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IntroductionAlthough individual antiretroviral drugs have been shown to be associated with elevated cardiovascular disease (CVD) risk, data are limited on the role of antiretroviral drug combinations. Therefore, we sought to investigate CVD risk associated with antiretroviral drug combinations.MethodsUsing an administrative health-plan dataset, risk of acute myocardial infarction (AMI) associated with current exposure to antiretroviral drug combinations was assessed among persons living with HIV receiving antiretroviral therapy (ART) across the U.S. from October 2009 through December 2014. To account for confounding-by-indication and for factors simultaneously acting as causal mediators and confounders, we applied inverse probability of treatment weighted marginal structural models to longitudinal data of patients.ResultsOver 114,417 person-years (n = 73,071 persons) of ART exposure, 602 cases of AMI occurred at an event rate of 5.26 (95% CI: 4.86, 5.70)/1000 person-years. Of the 14 antiretroviral drug combinations studied, persons taking abacavir-lamivudine-darunavir had the highest incidence rate (IR: 11/1000; 95% CI: 7.4-16.0) of AMI. Risk (HR; 95% CI) of AMI was elevated for current exposure to abacavir-lamivudine-darunavir (1.91; 1.27-2.88), abacavir-lamivudine-atazanavir (1.58; 1.08-2.31), and tenofovir-emtricitabine-raltegravir (1.35; 1.07-1.71). Tenofovir-emtricitabine-efavirenz was associated with reduced risk (0.65; 0.54-0.78). Abacavir-lamivudine-darunavir was associated with increased risk of AMI beyond that expected of abacavir alone, likely attributable to darunavir co-administration. We did not find an elevated risk of AMI when abacavir-lamivudine was combined with efavirenz or raltegravir.ConclusionThe antiretroviral drug combinations abacavir-lamivudine-darunavir, abacavir-lamivudine-atazanavir and tenofovir-emtricitabine-raltegravir were found to be associated with elevated risk of AMI, while tenofovir-emtricitabine-efavirenz was associated with a lower risk. The AMI risk associated with abacavir-lamivudine-darunavir was greater than what was previously described for abacavir, which could suggest an added risk from darunavir. The results should be confirmed in additional studies.

ObjectivesAbacavir's potential to cause cardiovascular disease (CVD) among people living with HIV (PLWH) is debated. We conduct a systematic review and meta-analyses to assess CVD risk from recent and cumulative abacavir exposure.MethodsWe searched Medline, Embase, Web of Science, abstracts from Conference on Retroviruses and Opportunistic Infections, and International AIDS Society/AIDS Conferences and bibliographies of review articles to identify research studies published through 2018 on CVD risk associated with abacavir exposure among PLWH. Studies assessing risk of CVD associated with recent (exposure within last 6 months) or cumulative abacavir exposure across all age-groups were eligible. Risks were quantified using fixed- and random-effects models.ResultsOf 378 unique citations, 68 full-text research articles and abstracts were reviewed. Seventeen studies assessed risk of CVD from recent or cumulative abacavir exposure. Summary relative risk (sRR) is increased for recent exposure (n=16 studies, sRR=1.61; 95% confidence interval: 1.48-1.75), higher in antiretroviral-therapy-naive population (n=5, 1.91; 1.48-2.46) and all studies reported RR>1. The sRR for recent exposure was similarly increased for the outcome of acute myocardial infarction, and for studies that adjusted for substance abuse, smoking, prior CVD, traditional CVD risk factors, and CD4 cell-count/HIV viral load. The sRR was increased for cumulative abacavir exposure (per year) (n=4, 1.12; 1.05-1.20) but no increase was seen after adjusting for recent exposure (n=5, 1.00; 0.93-1.08).ConclusionsOur findings suggest an increased risk of CVD from recent abacavir exposure. The risk remained elevated after adjusting for potential confounders. Further investigations are needed to understand CVD risk from cumulative exposure.

Clinical trial registrationClinical Trials.gov NCT00131677.

