September 30, 2006
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Eric Daar, M.D., Harbor-UCLA Medical Center in Los Angeles, Calif.
In addition, there have been some recent studies, including those presented at this meeting, illustrating the kind of massive loss of immune cells, in particularly the gut -- which represents the largest immune organ in the body -- during the first days and weeks of infection. [Click here to browse through these studies or click here to read Dr. Daar's coverage of these studies.] It turns out that over 80 percent of the memory CD4 cells that are present in the gut are wiped out in the first couple of weeks -- at least in a monkey model. There are some data in humans showing very similar results.
So, based on the ability to perhaps preserve specific immune responses, and the immune system overall, there has been a continued interest in treatment. Great biologic reasons to treat, but still no good clinical data to tell us that if you treat people earlier, their outcomes are better, particularly their outcomes if you stop therapy since we're treating these people so early. Susan Little summarized the clinical part of that symposium [on acute infection here at ICAAC]. [To view her PDF presentation, click here.] She summarized the data that's currently available, talked about a few studies with conflicting results, including one that was published in the last couple of months in the Journal of Infectious Disease by Rick Hecht. Using data from a large network of people, studying primary infection -- including our group [the Los Angeles County Primary HIV Infection Recruitment Network], Hecht looked at people who were started early on therapy and then discontinued treatment just on their own -- not as part of a randomized control trial -- and [he] compared them to a group of people who were identified early, as well, but chose not to start therapy. It demonstrated that in the people who started [treatment] very early and then stopped, there were some modest improvements in the viral set point in that group, compared to those who didn't start.
But that's really the extent of the data illustrating that there are some true clinical benefits. So right now -- I think Susan [Little] emphasized this, and I certainly believe it -- what we do is, if we find these rare people [who have recently seroconverted and are in the acute infection stage], we sit down, we explain to them the rationale for early treatment and emphasize, I think, the fact that it is [still] theoretical, and that there are real risks of early treatment. Of course, [we emphasize] that they're all going to do fine because we're going to monitor them closely no matter what, and they'll start therapy when they need it. And allow these patients to be a part of the decision, where they want to take advantage of what may be a unique, once-in-a-lifetime opportunity, recognizing the limitations in the data at this point.
Don't you think we're going to be finding more of these people now, with HIV testing being recommended as a universal thing by the CDC [U.S. Centers for Disease Control and Prevention]? It might open up a lot more opportunities.
No, it's a great point, in that we may find that as we're testing more people [for HIV], in general, and perhaps more often, that we'll be able to identify a growing number of individuals that have been infected during the last six months or so.
That's another important issue with primary infection -- how do you define it? Is there a benefit from early therapy? How early is early enough? Or how late is too late? Do we need to try to treat these people in the first days or weeks -- literally, days or weeks of infection -- or the first months of infection? Right now, most of the biology suggests probably the first days and weeks. There is an ongoing, randomized control trial being performed through this Acute Infection Network and the ACTG [AIDS Clinical Trial Group] to take those people in the first six months and treat them, versus not treat them, and see if there's a difference in outcome.
So I think it's great these studies are going on because you're right: we may encounter more of these individuals who are in the first months of [HIV] infection. And it would be nice to have additional information to counsel them with.
I wanted to ask you a little bit about first-line therapy. Do you think we're moving toward initiating treatment at 350 CD4 count, instead of the somewhat nebulous before-it-falls-to-200?
The question about when to start therapy is a continued area of interest, unfortunately, not driven by a lot of good data. Because I think we have all but given up on the idea of ever doing the randomized control trial to define the best time to start therapy. So we continue to look at these cohort studies. [We] look at when people started therapy and see if that translates into differences in outcomes. And there are so many problems with those cohort studies, that it's really difficult to interpret anything.
