Important note: Information in this article was accurate in 1996. The state of the art may have changed since the publication date.
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GMHC Treatment Issues; September 1, 1996
Dave Gilden
A major issue that remains unresolved with both delavirdine and nevirapine is how these drugs affect the body's metabolism of protease inhibitors. Like the protease inhibitor ritonavir, both NNRTIs affect the CYP3A enzyme system in the liver that breaks down many drugs. Nevirapine seems to increase destruction of protease inhibitors whereas delavirdine (and ritonavir) inhibits this loss. The result of these hepatic changes on protease inhibitor blood levels or efficacy has been little explored up to now.
Drug combinations that include both an NNRTI and a protease inhibitor appeal to many people with HIV. First are those who want to suppress HIV as much as possible early in disease through a four drug combination that also includes two nucleoside analogs. Then there are persons with advanced infection who have had long histories with nucleoside analogs. Their HIV may be largely resistant to these older agents.
As part of the run-up to the FDA meeting and to partially satisfy intense public interest, Pharmacia & Upjohn has released the preliminary results of its tests on combining delavirdine with the three marketed protease inhibitors. These initial data all come from tests with 13 or 14 HIV-negative volunteers and are hardly enough to make final recommendations.
* For saquinavir (600 mg three times daily) plus delavirdine (400 mg three times daily), there was a slight reduction in delavirdine's mean trough plasma concentration (minimum level between doses) while the mean tough levels of saquinavir increased almost six-fold. Raising saquinavir levels to this extent will make it a more potent drug, but the effect of delavirdine varied greatly from person to person. Furthermore, 13% of the volunteers experienced a rise in blood levels of ALT, a liver enzyme whose blood levels go up when the liver is inflamed. Doctors should monitor such levels in patients taking delavirdine and saquinavir.
* Ritonavir was tested at 300 mg twice daily (half the standard dose) along with delavirdine at 400 mg three times a day. Ritonavir was unaffected, but a slight lowering of delavirdine levels was seen. Full-dose ritonavir has yet to be studied. In the meantime, Pharmacia & Upjohn is advising "caution" when combining these two liver enzyme inhibitors.
* Indinavir so far has been tested as a single 400 mg or 600 mg dose given to volunteers receiving 400 mg of delavirdine three times a day. Delavirdine appeared to double the effective dose of indinavir -- so that 400 mg of indinavir resulted in the plasma levels usually found after 800 mg is given. Based on this sketchy information, Pharmacia & Upjohn is suggesting reducing the standard indinavir regimen of 800 mg three times daily to 400 or 600 mg three times daily when delavirdine is coadministered. Beware that raising indinavir blood levels heightens the risk of kidney stones.
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