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CROI 2010 Wrap-Up: Complications of HIV and Its Treatment
A Discussion With Pablo Tebas, M.D.

By Myles Helfand

March 30, 2010

Table of Contents


Introduction

Myles Helfand: The past couple of years have brought with them a slow, but steady, shift in our perception of the most noteworthy complications that threaten the health of HIV-infected patients in the United States and other developed countries. The annual CROI meeting tends to act as a barometer, of sorts, of this ever-changing climate in HIV medicine.

To help us get a better sense of where the clinical winds are now blowing, I'm pleased to have on the phone one of the top clinician-researchers in the field of HIV- and antiretroviral-related complications: Pablo Tebas, an associate professor of medicine at the University of Pennsylvania School of Medicine and principal investigator in the Adult AIDS Clinical Trials Unit at the University of Pennsylvania. Dr. Tebas, thank you so much for joining us.

Pablo Tebas: You're welcome.


Inflammation and Cardiovascular Risk: Is It All It's Cracked Up to Be?

Myles Helfand: I suppose we should begin with what has become one of the real hot-button issues: the issue of inflammation. What has CROI told us that will hopefully allow us to wrap our heads around what this is, what it does, and what we can do about it?

 Pablo Tebas, M.D.
Pablo Tebas, M.D.
Pablo Tebas: Definitely, inflammation has been one of the hottest, if not the hottest, topics related to HIV in the last couple of years. We know for a fact that patients with HIV, when they are not being treated, they have high levels of inflammation that are associated with high-level viremia. And when we treat them with antiretroviral therapy, those levels of inflammation decrease. But we know, too, that they don't become completely normal.

This residual inflammation -- we can call it that -- has been associated with a myriad of complications of HIV. Some people have said it's responsible for the lack of increase in CD4 cells in some patients. Some people have said it's responsible for accelerated progression of atherosclerosis in some individuals, for accelerated bone loss, for a lack of response to vaccines, for the increased incidence of cancers in patients with HIV.

So there has been a lot of focus on trying to understand why these patients have residual levels of inflammation that are not completely corrected with antiretroviral treatment, and what kinds of long-term complications are associated with this residual inflammation.

Myles Helfand: What kind of research did CROI provide that shed some new light on the subject?

Pablo Tebas: There were a lot of presentations from the UCSF [University of California, San Francisco] group -- from Priscilla Hsue, and also Steven Deeks and Peter Hunt, and other members of the UCSF group. Their focus has been, in patients treated with antiretroviral therapy, the role that this residual inflammation plays in the progression of atherosclerosis.

They looked at this issue in many different ways. They did ultrasounds of the carotids, and looked at the progression of atherosclerosis in the carotids. They looked at the elasticity of the blood vessels in response to this residual inflammation. They looked at the effects of starting [antiretroviral therapy] earlier versus later, and what the effects are on these surrogate markers of atherosclerosis.

I think the general theme of their studies is that patients with HIV infection, in spite of having good control of antiretroviral replication, have these increased levels of inflammation. And those levels are associated with a more rapid progression of atherosclerosis as measured by these different surrogate markers. However, there have not been a lot of studies presented from that group on what to do about it.

There was a study that looked at the effects of valganciclovir [Valcyte], which is a treatment for cytomegalovirus -- because there was a previous study from the same group showing that a lot of the immune responses of patients with well-controlled HIV [also apply to] cytomegalovirus. So the hypothesis was that if you control cytomegalovirus replication, you would decrease the level of inflammation. They did a study in which they gave valganciclovir to patients with well-controlled HIV. And, really, they didn't see a lot of difference in the residual levels of inflammation.

They have also tried to intensify HIV treatment, adding a drug like raltegravir [RAL, Isentress] in patients with well-controlled virus. They didn't see a lot of changes on residual inflammation.

