Clinical Phenotyping and Genotyping of HIV-Associated Sensory Neuropathy: The HIV-POGO Study
Conditions: HIV, Sensory Neuropathy, Neuropathic Pain
Sponsor: Imperial College London

HIV POGO Study Protocol Version 7 23/02/17 
Clinical Phenotyping and Genotyping of HIV-Associated Sensory Neuropathy : 
The HIV-POGO study 
 
 
NCT02555930 
 
 
Study Protocol Version 7.0 23/02/2017 
 
 

HIV POGO Study Protocol Version 7 23/02/17 
1. Introduction 
HIV associated sensory neuropathy (HIV-SN) is a frequent complication of HIV infection and its 
treatment, affecting between 20% and 57% of infected individuals [1]. It is a length dependent, 
sensory distal symmetrical polyneuropathy which causes altered sensation, numbness and pain. 
Despite a reduction in the use of the neurotoxic ‘d’ class of NRTI anti-retroviral medication, the 
prevalence of HIV-SN has remained at around 40% in the developed world [2, 3], and of those 
affected by HIV-SN, 38% to 90% experience pain [3, 4]. HIV-SN is a worldwide problem; a recent 
study in India showed an incidence of 40% in ART naive patients [5] and, in Malawi, a prevalence of 
56% has been reported in those taking stavudine-based antiretroviral  protocols [6].  
The introduction of newer combined antiretroviral treatment (cART) has changed the morbidity 
associated with HIV infection; mortality has decreased dramatically since that of the mid-1990s and 
HIV has become a chronic disease [7]. This has meant that co-morbidities associated with long-term 
HIV infection, especially those that are age related such as HIV-SN, cardiovascular pathology and 
neurocognitive dysfunction, are increasing in prevalence and becoming an important disease burden 
[8]. 
1.1 Diagnosis and Classification 
The treatment of pain related to HIV-SN remains difficult, despite growing knowledge about the 
pathophysiology and mechanisms involved in its development. This is due to three important 
factors. Firstly, the identification and classification of HIV-SN can be challenging, and there is no 
worldwide consensus on the criteria required for the diagnosis of HIV-SN. Detailed history, clinical 
examination, nerve conduction tests, quantitative sensory testing to assess small fibre function [9, 
10] and skin biopsies [11] to assess intra-epidermal nerve fibre density, are all used to aid diagnosis. 
However, some of these tests are expensive, time-consuming and, currently, are not universally 
available. Skin biopsies are also invasive, which limits their practical use as a longitudinal method of 
assessment. In other sensory neuropathies, it has been shown that loss of small fibre density can be 
monitored over time using corneal confocal microscopy (CCM), and that this correlates with results 
from skin biopsy [12]. This technique could potentially also be used for the long-term follow up of 
patients with HIV-SN and is the focus of further investigation. 
It is generally accepted that a combination of subjective symptoms and objective clinical signs are 
required for a screening tool in HIV-SN [13]. An easy, simple screening tool – ‘CHANT’ (Clinical HIV-
Associated Neuropathy Tool) has been recently developed, based on the detailed phenotyping of a 
group of patients with painful HIV-SN, in the cART era [14]. It is a 4 item tool which has been 
validated in both European and African patient groups [15]. 
The second reason for low treatment efficacy in HIV-associated neuropathic pain is the potential 
heterogeneity of pain mechanisms in the HIV population. Patients with HIV-SN related pain may 
respond differently to certain therapies because of a varying predominance in underlying pain 
‘driver’ for that population. Pain drivers that have been shown to be important in other neuropathic 
pain conditions, such as conditioned pain modulation and temporal summation, could potentially be 
involved in HIV-SN related pain [16, 17]. Identification of a predominant pain driver in the individual, 
could lead to a more targeted trial of therapy.  

