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Author Topic: Starting Haart Sooner rather Than Later  (Read 1035 times)

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Offline veritas

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Starting Haart Sooner rather Than Later
« on: January 13, 2009, 04:52:02 AM »


 
CD4+ T Cell Recovery with Antiretroviral Therapy: More Than the Sum of the Parts, EDITORIAL COMMENTARY
 
 
 
  Clinical Infectious Diseases Feb 1 2009
 
Elvin H. Geng and Steven G. Deeks_University of California, San Francisco
 
"Where do we go from here? One obvious conclusion is that HAART should be started early, certainly before CD4+ T cell counts decrease to 350 cells/mm3. Most treatment guidelines already reflect this evolving strategy. The controversy about when to start therapy is now focused on whether therapy should be started in everyone or delayed until the CD4+ T cell count decreases to the 350 cells/mm3 range (of note, in AIDS Clinical Trial Group protocol 384, there were subtle differences of unclear significance in T cell subsets between those starting therapy with CD4+ T cell counts of 350-500 cells/mm3 and those starting with counts >500 cells/mm3). Even if empirical data emerge that suggest that earlier HAART is preferred, for logistical and practical reasons, many patients will continue to delay therapy until much later in the infection. Given the persistent, perhaps indefinite, immunological defects among those starting therapy late, novel immune-based therapeutics aimed at reversing these defects are urgently needed."
 
We are now more than a decade into the HAART era. During these past 10 years, it has become abundantly clear that HAART can reverse many of the immunological deficiencies associated with untreated HIV infection. This is most apparent with regard to the peripheral CD4+ T cell count, which typically increases rapidly in the first few months of treatment, followed by a more gradual increase that continues until a normal value is reached. Patients who are able to achieve normal peripheral CD4+ T cell counts generally do well clinically [1] and may even have a normal life span [2].
 
Although most HAART-treated patients may eventually achieve an optimal CD4+ T cell count outcome, an important but poorly defined subset fail to achieve this result or do so only after many years of HAART. Those patients whose CD4+ T cell counts remain low during therapy have an increased risk of a number of complications, including those due to AIDS, as well as those not traditionally thought to be HIV related (e.g., cancer, cardiovascular disease, and liver disease) [3]. The longer someone's CD4+ T cell count remains low, the higher the risk of these events. Those patients who initiate HAART with a low CD4+ T cell nadir have the highest risk of failure to achieve an optimal immunological outcome. These observations raise several important questions that investigators are now just starting to address. For example, why does HAART fail to restore normal CD4+ T cell counts in some patients? Also, why does a low CD4+ T cell count during HAART result in persistently high risk of significant morbidity, even after viral suppression has been achieved?
 
Important information relevant to these questions is provided by Robbins and colleagues [4] in this issue of Clinical Infectious Diseases. A large subset of patients enrolled in a randomized clinical trial (AIDS Clinical Trial Group protocol 384) underwent intensive immunological monitoring before and during effective antiretroviral treatment. T cell subsets were quantified by flow cytometry, with use of a simple but informative set of cell surface markers (CD45RA/RO and CD62L to define naive and memory T cells and CD38/HLA-DR to define activated T cells). Patients were stratified into 5 groups on the basis of their pretherapy CD4+ T cell count (nadir CD4), as follows: <50, 51-200, 201-350, 351-500, and >500 cells/mm3. As has often been reported in the past, most (but not all) patients exhibited a rapid CD4+ T cell increase in the first few months of therapy, followed by a more gradual increase until a normal level was reached. The rate at which the total peripheral CD4+ T cell count increased was similar across each of the 5 CD4 nadir strata, at least through the first 3 years. Those who started therapy late spent much of the first 3 years with a CD4+ T cell count well below the normal range.
 
The great strength of this study-and the reason it requires careful consideration-lies in the extensive grouping by pre-HAART CD4+ nadir that was performed in a large number of patients (621 patients) during a relatively long period (3 years). The total number of CD4+ and CD8+ T cells that expressed a naive phenotype (CD45RA+ and CD62L+) increased in each stratum, but the manner in which this increase occurred differed markedly by pre-HAART CD4 nadir. Specifically, those who delayed therapy until their CD4 cell count was <100 cells/mm3 exhibited, during therapy, a T cell profile that was largely skewed toward a memory T cell phenotype. In contrast, those who started HAART earlier in their disease course (CD4+ T cell count, >350 cells/mm3) had a rapid increase in the naive-memory cell ratio, and this number returned to normal in most patients within the first few years of HAART. Even after 3 years of HAART, many patients who started HAART with a low CD4 nadir had a persistently low naive-memory cell ratio, an observation that is consistent with recent cross-sectional studies [5]. Patients who started HAART with a low CD4 nadir also had a persistently low CD4:CD8 ratio. These 2 trends-a low naive-memory cell ratio and a low CD4:C8 ratio-have been seen both in those with untreated HIV infection and in the elderly (>75 years of age) [6, 7].
 
