Starting last November, Merck recruited 635 volunteers without prior treatment to compare AZT/3TC plus either twice-daily or thrice-daily indinavir. For the 87 participants now out to 24 weeks, the picture is different than the first time around. Ninety-one percent on the standard regimen had viral loads under 400 compared to only 64% on the twice-daily regimen.
The pilot study results were received with skepticism because their preliminary nature said little about the durability of the response to indinavir twice a day. Many experts could not believe that this new dosing schedule would be as good as the old one. It seemed obvious that the trough blood levels of indinavir, reached at the six-hour point between doses, would be much lower than with the every eight hour, thrice-daily schedule. This would give HIV a window of opportunity to reproduce and evolve into drug-resistant strains.
While canceling the trials of twice-daily indinavir, Merck is continuing to test twice-daily indinavir combined with either ritonavir or nelfinavir. Both of these protease inhibitors have the side effect of reducing indinavir's breakdown by the liver. The result is to make indinavir more stable in the body and give a twice-daily schedule a better rationale.