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This Month in HIV: State-of-the-Art: HIV/AIDS Medications for the Treatment Experienced

April 2007

Eric Daar, M.D.

To help us learn more about dealing with multidrug resistance, I contacted Dr. Eric Daar, the chief of HIV medicine at Harbor-UCLA Medical Center in Los Angeles and a professor of medicine at the David Geffen School of Medicine. He has been an active HIV physician and researcher since the 1980s, and is an authority on multidrug resistance.

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.

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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.


Management of the Treatment-Experienced Patient

These guidelines come from the January 29, 2008 Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents, developed by the DHHS Panel on Antiretroviral Guidelines for Adults and Adolescents -- a working group of the Office of AIDS Research Advisory Council (OARAC)

Panel's Recommendations:

  • In treatment-experienced patients with suppressed viremia, assess adherence frequently and simplify the regimen as much as possible. Change individual antiretroviral drugs to reduce or manage toxicity, as needed.

  • Evaluation of antiretroviral treatment failure in a patient should include an assessment of the severity of HIV disease of the patient; the antiretroviral treatment history, including the duration, drugs used, antiretroviral potency, adherence history, and drug intolerance/toxicity; HIV RNA and CD4 T-cell count trends over time; and the results of prior drug resistance testing.

  • Virologic failure on treatment can be defined as a confirmed HIV RNA level >400 copies/mL after 24 weeks, >50 copies/mL after 48 weeks, or a repeated detectable HIV RNA level after prior suppression of viremia.

  • Drug resistance testing should be obtained while the patient is taking the failing antiretroviral regimen (or within 4 weeks of treatment discontinuation).

  • The goal of treatment for patients with prior drug exposure and drug resistance is to reestablish maximal virologic suppression, HIV RNA <50 copies/mL.

  • Use the treatment history and the past and current resistance test results to identify fully active agents to design a new regimen. A fully active agent is one that is likely to have antiretroviral activity on the basis of both the treatment history and susceptibility on drug resistance testing. Adding at least 2 (preferably 3) fully active agents to an optimized background antiretroviral regimen can provide significant antiretroviral activity.

  • Immunologic failure can be defined as a failure to achieve and maintain an adequate CD4 response despite virologic suppression.

  • For immunologic failure, current medications, untreated coinfection, and serious medical conditions should be assessed.

  • There is no consensus for when and how to treat immunologic failure.

  • Assessing and managing a patient who has antiretroviral experience, who exhibits drug resistance, and who is experiencing treatment failure is complex and expert advice is critical.

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.

"... we don't just look at the results from the current resistance test right now; 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."

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.

"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."

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?

"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."

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.

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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.

"We believe that viruses that have a lot of drug resistance don't grow as well and that maybe ... it's this inability of the virus to grow well in its mutated state that allows for these people [with multidrug-resistant virus] to remain relatively stable, despite [not] having complete viral suppression on therapy"

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.

Jeff Berry

Now, I'm pleased to welcome to This Month in HIV Jeff Berry, director of publications and editor of Positively Aware at Test Positive Aware Network, the oldest peer-led HIV service provider in Chicago. He has been working at Test Positive Aware Network in various positions since 1992.

I thought he'd be interesting to talk to since he just finished being immersed in this issue. The March/April issue of his publication Positively Aware is called "Hope for Survival -- Salvage Therapy Revisited." The issue focuses on how HIV therapy for the treatment experienced has changed. On a more personal note, Jeff is also familiar with this subject since he is moderately treatment experienced himself. He has been HIV positive since 1989 and has taken an assortment of HIV medications.

Welcome, Jeff, to This Month in HIV. I'm so glad you could join us for today's podcast.

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Thank you, Bonnie. Thanks for having me.

One of my first questions is about the terminology. There are so many terms for someone who is treatment experienced. What does it mean to you, a treatment-experienced person?

