Introduction

On June 6, investigators halted enrollment in ACTG 5057, a trial of the Remune therapeutic vaccine (see the June 2000 Treatment Insider). The halt came barely a month after the trial began. It occurred because of a newly surfaced analysis of data from Remune trial 806, a 2,500-person trial prematurely terminated over a year ago.

Remune consists of killed HIV stripped of its outer envelope and emulsified with mineral oil. Trial 806 was stopped because the introduction of protease inhibitors and potent antiviral combinations during this trial's recruitment masked any possible benefit that Remune might have in slowing disease progression. The Immune Response Corporation, which created Remune and sponsored this trial, has widely disseminated one analysis of 250 trial participants indicating that Remune conferred modest improvements in viral load at certain timepoints.

Unpublicized viral load analyses in five other subgroups failed to find any difference between Remune and placebo. The one that stopped ACTG 5057 was a preplanned analysis by statisticians at the Harvard School of Public Health. The Harvard experts looked at "virologic failure" among 435 participants in trial 806. These people had attained viral loads below 400 before entering the trial and were taking protease inhibitor-containing combinations at entry or soon afterward.

"Virologic failure" was defined as either changing two or more antiretroviral drugs or having a viral load that was substantially higher than baseline. Half the members of this substudy experienced such failure, regardless of whether they were receiving Remune or the placebo.

One notable outstanding issue is that the number of therapy switches due to drug intolerance rather than HIV breakthrough was not recorded. Two-thirds of the treatment failures were so designated because of therapy alterations.

The subgroup's experience nevertheless casts a pall on ACTG 5057, which is specifically designed to detect Remune's effect on the time to virologic relapse. It is highly unlikely that the trial will show the benefit from Remune that its organizers anticipated: a 50% reduction in virologic relapse in the course of 96 weeks.

This 50% figure comes from Remune trial 816, a 32-week, 43-person pilot study of administering Remune or placebo to persons with relatively early HIV infection who were starting an AZT/3TC/indinavir combination regimen. Trial 816 was primarily an investigation of Remune's effect on anti-HIV immunity. The viral load breakdown was an afterthought and had questionable results. Most of the viral load difference between the Remune and placebo arms occurred during the first sixteen weeks of treatment with anti-HIV drugs, a period in which trial participants received just one shot of Remune. It is doubtful that Remune can enhance the already substantial initial effect of antiviral drugs, especially given the results of trial 806.

ACTG 5057 was supposed to enroll 472 persons. Redesigning it so that it could statistically document a smaller benefit would require a much larger and more expensive trial. Documenting a 30% difference in HIV breakthrough might require 1,200 trial participants. A 10% difference might require 12,000.

It is unclear how a large government-financed trial like ACTG 5057 was first set up based on such spurious data. Where the extra financing will come from to alter the trial is anyone's guess.

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