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Putting an End to the Guesswork
Assays That Measure the Susceptibility of a Particular Viral Isolate to Particular Antiretroviral Agents Help Clinicians Devise Successful Successor Regimens for Patients Who Are Failing Therapy

By William G. Powderly, M.D., Editor-in-Chief

February 2001

On December 10, 1981, three interrelated articles appeared in The New England Journal of Medicine. These articles reported cluster outbreaks, in New York City and Los Angeles, of pneumocystis pneumonia, mucosal candidiasis, and chronic ulcerative perianal herpes-simplex lesions. What all three outbreaks had in common was that they occurred in previously healthy male homosexuals, and that in all cases the patients displayed evidence of profound cellular immunodeficiency. Moreover, this immune deficiency was not inherited; it had somehow been acquired.

No one could possibly have guessed, twenty years ago, that these intriguing but anomalous clinical cases were the first widely reported manifestations of a viral pandemic that would metastasize until it had enveloped the globe, condemned tens of millions of men, women, and children to agonizingly slow, premature death, and taken its place among the greatest plagues in all of human history.

This insidious and elusive new pathogen, which seemed to eradicate the body's immune system from within, baffled the best minds in the scientific community and unnerved all those who attempted to treat it. Here were patients with infections so reportably rare that most of us knew about them only from textbooks. And here was an underlying disease process that was unresponsive to any of the potent therapies in the modern clinician's armamentarium.

For the bleak first years of the HIV epidemic, we did not even know what was consuming the immune systems of our patients. And for an inexcusably long time after the causative agent was identified, legal wrangling over patent rights prevented us from being able to test, and treat, infected individuals. Not until fifteen long years after the first cases of acquired immunodeficiency syndrome were reported did we discover how to combine classes of antiretroviral agents in ways that would suppress viral replication -- and even this partial victory proved pyrrhic. Not all patients responded to these potent new regimens, not all patients whose viremia was reduced by these regimens achieved a durable response, and all patients experienced toxic side effects of therapy.

It took a long time to figure out how we could achieve near-total suppression of viral replication in patients who did respond to therapy . . . and it took even longer to figure out what was actually happening, at the cellular level, in these patients. For the first decade of the HIV pandemic, most clinicians were obliged to depend on serial CD4 counts to gauge disease progression in their patients. These measurements told us what had happened, not what was happening, in these patients. It was only with the advent of the HIV RNA assay, in 1995, that we finally had a clinical tool that could measure a patient's viral burden in what was, in effect, real time.

The problem was, of course, that these measurements told us only part of the story. All of us have patients who have never achieved maximal suppression of viral replication, patients whose viral load consistently measures between, say, 4,000 and 8,000 copies/mL. And yet many of these patients have clearly achieved some sort of steady-state relationship with their own viral isolate. Their HIV RNA levels never escalate into the six-figure range, and they remain in relatively good health.

How do we account for this? The explanation, as Drs. Andrew Luber and David Hardy explain in their article entitled "Entering the Era of Truly Individualized Antiretroviral Therapy," which appears in this issue, is that there is a significant amount of inter-patient variability in how particular individuals respond to particular antiretroviral agents. As a result, trough levels of these agents can vary widely, with some patients adequately protected even at the Cmin levels of all the drugs they are taking while other patients are unprotected for some part of every dosing cycle.

Dose-ranging studies, which are conducted during the early phases of a drug's development, usually enroll relatively small numbers of relatively sick patients. Dosing recommendations are extrapolated from the pharmacokinetic data obtained from these individuals -- and clinicians are left to work out, on their own, how to adjust these doses for children, for women, and for all patients who are cachectic, malabsorptive, or have demonstrated that they cannot tolerate standard doses of other drugs.

It is small wonder, then, that investigators have found such wide variance in the circulating levels of drugs used to suppress HIV replication -- even in populations well matched for age, degree of disease progression, and adherence. These individual variations can now be detected using two new clinical tools, resistance assays and drug-level monitoring. And once these variations have been detected, we can compensate for them -- by titrating a patient's drug dosages upward to effective therapeutic levels. Conversely, in patients who achieve supratherapeutic serum concentrations of particular drugs, we can titrate the patients' dosages downward, reducing the toxic side effects of therapy without reducing its efficacy.

As Drs. Luber and Hardy observe, the availability of commercial tests that measure both plasma drug levels and susceptibility to therapy gives clinicians the tools they need to evaluate an individual patient's responsiveness to individual antiretroviral agents -- information that can be used to devise truly individualized drug regimens. For the first time in the two decades since the first cases of acquired immunodeficiency syndrome were described, we have drugs that can suppress viral replication to levels so low that it cannot be detected by the most sensitive commercial assays -- and now we have the clinical tools we need to devise patient-specific regimens that will achieve that objective.

The value of the data derived from these new tests will be only as good as the clinician's ability to interpret those data, of course -- and accurate interpretation will depend on familiarity with both the advantages and the limitations of current methodologies. As more data are derived -- and as more clinicians gain comfort with the new technology -- significant advances in our understanding of the clinical implications of information derived from resistance testing and drug-level monitoring will undoubtedly occur.

At the moment, these new tests offer us a unique opportunity to evaluate individual responses to antiretroviral therapies. And this clinical advantage offers us an opportunity to prevent treatment failures and increase the durability of responses more fully and more effectively than ever before. Experience is the best teacher, and what our early experience with these new clinical tools teaches is that these tests provide potentially valuable assistance in devising antiretroviral regimens that achieve the greatest possible suppression of viremia with the lowest incidence of therapy-limiting toxicities.

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