WASHINGTON _ Trying to find a single-agent, "magic-bullet"therapy for AIDS may prove impossible, scientists said Thursday.

But Richard D'Aquila, of Massachusetts General Hospital inCharlestown, said there might be a better way. He advocates anextreme multidrug approach to AIDS treatment modeled on theapproach taken in leukemia, where chemotherapy with one, two andthen three drugs proved ineffective, but treatment with fourfrequently produced a cure.

"We're not going to get a magic bullet for this disease," D'Aquilasaid on the final day of the Second National Conference on HumanRetroviruses and Related Infections. "We're going to have to learn tolive with resistance; it's probably going to turn up no matter what wedo."

HIV's seemingly limitless ability to transform itself to survive theonslaught of antiviral drugs is likely, eventually, to doom even themost viricidal agents science can devise.

In a matter of weeks, in many cases, the virus can thwart years ofresearch simply by shuffling its bases with the apparent ease of acard shark shuffling cards. Indeed, viral resistance has alreadytrumped virtually every anti-HIV drug, ranging from thecommercially available agents AZT, ddI and ddC to the promisingexperimental compounds known as 3TC and the protease inhibitors.

Somehow _ and the how is not yet understood _ drug therapyinitiates a cascade of genetic changes that subtly alter the virus'biochemistry and render it impervious to the drug therapy in use.

Just two changes at codons 41 and 215 are sufficient to reduce HIV'ssusceptibility to AZT by 60 percent, and both changes usually occurwithin one and a half years, said Daniel Kuritzkes, of the Universityof Colorado Health Science Center in Denver.

During ddI treatment, Kuritzkes and others have reported, resistance-conferring mutations occur at codons 74 and 184. In patients takingddC, the mutations occur at codons 65, 69, 74 and 184. In thosetaking d4T, they occur at codons 150 and 75. In those taking 3TC,the mutation occurs at codon 184.

And new mutations appear all the time, Kuritzkes said.

Scientists recently have reported novel HIV-1 mutations at codons62, 75, 77, 116, 151 and other sites in patients taking both AZT andddI.

"Mutations occurs not because of mistakes in DNA repair butbecause of the sheer number of replication events and the large poolof circulating viruses," D'Aquila said. "The data is extremelycomplex; don't let anyone tell you this virus is simple."

The success of HIV's survival strategy has some scientistsstruggling to find rationales to keep from sliding into despair.

"One can take the pessimistic view that the virus has a highresistance rate and will get around anything we do," Kuritzkes said."If you feel that way, you might think: `Why do anything?' Butcertain regions of the virus are conserved, and if we can learn aboutthose regions, maybe we can find a way to box the virus in."

Scientists have achieved some level of success, however.

Evidence suggests that several drugs now in use can reduce the viralburden significantly _ producing a rapid rise in critical CD4 T cellcounts and well-being _ but the effect doesn't last.

Eventually, resistance develops and the virus starts replicating again.

But the recently released results of four studies into London-basedGlaxo Holding plc's 3TC suggests a tactic with potential for moresustained improvement. Used together, 3TC and AZT can produce a65-fold reduction in virus, and quickly.

Clive Loveday, of the division of virology at the University ofLondon Medical School, reported this week that the drop-off beginsrapidly, reducing the virus burden by 50 percent every 1.58 days.

And, although HIV rapidly becomes resistant to 3TC, 3TCinexplicably extends AZT's ability to kill off HIV, even after HIVdevelops mutations at codons 41 and 215 that ordinarily confer AZTresistance.

Another class of drugs, the protease inhibitors, also significantlyreduces the viral burden. Preliminary studies suggest that they are 10to 20 times more powerful than current drugs, but they, too,eventually lose their impact once HIV becomes resistant.

The challenge is to extend viral suppression by conqueringresistance, D'Aquila said. One drug won't do that; many drugsmight.

D'Aquila advocates developing an armamentarium of drugsdesigned to be used in combination _ perhaps even in cycles lastinga few weeks or months. Treatment would amount to changing thedrugs regularly and rapidly, before the virus has time to adapt. Theprocess would not be a simple one.

Treatment would have to be tailored to each additional patient.Clinicians would have to continually monitor the viral burden andthe pharmacokinetics of the drugs used so that they penetrate to thevirus.

"The more drugs the better," D'Aquila said. n

-- Steve Sternberg Special to BioWorld Today

(c) 1997 American Health Consultants. All rights reserved.