HIV POGO Study Protocol Version 7 23/02/17 
1.2 Genetic Risk Factors 
Thirdly, little is known about the genetic influences that may predispose an individual with HIV to 
develop a painful sensory neuropathy. So far, no genome-wide association studies have been 
published on HIV-SN. Instead, genetic investigation has focused on identifying ‘candidate genes’ that 
have been highlighted as being important in the pathophysiology of the disease. Research has 
focused on genes involved in mitochondrial function, as a potential mechanism for the neurotoxicity 
of NRTIs, and on genes involved in the inflammatory response, as a mechanism for direct viral-
induced neuropathy.  
A certain haplotype, involved in the electron transfer chain, has been identified in mitochondrial 
DNA as being a risk factor for the development of HIV-SN in Europeans on cART [18, 19], but only 
limited studies have been conducted in African ethnic groups. Some studies have also shown a link 
between polymorphisms of nuclear DNA, involved in the transcription of mitochondrial DNA [20]. 
Polymorphisms in the promoter region of the TNFα gene and the untranslated region of the IL12β 
gene have also been linked to an altered risk of developing HIV-SN in Europeans [21]. In general, 
very little is known about any genetic associations in the African and Asian populations. 
Even less is known about what genetically predisposes patients with HIV-SN to develop neuropathic 
pain. Currently only the GTP cyclohydrolase 1 (GCH1) gene, involved in the production of 
pronociceptiove molecules, has been shown to have an association with HIV-SN related pain [22]. 
Therefore, more work remains to be done to identify the genetic and epigenetic influences in the 
cART era and in different ethnic groups. 
1.3 HIV associated Neurocognitive Disorder and Neuropathic Pain 
HIV associated Neurocognitive Disorder (HAND) is now recognised as an important and frequent  
complication of HIV infection. The prevalence has been reported as high as 69% when asymptomatic 
HAND is included [23] and a large population study in Canada recently showed that 50% of patients 
with one neurological complication of HIV had at least one other neurological complication [24]. It 
also showed that the two most common pathologies were HAND and HIV-SN [24]. The co-existence 
of these conditions means that one may have an impact on the identification and treatment of the 
other, and that there could be a shared mechanism or group of risk factors, for example gp120 
induced neurotoxicity.  
HAND is a spectrum of neurocognitive impairment including asymptomatic functional impairment, 
mild symptomatic dysfunction and severe HIV-associated dementia. [25] Milder forms of HAND are 
characterised by cortical features, such as impaired retrospective and prospective memory, and 
executive functioning. [26]This milder end of the spectrum is very different to HIV-associated 
dementia, where subcortical features predominate (such as the rapid, progressive, loss of 
concentration, impaired motor function and behavioural change [8]). All types of neurocognitive 
impairment could affect how a patient perceives and reports pain, how they perform with QST and 
how they respond to therapeutic intervention. Mild cognitive impairment may influence the ability 
to use certain pain scales, to effectively describe pain symptoms [27] and associated motor 
impairment may influence the ability to respond to stimuli in QST.  

HIV POGO Study Protocol Version 7 23/02/17 
Interestingly, patients with dementia exhibit different responses to placebo due to a loss of 
expectation [28], however, this has not been explored in mild cognitive impairment. It has also been 
shown that patients with HIV-SN show a greater response to placebo than other neuropathic pain 
conditions [29]. This may mean that it is the altered response to placebo that is responsible for the 
heterogeneity in HIV-SN and that this may be due to differences in cognitive ability. 
Patients with subclinical or early HAND may show a predisposition to HIV-SN and vice versa. It is 
thought that both conditions occur as a result of chronic neuroinflammation. The HIV retrovirus 
infects macrophages and dendritic cells, and can remain in the brain, which acts as a reservoir for 
the disease. [30] From simian models, the virus has been shown to enter the nervous system early in 
the disease. These models have shown that the chronic immune activation associated with HIV 
disease progression, causes dysregulation of macrophage function and an alteration in the 
production of cytokines and chemokines (for review [25]).   This change occurs within both the 
central and peripheral nervous systems and has been shown to be crucial in the development of 
both HAND and HIV-SN. [31] 
The toxic effects of viral gene products, such as the viral coat glycoprotein 120(gp120), have been 
identified in the development of HAND [32, 33] and HIV-SN [34].  Rodent models of HIV-SN have 
been studied with perineural administration of HIV-gp120. The inflammatory reaction results in 
spinal gliosis, macrophage infiltration and upregulation of various chemokines in the dorsal root 
ganglion [35, 36]. It also results in the reduction in intraepidermal nerve fibre density and 
mechanical hypersensitivity, which correlates to what is observed in human HIV infection [35]. 
Similar genetic targets, such as polymorphisms in the promoter region of TNFα [21, 37], have also 
been highlighted in both conditions, and this could indicate a joint genetic predisposition (for review 
[4, 38]). 
 
2. Study Objectives 
a) To recruit a cohort of patients with HIV with and without HIV-SN and to identify genetic factors 
associated with sensory neuropathy and neuropathic pain. This will be used to compare these 
factors with other neuropathic pain aetiologies recruited within the NeuroPain collaboration.  
b) To further phenotype their symptoms with the use of well-validated questionnaires and sensory 
testing. 
c) To perform a neurocognitive assessment on these patients in order to identify any correlation 
between HIV-SN and HAND.  
d) To obtain blood samples for genetic analysis to further elucidate genetic risk factors for the 
development of HIV-SN and related pain syndromes. Analysis will be performed by collaboration 
with deCODE. This study represents a replication cohort for testing genetic hypotheses developed as 
a result of analysis of a much larger population. 
e) To provide a database resource from which to recruit patients for three imbedded studies (see 
diagram below- details to be confirmed). The smaller secondary studies aim to more highly 

HIV POGO Study Protocol Version 7 23/02/17 
phenotype patients with HIV neuropathy using conditioned pain modulation paradigms, corneal 
microscopy and placebo protocols. 
 
