A newly published study by investigators at the Center for AIDS Research at Case Medical Center, led by Benigno Rodríguez, MD, along with a nationwide team of AIDS/HIV experts, strongly challenges conventional thinking about the role of measurements of the amount of HIV particles in the blood as a method of predicting a patient's ability to fight off the disease. The study, published in the current issue of JAMA (Journal of the American Medical Association), indicates that the amount of HIV in a patient's blood (commonly known as the viral load) is much less reliable as a tool for determining the rate at which he or she will lose infection-fighting CD4 cells than previously thought.
HIV targets CD4 cells, a type of white blood cell, and as they decline after HIV infection, the complications that characterize the Acquired Immunodeficiency Syndrome (AIDS) become more common. These study results showed that the viral load explains only about 5% of the variation from person to person in the rate of CD4 cell loss. Thus, CD4 depletion cannot be viewed as a simple consequence of the amount of virus circulating in the blood.
"The results of this nationwide study may have profound implications in our understanding of how HIV causes disease and in our approach to the management of HIV-infected patients," says Dr. Rodriguez, infectious disease specialist at the Case Medical Center, a partnership of University Hospitals and Case Western Reserve University School of Medicine. "We hope that this study will provide impetus for a more thorough understanding of the mechanisms of HIV-induced damage to the immune system and for the design of strategies to block those mechanisms."
In the study, entitled Predictive Value of Plasma HIV RNA Level on Rate of CD4 T Cell Decline in Untreated HIV infection, Dr. Rodríguez and his colleagues report the results of analyses conducted on two large cohorts of HIV-infected patients who were not receiving treatment for HIV, totaling more than 2,800 individuals. The first cohort consisted of patients included in three data sources: a) four sites of the Centers for AIDS Research Network of Integrated Clinical Systems (CNICS), a database of real-time clinical care and laboratory data; b) the San Francisco Men's Health Study (SFMHS) and the Research in Access to Care for the Homeless Cohort (REACH). This cohort included approximately 12% female and 35% non- Caucasian participants. The second cohort, which the investigators used to validate their findings in the first group, included participants in the Multicenter AIDS Cohort Study, a long-standing federally funded study composed largely of Caucasian men who have sex with men.
The investigators sought to estimate how much of the person-to-person variation in the rate of CD4 cell loss could be accounted for on the basis of each patient's initial viral load, in an attempt to reproduce more closely the situation that a physician would encounter in clinical practice, where a patient presents with an initial set of laboratory results and the clinician must try to predict how quickly that person's CD4 cell count will reach the danger level at which treatment for HIV becomes most critical. Current clinical practice, based on previous work from other groups, is to focus on both the current CD4 count and the viral load to estimate how rapidly a person's CD4 cell count will decrease. This approach is based on comparisons of the average rate of CD4 cell loss among groups of patients with roughly similar viral loads, which indicate that generally speaking, patients with higher viral loads will tend to experience more rapid CD4 cell loss than patients with lower viral loads. Until now, however, there had been no attempt to quantify how well this observation held when considering the estimated rate of CD4 cell loss for each individual patient.
Using sophisticated statistical modeling, the researchers found that only 4-6% of an individual patient's CD4 cell loss rate can be explained by his or her presenting viral load. Moreover, the results were remarkably similar when the analyses were reproduced separately in each of the two cohorts, and changed only minimally when the investigators considered the possible effect of errors in the measurement of the CD4 cell count and the HIV viral load.
These results represent a shift in the paradigm that the rate of CD4 cell loss in a given HIV-infected individual can be accurately predicted by his or her viral load. Predicting disease progression is crucial in the treatment of HIV-positive people, such as in making the decision as to when it is best for starting antiretroviral therapy. Current treatment guidelines, while diminishing its importance, continue to include HIV viral load as one element in making decisions regarding when to begin antiretroviral therapy. Antiretroviral therapy, also known as HAART, is credited with saving millions of lives. However, potent side effects and issues of drug resistance, often cause doctors and patients to defer starting the medications, until it becomes medically necessary.
In addition to the clinical ramifications, the findings suggest that HIV-associated CD4 depletion cannot be thought of as a mere consequence of the amount of virus circulating in the blood. Instead, the findings suggest rather more complex scenarios of disease progression, and hint at indirect processes though which HIV can induce damage to the immune system, which cannot be adequately captured by measuring HIV levels in the blood.
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