April 2007

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Eric Daar, M.D.
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Dr. Daar, I was wondering if you could tell me a little bit about what you do.

Sure. I'm a clinician scientist. I work at Harbor-UCLA Medical Center, where we take care of about 800 to 900 HIV-infected individuals in our clinic. We have largely a Ryan White-funded program, and take care of a very diverse patient population. We're dealing with many of the complexities of both [patients'] life and HIV disease. We have a very active research program -- primarily clinical research -- as well as research to better define how HIV actually causes disease. We study people, looking at novel ways to treat, or optimize therapy, as well as to further understand what's going on with the interaction between the person and the virus.

How has the treatment of people who are treatment-experienced changed over the years? Are we in a new era now?

Yes. I don't think there's any question about it. Things have evolved over the last five years or so, and continue to evolve, particularly with the emergence of new drugs and new classes. We have, for a long time, realized that when people don't do well on their initial regimen that they can develop drug-resistant virus. In the early era of combination antiretroviral therapy, often that first regimen was the best shot at full suppression, and after that it became very difficult.

With new drugs, with new characteristics, we have had better success in people who have failed perhaps their first, or even second, regimen, with viral rebound. I think what we're finding now is that, even for people who are on their third, fourth or fifth regimen, we have a reasonable chance of achieving our goal, which has now evolved to being complete viral suppression -- even in these people who are more treatment experienced with multidrug-resistant virus.

Could we define treatment-experienced? If someone has a resistance test and they're resistant to almost everything, does that mean that they're now a treatment-experienced or rescue patient? What if someone only took one or two regimens; does that mean that they are suddenly in that category of "treatment experienced"?

Yes. Really, at least when I talk about somebody being treatment experienced, I'm thinking of the person who, for any one of a variety of reasons, has had difficulties with their first, early regimens, whether that's because they've experienced viral rebound with drug-resistant virus, or because they've not tolerated existing agents; I think of them as treatment experienced.

Then, from the perspective of resistance, we can further characterize them as having limited treatment options, being highly drug resistant -- or, perhaps, those who have a lot of options, because they don't have a lot of resistance but maybe have had some difficulties with their earlier regimens because of tolerability, or their ability to take the medications consistently.

So we really hate to put everybody in the same group, and we're thinking about a range of individuals who have been on treatment in the past and are looking at subsequent regimens, some of whom have many options as far as available treatments, and others who are more limited.

In terms of dealing with a resistance test that shows that someone is resistant to everything, what are the first things that you do?

One of the more complicated situations is in people who have a lot of drug resistance. The current guidelines have recommended for the last year or so, that our goal still be to see if we can come up with a new regimen that would allow them to have complete viral suppression, or get their viral loads to levels that are undetectable. The reason we do that is partly because, obviously, we think they'll do better. But even more importantly, it's because we believe if we can do that, we can prevent their virus from becoming resistant to the new drugs, as well. That's why it's our goal.

I'll preface this by saying that, while that is our goal, it's not always achievable in everybody. It's not to suggest that if you can't achieve that goal right now, all is lost -- because that's clearly not the case. It just means that we need to redefine the goals and be strategic.

Let me tell you how we work through a patient like this, who comes to us, who has perhaps been on therapy in the past and has experienced viral rebound on that treatment. The first thing we'll do is that we'll try to get a sense as to which group they fall within. Are they the kind of person who is treatment experienced, with minimal drug-resistant virus, or a lot of drug resistance? You mentioned a patient who has the more extensive resistance pattern. But it can really be everything in between.

We'll look at their drug resistance, usually with a drug resistance test, whether it be a genotype or a phenotype -- but one of these tests that can be performed in the clinic and will give us the sense as to which drugs their virus may still be susceptible to.

In addition (and this is extremely important), we don't just look at the results from the current resistance test; we'll also want to go back and look through the patient's medical record and perhaps look at previous drug resistance tests to further define what kinds of resistant virus they'd selected for in the past. We'll also look at their treatment history. Sometimes that will give us clues as to which drugs may or may not be active.

So then it's really important that patients keep a copy of their medical records.

