Protease Inhibitors for HIV Infection

Antiviral therapy directed against human immunodeficiency virus type 1 (HIV-1) is now approaching its 10-year anniversary. The initial clinical trial of zidovudine was completed in September 1986, and, with expedited review, zidovudine was approved by the Food and Drug Administration (FDA) early in 1987 [1]. The ensuing years have seen the introduction of many other nucleoside analogues that inhibit reverse transcriptase, including (in order of their approval by the FDA) didanosine, zalcitabine, stavudine, and lamivudine. All of these drugs inhibit HIV in vitro, all are associated with a decrease in viral RNA concentrations in serum, all are associated with an increase in CD4 cell counts, and four of the five are known to reduce rates of progression to the acquired immunodeficiency syndrome (AIDS) or prolong survival, or both. The principal problems of these drugs are their limited antiviral activity, their toxicity, and their lack of a durable antiviral effect, which is at least partly explained by the development of resistance. The result is what has come to be called a “time-limited benefit,” which has provoked substantial controversy about the relative merits of early and late initiation of treatment.

Early in 1995, investigators from the Aaron Diamond Research Center and the University of Alabama examined the kinetics of HIV replication in patients with CD4 cell counts of less than 500 cells/mm³ [2, 3]. Their work had astonishing results. The replication of HIV produced an average of about 10⁹ new virions daily, the half-life of HIV in serum was about 1 day, 30% of the plasma virus burden was turned over daily, and the rate of destruction of CD4 cells was also about 30%. This was accompanied by high rates of viral mutation, with estimates of more than 10⁸ HIV variants by mid-stage disease. Previous concepts about …