The story is a little bit different if you add a CCR5 antagonist, like maraviroc [MVC, Selzentry, Celsentri]. If you add maraviroc, you decrease the residual levels of inflammation. The study was [led by Timothy] Wilkin. It was a study from ACTG [AIDS Clinical Trials Group] showing that if you add maraviroc to [the antiretroviral regimens of] patients with well-controlled HIV, the inflammation goes down. But we don't know what the long-term effect is of that decreased level of inflammation. Would it benefit the patients with regard to cardiovascular outcomes, or CD4 outcomes, or bone outcomes? That is the kind of thing that we still don't know. If we intervene, to try to reduce these residual levels of inflammation, do we make a difference in the clinical outcome of the patients? I think that's going to be an area of intensive research in the next few years.

Myles Helfand: How sure are we, even at this point, that inflammation itself over the long term does result in actual clinical events that seriously impact the health and potentially threaten the lives of HIV-infected patients?

Pablo Tebas: We don't know from the HIV. We know that antiretroviral therapy works very well, and decreases morbidity and mortality in patients with HIV infection. We don't know what price we pay for having this low-level inflammation.

If we look at other fields like cardiology or geriatrics, inflammation has been associated with outcomes. If you look at the cardiovascular literature, in people with C-reactive protein -- which is a similar marker of inflammation -- people with higher C-reactive proteins have a higher risk of developing cardiovascular events. For decades now, we've known that atherosclerosis has a strong inflammatory component, [responsible] for both the progression and the risk of rupture of atheromatous plaques. The cardiovascular events associated with that are triggered by inflammation.

There was a study published a couple of years ago in the New England Journal of Medicine, the JUPITER study, that I think is probably like a proof-of-concept of the type of interventions that we are going to be using in patients with HIV infection. In that study, patients with normal lipids -- so, they have cholesterol that was in the normal range -- but that had high levels of inflammation, as measured by C-reactive protein, were randomized to receive a statin -- simvastatin [Zocor] -- or not. There was a decrease in the incidence of cardiovascular events [among those who received a statin].

So I think many groups around the globe are thinking about trying to add something to patients with HIV, something simple to take, probably like a statin, to see if that makes a difference in the long run for cardiovascular outcomes and other outcomes.

Myles Helfand: How related is that to inflammation, per se? We saw some data presented at CROI from the everlasting D:A:D study about the impact of triglycerides on MI [myocardial infarction] risk. How does that tie in with, or compare to, the impact of inflammation on potential cardiovascular risk?

Pablo Tebas: I think both are part of, or contributors to, the increased cardiovascular risk that we see in patients with HIV -- the alterations in the lipids that are seen associated with some drugs that we use for the treatment of HIV, and also the residual inflammation. The data from the D:A:D in this particular CROI, the question they tried to answer is: Does hypertriglyceridemia -- which is a risk factor for cardiovascular events, though not as powerful of one as cholesterol -- predict the risk of cardiovascular events in patients with HIV? And the answer is probably yes; it predicts. But it's much less powerful than cholesterol in predicting cardiovascular events.

I think the conclusion for a clinician from that trial is that if you have to focus on something to try to decrease the cardiovascular risk of the patient that is in front of you, you'd better focus on lowering the total cholesterol, and try to reach LDL [low-density lipoprotein] goals. You will get more benefit if you follow that approach than if you try to chase the triglyceride levels.

I usually worry about triglycerides when they are over 500, or over 1,000, because they increase the risk of pancreatitis. But most of my patients have triglycerides in the 200 to 300 range, and I usually don't worry too much about that. I recommend diet, basically, and for some people maybe adding fish oil. But I don't worry too much about that if the LDL cholesterol goals are within range, and if the patient is not a smoker. I try to focus on other cardiovascular risk factors, rather than in the triglycerides.

Myles Helfand: That seems to get to the heart of what D:A:D has essentially been all about over the past few years: Sure, there does appear to be some kind of relationship between cardiovascular risk and certain antiretrovirals. It's just that the overall risk of these kinds of things is still lower, right, than something like smoking, or BMI [body mass index], or having a family history of cardiovascular disease -- that kind of thing?

Pablo Tebas: Yes. I think the traditional risk factors play a stronger role than some of the treatment-related factors. We shouldn't forget that HIV by itself is a very strong predictor of cardiovascular risk. An old paper from the New England Journal of Medicine showed that when we started highly active antiretroviral therapy, the risk of cardiovascular events went down dramatically. We tend to forget about that, because we focus a lot on the lipid abnormalities associated with some of the HIV treatments. But that was a study that was done more than a decade ago, and it was a very strong result.

