March 8, 2010
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This is part one of a two-part interview discussing highlights from CROI 2010 related to antiretroviral therapy for HIV-infected patients. Part one focuses on antiretrovirals in development; part two focuses on already-approved antiretrovirals, the question of when to initiate antiretroviral therapy and the evolution of the CROI meeting itself. You can use the table of contents below to quickly jump from section to section.
Table of Contents
Myles Helfand: Although conferences such as CROI are research meetings at their core, the findings presented there have an undeniable power to alter clinical practice. As CROI 2010 slips into our rearview mirror, let's take a look at some of its key studies for signs of how the treatment landscape may evolve over the months to come.
Joining me for this examination is Joel Gallant, a professor of medicine and epidemiology at the Johns Hopkins University School of Medicine. Dr. Gallant, thanks for joining us.
Joel Gallant: My pleasure, Myles.
Myles Helfand: We've got a lot of research to get to, and obviously, we'd like to put it into as small an amount of time as possible. So let's dive right in.
Let's begin with what is always one of the more interesting topics in antiretroviral therapy: the drug development pipeline. What did CROI 2010 bring us?
Joel Gallant: We hear a lot of complaints that there's not much going on in the pipeline. The pipeline is certainly not as full as it used to be. But there were a few drugs discussed, including a new CCR5 inhibitor; a new integrase inhibitor; and, of course, the so-called Gilead [Sciences, Inc.] "quad" that consists of tenofovir [TDF, Viread], FTC [emtricitabine, Emtriva], elvitegravir [GS 9137, JTK-303], which is their integrase inhibitor, and their new booster, GS 9350.
Myles Helfand: Which has a new name, I believe: cobicistat.
Joel Gallant: That's right. Cobicistat. You need to learn that and be the first on your block to know it.
Myles Helfand: Or the first in your clinic, as the case may be.
Myles Helfand: Let's get into the quad tablet a little bit. How did this hold up in the study that was presented at CROI?
Joel Gallant: Cal Cohen presented three studies in 10 minutes, which was a tour de force. Because the organizers like to combine related topics, and make people have to rush through a lot of data. So he presented the study of the quad compared to Atripla [efavirenz/tenofovir/emtricitabine, EFV/TDF/FTC]. Then he also presented a study where the cobicistat, or GS 9350, was used in comparison with ritonavir [RTV, Norvir] to boost atazanavir [ATV, Reyataz].
In both studies, the results looked great. These are smaller, phase 2 studies. But basically, the quad looked comparable in efficacy to Atripla. The cobicistat looked comparable to ritonavir, in terms of its ability to boost atazanavir, in that study. But the unexpected finding, especially in the quad versus Atripla study, was that the serum creatinine was slightly higher in the cobicistat arm, or the quad arm. This resulted in a modest decline in estimated creatinine clearance, which is the way we measure kidney function.
This was concerning, of course, because we already know that tenofovir can sometimes affect kidney function. And the idea of developing a quad tablet that had two drugs that were toxic to kidneys was not very appealing. So they then did a quick study in healthy volunteers, where they gave cobicistat to people, and they measured their creatinine and their estimated GFR [glomerular filtration rate], and then they used iohexol clearance as a test of true GFR. It actually measures creatinine clearance, instead of estimating it.
What they found was that, while the estimated GFR went down a little bit, the actual GFR didn't change. Their theory is that this is not a kidney-toxic drug; it's simply that it inhibits the secretion of creatinine from the kidneys, and therefore, it elevates creatinine without actually doing any harm.
So that's the hypothesis. They're going to go ahead with the phase 3 clinical trials. The hope is that this is just a tiny decrease in apparent kidney function that occurs within the first week or two and then, from then on, remains stable. So if you needed to monitor for, for example, tenofovir nephrotoxicity, you'd do it just the way we do now. This was an unexpected finding; hopefully, not a big problem.
In terms of the ritonavir versus cobicistat comparison: Again, as I said, the efficacy was fine. I would say one of the disappointments was that it didn't look better, in terms of gastrointestinal side effects, than ritonavir. I think we were all hoping that this would be the booster that had none of the baggage that comes with ritonavir. But, at least in this small study, that didn't appear to be the case.
Myles Helfand: The cobicistat creatinine findings: Was that a substudy, or was it a separate study that was done in people who received cobicistat as monotherapy?
Joel Gallant: The study where they did the iohexol clearance was a completely separate study in HIV-negative volunteers.
Myles Helfand: OK. And they didn't receive tenofovir, as well?
Joel Gallant: No, this was just cobicistat.
Myles Helfand: Is it known whether there's a potential interaction between cobicistat and tenofovir?
Joel Gallant: They've looked at that. There's certainly no pharmacologic interaction. But if you look at the curve that they presented, two weeks of looking at kidney function after seven days of monotherapy, the actual GFR is completely stable across those weeks -- whereas, in the quad versus Atripla study, within a week, you saw this decline in creatinine. So it's a pretty convincing argument.
And, you know, there are other drugs we use that do this, too. Trimethoprim [Proloprim] is a good example. It inhibits creatinine excretion -- and you do see a very small increase in creatinine. It's something that we don't even notice, or look for. But things are a little different in this case, because of the fact that tenofovir is on board.
The examples I remember are cimetidine [Tagamet], which used to be used for peptic ulcer disease, before we had drugs that had fewer interactions; and trimethoprim. There may have been another example [Dr. Cohen] gave that I'm not remembering.
