December 17, 2007
Dr. Eron: Great, thank you very much. Hi, this is Joe Eron. Welcome everybody who has taken the time out to listen to this presentation tonight on new antiretroviral agents. I'm going to focus on the treatment-experienced patient and try to make it case based. We'll kind of talk through a case and I'll try to show you the data as it applies to this case, but I would encourage all of you to feel free to ask questions. I also have some questions during the presentation that I'll poll you with. We can have a discussion about your answers if you like.
The first slide just starts to talk about the case. This is a 50-year-old African-American man who's been HIV positive for a little over 12 years. It's important to know that he presented with a low CD4 cell count and with Pneumocystis, and his medical history includes pancreatitis, diabetes, elevated triglycerides, high blood pressure and obesity. His treatment history includes experience with multiple nucleoside analogs. He was a victim of full-dose ritonavir back in the day. He received indinavir, saquinavir/ritonavir, and lopinavir/ritonavir. He also was treated with two NNRTIs (non-nucleoside reverse transcriptase inhibitors), not together, but over the course of his therapy and had clear virologic failure on one of the NNRTIs (nevirapine). He also received enfuvirtide for six months in 2005 and he stopped secondary to an ISR, which is an injection site reaction, but at the time he stopped he had low-level viremia.
Since January of 2005, he's been on essentially a holding regimen. He's been on atazanavir/ritonavir, tenofovir, FTC in a fixed-dose combination, and abacavir. You can see in July of 2005, his CD4 cell count was 150 with a viral load of 18,000. Then two years later, he had a decline in his CD4 cell count down to 114 and his viral load was 25,000, so up slightly but probably not much different. The most recent genotype, which was drawn around the time of the CD4 and viral load, show multiple thymidine analog mutations, including M41L, 210W, and 215Y. He also has evidence of resistance mutations to ddI, which is the 74V, and the M184V mutation, which suggests resistance to 3TC and FTC. He has two NNRTI mutations, and he has a long list of protease inhibitor mutations that kind of correlates with his long history of protease inhibitor treatment.
So I have at this point, a couple of questions for you. We'll take them one at a time.
The first question is just: Is it time to change therapy in this patient?
So I'm going to send out the poll to you and you can go ahead and tally your answer. Go ahead and click yes, no, or we need more information. That'll give us a minute or two and we'll come back with the answer. I think most of you, most of the audience, said we really need more information.
In general, I think we all feel like this patient has a low CD4 cell count. It has fallen over the past couple of years. I haven't given any information on how the patient is doing clinically, but I think all of us have the sense that it's probably time to change therapy in this patient. I think, in order to change therapy, we really need to know a little bit more information. We really need to know what our treatment options are.
So this gets us to the second question, which is: What is your realistic treatment goal for a new regimen in this patient?
So I'm going to send out the poll to you again for this question.
The first choice is to suppress VL to <50, avoid resistance, and improve CD4. The second choice is to maintain clinical stability and preserve CD4 cell count.
Don't be shy. Nobody knows who's voting; it's great, you can vote for George Bush with no guilt whatsoever.
Two-thirds of us felt like the goal is to suppress to <50 and one-third of us thought, well, maybe this patient has quite a bit of resistance so perhaps the goal is just to maintain clinical stability and preserve CD4 cell count and accept some viral replication. I think that two years ago, B was the right answer. I think now actually choice A is the correct answer and it's reflected in both the DHHS (Department of Health and Human Services) guidelines and the IAS (International AIDS Society)-USA guidelines, where really with our new agents -- and what I'm hopefully going to talk to you about -- it really is time. We are really at a point where, for even our most treatment-experienced patients, like this gentleman, we have the potential to get the viral load to <50 copies and in fact, I see it as a giant responsibility. We as HIV clinicians really have a huge responsibility to these patients to actually get it right, to get them to <50 copies, in part because of the new agents that we have available to us.
The third question in a row is: Which new protease inhibitor is likely to have activity for this patient?