Then the SMART study was presented, showing that when you stop antiretroviral therapy, in fact, you see an increase in cardiovascular events. I think that reminded us of the benefits of therapy in reducing cardiovascular events, and the risk of having uncontrolled viremia. Remember, the SMART study randomized people to viral load-driven therapy versus CD4-driven therapy in which you would start and stop therapy based on your CD4 cell count. It was developed in part as a response to the perceived increased risk of cardiovascular events associated with treatment. It was a strategy to try to minimize total drug exposure, and it didn't work out. Because I think HIV is a more important risk factor than anything that you get from the treatment.

Myles Helfand: So is there a possibility that we're making more of inflammation than it actually is? Given that, as you said, antiretroviral therapy -- when it's effective, when it really suppresses the virus well -- significantly reduces inflammation risk? I mean, it's still there, but it's not necessarily as great. Is inflammation really worth the amount of time and attention that we're currently paying trying to figure out how to measure it, how to find markers that can actually gauge it, and figure out what to do about it?

Pablo Tebas: Well, some of it. I think inflammation has been a little bit of the flavor of the last year or two. I think eventually we will put it in adequate perspective.

I think treatment of HIV reduces inflammation remarkably. There is residual inflammation that we don't know why it's happening. There is some residual inflammation -- not in everybody; some patients have residual levels of inflammation. And if we understand that -- why it's happening -- and we develop interventions to deal with it, we will probably learn something that will probably not only benefit HIV-positive patients, but will benefit other people that have these inflammatory conditions that have been associated with cardiovascular events.

I think eventually that this is the way we will look at this: Treatment benefits patients. We should treat people earlier, so we don't let them go with very, very high levels of inflammation associated with high levels of HIV viremia. And then, when the viremia goes down, and the inflammation goes down, well, we will have to develop interventions to deal with this residual level of inflammation. And I think that will be it.

Yes, I think there has been an emphasis, maybe too much emphasis, on this. But it's an interesting thing. And we can learn a lot about this disease process, and other diseases. I think that's why there is so much scientific interest in this area.

Myles Helfand: The potential ramifications of this significant outpouring of scientific interest, though, is that a lot of HIV-infected people are reading about this research and are getting a sense that there's a lot going on in the area of inflammation, that it's potentially a big deal. So, as a practicing clinician, what do you tell an HIV-infected person who comes to you; who maybe has been living with HIV for five, 10, 15, 20 years; and who is on treatment and may be doing OK, but is really concerned about all of this research that is coming out saying that inflammation is a problem, and it doesn't seem to be going away, even when you're on really good treatment?

Pablo Tebas: Well, I try to put this into perspective with the patient. I think the best interventions to reduce inflammation are relatively simple: eat healthy; exercise; if you have cardiovascular risk, maybe take a lot of aspirin; if you smoke, definitely try to quit smoking; and if your lipids are a little bit high because of HIV or its treatment, then do an intervention like a statin. I think that, at this point, this sounds like the most prudent recommendation. If all my patients were able to quit smoking and stay that way, they would definitely decrease their levels of inflammation to a reasonable level, and I don't think they would have a dramatic increase in their cardiovascular risk.

In fact, there is some data that suggest that the risk of MIs in patients with HIV that are well controlled, and are taking these new medicines that aren't associated with lipid problems, and are being monitored and getting statins and quitting smoking -- you are basically going to have, down the road, the same risk as anybody else for cardiovascular events.

Drink a little bit of red wine at night and enjoy life. That's what I try to tell them.


Cancer and HIV: Addressing a Growing Threat

Myles Helfand: All right. Then let's shift gears a bit, over to cancers in HIV, another area of complications that has always been a concern in HIV medicine, but the specific nature of which has changed significantly in the past decade.

