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Failure to Normalize Immunity Despite Decade of Successful HAART
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"Despite a decade of sustained successful cART, complete T-cell phenotype normalization only occurred in 16% of patients, most of whom had initiated therapy at high CD4+ T-cell counts (>350 cells/mm3). The TCP parameter that was the least restored among patients was the CD4:CD8 T-cell ratio......Failure to normalize the complete T-cell phenotype was most apparent in patients who initiated cART with a CD4+ T-cell count <200 cells/mm3. The impact of this impaired T-cell phenotype on life-long immune function and potential comorbidities remains to be elucidated."
"In this pilot study, the analysis was specifically focused on patients with prolonged and optimal viral suppression, as this represents the ideal clinical context for long-term immune recovery. Our findings show that normalization of the T-cell phenotype is best achieved when cART is initiated at baseline CD4+ T-cell counts >350 cells/mm3. Furthermore, despite increases in CD4+ T-cell counts, very few patients who initiate therapy at advanced stages of HIV infection recover a normal T-cell phenotype, even after a decade of therapy. Overall, our findings indicate that HIV infection causes profound TCP alterations that are not completely reversed with treatment. Larger cohort studies will be important to determine the long-term clinical impact of this persistent dysregulation, in order to assess whether an altered TCP is a risk profile associated with higher morbidity and mortality among HIV-infected patients."
"At baseline, participants were classified into three groups according to pre-treatment CD4+ T-cell counts: Group I (CD4<200 cells/mm3); Group II (CD4: 200-350 cells/mm3); Group III (CD4>350 cells/mm3). Outcomes of interest were: (1) CD4+ T-cell count restoration (CD4>532 cells/mm3); (2) normalization of CD4:CD8 T-cell ratio (1.2-3.3); (3) maintenance of CD3+ T-cell homeostasis (CD3: 65%-85% of peripheral lymphocytes); (4) normalization of the complete T-cell phenotype (TCP).........At treatment initiation, the CD4:CD8 T-cell ratio was dysregulated in all patients except for two individuals in Group III. By year 10, the proportion of patients with normalized CD4:CD8 T-cell ratio was highest in Group III (73%) and lowest in Group I (11%). Less than half of Group II (43%) normalized this parameter.....Only 16% of all patients had a completely normalized TCP by the end of the follow-up period. Comparing individual groups, we observed that 45% of individuals in Group III achieved TCP normalization while only 7% of Group II and 5% of Group I normalized (Table 2). Overall, among the 44 patients, we found that the TCP parameter with the lowest normalization rate was the CD4:CD8 T-cell ratio with only 36% of all patients normalizing this parameter after a decade of suppressive therapy, 50% of those restoring this parameter belonged to Group III."
"Despite a decade of sustained successful cART, complete T-cell phenotype normalization only occurred in 16% of patients, most of whom had initiated therapy at high CD4+ T-cell counts (>350 cells/mm3). The TCP parameter that was the least restored among patients was the CD4:CD8 T-cell ratio........Failure to normalize the complete T-cell phenotype was most apparent in patients who initiated cART with a CD4+ T-cell count <200 cells/mm3. The impact of this impaired T-cell phenotype on life-long immune function and potential comorbidities remains to be elucidated."
"288 HIV+ patients, we identified 86 males (29.9%) who remained consistently on cART for at least 10 years without any treatment interruptions. Among these 86 males, 44 (51.2%) met the inclusion criteria. These individuals achieved and maintained plasma HIV-RNA under the level of detection (<50 copies/ml) throughout their entire treatment time......Throughout the course of the follow-up, 11 patients (25%) developed a cardiovascular event (CVE), as defined by the occurrence of an acute coronary syndrome (myocardial infarction, diagnosed unstable angina, or stroke). All of these individuals were co-infected with CMV. Overall, 32% of Group I and 36% of Group II developed a CVE. However, no CVE was observed among Group III patients (Table 1)"
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Delay in cART Initiation Results in Persistent Immune Dysregulation and Poor Recovery of T-Cell Phenotype Despite a Decade of Successful HIV Suppression
PLOSone April 7 2014
Patricia Ndumbi1*, Julian Falutz1, Nitika Pant Pai2, Christos M. Tsoukas1*
1 Immune Deficiency Treatment Centre, McGill University Health Centre, Montreal (Quebec), Canada, 2 Division of Clinical Epidemiology, McGill University Health Centre, Montreal (Quebec), Canada
Abstract
Background
Successful combination antiretroviral therapy (cART) increases levels of CD4+ T-cells, however this increase may not accurately reflect long-term immune recovery since T-cell dysregulation and loss of T-cell homeostasis often persist. We therefore assessed the impact of a decade of effective cART on immune regulation, T-cell homeostasis, and overall T-cell phenotype.