It's extremely important that patients keep a copy of their records, particularly in the current era, where people do move around a lot, or their insurance changes and forces them to seek out medical care in another environment. So as proactive as the patient can be in making sure that they have access to all their medical records, the better since it will assist their new provider in coming up with the best regimen.

Could you define viral rebound?

Yes. Viral rebound: What we're talking about in the most obvious case is somebody whose viral load went to undetectable, or below the limits of detection with the current assays [tests]. Then, while they're taking treatment, suddenly it's noted that their virus rebounds, or comes back up to detectable levels. We realize that sometimes that can happen at low levels, and it's meaningless. You simply repeat the results and it's back down to undetectable, in which case there's no problem. But in the people where it's persistently detectable, we think they have had viral rebound.

That can occur for a variety of reasons. The obvious one, and the one we're focusing on is that the person has actually developed resistance to their drugs. But there are other times where that may not be true. It may be because they are simply not taking their medications consistently.

Is HIV drug resistance always a consequence of someone not taking their meds?

No. Resistance can occur for a lot of reasons. One of the big risk factors for it occurring is not taking the medications consistently. But it can also occur if the regimen that's selected is not sufficiently potent or doesn't have enough active drugs within the regimen to get the virus down to undetectable. If you don't achieve that goal of getting an undetectable viral load -- that is our optimal goal -- then it's inevitable that some resistance or increasing resistance will occur.

Walk me through this. If someone has an undetectable viral load and they get the results of their most recent viral load test and their viral load is now detectable, how quickly should something be done? What should be done? Is it at that point that a drug resistance test should be taken?

I think the first step is to make sure the person's taking the medications consistently. This requires a very open dialogue between the patient and the provider. Because we really want our patients to feel comfortable sharing with us any problems they are having with taking their medications. This is a group effort. This isn't something that needs to be left to the patient alone. If they are having difficulties, whether it's because the medications make them sick, or the way the medications are given -- is it a bad time of the day for them, around their work or schedule, or other factors -- or if the person is using drugs, or depressed, or binge drinking on the weekends and missing their doses. The best thing that the patient can do is share that with their provider, so that we can work together to figure out what to do next to try to avoid the development of resistance.

So that's the first step. The next step is to make sure that that rebound in virus is consistent. So we'll generally repeat the test. I don't think there's any urgency -- meaning, days or minutes -- but over the next week, or month, these things need to be sorted out so a decision can be made as to whether to do a drug resistance test, and then how, or if, to modify therapy based upon those results.

So what's the timeline for all this? Let's say I get back a viral load test that is detectable. Then am I immediately given another test? Or do you wait a week or so?

I don't think there are hard and fast rules. I wouldn't wait three months. But I think, over the next week or several weeks or a month, depending on convenience for the patient, I don't think a lot is going to change over that period of time. But you don't want it to go on much longer than three to six weeks.

So you get another viral load test. If that test shows that you're still detectable, then is that the point when a resistance test is given?

Yes. I think that would be the right time [to give another resistance test]. There are some caveats. In people whose viral loads are low -- for example, less than maybe 1,000 -- there can be difficulties in doing drug resistance testing. So sometimes they need to be followed more closely, or occasionally decisions need to be made on changing therapy without resistance testing. That requires a more detailed discussion.

So is this the most complicated part of HIV treatment?

Oh, without a doubt, because then, even after you get the results and you have collected all the information, your goal is to try to get a sense as to what options are available for the patient. Are they willing to commit to taking a new regimen? How many active drugs are available for them?

I think what we've learned is that the more active drugs -- meaning the more drugs in which the virus is susceptible to that are included in the regimen -- the better the chance of getting to undetectable. Sometimes that's easy; if the person doesn't have a lot of resistance, it's easy to identify the reactive.

