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AIDS Treatment Data Network
(ATDN) Protease Inhibitors

August 1, 1995
Treatment Review; August 1995

Protease inhibitors are a new type of anti-HIV drug. Protease inhibitors are meant to inhibit, or block, a piece of HIV's machinery called protease. When this protease is blocked, HIV makes defective copies of itself. Protease inhibitors are different from nucleoside analogues (AZT, ddC, ddI, d4T, and 3TC) in a number of ways. They are more specific in what they do. Protease inhibitors block infected cells from producing new virus, while drugs like AZT cannot prevent the production of new virus. Because of their specific activity, protease inhibitors most likely do less damage to cells than nucleoside analogues.

Studies have shown that protease inhibitors reduce the amount of HIV virus that is measurable in the blood. In some cases, protease inhibitors have increased T4 cell counts even when they were low. These results have encouraged two drug companies that make protease inhibitors to start long-anticipated treatment programs for people with low T4 cell counts.

Most researchers believe that any protease inhibitor will need to be taken with one or more other drugs such as 3TC (an AZT- like drug expected to be approved by the FDA very shortly) to get the most benefit. It is also believed that protease inhibitor monotherapy - taking one protease inhibitor at a time - won't produce the best results, but no clinical studies are presently testing any protease inhibitor combinations. Testing one protease inhibitor at a time may, however, get at least one or more of them approved more quickly.

Studies have shown that, in some cases, the beneficial effects of protease inhibitors used alone quickly wear off, most likely due to the development of resistance. Resistance occurs because HlV makes billions of copies of itself every day. Each new HIV virus that gets made is slightly different, which means that the protease part of the virus might be slightly different, too. This new kind of protease may not be affected by a drug meant to stop the old kind of protease. Signs of resistance have already been seen in people taking all three of the protease inhibitors that are currently in the final stretch of development. Test tube studies have also shown that newer protease inhibitors like Agouron's AG1343 may not be effective in people who have developed resistance to other protease inhibitors. No one yet agrees on the extent or significance of resistance, but there are different opinions.

Many questions about protease inhibitor are still unanswered. Despite concerns about resistance, this class of drugs could be a promising treatment for HIV- infected people. Combining two or more protease inhibitors, or combining them with other anti-HIV drugs may slow down the development of resistance. Protease inhibitors are still experimental drugs. The more data that is collected from people who are actually taking them alone or in combinations, the more answers we'll be able to provide.