AIDS TREATMENT NEWS Issue #184, October 1, 1993
L-524 (L-735,524) has been in small human trials since February 1993. In laboratory tests, it gives 95 percent inhibition of HIV spread in cell cultures at concentrations of 50 to 100 nanomolar (0.05 to 0.1 micromolar). In people, anecdotal findings have shown about a 50 percent reduction in p24 antigen (comparable to AZT), with no viral resistance found so far. But since only a handful of people have taken L-524 for more than two weeks, all that can be concluded now is that more trials are justified. P24 antigen changes normally happen very quickly; the big question is whether they are sustained.
The new phase II trial will last six weeks, and may be extended. It will randomly assign volunteers to three groups: L-524, 200 mg every six hours; L-524, 400 mg every six hours; and AZT, 200 mg every eight hours. No toxicities have yet been found from L-524 in the 400 mg dose; however, some volunteers given a higher dose (600 mg every four hours) showed rises in liver-function tests.
Volunteers must by 18-65 years old, with T-helper count below 500 (there is no lower limit). They must not be pregnant. Creatinine must be less than 1.5 times upper limit of normal, and liver transaminases and bilirubin less than 2 times upper limit of normal. Volunteers cannot have previously used any protease inhibitor. They will be tested and need to have a positive p24 antigen (at least 25 pg/ml). Before entering the trial, they will need a 30-day washout of other investigational drugs, and a two-week washout of AZT, ddI, and ddC.
For more information, contact the study coordinator at one of the three trial sites:
* Pitt Treatment Evaluation Unit, University of Pittsburgh, contact Nancy Mantz, R.N., 412/647-8125.
* AIDS Treatment and Evaluation Unit, University Hospital, State University of New York at Stony Brook, contact Ruth Ann Burk, R.N., 516/444-1658.
* Bellevue Hospital Clinical Research Unit, New York University, New York City, contact Mary Ann Kiernan, R.N., 212/263-6565.
Comment
Protease inhibitors are generally considered the most promising class of experimental drugs at this time; they are being developed by a number of companies. Unlike other classes of anti-HIV drugs, protease inhibitors are able to completely shut off viral replication in laboratory tests. And because the protease is a small enzyme, it should offer few opportunities for the virus to mutate and develop drug resistance.
The major problem with protease inhibitors has been getting them into the body and to the sites where they are needed. The p24 antigen reduction seen in a few patients so far suggests that this drug is bioavailable. Similar results have been seen with a similar protease inhibitor being developed by Hoffmann-La Roche.
The fact that the p24 antigen result is only comparable to that of AZT does not necessarily mean that the drug will only work as well. With protease inhibitors, new virus continues to be produced by already-infected cells; however, this virus is immature and not infectious. The p24 antigen test may be detecting this defective virus, and therefore not giving a true picture of how well this class of drug is working.
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