The Basics on Maraviroc: An Interview With Joel Gallant, M.D., M.P.H.
August 6, 2007
It's been a year since the United States approved a new HIV medication, and four long years since we witnessed the birth of a whole new class of meds. But on Aug. 6, 2007, the U.S. Food and Drug Administration [FDA] gave the green light to maraviroc, which will be known by the brand name Selzentry. Maraviroc is the first in a new class of HIV meds known as CCR5 inhibitors. Maraviroc works in a fundamentally different way from every HIV med that has come before it -- and before you can even take it, you'll have to take a special blood test to determine whether maraviroc will even work against your HIV.
Which HIV-positive people stand to benefit the most from maraviroc? How can you know if maraviroc's a good fit for you? To get the answers to these questions, we spoke with Dr. Joel Gallant, a professor of medicine and epidemiology at the Johns Hopkins University School of Medicine and one of the leading HIV specialists in the United States.
So, we've got a new drug! What is it that makes maraviroc so special?
Well, first of all, it's the first oral entry inhibitor. An entry inhibitor is a drug that keeps HIV from getting into the cell. The only entry inhibitor we have had so far has been enfuvirtide, also known as T-20, or Fuzeon. But that's an injectable entry inhibitor. So [maraviroc] is the first one that's available by mouth. It's also the first in a class of what are known as CCR5 inhibitors, or chemokine antagonists. There are a lot of different names that are used for this class of drugs. But the idea is that the HIV virus first binds to the CD4 receptor that we're all familiar with. But then it has to bind to a coreceptor, or a chemokine, that's also on the surface of the cell. There are two coreceptors: CCR5 and CXCR4. Some virus uses CCR5 and some virus uses CXCR4, and some virus can use both. What maraviroc does is it blocks binding of the virus to the CCR5 coreceptor, so that prevents the virus from getting into the cell. It's the first oral entry inhibitor, and the first in a class of CCR5 inhibitors.
You had mentioned that it was an entry inhibitor like Fuzeon. But how is it different from Fuzeon?
Well, Fuzeon is an entry inhibitor, but entry inhibitors -- that's a pretty broad class, because there are several stages of entry. So the first step is binding to the CD4 receptor. The second step is binding to the coreceptor, or the CCR5, in this case. Then the third step is fusion, which means that the surface of the virus fuses with the membrane of the CD4 cell, and that lets the RNA inside the virus get into the cell.
Fuzeon inhibits that last step, the fusion step. So the CCR5 inhibitor is acting at the previous step. So although they both prevent entry, they do it in completely different ways.
So that takes care of the technical stuff. Now let's get down to the practical, brass tacks. What type of HIV-positive person is going to benefit the most from this drug?
This is an interesting question. Unfortunately, because of the way it works, we can't get away completely from the technical stuff. This drug is really unique among other HIV drugs, in that it's not going to work for everybody's virus. That's not because of resistance, but because of what we call "tropism."
As I mentioned before, some virus gets in through the CCR5 coreceptor, and that virus would be blocked by maraviroc. Some virus gets in through the CXCR4 receptor, and that virus would not be blocked by maraviroc. Then you can have virus that is either a mixture of the two, or individual virus particles that get in through both coreceptors.
Now, the only people who are going to benefit from maraviroc are people whose viral population is entirely composed of virus that gets in through CCR5 -- we call that R5 virus. To know if you have R5 virus, you have to do a test called a tropism assay. This is something new. We have never had a drug before where you had to do a special test just to find out if that drug was going to work. As it turns out, people generally start out with R5 virus, but as things progress -- as their CD4 declines, or as they get more experienced with HIV drugs -- there comes a time when they begin to get some X4-tropic virus, and they have a mixture of the two. So people who are going to benefit from this drug are the ones who haven't had that shift yet in tropism; they still have R5-tropic virus.
It gets tricky because, as I said, you are most likely to have R5-tropic virus when you have a fairly high CD4, or you haven't been treated with very many drugs before. But those are also the people who have lots of good options among the drugs we already have. And they are probably not the ones who are going to want to use this drug right away.
So the people who are most likely to want to use the drug are the people who are like the ones that were in the trial that got it approved: the MOTIVATE trials. And those are people who already had a lot of resistance to other classes of drugs. But about half of those people don't qualify for the drug because they have X4-tropic virus.
So it's a bit of a catch-22. And that's what makes this drug exciting, but also complex. There is a layer of complexity that we don't have with the other drugs.
