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JANSSEN's TIBO COMPOUND R 82913 REDUCED P24 ANTIGEN LEVELS

Executive Summary

JANSSEN's TIBO COMPOUND R 82913 REDUCED P24 ANTIGEN LEVELS in 14 of 22 patients with AIDS or severe ARC who received the drug in a Phase I pharmacokinetic study, Mike Youle, Kobler Institute, London, reported June 20 at the International AIDS Conference in Florence. Youle said the "41% relative change" in p24 antigen was significant but added that it is "very difficult to say if that really means anything." R 82913 was administered intravenously, escalated from an initial dose of 10 mg/day to 120 or 300 mg/day. Patients entering the study had CD4 counts less than 300. They received the drug for a combined total of 409 patient weeks. No toxicity was observed during the course of the study, Youle said. CD4 cell counts continued to fall during the first month, while in the second month mean absolute CD4 cell counts rose 21%. Youle commented that the changes were not significant. Youle, his colleagues at Janssen and the Hopital de I'Institut Pasteur in Paris are looking at two new TIBO compounds that will soon be entering Phase I/II trials. Boehringer Ingelheim and Merck, Sharp & Dohme have TIBO compounds that are similar in activity to R 82913, Youle noted. TIBO compounds appear to inhibit the process of reverse transcriptase. The American Foundation for AIDS Research reported in its AIDS Treatment Directory last year that another Janssen TIBO compound "inhibited HIV-1 in vitro at concentrations that were about 30,000 times lower than concentrations that were cytotoxic" ("The Pink Sheet" Oct 15, T&G-6). In another presentation, National Cancer Institute's Robert Pluda reported the results of an alternating regimen of AZT with acyclovir, ddI and ddC in 21 male patients with AIDS, ARC, or symptomatic HIV with CD4 counts less than 200. Patients were treated for 21 to 52 weeks in three-week cycles: week one, AZT 200 mg and acyclovir 800 mg every 8 hours; week two, ddI 3.5 mg/kg every 12 hours; and week three, ddC 1 mg every eight hours. Of the nine patients who had detectable serum p24 antigen at entry into the study, five had a greater than 50% decrease during therapy, Pluda stated, and no patient who was p24 negative at entry became positive. The overall decrease in p24 was sustained for 40 weeks of therapy. Patients had an increase in their CD4 count "to a maximum of 55 cells/mm3 from baseline after 10 weeks of therapy," Pluda said, adding that in many patients this increase was sustained for 40 weeks or longer, but after 48 weeks the mean CD4 cell count for 14 patients had returned to baseline. Thirteen of the 21 patients reported increased energy and 13 reported an increase in appetite, reflected by a mean weight gain of 3 kg after six months. Explaining the rationale for combining acyclovir and AZT, Pluda noted that the two drugs have been found to be synergistic against HIV in culture. In addition, he said researchers "hypothesized that acyclovir might reduce the incidence of herpes virus infections, some of which can enhance HIV replication." Pluda concluded that the study results do not show whether this regimen is superior, equal to or inferior to single agent therapy for HIV or other combination regimens. He said the usual dose-limiting toxicities of AZT, ddI and ddC were not observed in any of the patients, and most of the patients had evidence of clinical, immunologic and virologic improvement. The "most troublesome toxicities were fatigue and nausea" seen in some patients during the weeks they received AZT and acycolvir. As a result, the treatment was modified in five patients. Two trials presented at the conference examined AZT in combination with alpha interferon. In one trial, ARC patients were randomized into one of three groups: AZT at 100, 200, 400 or 600 mg/day; alpha interferon at 1, 2, 4, or 6 ug/day, or a combination of the two. After 12 weeks, all patients received the combination. Donna Mildvan, Mount Sinai AIDS Clinical Trial Unit, Beth Israel Medical Center, reported that 23 of 31 patients have completed 24 weeks of therapy and none have progressed to AIDS. Alpha interferon alone decreased p24 and HIV DNA, and AZT alone and in combination with alpha interferon was well tolerated and suppressed p24, Mildvan said. She noted that in 20 patients there are preliminary indications of synergy with the combination. Jos Frissen, University of Amsterdam, Dutch AIDS treatment group, reported the results of a study of low-dose AZT (200 mg b.i.d.) and alpha interferon vs. high-dose AZT (250 mg q.i.d.) over 36 weeks. Twenty subjects were randomized to each group. Using surrogate markers as efficacy parameters, no clear difference was observed between the two treatment groups by week 36, Frissen said. He noted that more toxicity, including fatigue, nausea and malaise, was observed in the combination group.
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