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How Drug Resistance Develops
Schematic Color Diagrams That Will Help You Explain to Your Patients What Resistance Is, How It Arises, and What Can Be Done to Prevent It

By Molly Cooke, M.D.

June 1998

As Dr. Paul Volberding, the editor-in-chief of HIV Newsline, observes in his editorial in this issue, "The technological and therapeutic advances of recent years have radically altered our approach to treating HIV infection, and they have dramatically altered the outlook for infected individuals." The advent of sensitive HIV RNA assays has enabled us to measure viral activity more directly and more precisely than once was possible -- and this, in turn, has permitted us to individualize therapy to a degree that was heretofore impossible. As importantly, the advent of powerful new antiretroviral agents, particularly the protease inhibitors, has made it possible for us to bring viral replication to a virtual halt in many treated patients.

We don't yet know how durable this effect will prove to be. All of us have patients who have broken through on maximally suppressive therapy. And all of us have patients who have no detectable viral burden, more than two years after they began combination therapy. What we do know is that these potent combinations must be given at optimal doses -- and must be taken exactly as prescribed.

Taking these potent drugs incorrectly can lead to the rapid emergence of high-level resistance. Give a patient a suboptimal dose of any of the protease inhibitors, for example, and you not only fail to suppress viral replication, you actually encourage the selection of drug-resistant viral strains. Give a patient any of these drugs as monotherapy, or add a single drug to a failing regimen, and the effect is the same. Indeed, in all instances the long-term result of prescribing the wrong dose or the wrong regimen is not simply to render a patient's viral isolates resistant to the chosen drug but to promote some degree of resistance to all drugs in that class.

In clinical practice, the great impediment to achieving durable suppression of viral replication is not suboptimal dosing, however, but suboptimal compliance. We now know that missing even a single day of combination therapy can promote the development of resistance, so it is imperative that we identify patients who are likely to have trouble complying with the dosing demands of a complex multidrug regimen. These patients are not good candidates for maximally suppressive therapy, and whenever possible antiretroviral therapy should be deferred until these individuals have developed the motivation they will need to adhere to their assigned dosing schedule.

Alternatively, patients who indicate that they would have trouble complying with the dosing demands and dietary restrictions of protease-inhibitor-containing antiretroviral therapies can be assigned a regimen such as the one used in the INCAS trial, which combined d4T, 3TC, and the NNRTI nevirapine. This combination has several advantages: it permits twice-daily dosing and it imposes no dietary restrictions. This regimen can bring viral replication to a virtual halt, and it has the additional advantage of deferring use of the protease inhibitors until a later date.

In my own clinical practice I have found it helpful to use a series of simple schematic diagrams like the ones below to explain how drug therapy works -- and how drug resistance develops -- to patients who are about to begin antiretroviral therapy. These diagrams help me reinforce the importance of compliance to all patients taking antiretroviral drugs.

I use these diagrams to introduce my patients to the linked concepts of good compliance and good viral suppression. I also use them whenever I suspect that a patient's compliance is faltering, or when I propose a change in regimen. Indeed, I often send patients home with the version of this patient aid that you will find in the Pull Out and Save section of the June issue of AIDS Care. I urge them to post it on the back of a closet door or the door of their medicine chest -- in a spot where it will serve as a daily reminder that the way to prevent drug resistance from developing is to take every dose of every drug every day.

Having explained how drug-resistant viral strains develop, you are now in a position to pose an all-important question to the patient: Are you ready to begin combination therapy? The great advantage that patients and providers have, when they make decisions about HIV therapy, is that time is on their side. Except in cases of acute infection, there is no hurry to begin -- or change -- an antiretroviral therapy. Patients can take the time they need to reach a decision they are comfortable with.

That level of comfort is crucial to compliance -- which, in turn, is crucial to the prevention of drug resistance. Patients who tell you that they have thought the matter through, have considered their options, and are ready to begin suppression therapy are patients who will do well. Patients who have doubts about their ability to comply with the demands of a maximally suppressive regimen are right -- and they should be offered a less suppressive, but also less demanding, alternative.

How to Present the Dilemma of Drug Resistance to Your Patients

A step-by-step explanation that helps identify patients who are likely to have adherence problems -- and that reinforces the importance of complete compliance with antiretroviral therapy

(Click the image to enlarge.)

In an effort to reduce the extraordinary complexities of viral mutation to their simplest form, I tell patients that this column represents all the blood in their body. As they can see, HIV is distributed fairly evenly throughout the circulatory system. Some of these viral particles are relatively weak (W) -- and therefore easily destroyed by antiretroviral drugs. But some of these particles are very strong (S), and their strength enables them to "resist" the onslaught of even the most powerful of these drugs. Indeed, a few of these viral particles are so strong that they cannot be killed by any of the drug combinations we now use to fight HIV.

(Click the image to enlarge.)

When a patient takes every dose of every drug every day, viral replication is suppressed almost completely. This is strong treatment, and the strength of the regimen approximates the strength of the strongest virus -- effectively eliminating all of the weak virus in the patient's body, and eliminating all but a very small number of strong viral particles (S). In fact, highly active antiretroviral therapy may eradicate all of the virus in a patient's blood, leaving only those particles that "hide" from antiretroviral drugs in the brain, lymph tissue, and other so-called sanctuary sites in the body. Patients need to appreciate this distinction -- because it can have an impact on adherence. "Undetectable" does not mean "virus-free," and patients who equate the two may become less vigilant about complying with their dosing schedules.

(Click the image to enlarge.)

Anything short of strict compliance with an assigned antiretroviral regimen leads to incomplete suppression of "strong" viruses -- and to the development of drug-resistant viral strains (R). The result of incomplete suppression is shown in this column, in which the original mix of strong and weak virus is being supplanted by a population of super-strong viruses. Patients need to understand that these new, drug-resistant particles can emerge if they miss even one day's doses of even one of their drugs. Patients also need to understand that once these super-strong particles develop, they will never again be susceptible to the drug combination the patient has been assigned -- even if adherence is henceforth perfect. Moreover, these drug-resistant particles may prove to be resistant to many of the other drugs we use to treat HIV infection. The resistant particles will continue to replicate, and nothing we can currently do will stop them.

(Click the image to enlarge.)

Since poor compliance leads to the emergence of super-strong viral particles that cannot be killed by any known drug combination, the best options are no treatment (Column 1) or full suppression (Column 2). With any of the highly active, protease-inhibitor-containing antiretroviral regimens, anything short of complete compliance leads to the situation seen here: rapid proliferation of drug-resistant viral particles (R).

Molly Cooke, M.D., is Professor of Clinical Medicine at UCSF Medical School, San Francisco, CA.

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