That's how we have ended up with these guidelines [click here to read the latest treatment guidelines in PDF] that we have that say, treat at less than 200 or, with symptoms, talk about treatment in the 200 to 350 and defer [treatment] in the greater than 350 [CD4 count] arm. It's mostly based on these cohort studies, and also the realization that treatment works, even when you start late. So all is not lost if you wait till people's T cells go to 200. I think the concern about the risks of treatment was a big driving force in the guidelines shifting towards deferring therapy: the concerns about [drug] toxicity and the emergence of resistance and cross-resistance in limiting [future] options.
I think that what has occurred over the last several years is that treatment has gotten a lot easier, I think [it is] much better tolerated. We're hoping that a lot of the long-term [drug] toxicities may start to go away with some of the treatment strategies today -- particularly lipoatrophy and lipohypertrophy. And if you get rid of some of the concerns about toxicity, and make therapy one, two, three, or four pills, once a day, without side effects; I think there's a lot of reasons to consider treating early.
The bottom line is that we're still treating individuals. Everybody is different and dealing with different situations in their lives. I work in an inner city clinic. Some of our patients are ready to commit to therapy at 300 or 400 T cells; there are others that need to deal with their issues of depression, or their drug abuse, or alcoholism. And they need to make those a priority before they start therapy. And in those people -- often they will defer it a little bit longer.
So I think it's reasonable to start thinking about treating earlier, perhaps at [a CD4 count of] 350, but not for everybody. We still need to individualize.
Do you have a favorite first-line regimen? If so, why?
Another great question that will never be answered by the definitive trial. We do have some interesting trials that have come out in the last few months. There was this [study from Sharon Riddler presented at the International AIDS Conference,] ACTG 5142, which was the first head-to-head comparison between what most people consider the sort of first-line preferred options, which the DHHS [Department of Health and Human Services] guidelines have recommended -- either an efavirenz [Sustiva]-based regimen, or a lopinavir/ritonavir/[Kaletra-] boosted PI-based regimen as first line [Click here to view the PowerPoint presentation of the study made at the 2006 International AIDS Conference, or to read a review of this study, click here]. ACTG 5142 is the first study to actually compare them head to head. What it showed was that, if you looked at the proportion of people at undetectable [viral load] levels, the NNRTI or efavirenz arm actually did better than the lopinavir/ritonavir arm. The lopinavir/ritonavir arm had a little bit better increase in CD4 cells that is not completely explained. Then the other issue is resistance, in that we know that if somebody doesn't do well on an NNRTI, they almost certainly develop resistance, where with boosted PIs [protease inhibitors], they don't.
So we have that head-to-head comparison. The results surprised some people; didn't surprise others. I still think it's reasonable to consider the preferred options, an NNRTI versus a boosted protease inhibitor. Then you're left again coming back to whom you're treating. All things being equal, in a perfect world, the idea of being able to give somebody one or two pills once a day that is perhaps the most effective regimen available with an NNRTI makes a lot of sense.
I would say that more and more people are using that option for first-line therapy. But we have to balance that with the reality that it is a higher risk regimen and if things don't go right, there's a lot more to lose because of the issues surrounding resistance.
So what we do in the clinic is, we sit down with our patients; we share with them the risks and benefits of the different types of regimens and we help them decide what's the right decision for them. There are some people in which the simple, easy regimen is the right one. They will take it every day, and they'll do great. There are other individuals where it may not be. Efavirenz, the preferred NNRTI, is probably not the best regimen for women of childbearing potential. There are [also] people who have significant, poorly controlled, psychiatric diseases that may have bad reactions to it [efavirenz]. There are other people who will start it and not tolerate it. Then there are those people who, as much as we would like to think we're not starting therapy until they're fully committed, it's very difficult to assess whether they really are committed to therapy, in that there's a lot of risk if they start that therapy and it doesn't go well [i.e., they are not adherent]. In those people where the NNRTI might not be right, I think many of us would still consider using a boosted PI, at least up front, to see how they do. Then we can reassess once they've done well and they're undetectable.
Now on to multidrug-resistant patients. Do you really think getting multidrug-resistant patients on treatment, to undetectable levels, has become a reasonable goal?
