June 28, 2006
So tell me, what's so great about the new protease inhibitor darunavir? Or are we still calling it TMC114?
That's up to you. TMC114, the chemical, whose generic name is going to be darunavir, and the brand name is Prezista.
Are you sure people will adopt the name darunavir? People have never stopped calling T-20 (enfuvirtide, Fuzeon) "T-20."
Correct, and 3TC [lamivudine, Epivir] is still "3TC."
Do you think the name TMC114 will stick?
I actually think "darunavir" is not bad -- it's been around long enough that people are starting to use it and get used to it. So it's kind of like Abbott378 became Kaletra [lopinavir/ritonavir] or lopinavir, so sometimes it sticks.
Can you tell us what's so important about this new drug?
Well, the results on darunavir have been nothing short of impressive for our field. When we saw the initial results, just about a year ago, we saw virologic suppression at rates we hadn't seen before, in which the majority of patients achieved less than 50 copies, even though historically, only a minority of patients on other regimens of this type had been successful. So what this drug represents is an ability to re-control HIV in the majority of people. For us that's a dramatic step in progress.
How resistant were the people who were on regimens with darunavir during the trial?
Well, there are different ways to describe resistance, but the patients who entered the definitive darunavir studies were triple-class experienced, so they had taken lots of protease inhibitors (PIs) in the past. They had high-level resistance, as measured phenotypically, to all of the other protease inhibitors, and they also had a lot of specific resistance mutations. It therefore wasn't surprising that the background regimen or the control group regimen -- which was essentially any approved protease inhibitor other than tipranavir [Aptivus], which hadn't yet been approved -- were far less successful at re-suppressing the virus. This, of course, wasn't surprising, since a low response rate, given those resistance mutations, was what you'd expect. Where the progress was, was how much better darunavir was in those patients.
What's the ideal way to use darunavir? Are there any other meds it works best with?
The ideal way to use this drug is in an effective regimen, and not as a single, solitary drug, since monotherapy certainly is not an ideal approach. Therefore, like every other drug, darunavir needs active drugs in a background regimen. What the active drugs are is, of course, going to vary from person to person. For some, the only active drug might be a drug like enfuvirtide, because they've already taken -- and have high-level resistance to -- all the nucleosides, some non-nucleosides, and we don't have any reason to think that a double PI combination which includes darunavir would be helpful. So for some people it's enfuvirtide and darunavir, and the data of that particular combination is what really sends the field into the enthusiastic state it is [in] -- because of that interaction and that combination.
On the other hand, if somebody has active nucleosides, if they hadn't developed a significant amount of nucleoside resistance, then enfuvirtide is just a drug, it's not magic, and if somebody has active nucleosides, then that could be used instead of, or in addition to, enfuvirtide, and the virus can be re-controlled that way.
As long as there are three active drugs?
Well, again, the precise number [of drugs] is really not the point, because it also comes down to: How active is the darunavir? Because if the darunavir is compromised, then you need the rest of the regimen to do some of the work. If darunavir is fully active -- which is, again, going to be determined by how much previous resistance there is -- if darunavir is fully active, it may be that just two active drugs are enough.
So, darunavir and a few nucleosides, darunavir and T-20 with compromised nucleosides, would be enough. But ideally, we always like to have three active drugs, but there may be combinations in which two might be enough. Fully active drugs, in other words -- that doesn't mean you give just two drugs, but maybe that enfuvirtide, darunavir and then some compromised nucleosides -- for example, like tenofovir [Viread], FTC [emtricitabine, Emtriva] -- even in the face of resistance, might have additional, small virologic suppression rates. That might get an extra half log [reduction in viral load; "1 log" means a 90 percent drop] or something out of it, so that's not where the work's going, but it's certainly supportive.
Will darunavir change the way physicians prescribe salvage regimens for people with a lot of drug resistance?
I don't think darunavir should change our approach to salvage, it just gives us a new way to implement the rules of salvage [for] highly treatment-experienced patients that we've known for years. We've known for many years the rules of the game. In highly treatment-experienced patients, what we haven't had are the tools to implement those rules. And now with darunavir, we have a very important drug that allows us to construct a fully active regimen in a majority of patients.
Again, it's not going to work for everybody. Unfortunately, in the studies that were done, approximately one third of the patients who entered these studies already had some degree of darunavir resistance. There can be cross-resistance to darunavir. Other PIs can select a resistance [mutation] that can, unfortunately, lead to darunavir cross-resistance. So, it won't be perfect, it's just an antiviral. But the good news [is that] it's only about a third [of patients]; two thirds were able to respond to the darunavir.
