Paul E. Sax, MD; Steven G. Deeks, MD


December 05, 2011

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HIV Drug Resistance Today

Paul E. Sax, MD: Hello. I am Dr. Paul Sax, Associate Professor of Medicine at Harvard Medical School and Clinical Director of the Division of Infectious Diseases at Brigham and Women's Hospital. I am here at the 2011 Infectious Diseases Society of America (IDSA) meeting in Boston, Massachusetts, with Dr. Steven Deeks, Professor of Medicine at University of California, San Francisco. It's a beautiful fall day, and Dr. Deeks has kindly taken some time to talk with us.

We are going to discuss HIV-infected patients who are resistant to everything. It's uncommon, but it's a very challenging problem. Let's talk about the situation with HIV drug resistance today.

Steven G. Deeks, MD: Let me go back a little in history. Over the past 20 years or so, the epidemiology of drug resistance has waxed and waned in dramatic ways. In the 1990s, a cohort of people received sequential monotherapy for the most part. These were people who had AZT (azidothymidine/zidovudine) and then d4T (stavudine) and 3TC (lamivudine) and eventually were placed on protease inhibitors in a suboptimal way, and then often placed on a nonnucleoside reverse transcriptase inhibitor in a suboptimal way. They essentially went from regimen to regimen to regimen.

This was very common in many urban centers, particularly in urban centers where the epidemic had been established quite early. San Francisco was a key epicenter of the epidemic in the 1980s. In San Francisco, where I had my clinic, we had a massive cohort of people. We began to study these people in detail in the late 1990s, and we enrolled several hundred people in a prospective cohort. These are people who had multidrug-resistant HIV.

Dr. Sax: Ironically, they were very adherent to therapy, right?

Dr. Deeks: They did everything that they were supposed to do -- well, perhaps not everything that they were supposed to do. They did everything that they were told to do. They took these drugs, and for the most part, this was a very motivated, highly engaged group of individuals.

Dr. Sax: They were individuals who had early access to these drugs.

Dr. Deeks: These patients went on these drugs as soon as they were available.

Dr. Sax: So, what changed?

A Dramatic Shift in Antiretroviral Treatment

Dr. Deeks: About 4 or 5 years ago, we were still treating patients this way. At that time, a lot of clinicians, including our group, stopped switching their patients' regimens. We said, "Every time we switch, these drugs fail, so then we just blew another option. Let's wait." Clinicians slowed down; they let patients "hang out" on their partially suppressive regimens and waited for the next big combination. That came out in 2008, and the whole world just shifted; it was dramatic. This was when darunavir, etravirine, maraviroc (a protease inhibitor, a potent nonnucleoside reverse transcriptase inhibitor, and a first-of-its-class CCR5 inhibitor), and most importantly, raltegravir (a very potent integrase inhibitor) became available.

Dr. Sax: I noticed that you didn't include enfuvirtide.

Dr. Deeks: This was the postenfuvirtide era. From our perspective, in San Francisco, once we saw that enfuvirtide was very fragile, we didn't really use it that much. We used it when we were desperate, but we stopped switching and were waiting for a tolerable regimen that could be administered indefinitely and would work in most people. That happened around 2008. I was shocked at what happened -- it was just dramatic. This entire population who we were following (maybe 500 people), within a matter of 1-2 years, all but 50 of them had achieved durable viral suppression often by mixing darunavir, etravirine, and raltegravir.

Dr. Sax: The famous TRIO study, done in clinical practice.

Dr. Deeks: I remember because I was the "go-to person" in our clinic for drug resistance. It got to the point where I just said, "I don't want to hear the details; give them A, B, and C." Essentially that's what happened. I had accomplished a pretty significant amount of work focused on trying to understand the natural history and pathogenesis of this, and essentially the problem disappeared.

I remember very distinctly that I gave an opening talk at the European HIV Drug Resistance meeting around that time, and the entire group of clinical people essentially said, "Steve, we don't really care about this issue anymore. We know how to treat it." I predicted at that time that it was going to be a transient thing. These drugs would probably work for most patients, but there will be a lot of failure in the future, but it hasn't happened. Everybody in care today -- there are exceptions and we'll get to those -- who is adherent, motivated, and has access to these drugs can achieve durable viral suppression.

Dr. Sax: Do you think that that can also be achieved internationally?

Dr. Deeks: That is a separate issue, about which I have less expertise, and from what I understand, no, it's not going to happen everywhere. As the rollout continues, we are increasingly giving antiretroviral drugs to people who may be less motivated or in whom something else is going on. From what I have heard anecdotally, these first-line regimens are perhaps not working as often as we would like and the second-line regimens are hard to get. There is no such thing as third regimens, so internationally in resource-poor regions, it is a very different story.

