A view from the lab: interview with Professor Clive Loveday

Polly Clayden, HIV i-Base

A Foundation Chair in Retrovirology at the Royal Free Hospital School of Medicine was established in 1996 and Professor Clive Loveday was then appointed as the first UK Professor of Retrovirology in April of that year. The department was built during the rest of that year and the new laboratories commissioned in January 1997 at which time departmental activities could commence. We talk to him about his work…

Where were you working prior to this appointment, can we have some Clive Loveday history?

At University College, with Richard Tedder, for about eight years, and I did a high professional training in virology there. If you go back historically, I did a degree in science and a PhD at Middlesex Hospital, and then I was working for an immunologist who said ‘You should do medicine if you really want a rounded career in research’, so I actually went back to med school, and that took us up to the early eighties, and while I was doing my house jobs, that’s when HIV first appeared.

So I started reading about it, with an interest in infectious diseases and a background in microbiology and thought, ‘this is an area that I should start working in’. So I applied back to University of London and I got what was called a ‘New Blood Lecturer’ post in GU medicine at Middlesex. I went back there in ’84 and my first job was looking after newly recruited patients with HIV infection – we’d just got the antibody test.

They’d just got a big MRC grant to study the natural history of HIV. Our job was quite simple – people got their antibody result and just came straight to us with a result and no one really knew what to do with it. We basically explained what it meant, what we knew and (mostly) what we didn’t, and offered to recruit them on to this MRC cohort. It meant they were at least part of a group being followed and then could take advantage of any benefits that were forthcoming as quickly as possible. We had about four or five hundred patients that we saw every three months, but if they had any problems they could be called straight up to us. It was horrendous really and the learning curve was exponential, we didn’t know what was going on and the patients didn’t know what was going on. Every time a patient coughed they thought they had PCP…

When I knew I was coming back to this post, I quickly, in my last year, did a general practice vocational training so I became a qualified GP – I promised my wife I would have some sort of post-graduate medical qualification in my back pocket before I entered the heady world of research.

In case you had to step down from your ivory tower?

That’s right, they dump you, in just two years, three years, four years -incredibly insecure. I always said though, that in those three and a half years when we were looking after that cohort, in fact what I probably used most of all was my general practice because that’s what we were doing really – looking after the community.

When did you go back to the lab full time?

In the late eighties, I wanted to get into harder core research and moved into Richard Tedder’s department who was the consultant virologist. I got an appointment, which was a Wellcome Fellowship appointment, called the HIV/AIDS Research Fellow; it was actually looking after the virology of the same group of patients. PCR had just appeared and my main brief then was to set up the molecular technologies for HIV within the department. We made a viral load assay by 1990 and we made a resistance assay by ’91, using those for our local patients and MRC studies, but they were what you would call ‘home brew’ now and when the kits came out it was easier for us to change over. Companies wanted us to do studies and they wanted to use the kits anyway, but it was used in the first combination study of AZT/3TC which we did with Glaxo, anyway that’s all history now and I got this appointment in ’96.

The school provided a building, set the labs up and provided an infrastructure and basically launched me on the world…

So you find support from outside monies?

Basically, yes – and it certainly focuses your mind.

And the objectives of your department?

In the modern jargon the ‘mission statement’ is, to set up the molecular technologies for HIV/AIDS to carry out research and development and support the clinical care of the patients at the Royal Free – we have a very strong commitment to them. To develop a programme of work around HIV and AIDS that would raise the profile of this institution. To publish, develop an academic profile. The model of the department, which I had in mind, because clearly retrovirology is a sub-division of virology so people would always ask ‘Why aren’t you part of virology’. By and large though in virology, you simply carry out virological procedures, you may give a virological opinion on a result but that’s all you do and you don’t have any other interactions outside; it’s very limited.

My concept was much more of a hybrid department that wasn’t just developing measures but actually we were working both in virology and interacting with everybody – clinical, epidemiological, statistical, pharmacological, and immunological and trials level. It’s a model that does upset some of our school political masters, because it’s not what you call conventional.

You grew remarkably quickly both in terms of reputation and turnover of activities; did you have a strict business plan?