One of the reasons, I think, we did this issue of Positively Aware on salvage therapy, is because there is some confusion out there about the different terms. You hear so many different terms. You hear "salvage" and you hear "rescue" and you hear "treatment-experienced," and you hear them used interchangeably. I thought it would be interesting to talk about some people's different experiences in salvage and rescue therapy. But treatment experience to me really just means that you have actually been on treatment. [Click here to browse a PDF of Positively Aware.]

It doesn't mean you're very treatment experienced. It just means that you have had some experience.

Correct. There are actually different levels of treatment experience. You know, we can get into that a little bit. But someone could be moderately treatment experienced. They could be in an intermediate stage or an advanced stage. Just as in HIV disease, there are different stages, different levels of disease, there are also different levels of treatment experience.

I guess when people say, "We need new drugs for the treatment experienced," I guess what they mean is for people who have multidrug resistance.

Right. So your probabilities for success with the different therapies that are currently available are less when you have multidrug resistant virus. If you are resistant to many drugs in one class, such as the non-nuke [NNRTI] class -- Sustiva [efavirenz, Stocrin] and Viramune [nevirapine] fall in that category -- then you are resistant to all [the drugs] in that class; you knock out the entire class. It's much harder to respond to treatment once you have knocked out one or two classes of drugs because you don't have many options left.

What percent of the patients, of people with HIV, are multidrug resistant? Do you know if there's a number?

I don't know that offhand; I'm sorry, I don't.

It's a small percentage, though, at this point.

I think it's 10 or 15 percent. But it's a small number. You have to also keep in mind that HIV resistant virus can be transmitted. Multidrug-resistant virus can be transmitted. This means that if you have never been on treatment and you contract the virus, become HIV positive, you can become infected with a virus that is already resistant to one or more classes of drugs. That's a reason to be even more extra careful in protecting yourself.

I think the number was 9 to 15 percent of patients in the United States with HIV, when they are told they have HIV, actually also have drug resistance as well. These people then start off their lives with HIV already resistant to one or more medications. In the U.S. people who are treatment na?ve and already have HIV drug resistance generally have resistance to NNRTIs, like Sustiva, which is kind of a problem because the only once-a-day, one pill dual-class combination drug: Atripla contains Sustiva. And if you're resistant to it, you can't take it.

Right. It's one of those medications that's on the preferred list for the treatment guidelines, so it's a very powerful drug. It's one that's very frequently used and recommended for first-line treatment. [To view the U.S. treatment guidelines list of preferred first-line medications, click here.]

Going back to terminology -- Which word fits your situation? Do you see yourself as a rescue patient? A salvage patient? A multidrug resistant patient? Or are you just treatment experienced?

You know, I probably fall somewhere in the intermediate level of treatment experience. I've been on many different regimens. However, I have a lot of options still available to me. My immune system is relatively intact. I would be really considered not to be on salvage therapy for those reasons.

If I were to develop resistance to drugs that I'm currently on, then I might be giving you a different answer because of my current regimen. I'm only on two different medications, from two different classes of drugs, and if I were to develop resistance to those then I could knock out two classes, potentially, very quickly. But right now, I'm just treatment experienced, and I'm probably at the intermediate level of treatment experience. I've been on HIV treatments since 1989, but I have been very lucky and very successful with my treatment.

Could you go through a little bit of your history?

Sure.

In '89, you were on AZT [Retrovir]?

Right. I started AZT monotherapy in 1989, and that was really the only drug that was around at the time. I saw a steady decline in my T cells over the next five years or so. Then I switched to d4T [Zerit, stavudine] monotherapy.

By monotherapy you mean just one drug?

Just one drug. I switched off the AZT and onto d4T.

Was there a reason?

At that point, my T cells had dropped below 200 and my doctor was concerned that the drug was not effective -- AZT -- so he switched me to Zerit, which was a newer drug at the time. And then, not even a year later, I added Epivir, or 3TC [lamivudine], to my d4T. Then about a year and a half after that, in September of '96, I switched to 3TC plus AZT, or Epivir plus Retrovir, which is Combivir -- now known as Combivir -- in one pill. But at that time it was two. Plus Viramune, which was the first time I was on an NNRTI.

