August 5, 2009
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I think it was pretty exciting. It exceeded people's expectations. There was a lot of grumbling before the conference that there wasn't going to be much new research, and that people were saving their data for CROI 2010 [the 17th Conference on Retroviruses and Opportunistic Infections]. But in the end, I think it turned out to be a great conference.
I think it also was especially good because it was back in Africa again. It's been nine years since the conference has been held in Africa. The Durban international AIDS meeting in 2000 was really a landmark meeting, because it brought attention to the developing world. I think that this conference brought attention back there, as well, especially to sub-Saharan Africa. There was a lot of participation by people from Africa. I thought it was a really great meeting.
Before we review various research categories, what do you think was the study that stands out, above all else?
I don't know if I would pick a single study. When I go to these meetings, I try to come away thinking: Was there a theme? Was there a kind of buzz? With respect to the best conferences over the years, you could always say, "I know the theme of that conference was such-and-such."
For this meeting, if there was a theme, it was the idea that the answer to a lot of the problems we face with HIV is treatment -- treatment, in terms of what's beneficial for the individual who is infected, and what's also beneficial for the prevention of HIV transmission from one person to another, or from mother to infant. On a population level, what is going to help us the most in trying to reduce the epidemic is treatment. [To hear the plenary webcast discussing HAART (highly active antiretroviral therapy) as HIV prevention and possible need for early treatment, click here.]
We've known this for a long time, of course, and there has been a lot of attention in the developed world -- the United States, Europe and other places like that -- on the benefits of early treatment. We're moving closer and closer to the idea of treating people much more broadly.
I think, at this meeting, we heard a lot about trying to apply this in developing countries. Of course, it's a huge task, and hard to know where the money's going to come from. But there was a lot of attention paid towards treatment as the most effective form of HIV prevention, and as a way of preventing death due to HIV.
Was there also talk about PrEP [pre-exposure prophylaxis], i.e., the idea of treating someone at high risk with HIV medications, and how that could be used?
There was talk about PrEP. Not a lot of data yet, but the studies are ongoing. We are beginning to see an interesting battle, or controversy, arise between the proponents of treatment as prevention versus the proponents of PrEP.
In other words:
It will be an interesting controversy, because they both probably work. But you have to wonder -- is it better to treat the people who have a disease, or to treat the people who don't? It will be interesting to see what happens.
Let's quickly go through a few research categories. The first on my list is: when to start HIV treatment. There's still a lot of talk about what's the right CD4 count for initiating treatment. Is it 500? Is it 350? Was there more information at this conference?
There was some information, although there was more attention on resource-limited settings than there was on the developed world.
I think, more and more, people are convinced that in the ideal world, if you have the money, and you have patients who are willing to take medications, that there's really a benefit to treatment at essentially any stage of disease, and that we, perhaps, have been focused for too long on CD4 thresholds.
In fact, there are bad things that happen to you with HIV, regardless of what your CD4 count is. And they are not necessarily due to immunosuppression, but due to the consequences of viral replication, which include chronic inflammation and chronic immune activation.
I think that that was less of a priority here in Cape Town. Instead, we were looking at data on when to start HIV treatment in developing countries.
Probably the most important study was the study that had gotten a lot of press right before this conference. It was the CIPRA HT 001 study that showed that people in Haiti, when randomized to start treatment at CD4 counts from 200 to 350, were less likely to die, and less likely to develop tuberculosis [TB] and serious complications, than those who waited until their CD4 counts were below 200, which was the standard in much of the developing world.
Now, of course, in developing countries, we're not at that point. [Editor's note: Current World Health Organization guidelines have not changed since 2006 and recommend treatment before someone's CD4 count falls below 200.] We have been advocating treatment at higher CD4 counts for some time. But I think it was really important that, for the first time, we saw a randomized trial that demonstrated this benefit in the developing world.
It's odd that anyone would wonder if there's a difference with respect to the developing world. We're all human beings, so why would there be any difference?
The issue, of course, is cost.
People hate to see double standards, but there are clearly a lot of double standards that were really brought to attention at this meeting -- not just with respect to the when-to-start question, but the fact that in developing countries, most people are using d4T [stavudine, Zerit] or AZT [zidovudine, Retrovir], which have almost been abandoned in developed countries.
