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.
About University Hospitals
With 150 locations throughout Northeast Ohio, University Hospitals serves the needs of patients through an integrated network of hospitals, outpatient centers and primary care physicians. At the core of our Health System is University Hospitals Case Medical Center. The primary affiliate of Case Western Reserve University School of Medicine, University Hospitals Case Medical Center is home to some of the most prestigious clinical and research centers of excellence in the nation and the world, including cancer, pediatrics, women's health, orthopedics and spine, radiology and radiation oncology, neurosurgery and neuroscience, cardiology and cardiovascular surgery, organ transplantation and human genetics. Its main campus includes the internationally celebrated Rainbow Babies & Children's Hospital, ranked best in the Midwest and first in the nation for the care of critically ill newborns; MacDonald Women's Hospital, Ohio's only hospital for women; and Ireland Cancer Center, which holds the nation's highest designation by the National Cancer Institute of Comprehensive Cancer Center. For more information, go to www.uhhs.com.
About Case Western Reserve University School of Medicine
Founded in 1843, the Case Western Reserve University School of Medicine is the largest medical research institution in Ohio and 12th largest among the nation's medical schools for research funding from the National Institutes of Health. Eleven Nobel Laureates have been affiliated with the school.
The School of Medicine is recognized throughout the international medical community for outstanding achievements in teaching. In 2002, it became only the third medical school in history to receive the best review possible from the national body responsible for accrediting the nation's medical schools. It ranks in the top 25 among U.S. research-oriented medical schools in the U.S. News and World Report guide to graduate education. Annually, the School of Medicine trains more than 600 M.D. and M.D./Ph.D. students. The School's Western Reserve2 curriculum interweaves four themes--research and scholarship, clinical mastery, leadership, and civic professionalism--to prepare students for the practice of evidence-based medicine in the rapidly changing health care environment of the 21st century.
The School of Medicine's primary clinical affiliate is University Hospitals Case Medical Center and the school is additionally affiliated with MetroHealth Medical Center, the Louis Stokes Cleveland Department of Veterans Affairs Medical Center, and the Cleveland Clinic Foundation, with which it opened the Cleveland Clinic Lerner College of Medicine of Case Western Reserve University in 2004. http://casemed.case.edu
Journal
JAMA