Targeting A Deadly Scrap Of Genetic Code

NINETEEN NINETY-SIX MAY GO down as the year AIDS treatment came of age. By combining new drugs called protease inhibitors with old workhorses like AZT, desperately ill patients are achieving miraculous remissions. Newly infected patients are holding HIV at exceedingly low levels in their bloodstreams. And researchers who once dreamed of turning HIV infection from a death sentence into a manageable condition now muse about clearing the virus entirely from people's bodies. Unfortunately, this doesn't mean the fight is over. The wondrous new drug combinations can be toxic, unwieldy and ineffective. And because they're so new, no one knows how long their best effects will last. ""We may be winning the battle,'' says Dr. Anthony Fauci, director of the National Institute of Allergy and Infectious Diseases, ""but we have a long way to go to prove that.''

To understand how far AIDS treatment has come, and how far it has to go, you need a sense of how HIV works. The virus is essentially a scrap of genetic code--a pack of nine genes dressed in a protein coat. When a copy of the virus encounters a susceptible white blood cell, it penetrates the surface through a complex of receptors (chart). Once inside, it uses special enzymes to splice its genes into the host cell's chromosomes. And when those viral genes are activated, the cell starts producing more HIV. Every step in this process offers a potential target for antiviral drugs. ""It's like an assembly line,'' says Jeff Chodakewitz, an infectious-disease specialist at Merck & Co. ""There are many places where you can block a reaction and prevent the finished product from coming out.''

It sounds simple enough. Researchers have developed a number of compounds that inhibit certain reactions, but none of them shuts down the assembly line for long. Within a few weeks of entering a person's body, HIV produces billions of genetically varied offspring. A given drug may shackle most of them, but it inevitably misses a few. And as the survivors go on reproducing, the offspring that are least affected by the drug quickly spread through the body.

When AZT hit the market nine years ago, researchers didn't realize what a wily foe they were up against. They knew from short-term studies that the drug (which blocks an enzyme called reverse transcriptase, or RT) could hobble the virus and improve patients' health. Common sense suggested that starting treatment early would produce the greatest benefits. But things didn't work out that way. Longer-term studies showed that AZT inevitably failed within six to 21 months. Early treatment might delay the onset of AIDS, but it was no better than late treatment for extending one's life, and long-term treatment was pointless.

For four years, AZT was the only weapon doctors had against HIV. Then, during the early 1990s, drug companies started introducing other RT inhibitors. First came ddI and ddC, followed by D4T and 3TC. None of the newcomers was very effective on its own. But patients who combined any of the new drugs with AZT fared better than those on AZT alone. AZT plus 3TC made an especially potent blend, for the mutations that helped the virus resist one drug left it more vulnerable to the other. By 1995, combination therapy was showing real promise, but the available drugs all targeted the same enzyme. The challenge was to find ways of disrupting other parts of the assembly line.

That's why the advent of the protease inhibitors was so epochal. The new era in treatment started last December, when Hoffman-La Roche introduced saquinavir (brand name Invirase), and it took off in March with the arrival of Merck's indinavir (Crixivan) and Abbott Laboratories' ritonavir (Norvir). Numerous studies have now shown that when infected people combine one of the new drugs with a couple of RT inhibitors (typically AZT and 3TC), the amount of virus in their blood drops precipitously--often to undetectable levels. The new three-drug regimens also seem to reach the lymph tissues, HIV's favorite breeding ground. The treatments don't rid the body of infected cells--they merely keep them from spewing virus. But if that feat could be sustained, HIV infection wouldn't be so deadly. It could become as manageable as diabetes.

For some people, anyway. The drugs in the current arsenal have many side effects, from diarrhea to bone-marrow suppression, and not everyone can tolerate an effective combination. And those who can tolerate combination therapy don't always respond to it. If a person has already developed resistance to AZT and its kin, adding a protease inhibitor to the mix is essentially the same as taking the new drug by itself. The patient may enjoy a period of vastly improved health while the virus responds, only to resume his demise as resistance sets in. AIDS doctors now routinely see moribund patients regain their mass, vigor and immune function through triple-drug therapy. But the patients' viral levels often explode six to nine months later. Jumping from one combination of drugs to another may buy more time, but no one views that as a viable long-term strategy. ""When you switch from drug to drug, you're giving the virus exactly what it wants,'' says Laurent Fischer, medical director of HIV products for Hoffmann-La Roche. ""If it can grow at all, it mutates. You have to suppress it completely.''

That means starting aggressive therapy early, while the body's HIV population is still small and homogenous. In several ongoing studies, patients who started three-drug regimens early in the course of infection still have undetectable levels of HIV in their blood after a year or more. If the new treatment has truly paralyzed HIV--and the patients never miss a dose--they may never develop symptoms. Indeed, some researchers suspect the patients' infected cells may die off naturally within one to three years, leaving them completely free of HIV. But for now, no one even knows whether long-term suppression is possible. If the new treatments have left stowaway virus slowly replicating in some hidden tissue, they will eventually fail just as past regimens have.

By the time that happens, patients may have other treatment options. At Glaxo Wellcome, the company that makes AZT and 3TC, researchers are developing another RT inhibitor--""1592''--which is reputedly 10 times as powerful as AZT but far less toxic. Pharmacia & Upjohn is seeking FDA approval for a new RT inhibitor called delavirdine, which promises fewer side effects than most drugs in its class. Meanwhile, Abbott Laboratories, the maker of ritonavir, is developing a more powerful protease inhibitor (ABT-378). And Agouron Pharmaceuticals will soon seek approval for nelfinavir, the first protease inhibitor formulated for children as well as adults.

While racing to expand the existing classes of HIV drugs, researchers are working to create a new class called integrase inhibitors. These compounds are still far from clinical testing, but they raise the possibility of disarming three of HIV's critical enzymes--reverse transcriptase, integrase and protease--all at once. Through that combination or some other, scientists will eventually create a set of obstacles that the ever-clever AIDS virus can't clear. For a tiny minority of the world's infected people, HIV infection will then be manageable--at least until a multidrug-resistant strain evolves. But the larger battle to prevent new infections will continue.

DIAGRAM:Disrupting the Assembly Line: HIV survives by invading white blood cells and turning them into virus factories. The process involves several steps, and each offers a potential target for therapy. This shows how HIV does its work, and how antiviral drugs do theirs.

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