Effects of Intermittent IL-2 Alone or with Peri-Cycle Antiretroviral Therapy in Early HIV Infection: The STALWART Study

Background

The Study of Aldesleukin with and without antiretroviral therapy (STALWART) evaluated whether intermittent interleukin-2 (IL-2) alone or with antiretroviral therapy (ART) around IL-2 cycles increased CD4⁺ counts compared to no therapy.

Methodology

Participants not on continuous ART with ≥300 CD4⁺ cells/mm³ were randomized to: no treatment; IL-2 for 5 consecutive days every 8 weeks for 3 cycles; or the same IL-2 regimen with 10 days of ART administered around each IL-2 cycle. CD4⁺ counts, HIV RNA, and HIV progression events were collected monthly.

Principal Findings

A total of 267 participants were randomized. At week 32, the mean CD4⁺ count was 134 cells greater in the IL-2 alone group (p<0.001), and 133 cells greater in the IL-2 plus ART group (p<0.001) compared to the no therapy group. Twelve participants in the IL-2 groups compared to 1 participant in the group assigned to no therapy experienced an opportunistic event or died (HR 5.84, CI: 0.59 to 43.57; p = 0.009).

Conclusions

IL-2 alone or with peri-cycle HAART increases CD4⁺ counts but was associated with a greater number of opportunistic events or deaths compared to no therapy. These results call into question the immunoprotective significance of IL-2-induced CD4⁺ cells.

Trial Registration

ClinicalTrials.gov {type:clinical-trial,attrs:{text:NCT00110812,term_id:NCT00110812}}NCT00110812     

Post-Stroke Epilepsy in Young Adults: A Long-Term Follow-Up Study

Background

Little is known about the incidence and risk of seizures after stroke in young adults. Especially in the young seizures might dramatically influence prognosis and quality of life. We therefore investigated the long-term incidence and risk of post-stroke epilepsy in young adults with a transient ischemic attack (TIA), ischemic stroke (IS) or intracerebral hemorrhage (ICH).

Methods and Findings

We performed a prospective cohort study among 697 consecutive patients with a first-ever TIA, IS or ICH, aged 18–50 years, admitted to our hospital between 1-1-1980 till 1-11-2010. The occurrence of epilepsy was assessed by standardized questionnaires and verified by a neurologist. Cumulative risks were estimated with Kaplan-Meier analysis. Cox proportional hazard models were used to calculate relative risks. After mean follow-up of 9.1 years (SD 8.2), 79 (11.3%) patients developed post-stroke epilepsy and 39 patients (5.6%) developed epilepsy with recurrent seizures. Patients with an initial late seizure more often developed recurrent seizures than patients with an initial early seizure. Cumulative risk of epilepsy was 31%, 16% and 5% for patients with an ICH, IS and TIA respectively (Logrank test ICH and IS versus TIA p<0.001). Cumulative risk of epilepsy with recurrent seizures was 23%, 8% and 4% respectively (Logrank ICH versus IS p = 0.05, ICH versus TIA p<0.001, IS versus TIA p = 0.01). In addition a high NIHSS was a significant predictor of both epilepsy and epilepsy with recurrent seizures (HR 1.07, 95% CI 1.03–1.11 and 1.08, 95% CI 1.02–1.14).

Conclusions

Post-stroke epilepsy is much more common than previously thought. Especially patients with an ICH and a high NIHSS are at high risk. This calls upon the question whether a subgroup could be identified which benefits from the use of prophylactic antiepileptic medication. Future studies should be executed to investigate risk factors and the effect of post-stroke epilepsy on quality of life.     