In terms of the business plan we didn’t want to be dependant on any one group – trusts, collaborative work with the MRC, external collaborations with international commercial and academic groups and some teaching and training. We started with a view that we’d do any job basically. I said that no project was too small, if a company just asked us to do one measure we did it, we were looking to give high quality and individualised attention to anybody that came to us and what happened was they’d come back with ten viral loads next time and then a hundred. And that’s the way things grow…

And the academic side of things…

I always emphasised the academic dimension with everyone we collaborated with – even with people we were doing service work for in other trusts. Effectively what happened with them would be, someone would ask for a viral load or a resistance because they needed it and then they’d say ‘we’re going to send you everything, it’s good it’s efficient, it’s quick’… We never really mail dropped anybody, more and more people started phoning up, at this point in time we probably work for about thirty-five trusts around the country plus our work for the Royal Free. What I’ve tried to do now is draw them into an academic, clinical research group so we can put together results from everything we’re providing for them to support their patients. We can also do bigger analyses and when we publish we’ll publish on behalf of the retrovirology academic research group – kind of a co-op element to it.

The thing is to keep the prices down as low as possible and to get the most academic, scientific information and push forward the frontiers all the time. In terms of the business plan everything went pretty much according, but there was a slight change because we discovered we had non-B viruses.

You’ve anticipated my next question. What about non-B clades in this hospital, did this discovery change things, what percentage of your patients are non-B?

I had to do a quick appraisal – this was ’97, we did a quick audit study about the size of the problem, and it looked like about ten to twenty percent of our patients might be non-B. We did a study of the whole clinic – everyone gets a serological sub typing now; we’re beginning to build up databases. Because the MRC recognised we were doing that, they gave us quite a big award last year to set up an epidemiological study for the next three years of all those patients, so we’ll try and find out who they are, where they came from, what viruses they had, what are the distributions and then look at their relative responses to therapy and their relative progression rates, in relation to sub type-B. We’re beginning to build up a picture.

What about the technology?

As you know, all the technologies we use for viral load and resistance are based on PCR, and if you have divergent viruses that are potentially non-B, the primers used in PCR may not fit. Most of the primers are developed in kits for laboratory strains of sub type-B because that’s all they make in America basically. We’ve told the companies about missing samples, and we hope they can improve their primers and start to pick up European viruses.

Were companies concerned at first, because presumably they weren’t missing any in America?

One of the biggest problems I had was I’d say ‘oh look this is a real problem you’re missing so many…’ and they’d say ‘no we’re not, what, where’ (all sub type-B there, so it wasn’t a problem). I’d say ‘I’m sorry you’re missing them in Europe, and the way things go these viruses are going to swarm across Europe and arrive in the United States’, and they have. Now in 2000, at the last conference, the US has ‘discovered’, non type-Bs, so it’s become an issue.

What systems do you run?

We established all the molecular viral load systems in the department, that is, the main three (Roche, Chiron and NASBA), and that was all done cost-free. We managed to impress people and get their support. The same for the resistance systems as well. We were in a unique position as the first Department of Retrovirology in the UK; we were trying to do comparisons between them within one institution. Also we looked at the relative sub-optimal performance of different assays, you’ll remember in ’96,’97,’98 the Roche 1.0 wasn’t detecting or was sub-optimally detecting, we were quite an important part of actually sorting all that out and sharing those viruses with Roche. We helped to field trial the new versions of the kit, the so-called 1.5.

How much work do you do with the MRC?

I’ve had a long working relationship with the MRC. When I was with Richard Tedder, I was a grant holder and virologist on Concorde, and from then I was a virologist on DELTA…Since then I’ve been part of the MRC studies and tried to support that activity. At the moment I’m the virology principle investigator for ERA and PERA and that’s quite a feather really to get a virologist as a principle investigator.

I now actually give the MRC a session a week going over everything we’re doing; we’ve got INITIO, FORTE, ERA and PERA. We’ve also been running the Vanguard with Mike Youle and steering that.

How’s ERA study doing?

