Participants
- Dr Martin Fisher, Consultant, Royal Sussex County Hospital, Brighton
- Dr Caroline Sabin, Lecturer in Statistics, Department of Primary Care & Population Sciences, Royal Free and University College Medical School, London
- Dr Ian Williams, Consultant, Mortimer Market Centre, University College Hospital, London
- Anna Poppa, editor, AIDS Treatment Update
- Keith Alcorn, editor, aidsmap.com
To view reports on this site regarding items under discussion, or abstracts, posters and sessions from the conference, click on the links within this article or go to the conference website.
Switching treatment to preserve fat
Keith Alcorn: Several studies reported on switching from d4T to abacavir with the aim of stopping or restoring fat loss - what did you think of these studies?
Ian Williams: There were three studies presented. One looked at switching from d4T to either AZT or abacavir; another looked at switching from d4T and a protease inhibitor to AZT/3TC/abacavir; and there was the Australian MITOX study. My overall impression was that they all showed minor improvements in peripheral fat wasting, particularly in the arms. But these were very minor improvements, only recognisable by DEXA scan - 0.3 kg over 48 weeks. Clearly there may well be a biological rationale, supported by previous hypotheses that d4T may be associated with greater mitochondrial toxicity, but this was a very minor improvement. In the Cooper study from Australia, neither the patients nor the physician noticed the improvement.
Martin Fisher: I share the concern that there was little clinical benefit, but maybe we were expecting too much too soon. The fact that there was some improvement, rather than further loss, is good news and perhaps we were over optimistic. It was disappointing that the rosiglitazone data suggests that it doesn't have a benefit when a lot of us were holding out some hope. The in-vitro models suggested it might have an effect.
Ian Williams: The Australian switch studies showed no difference in limb fat, leg fat or face fat. The main change was in arm fat so we'd have to say that, over 48 weeks to a year, it's not going to make that much of a difference [if you switch to abacavir].
Keith Alcorn: The Western Australia study did show that when people were switched to abacavir, the ones in the d4T arm did continue to lose a certain amount of fat. Is it your clinical experience that the fat loss goes on and on, or does it bottom out?
Ian Williams: I think it bottoms out. It tends to stabilise. But then we don't measure it at an absolute level in the clinic. We measure it from our own perception and that of the patient. We therefore don't know whether, over three or four years, you're actually continuing to see a very small loss. My own view is that it stabilises, and this means that it's not such a big problem for some people, although clearly it is for others.
Martin Fisher: Certainly from my own experience, people follow different patterns. For some people it's a continual loss, whilst for others it goes in phases. In lots of people it seems to plateau out whilst in others for reasons that I don't understand you get spontaneous improvement without any change in drugs. Maybe part of the problem is that we're looking at it without any objective measures. One of the interesting studies here was Andrew Carr's lipodystrophy case definition study, trying to hone down exactly what lipodystrophy is. The problem is that the answer he has come up with isn't exactly something which we'd be readily able to incorporate [into clinical care].
Ian Williams: It's become very complex, with anthropometric and DEXA scanning measurements which I wouldn’t be able to employ at all. I think that the switch studies show that there may well be differential effects between NRTIs. It's not saying that other NRTIs are clean, but emphasising that there may be a differential effect between different NRTIs over time. That's something which has been suggested by other cohort studies.
The other study which was of interest was the original ritonavir/saquinavir PI only study, which has been going some time and was intensified by adding some NRTIs. If you look at a five year follow up in the NRTI intensification arm, there was a fourfold greater risk of lipoatrophy compared to just taking PIs alone. If it you look at facial lipoatrophy I think it was ten fold. It just tells you that NRTIs generally are driving the problem with lipoatrophy.
Problems with interpreting cohort data on cardiovascular risk
Keith Alcorn: What about cardiovascular risk for people taking HAART? [Click here to view poster titles on this topic]
Caroline Sabin: One of the studies due in about a year's time is the DAD study, which should come up with some interesting data. They've recruited upwards of 17,000 patients from across Europe and they are monitoring any cardiovascular events which occur prospectively, and they are relating these to lipid profile and cardiovascular risk factors and antiretroviral treatment.
Follow up isn't available yet, but baseline cross-sectional data from patients in the study is. It shows that in patients currently receiving PIs and NRTIs, lipid levels are raised.