Clinical Heterogeneity of Ectopic ACTH Syndrome: A Long-Term Follow-Up Study

Objective: Ectopic adrenocorticotropic hormone (ACTH) syndrome (EAS) is a heterogeneous condition caused by neuroendocrine neoplasms (NENs) located in the lungs, thymus, or pancreas. Our purpose was to evaluate the long-term outcome of these patients.Methods: Retrospective study at a referral center. The charts of 164 patients with Cushing syndrome, followed at our center from 1993 to 2019, were analyzed.Results: EAS was found in 16 patients (9.75%, 9 women, mean age 36.01 years) who had been followed for a median of 72 months. The source of EAS was a NEN in 10 patients (8 bronchial and 2 thymic carcinoid tumors) and a mixed corticomedullary tumor, consisting of a pheochromocytoma and an adrenocortical carcinoma in 1 patient. In 2 of the 6 patients initially considered to have occult EAS, the source of the ACTH excess became apparent after adrenalectomy, whereas in the remaining 4 (25%) patients, it has remained occult. Of the 11 patients in whom resection of the NEN was attempted, 10 patients achieved an early remission (91%), but 4 (25%) of these patients had a recurrence during follow-up (biochemically and clinically silent in 2 patients). Three patients died (18.75%): the young woman with the mixed corticomedullary tumor, a man with a thymic NEN that evolved into a neuroendocrine (NE) carcinoma after 11 years of follow-up, and a woman with a bronchial NEN.Conclusion:The course of EAS varies according to tumor type and grade. Some patients have a protracted course, whereas others may evolve into neuroendocrine carcinomas.Abbreviations: ACTH = adrenocorticotropic hormone; CS = Cushing syndrome; CT = computed tomography; CV = coefficient of variation; EAS = ectopic ACTH syndrome; IQR = interquartile range; NEN = neuroendocrine neoplasm; SCCL = small cell carcinoma of the lung; TSS = transsphenoidal surgery; UFC = urinary free cortisol     

Onset Pattern and Long-Term Prognosis in Schizophrenia: 10-Year Longitudinal Follow-Up Study

Background

Although the duration of untreated psychosis (DUP) plays an important role in the short-term prognosis of patients with schizophrenia, their long-term prognosis generally is not determined by DUP alone. It is important to explore how other clinical factors in the early stage are related to DUP and consequent disease courses.

Methods

A total of 664 patients with untreated psychosis were surveyed for this study. At the first examination, we divided them into the severe positive symptoms cases (SC) or the less severe cases (NonSC) and compared the prognosis among the two groups after a 10-year follow-up. In all, 113 patients in the SC group and 43 patients in the NonSC group were follow-up completers.

Results

Whereas DUP was not different between the two groups, patients with nonacute onset in both groups had significantly longer DUP than those in patients with acute onset. For all clinical measures, there was no difference in prognosis between the two groups or among the four groups classified by mode of onset (MoO) and initial severity of positive symptoms. However, the degree of improvement of global assessment of functioning (GAF) was significantly smaller in the NonSC-nonacute group than in the SC-acute and SC-nonacute groups.

Conclusions

These results suggest that neither DUP nor MoO alone necessarily affects the initial severity of positive symptoms. Moreover, it is possible that patients with low impetus of positive symptoms onset within long DUP experience profound pathologic processes. Therefore, the current study results indicated that long DUP and nonacute onset were related to poor long-term prognosis, regardless of initial positive symptoms.     

Statin Use and Cognitive Function: Population-Based Observational Study with Long-Term Follow-Up

We aimed to evaluate the association between statin use and cognitive function. Cognitive function was measured with the Ruff Figural Fluency Test (RFFT; worst score, 0; best score, 175 points) and the Visual Association Test (VAT; low performance, 0–10; high performance, 11–12 points) in an observational study that included 4,095 community-dwelling participants aged 35–82 years. Data on statin use were obtained from a computerized pharmacy database. Analysis were done for the total cohort and subsamples matched on cardiovascular risk (N = 1232) or propensity score for statin use (N = 3609). We found that a total of 904 participants (10%) used a statin. Statin users were older than non-users: mean age (SD) 61 (10) vs. 52 (11) years (p<0.001). The median duration of statin use was 3.8 (interquartile range, 1.6–4.5) years. Unadjusted, statin users had worse cognitive performance than non-users. The mean RFFT score (SD) in statin users and non-users was 58 (23) and 72 (26) points, respectively (p<0.001). VAT performance was high in 261 (29%) statin users and 1351 (43%) non-users (p<0.001). However, multiple regression analysis did not show a significant association of RFFT score with statin use (B, −0.82; 95%CI, −2.77 to 1.14; p = 0.41) nor with statin solubility, statin dose or duration of statin use. Statin users with high doses or long-term use had similar cognitive performance as non-users. This was found in persons with low as well as high cardiovascular risk, and in younger as well as older subjects. Also, the mean RFFT score per quintile of propensity score for statin use was comparable for statin users and non-users. Similar results were found for the VAT score as outcome measure. In conclusion, statin use was not associated with cognitive function. This was independent of statin dose or duration of statin use.     

