Immunologic Biomarkers, Morbidity, and Mortality in Treated HIV Infection.
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SUBMITTER: Hunt PW
PROVIDER: S-EPMC5021241 | biostudies-literature | 2016 Oct
REPOSITORIES: biostudies-literature
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Immunologic Biomarkers, Morbidity, and Mortality in Treated HIV Infection.
Hunt Peter W PW Lee Sulggi A SA Siedner Mark J MJ
The Journal of infectious diseases 20161001
Despite marked improvements in the modern treatment era, human immunodeficiency virus (HIV)-infected individuals, particularly those who initiated antiretroviral therapy (ART) at advanced disease stages, continue to have increased age-related morbidity and mortality, compared with the general population. Immune activation and inflammation persist despite suppressive ART and predict many of these morbidities. The goal of this review is to examine the evidence suggesting a link between the persist ...[more]
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Project description:BackgroundIn the Strategies for Management of Anti-Retroviral Therapy trial, all-cause mortality was higher for participants randomized to intermittent, CD4-guided antiretroviral treatment (ART) (drug conservation [DC]) than continuous ART (viral suppression [VS]).We hypothesized that increased HIV-RNA levels following ART interruption induced activation of tissue factor pathways, thrombosis, and fibrinolysis.Methods and findingsStored samples were used to measure six biomarkers: high sensitivity C-reactive protein (hsCRP), interleukin-6 (IL-6), amyloid A, amyloid P, D-dimer, and prothrombin fragment 1+2. Two studies were conducted: (1) a nested case-control study for studying biomarker associations with mortality, and (2) a study to compare DC and VS participants for biomarker changes. For (1), markers were determined at study entry and before death (latest level) for 85 deaths and for two controls (n = 170) matched on country, age, sex, and date of randomization. Odds ratios (ORs) were estimated with logistic regression. For each biomarker, each of the three upper quartiles was compared to the lowest quartile. For (2), the biomarkers were assessed for 249 DC and 250 VS participants at study entry and 1 mo following randomization. Higher levels of hsCRP, IL-6, and D-dimer at study entry were significantly associated with an increased risk of all-cause mortality. Unadjusted ORs (highest versus lowest quartile) were 2.0 (95% confidence interval [CI], 1.0-4.1; p = 0.05), 8.3 (95% CI, 3.3-20.8; p < 0.0001), and 12.4 (95% CI, 4.2-37.0; p < 0.0001), respectively. Associations were significant after adjustment, when the DC and VS groups were analyzed separately, and when latest levels were assessed. IL-6 and D-dimer increased at 1 mo by 30% and 16% in the DC group and by 0% and 5% in the VS group (p < 0.0001 for treatment difference for both biomarkers); increases in the DC group were related to HIV-RNA levels at 1 mo (p < 0.0001). In an expanded case-control analysis (four controls per case), the OR (DC/VS) for mortality was reduced from 1.8 (95% CI, 1.1-3.1; p = 0.02) to 1.5 (95% CI, 0.8-2.8) and 1.4 (95% CI, 0.8-2.5) after adjustment for latest levels of IL-6 and D-dimer, respectively.ConclusionsIL-6 and D-dimer were strongly related to all-cause mortality. Interrupting ART may further increase the risk of death by raising IL-6 and D-dimer levels. Therapies that reduce the inflammatory response to HIV and decrease IL-6 and D-dimer levels may warrant investigation.