If you just look at people cross-sectionally then those on PIs and NNRTI combinations have even higher lipid levels. One of the problems with this is we don't know what's happened to people in the past, so why are they currently on a NNRTI combination? Maybe because in the past they were on a PI and their lipid levels started to shoot up so they switched. In the prospective follow up, we should be able to see if there was any beneficial effect from switching. In addition, there's no evidence that the increases seen will translate into increased risk of cardiovascular disease. Until the prospective data is there, we cannot show that.
Ian Williams: There were two other studies here. The Kaiser study - quite a large study looking at a database of HIV-positive and negative patients - they showed an excess of hospitalization [for cardiovascular causes including myocardial infarction] in their HIV patients.
Caroline Sabin: Yes, they are suggesting that it might be a consequence of HIV rather than a treatment effect. One of the problems with data sets like that is that patients go into it and then drop out, for example if they change employer, so you don't necessarily have the follow up. If people present for care at a non-Kaiser clinical centre, I'm not sure how that is picked up. They didn't seem to find a big difference between PIs and non-PIs. Nor did they look at duration of treatment, only if someone was on a PI or not.
Ian Williams: Another confounding factor was the higher number of people who smoked in the HIV-positive group compared to the HIV-negative.
Caroline Sabin: On the other hand, the VA study shows a deep decline in cardiovascular events which seems very strange.
Keith Alcorn: A decline over what time period?
Caroline Sabin: Over the past five years, it's actually gone down quite a lot. Their follow-up for the VA is pretty good – if you leave one area you will seek care at a VA centre elsewhere. But again, why we should be seeing a decline?
Martin Fisher: In the VA and DAD studies, one thing that concerns me is that, you may end up at a hospital where data isn't being collected. That's to say you can choose where you have your HIV care, but you can't really choose where you're going to have a heart attack! Therefore we may miss some of the follow-up we really need.
Caroline Sabin: Equally, another problem is that we're now actively looking for cardiovascular disease.
Ian Williams: Yes that's true; I certainly check blood pressure a lot more than I ever used to. And on top of that, we're now looking after an older patient population.
Caroline Sabin: In the States they are very aware that the population is ageing and as the population ages certain things happen more frequently and heart disease is one of them. We need to try and capture that natural ageing process. Sometimes it's not that easy to do, especially if you don't have a comparable population of HIV-negative individuals that you can follow with the same risk profiles. Therefore I think the issue of MIs is uncertain, and I think that there'll be more clarity in a few years, but that's something we'll have to wait for.
Ian Williams: We can certainly recommend that people should be looking actively for cardiovascular risk factors in their patients in the meantime.
Resistance in primary infection
Martin Fisher: There were a number of presentations regarding resistance in primary infection. Regarding primary resistance the picture panning out in the States is similar to that in the UK. There appears to be an increasing level of primary resistance being reported. However, it doesn't seem to be so true in data from France and Australia. The reasons are open to discussion.
One of the most interesting presentations was Susan Little's. Whereas in patients who develop resistance secondary to drug therapy, the virus reverts to wild-type, in patients who acquire resistant virus at the time of infection this appears to be maintained and the virus doesn't revert to wild-type to the same extent or as early. Therefore this would suggest that we should be more forthright about performing resistance tests on all newly diagnosed patients rather than just proven cases of primary infection.
Keith Alcorn: They found resistance persisted for up to a year.
Martin Fisher: Yes, up to a year is the degree of follow-up they have at the moment.They homed in on NNRTI resistance. There's a paper that could go alongside this one that suggested that NNRTI-resistant virus seems to be more easily transmitted. It's something which may be very relevant to the UK where we've used a lot more NNRTIs than other countries.
Ian Williams: There was another poster which looked at transmission of mutations which were seen for much longer, associated with AZT. It reflects what you'd see in patients who stop therapy. There are situations where mutations can hang around for a long period of time. In the Little study there was a fall in the mixture of populations, but it still remained quite detectable. The prevalence studies are interesting, given that there's differing data from parts of the world. I think the UK database needs to be confirmed. The prevalence of resistance reported by Deenan Pillay (PHLS) was from a small database and it needs to be looked at from a much larger sample, which I think the MRC is trying to do. At my own centre we hardly see transmitted resistance these days in our seroconverters. The Australian data seemed to show a decline in NRTI and PI transmitted resistance, which may be related to who's transmitting virus. It may not be those on therapy with well controlled HIV.
Martin Fisher: Absolutely, the Andrew Leigh Brown modelling paper suggested that given that people with primary HIV infection are a large source of new infections, similarly people with transmitted resistance may be the key source of primary resistance in the future [because they will be able to transmit drug-resistant virus during acute infection when they are most infectious]. There's a need to identify this group and see if the modelling study pans out into reality.