What happens if a person has no active drugs available, and they want to take this? Is it better to take it now, or to wait until Merck's integrase inhibitor [MK-0518] or some other drug is approved?
Well, the short answer to that is, it depends on what the price is for waiting. If somebody has highly advanced disease, very low CD4 counts, and is at risk of another OI [opportunistic infection] in the near future, and may or may not be healthy enough by the time the Merck integrase inhibitor gets here -- even if that's six months away -- if somebody says "I don't know if I'm going to make it six months," that kind of changes the equation.
You don't have the time to wait, if the person is not going to be here, so you have got to play the card.
But if somebody says, I've got 120 CD4s, my viral load is 30,000, the darunavir looks compromised -- it's already got some degree of resistance, by geno [genotype test], by pheno [phenotype test] -- it may be that darunavir has activity, but that the regimen itself is vulnerable, and won't work very well for very long, and that, as other drugs arrive that are fully active, we'll be more confident about reestablishing suppression.
That equation -- knowing how to wait, and how to delay, if it's better to delay, if it's better to play the card now, knowing when I'm confident that the regimen I have now is potent enough, knowing when the regimen isn't going to be potent and I should wait, also knowing if I can safely wait -- are extremely important skills that HIV-treating clinicians need to understand.
What about tipranavir, which was approved last year? If a patient has not tried tipranavir yet, and is at the point where they need another drug like tipranavir or darunavir, which one is a good one to choose, now that there are two options?
Well, we certainly don't have a randomized comparison of tipranavir versus darunavir. What we do have is at least one cross-study comparison that was authored by Andrew Hill, and he presented it at the British HIV Association meeting. [Click here for the abstract of this study, or click here to read a summary of the study.] And simply by just taking the two studies side by side, he asked two questions. One is, are these studies comparable? The RESIST [Randomized Evaluation of Strategic Intervention in Multi-Drug Resistant Patients with Tipranavir] studies with tipranavir and the POWER [Performance Of TMC114/r When Evaluated in triple-class-experienced patients with PI Resistance] studies with darunavir -- can we compare these studies? Did they enroll similar patients? The second question is: If they enrolled similar patients, how well do those drugs do?
Hill presents some reasonable data to support that these studies actually did enroll similar patients with similar degrees of baseline resistance, similar CD4 counts and similar viral loads. Not the same, but pretty close. And through a number of ways of supporting that, he was able, I think, to suggest that these studies are reasonably similar to each other. Including the response to the background regimen, the non-experimental PI was pretty similar in these studies, which all kind of put together says this might be a good way to judge one PI versus the other. And for all the different measures that he showed, he was able to show that darunavir was more successful at reestablishing HIV control. It had a better log drop, and had more people who were virologically suppressed below 400, below 50. And we also have some in-vitro data to suggest that if somebody developed darunavir resistance, tipranavir should still be reasonably active, and likewise in the reverse [case of] tipranavir resistance, darunavir probably would be active. So, if we have all of those facts in place, and we have everything except the last piece of the puzzle -- which is a randomized, head-to-head trial -- is that enough to choose?
Unfortunately, every clinician is going to have to decide that on their own, because right now all we have are these cross-study comparative data, and that's the best we're going to have for a long while. So in this sense, this question is going to come up over and over, and people are going to have to decide which drug they go with, and why. People might look at the difference in liver function test toxicities as one reason to choose darunavir instead of tipranavir. It actually remains to be clarified if there are resistance patterns for which tipranavir is a better choice instead of darunavir and vice versa. Hopefully, that's the kind of data that would emerge that would say: For this mutation pattern, one looks better than the other.
Do we yet have a notion of the resistance pattern for this drug?
What are darunavir's main side effects? You mentioned that tipranavir has liver issues.
Tipranavir does; it actually has a warning box around the fact that some people did develop elevated liver function tests or hepatitis when they took tipranavir, more so in people who were dually infected with hepatitis B or hepatitis C. So as a result, the FDA [U.S. Food and Drug Administration] cautions us, when we use that drug, to be careful, monitor liver function tests frequently.
What are the main side effects of darunavir?
The two categories of side effects are: how people feel, and then there are blood tests. In terms of how people felt, in terms of the standard range of [grade] 2, 3 and 4 adverse events people experienced, it's actually impressive how few toxicities there were on darunavir versus the comparative PIs. Meaning 2 to 3 percent [of patients] noticed the GI [gastrointestinal] toxicities, like diarrhea, vomiting, abdominal pain, so on, and on darunavir [they] didn't seem to be more frequent, in really hardly any of these -- maybe 1 percent more people having headaches on darunavir versus any of the comparative PIs. So, at least from a perspective of what do people feel, they apparently feel about the same on this drug as they did on any other PI, obviously with the chance of viral loads dropping more likely.
