The POPPY study is looking to assess the effects of HIV and antiretroviral therapy on ageing, and we spoke to its lead clinician Dr Alan Winston to find out more.
By Patrick Cash
Tell us a bit about yourself.
I’m Alan Winston, I’m a doctor, I’m a HIV and sexual health consultant in the NHS here in St Mary’s Hospital and I also 50% run our clinical trials unit, so we do studies and research looking into improving care for HIV and different infectious diseases and sexually transmitted infections.
And what is the POPPY study?
Okay. The POPPY study stands for Pharmicalkinectics and Clinical Observations in People Over 50, that’s what it stands for. But the POPPY study – people with HIV do extremely well on antiretroviral therapy nowadays and life expectancy is reaching up for people who have HIV infection. But what we know or what we’ve observed is that for people who don’t have HIV on treatment appear to develop other medical problems a little bit younger or prematurely to people who don’t have HIV. And there’s lots of different medical problems: heart disease, bone disease, kidney disease, brain disease, dementia, or cognitive impairment, but it’s very, very difficult to tease out what’s actually causing these problems. So for instance, if you think about heart disease, is it HIV and the antiretroviral therapy that’s leading to people developing heart disease a bit earlier, or is it that the groups of people with HIV that we’re looking after actually smoke more cigarettes, take different alcohol amounts, or have a different lifestyle compared to the control populations they’re being compared with? So we really don’t know how much of it is related to the antiretrovirals or the HIV, or how much is related to biases within studies. So what we’re actually doing with POPPY is recruiting individuals with HIV infection and matched individuals without HIV infection, so we can try and tease this out and answer some of these questions. So the control populations are the people without HIV, what we’re looking for are individuals who are closely matched to people who have HIV. Now the biggest groups that we look after are gay men and also individuals of black African heritage, and for this magazine, we’re really promoting to try and recruit gay men who don’t have HIV who are over 50 who can act as controls so that we can compare medical problems in people with and without HIV to actually answer what’s causing what.
And how did you get involved in the study, why are you particularly interested in this area of research?
Okay, so the actual large POPPY study involves seven centres across the UK and Ireland, including several London centres and a centre in Brighton and a centre in Dublin, and also our large statistical team at the Royal Free Hospital who are experts in statistics in this area. And I’m involved, as a clinician and a researcher and a lead for the POPPY study.
So it’s a nationwide thing that’s going on?
It’s not quite nationwide – it’s a UK study, at the current time there’s the seven centres, we would like to extend it out and involve more centres over time but the current funding is for the seven centres so it’s predominately the London/Brighton area with a view to hopefully expanding in the future.
Why was it thought so pertinent to do it right now, was there some kind of research that spurred it on?
It’s really the findings on these other medical problems that people with HIV seem to get and what we really want to answer is ‘why are we seeing them?’ Because everyone’s blaming the antiretroviral drugs or HIV infection but we really don’t know what’s causing it, so if we’re caring for people with HIV, I mean clearly we should be focussing on not smoking and a generally healthy lifestyle but what’s actually more important – is that more important or is changing the antiretrovirals more important and that’s what we don’t know.
If people are taking drugs to suppress their viral loads, or are at an undetectable level because of their medication, and the virus was thought to be causing these problems, then why would age-related diseases stemming at an earlier age?
So that’s a really good question. So the question is: why we might see medical problems in people with HIV who are otherwise effectively treated with a suppressed viral load? One hypothesis is that although you’re suppressing the virus, does the immune system fully recover or is there slight ongoing dysfunction in the immune system and could this be leading to these medical problems? Or is it other lifestyle factors like smoking and recreational drug use and everything else, and that’s what we’re trying to look into to answer is one area more important. But from the actual more medical HIV side it could be that their immune system doesn’t go back to functioning normally and people are talking about inflam-aging, an inflammatory condition that leads to early ageing but we don’t really know if that’s true or not and that’s one of the things POPPY’s really trying to tease out.
Because people on antiretroviral medication are just getting to this stage, aren’t they? Who’s the oldest person on the study?