AIDS-defining cancers, of course, were one of the defining features of people with advanced HIV disease in the '80s and '90s. In the more modern era of treatment, at least in developed countries, the nature of the cancers that have been diagnosed in HIV-infected people has shifted a bit, in terms of the incidence and the frequency of certain cancers -- particularly non-AIDS-defining cancers. What did we learn at CROI that might add to our knowledge of where this might be headed?

Pablo Tebas: I think this is an area we need to be concerned about. Patients with HIV are living longer, and we need to worry about the long-term consequences of living with an immune system that is good enough to protect you from opportunistic infections, but may not be completely normal [so that it would be able to] protect you from cancers and other long-term complications.

I think there were several studies [presented at CROI about this]. There was data from NA-ACCORD, which is a large cohort of North American clinics. There were studies from the CDC [U.S. Centers for Disease Control and Prevention], from the VA [U.S. Department of Veterans Affairs]. And the general theme is that not only are traditionally HIV-associated cancers increasing in HIV patients -- it's not only Kaposi's sarcoma or non-Hodgkin's lymphoma -- there are other cancers that we traditionally don't think of as HIV-related but that, in fact, their incidence is increased in patients with HIV, or they appear at a younger age in patients with HIV than in the general population. I'm talking about lung cancer, liver cancer, cancer of the anal area (that is probably associated with HPV [human papillomavirus]), melanoma. If you have HIV, your relative risk of having those cancers are probably twice, or a little bit more, than in the general population.

So there are two ways to deal with this. What does this mean for the clinician? It means, one, that probably it is a good idea to treat earlier in HIV. Because it seems that the increased incidence of this cancer is because your immune system is not completely normalized by treatment. But if you treat earlier, you will not allow your immune system to deteriorate to the point that you will lose some of these surveillance capabilities for cancer. So I think it's another one of the reasons, the growing number of reasons, that would tilt the balance to treat earlier, to try to prevent these long-term complications.

The other message is, as HIV has become more of a chronic disease, you need to be aware of this problem and stick to preventive measures: to really do your colonoscopy when you get to age 50; to really do, when you're a woman, Pap smears to rule out cervical cancer. If you are a gay man, then maybe do a Pap smear of the perianal area, to make sure that you are not going to have rectal cancer. And if you have warts, maybe have them checked more frequently by a colorectal surgeon.

I think the awareness about this problem should increase screening frequency. Make sure that you not only take care of your HIV, but also, that you have a regular internist that is going to be following up on these risks. And if you have a chronic cough, you have to have a chest X-ray to make sure that you are not developing lung cancer.

Some of my patients, what happens is that they tend to go to the HIV clinic, and they see their HIV doctor. And the HIV doctor tells them, "Oh, everything is going fine. You have an undetectable viral load, and your CD4 count is fine. Keep doing what you are doing." Well, they should be telling the patients, if they're worried about traditional risk factors for cardiovascular disease, but also cancers.

I think HIV care is becoming more and more like internal medicine, and we need to address all these issues that are being associated with living longer with well-controlled HIV.

Myles Helfand: I imagine there's a pretty delicate balance to strike here, particularly for a newly diagnosed patient who you don't want to freak out. I mean, it's probably a big enough thing for them to be dealing with their HIV diagnosis, period, and with the concept of starting antiretroviral therapy and then having to continue to take that every single day for the rest of their lives, potentially. To also throw onto that the prospect of a variety of cancers potentially developing earlier, or being more common among HIV-positive people, and the need to then get screened more frequently?

I had the opportunity to speak with Elizabeth Chiao, who presented a couple of studies on squamous cell cancer and the impact of antiretroviral therapy on maybe preventing it. One of the assertions that she had made during the conversation we had was that people don't love getting anal Pap smears. It's a difficult thing, in some cases -- and I think the same might be true of other types of cancer screenings. You're not necessarily going to get people to agree to get regularly tested for these sorts of things.

What does a clinician say to a patient who, number one, might not have thought they would have to deal with this prospect? And then, number two, might be not so thrilled with the idea of frequent cancer screenings?

Pablo Tebas: I try to have a very relaxed approach about this, and joke. I joke about my age, that I have to have my own colonoscopies. Nobody enjoys having a prostate exam, believe me. But you have to do it. You have to do screenings that have been proven to be effective -- I mean, mammograms after the age of 50, colonoscopy after the age of 50. Well, there is a big discussion about mammograms, but I mean, definitely, after the age of 50, the Pap smears.