Methods
We conducted a retrospective study of 288 HIV+ cART-naïve patients initiating therapy. We identified 86 individuals who received cART for at least a decade, of which 44 consistently maintained undetectable plasma HIV-RNA levels throughout therapy. At baseline, participants were classified into three groups according to pre-treatment CD4+ T-cell counts: Group I (CD4<200 cells/mm3); Group II (CD4: 200-350 cells/mm3); Group III (CD4>350 cells/mm3). Outcomes of interest were: (1) CD4+ T-cell count restoration (CD4>532 cells/mm3); (2) normalization of CD4:CD8 T-cell ratio (1.2-3.3); (3) maintenance of CD3+ T-cell homeostasis (CD3: 65%-85% of peripheral lymphocytes); (4) normalization of the complete T-cell phenotype (TCP).
Results
Despite a decade of sustained successful cART, complete T-cell phenotype normalization only occurred in 16% of patients, most of whom had initiated therapy at high CD4+ T-cell counts (>350 cells/mm3). The TCP parameter that was the least restored among patients was the CD4:CD8 T-cell ratio.
Conclusions
Failure to normalize the complete T-cell phenotype was most apparent in patients who initiated cART with a CD4+ T-cell count <200 cells/mm3. The impact of this impaired T-cell phenotype on life-long immune function and potential comorbidities remains to be elucidated.
Results
Characteristics of the Study Population
From the original cART-naïve group of 288 HIV+ patients, we identified 86 males (29.9%) who remained consistently on cART for at least 10 years without any treatment interruptions. Among these 86 males, 44 (51.2%) met the inclusion criteria. These individuals achieved and maintained plasma HIV-RNA under the level of detection (<50 copies/ml) throughout their entire treatment time. The number of participants per group was 19, 14, and 11 for Group I, Group II, and Group III, respectively. The median time from HIV diagnosis to treatment initiation was six years (IQR: 2-10) and there was no significant difference between the groups. All patients were initiated on a 2 NRTI (3TC, AZT, or d4T) plus 1 PI (indinivir, saquinavir, or ritonavir) regimen, except for one patient in Group I who was on a 2 NRTI plus 1 NNRTI (nevirapine) regimen.
At baseline, the mean age of the patients was 42 years (IQR: 38.5-49.5), all patients were male, 57% were men who have sex with men (MSM), 75% were CMV seropositive, and 20% presented with an AIDS defining illness (ADI). The mean baseline HIV-RNA was 4.5 log10 copies/ml (IQR: 3.8-4.9), and the median duration of HIV treatment with cART was 14 years (IQR: 13-14). Baseline characteristics are summarized in Table 1.
Table 1. Demographics and clinical characteristics for 44 HIV-positive patients on combination antiretroviral therapy.
Normalization Of The T-Cell Phenotype And Clinical Outcomes
Cd4+ T-Cell Count.
At baseline, only 2 of the 44 patients had a normal CD4+ T-cell count. These patients belonged to Group III. After a decade of suppressive cART, only 50% of Group I patients normalized their CD4+ T-cell count, while 86% of Group II, and 100% of Group III patients recovered this parameter (Table 2). Linear regression analysis showed that the rate of change in square root CD4+ T-cell counts was significantly higher in Group I (2.19/year, 95% CI = 1.47-2.92) compared to Group II (1.39/year, 95% CI = 0.64-2.16) and Group III (1.08/year, 95% CI = 0.41 to 1.75) within the first 5 years of treatment. In the subsequent 5 years, the annual change in square root CD4+ T-cell counts had decreased across the three groups (Group I: 0.64/year, 95% CI = 0.23-1.05; Group II: 0.57/year, 95% CI = 0.13-1.01, and Group III: 0.77/year, 95% CI = 0.38-1.15). However, there were no significant differences across the groups (Table 3).
Cd4:cd8 T-Cell Ratio.
At treatment initiation, the CD4:CD8 T-cell ratio was dysregulated in all patients except for two individuals in Group III. By year 10, the proportion of patients with normalized CD4:CD8 T-cell ratio was highest in Group III (73%) and lowest in Group I (11%). Less than half of Group II (43%) normalized this parameter (Table 2). Linear regression analysis showed that similarly to CD4+ T-cell counts, the annual increase in CD4:CD8 T-cell ratio within the first five years of treatment was highest in Group I (0.27/year, 95% CI = 0.17-0.37) compared to Group II (0.13/year, 95% CI = 0.03-0.23) and Group III (0.11/year, 95% CI = 0.02-0.21). However, no difference in the annual rate of change was observed during the last five years across the groups: Group I: 0.09/year, 95% CI = 0.04-0.14; Group II: 0.08/year, 95% CI = 0.02-0.14; Group III: 0.04/year, 95% CI = -0.01-0.09 (Table 3). A descriptive representation of the CD4+ and CD8+ T-cell percentage trajectories showed that the CD4:CD8 T-cell ratio imbalance was only successfully reversed in Group III (Figure 1).
Cd3+ T-Cell Homeostasis.
