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[Editor’s note: Researchers at the First International AIDS Society Conference, held in Buenos Aires, Argentina, July 8-11, 2001, presented findings that demonstrated the potency of a new type of antiretroviral medication: non-peptidic protease inhibitors (NPPIs). AIDS Alert asked Martin Markowitz, MD, an investigator with the Aaron Diamond AIDS Research Center in New York City, to discuss this new class of drugs. Markowitz and others have been conducting research on an NPPI named tipranavir, developed by Boehringer Ingelheim of Ingelheim, Germany. Tipranavir is the first NPPI to have Phase II data.]
AIDS Alert: What are the chief differences between how non-peptidic protease inhibitors (NPPIs) suppress HIV-1 infection and how protease inhibitors do it?
Markowitz: On a molecular level, I don’t think anybody is 100% certain. Theoretically, NPPIs are probably more flexible, but they were not rationally designed, but identified by high-throughput screening.
They act by inhibiting the HIV-1 protease enzyme. This is not a different class; it’s a different type of chemical within the same class. Though this drug is active against a panel of resistant viruses, it’s also less potent against non-resistant viruses. This drug will be used to treat protease-inhibitor-resistant virus.
AIDS Alert: The data you presented at the recent International AIDS Society Conference in Buenos Aires included 48-week data on two tipranavir-based treatment regimens. What were the most important findings?
Markowitz: The most important data are as follows: In a group of patients who had failed two protease inhibitor-containing regimens, the tipranavir-containing regimen resulted in a sustained, approximately 2.5 log reduction from baseline HIV-RNA, and approximately 80% of the patients on treatment had viral loads below 400 copies at 48 weeks. A substantial percentage of those patients had viral loads below 50. The other point is that the drug was relatively well-tolerated. Basically, for this experienced patient population, tipranavir holds promise.
AIDS Alert: Assuming tipranavir makes it to market within the next couple of years, how might clinicians include the drug in their antiretroviral treatment? What kinds of patients might be best suited for a regimen containing an NPPI?
Markowitz: It will be used as salvage therapy for patients who have failed PI-containing regimens. That should be the only use. I don’t see this drug being used in drug-naive patients. Unfortunately, there are a huge number of people out there who are desperate for new drugs that might work, and tipranavir may be one of them.
AIDS Alert: What about naive patients who have resistant virus that they’ve acquired?
Markowitz: Currently, the number of patients who contract multi-drug super-resistant virus to all current protease inhibitors is extremely low. Whether or not that will increase, time will tell. I don’t think that this will be a major usage. Certainly, if patients present with multidrug-resistant virus and need treatment, then they may need drugs like this.
AIDS Alert: What were the chief adverse effects reported by patients? Were there any signs of lipodystrophy or hyperlipidemia, which have been associated with protease inhibitor use?
Markowitz: Gastrointestinal symptoms and diarrhea were the chief adverse effects. Most of the patients came into the study with problems of lipodystrophy and hyperlipidemia, so you wouldn’t really be able to assess that. The study wasn’t designed to look at that.
AIDS Alert: It appears that this year there have been fewer announcements at AIDS conferences about new antiretroviral drugs in the pipeline. Is it becoming more difficult for investigators to find new avenues for fighting HIV infection, and what might this mean to HIV clinicians and their patients 10 years from today?
Markowitz: I would take a different point of view. I would say that basically you have completely new targets: binding and fusion. Drugs that are designed to block that process include the CCR5 inhibitor from Schering-Plough Corp., which soon will go to patients, and they have a follow-up compound called Schering D. And we heard that T-20 and T-1249 are well along in development. At this conference, we heard about tipranavir and we heard about another drug called mozenavir, which is a protease inhibitor that might be a lot cheaper to make and might be very useful for drug-naive patients. There’s also atazanavir, the Bristol-Myers Squibb protease inhibitor, which is a once-a-day drug that supposedly does not cause increases in cholesterol and triglycerides. There’s a protease inhibitor that was presented at the last Conference on Retroviruses and Opportunistic Infections meeting by Dr. John Erickson and Tibotec-Virco, which looks like a super-potent protease inhibitor that has activity against a wide array of drug-resistant viral isolates. As for nucleoside RT inhibitors, tenofovir is almost out there; DAPD is on its way; FTC is probably going to come up for approval. I think there’s a lot happening. I think that’s a huge amount, actually. The integrase program at Merck is moving along, and then we have the whole issue of therapeutic vaccines, which is starting to pick up interest, and people are exploring the use of other interleukins other than IL-2, like IL-12 and IL-15. So I think there’s a lot going on.
AIDS Alert: Does this mean there are reasons for HIV patients to be optimistic about the next decade or so?
Markowitz: My personal feeling, and this has been so from the very beginning, is extremely optimistic. You know, there are always going to be problems along the way, and you can’t save everyone. But I think that, given the progress, patients who do fail therapy will have options. The most important thing, and this needs to be reiterated over and over and over again, is that the reason many people fail therapy is because the drugs are hard to take, and our goal as researchers has to be to make these regimens easier to take. We have to think of ways or strategies so that drug exposure is finite, as opposed to infinite. So I think it’s wrong to blame it on the patients, because I think most people try as hard as they possibly can, but the prospect of taking drugs every single day without missing doses and dealing with lots of side effects is difficult. Drugs have gotten better over the years, and hopefully they will continue to get better.
AIDS Alert: Besides the data presented about tipranavir, were there any other new and promising developments in antiretroviral treatment announced at the Buenos Aires conference that you could briefly discuss?
Markowitz: I hate to say this, but I don’t think the field is in that mode. The field is not in a rapid advancing mode. It’s in more of a reflective mode, and it’s trying to figure out, for example, not if we can keep people alive, but what’s the best way to do it? Should we treat people now? Should we wait a little longer? What are the reasons to wait? What are the reasons to start? What are the risks? What are the benefits? Is hypercholesteremia really going to hurt people? We don’t know. I feel those kinds of issues are really pushing the field now, as opposed to really huge jumps in progress like we made five years ago.
I do think that as far as trying to look at data that’s been presented, it’s pretty clear to me that the underlying message is that simplicity is better than complexity. You don’t necessarily gain more by adding more drugs, and whatever you might gain in potency, you might lose in adherence, and you might also end up with worse resistance rather than better resistance.
It was a very good meeting in Buenos Aires. The talks were excellent, and there were a lot of interesting, good sessions, but in all honesty, I don’t think there was a ton of new things.
AIDS Alert: When might tipranavir make it to market?
Markowitz: We don’t know yet. First of all, there’s clearly an issue with dosing. The dose is not clear yet. It’s a drug that’s gone from one company to another, and they have to tie up some of the loose ends; the major loose end is that it’s not clear what the optimal dose is. Once they have an optimal dose, they can go into phase III studies, and the time from initiating phase III studies to the time of registration can vary from one year to two years to three. I hope this drug gets out there quickly, because people need it.