This Month in HIV: Top 10 HIV/AIDS Medical Stories of 2006
In The Body's inaugural "This Month in HIV" podcast, we shine a spotlight on the top HIV medical stories of 2006. To provide a rundown, we talked with Dr. David Wohl, a researcher and clinician at the University of North Carolina-Chapel Hill and an expert at The Body's "Ask the Experts" forums.
Each year, thousands of HIV-specific study results are reported in clinical journals and presented at an assortment of HIV/AIDS conferences. But at the end of the year, which of these studies really mattered?
That's where Dr. Wohl comes in: Since 2003, he's authored The Body's annual summary of the top 10 HIV research reports of the year. In this exclusive podcast, The Body's Editorial Director Bonnie Goldman talks with Dr. Wohl about what he thinks were the most important HIV-related medical stories of 2006. If you want to stay up-to-date on HIV medicine, this is one report you won't want to miss.
We've provided an assortment of options for you to listen to or read this inaugural broadcast. You can listen to the podcast online using our player. If you'd like to listen to the podcast later or put it on your digital music player, you can download the entire 62-minute podcast in a single file or download it in three parts (Part 1, Part 2, Part 3). Not in the mood to listen to a podcast? No worries; you can read a summary of the interview or plow into the full transcript.
Dr. Wohl, tell me: What did you think was the number one HIV research study of 2006?
I think, absolutely, the SMART study was the number one study of the last year. It got the most buzz; it generated the most controversy; and it was one of the most surprising results we have seen from a clinical trial in HIV in a long time. This is a very straightforward study, trying to answer a question that's been there for a long time, which was: Do you need to take therapy, HIV therapy, all the time? Or can you take breaks? Can you take holidays, and decrease exposure to the HIV drugs and therefore possibly limit the problems that we see in people who get HIV therapy -- namely, the complications of drugs, which are high lipids and diabetes and perhaps liver damage. [To read more coverage of the SMART study from The Body, click here.]
So the idea behind this was: Let's give people therapy until their T-cell counts hit around 350, stop it, and then start it up again at 250 -- versus people who just stay on therapy [the entire time]. So they randomized over 5,000 people, in 33 different countries, to treatment interrupt -- let's start it and then stop it, based upon your T-cell count -- or [in the other groups] continuously take their HIV therapy.
Lo and behold, what they found was that actually interrupting therapy, doing the treatment interruptions, was hazardous. People had more problems. First of all, more people died in that arm. Second of all, more people had the toxicities that we usually think about with HIV therapies. So this is bad news. The study was actually stopped early. So I think, on the weight on the evidence that they found, and the importance of their results, that has to be number one [HIV research story of 2006]. It teaches us that interrupting therapy, and tolerating low CD4 cell counts, in the history of bad ideas, is a pretty bad idea. [To read more about structured treatment interruptions, click here.]
But don't you think that one of the interesting things of the study was that the people who did get sick, or did die, did not have low T cells?
The way it turned out was not exactly that. It turned out that people with higher CD4 cells had an even greater risk with treatment interruptions than people who continued on therapy. That's where you saw the biggest difference, as far as bad outcomes, between the two arms of the study. In the low CD4 cell count group, both arms had people getting sick and people dying. So it wasn't that -- oh, you have a 50 CD4 cell count and you interrupt therapy and nothing bad happened to you. It did, but bad things happened to people who continued therapy, who had a low CD4 count, too. But it was the people who were doing really well -- high CD4 cell count, low viral load -- who did treatment interruptions, who suffered the worst.
Does this study end the idea of a structured HIV treatment interruption?
The notion of structured treatment interruption is not dead, but it's on life support. It's not doing well. This study really puts a chill on any notion of doing treatment interruptions. Granted, some people will say, well, the problem here wasn't so much treatment interruptions, but that they tolerated low CD4 cell counts [and] two hundred and fifty CD4 cells is just too low. Maybe if the safety net was raised a little higher, people could have done well. But, boy, it's going to be really hard to do a [treatment interruption] study now, unless you have incredible safety mechanisms built into the study.
So the take-home message is: HIV is bad, and treatment is good.
HIV is bad, treatment's good, and funny enough, cardiovascular disease, hepatic disease -- that's liver disease -- as well as kidney disease. So heart, liver, and kidney disease were more common in people who stopped their therapy -- meaning that maybe HIV itself has a role to play in these so-called complications of HIV therapy, and that actually being in HIV therapy might be better for you, as far as these are concerned. That's why it's number one.
