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T
Cell Activation and Maturation Help Predict Treatment Response
Accelerated
development of new drugs for the treatment of HIV-1 infection has
been made possible by the validation of 2 essential biomarkers that
serve as surrogates for clinical efficacy in antiretroviral trials--
CD4+ T lymphocyte counts and plasma HIV-1 RNA concentrations.
Together,
these markers do not fully explain the benefit of potent antiretroviral
therapy (ART) on clinical outcomes, such as AIDS progression and
death, as would the ideal biomarker. Still, their relevance to the
pathogenesis of HIV infection and disease has
been well established in natural history studies.
Their
consistent performance across trials as indicators of ART activity,
together with the demonstrated relationship between such activity
and a reduction in subsequent clinical events, has led to the uniform
(including regulatory) acceptance of HIV RNA and CD4+
T cell count as measurements signifying antiretroviral and immunorestorative
efficacy, respectively.
The
goal of the present study was to examine whether naive CD4+
T lymphocytes and activated CD4+ and CD8+
T lymphocytes, as measured by flow cytometry, contribute independent
information to HIV RNA load and CD4 cell count in predicting the
response to ART.
The
Immunophenotypic Markers and ART (IMART) study is a cross-protocol
analysis of 5 current multicenter Adult AIDS Clinical Trials Group
(AACTG) trials of potent ART that assayed these T cell immunophenotypic
markers by consensus methods, in subjects who were previously untreated
or treated only with nucleosides. Because the timely evaluation
of the markers would require access to data from ongoing trials,
novel data-sharing conditions were developed to limit the possible
negative effect on contributing parent studies
Additional
models showed the greatest increase in CD4+ T cell counts
in subjects with highest pretreatment naive CD4+ T cell
counts (P < .0001), which was enhanced by high CD4+
and low CD8+ T cell activation.
Total
lymphocyte count also predicted a subsequent CD4+ T cell
change. These results document the utility of T cell markers in
predicting treatment outcome and their potential value for the study
and management of HIV-1 infection.
Discussion
These
results demonstrate that immunophenotypic markers of T cell activation
and maturation, as measured by flow cytometry before the initiation
of potent ART, independently distinguish subjects who will achieve
the greatest and least favorable virologic and immunologic responses
24 weeks later.
A
significant finding in the IMART study was the demonstration, in
multivariate modeling adjusted for HIV RNA, CD4 cell count, and
other baseline factors, including study as a proxy for treatment
assignment, that a higher baseline level of CD8+ T cell
activation predicted a poorer virologic response at week 24;
10
percentage points higher baseline level of CD8+ T cell
activation resulted in an HIV RNA that was estimated to be 0.2 log10
higher 24 weeks later (P = .046). The model also identified
a higher baseline HIV RNA, which is a validated prognostic marker,
and younger age, which is a probable indicator of less-strict adherence
to treatment, as independent predictors of an unfavorable HIV RNA
response at week 24, along with a trend toward a lower baseline
CD8+ T cell count,
Consistent
with these observations, subjects with a week-24 percentage of CD8+
T cell activation above the median were significantly more likely
to have a detectable HIV RNA ( 400 copies/mL)
at week 24 (P < .001).
A
new finding in the present study is that the activation status of
both CD4+ and CD8+ T cells, although not predictive
individually, represent significant positive and negative modifiers,
respectively, of the baseline naive CD4+ T cell count
in predicting subsequent increases in CD4+ T cell counts effects that were
seen predominantly in individuals who had CD4+ T cell
counts >200 cells/mm3.
Conclusions
In
conclusion, immunophenotypic markers of T cell activation and maturation
are valuable prognostic and treatment-response indicators for ART,
and they hold promise for application to the design of trials and
guiding therapeutic choices to optimize outcome. The IMART study
complements and adds new information to its contributing parent
studies, thus confirming the usefulness of the developed methodology
for cross-protocol marker analysis as a template for future investigations
aimed at the timely evaluation of marker data from ongoing trials.
05/12/04
Reference
D
Mildvan and others. Immunophenotypic Markers and Antiretroviral
Therapy (IMART): T Cell Activation and Maturation Help Predict Treatment
Response.
The Journal of Infectious Diseases 189:1811-1820. May 15, 2004.
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