All these types of regular screenings: I think patients with HIV shouldn't forget about them. When everything is going well in their HIV, they still have to realize that their immune system is not 100% normal, and that because of that, they need to deal with it. And the way to deal with it is to make sure that they encourage their physicians to do these regular things that we should be doing for everybody, but particularly for patients with HIV.

I try to have a very light approach to it. But I encourage my patients to have all these things done at regular intervals. And I think, for some of the big programs like Medicare or Medicaid, they should really evaluate the quality of the HIV care that clinicians provide to HIV patients -- not only by HIV markers like how many people are taking antiretrovirals or how many people are undetectable, but how good the providers are in covering all these other areas. Because overall, I think we have to have a global approach to HIV care that includes dealing with these increased cardiovascular risks. Now we're talking about the increased cancer risk in this population.

When I look at these things, I also hope that people who are not infected realize that HIV, although we have had huge improvements in antiretroviral therapy, is not trivial. Your immune system is paying a price. Yes, we have better treatments for HIV. But even if your HIV is well controlled, there are all these other increased risks that, because of HIV, are still present.

Hopefully that message gets out. Because I think the perception that HIV is a disease for the long run has been lost. I think that's at least partially the reason why we still have more than 50,000 cases of new infections a year: People don't think about the long-term consequences of having HIV. They say, "Well, if I get HIV, I will take a pill, and everything will be fine." No. Not exactly that. You still have an increased cardiovascular risk that I think we can deal with, if we do regular interventions. And you still have an increased risk in cancer that is going to make you have to go to your provider periodically.


Bone Disease: The Need for Greater Screening

Myles Helfand: We saw a number of studies at CROI that said much the same thing about bone disease and related complications.

Pablo Tebas: Yes. This is an area I am interested in because, many years ago, we observed that patients with HIV are more prone to having a low bone mineral density than the general population -- and that this problem is not only related to HIV, but also to the treatment of HIV.

I think there were important studies presented at CROI. There was a study by the HOPS [HIV Outpatient Study] cohort from the CDC, and also a study from the aging cohort -- from the VA; Julie Womack, I think -- showing that patients with HIV are at increased risk of fractures when you compare them to the general population.

There was a study of WIHS [Women's Interagency HIV Study], the women cohort, that didn't show that. Although that group, that cohort, is a little bit younger. So I was not very surprised that they didn't see an increase in risk factor. The other thing that I think we don't understand very well yet is osteopenia and osteoporosis. It's much more common in males with HIV than in women [with HIV]. So it's exactly the opposite of what we see in the general population, and we don't know why.

So that was one of the messages regarding bone: that patients with HIV are at increased risk of fracture.

Then there was a large presentation from Grace McComsey of a huge ACTG study, 5224, that looks at the effects of antiretroviral therapy on the bone. When you start antiretroviral therapy -- and this is completely independent of the regimen -- whenever you start antiretroviral therapy, the patients lose between 2% and 4% of their total bone mass.

If you start a regimen that includes tenofovir [TDF, Viread], you lose a little bit more than if you start a regimen that doesn't include tenofovir. And this happens quickly. And then, after 24 to 48 weeks, the bone mineral density tends to stabilize.

This is similar to what happens when you start steroids, although to a lesser degree: When you start steroids, you lose around 10% of your bone mass. When you start antiretroviral therapy, you lose around 3% or 4% of your bone mass.

This is another thing that patients with HIV should be aware of: that, because of their HIV and because of the treatment, they are at increased risk of osteopenia/osteoporosis. And I think, again, it's something that the clinician has to deal with. Basically, I think patients that are older than 50 that have HIV infection should have a DXA [dual energy X-ray absorptiometry] scan, and see where they stand. If they have indications for treatment [for bone loss], then they might need to be treated. And if they have normal bone mineral density, then we need to do the standard things that we suggest to everybody that is under medical care: Take enough calcium. Take enough vitamin D.