In the developing world, they are not using viral load monitoring. They're using less frequent CD4 monitoring. They may have very limited options for second-line therapy, and almost no options for therapy beyond second line.
So, like it or not, we've got serious double standards. There was a lot of attention paid to how can we eliminate these double standards. How can we eliminate these discrepancies? But, at the same time, acknowledging that this is all being talked about in the setting of an economic crisis that's affecting the world and the money is not easily found.
I think in places like Haiti and Africa, where there's a lot of tuberculosis, in fact, you could argue that it's even more important to treat people early because tuberculosis is such an important cause of death, and tuberculosis can occur at relatively high CD4 counts, in contrast to the opportunistic infections that people in the U.S. tend to get at normally lower CD4 counts. So if cost weren't an issue, there would be a strong motivation to treat much earlier in places where TB is a highly endemic disease.
Were there other when-to-start-treatment trials?
No, not trials. Trials are, of course, few and far between. In fact, the START trial, which is being conducted in the U.S. and elsewhere, is still kind of controversial. [For information about the START trial, visit its Web site. If you're in the U.S., and want to join the trial, click here.] Some people feel that we need that trial to decide when to start HIV treatment. Others feel that the question has essentially been answered, that we don't need the trial.
Trials are obviously big and very expensive, and so a lot of our opinions and recommendations have been based, not so much on clinical trials, but on observational data, on scientific data about inflammation and immune activation, and also now on the growing data to support the idea that treatment decreases transmission of HIV.
Let's discuss the next category on my list: clinical trials of new and current antiretrovirals. I've noticed from the last few conferences that there doesn't seem to be that many drugs in the pipeline.
Not as much as we used to see, but it was encouraging that there still is a bit of a pipeline. The drug that got the most attention was the new integrase inhibitor from GlaxoSmithKline and Shionogi.4
It was a very short, 10-day monotherapy trial, but it showed really superb viral suppression at 10 days, with a well-tolerated drug that has a long half-life at a fairly low dose, and doesn't require ritonavir [RTV, Norvir] boosting, and is likely to be able to be co-formulated with other products. So that was pretty exciting.
But there weren't a whole lot of other drugs that were talked about at the same level.
Are there other drugs currently being studied that will be presented at future conferences?
Yes. There are still other nucleoside analogs [NRTIs], other non-nukes [NNRTIs], other CCR5 inhibitors. So there is still a pipeline. But I do continue to think that it will be several years before we see drugs that could rescue people who have resistance to the currently available options.
The next few drugs that are likely to be approved are:
So the next few drugs are going to be good drugs, but not drugs that are going to get us out of any messes or resistance that we might have developed. It will be longer than that before we see sort of rescue drugs, if you will. [For more on HIV drugs in development, click here.]
More reason to be adherent to therapy.
Yes. Take your meds and make sure you're on the right choice of drugs.
I noticed when looking at the IAS program, that there were a lot of drug trials for which longer-term data was presented.
Yes. Of course, this is important, but not always exciting, because you're seeing just longer-term data on studies that have already been presented. But these trials are important because they help establish the durability of drugs as well as the long-term safety.
For example, we saw data from a smaller, phase 2 study of Isentress for treatment-naive patients.5 We now have 144-week data (or essentially, three-year data) for this drug. It continues to be good. This was studied in combination with Truvada [tenofovir/emtricitabine, TDF/FTC], in comparison with Truvada plus Sustiva [efavirenz, EFV, Stocrin]. Since then there's been a larger phase 3 trial,6 but they don't have the same kind of long-term data that they have for this smaller study.
So Isentress still seems to be very tolerable.
Yes, very well tolerated and highly effective, with durability clearly demonstrated.
ARTEMIS is a study of the once-a-day Prezista [darunavir, TMC114] plus Norvir combination for treatment-naive patients, and CASTLE is a study of Reyataz [atazanavir, ATV] plus Norvir for treatment-naive patients. They continue to look good, with better lipid profiles and better tolerability, compared to Kaletra [lopinavir/ritonavir, LPV/r].