Despite differences in T-cell subset balance, the proportion of patients with normal T-cell homeostasis at baseline and at follow-up was similar across the groups (Table 2). Linear regression analysis showed that there was no significant difference in the annual rate of change in CD3+ T-cell percentage across the three groups during the first half (Group I: 0.90/year, 95% CI = -1.08 to 2.88; Group II: -0.5/year, 95% CI = -2.62 to 1.62; Group III: -0.02/year, 95% CI = -1.86 to 1.82), and the last half of the follow-up (Group I: -0.23/year, 95% CI = -1.32 to 0.86; Group II: -0.1/year, 95% CI = -1.26 to 1.06; Group III: -0.02/year, 95% CI = -1.03 to 0.99) (Table 3).
Complete T-Cell Phenotype.
Only 16% of all patients had a completely normalized TCP by the end of the follow-up period. Comparing individual groups, we observed that 45% of individuals in Group III achieved TCP normalization while only 7% of Group II and 5% of Group I normalized (Table 2). Overall, among the 44 patients, we found that the TCP parameter with the lowest normalization rate was the CD4:CD8 T-cell ratio with only 36% of all patients normalizing this parameter after a decade of suppressive therapy, 50% of those restoring this parameter belonged to Group III.
Clinical Outcomes.
Throughout the course of the follow-up, 11 patients (25%) developed a cardiovascular event (CVE), as defined by the occurrence of an acute coronary syndrome (myocardial infarction, diagnosed unstable angina, or stroke). All of these individuals were co-infected with CMV. Overall, 32% of Group I and 36% of Group II developed a CVE. However, no CVE was observed among Group III patients (Table 1). After ten years of follow-up, only three deaths occurred within the sample: 2 (11%) in Group I and 1 (7%) in Group II. There were no reported deaths among Group III patients.
Introduction
The immune system of healthy individuals is characterized by the maintenance of homeostasis via a balanced T-cell phenotype (TCP) [1]. Although the hallmark of HIV infection is progressive CD4+ T-cell depletion, other impairments in immune phenotype such as loss of T-cell homeostasis and severe T-cell subset dysregulation also occur.
T-cell subset dysregulation was the earliest noted surrogate marker of AIDS in the early 1980s [2], [3]. It is characterized by a low CD4:CD8 T-cell ratio (<1.2) resulting from the depletion of CD4+ T-cells and the concomitant expansion of the CD8+ population of T-cells in the peripheral blood. Studies have shown that in HIV seropositive individuals receiving long-term combination antiretroviral therapy (cART), CD4:CD8 T-cell ratio dysregulation is correlated with higher risk of developing coronary artery disease [4]. In non-HIV settings, low CD4:CD8 T-cell ratios are also associated with poor clinical outcomes in patients with common variable immune deficiency (CVID) and in healthy individuals over the age of 60 [5], [6].
T-cell homeostasis was first described in 1993 by Adleman and Wofsy as the normal physiologic state by which the immune system maintains a constant number of circulating CD3+ T-cells, irrespective of changes within the CD4+ and CD8+ T-cell compartments [7]. Loss of T-cell homeostasis often occurs in HIV-infected individuals, and is manifested by a failure to maintain normal levels of circulating CD3+ T-cells [8]. Data from 372 seroconverters enrolled in the Multicenter AIDS Cohort Study (MACS) showed that in the absence of adequate treatment, the loss of T-cell homeostasis in HIV infection could predict impending AIDS and death [9]. We recently showed for the first time that impairment in T-cell homeostasis is also associated with morbidity and mortality among HIV-positive patients who receive effective combination antiretroviral therapy (cART) [10]. In non-HIV clinical contexts, altered T-cell homeostasis has also been linked with deleterious clinical disorders such as rheumatoid arthritis, Crohn's disease and systemic lupus erythematosus [11], [12]. The triad of low CD4+ T-cell count, dysregulated CD4:CD8 T-cell ratio, and loss of T-cell homeostasis characterizes the abnormal T-cell phenotype induced by HIV infection [3], [13].
The goals of effective cART are to suppress HIV viral replication and restore immune competence. Successful cART usually results in increased CD4+ T-cell counts, yet the increase may not reflect a complete immune recovery since ratio dysregulation and altered T-cell homeostasis often persist [13]-[16]. Failure to recover a balanced T-cell phenotype may put HIV-infected patients at risk for non-viral morbidities despite cART-mediated viral control [4], [10], [17], [18]. However, there is a scarcity of information on the effect of long-term suppressive cART on the normalization of the TCP. It is currently unknown whether this parameter can be completely restored in successfully treated individuals.
A major impediment to the evaluation of true immune recovery among HIV-positive patients is the limited number of surrogate markers available for clinical use. Measuring the total number of circulating CD4+ T-cells often necessitates the simultaneous determination of CD8+ and CD3+ T-cell numbers. Therefore, monitoring CD3+ T-cell levels and CD4:CD8 T-cell ratio, in addition to CD4+ T-cell counts, may provide further insight into immune restoration. Due to the availability of more effective and better tolerated antiretrovirals (ARVs), HIV-positive patients are now able to achieve sustained viral suppression over longer periods of time, thus allowing for the evaluation of very long-term immune recovery. In this pilot study, we assessed the extent of T-cell phenotype recovery among a group of treated HIV-positive males who achieved and maintained viral suppression for at least a decade.
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