Delirium among people aging with and without HIV: Role of alcohol and Neurocognitively active medications.

BACKGROUND: People aging with and without HIV (PWH and PWoH) want to avoid neurocognitive dysfunction, especially delirium. Continued use of alcohol in conjunction with neurocognitively active medications (NCAMs) may be a largely underappreciated cause, especially for PWH who experience polypharmacy a decade earlier than PWoH. We compare absolute and relative risk of delirium among PWH and PWoH by age, level of alcohol use, and exposure to NCAMs. METHODS: Using the VACS cohort, we compare absolute and relative risk of inpatient delirium among PWH and PWoH by age, level of alcohol use, and exposure to NCAMs between 2007 and 2019. We matched each case based on age, race/ethnicity, sex, HIV, baseline year, and observation time with up to 5 controls. The case/control date was defined as date of admission for cases and the date corresponding to the same length of time on study for controls. Level of alcohol use was defined using Alcohol Use Disorder Identification Test-Consumption (AUDIT-C). Medication exposure was measured from 45 to 3 days prior to index date; medications were classified as anticholinergic NCAM, non-anticholinergic NCAM, or non NCAM and counts generated. We used logistic regression to determine odds ratios (ORs) for delirium associated with medication counts stratified by HIV status and adjusted for demographics, severity of illness, and related diagnoses. RESULTS: PWH experienced a higher incidence of delirium (5.6, [95% CI 5.3-5.9/1000 PY]) than PWoH (5.0, [95% CI 4.8-5.1/1000 PY]). In multivariable analysis, anticholinergic and non-anticholinergic NCAM counts and level of alcohol use demonstrated strong independent dose-response associations with delirium. CONCLUSIONS: Decreasing alcohol use and limiting the use of neurocognitively active medications may help decrease excess rates of delirium, especially among PWH.

The Association Between Hospital End-of-Life Care Quality and the Care Received Among Patients With Heart Failure.

CONTEXT: Improving end-of-life care (EOLC) quality among heart failure patients is imperative. Data are limited as to the hospital processes of care that facilitate this goal. OBJECTIVES: To determine associations between hospital-level EOLC quality ratings and the EOLC delivered to heart failure patients. METHODS: Retrospective analysis of the Veterans Health Administration (VA) and the Bereaved Family Survey data of heart failure patients from 2013 to 2015 who died in 107 VA hospitals. We calculated hospital-level observed-to-expected casemix-adjusted ratios of family reported excellent EOLC, dividing hospitals into quintiles. Using logistic regression, we examined associations between quintiles and palliative care consultation, receipt of chaplain and bereavement services, inpatient hospice, and intensive care unit death. RESULTS: Of 6256 patients, mean age was 77.4 (SD = 11.1), 98.3% were male, 75.7% were white, and 18.2% were black. Median hospital scores of "excellent" EOLC ranged from 41.3% (interquartile range 37.0%-44.8%) in the lowest quintile to 76.4% (interquartile range 72.9%-80.3%) in the highest quintile. Patients who died in hospitals in the highest quintile, relative to the lowest, were slightly although not significantly more likely to receive a palliative care consultation (adjusted proportions 57.6% vs. 51.2%; P = 0.32) but were more likely to receive chaplaincy (92.6% vs. 81.2%), bereavement (86.0% vs. 72.2%), and hospice (59.7% vs. 35.9%) and were less likely to die in the intensive care unit (15.9% vs. 31.0%; P < 0.05 for all). CONCLUSION: Patients with heart failure who die in VA hospitals with higher overall EOLC quality receive more supportive EOLC. Research is needed that integrates care processes and develops scalable best practices in EOLC across health care systems.

Polypharmacy Increases Risk of Dyspnea Among Adults With Serious, Life-Limiting Diseases.