What I also do for ERA that has not been done before, is that every resistance measure that comes out of Virco to go back to the physicians, I’ll have a copy sent to me as well, so I can have a quick look at it and sign it off. We don’t want to interfere with the study but just make sure that there’s nothing absolutely nonsensical about the result. So if you like we’re maintaining a clinical standard for that, if they don’t hear from me there’s not a problem, if there is we’ll discuss it. That’s new for the MRC, normally once things are running they like to cut virologists and physicians out of the loop and go onto autopilot.

What’s your turnaround time for viral loads?

I was the first one to propose real time virology for HIV so we turn our viral loads round in one or two days, that’s what everyone likes. Someone from Aberdeen phoned me and said ‘how long will it take, four weeks, six weeks?’ I said ‘you send it; I’ll get it tomorrow, and you’ll get the result either in the evening or the next morning’. She’s been sending everything ever since.

Having worked as a physician, the one thing you do need is those sort of results on the desk the next time a patient comes in, if you’re running tests once a week or once a fortnight it’s just not satisfactory, we do a run every day.

And resistance?

It’s harder with resistance, it’s a much more complex test, we’re having failures at the moment all that isn’t sorted out yet. We have a sign off form and it says ‘date sample received’ and that’s signed ‘date test done’ and that’s signed by the technician date test signed off by the lab and then I sign it off, so we will be able to audit these quite soon and see how long it’s actually taking but I have to say my sign-off date is getting much closer to the day of the test being done now.

The turnaround time is not optimal at the moment, we looking for a working week, which we’re achieving yet, but I think that it’s a good target. But this is against a background of being terribly under-resourced; if you throw money at something you can always achieve your target.

How many resistance tests did you do last year?

About 1000 to 1200, since we started so that’s just over a year. Some of those have been part of studies.

So who’s paying?

All sorts of sources – with Mike Youle we’ve begged and borrowed and stolen, calling things studies and audits…

You must be getting all sorts of information out of this creative accounting…

Yes, it’s actually evolved quite an interesting group of patients that we’re following in a salvage therapy audit and looking at resistance in that group. That’s evolving some interesting results, which you’ll see quite soon, in terms of strategies that might be used in patients who are very drug experienced, because clearly there are big problems that need to be resolved and they’re not going to go away. Mike’s actually presenting some results at the Salvage meeting in Chicago.

Other monies – we ask people to pay for tests, that is we ask clinicians who have research funds. We’ve been charging £210 per test, up to the beginning of the year, and considering that the kits cost £180 we are doing them for next to nothing. The price is going to go up just a little bit quite soon, to I think to £234. Still pretty cheap!

Which clinics? Is the pattern changing?

We’ve always worked with Brighton and with Ealing; we did quite a lot for Barts before they got set up, a whole host of centres around London and outside. From Cardiff to Aberdeen, it’s quite interesting there was a time when Aberdeen were discussing a resistance result with a key opinion leader in London and the key opinion leader was saying ‘How the hell did you get a resistance result?’

How aware are doctors of these tests, did you have to work hard to raise awareness?

That’s an interesting question, we always tried with whatever we did in virology to raise awareness and to develop a very intimate relationship, a personal service for people and this was never more important than in terms of resistance. So what I actually did was – we had a formal sign-off sheet which was based on the computer interpretation, I then signed that off, writing quite a detailed report of what I thought patients were resistant to. I never recommended treatments but just said what drugs I regarded as being a no-no and that point in time and I always wrote on the bottom ‘Please call me.’

What sort of reaction did or do you get to the interpretation?

About forty percent would call me, and in the early days calls would take about half an hour, I did a little tutorial and told them what we were doing how we were doing it, told them what you would see and did an explanation. But now, with the group I work with anyway, they’re enthusiastic about the tests, they’re going to lots of research meetings and developing a greater understanding, so we skip that part now, the calls are quicker.

What do you think would help doctors learn more about interpretation?

People within our co-operative group now are actually publishing, for example Martin Fisher’s group down in Brighton have recently presented at BHIVA. As that happens and as it is disseminated to grass roots everyone will understand more and more about what we know and what we don’t know and what are the applications.

