CROI 2010 Wrap-Up: The Evolution of Antiretroviral Therapy
A Discussion With Joel Gallant, M.D., M.P.H.
March 8, 2010
Myles Helfand: That may or may not be becoming more clear as a result of research presented at this conference, which we'll get into shortly.
Moving on to other drugs that are part of our first-line armamentarium: There were new data presented at CROI on darunavir.
Joel Gallant: Darunavir is already approved for both treatment-experienced and treatment-naive patients. It's now a preferred first-line PI at the dose of 800/100 once a day, with ritonavir [RTV, Norvir] boosting, based on the ARTEMIS data. But the package insert, the FDA [U.S. Food and Drug Administration] label, says that for treatment-experienced patients, you should use the original POWER study dose of 600/100 twice a day.
Everybody, I think, has assumed that although the label says "treatment experienced," what really matters is whether patients have PI resistance -- and, perhaps specifically, darunavir resistance. In my own practice, a patient may get the once-a-day regimen even though they are treatment experienced, if I know that they don't have resistance to darunavir.
This study set out to prove that, presumably so they could get their label changed. They took patients who had treatment experience, but no darunavir resistance, and they randomized them. They randomized them to either the once- or twice-a-day regimen. What they found was that the results were the same for the two arms.
The problem with the study is that, in fact, most of these people had no PI resistance at all. That's kind of what happens these days; when people fail PIs that are boosted, they tend not to have resistance. So again, this study was really comparing once a day versus twice a day [in PI-naive patients]. So it's no surprise that they would do just as well on once a day. But nevertheless, at the very least, it could lead to a change in the label to say that you would use this for patients with no PI resistance, or patients with no darunavir resistance. That would help a little bit.
Myles Helfand: Is there anything that's particularly new here? Presumably, even though it wasn't necessarily approved [for this use], I'm assuming at least some clinicians were already prescribing once-daily darunavir [in treatment-naive patients].
Joel Gallant: I would hope so. It just doesn't make any sense to go strictly by whether they are treatment experienced or not. I understand that the FDA had to do it that way, because that was the way the ARTEMIS study was set up. But from a scientific standpoint, what you care about is whether they are resistant to darunavir or not.
For me, the interesting part of this study was really the lipid results. There was a very significant difference, favoring the once-a-day arm, in cholesterol, LDL [low-density lipoprotein] cholesterol and triglyceride elevations. People on twice-a-day [darunavir] had quite a lot more -- almost double the amount of lipid elevations.
We've questioned whether the differences among PIs are due to the PI itself, or to the amount of ritonavir, or both. In this case, you can't be sure, because one group is getting 1,200 mg of darunavir and the other is getting 800. But I think the more significant difference is that one group is getting 100 mg of ritonavir and the other is getting 200. I suspect that that's what's really driving this difference, which I think supports the idea that we should be using 100 mg of ritonavir unless we have a good reason not to. In a naive patient, there's almost never a reason not to use a regimen that includes only 100 mg of ritonavir.
Myles Helfand: When is there a point in twice-daily dosing of darunavir/ritonavir?
Joel Gallant: There is a point for treatment-experienced patients. For those with PI resistance, that's definitely the dose to use. But what I think it tells us is that -- at least these lipid changes suggest to me that -- the guidelines are correct in narrowing the list of preferred PIs to boosted atazanavir and once-a-day boosted darunavir. Because why would you use a regimen where you had to use 200 mg of ritonavir unless there was a good reason? Why not use the lowest possible dose of a drug that clearly elevates lipids?
Myles Helfand: From here, let's move into a topic that I suppose has been growing in its urgency over the past couple of years, or at least has received a large amount of renewed attention: the idea of latent HIV reservoirs, and what happens when a person is on fully suppressive therapy over many years, but yet still appears to be developing potential complications, apparently related to HIV. There were a number of studies presented at CROI that examined the idea of taking suppressive therapy and further intensifying it with another drug, with the idea of maybe drawing out some of that latent HIV.
Joel Gallant: Well, there are two ideas around intensification. One is to try to improve CD4 response, and the other is to further suppress viral replication. So, for example, we had the ACTG study looking at maraviroc [MVC, Selzentry, Celsentri] intensification in people who were suppressed on antiretroviral therapy, but were having poor CD4 responses. And the hope was that, because maraviroc had been shown to have what appeared to be an independent effect on CD4 count, this would improve things. But in fact, it was pretty much a negative study: There were some people that seemed to benefit but, for the most part, there was no clinically significant gain in CD4 count.
That leaves us still not knowing what to do with patients who have poor CD4 responses. Although it's not much help to those patients, I would say that this further emphasizes the critical importance of starting people [on antiretroviral therapy] early, because then they won't get into that situation.