BACKGROUND: Polypharmacy is associated with dyspnea in cross-sectional studies, but associations have not been determined in longitudinal analyses. Statins are commonly prescribed but their contribution to dyspnea is unknown. We determined whether polypharmacy was associated with dyspnea trajectory over time in adults with advanced illness enrolled in a statin discontinuation trial, overall, and in models stratified by statin discontinuation. METHODS: Using data from a parallel-group unblinded pragmatic clinical trial (patients on statins ≥3 months with life expectancy of 1 month to 1 year, enrolled in the parent study between June 3, 2011, and May 2, 2013, n = 308/381 [81%]), we restricted analyses to patients with available baseline medication count and ≥1 dyspnea score. Polypharmacy was assessed by self-reported chronic medication count. Dyspnea trajectory group, our primary outcome, was determined over 24 weeks using the Edmonton Symptom Assessment System. RESULTS: The mean age of the patients was 73.8 years (standard deviation [SD]: ±11.0) and the mean medication count was 11.6 (SD: ±5.0). We identified 3 dyspnea trajectory groups: none (n = 108), mild (n = 130), and moderate-severe (n = 70). Statins were discontinued in 51.8%, 48.5%, and 42.9% of patients, respectively. In multivariable models adjusting for age, sex, diagnosis, and statin discontinuation, each additional medication was associated with 8% (odds ratio [OR] = 1.08 [1.01-1.14]) and 16% (OR = 1.16 [1.08-1.25]) increased risk for mild and moderate-severe dyspnea, respectively. In stratified models, polypharmacy was associated with dyspnea in the statin continuation group only (mild OR = 1.12 [1.01-1.24], moderate-severe OR = 1.24 [1.11-1.39]) versus statin discontinuation (mild OR = 1.03 [0.95-1.12], and moderate-severe OR = 1.09 [0.98-1.22]). CONCLUSION: Polypharmacy was strongly associated with dyspnea. Prospective interventions to decrease polypharmacy may impact dyspnea symptoms, especially for statins.

Increased CMV IgG Antibody Titer is Associated with Non-AIDS Events among Virologically Suppressed HIV-Positive Persons.

BACKGROUND: Among HIV-positive individuals, increased levels of inflammation and immune activation persist even in the setting of effective antiretroviral therapy (ART) and are associated with greater rates of non-AIDS events. The etiology of this persistent inflammation is incompletely understood. METHODS: Using a well-characterized cohort of 322 HIV-infected individuals on suppressive ART, we conducted a case-control study. Cytomegalovirus (CMV) immunoglobulin G (IgG) levels, plasma biomarkers, and T-cell phenotypes were measured/characterized from samples collected 1 year after ART initiation. Conditional logistic regression for matched case-control studies analyzed the associations of year 1 CMV-specific IgG level with the subsequent occurrence of any non-AIDS event. Correlations between continuous CMV IgG antibody levels and soluble and cellular markers were assessed. RESULTS: We found that higher levels of CMV IgG were associated with increased risk of non-AIDS events (OR = 1.58 per IQR [95% CI: 1.12, 2.24], P = 0.01) and with elevated soluble and cellular markers of inflammation. CONCLUSIONS: The magnitude of the host immune response to CMV may play a role in the persistent inflammation and resultant morbid events observed in the HIV-positive population.

Impact of aging on neurocognitive performance in previously antiretroviral-naive HIV-infected individuals on their first suppressive regimen.

BACKGROUND: Despite treatment with virologically suppressive antiretroviral therapy (ART), neurocognitive impairment may persist or develop de novo in aging HIV-infected individuals. We evaluated advancing age as a predictor of neurocognitive impairment in a large cohort of previously ART-naive individuals on long-term ART. DESIGN: The AIDS Clinical Trials Group Longitudinal Linked Randomized Trials was a prospective cohort study of HIV-infected individuals originally enrolled in randomized ART trials. This analysis examined neurocognitive outcomes at least 2 years after ART initiation. METHODS: All participants underwent annual neurocognitive testing consisting of Trail making A and B, the wechsler adult intelligence scale-revised Digit Symbol and Hopkins Verbal Learning Tests. Uni and multivariable repeated measures regression models evaluated factors associated with neurocognitive performance. Predictors at parent study entry (ART naive) included entry demographics, smoking, injection drug use, hepatitis B surface antigen, hepatitis C virus serostatus, history of stroke, ART regimen type, pre-ART nadir CD4 cell count, and plasma viral load and as well as time-updated plasma viral load and CD4 cell count. RESULTS: The cohort comprised 3313 individuals with median pre-ART age of 38 years, 20% women; 36% Black, non-Hispanic; 22% Hispanic. Virologic suppression was maintained at 91% of follow-up visits. Neurocognitive performance improved with years of ART. After adjusting for the expected effects of age using norms from HIV-negative individuals, the odds of neurocognitive impairment at follow-up visits among the HIV infected increased by nearly 20% for each decade of advancing age. CONCLUSION: Despite continued virologic suppression and neurocognitive improvement in the cohort as a whole, older individuals were more likely to have neurocognitive impairment than younger individuals.

