The moderator for this panel was David Evans, Information and Advocacy Associate, Project Inform and the panelists were Daniel Kuritzkes, M.D., Partners AIDS Research, Cambridge, Massachusetts; Dr. Stephen Becker, M.D., Pacific Horizons Medical Group, San Francisco, California; and Martin Delaney, Founding Director, Project Inform, San Francisco, California.

Mr. Evans: Welcome to the Antiretroviral Program of the AIDS Treatment Update 2004. I'm David Evans. I'm the Information and Advocacy associate at Project Inform in San Francisco. I want to thank the International Foundation for Alternative Research in AIDS (IFARA) for sponsoring this program. There will be two other panels; one on Metabolic Complications in HIV and another on Hepatitis C and HIV co-infection. I'll ask our panelists to please introduce themselves.

Dr. Kuritzkes: I'm Doctor Dan Kuritzkes. I'm the Director of the Harvard AIDS Clinical Trials Unit in Boston, Massachusetts, and head of the section on retroviral therapeutics at Brigham Women's Hospital.

Dr. Becker: I'm Stephen Becker, a physician from California Medical Center at the University of California, San Francisco.

Mr. Delaney: I'm Martin Delaney, founder of Project Inform. I'm not a physician but I've been to a lot of these conferences, like all of us.

Mr. Evans: You can start off by telling me and the audience what you felt were some of the most significant data presented at the conference, and was there anything you observed that was surprising.

Dr. Becker: I think the most important aspects of this retrovirus conference had to do with pharmacology, and particularly those aspects that extended our understanding and observations about the non-nucleoside agents. Particularly in terms of pharmacokinetic characteristics, their very long half-life and the variability within populations of that halflife, and associating that also with genetic or genomic factors -- differences in pharmacokinetic aspects dependent upon race. It appears from some of this early work that blacks metabolize and distribute at least efavirenz (Sustiva) in a fashion that is different from other racial populations, and this is a very important early observation that requires confirmation and further work. But I think sets us upon a course within the HIV therapeutic area to explore aspects of what's called pharmacogenomics.

Dr. Kuritzkes: I would agree with Steve's take on this. I think that the finding that African Americans had significantly higher efavirenz levels than did non-blacks and that this was linked to a particular polymorphism in the genes of African Americans so that it could be predicted -- because it's not all blacks, it's a subpopulation of blacks -- is extremely important. It allows us to continue to individualize our approach to therapy, either by monitoring drug levels so that we can lower doses when it's appropriate, or by predicting who might be at risk for having very high levels and try to dose appropriately. I think the information that we learned about efavirenz also plays an important role in our understanding of what to do when we stop drugs like efavirenz or nevirapine and why people may be getting into trouble in terms of selecting drug resistance with intermittent therapy. And particularly when nevirapine is used for the prevention of mother-to-child transmission, I think the data that we saw really continuing to play out the story of selection of drug resistance, and persistence of drug resistant variance, after single-dose nevirapine for the moms or after acquiring a drug resistant variant and setting up transmission ...

Mr. Delaney: I thought that was certainly one of the most significant findings on a global perspective, at least, and it really raises questions that have to be faced about how we're currently approaching mother-to-child transmission. Certainly the simplest ways to do it are with AZT and nevirapine as a combination, but the data that we saw here suggested that when you make that decision and take that route, those women then tend to have a less significant response to therapy later on themselves. We're asking them to make a trade off that I think wasn't clear early on.

Dr. Becker: But I believe that some of the inadequate response later on may in fact go back to these genetic factors. And I think that there's a certain symmetry that as we have used technology -- genotypes and phenotypes -- to try to individualize drug therapy given a specific viral type, we are on the threshold of being able to do that and look at the host factors, the individual's drug metabolizing machinery, and try to individualize the combination on that side of the equation as well.

Mr. Delaney: You know it's a very interesting trend that in one way the science is leading us there, but in other ways, in terms of policy, say within the federal guidelines the tendency is moving toward more and more of the standardization of a few regimens; that this has been the best in terms of the average response, therefore this is what everybody should start on. I think these two phenomena are going head to head at each other.

Dr. Kuritzkes: I'm not sure they're necessarily that contradictory. I think in terms of the guidelines what we've seen really is as there's been a larger and larger body of data and longer and longer term follow up for some key regimens, that we're able to say with greater certainty that a certain set of regimens is most likely to be successful for the largest number of patients. Recognizing still that, that's trying to apply things with a very broad brush and dealing with averages, and of course people are individuals and each situation is going to be unique. But even within those regimens, for example a non-nucleoside RT inhibitor based regimen is a preferred regimen, that doesn't necessarily mean that the same does of efavirenz will get used in everybody. Or it might mean that somebody who carried the polymorphism that predisposed them to get very high levels might use a protease inhibitor based regimen in place of an efavirenz based regimen.