What is number two, then?
Number two is a clinical trial. It's called ACTG, and that stands for AIDS Clinical Trials Group. That's a national, federally funded network of sites across the country doing research on HIV. [The] ACTG study is called 5142 and this study [was] straightforward. It pitted [against each other] the two major therapies that are listed on government guidelines for initial therapy of HIV: One is called Kaletra [generically known as lopinavir/ritonavir] and one is called Sustiva [generically called efavirenz, also known as Stocrin]. It pit them against each other in people who'd never been on therapy before.
There was a third arm, where people just took those two drugs without any other drugs. As you know, most people will take Kaletra or Sustiva with two nukes [NRTIs], such as Truvada [generically called tenofovir/FTC] or Combivir [generically called AZT/3TC]. People [in the trial] could choose their nukes in those two arms [of the study]. So there's a Kaletra arm and two nukes; there's a Sustiva arm and two nukes; and then there's a third arm of just Sustiva and Kaletra. [To read more coverage of this study from The Body, click here.]
The really interesting thing about this study was, again, unexpected results. After 96 weeks of therapy, people who got Sustiva -- a greater proportion of them -- had less than 50 copies on their HIV viral load, compared to the Kaletra group. The Kaletra/Sustiva arm together; that was sort of in between. It was significantly different between the Sustiva arm and the Kaletra arm, in favor of Sustiva.
When you look at T-cell count, however, though, remarkably the people on Kaletra and two nukes had a greater gain in CD4 cell count statistically than people on Sustiva. Both groups had increases of over 200, but there was a bit more of an increase in the people on Kaletra. Another aspect of this is the side effects. About the same proportion of people taking [either] Sustiva or Kaletra with two nukes had the same amount of side effects. It really wasn't that much of a difference between the two. When you look at really bad lipids, especially bad triglycerides, there was no difference seen at all. That's interesting because many people think that Kaletra, of all the drugs, is more likely to cause really big increases in triglycerides; [and most people think this is] much less [true with] Sustiva. But as far as high-grade triglyceride levels: We didn't see any difference between the two of them; [in fact] it was fairly unusual -- less than 6 percent of people [had high-grade triglyceride levels].
As far as [HIV drug] resistance goes: no surprise there. People on Kaletra just don't develop resistance to it that easily, even when they fail the drug, or a regimen with the drug in it. As opposed to Sustiva, where it's easier to get resistance. People who do fail it -- and remember; the majority of people didn't fail these drugs, or didn't have these drugs fail them -- but of the few who did develop resistance, you did see more resistance to Sustiva and to a nuke that they were taking, [for example,] Epivir [generically called 3TC or lamivudine]. So that's not a very big surprise.
On the whole of it, we see that these two drugs have some strengths and weaknesses, relative to each other. People are going to have to decide: "What's more important to me?" And different people will come up with different answers.
Do you think this study helps us individualize treatment choices better? For instance, if somebody is having problems adhering, then maybe Kaletra will be better, because there's less chance of resistance occurring. If somebody needs to boost their CD4 count, because they start treatment when they have a low CD4 count, they might want to try Kaletra, also.
Absolutely. I think that that's one example. Or it could be the convenience of Sustiva now -- which is included in the new one pill, once a day combination of Atripla [which contains Sustiva/Viread/Emtriva, generically: efavirenz/tenofovir/FTC]; maybe that would mean I'm willing to take the risk that if this person develops resistance, they're going to get resistance to two of the medicines in here. But it's simple and easier [than that]. A greater proportion of people [who were] taking the Sustiva got [a viral load of] less than 50. So I think, on one hand, you could look at it one way; on the other hand you could look at it a different way. The clinician and the patient have to take these [different options] and decide, well, what was more important for me in this particular study? What's better?
We're talking about two drugs that -- the majority of people do really, really well on these therapies -- and what we're talking about is actually really fairly moderate differences between the two. Not rip-roaring -- they're statistically different -- but I think both of these regimens are really good choices. But there are, again, some strengths and some weaknesses to each.
This was a government study?
It was. It wasn't funded by the pharmaceutical companies themselves. It was done by the U.S. government.
Is it really important to have a viral load of less than 50? Shouldn't the drug win if it can do that?