Regional variation in HIV clinical trials participation in the United States.

OBJECTIVES: To ensure generalizability of clinical research results, it is important to enroll a heterogeneous population that is representative of the target clinical population. Earlier studies have found regional variation in participation in human immunodeficiency virus (HIV) clinical trials, with the lowest rates seen in the southern United States. Rates of new HIV diagnoses are highest in the South, highlighting the need for in-depth understanding of disparities in clinical trial participation. We evaluated whether regional variation in study participation remains, and describe factors that facilitate or prevent HIV clinical trial participation by region. METHODS: A one-time, anonymous, bilingual, self-administered survey was conducted among HIV-infected adults receiving HIV care at all 47 domestic AIDS Clinical Trials Group clinical research sites, with a goal of completing 50 surveys per site. χ(2) tests were used to evaluate differences in knowledge of and participation in HIV clinical trials by region, including Northeast, Midwest, South, and West regions. Multivariable logistic regression was used to estimate odds ratios and 95% confidence intervals (CIs) for the effect of region on knowledge of and participation in HIV clinical trials. RESULTS: Of 2263 completed surveys, 2125 were included in this analysis. The proportion of respondents in the South who reported knowledge of studies (66%) was significantly lower than in the Northeast (76%), Midwest (77%), and West (73%) (P = 0.001). Respondents in the South also were the least likely group to report ever having tried to or having participated in a research study (51%) compared with respondents in the Northeast (60%), Midwest (57%), and West (69%; P < 0.001). After adjusting for age, sex, education, race/ethnicity, tobacco use, and alcohol use, the odds ratio for knowledge of and participation in clinical trials for the Northeast (1.36; 95% CI 1.07-1.72) and West (1.85; 95% CI 1.39-2.45) remained significant compared with the South. African American respondents in the South were the most likely population group to report not understanding research studies (15%) as a reason for not participating, compared with the Northeast (9%), Midwest (8%), and West (6%; P < 0.001). CONCLUSIONS: Significant regional variations in knowledge of and participation in HIV clinical trials exist. Our results suggest that increasing awareness and understanding of research studies, particularly among African Americans in the South, may facilitate HIV clinical trial participation that is more representative of the HIV-infected population across the United States.

Soluble markers of inflammation and coagulation but not T-cell activation predict non-AIDS-defining morbid events during suppressive antiretroviral treatment.

BACKGROUND: Defining the association of non-AIDS-defining events with inflammation and immune activation among human immunodeficiency virus (HIV)-infected persons with antiretroviral therapy (ART)-associated virological suppression is critical to identifying interventions to decrease the occurrence of these events. METHODS: We conducted a case-control study of HIV-infected subjects who had achieved virological suppression within 1 year after ART initiation. Cases were patients who experienced non-AIDS-defining events, defined as myocardial infarction, stroke, non-AIDS-defining cancer, non-AIDS-defining serious bacterial infection, or death. Controls were matched to cases on the basis of age, sex, pre-ART CD4(+) T-cell count, and ART regimen. Peripheral blood mononuclear cells and plasma specimens obtained at the visit before ART initiation (hereafter, baseline), the visit approximately 1 year after ART initiation (hereafter, year 1), and the visit immediately preceding the non-AIDS-defining event (hereafter, pre-event) were analyzed for activated CD4(+) and CD8(+) T cells, plasma interleukin 6 (IL-6) level, soluble tumor necrosis factor receptor I (sTNFR-I) level, sTNFR-II level, soluble CD14 level, kynurenine-to-tryptophan (KT) ratio, and D-dimer level. Conditional logistic regression analysis was used to study the association between biomarkers and outcomes, with adjustment for potential confounders. RESULTS: Higher IL-6 level, sTNFR-I level, sTNFR-II level, KT ratio, and D-dimer level at year 1 were associated with the occurrence of a non-AIDS-defining event. Significant associations were also seen between non-AIDS-defining events and values of these biomarkers in specimens obtained at baseline and the pre-event time points. Effects remained significant after control for confounders. T-cell activation was not significantly related to outcomes. CONCLUSIONS: Interventional trials to decrease the incidence of non-AIDS-defining events among HIV-infected persons with virological suppression should consider targeting the pathways represented by these soluble markers. Clinical Trials Registration. NCT00001137.