But only a few months after that, my viral load steadily increased. That was the first time I had gotten a viral load test, was when I switched to adding the Viramune. It was 20,000, and then a couple months later, it was up to 40,000. They took me off the Viramune, kept me on the 3TC and AZT, and added Crixivan [indinavir]. I did pretty well on that for a couple of years, and went to undetectable. But then I developed kidney stones.

A famous Crixivan side effect, right?

Yes, a famous Crixivan side effect. Even though it was working well for me, when I got the kidney stones, I had to, unfortunately, go off of it, and that's when I switched to Viracept [nelfinavir]. I never really did that well on Viracept plus Combivir, although I had a low viral load. I think it was, you know, hovering. But it was always detectable. It was always above the level of detection. I never could get it to undetectable at that point, after switching off of Crixivan. And then, when my viral load started to steadily increase, and after I had had a resistance test showing that I was indeed resistant to it, I switched to Kaletra [lopinavir/ritonavir] plus Sustiva. I have had great success with that regimen, and am still undetectable six years later on that regimen.

It's a very unusual regimen.

It is. It is. My doctor felt, I think, it was really important to hit hard and, you know, be aggressive, and he had had success with this regimen with other patients of his. The only caveat, or potential drawback, to the regimen is the potential for high lipids, and increased lipids, which, indeed, I have begun to experience. I'm also taking Lipitor to help control that. I may have to switch off this regimen, just because of the potential for metabolic complications and heart complications, but so far I have been lucky to have a very successful regimen with the Kaletra and Sustiva.

You went from, I guess, a low T cell count of 177 to 800 now?

"I have been very lucky for someone who has technically fallen below that 200 level, to come back up to where I am now."

Right. It's anywhere, like, 700, 800 T cells. The immune system is very hardy, in my case. I have been very lucky for someone who has technically fallen below that 200 level, to come back up to where I am now. My ratio of CD8 to CD4 cells is pretty high. It's interesting, because I think everyone responds differently to therapy, to treatment. What works for one person doesn't necessarily, obviously, work for another person. You have to take each case by case.

I think a lot of people, when they hear that somebody has been through a lot of treatments, they think it's odd that they're not taking a newly approved drug. They think they'll have to come up with something really weird, something that's in clinical trials. But the only thing that's different is that it's an unusual regimen, but the drugs that you're taking are very current. They are what are called by the U.S. treatment guidelines "preferred drugs." That's the thing that is not different.

Right.

A lot of people think if you're treatment experienced, you're going to be taking maraviroc or another drug that's in clinical trials. But there are a lot of people who haven't been exposed yet to Kaletra or Sustiva, who have been on treatment for years. They just never took those drugs -- and they could be good drugs for them.

That's the whole idea, too. You want to try to spare as many drugs and classes that you can. I know a lot of people who have been very successful and they are still on nukes [NRTIs] and maybe one non-nuke [NNRTI], like Viramune plus Truvada [tenofovir/FTC]. And they have been on that for years and they are doing very well with it. They have never had to even go on protease inhibitors yet.

It's a great option for many people to be able to take class-sparing type of regimens. This way they can save the protease inhibitor class or some of the newer classes like the integrase inhibitors and the entry inhibitors for down the road, when they may need them.

Are you very worried about taking your regimen on time and being really careful with that because you stand to lose so much if you become resistant to either of them.

"... adherence has just kind of become second nature to me. I think it's something that you learn, that you can teach yourself, and you can use different things to remind you ..."

That's a good point. I'm not worried, simply because I was on Crixivan. At the time it was unboosted, when I took it -- meaning, it wasn't boosted with Norvir [ritonavir], which is now recommended. I mean, the only time you would take Crixivan, if you would even take it, would be boosted with Norvir. But back when it first came out, you didn't. You took it every eight hours, and you took it on an empty stomach. That was the most difficult thing, one of the most difficult things, I have ever had to do.