And remember there was quite a long list of protease inhibitor mutations. So I'm going to send you this question and go ahead and answer it. But to be honest with you, if you gave me that long list of mutations and I had to give you the right answer I would need to actually get a little bit more information. Go ahead and vote, though. Do the best you can and we'll actually go over it and we can see what the best choice might be in this setting. We have just a few brave people that are voting so far. Go ahead and give it your best shot. Excellent! Very good. I'm going to send you out the results and you can take a look.
What you can see is that most of us thought that the darunavir/ritonavir was going to be active; and if you are real good, which you may well be, you have your IAS-USA card and you're able to count the mutations. The next biggest group thought, well, perhaps neither drug is likely to have much activity. There is certainly a long list of mutations here. Even people as smart and knowledgeable as the John Millers or Dan Kuritzkes or one of these resistance mavens I think would have trouble just looking at that list and coming up with which of these two protease inhibitors is likely to be more active. And there really are two ways to get at this and the first way is to know what mutations are associated with resistance. For each of the drugs, both tipranavir and darunavir, the investigators have worked out resistance scores, so it's essentially mutation counting. And while mutation counting may not be the most precise way to decide whether you have resistance, it actually turns out to be a pretty good way.
On this next slide, we're looking at the tipranavir score and across the top, just below the title, are the tipranavir resistance mutations and what you can see is this patient has 7 tipranavir resistance mutations. If you look at the results from the RESIST-1 and 2 studies, you can see that when a patient has 6 or 7 of these tipranavir resistance mutations, the likelihood that they're going to have a very potent antiviral effect is actually quite low and the level of resistance that they'll have to tipranavir is relatively high. There's a more recent publication from John Baxter in the Journal of Virology that suggests that in part these data are influenced quite a bit by the partner drugs that one is able to administer along with tipranavir. And in the RESIST studies, which were done earlier than some of the other data that I'll show you, the number of active partners was actually relatively low. But in this case, this patient has 7 tipranavir resistance mutations, and I think it's really not very likely that tipranavir is going to have potent activity in this patient.
What about darunavir? I think the good news about darunavir and tipranavir is they really don't have highly correlated cross-resistance. You certainly can find viruses that are cross-resistant to both tipranavir and darunavir. On the other hand, there are viruses that are pretty highly resistant to tipranavir that are sensitive to darunavir and visa versa.
On this next slide, you can see that the patient actually only has 2 darunavir resistance mutations. You can see that if you look at the bottom left-hand side of the slide -- these are from the POWER studies and it's looking at the proportion of patients that achieved a viral load of <50 copies at 24 weeks -- you can see that of patients that had no darunavir-resistance mutations, almost two-thirds of them achieved a viral load <50, whereas if they had 2 darunavir-resistance mutations, the activity was somewhat less, but still 40% were <50. If you had 3 or 4 darunavir-resistance mutations, you really saw a substantial diminution of activity. The folks who thought darunavir/ritonavir would retain activity in this patient were probably correct, at least based on counting mutations. But on the other hand, is it likely that darunavir is going to have full activity? That I'm not so sure about, because already there are the beginnings of darunavir resistance.
The next slide just shows you the data from the combined POWER studies that were presented a little bit over a year ago in Toronto. These are studies (POWER-1 and POWER-2) of highly treatment-experienced patients who were randomized to receive darunavir/ritonavir or a comparative protease inhibitor plus optimized background therapy. It was really this study that lead, to a large part, to the change in the treatment guidelines, because what you can see in this particular slide is that [among] those patients who are randomized to darunavir/ritonavir at a dose of 600/100 BID (which is the approved dose), about half the patients achieved a viral load of <50 and that viral load suppression was sustained through 48 weeks, compared to only 10% of patients who received a comparative PI. So I think what we've learned from the POWER studies and from the RESIST studies is that even in patients with substantial protease inhibitor resistance, there is the potential to get their viral load <50 copies. But I would argue that while 46% or 50% is quite good, that may not be as good as we can get it in these highly treatment-experienced patients. We can probably do better.
