Dr. Gallant and his colleague, the noted HIV researcher, John Bartlett, are coauthors of Medical Management of HIV Infection, a respected, annually updated clinical guide. Welcome to This Month in HIV, Dr. Gallant.
Thank you, Bonnie. It's good to be here.
Dr. Gallant, this podcast will focus on the latest research from the 14th Conference on Retroviruses and Opportunistic Infections which as you know took place at the end of February in Los Angeles. For our listeners who do not know about this conference, The Retrovirus Conference, which is also known as CROI, is the most important HIV/AIDS research conference of the year. Knowledge about HIV is incremental. Researchers and clinicians attend these conferences hoping to learn more about how to optimally treat HIV. But with 1,000 studies presented, it's a challenge to figure out which studies were most impactful and actually will change practice. I thought you might be able to help our listeners understand results of some of the studies that were presented.
The first question I had was related to first line, or initial, HIV therapy. Do you think we've come closer to knowing when it's optimal to start HIV therapy?
So for me, the more interesting question is: Who would I not treat? The only people that I can think of that I would not consider treating would be long-term nonprogressors, or people who might be long-term nonprogressors, or people who are unlikely to take their medication. Short of that, I think virtually anybody is a candidate for therapy. When we have such effective therapy against an otherwise fatal disease and the therapy has so few long-term toxicities, I think it makes sense to be more aggressive.
What does "more aggressive" mean to you? If I have a CD4 count of 500, would you start me on therapy?
It's never a question of me starting somebody [on HIV treatment]. It's a question of me talking to somebody about whether they want to start [on treatment]. I think if you had a CD4 count of 500, but you had a high viral load and there was evidence that your CD4 count was decreasing, I would at least talk to you about being treated. Because the [U.S. government treatment] guidelines don't say that [HIV treatment should be started in people with CD4 counts of 500] -- the guidelines currently say 350 -- I wouldn't push this too much [Click here to view a PDF of the U.S. treatment guidelines.]. If somebody said, "I don't really want to be treated yet; I'd rather wait till I have to," I wouldn't push the issue. But I do point out to patients that the guidelines are almost certainly going to change soon, and will almost certainly become more aggressive than they are now. I talk to them about the data showing that starting earlier is better from all different kinds of standpoints, including better CD4 responses, fewer opportunistic complications, fewer non-opportunistic complications and, ultimately, possibly better survival and better health. So I think we're getting to that point.
Are you saying that we may eventually recommended that people start treatment at any CD4 count? It's no longer 350. I know people are hanging their hat on 350.
No, we shouldn't. You know, that number is going to change soon. Don't get too fixated on 350. Dr. Mellors presented data from the MACS cohort, and then there was also data presented from the ALIVE [AIDS Link to Intravenous Experience] cohort at [Johns] Hopkins [University], showing that, in fact, the viral load is a much better predictor of progression to AIDS or death than the CD4 count is. We've kind of been ignoring the viral load recently when we make decisions about when to start. Maybe that was a mistake.
So, in terms of something related to first line primary infection: a lot of people who know -- I know there's just a very small population of people who know that they have just recently become infected, who get treatment. Do we know whether HIV treatment at that point is beneficial?
I wish I could say I knew the answer. The data presented at this conference, and at all the other conferences I've seen, have been very conflicting. You know, there's some data suggesting that it's a good idea; others not clearly making that point. I think we still don't know the answer.
I think if there's a group of people where I would be most likely to urge treatment, it would be people who are diagnosed very early, before they have even sero-converted -- when they are in the middle of the acute retroviral syndrome. I think there are some data to suggest that treating people at that point may help, in terms of reducing [viral] set point and reducing the loss of some of your CD4 cells in the intestinal tract that clearly disappear quickly with infection.
I think our uncertainty is why it's so important to diagnose people at this stage and get them into clinical trials. Because there are studies ongoing where we're comparing treatment versus no treatment [during acute or primary infection], to find out whether there's any benefit. We really need to be making these diagnoses [during acute infection]. It drives me nuts when I see people who had risk factors, went into a hospital, had a fever, and the doctor thought about mono, and the doctor thought about flu, but never thought about acute HIV and never did the right tests.
Would you describe acute HIV symptoms as resembling flu symptoms?
Yes. They are like flu or mono -- fever, maybe a rash, maybe swollen lymph nodes, fatigue. They're pretty non-specific; they could be symptoms of a lot of things. But I think the point is, if you're a physician and it crosses your mind that somebody could have mono then it should also cross your mind that they could have acute HIV, because the symptoms are identical. There's just no way you can think of one and rule out the other on the basis of symptoms.
What's the good thing about reducing one's set point? And could you clarify what that means?
Well, if it's true that you would reduce the set point, what it would mean is that, if you were to stop therapy after acute infection, you would have a lower baseline viral load than you would have had, had you not been treated. Therefore, presumably you might progress slower and not need to be restarted on therapy for a much longer period of time. Now, that has not been clearly shown, but that's the idea.
So we still don't know that much, I guess.
We still don't know. The reason we don't know is because so few people get diagnosed at this stage. That's a problem with medical care.
Why It's Important to Get A Resistance Test After Being Diagnosed
Okay, on to my next question. Resistance tests: Do we know if transmitted HIV drug resistance is on the rise? Is there any more proof of this?
If you look at the United States, it has been on the rise over the second half of the last decade, and the first half of this decade. It's sort of steadily been rising. In most of the rest of the industrialized world, especially in Western Europe, it hasn't really been rising very much. It's sort of leveled off. It could be that it will level off in the U.S., too. But clearly, there's enough of it going around here that it's absolutely critical to get resistance testing in everybody who's been diagnosed with HIV.
So a resistance test is one of the many monitoring tests, then, that HIV-positive people should be sure to get along with a viral load test and a CD4 count.