 
The NeuroPain research group 
This study is part of the NeuroPain Study Group investigating neuropathic pain and endogenous 
analgesic mechanisms through a broad range of animal and human studies. Imperial College London 
is Neuropain  Partner 11, and this protocol is part of Work Package 7 in this study. Work Package 7 
incorporates four partner groups. One group in Helsinki will be co-ordinating a phenotyping 
programme for patients following mastectomy that are at risk of chronic post-surgical pain.  Another 
group, based in Berlin, will be conducting a similar protocol with another cohort of HIV patients. All 
three centres will send blood for exome wide sequencing to deCODE in Iceland and there is 
consensus between the groups for the core phenotyping of patients. 
All three European patient cohorts are to be incorporated as ‘replication cohorts’; this is because 
deCODE already has large amounts of genetic information from previous work on pain syndromes 
and other disease states. From this information they can apply targeted analysis of the NeuroPain 
patient cohorts. This also means that the large population numbers usually required for genetic 
studies are not required. 
2.1 Justification for the study 
To our knowledge, this will be the first large, prospective observational cross sectional cohort study 
to have been conducted with HIV patients, using detailed genetic analysis targeted at sensory 
neuropathy and neuropathic pain in the UK population.  It will be the first prospective study to 
examine for any co-existence of HAND and sensory neuropathy and the effect on pain reporting and 
perception. Results from the HIV-POGO study will be examined in conjunction with patient cohorts 
with other neuropathic pain syndromes within the NeuroPain study. 
NEUROPAIN WP7 
HIV COHORT
Exome sequencing
Broad Phenotyping
n=200
PSYCHOPHYSICAL TESTING
QST
CPM
Placebo paradigms
n=?
LONGITUDINAL STUDIES
Corneal microscopy
IENFD
n=?
PLACEBO PARADIGM                            
n=?

HIV POGO Study Protocol Version 7 23/02/17 
3. Study Design 
The Clinical Phenotyping and Genotyping of HIV-associated Sensory Neuropathy Study (HIV-POGO) is 
an observational, single-cohort, cross sectional study conducted at St Stephens Centre and Chelsea 
and Westminster Hospital NHS Trust, London. 
3.1 Recruitment 
Subjects (n=200) will be recruited from the St Stephens Centre at Chelsea and Westminster Hospital 
and associated clinics via HIV and chronic pain clinic lists, and from the local HIV population. They 
will undergo a formal consent process.  
Patients already recruited to other studies by SSAT or those identified by the clinical team as having 
sensory neuropathy will be contacted by letter and telephone to ask whether they would be 
prepared to participate in the study and will be sent a patient information leaflet. 
It is intended that 200 subjects with HIV will be recruited over 36 months. Despite the genetic nature 
of this study, only 200 subjects will be required as our cohort represents a ‘replication cohort’ to 
enable genetic hypothesis testing devised from results of a much larger neuropathy cohort in 
Iceland.  
Patients will be identified as eligible from HIV and chronic pain clinic during a screening interview 
(see below for inclusion/exclusion criteria); they will be invited to attend a clinical appointment and 
at the end of the appointment will be given a booklet of questionnaires to be filled in at home which 
they will be asked to post back to the department. If they are able to fill the questionnaires in on 
their own, for any reason, they will be completed with the researcher during the appointment.  
3.2 Questionnaire booklet 
Patients will be asked to complete a series of questionnaires given to them at their appointment. 
They will be asked to post them back to the research group within 2 weeks and will be sent a 
reminder by text if the questionnaires are not received after 3 weeks. The majority of these 
scales are part of the ‘core phenotyping’, which has been agreed across different pain cohorts 
within the NeuroPain study, and with deCODE. These are described as ‘core’ phenotyping in the 
protocol. Some are specific to this HIV cohort and are described as ‘specific’ phenotyping. 
Questionnaires are expected to take approximately 45 minutes to complete. The questionnaires 
to be used have been summarised below. 
Questionnaire 
Time taken to complete 
(minutes) 
Core or specific 
phenotyping 
DAPOS : Depression Anxiety Positive 
Outlook Scale 
3 
Specific 
HADS : Hospital Anxiety and Depression 
Scale 
5 
Core 
BPI : Brief Pain Inventory 
5 
Core 
NPSI: Neuropathic Pain Symptom 
Inventory 
5 
Specific 
SF-36 : Quality of life index 
10 
Core 
ISI : Insomnia Severity Inventory 
3 
Specific 