We've seen more with Selzentry, the CCR5 inhibitor, with the longer-term follow-up of the MERIT study. This was a study where Selzentry plus Combivir [zidovudine/lamivudine, AZT/3TC] was compared with Sustiva plus Combivir.9
In that study, Sustiva plus Combivir actually looked better, initially, but that was due, in part, to the fact that they were using the old Trofile assay, and thereby missing some people who really shouldn't have been on Selzentry, because of the tropism of their virus.
When they redid the analysis using the updated Trofile assay, a lot of the differences disappeared. We're not widely using Selzentry for first-line therapy, but the data continue to support the idea of it.
On to a study by Heiner Bucher10 that I thought was really interesting. It showed that people on Sustiva were less likely to experience treatment failure than people who were on Kaletra.
It showed that you were less likely to have virologic failure with Sustiva, compared to Kaletra. But that's been shown before in head-to-head trials. We have the ACTG [AIDS Clinical Trials Group] 5142 study that was presented some time ago that showed the same thing11 -- i.e., that you were less likely to fail on Sustiva, compared to Kaletra. But if you did fail with Sustiva, you were more likely to develop resistance. So there was a trade-off.
But I think it's pretty well accepted now that nothing has really beat Sustiva in clinical trials. The only possible exception to that could be Isentress; in a study of Isentress plus Truvada versus Atripla [efavirenz/tenofovir/emtricitabine, EFV/TDF/FTC], the results looked as good, but with better tolerability.12
In all other cases, a combination with Sustiva generally has been a hard combination to beat. So this Swiss cohort data just confirmed that.
There used to be a lot of interest in an all-NRTI regimen. At IAS, I noticed there was a study that said that a quad-NRTI regimen didn't seem to be very good. Was this a new study?
This is a study of Trizivir [zidovudine/lamivudine/abacavir, AZT/3TC/ABC] plus Viread [tenofovir, TDF]. So, the regimen consists of four nucleosides. I won't go into the details, but it did not look to be as good as our standard therapy.
People have lost interest in this idea. When the idea first came out it was attractive, because it meant relatively few pills, and you didn't have to deal with all the protease inhibitor [PI] side effects and that kind of thing. Subsequently, our standard treatments have become much simpler: once a day, with fewer side effects. We're trying to avoid drugs like AZT. When you use Trizivir plus Viread, you're stuck with the AZT, and all of its side effects.
The one advantage that this does have is that it's relatively free of drug interactions. So in places where there's a lot of TB, and where you have to use TB drugs like rifampin [Rifadin, Rimactane] that are very hard to use with protease inhibitors and non-nucleosides, this could be an attractive option. But I don't think this study has a lot of relevance for most of the people listening to this interview.
Another interesting treatment strategy that has been looked at in the past is the use of a single HIV drug, such as Kaletra, instead of a combination of three drugs. There used to be so many studies about Kaletra monotherapy. I noticed at IAS there was a presentation of a study looking at Prezista monotherapy. Any thoughts on this?
It's interesting, because there have been so many Kaletra monotherapy studies. But they have all been pretty small studies. None of them have been big trials. In almost every case, Kaletra monotherapy has looked pretty good, but never quite as good as Kaletra plus two nucleosides. No one's gotten too excited about it, because these small studies always had some kind of a flaw in them.
In contrast, this MONET study from Spain was a much larger study, comparing boosted Prezista once a day as monotherapy versus boosted Prezista with nucleosides.13 In this study, it looked just about as good, or as good, as using it with the nucleosides.
In those patients who didn't respond as well, they could quickly be suppressed by simply adding nucleosides. And as we saw with the Kaletra monotherapy studies, the consequences of not doing well on this were pretty minimal. I mean, you didn't see people developing resistance. So it's interesting.
This trial, because it is larger, is a more definitive one than we've seen with Kaletra. In addition, it's a much easier combination to give as monotherapy, because you're talking about three pills, once a day, as opposed to two pills, twice a day.
I don't know how widely this will be used, but it certainly has relevance in places, especially in the developing world, where you're looking for low-cost alternatives, and where you can't do resistance testing to find out whether the nucleosides are active. It's very nice to know that a second-line regimen with a boosted PI is going to work, regardless of what you combine it with.