Absolutely. It should be done not when you're about to start therapy, which is how the original guidelines were written; it should be done when you're diagnosed with HIV. Because the sooner you get this test, the more accurate it is. Ideally, getting it at the time of infection would be great. The test will remain accurate for several years after diagnosis. But if you wait too long, some of those resistant mutants will start to disappear. They're still there, but they won't be picked up by the tests. So you don't want to wait on this test.
What's the most common drug resistance transmitted for people just diagnosed?
There are a lot of different mutations that are transmitted. But in terms of how those mutations affect drugs, in particular, the ones we worry about most are resistance to non-nucleosides [NNRTIs], which would be [resistance to] Viramune and Sustiva. The reason for that is because those mutations, they tend to persist for a long time. Even in people who have been on Sustiva and then stopped it; they'll still have the Sustiva mutation, so they can infect other people with that mutation. The other problem is that the single mutation can cause such high-level resistance. So if there were one class of drugs I would worry about, it would be those drugs.
Just to explain to our audience: If you are diagnosed with HIV and along with the HIV you got the person's HIV drug resistance and you don't get a resistance test, when you begin a regimen, let's say, with Atripla, it won't work.
Right. Not only will it not work; let's say you're infected with NNRTI resistance. So you're resistant to Sustiva, and you take Atripla, which includes Sustiva, but it also includes Viread and Emtriva. The Sustiva is not going to work, and that means that you're really only on two drugs. Then your virus could develop resistance to the Viread and the Emtriva component of the combination.
You started out with resistance to one drug and now you've got resistance to three -- not to mention cross-resistance to other [medications]. That's why it's so important to use these results when picking an initial therapy.
So, talking of initial regimens: As you know, there was a major study presented in Toronto, the AIDS Clinical Trial 5142, that compared Kaletra against Sustiva. It looked like Kaletra raised CD4 counts more, and Sustiva got viral loads down quicker. Two questions: What should this mean to people trying to figure out what their first regimen should be?
Well, the overall results of that study, 5142, were that Sustiva was better. The original results showed that more people achieved an undetectable viral load and maintained it with Sustiva than with Kaletra. Then, at this conference, we heard that maybe one of the reasons for that was that the Sustiva drove viral loads down quicker than Kaletra did. But Kaletra did have its advantages. So it wasn't a complete win for Sustiva. One was that CD4 is increased a little bit more on Kaletra. That could be important if you're starting out with a very low CD4 count; it's probably not much of an issue if you're starting out with a higher CD4 count. The other was that, although Sustiva was less likely to fail, if it did fail you were more likely to develop serious resistance on Sustiva than on Kaletra. So I think that's only an issue for people who are likely to interrupt their therapy -- you know, people who miss lots of doses and things like that. For people who plan on taking all their pills, it shouldn't be a problem. But the consequences of failure are greater for Sustiva or Viramune than they would be for a boosted protease inhibitor.
I see. Sustiva and Viramune, okay.
Those issues probably apply to both drugs.
If you're given a choice of what you should start on, are there advantages to starting on either a Kaletra regimen or a Sustiva regimen -- I mean, besides the CD4 count issue and the viral load issue -- are there side effect issues here, as well in terms of choosing a regimen?
Well, sure. I think all the drugs have their side effects. Certainly, Atripla is currently the regimen that has never been beat -- i.e., tenofovir, FTC and Sustiva, which is contained in Atripla. I look at that as sort of the gold standard regimen. But it's not for everybody. Certainly, for women who might become pregnant, it's not a good idea. For people who have kidney problems, it's not a good idea. For people who have baseline resistance to some of those drugs; they shouldn't be taking that. Then there are some people who just can't tolerate Sustiva. I would say, in my experience, maybe it's about 5 percent of people who try it and, they just can't get over those neurologic side effects that, for most people, occur quickly, and then go away. So for those people; they sometimes will have to switch [from Sustiva] to a protease inhibitor.
What about in terms of metabolic side effects?
Well, it's interesting. I think we thought we understood this ... until CROI. We have known that most protease inhibitors cause some lipid elevations, [i.e., elevations in] cholesterol and triglycerides, and that they're capable of causing blood sugar changes and insulin resistance and that the non-nucleosides, like Sustiva, don't do that. We've also known that drugs like AZT and d4T (Zerit) cause lipoatrophy -- the loss of fat you get in the face and the arms and the legs -- and that was pretty much it.
What was interesting was that at this conference, they presented data from that same study, 5142, and they found that, certainly, d4T was the worst drug, in terms of lipoatrophy. AZT was second. And tenofovir was pretty much almost innocent of causing [lipoatrophy]. But what was interesting and unexpected was that, if you were on d4T or AZT with Sustiva, you were more likely to get lipoatrophy than if you were on it with Kaletra. We haven't ever really associated either protease inhibitors or non-nukes [NNRTIs] with independently causing lipoatrophy. They probably don't, by themselves. But this suggested that, in combination with drugs that cause lipoatrophy, Sustiva was more likely to do it than Kaletra.
I think from a lipoatrophy standpoint, the moral of the story is, just stay off d4T and AZT, and you'll be okay. But these are unexpected findings that will need to be explained.
So if you're taking Sustiva and are very scared of lipoatrophy, should you become more scared?
There was an interesting study on bone density, showing that a great percentage of people who are HIV-positive have low bone mineral density. What does this mean to someone with HIV?
We're still trying to figure all this out, whether bone density is a result of drugs or whether it's just a result of having HIV for a long time. There's no question that decreased bone density is more common in people with HIV, but it isn't clearly a drug side effect. Having said that, I will say that we know that when you start antiretroviral therapy, you do get a small loss in bone density right away. Then that kind of levels off. We saw that in the studies with Viread and with Zerit. It's possible that this occurs every time you start therapy, which may be a really good reason not to do a treatment interruption (as though you needed another reason not to do it). If every time you restart therapy you take a hit in terms of your bone density, then repeated starts and stops could be bad for you.
