HIV measurement appears to be less reliable than thought in predicting loss of CD4 cells

Preliminary research indicates that the initial HIV RNA level in untreated HIV-infected patients appears to have little value in predicting the rate of CD4 cell count decrease, potentially limiting its clinical value concerning the decision of when to begin antiretroviral therapy for an individual, according to a study in the September 27 issue of JAMA.

Depletion of CD4 cells is a characteristic of progressive human immunodeficiency virus (HIV) disease and a powerful predictor of the short-term risk of progression to AIDS, according to background information in the article. Blood levels of HIV are also thought to predict HIV disease progression risk. In addition to their role as predictors of the clinical outcomes of HIV infection, CD4 cell count and plasma HIV RNA level are commonly used as markers of the success of highly active antiretroviral therapy (HAART). Until this study was completed, however, the degree to which blood levels of HIV could predict the rate of CD4 cell loss in HIV-infected individuals with similar demographic characteristics to those seen in clinical practice was unclear.

To address this question, Benigno Rodríguez, M.D., of Case Western Reserve University, Cleveland, and colleagues conducted a study to estimate the extent to which presenting blood levels of HIV can account for or "explain" the rate at which CD4 cells are depleted among an untreated HIV-infected population of patients including women and ethnic minorities. The study included repeated analyses of 2 multicenter groups, with observations beginning in May 1984 and ending in August 2004. Analyses were conducted between August 2004 and March 2006. The participants included antiretroviral treatment–naïve, chronically HIV-infected persons (n = 1,289 and n = 1,512 for each of the 2 groups) who were untreated during the observation period (6 months or greater) and with at least 1 HIV RNA level and 2 CD4 cell counts available. Approximately 35 percent were nonwhite, and 35 percent had risk factors other than male-to-male sexual contact.

The researchers found that only a small proportion of the rate at which CD4 cells are lost (only 4 percent - 6 percent) in a given individual patient could be explained by presenting plasma HIV RNA level, suggesting that in chronic untreated HIV infection over 90 percent of the determinants of CD4 cell decline are not reflected in the amount of virus in blood at the time of initial medical evaluation.

"Our findings confirm previous observations that the magnitude of HIV viremia [the presence of a virus in the blood stream], as defined by broad categories of presenting HIV RNA level, is associated with the rate of CD4 cell loss and extend this observation to patient populations comprising both men and women. Despite this association, however, only a small proportion of the interindividual variability in the rate of CD4 cell decline can be explained by plasma HIV RNA level, even after accounting for the effect of measurement error," the authors write.

"These findings represent a major departure from the notion that plasma HIV RNA level is a reliable predictor of rate of CD4 cell loss in HIV infection and challenge the concept that the magnitude of viral replication (at least as reflected by plasma levels) is the main determinant of the speed of CD4 cell loss at the individual level. The clinical implications are that in the majority of cases, an individual patient's plasma HIV RNA level at the time of presentation for clinical care cannot predict, to a significant extent, the rate of CD4 cell decline that he or she will experience over the subsequent years and is therefore of limited clinical value in shaping the decision to initiate antiretroviral therapy," the researchers write.

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(JAMA. 2006;296:1498-1506. Available pre-embargo to the media at www.jamamedia.org.)

Editor's Note: This work was supported in part by the Case Western Reserve University Center for AIDS Research and NIH grants. Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, funding and support, etc.


Editorial: Explaining, Predicting, and Treating HIV-Associated CD4 Loss - After 25 Years Still a Puzzle

In an accompanying editorial, W. Keith Henry, M.D., of the University of Minnesota, Minneapolis; Pablo Tebas, M.D., of the University of Pennsylvania, Philadelphia; and H. Clifford Lane, M.D., of the National Institute of Allergy and Infectious Diseases, Bethesda, Md., discuss the findings concerning HIV RNA levels and CD4 cell loss.

"The study by Rodriguez et al may have several important clinical implications. The first and more straightforward is that baseline measurements of viral load alone should have less of a role in driving decisions on when to start antiretroviral therapy for an individual patient; these initial viral load levels cannot predict how rapidly the disease will progress. … The seemingly useful practice of combining a CD4 cell count and plasma HIV RNA levels to assess an individual patient's prognosis for AIDS progression or response to highly active antiretroviral therapy needs reexamination."

"The second and potentially more exciting implication of the findings of Rodriguez et al is that future improvements in the treatment of HIV infection and AIDS may result from improved understanding of the 90 percent of CD4 cell depletion that remains enigmatic," they write. "A better understanding of the immunologic and genetic factors that drive HIV-associated CD4 cell loss may translate to novel therapeutic approaches that could favorably shift the pathogen-host balance. … Discovering and developing therapies that target key nonviral factors has the potential over the decades ahead to build on the success of antiretroviral therapy and expand access to sustainable effective therapy." (JAMA. 2006;296:1523-1525. Available pre-embargo to the media at www.jamamedia.org.)

Editor's Note: Please see the editorial for financial disclosures, funding and support, etc.


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