So I think that this is certainly an interesting study, and also may have relevance for people who have a lot of nucleoside side effects, or reasons not to be able to take nucleosides.
So monotherapy is back.
Well, it's here. It's not standard of care. I wouldn't recommend it right now. But, at least with the boosted Prezista, I think these are the best results we've seen yet for monotherapy.
They also did a study in treatment-experienced patients, with twice-a-day boosted Prezista monotherapy, compared to standard of care.14 It didn't look quite as good. It wasn't bad, but as we say, it was not non-inferior. So I definitely wouldn't recommend this for a treatment-experienced group of patients, or people who have PI resistance.
Another interesting study that I noticed looked at using Isentress in a different way to see if it would reduce low-level residual viremia.15
Yes, that was interesting. There have been several studies like this -- not all of them with Isentress; some of them using other drugs.
The idea here is not to come up with a treatment strategy. These are essentially pathogenesis studies. The idea behind this is to try and figure out whether the reason people have low-level viral loads (I'm talking about below 50 -- viral loads too low to measure by standard tests) is because the virus is replicating at a very low level. In this case, you would worry about long-term consequences, such as resistance. Or whether this is due to something else. Is it just that the virus is randomly being released by resting CD4 cells, and that's what's causing it?
If this is due to viral replication, then by adding an additional active agent, you should further drive the viral load down. If the viral load is 20, and you add a new active drug, it should go down. Whereas, if it's not viral replication, if it's just release of virus that isn't replicating, then adding an additional drug shouldn't make any difference.
In fact, most of these intensification studies, including the one presented in Cape Town, showed no difference. So you take somebody with a viral load below 50, but greater than 1, you add another drug, such as Isentress, and you really don't see any difference in the viral load -- which, to a lot of people, suggests that your virus is not replicating when it's suppressed.
The interesting thing, I think, about this study was not the major point of the study, it was the fact that patients who added Isentress had a rise in CD4 count that was higher than those who didn't.
In all of the patients they switched over -- so, patients who added Isentress then switched to placebo, and patients who were on placebo then were switched to Isentress -- the people who added Isentress experienced a rise in CD4 count, despite the fact that their viral loads were no different.
There may be something to that. It will be interesting to look at this idea in larger trials to see if we can stimulate a CD4 increase with the addition of another drug. Isentress is certainly one of the ones that will be looked at.
Some patients can get their viral load undetectable with a regimen, but their CD4 count does not budge. It's been a frustrating issue for both people living with HIV and their health care providers. Is Isentress one of the few drugs that might work?
It may be. I wouldn't have said so until this meeting. When I saw the intensification study, it was interesting that the CD4 count increased, even though there was no obvious virologic benefit. I think it's worth pursuing this in a larger intensification study for people who are having poor CD4 count responses.
There's currently an ongoing ACTG study using Selzentry for that purpose. We'll see what that shows.
It's interesting that despite the fact that Sustiva always seems to do the best virologically, it doesn't do the best from a CD4 standpoint. Almost everything that you compare it with has a better CD4 response. This has been shown for protease inhibitors, for Isentress, for Selzentry.
It's not a huge difference, and probably not a meaningful enough difference to make a change in what regimen you would decide to start with. But it could have relevance for those people who have poor CD4 responses on antiretroviral therapy. There may be something to this idea of intensification, at least with certain drugs.
I would point out, though, that this is only a problem for people who wait until their CD4 is very low to start therapy. If we would diagnose and treat people at much higher CD4 counts, we wouldn't have to deal with this issue.
By waiting until your CD4 is very low, you run the risk that you've exhausted your immune system's ability to recover, and that -- with the possible exception of these intensification ideas -- there may simply be not much that you can do about it. The answer probably isn't more drugs; it's earlier treatment.
On to trials that looked at using unboosted drugs versus boosted drugs.
The ARIES study, presented by Kathleen Squires,16 was a study where everybody initially got Epzicom [abacavir/lamivudine, ABC/3TC, Kivexa] with boosted Reyataz; later, half of them dropped the Norvir because their viral load was suppressed.