Cognitive Performance and Long-Term Social Functioning in Psychotic Disorder: A Three-Year Follow-Up Study

ObjectiveStudies have linked cognitive functioning to everyday social functioning in psychotic disorders, but the nature of the relationships between cognition, social cognition, symptoms, and social functioning remains unestablished. Modelling the contributions of non-social and social cognitive ability in the prediction of social functioning may help in more clearly defining therapeutic targets to improve functioning.MethodIn a sample of 745 patients with a non-affective psychotic disorder, the associations between cognition and social cognition at baseline on the one hand, and self-reported social functioning three years later on the other, were analysed. First, case-control comparisons were conducted; associations were subsequently further explored in patients, investigating the potential mediating role of symptoms. Analyses were repeated in a subsample of 233 patients with recent-onset psychosis.ResultsInformation processing speed and immediate verbal memory were stronger associated with social functioning in patients than in healthy controls. Most cognition variables significantly predicted social functioning at follow-up, whereas social cognition was not associated with social functioning. Symptoms were robustly associated with follow-up social functioning, with negative symptoms fully mediating most associations between cognition and follow-up social functioning. Illness duration did not moderate the strength of the association between cognitive functioning and follow-up social functioning. No associations were found between (social) cognition and follow-up social functioning in patients with recent-onset psychosis.ConclusionsAlthough cognitive functioning is associated with later social functioning in psychotic disorder, its role in explaining social functioning outcome above negative symptoms appears only modest. In recent-onset psychosis, cognition may have a negligible role in predicting later social functioning. Moreover, social cognition tasks may not predict self-reported social functioning.     

Urinary Concentration of Monocyte Chemoattractant Protein-1 in Idiopathic Glomerulonephritis: A Long-Term Follow-Up Study

Background

Monocyte chemoattractant protein-1 (MCP-1), which is up regulated in kidney diseases, is considered a marker of kidney inflammation. We examined the value of urine MCP-1 in predicting the outcome in idiopathic glomerulonephritis.

Methods

Between 1993 and 2004, 165 patients (68 females) diagnosed with idiopathic proteinuric glomerulopathy and with serum creatinine <150 µmol/L at diagnosis were selected for the study. Urine concentrations of MCP-1 were analyzed by ELISA in early morning spot urine samples collected on the day of the diagnostic kidney biopsy. The patients were followed until 2009. The progression rate to end-stage kidney disease was calculated using Kaplan–Meier survival analysis. End-stage kidney disease (ESKD) was defined as the start of kidney replacement therapy during the study follow-up time.

Results

Patients with proliferative glomerulonephritis had significantly higher urinary MCP-1 excretion levels than those with non-proliferative glomerulonephritis (p<0.001). The percentage of patients whose kidney function deteriorated significantly was 39.0% in the high MCP-1 excretion group and 29.9% in the low MCP-1 excretion group. However, after adjustment for confounding variables such as glomerular filtration rate (GFR) and proteinuria, there was no significant association between urine MCP-1 concentration and progression to ESKD, (HR = 1.75, 95% CI = 0.64–4.75, p = 0.27).

Conclusion

Our findings indicate that progression to end-stage kidney disease in patients with idiopathic glomerulopathies is not associated with urine MCP-1 concentrations at the time of diagnosis.     

