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Relationship Between Disease Progression and Baseline RNA Levels
An important study you may have heard about is AIDS Clinical Trials Group (ACTG) 175. Dr. Coombs uses some data from this study to illustrate some points about viral RNA that he thinks are important. This study was chosen, to make his points, simply because the plasma was collected specifically for RNA measurement. That is, the proper anti-coagulant was chosen, specimens were processed in a very fixed time period and stored appropriately.
In this study, the RNA was measured by Roche's recently FDA-approved RT-PCR assay. Many of the natural history studies and other studies that have been published use different RNA detection technologies; and, the retrospective studies usually deal with plasma banks that were not initially designed to measure RNA in. Therefore, trying to define what the absolute RNA level is, can be very difficult in these retrospective studies. Furthermore, the different assays have been run without a common standard, and that makes comparison between one assay type and another problematic. For the management of patients, I think we want to get down to the issue of what is the absolute RNA level in the patient and how does that correlate with their overall immune status. It's much more difficult to manage patients based on relative levels of virus, but at the moment we are sort of in the position of having to do that.
[Commentary: There are many factors affecting the accuracy and reliability of RNA test results, and we have not yet been able to adequately understand how each of these factors may affect a measure or series of measures.]
ACTG 175 was randomized, double blinded, and involving 2,467 individuals, who were randomized to either AZT, ddI, AZT/ddI, or AZT/ddC. A cohort of 400 individuals from this study had a very detailed virological analysis done: antiretroviral naive 55%, asymptomatic 85%, symptomatic 15%. The mean CD4 count of 343 was relatively high. Plasma was collected and stored specifically for RT-PCR assessment.
Dr. Coombs showed a graph of unpublished data that's been presented at meetings by Dr. David Katzenstein, that shows the relationship between the percent of progression to clinical endpoints and baseline RNA levels {baseline means that the RNA measure was before receiving study drug(s)}.
The endpoints are divided into three groups:
The progression to these endpoints for each of these 3 groups is compared between 4 different categories of baseline RNA ranges of measures. The first RNA group is those individuals with under 5,000 RNA copies; the second group is individuals between 5,000 and 19,000 copies; the third group is composed of individuals with between 19,000 RNA copies and 54,000; and the fourth group represents those with greater than 54,000 copies.
Those with over 54,000 RNA copies had, by far, the highest progression rates (prognosis), for each of the three clinical endpoint groups: the three markers; or progression to AIDS and death; or just death. Individuals with 19,000 to 54,000 RT-PCR copies had the next highest progression rate, in each of the 3 endpoint groups. Individuals with under 19,000 copies progressed the most slowly in each of the 3 endpoint groups; essentially, those from both groups, under 5,000 and 5,000 to 19,000, were quite similar in their rates of progression, as their was no significant difference. Clearly, in this study, disease is being driven by the people with the higher viral loads, more so with individuals with more than 54,000 copies, but also inclusive of those with more than 20,000 copies.
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About the author: Jules Levin is the Executive Director of NATAP, based in New York City.
The National AIDS Treatment Advocacy Project (NATAP) is a New York State non-profit corporation dedicated to facilitating the effort for development of effective treatment for HIV.
Last modified 9/3/96
by Jules Levin
Copyright © 1996 natap
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