By the way, the frequency of low vitamin D levels is extremely high, and not only in HIV-positive patients. There were studies [presented at CROI] from the U.S., from Switzerland, from other countries, proving that the prevalence of low vitamin D is very high among patients with HIV. But it's also very high in the general population. So increasing vitamin D intake is something important that patients need to do for their bone health.

Because of these increased risks of osteopenia/osteoporosis with HIV, I think it's also important that people get diagnosed. I would do a DXA in everybody that is older than 50. If they're younger than 50, I don't think it's indicated, because the risk of fracture is relatively low. These patients are independent, and they don't have a risk of falling.

But as you age, and you become older than 50 -- particularly when you become older than 60 and around 70 -- is when you start having frailty. And your risk of falling and then fracturing something is higher. And that is associated, ultimately, with a lot of morbidity and mortality.

So I think the message is that osteopenia is common, and osteoporosis; that we have to deal with it; and that, as in the general population, the presence of low bone mineral density, measured by DXA, is associated with an increased risk of fractures.

Myles Helfand: So, just to clarify: You wouldn't necessarily suggest any kind of screening intervention unless a patient is over the age of 50? If they are younger, is it more that they should just be taking preventive measures at that point? Actively doing something to ensure that they don't develop problems when they're older?

Pablo Tebas: Yes. That's my -- it's not only my; it's the National Osteoporosis Foundation's -- recommendation. So if you are older than 50, you should have a DXA, if you have a risk factor for osteopenia or osteoporosis. And I think HIV infection, by itself, is a risk factor for osteopenia/osteoporosis. So I would say anybody with HIV, men or women, older than 50 should have a DXA. Younger than 50, I think general health measures to improve bone health are the way to go.

If you have HIV and you have had a fracture before, independently of your age, you should have a DXA. So, if you fell down the stairs and you fractured your wrist and you were 40, and you have HIV and you are taking medicine, you should have a DXA. Because you might have osteopenia/osteoporosis. Having just the accident doesn't have anything to do with your bone health, but there is no way to know, except doing a DXA.

But in general, my recommendation will be, for the general HIV-positive population, I would do a DXA in everybody that is older than 50. That's the recommendation for the general population, if you have a risk factor for the disease. And, as I said, I think HIV is a risk factor. It's not included in the list of the National Osteoporosis Foundation, because it probably was an oversight. But definitely patients with HIV are at increased risk of osteopenia/osteoporosis. And now we know, thanks to some of the presentations at CROI, that they are also at increased risk of fractures.


CNS Complications and the Blood-Brain Debate

Myles Helfand: Speaking of complications that tend to emerge as HIV-infected patients age, we saw a number of studies that were presented at CROI having to do with CNS [central nervous system] complications, which seems to be the issue that never dies. AIDS-related dementia was a key concern a decade or more ago. Now we're seeing a number of different signs of CNS-related problems emerging over time in HIV-infected people, despite suppressive antiretroviral therapy.

Pablo Tebas: Yeah. There were several presentations from the CHARTER cohort, which is a large cohort, around 1,500 patients in San Diego and multiple other sites in the U.S., showing that in spite of virologic control, a sizable number of patients with HIV have what they call HAND: HIV-associated [neurocognitive disorders]. This is a subtle neurocognitive impairment. You might not notice it in the activities of your daily living. And you can only ascertain it if you do some of the sophisticated tests that are done as part of these cohort studies.

A significant proportion of patients with HIV infection have HAND, and it is not completely corrected -- although it's definitely improved -- with antiretroviral treatment. Some of the suggestions of the posters and the presentations that were made during the CROI meeting were that if you treat earlier HIV infection -- there was a theme about that -- that you decrease the risk of HAND. If your nadir CD4 count is higher, the probability of you developing this neurocognitive impairment is lower.

So it's another one of the reasons to try to push people to think about treating HIV earlier, to try to prevent these long-term complications. We talked first about cardiovascular complications. We talked later about cancers. Now we are talking about this neurocognitive impairment.

