Recovery In HIV-infected Patients Research Articles

Evaluation of Clinical Biomarkers Related to CD4 Recovery in HIV-Infected Patients-5-Year Observation.

Human Immunodeficiency Virus infection leads to the impairment of immune system function. Even long-term antiretroviral therapy uncommonly leads to the normalization of CD4 count and CD4:CD8 ratio. The aim of this study was to evaluate possible clinical biomarkers which may be related to CD4 and CD4:CD8 ratio recovery among HIV-infected patients with long-term antiretroviral therapy. The study included 68 HIV-infected patients undergoing sustained antiretroviral treatment for a minimum of 5 years. Clinical biomarkers such as age, gender, advancement of HIV infection, coinfections, comorbidities and applied ART regimens were analyzed in relation to the rates of CD4 and CD4:CD8 increase and normalization rates. The results showed that higher rates of CD4 normalization are associated with younger age (p = 0.034), higher CD4 count (p = 0.034) and starting the therapy during acute HIV infection (p = 0.012). Higher rates of CD4:CD8 ratio normalization are correlated with higher CD4 cell count (p = 0.022), high HIV viral load (p = 0.006) and acute HIV infection (p = 0.013). We did not observe statistically significant differences in CD4 recovery depending on gender, HCV/HBV coinfections, comorbidities and opportunistic infections. The obtained results advocate for current recommendations of introducing antiretroviral therapy as soon as possible, preferably during acute HIV infection, since it increases the chances of sufficient immune reconstruction.

DBP rs7041 and DHCR7 rs3829251 are Linked to CD4+ Recovery in HIV Patients on Antiretroviral Therapy.

Background: The lack of the recovery of CD4+ T-cells (CD4+ recovery) among immunodeficiency virus (HIV)-infected patients on antiretroviral therapy (ART) is not well known. We aimed to analyze the association between single nucleotide polymorphisms (SNPs) underlying vitamin D metabolism and the CD4+ recovery in naïve HIV-infected patients who started ART with low baseline CD4+. Methods: We conducted a retrospective study in 411 naïve individuals with plasma HIV load >200 copies/mL and CD4+ <200 cells/mm3. During 24 months of follow-up, all patients had plasma HIV load <50 copies/mL. DNA genotyping was performed using the Sequenom MassARRAY platform. The outcome variable was the change in CD4+ during the study. Results: CD4+ recovery was higher in patients carrying DBP rs7041 AA genotype (AA versus CC/AC) and DHCR7 rs3829251 AA genotype (AA versus GG/AG) (p-value < 0.05). DBP rs7041 AA genotype was linked to increase in CD4+ (adjusted arithmetic mean ratio (aAMR) = 1.22; q-value = 0.011), increase in CD4+ ≥P75th [adjusted odds ratio (aOR) = 2.31; q-value = 0.005], slope of CD4+ recovery (aAMR = 1.25; q-value = 0.008), slope of CD4+ recovery ≥ P75th (aOR = 2.55; q-value = 0.005) and achievement of CD4+ ≥500 cells/mm3 (aOR = 1.89; q-value = 0.023). Besides, DHCR7 rs3829251 AA genotype was related to increase in CD4+ (aAMR = 1.43; q-value = 0.031), increase in CD4+ ≥P75th (aOR = 3.92; q-value = 0.030), slope of CD4+ recovery (aAMR = 1.40; q-value = 0.036), slope of CD4+ recovery ≥ P75th (aOR = 3.42; q-value = 0.031) and achievement of CD4+ ≥500 cells/mm3 (aOR = 5.68; q-value = 0.015). Conclusion: In summary, DHCR7 rs3829251 and DBP rs7041 polymorphisms were associated with CD4+ recovery in HIV-infected patients who started cART with low CD4+ T-cell counts.

The effect of age on CD4+ T-cell recovery in HIV-suppressed adult participants: a sub-study from AIDS Clinical Trial Group (ACTG) A5321 and the Bone Loss and Immune Reconstitution (BLIR) study

Older age could be a risk factor for suboptimal CD4+ T-cell recovery in HIV-infected patients despite successful viral suppression. However, evaluation of this effect could be confounded by age-related immune processes such as decreased thymus output, increased immune activation and exhaustion. Here, we established a semi-mechanistic population model simultaneously describing naïve and memory CD4+ T-cell trajectories in 122 participants. Covariate analysis accounting for immune activation showed that older age was significantly associated with faster apparent elimination rate of the naïve T-cells. In addition, female sex predicted slower apparent elimination rate of memory T-cells. Simulations showed that the median maximal CD4+ T-cell count on ART treatment was 593 cells/μL (IQR 442-794) in patients aged 50 years or above and 738 cells/μL (IQR 548-1002) in patients aged 18-35 years. The differences in the percentage of subjects achieving sufficient immune reconstitution (CD4+ T-cell count> 500 cells/μL) between the two age groups were 15, 21 and 26% at year 1, 4 years and steady state, respectively, suggesting that advanced age may have a greater impact on long-term CD4+ T-cell recovery.