It definitely sounds that way. You said that about half the people who have a lot of drug resistance, those who tried to enroll in the trials on maraviroc, were unable to take the drug because they didn't have that CCR5-tropic virus. What's the percentage for people who haven't been on treatment yet?
First, let me just say: We don't know whether it has more to do with your CD4 cell count, or how much treatment experience you have. But regardless: Let's say you're somebody who's got a reasonably good CD4 count. You've never been on treatment. Then your chances of having R5 virus and being a candidate for this drug would be more like 85 percent or so. Of course, there is a lot of variation in between, just depending on how long you have been infected, and that kind of thing. But you can see it makes a big difference.
But this drug is only approved for people who are drug resistant, right?
Right. For now, that's all you would really want, the only type of person you would want to use it in. After all, this is a new class of drugs. It acts on the immune system, rather than directly on the virus, so there are long-term safety issues we don't understand yet. You have to do this expensive test before you can use it. It's not a drug that we would want to rush to use early on, until we have longer-term data -- especially when we have so many great options for people who are starting therapy for the first time, options that have been tried and true and used over the years. So, even though there are theoretical reasons why you would want to use it early, practically it wouldn't make sense to do that until we have more studies.
OK. So tell me about this expensive test, then, that people who are heavily drug resistant would need to take before they take maraviroc.
Well, anybody would need to take it. But of course, mostly it will be heavily treatment-experienced patients. The generic name is just called a tropism assay, but right now there's just one version of it. It's called the Trofile assay; it's the brand name, from Monogram Biosciences. It's a test that simply looks at your virus and tells you three possible options. It could be that you have R5 virus, that you have X4 virus, or that you have what we call "dual or mixed" virus.
The reason that we call it dual or mixed virus is because the test can't tell the difference between a single virus particle that can get in through both coreceptors, or a mixture of R5- and X4-tropic virus. So we just call it dual/mixed. Very few people have pure X4 virus. So most people are going to either be R5 or they are going to be dual/mixed. So that's what the test tells you.
It's a pretty accurate test, but it's kind of like resistance testing in that it can be wrong some of the time. For example, in the studies that led to the approval of maraviroc, everybody had to have the test when they were screening to participate in the study. The people who had dual/mixed or X4 virus got excluded from the study. But everybody who had R5 virus was able to enter in the study. But then they did one more test on the first day of treatment. They actually found that about 8 percent of the people showed that they had R5 at the time of screening, but at the time of starting the drug, they actually had some X4. It's probably not because their virus changed, but just because the test -- if there's a small amount of X4 present -- the test could miss it.
It's a very accurate test, but it's not 100 percent sensitive. Just like a resistance test: If you have a small amount of virus that is atypical, it may not pick that up.
If I'm a patient who has gone through four or five regimens now, and I'm looking for a drug that's going to work, would I take the tropism test at the same time I take another resistance test, before I switch regimens?
You certainly could. You need both bits of information. So you could do the tropism test, and you could do a resistance test, and then determine what your next regimen would be, based on both results. Because they are both very important, and they are both equally important, if you're going to be considering using this drug.
So this drug works almost exclusively on people who have this R5-tropic virus.
Yes. It's not to say that it's the end of the world if you should take it and you actually have dual/mixed-tropic virus. There had been some concern early on that this could be a real dangerous thing, to take this drug or this class of drugs if you have a mixture. The reason they were worried about that was because we know that people who switch from R5 to X4 virus tend to progress more rapidly after they switch -- their CD4 goes down faster. The thought was [that] maybe X4 virus is stronger, or more damaging to the immune system.
The concern was that if you gave maraviroc to somebody who had dual- or mixed-tropic virus, you'd suppress all their R5 virus and you'd leave only their X4 virus, which could be more dangerous. They have now done studies where they have given it to people who had mixed populations, and they didn't find that bad things happened to them. Their CD4 didn't go down.
On the other hand, remember that when you're taking a combination of HIV medications, you need for all of them to work to prevent resistance from developing. So the risk is that if you took maraviroc with a dual or mixed population, then the maraviroc is only treating some of your virus. That leaves the other virus to potentially become resistant to the other drugs in your combination. So that's the real safety concern -- not so much that it's going to breed this nasty virus.
