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The Body Covers: The 15th Conference on Retroviruses and Opportunistic Infections
CROI 2008 Highlights: An Interview With Keith Henry, M.D.
February 6, 2008
As CROI 2008 in Boston drew to a close, I spoke with Keith Henry, M.D., a professor of medicine at the University of Minnesota School of Medicine and the director of HIV research at Hennepin County Medical Center in Minneapolis, Minn. He has recently been appointed to the U.S. Department of Health and Human Services' Panel for Antiretroviral Therapy for Adults and Adolescents. In addition, he is the medical director of the AIDS unit of the St. Paul Department of Public Health and the medical director of the Sexually Transmitted Disease Clinic in the St. Paul Department of Health. He has been directly involved with caring for over 1,000 HIV-infected individuals and personally oversees the management of over 400 HIV-infected patients in his clinic. I asked him what he felt was the most significant research presented at the conference.
I think there's a shift once again back towards basic science, which has often been a hallmark of the conference. It lacks some of the sparkle of big studies of new drugs, but we're still coasting from all the new drugs from last year. There's an understanding, due to the bad news from the vaccine front, that we need to get more basic science behind us before we can approach vaccine development. So I think it's, again, back to the amazing basic science that's going on. What struck you at the conference in the basic science sessions? I often don't go to the basic science sessions; that's always a problem. There are things going on simultaneously, and I tend to go to the clinical sessions. To me, what's interesting are the mechanisms of what goes on with the virus, interacting with the human genome. There was an exciting publication just last year, finding a whole repertoire of possible interactions that will lead to lots of both drug development and possibly vaccine approaches. It's just amazing. It's a payoff on the genome project, etc. To me, genetics is probably the most interesting basic science. Also interesting is the further dissection of the anatomy of the virus. Some amazing photos of what's going on inside the cell and of the attachment to the cell were presented. I'm hopeful that in the next five years, it will pay off for some patients. What about on the clinical front? Was there anything interesting at the conference that struck you? There's an evolving tension, almost, between the results from randomized clinical trials and the results of cohort studies. Randomized clinical trials, with their limitations and strengths, are often very short-term, with small numbers. Studies using cohorts, where they combine cohorts from around the world, get large numbers of patients, follow them for a long period of time, and come up with results that really had not been hinted at much in some of the randomized clinical trials. That's an interesting development. The most notable example, perhaps, would be from the D:A:D study, specifically the issue with abacavir [ABC, Ziagen] that came up, linking it to an increased risk -- though the overall risk is very low, actually -- of cardiovascular disease.1 Another example would be from an Australian meta-analysis that was done by Andrew Carr, looking at, again, what are the best initial regimens, and his finding that ddI [didanosine, Videx] came out as a very strong initial regimen, although it's fallen out of favor in most Western countries.2 It's really hard sometimes to dissect how this happens. Guideline committees often preferentially weigh the randomized clinical trial as the stronger design. There's this tension of how we interpret some of these findings from some of the large cohort studies or meta-analyses. That's an interesting development to me. Are you going to change practice because of the results from the D:A:D study, and worry more about people with risk factors for heart disease? The overall risk is continuing to fall in the study, and I don't think that that's at all convincing. It needs to be confirmed. Again, it's back to the issues of: There are biases that get introduced in these cohort studies that randomized trials avoid. We need to see that confirmed by other groups. But it's a useful way to go searching or fishing for problems that were unrecognized from clinical trials, or from the adverse event reporting system, which is, more or less, not well organized in a lot of places in the world, including the United States. Do you think cohort studies serve as an adverse effect reporting system? Yes. I think it's a good place to find signals for that. Individuals, even myself included, have their own biases. One clinician may be having a good experience, whereas a clinician who's seen a couple of heart attacks in a small number of patients would say that this is a really bad idea. So, how do you handle these biases from a clinician standpoint, the biases of clinical trials? I think the D:A:D study is just another example of another dataset that needs to be considered. I don't find that abacavir data convincing, but it merits a follow-up by, particularly, other groups. It's been the talk of the conference. Have you found that a lot of people are talking about that study, as well? I think it's more in the context of the value of some of these large cohort databases, compared to the standard reporting system or randomized clinical trials. Back to the Andrew Carr study2: In his study, it was the ddI-based