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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