The Latest Word on Protease Resistance
A Turning Point
Treatment Activists Sit Down with Vancouver High Fliers, Try to Make Sense Out of the New Cries of ‘Eureka’
Several weeks ago, at the July 15th TAG meeting, we met to hear reports from the XIth International AIDS Conference in Vancouver, British Columbia. What was remarkable about that evening is that our usually skeptical crew was a tiny bit giddy over the scientific news from the great Northwest. The preliminary results from the antiretroviral studies presented in Vancouver were stunning. Several different triple combinations of AZT+3TC and a plethora of protease inhibitors could suppress viral replication to below the limit of detection of very sensitive PCR-based assays for many weeks. Even a combination of some old has-beens, AZT+ddI and nevirapine, turned out to be a potent blocker of HIV.
Further back in the pipeline, some new protease inhibitors and even a new nucleoside from the House of ddNs, the drug company formerly known as Burroughs-Wellcome, looked very promising. While caveats about the recent results were issued, the predominant feeling that night was that, as Polly Allen Mellen of Allure magazine says about Isaac Mizrahi’s new fall collection in Unzipped, “This erases everything.” Added to all this clinical good news from north of the border was the equally stunning development that the beta-chemokines, which Bob Gallo had claimed in January to be the elusive CD8+ T-cell associated HIV suppressor factor, were also the natural ligand for the second receptor HIV needs to get into T-cells. (This work came out of a series of labs, including Nate Landau’s at the Aaron Diamond AIDS Research Center here in New York City.)
The new therapeutic advances are likely to offer a significant improvement in our ability to delay disease progression and extend survival in people with HIV infection. In more wildly optimistic minds, the new therapeutic regimens may even offer the chance of eradicating HIV in some people. One thing is clear: talk like this is making people crazy. At that mid-July TAG meeting, we were talking about the need to revise HIV surveillance and testing policies in light of the new developments from Vancouver-all of this without anything remotely resembling long-term follow-up of these drug combinations.
The ratio of hype and hope to the amount of real knowledge we have about the new therapies is exceedingly large. The first order of business seems to make sure we adequately study these new combinations and treatment strategies before mounting an antiretroviral Marshall Plan. That being said, how do we go about doing all this? For instance, how do you study the clinical effects of triple combination therapy initiated in primary infection? In early disease? What are the appropriate controls when all of this looks so good? Should we just depend on viral load to guide us into the promised land? How can we quantify responses when the plasma viral load is below the levels of detection? Suppose there are some long-term deleterious effects of these combos? (Any drug regimen that makes you spew projectile vomit can’t be all good for you.) What do we do for those in later stages of HIV disease who may have run through many of these agents already? When is the best time to start therapy? Will people be willing to defer treatment to answer this question? What happens when people treated early break through and need to switch to another regimen? Is there a best regimen to start with? To move onto as second-line? Or are all regimens that bring viral load down to “undetectable” levels for a similar period of time equivalent? What is the effect of compliance on the development of resistance to these agents? Can people really take these drugs religiously for years and years? (I’m sure you can add your own questions to the list.)
We asked David Ho and Marty Markowitz to come to TAG to talk with us about the implications of the recent advances in antiretroviral therapy. David and his team at the Aaron Diamond AIDS Research Center here in New York City were responsible for a lot of the excitement in Vancouver. Marty’s studies of ritonavir, AZT and 3TC in patients with primary HIV infection and nelfinavir, AZT and 3TC in antiretroviral-naive patients showed that it was possible to suppress peripheral viral load to “undetectable” levels (below 25 copies per milliliter in the nelfinavir study). This has been done in other studies, but David and Marty peppered their presentations with that word, “eradicate,” which sent everyone into a frenzy. In David’s final talk entitled, “How Long Should Treatment Be Given If We Had An Antiretroviral Regimen That Completely Blocks HIV Replication?” he even theorized that it might be possible to burn out the lingering reservoirs of HIV over a relatively short period, ranging from a few months to a few years at which point therapy might be able to be withdrawn.