Maybe a little surprising to me was that people with unboosted Reyataz did just as well as -- in fact, they did a little better than -- the people on boosted Reyataz. Perhaps that was because those on boosted Reyataz missed more doses due to side effects. But that didn't appear to be the case. So this study suggests that unboosted Reyataz is an acceptable option -- at least if you're taking it with Epzicom.
If you are one of those people -- I call them "ritonophobes" -- who just can't tolerate Norvir, even at 100 mg a day, Reyataz is probably the best PI to use.
With some of the other PIs, you either can't use them unboosted -- and that would be the case with Prezista, for example -- or you can use them unboosted, but you probably shouldn't. Lexiva [fosamprenavir, FPV, Telzir] is a good example, where unboosted Lexiva can lead to cross-resistance to Prezista.
I would point out, though, that you can't apply these ARIES data to the use of Truvada with Reyataz. With Truvada -- because of the drug interaction -- you have to boost it. So this study only applies to Epzicom plus Reyataz combinations.
What about using it with Combivir, or something like that?
You could extrapolate it to Combivir, because there's no drug interaction. It's just that people are less willing to use Combivir because of side effects. The nice thing about Epzicom plus Reyataz is it's a once-a-day regimen, where you take everything all at once.
I noticed there was a study about pitching Viramune [nevirapine, NVP] against Reyataz.17
It was specifically looking at Viramune plus Truvada, versus Truvada plus boosted Reyataz. The reason this is interesting is because there have been three very small studies that all showed that when people took Truvada and Viramune together, they had a poor response. They had a lot of early treatment failure and resistance. Nobody could figure out why that would be. On the surface it seems like it's a perfectly reasonable combination.
This is a much larger study attempting to look at that. Their overall conclusions were that Truvada plus Viramune was as good as Truvada plus boosted Reyataz.
I still have some concerns about the study, because although the overall conclusion came out that way, there was more discontinuation of therapy in the Truvada plus Viramune arm early on. And there was more virologic failure that was due to the investigators' decision that the combination wasn't working.
It's possible that what we're seeing is something very similar to what we'd seen in these earlier studies. I need to see the published results before I would recommend this as a standard regimen.
We have pretty much covered all of the antiretroviral trials. Am I right?
There are probably more, but these are the ones on my radar screen.
Let's go on to some complication trials. There was a surprising one about vitamin D deficiency, wasn't there?
Yes. Vitamin D deficiency is becoming a hot topic these days, especially if you live in a place where during much of the year you're not getting a lot of sun exposure. When we see vitamin D studies, we're finding huge rates of deficiency, sometimes serious deficiency, and it's very clear that blacks are more likely to be deficient than whites. That probably has to do with the fact that their skin protects them from both the benefits of the sun, and the risks of the sun. Fortunately, blacks tend to have denser bones, and so they are less likely to get osteoporosis than whites.
But one of the long-term complications of having vitamin D deficiency is loss of bone density, and softening of the bones. This has become a very hot topic. This study was done in London where, of course, they never see the sun.18 There were very high rates of vitamin D deficiency in this population -- with blacks being more likely to experience it than whites. The highest rates were during the winter months.
What was interesting was that they found that another significant risk factor for vitamin D deficiency was the use of Sustiva or Atripla. This is not something that's been observed before. I'm not sure if anybody's ever looked for it.
They had a hypothesis of why it might be that Sustiva could do it, based on its metabolism and its effect on drug metabolizing enzymes. That's just a hypothesis. Of course, this doesn't mean you shouldn't use Sustiva or Atripla. But I do think that there's growing evidence that we should be supplementing vitamin D, probably checking levels more often than we have been, and especially being aware of it in older people, who are at greater risk for loss of bone density.
What sort of supplementation would be necessary?
It depends on what test you're using. We usually measure 25-hydroxy vitamin D. In our particular lab, if it's below, say, 32, we consider that deficient. When you have fairly serious deficiency, you often have to use more than just an over-the-counter supplement. You have to use very high-dose vitamin D supplements, which you take maybe weekly, or twice weekly, for a few months. Then you can switch over to a standard supplement.
I have to say that I'm increasingly coming around to the idea that just about everybody -- unless you're in the sun a whole lot -- should be on a standard vitamin D calcium supplement and those with a more serious deficiency need to have supplementation done at a higher dose.