Mr. Delaney: I think the bottom line is that no guideline is ever going to be a substitute for thinking.

Dr. Becker: But it's a guideline, and clearly identical treatment is not equal treatment, and I think we've come to that point in other therapeutic areas and, again, I think we're on the verge of understanding that and being able to apply some of that well within the HIV therapeutic area. The observations around efavirenz I think were very compelling. Efavirenz is metabolized by an enzyme in the liver called 2b6, and not everybody has the same amount of that enzyme and so that if you have more of it you'll metabolize efavirenz more rapidly, and may not have as good a therapeutic response because drug leaves the system too quickly; and if you have deficiency and a polymorphism or a gene deletion in that enzyme, the efavirenz will be metabolized more slowly, it will build up to higher levels, it can give rise to toxicity and the evidence, the data presented here seems to suggest that very much is the case.

Mr. Delaney: Steve led me to wonder how you incorporate that into clinical practice.

Dr. Becker: Well, you know, that's a broad question that goes beyond the HIV therapeutic area, and clinicians and diagnostic companies are wrestling with that. I think that there will, within the five to ten year period, we will be characterizing the metabolic capacities of all of us, and the day I think is not too far away where individuals will come to their physician with some knowledge of how they metabolize certain drugs. Clearly, not all of them, but commonly used drugs. So I think that there will be genetic tests that can be performed on blood samples that will inform a patient and his or her physician about how best to tailor therapy to avoid toxicities, on the one hand, or to avoid certain drugs entirely, or conversely to try to maximize the effectiveness of a regimen.

Mr. Evans: Was there anything presented at the conference that you feel might change the way we manage HIV in the short term, as opposed to the longer term?

Dr. Becker: Dan, do you want to talk about the implications of when and how to stop certain non-nucleoside therapies?

Dr. Kuritzkes: Yes, I think the biggest implication from these data are that we may need some kind of a tail to protect people against drug resistance when stopping drugs that have very long half-lives, and whether that means stopping efavirenz or nevirapine first and then allowing the nucleosides to be stopped a little later, or temporarily substituting a boosted protease inhibitor regimen so that you have some coverage for the non-nucleoside. I think there have been conflicting data in the context of full triple therapy regimens about whether that's really necessary or not, but it's made me a lot more reluctant to see people just stopping willy-nilly. I think the data that impressed me the most really is the new data about the persistence of drug resistant mutants after transmission of virus, and that we really need to be paying much more attention to identifying patients who have acquired drug resistant virus by new infection and that means more routinely doing resistance testing at the time of the first clinical encounter. That's going to be the time closest to transmission, when someone is newly diagnosed with HIV. It may be months, it may be years, but we know that these mutants are persisting for a good two to three years at a minimum, maybe longer in certain cases. So that's another thing that I would change as a result of the information I have learned here.

Mr. Delaney: There was another study that I saw that led me to more questions than answers, I think, but maybe you guys could work on it. It was a long term follow up looking at questions of resistance in a clinical setting. It basically showed that most of the resistant mutations to many of these drugs tend to show up within the first year of therapy; that the people who are going to get resistance get it relatively early, whether it's through poor adherence or the genetic mismatches that we're learning about. But as you get beyond that first year, those who have been stable through the first year tend to stay so for very long periods afterwards. I think that would seem to have some implications for how you'd manage that first year.

Dr. Kuritzkes: I think what that's really telling us is that there's a group of patients who find it difficult to initiate therapy, either because they're having minor side effects that make adherence a problem or because just taking medication is not fitting in well with their life at the time that they're starting. That they're more likely to have intermittent dosing of therapy and therefore to select for drug resistance and go on to have virologic failure. Once you've gotten beyond that period or if we've sorted out who those people are early, because they tend to fail and drop out, then the people you're left with are people who are really doing well on their therapy, and either they stop their regimen completely and have virologic failure or they continue on their regimen and have a long term success. I think those data are really very consistent with data that Andrew Phillips has shown in the past, that would tend to suggest that you have this group of people who fail in the first year and once you're beyond that, if people are able to continue taking their meds, they have a very high chance of continuing to be successfully suppressed.

Mr. Delaney: What can we suggest to clinicians for managing those patients that have that difficult first year? That's probably where we see ... that those are the people who ultimately go on and die of the disease. How can we do a better job for them?

