News Update on Protease Inhibitors

Some of the most exciting news from the 3rd Conference on Retroviruses and Opportunistic Infection involved the new protease inhibitors. It was standing-room-only at the oral presentations, and you even had to wait your turn to read the posters. Once the fuss over Magic Johnson had subsided, even the press caught on, and for once, so did their enthusiasm.

Preliminary data from an ongoing study of combination therapy using indinavir (Crixivan, Merck) were presented by R. Gulick from New York University. Ninety-seven patients with at least six months of prior AZT therapy, CD4 counts between 50 and 400, and plasma RNA>20,000 copies/ml (median 40,000 copies/ml) were randomized to receive indinavir monotherapy (800 mg tid), AZT/3TC, or the combination of AZT, 3TC, and indinavir. Patients randomized to receive AZT/3TC had mean reduction in viral load of 1.4, which had decreased to 0.6 by 24 weeks. In contrast, those on indinavir monotherapy had a 1.6 log reduction in plasma RNA (1.3 at 24 weeks), and those on the triple combinations regimen had a greater than 2 log reduction, which was sustained at 24 weeks. of these, over 85% had a reduction in viral load below the limit of detection by the Roche Assay (500 copies/ml), compared to 40% and 20% in the indinavir and AZT/3TC arms, respectively. Participants in the two indinavir containing arms had CD4 cell count increases of approximately 100 cells/mm ³, compared to 30 to 40 in the AZT/3TC arm.

Results of a phase II study of indinavir monotherapy versus AZT/ddI versus the combination of all three drugs were also presented. The study was conducted in 79 antiretroviral therapy-naive patients with CD4 cell counts < 500, and plasma RNA > 20,000 copies/ml (mean 102,000 copies/ml). Patients taking triple drug therapy had a maximum 2.9 log decrease in plasma RNA, which was sustained at approximately 2.5 logs throughout the 24 weeks study. Only 20% of the patients randomized to the AZT/ddI arm had a 2 log decline. 59% of the patients on triple therapy had plasma RNA below the limit of detection (200 copies/ml in this study) at some point during the trial, compared with 10 to 20 percent in the other arms.

The most common adverse event associated with indinavir is indirect hyperbilirubinemia, which does not appear to be clinically significant. Nephrolithiasis, although less common, is also associated with indinavir therapy, and patients taking the drug should take precautions to maintain adequate hydration.

J. Leonard from Abbott Laboratories presented results from a study in which ritonavir (Norvir, Abbott) 600 mg bid or placebo was added to existing antiretroviral therapy. Participants had CD4 counts < 100 cells/mm ³ (median 20) and must have had greater than 9 months of prior antiretroviral therapy with approved agents. although current therapy was not a requirement of the study. Viral loads were > 15,000 copies/ml by the Roche assay (mean approximately 200,000 copies). Over 1000 patients participated in this study, which demonstrated significant differences in clinical endpoints as early as 10 days. There was a 58% reduction in AIDS-indicator conditions or death with ritonavir compared tot placebo (16% versus 33%), with a relative risk of 0.435 (p<.001). There were 26 deaths (4.8%) among ritonavir recipients versus 46 (8.4%) in those on placebo (p=0.021). Viral load measurements were available in a subset of 168 patients. There was a maximum decrease of 1.3 logs in the ritonavir group, which peaked at 2 weeks, and returned to 0.6 logs at 16 weeks. (There was no change in patients on placebo.) Both CD4 and CD8 cell counts increased in patients taking ritonavir, with an increase of 40 and 200-300 cells/ ³, respectively. In contrast, CD4 cell counts did not change in placebo recipients, and CD8 cell counts declined by 50 cells.

There was little discussion of saquinavir (Invirase, Roche) at the Washington meetings. Although the drug has been approved by the FDA, enthusiasm has been tempered by its poor bioavailability, which results in lower efficacy compared to other protease inhibitors. However, there is evidence that bioavailability and efficacy can be improved by giving it in combination with ritonavir, and further clinical studies using this combination are planned.

The FDA has just approved both ritonavir and indinavir the beginning of March, so these powerful new agents will now be part of our armamentarioum. They will be most appropriately used in combination with nucleoside analogs, since resistance develops more rapidly with monotherapy. A number of questions, however, remain unanswered. What is the best nucleoside or nucleosides to use with these agents? At what CD4 count or plasm RNA level should therapy be initiated or changed? how will cross-resistance between protease inhibitors affect later therapy? And perhaps more importantly, how will we pay for double and triple-drug combinations containing these expensive new agents? The enthusiasm and renewed optimism generated by the development of the protease inhibitors is certainly justified, but we will need to continue to learn about them as we use them to treat our patients.