Tuberculosis associated immune reconstitution inflammatory syndrome in patients infected with HIV: the current state of the problem

Tuberculosis-associated immune reconstitution inflammatory syndrome (TB-IRIS) is an enhanced inflammatory immune response to Mycobacterium tuberculosis antigens due to immune system recovery in HIV-infected patients within 6 months of antiretroviral therapy (ART).&#x0D; Objective — to assess the incidence of TB-IRIS in patients with tuberculous meningitis. Evaluation of mortality caused by TB-IRIS.&#x0D; Materials and methods. A retrospective analysis of 60 cases of confirmed tuberculous meningitis in patients who were treated in anti-tuberculosis institutions in Kiev and Kiev region in 2017—2019 was carried out. The medical records of the patients were studied.Results and discussion. Co-infection with HIV-TB among patients was confirmed in 57 (95 %) cases. In 21 patients (36.8 %; CI 24.7—50.0 %) with HIV-TB co-infection, a link was established between the appointment of ART and the development of tuberculous meningitis. 19 (90.5 %) of them had risk factors at the time of ART. Fifteen (71.4 %) patients had other localizations of tuberculosis besides tuberculosis of the central nervous system (pulmonary tuberculosis, tuberculosis of intrathoracic lymph nodes, tuberculosis of peripheral lymph nodes, tuberculosis of the genitourinary system). The mean CD4+-lymphocyte count before ART was (61.6 ± 16.9) cells/µL (p ≤ 0.05). All patients were prescribed standard antimycobacterial therapy and ART. 9 (42.8 %) patients were cured. One (4.7 %) developed severe disability: peripheral tetraparesis and severe cerebrosthenia. 11 patients died, mortality was 52.4 % (CI 30.2—74.1 %).&#x0D; Conclusions. TB-IRIS is the cause of tuberculous meningitis in HIV-infected patients in 36.8 % of cases; (CI 24.7—50.0 %). Tuberculous meningitis always complicates the prognosis with TB-IRIS, while the mortality rate is 52.4 % (CI 30.2—74.1 %).

Gut lactate-producing bacteria promote CD4 T cell recovery on Anti-retroviral therapy in HIV-infected patients

Anti-retroviral therapy (ART) effectively suppresses viral replication in HIV-infected patients, however CD4 + cell restoration to normal value is not achieved by 15–20% of patients who are called immune non-responders. Gut microbiota composition has been shown to influence host immunity. Herein, to identify intestinal microbial agents that may influence the CD4 recovery in HIV-infected patients, we utilized a “Quasi-paired cohort” method to analyze intestinal metagenome data from immunological responders (IRs) and immunological non-responders (INRs). This method identified significant enrichment for Streptococcus sp. and related lactate-producing bacteria (LAB) in IRs. In a validation cohort, positive correlations between the abundance of these LAB and the post-ART CD4 + recovery was observed, and a prediction model based on these LAB performed well in predicting immune recovery. Finally, experiments using a germ-free mouse model of antibody-induced CD4 + cell depletion showed that supplementation with a lactate-producing commensal Streptococcus thermophilus strongly promoted CD4 recovery. In conclusion, our study identified a group of LAB that was associated with enhanced immune recovery in post-ART HIV-infected patients and promotes CD4 + cell restoration in a mouse model. These findings favour supplementation of LAB commensal as a therapeutic strategy for CD4 + cell count improvement in HIV-infected patients.

Dietary nitrate improves skeletal muscle microvascular oxygenation in HIV-infected patients receiving highly active antiretroviral therapy: a randomised, double-blind, cross-over, placebo-controlled study.