Dr. Kuritzkes: I think that's one of the areas where I think we could use some more exploration in strategy trials, trying to ask are we better off using a regimen that may be more resistant to developing resistance, in a sense; a resistance proof regimen, because it's going to allow for more flexibility and maybe a bit more forgiveness as far as missed doses, and in the long run is that preferable to starting with a simpler, potentially easier to take regimen but one that has greater chance of developing resistance from a few missed doses. In terms of practical advice in AIDS to clinicians, I think the key thing is just getting to know a patient before starting therapy and talking through the issues with the patient, and trying to tailor the regimen as closely as possible to what is going to fit best in the patient's lifestyle. As we were saying a few minutes ago, guidelines are just starting points and framework within which to think about how to select a set of drugs for patients, but it's not the end all and beat all.

Dr. Becker: I agree with that. I think, though, that we must not neglect and in fact give more attention to some of the human factors. I think that several papers made very clear the role of undiagnosed and untreated depression as a risk factor for virologic failure. I think those patients fail not because the drugs are necessarily wrong or they acquire drug resistant virus, but because they're not taking their medications. And I think that this is not rocket science, and this has certainly come up repeatedly in the past, but I think that we're not very good at spending that time and looking for certain non-HIV co-morbid conditions -- depression, mental health issues, substance abuse, alcohol -- that will degrade the compliance and adherence with the regimen and lead to virologic failure. And quite honestly we don't have enough good drugs in the pipeline for salvage purposes. We would be best to put some of that effort up front and keep our patients on drugs, and prolong the period that they remain undetectable.

Mr. Evans: In speaking of resistance and salvage therapy, there are a number of people who have resistance to all the current categories of drugs, who have cycled through a number of different opportunities, and were really looking hopefully at T-1249, and now that Roche has suspended development of that, I wonder if you can talk a little bit about what you plan to do in the coming year or so for people who are in this situation?

Dr. Kuritzkes: I think that any time a promising new drug is dropped from development for one reason or another it's always disappointing. I think we're fortunate that there are several other drugs in development that in many cases are at least as far along as T-1249 was, and will hopefully continue to move forward. Tipranavir (PNU-140690) is in Phase III development and is available on a limited basis currently through expanded access but will hopefully move forward, and if the studies are positive gain approval in the next year or so. There are several additional secondary protease inhibitors and even some newer nucleoside analogs that are moving through the pipeline. I think in the meantime it's really a matter of temporizing those patients, trying to figure out which patients are gaining adequate benefit from the drugs they're on right now and taking advantage of the relatively slow rate of immunological decline despite ongoing virus replication, and helping them to sit tight on what they're on rather than shuffling things around unnecessarily. For those who are progressing more, to consider T-20, to work hard to get them expanded access drugs, to find protocols of new agents whenever possible and suitable for them, and really trying to patch things together as best we can until things come along.

Dr. Becker: And I hope take a different strategic view and learn from the mistakes that we've made. Much of the current generation of patients who require T-20 were cycled through serial nucleoside therapy, were treated in an era where we felt it was not permissible to have any viral load, so were very quickly cycled through what turns out to be all of the drugs that we have. So now we have patients who have gone through all of these [drugs] and have T-20 available, but have nothing else to use with it. I think the data from the T-20 registrational trials makes very clear that as good as that agent is it's even better, with a greater viral suppression and a greater duration of suppression, if there are other active drugs that can be paired with it. So I think Dan's point is right, and I think many of the strategy trials that would be very useful would be around, how can we help people sit tight? How much virus is okay? Of what viral fitness or replicative capacity is all right? When do we have to play that last card, and when can we just sit tight and wait for drugs to come through development and have some agents we can pair with T-20? That really is the strategic question, so that we don't wind up with another generation akin to the generation that we started on T-20 once it became approved.

Dr. Kuritzkes: There's actually a study that Steve Deeks and John Bartlett and Sharon Rittler and I are doing through the AIDS Clinical Trials Group, that's getting very much at the question you're asking. For patients that have low level virologic failure, is it better to switch them right away or to let them coast for a while, and look at what happens in terms of the number of drug regimens that get used, and particularly how many drug options are burned in the process, and then where they wind up as far as virus and T-cell count. Hopefully we'll have data from that this time next year.

