Long-term HIV survivors are not alone in bearing witness to HIV medications' turbulent history -- and the effects that early meds left on the bodies of those who took them. Many engaged clinicians have spent their careers following the arc of discovery, research and management of these metabolic effects. Rick Loftus, M.D., who now sees many long-term survivors in his medical practice near Palm Springs, CA, is one such clinician. Read his account of this challenging part of his practice in Part Two of his two-part interview with TheBody.com. Read Part One of this interview.
I always tell people when I talk about lipodystrophy with them -- and I'm certainly not having to have that conversation at the initiation of therapy as much as I used to, but when I did, I would explain that there are probably at least four things that contribute to body shape changes: genetics, the virus itself, diet and exercise and treatment.
The presence of the virus, we don't have control over. I think people forget that there are untreated HIV-positive adults that get lipodystrophy. There are cases of wasting of fat tissue in people who have never been on any medicines. Those aren't super-duper common cases, but they happen. It's like the talking dog example: When you've seen one talking dog, you realize dogs can talk. So the fact that there were even ever cases reported of people never being treated with antiretrovirals who experienced wasting of fat tissue told us that the virus probably played a role in some of the mitochondrial toxicity that we think drives lipoatrophy.
Your genetics, we don't have control over. We do think that some of the belly fat gain looks an awful lot like metabolic syndrome, and 20 percent of Americans have the genetics for metabolic syndrome: abdominal fat (adiposity), high blood pressure, high uric acid levels, higher risk for cardiovascular events like heart attacks and strokes. The genetics we can't control.
Diet and Exercise
We can control your diet and exercise. That speaks less to the facial wasting and fat loss than to the abdominal fat, or visceral adiposity. That's where exercising and eating a low glycemic diet can be helpful -- although the relationship between diabetes and visceral adiposity, I think, is complicated. It's kind of a chicken and egg.
We can control which method we use for treating. I've certainly seen people who have had diabetes who couldn't get the weight off until we changed their antiretrovirals. Then, once we got them on less toxic regimens, their exercise finally got the weight off, and their blood sugar started to come under control, and they could stop their insulin. I definitely saw cases of that.
But those were people who were still parked on the old drugs, and who oftentimes, because of how things went in that part of the history of HIV, were a bit afraid to change their meds because they were working. Changing meds, not because they were not working but because there might be better-tolerated ones, was still kind of a new notion.
I remember one guy -- he was seeing me as a consultant, not as his regular primary care doctor: I begged him to let me change him from Zerit to tenofovir, which I thought would be friendlier to him, and was available -- and he wouldn't let me. About 18 months later, he came back for his pre-op for his second dorsocervical fat pad removal, i.e., "buffalo hump." He had had a recurrence. I said, "OK, now will you let me change you off Zerit?" We did, and it didn't come back.
Now we recognize the benefits of growth hormone in the treatment of lipohypertrophy. The challenge is getting people qualified to take growth hormone if they don't have wasting syndrome, because it's not approved for lipohypertrophy. Every once in a while I have a patient where we can medically make the case that their fat accumulation is truly causing problems for the rest of their medical picture, and get access to growth hormone, which works.
Full disclosure: I'm an investigator on an Egrifta (tesamorelin) study. With my research team here in the Coachella Valley, I'm doing a Phase IV study looking at Egrifta use in HIV-positive adults with diabetes. There was concern about whether that might affect their risk for retinopathy. We're working with a local ophthalmologist on that study, and following these patients over time.
I'm familiar with use of Egrifta, partly being an investigator. People are interested in it. People do ask about it. I think in terms of either advocacy or research bringing new ideas into what to do about body shape changes, we're all kind of seeing the same thing, which is that there isn't kind of that spark that there used to be around this issue. But it's still on patients' agenda.
I think we're seeing less facing wasting. I do think that was, in particular, a manifestation of the d-drugs [d4T (stavudine, Zerit); ddC (zalcitabine, Hivid); ddI (didanosine, Videx)]. We hardly use those anymore in the developed world. They're still being used quite a lot overseas in developing countries, and undoubtedly dealing with lipodystrophy syndromes related to that. But I think even in resource-limited places, they're moving increasingly towards the more metabolically friendly nucleosides as a foundation of care. I think that will help.
Obviously, it helps to get people diagnosed early, so they can have therapy when their systems are still intact. That's increasingly what's happening -- although, even in the States, we know that people usually present when their T cells are within a few points of an AIDS diagnosis. We're not catching people early enough in their infection, on average; we need to do a better job of that.
Rare Cases, and New Reasons for Hope
Getting back to control: We can't control the presence of the virus; we can't control a person's genetics. We can control what treatment we use, and we can control people's participation in diet and exercise, to try to curb inappropriate weight gain. But the question is always: How effective are those approaches?
It's imperfect. I have a patient with diabetes and HIV, a longtime survivor. I diagnosed him with HIV as a resident at UCSF. He presented with CNS [central nervous system] lymphoma and less than 50 T cells. He's been on treatment now for, gosh, maybe 15 years, and he's still my patient.
Just in the last year he's really struggled, all of a sudden, with an eruption of lipohypertrophy around his neck, which is totally new. He's consulted with a surgeon in Pasadena, who's somewhat familiar with this issue and has dealt with it. She sees HIV-positive adults out there. She said, "I think your HIV meds might be the culprit."