Genetic Determinants of Long-Term Changes in Blood Lipid Concentrations: 10-Year Follow-Up of the GLACIER Study

Recent genome-wide meta-analyses identified 157 loci associated with cross-sectional lipid traits. Here we tested whether these loci associate (singly and in trait-specific genetic risk scores [GRS]) with longitudinal changes in total cholesterol (TC) and triglyceride (TG) levels in a population-based prospective cohort from Northern Sweden (the GLACIER Study). We sought replication in a southern Swedish cohort (the MDC Study; N = 2,943). GLACIER Study participants (N = 6,064) were genotyped with the MetaboChip array. Up to 3,495 participants had 10-yr follow-up data available in the GLACIER Study. The TC- and TG-specific GRSs were strongly associated with change in lipid levels (β = 0.02 mmol/l per effect allele per decade follow-up, P = 2.0×10⁻¹¹ for TC; β = 0.02 mmol/l per effect allele per decade follow-up, P = 5.0×10⁻⁵ for TG). In individual SNP analysis, one TC locus, apolipoprotein E (APOE) rs4420638 (β = 0.12 mmol/l per effect allele per decade follow-up, P = 2.0×10⁻⁵), and two TG loci, tribbles pseudokinase 1 (TRIB1) rs2954029 (β = 0.09 mmol/l per effect allele per decade follow-up, P = 5.1×10⁻⁴) and apolipoprotein A-I (APOA1) rs6589564 (β = 0.31 mmol/l per effect allele per decade follow-up, P = 1.4×10⁻⁸), remained significantly associated with longitudinal changes for the respective traits after correction for multiple testing. An additional 12 loci were nominally associated with TC or TG changes. In replication analyses, the APOE rs4420638, TRIB1 rs2954029, and APOA1 rs6589564 associations were confirmed (P≤0.001). In summary, trait-specific GRSs are robustly associated with 10-yr changes in lipid levels and three individual SNPs were strongly associated with 10-yr changes in lipid levels.     

Lower Ipsilateral Hippocampal Integrity after Ischemic Stroke in Young Adults: A Long-Term Follow-Up Study

MethodsWe included all consecutive first-ever ischemic stroke patients, without hippocampal strokes or recurrent stroke/TIA, aged 18–50 years, admitted to our academic hospital between 1980 and 2010. One hundred and forty-six patients underwent T1 MPRAGE, DTI scanning and completed the Rey Auditory Verbal Learning Test and were compared with 84 stroke-free controls. After manual correction of hippocampal automatic segmentation, we calculated mean hippocampal fractional anisotropy (FA) and diffusivity (MD).ResultsOn average 10 years after ischemic stroke, lesion volume was associated with lower ipsilateral hippocampal integrity (p<0.05), independent of hippocampal volume. In patients with a normal ipsilateral hippocampal volume (volume is less than or equal to 1.5 SD below the mean volume of controls) significant differences in ipsilateral hippocampal MD were observed (p<0.0001). However, patients with a normal hippocampal volume and high hippocampal MD did not show a worse memory performance compared with patients with a normal volume and low hippocampal MD (p>0.05).ConclusionsPatients with average ipsilateral hippocampal volume could already have lower ipsilateral hippocampal integrity, although at present with no attendant worse memory performance compared with patients with high hippocampal integrity. Longitudinal studies are needed to investigate whether a low hippocampal integrity after stroke might lead to exacerbated memory decline with increasing age.     

Long-Term Study of Toxoplasma gondii Infection in a Swedish Sheep Flock

The infection rate of Toxoplasma gondii was studied during 6 years in a sheep flock in central Sweden. The flock consisted of 165-249 breeding ewes of which 20-35% were lambs less than 1 year old. Most ewes were slaughtered when 5 years old. The sheep were kept indoors from end of September to early May. Lambing took place in March and April. Individual serum samples were collected twice a year, once just before turning the sheep out to pasture in the spring, and again after housing in the autumn. Sera were analysed by ELISA for antibodies to T. gondii. The seroprevalence varied between 10% and 45% during the 6 years of observation. Seroconversion was detected predominantly at the autumn sampling, indicating that in most cases infection was acquired at pasture. Subclinical effects of T. gondii infection on lamb weight, litter size, total litter weight and ewe weight were also studied. Lambs born to chronically infected ewes were lighter at birth than those of uninfected ewes, but this disparity was no longer evident at weaning.     