Yes. Having a viral load of less than 50, I think, is really important. I think the less virus you have, the longer [you have it], the better [it is]. I think that for people who have had a lot of treatment history, who've been through the wringer and are veterans of lots of different therapies, and have had a really hard time getting their viral load down; they shouldn't feel bad that their viral load isn't necessarily undetectable. But for initially starting therapy, people who have never been on therapy before, getting your viral load less than 50 and keeping it there is really the hallmark of a drug therapy that works really well.
Both these drugs got a lot of people's [viral load] down [to] less than 50. The problem is that there were some differences where, in the Kaletra arm, you saw more people get [viral loads] above 50 subsequently, or not get below 50 when they needed to. In the Sustiva arm, you saw a little bit better success. But there are counterbalancing forces that you mentioned, such as the resistance, and also the T-cell count gain that we saw with Kaletra. So on the whole, it's hard to say that one of these drugs is better than the other. They're different.
We didn't talk about side effects profiles. Kaletra has more side effects -- stomach problems -- and Sustiva has other kinds of problems. So that's another choice people have to make. What's really interesting is that, when we looked at the study, when you look at people who come off of their therapy either because of viral problems -- their viral load is not responding the right way -- or toxicity; using those both together, we saw that Sustiva was better than Kaletra, in this particular study. When you look at serious side effects, though, we didn't see any major differences between the arms.
There's going to be more data coming out very soon about this study. We may see that there's more diarrhea on one arm or more sleep problems in the other arm, as you might expect. But so far, right now, when we have only just the serious adverse events that have been presented so far, we don't see major differences between the two arms. So tolerability wise, it may come down to some of the more mild side effects that can certainly be troublesome. But the life-threatening ones: We didn't see a big difference between the two at all.
I am a little confused why this is a top ten study when the results are similar. They're both very good drugs and they both did more or less the same in the study. So it's nice that it showed that, but we kind of knew that.
"So for me, and for, I think, a lot of clinicians who are, I'm sure [thinking]: 'Should I prescribe Kaletra or should I prescribe Sustiva?' ... Now we know for sure -- this is what this one does; this is what that one does; and that's why I'm going to choose this one over that one."
I think the part that we didn't know, and why I really feel it's important is: One, we really didn't understand how these drugs would perform when compared with each other. I think that that alone is helpful. They have each been studied against other drugs and they've always come out at least on top. Nothing's ever beaten these two drugs. So when they're pitted against each other, you really have a better sense of what they're able to do. So for me, and for, I think, a lot of clinicians who are, I'm sure [thinking]: "Should I prescribe Kaletra or should I prescribe Sustiva?", the ambiguity that we had is really eliminated. Now we know for sure -- this is what this one does; this is what that one does; and that's why I'm going to choose this one over that one.
For clinicians, for the doctors, this has really been a big deal because the [U.S. treatment] guidelines say we could choose either one, but there's been no data to help us understand. Well, which one should we choose? [When] a study comes out and shows that there's some balance between the two -- well, that's research. That could be good. Then it makes us feel maybe it's okay, no matter which one I choose. I could flip a coin, and people are going to do generally well. But the key thing here is, the drugs didn't perform exactly identically. There are differences between them. We're going to find out a lot more about their differences in the next month, because there's going to be a major U.S. conference here, and the second part of the data is going to be presented. I think we're going to see even more information that could help us understand the relative differences between these two agents. So stay tuned.
Great! Now we're up to top story number three.
Number three is actually three studies in one. I couldn't decide. No one of these trials was good enough to be number three, so I combined three different studies to make sort of a clinical trial potpourri. I'm going to go through them very quickly.
One is called the KLEAN study -- that's K-L-E-A-N -- the KLEAN study. Snazzy name. [To read coverage of KLEAN from The Body, click here.] It also was a comparative, head-to-head trial. Again, clinicians love these [head to head trials] because they help us understand what's the best thing to prescribe to patients. It compared our friend Kaletra again, versus Lexiva [generically called fosamprenavir, also known as Telzir]. Lexiva's another protease inhibitor. It's not been as popular [as Kaletra]. It's also boosted with Norvir [generically called ritonavir], and Norvir is already built into Kaletra. So [Kaletra and Lexiva] are similar in lots of different ways. This, again, was studied in patients who were treatment naive, [i.e., they] never had been on HIV therapy before. Lo and behold, as opposed to what we saw in the study I just described: these two drugs were almost exactly identical in getting the virus down, getting the T-cell count up, in how much resistance we saw, and in their tolerability.