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TIPI : Ten Item Personality Inventory 
3 
Specific 
PCS : Pain Catastrophizing Scale 
5 
Core 
EMQ: Everyday Memory Questionnaire 
5 
Specific 
Table 1. Summary of post-appointment questionnaires 
 
a) Basic Psychological Assessment 
Ø The Depression Anxiety Positive Outlook Scale (DAPOS) (specific) will be conducted as 
the confounding effect of psychological conditions are well recognised in neuropathic 
pain [39]. This scale has been validated in chronic pain populations and incorporates 
positive, as well as negative features, which are commonly associated with pain 
syndromes. Its use will retain backwards compatibility with the data from the HIV-PINS 
study, samples from which will be also genotyped by deCode within NeuroPain. It is 
important to recognise depression, as it may be that patients who are depressed are 
more likely to have pain, or that those with pain become depressed as a consequence of 
it [40, 41]. It may also be that patients with HAND have higher rates of depression. 
Ø The Hospital Anxiety and Depression Scale (HADS) (core) will be used as another 
measure of anxiety and depression [42]. This is to enable coherence with previously 
collected data by deCODE and will also allow a direct comparison with DAPOS data in 
HIV patients. 
 
b) Quality of Life 
Ø SF-36 (core) This is a generic quality of life questionnaire which incorporates the impact 
of pain [43] and has been shown to be reliable, and valid, across a wide range of 
populations and conditions. Normative data for a variety of patient populations is also 
available. Despite being generic, it is thought to be a more precise and functional 
assessment of quality of life than those targeted specifically at patients with HIV [44]. 
Ø Insomnia Severity Index (ISI) (specific). This is a subjective 7 item questionnaire [45] 
which has been shown to be reliable for pain patients with insomnia when compared to 
polysomnography and sleep diaries [46]. 
c) Pain Characterisation 
Ø Brief Pain Inventory (BPI) (core) Although originally developed for assessing the 
interference of function in cancer pain [47], the BPI has been validated to measure the 
effect of other types of pain on functional interference across seven domains; general 
activity, mood, walking ability, relations with others, sleep and enjoyment of life.  
Ø Neuropathic Pain Symptom Inventory (NPSI) (specific) This questionnaire gives further 
information about positive neuropathic symptoms and has been validated in chronic 
pain patients [48]. It has also been used to subgroup patients and has shown some 
correlation with QST results [49]. 
d) Temperament assessment 
Ø The Ten Item Temperament Inventory (specific) [50] is a modified, shortened version of 
the NEO-Five Factor Inventory. Such temperament inventories examine the ‘Big Five’ 

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personality traits; neuroticism, openness, extraversion, agreeableness and 
conscientiousness. Neuroticism has been shown to correlate with higher pain vigilance 
and fear related pain behaviours in chronic pain patients [51]. Temperament domains 
have not been rigorously tested in patients with HIV sensory neuropathy in the past. 
Ø The Pain Catastrophising Scale (PCS) (core) will be used to identify rumination, 
magnification and helplessness. It is a five minute, 13 item instrument, which has been 
validated in neuropathic pain [52, 53]. Catastrophizing has also recently been shown to 
impact on adherence to treatment in HIV patients [54]. 
 
 
3.3 The Clinical Appointment 
Patients will be asked to attend a clinical appointment at Chelsea and Westminster Hospital, which 
will last approximately one hour and 45 minutes. At the clinical appointment a number tests will be 
performed. These are summarised in the table below. 
Clinical Parameter 
Process 
Time taken to 
complete (minutes) 
Core or 
specific 
Collection of patient 
demographics 
Analysis of patient notes and 
history taking 
5 
Core and 
specific 
Structured neurological 
examination including blood 
pressure 
Examination 
10 
Specific 
Quantitative Sensory Testing 
(QST) 
Psychophysical testing 
30 
Specific 
CHANT : Clinical HIV-
Associated Neuropathy Tool 
History and examination 
5 
Core 
QUESTOR body map 
Body map representation of 
pain 
2 
Core 
DN4-i : Doleur 
Neuropathique 4 Interview 
Interview 
3 
Core 
‘CogState’ cognitive function 
testing 
Computer Based test 
45 
Specific 
Peripheral Blood Sample 
Blood Sample 
5 
Core 
Table 2. Summary of tasks to be performed at clinical appointment 
a) Gathering of patient information 
Information will be collected from the patient interview, and from prior analysis of paper and 
electronic medical records. The following will be documented: 
• 
Gender, age, ethnicity, sexual orientation 
• 
Hand dominance 
• 
Medical history including other potential causes for neuropathy and neurocognitive 
impairment 
• 
Date of HIV diagnosis, complications, drug history including previous and current ART 
regimens 
• 
Drug, smoking and alcohol history – both chronic and within the last 48 hours 
• 
Educational level, occupation and socioeconomic status 