Mr. Delaney: I think there's a really important point here for our work as treatment educators, too, and that is to not be steering patients into this belief that their only solution is the next new drug, or that they have to have perfect response from the drugs they get, because that's where I think we got so many people into trouble. That's kind of what the field was saying back in 1996, 1997, that if you didn't have undetectable viral load you had to switch at least one or two of the drugs. Where I think that's left people is, when people say to me they have nothing left that works for them anymore, my experience is that's not true. That usually what they mean is they don't have any perfect solutions left, but they may have combinations that are partially active and can be good enough to get them through to the next generation of drugs, and certainly not all of that hinged upon T-1249. The entry inhibitors are going to be here in two and a half or three years, there are a few things coming in that pipeline.

Dr. Becker: But you make a good point. The residual drug activity is probably more than we initially appreciated. By that I mean you can have a full resistance, multiple mutations that would suggest that drugs X, Y, and Z no longer work. And yet they still do work for many patients, at least for a period of time, and to some degree. I think that's certainly true for the nucleosides, and may well be true for some of the nonnucleosides as well. Whether protease inhibitors fall into that category I think remains to be determined. Keeping patients on a "failing regimen" as long as clinically and immunologically they remain stable, obviously the drugs are doing something. Tell me if you disagree; the concept of treatment interruptions, I think we've gone from endorsing that concept to stepping way back from that, and clearly keeping patients with advanced disease on therapy is a better thing to do than discontinuing them.

Dr. Kuritzkes: Oh yeah, absolutely. I think the key point to remember here is that as long as virus load is below what the patient's set point would ordinarily be, they are still accruing substantial benefit from that regimen. And there are good data, particularly studies that came out of the group up in Vancouver, British Columbia, that patients who were on therapy with drug resistance had much better survival than patients who were off therapy altogether, making the point that these regimens really do have continued activity and continued clinical benefit that's very important.

Mr. Evans: And not all resistant mutations are created equal. There was a lot of buzz this year about the K65R mutation and I'm wondering, how does that kind of issue factor into the decisions you make in helping people decide whether to stay on treatment, to go off of treatment, what treatments to begin?

Dr. Kuritzkes: The K65R story, I think, is probably the mutation of the year. We're learning about it for the first time now in all of its complexity. It's still not a very common mutation, because it's selected primarily by tenofovir, although other drugs may occasionally do that, and when drugs are used in the right combination it seems that you might avoid the selection of this mutation. Like some other mutations, such as the one that confers 3TC resistance and the mutations for ddI resistance, the K65R mutation has some important properties that makes the virus significantly less fit, and so we see sort of wimpy viruses that don't generate as high a virus load, and it also sensitizes the virus to other drugs, notably to AZT. I think these interactions could be very important. I think it's very hard to just look at a genotype or a phenotype and say, I'm going to throw this drug away completely, especially when we're dealing with patients who are highly treatment experienced and you're trying to pick a set of drugs to use. I think the proof in the pudding is, if you stop a drug and the virus load goes up, then that drug was having some benefit. We saw data here from Frank Maldarelli¹ at the National Cancer Institute that, surprisingly with d4T, in patients who had apparent d4T resistance, they stopped the d4T and their virus loads went up. Tom Campbell and I had a similar experience in a small study we did in Colorado, where we stopped 3TC and virus load went up; and Nancy Schulman² at Stanford had very similar data in a small number of patients. So I think these drugs really have much more activity in a setting of apparent resistance than we give them credit for. It's one thing if you have someone who is brand new to therapy and they've got one or two mutations and you're trying to pick the best regimen, you want to avoid using drugs to which the virus is resistant or for a second line regimen. It's a very different kettle of fish when you're dealing with someone who has been on their fourth or fifth regimen.

Dr. Becker: But the K65R is also the multi-drug resistant virus, because it impairs the activity of numerous drugs in addition to, as was mentioned, tenofovir. It impairs abacavir and 3TC and ddI, and a drug that has also been discontinued from development (DAPD). So it is a mutation to avoid if one possibly can, and has effects across the class. But I think part of it goes back to what you said. We're dealing with this mutation much more frequently now and in part because of the use of tenofovir, not solely because of that -- a new drug and everyone wants to use it. In the case of tenofovir, good reason for enthusiastic use of the drug, but it's created for us virus now with a four hundred percent increase in the frequency of the K65R mutation in a relatively short period of time, and strategies now designed to how deal with that. Maybe you want to take us into discussion of some of the triple nucleosides ...