But right now, we don't really know what to say about who we should be screening for bone density. I personally will screen anybody who has had low testosterone levels, because low testosterone levels also give you a risk for decreased bone density. I'm not doing it routinely in everybody, but we don't really have any good sense of who should be screened yet.
Should people take calcium and vitamin D, just in case?
There's no official recommendation about that. I think it couldn't hurt, in moderation. Or, if you're getting plenty of sun, you're probably okay with vitamin D. If you're drinking milk products and things like that, you're probably okay with calcium. You don't want to overdo these things, because both can be toxic in high doses. But I'm not routinely recommending it to all my patients, let's put it that way. But we may get to that point.
One thing I would say is that one of the best defenses against bone density loss is exercise, especially resistance-type exercise. So going to the gym is going to help a lot.
A few years ago there was a lot of talk and some studies about a higher rate of heart disease in people with HIV -- perhaps because of HIV, perhaps because of the protease inhibitors. Any news on this?
[There wasn't] too much news at this conference, but I think subsequent follow up data from some of those original studies showed that it didn't appear to be true across the board. So in other words, if you looked at people who were on non-nukes, like Sustiva, they didn't really appear to be at much increased risk. If you looked at people who were on PIs [protease inhibitors], [you saw that] that group accounted for most of the increased risk. But if you then treat their cholesterol or treat their blood sugar problems, you reduce the risk. So I think the good news is we've got new [HIV treatment] options that don't appear to affect cholesterol and heart disease risk like the old ones did. The other [good thing] is that we're getting better about realizing we need to be treating these problems when they occur. So I think that's going to decrease the risk [of heart disease] quite a bit.
Didn't several studies presented at CROI show that up to 40 percent of people with HIV smoke cigarettes, which increases the risk of heart disease?
If you're smoking, it's kind of crazy to be worried about your cholesterol and your protease inhibitors because the amount of benefit you would get by stopping smoking just dwarfs the risks [from those factors]. Smoking is such an enormous risk for heart disease that cholesterol and protease inhibitors are tiny in comparison. So if you quit smoking you have accomplished most of the battle.
I think people are also concerned about data showing that the incidence of cancer in people with HIV is growing. Anything you can tell me about that?
There was one interesting study, looking at cancers that are not typically thought of as being HIV cancers. [Click here to read coverage of studies on cancer and HIV presented at CROI.] So the HIV cancers are lymphomas and Kaposi's sarcoma, and things like that. But they were looking at the other cancers, and interestingly, found that the risk of those cancers was increased in people with HIV, and it was increased more in people with low CD4 counts. Obviously, although they are not strictly HIV-related cancers, there's clearly a link between immunosuppression and your risk of getting these cancers. This has actually been used as another argument for why we should be starting therapy earlier, to help prevent that risk.
Now, it's a little complicated in some studies, because people with HIV tend to smoke more and tend to do things that could increase their risk of cancer that's apart from their HIV status. But still, I do think that immunosuppression is a bad thing, and it can increase your risk for all sorts of things, other than just the traditional list of HIV-type complications.
What was the big news for people who have multidrug resistant HIV?
This conference is always about drugs and this was no exception. In fact, new drugs really took the limelight, I think -- at least [among the] clinical presentations. Probably the drug that got the most attention was raltegravir, which is the new name for the Merck integrase inhibitor, MK-0518. We heard data from two large, simultaneous multicenter clinical trials called the BENCHMRK trials, in patients who were highly treatment-experienced, had a lot of drug resistance. [Click here to read coverage of the BENCHMRK studies.]
The bottom line is, people did very well with raltegravir combined with other agents. They did much better if they were on raltegravir than if they were not on it. They especially did well if they were on raltegravir, along with at least one, if not two, other active drugs.
For example, if they were on raltegravir with Prezista and Fuzeon, they did extremely well. Or if they were on it with one of those drugs [they did well]. This drug is out there in expanded access right now. We hope it will be approved this year. The key thing is that, when it comes out, as with any new drug, it's going to be critical that you're taking it with something else that really works.
The other news was about maraviroc, which is the Pfizer CCR5 entry inhibitor. There was kind of a similar study -- or two studies -- called the MOTIVATE trials. [Click here to read coverage of the MOTIVATE studies.] [They were] very similar in design [to the BENCHMRK studies], people who were treatment-experienced and had drug resistance got an optimized background regimen, and then they either got maraviroc or placebo. People did better if they were on maraviroc.
The clincher with maraviroc, though, is that it is a CCR5 inhibitor, and so you really should only take it if your virus is R5-tropic -- which means that you have the kind of virus that uses the CCR5 coreceptor to get into the cell. So you have to do a test, called a Trofile assay, before you take this drug. If you're not R5-tropic, if you have other types of virus, specifically virus that gets in through the CXCR4 coreceptor, then you probably shouldn't be taking this drug. Of the people they screened for the trial, 44 percent were not able to join the trial because they had that kind of virus. This is not going to be a drug for everybody. But for those who had R5-tropic virus, it worked very well.
So is it reasonable, if you are resistant to many HIV meds, to be able to switch to medications that will get your viral load undetectable now? It used to be unreasonable. Now, is that an expectation anyone can have?
Yeah, absolutely. In fact, both the DHHS guidelines and the IAS [International AIDS Society] USA guidelines have changed their wording. [Click here to view a PDF of the International AIDS Society treatment guidelines.] They now say that the goal of therapy for everybody, regardless of the amount of treatment experience, is an undetectable viral load of less than 50. That's a major, major change.