Decreases in Colonic and Systemic Inflammation in Chronic HIV Infection after IL-7 Administration

Despite antiretroviral therapy (ART), some HIV-infected persons maintain lower than normal CD4⁺ T-cell counts in peripheral blood and in the gut mucosa. This incomplete immune restoration is associated with higher levels of immune activation manifested by high systemic levels of biomarkers, including sCD14 and D-dimer, that are independent predictors of morbidity and mortality in HIV infection. In this 12-week, single-arm, open-label study, we tested the efficacy of IL-7 adjunctive therapy on T-cell reconstitution in peripheral blood and gut mucosa in 23 ART suppressed HIV-infected patients with incomplete CD4⁺ T-cell recovery, using one cycle (consisting of three subcutaneous injections) of recombinant human IL-7 (r-hIL-7) at 20 µg/kg. IL-7 administration led to increases of both CD4⁺ and CD8⁺ T-cells in peripheral blood, and importantly an expansion of T-cells expressing the gut homing integrin α4β7. Participants who underwent rectosigmoid biopsies at study baseline and after treatment had T-cell increases in the gut mucosa measured by both flow cytometry and immunohistochemistry. IL-7 therapy also resulted in apparent improvement in gut barrier integrity as measured by decreased neutrophil infiltration in the rectosigmoid lamina propria 12 weeks after IL-7 administration. This was also accompanied by decreased TNF and increased FOXP3 expression in the lamina propria. Plasma levels of sCD14 and D-dimer, indicative of systemic inflammation, decreased after r-hIL-7. Increases of colonic mucosal T-cells correlated strongly with the decreased systemic levels of sCD14, the LPS coreceptor - a marker of monocyte activation. Furthermore, the proportion of inflammatory monocytes expressing CCR2 was decreased, as was the basal IL-1β production of peripheral blood monocytes. These data suggest that administration of r-hIL-7 improves the gut mucosal abnormalities of chronic HIV infection and attenuates the systemic inflammatory and coagulation abnormalities that have been linked to it.     

Short and Long-Term Effects of Telaprevir on Kidney Function in Patients with Hepatitis C Virus Infection: A Retrospective Cohort Study

Background

Recent reports suggest that telaprevir, a protease inhibitor used to treat hepatitis C infection, is associated with decline in kidney function during therapy, particularly in patients with baseline renal impairment.

Methods

Patients treated with telaprevir in a single healthcare network were retrospectively reviewed. Kidney function was determined at baseline, during therapy, and twelve weeks and twelve months after telaprevir discontinuation. Significant creatinine rise during therapy was defined as an increase in serum creatinine ≥ 0.3mg/dL from baseline during treatment with telaprevir.

Results

Between July 2011 to January 2013,seventy-eight patients began treatment. The majority completed the prescribed twelve weeks of telaprevir therapy; 32% discontinued due to side effects. The average rise in serum creatinine during therapy was 0.22mg/dL (standard deviation 0.22mg/dL). Thirty-one percent experienced a significant creatinine rise during therapy. Decline in estimated glomerular filtration rate (eGFR) was lower in those with baseline eGFR < 90 mL/min/1.73m² compared to the group with baseline eGFR ≥ 90 mL/min/1.73m² (12 vs. 18 mL/min/1.73m², P = 0.047). Serum creatinine fully normalized by twelve weeks after cessation of telaprevir in 83% of patients, however experiencing a significant creatinine rise during telaprevir use was associated with a 6.6mL/min/1.73m² decrease in estimated glomerular filtration rate at twelve months in an adjusted model.

Conclusions

Decline in kidney function during therapy with telaprevir is common and is not associated with baseline eGFR < 90mL/min/1.73m² as previously reported.     

