Drug Resistance: What It Is, How It Develops and What You Can Do to Prevent It

As Mark Twain once observed, "Everybody talks about the weather, but nobody does anything about it." The same could be said about drug resistance, which everybody is talking about these days. The difference is that you can do something about this force of nature. You may not be able to halt a hurricane in its tracks, but you can apply the brakes to viral replication. And by doing that, you can prevent the emergence of viral strains that "resist" the effect of the antiretroviral drugs you are now taking.

When these drugs are given in the right combinations and at the right doses, they bring viral replication to a virtual halt. The result is a sharp drop in viral load -- often to levels so low that standard tests of viral load cannot detect any particles of HIV in the bloodstream. With that drop in circulating virus comes an increase in CD4 cells -- often to levels that are high enough to protect people with HIV from most of the opportunistic infections that threaten individuals with very low CD4 counts. Thanks to these powerful new antiretroviral agents, particularly the protease inhibitors, it is now possible to apply the brakes to viral replication -- more fully and more effectively than ever before.

What no one knows at this point is how long we can apply the brakes. All of us know people who have "broken through" on the first multidrug antiretroviral regimen they tried. And all of us know people who still have no detectable HIV in their bloodstream after more than two years of combination therapy. What we do know is that these potent antiretroviral combinations must be given in the right combinations and at the right doses -- and must be taken exactly as prescribed.

Taking these potent drugs incorrectly can lead to the rapid emergence of viral strains that are resistant to the antiretroviral drugs you are now taking. We now know, for example, that missing even one day's doses of one of your antiretroviral drugs can promote the development of resistance -- and the more often doses are missed or days are missed, the more rapidly drug-resistant viral strains emerge. HIV is an exceedingly dangerous -- and exceedingly vigilant -- enemy. Drop your defenses for even a day, allow even a tiny breach to open in the barricade you have erected, and HIV will mutate into a shape that enables it to slip through the breach. Once that happens, it is nearly impossible to expel the mutants.

So the best battle plan is one that prevents any mutant strains of HIV from getting through the multidrug barrier that you and your care providers have erected. The schematic color diagrams below show how drug resistance develops -- and they show you the crucial link between good compliance and good viral suppression. Post this page on the back of a closet door, the back of a kitchen cabinet door, or the back of the door of your medicine cabinet -- in a spot where you will see it every day and it will serve as a daily reminder that the way to prevent drug resistance from developing is to take every single dose of every one of your anti-HIV drugs every single day.

Conclusion

Are you ready to begin combination therapy? That depends on many factors, among them your viral load, your CD4 count, and your frame of mind. The great advantage that people with HIV 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. Individuals 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. Because your frame of mind is so important to the success of therapy, it is important that you take your time deciding whether you want to begin highly active therapy or want to switch from one such therapy to another. Carefully think the matter through, consider all of your options, and solicit the opinions of people you trust. When you finally feel that you are ready to begin highly active therapy or change your current therapy, you are ready -- and you will do well. If you find that you have doubts about your ability to comply with the demands of a maximally suppressive regimen, you are almost certainly right -- and you should therefore consult with your care providers about antiretroviral regimens that are less suppressive, but also less demanding.

The Dilemma of Drug Resistance

A step-by-step explanation of what drug resistance is, how it develops, and what you can do to prevent it

Think of this column as a schematic representation of all of the blood in your body. As you can see, HIV is distributed fairly evenly throughout the circulatory system. Some of these viral particles are relatively weak (W) -- and these are 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.

When a person with HIV takes every dose of every drug every day, viral replication is suppressed almost completely. This suppression effectively eliminates all of the weak virus in the patient's body, and it eliminates 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. It is vitally important that you appreciate this distinction -- because it can have an impact on compliance. Having "undetectable" viral levels does not mean that you are "virus-free," and individuals who equate the two may become less vigilant about complying with their dosing schedules.

Anything short of full compliance with one's assigned antiretroviral regimen can lead to incomplete suppression of viral replication -- and to the development of drug-resistant viral strains (R). The result of poor compliance is shown in this column, in which the original mix of strong and weak virus (seen in Column 1) is being replaced by a new type of super-strong, drug-resistant virus. People with HIV 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. Every HIV-positive individual also needs to understand that once these super-strong particles develop, they will never again be susceptible to the particular drug combination that individual is now taking -- even if compliance 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.

Since poor compliance leads to the formation 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, UCSF Medical School, San Francisco, CA.