So with other PIs, what would be the side effects? Would it be GI side effects?
Yes. A lot of the drugs -- for example, lopinavir, boosted lopinavir, and so on, fosamprenavir [908, Lexiva, Telzir] -- typically have rates of diarrhea, a little nausea.
But all of these are side effects that patients can deal with?
Yes, most people are able to tolerate it. And sometimes we have to give some anti-diarrhea meds, for example, and those are the kinds of things we often do if someone's having a problem. But number one: The majority don't have these problems. And number two, the majority, if they have a good response, they can tolerate this regimen with few overall side effects.
In terms of lab toxicity, once again we have an interesting picture. In the randomized trials, in which darunavir is compared to any comparator PI, if we take again a look at lab toxicities, fewer people, 10 percent, had elevated liver enzymes compared to the comparator PI: for example, 10 percent versus 13 percent for AST [aspartate aminotransferase] levels, 7 percent versus 10 percent for ALT [alanine aminotransferase]. So overall, it actually looked pretty good.
There were a few things that did show up that were more common on darunavir. One is [that] pancreatic amylase was higher. The meaning of this isn't real clear since there [weren't] presentations that suggest people were developing pancreatitis, but there were about 4 percent more people with pancreatic lipase and about 8 percent more people with pancreatic amylase. So that's the one thing we're going to have to keep a watch on. Certainly, as always, we keep a watch on cholesterol and triglycerides, but at least triglycerides didn't seem that different on darunavir versus other comparator PIs.
Those are the main lab toxicities and differences that showed up in the studies. Otherwise darunavir was pretty good, and sometimes better, on a lot of these other tests. In terms of hep[atitis] B and C, by the way -- which is inevitably a concern for at least some people, the hepatitis C stuff -- there aren't a lot of patients with hep C who took these drugs, but the FDA was willing to say that there was no evidence of a higher instance of adverse events or blood-test abnormalities in darunavir versus other comparative PIs. And that is different from tipranavir. Tipranavir certainly has more of a warning around liver function test abnormalities for those whom it really affected.
So would you suggest clinicians proceed with caution with hepatitis B- or C-infected patients?
I would say that the FDA has said that whatever caution you use for currently available PIs, like Kaletra and so on, is appropriate here. And the additional caution that we were given for hep C or hep B and tipranavir was certainly not the case here.
Do you think darunavir will eventually be used as first-line therapy?
Randomized studies are being conducted of a different dose of darunavir; the standard dose that's approved here is 600 mg twice a day, boosted by ritonavir [Norvir]. There's now a treatment-naive trial that's going on using lower doses: 800 mg once a day for it to be used in naive patients, darunavir has to be at least as good, if not better, than our current, very impressive options for first-line therapy, which are anything from two nucleosides and efavirenz [Sustiva, Stocrin], to two nucleosides and a single boosted drug like atazanavir [Reyataz] or Kaletra. So we have some extraordinarily high levels of response rates. This drug is going to have to deliver not just potency, which is certainly likely, but on safety. And [we're going to have to learn more about] the differences of safety on lipids, on this pancreatic amylase story. So I think at this point it's too soon to say that we will be using it in naive patients, but certainly not too soon to say that it's a very important research question that's well under way.
What other meds are in the pipeline that look as exciting as, or more exciting than, darunavir?
Well, I'm not sure I would say more exciting, but we do have a number of drugs that are, in the near future, I think, going to be exciting for our field. One, of course, are the integrase inhibitors, Merck [MK-0518] and Gilead [GS 9137] both have one. There's also maraviroc, Pfizer's CCR5 inhibitor, which is certainly continuing to be studied in a clinical trial. And then Tibotec [the company that produces darunavir] has another non-nucleoside called TMC125 or etravirine, which is also looking pretty good.
How soon do you think approvals will come for any of these new drugs?
Obviously, the FDA is in charge of approvals, but we are certainly well under way with phase 3 studies with several of those drugs. So, it'll be up to the FDA which of those are next year's approvals.
Anything else you think people should know about darunavir?
Actually, there's one little minor fact, which may not be minor for some people: Darunavir was given a pregnancy category B by the FDA.
Can you explain what this means?
B means that they would consider the drug likely to be reasonably safe, based on the data. It's amazing; most of our drugs get C's [which generally indicates that the drug's safety in pregnant women hasn't yet been determined, but animal studies have found some risk to the fetus]. There's only some that get B's.
Well, thank you very much for your help.
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