Because they used to say that that was not a realistic goal for a lot of people. I think that by the end of this year, if we really get multiple drugs approved this year; I think it will be a realistic goal. But it will require that both people with HIV and their clinicians understand that no great drug is great without other backup. If you use a new drug without considering resistance, and without combining it with something else, then it's not going to be a great drug for very long. That rule has not changed in the many years of antiretroviral therapy. I hope that everybody knows that rule by now.
For my final question, I wanted to get your idea about mortality issues. Everyone newly diagnosed wants to know what his or her chances of living a normal lifespan is. Are there any new data about that?
Well, not so much data. You've heard different presentations, trying to estimate lifespan. There was a lot of fuss about the one that gave an estimate of 24 years. I tell my patients: Ignore those studies. Not that they are not good studies; they are very useful. But they are talking about large populations. In those populations are included people who don't take their medications, people who are actively injecting drugs, people who have hepatitis C, people who have renal failure .... If you're not one of those people, if you're just a healthy person who plans on taking every dose of your medications, then those kinds of estimates are meaningless to you.
I tell my patients that, granted, these new therapies ... the whole idea of suppressive therapy has been only around for 11 years, so it's still relatively young. But [in] people who have undetectable viral loads we're not seeing their virus evolve and become more resistant or harder to treat. So I tell [patients] that they should expect to live a normal lifespan, and to die of something other than AIDS, when they're old.
Can I promise this 100 percent? No. I do think that it's a pretty realistic prediction. But I know that every time somebody publishes some study about what the average lifespan is I'm going to get 40 e-mails and 20 calls from people, saying, "But you told me that I was going to live a long time." So, be careful how you extrapolate data to your own personal situation.
Basically, on the whole, would you say the news from CROI was positive for patients living with HIV?
Oh, yes. I think definitely the news from CROI and from other recent conferences, like [the International Conference on AIDS in] Toronto and some of the other meetings, [has been promising]. The fact is, we've got incredibly good initial therapy now that could last you for decades if you do it right. Then, if things don't work out with the initial therapy, or if you get toxicity or side effects, we've got a lot of options to go to that will work when the first line therapy fails.
We used to say you have got one or two good shots at antiretroviral therapy, and I would say we can go much further than that now. At the same time, people on initial therapy are much less likely to fail than people were in the early part of the HAART era. I think the news, from a treatment standpoint, is great.
Thank you very much.
People came away from CROI 2007 with a different take home depending, I think, on their perspective and who they were. We thought it would be helpful to get the viewpoint of someone with HIV. Nelson attended CROI and came back with a unique take on the research presented.
So, Nelson, tell me: As a long-term survivor and community activist, do you think we have come closer to knowing when it is optimal to start HIV therapy? If you were newly diagnosed, when would you begin treatment?
I think we're getting closer. But we still have guidelines that tell physicians to prescribe to people that have a CD4 count under 350 or viral loads over 100,000 or a combination of the two or somebody that is actually showing symptoms of HIV or AIDS.
But I think we're getting closer and closer to the reality that we used to actually embrace a few years ago -- to start people at an earlier stage of HIV infection. We don't have anything when it comes to the U.S. HIV treatment guidelines that says that yet. I think we're going to move towards that. That's because, I think, the main factor here is the fact that we have a lot more friendly, or friendlier, treatments -- HIV treatments that are not as toxic and problematic as we used to have. For instance, five years ago, or six years ago, many of us were taking Crixivan [indinavir] plus Zerit [stavudine, d4T] and Videx [didanosine, ddI], and we had a lot of problems with neuropathy, lipodystrophy, lipoatrophy, kidney stones, insulin resistance, diabetes ... you name it. So we kind of walked away from the concept of treating people earlier on in the disease, not only because, even though we had good CD4 response and viral load responses back then, the toxicities were a little too much to justify early treatment.
However, the past few years, we've had treatments come through the market that are a lot more friendly when it comes to toxicities. We have Viread and now, of course, Truvada [tenofovir/FTC], the once-a-day pill Atripla [efavirenz/tenofovir/FTC], Reyataz [atazanavir] a protease inhibitor that has definitely shown lower incidence of lipid abnormalities. We kind of got rid of Zerit. Zerit is not as popular in the United States as it used to be, although, of course, Zerit is being used everywhere else in the world. We cannot forget our brothers and sisters out in Africa and South America and Asia that are taking Zerit and AZT [Retrovir, zidovudine].
We have more and more data that shows there are, of course, immune benefits and viral load benefits to starting treatment earlier. The biggest factor in shifting the pendulum towards earlier treatment will eventually be less toxic treatments. We are already moving in that direction. I think the integrase inhibitor class is going to be shown, in my prediction, to be a lot cleaner in toxicities for treatment-naive patients, too. They are moving towards that. There's data from CROI on Tibotec's drug, TMC278. [Click here to read coverage of the study.] It's a non-nucleoside [reverse transcriptase inhibitor] like Sustiva [efavirenz, Stocrin] or Viramune [nevirapine] that may be as effective as Sustiva, yet not have the neurological complications.
The more drugs we have that are friendlier to patients' bodies, the more the pendulum will swing back to where we used to be, years ago. However, I'm also an activist, so the issue is, "Who's going to pay for earlier treatment?" We're already overburdened when it comes to getting funding from federal sources in the United States. The earlier we start people, the more money we have to spend on healthcare for HIV. That's a big factor, too, that we have to think about. It's not only about the health benefits. I think there's going to be some problems trying to -- especially under the current administration -- get programs funded that justify treatment, for instance, for somebody that has 450 T cells, instead of 350. That's what I'm trying to say.
There are many factors that determine when a person should start treatment. Some people may not choose to take treatment when they have high T cell levels and low viral loads. We have data now that show more and more that, for instance, the gut lymphatic tissue -- i.e., the T cells, the memory T cells in the lymphatic tissue in the gut -- are preserved better if we treat earlier, too.
Why is that important?