The next slide is two more questions, so we'll go to our poll, which I'll send out to you.
That fourth question is: What would you do at this point?
You're given four alternatives.
Go ahead and vote. Perfect; you are thinking. I'll show you the results and I'll go over them and it's a really interesting split.
So 25% of you would continue current therapy. I think at this point, depending on what drugs you have in hand, that may be the appropriate thing to do. Almost 40% of you would get more information and perhaps use novel agents and then another 40% would change to zidovudine, tenofovir/FTC, darunavir/ritonavir and enfuvirtide. And while I think in medicine there are commonly no right answers, I think that choice is probably not the best choice, because you'll remember that the patient, in his history, had experience with enfuvirtide, and while the patient stopped because of injection site reactions, the patient had a detectable viral load while on enfuvirtide.
What you can see in this next slide -- and I'm going to go back -- this is looking at the TORO studies, which were obviously done quite some time ago. This is looking at patients' enfuvirtide IC50 at baseline on the top line, which is the blue histogram. At baseline, there is a pretty good spread of enfuvirtide susceptibility. But what you can see is that patients that have a virologic rebound, detectable viral replication while on enfuvirtide (that's the lower line), you can see this dramatic shift and emergence of enfuvirtide resistance. Enfuvirtide really is a little bit like efavirenz or nevirapine, where you actually see, in patients who have virologic rebound or detectable viral replication on enfuvirtide, the likelihood that they'll develop resistance is quite high. Dan Kuritzkes and Steve Deeks have shown that even if the patient goes off enfuvirtide for weeks or months or even longer, when you reintroduce enfuvirtide then you rapidly reselect for resistant virus. So in the case of our patient, probably choice number 2 is really using one fully active agent, then partially active nucleosides and enfuvirtide -- which is likely not to provide the support you need for the darunavir.
So I'm going to go back and poll one more question and then kind of get into the new agent data.
The question is: If you now have this patient and you know you want to switch therapy but you don't know what to do precisely, what additional tests would you order? Would you order a phenotype? Would you order a tropism assay? Would you get both or neither at this point?
You are quickly voting on this one and I think we have a pretty good consensus. I'll show the results. Basically everybody would get both tests. While there may be a cost issue, there may be an access issue, in terms of your clinic. I think if you can have this information it really is quite helpful to have both a phenotype assay and a tropism assay.
Slide number 11 just reminds us that in today's world the goal, even in our most treatment-experienced patients, is to suppress the viral load to <50. While I think darunavir would have pretty good activity in this patient, I think that we probably need more than darunavir to have a high likelihood of suppressing virus in this particular patient.
If we look at the phenotype in this patient you can see that even though there are multiple TAMs, there is not a very high fold change to zidovudine (Retrovir) and that's in part because there were two AZT-sensitizing mutations (74V and the 184V). You can also see that tenofovir, despite the fact that the patient is still on tenofovir, probably still has some residual activity, and I think most of us in this next regimen would probably include a nucleoside analog. On the other hand, if you look at the conventional or the first-generation NNRTI, really there's high-level resistance with a 103N and a 181C mutation. If we look at the protease inhibitor susceptibility, I highlighted that [for] darunavir/ritonavir or Prezista, you can see the range of susceptibility. The lower cut off is 10, the upper cut off is 90, so the patient did have darunavir-resistance mutations. So the fold change is not zero, the fold change here is 7.4, but that would fall in the "fully susceptible range." On the other hand, you'll remember there were seven tipranavir (or Aptivus) mutations and while there might be partial activity of tipranavir/ritonavir in this case, the fold change is very close to that upper cut off. So those of us who were kind of guessing or counting mutations, I think that the phenotype confirms that the darunavir/ritonavir is likely to be the more active of our novel or new protease inhibitor regimens.
So this is just a summary. This is a current treatment regimen reminding you of the viral load and CD4 cell counts, and you now have maraviroc and raltegravir approved. Etravirine, which is a second-generation NNRTI, may be available to you through expanded access, though I don't know for sure. There is I think a strong likelihood that etravirine will be an approved drug some time early in 2008.
