The studies, one led by John W. Mellors, M.D., of the
University of Pittsburgh School of Medicine, and Alvaro Munoz, Ph.D.,
of the Johns Hopkins School of Public Health, the other by Michael D.
Hughes, Ph.D., of the Harvard School of Public Health, and Richard
T. D'Aquila, M.D., of Massachusetts General Hospital and Harvard
Medical School, appear in the June 15 issue of the Annals of Internal
Medicine. An editorial by NIAID grantee Michael D. Saag, M.D., of
the University of Alabama at Birmingham, accompanies these reports.
"These studies help refine our understanding of prognostic markers for
HIV infection and underscore the value of routinely using both viral
load measurements and CD4+ T cell counts in the care and management
of individuals with HIV/AIDS," says NIAID Director Anthony S. Fauci,
Last year, Dr. Mellors and his colleagues in NIAID's Multicenter AIDS
Cohort Study (MACS) reported that measuring the amount of HIV RNA
in the bloodstream, commonly referred to as viral load, is the single
way to predict an HIV-infected person's risk for developing AIDS or
The current MACS study confirms and extends those findings.
"Our study showed that, while viral load is the most powerful
single predictor of outcome in HIV-infected individuals, combining it
with CD4+ T cell counts allows a more precise estimation of
prognosis," explains Dr. Mellors.
The researchers measured HIV viral load in baseline blood
samples obtained from more than 1,600 HIV-infected men who
enrolled in the MACS study between March 1984 and April 1985.
Physicians measured the participants' CD4+ T cell counts at study
entry and monitored the men for signs of HIV disease progression
over a 10-year period. Nearly 1,000 participants developed AIDS
during this period.
Using a technique known as regression tree analysis, the
researchers divided study participants into 12 categories defined by
discrete intervals of viral loads and CD4+ T cell counts and
determined how many persons in each category had developed AIDS
within three, six and nine years of their entry into the study.
The researchers found that CD4+ counts provided important
information for discriminating the relative risk for disease progression
among individuals with similar viral load levels. For example, only 3.6
percent of study participants with 500 or fewer copies of HIV RNA per
milliliter (ml) of blood and more than 750 CD4+ T cells per cubic
millimeter (mm3) of blood progressed to AIDS within nine years. By
comparison, 22.3 percent of persons with the same viral load but 750
or fewer CD4+ cells/mm3 progressed to AIDS within the same period.
At the other end of the risk spectrum, 97.9 percent of persons with
baseline viral loads greater than 30,000 copies/ml and less than 200
CD4+T cells/mm3 progressed to AIDS within six years, compared with
66.8 percent who had the same viral load but greater than 500 CD4+
The MACS study was initiated prior to the availability of anti-HIV
drugs. Therefore, only 60 percent of the participants were treated with
antiretrovirals during the 10-year study period. Those who were treated received
monotherapy with AZT or other nucleoside analogue drugs.
"Our results were not confounded by subsequent therapy
because there were no baseline differences in the values of the
markers between treated and untreated individuals," says Dr. Mellors.
"These markers," he adds, "were highly predictive of outcome
independent of subsequent treatment with nucleoside monotherapy.
The value of this study is that it accurately estimates prognosis for
the HIV-infected individual considering therapy."
In a study of the use of these measures during combination
antiretroviral therapy, Drs. Hughes, D'Aquila and colleagues in
NIAID's AIDS Clinical Trials Group (ACTG) found that prediction of
disease progression can be optimized by measuring viral load and
CD4+ T cells before, and viral load shortly after, treatment begins.
The researchers measured baseline viral load and CD4+ T cell counts
in 198 HIV-infected individuals participating in ACTG study
241, which compared treatment with AZT and didanosine (ddI) to
treatment with AZT, ddI and nevirapine. These measurements were
repeated eight and 48 weeks after treatments started. Over a one-year
treatment period, the investigators monitored study participants
for signs of disease progression.
A total of 34 individuals developed opportunistic infections,
malignancies or died during the treatment period. There was no
significant difference in the number of these events between the two
treatment groups. The researchers found that low CD4+ T cell counts
and high viral loads at baseline independently predicted the risk of
disease progression and death. However, they also found that the
combined use of these measures improved their predictive value:
individuals with high viral loads and low CD4+ T cell counts were
more likely to develop AIDS than were those with high viral loads and
relatively higher CD4+ T cell counts.
Measuring viral load eight weeks after treatment started
provided still more prognostic information -- there was a 52 percent
reduction in risk of disease progression for every 10-fold decrease in
viral load at this point.
"We also found that a 2.5-fold or greater change in viral load
probably indicates a true biological change in an individual patient,
rather than a random fluctuation," says Dr. D'Aquila. "Our results,
and those of other studies, suggest that clinicians might consider
alternate treatments if a patient's viral load is not decreased by at
least 2.5-fold within several weeks after a new antiretroviral regimen
NIAID, a component of the National Institutes of Health (NIH),
supports research on AIDS, tuberculosis and other infectious
diseases, as well as allergies and immunology. NIH is an agency of
the U.S. Department of Health and Human Services.
Note: MACS investigators measured viral load with a branched DNA
assay manufactured by Chiron Corporation (Emeryville, Calif.). In the
ACTG study, researchers measured viral load with a quantitative
reverse transcription-polymerase chain reaction assay made by
Roche Molecular Systems (Alameda, Calif. and Branchburg, N.J.).
Supplemental support for viral load testing in ACTG 241 was provided
by Boehringer Ingleheim Pharmaceutical, Inc. (Ridgefield, Conn.).
Boehringer Ingleheim, Bristol-Myers Squibb Co. (Wallingford, Conn.)
and Glaxo Wellcome Co. (Research Triangle Park, N.C.) provided
study medications for ACTG 241.