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Invirase

Saquinavir, with trade name Fortovase® is a protease inhibitor used as a component of highly active antiretroviral therapy (HAART). more...

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Saquinavir mesylate is a different formulation, designed to be combined with another protease inhibitor that increases the bioavailability of the saquinavir.

History

Saquinavir was the first protease inhibitor (and sixth antiretroviral) approved by the Food and Drug Administration (FDA). It was approved on December 6, 1995, as Invirase®, a poorly-absorbed hard gel capsule which quickly led to viral resistance in many of the pioneer patients.

It was approved again on Nov 7, 1997 as Fortovase®, a soft gel capsule reformulated for improved bioavailability. The manufacturer, Roche, is alleged to have rushed Invirase® to market, but the conditions that prevailed at the time were very bad and there was a lot of pressure to produce products quickly.

Method of activity

When given alone, the HIV Protease Inhibitor (HPI) saquinavir has a very low oral bioavailability. In the clinic, it was found that the oral bioavailability of saquinavir significantly increases when patients also receive the HPI ritonavir. For patients, this has the major benefit that they can take less saquinavir, while maintaining sufficient saquinavir blood plasma levels to efficiently suppress the replication of HIV.

The mechanism behind this welcome observation was not directly known, but later it was determined that ritonavir inhibits the enzyme Cytochrome P450 3A4. Normally, this enzyme metabolizes saquinavir to an inactive form, but with the ritonavir inhibiting this enzyme, the saquinavir blood plasma levels increased considerably. Additionally, ritonavir also inhibits multidrug transporters, although to a much lower extent.


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Weekend treatment interruptions for certain well-controlled patients: interview with Cal Cohen, M.D
From AIDS Treatment News, 11/1/04 by John S. James

Dr. Cal Cohen is the research director of the Community Research Initiative of New England, teaches at Harvard Medical School in Boston, and is affiliated with Harvard Vanguard Medical Associates. Dr. Cohen spoke with AIDS Treatment News on September 10, 2004. We published part I of the interview in issue #405.

AIDS Treatment News: Explain the short-cycle treatment interruptions being tested at the Community Research Initiative in Boston. Is this still research only, or something people might try?

Dr. Cohen: Over a year ago we decided to study what would happen when patients take antiretrovirals five days a week instead of seven days. The rationale was based partly on data presented four years ago at the Durban conference in South Africa. Doctors Mark Dybul and Tony Fauci were excited by their data on antiretrovirals taken seven days on followed by seven days off, in patients whose virus was very well suppressed when they started. It seemed to work with boosted indinavir; then Dybul tested a cohort of eight people on ddI plus 3TC plus efavirenz, and again had excellent response alternating seven days on and seven days off. Some of my patients wanted to try it because they wanted to have the week without pills, and it seemed to work for them.

But this regimen did not gain wide acceptance, and the field retreated from it after the Paris meeting in the summer of 2003, where we saw that Thai and European researchers tried seven days on and seven days off but found a fair amount of virologic failure. While it worked for some people, it did not work for all who were virologically well suppressed when they started. Clearly there were rules that had to be worked out.

We decided to try a next step. If 7 days off was at least sometimes too long, what other ratios might be more appealing? Since about age 5, all of us have a schedule of five-two in our lives; we went to school five days a week and had weekends off; and usually in the workplace it was five to two as well.

As we started to explore, we found that even as far away as Botswana people have a five-day workweek and a two-day weekend. This ratio seems to be surprisingly common among several human cultures.

And the point of the "short-cycle" (or short periods of time off, versus "long cycle" meaning taking many weeks to months off) interruption was to improve adherence and make treatment easier--to give people a break and also have it be as intuitive as possible for them. And if being off a week was working for some people, then being off two days should work for even more people.

So we decided to test it.

Another reason for doing the research is that some patients were stopping drugs on weekends anyway, and doctors need to know how to advise them.

So we enrolled 10 people who had virologic suppression on Sustiva (efavirenz), ten others taking Viramune (nevirapine), and 10 taking protease inhibitors, to join our study. We are now beyond a year in this study for most of those involved. We presented our 24-week findings at the Bangkok conference in the summer of 2004.

Five-On-Two-Off Study Early Results

Dr. Cohen: What we found depended on the drug regimen the patients were taking. We saw uniform success (at 24 weeks) for the people taking Sustiva; they all had undetectable viral load at that time. We are continuing to follow them and so far we are able to keep going with this research. While there have been rare blips of viral load, we have not seen virologic failure in this group.

With Viramune we had only seven people out to week 24, but those seven also remained suppressed with viral load under 50 copies. While there were occasional blips of viral load, even in rare cases to a few hundred copies, when we kept them on the five-day on two-day off they would re-suppress, at least out to week 24.