We forget that most of our immune system, most of our T cells, memory or naive T cells, are in the gut. In the past three years I myself, as a patient, I have experienced a lot of gut problems. I have had GI [gastrointestinal] problems since day one. I have lived with this for twenty-some years, and I'm always concerned about my gut. It seems like a huge loss of T cells, CD4 cells, memory cells, in the gut lymphatic tissue occurs early on in the disease. That [early loss of CD4 cells in the gut] basically predicts, or predisposes us, to a lower immune response with treatment in the future. So it seems like we lose a lot of memory T cells early on. If we treat it early on -- it's a hypothesis; I think we need to prove it; nobody has really proven it yet -- we may preserve immune function for the longer term.
You asked me a question which I don't think I've answered yet. If I just turned out to be positive today, let's say, and I had 400 T cells and maybe, let's say, 50,000-60,000 viral load, which would not qualify me for HIV treatment under the DHHS [U.S. Department of Health and Human Services] guidelines, would I take treatment? I probably would, as long as I could take a treatment that I can tolerate -- maybe a Truvada or Sustiva -- although I don't tolerate Sustiva very well. Or Truvada + Reyataz. Things of that nature that would not affect me metabolically, or my gut would not be affected. Diarrhea is a big issue for me. Yes, I would definitely consider it. I would be more open to that knowing the data that I've seen at CROI.
Would you consider starting treatment with a CD4 count of 450?
Yes, but I'm also a pill popper. Some people do not want to pop pills, and they have a big barrier to taking medication of any kind. So I think we have some more work to do. I think we're going to move towards that. I think it will probably take a few -- two or three -- years to get there. I really think so ... It's looking more and more promising with less toxic drugs.
My second question is related to my first. Should people who are lucky enough -- or unlucky enough -- to find out they have HIV immediately after getting infected (that's called primary infection) -- start treatment immediately? Did you see any interesting research on the topic at CROI?
It's kind of a gray area. And also, who's lucky enough to run to a doctor while they're going through basically primary infection? They just find out. They don't even find out, actually. They have unsafe sex, and they can feel their bodies changing. They're having night sweats. They're having flu-like symptoms. Their lymph nodes are inflamed. They run to the doctor. The doctor runs their viral load and T cells. Of course, their viral load, it really increases dramatically in that phase. And they get treatment.
Very few people do that. Very few people. [Laughs.] Most people are actually in denial in the first months, or actually, years, of infection, anyway. We are talking about people who actually are smart enough to do that, to run to the doctor and say, "Hey, I may have been infected. Test me. Let's run a viral load, and let's do something about it."
For those people, some studies have shown some benefits from early treatment. Of course, we have studies that show no benefits. But two studies that were presented at CROI were very interesting. One was done in Amsterdam with 332 patients. ... Sixty-four people enrolled in the study started HAART within 180 days of seroconversion, and 32 of these patients then stopped treatment. I forget how many months later, but it was a few months later. What they found out is that for those patients that started treatment right away, within 180 days of seroconversion -- I don't think that's really right away, by the way; it could have been, probably, earlier, to be more effective -- they found that their viral set point was a lot lower once they interrupted HAART. They went on a treatment interruption.
The viral set point for patients treated within 180 days of infection was lower compared to patients who began treatment more than 180 days after seroconversion?
Right. Compared to the arm that was not treated early. But they say that that benefit tended to disappear with time. Of course, viral loads started going up after that. But when they interrupted, compared to those that were not treated early, their viral load was almost .6 log lower.
That makes sense. If you treat early maybe you have some preservation of immune response, but with time, that effect may disappear.
There's another study from Munich, too, that enrolled 200 patients with primary HIV infection. One hundred forty-four were treated right away, and 56 patients delayed treatment. Then they stopped -- 100 patients stopped treatment after almost ten months. And in this study they didn't quite see the differences, the huge differences, in viral load, between treated and untreated that were seen in the study done in Amsterdam, but they saw 87 T cells more in patients who were treated early. The treated arm had a lot more T cells than those others that delayed treatment.
There's actually another study that I haven't mentioned that says that, once again, the gut lymphatic tissue, can be preserved. The CD4 loss that occurs early on in HIV infection can actually be improved if you give treatment early on. That's another area of research that I think we're going to see a lot more studies on.
It's very exciting. I don't think we have an agreement. I think actually this is probably the most controversial part of HIV treatment. I think there are trends that will show us that maybe it is not a bad idea to treat people -- especially now that, once again, we have less toxic drugs to treat them, at least for the first year of their infection. We can see what happens afterwards.
One more thing I wanted to add that was really shocking for me is that, in the Munich study, [of] those that started treatment and then stopped 12 months later there were two patients that remained undetectable, even after they stopped treatment. I'm hearing a lot more of that. When I go out on my lectures, people raise their hands and say, "Well, I was in treatment. My T cells went up, my viral load went undetectable. Then I wanted a break and had some issues with side effects and took a treatment interruption, and I'm still undetectable. What do you think about that? Am I cured?"
Back two years ago, I thought, "Hmm. Maybe you were diagnosed wrong, right?" [Laughs.] But now I'm seeing more and more of that. So there are some patients -- very few of them -- that start treatment early, go on a treatment interruption and remain undetectable. I'm not saying this is a rule, obviously. Only two out of 100 remained undetectable after months of stopping therapy. That means we need to look at these patients more closely, too. We should ask what's happening to them and why treating them early gave them this kind of response.
We have to jump to the next topic, because our time is limited. Can we talk about your specialty, metabolic complications? Did you see anything interesting on the topic at CROI?