Viral blips
Keith Alcorn: I was struck by Fiona Lampe’s abstract looking at the proportions with controlled viremia amongst patients at the Royal Free and the remarkably small number of people who were rebounding once their viremia was actually controlled by therapy.
Caroline Sabin: That's repeating an analysis we conducted with the Frankfurt data set which showed exactly the same thing. If a patient's viremia is controlled then as long as they maintain adherence, then there's a very low rate of rebound with the treatments which are currently available. There will be problems with toxicity, but if you can get through these or alleviate them, then really the drugs are very good. Rebound rates are lower than we'd previously assumed, and we've found this both at the Royal Free and at Frankfurt. Nor did it seem to be increasing rapidly over time. One thought was that it would take a long time for some of the failure to be seen. Well, actually the failure rate wasn't particularly high and didn't seem to get higher with increased time on therapy.
Ian Williams: Relating to the presentations on viral blips, which looked at viral blips in treatment-experienced patients, which showed that blips, even in this patient group, wasn't associated with increased risk of rebound. In the dynamic modeling data for viral blips, the group most likely to experience failure were those who stopped their drugs rather than those who missed a dose. Viral blips weren't associated with this at all.
New agents
Keith Alcorn: Which presentations on new agents stood out?
Martin Fisher: TMC125. The data were very exciting. The first of the new NNRTIs to get to phase II, it showed that in patients new to therapy it achieved a substantial viral load reduction in a short period of monotherapy. The new data presented by Brian Gazzard concerned patients with proven resistance to efavirenz, and again, good viral load reductions were achieved in an eight day period of monotherapy. The two caveats I'd have are: in the initial study, the pill burden was 18 capsules twice day, but it's now refined to three twice a day and they're trying to improve this even further. The second would be that the slope of V/L was much less, although still impressive, in the NNRTI-experienced study, compared to the naive study, suggesting some element of cross resistance, although we can't explain it on the currently available techniques.
Ian Williams: There was one patient who'd failed with more than four NNRTI mutations. There was an intermediate mutation associated more with susceptibility to TMC. I'd agree that this looks like a good drug for a patient population where we need more options. One other concern though - these were seven day studies and this gives no idea what the toxicity is going to be like - what the rash rate will be or other problems.
Martin Fisher: I think we should remember that capravirine looked good on seven day data and that isn't with us anymore!
Ian Williams: I think it’s worth noting that HIV entry inhibitors are coming of age slowly. T-20 data was presented at the conference. There were also data on Schering Plough’s new drug which showed short term, good virological effects. Particularly encouraging is that it’s taken orally. The only concern I'd have is the potential cardiotoxicity - basically it could lead to heart block. There were two other new entry inhibitors looked at in-vitro, so this is an area which is certainly promising.
Martin Fisher: Another area was "old drugs in new ways." For example once daily Kaletra, which suggested that the pharmacokinetic profile means it may fare just as well, taking it once a day instead of twice.
Also once a day atazanavir data - a message of concern was that the interaction with efavirenz showed a significant reduction in atazanavir levels. Further papers looked at combinations of Kaletra with other PIs, particularly amprenavir, and it was interesting that a number of different pharmacokinetic outcomes were presented at the conference (1, 2). A lot of us are concerned about using the two drugs together.
Ian Williams: The amprenavir levels do appear to go down when combined with lopinavir. There was also concern about once a day lopinavir. A proportion of patients had trough levels of lopinavir which were much lower than you'd expect with twice daily regimens which might suggest that they may have less drug exposure which may be a particular problem for treatment experienced patients, particularly as concerns IC50.
Martin Fisher: We had our fingers burnt with indinavir, trying to push for twice daily, so we should be wary of trying to push drugs too much into a once daily dosing regimen.
CMV viremia
Anna Poppa: I was interested by the report on CMV viremia as a marker of future risk of illness or death whilst on HAART. Can you say more about it?
Caroline Sabin: Looking at people whose CD4 count had ever fallen below 100, CMV viremia was examined, alongside viral load and CD4 count. A simple of measure of CMV-positive or negative was strongly indicative of progression to another AIDS-defining event and survival, independent of a CD4 count and viral load. This suggested that changes in CMV status were important. So if someone starts HAART and their CD4 count goes up and their viral load goes down, but they remain CMV viremic or they become viremic again on HAART, that’s a bad sign.
Martin Fisher: Now is this a direct effect of CMV or a marker for some other immune function we're not measuring?
Caroline Sabin:It depends on who you talk to. One way of trying to identify what it is would be to treat CMV. One of the major problems is that there are so few candidates, so you'd have to have a study over quite a long time.