HIV POGO Study Protocol Version 7 23/02/17 
• 
Results of clinical investigations previously performed: 
Ø Nerve conduction studies, QST and skin biopsy (where available)  
Ø Most recent CD4 count and viral load and CD4 nadir 
Ø LFTs/TFTs/B12/triglyceride levels/HepB/HepC/syphilis 
Ø CT/MRI/PET imaging of the brain (where available) 
 
 
b) Basic examination 
• 
Height 
• 
Weight 
 
c) Structured Neurological Examination  
An upper and lower limb neurological examination will be performed to detect for clinical 
neuropathy. This will include an assessment of light touch and pinprick sensation, joint position 
and vibration sensation, deep tendon reflexes, muscle wasting and motor power, as described 
by the NeuPSIG guidelines [55]. 
A lying and standing blood pressure will be measured as an indicator of autonomic dysfunction. 
A lying non-invasive blood pressure will be recorded after lying for 5 minutes. The patient will be 
asked to stand and their blood pressure recorded at 1 and 3 minutes. A diagnosis of orthostatic 
hypotension will be made if there is a fall in systolic pressure of at least 20mm Hg or diastolic 
pressure of at least 10mm Hg [56] 
 
d) Case Definition: Diagnosis of HIV-SN 
All patients will be screened for HIV-SN based on the CHANT (Clinical HIV-associated Neuropathy 
Tool) screening tool [15] 
This is a simple 4-item tool comprised of two subjective questions (self report of foot pain and of 
foot numbness), and two objective measures on clinical examination (loss of vibration sense and 
loss of ankle reflex). If the patient is positive for one symptom and one sign in a bilateral 
distribution they will be defined as having sensory neuropathy. 
 
e) Diagnosis of HIV-SN related neuropathic pain (HIV-SNP) 
Patients will be given a body map to illustrate any sites of pain, and the 7-item DN4-i (Douleur 
Neuropathique 4-interview) interview will be conducted to identify the probability of the patient 
having neuropathic pain. A score of ≥3 out of 7 from the patient reported outcome section of 
the DN4-i will be used as a positive diagnosis of neuropathic pain [57] as this cut-off has been 
shown to have sensitivity of above 80% in neuropathic pain conditions[58].  
 
Patients will also be asked to indicate the areas that they experience pain. Symptoms must also 
be in a neuroanatomically plausible distribution, which could be attributable to HIV-SN; for 
example in a distal, symmetrical distribution. A QUESTOR legend for body areas will be used for 
this. Both a score of ³3 on DN4-i and a plausible anatomical distribution will be required for 
definition of HIV-SNP. 
f) Neurocognitive Assessment 
Ø Although full neuropsychological testing is the gold standard for the diagnosis of HAND 
[60], it is very time consuming and requires specialist delivery which is not universally 
available. It is also used for the diagnosis of HAND rather than the measurement of it, 

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and such quantification of the disorder is important for this study, and for longitudinal 
follow up of patients. One computerised battery of tests (CogState) has been studied in 
HAND and has been shown to have a positive predictive value of 81%[61]. It also 
appears to be sensitive enough to monitor changes in ARV therapy and mirrors 
structural changes identified on MRS[62]. It includes eight tasks conducted with a 
computer screen and keyboard. There is a 15 minute ‘training session’ and the test takes 
approximately 20 minutes. It assesses eight attention, memory and executive function 
domains (specific phenotyping). 
Ø A baseline level of intelligence quotient, such as the National Reading Test has not been 
included as it is not a longitudinal study and would not accurately assess IQ in such a 
multicultural population where English is frequently not the first language. 
Ø A subjective measure of cognitive function will also be performed using the Everyday 
Memory Questionnaire (EMQ). This provides a patient reported measure of memory and 
attention to compare with the objective computerised measure. 
g) Quantitative Sensory Testing (specific phenotyping) 
Quantitative Sensory Testing (QST) will be conducted the German Research Network on Neuropathic 
Pain QST protocol [10]. This is a battery of somatosensory testing which uses mechanical, cold, warm 
and pinprick stimuli in 13 domains; detection thresholds (cold detection threshold (CDT), warm 
detection threshold (WDT), paradoxical heat sensation (PHS), thermal sensory lime (TSL), mechanical 
detection threshold (MDT) and vibration detection threshold (VDT)), pain thresholds (cold pain 
threshold (CPT), heat pain threshold (HPT), mechanical pain threshold (MPT) and pressure pain 
threshold (PPT)), and stimulus-response functions (mechanical pain sensitivity (MPS), wind-up ration 
(WUR) and dynamic mechanical allodynia (DMA)). 
Full QST testing has been performed on patients with HIV-SN in a previous study [14]. This study 
showed that although 86% of HIV-SN patients showed a loss of function in at least one modality, no 
single sensory parameter was had a useful diagnostic utility. This study showed that there were no 
significant differences in CPT, DMA, MPT and MPS between those with HIV-SN and healthy controls, 
and between those who reported pain and those that did not. Other studies have however, 
highlighted MPT and MPS as useful parameters [49] in HIV-SN. Therefore, in this study, the full DFNS 
QST protocol will be performed. The testing will be performed at the site of maximum pain or, in 
those with no pain, on the dorsum of their right foot, in the S1 dermatome. 
QST results have been shown to differ in populations with cognitive impairment, such as Alzheimer’s 
disease [63], but have not been assessed in comparison to mild cognitive impairment in HIV. It has 
however, been shown that there is good test-retest correlation when conducting QST in mild to 
moderate Alzheimer’s, indicating that despite the requirement for short term memory and other 
executive functions, QST can still be performed in a reliable manner [63]. 
h) Blood Testing  
A peripheral blood sample (30ml) will be taken from each patient.  
10ml will be processed and stored as per protocol, from deCODE, and will be used for genetic 
analysis. Patients will be consented for using the blood for genetic analysis and that further genetic 