Yes. The study [ACTG 5142] considering Sustiva plus nucleosides, versus Kaletra plus nucleosides, versus Kaletra plus Sustiva without nucleosides. Very interesting. They found a higher incidence of lipoatrophy in the Sustiva plus nucleoside arm versus Kaletra. Definitely something we did not expect at all. So, of course, the nucleosides included AZT, d4T, and I think some patients were also on tenofovir [Viread]. But what we saw is there's a higher incidence of lipoatrophy in the Sustiva arm than in those who are taking also AZT or d4T. I think somebody needs to explain this, and we're going to see data on this eventually, I guess: Why is Sustiva causing a higher incidence of lipoatrophy in the presence of nucleosides? Is it because of the increase of intercellular levels of AZT or d4T? Or is it related to something, when it comes to mitochondrial toxicity of insulin resistance? So it's very intriguing, very intriguing.
There's another study that ... looked at bone density and the treatment of people with low bone density with Fosamax [alendronate] once a week, and calcium and vitamin D supplements. There was a response to Fosamax. It was almost like a 3 percent or so increase -- yes, a 3.38 percent increase in 48 weeks. People say, "Well, that's not much," but the encouraging thing is that it's actually the same response that has been shown in HIV-negative studies in the past. At least we know that this treatment, Fosamax with supplements of calcium and vitamin D, works the same way for HIV-positives and negatives. That was very interesting, too.
I'm one of those activists trying to push for early diagnosis of bone density loss with the use of DEXA [dual energy X-ray absorptiometry] scans. There's also no recommendations, no guidelines, on this topic. I think the earlier we find out whether or not you have problems with bone density, the better. Most people wait until they have a fracture.
Have you gotten a DEXA scan?
Oh, yes, yes. DEXA is a beautiful thing. DEXA scans cost under $150. With them you can get information about your bone density, your lean body mass, your fat mass, in every single part of your body. Let's say we were in an extremely rich society where everybody had good health care. Having a baseline DEXA scan for all of us -- and probably you could get one every two years or so, three years, to see how our bodies are changing, not only because of HIV, but because of aging -- and treating accordingly would be ideal. In a perfect world, that's what we should be doing. DEXA gives you three pieces of information.
So if someone's insurance covers it, you would recommend DEXA?
Yes. I don't recommend anything; I'm a patient. I'm not a doctor. But, yes, yes. It should be a full body scan, though. There are three types of DEXA scans. You can do a spinal DEXA. No. Get a full body DEXA that tells you how much lean body mass, muscle, of course, and fat and bone density you have in every single part of your body. Put it in your chart and have your doctor recheck it two or three years later. Make sure you're doing OK. If not, treat.
Also, I tell people to exercise with weights. Make sure your testosterone is normal and your thyroid hormones are normal because low hormones can decrease bone density and exercise has been shown to increase bone density.
On to the next subject: heart disease. A few years ago, as you remember, there was a lot of talk about a higher rate of heart disease in people with HIV. There's less and less talk about that.
Yes. As I said, it's another gray area. The D:A:D study has shown a 26 percent increase in cardiovascular disease in HIV. Is that induced by the virus? Is that induced by the drugs? We people with HIV have all the typical risk factors -- high cholesterol and triglycerides, low good cholesterol or HDL. [To read more about heart disease and HIV, click here.]
Forty percent of us are smoking. So we have the normal risk factors that most Americans have, too. However, we know that many drugs, many HIV medications increase cardiovascular risk factors -- particularly triglycerides. We do have low HDL, even before we start taking medications. When we become infected our cholesterol is pretty low. Our cholesterol actually goes down -- our good and bad cholesterol. Triglycerides tend to spike up a little bit.
Then, when we take HIV meds, the HDL sometimes goes up and improves a little, but it never reaches normal levels. Triglycerides go up even higher. So, yes. There is an influence from HIV medications, and it is not clear whether or not treating HIV itself, the virus, and decreasing all the inflammatory factors around that, how that measures against increasing risk factors, especially when it comes to lipids.
So, I think that we're not clear. I do tell people: Just keep an eye on your lipids. You'll be amazed how many patients don't know that they should be monitoring their lipids.
Meaning the cholesterol and triglycerides.
The cholesterol and triglycerides. You would be amazed! Most people tell me in my lectures, "Well, I really don't know. I guess they don't tell me my lipid levels because they're OK, right? They would tell me if they were not."
I say, "Well, never assume; always ask."
At least every six months, you should get your lipids and your cholesterol checked, especially right before you start HIV therapy. And it's a good idea to talk to your doctor about more lipid-friendly medications, especially if you have a history of heart disease in your family. Definitely, I tell people, "Do not smoke." If you are smoking you may as well forget about your cholesterol, because you are defeating the purpose. Cardiovascular exercise is important. Of course, so is eating less fats, decreasing your sugar intake, etc., etc.
Then next to heart disease is another depressing subject: cancer. There were a lot of studies about that at CROI. There seems to be incremental data coming out about a growing incidence of cancer seen in people with HIV. As a community activist, and as a long-time survivor, what do you think of that?
I have a lot of interest in this, I have to say. I have been living with this disease for so long, and I'm always wondering, "Well, is it going to be a heart attack, or is it going to be a cancer that's going to get me eventually?"
The D:A:D study, the data collection on adverse events of antiretroviral drugs [Data Collection on Adverse Events of Anti-HIV Drugs, a collaboration between 11 observational groups of HIV-infected persons in Europe, North America, and Australia], followed 23,000 -- almost 24,000 -- patients, all over the world. What they have found is that, yes, we're living longer, obviously, and cancers are starting to show up a lot more. [To read more about cancer and HIV, click here.] They looked at two types of cancer: non-AIDS related and AIDS-related. Among the non-AIDS related cancers, the biggest one was lung cancer. So I tell people, "Definitely do not smoke or be around smokers." GI tract cancers, like liver cancer were also common. ... A lot of us that have hepatitis B have to be very careful because we have a much higher risk for liver cancer. I tell people, "If you are not hepatitis B positive, get vaccinated. Please get vaccinated."