regimens that seem to do the best, and they're not really on the recommended list of any of the guideline panels, as an example.3 Many of the combinations that have been widely recommended in guidelines fall a little bit lower in his study, including even tenofovir [TDF, Viread], abacavir or AZT [zidovudine, Retrovir] in combination with 3TC [lamivudine, Epivir] or FTC [emtricitabine, Emtriva]. That raises some interesting analytical issues that I think we'll have to grapple with in the couple of years ahead, particularly as the number of large randomized clinical trials not sponsored by [the pharmaceutical] industry seems to be diminishing because of funding constrictions. I think it's going to be imperative for the research community to weigh the strengths and weaknesses of these sources of information, and how to apply them. This conference was much more subdued than previous conferences, in terms of blockbuster news. We had news from the SMART trial,4 and we had all these new drugs last year. I understand you have a lot of patients who are on expanded-access programs because of these new drugs. That's correct. There are several questions you asked me there. On the subdued part: When you have the major findings of the Merck vaccine trial highlighted as a presentation, with findings that the vaccine not only didn't work, but in subanalyses, they were able to find populations in which the vaccine seemed to even accelerate transmission, that's very disappointing.5 Then the vaccine plenaries, basically, felt that we had to go almost back to the drawing board of basic science.6 [Click here to listen to this plenary. Click here to view it.]
Having listened to these vaccine presentations since, really, the inception of CROI, it's kind of déjà vu. It's very disappointing that this is where we're at. That is a pall that hangs over the whole conference -- telling us that we've maybe gone in some wrong directions. That's one issue. There's the issue of restricted funding for clinical research in the United States due to budget problems. That percolates through the investigators, as to what they would like to do. People are still very interested in metabolic problems, bone problems, renal problems and non-AIDS events that are still related to HIV infection. Yet the studies in the United States that are focusing on that are fairly limited. There's a frustration that's going on. However, from the patient and clinical perspective, what I observed and what I hear from a lot of my colleagues, they are still amazingly excited about all the new drugs. In fact, we haven't even figured out how to use all the new drugs. The new drugs, obviously, were generally developed in the context of salvage therapy, and were available through expanded-access protocols. My site, in Minneapolis, thanks to the hard work of mostly my research nurses, offered all three drugs [maraviroc (MVC, Selzentry, Celsentri), raltegravir (MK-0518, Isentress) and etravirine (TMC125, Intelence)] to patients. We took referrals from the whole region. To me, it was like 1996 [with the advent of highly active antiretroviral therapy (HAART)] all over again: I had not seen that number of very sick patients with highly resistant virus, high viral loads, low CD4+ counts, basically in a panic situation, since then. We would assess their eligibility for maraviroc. You have to wait for the Trofile assay to come back for CCR5 receptor. That would take about two or three weeks. Then, if they were eligible for that, they would most often get maraviroc and raltegravir and etravirine, and usually darunavir [TMC114, Prezista], boosted, and other drugs, as necessary, including Fuzeon [enfuvirtide, T-20]. To make a long story short: Essentially, every patient that we saw had a rapid virologic response, sometimes undetectable within one month, from viral loads of over a half a million. Frankly, I've never seen viral load responses that impressive that fast, even in treatment-naive patients. It was really amazing. Of course, it's nice when the blood tests come back so encouraging. But more importantly, you always worry, are the patients going to respond? When they come in, having gained weight and their skin is better, and they've got a smile on their face, and are so grateful and thankful ... It is amazing. That's really the carry-over from last year's conference. It's hard to top that. It's always hard to top what happened in 1996 with HAART. It never was quite the same, because we were still so excited about that. Well, this reinvigorated the whole HAART arsenal. We're still trying to figure out where to use these drugs in earlier infection, etc. It's going to take years to sort that out. That's not such a bad problem. Last year was so amazing that it's almost expected to be kind of a let-down the following year, because we don't have quite that number of new drugs available. Have you looked at the MERIT study on maraviroc as first-line therapy? When it was first presented there was some doubt that it was equal to efavirenz [EFV, Sustiva, Stocrin].7 Right. There are still some issues. Of course, at this conference, they looked at: Could they have done a better job screening patients? Some of the failures were due to low-level dual/tropic or CXCR4 virus. How to really use the more sensitive assay, which is still incredibly expensive, hasn't been sorted out. If you look at the results, even in the efavirenz arm in that study, it wasn't really all that impressive. Most of us sense that we can do much better with other options. Where that fits in right now, and