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