May 26, 2011
Table of Contents
Ah, there's nothing like the smell of a fresh antiretroviral in the morning. It's been more than three years since we've gotten a whiff of that lovely scent here on the HIV treatment ranch: The last HIV medication approved in the U.S. was the non-nucleoside reverse transcriptase inhibitor (NNRTI) Intelence (etravirine, TMC125), back in January 2008.
Now we have another NNRTI: The U.S. Food and Drug Administration (FDA) approved Edurant (rilpivirine, originally known as TMC278) on May 20, and it should hit U.S. pharmacies sometime next month, according to the drug's manufacturer, Tibotec.
Unlike Intelence, which was approved for use in people who had developed resistance to other HIV medications -- particularly those within the NNRTI class, such as Sustiva [efavirenz, Stocrin] and Viramune [nevirapine] -- Edurant was approved as a first-line treatment option. (This AIDSinfo fact sheet provides much more info on the basics of Edurant, including dosing and side effects.)
We wanted to delve more deeply into Edurant's approval, what makes the drug unique, what side effects and other concerns people should watch out for, and how the introduction of Edurant may change the answer to the question, "What should I start HIV treatment with?" So we spoke to one of the people most qualified to answer those questions: Cal Cohen, M.D., a prominent HIV clinician-researcher who was the lead investigator for the clinical trials that led to Edurant's approval.
Incidentally, as Dr. Cohen and a Tibotec representative both confirmed, the correct pronunciation of Edurant is EE-der-int, and the generic name, rilpivirine, is pronounced rill-PIHV-er-in.
[Disclosure: Dr. Cohen conducts research on behalf of and consults on the advisory board for Tibotec Therapeutics, as well as for Bristol-Myers Squibb Company, Gilead Sciences Inc., and Roche. However, Dr. Cohen notes he has not received compensation from Tibotec for his role as lead investigator of the ECHO and THRIVE studies that led to Edurant's FDA approval.]
What makes Edurant different from the other 30 HIV pills and combo drugs that have been approved by the FDA?
One reason this drug is distinct is that it went up head-to-head against efavirenz, which is amongst the drugs that have always performed the best in terms of establishing virologic suppression. Edurant, in combination with two nucleosides, allowed patients to get their viral load controlled at a rate that, looking at the entire population, was similar to patients on efavirenz -- and it did so with fewer side effects.
That, of course, is the combination we all want: a simple, once-daily combination that will get your viral load controlled with as few side effects as possible. That's the constant search; that's why we look for new drugs. And Edurant provided many of these attributes in these studies.
What are we talking about in terms of the efficacy numbers when they were comparing Edurant against Sustiva?
In the overall analysis, in terms of getting the viral load controlled, the percentage of volunteers who reached an undetectable viral load on Edurant was 83 percent, versus 80 percent for those taking Sustiva.
You mentioned that Edurant appears to be more tolerable than Sustiva. In what way? How do the side effects compare?
For me, one of the easiest ways to summarize the fact that there were fewer side effects is to look at how often people stopped participating in the study due to adverse events, due to side effects, at the end of one year. Because, I think, while people might have a side effect for a week or two and then it goes away, it's a bigger deal for somebody to say, "I've tried this, I've tried it a while more, and it's just not good enough. I can't do this. I have to leave your study." That's a bigger thing.
One of the more striking findings in the study is that only 2 percent of people on Edurant stopped study participation. But in contrast, 8 percent on efavirenz did so, if I have the numbers exact. To me, that's an important thing, because I think what we're all looking for is a combination that allows me to say to somebody, "If you take this, the odds that you're gonna tell me you don't want to stay on this medicine anymore due to side effects is amongst the lowest we have in our field." And that's a pretty reassuring start.
Is that one of the reasons why this was approved for first-line therapy, because of the low toxicity, as opposed to an attempt to develop it as a more treatment-experienced option?
The studies were only done in treatment-naive patients, or patients just starting therapy for their first time, so the label is limited to that because those are the only populations that were studied for this drug. I think there are many reasons for that, including: These days, most people -- though not everybody, most people -- who start on a combination can, with either the first or second combination, stay on that regimen for hopefully the rest of their lives, and certainly our studies are pretty reassuring [that this can be the case].