BackgroundThere is ongoing controversy regarding abacavir use in the treatment of HIV infection and the risk of subsequent development of cardiovascular disease. It is unclear how the risk varies as exposure accumulates.MethodsUsing an administrative health-plan dataset, risk of cardiovascular disease events (CVDe), defined as the first episode of an acute myocardial infarction or a coronary intervention procedure, associated with abacavir exposure was assessed among HIV-infected individuals receiving antiretroviral therapy across the U.S. from October 2009 through December 2014. The data were longitudinal, and analyzed using marginal structural models.ResultsOver 114,470 person-years (n = 72,733) of ART exposure, 714 CVDe occurred at an incidence rate (IR) (95% CI) of 6·23 (5·80, 6·71)/1000 person-years. Individuals exposed to abacavir had a higher IR of CVDe of 9·74 (8·24, 11·52)/1000 person-years as compared to 5·75 (5·30, 6·24)/1000 person-years for those exposed to other antiretroviral agents. The hazard (HR; 95% CI) of CVDe was increased for current (1·43; 1·18, 1·73), recent (1·41; 1·16, 1·70), and cumulative [(1·18; 1·06, 1·31) per year] exposure to abacavir. The risk for cumulative exposure followed a bell-shaped dose-response curve peaking at 24-months of exposure. Risk was similarly elevated among participants free of pre-existing heart disease or history of illicit substance use at baseline.ConclusionCurrent, recent, and cumulative use of abacavir was associated with an increased risk of CVDe. The findings were consistent irrespective of underlying cardiovascular risk factors.

BackgroundA low proportion of CD28CD8 T cells that express CD57 is associated with increased mortality in HIV infection. The effect of increasing body mass index (BMI) changes in the proportion of CD57CD28CD8 T cells among HIV-infected individuals on antiretroviral therapy is unknown.SettingIn a US cohort of HIV-infected women, we evaluated associations of BMI and waist circumference with 3 distinct CD8 T cell phenotypes: % CD28CD57CD8 T cells, % CD57 of CD28CD8 T cells, and % CD28 of all CD8 T cells.MethodsMultivariable linear regression analysis was used to estimate beta coefficients for each of 3 T-cell phenotypes. Covariates included HIV parameters (current and nadir CD4, current viral load), demographics (age, race, income, and study site), and lifestyle (tobacco and alcohol use) factors.ResultsOf 225 participants, the median age was 46 years and 50% were obese (BMI >30 m/kg). Greater BMI and waist circumference were both associated with higher % CD28CD57CD8 T cells and % CD57 of all CD28CD8 T cells in multivariable analysis, including adjustment for HIV viral load (all P < 0.05). The association between greater BMI and the overall proportion of CD28 CD8 cells in fully adjusted models (0.078, 95% confidence interval: -0.053 to 0.209) was not significant.ConclusionsIn this analysis, greater BMI and waist circumference are associated with greater expression of CD57 on CD28CD8 T cells and a greater proportion of CD57CD28 CD8 T cells. These findings may indicate that increasing BMI is immunologically protective in HIV-infected women. Future research is needed to understand the prognostic importance of these associations on clinical outcomes.

BackgroundUrine biomarkers have helped identify persons at risk for progressing to kidney disease in the setting of HIV infection. We explored factors associated with changes in 3 urine biomarkers over 10 years among women living with HIV.MethodsProspective cohort of 294 HIV-infected women from the multicenter Women's Interagency HIV Study. Predictors included HIV viral and immunological parameters, comorbid conditions, and health-related behaviors. Outcomes were patterns of changes of urine interleukin-18 (IL-18), albumin-to-creatinine ratio (ACR), and alpha-1-microglobulin (α1m) over 10 years. We used quantile regression to examine patterns of change in each urine biomarker during follow-up and multivariable analysis of variance regression to identify predictors of biomarker changes.ResultsOver 10 years, the median concentrations of IL-18 declined from 120 to 64 pg/mL, α1m rose from 0.7 to 1.5 ng/mL, and ACR remained stable (9-8 mg/g). In multivariate analyses, the strongest predictors of increases in IL-18 were higher baseline body mass index, increase in waist circumference, higher follow-up HIV viral load, lower follow-up CD4 cell count, hepatitis C virus (HCV) coinfection, and higher follow-up high density lipoprotein cholesterol. Predictors of increasing concentration of α1m were lower CD4 cell counts, higher diastolic blood pressure, HCV coinfection, and smoking. Finally, determinants of ACR increases during follow-up were higher follow-up diastolic blood pressure, HCV coinfection, higher follow-up HIV viral load, and triglyceride concentration.ConclusionsOver 10 years, HIV disease status had different associations with each urine biomarker under study. Overall, the associations with changes in each biomarker support research into their use for longitudinal monitoring of kidney health.