HIV-1 proteins and highly active antiretroviral therapy (HAART) have been associated with microvascular endothelial dysfunction. Although nitrate-rich beetroot juice (NR-BJ) consumption has been shown to improve endothelial function in clinical population, its effects in HIV-infected patients has not been addressed. We investigated the effect of a single dose of NR-BJ on muscle oxygen saturation parameters in response to a handgrip exercise in HIV-infected patients. Fifteen HIV-infected patients received NR-BJ or nitrate-depleted beetroot juice (ND-BJ) in a double-blind cross-over design. Near-IR spectroscopy was utilised to assess muscle oxygen saturation parameters during rhythmic handgrip exercise after NR-BJ or ND-BJ supplementation. A significant faster muscle oxygen desaturation rate during exercise (-7·97 (sd 5·00) v. -5·45 (3·94) %/s, P = 0·005) and muscle oxygen resaturation rate during exercise recovery (0·43 (0·24) v. 0·28 (0·24) %/s, P = 0·030) after NR-BJ ingestion was found. However, no significant difference in exercise time until fatigue was observed. Salivary nitrite and urinary nitrate concentration were analysed after NR-BJ or ND-BJ. A significant increase in salivary nitrite and urinary nitrate in NR-BJ was observed compared with ND-BJ (P < 0·05). Our findings suggest that NR-BJ consumption may acutely improve muscle oxygen saturation during exercise and exercise recovery in HIV-infected patients undergoing HAART and who are expected to present microvascular damage. Thus, future studies investigating the chronic effects of NR-BJ are warranted to delineate a better nutritional strategy based on nitrate-rich foods.

IL7RA rs6897932 Polymorphism is Associated with Better CD4+ T-Cell Recovery in HIV Infected Patients Starting Combination Antiretroviral Therapy.

Interleukin-7 receptor subunit alpha (IL7RA) rs6897932 polymorphism IS related to CD4+ recovery after combination antiretroviral therapy (cART), but no studies so far have analyzed its potential impact in patients with very low CD4+ T-cells count. We aimed to analyze the association between IL7RA rs6897932 polymorphism and CD4+ T-cells count restoration in HIV-infected patients starting combination antiretroviral therapy (cART) with CD4+ T-cells count <200 cells/mm3. We performed a retrospective study in 411 patients followed for 24 months with a DNA sample available for genotyping. The change in CD4+ T-cells count during the follow-up was considered as the primary outcome. The rs6897932 polymorphism had a minimum allele frequency (MAF) >20% and was in Hardy–Weinberg equilibrium (p = 0.550). Of 411 patients, 256 carried the CC genotype, while 155 had the CT/TT genotype. The CT/TT genotype was associated with a higher slope of CD4+ T-cells recovery (arithmetic mean ratio; AMR = 1.16; p = 0.016), higher CD4+ T-cells increase (AMR = 1.19; p = 0.004), and higher CD4+ T-cells count at the end of follow-up (AMR = 1.13; p = 0.006). Besides, rs6897932 CT/TT was related to a higher odds of having a value of CD4+ T-cells at the end of follow-up ≥500 CD4+ cells/mm3 (OR = 2.44; p = 0.006). After multiple testing correction (Benjamini–Hochberg), only the increase of ≥ 400 CD4+ cells/mm3 lost statistical significance (p = 0.052). IL7RA rs6897932 CT/TT genotype was related to a better CD4+ T-cells recovery and it could be used to improve the management of HIV-infected patients starting cART with CD4+ T-cells count <200 cells/mm3.

The use of corticosteroids does not influence CD4+ lymphocyte recovery in HIV-infected patients with advanced immunodeficiency

ABSTRACTCorticosteroids inhibit HIV-related immune activation and seem to have a mild favorable effect on immunological recovery in patients with CD4+ counts ≥200 cells/mm3. Data in patients with advanced immunodeficiency are lacking. We analyzed whether corticosteroids negatively influence the short-term CD4+ lymphocyte recovery in patients with CD4+ cell counts <200 cells/mm3 started on combination antiretroviral therapy (cART). We performed a retrospective cohort analysis including all HIV-infected patients under follow-up in our hospital with a documented episode of Pneumocystis Jirovecii Pneumonia (PJP) in the cART era. CD4+ lymphocyte recovery was assessed at three months after the episode of PJP and subsequent start of cART, comparing patients that received adjunctive corticosteroids (AC) versus patients that did not receive corticosteroids (standard care (SC)). In total, 66 patients with an episode of PJP were identified with 38 patients in the AC-group versus 28 patients in the SC-group. Almost all baseline characteristics were similar, including mean CD4+ lymphocyte counts. After three months, the mean CD4+ cell count did not differ; 222 cells/mm3 for the SC-group versus 259 cells/mm3 for the AC-group (p = .29). The use of corticosteroids does not alter CD4+ lymphocyte recovery in HIV-infected patients with advanced immunodeficiency in the first months of antiretroviral therapy.