So what are the data for these new drugs? In terms of the new agents from the new classes, we have the CCR5 inhibitors and I'm going to focus on maraviroc because that's an approved drug at this point. As all of you probably know, HIV enters the CD4 cell by first binding to the CD4 receptor but then in order to enter the cell it has to bind to one or two second receptors -- either CCR5 or CXCR4. This cartoon shows you kind of a schematic of what the virus sees as it might be entering a cell. There are to my mind really two types of virus. There are really three, but I think you can lump them in two categories.
First there are the R5 viruses, and these are viruses that really utilize only the CCR5 co-receptor and back in the day these were known as the non-syncytium-inducing phenotype. These are the most frequently transmitted [type of HIV] virus. So 99% of recently or acutely infected patients are infected with R5 viruses and they're prevalent in early disease depending on when you look in the patient's treatment history.
The second group of viruses is really made up of two. They are dual-tropic viruses that can use either R5 or X4, and they're X4 viruses that can only use X4. These viruses use CXCR4 co-receptor; of course the dual-tropic viruses can use either one. These are the syncytium-inducing phenotype; they emerge later in disease in up to about half the patients. When they do emerge, they [are] associated with an accelerated CD4 decline and with disease progression. So remember these two types of virus. In early studies of maraviroc, we learned that maraviroc really does not have antiviral activity in patients who have either dual-tropic or X4 viruses. There really was no advantage or improvement in viral load over placebo when maraviroc was given to patients with dual-tropic or X4 viruses. They probably didn't cause harm and there's a question about this that's pending here, but I think that one needs to carefully think about how to use maraviroc because you want to count on it to be a fully active agent.
In the Phase III trials, which were called MOTIVATE 1 and MOTIVATE 2, these were patients that were triple-class experienced. It was a 1:2:2 randomization, so patients had a resistance test done at baseline. They were stratified by whether they were going to use enfuvirtide or not and [by] their baseline viral load. They were then randomized to receive optimized background therapy, which was selected by their investigator and their clinician, and then they were randomized [to] either placebo or 1 of 2 does of maraviroc (150 mg once daily or 150 mg twice daily). There are some subtleties about the dosing of maraviroc. These patients all had to have R5 virus by a tropism assay at baseline, so these patients had R5-only virus. It's important to remember [that when] this study was started, there was no darunavir/ritonavir available. So there was not darunavir/ritonavir in background therapy. A small proportion of patients did receive tipranavir/ritonavir.
The next slide shows you basic results of the study. These patients were highly treatment-experienced with highly resistant virus. You can see that patients who received maraviroc at either of the doses (either the QD or the BID dose) had substantial virologic suppression. Approximately 45% -- if you look at both studies, MOTIVATE 1 and MOTIVATE 2 -- had <50 copies (50c) at 24 weeks. In MOTIVATE 1, the data we [were] shown at ICAAC by J. Lalezari, if the patient suppressed to <50 at 24 weeks, then that activity was sustained out to 48 weeks. In fact MOTIVATE 2, which is on the right-hand side of the slide as you look at it, shows the 24-week data. But actually the 48-week data were also presented in the EACS meeting (the European AIDS Clinical Society meeting in Madrid) and again showed sustained activity out to 48 weeks. So maraviroc, when given to patients with R5 virus, clearly has a substantial activity. But again we're looking at around 50% or a little bit less and we're talking about trying to do better than that and I think that's where we really want to combine active agents.
The next slide gives you a clue showing you that this is the proportion of patients <50 copies at 24 weeks. This is the combined analysis of MOTIVATE 1 and MOTIVATE 2. Green is placebo, gray is maraviroc QD with an optimized background, and dark blue is maraviroc twice daily with optimized background. What you can see is, the more active drugs that are in the regimen, the more likely it is that the patient will suppress to <50 copies. With maraviroc plus two additional agents, you get up around the 50% range. Having three or more active agents, you don't see a dramatic improvement in response so the overall response is now closer to 60%. Some people have taken this to mean that really all you need is three active agents in treatment-experienced patients. That's probably correct. Though I worry a little bit about, if 60% are <50, that means 40% are not <50 and those that are not <0, those patients are at risk for selecting for a dual-tropic or X4 virus.
