With respect to M184V and K103N, should physicians be trying to maintain these "beneficial" mutations?
Moderator: OK, why don’t we move on, since Charles is on, and Mark, and Mark’s got to catch a plane here. Let’s move on to the second one, which touches on much the same thing. And this actually has to do with the issue of viral fitness and specific mutations. And this is actually one that I put out here, obviously because of the controversial area. And that is, that virtually every single company has their own favorite mutation that their drug selects for, that somehow impairs the virus, and therefore, this is a beneficial thing.
And it almost reminds of the Democratic and Republican parties, is that, nothing is bad, it’s just a matter of how you look at it. That somehow, resistance to your drug is a good thing now. So, the question is, what is a clinician supposed to do for Mark, you’ve spent a lot of time dealing with 184. Others have looked at K103N. These mutations certainly are not beneficial to the virus since they would be there a while if they were, but they are beneficial to the virus in the presence of drug pressure. So what’s a physician supposed to do? Are they supposed to try to maintain these "harmful" mutations, or is? Mark why don’t you go first cause you’ve got a lot of experience with 184.
Mark Wainberg: Well I think it’s a bit unfair to tie, to lump all of these mutations, K103N, D30N, and M184V into the same bread basket. I think there really is a tremendous amount of work that’s been done on M184V that has taught us, from a mechanistic standpoint, not only that it is a mutation that impairs fitness, but that has also taught us, mechanistically, how it impairs fitness. We have not, I don’t believe, achieved the same level of understanding in regard to the other mutations that we’re going to talk about.
So while I fully accept that there may be parallels, I don’t think our knowledge base thus far, in regard to the other mutations, is a high as where we are with 184V. I, as you know, would articulate that for 184V, we have the most compelling evidence in regard to all of the mutations, that it can confer benefit under drug pressure, at least for a while. Putting in the caveat ‘at least for a while’.
And therefore, again, within that caveat, I would argue that we should try to maintain that mutation once it appears, although, as you’ve heard me say before, I think one can certainly discuss what the best means might be to keep the 184V mutation in place. I don’t think we’re really there in regard to the other mutations. I know about the data with regard to nevirapine and efavirenz, for example, and why you know, if you get a 103N you could still benefit from Sustiva, but I think that’s still a lot more conjecture and does not translate in the same way into considerations of fitness, in the manner that our 184V hypothesis, or I should say, the 184V hypothesis does.
Moderator: Mark, I want to come back to actually something that Bob Shafer mentioned earlier, and that is, this again is meant to be provocative. In Diane Havlir’s report, the single most common mutation associated with low level viral replication and detection in the plasma, was the single 184 mutation.
So, I mean, if you were to argue that its presence somehow made AZT even better than it way, I mean, it should be, you shouldn’t detect it at all, isn’t that true?
Mark Wainberg: Well, except that we know, the fact that it may impact on fitness and so forth because of it’s position within the active site of the enzyme is one consideration. At the same time, we all know that it’s a single mutation that confers extremely high level resistance, so it has you know, among the lowest genetic barrier of any of the mutations we know about, and that’s the reason that it’s seen so often in studies like Diane [Havlir]’s. I don’t think there’s a contradiction there.
Charles Boucher: I think, referring to the 184, I think there are other reasons to keep the 184 mutation. I think the main reason to work with the 184 is that it delays replication capacity.
I mean, one of the main reasons to keep 184, is that it neutralizes some of the AZT mutations. I think if you talk about fitness, you have to define your fitness, and I assume you all talk about replication capacity. I mean, at least Mark talked about replication, right?
I think as soon as you start to talk to mutations, then I assume you’re option of taking is not complete…?
OK, that, I would almost drive your decisions by RNA and CD4. And to keep or select a specific mutation is really of third importance.
