South Africans with HIV-related pain are surprisingly active, but not due to their resilience.

Antonia Wadley

When one thinks about chronic conditions that are commonly painful, HIV doesn’t typically spring to mind. However, more than 50% of HIV-positive individuals experience painful conditions like headache, chest pain or neuropathy, and that pain is frequently experienced as moderate to severe in intensity.

 

What struck researchers from the Brain Function Research Group (BFRG) at Wits University as odd was that despite this high burden of pain in HIV, a couple of papers have emerged suggesting that, having asked patients, functional interference (having difficulty with things like walking or going to work) was not as great as they might have expected. One of these papers was from the BFRG and had been completed locally in Johannesburg, South Africa.

 

To investigate whether pain does actually affect function in HIV (as it does in many other clinical conditions), researchers Dr Antonia Wadley, Emeritus Professor Duncan Mitchell and Associate Professor Peter Kamerman from the BFRG, based in the School of Physiology, Faculty of Health Sciences at Wits, conducted a cross-sectional study.

The results from the study, titled: Resilience does not explain the dissociation between chronic pain and physical activity in South Africans living with HIV, are published today, 13th September, in the journal PeerJ.

 

To explain why pain may not affect function, the researchers first put it down to African patients being resilient – the ability to cope with adversity.

 

Explains Wadley: “Nobody’s assessed resilience in people living with HIV and chronic pain before. We hypothesised that people living with HIV would generally be pretty resilient and those who were more resilient, would be more active and report lower pain intensity.”

 

Measuring resilience in HIV-patients objectively for the first time

For the study, the researchers recruited HIV-positive patients from an HIV clinic in Johannesburg: half with chronic pain (defined as having had pain most days for at least three months) and half without. They then assessed resilience and, as well as asking patients about their activity, the researchers measured it objectively for the first time in a subset of patients using accelerometers, which are like sophisticated pedometers. They also asked the patients about their day to day worries.

 

“It turns out,” Wadley says, “that we were right on one thing, HIV-positive patients in our study were really resilient, but our hypothesis was wrong: being more resilient didn’t associate with being more active or having lower pain intensity. In fact, the activity results astounded us. Not only was patients’ activity not as affected as one might expect, it wasn’t affected at all.”

 

There was no difference in activity intensity, duration, or time spent at different intensities of activity between those with and without chronic pain. “This is something you just don’t see in other types of long term pain,” she adds.

The researchers then looked at how frequently patients worried about their health, money, food and family. “We thought that if patients were worried about money and having enough food that pain might be relegated to a lower priority.” They found that patients in chronic pain worried more frequently about each of these things compared to their pain-free counterparts and that health was lowest down the list.

“So it really does appear that if you are poor, pain may be relegated to a lower priority. Indeed, our analysis showed that worrying more about food associated with higher levels of activity,” says Wadley.

 

Going forward

The researchers also asked the patients in pain what else they worried about and who they had told about their pain.

 

“It turns out that HIV-related stigma is a real problem and that half the patients in pain had not told their closest friends and some not even their family about their pain, for fear that it might reveal their HIV status.”

 

Wadley says it thus seems that economic stresses and fear of HIV-related stigma may drive people to maintain high levels of activity, even when they are in severe pain.

 

“What’s not clear is whether this kind of level of activity in the face of pain is helpful or harmful and that’s something we will be looking into next,” she adds.

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PainSA Congress 13th -15th May 2016, Umhlanga

Toni Wadley

 

Last month, I headed over to Umhlanga with some of the other Pain lab members for the annual PainSA Congress. PainSA  is the South African chapter of the International Association for the Study of Pain and the Congress is a meeting of health care professionals and scientists from across the country who work with pain.

