavudine Winston
2005
Recent SN incidence data
(SN based mainly on symptoms)
Location
Patients
Incidence Follow up
Risks
Uganda
894 ART
clinic patients
36% in 18 78 weeks
months
Forma
Age
Isonaizid 2007
Stavudine
Mozambique 146 pregnant
women given
HAART
18% in 9
months
Not stated Jamisse
2007
Sydney
0% - AZT 4 weeks
6% - d4T
in 1 month
385 HIV neg
(137 given
stavudine)
39 weeks
(median)
Source
Stavudine Winston
2005
Recent SN prevalence data
(SN definition included neuropathic signs)
Setting
Patients Prevalence Risks
Source
Uganda
95
47%
Not stated
Nakasujja 2005
Thailand
34
50%
Stavudine use
Lower CD4
Konchalard
2007
APNAC
640
19%
Stavudine use
Wright 2006
Melbourne 100
42%
Increasing age
Stavudine use
Indinavir use
Smyth 2007
USA
101 (CD4
<300)
52%
Not stated
Simpson 2006
Jakarta
96 (all took
d4T)
34%
Cherry 2007
Increasing age
Increasing height
TNF genotype
Recent SN prevalence data
(SN definition included neuropathic signs)
Setting
Patients Prevalence Risks
Source
Uganda
95
47%
Not stated
Nakasujja 2005
Thailand
34
50%
Stavudine use
Lower CD4
Konchalard
2007
APNAC
640
19%
Stavudine use
Wright 2006
Melbourne 100
42%
Increasing age
Stavudine use
Indinavir use
Smyth 2007
USA
101 (CD4
<300)
52%
Not stated
Simpson 2006
Jakarta
96 (all took
d4T)
34%
Cherry 2007
Increasing age
Increasing height
TNF genotype
Recent SN prevalence data
(SN definition included neuropathic signs)
Setting
Patients Prevalence Risks
Source
Uganda
95
47%
Not stated
Nakasujja 2005
Thailand
34
50%
Stavudine use
Lower CD4
Konchalard
2007
APNAC
640
19%
Stavudine use
Wright 2006
Melbourne 100
42%
Increasing age
Stavudine use
Indinavir use
Smyth 2007
USA
101 (CD4
<300)
52%
Not stated
Simpson 2006
Jakarta
96 (all took
d4T)
34%
Cherry 2007
Increasing age
Increasing height
TNF genotype
A role for protease inhibitors?
Cohort
PI
Author
HOPS (n=2515)
Indinavir, Ritonavir, Lichtenstein 2005
Saquinavir,
Nelfinavir
A role for protease inhibitors?
Cohort
PI
Author
HOPS (n=2515)
Indinavir, Ritonavir, Lichtenstein 2005
Saquinavir,
Nelfinavir
Neuro AIDS clinic in Indinavir, Ritonavir, Pettersen 2006
Calgary (n=221)
Saquinavir
in vitro support
Indinavir and HIV are associated with
reduced neurite growth in vitro
CD4 and CCR5 expressing DRGs from transgenic rats
(Pettersen et al 2006)
A role for protease inhibitors?
Cohort
PI
Author
HOPS (n=2515)
Indinavir, Ritonavir, Lichtenstein 2005
Saquinavir,
Nelfinavir
Neuro AIDS clinic in Indinavir, Ritonavir, Pettersen 2006
Calgary (n=221)
Saquinavir
in vitro support
Alfred Hospital,
Melbourne (n=100)
Indinavir
Smyth 2007
A role for protease inhibitors?
Cohort
PI
Author
HOPS (n=2515)
Indinavir, Ritonavir, Lichtenstein 2005
Saquinavir,
Nelfinavir
Neuro AIDS clinic in Indinavir, Ritonavir, Pettersen 2006
Calgary (n=221)
Saquinavir
in vitro support
Alfred Hospital,
Melbourne (n=100)
Indinavir
Smyth 2007
Kuala Lumpur
(n=99)
Indinavir
Unpublished data,
2007
A role for protease inhibitors?
Cohort
PI
Author
HOPS (n=2515)
Indinavir, Ritonavir, Lichtenstein 2005
Saquinavir,
Nelfinavir
Neuro AIDS clinic in Indinavir, Ritonavir, Pettersen 2006
Calgary (n=221)
Saquinavir
in vitro support
Alfred Hospital,
Melbourne (n=100)
Indinavir
Smyth 2007
Kuala Lumpur
(n=99)
Indinavir
Unpublished data,
2007
Direct drug toxicity, or an indirect effect?
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?
Cytokine genotype predicts ATN in
Australian patients
(36 d4T treated patients: 16 ATN and 20 ATN-free)
Odds ratio 95% confidence p value
interval
BAT1(intron 10)*2
16.5
1.2 – 227
0.036
TNFA-1031*2
13.8
1.4 – 134
0.024
IL12B(3’UTR)*2
0.16
0.02-1.1
0.056
Overall model p=0.001
Cherry et al 2007
Cytokine expression in
painful and painless neuropathies
Uceyler et al, Neurology 2007
Macrophage
activation in
DRG / nerve
HIV-SN
Neuronal +/mitochondrial
injury
HIV
Macrophage
activation in
DRG / nerve
HIV-SN
Neuronal +/mitochondrial
injury
HIV
Macrophage
activation in
DRG / nerve
HIV-SN
Neuronal +/mitochondrial
injury
d4T / ddI
? PIs
Cytokine genotype
HIV
Macrophage
activation in
DRG / nerve
Host vulnerabilities
•
•
•
•
•
•
Nutritional
Age
Height
Genetic
Metabolic
Other?
HIV-SN
Neuronal +/mitochondrial
injury
d4T / ddI
? PIs
Management of HIV
neuropathies
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
Controlled analgesic trials in HIV-SN
Agent/s trialled
Effect on NS symptoms
0.1% capsaicin cream
Pain worsened (p=0.042)
Mexiletine
No effect
Amitriptyline & mexiletine
No effect from either / both
Amitriptyline & acupuncture
No effect from either / both
Memantine
No effect
Lamotrigine
Pain improved
Acetyl L-carnitine (for ATN)
No effect
rh nerve growth factor
Pain improved
Smoked cannabis
Pain improved
Controlled analgesic trials in HIV-SN
Agent/s trialled
Effect on NS symptoms
0.1% capsaicin cream
Pain worsened (p=0.042)
Mexiletine
No effect
Amitriptyline & mexiletine
No effect from either / both
Amitriptyline & acupuncture
No effect from either / both
Memantine
No effect
Lamotrigine
Pain improved
Acetyl L-carnitine (for ATN)
No effect
rh nerve growth factor
Pain improved
Smoked cannabis
Pain improved
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.”
Smoked cannabis vs placebo
D Abrams et al 2007
• 50 patients
• Painful HIV-SN
• Cannabis vs placebo 3 x daily
for 5 days
SIGNIFICANT FINDINGS
• 34% (vs 17%)  pain
• >30%  pain in 52% (vs 24%)
• No serious adverse events
Controlled analgesic trials in HIV-SN
Agent/s trialled
Effect on NS symptoms
0.1% capsaicin cream
Pain worsened (p=0.042)
Mexiletine
No effect
Amitriptyline & mexiletine
No effect from either / both
Amitriptyline & acupuncture
No effect from either / both
Memantine
No effect
Lamotrigine
Pain improved
Acetyl L-carnitine (for ATN)
No effect
rh nerve growth factor
Pain improved
Smoked cannabis
Pain improved
SN management strategies
under investigation
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: p=0.0025 (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
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 (n=10)
– 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)
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
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