While we're on the subject of safety, let's talk side effects, since that's a major concern for anybody who is taking HIV medications. Maraviroc is a member of a class of drugs that has had a little bit of trouble getting through the development pipeline, because of various issues with side effects. During the lead-in to the drug's approval, there were a lot of concerns raised about different kinds of side effects that it might, or might not, cause. What does the actual data show on that?
The biggest studies are these two MOTIVATE trials that have hundreds of patients in them. Frankly, the drug looked very well tolerated in those studies. In fact, there really wasn't much of a difference between people who got maraviroc and people who got placebo. There had been concerns from an earlier CCR5 study, with a drug called aplaviroc [also known as GSK873140], where there was some serious liver toxicity. The development of that drug actually got stopped. But that doesn't appear to be the case with [maraviroc]. There really doesn't appear to be much in the way of liver problems.
There had also been some concerns with another CCR5 inhibitor that's in development now, vicriviroc [also known as SCH 417690 or SCH-D] -- they all sound like Flintstones medicines to me, with the "roc" at the end -- but the vicriviroc study showed that there was a surprising number of cancers in the people who took vicriviroc. However, the cancers were all different kinds of cancers, so it's kind of hard to say that it was causing this cancer. So far, the FDA doesn't feel that these cancers are necessarily drug related, and has not stopped the studies of this drug. But suffice it to say that that hasn't been seen with maraviroc.
So, so far, it looks good. But of course, with any drug in a brand new class of drugs, with an entirely new mechanism of action, we're going to need to see long-term data to be absolutely certain.
Of the data that's available so far, how long have people been on the drug?
The MOTIVATE trials that were presented in Los Angeles, at the CROI [14th Conference on Retroviruses and Opportunistic Infections] meeting, had data up to 24 weeks. Now, there have been earlier studies with longer-term data, but of course, they have much smaller patient numbers.
Is 24 weeks normal for the amount of time that a drug is studied before it gets approved?
Well, 24 weeks can be used for accelerated [FDA] approval. Of course, the data that were presented in Los Angeles were 24-week data, but subsequently, more data have accumulated. And the FDA will undoubtedly have been privy to more data than just what was presented in L.A.
OK. So, liver looks OK. Cancer looks OK. What about some of the problems that, for better or for worse, have become very strongly associated -- if not in fact, at least in the minds of a lot of people -- with HIV medications? Lipid-related problems, cardiovascular issues, fat changes: Is there any sign that maraviroc might cause any of those problems?
Of course, fat changes like lipoatrophy -- fat loss -- take a long time to develop, and you wouldn't necessarily see signs of that this early. Although as far as lipoatrophy and fat loss [go], we're pretty convinced right now that this is due to mitochondrial toxicity from the thymidine analogs, AZT [Retrovir, zidovudine] and d4T [Zerit, stavudine], and we really haven't seen it with other drugs in other classes. So there's not really a reason to think that would happen here.
In some of the studies of maraviroc, there has been at least a kind of suggestion that maybe it could increase cholesterol a little bit. It's way too early to say whether that could also cause fat gain, although there are a lot of questions, even today, about whether any of the HIV drugs specifically cause fat gain or whether it's sort of a secondary phenomenon, due to improved immune status and improved overall health.
Maraviroc doesn't appear to be a drug that's going to have a big increase in that kind of risk. There is one side effect that is sort of unique to maraviroc, at least if you use higher doses than what are going to be used in clinical process. That is what's called postural hypotension, which means that when you're lying down and then you suddenly stand up, your blood pressure drops and you get dizzy. That's seen when you use high doses of this drug. But in the clinical trials, that hasn't been a big problem.
Then there was some suggestion in some of the early studies of maybe a little bit of an increase in things like thrush or herpes, but [it's] pretty hard to say -- it certainly wasn't a striking difference between maraviroc users and placebo users. So it's not something that I'm too concerned about.
In sum then, it sounds by and large like things are pretty much looking OK. But it's still sort of -- what? A "wait and see"?
Yes, I think we have to see. And that's why we're not going to be rushing to use these in people who have other options. You know, it's interesting because this drug is blocking CCR5, which is part of our immune system. None of our other HIV drugs do that; they all act on the virus or parts of the viral life cycle, but they're not acting on aspects of our immune system that might be necessary.