The evening’s court drew quite an array of loyal subjects, including writers from the New York Times, the New York Daily News and the Village Voice. Once Gregg set the stage with a quick summary of the Aaron Diamond work that had been presented in Vancouver, the questioning began-and continued for nearly two hours. Believers and disbelievers alike clearly wanted to hear more. The most spirited (and sometimes provocative) exchanges have been painstakingly transcribed in the pages which follow. Unfortunately, space restrictions prevent us from running even the evening’s highlights in a single issue. So look to October’s TAGline for the balance of this immensely compelling and valuable discussion.
Q: At one of the late-breaker sessions in Vancouver, a San Francisco physician got up and described a case of a patient who had become aviremic on a potent antiviral combination and whose lymph node biopsy was negative. But when therapy was stopped some 20 months later, the patient’s viral load came right back up. Do you know of any other cases like that? And what are your thoughts about what was going on there?
MM: Well, it’s difficult to comment on other people’s work, but basically there were five drugs used at sub-therapeutic levels. And they achieved aviremia as far as they say on the test. But again, I don’t know who did the viral load measurements. I know that the lymph node was looked at and it was clinically clean. The way things were presented, though, you really don’t have the details. So I think I’d say, Beware of a case of one.
Q: I guess I wonder what your thoughts are about the potential for, within weeks I think, he reported that the viral load was back up to pre-treatment levels.
MM: Well, that’s what one would expect. I mean, if there’s infectious virus capable of re-igniting a process, the process cannot be subtle. It will re-ignite quickly, because that’s the dynamics of viral replication. If you turn if off, it goes down quickly. If you relight it, it goes up quickly. That’s not a surprise; that’s what you’d expect. When we write our studies, and eventually-if we decide to-take people off drug at a certain point, they will initially be seen weekly to look for viral rebound.
DH: Yes, that study was done with four nucleoside analogues, some at sub-optimal doses, and interferon. But let’s say, indeed, they did shut everything off. And they stop at 18 months and everything comes back. That’s still consistent with predictions. In certain cases, if the half-life of virus in the compartments with slow decay [exceeds the time on therapy], you would expect there to be some residual virus there at 18 months, and it may take 24 or 30 months before that will burn out.
Q: A number of protocols and concept sheets have come out [of the ACTG] since Vancouver which plan to look at either maintenance therapy once viral load has become “undetectable” or actually withdrawing therapy altogether. Do you think it’s too soon to have such strategy protocols up and running? When would you feel comfortable about either dose reducing (switching to monotherapy or from three drugs to two) or stopping therapy? What would you need to see before you could say to a patient, “I’m going to take you off all drugs.” What would you want to know?
MM: First, virologically it doesn’t make a lot of sense to reduce the pharmacologic barrier. You know, monotherapy is like a hurdle. And once the virus jumps over the hurdle its legs grow a little longer, so it jumps over the next hurdle more quickly. So you erect a barrier: you suppress the virus. If you feel that there is still a need for antiviral therapy, why reduce the barrier so that you give the virus a chance to jump? So the concept of “maintenance,” which is not terribly effective in acute leukemia, doesn’t make a lot of sense. I would personally sweep that notion aside. If you think you need to treat, then you treat optimally-and strive to develop regimens that are less toxic and more convenient and therefore more acceptable, as opposed to reducing the barrier.
I think that it is far too early, frankly, to be designing studies where you are going to stop therapy at, say, 12 months in chronically infected people. Our cohort is going to come to “maturity” relatively soon. Let these patients at least get there before you start planning large-scale studies. People now are asking, “What’s the fear of stopping therapy?” Well, there’s a little bit of viral load and you restart the drugs [to which the virus] is sensitive and you stay on drug for another period of time. I mean that’s the real fear. It’s not as if something terrible is going to happen if you stop drug. I don’t get it. Frankly, at this stage I think the whole idea of doing these kinds of experiments is to create a paradigm. So why not wait until the paradigm is created before you start testing the hypothesis?
DH: I think we have to balance different considerations. From the perspective of the investigator, there are times when you could stop therapy and gain a lot of information on the rise [in viral load]-if that’s carefully analyzed. So one could make the argument that, okay, let’s just do that and monitor the patient very closely. As long as the drugs are removed simultaneously so that the virus remains sensitive, all you are doing is basically interrupting treatment. So, in the absence of a cure, you say, “Well, that doesn’t matter much.” But if you’re striving for getting the virus to as low a level as possible, from the patient’s perspective, there is some harm.
