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Editorial
Enthusiasm Tempered by Caution
What Experience Has Taught Us About Protease Inhibitors, Protease Resistance, and Protease Sequencing

By Paul A. Volberding, M.D.

June 1997

Each passing month brings further confirmation of the clinical utility of the protease inhibitors. In patients who respond to combination therapy that includes a protease inhibitor, we see significant -- and sustained -- reductions in viral load, and this near-total suppression of viral activity leads to manifest clinical improvement in these patients.

In is now clear that successful combination therapy depends on two interrelated factors: a high degree of compliance on the part of the patient, and a high degree of suppression on the part of the regimen. Whenever suppression of viral replication begins to falter, either because the patient is only fitfully compliant with therapy or because the virus has begun to develop resistance to one or more of the drugs the patient is taking, the clinician must intervene -- before high-level resistance renders therapy ineffective.

In their article on the problem of protease resistance, Drs. Steven G. Deeks and James O. Kahn analyze this diagnostic dilemma and conclude that certain protease inhibitors may make a better choice for initial antiretroviral therapy (see "The Problem of Protease Resistance"). The resistance data these authors present suggest that all of the currently available combination therapies will eventually fail. With that inevitability in mind, clinicians should think in terms of successive antiretroviral regimens, rather than a single, once-and-for-all antiretroviral combination.

Clinicians should plan, from the outset, that patients will require an initial drug regimen, a back-up regimen that can be substituted when resistance develops to the first-line therapy, and quite possibly some form of salvage therapy. That back-up regimen might well include one of the investigational drugs discussed by Dr. Harold A. Kessler in "The Next Generation of Antiretroviral Agents." Although several of these compounds hold considerable clinical promise, all of them will require a high level of compliance on the part of patients, lest resistance develop to these drugs as well.

As Dr. Margaret A. Chesney observes in "Compliance: How You Can Help," this is the clinical conundrum of current antiretroviral therapy: When taken conscientiously, regimens that include a protease inhibitor suppress viral burden to undetectably low levels and stimulate a rebound in CD4 cells. But when compliance with these multidrug therapies is less than optimal, fluctuating serum drug levels can actually promote the development of drug resistance -- thereby restricting the clinician's therapeutic options and reducing the patient's chances of remaining clinically stable.

Given the effort that so many of our patients on these regimens must expend, day in and day out, week in and week out, to remain compliant with their assigned therapy, we are under a particular obligation to assist them in every way we can. Clinicians can promote compliance with antiretroviral regimens -- by devising dosing schedules that can be integrated into patients' daily routines, by encouraging compliance in every encounter with every patient, and by providing patients with tools that will help them achieve and maintain a high level of compliance. To assist practitioners in this crucial task, we have provided a number of helpful suggestions in the PULL OUT AND SAVE feature in this issue.

Paul A. Volberding, M.D., is Editor-in-Chief of HIV Newsline and AIDS Program Director at San Francisco General Hospital.


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