The Clinical Impact of Continuing to Prescribe Antiretroviral Therapy in Patients with Advanced AIDS Who Manifest No Virologic or Immunologic Benefit

Introduction: Despite the efficacy and tolerability of modern antiretroviral therapy (ART), many patients with advanced AIDS prescribed these regimens do not achieve viral suppression or immune reconstitution as a result of poor adherence, drug resistance, or both. The clinical outcomes of continued ART prescription for such patients have not been well characterized. Methods: We examined the causes and predictors of all-cause mortality, AIDS-defining conditions, and serious non-AIDS-defining events among a cohort of participants in a clinical trial of pre-emptive therapy for CMV disease. We focused on participants who, despite ART had failed to achieve virologic suppression and substantive immune reconstitution. Results: 233 ART-receiving participants entered with a median baseline CD4+ T cell count of 30/mm3 and plasma HIV RNA of 5 log10 copies/mL. During a median 96 weeks of follow-up, 24.0% died (a mortality rate of 10.7/100 patient-years); 27.5% reported a new AIDS-defining condition, and 22.3% a new serious non-AIDS event. Of the deaths, 42.8% were due to an AIDS-defining condition, 44.6% were due to a non-AIDS-defining condition, and 12.5% were of unknown etiology. Decreased risk of mortality was associated with baseline CD4+ T cell count ≥25/mm3 and lower baseline HIV RNA. Conclusions: Among patients with advanced AIDS prescribed modern ART who achieve neither virologic suppression nor immune reconstitution, crude mortality percentages appear to be lower than reported in cohorts of patients studied a decade earlier. Also, in contrast to the era before modern ART became available, nearly half of the deaths in our modern-era study were caused by serious non-AIDS-defining events. Even among the most advanced AIDS patients who were not obtaining apparent immunologic and virologic benefit from ART, continued prescription of these medications appears to alter the natural history of AIDS—improving survival and shifting the causes of death from AIDS- to non-AIDS-defining conditions

Dynamics of Immune Reconstitution and Activation Markers in HIV+ Treatment-Naïve Patients Treated with Raltegravir, Tenofovir Disoproxil Fumarate and Emtricitabine

Background: The dynamics of CD4+ T cell reconstitution and changes in immune activation and inflammation in HIV-1 disease following initiation of antiretroviral therapy (ART) are incompletely defined and their underlying mechanisms poorly understood. Methods: Thirty-nine treatment-naïve patients were treated with raltegravir, tenofovir DF and emtricitabine. Immunologic and inflammatory indices were examined in persons with sustained virologic control during 48 weeks of therapy. Results: Initiation of ART increased CD4+ T cell numbers and decreased activation and cell cycle entry among CD4+ and CD8+ T cell subsets, and attenuated markers of coagulation (D-dimer levels) and inflammation (IL-6 and TNFr1). These indices decayed at different rates and almost all remained elevated above levels measured in HIV-seronegatives through 48 weeks of viral control. Greater first and second phase CD4+ T cell restoration was related to lower T cell activation and cell cycling at baseline, to their decay with treatment, and to baseline levels of selected inflammatory indices, but less so to their changes on therapy. Conclusions: ART initiation results in dynamic changes in viral replication, T cell restoration, and indices of immune activation, inflammation, and coagulation. These findings suggest that determinants of T cell activation/cycling and inflammation/coagulation may have distinguishable impact on immune homeostasis. Trial Registration Clinicaltrials.gov NCT0066097

Metastatic Breast Cancer in Kenya: Presentation, Pathologic Characteristics, and Patterns-Findings From a Tertiary Cancer Center

Purpose: The purpose of this research was to describe the sociodemographic and clinical characteristics of Kenyan women with metastatic breast cancer diagnosed and treated at Aga Khan University Hospital in Nairobi, Kenya from 2012 to 2018. Patients and Methods: We reviewed charts of Kenyan women with metastatic breast cancer and analyzed sociodemographic data, breast cancer risk factors, and tumor characteristics associated with stage at diagnosis, receptor status (ie, estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2 [HER2]), and site of metastasis using χ2, analysis of variance, two-sample t tests, and logistic regressions. Results: A total of 125 cases with complete medical records were included in the analysis. Forty women (32%) had metastases at diagnosis. Of the others, those diagnosed in stage III developed metastases sooner than those diagnosed in stage II (P \u3c .001). Fifty-eight percent of patients had metastases to bone, 14% to brain, 57% to lungs, and 50% to liver. Seventy-four percent of patients presented with more than one metastatic site. Metastases to bone were associated with greater age at diagnosis (P = .02) and higher parity (P = .04), and metastases to the brain were associated with early menopause (P = .04), lower parity (P = .04), and lack of breastfeeding (P = .01). Patients whose tumors were triple negative (estrogen receptor-negative, progesterone receptor-negative, and HER2 negative) were more likely to develop brain metastases (P = .01), and those whose tumors were HER2 positive were more likely to develop liver metastases (P = .04). Conclusion: Although our data on patterns of metastases and pathologic subtypes are similar to those in published literature, some unique findings concerning hormonal risk factors of women with metastatic breast cancer and specific metastatic sites need additional exploration in larger patient populations