David Katzenstein: I think Charles is hitting on a very important point, which is the clinicians are making their decisions and I certainly, when seeing patients make my decisions based on, primarily for and secondarily RNA, but if someone is doing well from a clinical as well as immunologic point of view, it’s resistant virus, I assume that this represents the advantage of resistance providing decreased fitness and I think many of us, looking at Steven Deeks’ data, as well as Veronica Miller’s, see clear evidence that highly resistant virus may be less fit. Now Charles has done the definitive in studies with Monique [Nijhuis] and some protease inhibitors, to show that can in fact be demonstrated. How clinicians are functioning, I think, is it’s very important for us to keep people from jumping the gun at low virus loads, by switching to multiple new drug regimens when in fact, we don’t have good evidence that that continued pursuit of the goal of complete suppression, ultimately does the patient the most good.
Jonathan Schapiro: Right, sorry, Dave, but didn’t Monique [Nijhuis]’s data actually show that the virus actually compensated and became replicating again very well?
David Katzenstein: Over time.
Charles Boucher: That’s also what [Steven] Deeks is seeing now in the protease. If you give him two years, then ultimately they’re back to the baseline replication capacity.
Man: Or more, right?
Charles Boucher: More is still to be definitely proven. But at least as good as the…
Moderator: Yes, I’ve got a healthy respect for the virus. I mean I’ve seen innumerable numbers of mutations, and the virus seems to be able to replicate just fine.
Jonathan Schapiro: Can I give two bits about the protease inhibitors? Cause we mentioned, regarding the 30 mutation, I think this is very important, because I think some of the data which comes out, we jump from an isolated snapshot observation to making a clinical decision. I think you gave the example of the 30 mutation, which is very good. Because multiple studies will show that when a patient is failing, it is good to have a 30 mutation. We’ve seen those studies and I think they’re true, that if you take a snapshot of a patient given the first protease, and you want to give a second protease regimen, be it a single or a dual protease, having the 30 mutation of that specific time point is a good prognostic marker.
Now, that’s taken and translated into saying, let’s start with a drug which will do for the 30 mutation. And I think that is wrong. That’s the problem, because we cannot make that fit. I think to say that had you started back there, with different drug or combination of drugs, ultimately the ultimate clinical out point may actually be better than starting with nelfinavir and then developing the 30 mutation.
So I would caution that it’s very easy to show data and then give interpretations with actually no data to support them. So I would say that it’s better not to have a 30 mutation. I don’t even know if it’s better to start with nelfinavir, develop a 30 and then have another shot, or from the very start, go with a more potent regimen, then true, if you fail it, you may have more and worse mutations, but it may be you have less chance of failing it, so it might be a better clinical decision.
So I think it’s very important to tease out from the specific resistance observations what clinical relevance they have, and I think we have to be very, very careful about it. My, I would say my rule of thumb is that the patients are bad, and some may be worse, and some might be less bad, but there may be reasons for that. And one of the reasons often is, the mutations which are more weak or easier to deal with, are generated by drugs which are weaker.
Moderator: Right. I think that’s a really good point, Jonathan, because I’ll tell you that it’s been my impression that clinicians are doing exactly what David and Charles were concerned about, and that is, they look at it, and they say, OK, I need to choose a new drug regimen, and because there’s 184 present, I’m going to continue to choose a drug that selects for 184 when that may not in fact be the best regimen for the patient. A more fully suppressive regimen which uses some other drug might actually be better than going with, making an attempt to maintain 184. So, it may be that 184 helps you, but how that is relative to choosing an entirely new regimen and your other options, really needs to be taken into consideration when we do that. OK, let’s move on.
Mark Wainberg: Let’s also agree then, that if a mutation ever does confer a so-called ‘benefit’, that kind of secondary benefit is something that we would not regard as a priority. We want to use drugs for their intended purpose as antivirals, not for a secondary purpose like keeping a mutation in place.
Moderator: I agree, and you know, I mean I keep trying to get across to doctors that mutations are never valuable. You want to give drugs that don’t select for mutations, period.
Mark Wainberg: If you have all the options.
Moderator: That’s exactly right. I mean, if a mutation was beneficial, it would be wild.
