TREATMENT ISSUES, Volume 6 no. 4 - April, 1992; Gay Men's Health Crisis
Gabriel Torres, M.D.

Laboratory Studies

Test tube studies have demonstrated that this new agent can indeed stop the replication of HIV and related retroviruses. It works in a manner very similar to AZT, interfering with DNA production in newly-infected cells. One early experiment showed that FLT is converted into an active form more readily than AZT is able to convert. Therefore FLT may be able to protect cells from the harmful effects of HIV.[1]

Animal studies have been performed using rats, cats, dogs, monkeys, and macaques to establish absorption rates, toxicities, and safety of this drug.[2] One experiment showed that FLT inhibited reproduction of the feline leukemia virus (FeLV) within six weeks when used in two chronically-infected cats with seriously progressing disease.[3] Both cats, however, developed severe anemia and leukopenia within four weeks. Another experiment using monkeys showed that FLT was ten times more potent than AZT in preventing the replication of the simian immunodeficiency virus (SIV), the virus which causes AIDS in monkeys.[4] In addition, experiments conducted in Sweden with FLT have shown that it can prevent infection of monkeys with SIV and HIV-2 when administered prior to infection with these viruses.[5] FLT also seems to penetrate the brains of monkeys, which may make it suitable for treatment of AIDS-related neurological symptoms.[6]

Human Studies

The first phase I study of FLT was performed at Johns Hopkins University by Dr. Flexner and others.[7] The study observed 16 asymptomatic HIV-positive peo-ple. FLT was given to each group of four participants at a different dose. The drug was swallowed as a liquid after an overnight fast. FLT was observed to be absorbed quickly; peak amounts of the drug appeared in participants' blood within 90 minutes. The half-life of the drug was 3-4 hours, which is 2-4 times longer than that of AZT. This means that the drug can be given less often than AZT and still achieve levels in the blood that will inhibit HIV.

Another clinical trial of FLT was completed in September 1991 by Dr. Bruce Polsky and others at Memorial Sloan Kettering Hospital in New York City. Several of the participants in the study developed severe blood-related toxicity and had to have dose levels of FLT reduced. The bone marrow toxicity was reversible when the drug was stopped. The toxicity was not seen with reduced doses. In addition, the lower doses seem to inhibit replication of HIV as measured by reduction in p24 antigen levels.

A follow-up study is being conducted by the same group at Memorial Sloan Kettering to evaluate different doses of an oral liquid formulation of FLT in patients with AIDS or ARC with T4 cell counts under 300. In this trial, 12 patients will be randomly assigned to one of three doses (0.125, 0.063, and 0.031 mg/kg/day), which will be taken every 12 hours. Participants will be closely monitored with blood tests every week for the first two month and every two weeks thereafter for two more months. T4 cell counts, p24 antigen levels, and viral cultures will be performed free of charge. The sponsor of the study, Lederle Laboratories will pay for all costs of the study except transportation. In order to enroll or obtain more information, contact Bruce Polsky, M.D. at (212) 639-8361 or Mark Dickmeyer, RN at (212) 639-8404.

Conclusion

FLT is an additional nucleoside analogue (like AZT, ddI, and ddC) which has just recently made the transition from the laboratory to the clinic. It seems able to increase potency, and has a long half-life, and good brain penetration. Still, the drug remains very toxic to the bone marrow. It is hoped that toxicities will be prevented by using low doses, or that the toxicities may be managed with colony-stimulating factors such as EPO and GM-CSF. Once its safety, efficacy, and tolerance are determined, a comparative study with AZT, ddI, and ddC will be required to measure its effects against those of the better known agents. Combination trials with ddI and ddC will surely follow to determine whether the drugs work well together and avoid the development of resistance.

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