Well, certainly the guidelines have told us that that is the goal. I think that's good news, and reflects some of the improvements in therapy -- particularly with the new sort of second-generation protease inhibitors like tipranavir [Aptivus] and darunavir [Prezista] -- which are going to be active PIs for a lot of [drug] resistant patients. The reality is, even if you look at the randomized controlled trials, and you look at what we're going through in clinical practice, there are many people that that's not going to be enough.
But that's all changing. And one of the highlights of the last six months is the realization that, in addition to those new second-generation PIs recently being available, and T-20 still being an active drug for a lot of people who haven't taken it yet, we also now have an expanded access -- the first, so-called second-generation NNRTI -- which may prove to be a very active additional drug for people. And that's etravirine or TMC125.
Then we have an expanded access, this Merck integrase inhibitor [MK-0158]. And there's a lot of excitement about the data from a naive trial in Toronto, showing these dramatic responses to dual nuke therapy with an integrase inhibitor [to view study, click here]. Then, here at ICAAC, they gave us the follow up data, the 24-week data of a randomized controlled trial of highly treatment-experienced patients who were given optimized background [therapy] with either placebo, or one of three different doses of this integrase inhibitor; and showed really amazing response rates, in the 60, 70, even 80 percent of people getting to less than 400, or less than 50. [To view a PDF of the slide presentation of the study made at ICAAC, click here. For our review of the trial, click here.]
So with these new drugs, along with the drugs that have been approved in the last year, it's going to probably increasingly become a reality. We still have to deal with some of the social issues that are obstacles to success. A lot of our patients who aren't doing well aren't doing well for a reason. They are dealing with some of the psychological and social factors -- the homelessness, the drugs, the alcohol -- that we still need to overcome in order to be successful. I think if we've learned anything, [it's that] it's great to have all of these drugs, but let's not rush to use them until the patient's really ready to do it.
How safe or recommended do you think structured treatment interruptions are?
There are so many different permutations of structured treatment interruptions. We have sort of been going through this over the last five years. There was the concept of using it in highly treatment-experienced patients with pan-resistant virus with the hope that their virus would then become susceptible, and then everything would go well on their next regimen. That clearly doesn't work. I think the majority of the data, or the bigger data set, suggests that not only doesn't that work, but it's risky. These people's T cells plummet, and they can get sick.
So we don't use it there. We're not recommending it routinely as a strategy to boost immune responses if people are fully suppressed. That's been looked at. There's no data to support that.
Really, the issue is: can you use it in a way to minimize the amount of exposure to the drug? That's one of the areas in which there is still active investigation. And there are a variety of different strategies that have been looked at. The one that's gotten the most attention was in the SMART trial, which is a large, randomized controlled, clinical endpoint trial where they took patients who had over 350 T cells and randomly assigned them to either continue their combination therapy, or to stop their therapy with the plan to restart it when they dropped below 250. [Click here to view the original trial presentation. For our review of the trial, click here.]. And that was presented earlier in the year, and demonstrated that there were worse outcomes in every assessment in the people who interrupted therapy. So the recommendations from that were that that's not a viable strategy.
Then the Staccato trial got presented actually at the same meeting [to see the published trial results, click here], and then published about a month or two ago -- which used a little bit of a different strategy, where they stopped people when their T cells were over 350. The only difference was that they restarted them when they dropped to less than 350, not less than 250. There, in a much smaller study, they showed no difference in outcomes with a lot less exposure to the drug.
So I think the bottom line is, right now, it's [structured treatment interruptions] probably not something that we should be routinely considering doing in our patients. But that doesn't mean that they can never stop therapy. There are lots of good reasons for people to stop therapy -- whether it's because of side effects, whether it's because they are having difficulties adhering with their therapy, because of drugs, alcohol, or depression, or any one of the other factors. Those are all good reasons to consider stopping therapy. It's just we need to realize that if those people have had low T cells in the past, in all likelihood their T cells will go down again. We need to be prepared for that and have a plan in mind to try to keep them from getting sick during the interruptions. But the idea of a planned strategy, where we're going to have you on therapy and then off therapy and back on therapy until we have more information is probably not a great idea.
