GMHC Treatment Issues - Vol. 9, No. 12 - December 1995

The study was conducted by researchers at the University of Washington who injected 25 macaques with PMPA (20 or 30 mg/kg of body weight) daily for four weeks, beginning either 48 hours before, four hours after or 24 hours after inoculation with SIV. Ten untreated monkeys were inoculated with SIV as a control. During the course of the study and through the 56 weeks of follow-up, the team could find no evidence of SIV infection in the blood or lymph nodes of any of the macaques that received PMPA. Nor could they find any trace of SIV in two monkeys killed at forty weeks for extensive testing of organs and tissue. All of the untreated monkeys, in contrast, developed SIV.

According to Norbert Bischofberger of Gilead Sciences, there also are indications that the PMPA-treated monkeys have developed cytotoxic T-lymphocytes capable of killing SIV-infected cells. The treated monkeys may have, in effect, been vaccinated against SIV by exposure to a limited amount of live virus. The researchers are now studying this immune response in lab cultures. They plan to rechallenge the macaques soon with a new dose of SIV in the absence of treatment.

A group at the California Regional Primate Research Center in Davis is now studying PMPA in baby rhesus macaques. The monkeys are infected with SIV at birth and therapy begun three weeks later. Preliminary data at six months show that this regimen preserves health while reducing viral load one thousand-fold. Further studies are underway in adult monkeys exposed to SIV via their mucosal membranes rather than intravenously.

PMPA may yet prove to be unprotective in HIV or in mucosal infections (the most common kind of initial exposure to HIV) because different, more long-lived cells (such as macrophages) are predominantly the target of sexually transmitted virus. If such a cell is infected, it may serve as a reservoir for the virus for a much longer time than infected T-cells, which usually die within two days.

PMPA has proved relatively nontoxic in cell culture and animal studies, so comparatively high doses may be safely administered. Gilead plans to quickly evaluate the activity of PMPA in both perinatal transmission and primary HIV infection. Before the end of this year, the company will start with a pharmacokinetic study comparing intravenous and oral administration. -- TS

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