WASHINGTON _ More than a decade into the AIDS epidemic,advances in drug development soon may enable researchers toconquer the changeling virus's capacity to rapidly develop drugresistance.
The best opportunity lies in strategic use of multiple drugs, which,given early and at high doses, can prevent the virus from replicatingor select for mutations that weaken the virus, Douglas Richmond toldthe Third Conference on Retroviruses and Opportunistic Infectionshere.
Numerous studies have shown that drug treatment does not "induceresistance," said Richmond, professor of pathology and medicine atthe University of California, San Diego, School of Medicine. Instead,drugs select for resistance by killing off non-resistant viruses, leavingresistant mutants that then repopulate in the patients lymphoidorgans.
"Single mutations are present all the time in all patients, and we haveto deal with that in our calculations of we manage drug therapy,"Richmond said.
"The likelihood that drug resistant infections will emerge," he said,"is a function of several factors: the frequency of viral mutations, themutability of target proteins and the selective pressure of antiviralsand the magnitude and the rate of viral replication."
Researchers have found that HIV's mutation rate is probablyconstant, at three times 10 to the minus fifth. Those mutations are theresult of errors that occur during replication. "This is a relativelyerror-prone virus," Richmond said.
That does not mean HIV is uniquely error prone, however. It mirrorsthose of murine leukemia virus, the equine encephalitis virus,influenza and other single-strand RNA viruses.
As for the intrinsic mutability of the target protein of a given drug, hesaid, nucleoside analogues with "less physiologic sugars" such asAZT and 3TC, will select for higher level resistance than DDC orDDI.
AZT and 3TC are marketed by Glaxo Wellcome plc, of London.Biochem Pharma Inc., of Laval, Quebec, developed 3TC incollaboration with Glaxo. The nucleoside analogue, DDC, is made byRoche Holdings Ltd., of Basel, Switzerland. DDI is a nucleosideanalogue made by Bristol-Myers Squibb Co. of New York.
High Doses Heighten Selective Pressures
Selective pressures also play a significant role in the development ofresistance. Giving higher doses of AZT, for instance, heightensselective pressures and accelerates the rate at which HIV acquiresresistance, Richmond said.
That evidence emerged in studies showing that patients given theoriginal doses of AZT _ one to two grams _ proved far more likelyto develop resistant infections than those given lower doses of 600mg or less.
That does not mean, however, that AZT is approaching obsolescence.Several studies have shown that the development of AZT resistanceslows when 3TC or saquinavir, made by Roche, is added to the mix,he said.
The state of patients' immune system when therapy begins also cangovern how quickly resistance develops. Patients with CD4 cellcounts of lower than 100 develop resistant infections more rapidlythan patients with CD4 counts of 400 or higher.
This is a critical observation, Richmond said.
"As we diminish viral replication, you get less resistance. If we caneliminate replication resistance can't occur. So that means the virus'sstrategy for adapting to selective pressures requires persistentreplication. From the point of view of treatment strategy, preventionof resistance requires the complete suppression of viral replication.
"This is the game," Richmond said.
However, HIV has repeatedly proven itself a wily virus that canthwart drug therapy not only by mutating but by recombining withother resistant viruses in patients who have co-infections with twostrains of virus.
This is a worldwide phenomenon. Several studies have shown thatrecombination occurs regularly in patients who dwell in African andAsian countries where several viral sub-types are circulating at anygiven time.
Laboratory studies have conclusively demonstrated this. In theexperiments, AZT- and protease-inhibitor resistant viruses growequally well alone. As expected, when AZT is added to the virusesonly AZT-resistant viruses will grow. And in the presence of proteaseinhibitors, only viruses resistant to protease inhibitors will grow.
But when the viruses undergo recombination, they become resistantto both drugs, whether added singly or together.
"Recombinant viruses were completely resistant to both drugs,"Richmond said.
Regardless of the mechanism that confers resistance, he said, thestrategy is the same: "the only way to prevent the outgrowth of newselective pressures is to completely suppress replication."
One way to do that is by prescribing drugs in sufficiently high dosesthat the plasma level exceeds the susceptibility of resistant virus.Another is to prescribe drugs that select for mutations that weakenthe virus, and slow its replication rate. A third is to prescribeconvergent therapy _ combinations of drugs that attack the sametarget, regardless of whether it is reverse transcriptase or protease.
In convergent therapy, Richmond said, "mutations that arise in thepresence of drug one either increase the virus's susceptibility to drugtwo or constrain the virus's evolutionary options for acquiringresistance to drug two."
Glaxo's 3TC can play an important role in this approach, he said.When 3TC is given singly or in combination with AZT, viralreplication slows markedly in the first two weeks of therapy. Andpatients who began with 90,000 copies of wild-type virus do notreturn to that level even after 3TC has been discontinued. The reasonmay be that that the only virus remaining has mutated in ways thatdecrease its ability to reproduce itself.
"This is an impaired virus," Richmond said. "It doesn't replicatequite as well as the wild-type virus."
The task for drug manufacturers is to develop more "practical, usefuldrugs" that can take advantage of these mutations to completelysuppress the virus's ability to replicate and mutate in ways that conferresistance.
Richmond said the next "incredible challenge for drug discovery is tofind two protease inhibitors that box in the virus" and rob it of itsevolutionary options for survival. n
-- Steve Sternberg Special To BioWorld Today
(c) 1997 American Health Consultants. All rights reserved.