The big thing from this study was, a lot of people perceived that Kaletra would cause more lipid problems [than Lexiva]. It turned out there were no differences as far as cholesterol and triglycerides in this study -- between the two arms. So I think this is a very neat study. I think it was nice to see the differences, that there were no major differences at all, and that these different protease inhibitors are acting very similar. There are other data, looking at each of these drugs compared to other protease inhibitors, that show similar sorts of equivalents. I think that this whole class of drugs is going to turn out to be more alike than disalike. So that's why I like that study.
Was it this study that gave Lexiva a place in the preferred list?
It absolutely helped secure Lexiva a preferred spot on our [U.S.] government guidelines. No longer does it just list Sustiva and Kaletra; now Lexiva's there, as well.
That's a perfect segue to the second study that I'm going to mention as part of number three, and that's a study of Reyataz [generically called atazanavir], because Reyataz has also been added as a preferred agent to the public health service [U.S. Department of Health and Human Services HIV treatment] guidelines. This is a study that compared Reyataz against itself. How's that for being clever? They took Reyataz, which is usually boosted with Norvir, and compared it to Reyataz without Norvir. The idea here is that Reyataz without Norvir has been studied against Sustiva in the past, and turned out to be just as good as Sustiva. [To read an abstract of this study, click here.]
So, here, they wanted to say: What happens when you boost it with Norvir? What happens, as far as getting the virus down, and as far as side effects? The bottom line for this study as well was that there was a difference. Overall, both drugs performed rather well. But what we saw was that the people who got the boosting [of] Norvir with their Reyataz: we saw more side effects.
"We can see that triglycerides and total cholesterol actually went up significantly more in the people who got Norvir with their Reyataz [as opposed to] the people who just took Reyataz without Norvir."
On the other hand, when you look at the people who didn't get the Norvir with their Reyataz, there were a little bit more virologic failures. The last part of it was, when you look at lipids: Reyataz has been touted as a drug that is lipid friendly, as opposed to the other protease inhibitors. Well, when you take some Norvir, some of that friendliness goes away, and we can see that triglycerides and total cholesterol actually went up significantly more in the people who got Norvir with their Reyataz [as opposed to] the people who just took Reyataz without Norvir.
I think these are really helpful data for people to understand. Previous to this, believe it or not, despite Reyataz plus Norvir being a very popular therapy, we didn't have data on that combination of Norvir and Reyataz in people who'd never been on HIV therapy before. So it was really just long in coming and was refreshing to see. For people who are really interested in their cholesterol -- as many, many patients are -- it was good to understand just exactly what Reyataz plus Norvir does to lipids.
Has there ever been a study comparing Reyataz and Norvir with Kaletra?
There is a study that's going on right now. It's being sponsored by the makers of Reyataz. Again, it's a treatment naive study -- people who've never been on treatment before. I'm really looking forward to those results.
With those results available, we'll really know more. Like the other study, the 5142 study, we'll know how Reyataz rates in terms of the top preferred drugs.
Because we still don't know that, right?
We don't know. I think that as you get these drugs on the preferred list, we have to understand: Which one of them might be better than another? Of course, this comes down to [the question]: Is this just us comparing apples and apples? We might be. But these are major decisions. When we prescribe a therapy for someone, this is going to maybe be for years, if not life, for some people, who do extremely well. I think it's worthwhile to have a study tell me [when] one of these preferred therapies might have some advantages over another.
Exactly. Okay. Are we done with three, and up to four?
No. The last thing on three -- and it doesn't require even as much conversation, because these are results that have been talked about before. This is a Gilead study -- Gilead 934. [To read coverage of Gilead 934 from The Body, click here. To read an abstract from the study, click here.] The study looked [at] Combivir versus Truvada when either one of them are paired with Sustiva. Now this is shifting from the protease inhibitors and the non-nukes [NNRTIs], like Sustiva, and shifting over to look at the nukes. Combivir and Truvada have been in a death battle for the last several years for market share. Really, there weren't a whole lot of data that were out there comparing the two. This study is really the definitive study. It's gone on for long enough now that we've got some really good data.