Can patients actually call you direct?

I have spoken to patients. I regard the relationship between a doctor and a patient as so important that, basically, if a patient gets through to me I’d talk to them and that’s not a problem. The frustrating thing is that it’s not always easy to get through to me. If people are patient enough to keep trying then I just talk to them, one of my failings is I like to chat about my work…

What are your views on resistance guidelines?

Do you know, I still haven’t seen the BHIVA guidelines, one thing I found almost a conflict having written American guidelines and then European guidelines, to start addressing another set is actually quite difficult. As I wasn’t on that guideline committee, my opinion was that they’d reach the same conclusion as the other two committees. But I still haven’t actually seen a copy.

The US Guidelines for the International AIDS Society are completed; they’re going to be published in JAMA. The European Guidelines, you probably know where they are, we’ve all fed back after the Frankfurt meeting, and they’re doing the final draft now, I think they’re targeted to Lancet.

I’m excited because, unlike the ’98 guidelines, both the committees I’ve worked on, they’re putting their money where their mouth is. They are saying either recommend or consider for different patient situations and the groups have basically discussed the evidence or lack of evidence and often that may result in ‘well, consider doing it’.

What sort of trials do you think would be needed to persuade people these tests are worth funding once and for all?

A good single randomised controlled trial is what one would say is required to justify it becoming a guideline, but it actually becomes a protocol at that stage, you don’t need a guidelines committee. But the complexity of resistance measurement and everything that surrounds it in terms of pharmacoeconomics, and so on is such that I don’t think one trial will answer those questions.

I think what we’re both saying, is no matter what trial you do, someone who doesn’t want to pay the money can find a reason… And all we can do is generate more trials that will address the problems; at the moment there are about eleven trials underway in Europe and America, trying to develop that information. ERA will go out for longer and ask the question ‘does the benefit last for six month or a year?’ PERA will be the first one I’m aware of in children and that’s an important area because you’ve got less drugs to offer your patients in the first place. We will be enhancing the data basically to show there is a benefit.

All the evidence that has been put down so far is in patients who are quite or very experienced and have been followed up for a very short time. So I suppose less experienced patients, and ERA includes that group, and maybe first change.

Do you recommend people having resistance tests before they start therapy first line?

I personally do, it’s something I feel quite strongly about. But most of my guidelines colleagues for one reason or another don’t feel as strongly or haven’t come down on that side of the argument. But if it were you, would you like to think that the first therapy you’re embarking on would be optimal therapy? I’d probably be prepared to pay for it. So yes is the answer to that.

What do you think about the nevirapine resistance data at Retrovirus?

In terms of the 103N in pregnant mums who have a single dose to prevent vertical transmission – clearly the benefit of that strategy to the greater group of patients is enormous, if prevention can be carried out, because there’s one thing we’ve seen from the strategies like the French had following the 076 study was that they practically eradicated vertical transmission in France. But equally drugs, which can become or generate highly resistant viruses just by the development of a single mutation, so called low genetic barrier, are to be approached with caution if used alone.

Back to other sorts of diagnostic tests, at one meeting you said that viral load was only going to go so far, and eventually we were going to need to use quantitative DNA testing. Can you elaborate?

Essentially my own view is that if we get another class of drug like the protease inhibitors – which could well be the fusion inhibitors – and we are giving patients these three classes of drug, I think we’ll see another quantum drop in viral load. At the moment we’re going along at less than fifty or less than twenty copies and that technology won’t go any lower, PCR itself will only detect one copy. You can really see we’re getting pretty close to the bottom of the river, but we do know that proviral DNA is stored in cells, and attempts to quantify that have been carried out and been quite successful.

If you have an image in your mind of someone responding to therapy as it is at the moment, you’ll see a fall in viral load. Over twelve to sixteen weeks it goes undetectable. If you measure DNA in those patients it would have a certain value and it may, over six months drop less than a log – there’s a little shallow curve for DNA in cells. What I think will happen is if you get this extra fall in viral load, so it goes really seriously undetectable, you’ll actually change the curve of the DNA and you will start to see a fall in the way that we currently see plasma viral load. So what we are going to end up measuring, as a routine is DNA fall, we may do viral load when someone first comes in or if someone’s failing otherwise we may not need it.