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or biochemical tests may be performed in the future on the sample to investigate potential links 
with pain, neuropathy or HAND. A material transfer agreement (MTA) will be in place between 
Imperial College London and deCODE in Iceland outlining the responsibilities of each party in the 
transfer of the blood samples. The remainder of the blood will be stored at Chelsea and Wesminster 
Hospital until the end of the study. It will then be transfer to a secure tissue bank after processing at 
Chelsea and Westminster Hospital. This is for independent genetic or biochemical analysis in the 
future, for which patients will be fully consented. 
i) Conditioned Pain Modulation (Specific phenotyping) 
Conditioned Pain Modulation (CPM) is a method of testing a subjects intrinsic descending pain 
modulation. It is a way to measure the phenomenon that pain at one site can inhibit the sensation of 
pain at a distant site. It is it thought that deficiencies in CPM exist in a number of chronic pain 
conditions such as fibromyalgia, diabetic polyneuropathy and osteoarthritis. The protocol for CPM 
has now been established in our laboratory. It involves using a warm thermode which is placed on 
the patients forearm; the thermode it heated until the patient describes a pain score of 60 out of 
100. This stimulus lasts for a maximum of 30 seconds. An alternative method is to use a pressure 
algometer to measure pain pressure threshold three times as a pressure test stimuli at the dominant 
upper arm (on the deltoid muscle). Either the thermal OR the pressure stimuli will be used, not both. 
Only patients unable to tolerate the pressure threshold will undergo thermal testing. The patient 
then is asked to place their hand in a bath of cold water (12°C) for one minute before the warm or 
pressure stimulus is repeated. The score the subject gives for the test stimulus before the cold 
stimulus is then subtracted for the score they give during the cold stimulus to give a value for ‘CPM 
effect’. It is hypothesised that patients with pain will have a smaller CPM effect. To identify any 
placebo or nocebo effects from the cool water, the experiment will be repeated using room 
temperature water as a ‘sham’. 
Since subjects recruited up to the 30th October 2015 underwent the paradigm with the thermal test 
stimuli and the pressure pain threshold stimuli has been shown to be more reliable, patients tested 
between 1st December 2014 and 30th October 2015 will be invited to return to undergo the paradigm 
again, using the pressure pain threshold. Only patients who have indicated on their written consent 
form that they are happy to be contacted about future studies will be approached. They will be 
contacted by email or telephone and sent the additional patient information leaflet (PIL additional 
information version 1.0). At the clinical appointment they will undergo only CPM testing after signing 
a Consent Form Addendum (version 1.0). Reasonable travel expenses will be reimbursed. 
j) Hand Held Nerve Conduction Studies (Specific phenotyping) 
Formal nerve conduction studies (NCS) are used clinically to aid the diagnosis of small fibre 
neuropathy and are commonly used in the HIV population. However, formal NCS takes a 
considerable amount of time and must be performed at by a neurophysiologist at a specialist centre. 
Two new devices have been developed to identify sural nerve conduction abnormalities in a user-
friendly way. These devices, the ADVANCE NCS System and the NC-Stat DPNCheck (both 
manufactured by Neurometrix) take only a couple of minutes and can be used by the non-expert. It 
involves passing an electric current through the ankle and measuring the speed and size of the nerve 
conduction of the sural nerve. These devices have been validated and are used clinically in the 