Impact of chemotherapy for HIV-1 related lymphoma on residual viremia and cellular HIV-1 DNA in patients on suppressive antiretroviral therapy.

The first cure of HIV-1 infection was achieved through complex, multimodal therapy including myeloablative chemotherapy, total body irradiation, anti-thymocyte globulin, and allogeneic stem cell transplantation with a CCR5 delta32 homozygous donor. The contributions of each component of this therapy to HIV-1 eradication are unclear. To assess the impact of cytotoxic chemotherapy alone on HIV-1 persistence, we longitudinally evaluated low-level plasma viremia and HIV-1 DNA in PBMC from patients in the ACTG A5001/ALLRT cohort on suppressive antiretroviral therapy (ART) who underwent chemotherapy for HIV-1 related lymphoma without interrupting ART. Plasma HIV-1 RNA, total HIV-1 DNA and 2-LTR circles (2-LTRs) in PBMC were measured using sensitive qPCR assays. In the 9 patients who received moderately intensive chemotherapy for HIV-1 related lymphoma with uninterrupted ART, low-level plasma HIV-1 RNA did not change significantly with chemotherapy: median HIV-1 RNA was 1 copy/mL (interquartile range: 1.0 to 20) pre-chemotherapy versus 4 copies/mL (interquartile range: 1.0 to 7.0) post-chemotherapy. HIV-1 DNA levels also did not change significantly, with median pre-chemotherapy HIV-1 DNA of 355 copies/106 CD4+ cells versus 228 copies/106 CD4+ cells post-chemotherapy. 2-LTRs were detectable in 2 of 9 patients pre-chemotherapy and in 3 of 9 patients post-chemotherapy. In summary, moderately intensive chemotherapy for HIV-1 related lymphoma in the context of continuous ART did not have a prolonged impact on HIV-1 persistence. Clinical trials registration unique identifier: NCT00001137.

Anthropometric differences between HIV-infected individuals prior to antiretroviral treatment and the general population from 1998-2007: the AIDS Clinical Trials Group Longitudinal Linked Randomized Trials (ALLRT) cohort and NHANES.

OBJECTIVE: To assess differences in body circumferences and body mass index (BMI, kg/m(2)) between antiretroviral treatment (ART) naïve HIV-infected and HIV-uninfected persons. METHODS: Waist, arm, and thigh circumferences and BMI were measured within the ALLRT and NHANES cohorts between 1998 and 2007. ALLRT is a prospective, longitudinal study of U.S. participants enrolled in randomized HIV treatment studies conducted by the AIDS Clinical Trials Group (ACTG). NHANES is a representative group of the US population. The cohorts were analyzed in two time periods, to account for trends towards increased adiposity. Anthropometrics were displayed in percentiles by age and sex. Multiple linear regression models examined differences between cohorts. RESULTS: ALLRT had more males (82% versus 48%, p<0.0001), more black participants (32% versus 23%, p<0.0001), and less Hispanics (21% versus 30%, p<0.0001) than NHANES. Mean BMI was smaller in ALLRT males and females compared to NHANES by 1.6-2.4 kg/m(2) (p<0.0001). Mean waist and arm circumferences in both sexes and time periods were significantly smaller in ALLRT than in NHANES (p<0.0001). Mean thigh circumference in ALLRT was also smaller than NHANES among males (p<0.0001 in both time periods) and females (p = 0.01 in the early time period). CONCLUSIONS: Differences in anthropometrics existed prior to ART initiation, in this large national cohort of HIV-infected individuals, compared to a representative HIV-uninfected cohort, indicating that HIV and its complications have important effects on body shape. Further longitudinal examination of anthropometrics in this HIV-infected cohort may provide additional insight into disease risk. TRIAL REGISTRATION: NCT00001137 at www.clinicaltrials.gov.

