Protease Inhibitors: Patient Education Critical

It is widely agreed that successful use of the new protease inhibitors -- especially indinavir (Crixivan(R)) from Merck & Co., and ritonavir (Norvir(TM)) from Abbott Laboratories -- will depend on effective patient education. This education is not yet in place; for example, some important materials are not ready yet, and some are ready but not being distributed successfully.

One major concern is drug safety, especially drug interactions with Abbott's ritonavir. Many drugs must not be taken together with ritonavir, because ritonavir prevents those drugs from being metabolized by the body, resulting in a large overdose (not of ritonavir, but of the other drug). Abbott has prepared a card for patients to carry, listing some of the most important drugs to avoid; unfortunately this card has not yet been distributed with many of the prescriptions dispensed so far. Therefore, we are reproducing it below, with permission [not reproduced online]. But be sure to check with your doctor, because this list is not complete, and it will probably change as new interaction problems are discovered. (Merck's indinavir seems to cause much less problem with drug interactions and with side effects, although there are some of each.) And the different protease inhibitors MUST NOT be combined until clinical trials have shown whether, and how, this might be done safely.

The other major concern, with both Merck's indinavir and Abbott's ritonavir, is that the drugs must be used properly, or viral resistance will develop rapidly -- and once resistance develops to either of these drugs, then both are likely to be much less useful (if useful at all) for that patient, at any time in the future. (With the only other protease inhibitor which is now approved -- saquinavir (Invirase(TM)) from Hoffmann-La Roche -- resistance seems to develop more slowly, so the problem is not so critical.) Because of the resistance problem, past practices such as casual dose reductions, "drug holidays," or general laxity in following instructions, must now be changed with the Merck and Abbott drugs. Compliance with instructions on prescription drugs is always a problem, and there is much concern that patients may not comply closely enough to use these new drugs effectively.

Also, resistance can be minimized and patients can get maximum benefit from these drugs if they are used in combination with other approved antiretrovirals; this keeps the overall level of viral replication at a minimum, and reduces the chance that a mutant virus will be resistant to all the drugs. One combination of interest is indinavir plus AZT plus 3TC. But combinations are likely to work best when all of the drugs are new to the patient, so that the virus has never seen any of them before. Since many patients have already taken AZT for a long time, and may have virus resistant to it, other combinations might be better for them. Research is urgently needed to learn more about which combinations are best for which patients.

For these reasons we believe that if people are doing fairly well and can afford to wait, they should consider waiting before starting protease inhibitors. In the next few months, more will be learned about longer-term safety, and how to use these drugs most effectively. Since most or all HIV drugs are likely to work best the first time they are started (due to the absence of resistant virus), it may be worth waiting in order to get the maximum benefit out of one's first exposure to these drugs.

But many people cannot afford to wait. If you do plan to start using Merck's indinavir within the next few months, while supplies are limited, you may want to start as soon as possible, in order to have the best chance of obtaining this drug -- see article below. (There seems to be no supply problem with Abbott's ritonavir, however, and therefore no occasion to hurry to get in line for it.)