CD4+ T-Cell Cycling in HIV-Infected Patients with the Discordant Immunologic Response to the Antiretroviral Therapy

Discordant immune response to antiretroviral therapy (ART) in HIV infection is characterized by insufficient reconstitution of peripheral CD4+ T lymphocyte numbers despite suppression of virus replication. The causes of inefficient regeneration of CD4+ T cells on ART remain elusive. The paper reports the study involving two groups of HIV-positive patients: patients with discordant response to ART (n = 20) and patients with standard response to therapy (n = 21). The numbers of cycling (Ki-67+), senescent (CD57+), and exhausted (PD-1+) CD4+ T lymphocytes of varying degree of maturity have been determined in peripheral blood and lymph nodes of HIV-positive individuals. CD4+ T cell division asymmetry index after in vitro stimulation has been analyzed. Histological study of the lymph nodes of HIV-infected patients was carried out. It has been demonstrated that in the individuals with discordant immune response to ART, intensive CD4+ T cell cycling does not result in the increase in their count neither in peripheral blood, nor in the secondary lymphoid organs. At the same time, in the patients with impaired immune system recovery, increased cell proliferation is followed by the accumulation of exhausted CD4+ T lymphocytes. Moreover, patients with discordant immune response to ART revealed an asymmetric division of in vitro stimulated CD4+ T cells. The observed defects may be the cause of inefficient immune system recovery in HIV-infected patients on ART.

Mitochondrial haplogroup H is related to CD4+ T cell recovery in HIV infected patients starting combination antiretroviral therapy

BackgroundThe mitochondrial DNA (mtDNA) seems to influence in a large number of diseases, including HIV infection. Moreover, there is a substantial inter-individual variability in the CD4+ recovery in HIV-infected patients on combination antiretroviral therapy (cART). Our study aimed to analyze the association between mtDNA haplogroups and CD4+ recovery in HIV-infected patients on cART.MethodsThis is a retrospective study of 324 naïve cART patients with CD4+ < 200 cells/mm3, who were followed-up during 24 months after initiating cART. All patients had undetectable HIV viral load during the follow-up. Besides, we included 141 healthy controls. MtDNA genotyping was performed by using Sequenom’s MassARRAY platform. The primary outcome variable was the slope of CD4+ recovery. Patients were stratified into two groups by the median slope value of CD4+ (9.65 CD4+ cells/mm3/month). Logistic regression analyses were performed to calculate the odds of CD4+ recovery according to mtDNA haplogroups.ResultsOur study included European HIV-infected patients within the N macro-cluster. The baseline values of CD4+ T-cells were similar between groups of patients stratified by the P50th of the slope of CD4+ T-cells recovery. Patients in the low CD4+ T-cells recovery group were older (p = 0.001), but this variable was included in the multivariate models. When we analyzed the frequencies of mtDNA haplogroups, no significant differences between HIV-infected individuals and healthy controls were found. We did not find any significant association between mtDNA haplogroups and the slope of CD4+ T-cells recovery by linear regression analysis. However, Patients carrying haplogroup H had a higher odds of having a better CD4+ recovery (> 9.65 CD4+ cells/mm3/month) than patients without haplogroup H (p = 0.032). The adjusted logistic regression showed that patients carrying haplogroup H had a higher likelihood of achieving a CD4+ recovery > 9.65 CD4+ cells/mm3/month [adjusted odds ratio (aOR) = 1.75 (95% CI = 1.04; 2.95); p = 0.035].ConclusionsEuropean mitochondrial haplogroup H was associated with the improved CD4+ recovery in HIV-infected patients starting cART with CD4+ < 200 cells/mm3.