One of the things that people have been talking a lot [about] in the last few years is, do we need to use medications that penetrate well in the spinal fluid? There was a study from England, I think it was, looking at individuals who had started antiretroviral therapy that penetrated well on the CSF [cerebrospinal fluid], versus individuals who started antiretroviral regimens that didn't penetrate that well on the CSF. And they didn't see a big difference in the frequency of these neurocognitive impairments.

The penetration on the CSF might not be that relevant when the drugs get into the tissue as opposed to crossing the blood-brain barrier and getting into the CSF. Obviously, we are not going to be doing biopsies of the brain in people. So any drug that suppresses viral replication probably is active within the brain tissue, even if it doesn't cross the blood-brain barrier.

But there are a lot of people, particularly neurologists, who think we should try to give medications that penetrate well in the CSF. I don't think the evidence is there yet to prove that that prevents neurocognitive impairment. And in fact, I think the evidence is the other way around: that any drug that will suppress viral replication will decrease the risk of these complications.

Myles Helfand: So if you have a patient who is on suppressive antiretroviral therapy, and maybe has been for, let's say, 15 years or so, or even longer, but is starting to develop some symptoms of early onset dementia -- maybe they are developing some memory problems, or similar CNS-related issues -- you wouldn't suggest maybe a shift to a drug that has been found through study to penetrate the blood-brain barrier a little bit better?

Pablo Tebas: With a patient like that, you start worrying about other causes of dementia -- vascular [disease], or degenerative [disorders], or Alzheimer's. You have to do a real workup for dementia before blaming it on the drugs that do not penetrate [the CSF]. So a patient that has neurocognitive impairment, in spite of successful antiretroviral therapy, I think needs a complete workup by an HIV doctor, and also by a neurologist, to try to rule out other causes of dementia that patients with HIV are not protected from. I mean, patients with HIV are aging like the general population, and they will have the problems that the general population has.

In the course of that evaluation -- which probably will include an MRI [magnetic resonance imaging], and probably a spinal tap -- I will measure the viral load in the CSF. If it's positive, and it's different from the general circulation, probably I will change the antiretroviral therapy. If the viral load is undetectable in the CSF, as it is in the serum, then I will probably think that the cause of that neurocognitive impairment doesn't have anything to do with ongoing HIV infection, and probably will not adjust the antiretroviral regimen that the patient is taking.

I think it's something that we need to worry about, and make sure that we monitor for. If it appears, then [we need to] consider more thorough evaluation of the neurocognitive function and possibly other causes that can be associated with neurocognitive impairment.

Myles Helfand: I suppose that, as with all things, there's a certain amount of perspective that this needs to be placed in. You had mentioned earlier in our talk about CNS issues that the studies that were presented here generally found that we're talking about very subtle shifts, right, in CNS function? We're not talking about anything that's necessarily something that a person would even notice in their day-to-day lives. So it's not something that we necessarily need to actively monitor, or that an HIV-infected patient, the average patient, even needs to be that concerned about, right?

Pablo Tebas: I agree with you completely. It's not that our clinics are full of patients with severe neurocognitive impairment who cannot drive to the clinic. This is not what we saw in 1990-1991, when HIV dementia was so prevalent and so disheartening because many, many people were developing it, HIV was progressing, and they were losing all of their mental capabilities.

I think, if you come to our office, or any office with HIV, patients with severe neurologic dysfunctions are rare. Occasionally, we have some. But in general patients the effect of antiretroviral treatment has been incredible, and basically AIDS-associated dementia has almost disappeared from our clinics. In some neurology clinics, I'm sure they see some of it. But as soon as we start treating HIV with potent antiretroviral therapy, and you control HIV replication, the severe neurocognitive impairment tends to improve. Then you are left with these subtle abnormalities that you just have to monitor and deal with.

Usually patients can deal with them with extra support from their surroundings. And if they have small memory losses, there are tricks to go around it. It's probably one of the reasons why GPSes [global positioning systems] for cars have become so popular.