I'd like to ask you about HIV drug development. What are your thoughts about the new drugs in development, and how they're going to change HIV management?
The new drugs are very exciting. In addition to the new PIs and the new non-nucleoside [NNRTI, TMC125], we have these new drugs in new classes that are oral agents that, at least preliminarily, look to be fairly well tolerated. The integrase [inhibitor] [MK-0158] is probably leading the pack, both because it's now available in expanded access and we've seen very promising early data in both treatment-naive and treatment-experienced [patients]. Not only have we seen good efficacy, but at least preliminarily, it looks like it's very well tolerated, and [there is] probably not a lot in the way of drug-drug interactions.
So you can envision right away it [MK-0158] being a useful drug for the treatment-experienced patient. In addition, there is this possibility that it could move earlier up in care. We have the small study showing that with two nucleosides -- sort of a traditional two-nukes-and-a-third-drug regimen, it was very effective. But you can envision it being in a nuke-sparing regimen, with the integrase inhibitor with a non-nuke, or integrase inhibitor with protease inhibitors ... or any one of a number of other combinations. So it could really have a big impact on how we manage patients, both up front, and further down the road.
Then the CCR5 inhibitors are another novel class. It's projected -- you know, we will see -- that one of them, maraviroc, will become available in expanded access, perhaps, in the first quarter of next year, if not sooner. We saw the first positive study in Toronto in a treatment-experienced population of patients, who were selected to only have viruses detectable that use CCR5s, since the drug is a CCR5 inhibitor. It illustrated those who receive an optimized background with the CCR5 inhibitor, compared to placebo, had significantly better reductions in viral load. So again, another active drug. Likely, up front, it's going to be used mostly in more treatment-experienced patients until we have a little bit more data. There's a lot more we need to learn about them. But it is an exciting new class to provide additional options.
So, we've got new drugs in existing classes that hold promise for experienced patients. We have two new classes in which the integrase -- virtually everybody who's not been exposed to it is likely to respond to it -- CCR5 inhibitors will be for the subset of people, probably, who have viruses that primarily use CCR5. It's very exciting. There are maturation inhibitors that also seem to be moving along pretty well in the clinical trials, also.
Another hot topic I want to ask you about is metabolic complications. Although there seems to have been a lot of research, we're no closer to finding out what causes these complications and, more importantly, how to reverse them. What are your thoughts?
When you talk about metabolic complications, you really have to break it down, I think, into its components. So we've got the problems with lipids, high triglycerides, high cholesterol. We have got the problems with glucose metabolism, diabetes. Then we have what's probably most troubling to our patients, the fat changes, the fat loss, and the fat accumulation syndromes. I think we have learned a lot about how the drugs contribute to the lipid and glucose problems. The glucose problems seem to be much less of an issue with some of the protease inhibitors more commonly used now than what were used in the past. Lipids continue to be an issue, but as we have more options, it's easier to work around that. We fully appreciate now, I think, what contribution [to these complications] various nucleosides have, and different protease inhibitors, and even non-nukes. So we can at least consider switching therapy as a strategy for people in which these become significant problems, along with [prescribing] lipid-lowering therapy and, of course, counseling people about other ways to reduce their overall risk for cardiovascular disease.
The fat loss and fat accumulation syndrome, I think, is the big issue. That's where patients are really disturbed. It's stigmatizing. It causes real significant physical complaints. As you say, there have been ten years of research and a real focus. There's been some progress, but we still have a lot of unanswered questions. I think we know a lot more about the lipoatrophy part, which is probably the more common, at least in the previous era, in that there seems to be a strong association with nucleosides, and particularly select nucleosides -- d4T [stavudine, Zerit]; I think every study suggests that was the biggest culprit -- much less so, AZT [Retrovir]. We have seen some real promising data in the past with abacavir-containing regimens, suggesting that this is not going to be a big problem with those drugs. We have even more compelling information recently with tenofovir, and follow up data from the 934 study, which randomly assigned people to AZT and 3TC [lamivudine, Epivir], versus tenofovir and FTC with efavirenz [emtricitabine, Emtriva]. And they actually looked at subcutaneous fat in the populations that received the different drugs, and showed not only was there more fat in the tenofovir/FTC arm in this subcutaneous compartment; but it actually seemed like it was increasing, at least during the second year of therapy.
