Tuesday, November 28, 2023
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Editor's Note:
A substantial number of people with HIV around the world have benefited from highly active antiretroviral therapy (HAART), a remarkable medical advance that was first introduced on a broad scale 10 years ago. Unfortunately, many of the patients who have experienced the greatest benefits of these drug therapies are now also those who have the most limited therapeutic options. Furthermore, others continue to become infected with drug-resistant viral strains, which can dramatically limit the utility of some antiretroviral drugs. The good news is that researchers and front-line clinicians have learned much in the last decade, and the antiretroviral drug pipeline holds many promising investigational agents. At HIV Management 2006: The New York Course, held May 5-6, 2006 in New York City, Scott Williams, Editorial Director of Medscape HIV/AIDS, interviewed Eric Daar, MD, Chief of HIV Medicine at Harbor-UCLA Medical Center and Professor of Medicine at the David Geffen School of Medicine at UCLA in Los Angeles. Dr. Daar, an expert on HIV salvage therapy, spoke about this topic at the meeting and afterward shared some insights and highlights from his presentation.
Medscape: Dr. Daar, you gave a talk today at HIV Management 2006: The New York Course on recent data and emerging strategies for highly treatment-experienced patients with HIV. Sometimes it's difficult to give broad principles on this patient population, as patient characteristics and treatment histories vary widely, but let's see what important advice you can offer. With patients who have viral rebound and who have had substantial treatment experience, what is your own risk-benefit checklist before you proceed with switching individual antiretroviral agents or building a new regimen?
Dr. Daar: Clearly, the highly treatment-experienced, often multidrug-resistant patients represent some of our greatest challenges. What we need to always do with these patients is define our goals, and this is the most important initial task facing us in the clinic. Is our goal to achieve undetectable levels of virus, as it certainly is in treatment-naive patients? The US Department of Health and Human Services (DHHS) guidelines[1] suggest that that should be the case if at all possible, and it's a consequence of new drugs and better strategies for managing these people.
We make this assessment by defining how many active drugs are available for a given patient -- either those that are currently approved or that are available through expanded access -- that we think they'll be able to take and tolerate. We know that if we can't use at least 2 active drugs, the likelihood of achieving an undetectable viral load is very low, in which case all we do is risk losing more drugs. I would say that it's like throwing good drugs after bad. We really want to define those people in whom we can use 2 or more active drugs to achieve undetectable levels of virus, and in these individuals use what we have. If 2 active drugs are not available, perhaps we might back off and leave the person on their current regimen while we wait for new option -- if they're clinically and immunologically stable. This is more important now than ever, in the context of drugs like T-20 (enfuvirtide), which is an active drug for anybody who's never been on it before. But if we start them on a new regimen that doesn't have enough other drugs to support T-20, they'll just lose that drug and not have it in the future when new drugs come along.
Medscape: What about the clinical problem of only having one active agent following the results of a resistance test? What would you do in that situation?
Dr. Daar: It's a really difficult challenge, and in general, if we've learned anything during the course of treating these patients, it's that so-called sequential monotherapy doesn't work, and we lose options as a result of it. In the scenario that you describe, adding just one active drug is in essence sequential monotherapy, so my bias is not to do it. Does that mean that there's never a situation where you might not try? Never say never. Certainly in somebody who has very advanced disease, low CD4+ cell counts, and particularly if they have symptoms, sometimes you just have to do the best you can. But I like to resist the temptation to just add 1 drug since I am always keeping in mind what new agents are coming, as there are more new agents in the pipeline than ever before. It used to be that in highly treatment-experienced patients there wasn't a lot to lose because there was just not a lot of future options for them. That's not true anymore with new drugs.
Medscape: We'll talk about some of the new drugs in just a minute, but a couple of other questions first. What about adherence? This has been a much-studied topic in HIV care for many years. In the event of viral breakthrough because of suboptimal adherence, what do clinicians at your institution do to help patients improve their adherence level?
Dr. Daar: Adherence is an enormously important issue. Obviously the most important thing that we can do before we ever start therapy, and in people who are failing therapy, is to make an assessment as to whether they'll adhere to their treatment regimen. Sometimes the difficulty is detecting low adherence, because a lot of patients don't admit to it. So when somebody is not doing well, we have to really ask them very open-ended, nonjudgmental questions about how they're taking their medications, how many doses they're missing. We often will rely heavily on our pharmacists. We'll call the pharmacy and ask how our patients are doing on refilling their meds. Sometimes it becomes pretty obvious that no matter what they're telling us, they haven't refilled their medications in 3 months, so we can use that as a tool. Once we've identified somebody who's not adhering, then we try to work with them to figure out why. Ask them why they're missing doses: Is it because they're drinking, because they're using drugs, because they're depressed? Is it because the drugs are not making them feel well? Sometimes people will say, "Well, you know, I can take them, but I don't feel great when I'm taking them so I tend to miss doses." Then we try to identify the problem: Are you missing it in the evening because you fall asleep, or in the morning because you have a strange work schedule?
