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The Younger Generation

By Ken Fornataro & Richard Jefferys

August 1999

"Simply Medical" presents information on a variety of topics in HIV/AIDS treatment and research. It is published as a service to our readers and is intended for information purposes only. Treatment decisions should always be made in consultation with physicians and other healthcare providers.

The most well-known type of drugs used to treat HIV are protease inhibitors. There are five protease inhibitors approved by the federal government, each with its own strengths and weaknesses. The currently approved protease inhibitors, sometimes referred to as first-generation protease inhibitors, are Crixivan, Norvir, Fortovase, Viracept, and Agenerase.

Although these drugs have been used in combination with other types of anti-HIV drugs for several years now, it's clear that they won't work forever. In fact, some drug combinations don't work well at all for some people. None of the currently approved protease inhibitors or other types of anti-HIV treatments are able to eliminate HIV from the body completely.

Fortunately, a younger generation of protease inhibitors, hoped but not yet proven to be stronger, easier to take, and better at getting rid of HIV throughout the body, is now being looked at in doctors' offices, clinics, and research centers throughout the United States.

Second-generation protease inhibitors will probably be taken once or twice a day. The hope for these new drugs, which behave differently in the body than do their predecessors, is that HIV will have less chance to develop resistance to them and that any resistance that does develop will be different from the resistance caused by the already approved protease inhibitors.

In some cases, these new studies are looking for people who need new treatment options because they are not responding well to already approved treatments -- always one of the main reasons that people consider joining research studies. In other cases, these newly opened treatment studies are looking for people who are treatment naive.

The clinical trials described below have specific eligibility criteria. For example, if you have already taken a protease inhibitor combination, you may not be eligible for some studies, while other studies have gone out of their way to test new drugs in people who have already taken quite a few other HIV drugs.


The Candidates

L-756,423. A new experimental protease inhibitor, L-756,423 is being compared with the already approved protease inhibitor Crixivan. The drug company Merck makes both of these drugs. L-756,423 is believed to stay in the blood longer than Crixivan, so researchers are trying to see if it should be taken once or twice a day. Participants in the study will be divided into four groups, each being given different dosages and combinations of L-756,423, Crixivan, and other HIV drugs.

Tipranavir. For several years the drug company Pharmacia & Upjohn has been studying a new kind of protease inhibitor that is not supposed to have the same resistance mutations as the currently approved ones. Several other companies are developing this kind of protease inhibitor, called non-peptidic- type PIs, as well. It is not yet known if these new drugs are safe and effective, but studies continue.

Pharmacia & Upjohn is actively recruiting participants for a study of one such drug, tipranavir. This study is for people who have used at least two protease inhibitors. Participants must have a CD4 count over fifty and a viral load over 5,000. Previous studies have shown that adding ritonavir increases levels of tripranavir in the body. Therefore, both groups in the study will receive both tipranavir and ritonavir, but in different dosages. In addition, both groups will take one new NRTI and one new NNRTI.

BMS232632. The makers of ddI, Bristol-Myers Squibb, have chosen to use a once-a-day dose of ddI in their study of their new protease inhibitor, currently called BMS232632. The control group in the study takes a combination of ddI, d4T, and the protease inhibitor nelfinavir. The other three groups take ddI once a day, along with the experimental protease inhibitor. Everyone also takes d4T, another Bristol-Myers Squibb drug, twice a day; studies so far have shown that d4T can-not be taken once a day.

Although little is known about how the new protease inhibitor will work, it is useful that Bristol is testing an unapproved dose of an already approved drug. Many doctors are already prescribing once-a-day ddI. Assuming that the study enrolls enough people to provide a solid basis for comparison, this study could add to our understanding of the drug ddI. The ddI used in this study, however, is not the new encapsulated version.

ABT-378(r). One of the promising second-generation protease inhibitors currently being developed is Abbott Laboratories' ABT-378(r). In clinical trials conducted so far, the drug had a very strong anti-HIV effect. The majority of people who took the drug reduced their HIV viral levels to undetectable in a matter of weeks and experienced increases in their T4 cell counts. It is hoped that ABT-378(r) will be effective against strains of HIV that are resistant to other protease inhibitors, although the HIV virus of the people in the studies has, in some cases, show signs of mutations that could lead to resistance.

Clinical trials have opened for people who have never taken any HIV treatments before, as well as for people who have. Both studies have highly restrictive eligibility criteria. Unfortunately, none of the currently enrolling clinical trials for ABT-378(r) allow people who have already taken an NNRTI type, such as Sustiva or Viramune, to join. There is no expanded Access program for the drug at this time.

Abbott plans to continue to develop the drug as a combination of ABT-378 and a small amount of their other protease inhibitor Norvir (ritonavir). The ritonavir is added because it greatly increases the amount of ABT-378 that gets into the body. It appears that using a small dose of the already approved PI ritonavir greatly increases the levels of ABT-378 in the body. This may allow the drug to overpower PI-resistant strains of HIV.

One study, AD-378, is for people who have had experience with at least two protease inhibitor combinations for at least twelve weeks apiece. Everyone in this study must have taken at least two protease inhibitors in the past. There is also another study for people with single protease experience, M98-888. You cannot ever have taken Sustiva, Viramune, or Rescriptor.


Some Tips

A note of caution to people considering switching their current treatment: There are many "switching studies" that are closely looking at the effects of this treatment strategy. In most cases, however, you will not be eligible for a study if you have already switched to another class of drugs, even for a short time. Ask your doctor if a clinical trial would be a good idea if you were about to switch drugs. You would be making a very valuable contribution to everyone's knowledge of HIV treatment.

There is also another thing to keep in mind. Many studies require that you have never taken certain types of drugs before. But there is a little-recognized exception that might be of great benefit. Some studies are looking for people who are treatment naive, although the definition of naive doesn't always mean that you can never have taken the drug. In many studies, for example, it is all right if you have taken a protease inhibitor for less than two weeks or ten days. If you tried taking a protease inhibitor for a week, then stopped because you couldn't tolerate it, many studies will still consider you naive. This is often true regarding NRTI-type drugs such as ddI or d4T. In some cases, you are still considered eligible for a study if you have taken one or more of these drugs for less than four weeks.

People who have never participated in a research study, or who would like to know more about the process of testing HIV treatments, can request a free copy of The Network's handbook, Should I Join an AIDS Drug Trial?. This handbook includes important questions you should know the answers to before you agree to participate in any clinical trial. The Summer 1999 edition of The Experimental Treatment Guide is also available free of charge to people interested in knowing about the many different drugs and types of studies they may be interested in.

Ken Fornataro is Program Director of the New York City Case Management Program and Richard Jefferys is the Access Project Director at the AIDS Treatment Data Network. For more information, call (800) 734-7104. Affiliation is provided for purposes of identification, not representation.


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