HIV drug shows promise in post-exposure prevention

Monkey trials a success

Promising animal research that could be critical for the eventual development of an effective HIV post-exposure prophylaxis to prevent occupational infections in health care workers was recently published on an experimental drug called PMPA.1

"It is a conceptual promise because it hasn't been tested in humans yet," says Anthony S. Fauci, MD, director of the National Institute of Allergy and Infectious Diseases (NIAID) in Bethesda, MD, which directed the study.

In the study, PMPA was given to 25 macaque monkeys up to a day after they were exposed to simian immunodeficiency virus (SIV). The drug safely blocked all traces of infection in the animals. 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.

"Such complete protection with no toxicity is unprecedented in the monkey model," Fauci notes.

Each monkey had a groin lymph node biopsied 16 or 26 weeks after SIV exposure. All of the monkeys who received the placebo showed evidence of SIV infection in the biopsied tissues, while none of those who were treated did so. Two treated monkeys underwent more extensive study 40 weeks post-inoculation that included examination for SIV using co-culture, polymerase chain reaction, and immunohistochemistry. In all tests, both monkeys tested negative for SIV and its genetic material.

Research to look at newborns next

PMPA is a nucleotide analogue made by Gilead Sciences of Foster City, CA. Like AZT and other nucleoside analogues, it inhibits reverse transcriptase, an enzyme essential to HIV replication. Unlike nucleoside analogues, however, the nucleotide analogue PMPA is already activated. Thus, it can enter uninfected cells and infected cells, and form a reservoir of drug that pre-arms them against the virus, the authors note.

In addition to its possible use in post-exposure prophylaxis, PMPA also may play a role in other settings, according to the researchers. They are now planning experiments to determine if immediate post-exposure therapy with PMPA can prevent SIV infection in newborn monkeys. The study could have important implications for pediatric AIDS because as much as 80% of neonatal HIV transmission is thought to occur during the birth process. Pending development of an oral formulation, the authors note that PMPA also may be used in combination with other antivirals in an attempt to enhance the efficacy of HIV treatment.

"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," says Roberta Black, PhD, co-author and microbiologist in the NIAID AIDS division. "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."

Reference

1. Tsai, CC, Follis KE, Sabo A, et al. Prevention of SIV infection in macaques by (R)-9-(2-phosphonylmethoxypropyl) adenine. Science 1995; 270:1,197-1,199. *