A 2 log RNA Reduction Is Not The Same For Everyone

Viral Load Testing

By Jules Levin, Executive Director of NATAP

The issue of relative changes is important. Dr. Coombs displayed a chart of 3 RNA measures: 1,000,000, 100,000 and 10,000. If each had a 2-log reduction in viral load, the 1 million would be reduced to 10,000---the 100,000 would be reduced to 1,000 and the 10,000 would be reduced to 100. The question to us--is the clinical benefit of driving the viral load down 2 logs, the same for individuals in the different ranges of RNA measure? Biologically and intuitively, you can surmise that those with the highest measure at baseline of 1 million, would be the group that would benefit most from driving the viral load down as low as possible.

This is a crucial question because it impacts how aggressively one pursues initiating or changing therapy, and at what cost do we drive the viral load down. Now that we have these very potent drugs--protease inhibitors--the practical use of these drugs is vital to individuals, in the hopes of optimizing and not wasting the potential benefits that may accrue to you from this class of drugs.

Following is a review of data that approaches this concern differently. This data was presented by Upjohn & Pharmacia at the 3rd Conference on Retroviruses and Opportunistic Infections in January 1996. It looks at the relationship in the change in viral load for the patients in their two studies (n=1740) of delavirdine, a non-nucleoside reverse transcriptase inhibitor, as measured by their own in-house assay, . The study participants have been randomized to different treatment regimens, and have been taking study drug for an average of 10 months (range 2 to 18 months).

The patients were grouped into 3 different viral load ranges of measures: greater than 1,000,000 copies; under 100,000 copies; and the middle group of 100,000 to 1 million. We don't know how these numbers correlate with the RT-PCR assay or the bDNA assay because the in-house test used by Upjohn wasn't run with the same set of standards as the other tests.

Commentary: [However, Upjohn says their assay was validated and it has the same degree of efficiency and reproducability as the RT-PCR assay; and, the RNA measure is 5 times that of the RT-PCR measure, i.e. a 1 million RNA measure, by the Upjohn assay, is equal to 200,000 RT-PCR copies, 100,000 copies by Upjohn assay is approximately equal to 20,000 RT-PCR copies.]

Individuals were also grouped by changes in viral load, that resulted from the study therapy to which they were randomized; the 5 groups were: (1) individuals with an increase in RNA; (2) a RNA reduction of a 0.5 log to 0.3 log or 2-3 fold; (3) a reduction of 3 to 5 fold; (4) a decrease of 5 to 10 fold or 1 log; (5) a decrease of more than 1 log.

The graph shown by Dr. Coombs illustrated the point that individuals with the highest viral load (the group with more than 1 million copies), in this study, benefitted the most, as measured by clinical progression. In this group with viral load above 1 million (at baseline), individuals: in group (1) with an increase in viral load (subsequent to initiating therapy), showed the least benefit in clinical progression; there is a linear relationship in the amount of benefit each group had, as measured by clinical progression; that is, the more of a reduction in RNA that individuals had, then the greater their benefit, as measured by clinical progression.

The linear relationship between these groups was clearly evident in the group of individuals with greater than 1 million copies. In the middle group, of individuals with RNA between 100,000 and 1 million, the relationships between the 5 groups weren't quite as linear but, viral load reductions, even modest ones, showed reductions in clinical progression. In the group with under 100,000 RNA copies (20,000 RT-PCR copies), there seemed to be no difference in benefit to clinical progression, between the 5 groups.

Dr. Coombs said, this suggests to him that individuals with higher viral load may receive more benefit than individuals with lower viral loads from therapy that results in similar reductions in viral load. Again, he suggested this may be a factor in how aggressively we use therapy to drive the viral load down. [Commentary--However, As I suggest in discussion below, because this group is a healthier population, it may take much longer to detect differences in clinical responses.]

[Commentary: His earlier point was--what is the cost/benefit ratio of driving viral load down "as low as possible"? The results of this study indicate that at least among individuals with higher viral load (most likely for those with above 54,000 RNA, and mostly for those above 20,000), the amount of viral load reduction correlates with clinical progression, i.e. even incremental changes (a difference between 3-5 fold and 2-3 fold) in viral load produce differences in clinical progression (prognosis).

The Upjohn studies will not be completed until 1997, but data has been accumulated and analyzed for individuals with an average of 10 months in the trials (range 3-18 months). Although the analysis is preliminary, because the study is still ongoing, you can surmise some confirmation of viral load's correlation with clinical progression (prognosis). There are two studies. For protocol #17, the average CD4 was 135 at study entry, study participants averaged 1 to 1.5 years of AZT-experience. Subjects were randomized to either ddI alone or delavirdine + ddI. For the 2nd study, protocol # 21, subjects averaged 335 CD4, were AZT-naive or with under 6 months experience, and were randomized to either AZT, or AZT+delavirdine (Individuals were randomized to receive 3 different doses of delavirdine: 200, 300 or 400 3X/day).

Proportion of subjects progressing to AIDS or death

	protocol #17	protocol #21
greater than 1 million RNA at baseline	30%	12%
between 100,000 to 1 million	11%	1%
less than 100,000	1%	0%

As you can see, individuals with higher CD4 (335) in #21, progressed more slowly, than those with lower CD4 (135) in #17. These are individuals whose viral load changed as a result of therapy, but therapeutic intervention did not occur because viral load was increasing, for any particular individual (that is the FDA's point). It is only 10 months of follow-up, and we do need longer-term data, but the implications are encouraging.

Commentary (cont.): This study, in summary, makes 4 points: (1) changes in viral load measures, that occur from therapy correlate with clinical progression, at least at 10 months; but, as mentioned earlier if an individual's viral load is rising and you then intervene with therapy and the viral load declines--will that person's course of disease progression be positively altered? As Dr. Coombs said, we are surmising that it will alter the course of disease progression, but, he and the FDA say we need studies to confirm this; however, the concern is that some individuals in such a study would be randomized to the control group and thereby potentially suffer; (2) together, CD4 and viral load may be more predictive than either alone; (3) individuals with higher viral load may benefit more, from an equal viral load reduction, than those with low viral loads (under 20,000). Although this needs confirmation, it brings into the equation, the consideration of the cost/benefit ratio; (4) each incremental reduction in viral load (for example, a difference between a 2-3 fold and a 3-5 fold reduction) may result in a difference in clinical progression, which again may be more pronounced at higher viral load levels.

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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.

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