In other cases, it's more difficult, and it really does require an expert provider to be able to interpret the test, as well as use their own experience to give the patient an idea as to whether they think there is a regimen available to them at this moment for which there's a good chance undetectable virus can be achieved. It's important to discuss what are the risks of going down this path, both with regards to new toxicities associated with those drugs, as well as if things don't go right, and the viral load doesn't go to undetectable. What other options might be lost, as far as new drugs for which resistance will develop that might otherwise be important for future regimens? I think right now we need to be cognizant of that more than ever because there are a lot of new options that are going to be available to people in the next six months. So we don't want to waste drugs now. We want to use them very strategically to make sure that we have as many options available to our patients in the future as these new drugs emerge onto the scene.

You didn't discuss CD4 count. How does that relate, in terms of changing regimens? If your CD4 count is in the 200s, and it sort of stays there, more or less; goes up maybe 20, just very, very little, but you are undetectable. Does this signify that something should be done? That perhaps you should change your treatment regimen?

That's a great question. Because really, when we think about treatment failure, we can think about it in three different ways. The one we focus on is virologic failure, the viral rebound of drug resistance. I think that's probably the most important one for most patients because, in general, we believe that if you can keep viral load to undetectable, regardless of what's going on with CD4 counts, for the most part people are going to stay healthy. But there are other ways in which people fail. There are people who are failing therapy, not just because their virus has rebounded, but also their CD4s are going down, or they're getting sick with AIDS-related complications.

So I think we focus on the virus, initially, with our goal being to try to get it to undetectable. If we achieve that goal, we worry less about CD4s. Sometimes they'll go up a lot; sometimes they won't. But again, in general we feel comforted by the fact that most of our patients won't get sick with undetectable viral loads, even if their CD4s stay around 200.

There was a study at the international CROI conference, and I think it was about cancer and HIV. I think the take-home from that study was that it was dangerous to have a suppressed immune system for a long period of time. I don't know what you felt. I thought it was a scary study. I thought the results signified that people should be proactive about doing whatever they can to raise their CD4 count above the 200s. What did you think?

I think the studies -- there are actually several studies now that have sort of come on the scene that suggest that, in addition to AIDS-related complications with traditional infections, there may be some non-AIDS-related issues that can emerge in people with lower T cells [CD4 counts] -- everything from liver disease to even non-AIDS cancers.

I think we should use that, perhaps, to make the case for when we start therapy. I don't think it helps us too much in what to do in the person who has undetectable levels of virus but has only modest increases in CD4s, perhaps to 200, because most of those studies really haven't addressed that population. They're looking at all people, based on CD4 counts, where the majority of the ones with low CD4 counts are unlikely to have undetectable levels of virus. I think this is an important point, because it does happen, and patients are concerned about it, when they're doing great virologically but their CD4s haven't gone up as much as they like. I think, in general, we don't have a lot of good ideas or data to tell us what to do in the person with undetectable viral loads whose T cells are sort of stalling at around 200. There's little data to suggest that modifying therapy [in patients with undetectable viral loads and low CD4 counts] will have a dramatic impact, or that there's some other immunologic intervention that can be recommended.

So I have generally -- and I think most of my colleagues [would agree] -- have simply tried to reassure our patients that as long as their viral load is undetectable, we would love their T cells to go higher, but the most important thing is to continue to take their medications consistently, and we'll focus on the viral load. Our experience is that the majority of these people are not going to get sick as long as we keep their virus in check.

Let's go back to the HIV drug resistant patient. Can you explain something that I think is still not understood by a lot of people: Why would it still make sense to take HIV medications, even if you're resistant to them?

It turns out that resistance testing, like everything else in life, is not perfect. We realize that it's not an all-or-nothing thing for many drugs. For a lot of the drugs, you have people who have no resistance at all, and you have other people where their virus is 100 percent resistant, for which they derive no additional benefit from the drugs, and then there are a lot of people who are in between. And we take advantage of that. People who have enough drug-resistant virus that we don't have lots of great new drugs to give them, we have realized, from a variety of different studies, that leaving them on some therapy is better than none. Now, these are people who we may not be able to get to undetectable, in which case our goals change a little bit.

In this situation because these people have so much drug-resistant virus, or because they don't tolerate the available drugs that they need -- our goal is to keep them clinically and immunologically stable. Although we can't get their viral load to undetectable, but we don't want them to get sick. We know from experience that leaving these people on some regimen, on some drugs -- and picking which of those drugs are most important -- is really more of an art than a science. But by doing that, we can keep their T cells stable, keep them from getting ill while we're waiting for new drugs to become available with the idea that eventually we're going to be able to come up with that regimen that will suppress their virus to undetectable levels.