So that’s a good point as well, that twenty years ago we didn’t see so many older people with HIV, so now a lot of the people that we look after are over the age of 50, almost a third in the UK, and the reasons for that are firstly people with HIV are living many decades. So, we’re seeing people entering their 50s, 60s and 70s, but not only that we’re also seeing a lot of new diagnoses of HIV in people who are older, so people presenting for the first time with HIV who are in their 50s and 60s and it’s probably because of the clubbing and drug use etc in gay men. It’s no just 20-year-olds, it’s 50 and 60-year-olds as well, so we’re seeing new diagnoses. So there’s two reasons we’re seeing older people with HIV, and also remember that what we are calling older isn’t what other doctors and geriatricians are calling older which is 70 or 80, but it’s still ‘old’ for this disease area. And then the questions you actually asked is what is our oldest individual, well we have people over the age of 80 in our clinics, and we have some people over the age of 80 who have entered into the POPPY study.
When you were talking about clubs and recreational drug use, as someone who works in sexual health yourself, does the current ideas of the chemsex syndemic amongst gay men, does it have any bearing upon the POPPY study?
So we will be looking at that, anybody can enter into the POPPY study, we’re not limiting it to people who are on a specific treatment or not taking recreational drugs, we want it to be a real life study. So we will be able to look at recreational drug use in people with HIV and without HIV to see if there’s any difference, the impact it does have that we know is that the chemsex revolution or whatever’s going on, we see other infections associated with it, so syphilis and hepatitis c and another condition called lymphagranuloma, type of chlamydia infection and again how the complications of that and the natural history of that, of people with HIV verses people without HIV are some of the other things we may be able to look at in the POPPY study.
So if someone volunteers to take part in the POPPY study, what would it entail? What kind of tests would they be going through?
So before I answer that, there’s the main study and also there’s the sub-study that we’re running here. The main POPPY study is three groups: two groups of people with HIV infection and one group without. The groups of people with HIV infection are firstly people below the age of 50 and the second is people above the age of 50 with HIV infection and the third group is people over the age of 50 without HIV infection. And the main POPPY study is recruiting in total 2000 people across the seven sites and the actual study involves a detailed –it’s a visit that takes quite a long time, it’s a whole morning or a whole afternoon, because we go in to your medical history in a lot of detail but it’s only one visit at the start and one visit two years’ later. And the actual visit involves a nurse or a trained health care practitioner to go through your medical history in detail; so when you see your GP, when you see your hospital specialist, whatever health care resources you use. Any medication you’re on, and also a questionnaire that you fill in on recreational drugs and different lifestyle aspects, and then we’re specifically looking at two organs in the body in details, we look at the memory and brain in detail, and there’s what we call cognitive testing or memory testing that’s done on a computer that’s sort of like playing card games that takes half an hour or forty minutes to do and the nurses help you do those tests and it records your reaction time and memory and gives us an assessment on your cognitive ability. And then everyone also has a DEXA scan which looks at your bone health, so it’s like how strong your bones are, and there’s also some blood tests which are taken, which are just stored to be used within the study in future. The one bit of the result that you get back which, if you are a healthy volunteer, if you don’t have HIV infection then the DEXA scan, the bone scan, will go to your general practitioner. So you also get that result. For people that are taking part in the POPPY study there’s also a sub-study which is just here at St Mary’s Hospital and that’s looking at the brain function in much, much more detail. So in that study you get a MRI scan of the brain, which is a magnet scan of the brain so that’s a scan that doesn’t involve any X-rays or any dies, it’s just a magnet, but you lie on a scanner for about forty-five minutes, it’s a little bit claustrophobic as the scanner goes around your head but as I said there’s no radiation or anything. It looks at your brain and then it also measures things in the brain but the basic pictures of the brain, we get a formal report on that and that report is available, you then also have more formal memory testing, so not just the computer test but an interactive test with the nurse for further cognitive domains, so memory testing and learning tests. And lastly, there’s a lumbar puncture, so that’s a test where we take fluid from the base of the spine, and a lumbar puncture test – the brain is bathed in a fluid called CSF or cerebral spinal fluid and we can take a little bit of that from the base of the spine. Now people always worry about lumbar puncture tests, but the risk of serious medical complications are virtually – I mean nothing in this world has a risk of zero, but the risk of serious medical problems from a lumbar puncture is very, very low and we wouldn’t be doing it in a research study if there was a high risk. So clearly it’s done under what we call aseptic techniques so the skin is cleaned and a local anaesthetic is put in, so the risk of infection is extremely low. And it’s a part of the spinal cord where the nerves move, so the risk of any nerve damage or paralysis is again minimal. The main problem with the lumbar puncture is after the lumbar puncture the next day a tiny bit of fluid can leak out internally which can give you a bit of a headache and about 5% of people, one in twenty will get headaches the next day, but we use a special needle that’s very, very thin, so the next day the chance of anything leaking is very, very low, to reduce the chance of that headache. But that is the major problem we have with doing a lumbar puncture, and 1 in 20 people they might find the next day that if they do get a headache they might not be able to work and they might have to take it easy.