More thoughts about the future?

In terms of the disease, of pathogenesis and virology, we’re getting to a very interesting stage. I think in terms of therapy at the moment, we’re very near the cusp. If you look at how the host handles infectious disease; it’s a combination of the therapy that we give them and their own immune system – that’s always been the balance for any infection. Without the host’s immune system functioning as well, usually infections are devastating.

I think when we introduce another new class of drug and it produces a much more profound effect we will shift the whole balance of what the host does in relation to the disease. In other words the pathogenesis of the disease will change once we get a successful third class. What we’ll see is much lower viral loads allowing a much better immune reconstitution – just think what immune reconstitution was like just after PIs in relation to what we had before. The balance of the disease may truly shift towards a chronic, quiescent infection. I’m very excited about that next step – this is all theoretical though but with what we have already, I think it will happen.

Do you think this will have a profound effect on all patient groups, including very late stage and experienced?

There are always going to be exceptions, but if you think – and I know what happened to some of our late stage patients with protease inhibitors when they first came out – it was miraculous and so potentially, it’s an option. The thing against it is if you’re very late stage you may loose certain clonal memories in the immune system, which just cannot be regenerated, but if you’re regenerating the immune system anyway and you have naive cell populations, there’s the issue of re-immunisation with traditional antigens, which may also encourage the immune system to become whole again.

The whole model then shifts if what I speculate becomes fact, all viral load systems then get thrown out the window and we’ll be looking at completely different issues.

What about the future for your department?

What the future now offers is the opportunity to develop and break the department up a little. So that we have a research department doing academic research, we have our clinical research activity being done as a unit of activity and maybe even a third group working there. What we’re trying to set up is an academic clinical research unit.

In terms of where we’re going now – we’ve got sufficient funding to set up a separate site. We’re looking at doing it with the trust, as the school doesn’t have enough room geographically. There are a number of options locally or we may even rent something a little bit further away. That will be the site for academic, clinical research and the core of it is around resistance. We’ve got a grant award for the next two years to evaluate the system that has been set up to measure resistance, that’s genotypic resistance, and develop it so that it will function as a clinical research tool as opposed to just a research tool. At the moment it’s a research tool, it’s a single unit with maybe one plate reader with it. We get ten samples, which we can run in that system and of those five works, five don’t work. We report the five that work, of the five that don’t, we’ll play with, juggle with, try extracts on, and we’ll maybe make another three work. The last two we finally have to give up on. That’s a research way of doing it.

If you think how a diagnostic lab needs to run, they need to run that system with a guaranteed throughput, it needs to have the flexibility to handle ten samples one day and maybe a hundred the next because they’ll be a mixed demand and it’s unpredictable. What we have persuaded the company to do is to set us up with their optimum system so it can do eight resistance measures per hour. It’s not a big machine – it’s a single computer reading system – but you just have more and more of these towers, each one is running a gel and one computer will take up to eight of these.

What we’re going to then do, is research and evaluate how it performs in terms of speed of production of results and how it will handle an increasing number of samples. So the research is all about developing the system to have a routine virological process, the by-product is the resistance measures. What we’re actually evaluating is the machinery and the technicians that run it. Those measures will provide results for patient care. We’ve contracted to evaluate the system using 2000 measures a year, so that’s one strategy to get reduced costs.

Finally, what do you feel is the role of an activist group such as ours?

My view is having been in HIV right from the start it is a disease that has actually revolutionised medical care. Community group responses have made patients question every step of the way what it is they’ve got, what it’s doing, what it causes and what they’re going to do about it. Prior to that medical practitioners of all shapes and sizes had never ever had that sort of response to a disease before and had never been asked those questions.

It troubles me not at all to say to a patient ‘I don’t know’ and that is the most important hurdle. It’s an enormous benefit and it has dragged clinical care kicking and screaming into the 21st century, particularly with the Internet and I think you have to take a lot of credit for making that happen. You have my hearty support.