So how often is maraviroc going to be useful in our highly treatment-experienced patients? These are data on coreceptor prevalence from a variety of different studies. The top three studies are in treatment-naive patients. You can see that roughly 80% to almost 90% of patients who are treatment naive have R5-only virus by the tropism assay. On the other hand, if you look at more and more experienced patients, the likelihood that patients will have R5-only virus declines. Then [in] the highly treatment-experienced patients, it's around 50% [who] will have R5-only virus. I think a really important point is that, like every test, the tropism assay is not perfect. The tropism assay that was used in this particular study misclassifies patients probably somewhere between 5% and 10% of the time. So in other words, they'll be determined to be R5 on one tropism assay. Then you'll repeat that same assay four weeks later and [the results will be different.] About 5% of the patients in the MOTIVATE study actually had a switch or an emergence of X4 dual-tropic virus -- what we called dual/mixed virus -- before they ever experienced any maraviroc therapy. So this current assay probably miscategorizes patients because of minority variance about 5% to 10% of the time. A newer version of the assay that's coming online is more sensitive and is less likely to misclassify patients.
So what about the integrase inhibitors? There are two integrase inhibitors: raltegravir, which was recently approved, and elvitegravir, which is still in development. I'm going to focus on raltegravir (which is also known as Isentress).
HIV integration is a multi-step process. Obviously there's viral DNA synthesis by the reverse transcriptase. That viral DNA moves into the nucleus and the DNA has to be integrated into the human chromosome in order for the virus to complete its life cycle. If the virus doesn't integrate, it doesn't replicate and the important step in integration is the strand transfer. It was Daria Hazuda and her colleagues at Merck that demonstrated clearly that if you inhibit strand transfer, you can inhibit integration and if you inhibit strand transfer, you end up with an active antiretroviral agent. In fact, all of the integrase inhibitors that are in development, either in clinical development or in preclinical development, the effective ones right now are all strand transfer inhibitors and raltegravir is a strand transfer inhibitor.
What are the data on raltegravir? Well there are two studies, BENCHMRK 1 and BENCHMRK 2, and you might see there's a trend here. We have TORO 1, TORO 2, RESIST 1, RESIST 2, POWER 1, POWER 2 and then we just saw MOTIVATE 1, MOTIVATE 2. Well this is BENCHMRK 1 and BENCHMRK 2 and this was raltegravir in highly treatment-experienced patients. The patients had to be triple-class resistant. They had to have a viral load >100,000. They had a resistance test at baseline, which was a Phenosense GT so they got both phenotype and genotype. Investigators were then allowed to pick optimized background and then patients were randomized 2:1. So twice as many patients received raltegravir at 400 mg twice daily compared to placebo. If darunavir/ritonavir was available, [these patients] could receive darunavir/ritonavir in this particular study. The BENCHMRK study really, for our highly treatment-experienced patients, I think sets the bar for getting patients to <50c. You can see now in the 24-week data we presented at the EACS meeting in Madrid just a month and a half ago or so, basically a little over 60% of patients in the two studies were <50c at 24 weeks. This is the kind of result you know we saw in the original treatment-naive studies when we were first using triple-combination therapy. So with raltegravir we have a very, very active drug that contributes to suppression in these highly treatment-experienced patients. I think the other important point here is that raltegravir is likely to be active against really any virus in our patients, provided that they're integrase inhibitor naive. Again, the same lesson comes across in the BENCHMRK study.
