November 20, 1995
An experimental drug called PMPA given to 25 macaque monkeys up to a day after they were exposed to simian immunodeficiency virus (SIV), an HIV-like monkey virus, safely blocked all traces of infection in these animals.
"Such complete protection with no toxicity is unprecedented in the monkey model of AIDS and suggests a potential role for PMPA in preventing HIV infection in health care workers or others accidentally exposed to the virus," comments Anthony S. Fauci, M.D., Director of the National Institute of Allergy and Infectious Diseases (NIAID), which helped fund the study.
Che-Chung Tsai, Ph.D., D.V.M., of the University of Washington Regional Primate Research Center, Primate Field Station in Medical Lake, near Spokane, led the collaborative group reporting these results in the Nov. 17 Science. The team gave each macaque a daily injection of PMPA for four weeks, beginning either 48 hours before, four hours after or 24 hours after inoculating it with SIV. The investigators looked for laboratory and clinical evidence of SIV infection for up to 56 weeks but found none, even in lymph nodes, in any treated macaque. Moreover, the drug caused no adverse side effects. In contrast, all 10 untreated control macaques became infected within three weeks following exposure to SIV.
PMPA is one of a class of antiviral compounds, known as nucleotide analogues, made by Gilead Sciences of Foster City, CA. Like AZT and other nucleoside analogues, they inhibit reverse transcriptase, an enzyme essential to HIV replication. Unlike nucleoside analogues, however, PMPA is already activated. Thus, it can enter uninfected as well as infected cells and form a reservoir of drug that pre-arms them against the virus. In contrast, AZT and drugs in its class work only in cells that have the machinery to activate the drug. The impetus to develop PMPA came from laboratory and animal model studies showing it to be potentially better tolerated than its parent compound, PMEA. Since the late 1980s, NIAID's Division of AIDS (DAIDS) has encouraged the development of this class of compounds and provided animal models in which to test these compounds. DAIDS microbiologist Roberta Black, Ph.D., one of the paper's co-authors, comments, "This study is a significant step forward.
Although further research is necessary to determine PMPA's potential for human use, the compound will serve as an extremely important tool for understanding AIDS pathogenesis in the context of the SIV monkey model. For example, we now have the means to study early stages of virus infection in 'freeze frame' by stopping the virus life cycle with PMPA."
For the study, the 35 longtailed macaques (Macaca fascicularis) were divided into five treatment groups. Group 1 received 20 milligrams (mg) of PMPA per kilogram (kg) of body weight starting 48 hours before SIV inoculation (five monkeys). Groups 2 to 4 received 30 mg/kg of PMPA starting 48 hours before inoculation (10 monkeys), four hours after inoculation (five monkeys) or 24 hours after inoculation (five monkeys). Group 5 received a placebo starting 48 hours before inoculation (10 monkeys).
All monkeys were given a 100 percent infectious dose of SIV intravenously. The investigators collected blood samples weekly during the four weeks of treatment, biweekly for the next two months, and then every four to eight weeks until the study ended. Throughout the study, they found no evidence of SIV, SIV DNA, or SIV-specific antibodies in the plasma or peripheral blood mononuclear cells of the treated monkeys. In contrast, from three weeks post-inoculation onward, all placebo-treated macaques had SIV and persistent SIV-specific antibodies in their blood.
Each monkey also had a groin lymph node biopsied 16 or 26 weeks after SIV exposure. None of the treated monkeys, but all that received placebo, showed evidence of SIV infection in the biopsied tissues.
Two treated monkeys, one each in groups 1 and 2, underwent more extensive study 40 weeks post-inoculation. Various tissues, including lymphoid tissue and major organs, were examined for SIV using coculture, polymerase chain reaction, and immunohistochemistry. Across the board, both monkeys tested negative for the virus and its genetic material.
The study authors say their results in the macaque model are "extremely encouraging" when compared with data obtained from chemoprophylactic efficacy studies of similar compounds such as AZT. Although AZT is an accepted option for post-exposure HIV prevention, the Public Health Service has remained neutral in its recommendations for those accidentally exposed to the virus because AZT's protective effectiveness in this setting has not been proved. In fact, the Centers for Disease Control and Prevention has reported several cases where post-exposure AZT prophylaxis has failed to work.
In addition to its possible use in post-exposure prophylaxis, PMPA also may play a role in other settings, according to Dr. Tsai and his colleagues. They are now planning experiments to determine if immediate post-exposure therapy with PMPA can prevent SIV infection in newborn monkeys. "This study could have important implications for pediatric AIDS," Dr. Tsai comments, "because approximately 70 to 80 percent of neonatal HIV transmission is thought to occur during the birth process."
Pending development of an oral formulation, they speculate that PMPA also may be used in combination with other antivirals in an attempt to enhance the efficacy of HIV treatment. Ongoing studies will provide important data regarding PMPA's future prospects.
Drs. Tsai and Black's co-authors include Kathryn E. Follis; Alexander Sabo, Ph.D., D.V.M.; Thomas W. Beck, Ph.D.; and Richard F. Grant, Ph.D.; all of the University of Washington Regional Primate Research Center; Norbert Bischofberger, Ph.D., of Gilead Sciences; and Raoul E. Benveniste, M.D., Ph.D., of the National Cancer Institute. The National Center for Research Resources at the National Institutes of Health provides major funding to the University of Washington Regional Primate Research Center.
NIAID, a component of NIH, supports research on AIDS, tuberculosis, and other infectious diseases as well as allergy, immunology, and transplantation. NIH is an agency of the U.S. Public Health Service, part of the Department of Health and Human Services.
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