Heart Disease in People with HIV: An Interview with Joseph Sonnabend, M.D.

While much attention has been focused on strange fat deposits in the abdomen and between the shoulder blades of some people receiving protease inhibitors, little has been said about the long-term effects of the high blood lipid levels also observed in those on protease inhibitors (see two reports on abnormal fat deposits in the March 21, 1998 issue of The Lancet). The Lancet on May 4 included a brief report on this subject from Keith Henry, M.D., and colleagues at Regions Hospital in St. Paul, Minnesota. The report described two relatively young men who developed coronary heart disease while on protease inhibitors. A review of 124 patients on protease inhibitors in the Regions HIV clinic identified 41 (33%) with raised lipid concentrations. They were put on a cholesterol-lowering regimen of either diet and exercise or medication according to guidelines for the general, non-HIV infected public issued by the NIH.

Many other physicians are also noticing heart attacks, angina or other cardiovascular symptoms in their patients with HIV. Indeed a tendency toward increased heart attack risk in people with HIV was noted many years ago, long before protease inhibitors. Treatment Issues talked with Joseph Sonnabend, M.D., about the multitude of factors that could increase the risk of coronary heart disease in people with HIV. These range from aspects of the infection itself to lifestyle factors such as smoking to the various medications patients may be taking. Within this overall picture, protease inhibitors may magnify the risk through their effect on blood lipids.

Many Contributing Risk Factors

Treatment Issues: There's been a lot of talk lately about protease inhibitors and heart disease.

Joseph Sonnabend: Well, what seems to be emerging is that a variety of factors, not just the use of protease inhibitors, contribute to accelerated heart disease.

First, the protease inhibitors are connected with disorders of lipid metabolism. People who receive protease inhibitors have elevations in triglycerides. They have elevations in cholesterol and they don't seem to have much in the way of elevation of their HDL [high density lipoprotein], which is the kind of cholesterol associated with lower cardiovascular disease.

Now, AIDS itself causes disorders of lipid metabolism. Low cholesterol used to be totally characteristic of this disease; and low HDL, for those of us who obtained them, was just a very early manifestation of HIV infection. I have hundreds and hundreds of records showing these low HDLs. It's quite common to see abnormally low HDLs in untreated people who have 500 CD4 cells, and lowish viral loads. And there's the LDL [low density lipoprotein] cholesterol that everybody is sort of aware of -- it's more commonly on the lab panel than the HDL -- and elevated triglycerides.

There's also something that I did, which is sort of a fat tolerance test in people who are HIV-infected with more advanced disease who didn't have tremendously high triglyceride levels. You feed people fat and measure the triglycerides in their blood before and then hourly. In normal persons, I did this with controls, the fat would go up and then in a few hours would clear. In people with HIV, the level just keeps going up. So they can't handle fat.

TI: And what is the reason for this?

JS: The triglyceride elevations are due to alpha interferon and possibly contributed to by TNF. Both inhibit an enzyme, lipoprotein lipase, necessary for the metabolism of triglycerides. People with untreated advanced HIV have tremendous amounts of interferon in their blood. Giving AZT to such people removes the interferon very, very promptly, and at the same time, it lowers the triglyceride levels.

TI: What do the protease inhibitors do?

JS: The protease inhibitors apparently also are associated with a reduction in interferon, and therefore there are contrasting things going on. If patients use the protease inhibitors, one would expect to lower the triglycerides, but the fact that they go up means that probably the force that's driving them up is quite powerful.

Quite often before the protease inhibitor, you'll see the triglycerides start off moderately high, and they tend to go even higher. We've seen some astronomically high triglyceride levels, although in earlier days before treatment, people with AIDS had tremendously high triglyceride levels, too.

TI: And what about cholesterol -- that's the main, completely established risk factor for heart disease?

JS: So as far as cholesterol goes, if you look at people before the protease, their cholesterols were characteristically low. And then when they start treatment, the total cholesterol would be in the abnormally high range. The HDLs seem to have a very slight increase with the protease inhibitors, but it's just so minute. I can only speak about the few people I've looked at, though I have tons of records. This is something that needs to be formally studied.

The published risk factors for heart disease are low HDLs, high total and LDL cholesterol -- and now triglycerides are a risk factor for heart disease, independent of HDL. So people who are on protease inhibitors do indeed have these risks for cardiovascular disease.

TI: Beyond the affects of HIV and anti-HIV therapy, what other factors add to the heart disease risk?

JS: You have these risks for coronary artery disease already. And you add to this the fact that many people with HIV infection receive androgenic and anabolic steroids. As much as I can recall -- I've seen lots of patient material about testosterone and nandrolone and oxandrolone -- I don't think I've ever seen any kind of cautionary statement about the effect of these steroids on red blood cell metabolism. These androgenic anabolic steroids are known to increase the red blood cell mass. They do this and that's part of the reason, I'm told, that men have higher hematocrit [the percent of blood taken up by red cells] than women.

TI: Do you mean that the steroids increase the number of cells or the volume of the individual cells?