Fortunately, we actually have a human model of CCR5 depletion. There are people who are genetically lacking in this CCR5 coreceptor. We believe that the reason for that is because, for whatever reason, not having that coreceptor helped protect people from the bubonic plague during the plague years -- the Black Death epidemic during the Middle Ages. So there was sort of a selection of people who had that deletion, especially in Northern Europe. Those people seem to live perfectly normal lives, without much in the way of medical problems, despite not having that coreceptor.
So it gives us at least some reassurance that you can do OK without that coreceptor. But of course, blocking it is different than not having it. We're still going to want to see what the long-term data show.
That's right: The CCR5 inhibitors made headlines a year or two ago, didn't they? There was a bit of news about West Nile virus and how people who don't have that CCR5 receptor were more prone to having brain-related problems?
Well, yes. That's the interesting thing, because as far as I know, that's the first human disease that's been associated with having this mutation in CCR5: You are more likely to get seriously ill with West Nile virus than you would if you had the CCR5 coreceptor. You are probably aware that not having the CCR5 coreceptor also -- in addition to preventing you from dying of the Black Death or the bubonic plague -- it also makes you more resistant to HIV infection. If you're missing the coreceptor entirely, if you are homozygous (meaning you have two defective genes), then it's pretty hard for you to become HIV positive, to become infected.
If you only have one of the genes that's abnormal, then you can get infected, but you progress more slowly with HIV. So, [the] good news: [You have a] lower HIV risk. [The] bad news: Don't get West Nile virus. Whether that's going to have much to do with the use of the drug is completely unclear. Would maraviroc make you more likely to get sick from West Nile? We just can't say.
What other questions are there about maraviroc that have yet to be answered?
The main one, of course, is long-term safety and durability of the effect [of maraviroc on HIV]. But I think we are going to see clinical trials on CCR5 inhibitors in treatment-naive people as a first-line therapy. So that's going to be an important kind of data to get.
I guess I would just say that one of the other questions is: How will doctors and other health care providers deal with the need to incorporate a new blood test in managing patients?
HIV is already pretty complicated: We've got monitoring of CD4 counts and viral loads, genotypes, phenotypes, virtual phenotypes, and now we've got the HLA-B5701 assay to look for abacavir [Ziagen] hypersensitivity. And now we're throwing in another test that is expensive. It's not very complex, in terms of interpreting it. But, you know, we're simplifying therapy for people with HIV, but we're making it more complex for health care providers!
I don't think that's going to be a big deal for HIV experts, but I do think it continues to make it harder and harder for non-experts to be managing this disease. And I think we need to be aware of that. To me, it's an argument for why everybody should be cared for by somebody who is an expert in the field.
We have no idea yet of what the cost of the drug is going to be. But you mentioned that the test for it is probably going to be expensive. Is there any indication that health care providers, or health insurance companies, or AIDS Drug Assistance Programs (ADAPs) might balk at the cost of this drug? I know that many ADAPs had issues with Fuzeon when it first came out.
It's a little tricky, because with ADAP, they are paying for drugs; they're not paying for tests -- at least, that's how it works in Maryland. So ADAP is only going to pay for maraviroc. And they're going to say, "Well, it's up to you to figure out how to pay for the test." Tests get paid for either by insurance, or by Medicaid, or, in the case of uninsured people, by Ryan White funding.
Our concern is that, in our clinic, we get X amount from the Ryan White programs per year. We can use that for lab tests and visits and things like that. But if we run out in September, we're done. So if you suddenly have to add a test that's quite expensive, you are going to use up your pot of money faster. And ADAP is a different pot of money.
So those kinds of questions haven't been answered yet. I think, at least in the beginning, until we figure out how to do this, it clearly will mean that ... it's certainly not going to be a routine screening test. Some people have said, "Well, maybe you should get the test before you start treatment with any combination, even if you're not using maraviroc."
The reason for that argument is that once your viral load is undetectable, you can't get the test. So let's say you start somebody on regimen X and they do well and have an undetectable viral load. But they have side effects, and they switch to regimen Y, and then they have side effects from that. Now you say, well, maybe I can use maraviroc. But their viral load is undetectable. You didn't get the test before you started. So you're not going to be able to use it, because you can't get the test.
But the problem is, that would mean you doing this test in everybody, even though only a small proportion were going to actually use the drug -- the cost would be prohibitive.
Did you just say that if you had an undetectable viral load, you would not be able to take the test?