I learned a lot from that experience, in the sense that I was adherent for over two years. I maybe missed one dose in that time. I never developed a resistance, and it was very, very effective. But it was a very, very tough regimen. It was always drilled into me, from very early by all my doctors, luckily, how important it was to be adherent and to stay on and take the drugs on time and to take the right dosages. I would sometimes wake up in the middle of the night just to take my Crixivan on an empty stomach, if I had to.

That experience really taught me, and now adherence has become second nature to me. So I think it's something that you learn, that you can teach yourself and you can use different things to remind you to be adherent. I don't even really think about it anymore. I always take my Kaletra 12 hours apart: one dose with breakfast and one with dinner. And then I take my Sustiva when I go to bed. So it's just second nature, like brushing my teeth.

So for other people, for people listening to this, if they are multidrug resistant or treatment experienced and they know they have some resistance: what do you recommend that they do? I know the latest issue of Test Positive Aware Network magazine is called "Hope for Survival, Salvage Therapy."

Well, for people who are treatment experienced, I think the most important thing is to find a good provider.

How would you define a good provider?

One who has a sizable percentage of patients with HIV, if you're lucky enough to have one like that in your area. If not, maybe you could drive to an area where they do, where there is that kind of doctor.

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How do you find that out? You call the doctor and say, "How many HIV-positive patients do you have?" And you hope they'll answer honestly? They'll say they have a lot, so come on over. I mean, should you just call an AIDS organization, like Test Positive Aware Network in Chicago, and say, "I need a doctor nearby?" Is that the best way?

Yes, that's a really good point. There are many HIV/AIDS service organizations. Test Positive Aware Network is here in Chicago and we produce an Illinois HIV/AIDS services directory. [Click here to browse this directory.] So you can call us; we'll send you a directory, and you can look up, or you can go online and do the same thing.

There are directories in other cities, as well, where you can find service providers in your area. You can call an HIV/AIDS service organization and you can say, "Hey, look. You know, I'm HIV positive and I don't know any doctors, and I just moved here to this area. Would you recommend anyone?" Many times, they'll give you recommendations over the phone. So that's a great tool for people to use. [To find an HIV/AIDS organization near you, click here.]

For someone who has multidrug resistance, or someone who is treatment experienced, finding a health care provider with lots of experience is critical. I don't know if it's as critical for someone just beginning treatment, but it's critical for someone with some treatment experience because of the resistance test. You want a healthcare provider who is very able to understand your resistance test results. Treating somebody with HIV drug resistance is an art, I think, at this point. At The Body we still get letters from people out there who say, "My doctor says I'm resistant to everything and I should just pack up my bags and prepare to die." It's frightening!

Absolutely. I mean, we get letters, too. It's kind of scary looking at some of the letters that we get...and what some doctors are telling people to do. But even with the guidelines, the treatment guidelines [click here to view a PDF of the latest U.S. HIV treatment guidelines] that are there for doctors; if they don't use them, or if they don't --

If they don't know they exist.

Right. If they don't even know they exist, then you're really pretty much out there on your own. So definitely use resources in your area. Because many of these AIDS service organizations, including Test Positive Aware Network in Chicago -- a lot of the people that work here, that I work with are HIV positive themselves. So you can talk to a staff member or a client or a volunteer, somebody at the organization, who's gone through some of these experiences themselves. They can kind of hold your hand and kind of talk you through, and give you some suggestions on what to do and where to go for treatment.

So do you think most people are proactive about getting a resistance test and making sure it's understood by their doctors?

You know, I don't know. That's an interesting question. I would hope that they are. If you're failing --

If the regimen's failing you ...

"Remember: You don't fail your regimen, it fails you. If your treatment is failing, then you want to get a resistance test."

If your regimen's failing you, thank you. [Laughs.] Because remember: You don't fail your regimen, it fails you. If your treatment is failing, then you want to get a resistance test. You definitely always want to get a resistance test.

While you're still on the regimen.

Right. If your viral load becomes detectable -- because it has to be detectable for the resistance test to be even useful -- and then an expert can look at that and decipher the different mutations.

