This Month in HIV: Top 10 HIV/AIDS Stories of the Past Year
On to number three.
Number three has to do with an ongoing concern regarding the side effects of HIV medicines, particularly the cardiovascular effects. There was a really important paper published in the New England Journal of Medicine by the D:A:D group.15 The D:A:D study is a large, metacohort study, meaning that it's a collection of different large studies all pooled together. It's pretty powerful; over 30,000 people are enrolled in this study currently. What the researchers are able to do with that kind of data is look for trends that occur during HIV therapy. One thing they've been able to do is look at the risk of heart attack, and the rates of heart attack.
In this analysis, which was published at the end of 2007, what the researchers found was that there were about 350 or so heart attacks in the group of patients that they had -- about 23,000 at the time of this analysis. They were looking at what the risk factors were that led to individuals having a heart attack. One of the things they looked at was a patient's exposure to HIV therapy. They've shown that over time, as you're on combination HIV therapy, your risk of heart attack increases incrementally.
What the researchers were able to also do is tease out which type of HIV therapy might have this effect, and they found that protease inhibitor therapy was associated with this increased risk of myocardial infarction. Whereas the non-nucleosides, like Sustiva and Viramune, were not.
This is kind of controversial and we'll have to think more about this over time as more data come in. But what they were able to show is a pretty clear signal for protease inhibitors.
The non-nucleosides, like Sustiva and Viramune, did not have as clear a signal. It was a little bit of a wiggle line; it went up and then it went down a little bit. So, it was not as clear. Part of the reason for that is that there are not as many people on those drugs in this cohort -- this cohort is mostly European, with some North American patients included. For protease inhibitors, which were much more popular in this group of people, there was a clear trend that was significant.
The bad news is that protease inhibitors seem to increase your risk of heart attack. The good news is that the risk of heart attack in this study was really low. As I said, we're talking about 350 heart attacks among 23,000 people. Not tremendous numbers, and it's important to remember that not every single one of those heart attacks was due to medicines. If you followed 23,000 people without HIV, there would be some number of heart attacks. Some of these were inevitable; some were influenced by HIV; some were influenced by HIV medicines.
Other important data have shown us that if you're not on HIV medicines -- for example, if you are someone who started on HIV medicines and then stopped taking them -- your risk of cardiovascular disease goes up.16
That is, stopping HIV medicine, allowing your virus to go kablooey, and all the subsequent inflammatory changes and things your body has to do to deal with the virus are really bad for your heart.
Overall, protease inhibitors probably increase the risk somewhat of a heart attack, but it's better than being off HIV medicines. I think this is an important study that helps us quantify the risk, but also reassures us, because at least during the time period of the study (about seven years) heart attacks were fairly rare.
The researchers never did tease out how many of the people in this study were smoking cigarettes, for instance.
"We know that uncontrolled virus puts a strain on the body in many ways, leading to more problems with liver disease, leading to more problems with heart attacks, and leading to more problems with kidney disease. The virus itself is probably worse than anything else."
Right. So there are other risk factors, and they try to correct for them. The other thing that they don't really do a great job of is telling us, in the people who got heart attacks and were on protease inhibitors, were the protease inhibitors working? Did the people have uncontrolled virus [i.e., a high viral load]? We know that uncontrolled virus puts a strain on the body in many ways, leading to more problems with liver disease, leading to more problems with heart attacks, and leading to more problems with kidney disease. The virus itself is probably worse than anything else. Protease inhibitors are making a rare event a little bit less rare, but that is better than not being on protease inhibitors.
What would you say to a 25-year-old person living with HIV, who's worried by this kind of study and who's on a protease inhibitor? What can he or she do?
I think the most important thing is to understand that the magnitude of the change of risk in heart attacks with protease inhibitors was a fraction, really, of what you get with smoking or with uncontrolled high blood pressure -- those are the things that we can change.