 

PainSA Group photo

Me (far right) and the rest of the team, (from the left) Sean Chetty, Peter Kamerman, Prinisha and Dershnee Devan at the PainSA congress. (Photo by Toni Wadley)

 

In the pain lab, we’re always going on about how pain is under-recognised and under-treated in African HIV+ patients. Every PainSA congress, the sentiment that access to opioids in Africa for severe pain is woefully inadequate is repeated. Yet at this year’s congress we heard the opposite angle. US.  Professor Tracy Jackson, medical director of outpatient pain clinics at Vanderbilt, gave hard hitting talks about the ineffectiveness of current chronic pain therapies despite the US spending $630 billion a year on the problem. She spoke about the over-reliance on opioids in a country that uses 80% of the world’s stock and where opioid overdose is the leading cause of accidental death.

 

Tracy is a big advocate of non-pharmacological interventions including functional rehabilitation programmes. These programmes are residential and involve an entire multidisciplinary team of healthcare professionals aimed at getting patients back to being functional, even if that means their pain staying the same. Her new take on these programmes is to offer ‘Relief retreats’ where restoration programmes are held at retreat centres rather than in a typical clinic setting.

 

Tracy is really entertaining to listen to. Follow this link for a TEDx talk she gave in Nashville very recently on the topic of non-pharmaceutical treatment of chronic pain.

 

The theme of getting patients with chronic pain back to work was echoed throughout the congress. Dershnee, an MSc student in the pain lab, gave a workshop on the topic. Dershnee has a background in occupational therapy. Through her current work in medical insurance she knows only too well that absenteeism from work costs South Africa R12 billion a year.

 

Peter, the head of our pain lab, gave a plenary talk on “Neuropathic Pain: so many people, so few drugs”. Sean Chetty, a pain lab PhD student and anaesthesiologist, gave a plenary on pain management being a human right. In the largest research paper session a PainSA congress has had, I spoke about the effect of HIV stigma on pain, and Prinisha presented some of her PhD data about the pharmacological treatments that are actually being used in the clinic for HIV-associated sensory neuropathy. Prinisha won the joint first prize for best talk along with Tory Madden a new postdoc at UCT.  Well done Prinisha!

Presentation

Prinisha giving her winning talk. Photo by Toni Wadley

Our genetics can be painful

Liesl Hendry

“It must be in your genes”. This is a phrase that gets thrown around quite often, usually to explain some sort of behaviour or (often unwanted) physical trait. Our genes and the variation within them can, to a large extent, tell us a lot about ourselves, why we are the way we are and explain what makes us different from other humans and other organisms. Interestingly, we are about 99.5% genetically similar (when looking at the DNA sequence) to our fellow humans and about 98% similar to our furry chimpanzee friends. We do, however, differ in some parts of our genome and it is this unique “pattern” or variation that, along with some environmental and other factors, influences the way we look, the way we behave and the way we respond to certain things. For example, something as simple as whether or not one tastes the unpleasant bitter taste of Brussels sprouts is determined by the presence or absence of a certain genetic variant!

 

I have been interested in the field of genetics for a while now and am fascinated by the role that genetics plays in our lives. A more serious part of genetics and a main focus of research in the field is that of genetics related to disease. Our genetic makeup is believed to influence our susceptibility to developing certain diseases and the seriousness of a particular illness or associated symptom. My first exposure to this line of research was during my MSc degree where I was involved in a joint project between the Human Genetics department at Wits/NHLS and the pain lab of the BFRG. My research investigated the association of previously associated neuropathy and pain genes with susceptibility to developing HIV-associated sensory neuropathy (HIV-SN) and pain and variation in pain intensity. This was looked at in a black Southern African population. The population of choice was specifically significant as African populations have been largely understudied in the field of disease genetics compared to non-African populations. Based on the knowledge of genetic susceptibility to disease, it comes as no surprise that the risk of experiencing pain and neuropathy as well as the intensity of the pain experienced in HIV patients are considered to have a genetic component, but the big (and still not completely answered) question is exactly what genes and variants within the genes are involved? Having a supervisor from both the genetics and physiology departments offered the necessary expertise to understand the relationship between the genes and phenotypes under investigation and to try to come a bit closer to answering this question.