Ultrastructural Study of Long-Term Measles Infection in Cultures of Hamster Dorsal-Root Ganglion

The morphogenesis of the Edmonston strain of measles is described in cultures of hamster dorsal-root ganglion maintained for as long as 63 days postinoculation. The patterns observed confirmed those previously reported in both neural and non-neural tissue. However, in the present tissue, the development of viral material could be followed chronologically within different cell types such as neurons and Schwann cells. Active replication was visualized up to 63 days postinoculation. The appearance of cytoplasmic nucleocapsid preceded that of intranuclear nucleocapsid, the latter occurring after 14 days. These intranuclear inclusions were formed after the transformation of the nucleoli into bizarre pleomorphic bodies which eventually segregated into clumps of nucleocapsid. These intranuclear inclusions mimic those seen in subacute sclerosing panencephalitis, now known to be etiologically related to a measles-like virus.     

Risk Factors for Long-Term Mortality after Hospitalization for Community-Acquired Pneumonia: A 5-Year Prospective Follow-Up Study

Background

Contributors to long-term mortality in patients with community-acquired pneumonia (CAP) remain unclear, with little attention paid to pneumonia etiology. We examined long-term survival, causes of death, and risk factors for long-term mortality in adult patients who had been hospitalized for CAP, with emphasis on demographic, clinical, laboratory, and microbiological characteristics.

Methods

Two hundred and sixty-seven consecutive patients admitted in 2008–2011 to a general hospital with CAP were prospectively recruited and followed up. Patients who died during hospital stay were excluded. Demographic, clinical, and laboratory data were collected within 48 hours of admission. Extensive microbiological work-up was performed to establish the etiology of CAP in 63% of patients. Mortality data were obtained from the Norwegian Cause of Death Registry. Cox regression models were used to identify independent risk factors for all-cause mortality.

Results

Of 259 hospital survivors of CAP (median age 66 years), 79 (30.5%) died over a median of 1,804 days (range 1–2,520 days). Cumulative 5-year survival rate was 72.9% (95% CI 67.4–78.4%). Standardized mortality ratio was 2.90 for men and 2.05 for women. The main causes of death were chronic obstructive pulmonary disease (COPD), vascular diseases, and malignancy. Independent risk factors for death were the following (hazard ratio, 95% CI): age (1.83 per decade, 1.47–2.28), cardiovascular disease (2.63, 1.61–4.32), COPD (2.09, 1.27–3.45), immunocompromization (1.98, 1.17–3.37), and low serum albumin level at admission (0.75 per 5g/L higher, 0.58–0.96), whereas active smoking was protective (0.32, 0.14–0.74); active smokers were younger than non-smokers (P < 0.001). Microbial etiology did not predict mortality.

Conclusions

Results largely confirm substantial comorbidity-related 5-year mortality after hospitalization for CAP and the impact of several well-known risk factors for death, and extend previous findings on the prognostic value of serum albumin level at hospital admission. Pneumonia etiology had no prognostic value, but this remains to be substantiated by further studies using extensive diagnostic microbiological methods in the identification of causative agents of CAP.     

Stereotactic LINAC-Radiosurgery for Glomus Jugulare Tumors: A Long-Term Follow-Up of 27 Patients

Background

The optimal treatment of glomus jugulare tumors (GJTs) remains controversial. Due to the critical location, microsurgery still provides high treatment-related morbidity and a decreased quality of life. Thus, we performed stereotactical radiosurgery (SRS) for the treatment of GJTs and evaluated the long-term outcome.

Methods

Between 1991 and 2011, 32 patients with GJTs underwent SRS using a linear accelerator (LINAC) either as primary or salvage therapy. Twenty-seven patients (median age 59.9 years, range 28.7–79.9 years) with a follow-up greater than five years (median 11 years, range 5.3–22.1 years) were selected for retrospective analysis. The median therapeutic single dose applied to the tumor surface was 15 Gy (range 11–20 Gy) and the median tumor volume was 9.5 ml (range 2.8–51 ml).

Results

Following LINAC-SRS, 10 of 27 patients showed a significant improvement of their previous neurological complaints, whereas 12 patients remained unchanged. Five patients died during follow-up due to old age or other, not treatment-related reasons. MR-imaging showed a partial remission in 12 and a stable disease in 15 patients. No tumor progression was observed. The actuarial overall survival rates after five, ten and 20 years were 100%, 95.2% and 79.4%, respectively.