As a result, there really aren't a lot of people in search of rescue regimens. And as a result [of that], a lot of the emphasis in clinical trials these days is to find the best way to start, because if you do that, odds are good you'll be able to stay on that from now on.
Are there any side concerns that come into play when considering starting treatment with Edurant?
The main concerns I think are the following, and the FDA label certainly points these out: One thing is that this drug needs to be taken with food to be absorbed. Therefore, somebody has to time this around meals. It's fair to say almost everybody eats at least once a day, so I don't think that's a particular burden. Nevertheless, it's something that people need to be mindful of. If somebody takes it in between meals, this drug won't be as well absorbed, and we want this drug to be absorbed so that it can do its work.
The other concern that the FDA label points out is that in people who had a high viral load, over 100,000, there was more virologic failure observed on Edurant than there was on efavirenz. We certainly have seen that in other drugs that we use, and it's also showed up here. Which means that there's at least a question, or a caution, for clinicians in terms of when this is the right drug [to take]. I think we can say with confidence that this is an excellent choice for people whose viral load is less than 100,000, and there's ongoing research to understand if or when this is the right drug for people whose viral load is over 100,000.
What we want to do is understand how best to use Edurant -- when are we confident that it is the right choice -- with the highest degree of confidence that we can have. The FDA certainly highlights that baseline viral load is one way to ensure that kind of confidence. There's an ongoing study that the manufacturers are doing to further understand why this drug had some question marks at higher viral loads.
It gets into, I guess, a larger question about the growing number of first-line options, too, which we can get into in a couple of minutes. First, how about drug interactions? Anything in particular that people should be on the lookout for?
Probably the single most important thing is that, as I mentioned, this drug needs food in order to be absorbed. It also needs stomach acid, so this drug is not the right choice for somebody who must take potent drugs that lower stomach acid -- specifically drugs we call proton-pump inhibitors, like omeprazole [Losec, Omesec, Prilosec]. Edurant needs acid, so somebody who requires medicine to reduce stomach acid will find that this is not the ideal choice. Note that we already have seen this with atazanavir [Reyataz], for which there is a similar issue, and the field has learned to work with this issue.
Some people are on a proton-pump inhibitor every day. These days, in fact, the field of medicine is revisiting whether somebody who's on those drugs should stay on them the rest of their lives, or if maybe there is an opportunity to come off those drugs, because of some long-term toxicity issues with the proton pumps. Nonetheless, there are people who can't come off them, and for them Edurant is not the best choice.
Looking over the volunteers who were involved in the clinical trials for this drug, how diverse was that study population? Were there any differences, let's say, in terms of how the drug acted in women, African Americans or Hispanic Americans?
To answer your first question, the drug was studied worldwide, so there were participants from all over the globe, on several continents. And in terms of diversity, if we take a look at the pooled data sets, it certainly had amongst the most diverse populations for any kind of initial trial population. So I think on that level, we can be confident of these results.
At the Glasgow meeting, and also at the IDSA meeting, we presented data with regards to specific subsets, including what you're asking about. Probably the simplest way to summarize that is that efavirenz and Edurant perform similarly regardless of the population: similarly in women, similarly in men, similarly by race, and so on. There weren't kind of striking differences of, "This is the right drug for this population, but not for that population." That did not show up.
That doesn't mean every population does the same. We certainly see different patterns of adherence in different countries and different races. But nevertheless, there was certainly no evidence that rilpivirine and efavirenz are better in one population versus another. It was similar response rates for both the drugs within each of the populations.
Is it safe to take if you're pregnant?
The FDA gave this drug a pregnancy category B. What that translates to is that there's always a need to be cautious, because we don't have as much data -- if any -- in any woman who becomes pregnant while taking this drug. Nevertheless, the FDA reviewed the animal data and did not find anything to raise a caution.
B is the most permissive criteria that the FDA gives in the absence of a lot of human experience to show that the drug is in fact safe when pregnant women take it during pregnancy. As I understand it, this category rating is the most reassuring categorization that a new drug will get.
Let's switch to resistance for just a minute. There were some findings in the clinical trials about how Edurant appears to be a little bit more susceptible to cross-resistance if a person fails treatment on it. Can you talk a little bit more about that?
