The presentation covers the epidemiology of painful HIV-associated sensory neuropathy and its treatment. It was presented at the 16th World Congress on Pain, Yokohama, Japan, 2015 (Workshop title: Neuropathic pain in infectious diseases; chair: ASC Rice, UK). The presentation, along with additional supplementary files used to generate some of the figures can be located at figshare.com (http://dx.doi.org/10.6084/m9.figshare.3988914). If you use any of the slides, please include the DOI in the citation.

1. Painful HIV-associated sensory neuropathy
Peter Kamerman
16th World Congress on Pain, Yokohama, Japan, 2016

2. Major neurological complications of HIV infection
Central nervous system
HIV-associated neurocognitive disorders (HAND)
Myelopathy
Peripheral nervous system
HIV-associated sensory neuropathy (HIV-SN)
Inflammatory demyelinating polyneuropathies
Polyradiculopathy
Mononeuritis multiplex
Ferrari et al., 2006; Pardo et al., 2001; Power et al., 2009

3. Global prevalence of HIV-SN (adults): 30-60%
For review: Kamerman et al., 2012a

4. Global prevalence of HIV-SN (children): 13-38%
Araujo et al., 2000; Esteban et al., 2009; Peters et al., 2014;
Benjamin et al., manuscript in preparation; Floeter et al., 1997

5. Typical clinical features
SIGNS
Reduced:
Pin-prick sensitivity
Vibration sense
Reflexes
Temperature sense
SYMPTOMS
Pain
Numbness
Paraesthesias
Bouhassira et al., 1999; Tagliati et al., 1999; Martin et al., 2003;
Wadley et al., 2011; Freeman et al., 2014; Phillips et al., 2014

6. Pathogenesis

7. Pathogenesis of HIV-SN
For review: Kamerman et al., 2012a and 2012b
Dorsal root ganglion Axon and peripheral terminalSpinal cord
HIV Neurotoxic
antiretroviral drugs
(d4T, ddI, ddC)

8. Macrophage infiltration from the skin to the DRG
Goullée & Price, unpublished
athy. Selective degeneration of gracile tract in patients
with sensory neuropathy, characterized by loss of ax-
ons and myelin sheaths in the cervical and upper tho-
racic cord, described and suggested a “dying-back” de-
generation process of DRG neurons (Dal Pan et al.,
1994; Rance et al., 1988; Scaravilli et al., 1992). Other
studies have shown a frequent presence of peripheral
neuropathy in patients with vacuolar myelopathy (Brew,
1994; Dal Pan et al., 1994; Grafe and Wiley, 1989; Tan
and Guiloff, 1998).
Epidermal nerve fiber pathology
The recent introduction of epidermal nerve fiber
analysis by immunocytochemical techniques using the
panaxonal marker PGP 9.5 (protein gene product 9.5), a
neuronal ubiquitin hydrolase, has contributed to the in-
vestigation of PNS disorders. This technique allows the
study of epidermal innervation by small-caliber C and
A␦ nerve fibers (Holland et al., 1997; McCarthy et al.,
1995). Studies of skin biopsies of patients with HIV-
associated sensory neuropathy developing during treat-
ment with didanosine or zalcitabine showed reduction
in the number of epidermal fibers in distal areas of the
lower extremities with an inverse correlation between
neuropathic pain intensity and epidermal nerve fiber
density (Polydefkis M, 2000). In some of these pa-
tients, there was an increase in the frequency of fiber
varicosities and fragmentation in the dermis likely to be
representative of degenerating fibers and absence of
PGP 9.5 fibers in the epidermis (Fig. 3). There were also
fewer epidermal fibers in HIV-seropositive patients with-
out clinical evidence of neuropathy than in seronegative
controls. This finding suggests that HIV infection may be
associated with the loss of cutaneous innervation even
before the onset of sensory symptomatology (McCarthy
et al., 1995). A recent clinical trial that evaluated the use
of nerve growth factor in the treatment of HIV-associ-
ated sensory neuropathy used epidermal nerve fiber
density analysis as a secondary therapeutic outcome
(McArthur et al., 2000).
ure 2. Dorsal root ganglia pathology in HIV neuropathy is
acterized by foci of macrophage-lymphocytic infiltration
and Nagoette nodules (B). Infiltration by activated mac-
hages is demonstrated by immunostaining with anti-CD68
bodies (C) (bar 50 ␮m).
Figure 3. Skin biopsy from a normal control (A) and an HIV
patient with DSP (B). Note the decreased number of epider-
mal fibers and varicosity formation (B) (bar 50 ␮m).
50µm
Pardo et al., 2001
been shown in DSP, but the reduction is more modest
than the distal axonal loss [28]. Furthermore, selective
degeneration of the gracile tracts in patients with DSP,
characterized by loss of axons and myelin sheaths in the
cervical and upper thoracic cord, has been described
[29]. This finding represents degeneration within the
centrally directed extensions of the sensory neurons,
and is the central nervous system’s counterpart of the
dying back process seen in the peripheral nerve.
Immunopathological studies in DSP have shown pro-
minent macrophage activation with the local release of
proinflammatory cytokines in areas of axonal degenera-
tion (Fig. 2). Moreover, there has been consistent
demonstration of increased frequency of Nageotte
nodules. Nageotte nodules are compact areas of pro-
liferation of satellite cells that frequently accompany
DRG neuronal loss from any cause. DRG inflamma-
tory infiltrates are seen (Fig. 3) comprised mainly of
lymphocytes and activated macrophages, with conco-
mitant immunostaining for pro-inflammatory cytokines
such as tumor necrosis factor (TNF)-Æ, interferon-ª
Fig. 1. Skin biopsy from a normal control (a) and a HIV patient with DSP (b). Note the decreased number of epidermal nerve
fibers and formation of nerve fiber swellings (b) (bar, 50 ìm).
AIDS 2002, Vol 16 No 162108
50µm
Pardo et al., 2001
Spinal
cord
Skin
DRG Nerve trunk Skin
Dorsal root ganglion Axon and peripheral terminal
Spearman's rho = −0.68, p = 0.05
0
2
4
6
8
10
12
14
0 2 4 6 8 10
Epidermal macrophage count (cells/mm)
Epidermalnervefibredensity(fibres/mm)
Healthy controls
HIV neuropathy