This is looking at the proportion of patients responding based on the number of active agents in addition to raltegravir. Now this is looking at <400c (400 copies) not <50c at week 16, but data have now been presented with the <50c assay at 24 weeks and if you just go to the GSS [genotypic susceptibility score], you can see that a GSS of zero means there were no fully active agents in the background and you say, wow, 57% were <400c at 16 weeks. That's terrific but again, that means that 43% [were >400c]. On the other hand, if there were two or more active agents in the background, then almost 90% of patients were <400c at 16 weeks. If patients received raltegravir, darunavir/ritonavir and T-20, then 98% (43/44) were <400c at 16 weeks. So not a big number of patients, but really, a very impressive result if we combine fully active agents.
This next slide looks at the <50c result in patients who received enfuvirtide and darunavir and raltegravir. So that would be the green line in the second set of histogram bars as you move down the slide. You can see at 16 weeks, almost 90% of patients that received raltegravir, enfuvirtide, and darunavir -- so three fully active agents, these were patients who were naive to enfuvirtide and naive to darunavir -- [were <50c]. You're really getting up there, 90% <50, and that's really what our goal should be. If patients used either only enfuvirtide or only darunavir, you can see it's more like 70%. Again, a good number but we can do better. If they use neither enfuvirtide nor darunavir with raltegravir, you see a greater difference between placebo and raltegravir, but the proportion <50 goes down to 61%. So again, emphasizing the importance of combining multiple active agents.
On this next slide -- really, I think it's perhaps one of the most important slides --it's not projecting perfectly here but this has to do with integrase inhibitor resistance and the first two bars are for raltegravir. The first bar is from the Phase II study and what it's telling you is that there were 38 patients who in the Phase II study had a rebound in viral load while on raltegravir. The investigators were able to do an integrase genotype. What you can see is that 35/38 developed integrase inhibitor resistance. The second bar is for the BENCHMRK studies. There were 47 patients that had virologic failure at the time of this analysis; 41 had genotype available, and again 32/41 or 75% had integrase inhibitor resistance. I think the really important point here is that while raltegravir is a potent drug that leads to suppression, especially when combined with other active agents, in our treatment-experienced patients, if we choose wrong -- if we don't fully suppress the virus -- then the likelihood that that virus will acquire integrase inhibitor resistance is actually relatively high. Most of the patients have multiple mutations so you can argue whether there's a low barrier or a high barrier to resistance. Most actually have more than one mutation, but the point is if you have rebound on raltegravir it is likely that you'll see integrase inhibitor resistance.
Then the next slide is looking at elvitegravir and raltegravir. These are in vitro assays but basically [they are] showing you that, if a patient's virus develops resistance to raltegravir, the likelihood that that virus will be cross-resistant to elvitegravir is actually pretty high. So unfortunately it looks like there is at least a substantial risk of cross-resistance among the integrase inhibitors that are currently either approved or in development. The red bars along the front are a Merck integrase inhibitor that's in preclinical development. So it hasn't yet been given to humans.
So my final set of slides, before we get to our last question, is dealing with etravirine. Etravirine is a new drug in an old class. Etravirine is an NNRTI and again there were two studies, DUET-1 and DUET-2. Much like the BENCHMRK and MOTIVATE studies, these were very highly treatment-experienced patients. In fact, these patients had to have three or more primary PI-resistance mutations. So these are the most resistant patients that have been studied to date and these patients also had to have at least one NNRTI mutation either at screening or documented in a previous genotype. There were 600 patients per trial so when looking at combined analysis we're talking about 600 patients per treatment arm. The 48-week study with an extended follow-up, the primary endpoint was at 24 weeks and the primary endpoint was the proportion of patients <50c.
In this next slide these are the combined endpoints for both studies. You can see a statistically significant and I think important increase in the proportion of patients <50c -- again, we're getting up to about 60% of patients <50c at 24 weeks. The 48-week data will likely be presented at CROI (Conference on Retroviruses and Opportunistic Infections). In this particular study, all of the patients received darunavir/ritonavir. Half of the patients received etravirine or TMC125, the other half received a placebo and you can see the placebo arm, you know 41% <50, is very similar to the POWER study that we started this presentation out with.