Antihyperglycemic activity with DPP-IV inhibition of alkaloids from seed extract of Castanospermum australe: Investigation by experimental validation and molecular docking.

The antidiabetic actions of Castanospermum australe Cunn., seed (CAS) extract were evaluated in Poloxamer-407 (PX-407) induced T2DM rats. The CAS extract (100 and 150 mg/kg body weight) was administered orally once a day for 5 weeks after the animals were confirmed diabetic. A significant increase in blood glucose, HbA1c and serum insulin levels were observed in T2DM rats in comparison to citrate control rats. Treatment with CAS extract in T2DM rats reduced the elevated levels of blood glucose, HbA1c and insulin with significant (p≤0.001) improvement in OGT. The CAS extract treatment also increased (p≤0.001) the K(ITT) and prevented increase in HOMA-R level in T2DM rats. The DPP-IV inhibitory potential of CAS extract showed IC50 value of 13.96 µg/ml whilst the standard Diprotin A displayed the IC50 value of 1.543 µg/ml. Molecular docking of the three reported alkaloids from the seeds of C. australe showed comparable DPP-IV inhibition with berberine. Our data suggest that CAS extract (150 mg/kg body weight) normalizes hyperglycemia in T2DM rats with strong DPP-IV inhibitory potential. The molecular docking showed that among the three alkaloids of seed extract 7-Deoxy-6-epi-castanospermine is a potent DPP-IV inhibitor similar to berberine.

Incidence of non-AIDS-defining cancer in antiretroviral treatment-naïve subjects after antiretroviral treatment initiation: an ACTG longitudinal linked randomized trials analysis.

BACKGROUND: Prospective data on factors associated with the non-AIDS-defining cancer (NADC) incidence in HIV-infected individuals are limited. METHODS: We examined the NADC incidence in 3,158 antiretroviral treatment (ART)-naïve subjects after ART initiation in AIDS Clinical Trials Group trials; extended follow-up was available for 2,122 subjects. Poisson regression was used to examine the associations between covariates and incident NADC. RESULTS: At ART initiation, subjects (median age 37 years) were 40% non-Hispanic whites, and 82% were male; 23% had CD4+ T cell count ≤ 50 cells/mm³ and 25% had CD4 >350 cells/mm³. Median follow-up was 3.8 years. Among 64 incident NADCs, the most common were 8 anal cancers, 8 basal cell carcinomas, 8 Hodgkin's disease, and 6 lung cancers. In univariate models, age, smoking and recent (time-updated) CD4 were associated with incident NADC. There was no association between initial ART drug class (protease inhibitor, nucleoside reverse transcriptase inhibitor and nonnucleoside reverse transcriptase inhibitor) and NADC. After adjusting for age, race and sex: smoking [relative risk = 2.12 (95% CI = 1.1-4.08)] and recent CD4 (≤ 50 cells/mm³: 3.58, 1.22-10.45; 51-200 cells/mm³: 2.54, 1.30-5.0; 201-350 cells/mm³: 2.37, 1.32-4.26 vs. >350 cells/mm³) were associated with NADC. CONCLUSION: Smoking and lower recent CD4 levels, but not initial ART drug class, were associated with NADC. Strategies for maintaining higher CD4 cell counts and successful smoking cessation may reduce the NADC incidence in the HIV-infected population.

Socioeconomic status and incidence of type 2 diabetes: results from the Black Women's Health Study.