9. Typical clinical features
SIGNS
Reduced:
Pin-prick sensitivity
Vibration sense
Reflexes
Temperature sense
SYMPTOMS
Pain
Numbness
Paraesthesias
Bouhassira et al., 1999; Tagliati et al., 1999; Martin et al., 2003;
Wadley et al., 2011; Freeman et al., 2014; Phillips et al., 2014

10. Pain is a common symptom of HIV-SN
Sadosky et al., 2008

11. HIV-SN is a major cause of chronic pain
Primary source of pain
Painful peripheral neuropathy 45-48%
Low back pain 22-28%
Arthralgia 6-13%
Koeppe et al., 2010
o Participants:
324 HIV-positive out-patients with a diagnosis of chronic pain.

12. The impact of painful HIV-SN
Having pain is associated with
being unemployed
↑ depression and anxiety
↑ severity of depressive symptoms
↑ sleep disturbance
↓ independence
↓ social functioning
Ellis et al., 2010; Phillips et al., 2014

13. Painful HIV-SN in children
Benjamin et al., manuscript in preparation
o Participants:
- 135 HIV-infected children
- 50% female
- Age: 7 (3 - 11) years
- CD4: 1184 (927-1440) cells/ml
- All exposed to stavudine (d4T)
o SN diagnostic criteria:
Bilaterally reduced / absent
ankle reflexes OR vibration sense
0
5
10
15
20
HIV-SN Symptomatic
HIV-SN
Painful
HIV-SN
Mean(95%CI)prevalence(%)
Low rates of symptomatic HIV-SN
in children

14. Symptoms are typically moderate to severe
Phillips et al., 2014
Intensity rating
Severe (7-10)
Moderate (4-6)
Mild (0-3)
o Participants:
21 patients with
painful HIV-SN
o Assessment:
Neuropathic Pain
Symptom Inventory
(NPSI)

15. Risk of painful HIV-SN

16. Risks for developing painful HIV-SN
Malvar et al., 2015
493
pain-free
HIV+
Median follow-up: 24 months
(IQR: 12-42; 1961 visits)
Assessment at each visit
o Pain: Yes / No
o Signs: Bilaterally reduced / absent pin-prick OR vibration sense OR ankle reflexes.

17. Incidence of painful HIV-SN
Malvar et al., 2015

18. Risks for developing painful HIV-SN
Malvar et al., 2015

19. Risks for having painful HIV-SN
Pillay et al., under review
Assessment:
o Pain: Yes / No
o Signs:
Bilaterally reduced / absent
pin-prick sensation OR
vibration sense OR
ankle reflexes.
n = 129
painful
HIV-SN
n = 72
pain-free
HIV-SN
• anxiety / depression
• total pain burden

20. Risks for having painful HIV-SN
Pillay et al., under review
Depression and anxiety
Painful HIV-SN (n = 129)
Non-painful HIV-SN (n = 72)
1 tile = 1%
I am not
depressed or anxious
I am moderately
depressed or anxious
I am extremely
depressed or anxious

21. Risks for having painful HIV-SN
Pillay et al., under review
Percent with other pain sites
Painful HIV-SN (n = 129)
Non-painful HIV-SN (n = 72)
1 tile = 1%
No
Yes
Pain intensity at other sites
Painful HIV-SN (n = 129)
Non-painful HIV-SN (n = 18)
1 tile = 1%
Mild pain
Moderate pain
Severe pain

22. Cause or effect: reduced cortical volume?
Keltner et al., 2014
ProportionwithpainfulHIV-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
o Participants:
241 patients HIV-SN
from 5 study centres in
the USA (CHARTER)

23. Pharmacological management

24. Treatment: there is a lack of evidence
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”

25. Large placebo response
Cepeda et al., 2012

26. Large placebo response?

27. Pillay et al., 2015
What is being used to manage the pain?
* Median (IQR) amitriptyline dose: 25 (25-75) mg/day | APAP: Paracetamol
o Participants:
130 adults with painful HIV-SN
o SN diagnostic criteria:
Bilaterally reduced / absent ankle reflexes OR vibration

28. Summary

29. Acknowledgments
University of the Witwatersrand
Antonia Wadley
Zané Lombard
Prinisha Pillay
Liesl Hendry
Asma Shaikh
Burnet Institute, Melbourne
Kate Cherry
University of Western Australia
Patricia Price
Hayley Goullée
Constance Chew
Funding
• National Research Foundation,
South Africa
• South African Medical Research
Council
• International Association for the
Study of Pain
• University of the Witwatersrand
…and
• The Honey Badger