Mr. Delaney: Yeah, that kind of gets us into there. There have been a lot of papers at this conference and in recent months about the triple nucleosides, and there are certainly some disappointing results in triple nucleoside therapy over this last year. Some in combinations that included tenofovir and abacavir together, in particular, put those two together with a third nucleoside and what you get is a mess it seems. I think the challenge of this, though, is that people have a tendency to just jump on something as if we have absolute black and white answers, and the black and white answer this year is triple nucleosides are bad. I'm not sure that's what the data shows. I think, for example, the Trizivir question where it got knocked out of the box by comparison to a really superior regimen, well, to me what that said is that, no, it's not quite as effective as our best regimen. Does that mean it's worthless and no one should ever use it? I don't think so. I think you still have to take into account various factors. For some people it might still be the right regimen, because of its ease of use and simplicity in a lot of settings. I think with all of us, what we have to be reminded of is that there is a constant learning curve going on here. When a new drug comes out, like tenofovir, no matter how much research has been done there's a lot you don't know yet until you get it out there to tens of thousands of people. Then you begin to learn this stuff.

Dr. Becker: But there's a place where the learning is now. I think that the tenofovir-abacavir-3TC use and the studies are a good example of that. Here were three drugs that had inherent potency that was as good as any others that we had. They were simple to take, they had low toxicity, and there was every reason to ... It sounded really good, exactly right. But nobody had ever tested it. No one had ever used those drugs [in combination], and when they were used and were tested, fortunately in the setting of some clinical trials, we realized that for whatever the reasons that explain it, it performs miserably, and hurts you. Nobody would have known that had we not tested it. Had it been just clinicians and physicians in the community using this in the absence of clinical trials, either those done through federal agencies like the ACTG or industry sponsored trials, I don't think we would have come to the answer. And I don't think we would have been able to perhaps peel away the layers of the onion to get down to why that actually happened.

Mr. Delaney: And I think the reminder is that this is going to continue to happen as new drugs come on the scene, as tipranavir and the entry inhibitors, we're going to continue to go through those learning curves and things we don't expect are almost certain to happen.

Mr. Evans: There were presentations on at least four entry inhibitors at this conference, and I wonder what you think about them.

Dr. Kuritzkes: I think the entry inhibitors are really a very exciting class of drugs. They're really several classes within a big class, because we have attachment inhibitors like a drug being developed by Bristol-Myers Squibb that prevent binding of the virus to its receptor, we have drugs the prevent the virus to find its co-receptors -- the CCR5 inhibitors and the CXCR4 inhibitors, although we didn't hear much about those at this conference. And then there's another drug, which is an antibody that works sort of somewhere in between, after the virus has attached but before it interacts with CCR5. And then the fusion inhibitors, of course, of which T-20 is already an approved member. The encouraging data here were data on the new CCR5 inhibitor from GlaxoSmithKline (GSK) where preliminary pharmacokinetic data in uninfected volunteers looked promising. The drug is orally bioavailable, can be dosed infrequently, and at least in these early stage studies looks like it's safe. Schering-Plough had data on the next in their series of inhibitors, Schering D (SCH-D), which now seems to be the drug that they're taking forward that had very nice activity in treatment naive patients, and a larger study is being planned now in collaboration with the AIDS Clinical Trials Group (ACTG). And there was further data on this antibody that I mentioned, the TNX-355 antibody that now over eight weeks of therapy reproduced the results we saw with the single dose. It's a bit disappointing that we already saw evidence of resistance emerging within eight weeks. That was somewhat unexpected and means that this drug, like all others, will have to be retested in combination.

I think there's good reason to be optimistic about these drugs. It's a brand new class. For the most part, viruses are not going to be resistant. There may be shades of sensitivity in some strains. It offers us an opportunity to reconsider how we approach therapy. If we can reshuffle the deck we shouldn't feel that we're locked into a paradigm of two nucleosides and the next new drug for all time. It could be an entry inhibitor and a protease inhibitor. Could be an integrase inhibitor, if we ever see those, or an entry inhibitor followed by triple nucleoside therapy or something.

Mr. Delaney: I'm enthused about the entry inhibitors coming as a new class. I have to say I was a little surprised, though, at some of the data in that I had expected them to show a higher level of potency in these monotherapy studies. The levels of viral suppression they're reporting at this stage is about what you'd see from a good nucleoside. In fact they're almost exactly the same as one of the new nucleosides, Reverset (DD4FC) that they were also presenting. I don't know if that means that they haven't worked out the best doses yet or that's how potency is going to be and they're going to have to combine them, so there's a lot to learn about these. We don't know also yet whether they work by down-regulating the receptor, do they block the receptor, each of those might have very different consequences in terms of long-term issues. The fact that there's a new class out there and coming to fruition, I think, is very good news, but we need to learn a whole lot before we know what we're going to get out of them.