The authors examined the relation between individual and neighborhood socioeconomic status (SES) and type 2 diabetes incidence among African-American women in the prospective Black Women's Health Study. Participants have completed mailed biennial follow-up questionnaires since 1995. US Census block group characteristics were used to measure neighborhood SES. Incidence rate ratios were estimated in clustered survival regression models. During 12 years of follow-up of 46,382 participants aged 30-69 years, 3,833 new cases of type 2 diabetes occurred. In models that included both individual and neighborhood SES factors, incidence rate ratios were 1.28 (95% confidence interval: 1.15, 1.43) for < or = 12 years of education relative to > or = 17 years, 1.57 (95% confidence interval: 1.30, 1.90) for household income <$15,000 relative to >$100,000, and 1.65 (95% confidence interval: 1.46, 1.85) for lowest quintile of neighborhood SES relative to highest. The associations were attenuated after adjustment for body mass index, suggesting it is the key intermediate factor in the pathway between SES and diabetes. The association of neighborhood SES with diabetes incidence was present even among women who were more educated and had a higher family income. Efforts to reduce the alarming rate of diabetes in African-American women must focus on both individual lifestyle changes and structural changes in disadvantaged neighborhoods.

Glycemic index, glycemic load, and cereal fiber intake and risk of type 2 diabetes in US black women.

BACKGROUND: Previous studies of carbohydrate quality and risk of type 2 diabetes mellitus have yielded inconsistent findings. Because diet is in part culturally determined, a study of dietary factors in US black women is of interest. METHODS: We used data from the Black Women's Health Study, a prospective cohort study of 59,000 US black women, to examine the association of glycemic load, glycemic index, and cereal fiber with risk of type 2 diabetes. Diet was assessed at baseline in 1995 with a modified version of the National Cancer Institute-Block food frequency questionnaire. RESULTS: During 8 years of follow-up, there were 1,938 incident cases of diabetes. Cox proportional hazards models were used to estimate incidence rate ratios (IRRs) for quintiles of dietary factors, while controlling for lifestyle and dietary factors. Glycemic index was positively associated with the risk of diabetes: the IRR for the highest quintile relative to the lowest was 1.23 (95% confidence interval [CI], 1.05-1.44). Cereal fiber intake was inversely associated with risk of diabetes, with an IRR of 0.82 (95% CI, 0.70-0.96) for the highest vs lowest quintiles of intake. Stronger associations were seen among women with a body mass index (calculated as weight in kilograms divided by height in meters squared) lower than 25: IRRs for the highest vs lowest quintile were 1.91 (95% CI, 1.16-3.16) for glycemic index (P value for interaction, .12) and 0.41 (95% CI, 0.24-0.72) for cereal fiber intake (P value for interaction, .05). CONCLUSION: Increasing cereal fiber in the diet may be an effective means of reducing the risk of type 2 diabetes, a disease that has reached epidemic proportions in black women.

Overall and central obesity and risk of type 2 diabetes in U.S. black women.

OBJECTIVE: Obesity has risen to epidemic proportions in the United States, leading to an emerging epidemic of type 2 diabetes. African-American women are disproportionately affected by both conditions. While an association of overall obesity with increasing risk of diabetes has been documented in black women, the effect of fat distribution, specifically abdominal obesity, has not been studied. We examined the association of BMI, abdominal obesity, and weight gain with risk of type 2 diabetes. RESEARCH METHODS AND PROCEDURES: During eight years of follow-up of 49,766 women from the Black Women's Health Study, 2472 incident cases of diabetes occurred. Cox proportional hazard models were used to estimate incidence rate ratios (IRRs), with control for age, physical activity, family history of diabetes, cigarette smoking, years of education, and time period of data collection. RESULTS: Sixty-one percent of participants had a BMI>or=25 kg/m2 (WHO definition of overweight). Compared with a BMI of <23 kg/m2, the IRR for a BMI of >45 kg/m2 was 23 (95% confidence interval, 17.0 to 31.0). The IRR for the highest quintile of waist-to-hip ratio relative to the lowest was 2.3 (95% confidence interval, 2.0 to 2.7) after control for BMI. Furthermore, at every level of BMI, an increased risk was observed for high waist-to-hip ratio relative to low. DISCUSSION: Central obesity, as well as overall obesity, is a strong risk factor for diabetes in African-American women. Efforts to reduce the prevalence of obesity in African-American women are of paramount importance.