Summing Up: A New, More Holistic Era for the HIV/AIDS-Treating Clinician

Myles Helfand: Taking a step back: We just spent a good amount of time wading through a significant number of studies that talk about the long-term impact of HIV -- and maybe, to an extent, antiretroviral therapy -- on a range of different key complications: cardiovascular, inflammation, cancers, bone issues, CNS. All of this gets at something that you said a little bit earlier in our conversation about how the nature of what it means to be an HIV care provider seems to really be changing. These studies presented at CROI don't revolve so much around specific issues of which drug to take. It's becoming more about the management of all of the other things that a person might encounter as they live with, and deal with, the impact of HIV.

Pablo Tebas: I think you're absolutely right. If anything, this CROI meeting was about the complications of HIV and its treatment more than new antiretroviral drugs. There were no earth-shattering new antiretroviral treatments or paradigm shifts in the treatment of HIV. The general theme of this CROI meeting was about the complications of HIV: cardiovascular, cancer. There was even a session about H1N1, CNS, bone disease.

So, yes, the nature of being an HIV doctor is shifting. For a while, for a few years, we needed to know about all the antiretroviral medications, the resistance patterns. And we still need to know about all that. But now, it's becoming much more general internal medicine. You have to deal with all these things, and you have to learn how to manage them, and to be proactive in managing them.

Being a provider is going to be different in different states or even different payment environments. Sometimes HIV providers are also the primary care provider for the patient. If that's the case, they have to take full responsibility for monitoring for all these other issues. In some states, or in some markets, the HIV provider is a specialist, where the patient is just referred to them for HIV care.

What happens is that the patients usually see their HIV provider four or five times a year, and they might see their primary care provider only one time a year. It would really be a pity and a waste of opportunities if the HIV provider doesn't try to do some interventions to improve the overall health of their patients.

I think HIV providers are going to become more and more general internists in the care of HIV patients, which I think is a good development, because I like internal medicine, to tell you the truth.

Myles Helfand: This isn't a bit of a tall order to ask of practicing HIV physicians? Or ID [infectious disease] docs who take care of some HIV-infected patients, who suddenly need to take on knowledge and understanding of a wide range of other areas?

Pablo Tebas: Well, yeah. It may be a tall order. But I think it's the nature of the thing. And I think the HIV providers in general have been very adaptable and have adapted themselves to the changing circumstances of HIV care. And I think this is going to be the way of the next decade, until we find a cure for HIV. We're going to have to deal with all these other complications.

Hopefully this challenge will attract young physicians into HIV care, which I've been worried about -- losing some of the romantic ideas about HIV from the early '90s that attracted many young physicians into HIV care. We have not seen that in the last five years. I think if residents and new physicians see that HIV care is a challenge, that it will require a very broad knowledge base but, in addition to that, you have all the science and all the excitement of antiretroviral treatment, I hope we can attract new providers into our field.

Because what is really a fact is that the number of patients with HIV is going to grow, because of increased survival, and that we are going to need more and more providers taking care of these patients. I hope we can attract providers, and that this new challenge of having to have a global knowledge, and global perspective, will attract some clinicians. Because the population of HIV providers is aging. And we need younger people doing this.

Myles Helfand: Are you listening, med students of the United States and Europe?

Pablo Tebas: Today is Match Day in the U.S. [this discussion was recorded on March 18, 2010], so I don't know if they will be listening. But maybe in the future they will. They probably are celebrating, or very worried, where they matched.

Myles Helfand: Well, it sounds like if they end up at U. Penn. that they will be in pretty good hands. It sounds like you might be the kind of person who would try to take a more aggressive stance on their training, to get them to take more things into account than just HIV specifically.

Pablo Tebas: Yes. I think that's one of the most attractive things of being an HIV care provider -- that you have to have a holistic approach to your patients; that you just cannot focus exclusively on HIV issues. All of these issues that people in the past thought were not related to HIV: You know what? They were related to HIV. And they are related to HIV. The increased cancers, the increased cardiovascular disease, the bone issues -- all of that is somewhat related to HIV and its treatment. You need, also, to deal with those.

Myles Helfand: Pablo Tebas is an associate professor of medicine at the University of Pennsylvania School of Medicine. Dr. Tebas, thank you so much for taking the time to talk.

Pablo Tebas: Oh, you are more than welcome.

This transcript has been lightly edited for clarity.


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