Q: My question concerns therapy in the real world. It’s great to create treatment models, but several doctors I talked to in Vancouver and afterward are still convinced that it’s going to be very difficult to get-and keep-patients on these drugs, especially patients in early disease who are basically healthy, considering the side-effects, the complicated dosing schedules and that fact there are sometimes several dozens of pills that need to be taken a day. You even pointed out that three patients [out of twelve] in your seroconversion study dropped out.
MM: We’re not necessarily advocating that doctors take all their newly infected people and treat them immediately with these three drugs. I think this is what we’re doing, and I would hope that other people are going to set up similar studies to try to learn something. We’re not doing models of treatment in the community; we’re trying to answer scientific questions and trying to get an answer as to whether or not HIV can be eradicated in the best of situations-period. And to what that then goes to is somebody else’s decision.
Unfortunately, the physicians also are the ones who are doing serial monotherapy. They’re not thinking! Many, many physicians in New York City and elsewhere are just plucking patients onto ritonavir or indinavir on top of failing nucleoside regimens and seeing breakthroughs in 6 months and then what do the patients do? So I think a thoughtful approach to all patients is really required in approaching HIV, not just “our-ivory-tower-as-opposed-to-the-real-world.”
JM: Just look at it from a common sense perspective. When the data from these studies are all in; if the conclusions are as positive as people would like to think they are at this stage; the treatment might be bad, but the consequences of not taking the treatment are a hell of a lot worse. No matter how inconvenient it might be-if it truly works-you can lead a horse to water, and if they don’t want to drink, it’s their own fault.
Q: I would disagree with that. It’s great to develop treatments that somehow work in theory, but in the real world if you can’t apply them because of intolerance or because the patients can’t follow the schedule, then in fact they are not practical treatments. You can’t just say, “It’s the patient’s fault.”
MM: Oh, I agree with you there. You have to strive to make these regimens acceptable. When I design studies, I strive for convenient BID dosing as opposed to three times a day to try to make things easier. And there’s a lot of work going on along these lines. AZT+3TC is being re-formulated into one capsule. That’s a big deal, I think. And with ritonavir [Abbott is] trying to make pills that have more milligrams in them. This is all a work in progress, but it doesn’t all happen at once. It’s unfortunate, but the drugs are still there and the results are still there and I think the optimism should be there-compared to what was there 5 years ago.
DH: Just a comment on the initial drop-outs [in the AZT+3TC+ritonavir acute seroconverter study]. Yes, the patients that dropped out couldn’t tolerate the therapy, primarily ritonavir. But remember when we started this we were using the liquid formulation. We also went with the full dose from the outset. And now we know that the capsule formulation is much better and we can scale-up the first couple of weeks. It’s still not great, but it’s a lot better than the old strategy. So there are improvements made. And I think if we had done it correctly last August, that would have helped in retaining some of the patients.
MM: Plus at the time we wrote the study there were no alternatives to ritonavir. Abbott was the only company that would accept the study design, so therefore that was it. The second company to accept the study design-grudgingly-was Merck. Since then, it’s been a hell of a lot easier to get those patients. And the AZT+3TC+nelfinavir study has been a relative walk in the park by comparison. So there is progress. And there is improvement in patient acceptance. And it’s just a start.
Q: In Vancouver there were studies of ritonavir+ saquinavir and studies of 1592 being combined with other nucleoside analogues that produced viral suppression equivalent to what is being seen with these 3-drug combinations. If you can get the same viral suppression with 2 drugs as you get with 3 drugs, wouldn’t it make more sense to use 2 drugs-such as ritonavir and saquinavir?
MM: I worry about two proteases alone because the pharmacokinetics of these drugs are very unpredictable day in and day out. I think basically that the reason that these triple therapies work so well is because you combine the potent protease with its unpredictability with a less effective nucleoside regimen, but because it accumulates in cells it protects the patient from those times where the pharmacokinetics of the drugs are altered. I wouldn’t feel comfortable with a 2-drug regimen at this point in time.
Our plans are basically to optimize with 4 drugs. Maybe you can treat for a shorter period of time. We are planning a combination of AZT+3TC+1592 and the Vertex compound [141W94]-which has enormous central nervous system penetration. Perhaps you can treat for 8 months or 12 months or 16 months or 18 months with that particular regimen.