Robbins and colleagues [4] also examined the impact of HAART on measures of T cell activation. HIV infection results in marked and sustained increases in levels of inflammation. The degree to which T cells express certain markers of cellular activation (or cellular dysfunction) is strongly predictive of subsequent disease outcomes, independent of other factors [8, 9]. HAART reverses this effect, but this reversal is often incomplete, even after years of effective viral suppression [10]. In the work by Robbins et al. [4], those who initiated HAART with a low CD4 nadir had an early decrease in immune activation, but levels quickly reached what appeared to be a stable plateau that was well above the normal range. Collectively, these data show that a delayed initiation of HAART is associated with what may be an irreversible skewing of the T cell repertoire to a more differentiated and activated T cell phenotype.
 
Although these data were generated in the early HAART era involving regimens that are no longer recommended, the work by Robbins and colleagues [4] is still highly relevant and timely. Treatment-mediated suppression of HIV replication results in marked improvements in health, yet patients receiving otherwise effective HAART remain at risk of a number of important non-AIDS conditions (e.g., cancer, cardiovascular disease, and liver failure). This is at least partially due to residual HIV-associated immunodeficiency, as evidenced by the consistent observation that the CD4+ T cell count nadir and the proximal CD4+ T cell count during HAART each strongly and consistently predict the risk of non-AIDS events and/or mortality [3, 11].
 
We believe that the conclusions reached by Robbins et al. [4] 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 [12]. It has recently been shown that chronic inflammation contributes to failure of naive T cell homeostasis [13], either by causing too much proliferation [14] 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) [15-17]. 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 [4, 10, 18], suboptimal CD4+ T cell gains [19], skewed immunophenotypic profiles [4], persistent T cell dysfunction [20], and increased risk of all-cause morbidity and mortality [3, 11, 21]. 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. Careful measure of immunological function before and during HAART in well-characterized patients might be informative. Such studies should go beyond the simple naive-memory cell dichotomy set forth by Robbins et al. [4], to focus on the role of other cell types, including central memory cells and immunoregulatory cells [22]. Tissue-based studies will also be needed.
 
These questions are of paramount importance to the global epidemic as well. In Africa, most of the 3 million persons who have received therapy in the first wave of the HAART rollout started therapy with a low CD4 nadir. Across several large studies, the median pretherapy CD4+ T cell counts had a range of 108-131 cells/mm3, with 18%-25% starting with a CD4+ T cell count <50 cells/mm3 [23-25]. With the assumption that the trends observed by Robbins and colleagues [4] apply to those individuals living in resource-poor regions, then persistent inflammation and immunological defects are likely the norm among treated patients globally. If anything, the greater prevalence of chronic viral, helminthic, and protozoal infections in these regions is likely to exacerbate the persistent T cell subset derangements observed in AIDS Clinical Trial Group protocol 384, with potentially negative consequences.
 
Where do we go from here? One obvious conclusion is that HAART should be started early, certainly before CD4+ T cell counts decrease to 350 cells/mm3. Most treatment guidelines already reflect this evolving strategy. The controversy about when to start therapy is now focused on whether therapy should be started in everyone or delayed until the CD4+ T cell count decreases to the 350 cells/mm3 range (of note, in AIDS Clinical Trial Group protocol 384, there were subtle differences of unclear significance in T cell subsets between those starting therapy with CD4+ T cell counts of 350-500 cells/mm3 and those starting with counts >500 cells/mm3). Even if empirical data emerge that suggest that earlier HAART is preferred, for logistical and practical reasons, many patients will continue to delay therapy until much later in the infection. Given the persistent, perhaps indefinite, immunological defects among those starting therapy late, novel immune-based therapeutics aimed at reversing these defects are urgently needed.   
 
 
 
 veritas
 
 
 
 
 

 


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