A US study presented immediately beforehand found a relationship between CMV positive and negative status, and CD4 count above 250 and progression to AIDS.
Ian Williams: It may become more important. The problem with the CMV prophylaxis trial was the drug was difficult to take and expensive. If there was an anti-CMV agent easier to take and less expensive and there was a sub-population of people who you could easily do CMV viremia tests on, it would be a very nice hypothesis to explore.
Martin Fisher: Valganciclovir would fulfil all these criteria except cost.
Ian Williams: Cost wouldn't be the over-riding concern, but the cost benefit analysis was so decisive against giving CMV prophylaxis at the time, especially as PIs came along at the same time.
Ian Williams: Just to change tack slightly, Eurosida presented some data on the incidence of clinical progression - which was practically zero - in those with CD4 counts above 250 who interrupted therapy. They also looked at patients with CD4 counts below 50. For those people who remained on therapy, clinical progression was so much lower than those who stopped therapy. That wasn't mediated in any way by CD4 or viral load, so there must be other mechanisms mediating this.
Caroline Sabin: One of the concerns that I have as well with observational data is there's always a reason why a patient decides to stop therapy and restart. I'm not sure we capture the reasons, as it's not just a function of CD4 count or V/L. It's all the other factors such as side effects, or inconvenience.
Abacavir hypersensitivity
Martin Fisher: There were two papers, from Glaxo-Smith Kline and an independent paper from Western Australia, both of which suggested that there was a strong genetic component to abacavir hypersensitivity. Both were identifying the same area of the human genome which appeared to strongly predict individuals with abacavir hypersensitivity, which may help in the future if one can use it as a screening tool to identify individuals in whom abacavir should be avoided.
He recommended that the study should be repeated in other populations. The other caveat was that you shouldn't use the test in a person with hypersensitivity and rechallenge them if they are negative for the polymorphism - the current guidelines on hypersensitivity reaction remain.
Ian Williams There was also the paper presented looking at polymorphism expressed in MDR1 gene and the likelihood of virological failure. People were divided into three groups according to MDR1 genotype. There was an association between MDR1 polymorphism and the likelihood of virological failure – it didn’t quite reach significance but there was nevertheless the suggestion that people handle drugs in different ways and this may have an effect on their outcome.
Martin Fisher: Genetic research could help us to use drugs a little more cleverly rather than turning to "drug of the month."
Hepatitis B
Martin Fisher: On the subject of drug of the month, can I just mention tenofovir and HBV? There were a couple of papers regarding the impact of HIV on HBV. The first showed the massive impact of HBV co-infection on liver related deaths compared to people with either virus alone. One paper showed that there was a seven fold increase in the rate of liver-related death if an individual was HIV-HBV co-infected compared to just HIV-positive and a 14-fold increase compared to people who just had HBV.
There were some papers which were hopeful on HBV treatment. One was on adefovir, which was effective in individuals with co-infection who had 3TC-resistant HBV. The adefovir was given at a much lower dose than in HIV, which didn't seem to have the same kidney toxicity.
There were a paper looking on the impact of tenofovir on HBV viral load showing it was effective and this raises important issues about how you might choose to treat patients who are co-infected.
Ian Williams: Can I go back to the issue of liver disease? Are you saying that the natural history of HBV in patients co-infected has changed or that the morbidity and mortality is associated with the impact of drug therapy in patients with underlying liver disease?
Martin Fisher: In that particular study they clumped together all liver related deaths. There was also a presentation on the impact of co-infection, suggesting that when HAART is commenced in a co-infected patient, there's a risk, when the immune system rebuilds, of the HBV deteriorating due to immune reconstitution; ie when you start HAART you run into problems and this reflects our own clinical experience over the last year or two.
Ian Williams: Natural history studies to date haven't really shown a very great interaction of HBV and HIV; they've shown that if you're exposed to HBV if you're HIV-positive, you may well be more likely to become a carrier, but that the natural history of HBV isn't that different in someone who is HIV-positive, although this might be different with HCV. Are you now saying that with immune reconstitution this might well change?
Caroline Sabin That was the picture I was getting from the overview session, that it was immune reconstitution [click here, then select Webcasts to view the lectures on hepatitis B co-infection online].
Martin Fisher When you start treatment for HIV do you also use a drug that is active against hepatitis B, or do you wait until how you should treat hepatitis B becomes clearer? The speaker in this session was very definite - if you're going to treat HIV you have to treat HBV simultaneously.