So a lot of us are optimistic. I think we're starting to see in our clinic that, as we move away from some of the older nucleosides -- particularly the thymidine analogs, like d4T -- and move to some of the non-thymidine analog contained nucleosides, that perhaps lipoatrophy will become a thing of the past for people on their first or second line regimens. But we're still going to have those salvage patients that we need to use whatever we have, in which we may still see it.
We also realize that we have data -- again, mostly with d4T, but a little bit with others -- that if you identify this problem, and you switch, it may be at least in part reversible, or you can stop the progression.
So I'm optimistic about the lipoatrophy part. [In terms of] the lipohypertrophy [fat accumulation]: I continue to be convinced that we really have no idea what's doing it. A lot of people have this perception that it's protease inhibitors. But I'm not sure the data is very strong about what drugs we can avoid to prevent it from happening, or what to do when it starts to happen. So I think that's an area where we still need a lot more research.
Related to this, I think, one of the most feared of the complications of HIV or HAART is cardiovascular disease. Do you think the risk is HAART, HIV, a combination of the two, or something else altogether?
It certainly has gotten a lot of focus, based on some case series showing some premature cardiovascular disease in people with HIV disease. There's reason to believe that some of the traditional risk factors are contributing into it -- you know, inactivity and obesity, and certainly, smoking, which has been a very common finding amongst many of the people who are presenting with cardiovascular disease. Then there's the lipid issue. You know, some of it is, people are getting older. So they are going to have the usual risk factors. Some of them are just genetically predisposed to having this dyslipidemia. Then, as we were talking about, some of the drugs are contributing to the problem, as well.
We have pretty good data from the D:A:D study that demonstrates following a large number of people over time that there's a relationship, an independent relationship, of the duration of what they call combination antiretroviral therapy and the development of cardiovascular and cerebrovascular events [for coverage of this study, click here.]. The number of events continues to be very small. There are a lot of other factors that are contributing. Yes, therapy is contributing to some extent. But other factors, some of which you can do something about -- like smoking -- are probably contributing even more.
So I think the focus right now is that we need to monitor people for the traditional risk factors, we need to monitor the lipids, we need to do what we can to keep dyslipidemias under control -- whether it's by shifting their therapy, if it's appropriate, or putting them on lipid-lowering therapy, we need to encourage people to watch their diet and exercise -- these are the hard things -- and certainly quit smoking, if they're smokers. Those are probably the most important things we can do to try to prevent this problem as we learn more about it.
And my final question: What do you think has been the most unexpected news in HIV research this past year?
I think there are probably a lot of things that are worth mentioning. But to me, the evolution of new drugs, and the fact that we have new drugs and new targets all emerging almost simultaneously, makes me and a lot of my colleagues think that we may be at another sort of turning point in the epidemic -- at least in the developed world. Probably nothing like what we saw in '95, '96, with the availability of protease inhibitors and the recognition that combination therapy really dramatically reduced morbidity and mortality. But it may be something close to that -- something that will actually be palpable and that we'll feel -- that opportunity to be able to give even the most treatment-experienced people two, three, or more active drugs, and perhaps get them to undetectable levels, with the hope that they'll stay that way forever is really extraordinary.
Throw on top of that the fact that many of the drugs that we have used in the past have gotten increasingly easy to take. I mean, one pill, once a day, for some of our treatment-naive individuals, is a huge milestone. While I think we all predicted that was going to come, you put that together with all of the new drugs and new classes that are all coming on the scene simultaneously ... We had two drugs become available in expanded access almost in the same week. I think it's really extraordinary!
Thank you, Dr. Daar.