MACS Study: HIV RNA Levels Predict Clinical Outcome
Measuring the amount of HIV in the bloodstream is the best available method for predicting an HIV-infected person's risk of developing AIDS or dying, according to investigators of the Multicenter AIDS Cohort Study (MACS), a project of the National Institute of Allergy and Infectious Diseases (NIAID).
John W. Mellors, M.D., of the University of Pittsburgh Medical Center and his colleagues report their findings, which build on previous studies in the MACS and elsewhere, in the May 24 issue of Science. An accompanying editorial by NIAID grantee David D. Ho, M.D., of the Aaron Diamond AIDS Research Institute, appears in the same issue.
In their study, the MACS researchers found that the level of HIV RNA (the genetic material of HIV) in a person's plasma was a better predictor of the risk of disease progression than the CD4+ T cell count. Measurements of CD4+ T cells, the immune cells typically depleted during HIV infection, are routinely used as an indirect or "surrogate" marker of HIV disease progression.
"The ability to predict HIV disease progression more accurately may help doctors better manage their HIV-infected patients," says Anthony S. Fauci, M.D., NIAID director.
The MACS investigators analyzed blood samples obtained every six months from 180 HIV-infected men who enrolled at the Pittsburgh site of the MACS between April 1984 and March 1985.
The patients in this study were followed for a longer period than those in any previous study of viral load. Median follow-up for patients who developed AIDS was 5.6 years (range, 0.02 to 10.6 years); for those who did not develop AIDS, median follow-up was 10.6 years (range, 3.2 to 11.2 years).
For their analyses, the investigators measured HIV RNA using an ultra-sensitive branched-DNA signal amplification assay, one of several new tests used in research settings to measure viral load. The assay yields reproducible results and is relatively simple to perform. It uses a light-detecting system to find HIV RNA in virus particles in a blood sample. The intensity of light generated by the captured particles is proportional to the amount of HIV RNA present.
The researchers found that only 8 percent of patients with fewer than 4,350 HIV RNA copies per milliliter (ml) of blood progressed to AIDS within five years of study entry, whereas 62 percent of those with more than 36,270 HIV RNA copies developed AIDS within five years. Individuals with intermediate viral loads had progression rates of 26 percent to 49 percent.
Only 5 percent of patients with an initial viral load below 4,350 copies/ml died within five years, whereas 49 percent of those with baseline viral load above 36,270 copies/ml died in the same period. Individuals with intermediate viral loads had mortality rates of 10 percent to 25 percent.
The researchers also found that approximately 95 percent of patients with persistently high viral loads, as assessed by two or more consecutive measurements, progressed to AIDS and died within 10 years.
In contrast to the close relationship between viral load and subsequent disease progression, initial CD4+ T cell counts were considerably less predictive of clinical course.
One analysis in particular underscored the independence of viral load and CD4+ T cell counts in influencing prognosis. Among patients with CD4+ T cell counts greater than 500/mm3 of blood at study entry (mean, approximately 780 cells/mm3), 50 percent of those with viral loads above 10,900 died within six years. By comparison, of individuals with similar CD4+ T cell counts but HIV RNA levels below 10,900, only 5 percent died.
"These data indicate that treatment strategies should not be based solely on CD4+ T cell numbers," says Dr. Mellors.
The MACS is one of the largest prospective HIV studies in the world. More than 5,000 homosexual and bisexual men were enrolled into the MACS between 1983 and 1991 at MACS clinical sites in Baltimore, Los Angeles, Pittsburgh and Chicago. Each volunteer is seen every three to six months for an assessment of their virologic, immunologic, clinical, behavioral and neurologic status.
NIAID, a component of the National Institutes of Health, conducts and supports research to prevent, diagnose and treat illnesses such as AIDS and other sexually transmitted diseases, tuberculosis, asthma and allergies. NIH is an agency of the U.S. Public Health Service, U.S. Department of Health and Human Services.
References:
Ho DD. Viral counts count in HIV infection. Science 1996;272:1124-5.
Mellors JW, Rinaldo CR, Gupta P, White RM, Todd JA, Kingsley LA. Prognosis in HIV-1 infection predicted by the quantity of virus in plasma. Science 1996;272:1167-70.
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