Improving Interpretation of the Patient-Reported Outcomes Measurement Information System (PROMIS) Physical Function Scale for Specific Tasks in Community-Dwelling Older Adults

Background and purpose: New generic patient-reported outcomes like the Patient-Reported Outcomes Measurement Information System (PROMIS) are available to physical therapists to assess physical function. However, the interpretation of the PROMIS Physical Function (PF) T-score is abstract because it references the United States average and not specific tasks. The purposes of this study were to (1) determine convergent validity of the PROMIS PF scale with physical performance tests; (2) compare predicted performance test values to normative data; and (3) identify sets of PROMIS PF items similar to performance tests that also scale in increasing difficulty and align with normative data. Methods: Community-dwelling older adults (n = 45; age = 77.1 ± 4.6 years) were recruited for this cross-sectional analysis of PROMIS PF and physical performance tests. The modified Physical Performance Test (mPPT), a multicomponent test of mostly timed items, was completed during the same session as the PROMIS PF scale. Regression analysis examined the relationship of mPPT total and component scores (walking velocity, stair ascent, and 5 times sit to stand) with the PROMIS PF scale T-scores. Normative data were compared with regression-predicted mPPT timed performance across PROMIS PF T-scores. The PROMIS PF items most similar to walking, stair ascent, or sit to stand were identified and then PROMIS PF model parameter-calibrated T-scores for these items were compared alongside normative data. Results and discussion: There were statistically significant correlations (r = 0.32-0.64) between PROMIS PF T-score and mPPT total and component scores. Regression-predicted times for walking, stair ascent, and sit-to-stand tasks (based on T-scores) aligned with published normative values for older adults. Selected PF items for stair ascent and walking scaled well to discriminate increasing difficulty; however, sit-to-stand items discriminated only lower levels of functioning. Conclusions: The PROMIS PF T-scores showed convergent validity with physical performance and aligned with published normative data. While the findings are not predictive of individual performance, they improve clinical interpretation by estimating a range of expected performance for walking, stair ascent, and sit to stand. These findings support application of T-scores in physical therapy testing, goal setting, and wellness plans of care for community-dwelling older adults

Behavioural activation by mental health nurses for late-life depression in primary care: a randomized controlled trial

Background: Depressive symptoms are common in older adults. The effectiveness of pharmacological treatments and the availability of psychological treatments in primary care are limited. A behavioural approach to depression treatment might be beneficial to many older adults but such care is still largely unavailable. Behavioural Activation (BA) protocols are less complicated and more easy to train than other psychological therapies, making them very suitable for delivery by less specialised therapists. The recent introduction of the mental health nurse in primary care centres in the Netherlands has created major opportunities for improving the accessibility of psychological treatments for late-life depression in primary care. BA may thus address the needs of older patients while improving treatment outcome and lowering costs.The primary objective of this study is to compare the effectiveness and cost-effectiveness of BA in comparison with treatment as usual (TAU) for late-life depression in Dutch primary care. A secondary goal is to explore several potential mechanisms of change, as well as predictors and moderators of treatment outcome of BA for late-life depression. Methods/design: Cluster-randomised controlled multicentre trial with two parallel groups: a) behavioural activation, and b) treatment as usual, conducted in primary care centres with a follow-up of 52 weeks. The main inclusion criterion is a PHQ-9 score > 9. Patients are excluded from the trial in case of severe mental illness that requires specialized treatment, high suicide risk, drug and/or alcohol abuse, prior psychotherapy, change in dosage or type of prescribed antidepressants in the previous 12 weeks, or moderate to severe cognitive impairment. The intervention consists of 8 weekly 30-min BA sessions delivered by a trained mental health nurse. Discussion: We expect BA to be an effective and cost-effective treatment for late-life depression compared to TAU. BA delivered by mental health nurses could increase the availability and accessibility of non-pharmacological treatments for late-life depression in primary care. Trial registration: This study is retrospectively registered in the Dutch Clinical Trial Register NTR6013on August 25th 2016. © 2017 The Author(s)

A genome-wide association study of resistance to HIV infection in highly exposed uninfected individuals with hemophilia A

Human genetic variation contributes to differences in susceptibility to HIV-1 infection. To search for novel host resistance factors, we performed a genome-wide association study (GWAS) in hemophilia patients highly exposed to potentially contaminated factor VIII infusions. Individuals with hemophilia A and a documented history of factor VIII infusions before the introduction of viral inactivation procedures (1979-1984) were recruited from 36 hemophilia treatment centers (HTCs), and their genome-wide genetic variants were compared with those from matched HIV-infected individuals. Homozygous carriers of known CCR5 resistance mutations were excluded. Single nucleotide polymorphisms (SNPs) and inferred copy number variants (CNVs) were tested using logistic regression. In addition, we performed a pathway enrichment analysis, a heritability analysis, and a search for epistatic interactions with CCR5 Δ32 heterozygosity. A total of 560 HIV-uninfected cases were recruited: 36 (6.4%) were homozygous for CCR5 Δ32 or m303. After quality control and SNP imputation, we tested 1 081 435 SNPs and 3686 CNVs for association with HIV-1 serostatus in 431 cases and 765 HIV-infected controls. No SNP or CNV reached genome-wide significance. The additional analyses did not reveal any strong genetic effect. Highly exposed, yet uninfected hemophiliacs form an ideal study group to investigate host resistance factors. Using a genome-wide approach, we did not detect any significant associations between SNPs and HIV-1 susceptibility, indicating that common genetic variants of major effect are unlikely to explain the observed resistance phenotype in this populatio