Q: There’s a certain cognitive dissonance here. On one hand we use the word “experiment” for what you guys are doing and on the other you’re saying, “It’s time to end clinical endpoint trials as we know them.” I agree, it’s probably time to do trials differently, but I think there are two populations for whom trials would be necessary and in one of them clinical endpoints unfortunately are going to be inevitable. And that is the more advanced population that has burnt through a lot of the available drugs and that will be failing for whatever reason — whether they have an inability to absorb the drugs or they have taken many of the other combinations [before]. We still need to find out what’s best for treating people in that situation, and we know from the Abbott study that this can be done.
The other population that is very hard to study is the one between acute seroconversion and, say, 400 CD4s. Now when I looked at your data, I also looked at Trip Gulick’s [Merck 035] data. Trip’s patients had been on AZT for about 2 1/2 years, and he got the exact same viral load reduction that you got with acute seroconverters. Now, I understand all the arguments about resistance and immunologic holes in the repertory, but from a public health standpoint, if I’m seroconverting now it’s going to be a lot harder for me to be compliant for 20 years than it would for me to wait to, say, 500 or 400 CD4s and then get nervous about my health.
Unless there’s definitive data that shows you can actually eradicate the infection, I’m worried that we’re going to go through [ACTG] 019 in 1990 all over again and everyone’s going to start triple drug now and there will be some patients who may not have actually needed it. We’re not going to know the answers from your study until a year or so from now. You’re not saying that this should be regarded as the standard-of care-for all stages of disease. Are you?
MM: That was a very loaded question, Mark. You covered a lot of ground. I think the point that I was trying to make initially was whether you have 50 or 500 CD4 cells, you can test the efficacy of a regimen. You cannot accept — you must not accept — that drug development stops and this is it. You have to look and be creative. I mean, one thing that ticks me to hell is that nevirapine was approved without any drug-drug interactions with the available protease inhibitors, knowing full well that these drugs are similarly metabolized. Now, had that been worked out adequately by the company responsible, Boehringer Ingelheim, and the companies that make the proteases, people who have been extensively exposed to nucleosides could go on two proteases and a non-nuke tomorrow — three new drugs. But they can’t because no one knows how the hell to dose nevirapine (or delavirdine) in the presence of, say, ritonavir plus saquinavir. Not an easy regimen, but still an option. And an option that can make a heavily pre-treated patient aviremic-just like a person who’s [drug] naive.
I think one has to take the point of view that, Yes, develop new drugs, but assess them fairly. Don’t insist that, if Upjohn Pharmacia develops a new protease inhibitor that has total non-cross resistance to all the peptide-based compounds, don’t make them go through the same hoops that Abbott had to go through. Twenty-eight day trials. Fast assessment of efficacy in the right patient populations: ritonavir exposed, indinavir exposed. Get a good idea of what this drug is capable of doing and don’t mess with people. That’s all I’m saying. Don’t wait. You have a good way of assessing antiviral efficacy. It’s an antiviral, and you have a good measurement of antiviral activity. But if you stick to these old ways of drug development, you make everybody jump through the same hoops. And that’s why you get studies [ACTG 320] like what Merck’s doing right now through the ACTG. They’re freezing people into AZT+3TC again, but the AZT+3TC arm is clearly inferior to the triple. The data is there. So why do it again and again and again?
Q: So you’re saying that everyone should go on a triple drug combo?
MM: I’m just saying that in the real world I think that when you do clinical trials and freeze people into clearly inferior arms, I think it’s wrong. Do I think that people should take AZT+3TC alone? I don’t. Personally, no. I think that’s wrong. I think the majority of patients will develop resistant virus in a relatively short period of time. If you look at the curves, it’s pretty clear. The AZT+3TC data is inferior to AZT+3TC+indinavir. There’s no doubt about that — and that’s in both the AZT-experienced and the AZT-naive.
I mean, we can sit here and argue about this, but it’s true. AZT+3TC does not shut down viral replication, and you get the emergence of resistant virus. When you do, your nucleoside card is severely limited. So when you want to play your protease card, what do you play it with? So you screw everybody by giving them [the] 184 [mutation] which makes them resistant to ddI and ddC, and then they’re stuck. Then their doctors just add indinavir to a failing regimen and they end up with super resistant virus at the end of 12 months. That’s my point.