 

The project was an extension of work being done at the time by Toni Wadley for her PhD, with a deeper look into some of the regions of the genome that she had looked at, and was part of a larger study, headed by Prof Peter Kamerman, looking at various aspects of HIV-SN. The project used DNA samples from adult HIV positive patients, attending the Virology Clinic at the Charlotte Maxeke Johannesburg Academic Hospital, who had been on antiretroviral therapy for at least six months. This DNA was genotyped for a range of carefully selected single nucleotide polymorphisms (mutations/variants within genes) across the genes under investigation with the aim of being able to determine, as best we could, the role that the genes play in neuropathy and/or pain.

 

Apart from the specific statistical associations which resulted from analysing the genotype data against the phenotype data (HIV-SN status, pain status and pain intensity, etc; there is too much to mention here!), the research led to several observations/conclusions. The first thing to point out is that pain is very common in individuals with HIV-SN. Over 90% of individuals with the neuropathy experienced some sort of pain, mostly moderate to severe in nature. This made studying pain risk in these individuals rather difficult as the number of cases (those with pain) far out-weighed the number of controls (those without pain), therefore making the reliability of the pain risk results questionable. Secondly, it is clear that both HIV-SN and pain are complex traits. Unlike disorders such as Huntington’s disease or cystic fibrosis, which are monogenic, the results pointed towards several genes being associated with HIV-SN and pain risk and pain intensity. This brings about a particular challenge: how do we know what the exact causative genes/variants are? To answer this question, genetic association studies need to be coupled with functional studies to determine the actual functional role that the variants play, for example in altering the expression of the gene product, which could ultimately lead to differences in disease susceptibility and intensity. Lastly, there were inconsistencies between what was previously discovered in non-African populations and what we discovered in our African population, leading to us concluding that associations (in this study and in fact in most genetic association studies) are population-specific. This could be explained by the differences in diversity and structure of the genome among populations of different ethnicity, leading to different variants within different genes being associated with a particular trait.

 

A question you may have on your minds (possibly as non-geneticists) is “why is it so important to discover which genes are associated with a particular trait?”. Apart from the hunger for knowledge, one of the biggest factors to consider is that of treatment. Looking specifically at HIV-SN, treatment generally involves slowing the progression of the neuropathy or managing symptoms, rather than actually curing the neuropathy. What I haven’t yet mentioned is that the neuropathy and associated symptoms are often caused by the antiretrovirals that the individuals receive. Identifying individuals who are at a greater risk genetically for developing HIV-SN and pain associated with the neuropathy can result in these individuals being monitored more carefully and having the chance of being administered different antiretrovirals in the future.

 

The questions that I’m sure many geneticists ask themselves…Will the research ever end? Have we found all the answers yet? The answer, quite simply, is “no”. The genetic differences between populations and the complex and multifactorial nature of many traits/diseases make the research in this field anything but simple. With the advancing technologies and the increased ability to handle and analyse large sets of data, researchers seem to be getting a little closer, but, in many cases, the findings recorded so far are just the beginning with so much still to be uncovered…

 

References:

1) Hendry L, Lombard Z, Wadley A, Kamerman P. KCNS1, but not GCH1, is associated  with pain intensity in a black southern African population with HIV-associated sensory neuropathy: a genetic association study. J Acquir Immune Defic Syndr. 2013 May 1;63(1):27-30. doi: 10.1097/QAI.0b013e318285cf36. PubMed PMID: 23314412.

 

2) Wadley AL, Hendry LM, Kamerman PR, Chew CS, Price P, Cherry CL, Lombard Z. Role of TNF block genetic variants in HIV-associated sensory neuropathy in black  Southern Africans. Eur J Hum Genet. 2015 Mar;23(3):363-8. doi: 10.1038/ejhg.2014.104. Epub 2014 Jun 4. PubMed PMID: 24896147; PubMed Central PMCID: PMC4326702.

 

 

3) Hendry LM, Wadley AL, Cherry CL, Price P, Lombard Z, Kamerman PR. TNF Block Gene Variants Associate With Pain Intensity in Black Southern Africans With HIV-associated Sensory Neuropathy. Clin J Pain. 2016 Jan;32(1):45-50. doi: 10.1097/AJP.0000000000000224. PubMed PMID: 25756557.