Sorry to belabor the point, but I think this is something that our audience is interested in. What would you consider a standard vitamin D calcium supplement?
They have the over-the-counter kind that often have about 400 units of vitamin D, with some calcium. If you took one of those twice a day, that would be a decent dose. If you're taking vitamin D by itself, maybe 1,000 units a day.
I think people are realizing that our old recommendation for what a standard amount of vitamin D is, was probably not enough. So, roughly 1,000 units a day. Of course, dairy products are a good source of vitamin D, as is modest sun exposure.
Now, on to a drug that has been talked about so much this year, that is Ziagen [abacavir, ABC,]. The big question remains: Does it pose a heart disease risk or not? Every scientific meeting held during the last year or so seemed to bring us a new take on this. Dr. Gallant, what was the news from IAS?
This has been a very interesting controversy. We first heard the data from the D:A:D study, and then the SMART study, and then the French Hospital Database study, saying that abacavir increased the risk of heart attack.19-21
The data became so overwhelming that people finally said, "Well, I guess it does." But everybody acknowledged that the data came from these observational cohort studies that have their limitations. They weren't randomized trials. But it just seemed like study after study after study was showing this association. You just couldn't ignore it.
The DHHS [U.S. Department of Health and Human Services] guidelines reacted, in part, to that information and switched abacavir from a preferred nucleoside to an alternative nucleoside.22 It was also based on ACTG 5202, which suggested that Epzicom was less effective than Truvada at high viral loads.23
But at this conference, now we have some data going the other way. There's a very large study from the Veteran's Administration database, which initially did find a higher rate of MI [myocardial infarction] with the use of abacavir.24 What they found was that if you controlled for two things, standard cardiac risk factors and chronic kidney disease, then that association between abacavir and heart attack essentially went away.
Their argument was that people with chronic kidney disease are much more likely to get abacavir because they can't take tenofovir, and people with chronic kidney disease are much more likely to have heart attacks. Thus, the reason you see this association between abacavir and MI is because you're taking the people at highest risk for heart attack and giving them abacavir.
At the same time, the investigators from the French Database study, which was presented at CROI in Montréal,21 also found an association but said if you corrected for things like substance abuse and injection drug use, the association went away.
I don't think this means that we have the answer. I don't think it invalidates the results of the other observational studies. We have to keep in mind that the methodology is different. The D:A:D study did, in fact, look at kidney disease. Even after adjusting for that, they still found an association. But they had a lot less kidney disease in their cohort.
I think this just reinvigorates the debate. It means that we don't know the answer yet. I'll be interested to see further analyses from the original studies, to see what kind of light that can shed on this controversy.
So it's not over yet.
No, I don't think it's over yet. I'm sure there will be a defense of the original studies. We'll have to see the publication of this VA [U.S. Department of Veterans Affairs] study. I would also point out that the VA study did not look at exactly the same thing as the D:A:D study. The D:A:D study found an association with recent abacavir use, but the VA study didn't look at exactly that. Because their data is different, they don't necessarily have the ability to look at exactly the same analysis.
But I think it throws a little cold water on this. It means that we're a lot less certain about this association than we were a few months ago, after the Montréal conference.
But the recommendations remain the same: If you have a preexisting risk for heart disease, then abacavir would not be the right choice.
It's not if you have a risk, but generally, multiple cardiac risk factors. The cardiac risk factors are high LDL [low-density lipoprotein] cholesterol, smoking, diabetes, hypertension, a strong family history of early heart disease -- things like that. If you have a number of those risk factors, the current recommendation is to try to avoid abacavir. But I think we just have to acknowledge that at this point we can't be certain whether what we've seen so far is a true risk with abacavir, or whether it's just a phenomenon of observational database analysis.
On to gender and race: Researchers presented the 44-week results for the GRACE study, correct?25
Yes. GRACE was an interesting study. It was using a Prezista-based regimen. But the point of the study was not what drugs you're taking. It was trying to enroll the types of people who don't tend to get enrolled in standard clinical trials -- specifically, women, inner-city women.
