ACTG 5202 Substudy Finds Little Lipoatrophy but Signs of Bone Loss Across the Board; Devil Is in the Details

Below is the transcript of a press conference held at CROI 2010 on Feb. 18, in which Grace McComsey, M.D., of Case Western Reserve University in Cleveland, Ohio, discusses a study she presented on bone and limb fat outcomes in a substudy of the landmark ACTG 5202 trial that compared four first-line HAART regimens: abacavir/lamivudine or tenofovir/emtricitabine paired with either atazanavir/ritonavir or efavirenz.

Grace McComsey: I presented a little bit ago a study called ACTG 5224.¹ It was a metabolic substudy of a large, 1,800-patient clinical trial. There were 1,800 who are taken naive, never been on meds before. And they were randomized to four possible regimens that are very commonly used in the clinic because they're once a day and they're well tolerated by patients.

Grace McComsey, M.D.

The substudy had 269 patients who underwent a test called DXA [dual-energy X-ray absorptiometry] scan at baseline, and then frequently during the study, to look at two things: bone mineral density, as well as fat in the limbs -- meaning in the upper and lower extremities -- and the trunk fat, in the abdomen.

The reason we did all that is there are two complications that are very important in HIV-infected patients: The first one is bone; they get thin bone or low bone mineral density. And we know that HIV-infected patients are at higher risk of fractures. So even though they're mostly men, active, young, the issue of bone disease is surfacing as very important in HIV. So that's why we looked at bone.

The reason we looked at fat is there's a complication called lipodystrophy where patients with HIV who are taking their meds suffer from changes in fat. The changes could be accumulation of abdominal, or trunk, fat; or lipoatrophy, which is wasting of fat in the periphery, in the arms and legs. So that's why we looked at those two issues.

What we found, in terms of bone, is that all the regimens that were studied, all the four different arms, led to a decrease in bone mineral density, which was the worst the first year into treatment. And after that, even though it continued, it seemed to plateau and not deteriorate any further. But they did get a significant hit in their bone, whichever regimen they're on. Some regimens were worse: Regimens that had tenofovir/FTC [tenofovir/emtricitabine, Truvada] did worse, in terms of bone, than regimens that had abacavir/3TC [abacavir/lamivudine, Epzicom, Kivexa].

This is important because for clinicians who know a woman -- perimenopausal woman or postmenopausal -- or a man that has a history of fracture, for example, they know that they're at higher risk of having bone disease. And that can help to tailor which medications to give them.

One other thing on bone that we found is we used, in two of the arms, a protease inhibitor called atazanavir/ritonavir [ATV/r, Reyataz/Norvir], and in two of the other arms efavirenz [EFV, Sustiva, Stocrin], a non-nucleoside reverse transcriptase inhibitor [NNRTI]. We found that at the lumbar spine, bone mineral density was worse with the protease inhibitor, but at the hip, it was the same [as it was with efavirenz]. So that tells you that every regimen can cause bone changes, although some of them are worse than others.

In terms of the fat issues, again, we looked at limb fat and trunk fat. And we found that all the regimens increase both limb fat and trunk fat. Now, the increase in limb fat is a good thing. Remember, we're worried about lipoatrophy, about the loss of limb fat, which is something that we used to see a lot with the older regimens. We did look to see how many of the patients lost 10% of limb fat and how many lost 20%. And really, the numbers were very low. So it was very encouraging results that these new antiretrovirals are not going to lead to a lot of lipoatrophy. A very small number of patients, at the end, had lost any of the limb fat, by 96 weeks or two years of the study. So, very encouraging results in terms of lipoatrophy down the road.

In terms of the accumulation of abdominal fat or trunk fat, we found that all the regimens led to significant accumulation of trunk fat. So everybody gained a lot of trunk fat. Now, some of this is what we call "return to health." HIV made them lose a lot of fat, and now we're giving them medications to make HIV better, so the fat's going to increase. We found that the protease inhibitor atazanavir/ritonavir was associated with worse trunk fat: They gained trunk fat more than with the efavirenz. But tenofovir/FTC and abacavir/3TC did the same in terms of trunk fat: Both regimens increased, but to a similar extent.

So again, for a patient that comes and needs treatment, and says, "I'm very concerned about fat changes; I don't want to take anything that makes me gain fat," that would help us to tailor a little bit which regimens are better than the others, in terms of risk of the patient developing fat changes.