I think the data is really strong for leaving people on some drugs in that setting, i.e., where you may not be able to get them to undetectable now, but you want to keep them healthy while you're waiting.

There's a test called the replication capacity test. Is this used in this kind of situation?

Yes. The replication capacity test is part of one of the companies that makes a drug resistance test, the phenotype test. They have that as an add-on. They simply give you this result. It gives you a sense as to how well your virus grows in the test tube. We believe that viruses that have a lot of drug resistance don't grow as well and that maybe -- and there's some evidence to support this -- it's this inability of the virus to grow well in its mutated state that allows for these people to remain relatively stable, despite [not] having complete viral suppression on therapy.

Despite having viral suppression? Or despite not having viral suppression?

Despite not having viral suppression, or only partial suppression. So right now, I think what we've learned is that that measurement probably explains, at least in part, some of the benefit we're getting from leaving someone on partially suppressive therapy. How we use it in clinical practice continues to be the challenge. Right now it seems to explain what's going on, rather than allowing us to guide therapy.

Tell me about access to the new medications. I know there are a couple of expanded access programs for some of the new medications. But I understand that universities and a number of other entities do not get involved with expanded access. So is your university able to get the new drugs through expanded access?

Expanded access is a system that really evolved from the HIV epidemic, where it became clear to the Food and Drug Administration that there are people in desperate need of new drugs. And that, while we want these drugs to be thoroughly tested in clinical trials, once they appear to be promising, we would like them to be available as soon as possible for the people who have desperate needs. That's what really started many years ago.

Well, it was an activist thing. I think the activists sort of fought for it ... because it doesn't exist in other disease states.

Absolutely. It was really a byproduct of the activist movement for HIV and AIDS. It started 15 years ago and continues today. We now have three drugs -- new drugs -- that have been developed and will have activity against otherwise drug-resistant virus. One is an NNRTI -- so this is a drug related to Sustiva and Viramune -- but it's active in people who have had resistance to those previous drugs.

Then there are two drugs in new classes. One of them is a so-called integrase inhibitor, and the other is a CCR5 inhibitor. So these are drugs that work in a completely new way, unlike the previous nukes and non-nukes and protease inhibitors. They are all available through expanded access programs.

You're right. Not all centers, whether it's academic or otherwise, are involved in expanded access programs. A lot of it is based upon the individual sites and what the perceived needs are. Unfortunately, it requires a considerable amount of work for sites to get these set up. In some centers, it takes so long to get approval that basically the drug becomes approved and readily available before they get the expanded access program set up. Other centers may not find a need for it, because they have these drugs available through the clinical trials. We've generally not routinely done expanded access programs because we participate in the clinical trials. That's the mechanism we have used for getting these drugs available for our patients.

But certainly, if you need new drugs, talk to your providers about it. If your provider is not doing it in their program, you can -- either through them, or contact with the companies directly -- find out which providers in your community do have the expanded access program available.

Let's go back to the patient. A patient takes a resistance test, and has a lot of resistance. But resistance tests currently available do not show any of the new medications. Is one to just presume that the new agents would be active?

That's a challenge. It's particularly a challenge for new drugs in old classes. So for example, when a new protease inhibitor comes along, initially we really don't know whether the patient will respond. We know that, if you look at a group of people who are protease resistant, that a proportion will respond. But we don't really know how to define which individuals within that group will respond.

That's the case, certainly, with the new NNRTI -- this etravirine, previously known as TMC-125. Not everybody who is otherwise resistant to the first generation non-nucleosides will be susceptible to this drug, and we don't really know yet how to predict that. Eventually we'll have more information, but right now, it's a bit of guesswork.

For the new drugs in novel classes -- so, for example, integrase inhibitor -- I think it's safe to assume, based on what we know so far, that anybody who's never been on an integrase inhibitor will have a virus that's fully susceptible to that drug. So the absence of that on a resistance test probably isn't that important, because you can pretty much rely on susceptibility for now. Once people start taking these drugs, then it's a different story.