Staphylococcus aureus bacteremia (SAB) is a tremendous health burden. Previous studies examining the association of vancomycin MIC and outcomes in patients with SAB have been inconclusive. This study evaluated the association between vancomycin MICs and 30- or 90-day mortality in individuals with SAB. This was a prospective cohort study of adults presenting from 2008 to 2013 with a first episode of SAB. Subjects were identified by an infection surveillance system. The main predictor was vancomycin MIC by MicroScan. The primary outcomes were death at 30 and 90 days, and secondary outcomes included recurrence, readmission, or a composite of death, recurrence, and readmission at 30 and 90 days. Covariates included methicillin susceptibility, demographics, illness severity, comorbidities, infectious source, and antibiotic use. Cox proportional-hazards models with propensity score adjustment were used to estimate 30- and 90-day outcomes. Of 429 unique first episodes of SAB, 11 were excluded, leaving 418 individuals for analysis. Eighty-three (19.9%) participants had a vancomycin MIC of 2 μg/ml. In the propensity-adjusted Cox model, a vancomycin MIC of 2 μg/ml compared to

Little is known about the clinical presentation and outcomes associated with spinal implant infections. Here, we describe a single center's experience in a retrospective cohort of 109 individuals with spinal implant infections, including clinical, microbiological, therapeutic, and outcome data.

ObjectiveTenofovir disoproxil fumarate is a commonly used antiretroviral drug, but risk factors for tenofovir (TFV)-associated kidney disease are not fully understood. We used intensive pharmacokinetic studies in a cohort of HIV-infected women on TFV-based therapy to study the relationship between TFV exposure and subsequent kidney function.DesignThis is a nested study within the Women's Interagency HIV Study, a multicenter, prospective cohort of HIV-infected women. Participants on TFV-based therapy underwent 24-h intensive pharmacokinetic sampling after witnessed dose. Kidney function was measured over the succeeding 7 years by serum creatinine [estimated glomerular filtration rate calculated by serum creatinine (eGFRcr)].MethodsMultivariable linear mixed models evaluated the relationship of baseline TFV area under the-time concentration curves (AUCs) with subsequent changes in kidney function. Covariates included age, diabetes, hypertension, race, BMI, ritonavir use, duration of TFV exposure, current CD4 cell count, and HIV viral load.ResultsOf the 105 participants, persons within the highest baseline TFV AUC tertile had significantly lower eGFRcr compared with those in the lowest tertile (mean ± standard error: 80 ± 4.3 vs. 104 ± 2.5 ml/min per 1.73 m, P

Coccidioidomycosis is an insidious fungal disease, endemic to arid regions of the Americas, which is becoming more frequently recognised worldwide. While most infections resemble a mild respiratory illness, a subset of cases progress to severe pneumonia or systemic dissemination. Here, we describe a case of disseminated coccidioidomycosis in a 54-year-old immunocompetent African-American man with geographic and demographic risk factors for Coccidiodes acquisition who presented with 2 months of fevers, fatigue, weight loss and painful skin lesions. Blood count and serum chemistry studies initially demonstrated leukocytosis, anaemia, hyponatraemia and acute renal failure. Chest imaging revealed numerous small pulmonary nodules and skin biopsy, serological studies and blood cultures eventually confirmed disseminated infection with Coccidioides immitis. This case highlights important features regarding the risk factors, spectrum of clinical findings, evaluation and treatment of coccidioidomycosis relevant to providers in endemic areas and throughout the world.