The effect of plasma auto-IgGs on CD4+ T cell apoptosis and recovery in HIV-infected patients under antiretroviral therapy

Although effective antiretroviral therapy (ART) suppresses HIV viral replication, prevents AIDS-related complications, and prolongs life, a proportion of patients fails to restore the patients' CD4+ T cell number to the level of healthy individuals. Increased mortality and morbidity have been observed in these patients. In the current study, we have investigated the role of auto-IgGs in CD4+ T cell apoptosis and recovery in a cross-sectional study. All HIV+ subjects were on viral-suppressive ART treatment with a different degree of CD4+ T cell reconstitution. Total auto-IgG binding on CD4+ T cell surfaces and its associated apoptosis and CD4+ T cell recovery were analyzed by flow cytometry ex vivo. Total IgGs from plasma were tested for their binding capacities to CD4+ T cell surfaces and their mediation to CD4+ T cell death through NK cell cytotoxicity in vitro. HIV+ subjects had increased surface binding of auto-IgGs on CD4+ T cells compared with healthy controls, and IgG binding was associated with elevated CD4+ T cell apoptosis in HIV+ subjects but not in healthy controls. Plasma IgGs from HIV+ subjects bound to CD4+ T cells and induced cell apoptosis through NK cytotoxicity in vitro. Soluble CD4 (sCD4) preincubation prevented NK cell-mediated CD4+ T cell death. Our results suggest that plasma autoantibodies may play a role in some HIV+ patients with poor CD4+ T cell recovery under viral-suppressive ART.

Failure to achieve immunological recovery in HIV-infected patients with clinical and virological success after 10 years of combined ART: role of treatment course.

We assessed factors, including treatment course, associated with failure to obtain a 10 year immunological response after starting first-generation PI-containing combined ART (cART). In the prospective COPILOTE cohort of HIV-infected patients started on a first-generation PI-containing regimen in 1997-99, the impact of cART history on the failure to achieve immunological response measured at 10 years was assessed by multivariate logistic regression models in the 399 patients with clinical and virological success of cART. Failure of CD4 response (CD4 >500/mm3) was associated with age ≥40 years at baseline (P < 0.001), CD4 cell counts ≤500/mm3 at month 4 (P = 0.016) or month 12 (P < 0.001) and ≥3 months of cART interruption (P = 0.016). Factors associated with failure to achieve complete immunological response (CD4 >500/mm3 and CD4:CD8 ratio >1) were CD4:CD8 ratio ≤0.8 at month 8 (P < 0.001) or month 12 (P < 0.001), ≥3 months of cumulative cART interruption (P = 0.011), ≥3 antiretroviral regimens (P = 0.009) and ≤4 treatment lines (P = 0.015). Baseline CD4 and CD4:CD8 ratio were not predictors of the 10 year immunological outcomes. In this therapeutic cohort of patients starting first-generation PI-containing cART in 1997-99, poor initial immunological response had a negative impact on 10 year CD4 and CD4 plus CD4:CD8 ratio response, despite prolonged virological success. Lack of treatment interruption may improve long-term immunological outcome in HIV infection.

Immune recovery in HIV-infected patients after Candida esophagitis is impaired despite long-term antiretroviral therapy.

Objective:Candida esophagitis belongs to the most common AIDS-defining diseases; however, a comprehensive immune pathogenic concept is lacking.Design:We investigated the immune status of 37 HIV-1-infected patients from the Swiss HIV cohort study at diagnosis of Candida esophagitis, 1 year before, 1 year later and after 2 years of suppressed HIV RNA. We compared these patients with three groups: 37 HIV-1-infected patients without Candida esophagitis but similar CD4+ cell counts as the patients at diagnosis (advanced HIV group), 15 HIV-1-infected patients with CD4+ cell counts higher than 500 cells/μl, CD4+ cell nadirs higher than 350 cells/μl and suppressed HIV RNA under combination antiretroviral therapy (cART) (early cART group) and 20 healthy individuals.Methods:We investigated phenotype, cytokine production and proliferative capacity of different immune cells by flow cytometry and enzyme-linked immunosorbent spot.Results:We found that patients with Candida esophagitis had nearly abolished CD4+ cell proliferation in response to Candida albicans, significantly increased percentages of dysfunctional CD4+ cells, significantly decreased cytotoxic natural killer cell counts and peripheral innate lymphoid cell counts and significantly reduced IFN-γ and IL-17 production compared with the early cART group and healthy individuals. Most of these defects remained for more than 2 years despite viral suppression. The advanced HIV group without opportunistic infection showed partly improved immune recovery.Conclusion:Our data indicate that Candida esophagitis in HIV-1-infected patients is caused by an accumulation of multiple, partly Candida-specific immunological defects. Long-term immune recovery is impaired, illustrating that specific immunological gaps persist despite cART. These data also support the rationale for early cART initiation to prevent irreversible immune defects.