In this group of patients, about 60 percent smoke.17 That's an incredible amount -- and we see this consistently in HIV-positive people!
When you look at Americans and Europeans with HIV infection, the Americans smoke like Europeans. It's incredible! HIV-infected people smoke like French people do.
In comparison, in the general population of the United States, only 21 percent of people smoke,18 so we see that smoking is very prevalent in patients with HIV.
What we should do, rather than mess with their HIV medicines, is:
"We need to take care of the usual, traditional things when we think about risk for cardiovascular disease. I think HIV medicines are secondary in that respect."
These are things people should be motivated to do if they want to survive. I think this is important, but it really puts this into perspective. We need to take care of the usual, traditional things when we think about risk for cardiovascular disease. I think HIV medicines are secondary in that respect. So I'd tell that young person, "Your risk is pretty darned low because you're young. You've got to stop smoking because you're aggravating your risk and we want to see you be here for a really long time. I wouldn't worry so much about your medicines; we can handle it."
Would you say something similar to someone who's 45, doesn't smoke, and doesn't have genetic risk factors, but is on a protease inhibitor? Is there a greater worry for that person?
I think there is greater worry the more risk factors someone has that you can't control -- such as a family history of early heart attacks, under 55 for a close male relative and under 65 for a close female relative; a history of blood pressure problems, even though it's controlled right now; and diabetes.
People who've done everything they can to control their risk factors, but have these immutable, unchangeable risk factors, including genetics, are the people for whom you really try not to put another straw on the camel's back. It's one of the factors that you have to weigh when deciding what HIV medicines to be on.
In this particular study, it looks like protease inhibitors are worse than non-nucleosides, but it's going to take a little bit more time to make sure that's actually so. If it is, then yes, given the data we have now -- yes, that may gravitate the clinician and the patient to think, let's stay away from protease inhibitors.
When we look at lipids, there's not as much of a difference between protease inhibitors and Sustiva as we once thought there was. It's not all about cholesterol; there's something else going on here. So yes: It's one important factor. For someone with very few risk factors, for me, it's not a big deal; it's not a big factor.
So really, the answer is that it depends on who you are, and what your story is.
I think these data are important in light of recent data from the same study group, looking at Ziagen [abacavir; this drug is also contained in Epzicom (abacavir/3TC, Kivexa)]. The data suggested that Ziagen -- and Videx [didanosine, ddI] -- also increased the risk of heart attack.19 It's the same sort of story. I think we have to look closely at the patients we're seeing, their risk for cardiovascular disease, and weigh the benefits from this particular study of giving a drug or not giving a drug.
On to number four.
Number four follows a similar vein; it looks at a different metabolic complication of HIV medication, and that's body shape, with some hint of lipids here, too. It was a really, really important HIV study that we in the HIV field got very excited about, because it was done not by a drug company; it was done by the federal government here in the United States, and it was done across the country.19
It really was a nice representative study of treatment for people who'd never been on HIV therapy before. The study was done by the ACTG, and that stands for AIDS Clinical Trials Group. AIDS Clinical Trials Group is a federally-funded network of study centers across the country. This study is called ACTG 5142. The ACTG numbers their studies; they don't have cute little acronyms or abbreviations.
This study pitted Kaletra [lopinavir/ritonavir], a protease inhibitor that's very popular for initial therapy, against Sustiva. People could take either one of these drugs plus two nukes [nucleoside reverse transcriptase inhibitors], like Retrovir [zidovudine, AZT; this drug is also part of Combivir (AZT/3TC)], Epivir [lamivudine, 3TC; this drug is also a part of Combivir], Zerit [stavudine, d4T] or Viread [tenofovir; this drug is also a part of Truvada (tenofovir/FTC)] -- commonly used drugs. There was a third arm in which people didn't use any of those nukes, but just took Kaletra and Sustiva together.