A 70-year-old female Eritrean immigrant living in the USA presented with classic findings of genitourinary (GU) tuberculosis (TB), including risk of tuberculosis exposure based on country of origin, chronic urinary tract symptoms and persistent sterile pyuria despite antibacterial therapy. Furthermore, this patient had the hallmark radiographical findings of ureteral stricture, a dilated pelvic calyceal system, hydroureteronephrosis and bladder wall thickening, as well as a bladder wall biopsy that revealed granulomatous disease. The patient was evaluated multiple times over the course of 3 years in outpatient and inpatient medical settings before a diagnosis was made and appropriate treatment initiated. As with many cases of GU TB, a protracted diagnosis allowed for advanced disease progression and significant morbidity from obstructive uropathy and chronic kidney disease.

ObjectiveTenofovir is used commonly in HIV treatment and prevention settings, but factors that correlate with tenofovir exposure in real-world settings are unknown.DesignIntensive pharmacokinetic studies of tenofovir in a large, diverse cohort of HIV-infected women over 24 h at steady state were performed and factors that influenced exposure [assessed by areas under the concentration-time curves (AUCs)] identified.MethodsHIV-infected women (n = 101) on tenofovir-based therapy underwent intensive 24-h pharmacokinetic sampling. Data on race/ethnicity, age, exogenous steroid use, menstrual cycle phase, concomitant medications, recreational drugs and/or tobacco, hepatic and renal function, weight, and BMI were collected. Multivariable models using forward stepwise selection identified factors associated with effects on AUC. Glomerular filtration rates (GFRs) prior to starting tenofovir were estimated by the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation using both creatinine and cystatin-C measures.ResultsThe median (range) of tenofovir AUCs was 3350 (1031-13 911) ng × h/ml. Higher AUCs were associated with concomitant ritonavir use (1.33-fold increase, P = 0.002), increasing age (1.21-fold increase per decade, P = 0.0007), and decreasing BMI (1.04-fold increase per 10% decrease in BMI). When GFR was calculated using cystatin-C measures, mild renal insufficiency prior to tenofovir initiation was associated with higher subsequent exposure (1.35-fold increase when pre-tenofovir GFR

BackgroundRecently the use of indoor residual spraying of insecticide (IRS) has greatly increased in Africa; however, limited data exist on the quantitative impacts of IRS on health outcomes in highly malaria endemic areas.Methodology/principal findingsRoutine data were collected on more than 90,000 patient visits at a single health facility over a 56 month period covering five rounds of IRS using three different insecticides. Temporal associations between the timing of IRS and the probability of a patient referred for microscopy having laboratory confirmed malaria were estimated controlling for seasonality and age. Considering patients less than five years of age there was a modest decrease in the odds of malaria following the 1(st) round of IRS using DDT (OR = 0.76, p

Background: Coronavirus disease 2019 (COVID-19) can lead to acute respiratory distress syndrome (ARDS) but it is unknown whether prone positioning improves outcomes in mechanically ventilated patients with moderate to severe ARDS due to COVID-19. Methods: A cohort study at a New York City hospital at the peak of the early pandemic in the United States, under crisis conditions. The aim was to determine the benefit of prone positioning in mechanically ventilated patients with ARDS due to COVID-19. The primary outcome was in-hospital death. Secondary outcomes included changes in physiologic parameters. Fine-Gray competing risks models with stabilized inverse probability treatment weighting (sIPTW) were used to determine the effect of prone positioning on outcomes. In addition, linear mixed effects models (LMM) were used to assess changes in physiology with prone positioning. Results: Out of 335 participants who were intubated and mechanically ventilated, 62 underwent prone positioning, 199 met prone positioning criteria and served as controls and 74 were excluded. The intervention and control groups were similar at baseline. In multivariate-adjusted competing risks models with sIPTW, prone positioning was significantly associated with reduced mortality (SHR 0.61, 95% CI 0.46-0.80, P < 0.005). Using LMM to evaluate the impact of positioning maneuvers on physiological parameters, the oxygenation-saturation index was significantly improved during days 1-3 (P < 0.01) whereas oxygenation-saturation index (OSI), oxygenation-index (OI) and arterial oxygen partial pressure to fractional inspired oxygen (PaO2: FiO2) were significantly improved during days 4-7 (P < 0.05 for all). Conclusions: Prone positioning in patients with moderate to severe ARDS due to COVID-19 is associated with reduced mortality and improved physiologic parameters. One in-hospital death could be averted for every 8 patients treated. Replicating results and scaling the intervention are important, but prone positioning may represent an additional therapeutic option in patients with ARDS due to COVID-19. [ABSTRACT FROM AUTHOR]