Comparative Impact of Suppressive Antiretroviral Regimens on the CD4/CD8 T-Cell Ratio: A Cohort Study.

Although different factors have been implicated in the CD4/CD8 T-cell ratio recovery in HIV-infected patients who receive effective antiretroviral therapy (ART), limited information exists on the influence of the regimen composition.A longitudinal study carried out in a prospective, single-center cohort of HIV-infected patients. ART regimens including non-nucleoside reverse transcriptase inhibitors (NNRTI), protease inhibitors (PI), or integrase strand transfer inhibitors (INSTI) from patients who achieved long-term (≥6-month duration) virological suppression (HIV-RNA < 400 copies/mL) from January 1998 to June 2014 were analyzed. The impact of ART composition on the changes of the CD4/CD8 T-cell ratio was modeled using a mixed linear approach with adjustment for possible confounders.A total of 1068 ART regimens from 570 patients were analyzed. Mean (SD) age of the patients was 42.15 (10.68) years and 276 (48.42%) had hepatitis C virus (HCV) coinfection. Five hundred fifty-eight (52.25%) regimens were PI-based, 439 (40.10%) NNRTI-based, and 71 (6.65%) INSTI-based; 487 (45.60%) were initial regimens, 476 (44.57%) simplification, and 105 (9.83%) salvage regimens. Median (IQR) number of regimens was 1 (1–2) per patient, of 29 (14–58) months duration, and 4 (3–7) CD4/CD8 measurements per regimen. The median baseline CD4/CD8 ratio was 0.42, 0.50, and 0.54, respectively, with the PI-, NNRTI-, and INSTI-based regimens (P = 0.0073). Overall median (IQR) increase of CD4/CD8 ratio was 0.0245 (−0.0352–0.0690) per year, and a CD4/CD8 ratio ≥1 was achieved in 19.35% of the cases with PI-based, 25.97% with NNRTI-based, and 22.54% with INSTI-based regimens (P = 0.1406). In the adjusted model, the mean CD4/CD8 T-cell ratio increase was higher with NNRTI-based regimens compared for PI-based (estimated coefficient for PI [95% CI], −0.0912 [−0.1604 to −0.0219], P = 0.009). Also, a higher CD4/CD8 baseline ratio was associated with higher CD4/CD8 increase in the adjusted model (P = 0.001); by contrast, higher age (P = 0.020) and simplification of ART regimen (P = 0.003) had a negative impact on the CD4/CD8 ratio.Antiretroviral regimen composition has a differential impact on the CD4/CD8 T-cell ratio; NNRTI-based regimens are associated with enhanced CD4/CD8 T-cell ratio recovery compared to PI-based antiretroviral regimens.

Factors associated with long-term CD4 cell recovery in HIV-infected patients on successful antiretroviral therapy.

The aim of the study was to study the factors associated with immunological recovery in HIV-infected patients with suppressed viral load. Nadir and current CD4 cell counts were recorded in 821 patients, as well as many demographic, epidemiological, lifestyle, clinical, therapeutic, genetic, laboratory, liver fibrosis and viral hepatitis parameters. The median age of the patients was 44.4 years [interquartile range (IQR) 40.3-48.0 years], the median time since HIV diagnosis was 15.3 years (IQR 10.5-18.9 years), the median time of suppressed viral load was 7.0 years (IQR 4.0-10.0 years) and the median time on the current antiretroviral regimen was 2.8 years (IQR 1.4-4.7 years). The median nadir and current CD4 counts were 193.0 (IQR 84.0-301.0) and 522.0 (IQR 361.0-760) cells/μL, respectively, separated by a median period of 10.2 years (IQR 5.9-12.9 years). The median CD4 count gain during follow-up was 317.0 (IQR 173.0-508.0) cells/μL. Many variables were associated with CD4 cell gains in univariate analyses, including age, gender, epidemiology, prior clinical conditions, fibrosis stage, transient elastometry, aspartate aminotransferase (AST), nadir CD4 count and hepatitis B and C virus infections and genotypes, as well as the durations of follow-up since nadir CD4 count, overall antiretroviral treatment, current antiretroviral regimen, protease inhibitor therapy and suppression of viral load. Multivariate analysis revealed that longer duration of HIV suppression (P < 0.0001), more advanced clinical Centers for Disease Control and Prevention (CDC) stages (P < 0.0001), younger age (P = 0.0003), hepatitis C virus genotypes 1 and 4 (P = 0.003), sexual acquisition of HIV (P = 0.004), and lower transient elastometry values (P = 0.03) were independent predictors of CD4 cell gains. Overall, the model accounted for 14.2% of the variability in CD4 count. In addition to the duration of HIV suppression, HIV-related diseases, HIV epidemiology, age, hepatitis C virus genotypes, and liver fibrosis were independently associated with long-term immunological recovery.