Unhealthy Alcohol Use Is Associated With Suboptimal Adherence to Isoniazid Preventive Therapy in Persons With HIV in Southwestern Uganda.

BACKGROUND: Unhealthy alcohol use is associated with increased progression to tuberculosis (TB) disease, but its effect on adherence to isoniazid (INH) preventive therapy is not known. METHODS: This was a prospective study of persons with HIV with latent TB in southwestern Uganda reporting any current (previous 3 months) alcohol use or no alcohol consumption in the previous year (2:1 ratio). All received INH. We defined suboptimal adherence as <90% of days with at least 1 Medication Event Monitoring System cap opening, over the previous 90 days. Alcohol use was categorized as follows: none: no self-report and phosphatidylethanol (PEth) <8 ng/mL; moderate: Alcohol Use Disorders Identification Test-Consumption (AUDIT-C) 1-2 (women) or 1-3 (men) and/or PEth 8 ≥ 50 ng/mL; and unhealthy: AUDIT-C ≥3 (women) or ≥4 (men) and/or PEth ≥50 ng/mL. We used generalized estimating equation logistic regression analyses to assess the association between the level of alcohol use and suboptimal INH adherence. RESULTS: Three hundred two persons were enrolled; 279 were on INH for 3 or more months. The prevalence of suboptimal INH adherence was 31.3% at 3 months and 43.9% at 6 months. The odds of suboptimal INH adherence were higher for unhealthy (adjusted odds ratio, 2.78; 95% confidence interval: 1.62 to 4.76) and moderate (adjusted odds ratio, 1.59; 95% confidence interval: 0.94 to 2.71) compared with no alcohol consumption. CONCLUSIONS: Suboptimal adherence to INH at 3 and 6 months was high among prospective study of persons with HIV and associated with unhealthy alcohol use. Adherence support and alcohol reduction strategies are needed for this group at high risk for active TB

Air Pollution, Urgent Asthma Medical Visits and the Modifying Effect of Neighborhood Asthma Prevalence

Background: Social and environmental stressors, may modify associations between environmental pollutants and asthma symptoms. We examined if neighborhood asthma prevalence (higher: HAPN vs. lower: LAPN), a surrogate for underlying risk factors for asthma, modified the relationship between pollutants and urgent asthma visits. Methods: Through zip code, home addresses were linked to New York City Community Air Survey’s land use regression model for street-level, annual average nitrogen dioxide (NO2), particulate matter (PM2.5), elemental carbon (EC); summer average ozone (O3); winter average sulfur dioxide (SO2) concentrations. Poisson regression models were fit to estimate the association (prevalence ratio, PR) between pollutant exposures and seeking urgent asthma care. Results: All pollutants, except O3 were higher in HAPN than LAPN (P0.05). Conclusions: Relationships between modeled street-level pollutants and urgent asthma were stronger in LAPN compared to HAPN. Social stressors that may be more prevalent in HAPN than LAPN, could play a greater role in asthma exacerbations in HAPN versus pollutant exposure alone

Use of Self-Care and Practitioner-Based Forms of Complementary and Alternative Medicine before and after a Diagnosis of Breast Cancer

Purpose. We examine factors associated with self-care, use of practitioner-based complementary and alternative medicine (CAM), and their timing in a cohort of women with breast cancer. Methods. Study participants were women with breast cancer who participated in the Long Island Breast Cancer Study Project. Self-care is defined as the use of multivitamins, single vitamins, botanicals, other dietary supplements, mind-body practices, special diets, support groups, and prayer. Within each modality, study participants were categorized as continuous users (before and after diagnosis), starters (only after diagnosis), quitters (only before diagnosis), or never users. Multivariable logistic regression was used for the main analyses. Results. Of 764 women who provided complete data, 513 (67.2%) initiated a new form of self-care following breast cancer diagnosis. The most popular modalities were those that are ingestible, and they were commonly used in combination. The strongest predictor of continuous use of one type of self-care was continuous use of other types of self-care. Healthy behaviors, including high fruit/vegetable intake and exercise, were more strongly associated with continuously using self-care than starting self-care after diagnosis. Conclusions. Breast cancer diagnosis was associated with subsequent behavioral changes, and the majority of women undertook new forms of self-care after diagnosis. Few women discontinued use of modalities they used prior to diagnosis