| S-EPMC2570418 | biostudies-literature
Project description:ObjectiveTo assess the burden of mortality and hospitalized morbidity in newly treated epilepsy patients.MethodsWe extracted relevant data of patients with newly treated epilepsy between September 16, 2005, and September 15, 2010, from the data repository covering all public hospitals in Hong Kong. Patients were followed up until September 15, 2011. Mortality and hospitalized morbidity were assessed, stratified by baseline comorbidities, number of antiepileptic drugs (AEDs) used, and treatment with enzyme-inducing AEDs (EIAEDs). Mortality was compared to the age- and sex-specific general population in Hong Kong.ResultsOf the 7,461 newly treated epilepsy patients (55% male; median age 60 years), 2,166 (29%) died during the study period. The standardized mortality ratio was 5.09 (95% confidence interval [CI] 4.88-5.31), and was higher among those with physical or psychiatric baseline comorbidity (5.46; 95% CI 5.22-5.71) than those without (3.28; 95% CI 2.87-3.73). Standardized hospitalization ratio was 6.76 (95% CI 6.70-6.82). Baseline physical comorbidity-free patients (n = 3,514) exhibited higher risk of developing stroke (standardized incidence ratio [SIR] 4.96; 95% CI 4.19-5.84) and ischemic heart disease (SIR 4.18; 95% CI 3.54-4.91), and male patients had elevated risk of developing cancer (SIR 2.30; 95% CI 1.75-2.97). Patients treated with EIAEDs had higher risk of being subsequently recorded with new physical comorbidities than those with non-EIAEDs (relative risk [RR] 1.48; 95% CI 1.19-1.85), especially for cerebrovascular disease (RR 1.78; 95% CI 1.14-2.77).ConclusionsNewly treated epilepsy patients bear excess mortality and hospitalization risks. They have higher risk of developing stroke, ischemic heart disease, and cancer. Treatment with EIAEDs was associated with increased overall morbidity.
| S-EPMC4999164 | biostudies-literature
Project description:Infection-related morbidity and mortality are increased in older patients with diffuse large B-cell lymphoma (DLBCL) compared with population-matched controls. Key predictive factors for infection-related hospitalization during treatment with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) and deaths as a result of infection in older patients during and after treatment with R-CHOP remain incompletely understood. For this study, 690 consecutively treated patients age 70 years or older who received full-dose or attenuated-dose R-CHOP treatment were analyzed for risk of infection-related hospitalization and infection-related death. Median age was 77 years, and 34.4% were 80 years old or older. Median follow-up was 2.8 years (range, 0.4-8.9 years). Patient and baseline disease characteristics were assessed in addition to intended dose intensity (IDI). Of all patients, 72% were not hospitalized with infection. In 331 patients receiving an IDI ≥80%, 33% were hospitalized with ≥1 infections compared with 23.3% of 355 patients receiving an IDI of <80% (odds ratio, 1.61; 95% confidence interval, 1.15-2.25; P = .006). An increased risk of infection-related admission was independently associated with IDI >80% across the whole cohort. Primary quinolone prophylaxis independently reduced infection-related admission. A total of 51 patients died as a result of infection. The 6-month, 12-month, 2-year, and 5-year cumulative incidences of infection-related death were 3.3%, 5.0%, 7.2%, and 11.1%, respectively. Key independent factors associated with infection-related death were an International Prognostic Index (IPI) score of 3 to 5, Cumulative Illness Rating Scale for Geriatrics (CIRS-G) score ≥6, and low albumin, which enabled us to generate a predictive risk score. We defined a smaller group (15%) of patients (IPI score of 0-2, albumin >36 g/L, CIRS-G score <6) in which no cases of infection-related deaths occurred at 5 years of follow-up. Whether patients at higher risk of infection-related death could be targeted with enhanced antimicrobial prophylaxis remains unknown and will require a randomized trial.
| S-EPMC8095135 | biostudies-literature
Project description:IntroductionTuberculosis (TB) is a common opportunistic infection among people living with HIV. Diagnostic tests such as culture, Xpert-MTB-RIF, and ULTRA have low sensitivity in paucibacillary TB disease; a blood biomarker could improve TB diagnostic capabilities. We assessed soluble factors to identify biomarkers associated with TB among persons with advanced HIV.MethodsA case-control (1:1) study was conducted, with participants from Rio de Janeiro and Manaus, Brazil. People living with HIV presenting with CD4 count ≤100 cells/mm3 were eligible to participate. Cases had culture-confirmed TB (N=15) (positive for Mycobacterium tuberculosis [Mtb]); controls had HIV-infection only (N=15). Study visits included baseline, month 2 and end of TB therapy, during which samples of peripheral blood were obtained. A panel containing 29 biomarkers including cytokines, chemokines and growth factors was utilized to assess candidate biomarkers using Luminex technology in cryopreserved EDTA plasma samples. We used neural network analysis, based on machine learning, to identify biomarkers (single or in combination) that best distinguished cases from controls. Additional multi-dimensional analyses provided detailed profiling of the systemic inflammatory environment in cases and controls.ResultsMedian CD4 count and HIV-1 RNA load values were similar between groups at all timepoints. Persons with TB had lower body mass index (BMI) (median=19.6, Interquartile Range [IQR]=18.6-22.3) than controls (23.7; IQR: 21.8 = 25.5, p=0.004). TB coinfection was also associated with increased frequency of other comorbidities. The overall profile of plasma cytokines, chemokines and growth factors were distinct between the study groups at all timepoints. Plasma concentrations of IL-15 and IL-10 were on average lower in TB cases than in controls. When used in combination, such markers were able to discriminate between TB cases and controls with the highest degree of accuracy at each study timepoint.ConclusionAmong persons with advanced HIV, plasma concentrations of IL-15 and IL-10 can be used in combination to identify TB disease regardless of time on anti-TB treatment.