Increased Tryptophan Catabolism Is Associated With Increased Frequency of CD161+Tc17/MAIT Cells and Lower CD4+ T-Cell Count in HIV-1 Infected Patients on cART After 2 Years of Follow-Up

HIV infection is associated with increased ratio between kynurenine and tryptophan (KTR) in plasma, increased microbial translocation, expansion of regulatory T cells (Tregs), and depletion of Tc17/mucosa-associated invariant T (MAIT) cells. The association between these parameters and the impact of KTR on CD4 T-cell recovery in HIV-infected patients on combination antiretroviral therapy (cART) after 2 years of follow-up was investigated.Forty-one HIV-infected individuals treated with cART for a minimum of 2 years were included. Tregs, CD161Tc17/MAIT cells, naive cells, immune activation, senescence, and apoptosis were measured using flow cytometry. Soluble CD14 (sCD14), lipopolysaccharide, and tryptophan metabolites in plasma were measured retrospectively before cART and at inclusion initiation using Limulus Amebocyte Lysate colometric assay, enzyme-linked immunosorbent assay, and tandem mass spectrometry, respectively. KTR was calculated, and patients were divided into 2 groups defined by high vs. low KTR. CD4 T-cell count was determined at inclusion and after 2 years of follow-up.KTR decreased after cART initiation. Patients on cART with high KTR displayed an immunological profile with high sCD14, high percentage Tregs, low percentage CD161Tc17/MAIT cells, low percentage naive cells, low CD4/CD8 ratio, and poor immune reconstitution after 2 years of follow-up compared with patients with low KTR.Our results support the hypothesis that tryptophan catabolism, indoleamine 2,3-dioxygenase 1 (IDO1) activation, microbial translocation, and perturbed distribution of Tregs and CD161Tc17/MAIT cells are part of a vicious circle that perpetuates exhaustion of the immune system and progression of untreated HIV infection and challenge immune reconstitution in patients on cART.

IL7RA polymorphisms predict the CD4+ recovery in HIV patients on cART.

The IL7RA polymorphisms have recently been associated with CD4+ T-cell decline in untreated HIV-infected subjects and CD4+ T-cell recovery in patients on combination antiretroviral therapy (cART). The aim of this study was to evaluate whether IL7RA polymorphisms are associated with CD4+ T-cell recovery in HIV-infected patients on long-term cART. We performed a retrospective study in 151 naïve cART patients with severe immunodeficiency (CD4+ counts ≤200 cells/mm(3) ). IL7RA polymorphisms' genotyping was performed using Sequenom's MassARRAY platform. The outcome variable was the time to achieve the first value of CD4+ count ≥500 cells/mm(3) during the follow-up. Two different trends of CD4+ T-cell recovery were found in Kaplan-Meier analysis. During the first 48months, 60 of 151 (39·7%) of the patients reached CD4+ T-cell values ≥500 cells/mm(3) , and no differences were observed between IL7RA genotypes. After the first 48months of follow-up, 27 of 151 (17·8%) of the patients reached CD4+ T-cell values ≥500 cells/mm(3) , with a different pattern of CD4+ recovery depending on IL7RA genotype. Patients with rs10491434 TT genotype and rs6897932 TT genotype were more likely of achieving CD4+ value ≥500 cells/mm(3) than patients with rs10491434 CT/CC genotype (adjusted hazard ratio (aHR)=3·59; P=0·005) and patients with rs6897932 CC/CT genotype (aHR=11·7; P<0·001). The IL7RA polymorphisms seem to be associated with CD4+ T-cell recovery in HIV-infected patients who started cART with severe immunodeficiency, in the second phase of CD4+ T-cell recovery after long-term cART.

Pattern and predictors of immunologic recovery in HIV infected patients.