Leukemia, lymphomas and anal cancers were documented. That's a particularly interesting part of my activist work, because I don't think there's enough work being done on anal cancer, especially on its diagnosis.
Do you think most men who have anal sex are getting Pap smears?
No. No. The interesting thing -- and I have read a lot about anal cancer -- is that it's not only the gay men who are getting it; the straight men with HIV also have a higher incidence. People who have never had anal sex, also get it. It's all related to HPV, the HPV [human papillomavirus] virus, and most of us are positive to HPV. So, yes. Gay men that have anal sex and are HIV-positive have a higher incidence. But I'm trying to make a clear distinction: Heterosexual men and women with HIV also have a higher incidence.
Anal Pap smears are not part of the standard of care. Most doctors are not trained to do that -- at least most doctors in HIV care. I, myself, I'm very blessed and lucky. I fly from Houston to New York City to see somebody there, Dr. Goldstone. [To read an interview with Dr. Goldstone, click here.]
Goldstone, right. He specializes in it.
Yes. I have to fly to New York to see him. He asked me, "Why do you fly to New York to do this?" It's because I can't find anybody else that has the expertise in diagnosis and treatment. I had precancerous lesions, myself. It's definitely something that I'd like to see a lot more work on, because it seems anal cancer is already starting to show up.
On the AIDS-related cancer side, the non-Hodgkins lymphomas and Kaposi's sarcomas have lower incidence today than at the beginning of the epidemic. But yet, they're still there. So, yes, we have to keep an eye on this. I tell people, "Decrease your risk factors. The smoking definitely has to go. The hepatitis B treatment and/or prevention should be taken care of. Have somebody look at your butt. Have your butt checked, even if you think you never have had anal sex because research definitely shows that HIV increases the incidence of anal cancer."
Another of your areas of expertise is salvage therapy or, as I prefer to call it, rescue therapy. What was the big news at CROI for people with multidrug-resistant HIV?
This was the best year ever, I think. It reminds me of '96, '97, back in the days where we were so excited about HAART. This is a second wave of HAART. We had data presented about the Merck integrase inhibitor, and about Pfizer's maraviroc, an R5-tropic virus inhibitor. And, yes, we saw some data on TMC278, which is a non-nuke [non-nucleoside reverse transcriptase inhibitor or NNRTI] -- although the data was for naive patients -- and also TMC125 [etravirine], which is also a non-nuke that has been tested in patients with multidrug resistance.
So we're very excited. The response rates are really good, especially for the Merck MK-0518 [raltegravir] integrase inhibitor. [Click here to read coverage of these studies.] We've never seen that kind of response in people with multidrug resistance -- around 79%.
Seventy-nine percent of patients who took MK-0518 plus other durgs selected by their doctors had a viral load under 400 at week 16, I believe.
Seventy-nine percent of people.
What's the usual percentage of people with multidrug resistance who respond? It's like 30, or something?
Even back a year ago, two years ago, the Tibotec TMC114 data: 50. After 48 weeks, 45 to 50 percent of people ...
Yes. Over 45 percent of people taking darunavir had a viral load under 50 at 48 weeks. Tipranavir, actually showed similar results. This is with one additional active agent, by the way. We forget that. We always talk about drugs, but we very seldom talk about their background -- their optimized background therapy: what the patients take with that drug, how many patients actually have one more active agent with that drug. Of course, the more active agents, the better the response.
So the 79 percent number was with one [other active agent]?
Yes. I think it came down to 60-some percent without.
The biggest number was 90 percent, with darunavir.
Yes. That's with Fuzeon, with Fuzeon or darunavir. Yes. If you had two active agents and you took the Merck product MK-0518 almost 100 percent of those patients responded. These are patients that had multidrug resistance -- they had an undetectable viral load on this regimen. Of course, let's keep in mind that this is ... I think this was week 16 data. Although some data may actually show in the future that it is a very strong response, anyways. It's too early to judge how useful MK-0518 will be, but it looks very good.
The most interesting, and the most exciting, part of this study, was the side effects, or the lack of side effects. We didn't see any increases in cholesterol or triglycerides with the integrase drug. There's some flatulence and some problems like that, but really, compared to all the other drugs we've seen in the past, it looks like a very friendly class. I'm very excited. I think the integrase class is going to make a huge difference for those that are in what we call rescue or salvage therapy.
The maraviroc R5 inhibitor also looks very strong, very good, so far. We've been afraid of that class for a while because of fears of what happens when you block a receptor on the T cells, what happens long-term. We were afraid of lymphomas. It didn't seem like lymphoma was a big issue there. Of course, as I said, we need more time. Sometimes things show up after a long time. But this is going to be a drug that may help 50 percent of patients with HIV, because not everybody's going to be lucky enough to have an R5-only virus. You know, 50 percent of us may have a dual-tropic strain of HIV -- meaning our virus uses both an R5 and an X4 receptor.
The CCR5 inhibitor only works on people with the R5 virus, but most people who are just diagnosed probably have an R5, right?
Yes, however, it's almost impossible to predict who is going to have R5 or X4 receptors. There are some studies that show the higher your T cells levels the better your chances of being R5 only. The longer survivors like myself: We may be more likely to be dual-tropic, possessing both X4 and R5 receptors. We don't know. But the only way to find out is doing the test, a tropism test -- Trofile, it's called -- that will be provided as part of the expanded access program for maraviroc, which is starting right now.
Expanded access means that people can get it for free through their doctors?
Yes. Those drugs have not been approved by the U.S. Food and Drug Administration. They are in the process of hopefully being approved. Companies basically provide the drug for free for anybody that needs them, as long as your doctor applies for it. Not every doctor is willing to apply for EAPs [expanded access programs]; it takes a lot of work, and most doctors will not get paid for that work. So not every patient is lucky enough to have a doctor that provides access to new drugs through expanded access. That's very important to make clear, because people assume that expanded access is available to anybody in this country; it is not.
