THERE'S MORE TO LIFE THAN JUST AZT: AN INTRODUCTION TO PROTEASE INHIBITORS

What is a Protease Inhibitor?
Protease (Pro-tee-ace) inhibitors are a new group of drugs. They fight HIV directly. Some are approved and some are still experimental. Believe it or not, there are about 20 different kinds of protease inhibitors. They have different strengths. Some are close to approval. Others are just getting studied.

How do you do the things you do?
In order for HIV to cause damage, it needs to reproduce over and over. This takes many steps. The enzyme protease is one important step. HIV needs this enzyme so that it can make copies of itself. These drugs stop the protease enzyme.

Are these drugs like AZT?
No. AZT, ddI, ddC, d4T and 3TC are a different family of drugs. They are called nucleoside analogues. They work against HIV by trying to stop a different enzyme - one called reverse transcriptase. AZT-like drugs work well in some people, but not in everyone.

Why not?
First, these drugs are not specific. They may attack lots of white blood cells, even ones that don't have HIV in them. Second, these drugs can cause serious side effects. Third, they stop working in most people after 6-12 months.

What else?
AZT-like drugs are not as strong against HIV as some of the protease drugs. Also, they only protect white blood cells that are not infected. They do not fight the HIV that is already in a cell. Protease inhibitors can enter infected cells and stop HIV from reproducing.

So far, protease inhibitors seem much safer than AZT and the other nucleoside analogues. They are so specific that they don't hurt your bone marrow, or other white blood cells, but there is no data on long-term safety.

Are there any problems with protease inhibitors?
Yes. One of the big problems with protease inhibitors is the same problem I forgot to tell you about with nucleoside analogues. With all drugs that fight HIV, like AZT or 3TC or protease inhibitors, resistance can be a big problem. Resistance happens when HIV learns to keep growing in spite of a drug. When HIV is resistant to a drug, that drug can no longer fight HIV.

Resistance is a big problem with these drugs. For example, if your HIV learns to get around AZT, you can (if you want), switch to ddI. This is probably not true with protease inhibitors. Taking one protease drug might change the HIV in your body so that no other protease will work for you. This is called cross resistance. Unfortunately, it seems that all the protease inhibitors can cause cross resistance, although it might not happen on an individual basis.

Can resistance be stopped?
The HIV virus is very smart and can learn to resist a lot of drugs. However, we hope that combining drugs (taking more than one anti-HIV drug at a time) will confuse HIV. When drugs are combined, HIV has a harder time learning to get around the drugs. And if a combination doesn't stop resistance, it might slow it down.

Some doctors feel that protease drugs should be taken with other anti-HIV drugs like AZT and 3TC to slow down resistance. We have no idea right now if this will work. Hopefully, trials studying this combination will let us know.

Are there any side effects from taking protease inhibitors?
Like so many things that appear to help us fight HIV, there are side effects with protease inhibitors.

First, you will have to take a lot of these drugs for them to work. The body can't absorb protease very well. Taking a high amount of any drug can often mean trouble for your liver, kidneys, and stomach. The more drug you have to take, the harder your liver needs to work to break it down, causing problems.

Second, there are many drugs you will not be able to use depending on which protease inhibitor you decide to take. These include rifampin, rifabutin, Prozac, and Seldane. Side effects reported are headaches, short term diarrhea, upset stomach, and some rashes, more rarely kidney stones and blood pressure problems.

Okay, so which protease inhibitors should I keep my eyes on?
There are three protease drugs that are approved. We still do not know if taking these drugs will keep you from getting sick in the long run.

Invirase (saquinavir) is sold by Hoffman-LaRoche. This drug is the weakest, working only with other antivirals like AZT on a good day. But it causes weaker cross resistance than Norvir or Crixivan.

Norvir (ritonavir) is made by Abbott. It is absorbed more easily. It appears to be very strong and was approved in February by the FDA for people with 'Advanced HIV Disease. It will continue to be in trials with different combinations of nucleosides and protease inhibitors.

Crixivan (indinavir) is made by Merck. This is also a very strong drug. It was also approved in February by the FDA, has fewer side effects and may have longer lasting antiviral effect than ritonavir.

To learn more about open protease trials, call the AIDS Treatment Data Network: 1-800-734-7104. You can also call the NIH AIDS/HIV trials hotline: 1-800-TRIALS-A, and of course, us.

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last modified: 5/12/96