When he came to see me I said, "I don't disagree with that, but this is exactly why, several years ago, I changed you away from your older nucleoside and put you on a metabolically friendly nucleoside" -- because, when I think about treatment choices, I think about all the possible problems with mitochondrial toxicity, including lipodystrophy.
The guy had already made the proper changes, and yet he still got it. Now, to be fair, he was higher risk already, because he initiated therapy when his T cells were terribly low. We have literature that tells us that people who start therapy when their T cells are low are at greater risk. So I was a bit surprised and chagrined that, despite having made what I felt were the best possible preventive maneuvers as far as the HIV medications he was on, he still wound up having to deal with lipohypertrophy.
We tried Egrifta for him. It didn't help enough. Now we're looking at surgical correction of the neck pad to help him, and fighting with his insurance about covering the surgery. I hope we'll be successful.
I thought if it hadn't shown up by now we were out of the woods. But, not so much. I've made this statement before: a drug that's well tolerated for a year is not the same drug that's well tolerated for a decade, is not the same drug as the one that's tolerated for a lifetime. The drugs we've been accustomed to using that all started coming out around 2005-ish -- Prezista (darunavir) and Intelence (etravirine) came out, and we started to codify the use of the metabolically friendly backbones, Truvada (tenofovir/FTC) and Epzicom (abacavir/3TC, Kivexa). There was the sense that maybe we had the tools in place to deter the development of lipodystrophy. But what this case shows us is that, in this day and age, even those who have gone quite a long time with no problems, it can rear its ugly head at random times, all of a sudden, for no really obvious reason. Is it because their metabolisms are compensating and then, finally, they just reach their limit and fall off a cliff? In terms of the physiology, we don't really know.
I think we recognize that, in addition to choosing meds that are friendlier to the body, getting people on treatment whose T cells are still high goes a long way towards minimizing their risk. I probably always have a strong bias of interest toward nucleoside-sparing regimens as a treatment approach. I did a lot of nucleoside-sparing treatment when I was in San Francisco, partly driven by my concern that nucleosides as a class, even the best behaved of them, put people at risk for lipodystrophy.
Could it be that this guy, even after 15 years, his exposure to the older nucleosides set him up for a problem, no matter what we did later? We don't know. Genetic damage tends to be cumulative; mitochondrial damage would be cumulative. So if there were drugs on board that were screwing up the gamma pulling rays, it's not like those genetic injuries are necessarily going to be readily fixed at the level they would need to be to prevent lipodystrophy showing up later.
How much of this has to do with just aging-related changes? I think that plays a role in this as well. As somebody who's now increasingly asking the question, "How do we promote healthy aging in HIV-positive adults?" that's where my vision and work out here in the Coachella Valley is focused right now. There's a group of us at different clinics who are trying to move the various centers for HIV care out here into an explicitly collaborative working group, to try to get a cohort study started here, kind of like what Washington, DC, has. But the DC Cohort has 11 clinics; we just have four. That's in the best interest of all the people with HIV that live in the Coachella Valley, and who are increasingly retiring here and needing expertise available to keep them healthy as they deal with the diseases of aging.
We have two big hospitals in Coachella Valley: one's more of our trauma center/county hospital; and the other is the little old retired people's hospital. I'm at that one. But it's had an interest in opening practices in the Palm Springs area, and it's attracted a boatload of gay doctors who are also in HIV care, like me.
I think we're on the kind of 2.0 questions about lipodystrophy prevention. Those are going to be more difficult for us to answer than was true when we were learning basic things like start people early on treatment, and don't use d-drug nucleosides. It's going to be harder to do the kind of research that can answer the more sophisticated questions we can ask to help protect people from this.
That may be partly why people are putting their focus on other issues and questions. These are quite challenging ones to address. But for this patient who now, all of a sudden, 15 years into therapy, is suddenly dealing with it, it is a big deal. It's our whole focus right now on his care.
Cohort projects may ultimately be the way, because they're designed to be long-term and they may give us some insight. I think there's a lot of hope that integrase medicines, since we've seen they're pretty friendly to the cholesterol system, will also avoid lipodystrophy changes. We kind of make inferences, like I was saying way in the beginning: We saw fat loss, fat gain, and cholesterol disturbances -- all three of those -- and thought they were all intertwined. But we then started to realize that they weren't all necessarily the same thing, and the cause of one wasn't the cause of all of them.
But I don't think we know that. I think we're hopeful that's true and that, in an era where we are kind of basing therapy more on integrase inhibitors, that we won't be seeing lipohypertrophy as much, or will avoid it. But I don't know if that will turn out to be true. There is still merit to looking at some of these questions.
It's appropriate for us to remember: Lipodystrophy is still happening! Like everything else, it's going to take time in order to get answers. But if we don't embed the questions in the research we're conducting now, we won't get those answers when the research comes to fruition years down the line. We need to keep thinking about it when we're designing studies that have the potential to answer questions about how we avoid lipodystrophy, or cope with it better, as we treat people with HIV to get them into a healthy old age.
This transcript has been edited for clarity.
Read Part One of this interview.
Rick Loftus, M.D., is an Associate Program Director of the Internal Medicine Residency Program at Eisenhower Medical Center in Rancho Mirage, CA.