Conclusions

Stereotactic LINAC-Radiosurgery can achieve an excellent long-term tumor control beside a low rate of morbidity in the treatment of GJTs. It should be considered as an alternative therapy regime to surgical resection or fractionated external beam radiation either as primary, adjuvant or salvage therapy.     

Regulatory T Cells Negatively Affect IL-2 Production of Effector T Cells through CD39/Adenosine Pathway in HIV Infection

The mechanisms by which Regulatory T cells suppress IL-2 production of effector CD4+ T cells in pathological conditions are unclear. A subpopulation of human Treg expresses the ectoenzyme CD39, which in association with CD73 converts ATP/ADP/AMP to adenosine. We show here that Treg/CD39+ suppress IL-2 expression of activated CD4+ T-cells more efficiently than Treg/CD39−. This inhibition is due to the demethylation of an essential CpG site of the il-2 gene promoter, which was reversed by an anti-CD39 mAb. By recapitulating the events downstream CD39/adenosine receptor (A2AR) axis, we show that A2AR agonist and soluble cAMP inhibit CpG site demethylation of the il-2 gene promoter. A high frequency of Treg/CD39+ is associated with a low clinical outcome in HIV infection. We show here that CD4+ T-cells from HIV-1 infected individuals express high levels of A2AR and intracellular cAMP. Following in vitro stimulation, these cells exhibit a lower degree of demethylation of il-2 gene promoter associated with a lower expression of IL-2, compared to healthy individuals. These results extend previous data on the role of Treg in HIV infection by filling the gap between expansion of Treg/CD39+ in HIV infection and the suppression of CD4+ T-cell function through inhibition of IL-2 production.     

Effects of Prednisolone on Disease Progression in Antiretroviral-Untreated HIV Infection: A 2-Year Randomized,Double-Blind Placebo-Controlled Clinical Trial

Background

HIV-disease progression correlates with immune activation. Here we investigated whether corticosteroid treatment can attenuate HIV disease progression in antiretroviral-untreated patients.

Methods

Double-blind, placebo-controlled randomized clinical trial including 326 HIV-patients in a resource-limited setting in Tanzania (clinicaltrials.gov {"type":"clinical-trial","attrs":{"text":"NCT01299948","term_id":"NCT01299948"}}NCT01299948). Inclusion criteria were a CD4 count above 300 cells/μl, the absence of AIDS-defining symptoms and an ART-naïve therapy status. Study participants received 5 mg prednisolone per day or placebo for 2 years. Primary endpoint was time to progression to an AIDS-defining condition or to a CD4-count below 200 cells/μl.

Results

No significant change in progression towards the primary endpoint was observed in the intent-to-treat (ITT) analysis (19 cases with prednisolone versus 28 cases with placebo, p = 0.1407). In a per-protocol (PP)-analysis, 13 versus 24 study participants progressed to the primary study endpoint (p = 0.0741). Secondary endpoints: Prednisolone-treatment decreased immune activation (sCD14, suPAR, CD38/HLA-DR/CD8+) and increased CD4-counts (+77.42 ± 5.70 cells/μl compared to -37.42 ± 10.77 cells/μl under placebo, p < 0.0001). Treatment with prednisolone was associated with a 3.2-fold increase in HIV viral load (p < 0.0001). In a post-hoc analysis stratifying for sex, females treated with prednisolone progressed significantly slower to the primary study endpoint than females treated with placebo (ITT-analysis: 11 versus 21 cases, p = 0.0567; PP-analysis: 5 versus 18 cases, p = 0.0051): No changes in disease progression were observed in men.

Conclusions

This study could not detect any significant effects of prednisolone on disease progression in antiretroviral-untreated HIV infection within the intent-to-treat population. However, significant effects were observed on CD4 counts, immune activation and HIV viral load. This study contributes to a better understanding of the role of immune activation in the pathogenesis of HIV infection.

Trial Registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT01299948","term_id":"NCT01299948"}}NCT01299948