Human Immunodeficiency Virus Protease Inhibitors

Summary Continued surveillance of the acquired immunodeficiency syndrome (AIDS) pandemic has shown that it has now spread to most areas of the world. Recent estimates suggest that more than six million people have already died from human immunodeficiency virus (HIV)-related diseases, and that more than 25 million are currently infected with the virus. The first drugs to be approved for the treatment of AIDS, the nucleoside analogue reverse transcriptase inhibitors, are of limited value in extending life; moreover, many of them have serious, and often dose-limiting, side-effects. The effectiveness of some of these drugs has also been compromised by the fairly rapid emergence of resistant strains of virus. The discovery of an essential virally-encoded protease in the mid-1980s provided the basis for a new class of rationally-designed antiretroviral agents, the protease inhibitors. Three protease inhibitors have already been licensed (saquinavir [Invirase ® , Hoffmann-La Roche, 1995], ritonavir [Norvir™ , Abbott Laboratories, 1996] and indinavir [Crixivan ® , Merck & Co., 1996]), with many more in varying stages of development. Three of the most advanced compounds in clinical development are believed to be nelfinavir (Viracept ™ ) from Agouron (Phase III), VX-478 which is being developed jointly by Vertex and Glaxo Wellcome (Phase II), and KNI-272 from Nippon Mining Co. Ltd. (Phase II). Although treatment with all of these inhibitors as monotherapy has led to improvements in surrogate markers of disease, there is increasing evidence that combination therapy is more effective than any agent used alone, both in reducing viral load and in delaying the emergence of resistant strains of virus, and it is likely that all of the protease inhibitors will find their major application in such combination therapies. As more information about resistance and cross-resistance becomes available, it seems likely that these issues will also be of great importance in choosing drug regimens.