Well, couldn't you bring it to the attention of your doctor, somehow? And see how you can expedite it?
Yes. But he or she can still show no interest, due to manpower. Most academic settings, universities, are not providing expanded access, because it's too expensive for them. So what you have to do if you are a patient and you need help ... Well, I have a Web site: salvagetherapies.org. You can go there and e-mail me, too; my e-mail is there. And there are sites in every city, and every drug has a Web site. Some of them are listed, some of them are not. But you can always go to my Web site, and I can probably help you find somebody in your city that will help you get expanded access if you need it.
However, I tell people: Not everybody needs new drugs. If your viral load is stable and your T cells are not under 250 or 200, you're pretty healthy; you can wait till these drugs get approved. Then, wait. If you're really in dire need, meaning, your health is declining, your T cells are low, your viral load is high, you've tried everything you can, you've tried Fuzeon [enfuvirtide, T-20] then enrolling in an expanded access program is probably a good thing to be thinking about and talking to your doctor about. But as I said, let's not assume that everybody has access to expanded access programs in this country, because it is not true.
That's a really good point. I have a couple more questions, and then we have to end. Treatment interruptions. We learned last year that treatment interruptions can really be dangerous. But you probably know a lot of people who have, or want to, take a treatment interruption. Anything at CROI that weighed in on whether this is still considered a bad idea?
Yes. This is another area of a lot of controversy. I think we have a lot of controversies in AIDS, I think. There was a study that actually followed -- well, you know, the SMART [Strategies for Management of Antiretroviral Therapy] study -- there was a sub-study there that looked at cardiovascular disease in those that continued therapy uninterrupted versus those that interrupted therapy. They found a slightly increased incidence of cardiovascular disease in those that interrupted therapy. Some people have a hypothesis ... that maybe inflammatory markers are reduced while on therapy. Once we stop therapy, inflammation has to increase, and maybe that affects the cardiovascular system.
That's only a theory. I don't think anybody has really proven it. But the SMART sub-study presented at CROI showed some trends that may indicate that starting and stopping therapy may not be very good for the cardiovascular system. That's definitely one set of data that tends to point towards people not stopping therapy.
Another potential disadvantage of treatment interruptions is that one or two studies have shown that people tend to be more infectious to others once their viral load increases. For instance, you are on treatment; you're doing well. Your viral load is undetectable. You're doing okay. Then, for any reason -- you probably went on vacation or encountered a side-effect related issue -- you stop therapy. You're still playing unsafe sex. You're not protecting yourself and others. Your viral load goes up, and you could infect somebody else a lot easier, or more easily, than if you were treated and had undetectable viral load.
So that's another issue that -- there's a public health issue that we should address, too, for treatment interruptions. Not everybody should be on continuous treatment. I don't think we should even be preaching, or thinking, about that, especially if you have good numbers and low viral load. But definitely the pendulum, I think, is starting to show that we may be moving again towards earlier treatment and continuous treatment, especially if we can find combinations of drugs that are not as toxic as the ones we used to have. I think we're almost there. I think there's some more work to be done. But we're getting there.
Finally, everybody newly diagnosed wants to know what their chances of living a normal lifespan are. There was a bunch of interesting studies on the topic at CROI. Did you get a chance to see them?
I read them. I read those papers, but I try not to think about it too much because I've been positive for this long and I am getting old, too. But, hey, I want to live even longer. I love my life. Telling people you may have 20 more years, or 25 more years -- that can impact them psychologically.
However, I'm starting to see more and more studies on this subject. This is all modeling stuff -- data that comes from modeling. I think we have to be very careful in how we analyze it. There's some data from a Swiss cohort that shows that most of us are probably going to have a full life -- over 25, 30 years. [Click here to read coverage of the study.] Look at me. I have been positive for 24, 23 years, and I've had an undetectable viral load only for six months out of all those years.
But you're a miracle story.
Yes. But I'm trying to say: If you have an undetectable viral load, you are taking care of yourself and your T cells are still within range -- even if you have low T cells, but your viral load is undetectable, you're taking care of yourself, taking your vitamins, working out, managing your stress, definitely -- there's no compelling reason why we should not be thinking that we're going to live to be old men and women.
If we don't smoke and exercise ...
Yes. On the other hand, we might have cancers or cardiovascular problems that are due to genes, bad genes -- so we can always blame our parents.
There was a study -- I don't know if it was presented at CROI -- that showed that heart disease in people with HIV is mainly caused by lifestyle factors. The people who were getting heart disease were people who would have gotten heart disease, even without HIV. They were overweight, they didn't exercise and they smoked. They were just high-risk people.
We also have to be very careful when we say things like this, too, because there are people who are actually taking care of themselves that are still struggling with their health. So I try to be careful. But, yes. Control things that are within your control, I tell everybody. What's within your control? Not smoking. Eating more healthy. Exercising. Taking your meds on time. Probably doing some meditation, practicing yoga, reducing your stress, doing support groups, getting involved. Especially treating depression. I mean, depression has been really linked to lack of adherence and lowering immune function. You know, it takes a lot of work to stay healthy. I tell people it's a lot easier just to give up and die than it is to get the discipline that it takes to take care of yourself. That's what HIV is. HIV is a wake up call to get disciplined. If you don't have discipline, you better get it.
Being vigilant about your health -- finding out the latest research, doing things before your doctor tells you to do them.
Yes. Use the Internet. Really get involved with Internet groups. Read a lot. Yet be very careful. Don't stress yourself out so much when you read things. Get some input from your doctor. And have a little faith, you know.
Well, this has been great, Nelson. Thank you so much.
Well, thanks a lot for giving me the chance to speak on behalf on patients and activists. Thanks a lot.