This study actually had a target goal trying to enroll a lot of women. More than men. If you look at most clinical trials, they are mostly comprised of men. They actually had rules at the various sites that did the study that you couldn't enroll a man until you had enrolled several women -- that kind of thing.
Unfortunately, what they found is that women did not do as well as men in responding to therapy. They talked about the reasons for the poorer response. They were reaching a group of patients who are very hard to enroll in trials, and often very hard to maintain in care. These were often inner-city clinics, with a lot of minorities, poor people, people with substance abuse issues.
The investigators are to be commended for the enormous efforts they went to, to recruit and try to retain these patients in care. But it demonstrates what a lot of people are up against.
I will say this: There is a potential for what we call selection bias in this study -- selection bias meaning that because of the way you select people for a study, you have results that aren't equal.
To try to explain this in the context of the GRACE study: If you're trying harder to enroll women than to enroll men, you may enroll more women who are not great study candidates than men.
In other words, you're going to really work hard to get women in, even if you have your doubts about whether a particular woman is likely to show up for visits and take her medications.
Whereas for the men, you're not making any extra efforts. You're just enrolling the men who show up and appear to be motivated. So this may be saying more about that process of candidate selection than it is about real differences between men and women.
On the other hand, there have been other studies that have shown similar results. Of course, women have issues with child care, with pregnancy, and sometimes with just less ability to make decisions for themselves. So some of this could be reflecting very real-life situations.
In terms of the treatment response in the women, what was the specific issue?
It was a greater rate of virologic failure. Interestingly, despite the poor virologic response, women seem to have better CD4 count responses, which was an interesting observation.
How soon after did the virologic failure occur?
Over time, the curves began to separate. So there's not any one particular time. The longer the study goes on, the more of a difference you saw in the study.
This wasn't related to adherence or anything like that?
I'm sure it was related to adherence, because there's no biological reason why a woman would not respond as well as a man. In other clinical trials, where you're enrolling a much more typical study population, you don't see differences between men and women.
I think that what this study is telling us is not that women are less likely biologically to respond to treatment, but that in real world settings -- where HIV is happening in disadvantaged populations -- there are enormous challenges for adherence for both men and women, but that women, in many cases, have more of those challenges that get in the way of their ability to remain on medications.
So it's a sociological finding.
Yes, I think it's sociological. It's very important. But I don't think it's important because of what it's telling us about the drugs, or about biology, but just about the obstacles to good adherence.
Then for women who are living with HIV and listening to this, it doesn't mean that they are more likely to fail as long as they're adherent?
Absolutely not. No. And we've seen that now in many, many other studies, where women do just as well as men if they're taking their medications at the same rate of adherence.
On to another interesting study, the FOTO study, which evaluates a treatment strategy involving five days on, two days off a Sustiva-based regimen.26 It's one of the few treatment interruption studies still around.
Yes. The argument, I think, the investigators make is that it's not really treatment interruption because adequate levels of the drugs remain in the blood during the two days you are off treatment. It's using Atripla, essentially, and the drugs that are contained in Atripla have such long half-lives that over the course of a weekend, you've still got adequate drug levels in your blood.
When you resume taking the drugs on Monday, you may have interrupted your dosing, but you really haven't interrupted your drug levels.
In this study, they found that people did as well with this five day on, two day off schedule as they did if they took it all week long.
Now, personally, I don't think this means you should do this. It's a relatively small study, and so they could have easily missed differences in effectiveness that would have been seen if a much larger study had been done.
But I do think that what it tells us is that, when you're using drugs like the ones in Atripla, which have long half-lives, you're protected against the occasional late or missed dose. It's probably one of the important reasons why Atripla always looks so good in clinical trials; it maintains really good drug levels, even when people don't have perfect adherence.
Think back to the old days of Combivir and Crixivan [indinavir, IDV], when perfect adherence was really what it took to succeed. It's just not that way anymore. I would not at all use this as an argument for taking five, out of seven, days of therapy, or even of intentionally missing doses. But I think what it means is that this is a pretty forgiving regimen if someone occasionally misses a dose.
It's ironic that you say it's a forgiving regimen, because when HIV drug resistance happens, it really happens.
