PMPA: AIDS Treatment Breakthrough on the Horizon?

A young boy takes a short cut through an alley one morning on his way to school. There he sees a syringe on the ground. Unaware the needle is contaminated with HIV, the virus that causes AIDS, he yields to curiosity and bends to pick it up. In the process, he accidentally pricks himself, drawing blood from one finger. Dropping the needle, the frightened boy instinctively puts the finger to his lips. Then he runs off to school, keeping his secret all day. Not until later that evening does the boy's mother hear about the incident and rush him to the emergency room of a local hospital. On hearing the mother's story, the attending physician doesn't panic; instead, he prepares a dosage of the drug PMPA, injects the boy and assures the frightened mother that her son will be 100 percent free of HIV. It may sound like wishful thinking on the part of a society terrified by AIDS, but the above scenario may be one step closer to reality thanks to the work of Che-Chung Tsai, a University of Washington senior scientist and pathologist working at the Spokane Primate Field Station, 14 miles west of the Eastern Washington city. Like many primate centers around the country, the station has been in the news more as a target of animal advocates than for scientific discoveries.For the past 10 years, from this little-known facility in Medical Lake -- far from the storied laboratories of Stanford and Harvard -- Tsai and his research team have been quietly investigating potential anti-HIV agents. And only a few short months ago, they announced a discovery that many hope will change the model for prevention and treatment of AIDS.Tsai and his team found that injection of the drug PMPA up to 24 hours after infection by the AIDS-like Simian Immunodeficiency Virus (SIV) completely stopped the spread of SIV in 25 of 25 macaque monkeys tested. Ten other monkeys not treated with PMPA developed SIV infection within three weeks, while the 25 treated monkeys remained free of SIV throughout the 56 weeks they were monitored. Tsai and his University of Washington research team are elated by the results. Why? Because SIV in monkeys has been shown to run the same course of infectivity, immune deficiency, latency, progression and symptomology as HIV. Moreover, the immune system of monkeys is extremely close to that of humans. The hope is that HIV may respond to PMPA treatment in a similar manner as SIV. With this prospect in mind, in vitro, or test-tube experiments with PMPA and HIV have been performed by Tsai and fellow researchers in hopes that promising results, when taken with the SIV results, will encourage the FDA to quickly allow testing on humans."I'm very encouraged," says Tsai, "because the drug is also very effective against HIV in the test tube."Amazingly, PMPA testing may never have taken place at the Medical Lake facility, or anywhere else, if Tsai hadn't personally barraged companies developing new drugs with letters back in 1993. Since 1986, he and fellow researchers had tested more than 100 anti-viral agents with little success. Because only the most promising in vitro results ever lead to tests on live subjects like those at the Primate Center, Tsai hoped to expand the number of promising anti-virals at his disposal, even if they weren't designed to combat HIV, by inviting manufacturers to send him test samples. In other words, he tried to improve his results by getting more studies underway.Few companies responded, but one that did was Gilead Inc., a Foster City, Calif., biotechnology company. Gilead had earlier licensed worldwide rights to PMPA from its Czechoslovakian and Belgian co-inventors, two men who believed the drug held promise in the treatment of herpes.Like AZT, which is widely used to treat AIDS patients, the drug PMPA blocks reverse transcriptase, the enzyme that allows both HIV and SIV to copy themselves. "But unlike AZT," says Gilead's Norbert Bischofberger, "PMPA enters the anti-HIV fray already activated." Put another way, PMPA behaves like a car entering the freeway at 60 miles an hour, while AZT is comparable to one that stops at the end of the on-ramp before joining the stream of traffic. Whereas PMPA immediately becomes part of the flow and gets where it's going, AZT enters the stream of traffic slowly, hesitantly, before getting up to speed.Just as exciting as PMPA's effects on infected monkeys are its apparent preventive applications. In tests at the Medical Lake facility, the injection of PMPA up to 48 hours before a monkey's exposure to SIV stopped the virus from spreading in each subject animal. If proven safe and effective for humans, PMPA might be used not only in scenarios like the young boy who accidentally becomes infected, but also in high-risk medical environments like emergency rooms and laboratories. Researchers are especially excited about its potential use in birthing rooms with HIV-positive mothers. In 70 to 80 percent of such deliveries, infants born to these mothers become infected with HIV while passing through the birth canal. But if babies could be injected with PMPA during delivery or immediately after birth, their contraction of AIDS might be prevented. Tests have already begun on newborn monkeys.Finally, there may be a role for PMPA in treating those who already have full-blown AIDS. Veterinarian Koen Van Rompay of the Regional Primate Center in Davis, Calif., is studying this aspect of the drug's use. Rompay's tests have measured the effect of PMPA on monkeys infected with SIV three weeks before treatment with the drug; to his surprise, the animals have recovered rapidly and exhibited low residual levels of SIV in their blood as long as six months later."If I hadn't done the research myself," says Rompay, "I would have doubted it." He adds they have yet to find any PMPA-resistant strains of SIV in the treated animals -- an unfortunate negative aspect of AZT and other anti-HIV drugs. Tsai, who immigrated to the U.S. from Taiwan in 1964, believes PMPA might be most effective in combination with other therapies or as a replacement for AZT, which is 100 times more toxic than PMPA and loses potency far more quickly. AZT also is fraught with side effects and often ineffective in stopping the spread of HIV after even minuscule exposures.Scientists around the country, although characteristically low-key in responding to "dramatic" new discoveries, share Tsai's enthusiasm about his findings."There's a great deal of guarded optimism that this is very different from all the anti-HIV drugs we've tested," said Nava Sarver, a molecular biologist with the Division of AIDS at the Bethesda, Md., National Institute of Allergy and Infectious Diseases (NIAID) in a recent issue of BioWorld Today, a biomedical industry publication. NIAID Director Anthony Fauci told BioWorld that "such complete protection with no toxicity is unprecedented in the monkey model of AIDS."Meanwhile, Gilead's Bischofberger is hopeful that human trials for PMPA can begin as early as this year.The development comes just as Tsai and his research team are preparing to leave the Spokane Primate Field Station and will return to University of Washington at Seattle in the fall.

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