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.
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.
This article was provided by Johns Hopkins AIDS Service. It is a part of the publication Moore News for Care Providers.