Ian Williams: If immune restoration causes the reactivation of HBV and consequent liver damage then this would be a reasonable thing to do.
Martin Fisher Absolutely, we need more data, but this would be a strategy which I could support.
GBV
Caroline Sabin: GBV was flavour of the month about six months ago. Some background, since I’m not sure if everyone is aware of the history. About three years ago this hepatitis virus was identified and a number of papers looked at the effect of co-infection with GBV on the natural history of HIV and the results weren't consistent. Partly this was to do with the way we measured whether people were infected with GBV. There a number of antibodies which could be looked at and it's not clear which one should be taken as a marker. Anyway, that all died a death and people seemed to lose interest very rapidly. But six months ago a paper was published in the New England Journal which brought the issue back again. In this study people with active GBV seemed to be doing better in terms of HIV disease progression. A number of people therefore asked if there were benefits from infecting people with this virus. There were a number of posters at this conference which once again showed conflict, and the lack of a consistent pattern.
There was one poster suggesting that in some people with GBVC and HIV, the response to HAART may be better.
There was a very small study looking at the interaction between GBVC and HCV and long term response to HAART. There have been some papers suggesting that HCV impair immune responses to HAART.
It's unclear if this virus does have an effect on HAART, and if it is something to do with the fact that you have managed to clear active infection and have developed antibodies. The studies which have looked at this have found a negative effect, whilst those looking at RNA have found a positive effect, raising the question “is there something in the way that your immune system deals with that virus which affects your response to HIV?”. We need to look further to see if this infection impacts on HIV.
Keith Alcorn: Was there any suggestion in the New England Journal that GBV co-infection tempered the negative effect of HIV on HCV co-infection?
Caroline Sabin: In the subsequent correspondence people have pointed out that the impact of HCV wasn't considered.
Adherence studies
Ian Williams:There were several adherence studies presented, a couple of which were randomised interventions. None of studies showed long term benefit in virological outcome.
I'd say they give out the wrong message, because it depends on the intervention. People who are randomised into a clinical study are the ones who are going to do well. How do you control for the trial effect in a control population?
Caroline Sabin: People in trials are probably the least likely to benefit from additional adherence support because they are already motivated enough to join a study.
One of the issues for me, is that in order to see a very good virological effect we need 95% adherence and a lot of these adherence trials may be improving adherence to 80-85% but not shifting it above the crucial 95%.
Ian Williams: You also have to look at what the outcome is. Virological outcome is important, but you also have to look at tolerability. A lot of adherence work involves choosing the right regimen for the right patient. You need to look at tolerability, toxicity, acceptability as well as virological outcomes.
Caroline Sabin: I think that now most of the available drugs would give a good initial response in naive patients and people's adherence is very good at the start. The problem is 6-9 months later when the initial motivation is gone. That's perhaps the time that we need the adherence support. It's long-term outcomes we're looking for, rather than short-term initial responses.
Ian Williams: I agree that many people are motivated up front, but I think that there may well be a sub-population who clearly need a lot of help to make sure that they take their dose in the right way and that they are on the right regimen. I'm not saying that these posters weren't any good, but we need to be very careful how they are interpreted and what messages are relayed back.
Caroline Sabin: I know we don’t want to talk about cost, but a lot is riding on these drugs and adherence support costs time and money. You have to justify this, especially if you're thinking of employing somebody.
Ian Williams: We audited our patients new to therapy. There was a trend towards better virological outcome in those patients who were referred to an advice clinic. We are looking at trying to evaluate this further.
Caroline Sabin: The question then is, why is somebody referred to adherence advice?
Ian Williams: It way well be the ones who are referred are the ones who either feel themselves, or their doctors think, are less likely to adhere, so if we get better outcomes that's actually very good. There are very few studies published which show a positive benefit from behavioural interventions in any area of medicine. It's therefore easy to over-interpret the data.
Keith Alcorn: It's important to talk about this because there's a view around that there's no evidence that any sort of adherence support has ever been proven to work. As Caroline says, if money is short should we be spending it on this, rather than say, resistance testing, or drugs?
Ian Williams: How do you define adherence support? Adherence support is a lot of things which were going on in the control arms of these studies in any case. Like written information - that's all adherence support. If you compare just giving a patient a script without telling them the objective of therapy, without giving any written information and a session to talk about it, to doing these things, I think you’ll see a difference!
Caroline Sabin: I think you're right. So what we're trying to do is improve something which is already pretty good, so you're not going to see much improvement in these randomised trials. The problem is when somebody asks for data to justify why this money is being spent.