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diabetic population to detect a similar small fibre neuropathy to that seen in HIV patients. We intend 
to validate the use of these devices in HIV patients 
k) Lower leg skin biopsy (Specific phenotyping but OPTIONAL for a small proportion of patients).  
Skin biopsy together with clinical examination is the gold standard for diagnosing HIV-SN in the 
clinical setting. This study attempts to use non-invasive means for defining HIV-SN based on 
examination findings and patient history, using a validated tool. Skin biopsies in a small proportion of 
patients with extreme phenotypes would allow for comparison with other measures obtained in this 
study such as NCS, genetic testing and cognitive function which have not been assessed in the 
context of skin biopsy previously. Biopsies will be taken, fixed and analysed using 
immunohistochemistry as per the European Federation of Neurological Societies guidelines and 
biochemical analysis may also be performed. Biopsies will be stored at Chelsea and Westminster 
Hospital until the end of the study, after which they will be transferred to an HTA approved Tissue 
Bank. 
It is anticipated that upto 30 patients out of the cohort of 200 will undergo skin biopsy and this will 
be an optional section on the consent form. Patients will be excluded if they are known to be 
coagulaopathic or if they are taking anti-coagulant medication or if they have an allergy to local 
anaesthetic. They will be given an information leaflet and contact details should there be a problem 
with bleeding or infection. 
3.4 Study Outcome Measures 
The aim of the HIV-POGO study is to phenotype a cohort of HIV positive patients with and without 
HIV-SN and to identify factors associated with neuropathy and, in patients with neuropathy, factors 
associated with neuropathic pain. It is anticipated that genetic analysis will show differences 
between the phenotyped groups. We also aim to elucidate any neurocognitive impairment in the 
cohort and to examine whether there is any correlation with the HIV-SN phenotype or with how pain 
is reported. 
4. Participant Entry 
4.1 Pre-registration evaluations 
All adult patients aged 18 years or older, attending HIV or chronic pain clinics at St Stephens Centre 
and Chelsea and Westminster hospital, or partnered clinics, will be invited to participate. Their 
eligibility for inclusion in the trial will be assessed with a brief questionnaire and those eligible will be 
offered patient information on the study. 
4.2 Inclusion criteria 
• 
Aged 18 years or older 
• 
HIV positive 
4.3 Exclusion criteria 
• 
Pregnancy 
• 
Refusal to consent, including for genetic analysis 

HIV POGO Study Protocol Version 7 23/02/17 
• 
Pain ≥4 on NRS due to a pathology other than HIV-SN 
• 
Co-incident severe CNS disease (as determined by the investigator) including a diagnosis of 
dementia 
• 
Co-incident major psychiatric condition (DSM V criteria[64]: Depression 296.30-36 and 
Anxiety 300.0-3/21-23/29) 
• 
Limited English language skills as unable to complete questionnaires 
4.4 Withdrawal criteria 
If a patient wishes to withdraw from the study, including their data and blood, they can do so at any 
stage during the protocol. This will not have any effect on their treatment or inclusion in future 
studies. 
5. Adverse Events 
This is an observational study and we are not expecting any adverse events (AE). The only potential 
anticipated AE would arise from the complications of phlebotomy. Any AEs will be recorded in a AE 
log and securely stored. Any serious AEs will be reported to the Chief Investigator (AR) within 24 
hours. If the SAE was related to the study or occurred unexpectedly, it will be reported to the 
Sponsor and REC within 15 days. 
6. Assessment and Follow up 
Patients will be given the contact details for the Chief Investigator and the investigator conducting 
the appointment if they have any concerns in the period following the study. 
The study will be complete one year after the 200th patient has completed their clinical 
appointment. This is to allow for further contact with the patient for clarification of information 
during the analysis phase. 
7. Data storage and Data Analysis 
7.1 Data Management 
All data will initially be collected on paper case report forms (CRF). Subjects will be given a study 
specific identification number that will be used on the CRFs. Therefore no patient identifiable data 
will be entered on the CRFs. An anonymization log will be stored in the trial master file (TMF) as well 
as the original completed CRFs; the TMF will be kept in a locked room at Chelsea and Westminster 
Hospital.  
Study information from the paper CRFs will be transcribed onto a password-protected database. Any 
patient identifiable data will be stored on NHS computers at Chelsea and Westminster Hospital. Such 
computers require password access and are only accessible to staff. Only anonymized data will be 
stored on a secure Imperial College computer at Chelsea and Westminster Hospital. Only the 
research team for this study will have access to this computer. 
Relevant data will be shared with deCODE as collaborators, using a secure, encrypted database  
7.2 Statistical Analysis 