having to use an expensive assay up front, is still very unclear to me. I've heard people talk about induction maintenance with maraviroc. People are just trying to think of creative ways to use it. I've been a big fan of induction maintenance for years, and in our area and Twin Cities, where we've been a stronghold for boosted protease inhibitor-based regimens, we have very little resistance. That's been the case for many, many years. Often, after initial suppression, efforts were made to tweak the regimen to make it easier, once a day -- let's say you go from a Kaletra [lopinavir/ritonavir, LPV/r] regimen to another boosted protease inhibitor once-a-day option, or even a Sustiva-based option. We really have been doing very well already. There isn't a crying need to change our practice. How a new drug fits into an already winning formula, without a really definitive study, is still unclear to me. We weren't having that many problems before [with our first-line treatment options], and we now simply have even more options. I think many of us are just scratching our heads, deciding where we introduce these drugs. It's a really nice problem to have. What it really means is that patients and their clinicians are very confident that we have an incredibly good back-up safety net, should a regimen fail. Again, my view is that the biggest problem is maintaining adherence and access to the treatment. It's not a lack of drugs right now. What I struggle with in the public hospital are people without insurance, not being able to afford copays, unstable housing and mental illness. It's really access issues. For many patients, the HIV part of their care is almost the easiest thing for me to handle. Dr. Henry, I have a few more questions. What were your thoughts about the circumcision presentations? It's good for men, not so good for women, basically. The data show consistently some protection for males in the order of 50% reduction, which is impressive, and it's been consistent. But it's disappointing because the unanswered question from the earlier studies was: Are females protected in some way? That, so far, doesn't seem to be the case.8 Since over half the people getting infected in the developing world are women, that's an issue. You also wonder whether the men think that they're protected and get infected. Basically, they have a disinhibition of behavior over time, because they say, "I'm circumcised. I've done all I need to do." That doesn't seem like a behavioral situation that's going to be at all helpful for women. How that plays remains to be seen. Certainly, I don't think we're anywhere close to strongly considering circumcision as a recommendation here in the United States. It's interesting that there were some small studies in the United States, and they did not show a benefit.9 There's more to all that than meets the eye. Like I said, the data to me just say that it's not going to be realistically a strong public health option to consider here in the United States. There's been a lot of talk at this conference about HIV and aging. Are you seeing higher rates of some problems such as malignancies and non-AIDS-related events? I was one of the first to report heart disease in that setting.10 We're doing the CDC [U.S. Centers for Disease Control and Prevention] SUN study, which was alluded to during that plenary on aging. That stands for the Study to Understand the Natural History of HIV Infection. It's a study that is focusing on cancer, heart disease, bone disease and renal disease. It's collecting samples for things that we don't even realize are occurring yet, in patients who are doing well on antiretroviral therapy. This has been a big issue for us. There's also the issue of non-AIDS, HIV-related clinical events. That was highlighted at last year's conference, and once again here -- that heart disease, cancer, and renal, hepatic and other issues may be related to immune deficiency that is tied into HIV. They're not standard AIDS-defining events. Almost all the old research missed that, didn't even count those very well. Everybody's looking at that. We really need data on those issues, which occur in aging already, and as several of the speakers mentioned, it is very hard to tease out how much of this is related to aging, how much of it is drug-related, and how much of it is HIV-related. You really need good, thoughtful studies of a large number of patients followed for a long time. Again, as I mentioned before: The amount of money in the United States going into that type of research is actually flat, or decreasing. All the excitement tends to be with the new drugs. But these long-term issues, I think, are where the action is going to be in the West. So we need to, again, think about how to use our scarce resource dollars to learn the most possible for resources which are limited. Do you think that because of this heightened risk of heart disease and other non-AIDS-related complications, HIV specialists are making an effort to educate patients about lifestyle changes they can make to lower their risk? I would hope there would be an effort. Again, one of the things I say most often to patients is that they have become boring, HIV-wise. In fact, there's a study11 here saying that we could probably stretch out our visits to six months pretty easily, from a cost-effectiveness standpoint, as far as checking on adherence and blood evaluations for people that are doing well on therapy. That gives us lots of opportunity to go back to something that most specialists are not very good at and, in fact, the