Dr. Kuritzkes: I think one thing we have to be a little cautious about, particularly with the CCR5 inhibitors, is that it's important to keep in perspective that these drugs may not be useful in all patients, because some patients have already had a transition from virus that uses CCR5 to virus that uses CXCR4, and we saw some data presented in posters here that it's pretty clear the R5 inhibitors don't block X4 virus. Patients with more advanced disease are much more likely to have an X4 virus, as you know, and that's where these other inhibitors may play a more important role.

Mr. Delaney: They may be less likely to be a salvage therapy in that sense.

Dr. Becker: Yes, the R5 inhibitors may be used further toward the beginning of therapy when virus hasn't transitioned from R5, which is the predominant, to X4 or back.

Mr. Evans: Or is there potential to perhaps combine them in some way, producing the pressure on both sides?

Mr. Delaney: I think the thing we don't know yet is, what else does the body use those receptors for? There may be some surprises ahead of us.

Dr. Becker: And clearly it also is going to require that we have the diagnostic capabilities of determining what type of virus we're dealing with. You don't want to use an R5 inhibitor if most of your virus is not R5. So that will require the development, commercialization, insurance coverage, it's a whole cascade of events that's going to have to happen for us to be able to employ these agents.

Mr. Delaney: Do you worry about whether that will ever be transferable to the developing world?

Dr. Kuritzkes: I think that's an interesting problem. I think there are a lot of unknowns there. It had been said, at least last year, that the virus that's most predominant in the developing world -- subtype C virus -- is much less likely to develop into an X4 virus, although some posters here talked about persistence of X4 virus for a long time despite treatment. I think the whole issue of technology transfer to the developing world and appropriate pricing for technology for the appropriate monitoring of HIV in therapy, is the next threshold now that we've got a general agreement that there need to be lower prices for drugs in resource-poor settings. There also have to be lower prices for diagnostic systems, and there's a lot of effort being spent through National Institutes of Health and many of the government sponsored programs to help build capacity in resource-poor settings, not just for the rollout of therapy but also for the monitoring of therapy and to develop a scientific capacity that will allow people to train others locally. Because it's clear that these Centers of Excellence in which clinical research is being done -- in Johannesburg, in Durban, in Malawi, in Uganda -- are the places that are really going to train local physicians and other health care workers to be the vanguard in the epidemic and help with the rollout of care.

Mr. Evans: I would imagine that some way of following patterns of the transmission of resistance in those countries would be important as well. As we saw at this conference there were data presented about the continuing rise and the prevalence of new infections where people have resistant mutations.

Dr. Kuritzkes: Yes, the World Health Organization (WHO) has been developing a plan to do monitoring for the emergence of resistant virus at sentinel sites and in sentinel populations as therapy becomes more available and it becomes appropriate to do that. There's already monitoring going on in Brazil and in South Africa. We've seen the studies that have looked at resistance as it's occurred in the setting of mother-to-child transmission studies in Uganda, and so forth. That's clearly going to be a central component in the rollout of antiretroviral therapy.

Dr. Becker: Yes, I was going to emphasize that point. I think the maternal-child transmission issue is about how to effect that, and it's very clear that antiretroviral therapy does effect that in a very positive way. But at the same time we have to come up with methods of doing that that does not prejudice our ability to treat either the mother or the child at some later point by engendering high rates of resistance. That's a very short-term gain, and I think that's a major challenge.

Mr. Evans: Something that may seem a little bit more esoteric for the developing world but is also all about the advancement of science, I'm wondering if there are other new drugs in development that seem particularly exciting to you?

Mr. Delaney: I don't know that there was a lot more at the conference than we've talked about. I'd say it probably had fewer new drug presentations than any meeting I've been to in the last umpteen years. But there are some that we know are in process, and maybe studies weren't ripe for presentation. There's a few new non-nucleosides that may be active in spite of the current resistance patterns. There's some second-generation protease inhibitors. There's at least one integrase inhibitor that's still in testing but somewhat mysteriously we don't get much data about it. So there are some things going on, and like I said there's one very promising new nucleoside -- I find that data kind of striking -- that Rob Murphy presented.

Dr. Kuritzkes: There was a compound presented last year by Panacos, that is a new mechanism of inhibition that they're calling a maturation inhibitor that is making its way into human studies, so there's some hope that that agent could turn out to be a novel kind of inhibitor. There are still many groups working on different aspects of entry inhibition and searching for new targets.