The CCR5 inhibitors are a whole other animal, in that while people who have never been on a CCR5 inhibitor are likely to have a virus that will be susceptible to it, the drug actually blocks CCR5, which is a receptor for the virus on the surface of the cell; that's how it works. It turns out, for reasons we don't completely understand, that during the course of the disease, upwards of 50 percent of people will develop viruses that actually use another receptor [to enter the cell] called CXCR4. The CCR5 inhibitors won't block those viruses.

So, while it's not an issue of resistance, there is a subset of individuals who may not respond as well to CCR5 inhibitors as others. There's an assay [test] that's being developed and will be implemented along with the CCR5 inhibitors to tell patients whether their virus uses CCR5 alone, in which case they should be a good candidate for the drug, versus whether it uses that other receptor, as well, in which case they may not be as good a candidate for the drug.

Do you think these new drugs that are nearly available for use in the clinic are instrumental in the sea change of what it means to be treatment experienced in 2007, or is it something else?

Oh, I think clearly the new drugs are having a big impact. Because for the highly treatment-experienced patient who has limited options, to suddenly say, well, we've got some new protease inhibitors -- like tipranavir [Aptivus] and darunavir [Prezista], which were approved in the last year or so, that are going to be active for many of them (not all, but many). Now we have a new non-nucleoside [NNRTI], etravirine, for people who are resistant to the older NNRTIs. Then on top of that, we also have new drugs and new classes, for which most people will be susceptible -- like integrase and CCR5 inhibitors. The idea of creating a regimen with two or three fully active drugs suddenly doesn't appear as daunting in the setting of highly treatment-experienced patients, when you have all these new options that you may be able to combine.

In addition, you can't forget about T-20, or enfuvirtide [Fuzeon], which is also another novel drug, in a unique class [fusion inhibitors], for which their virus should be very susceptible if they've not been on it in the past.

This is all great news ... but do you think that patients and doctors are really aware of these dramatic changes? You answer questions at The Body's Ask the Expert forum and I know you've seen the questions from people who say, "My sister's doctor says she's resistant to everything and she should just pack up her bags and get ready to die." With all the new medications that have been recently approved and all those in clinical trials, is this scenario still possible in 2007?

Almost never. You know, like I said: Even partial suppressive therapy can keep people clinically stable. Even people who have very low T cells often will remain clinically stable for a long period of time -- meaning having no symptoms of AIDS for months or even years. We can't predict. Obviously, if somebody has been ravaged by AIDS-related complications, there is a point where there's nothing left to do. But just because someone has a lot of drug resistance -- you never give up.

You know, we saw a lot of people who were in desperate straits back in 1995, who held on for protease inhibitors, and who are now alive today with undetectable viruses and normal immune systems and, in all likelihood, will never suffer the consequences of AIDS.

I think we're at a point very similar to that now, with these new drugs coming along. Even those people who are highly treatment experienced -- maybe even those who have low T cells but are otherwise relatively asymptomatic -- if we can just get them to hold on for another 6 to 12 months, we may have the tools we need in the clinic to offer them what we offered many people back in '95, '96 ... where we'll be able to put them on a new regimen, get their viral loads to undetectable, get their immune systems strong again, and perhaps they, too, will never suffer the consequences of AIDS. So I think there's reason for optimism right now.

Hopefully this information will spread throughout the country. There are a lot of physicians, I think, who are not clear about that. They get a resistance test back and it looks like the patient's resistant to everything and that's the end of that. They don't know, I think, about the new drugs in development or the expanded access programs ... or that their patients can be taking an HIV regimen and still do okay. On our site we get a lot of e-mails from people whose doctors have given up on them.

Again, I don't want to suggest ... there are certainly people who are so sick already that there are limitations. But that's different from somebody who just has a lot of resistant virus; that's a completely different scenario. I think there's very good reason to continue to be optimistic.

Okay, great. Well, thank you very much, Dr. Daar.

Thank you.

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