That's exactly right. But I think that has to do more with how you miss doses than whether you miss doses. FOTO tells us that if you miss a dose here and there, it's probably not the end of the world. Where you see resistance is with a pattern of missed doses, where it's almost like a treatment interruption. People who go away for vacation and forget their meds for a week, or people who don't refill their meds and show up in clinic two months later. That pattern of repeated, sequential missed doses, where you get slowly declining levels of the Sustiva, such that your virus has a chance to learn how to become resistant. Then it's very, very easy to become resistant to this.
We've seen this. There was a Spanish treatment interruption study, where they stopped therapy for periods of time in patients taking Sustiva. They found that with every interruption, more and more people developed resistance. So a missed dose is one thing, but a missed week is a very different thing.
That just about wraps up the treatment-related research presented at IAS. Dr. Gallant, were there any other studies presented that you think were important for our audience?
I think we've hit on the ones that have the most relevance to the developed world. There are a lot of other studies about the prevention of transmission from mother to child, treatment during breastfeeding, and the effect of HIV therapy on TB that were probably some of the most important studies presented at this meeting, but are of less relevance to an audience here in the U.S.
When I was looking over the program, I noticed that there were more studies presented about developing world issues than in any other IAS conference that I've ever seen.
Yes, I think that's true. Part of it was because of where it was being held. This is the first IAS meeting being held in sub-Saharan Africa. The previous one was actually an International AIDS Conference. With every year, we see more and more research being done, more research money being available for resource-limited countries. And there's more data to be presented.
Because it was in South Africa, a lot of us said, "Oh, it's too far to go. It's too expensive. It takes too long to get there." That may be true for us, but it made it a lot easier for people in sub-Saharan Africa to go -- much cheaper than it would have been if it had been in Europe or the U.S. or Australia. So I think that really enriched the conference, and enhanced the value of it -- because there was so much data from Africa and so much participation from Africa.
I wonder too if many of the researchers from the resource-rich countries felt intimidated being in South Africa. After all, only 30 percent of the millions of people who need treatment can access it in South Africa. Was there discussion of this in the research community?
There was a lot of discussion of that. One of the other concerning things that came up repeatedly in this conference was the issue of interruption of supply of drug, and of the non-sustainability of some treatment programs, especially now with the global economic crisis -- with cutbacks in funding from both local governments, from resource-rich governments, and from other sources of drugs and money for treatments.
There is a real concern that we may see backsliding; we may see a loss of many of the gains that we've seen over the years in patients who have been on therapy. Then of course, there's the fact that, although we're doing better at getting people treatment, the rate of increase, the rate of spread of HIV, is still faster than the rate of increase in treatment. So we're always falling backwards, even in the best of economic times.
This is a real concern because, of course, the situation in places like Africa has always been tragic. But at least there's been this glimmer of hope that we're getting more and more people on treatment. To think that some of those people will not be able to stay on treatment, for economic reasons, is just heartbreaking, especially if you've been to these places and see what antiretroviral therapy has brought to these communities -- a new hope for survival and for health. It's heartbreaking to think that we may see a loss of that.
So, even as the news gets better and better in the United States, and in developed situations, it's also sad to see what's going on there.
Yes. I hope we'll continue to prioritize this. People say it's just one disease, and that there are lots of other diseases. There are all sorts of health issues in resource-limited countries -- everything from diarrheal disease, to malaria, to TB, to just the lack of clean water and basic health care provision. But I don't think it's fair to put HIV on the same level as those things.
First of all, HIV is a transmitted infectious disease that is causing one of the worst global pandemics in our time -- and in history. To just talk about it as another disease is to deny its potential for spread, and for global catastrophe.
The other thing is -- and we saw this in a lot of studies presented at IAS -- just how much HIV affects all of those other things I mentioned. It increases risk of malaria. It certainly has had a devastating impact on tuberculosis epidemiology. We're seeing that so much of the tuberculosis epidemics around the world are directly related to HIV. It's the underlying cause for so many other health problems that are devastating a lot of these countries.
Unless we can control, prevent and treat HIV, we're not going to have any hope of dealing with the TB epidemic, or of dealing with a lot of these other medical conditions.
Thank you so much for this great wrap-up.
This transcript has been lightly edited for clarity.
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