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Executive Summary

Early therapy with AZT (Burroughs Wellcome's Retrovir) in asymptomatic HIV-infected individuals produces an average CD4 cell count that is 35 cells per mm higher than deferred therapy, according to findings of the Concorde trial presented June 6 during a symposium in Berlin preceding the Ninth International Conference on AIDS. The symposium included a more complete report of the 38- center, 1,749-subject European trial, a preliminary analysis of which was published as a letter to the editor in the April 3 issue of the British medical journal Lancet. Concorde was originally designed in 1988 as a double-blind, placebo-controlled trial of AZT (zidovudine) monotherapy in HIV- asymptomatic persons with any CD4 count that was to have compared initiation of AZT therapy in symptom-free people to those whose treatment was deferred until the onset of symptomatic disease. The protocol was modified in October 1989 to allow participants with persistently low CD4 cell counts (under 500) who had been enrolled for at least six months to begin taking AZT. More than 300 individuals in the placebo group later switched to open AZT. The dosage tested was 1,000 mg per day. The study found no significant difference in progression to AIDS or death between the two groups after three years. The discrepancy suggested by the clear difference in CD4 counts with no corresponding difference in clinical outcomes "[casts] serious doubt" on the value of using "moderate increases in CD4 cell count as a surrogate marker for clinical effects of antiviral monotherapy," Concorde investigator Maxime Seligmann, Hospital Saint-Louis, Paris, maintained. In a June 9 press release, Burroughs Wellcome weighed in on the issue of CD4 cell counts: "While it is a strong indicator of clinical deterioration, it is a less precise marker of a drug's efficacy," the company said. "In the future, we suspect that markers such as virus replication and viral resistance as measured by polymerase chain reaction technology may gain wider use." On the results of Concorde, Wellcome said the trial is "consonant with other monotherapy trials that were initiated in the 80's. However, the management of asymptomatic HIV infection has changed considerably with current scientific opinion suggesting that early combination therapy might provide a better strategy." While FDA has approved nucleoside analogues for treatment of AIDS based on surrogate marker data, both the Antiviral Drugs and the Vaccines & Related Biological Products Advisory Committees have expressed concern about relying solely on CD4s as a measure of efficacy. During its last meeting May 11, the antivirals committee expressed interest in reviewing the Concorde results. The committee's next meeting is tentatively scheduled for September, although an agenda has not yet been set. At the June 6 symposium, John Hamilton, V-A Medical Center, Durham, N.C., reported longer-term follow-up results from a Department of Veterans Affairs study that appeared to support the conclusions of the Concorde trial. After a mean follow-up of 4.25 years in two groups of HIV-symptomatic subjects treated with AZT, "there is no statistically significant difference" in time to AIDS between therapy administered early in the course of disease or late, when CD4 counts fall below 200, Hamilton said. Earlier reports of the trial (V-A 298) also had showed no survival advantage with early AZT treatment compared to later therapy. The study included 338 individuals. With regard to cost analysis, the V-A has found that in- patient costs associated with early therapy are higher than with treatment administered later, while out-patient costs are comparable. Drug costs are about three times higher for early treatment patients, Hamilton reported, resulting in "substantially different" total costs for the two therapeutic strategies. Overall, AZT is "a costly form of intervention," he remarked.

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