| S-EPMC9226490 | biostudies-literature
Project description:The plasma kynurenine/tryptophan (KT) ratio, a marker of adaptive immune defects, strongly predicts mortality during treated human immunodeficiency virus (HIV) disease in Ugandans as compared to US-based populations. Here, the KT ratio and T-cell and plasma biomarkers of immune activation were measured among 535 HIV-infected Ugandans prior to ART initiation and at month 6 of viral suppression. The month 6 KT ratio (adjusted hazard ratio [aHR], 2.74), soluble CD14 level (aHR, 2.32), interleukin 6 level (aHR, 2.34), and D-dimer level (aHR, 1.95) were associated with mortality occurring ≥6 months after ART initiation. The KT ratio remained significantly predictive of mortality even after adjustment for the additional biomarkers, suggesting an independent contribution to clinical outcomes in resource-limited settings.
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Project description:BackgroundWhile inflammation predicts mortality in treated human immunodeficiency virus (HIV) infection, the prognostic significance of gut barrier dysfunction and phenotypic T-cell markers remains unclear.MethodsWe assessed immunologic predictors of mortality in a case-control study within the Longitudinal Study of the Ocular Complications of AIDS (LSOCA), using conditional logistic regression. Sixty-four case patients who died within 12 months of treatment-mediated viral suppression were each matched to 2 control individuals (total number of controls, 128) by duration of antiretroviral therapy-mediated viral suppression, nadir CD4(+) T-cell count, age, sex, and prior cytomegalovirus (CMV) retinitis. A similar secondary analysis was conducted in the SCOPE cohort, which had participants with less advanced immunodeficiency.ResultsPlasma gut epithelial barrier integrity markers (intestinal fatty acid binding protein and zonulin-1 levels), soluble CD14 level, kynurenine/tryptophan ratio, soluble tumor necrosis factor receptor 1 level, high-sensitivity C-reactive protein level, and D-dimer level all strongly predicted mortality, even after adjustment for proximal CD4(+) T-cell count (all P ≤ .001). A higher percentage of CD38(+)HLA-DR(+) cells in the CD8(+) T-cell population was a predictor of mortality before (P = .031) but not after (P = .10) adjustment for proximal CD4(+) T-cell count. Frequencies of senescent (defined as CD28(-)CD57(+) cells), exhausted (defined as PD1(+) cells), naive, and CMV-specific T cells did not predict mortality.ConclusionsGut epithelial barrier dysfunction, innate immune activation, inflammation, and coagulation-but not T-cell activation, senescence, and exhaustion-independently predict mortality in individuals with treated HIV infection with a history of AIDS and are viable targets for interventions.
| S-EPMC4192038 | biostudies-literature
Project description: Not available
| S-EPMC10126948 | biostudies-literature
Project description:BackgroundDespite advances in HIV treatment, bacterial pneumonia continues to cause considerable morbidity and mortality in patients with HIV infection. Studies of biomarker associations with bacterial pneumonia risk in treated HIV-infected patients do not currently exist.MethodsWe performed a nested, matched, case-control study among participants randomized to continuous combination antiretroviral therapy (cART) in the Strategies for Management of Antiretroviral Therapy trial. Patients who developed bacterial pneumonia (cases) and patients without bacterial pneumonia (controls) were matched 1?1 on clinical center, smoking status, age, and baseline cART use. Baseline levels of Club Cell Secretory Protein 16 (CC16), Surfactant Protein D (SP-D), C-reactive protein (hsCRP), interleukin-6 (IL-6), and d-dimer were compared between cases and controls.ResultsCases (n?=?72) and controls (n?=?72) were 25.7% female, 51.4% black, 65.3% current smokers, 9.7% diabetic, 36.1% co-infected with Hepatitis B/C, and 75.0% were on cART at baseline. Median (IQR) age was 45 (41, 51) years with CD4+ count of 553 (436, 690) cells/mm(3). Baseline CC16 and SP-D were similar between cases and controls, but hsCRP was significantly higher in cases than controls (2.94 µg/mL in cases vs. 1.93 µg/mL in controls; p?=?0.02). IL-6 and d-dimer levels were also higher in cases compared to controls, though differences were not statistically significant (p-value 0.06 and 0.10, respectively).ConclusionsIn patients with cART-treated HIV infection, higher levels of systemic inflammatory markers were associated with increased bacterial pneumonia risk, while two pulmonary-specific inflammatory biomarkers, CC16 and SP-D, were not associated with bacterial pneumonia risk.