Dr. Becker: I agree that I didn't see a great deal, as much as some of the other conferences. Tipranavir, which is probably furthest along among the agents, there was no information. That's likely simply a function of their large trials that are fully enrolled and data that's still coming in and being analyzed. But I think the other point is, not to forget about the drugs that we have. An example of that to me is this K65R that we talked about earlier, it may be that AZT is going to be able to interdict the development or decrease the frequency of development of that mutation. I think we have to remember to use the new drugs in a sensible way, and there may be advantages from some of the old drugs, particularly when combined with some of the newer agents. It's not just a question of leaving everything behind and going on just to the next drug.

Mr. Delaney: I would be interested in your comments on this. Do we reach a saturation level, in any disease, where industry and science says, you know you've got twenty five drugs out there; enough is enough. Even if none of them is perfect.

Dr. Kuritzkes: I think it's an important question to ask. We need to set the bar appropriately high for new drugs, so we don't need a lot of "me too" drugs, we don't need another twice a day protease inhibitor that has no dramatic advantage in terms of its resistance profile or its side effects profile. We don't need a seventh or an eighth nucleoside unless it brings something really new. We do need new drugs. We need new drugs for several reasons. We're still working on simplifying therapy and trying to generate a range of options for once daily therapy of combinations of drugs. We know that resistance is going to continue to be a problem, and just as it is with antibiotics we need to try and stay two or three steps ahead of the virus, and that's always been a difficult challenge. And we need drugs that are better tolerated, and that may be the biggest challenge for us, because it's easy to screen for drugs that are active against the virus, it's easy to screen for a drug that works against a resistant virus, but it's a lot harder to screen for a drug that doesn't cause headache or nausea. So you get very far down the road into human testing before you realize, well that one really isn't all that much better and what did we spend a couple million dollars on? That's the big challenge.

Dr. Becker: Although hopefully, again, the genetic screening of individuals as drugs are developed and certainly in Phase II, I think that it's only a matter of a short period of time before regulatory agencies, such as the FDA, are going to require the genomic aspects be included in drug development, likely at Phase II. So we will be able to understand whether headaches or nausea are a routine feature of the drug, and if so let's finally decide to get on with it or we don't, or if it's confined to a certain patient population.

Dr. Kuritzkes: I think more exciting would be to be able to identify the molecular targets that cause these side effects, and we're making a bit of progress toward that in terms of the lipid abnormalities and the glucose intolerance with the protease inhibitors. We still don't have a clear idea of what actually causes the toxicity of some of these drugs. But if we could identify those and then you could design out that part of the molecule or screen new molecules to see whether they interact with it, then we'd really be on to something. Otherwise, what we do is important, but you sort of limit the pool. You say, well, we're not going to give you this drug, because it's going to cause an effect in you that it might not cause in someone else. That's useful, but unless there's something else there that is going to work, then that's a problem. Then we become like oncologists where we define this very small set of people who are going to respond to the drug, and they do well, but everybody else still has a problem.

Mr. Delaney: This is a point in the new drug discussion where I always feel compelled to say, new drugs, better drugs, all of that is terrific, but ultimately I think people with HIV really want to see a cure someday, not just lifetime expensive drug maintenance therapy. I'm a little concerned that the focus of research really isn't on that any more. You don't see many people looking at how do we make a home run here? How do we really shut down the disease process once and for all? I hope we can get some focus back on that.

Dr. Kuritzkes: I think that's an important point, and I guess the question is, is that because people have become complacent with the success that we've had with therapy? Or is it because people have become more realistic? I think there's room for debate there. I would argue that maybe our ambitions were a little too optimistic when HAART came along and the viral decay curves were all being looked at. Oh yeah. Gee, wow ... if that keeps going down maybe it's got to go to zero someday. With a virus that establishes a stable reservoir, maybe that's asking a bit much. Maybe we do need to get much more inventive, though, with gene therapy approaches and ways of basically replacing some of these immune systems. Those are going to be very expensive, very cumbersome approaches that may start off as boutique medicine. It's hard to envision, at least with current technology, how we'd translate that to a million people with HIV infection in the United States.

Mr. Delaney: But you do have to look at it. You know, the first microchip that you make in a series costs you a billion dollars these days, but about two years down the road they're fifty cents.

Dr. Becker: As long as it's not an either or, as long as they're not counter-posed. There are issues around vaccine development and microbicide development, all of these things have to occur. They'll occur, obviously, at different rates for financial and economic reasons, as well as scientific reasons.

Mr. Delaney: I don't know about you but I found this to be a pretty discouraging meeting as far as vaccines came, you know, that most of the news was pretty gloomy. Did you read it that way too?