It's very complicated. So they really have to have some experience with that. That's why it's important to have an experienced provider. Then they can help you make a treatment decision based on your resistance profile. But I don't know if people are very proactive in that. I would hope that people understand the usefulness of resistance testing. And again, in the treatment guidelines, it will spell out very clearly when and where you should be using resistance tests, and when they are recommended for people in the course of their treatment.

I know that the new recommendations are that if you have a detectable viral load for a length of time -- I don't know how that's defined -- but for a length of time, that you should get a resistance test. You should not stay with a detectable viral load. I believe that's the new recommendation -- that there are so many new medications out there that you can be switched, whether these medications are still in development in clinical trials or under expanded access or just newly approved. But I know it's not just a marketing slogan. It's a physician recommendation, at this point. For most people there's no reason to stay with a detectable viral load.

For most people, correct.

I mean, there are some people who are still resistant to everything, but there are these new classes, integrase inhibitors. And if they could get people on that, or get people on the CCR5 inhibitor; those are two new classes that nobody can be resistant to, really.

Correct. And even though these drugs aren't approved yet, they are currently in expanded access, so they all have expanded access programs: Merck's integrase, raltegravir, MK-0518, and Pfizer's entry inhibitor, maraviroc, have expanded access programs. So they should be able to get access to these drugs if they need them. So, right. They shouldn't have to not have any options; they shouldn't be resistant to those drugs.

So it is a different world.

It is. The entire landscape is changing. It's an exciting time, and I think this year is going to be an exciting year for HIV therapy. It already is. There are other drugs, in addition to the two that I mentioned, that are being developed and in clinical trials. There's a new non-nuke, etravirine, by Tibotec, and that's also in expanded access. And Prezista, the new protease that was released last year, I believe, is really good for people with resistant mutations -- already resistant to many of the current protease inhibitors -- so it was, in fact, developed for those patients specifically in mind.

So hopefully this information has gotten out there. I know a lot of people were waiting for the next drug to come along, so they did not change medications, even though their viral load was 50,000. Hopefully the news got out to everybody that there are new meds, and if they switched, they could possibly get their viral load to undetectable. You know a lot of people who are positive, as I do, and a lot of people are telling me they are undetectable for the first time in 25 years.

Exactly. It's exciting. They are doing clinically very well, and they're feeling better and they're looking better. A term that was used ten years ago when the protease inhibitors first came out was "Lazarus syndrome," people literally rising from the dead. This is another time that's hopefully going to offer a lot of new hopes and a lot of new options for people that haven't had them.

So it's exciting. We're really lucky to have these new drugs and the development, the research that's going into the new, different classes of drugs. Because it definitely opens up the doors. As you said, there are a lot of people now that are, for the first time, undetectable. And in the course of their treatment history, this is the first time it's ever really happened for them.

I guess we need a new term for this era. Like we had the term "Lazarus syndrome," a wonderful term to name the new era. We need a new name ... that's not a marketing slogan. I guess we'll have to think of something. So, anyway, thank you so much, Jeff. Good luck with your regimen. I hope you don't have to go off of it. We'll give everyone your e-mail so that they can contact you for questions. Thank you so much! Congratulations on getting your issue out on time.

Thank you so much, Bonnie. Yeah, if people want to, they can contact us for copies of the March/April issue.

So they can just get it via mail, as well? If they want it mailed to them?

Yes. We can mail it out to them, or we can let them know where they can get it in their area, if they would rather pick it up in an AIDS service organization in their area. It's also available online on our Web site: www.tpan.com. In the May/June issue that will be coming out next month, we'll be talking about some of the new drugs that were reported on at the retrovirus conference in L.A. in February [14th Conference on Retroviruses and Opportunistic Infections (CROI 2007)]. There are a lot of new drugs that we didn't even talk about that are coming down the line, that give a lot of reason for hope for a lot of people. It's an exciting time.

Thank you for having me. I really appreciate it.

Thank you.

To e-mail Jeff Berry, click here.

To read a copy of Test Positive Aware Network's March/April issue of Positively Aware, click here for a PDF.




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