The Wall Street Journal - Thursday, 6 February 1997.
Stephen D. Moore

Take drug resistance - the uncanny ability of HIV, the virus which causes AIDS, to mutate over time and eventually thwart the effects of every drug tested so far.

AZT, the first widely used AIDS treatment, seemed a panacea until resistant strains of HIV began to appear, sapping the drug's early clout. At that point, with nowhere else to turn, physicians began experimenting with two and three drug cocktails.

The rationale was simple: A combination of drugs might drive the virus so far into a corner that resistance could develop only after an improbable series of mutations.

Over the past 18 months, the emergence of a new class of drugs known as protease inhibitors has enabled physicians to brew supercharged cocktails that have driven the virus down to undetectable levels in thousands of patients, reducing hospitalizations and deaths.

However, knowledge about exactly how viral resistance develops is still sketchy - and nobody really knows how long the cocktails may hold HIV at bay.

'Therapeutic strategies are leapfrogging far ahead of those of us in labs trying to back this up with scientific information on resistance,' says Clive Loveday, a retrovirology professor at the Royal Free Hospital medical school in London. 'We still haven't worked out a definitive measure of resistance that can be equated biologically with the treatment a patient needs.'

Last week, the world's largest drug maker Glaxo Wellcome (GLX) stormed into that vacuum with a bold, trans-Atlantic research blitz designed to unravel the resistance riddle.

Together with San Diego-based affiliate Affymetrix (AFFX), Glaxo will analyze the DNA of mutant HIV strains collected from thousands of patients, and try to correlate the efficacy of existing drugs against those myriad versions of the virus.

If successful, the results will be assembled in a data base, which physicians would be able to consult for advice in planning treatment for their patients.

Glaxo already markets two of the world's best-selling AIDS treatments - AZT, marketed under the brand name Retrovir, and 3TC, a newer drug marketed as Epivir. The U.K. concern also has a bulging pipeline of new medicines under development.

But competition is heating up. Merck has entered the anti-AIDS market with a popular protease inhibitor called Crixivan. Roche Holding and Abbott Laboratories are promoting packages of protease inhibitors plus diagnostic tests to allow physicians to monitor the efficacy of the expensive new drugs.

For Glaxo, a well-documented clinical management service dispelling the guesswork that currently prevails in AIDS therapy would be a powerful marketing tool.

Though the company isn't directly involved in diagnostics, the pact with Affymetrix gives it exclusive rights to the affiliate's GeneChip system that packs thousands of DNA probes on a wafer - and features instruments to process and interpret the genetic data.

Nonetheless, industry analysts caution that the project is a daunting scientific gamble likely to cost hundreds of millions of dollars and require several years of complex sleuthing.

'Scientifically this is an important contribution,' says Dr. Loveguy, the London professor. 'Obviously, with support from Glaxo a data base probably can be built up much more rapidly than through efforts of poor academics like ourselves. But it still requires a quantum leap of faith to believe this is going to be useful to every clinician out there.'

Virtually every physician treating AIDS patients has first-hand experience with viral resistance. Sometimes it crops up at the outset of therapy - when a patient has been infected with a mutant HIV strain already resistant to certain drugs.

But resistance usually develops weeks or months after a patient begins drug therapy. The tip-off is an abrupt rise in the amount of virus measured in the patient's blood, indicating that a mutant, resistant strain has begun replicating rapidly, despite the continued presence of a previously lethal drug.

Mutations that confer resistance usually occur in parts of the virus where the drug acts. AZT, for example, works by jamming an enzyme essential to replication of the AIDS virus, and resistance usually is a result of four or five random, but very specific and very predictable mutations, explains Brendan Larder, head of clinical virology at Glaxo's research center in Stevenage, England.

The first combination therapy Glaxo and Affymetrix will examine will be an in-house mix: AZT and 3TC. That cocktail produced exciting initial results. Resistance, as hoped, developed more slowly when used in combination than when either drug was taken alone.

'One of our initial projects will be to asess the durability of 3TC's ability to resensitize AZT,' Dr. Larder says.

Blood samples collected from about 200 patients during various phases of earlier clinical trials of the drugs will be re-tested with the Affymetrix system.

By tracking development of mutations over time, 'we hope to be able to predict which viral strains promise a good response and which ones probably would have a better outcome if treated with other drugs,' the Glaxo researcher adds.

If the initial efforts succeed, Glaxo intends to proceed to similar analysis of other cocktails. 'There are nearly a dozen AIDS drugs already available - at this point we need to look more systematically at the best ways of using them to the best advantage of patients,' Dr. Larder says.

'We still have to prove the principle, the science, which I think will take a couple of years. But until we look at this in a controlled way, in a large population with quite sophisticated technology, we're just never going to know.'

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