Dr. Kuritzkes: Yeah, I would have to agree. I think that perhaps the best way of characterizing the vaccine effort to date is that we've learned an awful lot about the human immune response to HIV and we still don't know how to put it together to make a vaccine.

Dr. Becker: But I think also -- and Susan Buchbinder³ in her plenary session addressed this -- I think we have to take a historical view as well. Following the Concord trial we were certain that we had no drugs that were going to be effective against HIV, and I think that there clearly are going to be disappointing times. That's the nature of science and therapeutics. But you're right, we don't know how to do it and the first major vaccine trial, the abstract that was presented at this meeting, everybody knew the results of it from press publications of it, was a resounding failure.

Mr. Delaney: A lot of people felt they knew the results of that before it ever started.

Dr. Kuritzkes: The important issue here is really one of balance. There needs to be concerted broad-based effort on vaccine development, on understanding and trying to identify correlates of immunity and protection, and have a systematic approach to testing candidates as they come along through the usual phases of safety and immunogenicity,⁴ and when appropriate looking for hints of efficacy. But that can't be to the exclusion of other efforts, because a vaccine would be a home run but it's still a big question mark about whether it's feasible and when we might see that. In the meantime there are a lot of things we can do. We can redouble our efforts in prevention, we can do work to bring microbicides to the market or to clinical use so that we have a stopgap approach in the meantime, and treatment is an important part of that.

Mr. Delaney: I think an interesting trend that we see this year that was talked about at the conference, is that, perhaps to some degree because of the absence of a vaccine and continuing discouragement there, that we're now seeing efforts to test the use of treatment in effect as a preventive agent. We're seeing it in the Vietnamese trial with female sex workers, and in men having sex with men in Atlanta and right here in San Francisco. In some ways that's a very intriguing prospect, and it's a scary one, too.

Dr. Becker: And I think in some ways born out of the failure of our other efforts. That doesn't mean that it shouldn't be investigated. Clearly it should.

Mr. Delaney: It's coming whether we like it or not.

Mr. Evans: You have mentioned that we've learned a lot about the immune system from our attempts to work with vaccines, and I'm wondering if there have been any basic science discoveries in the last six months to a year that start to point us in some directions that look promising.

Dr. Kuritzkes: I think the most interesting basic science discoveries that have been made over the last year that were summarized at the meeting here, and were the subject of several presentations, is a better understanding of how the cell itself can protect itself against infection with HIV and other viruses. It turns out that there's an enzyme that most cells have, called APOBEC-3G,⁵ that seems to function by introducing lots and lots of mutations into viral RNA or DNA that essentially causes the virus to self-destruct. Viruses really can't go anywhere. The virus (HIV), of course, has developed a way to counteract that and to deal with that, and that's the function of the Vif protein. It seems that Vif prevents the production of APOBEC-3G or it's function, and that means there's another target for us to go after.

Mr. Delaney: I've also been following some of the immunology work that's of particular interest to us, one of the things that was striking to me was what I think is soon to be the death knell of the long-term non-progressor studies. All the things that we've thought over the years that might explain that long-term non-progression now seem not to be true, and that in fact it's just a multi-factorial situation where many things contribute to it.

Mr. Evans: I'm afraid that's all the time we have for this session. Thank you all for appearing and for sharing your insights.

Notes

1. Abstract 623: A Short-Duration, Single-Dug Interruption Determines the Activity of Individual Drugs in Patients on Failing Antiretroviral Therapy. www.retroconference.org/2004/cd/Abstract/623.htm

2. Abstract 630: The Genetic Correlates of NNRTI Hypersusceptibility in 444 Paired Isolates From Nucleoside-Experienced Subjects. www.retroconference.org/2004/cd/Abstract/630.htm

3. Plenary Session: Wednesday, February 11, 2004 -- HIV Vaccine Efficacy Trials: Lessons Learned and Future Directions, Susan Buchbinder. Available at www.retroconference.org/2004/pages/webcast.htm

4. immunogenicity: The capacity of an antigen to stimulate an immune response.

5. APOBEC3G: A human protein that interferes with the replication of HIV by incorporating itself into virus particles and damaging the genetic material of the virus. The viral protein Vif can halt this process in two ways: (1) by binding to APOBEC3G and preventing it from incorporating into virus particles; and (2) by targeting APOBEC3G for destruction and almost completely eliminating it from the cell. APOBEC3G stands for apolipoprotein B mRNA-editing enzyme, catalytic polypeptide-like 3G. MedicineNet Medical Dictionary.

Back to the Spring 2004 issue of Positives for Positives.