Press room ... 1998 archive

Indinavir (Crixivan) Alert!

November 21, 1998

San Francisco, CA—New information from the study of indinavir (Crixivan) used in twice daily dosing has yielded important information. The information is not encouraging. The new findings are contrary to a previous, smaller study which suggested that twice daily dosing was at least equivalent to the standard 3-times daily dosing. That study, however, was quite small and ran only for about 24 weeks. A larger study, called Merck 069, was initiated to confirm these early results.

Today, Merck Pharmaceuticals announced that it was stopping the arm of study which employed twice daily dosing because a strong trend had developed showing this arm to be inferior to the results observed among those receiving the standard thrice daily dosing regimen. The study was made up of people who had never previously taken a protease inhibitor and never previously taken 3TC (lamivudine, Epivir). The regimen being studied in the Merck 069 study included AZT (zidovudine, Retrovir), 3TC and indinavir.

In the data summary listed below, the number of volunteers differs at week 16 and week 24 because this is an interim report and looks only at the people who have reached the 24 week endpoint.

Study arm % below 400 copies RNA
@ 16 weeks (287 patients) % below 400 copies RNA
@ 24 weeks (87 patients)
3 times daily 78% 91%
Twice daily 72% 64%

Based on these findings, the company is encouraging everyone using twice daily dosing to switch back to 3-times daily.

While this is discouraging, it’s hard to interpret. Data from other studies of protease inhibitors which included similar populations with similar treatment histories have produced results no better than the twice-daily dosing regimen being rejected here (notably some saquinavir studies and some nelfinavir studies). Merck spokespeople make the point that they are essentially competing with themselves in a study like this, and that the standard 3-times daily indinavir regimen is hard to beat. In any case, it’s important that health care providers and people living with HIV are aware of the superiority of the 3-times daily dosing of indinavir, as many doctors and patients have already made the switch to twice daily dosing. Having said that, it’s still unclear whether a patient who simply can’t adhere to a 3-times daily dosing is better off to continue struggling with that regimen (and possibly failing to adhere) or to commit to twice daily and really stick to it.

One additional regimen under study which might still permit twice daily indinavir dosing is the combination of ritonavir and indinavir. Preliminary, short-term studies of this regimen appear to make indinavir quite suitable for twice daily dosing, while also eliminating the requirement that the drug not be taken with food. However, it’s important to recognize that this is based on early data, covering a short period, in two small clinical trials.

It’s possible that more people than ever are currently employing the indinavir twice-daily dosing regimen as news from the previous smaller study, which suggested equivalence of the 2- and 3-times daily dosing schedules proceeded the announcement of a shortage in supply of another protease inhibitor, ritonavir (Norvir ) capsules. When the supply problem was announced, it’s likely that some people began re-thinking their anti-HIV regimens and may have been making changes in their regimens, possibly to an easier-to-use regimen employing indinavir twice daily dosing.

The lesson learned here is something that Project Inform has been cautioning about for some time with regard to simpler and easier regimens using the currently available therapies. When these drugs were approved, the reason they were dosed according to schedules in their label instructions (e.g. three times daily) is because studies demonstrated that these schedules were necessary in order to maintain optimal blood levels of drugs. While certainly people want, need and deserve simpler regimens, simply changing a regimen from three-times to twice daily dosing is not the solution.