Yes. I should have mentioned that before because it really becomes an issue. It's a lot like a resistance test. You have to have enough virus to be able to amplify the virus to be able to do the test. This is something I wanted to bring up: Many patients of mine, and of other doctors, are taking Fuzeon. It's a great drug, and it's helped them and really made a big difference. But they usually don't like the injections, and they don't like the injection-site reactions. They have been waiting for a new drug to come out so they can get off the Fuzeon. I'm worried that a lot of people are going to think that they can just switch to maraviroc. But because the test requires detectable virus -- you know, requires a reasonably high viral load -- if you're undetectable, you can't get the test. Therefore, switching from Fuzeon to maraviroc would be quite a gamble because you might have a 50/50 chance of losing control of the virus because of X4-tropic virus.
As a physician, would you be willing to take that risk? Let's say, a person can't get access to that test, and, whether undetectable or not, it's not a great situation with their treatment. Would you prescribe maraviroc just to see if it works?
I would be very nervous about that. I mean, if I had a patient with undetectable viral load on a Fuzeon-based regimen ... To me, switching to maraviroc without being able to get a tropism test is kind of like flipping a coin with their virologic control. The downside, of course, is that if you lose the coin toss and the viral load goes up, then you may have developed a resistance to some of the other drugs in that combination, and then not be able to suppress [HIV] again.
I think the only way I would let somebody do that is if they told me that there was no way they were going to take another day of Fuzeon, no matter what I said, and a 50/50 chance was better than nothing. Then I'd go along with it. But there are other drugs coming. Raltegravir (MK-0518), the Merck integrase inhibitor, is already available in expanded access. That doesn't have those same issues. You can use that drug in anyone; there are no tropism issues to consider. So I would feel more comfortable seeing somebody switch from Fuzeon to that drug, rather than to maraviroc, if they had an undetectable viral load on Fuzeon.
Would it be OK to tack maraviroc onto an existing regimen? Are there any risks of it interacting with any other drugs?
We're working out all the interaction details now, but we pretty much have a good handle on drug interactions with most of the drugs you'd be likely to use. And with appropriate dose adjustments, [maraviroc] can be combined with most of the HIV drugs. But tacking on, adding on a drug, is always a risky proposition, and certainly not something we recommend doing if your viral load is detectable. If your viral load is undetectable, then, in the case of maraviroc, it's unclear what you would be gaining since you are already undetectable. Then, in about half of the patients, it might not be working, anyway.
Are there any other drugs like maraviroc that are currently in the works?
Yes, vicriviroc, which is another one being studied. It's a little further behind [in development]. It's being developed by Schering-Plough, and is another drug in the same class.
Those are the two that are in clinical testing. As I mentioned, aplaviroc was nixed because of toxicity. So at least, in terms of the ones that are being tested in people now, those are the two.
What about drugs for the other half of treatment-experienced people, who would not be able to take maraviroc? Are there any drugs in development that would hit that X4 coreceptor?
Actually, the answer is no. The class is in development, in the sense that people have been working on CXCR4 inhibitors for some time. But there have been a lot of problems with the development of those drugs. Although we can say that the compounds that have been studied so far do work, in that they suppress X4 virus, for one reason or another, none of them have been developed any further, usually because of issues of toxicity.
So those drugs are years away. Of course, because almost no one has purely X4 virus, if you were to use an X4 inhibitor, you would have to use it in combination with an R5 inhibitor to get all of the virus. So we're not going to see that anytime soon.
Instead, people who have X4 virus or dual/mixed virus are going to have to take other drugs, such as raltegravir or etravirine [TMC125], which is the new non-nucleoside [NNRTI], or other drugs that are being developed in clinical trials.
So what's the bottom line on maraviroc? Is it likely to change the way that HIV-positive people are treated?
Well, the MOTIVATE trials show that it's a great drug. In the right people, it really did well. It really added something to the background regimen that they were using, and people did much better on it than on placebo. Remember, this is not just placebo: It's placebo plus the optimized background regimen [a selection of older HIV meds that are likely to work based on the results of resistance tests] that we talked about in clinical trials. It was a great drug, but we have to keep in mind that it was a great drug for that 50 or so percent who were eligible for it. It's going to have a more limited niche for who it can be used in. But for those people, it really does look like a good drug. And, at least so far, it looks to be safe and well tolerated.
I think it's going to offer something for a lot of people, but it's not going to be the answer for everybody.
I guess we'll keep our fingers crossed, then. Dr. Gallant, thank you so much.
This article was provided by TheBody.