Earlier this week in Boston, children found a needle andsyringe in their school bus. Apparently, it had fallen fromthe pocket of an unidentified adult rider as he left thevehicle.
Kids being kids, one young passenger began jabbing athis classmates. A nine-year-old girl and 10-year-old boysuffered needle sticks on their hands, and were promptlytaken to Boston Childrens Hospital. There they gottetanus shots and tests for HIV.
Local news media reported that the syringe was beinganalyzed for possible viral contamination, and that thechildren might receive preemptive anti-HIV treatment. Insuch cases of accidental exposure to infection, whichhealth care and lab workers often confront, theprophylactic drug of choice is AZT.
Although AZT is the first, and still foremost, HIVantiviral in use today, the U.S. Centers for DiseaseControl and Prevention in Atlanta has reported severalcases where post-exposure AZT prophylaxis failed towork.
Now an experimental compound acronymed PMPA isgetting favorable notice as a more potent and specificpreventive in such accidental situations. PMPA owesthese favorable reviews to 35 long-tailed macaquemonkeys at the University of Washington's RegionalPrimate Research Center, near Spokane.
For lack of an expendable animal that can faithfullymodel HIV, the human immunodeficiency virus,researchers fall back on HIV's simian look-alike virus,SIV. In macaques, SIV runs the same course ofinfectivity, immune deficiency, latency, progression,opportunistic infections and symptomology as AIDS doesin humans.
At his Washington primate center, research veterinarianChe-Chung Tsai put out a circular letter in 1993 invitingselected developers of new AIDS antivirals in the U.S.and Europe to screen them in his monkeys. One who tookTsai up on his offer was Norbert Bischofberger, vice-president for research at Gilead Sciences Inc., of FosterCity, Calif.
Gilead had licensed exclusive, worldwide rights toPMPA, Bischofberger told BioWorld Today, from its co-inventors, chemist Antonin Holy, who synthesized it atthe Institute of Organic Chemistry and Biochemistry inPrague, Czech Republic, and Erik De Clerq at Belgium'sRega Institute of Medical Research in Louvain, whoassayed the PMPA for antiviral activity.
Bischofberger supplied Tsai with enough of the novelcompound to carry out extensive in vivo monkey trials.The results appear in today's Science, titled: "Preventionof SIV infection in macaques by (R)-9-(2-Phosphonylmetho-xypropyl)adenine [PMPA]." Tsai is itsfirst author.
Long-Tail Macaques Tell The Tale
In mid-1994, he and his co-workers at the primate centerinjected PMPA into 25 macaques, at various daily doselevels and time intervals, for four weeks. Five animals gotlow doses of the drug, and 10 animals high doses. Forty-eight hours later, they all received 100-percent, sure-fireinfectious inoculations with SIV.
Five others got the high PMPA dose four hours after theviral challenge, and another five, 24 hours after.
That left 10 control macaques shot full of highlyinfectious SIV virions, but with no pre- or post-challengePMPA therapy. Three weeks later, all 10 of them werevirulently infected, and went on to develop the HIV-likesigns and symptoms of SIV.
But from 36 to 56 weeks following their varied PMPAregimen, before and after challenge, all 25 treatedmonkeys were healthy, with no trace of SIV in their bloodor lymph nodes. Moreover, they showed no side-effectsor signs of toxicity.
As Tsai told BioWorld Today on Thursday, "Two weeksago we checked up on half of those 25 animals, and wecan now extend their initially reported 56 weeks ofhealthy virus-free survival by another 25 weeks." He alsonoted that the National Institute of Allergy and InfectiousDiseases (NIAID) had helped fund his study.
NIAID's director, Anthony Fauci, said of Tsai's results,"Such complete protection with no toxicity isunprecedented in the monkey model of AIDS. It suggestsa potential role for PMPA in preventing HIV infection inhealth care workers or others accidentally exposed to thevirus."
Such exposure afflicts 70 to 80 percent of babies born toHIV-positive mothers, Tsai pointed out. They usually areinfected, he said, during passage down the birth canalduring delivery.
"Within the next couple of weeks," he added, "weanticipate starting a trial of PMPA in newborn monkeys,both before and after SIV challenge. Right after birth," heexplained, "we'll expose them to the virus, then within 24hours treat with PMPA."
It Might Also Work For Established Cases
He also alluded to a recent unpublished trial of the drugas therapy for already-established cases of the simianinfection. "Four or five months ago," Tsai said, "we gavePMPA to infected monkeys with very high-titer SIVviremia, and reduced their viral load almost geometricallyfor a full month. It was very encouraging preliminarydata, but not 100 percent elimination of the virus."
Tsai tested it for four weeks, and the SIV completelydisappeared. But when he stopped it, the virus came back.
Unlike AZT, which is a nucleoside analog, Gilead'sBischofberger pointed out, PMPA is a nucleotidemolecule. Both antivirals block reverse transcriptase, theenzyme that enables HIV and SIV to replicate in theirtarget cells.
The crucial difference between them _ and between allnucleosides and nucleotides _ is that PMPA enters theanti-HIV fray already activated. "A nucleotide,"Bischofberger explained, "has a phosphorus attached; anucleoside doesn't."
"The first thing we have clearly shown," he concluded,"is that at least in monkeys, you can use it as aprophylactic, also for accidental exposure, such ascontaminated needle-stick injury. How that ultimatelytranslates into humans, ultimately, only human clinicaltrials will show.
"What we are doing actively," he said, "is making surethat this compound is available to patients, eventually inoral formulation. We are actively developing it for PhaseI/II clinical trials, maybe by the middle of next year." n
-- David N. Leff Science Editor
(c) 1997 American Health Consultants. All rights reserved.