"The bottom line for this study is that both of these drugs [Combivir and Truvada] -- when combined with Sustiva -- can get the viral load down about the same."
The bottom line for this study is that both of these drugs [Combivir and Truvada] -- when combined with Sustiva -- can get the viral load down about the same. There are no major differences between the two in getting people less than 50 copies on their viral load.
The differences are that early on, during the first year of therapy, there are more side effects that you see in patients on Combivir. These are initially starting patients [treatment naive]. It's not people who have been on therapy for years and years. These are people who are just starting therapy, during the first year. [We saw] more anemia and more AZT-related side effects [were seen] in the Combivir arm than we saw in the Truvada arm. But overall, when you just look virologically, it looks better.
Immunologically, there is a bit of a bump [increase] in T-cells in people who are taking Truvada, a greater bump than we saw in the Combivir arm. But overall, I think, it's reassuring that these therapies look pretty equivalent, and that Truvada can hold its own. A lot of people complain there's not as much data about Truvada. But I think this study and other studies of Truvada, or drugs like Truvada -- Viread [generically called tenofovir] and Epivir [known generically as 3TC, lamivudine] -- previous studies of that have looked good. I think it shows us that Truvada certainly deserves its place as a preferred agent, up there along with Combivir.
So I think this is an important study. Again, with the other ones, I think this helps us understand a little bit more about how to take therapy, and how to prescribe therapy.
"So in the most strict sense -- just looking at the proportion of people who get [to a viral load of] less than 50 -- there wasn't any difference between the two drugs [Combivir and Truvada]."
There was a lot of press after the study results were released. The implication, in some of the coverage, was that if you're on Combivir you should change to Truvada because it was so much better. Is that what the study suggested?
Yes, well, it's interesting because when the study was designed, the major result that they wanted to look at, was how many people got down [to a viral load of] less than 400 copies, not less than 50. That's been a strategy that's been used a bunch of different times. When you do look at getting less than 400, the advantage goes to Truvada. But I feel we should be looking at the same sorts of things we look for in our clinic. I look for people to get less than 50. So in the most strict sense -- just looking at the proportion of people who get [to a viral load of] less than 50 -- there wasn't any difference between the two drugs [Combivir and Truvada].
So is one better than the other? I think this study shows that, again, they both are potent. There are some differences: Tolerability-wise there are some differences between the two. But, boy, it wasn't like completely blown out of the water. Combivir wasn't blown out of the water in this study. I think that people who are on Combivir and are not suffering from any of those side effects and have been on the drug for more than a year can expect not to really develop a whole [lot] of them -- should not expect to develop new toxicities related to this. So I think that I have been reluctant to switch people who are doing very, very well. That's not to say people who've been on Combivir, which is a twice-a-day medicine, haven't come into the clinic saying, "I read about this new once-a-day medicine. Can I switch over?" I have no problem switching them over.
What about fat wasting and Combivir?
I'll touch upon this in a few minutes, when I talk about another study. But in this particular study there were DEXA [dual energy x-ray absorptiometry] scans done, and those are scans that can look at fat in the body, in different compartments. It found that there was a difference between the two study arms, in that people on Combivir tended to lose fat in their arms and legs, where people on the Truvada gained some fat.
Now the rub comes in: The sponsor of the study did not build in these DEXA scans at baseline. So they don't know what people were like when they first started. The first time DEXA scans were performed were at week 48. So that means people had been on therapy for 48 weeks. Then they got another scan at week 96 of the study. So we're looking at changes that occur after week 48; that's not the cleanest way to do things. There will be another study, that I'll talk about in a few seconds, that found a very different result; that was done a little bit more rigorously.
So we still don't know. Perhaps it's the Retrovir in Combivir that might be causing the wasting.
It might be. Retrovir or AZT has been described as being responsible for fat wasting -- certainly nowhere near Zerit [generically called stavudine or d4T] -- but I think that the data are pretty mixed right now. I do think that -- and we'll talk about this again in a minute when we talk about this other study -- it also depends what you're taking with your AZT or Retrovir [generically called zidovudine or AZT]. If you're taking certain medicines, it seems to make things worse. So I think that a year ago, I would have told you that I thought AZT can cause some fat wasting. Now I'd have to qualify that a little bit, based upon some of the results we're seeing from other studies, as well.
Great. So, on to the next one?
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This article was provided by TheBody.com. It is a part of the publication This Month in HIV.
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