Dr. Sax: They may be repeating some of the mistakes that we made.

Dr. Deeks: I suspect that things are not going to be as good as we had hoped.

Dr. Sax: If you take a typical large clinical practice -- a large service -- and say that almost everyone who can take their medicines is virologically suppressed, who are the exceptions?

Six-Class Resistance

Dr. Deeks: There are some major exceptions. One is patients who don't take their medications, and that is a huge issue. There are approximately 20%-30% of people in our clinic, which is an urban public health clinic that primarily serves people who are poor and have multiple other issues going on, and how to deal with them is not entirely clear. However, there still is a remnant of that initial generation who are hanging on there who essentially failed because of all the drug resistance that they had to darunavir, etravirine, and raltegravir; they often have X-4 virus. When we were following them, about a year or two ago, we identified 50 patients in our cohort throughout San Francisco who were essentially resistant to all 6 classes of drugs.

Dr. Sax: Fifty is a large number.

Dr. Deeks: Right. We were used to hundreds or thousands. If we had wanted to do a study on drug resistance 3 years earlier, there were thousands of people. So to us 50 was small, but then I started traveling around, and most clinics had 1 or 2.

Dr. Sax: That's right. We have 3.

Dr. Deeks: So we had 50 or so people who had documented resistance to these drugs or could not tolerate T20 [enfuvirtide], for example. What happened with those patients? Three things have happened. These are people who have pretty advanced disease. Some have hung on; some have died; and many have developed age-related complications, and unfortunately that generation won't be around for the next series of drugs, if there is a next series. A few have gone on the dolutegravir-based regimens, and they have actually done quite well in this setting despite the fact that they have failed [to respond to] everything, including raltegravir.

Dr. Sax: They have done that in clinical trials.

Dr. Deeks: In clinical trials, yes. The rest are essentially hanging out, doing what they can, what we did 10 years earlier, which is the waiting game, trying to wait for new drugs to come out. Of the 50 or so people who we are following, only 10-15 are truly on therapy, resistant to 6 classes of drugs, and waiting for the next regimen.

Dr. Sax: You are keeping them on some form of therapy.

Managing the Waiting Game

Dr. Deeks: One thing that we have learned a lot about is how to manage the waiting game. For complicated reasons (we can revisit that old story), essentially each of the available drugs has a specific role in helping people maintain their CD4 counts in health as best they can while waiting. We are big fans of the nucleoside analogues, which almost always work, and complete resistance to those drugs is rare. There is always partial activity, the more the better, so we essentially give people as many nucleoside analogues as we can. We don't see much of a role for nonnucleoside reverse transcriptase inhibitors in this group, so we don't typically use those drugs.

Since the mid-1990s, some unexplained relationship has been observed between resistance to protease inhibitors and immunologic benefit. It's real; it has been seen in multiple studies; and so we essentially maintain people on a protease inhibitor for that special, unexplained fact. We don't typically continue people on maraviroc because they have the X-4 virus, and T20 doesn't have much of a role in this setting. Essentially, we do what we did 10 years ago: multiple nucleoside analogues, protease inhibitors, and waiting.

Dr. Sax: We heard about dolutegravir; that's the integrase inhibitor in development, but not a whole lot else.

Dr. Deeks: Industry has done quite well by using these individuals to get drugs approved rapidly and then move them up the chain quickly where there is more profit to be made. That isn't a viable pathway for industry anymore.

Dr. Sax: Because it's so rare.

Dr. Deeks: It's not a common problem.

Dr. Sax: Would you say that this problem should really push for collaborative approaches because if each site has only a few of these patients, how do we study them and how do we find out how to help them?

Shaking the Pipeline

Dr. Deeks: A group of community-based activists who have worked with industry, along with people from academia and the clinical world, has been trying to come up with a collaborative approach to this problem. Nelson Vergel from Texas has been spearheading this, and he has done a wonderful job doing what he can. Industry realizes that this is a population that they can't enroll in clinical trials, and they are open to working with other companies to get these patients access to these drugs, which they are ethically obliged to do because this is the generation of patients from whom they got their drugs approved in the first place.

I feel quite passionate that few barriers should exist for these patients with 6-class failures to access these drugs. I'm not entirely sure that other people agree, but there has been a move, for example, to try to get dolutegravir. There are attachment inhibitors: monoclonal antibodies that bind CD4 in development. Many of them are in phase 1 or 2, and the companies are struggling to get them moving forward. An effort to come up with an expanded access program for this population to access all these drugs at once is needed.

Dr. Sax: This is really interesting. The numbers may be small, but those of us caring for these individuals know that they are really quite desperate for some help.

This is Paul Sax talking with Steve Deeks about patients with HIV who are resistant to everything, here at the 2011 IDSA meeting. Thank you for your attention.


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