The Bar Area Reporter - March 19, 1996
Martin Delaney, Project Inform

The most recent news reports have raised an unprecedented flurry of excitement about the new generation of antiviral drugs known as protease inhibitors. Much of the excitement is warranted since the results being reported, although still preliminary, are easily the best ever seen in the treatment of HIV infection. Data from studies of the Abbott protease inhibitor ritonavir (Norvir(r)) demonstrated a 46% reduction in the death rate over 5 months in people with advanced disease and a similar reduction in the rate of new opportunistic infections. Studies of the Merck drug indinavir (Crixivan(r)) showed that when that drug was used as part of a 3-drug combination along with AZT and 3TC, 90% of the people in a modest-sized small study saw their levels of virus reduced below the level of detectability, an effect that has now been sustained for 32 weeks (and holding).

Perhaps the most striking aspect of this study was not just the depth of the effect, but its uniformity. Despite the fact that the majority of people in the study were proven resistant to AZT, the combination clearly worked, and in nearly everyone. While the drugs are not without side effects (no drug is), they neatly avoid most of the problems common to older drugs. The Roche (saquinavir) and Abbott (ritonavir) drugs are already in the pharmacies. Due to a potential supply shortage, the Merck drug (indinavir) will be sold only through a single mail-order pharmacy (Statlanders) for the next five months.

A Sobering Conclusion

Yet not all is perfect in this new era of treatment, and there is a real danger that much of this potential might not be realized. A careful look at the data, along with accumulating knowledge about protease resistance (and multi-drug cross-resistance) leads to a sobering conclusion. However potent, these drugs will have to be used with great care and deliberation. If not, the benefit will be short-lived. Resistance can develop rapidly to these drugs if they are used alone, or if they are used too casually.

Resistance is also hastened when dosing is inconsistent, whether by taking less than the full recommended dose, skipping an occasional dose, or perhaps even by poor timing of doses.

In every way, therapy for HIV disease is coming to make the same demands as therapy for tuberculosis. In combating TB, physicians wouldn't dream of letting people use single drug regimens, and they are adamant about the need for stable, consistent dosing of the whole combination of drugs prescribed. This is required in TB for the same reason it is required in HIV: because the infectious organism mutates rapidly, making it possibly to overcome the effect of therapy.

To make matters worse in HIV disease, it is now evident that a number of protease inhibitors share the same patterns of viral resistance. In other words, if you become resistant to Merck's indinavir, you can also write off Abbott's ritonavir or vice-versa (and the upcoming Agouron nelfinavir as well).

Resistance to Roche's saquinavir doesn't automatically result in resistance to the others, but at least takes a step or two in that direction. In short, people may only have one chance with the protease drugs, so they better get it right. Once resistance sets in, there is no alternative waiting in the wings. And that protease-resistant virus could then be readily passed on sexually to someone else.

It's critical that physicians and patients get a stiff education in the way to treat a rapidly mutating organism. Many of the practices routinely employed in the treatment of HIV disease in the past are dead wrong and must be corrected if people are to have any hope of long-term benefit from protease inhibitors. People might even be better off not using them at all if they cannot commit to using them properly. "Improper use" includes such old habits as:

reducing doses to combat side effects (it's wiser to stop the drug altogether; they should never be used at reduced doses);

"tapering up" the dose (starting at a very low dose and gradually increasing it in an effort to improve tolerance: with protease, this will virtually guarantee rapid onset of resistance);

simply adding protease to whatever else a person is doing, without regard for a strategy to combat resistance; and

sloppy dosing (skipping a dose now and then, not paying attention to the timing between doses; all of these will hasten resistance)

It's very likely that greater attention to these issues would have produced better results even from the older generation of drugs.

A Word of Caution

For some people, the availability of the new drugs will be godsend. We have already seen many people over the last year or so go on to have truly remarkable and lasting responses to these drugs. But we have also seen people whose benefit was short-lived. For those who have no other choices, immediate use of the new drugs is an obvious and easy call. For many others, perhaps people who are stable and have low viral loads, a slight word of caution might be appropriate.

Yes, the drugs are a big improvement, but that doesn't mean everyone should jump on them immediately. By waiting a little longer, it may be possible to use the drugs in the best possible combinations, securing the largest and longest-lasting benefits. A mindless stampede to the protease camp, without use of carefully thought-out medical strategies, could instead lead to the waste of a greatest opportunity.

People have a choice here: move wisely and work with your doctor to establish a careful strategy for using the protease, and in turn get the potential for a large and long-lasting benefit. The alternative is simply to jump in hastily and get a short-term benefit that will quickly be followed by the development of multi-drug cross-resistance to the whole new generation of therapies.

On paper, at least, it's an easy choice to make. Time will tell.

More information about how to best use the new generation of drugs is available in writing or on the Hotline from Project Inform.

Pull-Quote:

In short, people may only have one chance with the protease drugs, so they better get it right.
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