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Should We Start HAART Early Due to Gut Immune Depletion by HIV
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"CD4 Reconstitution of Lymphoid Tissues Is Dependent on Earlier Initiation of HAART"
CROI, Feb 2007, Los Angeles
Reported by Jules Levin
J Estes1, J Brenchley2, J Bathold1, A Khoruts1, G Beilman1, J Baker1, C Reilly1, D Douek2, A Haase1, and Timothy Schacker*1
1Univ of Minnesota, Minneapolis, US and 2Vaccine Res Ctr, NIAID, NIH, Bethesda, MD, US
note from Jules Levin: "....the damage that takes place in these compartments early can have a large impact on the ability to repopulate later on HAART...." However, John Coffin said at the microphone after Estes' talk "you very clearly showed that you have what appear to be virtually irreversible changes early in infection that can be blocked by early treatment. The fact remains however a very small fraction of patients are caught and treated in the very early stages of infection. Patients treated later and even in fairly late stage AIDS do very well and living for very long periods of time. So the real question I have for is what are the actual clinical consequences of these irreversible changes you see earlier and would they justify in a clinical sense early treatment with its toxicities and other long-term consequences such as its stress on the healthcare system and so-on". In addition, Coffin didn't bring it up but what about the consequences of developing drug resistance if treatment is started very early and what this might mean to long-term control of HIV??. Estes did not give a good answer to this question but said.... we are following patients long-term to see how does this early damage in the gut affect long-term clinical outcome. Its pretty early in our research but we are trying to answer these questions. Another questioner asked are the cells damaged early on, which are not improved by starting HAART later in progression, really important since we see how much the longevity and health of patients is improved. Estes said "that's a good question, I can only speculate"......and his response was that perhaps therapy is started before a critical threshold of depletion is reached.
Studies of CD4 depletion and reconstitution in HIV infection have focused on peripheral blood, a fraction of total CD4 T cells, and have not examined preservation and restoration of the CD4 T cells in lymph nodes or gut-associated lymphoid tissue (GALT).
We obtained inguinal lymph nodes and ileum biopsies (via colonoscopy) from 32 HIV+ and 11 HIVŠ individuals with a second set of biopsies obtained after 6 months of HAART in 15 of the HIV+ individuals. Using flow cytometry and quantitative image analysis (QIA), we determined the size of the total, naive, central and effector memory CD4 populations in peripheral blood, lymph nodes, Peyers patches, and lamina propria.
We found that all compartments were significantly depleted (p< 0.0001, 2-sample t-test) and that there were significant increases after 6 months of HAART in peripheral blood (p = 0.0003) and lymph node (p = 0.0001), but no change in lamina propria (gut). However, in Peyers patches, the inductive site where naive and central memory CD4+ T cells in GALT reside, there was a significant increase (p = 0.0076) that was restricted to only the central memory population.
We compared stage of infection and entry CD4+ T cell count to reconstitution of CD4+ T cells in each compartment and found significant correlations in peripheral blood and lymph node (p = 0.008 and 0.02, respectively, F statistic from ANOVA). For HAART started in the acute/early and presymptomatic stage of infection, the mean increase in peripheral blood CD4+ T-cell count was 388 cells/mm3 and 176 cells/mm3, respectively.
In lymphoid tissue, the corresponding values were 12.5% and 13.65% of parafollicular T-cell zone occupied by CD4+ T cells, respectively. There was no change in any CD4+ subset if HAART was begun when the patient had AIDS. We found that baseline peripheral blood CD4+ T-cell count was an even stronger predictor of immune reconstitution in peripheral blood and lymph node (r2 = 0.38, p = 0.01 and r2 = 0.71, p = 0.0002, respectively).
Importantly, we found that earlier initiation of HAART was associated with greater increases in the central memory population of Peyers patches, especially if begun in the acute/early stage of infection. This is important because, in the non-human simian immunodeficiency virus (SIV) model of infection, the size of the central memory population in GALT is associated with longer survival.
Estes concluded: CD4 T cell populations are significantly depleted in all compartments. GALT CD4 T cell loss occurs rapidly after acquisition. CD4 T cell repletion is more significant when HAART is initiated early. Lymphatic tissues do not uniformly reconstitute CD4+ T cells with HAART. Lymph node and Peyers patches are capable of limited reconstitution, the degree of which depends on earlier initiation of HAART than is currently recommended. This was most striking for central memory CD4 cells in Peyers patches. GALT fibrosis may be important in limiting gut reconstitution.
In another talk Connick reported on a more limited look at CD4 reconstitution and found reconstitution:
CROI: Substantial CD4+ T-cell Recovery and Reconstitution of Tissue Architecture in Gut-associated Lymphoid Tissue in Advanced HIV-1 Infection following Initiation of HAART with Nevirapine plus Trizivir (03/09/07)
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