With the cognitive thinking tests, how do you factor into the variability that some people are going to be more cognitively capable than others regardless of whether they’ve got HIV or not?
So that’s a good question as well. The cognitive tests can be a bit difficult to interpret because everyone’s so different, so with the test there’s a couple of other questions that we do. We do a quick question that sort of looks at an IQ if you like. So what we’d expect that person’s cognitive test to be, so there’s some expectation of how to interpret the result and also we know the person’s age and gender so we’re able to normalise it or have something to think what it should look like. But cognitive testing is quite variable so that’s one of the main reasons why we’re doing things like the MRI scans and the lumbar puncture to actually give us blood markers or a marker that’s less variable than a cognitive test. But the cognitive tests are really important because we have to be able to link biological tests to something that’s clinically relevant. There’s no point in us saying a blood test shows this but people don’t have symptoms, so that’s why it’s really important we do it.
Penultimate question, and we’ve kind of spoken about this already, there was a study out last year from Positively UK talking about living with HIV in the UK and mental health wellbeing, influenced by stigma etc – do you think this could affect people’s brain health, rather than the virus and the medicines themselves?
I think brain health, the nice term that you called it, in HIV is multi-factorial, there’s loads and loads of factors. There’s a whole social group of factors, the stigma of living with HIV as you said, there’s other mental health factors so how much is HIV associated with depression and anxiety and how that affects your cognitive ability. You’ve then got the whole area of the other medical problems that we’ve mentioned, now if you’ve got heart disease or kidney disease that also affects your brain health and we are understanding of the interaction between them is not great and then we also have the HIV factors and the antiretroviral factors and it’s very naïve to think that cognitive function or brain health is just related to one of these. It’s how they all fit together and it’s large cohort studies like POPPY that will hopefully help us tease out which of these factors plays differently; how they interact and how they play.
And finally, can you share what kind of results you’re seeing already, and if not, what kind of results would you expect to see?
It’s not that I can’t share results, it’s that we haven’t yet analysed results. Currently in the main POPPY study over 400 people have been enrolled and almost a hundred of them without HIV, and in the substudy with the MRI scan here at St Mary’s we’ve recruited 50 subjects and we’re looking for 125 in total. So for the main study and the substudy recruitment is going well and I think it’s showing that we can recruit and part of this advertising and speaking to you is to help us recruit more HIV uninfected individuals. So the studies have shown a feasibility that we can recruit. We’ve got about 150 in the main POPPY at St Mary’s because we started first. We’re not going to wait for the full 2000 so we will have some results which we’ll start seeing at conferences towards the end of this year and the start of next year when we have a large enough cohort in the study to actually with the statisticians look at the results and start seeing some outcomes. What do I think we’re going to see? Well, there’s a similar study in the Netherlands, a group in Amsterdam have done a study called AGE-IV, and we are linked in with them, so POPPY and AGE-IV have got some linkage and we’re doing some things in the same way, and there’s been some results from AGE-IV already reported and what we’ve seen there, is, in fact, for some of the medical problems that we’re seeing in HIV the traditional risk factors are playing a much more important role in these medical problems then I think we had envisaged. So for instance they’ve shown that if you look at bone health, it’s not predominately been anti-retrovirals and HIV that’s predominately been the biggest problem for people living with HIV, it’s been smoking and the lack of exercise.
That relates to mental health wellbeing as well, doesn’t it?
Exactly. And it’d be naïve to think that we don’t see too dissimilar a picture in the UK.
Excellent. Thanks very much.
To find out more about the POPPY study, click here.
