Saquinavir (Roche Protease Inhibitor) At Higher Doses

Saquinavir, a protease inhibitor developed by Hoffmann-La Roche, is currently in large-scale clinical trials at a dose of 1800 mg per day (600 mg three times a day). [Recently a new formulation of the same drug has been developed to increase the low bioavailability of saquinavir (the low absorption into the bloodstream after the drug is taken orally); see the notice about the new saquinavir trial in this issue of AIDS TREATMENT NEWS]. Meanwhile, a small (40-patient) study at Stanford University has tested higher doses of the original formulation, with intensive patient monitoring, to make sure that higher blood levels are safe, and do increase antiviral activity. Results of that study, which compared doses of 3600 and 7200 per day (twice and four times the dose used in other trials), were reported in the late-breaker session at ICAAC.

Twenty patients with CD4 counts from 200 to 500 were given each of the doses. This trial lasted for 24 weeks.

Both doses significantly decreased viral load and increased CD4 count. But the high dose resulted in greater and more sustained responses.

This study also looked for two mutations in the virus which are critical in the development of resistance to this drug -- mutations at positions 48 and 90 of the HIV protease gene. These mutations developed more slowly in the high-dose arm, with four out of 19 patients having one of them when the study ended on week 24, compared to 9 patients out of 20 having a mutation with the low dose. No patient developed both mutations.

Some adverse effects were found, somewhat more at the higher dose; all resolved when the drug was discontinued. Only one patient, at the high dose, chose to discontinue the study, due to transient diarrhea and confusion. Three others (also on the higher dose) needed a brief drug holiday due to abnormalities in various blood tests (one for modest elevation of liver-function tests, one for increased CPK, and one for neutropenia); but these three were able to re-start and continue drug at the full dose. There were also some milder side effects, mostly at the high dose, but most patients finished the study without dose modification.

The low-dose group had a maximum average CD4 increase of 72 at week 4; this increase declined and was only 31 at week 24. In the high-dose group, the CD4 count continued to rise until it reached an average increase of 121 at week 20; it was still 82 above baseline at week 24. The high-dose group had a maximum viral-load drop of 1.34 logs (22-fold), vs. 1.06 logs (11-fold) maximum drop for the low dose. At week 24, the high-dose group had an average reduction of 0.85 logs (7-fold) vs. 0.48 logs (3-fold) at week 24.

Some patients were also tested for the amount of drug in their blood (using the AUC, or area under the curve, measurement of blood levels). There was a clear relationship between higher AUC and greater drop in the viral load, with the higher dose clearly showing the greater drug levels. But there was considerable patient-to-patient variation in AUC within each dose level.