The first point I think we should start with is that we should make sure people understand the basics: Resistance only happens in people who did not achieve virologic suppression, in whom the viral load doesn't go down and stay down. In most patients who started both drugs (Edurant and Sustiva), the viral load went down and stayed down. So resistance is not a consequence of treatment, it's a consequence of treatment that was not successful.
For the subset, for example, of people whose viral load was less than 100,000 who took rilpivirine and two nukes, nine out of 10 had virologic response, they got their viral load down. So when we talk about resistance, we understand we're talking about that other 10 percent, the people in whom the viral load didn't go down or didn't stay down. Sometimes that's a consequence of inadequate adherence -- not taking it with meals, for example -- though sometimes that may be a consequence of the baseline viral load, despite excellent adherence. Why failure happens is an important piece that we are still learning about. Clearly we don't want failure, and thus far adherence is one important contribution to ensuring success. Nonetheless, there were patients who had, for any number of reasons, some degree of inadequate response, and therefore resistance can occur.
The pattern of resistance for Edurant is different than for efavirenz. The main difference comes down to another non-nucleoside called etravirine. A couple of years ago, Intelence was approved by the FDA based on studies in people who had already been on, and had resistance to, NNRTI drugs including efavirenz. We needed a drug that would work against efavirenz-resistant viruses, because we had, unfortunately, a lot of people who had efavirenz-resistant viruses -- because whether it was efavirenz or nevirapine, we sometimes used them in unsuccessful combinations. So we had thousands of patients who really needed a drug like Intelence. And it worked.
Now we're talking about treatment-naive patients. It is fair to say that people who start therapy are, first of all, unlikely to have any resistance at all, so Edurant will work for them, and most people will respond. But it is true that if someone takes Edurant and doesn't respond, if there is resistance, then there will be cross-resistance to Intelence. These two drugs are related in terms of resistance patterns. So the use of Edurant will, when successful, maintain all options, and when unsuccessful, unlike efavirenz, etravirine may not be the best choice to follow it.
Fortunately, it is entirely possible that one might never need to use etravirine. If someone takes Edurant and two nucleosides as his or her first combination, and it stops working, that person can still take all the protease inhibitors, the integrase inhibitors, and probably the CCR5 inhibitors, as well as some of the nucleosides, like tenofovir [Viread]. [Editor's note: Two nucleoside reverse transcriptase inhibitors (NRTIs), Emtriva (emtricitabine, FTC) and Epivir (lamivudine, 3TC), which are a part of many antiretroviral combo pills, do appear to often lose their effectiveness as well if a person develops resistance to Edurant. Research is continuing in this area.]
So, if resistance should occur with someone on rilpivirine, it is entirely likely that we would have an excellent combination that should work quite well to reestablish virologic control. While they may have lost etravirine, they are still quite likely to be successful in terms of reestablishing suppression with another regimen.
So then, when you pull all that together -- the resistance, the baseline viral load, the ability to tolerate specific kinds of side effects or not, potential issues with drug interactions -- how does the average HIV clinician and HIV-positive person start to come to a decision about what to take first when the number of options just continues to grow?
Well, let me start by saying I think it's a great problem to have, isn't it? We have many competing options, all of which have something good to offer. So it's a wonderful conundrum to have in our field.
The second is to probably just note for a moment that while Edurant is now available as a single, stand-alone tablet, it is widely expected that in a few months we'll also have a single-tablet regimen combining Edurant with tenofovir and FTC, which was one of the most-studied combinations in the ECHO and THRIVE studies [that led to Edurant's approval]. The single-tablet piece of it, while not approved simultaneously, is expected in a few months.
Edurant certainly provides some important attributes now -- the ability to take it once-daily with something to eat and have very few expected toxicities, as well as the virologic suppression rates, albeit with differences based on the pre-treatment viral load that we talked about -- that combination of factors for the right person is overall a useful addition. With two pills a day -- a single combination nucleoside pill [e.g., Truvada] and an Edurant -- we could do very good work.
But when this becomes a single tablet, I think there's an additional reason for enthusiasm, because I think many of us have experienced that when we put all the factors together, many people are just drawn to the simplicity of a single tablet.
It isn't the only factor, of course. But when all those attributes line up -- when you have confidence that the drug can work in the right population; when you gave a drug with few expected side effects; and you have the simplicity of a single tablet -- I think that there'll be enough patients who are glad to have yet another combination in a single tablet, one with a different toxicity profile than the current one available [i.e., Sustiva], and one that some patients may prefer to be on.