BackgroundAlthough anti-retroviral therapy has generally improved the survival of HIV infected patients in many developing countries including Ghana, specific socio-demographic factors could still influence outcome of treatment. This study was designed to identify patient-specific factors that could influence the immune recovery of absolute CD4 count in HIV infected patients.FindingsHospital records were extracted from two health facilities in Ghana. The impact of socio-demographic factors type of ART and baseline category of CD4 counts were assessed at six monthly interval using robust linear mixed models.ResultsA total of 214 follow up records were reviewed at Komfo Anokye Teaching Hospital (KATH) and the Kumasi South Hospital (KSH). One hundred (46.7 %) were from KATH and 114 (53.3 %) were from KSH. There was a general increase in the level of CD4 counts with time, however this increase significantly slowed down with subsequent reviews (p < 0.001). On the average the rate of CD4 count recovery slowed down by 43.6 cells/µl for every 6 months of follow up (SE = 7.69; p < 0.001). Similarly the recovery of CD4 counts in subjects with an initial high baseline CD4 counts decreased by 192.6 cells/µl (SD error = 42.3, p value ≤0.001). All other variables were not significantly associated with recovery of CD4 counts.ConclusionOur study has demonstrated the well-known phenomenon of CD4 counts increasing after administration of ARTs. CD4 counts increased more rapidly in those with relatively lower initial counts, catching up with those with high CD4 count by 2 years post treatment.

Association between discordant immunological response to highly active anti-retroviral therapy, regulatory T cell percentage, immune cell activation and very low-level viraemia in HIV-infected patients

The mechanisms sustaining the absence of complete immune recovery in HIV-infected patients upon long-term effective highly active anti-retroviral therapy (HAART) remain elusive. Immune activation, regulatory T cells (T(regs)) or very low-level viraemia (VLLV) have been alternatively suspected, but rarely investigated simultaneously. We performed a cross-sectional study in HIV-infected aviraemic subjects (mean duration of HAART: 12 years) to concomitantly assess parameters associated independently with inadequate immunological response. Patients were classified as complete immunological responders (cIR, n = 48) and inadequate immunological responders (iIR, n = 39), depending on the CD4(+) T cell count (> or < 500/mm(3)). Clinical and virological data (including very low-level viraemia) were collected. In parallel, immunophenotyping of CD4(+) lymphocytes, including T(reg) subsets, and CD8(+) T cells was performed. Percentages of activated CD4(+) T cells, T(regs), effector T(regs) and terminal effector T(regs) were found to be significantly elevated in iIR. Neither the percentage of activated CD8(+) T cells nor VLLV were found to be associated with iIR. In the multivariate analysis, nadir of CD4(+) T cell count and percentage of T(regs) were the only two parameters associated independently with iIR [odds ratio (OR) = 2·339, P = 0·001, and OR = 0·803, P = 0·041]. We present here the largest study investigating simultaneously the immune response to long-term HAART, activation of CD4(+) and CD8(+) T cells, T(reg) percentages and very low-level viraemia. Causative interactions between T(regs) and CD4(+) T cells should now be explored prospectively in a large patients cohort.

European mitochondrial haplogroups are not associated with hepatitis C virus (HCV) treatment response in HIV/HCV‐coinfected patients

Mitochondria are multifunctional organelles with a key role in the innate immune response against viral infections. Mitochondrial DNA (mtDNA) haplogroups have been related to AIDS progression and CD4 T-cell recovery in HIV-infected patients, and to a delay in the development of liver fibrosis in HIV/hepatitis C virus (HCV)-coinfected patients. We performed a study to investigate whether mtDNA haplogroups may be associated with HCV treatment response in HIV/HCV-coinfected patients on pegylated interferon (pegIFN) plus ribavirin (RBV). We performed a retrospective study in 304 patients who completed a course of HCV therapy. mtDNA polymorphisms were genotyped using Sequenom's MassARRAY platform. The interleukin-28B (IL-28B) polymorphism (rs12980275) was genotyped using the GoldenGate® assay. Sustained virological response (SVR) was defined as an undetectable HCV viral load at week 24 after the end of treatment. The statistical analysis was carried out using on-treatment data. The SVR rates were 52.6% (160 of 304) for all patients, and 37.8% (46 of 201) for patients with HCV genotype 1 or 4 vs. 81.4% (83 of 102) for patients with HCV genotype 2 or 3 (P < 0.001). No significant associations were found between mtDNA haplogroup and SVR when all patients were included in the analysis and when patients were stratified by HCV genotype (i.e. those with genotypes 1/4 and 2/3 analysed separately) or IL-28B rs12980275 genotype. European mtDNA haplogroups were not related to HCV treatment response in HIV/HCV-coinfected patients on pegIFN-α/RBV therapy.