So clearly, etravirine adds a substantial benefit, and again kind of beating the point across, if you add additional active agents. I'm sorry that the slide didn't come through as well as it should have. This is PSS (phenotypic sensitivity score), so the top bars are PSS of zero, so zero fully active agents. The second is a PSS of 1 and the third is a PSS of 2 or greater and what you can see again, this incremental increase. Where you have at least three active drugs in the regimen -- so etravirine plus at least two other active drugs -- you're getting up to 70%, almost 75% of patients, <50c and that is really the goal for our treatment-experienced patients.
What about resistance to etravirine? There are mutations associated with etravirine resistance. Some of them are familiar to you. For example, Y181C is a relatively common NNRTI-resistance mutation. G190A is also a relatively common resistance mutation. What you can see is, if there are no etravirine-resistance mutations at baseline, then the proportion of patients that get <50c is upwards of 70%. You really don't see a dramatic decrease in activity until there are three or more etravirine-resistance mutations. So I think again, because this is a new drug in an old class, there is some risk of cross-resistance. Right now we're stuck counting mutations. We don't have phenotypic cutoffs yet for etravirine. It's important if you're already using etravirine as expanded access that you know these mutations and that you keep in mind that the presence of certainly two or three or more of these mutations are going to diminish etravirine activity to some extent.
Let's go back to our patient; we have our last question here. So remember, [we're discussing a] highly treatment-experienced [patient] on a holding regimen that includes tenofovir. Remember that tenofovir on phenotype anyway was shown to still have some activity. You now have both maraviroc and raltegravir approved and available to you. Etravirine may be available to you through expanded access and is likely, I think, to be approved in the next couple of months or so. Our resistance summary, you remember that there's a five-fold increase in IC50 to darunavir. That is below the lower cutoff, so darunavir is likely to have full activity or nearly full activity. Tipranavir, however, the fold change is a little bit above 7, so tipranavir is not likely to have substantial activity. Zidovudine was just above the resistance cutoff. The patient is enfuvirtide-experienced and the tropism assay in this particular patient shows dual/mixed virus.
So my last slide is our final question, which is: Well, what are you going to do?
So I'm going to send you out the poll and you can vote. What regimen would you choose for this patient? Look at the choices carefully. So you could use raltegravir plus 2 or 3 nukes. You could use raltegravir plus darunavir plus 2 or 3 nukes. Raltegravir, darunavir, and enfuvirtide. Raltegravir, darunavir, and maraviroc, or raltegravir, darunavir, and etravirine and if you don't have etravirine available you're actually going to choose to wait. So if any of you are still out there, go ahead and vote. Don't be shy; go ahead and pick an answer. Great. I'm going to send you these results and I think either I've done a good job or you didn't really need this talk.
Basically, I think you got the message. Almost 30% would choose raltegravir, which would be fully active; darunavir, which would be fully active; and 2 or 3 NRTIs. In this case tenofovir is likely to have activity, 3TC or FTC probably has some residual activity so I think that's a very reasonable choice. The majority of you, and I would fall in with the pink people, are either going to use raltegravir, darunavir, and etravirine even if it means waiting for etravirine and it may be kind of overkill. Do we really need to add that third active agent? There's no study that can answer that study right now, there's no data that I can point to, to say you must do this, but I think the thing that concerns me a tiny bit is there are a couple of darunavir-resistance mutations. Again the fold change is less than 10, which is the lower cutoff but it's not 1, it's 7; so there is some decreased susceptibility to darunavir. If this were my patient, I would probably use darunavir, raltegravir, etravirine and I would probably go with at least two nucleosides, tenofovir, FTC, or maybe even tossing in zidovudine. You could argue, God you're going to break the bank Eron, maybe that's a little bit too much. But I think if we undertreat -- if we say, oh well I'll just go with a couple of active agents here plus nucleosides -- the risk is that if you don't get the patient below detectable they will select for integrase inhibitor resistance and then your treatment options will be quite limited. I think that while there are drugs in development -- there's elvitegravir, there's vicriviroc -- those drugs are probably not going to add a lot to raltegravir and maraviroc. They'll add treatment options but they're unlikely to salvage patients who fail raltegravir or maraviroc.