The protease inhibitors were a different story. At week 24, of the 10 people, two of them had virologic rebound, one to 1300 copies and the other to 3,000. So following our protocol we put them back on continuous treatment and got resistance testing. The good news is that neither person on the boosted protease inhibitors developed any resistance we could measure to those drugs. They were able to re-suppress on continuous treatment, so they didn't lose any ground.

Why would these drugs differ? One possible explanation is that Sustiva has a long half-life in the body. With two days off, essentially everybody still had enough of the drug in their blood to provide an adequate antiviral effect, even 48 hours alter the last dose. And some of these people were also on tenofovir, which also has a long half-life.

This is very different from the protease inhibitors. Both people who had the virologic failure were on Kaletra and saquinavir (either Invirase or Fortovase). And both these drugs were below detectable levels in the blood after two days off.

The fact that drug level goes down sets the stage for rebound, but does not fully explain it. For Dybul had found that some people could maintain suppression even alter a week off a protease inhibitor. While they were on boosted indinavir, it would be expected to be gone alter two days off. Why could they maintain suppression when they were off effective drug for five more days every two weeks?

A possible answer is the nucleosides. It turned out that both of the people in our study who had rebounded by week 24 were not on effective nucleosides. One person was just on Kaletra and saquinavir with no nucleosides, and the other was on nucleosides but had high-level resistance to them. So it may be that at least some of the nucleosides are essential in maintaining long-term suppression after you stop the medications, in a way that is perhaps beyond half-lives. Maybe these drugs interfere with rebound alter interruption in a way that we don't understand yet. Mark's studies all include nucleosides.

Mark Dybul is now doing a randomized trial in Africa of the five-two schedule, and he mentioned interim results at the Bangkok meeting suggesting that it was working for all but one participant. It looks like many people can be off on weekends on Sustiva-based regimens and maintain suppression.

Does this mean that a five-two regimen is ready for general use in well-suppressed patients, that we know enough to recommend it? No, there might still be people who have viral rebound with as little as two days off: There may be people in whom the virus is less than 50 and not all the way suppressed, but 49 copies and ready to come roaring back. We computed a statistical confidence interval and can be reasonably confident that this works for Sustiva-based regimens, but it might still have virologic failure some percent of the time. We are not ready to recommend it outside of a research framework without more data.

Quality of Life Improvement

Dr. Cohen: Certainly this research needs to be done. We gave people on our study a quality-of-life survey. We asked if five days on and two days off mattered to them, compared to the continuous therapy they had been on. We gave them a scale of zero to 10--10 meaning they strongly prefer five on two off, and five meaning they don't care one way or the other.

Essentially everybody circled 10. There was a strong preference for this schedule. Even thought it was just two days, people liked having their weekends off the medicines. That shouldn't surprise us, as people like having their weekends off in the rest of their lives as well.

So in terms of patient preference, this regimen deserves more study.

And it reduces drug costs by more than 25%. If we had a 25% price decrease for these drugs, people would be amazed at how important that was. Here we have such a decrease for some patients--obviously important for governments and insurers. So we think that interest will be sustained, and hopefully more research will be done.

But it is not clear who will pay for the research. For obvious reasons the pharmaceutical industry has had a very cautious attitude. Though we should acknowledge and complement Boehringer Ingelheim, the only pharmaceutical we could find that was willing to support this research.

ATN: One thing to make clear to people--how suppressed did the volunteers have to be to get into the study in the first place?

CC: Our requirement was very simple. You had to have a viral load undetectable (on an ultrasensitive assay) for at least the past 3 months. And we also required a CD4 count above 200 for three months, in this study. Because of the fragility of people with CD4 below 200, we didn't want to take the risk with them.

ATN: Where can readers find out more?

Dr. Cohen: A poster was presented at the Bangkok conference [1].

Funding: This trial was funded by The Linda Grinberg Foundation for AIDS and Immune Research (currently "Foundation for AIDS and Immune Research," now changing its name), The Campbell Foundation, and Boehringer Ingelheim (which contributed lending for the nevirapine cohort).

References

[1.] Cohen CJ, Morris A, Bazner S and others. The FOTO study: A pilot study of short-cycle treatment interruption, taking antiretroviral medications for five days on, two days off (FOTO), for those with viral load suppression on either PI or EFV-based regimens. XV International AIDS Conference, Bangkok, Thailand, July 11-16, 2004 [abstract #TuPeB4575]. Note: This abstract is available at http://www.iasociety.org/ejias/search.asp? (search for FOTO in the "Abstract title" field (you might have to click the Search button twice), then click the title to get the full abstract).

COPYRIGHT 2004 John S. James
COPYRIGHT 2005 Gale Group

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