whole U.S. health care system is very poor at, which is primary care. I have been focusing on cardiovascular risk for 10 years, so lipids, diabetes issues and smoking are what I talk about more in our HIV clinic than I do antiretroviral therapy. A high percentage of the patients have actually become boring: They don't mind the [HIV treatment] regimen. They're not complaining about the regimen. They're suppressed. Their blood test results are fine. We've moved on to more pressing health issues as these patients aim towards a normal life expectancy. All the other problems that people have in life are there, and there may be some increased risk for those. That's what we're talking about. I think we need to be aggressive and figure out ways to help the system, which does a very lousy job regarding primary care. It doesn't reimburse very well for a lot of these things. That's a struggle we all have. I haven't talked to anybody that has a wonderful system, that's well reimbursed within the United States, providing really good primary care. That's a challenge that we still have. It's a major challenge. I don't know if you read the statement last week by the Swiss AIDS Commission.12 The statement said that HIV-infected people who are taking antiretroviral drugs cannot transmit HIV during sex under certain circumstances. I believe the circumstances were that: they had to be in a monogamous, mixed-status relationship, with the HIV-infected partner taking antiretroviral drugs and adhering to their treatment regimen; their viral load had to be suppressed for at least six months; and the HIV-infected partner could not have any other sexually transmitted diseases. This is a complicated list! This statement caused a lot of controversy and I wonder if you could comment. I think it's premature. The data is not convincing. There is certainly some data and some theoretical concerns about what that will do, as far as disinhibition for people that aren't in those ideal situations that they alluded to. Actually, there are a lot of people who are in what they think are monogamous relationships, that are suppressed, and have no STDs [sexually transmitted diseases] in their partner or themselves. That's the target group that they were referring to. There are a fair number of people that think they are in that situation, and they have not been well studied. I am very concerned about that, because we are already seeing what we think are increases in HIV transmission in the United States. We don't do that well with our prevention for positives message. Then this sends another message that I think can be either misinterpreted, or seem sto give a green light to what we would term unsafe sex. It begs the issue of superinfection, which was discussed here, which is a problem involving introduction of resistant strains in someone already infected. Even in our clinic, when we have couples that are trying to get pregnant and don't have much money -- we can't use fertility specialists, etc. -- we occasionally sanction unsafe sex during the period of ovulation, sometimes providing pre- or post-exposure prophylaxis in short bursts to a partner that's very careful, to try to get pregnant. That's something that may be unspoken, but it happens quite a bit under idealized situations to get pregnant. I think that's an appropriate venue to do it, without resources to bring in a fertility specialist or have sperm washing available. But it's not a good idea to broaden it to the more general population in this era where, even in Europe, the HIV rates are going up in certain populations. We're not doing a very good job with prevention. A focused recommendation like that is so easily misinterpreted by the population at large that it makes that prevention message -- which was already not being well acted on -- even more difficult for the public to understand. I think it's premature and I hope that other bodies will not follow the lead; studies need to be done. It was really blown out of proportion. It was a statement released to physicians in Switzerland that suddenly became global. They didn't mean it for wide distribution to patients. What world do they think they're living in? This is the YouTube era. Everything's on the Internet. That's a, pardon the expression, very sexy statement to make that I would predict would be picked up, that some official agency, government, sanctions this. I would be surprised if it wasn't picked up, broadcast internationally, and causing actual problems to develop. These guideline panels and the actual recommendations really need to be thoughtful these days, with as much data as possible. That's an example, I think, of something that was for a very narrow set of scenarios, and something to talk about in professional circles. To get released to the public like that, I think, sends a message that's going to be hard to reverse in the minds of people around the world. They don't look at the fine print. They just look at -- it's safe to not use a condom. If I'm HIV infected and suppressed, and if my partner agrees to it, then let's go at it. I think that's almost a dangerous message right now. Did you find that there was any interesting news at CROI about mother-to-child transmission and breastfeeding? I have only read the abstracts because they were going on in concurrent sessions. It's a very complicated area, clearly. But potentially, again, antiretroviral therapy can fix a lot of the problems that are out there. One thing I learned, actually, from last year's conference, is that issues around breastfeeding are