Myles Helfand: Is he right in that comparison?
Joel Gallant: Well, he's certainly right that those drugs do that. And it sounds like he's right that cobicistat doesn't affect true creatinine clearance. Whether the hypothesis that this is due to inhibition of tubular secretion is correct, I don't think we know. The assumption is based on the fact that other drugs that have this effect on creatinine, without actually damaging kidneys, do it in this way. So it's a reasonable hypothesis, but it probably needs to be established more firmly.
Myles Helfand: I imagine phase 3 trials will help.
Joel Gallant: Phase 3 trials will definitely help to determine whether this is indeed a problem that occurs quickly and then doesn't progress. That's what we care about. The last thing we want to do is have something that is causing even just an apparent alteration in creatinine clearance. If it goes on over time, then the problem with that is that it makes it very difficult to monitor for tenofovir toxicity. But if it's just something that happens within a week and then doesn't change, then it's not difficult to monitor for tenofovir toxicity the way we always do.
Myles Helfand: The quad versus Atripla comparison, was that in treatment-naive patients?
Joel Gallant: Yes. That's what this combination is being studied for: as a potential replacement for Atripla.
Myles Helfand: Thus far, from what you've seen, how is it stacking up?
Joel Gallant: So far, I think it looks very good. It certainly was associated with a lot fewer neuropsychiatric side effects. If you look at things like dreams, dizziness, fatigue, sleepiness, those things were much lower. So, at least in a phase 2 study, this seems to fulfill the promise that it's a combination that's as good as Atripla, but without the side effects [that are unique to Atripla].
Now, of course, the quad is not the only combination that is going for that Atripla place. There are several other competitors that are doing the same thing. So it's just a matter of time, I think, before we have something that's going to be as good as Atripla, but better tolerated. It's a question of which of these various regimens will win.
Myles Helfand: This may be an overly provocative question, but given that Atripla and quad share two ingredients, how much of a furthering of the evolution of treatment options is the quad drug, really? Half of its components are already being utilized in first-line treatment.
Joel Gallant: I think that where it's an advantage is for patients starting therapy. When I start somebody on Atripla, which is certainly something I use a lot of, I have to spend several minutes sitting and talking about how to deal with getting used to the drug, and the changes they are going to go through, in terms of the neurologic side effects, the dizziness and the dreams, the difficulty concentrating, and the potential for rash. I can't just hand over a prescription and say, "Take this once a day."
We would love to have a drug, or a combination pill, that we could just hand a patient a prescription to and say, "Take this once a day." We need something without a lot of baggage. I would say this is looking good for that.
Atripla has always had -- as good as it is, and as effective as it is -- it's always had its downside. So while you could say that this isn't all that new -- two of the drugs are the same -- I think from a patient standpoint, it's very important that something [be available to potentially] replace Atripla. And in fact, all three of the drug regimens that we're looking at now that could potentially replace Atripla have tenofovir and FTC in them. It's just a question of the third drug.
Myles Helfand: What are the other ones?
Joel Gallant: There's the coformulation of tenofovir, FTC and rilpivirine [TMC278], which is a new NNRTI [non-nucleoside reverse transcriptase inhibitor]; and then there's the idea of using tenofovir, FTC and raltegravir [RAL, Isentress] once a day, which is also being studied.
Myles Helfand: How important do you feel is the "one-pill, once-a-day" scheme? There are a number of other regimens that are on the preferred list on the U.S. DHHS [Department of Health and Human Services] guidelines -- boosted darunavir [TMC114, Prezista], for instance, boosted raltegravir -- that a person could turn to, but that involve more than one pill. Why would they not already be preferable to, say, Atripla, or a quad drug?
Joel Gallant: I think once-a-day dosing is quite important to many, many patients. Not all: There are some that would prefer, for example, Truvada [tenofovir/emtricitabine, TDF/FTC] plus Isentress, even though it's twice a day, just because of the tolerability. We have patients who are popping seven or eight vitamins a day. They don't care if their meds are one, two, three or four pills a day.
It really comes down to side effects and some of the other considerations that we take into account when we start a regimen. I have many patients who come in saying, "I want the one pill, once a day. I want Atripla." I give them Atripla. And there's always going to be a small number of them who just don't tolerate it, and who switch over to, for example, Truvada plus a boosted PI [protease inhibitor]. They are happy with the drug, because it doesn't have the side effects that they had with Atripla. So they don't mind that it's three or four pills a day.
It just depends on patient preference. For people who have a real pill phobia, or who are paying enormous copays on medications, sometimes the number of pills can really make a difference.
Myles Helfand: OK, fair enough. It seems like, on balance, the further development of the quad tablet is good news. We're looking at something that, at least for now, looks like it has the potential to enhance treatment options for naive patients.
Joel Gallant: Oh, definitely. It was concerning that elvitegravir was not going to get developed because, as we'll come to, it's becoming very, very difficult to develop a new drug for a treatment-experienced patient population. So the development of this booster, cobicistat, was a big plus, because it allowed them to do studies in naive patients. If you remember, this drug was going to need to be boosted by ritonavir, and they couldn't study a ritonavir-containing combination in a naive patient unless it included a protease inhibitor, because there was concern that even low-dose ritonavir could lead to drug resistance. So they were kind of stuck with studying this in an experienced population. The booster came along and rescued them, allowing them to use this up front.
No comments have been made.
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