The other type of intensification [we saw presented at CROI] was raltegravir. There was a twofold rationale for this. One was, again, looking at CD4 increases. There had been a little hint of CD4 improvement with earlier raltegravir intensification studies. That was not seen with these [studies at CROI, in which raltegravir intensification] didn't seem to make much of a difference in CD4.
The other idea was to see whether you could take people whose viral loads were under 50 copies/mL, but not under 1 -- in other words, they have some low-level viremia in that 0 to 50 range -- and further suppress it. The idea there being that maybe it's better to have a viral load of less than 1; maybe that would reduce inflammation and immune activation. But also because, from a pathogenesis standpoint, it would tell us whether or not there is ongoing replication of HIV despite therapy -- and that's a really important question.
Most of these studies have not shown any change. You take a person whose viral load is, let's say, 20, and you give him raltegravir, or other drugs. In almost all of the studies, we've seen no difference. What that probably indicates is that there really isn't viral replication going on. This low-level viremia that we see is probably not a function of replication, but a function of release of virus from reservoirs. That's good news, in the sense that we really are suppressing patients' viral replication with the therapy we have. But it perhaps also tells us that we're not going to be able to deal with eradicating reservoirs just with antivirals alone.
Myles Helfand: How long can reservoirs continue to release particles of HIV?
Joel Gallant: Probably as long as they exist. I don't think that the release of these particles is a bad thing; it's not doing any harm. It's just a sign that these reservoirs exist. These aren't viruses that are going on and infecting new cells, and replicating. The real issue is how we eradicate HIV from the reservoirs, not so much how we stop them from releasing virus.
Myles Helfand: As a whole, then, what does this tell us about the nature of latent infection and the power of intensification to really do anything of benefit?
Joel Gallant: I think it says that the way to deal with latent infection is not antiretrovirals, at least not the ones we have now; that we've already done the best we can do at suppressing the virus; and that if we're going to eradicate HIV, or if we're going to try to achieve what Dr. [Anthony] Fauci calls "functional cures," it's not going to be by giving more drugs. It's going to have to be by something that activates latent cells, wakes up the reservoir, or provides some sort of improved anti-HIV immunity. We've done about as much as we can do, in terms of viral suppression.
Myles Helfand: Anthony Fauci, who is the head of NIAID [U.S. National Institute of Allergy and Infectious Diseases], which is a major funder of U.S. HIV research, seems to be thinking in the same direction. He actually announced at this conference that NIAID was going to be focusing its efforts much more on issues related to prevention -- particularly vaccine development -- and eradication, perhaps at the sacrifice of research that focuses on existing treatment.
Joel Gallant: Yeah. You can see the bright side, and the dark side. I mean, who knew that in 2010 we would hear that NIAID was going to really focus on eradicating or curing HIV? For so long, the idea of eradication or a cure was just kind of pie-in-the-sky, and people didn't really talk about it seriously. Now they are, which is great.
Who could predict that we would be really downplaying the role of treatment? The implication is, well, treatment is good enough now, and it's time to move on. Maybe that's correct, in terms of having the greatest impact on the epidemic. But for people who have HIV, obviously treatment research is very, very important to them. So it's a good news/bad news sort of thing.
Myles Helfand: Yeah, exactly. I think it's a tough pill to swallow, no pun intended, for people who are living with HIV, particularly in light of the past couple of years in which we have seen growing signs of people with HIV developing a range of complications, particularly ones -- cardiovascular disease, inflammation, bone disease, CNS [central nervous system] issues, cancers -- that appear to develop at an earlier age than people who are HIV uninfected.
There was a good amount of research that was presented about all of these things at CROI. But the question is, how much of that [research] is going to actually continue?
Joel Gallant: Yeah. That's a very concerning question. I think that's really what's hot right now, is trying to figure out whether this so-called premature aging -- and I say so-called because I don't think it's necessarily a single phenomenon; it may be a collection of multiple phenomena going on at once -- but I think the question is, to what degree do we prevent that with HIV therapy, versus how much of that is going to happen regardless of therapy. I think that's one of the big unanswered questions. There's no question that people do better if they are on therapy than if they're not. But do we completely eliminate the risks by putting people on therapy?
I think the answer we're beginning to see is no, that there are still things that happen, even when you're treated. And we desperately need to continue to research those issues if we're going to begin to see these long-term complications over decades of therapy.
Myles Helfand: What did the research at CROI tell us that's new in those areas?
This article was provided by TheBodyPRO. It is a part of the publication The 17th Conference on Retroviruses and Opportunistic Infections.
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