So now I think we can open the questions. You can type in questions if you like or I think the operator can open the line so you can ask questions if you like.
There is a question, it reads: This afternoon, Dr. Bartlett suggested that maraviroc, even if used in mixed or X4-tropic virus, shouldn't cause harm. He suggested that X4 tropism is the result of disease progression, not the cause.
Do I agree? Well I agree that when maraviroc was given to patients that had X4 virus, then we didn't see a dramatic fall in CD4 cell count. In the MOTIVATE studies [in] patients who didn't suppress, about 2/3 of them had emergence of X4 virus. When that X4 virus emerged, those patients did not have a dramatic fall in CD4 cell count. So you didn't see this precipitous decline in CD4 cell count. So I think that maraviroc didn't cause any harm in those patients. On the other hand though, if you're counting on maraviroc to be a fully active agent and let's say you're pairing it up with raltegravir, unless the patient has R5 virus, maraviroc is not going to have full activity. While you might not cause any harm if you don't get the antiviral activity of maraviroc, you may be leaving your raltegravir or darunavir essentially kind of out in the breeze and run the risk of selecting for integrase inhibitor resistance or further protease inhibitor resistance. In terms of the second part of this question, is X4 virus the result of the disease progression or does it cause disease progression? I think the jury is still out on that one. I think it's different selecting for X4 with an R5 inhibitor than actually having X4 emerge. I'm not sure of the answer there; I don't think we have enough data yet.
There's another question that just came in that asks: Is it reasonable to use raltegravir after a triple failure?
I think that's also a good question. I think the kind of wimpy answer is well, we don't have any data so I don't really know. But I think the alternative answer is that if paired with appropriate active agents, it's likely that raltegravir will be a well tolerated and very active second-line therapy. It has some advantages; there really are no negative effects of raltegravir. On the other hand there's some disadvantages. It's a twice-daily drug; it's not a once-daily drug. I think [that] given what we know about the pharmacokinetics at least at this point, it's really going to stay a twice-daily drug in the foreseeable future. While atazanavir boosts raltegravir levels to a modest degree, it really doesn't boost them enough to turn raltegravir into a once-daily drug. So I think it's reasonable to consider it and you have to balance the risks and benefits. I didn't really talk about the side effect profile of raltegravir or maraviroc or etravirine. In the MOTIVATE studies, there really were very few differences between maraviroc and placebo in terms of lab or clinical toxicity. Really the same for raltegravir -- very few differences between placebo and raltegravir in the BENCHMRK studies. In the DUET studies, the main problem was that etravirine is associated with a rash. In general, it's typically a mild rash.
Then there's one more question that says: Given the cost of the tropism assay, how would you recommend clinicians use maraviroc in practice?
This probably should be our last question because we are running out of time. I really think at this point maraviroc is a drug that will be used predominantly in highly treatment-experienced patients where you really are trying your best to construct an active regimen in patients that have limited treatment options. I think while maraviroc may be a useful drug kind of earlier in the treatment sequence, as yet we don't have data to fully support that so I think that maraviroc is predominately going to be used in more advanced patients.
Is it known whether or raltegravir, etravirine, or maraviroc cause fat accumulation or lipoatrophy?
I don't think we have all the data yet on that. I don't know of specific kind of DXA studies that have been carried out. It seems unlikely that they're going to be associated with either fat accumulation or lipoatrophy but I don't think we have all the data yet to answer that question.
So I think I better close now. I appreciate everybody taking time in their evening to listen to the talk and I know you can also listen to it again online if you want and I really appreciate your time. Thank you.
Moderator: Thank you. Ladies and gentleman, this concludes today's teleconference. Thank you for your participation.
This presentation was also webcast on Dec. 17, 2007 and Dec. 18, 2007.
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