Novel technology could optimize drug therapies
Diagnostic monitors real-time disease progression
A new diagnostic tool that can measure the daily production and destruction rates of T cells and HIV virus has the potential to subtype patients and help assure they receive the right treatment regimen at the right time, say academic researchers studying the technology.
Research developments related to the test, which utilizes isotope mass spectrometric technique, were reported at the 5th Conference on Retroviruses and Opportunistic Infections in Chicago in January. A description of the technique was published in the Jan. 20 issue of the Proceedings of the National Academy of Sciences.
"The implications of the technology’s capability to quickly and accurately monitor the status and progress of this disease in real time are significant," says Joseph Adlerstein, PhD, president of SpectruMedix, the State College, PA, company developing the diagnostic. "A physician should be able to go beyond merely improving and optimizing the diagnosis and therapy by individually selecting the optimum treatment, and pinpointing its initiation, duration, and dosage."
Using sophisticated instruments called mass spectrometers, researchers have developed a test for measuring the daily rate of T cell formation and their life span. The test also allows researchers to measure the rate of change in new cell development, or the "T-cell kinetics." This kinetic representation can tell physicians such important information as how many T cells are being destroyed and regenerated, how many atherogenic particles flow in and out of blood cell walls, and the rate at which epithelial cells proliferate.
Among the new generation of diagnostic tools, the test opens up opportunities for direct measurement of the immune system that have the potential to help clinicians assess issues ranging from when a patient should initiate therapy to how patients with high CD4 counts and high viral load should be treated, says Marc Hellerstein, MD, PhD, associate professor of medicine at University of California at San Francisco and Berkeley University.
"This will give us the ability to have more specificity in understanding a patient," he tells AIDS Alert. "Basically it will enable us to subtype patients."
Procedure uses natural substances
The procedure is fairly simple. Patients are infused with small amounts of glucose containing a non-radioactive chemical called deuterium, which occurs naturally in the body and is used here to label new cells. A week or so later, the patient has his blood drawn and the blood is processed. When cells replicate, they use glucose to build new DNA. Although the body can’t differentiate between DNA molecules that contain deuterium and those that don’t, a mass spectrometer can determine the amount of deuterium-labeled sugar, which indicates new cell development, and thus measure the daily rate of T cell formation and life span.
"The difference between kinetic and static measurements in biochemistry is analogous to motion pictures vs. snapshots in photography," says Bernard Sonnenschein, a spokesman for Spectrumedix. "Just as a snapshot of a stormy sky doesn’t tell you what you really want to know — how fast the rain clouds are moving — snapshots of T cell counts, blood cholesterol concentrations, or the BRCA-1 polymorphism, for example, do not tell physicians what they really need to know."
The technique has potential clinical benefit for other diseases besides AIDS, but so far the only published research has been limited to a discussion of the technique. However, a study is being submitted for publication using the test in patients who are HIV-negative compared to those who are HIV-positive and taking triple-combination therapy or no therapy, Hellerstein says.
As an example of how the test might be used in the clinical setting, Hellerstein describes a patient who is on aggressive antiretroviral therapy and experiencing viral suppression, yet his T cells aren’t rising. Are the patient’s T cells being killed by the virus, even though it is in low abundance, or is the immune system so weakened it can no longer make new cells? If it’s the later scenario, which kind of new cell is the immune system failing to make — naive T cells or memory T cells?
"There is a whole different kind of biological basis for these two, so it would be critical to know," he explains. "In the one case you need thymic epithelial cells and bone marrow cursors, and in the other case you need memory clones and dendritic helper cells and so on."
With increased interest in co-immunologic therapy, that type of information becomes critical if clinicians are to get beyond merely guessing at what treatment will be most effective, he adds.
Hellerstein sees another, more routine potential application of the test. One of the most difficult dilemmas clinicians face is when to initiate therapy in a patient who has CD4 counts above 500. Without more information on those T cells, the decision cannot be based on hard data — and probably never will be, as a randomized study following patient outcomes 10 years or more down the road is not feasible.
"Nobody has a clue, so wouldn’t it be nice if we had an index of some early evidence of stress in the system, that something is giving [out] that I can see down the road?" he asks. "This person has 600 CD4 cells but the body is working hard making a lot of cells or is starting to fail to make naive cells. So you might do this test early in disease and have the ability to tell them now is the time for you [to start treatment]."
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