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HIV-related neuropathy
Peter KamermanXXII World Congress of Neurology, Santiago, Chile, 2015
PAIN MT 30.1 - Management of difficult neuropathic pain conditions
Disclosures
I have no actual or potential conflicts of interest related to the material being presented.
Nor do I discuss off-label indications for any medications.
Overview
Characteristics
SIGNS
Reduced:
Pin-prick sensitivity
Vibration sense
Reflexes
Temperature sense
SYMPTOMS
Pain
Numbness
Paraesthesias
Typical clinical characteristics
Bouhassira et al., 1999; Tagliati et al., 1999; Martin et al., 2003; Wadley et al., 2011; Freeman et al., 2014; Phillips et al., 2014
Australia: Smyth et al., 2007; Malawi: Beadles et al., 2009; van Oosterhout et al., 2005; South Africa: Maritz et al., 2010; Wadley et al., 2011; SE Asia: Affandi et al., 2008; Wright et al., 2008 ; Uganda: Nakasujja et al., 2005; USA: Simpson et al., 2006; Ellis et al., 2010
Global prevalence: 30-60%
Prevalence
For review: Kamerman et al., 2012a, 2012b
Dorsal root ganglion Axon and peripheral terminalSpinal cord
Pathogenesis
Risk factors
For review: Kamerman et al., 2012b
HIV-SN is down, but not out
Newer, less toxic treatments
Ellis et al., 2010; Kamerman, 2015
Hung et al., 2005
HIV-SN is down, but not out
Newer, less toxic treatments
Neurotoxic drug regimen Other drug regimens
Pro
porti
on w
ithw
orse
ning
sig
ns
Pro
porti
on w
ithw
orse
ning
sym
ptom
s
• HIV-SN is common
• Expected to remain a problem
Summary
Painful HIV-SN
Painful HIV-SN
Pain is a common feature
Veves et al., 2007; Sadosky et al., 2008; Haanpaa et al., 2009; van Hecke et al., 2014
Common causes of chronic pain in HIV
Painful peripheral neuropathy 45-48%
Low back pain 22-28%
Arthralgia 6-13%
Koeppe et al., 2010
Major cause of chronic pain in HIV
Painful HIV-SN
Ellis et al., 2010; Hung et al., 2008; Malvar et al., 2015; Pillay et al., 2015
Risk of pain↑ riskPrevious neurotoxic drug use
Past or current cART
↑ nadir CD4 T-cell count
Current major depressive disorder
Number of other pain sites
↑ age
Female sex
↓ riskCurrent neurotoxic drug use
↑ time since HIV diagnosis
Risk factors for having pain
Painful HIV-SN
Keltner et al., 2014
Pro
porti
on w
ith p
ainf
ul
HIV
-SN
0.6
0.4
0.3
0.2
0.1
0.0
0.5
Q1 Q2 Q3 Q4
Quartiles of adjusted log cortical volume loss
Pain is associated with reduced cortical volumes
Painful HIV-SN
Pain intensity↑ intensity↑ viral load
↓ intra-epidermal nerve fibre density
↑ pain catastrophizing
↑ depressive symptoms
↑ number of pain sites
Genetic polymorphisms in KCNS1/TNFA/MHCIII
Simpson et al., 2002; Polydefkis et al., 2002; Zhou et al., 2007; Lucey et al., 2011; Hendry et al., 2013; Hendry et al., 2015; Pillay et al., 2015
The pain typically is moderate-to-severe
Painful HIV-SN
Having painful HIV-SN is associated withBeing unemployed
↑ depression and anxiety
↑ severity of depressive symptoms
↑ sleep disturbance
↓ independence
↓ social functioning
Ellis et al., 2010; Phillips et al., 2014
Impact of the pain
Painful HIV-SN
• Pain is common
• Typically is moderate-to-severe
• Causes a significant decrease in QoL
Summary
Treatment
Can we treat the pain?
Phillips et al., 2010; Clifford et al., 2012*
Treatment Pain relief superior to placebo
Yes NoTopical lidocaine gel (5%)
Capsaicin patch (8%) ?*
Amitriptyline
Lamotrigine
Mexilitine
Gabapentin / Pregabalin
Can we treat the pain?
Finnerup et al., 2015
“Pain due to HIV-related painful polyneuropathy…seems more refractory [to treatment] than other types of pain in our meta-analysis.”
“This difference might be due to large placebo responses in HIV-related neuropathy trials”
Confounding by the placebo response
Cepeda et al., 2012
HIV-SN trials show larger placebo response
Confounded by the placebo response
...and more placebo responders
Cepeda et al., 2012
Failed drug or failed study?
Simpson et al., 2010
Failed drug or failed study?
Tuttle et al., doi: 10.1097/j.pain.0000000000000333
Increasing placebo response is a general phenomenon
Failed drug or failed study?
Simpson et al., 2014
“Methodological refinements...to minimize the potential placebo response, which was quite large in the previous study”
Failed drug or failed study?
“Methodological refinements...to minimize the potential placebo response, which was quite large in the previous study” ● High baseline pain scores● Low baseline pain variability● Long baseline period + single-blind placebo lead-in● Restricted use of concomitant medications for pain● Improved phenotyping
Simpson et al., 2014
Failed drug or failed study?
Simpson et al., 2014
Failed drug or failed study?
“Methodological refinements...to minimize the potential placebo response, which was quite large in the previous study” ● High baseline pain scores● Low baseline pain variability● Long baseline period + single-blind placebo lead-in● Restricted use of concomitant medications for pain● Improved phenotyping
Simpson et al., 2014
Failed drug or failed study?
Simpson et al., 2010
“HIV-associated DSP was confirmed by the clinician at screening, ensuring that the patient had at least two of the three following neurological signs...reduced superficial sensation in the distal lower extremities bilaterally (using the pin-prick test)”
Simpson et al., 2014
Failed drug or failed study?
Summary
• HIV-SN is common
• Is expected to remain a problem
• Pain is common
• Typically is moderate-to-severe
• Causes a significant decrease in QoL
• The evidence-base to guide treatment is poor
University of the WitwatersrandAntonia WadleyZané LombardPrinisha PillayLiesl Hendry
Burnet Institute, MelbourneKate Cherry
University of Western Australia, PerthPatricia PriceHayley GoulléeConstance Chew
Funding• National Research
Foundation, South Africa• South African Medical
Research Council• International Association for
the Study of Pain• University of the
Witwatersrand
Acknowledgements
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