The real important data, for our purposes, was the comparison of the people who took Kaletra with two nukes with the people who took Sustiva with two nukes. We had assumed that the Kaletra was going to lead to more body shape changes and higher cholesterol and all that stuff. But that turned out not to be the case.
In a rigorous study of a large number of people -- 700 people -- what we found was that the differences between these two drugs was not that stark when it came to big bellies. Both drugs made people's bellies increase in size. Both drugs led to increases in cholesterol -- not only the good cholesterol (HDL cholesterol), but also the bad cholesterol (LDL cholesterol).
Importantly, triglycerides were a little bit higher with the Kaletra than the Sustiva, and that's been shown in other types of studies as well. Not a big surprise there. The surprise was that cholesterol was not a big deal; also, bellies were not a big deal.
What also was a big surprise was, when we looked at limb fat -- that's fat on the arms and legs -- that's where we saw a difference. Surprisingly, it was against the Sustiva. People who took Sustiva, regardless of what other medicines they were taking in their HIV regimens, had more wasting of fat in their arms and legs than people on the Kaletra.
"These results totally blew people away. ... It opened up our eyes that we have to think anew about body shape changes, that it's not a protease inhibitor thing. In fact, if anything, the protease inhibitor was associated with protection against fat wasting of the arms and legs."
These results totally blew people away; these were completely unexpected results for most people in the know, who are really interested in this. It opened up our eyes that we have to think anew about body shape changes, that it's not a protease inhibitor thing. In fact, if anything, the protease inhibitor was associated with protection against fat wasting of the arms and legs.
There was no data about fat wasting of the face included in the study. These were all objective measures using scans of the body, so we don't have any important data yet about facial fat wasting. What we do see is that fat wasting of the arms and legs, which generally correlates with fat loss elsewhere, was worse with Sustiva.
With Truvada and Sustiva [this is the combination of drugs in Atripla], the risk was pretty darn low. It was higher than if you took those two nucleosides with Kaletra, but the good news is for people who are on Atripla, the risk of having significant wasting of fat in the arms and legs was fairly low and uncommon. I feel somewhat reassured in giving people that combination. The problem was more when you took Retrovir or Zerit along with Sustiva; then you saw unacceptable rates of fat wasting.
It was a really important study that helped debunk some of the myths we've had even in the absence of data about what these medications do to body shape and to lipids. I think that's important and that's what research is about.
But this is just a clue about some of the body shape changes that happen with these drugs. Isn't it true that we still don't know how to treat those problems and we don't completely understand them?
No, in fact, a lot of people after this felt like we had to just throw away everything we understood about fat wasting. If anything, people are thinking that maybe it's not so much that the Sustiva causes fat wasting, but that the Kaletra protected against fat wasting. There may be suggestions from other studies that that may be the case -- that there's something with protease inhibitors, ironically, that protects against fat wasting.
I think you're right that this really makes us have to think outside the box about this. It says nothing about treatment, but it may say something about prevention.
It may be that we're understanding that, if you want to avoid fat wasting, you shouldn't use Retrovir; that Viread would be a better drug than Retrovir. That's important information for people to think about when starting medicines. It depends how big a deal this is to you. There are people I see who say, "I'll take anything, but I don't want to look bad." I steer them away from those regimens that were associated with fat wasting in this particular study.
Which would be?
Sustiva with Retrovir and Epivir. Certainly Zerit, which we don't use anymore. I wouldn't even use Combivir with Kaletra.
I would prefer to use alternative nucleosides. In this case, Viread looked really good. Ziagen was not studied in this study, and there are other issues with Ziagen that are emerging.19,20 Right now, there's a limited choice as far as nucleosides for people who are concerned about this complication, so you just have to pick from that short list. When body shape is a major issue, we've got to look at the data and we shouldn't just rely upon assumptions or perceptions.
Copyright © 2008 Body Health Resources Corporation. All rights reserved. Podcast disclaimer.
This article was provided by TheBody. It is a part of the publication This Month in HIV.
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