Outsmarting The Virus

Promising tests can map HIV's evolving resistance to drugs

In the never-ending war between man and microbe, the bugs have an uncanny ability to stay one step ahead. New studies reported in Chicago in early February at the Sixth Conference on Retroviruses and Opportunistic Infections reveal that the AIDS virus is developing resistance to potent anti-HIV drugs at an alarming rate--higher than researchers had expected. In some cities, more than one-quarter of new HIV infections involve drug-resistant viruses. And HIV's ability to mutate is causing once successful drug treatments to fail in as many as half of all AIDS patients in many clinics. "Drug resistance is a big problem, and it's not going away," warns Dr. John W. Mellors, professor of infectious diseases at the University of Pittsburgh.

But doctors are now getting a new weapon to use in the battle with the virus. It's called resistance testing, and the basic idea is simple: Researchers analyze the virus from an individual patient to see what mutations it has acquired--and what drugs it has become resistant to. Then they can pick and choose among the dozen or so available drugs to put together the best combination. Such individually tailored drug regimens represent "a whole new kind of medicine," says John Stevens, the aggressively evangelical CEO of Toronto-based Visible Genetics Inc.

SURPRISED SKEPTICS. In short-term studies reported at the AIDS meeting, the approach worked well enough to surprise many skeptics. Patients whose viruses were tested for resistance and whose drugs were picked accordingly did up to twice as well as those who didn't get the tests.

Those results could open the door to a large market for resistance-testing companies. There are now about 335,000 people in the U.S. taking anti-HIV drugs. If doctors test their viruses for new mutations twice a year at $400 per test, the U.S. market alone is $270 million. Add in Europe, Latin America, and Asia, and it's easy to see why testing labs like Specialty Laboratories in Santa Monica, Calif., and North Carolina's Laboratory Corporation of America (LabCorp) along with start-ups like Visible Genetics and Virco in Belgium are pushing hard to get their tests into the clinic. "The companies have a lot at stake," says David Melnick, AIDS treatment expert at Kaiser Permanente.

But are the companies pushing too hard? Many researchers think so--and that has touched off a controversy that has turned ugly at times, as researchers and companies questioned each other's motives. The critics do not object to the idea of testing, but they worry about the difficulties of putting it into practice. For instance, some doctors question whether testing tells them anything they can't learn from patients' treatment histories.

GRAY AREAS. The problem is the sheer complexity of the AIDS virus. When physicians test bacterial infections to see if the bugs are resistant to antibiotics, they get a clear "yes" or "no" answer. But with HIV, there can be many shades of gray. In one approach to testing, used by Visible Genetics, Specialty, Virco, PE Biosystems (a division of Perkin-Elmer Corp.), and others, technicians read the genetic code of two key HIV genes. (They code for the enzymes reverse transcriptase and protease.) Certain mutations in these genes are known to give the virus resistance to one or more drugs. But this genotyping, as it's called, can reveal scores of other mutations--and combinations of mutations--whose effects are less clear. "Genotyping is very complicated," explains Dr. Douglas Richman of the University of California at San Diego. "At times, you look at a sequence and say: `I'm not sure what this means."'

Another approach to resistance testing, called phenotyping, circumvents this problem by actually assessing drugs' effects on the virus in the test tube. But phenotyping, offered by ViroLogic Inc. in South San Francisco and Virco among others, has disadvantages, too. It costs about $800, roughly twice the price of genotyping, and it takes weeks instead of days. In addition, the virus' behavior in the test tube can be different from its behavior in the body. And it offers just a snapshot of the virus' evolution, rather than revealing the pattern of mutations needed to predict future changes.

A further problem with either test is that it might not spot strains of the virus that are present only at low levels in a patient, but which could rapidly take over when other strains are knocked out with drugs. Given all these difficulties, "we have to be sure that resistance testing is driven by research needs, not by companies' commercial agenda," says Stanford University professor of medicine Dr. Jose G. Montoya.

To win over the skeptics, companies have been supporting trials to find out whether resistance testing makes a difference. Doctors send in blood samples for genotyping or phenotyping when patients' drugs begin to fail and their viral levels soar. Based on the tests, experts recommend new drug regimens. Then researchers compare the patients to similar people whose new drug regimens were based on the traditional approach, an analysis of past treatment history.

The results of the first such trials have been promising enough to convince many doubters. One study, led by Dr. John D. Baxter of Cooper Hospital/University Medical Center in Camden, N.J., found that 51% of patients who received new drugs based on genotyping knocked their viral loads back down to undetectable levels, compared with only 25% of those who didn't get resistance-testing advice. Such results "were a surprise," says Dr. John D. Stansell, medical director of the AIDS program at San Francisco General Hospital. "Most people were skeptical, as I was, that this would pan out as a useful tool." Stansell is now getting constant reminders of the value of resistance information. He predicted, for instance, that one recent patient whose drugs were failing would harbor a viral strain resistant to the drug AZT. But when Stansell actually tested the virus, "it was clear it did not have the resistant mutation--and it responded beautifully to AZT," he recalls. Similarly, doctors are learning that the failure of a three-drug regimen doesn't mean that all three drugs are useless, as physicians had thought.

A rear guard of doubters is still arguing that the studies are too short to prove lasting benefits. But overall, "conviction is growing that resistance testing is valuable," contends Kurt Hertogs, director of research and development for Virco in Mechelen, Belgium.

The final obstacle for the new technology is to convince insurers and health-care providers to pay for it. Proponents believe that the $400-$800 tests will actually save money. "Compared to the cost of weak treatment [everything from wasted drugs to more hospitalizations], the cost of the test is a drop in the ocean," argues Dr. Brian Gazzard of London's Chelsea & Westminster Hospital. Big health-care providers like Kaiser Permanente are withholding judgment until they finish their own studies, says Kaiser's Melnick. But resistance testing is expected to pass this hurdle too. That will open up a major market--and give thousands of AIDS patients a better chance of keeping up with their deadly viruses.

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