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Statistical advice was sought from deCODE genetics statisticians with regards to sample size and 
analysis.  
Genetic Analysis 
Single nucleotide polymorphisms (SNPs) that show significant association to defined neuropathic 
pain phenotypes after genome-wide adjustment will be validated in several independent case-
control groups. The validation of the associated signals identified in the GWA study is essential, as 
successful validation in additional groups would substantially increase our confidence in the 
associations observed. It will also allow us to determine if an allelic frequency is significantly 
different between cases and controls, since the familial correction factor will be much less than in 
the discovery cohort. These single-marker association studies will be analyzed, including adjustment 
for any familiality in patients or control groups. The p-values in each cohort will be adjusted by 
Bonferroni correction for number of markers tested or by randomization of phenotype procedure.  
In those regions where we observe genome-wide significant associations to neuropathic pain 
phenotypes that are validated in a second set of independent samples, we intend to select 
additional markers for genotyping in order to refine the observed association signal and search for 
possible functional variants.  
Re-sequencing will be done to screen for the actual mutation and/or to identify haplotypes that are 
rarer and have higher risk (for diagnostic purposes). The sensitivity of this method may allow us to 
detect different frequencies of rare variants such as 3% vs 10% in the general population between 
patient and control pools. Variants that show association to the phenotypes selected will be 
converted to a SNP assay and rerun on the entire sample set of the selected phenotype and controls 
for confirmation of the signal. 
Power Calculations 
The study design should ensure that large enough sample sizes will be typed in order to detect 
variants of moderate risk in the range of 1.4-2.0. Power calculations are used to estimate the 
minimum risk and frequencies that can be expected to detect given the sample size proposed. An 
example of 1100 subjects and 5000 controls in a GWA-study is presented. For example, we have 
over 90% power to detect a risk variant in 15% allelic frequency or higher with a risk ratio of 1.6, and 
more than 98% power to detect a risk variant in 20% allelic frequency or higher with a risk ratio of 
1.6. The power is computed for a SNP surrogate of the mutation, which may or may not be a SNP, 
with R2 between the SNP and the mutation assumed to be 0.8. A multiplicative model for risk is 
assumed (Falk & Rubinstein, 1987), and relative risk (RR) is defined as the risk of the mutation 
relative to the wild type. 
The wider collaboration and use of replication cohorts 
DeCODE will pursue 2 parallel approaches to replication of variants that they find in their discovery 
cohorts in Iceland.   Firstly they will attempt cross-replication of variants found to have significant 
association in one type of chronic pain, after correction for multiple testing, to other types of chronic 
neuropathic pain.  
They will test variants found in Iceland in well-phenotyped chronic pain cohorts from the US, 

HIV POGO Study Protocol Version 7 23/02/17 
Canada, UK, and Israel, totaling over 12,000 patients. For all variants found in Iceland they 
will also look for association to other chronic pain phenotypes not represented in the 
discovery cohorts:  HIV painful neuropathy from this group (200 patients) and 2 limb 
amputation cohorts collected by Dr. Seltzer from Israel and Cambodia (500 and 5500 
patients, respectively). 
8. Regulatory Issues 
8.1 Ethics Approval 
The Chief Investigator has obtained approval from the >>> Research Ethics Committee. The Chief 
Investigator will have a letter of approval from the Trust R&D department before the recruitment 
process can start. The study will be conducted in accordance with the recommendations adopted by 
the 18th World Medical Assembly, in Helsinki 1964. 
8.2 Local Approval and NIHR portfolio adoption 
Local approval will be sought from Chelsea and Westminster Hospital research and development 
department. The study will not start until permission has been granted. 
The project is eligible for inclusion in the NIHR Clinical Research Network and this will be applied for 
via the IRAS system. 
8.3 Consent 
Consent to enter the study will be sought for each participant after full explanation has been given, a 
patient information leaflet offered and time allowed for consideration. The right of the patient to 
refuse to participate without giving a reason will be respected. All participants are free to withdraw 
at any time without giving reason and without prejudicing further treatment. The anonymisation log 
will include the bar code used on the blood sample; this means that an individuals sample can be 
traced should they wish to withdraw consent. 
8.4 Confidentiality and Data Protection 
The Chief Investigator and his team will preserve the confidentiality of participants. Access to data 
will only be granted in accordance with the Data Protection Act 1998. It will be the responsibility of 
the chief investigator to make sure that data stored in accurate. All subjects have the right to 
withdraw permission for the processing or storage of their data at any time. 
8.5 The Human Tissue Act 
Blood samples will be stored in accordance with the Human Tissue Authority.  
The sample for analysis by deCODE will be labelled using their own barcode sticker system, but the 
barcode will be documented in the anonymisation log. 
The samples stored for future analysis will be stored in a secure tissue bank. Subjects will be offered 
the patient information leaflet ‘Donating Biological Samples for Research – Information for Donors’ 
and will be asked to sign the Donor Consent Form. Each sample will be given a unique identification 

HIV POGO Study Protocol Version 7 23/02/17 
number and the storage database will be maintained by Tissue Bank staff in accordance with the 
HTA. 
Patients have the right to withdrawn permission for the storage or analysis of their blood sample at 
any time and this will be possible using the anonymization log. 
8.6 Indemnity and Sponsorship 
Sponsorship has been confirmed with Imperial College. As part of the approval an insurance 
assessment has been conducted and certification provided. 
8.7 Funding 
This study is funded by the NeuroPain FP7 Grant, awarded by the European Union (Code: WSSA 
P44758). 
8.8 Audit and Inspection 
The study may be subject to inspection and audit by Imperial College under their remit as Sponsor, 
to ensure adherence to GCP. 
9. Study Management 
The trial will be managed and conducted in accordance with GCP guidance. The Chief Investigator 
will be responsible for the development, management and security of the trial master file (TMF).  
All trial documents will be archived in a secure, environmentally controlled location at Chelsea and 
Westminster Hospital for 10 years following termination of the study. Access to the archive will be 
limited to the Chief Investigator, the Sponsor and regulatory authorities. 
10. Publication policy 
Findings from this project will be primarily disseminated using the conventional format of peer 
review publication, in association with conference presentations. 
 
 
 
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