A free access paper and accompanying commentary in Clinical
Infectious Diseases address the issue of long-term immune recovery on antiretroviral
therapy (ART). The paper describes results from AIDS Clinical Trials Group (ACTG) study
384, the largest and most detailed evaluation of the effects of ART
on CD4 T cell counts and other immune parameters. The commentary by Elvin Geng
and Steve Deeks provides an excellent overview of the findings.
ACTG 384 stratified participants using baseline CD4 count,
and the most striking consequence of being below 50 cells/mm3 was the depletion
of naïve CD4 T cells and the consequent skewing of the naïve-memory ratio. The
strata used in the study were <50,
51–200, 201–350, 351–500, and >500 cells/mm3, and the median baseline CD4+
naive‐memory cell ratio for individuals starting with a CD4 cell count <50
cells was 0.21 at baseline and increased to only 0.43 at week 144 – this was
still lower than the median pre-treatment ratio for the higher CD4 strata. The
lower CD4 strata also had the poorest improvement in CD4/CD8 ratio, and as Geng
& Deeks note in their commentary “These two trends—a low naive‐memory cell
ratio and a low CD4:CD8 ratio—have been seen both in those with untreated HIV
infection and in the elderly (>75 years of age).” Conversely, individuals
who started ART with CD4 counts >350 attained immune profiles that
overlapped with HIV-negative individuals. The ACTG 384 data complement the findings recently reported by Rita Effros and colleagues
regarding the premature aging of the immune system in HIV infection.
Geng & Deeks also offer some intriguing thoughts as to
how the results may relate to the elevated risk of clinical disease that has
been reported in individuals with a poor CD4 T cell recovery on ART:
“We believe that the conclusions reached by Robbins et al. might provide a mechanistic explanation
for why some patients who receive HAART remain at risk of disease. Naive T
cells are critical in both mounting an effective adaptive immune response
against novel antigens and maintaining normal T cell homeostasis. Those naive T
cells that survive untreated HIV infection are at least partially dysfunctional
and have impaired proliferative capacity. It has recently been shown that
chronic inflammation contributes to failure of naive T cell homeostasis, either
by causing too much proliferation or by causing failure of naive T cells to
proliferate in response to either homeostatic signals (which leads to lack of
robust peripheral CD4 gains) or to novel antigens (which leads to disease).
Tying this together, it is possible to construct a testable model in which
those patients who initiate HAART late in their disease course have residual
inflammation, suboptimal CD4+ T cell gains, skewed immunophenotypic profiles,
persistent T cell dysfunction, and increased risk of all‐cause morbidity and
mortality.”
Among the studies cited in support of this model is the
recent Christine Bourgeois paper suggesting that naïve T cell depletion can
lead to microbial translocation, which in turn contributes to ongoing immune
activation and naïve T cell depletion. However, the commentary also cautions
that: “determining the causal association among these factors will be a
challenge, given the complexity of the human immune system and the lack of
therapeutic interventions.” One important implication of the data is that the
few therapies that might have the potential to increase naïve T cell levels
(currently, IL-7 and human growth hormone derivatives) deserve urgent and
careful evaluation in people with suboptimal immune recovery on ART, as there
may be the potential for these approaches to offer significant clinical
benefits.
Clinical Infectious Diseases 2009;48:362–364
DOI: 10.1086/595889
EDITORIAL COMMENTARY
CD4+ T Cell Recovery with Antiretroviral Therapy: More Than
the Sum of the Parts
Elvin H. Geng and Steven G. Deeks
University of California, San Francisco
Clinical Infectious Diseases 2009;48:350–361
DOI: 10.1086/595888
HIV/AIDS
MAJOR ARTICLE
Gregory K. Robbins,1 John G. Spritzler,2 Ellen S. Chan,2
David M. Asmuth,4 Rajesh T. Gandhi,1 Benigno A. Rodriguez,6 Gail Skowron,7 Paul
R. Skolnik,3 Robert W. Shafer,5 Richard B. Pollard,4 and the AIDS Clinical
Trials Group 384 Team
1Massachusetts General Hospital, Harvard Medical School,
2Harvard School of Public Health, and 3Boston University School of Medicine,
Boston, Massachusetts; 4University of California–Davis Medical Center,
Sacramento, and 5Stanford University Medical Center, Stanford, California;
6Case Western Reserve University School of Medicine, Cleveland, Ohio; and
7Roger Williams Medical Center, Providence, Rhode Island
Background. Initiation of combination antiretroviral therapy
(ART) results in higher total CD4 cell counts, a surrogate for immune
reconstitution. Whether the baseline CD4 cell count affects reconstitution of
immune cell subsets has not been well characterized.
Methods. Using data from 978 patients (621 with
comprehensive immunological assessments) from the AIDS [Acquired
Immunodeficiency Syndrome] Clinical Trials Group protocol 384, a randomized
trial of initial ART, we compared reconstitution of CD4+, CD4+ naive and
memory, CD4+ activation, CD8+, CD8+ activation, B, and natural killer cells
among patients in different baseline CD4+ strata. Reference ranges for T cell
populations in control patients negative for human immunodeficiency virus (HIV)
infection were calculated using data from AIDS Clinical Trials Group protocol
A5113.
Results. Patients in the lower baseline CD4+ strata did not
achieve total CD4+ cell counts similar to those of patients in the higher
strata during 144 weeks of ART, although CD4+ cell count increases were
similar. Ratios of CD4+ naive‐memory cell counts and CD4+:CD8+ cell counts
remained significantly reduced in patients with lower baseline CD4+ cell counts
(350 cells/mm3). These immune imbalances were most notable for those initiating
ART with a baseline CD4+ cell count 200 cells/mm3, even after adjustment for
baseline plasma HIV RNA levels.
Conclusions. After nearly 3 years of ART, T cell subsets in
patients with baseline CD4+ cell counts >350 cells/mm3 achieved or
approached the reference range those of control individuals without HIV
infection. In contrast, patients who began ART with 350 CD4+ cells/mm3
generally did not regain normal CD4+ naive‐memory cell ratios. These results
support current guidelines to start ART at a threshold of 350 cells/mm3 and
suggest that there may be immunological benefits associated with initiating
therapy at even higher CD4+ cell counts.
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