| S-EPMC3574140 | biostudies-literature
Project description:BACKGROUND:Survivors of Hodgkin's lymphoma (HL) treated as adults are at risk for late effects of therapy. However, the burden of late morbidity and mortality among adults treated for HL remains incompletely characterized. METHODS:Vital status and, for deceased, cause of death were determined for 746 adults treated on a first-line trial at a single center from 1975 to 2000. Survivors completed a detailed survey describing their physical and mental health. A severity score (grades 1-4, ranging from mild to life-threatening or disabling) was assigned to self-reported conditions. RESULTS:At a median follow-up of 22 years, 227 of patients (30.4%) had died, 107 (47.1%) from HL, 120 (52.9%) from other causes, including second primary malignancies (SPMs) (n = 52) and cardiovascular disease (n = 27). Across the duration of follow-up, all-cause and SPM-specific risk of death remained higher than predicted by normative data. Among survivors, late morbidity survey data are available for 238 patients (45.9%). Ninety-four-point-one percent of respondents reported at least one morbidity, and 47.5% reported at least one grade 3 or 4 morbidity; 20.2% reported two or more grade 3 morbidities. Commonly reported morbidities included cardiovascular (54.6%), endocrine (68.5%), pulmonary disease (21.4%), and nonfatal second malignancy (23.1%). Anxiety, depression, and fear of recurrence were frequently reported. CONCLUSIONS:Among a large cohort of patients treated for HL with extensive follow-up, risk of late mortality from causes other than HL and prevalence of late medical morbidity are high. Guidelines for prevention, screening, and management of late effects in adult survivors of HL are needed.
| S-EPMC6281032 | biostudies-literature
Project description:ObjectiveIn this study, we aimed to quantify short- and long-term outcomes of Clostridium difficile infection (CDI) in the elderly, including all-cause mortality, transfer to a facility, and hospitalizations.DesignRetrospective study using 2011 Medicare claims data, including all elderly persons coded for CDI and a sample of uninfected persons. Analysis of propensity score-matched pairs and the entire population stratified by the propensity score was used to determine the risk of all-cause mortality, new transfer to a long-term care facility (LTCF), and short-term skilled nursing facility (SNF), and subsequent hospitalizations within 30, 90, and 365 days.ResultsThe claims records of 174,903 patients coded for CDI were compared with those of 1,318,538 control patients. CDI was associated with increased risk of death (odds ratio [OR], 1.77; 95% confidence interval [CI], 1.74-1.81; attributable mortality, 10.9%), new LTCF transfer (OR, 1.74; 95% CI, 1.67-1.82), and new SNF transfer (OR, 2.52; 95% CI, 2.46-2.58) within 30 days in matched-pairs analyses. In a stratified analysis, CDI was associated with greatest risk of 30-day all-cause mortality in persons with lowest baseline probability of CDI (hazard ratio [HR], 3.04; 95% CI, 2.83-3.26); the risk progressively decreased as the baseline probability of CDI increased. CDI was also associated with increased risk of subsequent 30-day, 90-day, and 1-year hospitalization.ConclusionsCDI was associated with increased risk of short- and long-term adverse outcomes, including transfer to short- and long-term care facilities, hospitalization, and all-cause mortality. The magnitude of mortality risk varied depending on baseline probability of CDI, suggesting that even lower-risk patients may benefit from interventions to prevent CDI.
| S-EPMC6624072 | biostudies-literature