After that, it's very important to use strategies to try to overcome the problem. If it's toxicity, we try to modify their therapy. If it's missing a dose in the evening or in the morning, we try to see if we can come up with a regimen that doesn't require a dose be given at that time. We use pillboxes extensively, and a lot of pharmacies will actually provide those. We have beepers, or little pagers that go off at regular intervals for people who need those kinds of reminders.
Medscape: Many different clinicians could be involved in this labor-intensive process, but it's a critical foundation of a successful outcome.
Dr. Daar: Absolutely, and one size doesn't fit all. That's the most important thing; you really need to spend the time with that patient to figure out what's going on and to tailor a strategy or an intervention that's specific for their issues.
Medscape: Both Dr. Mark Wainberg and you talked about a topic today at the meeting that's been studied for many years, and that's maintenance of certain antiretroviral resistance mutations, particularly in heavily treatment-experienced patients. Please tell us about the potential clinical utility of maintaining the M184V mutation, other nucleoside mutations, perhaps protease inhibitor (PI) mutations, in patients who have few therapeutic options.
Dr. Daar: The easiest group to focus on are those patients for whom you can't achieve full viral suppression. Once a clinician has made the assessment that there are not enough active drugs currently available for a given individual, alternatives to full suppression must be considered. The reality is that some of these patients are still doing well and our goal may shift to maintaining their good clinical standing. We've also learned over the years that stopping their therapy isn't the answer; just because they're resistant to the drugs doesn't mean that they're not benefiting from them. Extensive clinical experience shows that in patients who are immunologically and virologically stable with resistance to all of their drugs, stopping all antiretroviral medication consistently results in the CD4+ cell count plummeting, and some people in some studies actually become ill. The answer is to leave them on something. You can leave them on what they're on if they're tolerating it and if they're doing well, but sometimes you can't. At times we try to fine-tune the strategy and determine which drugs may be most important.
M184V is the 3TC (lamivudine)- and FTC (emtricitabine)-associated mutation that's probably been the best characterized. It clearly alters viral fitness, or the ability of the virus to grow in the test tube. That translates into something real, because when you take that drug away from somebody who's on a stable regimen, viral loads do go up and CD4+ cell counts go down.[2] We generally will leave everybody who's on a failing regimen on 3TC or FTC in order to maintain the 184V mutation.
Beyond that, a lot of the other mutations are associated with differences in fitness, but outcomes are not always as clear. What we have data on is that if you stop nucleosides in many of these people, they will worsen. The best data probably were presented from Steve Deeks' SCOPE cohort,[3] in which they took a group of people on stable nucleoside and PI regimens and stopped the nucleosides; CD4+ cell counts went down and viral loads went up. In contrast, when they stopped the PIs, it wasn't clear that anything happened, and when you stopped the nonnucleosides in someone with resistance, nothing seemed to happen. Some of the data with T-20 suggest that probably not much happens to CD4+ cells or viral load in people who have T-20-resistant virus when you stop that fusion inhibitor.
We don't have it all sorted out, but if we extrapolate a little bit and decide that we're going to maintain a patient in this situation on a stable regimen, they're going to probably get 3TC or FTC and other nucleosides. Regarding the decision about whether to leave patients on PIs, we generally individualize [on the basis of results of resistance testing]. I don't think anybody right now is leaving on NNRTIs because they don't do any good, and there may be harm. With T-20, it's not clear that it does any good once resistance has developed. Because of the toxicity and the twice-daily injections, most people would stop that med as well.
Medscape: Tipranavir is the latest PI to gain FDA approval, and it has particular utility for highly experienced patients. You talked a fair amount about the genotypic mutation scores associated with tipranavir. This is a somewhat complicated subject, so could you just share with us the top-line points that clinicians need to know about this issue, and where they can go for a reference for additional information if they really want to get a more in-depth analysis of it for their own practice?
Dr. Daar: The most important point is that randomized controlled trials have been done in populations of patients demonstrating that using tipranavir compared with available PIs translated into better outcomes.[4,5] However, these data are based on populations. We don't treat populations -- we treat individuals; and not everybody responds to tipranavir who's highly PI-resistant. When deciding whether we have a combination of active drugs to employ right now we need to determine who the patients are that will respond to tipranavir or other new drugs, and who will not respond. That's why we use these genotypic and phenotypic scores.
They are complicated and imperfect. For tipranavir there are 21 mutations at 16 different locations, and there's a lot of discordance. I think the most important thing to do is realize that this kind of data are out there. Tipranavir is now on some of the phenotype tests as well, and there's a phenotypic cutoff that's been defined, yet it differs a little bit from assay to assay. We can use these cutoffs to provide an indication as to whether it's likely that a patient will respond to a given drug. If yes, then we would use it as part of a new regimen; if they are unlikely to respond, we may just wait for another drug to come out.