JS: People become polycythemic, which means they have too many red blood cells. This too can add to the risks of a heart attack. The reason for this is that the red blood cell mass increases the blood viscosity. The blood becomes more sludgy, and that can very definitely contribute to myocardial infarction. If you add plaque [fat deposits in the arteries] and other problems it increases clotting -- it's known to do that.

TI: So all the factors add up?

JS: You put everything together. There's also the fact that people have other risk factors for heart disease. We're dealing with a population that's living longer now, and they're reaching an age when these things become important. Many people have a family history [of heart disease], which is a risk factor. Some people smoke, unfortunately, which is yet another risk factor, as is high blood pressure. You compound the risk. With these new treatments, I think it's going to be an increasingly relevant problem, and now there are some reports of heart problems appearing [in patients on protease inhibitors]. Now that one is more sensitized to it, I think we'll be seeing more of it.

TI: Have you seen cases of heart attacks in your patients?

JS: Yes. That is the case with a 40 year-old patient of mine who about six months ago had a heart attack that was quite serious. He was on Crixivan for about a year, and he also was on a fairly large dose of testosterone and nandrolone. And he felt better on it. I mean, he had more energy; it seemed to relieve his fatigue. But his hematocrit was higher. It was just above the normal range, and he went to the hospital with chest pain. While he was in the hospital, the hematocrit increased to even greater levels, and he had a heart attack.

Preventive Measures

TI: So how do we prevent these incidents?

JS: As far as the steroids are concerned, it just means that people taking them should watch their hematocrit and possibly also watch their testosterone levels in the blood and not overshoot. Testosterone replacement therapy by itself shouldn't be a problem.

As for abnormalities in blood lipids, it is important to check for them under the right conditions. Lipid measurements should be done without food -- people should not have eaten for eight to 12 hours. The most convenient time to test is before breakfast.

The kinds of interventions that one might think about are diet and exercise and the use of some drugs. And whether this translates into clinical benefit, if you can bring them down, I don't really know, and I would have thought that this would be the ideal kind of trial a community group could do. It is not something that's going to be funded by a drug company. Even so, one could easily think of putting together a protocol that would compare an exercise program, dietary interventions and possibly have a part of it that looks at the effect of a lipid-lowering drug. The outcome measure for such a trial would be normalization or changes in lipids -- triglycerides, HDLs, LDLs, total cholesterol. If there are some beneficial effects, it may be worth considering a sort of clinical trial to see whether this translates into longer life -- but the problem with that, serious as they are, I don't think there are a tremendous number of cases of heart attacks.

TI: And right now, what are you doing with your patients?

JS: About lipid abnormality? I don't know what to do. I'm giving some of them drugs to lower it. I first propose exercise and diet, but I have no formal way of knowing whether this works. My impression so far is that it's not really successful, but then of course, it's too casual, the way I'm doing it. You need a formal program of exercise and a structured diet, not just a haphazard sort of thing -- do it the way you would do it to anybody else with cholesterol problems. Maybe we should emphasize the sorts of things that we would do with the person who is not HIV-infected who came in with low HDL, high total cholesterol and triglycerides. I suppose we have been so focused on HIV as the killer that we forget the other things that can get you too. HIV doctors haven't taken them all that seriously till now.

TI: So which drugs would you use for lipid abnormalities?

JS: Among the doctors I've spoken to, there seems to be a tendency to favor a drug called Lipitor. For my own cholesterol, I have taken another statin drug -- simvastatin, also called Zocor. And maybe because I'm familiar with it myself, I prescribed this. One is concerned to use drugs that have the least hepatic toxicity. The statins are once-a-day drugs that appear to be pretty well tolerated, though they cause some kinds of muscle problems -- very rarely, and I haven't really seen it. But I can't say that I've seen them do wonders for the people I've given it to -- you really need to do a more controlled kind of observation. And it may be that diet and exercise can do it, I don't know. That's the study that really should happen.

TI: Are there any drugs that can be given just to reduce people's hematocrit?

JS: No, the way you do that is by bleeding them.

TI: That's a switch. People have been getting blood transfusions all these years for anemia.

JS: Well, this gentleman I'm talking about, my patient, every few weeks, he goes to Mt. Sinai Hospital, and they take a pint of blood out of him.

TI: How is he faring now?

JS: Well, he's suffering from testosterone deprivation, because it helped him a lot. His hematocrit is gradually dropping but it's taking forever to do so. He's hoping that when it's done and we measure his testosterone levels, that he'll be able to go back to an appropriate dose. It made a big difference in his energy, in his ability to function and his depression. So he's not doing very well, because he says he sleeps much of the time, which was the case before the testosterone.

He also stopped smoking. It's amazing. I wouldn't have believed it. He was an incredibly heavy smoker and I suppose it takes an event like this, when you're in the coronary care unit with all the beeps going and the tubes and all of that. And people sort of dying around you, and you realize that you may just go.

TI: And what about the protease inhibitor? Is he still on it?

JS: No, he's not. He's on Viramune and three nucleoside analogs.