Reporter #1: All these patients in your study were antiretroviral-naive. How long had they been infected with HIV before they went on the study? And is there any way to determine what their healthy baseline fat distribution was?

Grace McComsey: Unfortunately, actually, one of the hardest things to collect at the start is duration of HIV. So we don't have that information. We don't know for how long they had HIV. We do know by DXA scan what was the trunk fat and limb fat at baseline. The limb fat was 7 kilograms, with normal being 7 to 10, so it's not bad. It's the lower number, the lower limit of normal, but it's not very bad. The trunk fat, the median was 9.4, which again is within the normal trunk fat, even of a U.S. population. So I think they didn't have -- even though lipoatrophy cases have been diagnosed, a few of them, in naive patients, they seem to have almost normal fat at baseline.

Reporter #2: Can you tell us more about the few cases of lipodystrophy that you observed in that study? Were they more frequent in any of the arms? Did you see any facial lipoatrophy? And was that a clinical significance? I mean, were the patients concerned about that or was that just an observation that you found?

Grace McComsey: Yes, I'll try to answer. These were the initial results. There's still a lot of analysis that we need to do on the fat. Remember what I presented actually were people who had lost 10% and 20% of the fat by 96 weeks. This is by no means clinical lipoatrophy. So even if you lose 20%, now we know -- when we designed the study, that was five to six years ago -- now we know that even 20%, you don't see it on the patient, and they wouldn't notice it. When we looked at the 20% cutoff, only 5% of patients had lost 20%, which is quite low. So if you think about clinical lipoatrophy, they probably need to lose 35% to 50% of their fat before they can see it clinically. You can imagine how much even lower than 5%. So we probably will end up with a handful, very few patients, who have clinical lipoatrophy, which is very good news knowing that with the old regimens, about 50% of patients sometimes developed lipoatrophy. So I think it was very encouraging results that the new regimens will not give us clinical lipoatrophy.

We did collect, actually, only subjective reports of facial [lipoatrophy]. We haven't analyzed them yet. We did not do anthropometrics. They're painful, they're quite hard to do in studies of that size, so we didn't do them. But we did collect the subjective assessment of lipoatrophy in the face. We'll be presenting that later.

Reporter #3: I was wondering if Dr. McComsey and Dr. Womack could speak about each other's bone mineral density results. Outright for clinicians, you both said it's important, but then Dr. Womack said that the rates were not that high -- of course this is male veterans, which is a different risk group than, for example, perimenopausal women. I just wondered if you could comment about the results of each other and the significance of bone mineral.

Grace McComsey: Sure. I did comment on the fractures in general being more common in HIV. There has been at least one study looking at that, so not specifically, fragility fracture, just any fractures were more common in HIV patients versus not HIV. And as you mentioned, my study, for example, 85% were males and the median age was 38 years. So these were young people. The fact that we don't see fractures yet on them, it doesn't mean that it won't happen. Fractures are like hypertension and stroke: If you have a decrease in bone density and you don't quite see fractures during the study, it doesn't mean it's not clinically relevant, because they will develop later on. It just -- all that my study means is bone mineral density went down. It puts them at higher risk of fractures.

Now we did look, if you were at my presentation, we did look at fractures during the study. It's a two- to four-year study, but we still saw about 5% of patients develop fractures during the study. There was no significant difference between the arms. The fractures were distributed equally among all the arms of the study.

So I do think, even though the increased risk that was reported of fragility fracture is modest -- it's not huge -- it is increased, even in this population that shouldn't be at high risk of a bone mineral density issue. I didn't hear about smoking. Probably all veterans smoke, so you can't really tease out the smoking, but that would be another important risk.

Julie Womack: We actually did not look at bone mineral density. We just looked at fragility fractures based on ICD-9 [International Statistical Classification of Diseases and Related Health Problems] codes, so that may be one of the explanations for the difference in the outcomes. And we didn't look at smoking. The reason for that is that we don't have that information in the data set. However, in a subset of the patients for whom we do have the data, smoking history didn't really differ much by HIV status.

This transcript has been lightly edited for clarity.

Reference

1. McComsey G, Kitch D, Daar E, et al. Bone and limb fat outcomes of ACTG A5224s, a substudy of ACTG A5202: a prospective, randomized, partially blinded phase III trial of ABC/3TC or TDF/FTC with EFV or ATV/r for initial treatment of HIV-1 infection. In: Program and abstracts of the 17th Conference on Retroviruses and Opportunistic Infections; February 16-19, 2010; San Francisco, Calif. Abstract 106LB.

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