As far as where to get the information, these data have not yet been published, and they've mostly been presented at meetings. There are various Web sites that might have that information. I suspect that some of the Medscape coverage from various meetings will include this information. Stanford's HIV drug resistance database probably includes it as well.
[Editor's note: See recent, relevant Medscape coverage by Dr. Richard D'Aquila, Dr. Eric Daar, and Dr. William O'Brien at these links: http://www.medscape.com/viewarticle/527642, http://www.medscape.com/viewarticle/527639, http://www.medscape.com/viewarticle/508768]
Medscape: Another presenter here, Dr. Marta Boffito from Chelsea and Westminster Hospital in London, talked about double-boosted PIs. She noted a few limitations of this strategy or at least studies that have been done on this strategy. One was a significant interpatient variability in terms of the pharmacokinetics, lack of randomized clinical trial data, and small sample sizes in studies done to date. Given those limitations, what are your recommendations to clinicians about enlisting these types of regimens in their practice if they're presented with very few options and it might be a strategy that's viable?
Dr. Daar: All of that is true, and I think the setting in which they'll be of greatest interest is in highly treatment-experienced patients who do not have many options. Many patients don't even have a single active PI to use, and in that case providers will be looking for new agents that tend to have preserved activity in PI-resistant patients. For example, tipranavir is one of the newer drugs that appears to perform well in this patient population. The question is whether we can mix tipranavir with other PIs to create a double-boosted PI? Unfortunately, you simply can't. Tipranavir induces the metabolism of both itself and other drugs even though it's taken with ritonavir; markedly reducing the levels of other PIs when it's coadministered with them.[6] Even if you thought this strategy would work, even in the absence of data, the pharmacokinetics really prevent us from doing it. We don't have a lot of data yet with darunavir, so right now the pharmacokinetics are probably the biggest obstacle to not only using it but also to even exploring it in a clinical trial. A few years ago, ritonavir-boosted lopinavir, and fosamprenavir were the new kids on the block, and these meds had activity against PI-resistant virus. People asked this very question: Will patients respond better if they get one of the drugs individually or combined with the other drugs? One study determined very early on that there was a very adverse drug-drug interaction, and the study was stopped early.
Medscape: Should clinicians be using therapeutic drug monitoring if they do have a patient on a double-boosted PI?
Dr. Daar: Almost certainly. If they're going to go down that path at all, they should be using therapeutic drug monitoring, and there are certain situations in which I don't think they should go down the path, such as with tipranavir, at least on the basis of the available data.
Medscape: What about TMC-114 (darunavir)? This agent has been extensively studied and is now in advanced phase 3 trials, and many of us expect that it will probably gain FDA approval shortly. Please tell us what is known thus far about its activity, tolerability, and resistance profile in the highly experienced patient population.
Dr. Daar: It's almost certainly going to be the next drug available, and it is already available through expanded access. Some of the same issues that came up with tipranavir will likely come up with darunavir. It's clearly a good drug, and if you compare it with the optimized PI it did better, but did not result in a 100% response rate.[7-9] In fact, half of the patients didn't achieve undetectable viral load, so we're left trying to predict who the responders will be. Current research is attempting to use data from the clinical trials to tease out the genotypic and phenotypic predictors of response.
The very preliminary data presented thus far shows a complex genotypic pattern of resistance. There are some key mutations that they've identified, but we don't quite yet know how to use them to determine whether patients will respond. There was also a study on darunavir phenotype[10] at the British HIV meeting that described the cutoff that appeared to predict lack of response, if the patient's virus was above a 10-fold cutoff. About 50% of the people below 10-fold got to undetectable viral load. Further research is needed to thoroughly assess the most relevant cutoffs for predicting resistance. Regardless, we do not have access to phenotypic testing for this drug at this time; however, as soon as it is approved it will likely be added to the phenotype tests.
Medscape: It's certainly hard to predict how clinical trials will pan out, but what do you see as the next novel treatment advance in HIV over the near to medium term that will be most important for the population of patients who now have extensive drug resistance to existing agents and are really waiting for the next big thing?
Dr. Daar: Like you say, we don't have a crystal ball and we've tended to be wrong more often than right when we try to predict the future. But I think the integrase inhibitors right now look the most promising. We have some preliminary data showing the activity of integrase inhibitors in treatment nave individuals as well as with one of the drugs in development in treatment-experienced subjects.[11,12]
These integrase inhibitors really showed a dramatic difference in those patients who received it. It's a completely new class, which will be critical if we're able to combine it with a drug like T-20 that we need to use with other agents that retain activity. If I had to place my bet on a drug that might have a major impact on treatment-experienced individuals it would be integrase inhibitors. The entry inhibitors may also show great promise and are in active development.
