New ultrasensitive test may cause ultra-confusion
New ultrasensitive test may cause ultra-confusion
More accurate viral-load assay is finding its niche
Just when clinicians and patients were becoming familiar with the meaning of viral-load measurements, diagnostic companies are developing more sensitive assays that could be on the market by next year. The need for the ultrasensitive assays is greatest in clinical trials, but researchers expect them to be used in certain clinical situations, such as monitoring the success or failure of drug regimens.
In August, Roche Diagnostic Systems of Nutley, NJ, submitted its Ultrasensitive Method Test to the Food and Drug Administration for approval in clinical trials. The test is designed to quantify HIV RNA at levels significantly lower than the limits of detection for its Amplicor HIV Monitor Test, which is 400 copies per milliliter of plasma.
Since studies have shown that viral load can be used as a predictor of clinical progression to AIDS, viral-load testing has become a standard of care both for monitoring the natural history of HIV and the success or failure of treatment. The FDA has approved viral load testing for assessing a patient’s prognosis by measuring baseline RNA levels and comparing them over time. In July, however, Roche requested FDA approval for using its test to monitor the effects of antiretroviral therapy as well. It based its application on data collected as part of a clinical research program conducted to establish the efficacy of saquinavir.
The ultrasensitive test has been used as a research tool for more than a year in several studies. The assay has a sensitivity that ranges from 50 copies to upward of 30,000 copies. At press time, Roche was still analyzing its data before deciding on the upper limits it would submit for its application. It is possible the company would lower its claim for upper limits to 10,000 to 20,000 copies, says Alex Wesolowski, Roche Molecular System’s director of regulatory affairs. Roche’s standard viral load assay claims sensitivity ranging from 400 copies to 750,000 copies.
Tests must show one-to-one correlation
In order to seek approval, the company has had to prove tight correlation between the ultrasensitive and standard tests. In the range where they overlap in values from 400 to 30,000 there has to be a one-to-one correlation or transference in order to receive a new protocol for the test, says Beverly Dale, PhD, director of scientific affairs for Roche Molecular Systems. The precise overlap eliminates the need to convert numbers from one test to the other, she adds.
The Laboratory Corporation of America has been using the ultrasensitive method, primarily for validation studies, reports Tim Alcorn, MD, the company’s director of infectious diseases. The addition of the new test essentially gives labs a single assay that ranges from 50 to 750,000 copies. The assay would become part of a package that Roche is putting together that would include resistance testing as well as viral-load testing, he adds.
A more sensitive viral-load assay has obvious advantages in assessing the efficacy of new drugs in clinical trials. Its role in managing patients, however, is less clear. Indeed, the addition of a more sensitive assay will cause widespread confusion at first, said Michael Saag, MD, director of the AIDS Outpatient Center at the University of Alabama in Birmingham. A patient whose virus was undetectable under the standard test could be told he or she actually has 200 or 300 copies after being tested with the new assay.
"We are about to reach viral-load freakout," he recently told a panel of AIDS experts. "We have been celebrating with a bunch of patients who have been less than 400 counts [undetectable by standard assay]. They have been thinking everything is hunky-dory, and now we are going to switch our assay from less than 400 copies to less than 50."
The problem is that researchers don’t have enough experience with protease inhibitors and sensitive assays to know the clinical significance of a viral load of 50 copies vs. a viral load of 400 copies. Several studies are under way to assess those differences, and preliminary data indicate that the difference could be significant, says John Mellors, MD, director of the HIV/AIDS program at the University of Pittsburgh.
We should aim for zero copies’
"I don’t think we have enough experience with a copy number of 200 on triple combination to know whether that is going to result in failure," he said. "We do know the converse: Those who remain suppressed generally have less than 50 copies. My personal view is that we should aim for zero copies."
Mellors is using the ultrasensitive test for a retrospective analysis of stored plasma from a large cohort of gay men. In earlier studies of this population, he was able to establish viral load cutoff points that correlated with disease progression down to 400 copies. It is possible that a lower threshold might be established, indicating a clinical advantage to reducing viral load below the "undetectable" level in the standard assay, says William O’Brien, MD, chief of the AIDS pathogenesis research program at the University of Texas in Austin.
"The concept now is that you want to reduce the viral load as much as possible because those with the greatest viral-load reduction will have the longest duration of benefit. This is where the 20- or 50-copy assays will most be used," he says. "You will see detectable virus sooner with more sensitive assays, and perhaps move faster than if you were blind to these changes by less sensitive assays."
Alcorn notes from his experience using the assay that many patients who have undetectable virus using the standard assay still have significant levels of circulating virus. With the ultrasensitive test they now have a number that can be monitored. "Whether those trends suggest switching therapy when a patient goes from 50 to 250 it will take some time before that data is gathered," he notes.
Because the upper limit of the ultrasensitive assay is so much lower compared to the standard assay, it would not be appropriate for initial screening of patients or for patients who are known to have high viral loads, he says. Indeed, at a cost of $225 per test, clinicians will want to avoid duplicating tests, he adds.
Future may require DNA testing as well
Looking farther into the future, Roche Diagnostics is developing a DNA assay that would be the next logical test after a patient’s virus becomes undetectable with the ultrasensitive assay, says John Sninsky, PhD, senior director of research for Roche Molecular Systems. A DNA test is the only way of knowing whether virus has been completely eradicated from the body, he adds.
Although the commercial use of such an assay is premature, it is being used in the research setting and would be a necessary diagnostic tool if the much-touted eradication theory holds true that is, it may be possible for a patient to discontinue therapy after a period of complete suppression and experience what would amount to a cure. In the upcoming year, a dozen or so patients at the Aaron Diamond AIDS Research Center will be making that decision, and researchers there are considering making a negative DNA test part of the criteria for allowing them to discontinue therapy, Sninsky says.
"The hope, as indicated by the eradication theory, is that one will have to know when to switch from an induction to a maintenance phase, or when to productively consider removing therapy," he explains.
Meanwhile, the DNA assay is being used in several small studies in the United States and Europe to determine if it has commercial value, Sninsky adds.
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