So is this really just a case-by-case type decision in which the patient and the clinician need to take into account all of the different pluses and minuses of each of the different options? Right now, the U.S. treatment guidelines already recommend four options: Atripla, which is Sustiva plus Truvada (tenofovir/FTC) ; Reyataz with Norvir (ritonavir) and Truvada; Prezista (darunavir, TMC114) with Norvir and Truvada; and Isentress (raltegravir) with Truvada.
Obviously, it's a little bit too soon to conjecture what's going to happen the next time the guidelines are updated in regards to Edurant. But that's potentially a handful, literally, of different options to choose between, and a lot of things to weigh. Which can get pretty complex, I would imagine, for some clinicians and patients.
Well, how complex it is, or how reassuring it is, is perhaps at the center of your question. It's complex if you feel overwhelmed by choice and don't know the data, and don't know what makes these distinct. On the other hand, I find it wonderfully reassuring that, in the current era, I can sit with a patient who is facing starting therapy and describe five different combinations -- amongst others, I can describe the five you just mentioned -- and say, "Here's what makes this great, and here's its asterisk -- here's the issue with this drug."
So, with Edurant, I would consider the viral load, and if it was below 100,000, I could say, "You have to take it with food, and do you have heartburn? Because if you take certain heartburn medicines, this is not the right drug." And that would allow me to decide whether Reyataz or Edurant is on or off their list.
Raltegravir is twice-daily. Some people say, "Sure, I could do twice-daily, no problem," and other people say, "Ooh, I might forget. I'll stick with the once-dailies."
We individualize this through a number of questions that all of us, I think, routinely ask. And as a result of those questions, I think we go from having a field of five that are all perhaps competing for attention to feeling like we can match somebody up with the right drug.
My sense of it, to risk dating myself, is it's kind of like the Dating Game, if that's even still on TV anymore. It's really a question of "Bachelor Number One, do you have heartburn? Bachelor Number Two, can I take you with food, or without, or does that matter?"
The way we go through it is a series of questions, and I ask the people I see, "What's the most important thing to you? Are the number of pills important to you? If I said the combination was one pill or four pills a day, does that matter?" Some people say, "Wow, that matters a lot! Four pills, yikes, that's scary!" And other people say, "Four pills? I'm already taking five vitamins; why would four pills matter?"
So everybody is different, and these regimens have ways in which they're distinct. I don't think it's all that complicated to review the options and match somebody up with a drug that meets that person's criteria with the most check boxes.
You mentioned that a few months down the road, hopefully, there will be a single combination pill that includes Edurant and Truvada together.
That's now up to the FDA. There is one in development, and now it's up to the FDA to agree.
What else is on the horizon as far as drugs in development?
Probably the next drug that's closest to completing its phase 3 work is what's affectionately known as "the Quad," the Quad being the same two nucleosides, tenofovir and FTC, and then Gilead has two new drugs in development, one is an integrase inhibitor and one is a booster. That drug is being now studied in phase 3 as a single combination. How successful it will be is not something we yet know, because the phase 3 studies aren't done.
Behind that is an integrase inhibitor that ViiV is developing, and that's entering phase 3 studies now, so we've got a little while before we're gonna know that data. But we do have a pipeline, and it's great that the industry is still finding drugs that it wants to develop with us.
And it sounds like, within the course of a year, options for first-line therapy are gonna get even more diverse and interesting than they already are.
Well, I hope so. I want more options, because the more we have, the more I can be confident that I can pair this person with what seems to be the best choice for him or her. Because, again, this person might be on this pill the rest of his or her life. So because people differ, I would like to have more options and start somebody on something that has as many of the right attributes for him or her as possible -- and if, after a week or two, it's not the right one, to be able to switch to something that is equally attractive and should work as well, and address some of the limitations of wherever we started. So I think the more options the better.
Now, just to clarify, you say a week or two -- that's usually because of side effects you can't handle, right?
Correct. The most common experience, for example, on efavirenz is that some people in the first week or two experience either a rash or some of the well-known neuropsychiatric toxicities, and in that first month some people find that it's just not going away, and they need to switch.
Thank you, Dr. Cohen.
Myles Helfand is the editorial director of TheBody.com and TheBodyPRO.com.
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