very complicated. Formula feeding and options other than breastfeeding also cause their own sets of problems. That was one of the major presentations last year: When you have contaminated water and other problems going on around you ... The formula feeding basically was a disaster in certain situations. So breastfeeding is a good option, and how to wisely use antiretroviral therapy.13-16 In the developing world. Correct. You told me about the issue, which, again, I haven't had a chance to digest, but which is very intriguing, about mothers who are chewing food for their children and then basically feeding that chewed food to their children, resulting in cases of transmission apparently through that means. I have to admit that I wasn't aware that was going on. More data is necessary.17 But again, these issues are not going away. Those people want to feed their infants in the best way possible, culturally and safely. So these things need more studies. So there are still things that we don't know about. Yes. Very basic stuff, such as what people are actually doing, behavior-wise, and how that interacts with HIV transmission. Twenty-five-years-plus into the epidemic, and we don't even realize that this is happening. It's pretty amazing, but the variety of human behavior never ceases to amaze me. There were a couple of other tidbits that I thought were interesting. There was a poster presented about chromium that showed that it helped people with some metabolic disturbances.18 Did you happen to see that? I saw that. But there's been, over the years, selenium here, chromium there. It's always very difficult to sort out. A study on that subject was presented in the New England Journal of Medicine several years ago.19 It looked at the use of a Centrum-like vitamin versus a placebo in Africa. Use of the vitamin showed a statistically significant modest clinical benefit, but paled compared to antiretroviral therapy, even when you have people getting no vitamins and they are deficient, versus providing lots of vitamins. There may be something there, but teasing out which specific mineral or vitamin has been very difficult. Almost every year there's another vitamin or mineral that gets identified. Then follow-up studies often have a hard time confirming it. So that's interesting. There's still a lot to learn in that whole area. But let's just say I've been disappointed. It seemed like it would be so nice to have something simple that we could be doing, that's inexpensive and likely to be safe. Those studies just need to be repeated by other investigators. So you're not convinced by anything. Not convinced, no. Finally: I know you have some interest in immune-based therapies. There were some presentations. Anything interesting? I think perhaps this time next year, IL-2 [interleukin-2] will be the major buzzword. It is a major immune-based therapy that's been studied, but no definitive answer has been provided. Three major IL-2 studies are going to be presented, possibly, at this meeting next year, including SILCAAT and ESPRIT. Immune-based therapy can increase CD4+ counts, but the question is: How safe is it and how effective are those CD4s at preventing clinical problems? I think that there will be a lot next year on immune-based therapy. Whether it's going to be good or bad, I can't predict yet. But there's still interest in that. Again, it has been a struggle. Because antiretroviral therapy has been so effective and because of how the FDA [U.S. Food and Drug Administration] evaluates immune-based therapy, the development pathway for immune-based therapy has been a much rockier, difficult one. There's really been no successful one approved yet. So it would be nice to have some good news in that area. One thing I'm looking forward to next year is hopefully hearing some. Do you think that immune-based therapy could be helpful for patients who are immune-discordant -- patients whose CD4+ count doesn't move much, even though they are suppressed? Theoretically, yes. But whether that actually turns out to be true is very unclear to me. There have been hints from small studies that, yes, you can get people with lower CD4s to higher CD4s with IL-2, for example. Maybe there's some modest clinical benefit from that. But they really were not anywhere near definitive trials. The trials I just alluded to will be, I think, definitive on that, and if positive, will open up a lot more interest, and hopefully funding, for immune-based therapies. Being on effective antiretroviral therapy and suppressed benefits more than just the CD4s. People do better with that. There's a lot more out there than we really understand. This tells us why more research is necessary, even in the clinical arena. I hope that this time next year and in the years after that, we'll see continued research and new, exciting presentations. Do you have any strategies for patients whose CD4+ count doesn't rise very much? We try to maximize nutrition. We sometimes tweak their regimen to get them off all bone marrow-suppressive drugs. We sometimes intensify temporarily to see if intensification helps. That's being studied by several groups. We have a few patients that are getting IL-2, and have CD4+ counts increase due to IL-2. But frankly, I don't know whether I'm really doing anything for them. That's why I'm waiting for the results of the trials. I think we've covered everything. Thank you very much, Dr. Henry, for taking the time to chat. This transcript has been lightly edited for clarity. Footnotes
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