Background: A low proportion of CD282CD8+ T cells that express CD57 is associated with increased mortality in HIV infection. The effect of increasing body mass index (BMI) changes in the proportion of CD57+CD282CD8+ T cells among HIV-infected individuals on antiretroviral therapy is unknown. Setting: In a US cohort of HIV-infected women, we evaluated associations of BMI and waist circumference with 3 distinct CD8+ T cell phenotypes: % CD282CD57+CD8+ T cells, % CD57+ of CD282CD8+ T cells, and % CD282 of all CD8+ T cells. Methods: Multivariable linear regression analysis was used to estimate beta coefficients for each of 3 T-cell phenotypes. Covariates included HIV parameters (current and nadir CD4, current viral load), demographics (age, race, income, and study site), and lifestyle (tobacco and alcohol use) factors. Results: Of 225 participants, the median age was 46 years and 50% were obese (BMI >30 m2/kg). Greater BMI and waist circumference were both associated with higher % CD282CD57+CD8+ T cells and % CD57+ of all CD282CD8+ T cells in multivariable analysis, including adjustment for HIV viral load (all P < 0.05). The association between greater BMI and the overall proportion of CD282 CD8+ cells in fully adjusted models (0.078, 95% confidence interval: 20.053 to 0.209) was not significant. Conclusions: In this analysis, greater BMI and waist circumference are associated with greater expression of CD57 on CD282CD8+ T cells and a greater proportion of CD57+CD282 CD8+ T cells. These findings may indicate that increasing BMI is immunologically protective in HIV-infected women. Future research is needed to understand the prognostic importance of these associations on clinical outcomes. [ABSTRACT FROM AUTHOR]

Effective antiretroviral (ARV) therapy depends on adequate drug exposure, yet methods to assess ARV exposure are limited. Concentrations of ARV in hair are the product of steady-state pharmacokinetics factors and longitudinal adherence. We investigated nevirapine (NVP) concentrations in hair as a predictor of treatment response in women receiving ARVs. In participants of the Women’s Interagency HIV Study, who reported NVP use for >1 month from 2003–2008, NVP concentrations in hair were measured via liquid-chromatography-tandem mass-spectrometry. The outcome was virologic suppression (plasma HIV RNA below assay threshold) at the time of hair sampling and the primary predictor was nevirapine concentration categorized into quartiles. We controlled for age, race/ethnicity, pre-treatment HIV RNA, CD4 cell count, and self-reported adherence over the 6-month visit interval (categorized ≤ 74%, 75%–94% or ≥ 95%). We also assessed the relation of NVP concentration with changes in hepatic transaminase levels via multivariate random intercept logistic regression and linear regression analyses. 271 women contributed 1089 person-visits to the analysis (median 3 of semi-annual visits). Viral suppression was least frequent in concentration quartile 1 (86/178 (48.3%)) and increased in higher quartiles (to 158/204 (77.5%) for quartile 4). The odds of viral suppression in the highest concentration quartile were 9.17 times (95% CI 3.2–26, P < 0.0001) those in the lowest. African-American race was associated with lower rates of virologic suppression independent of NVP hair concentration. NVP concentration was not significantly associated with patterns of serum transaminases. Concentration of NVP in hair was a strong independent predictor of virologic suppression in women taking NVP, stronger than self-reported adherence, but did not appear to be strongly predictive of hepatotoxicity. [ABSTRACT FROM AUTHOR]

Background: A low proportion of CD28CD8 T cells that express CD57 is associated with increased mortality in HIV infection. The effect of increasing body mass index (BMI) changes in the proportion of CD57CD28CD8 T cells among HIV-infected individuals on antiretroviral therapy is unknown., Setting: In a US cohort of HIV-infected women, we evaluated associations of BMI and waist circumference with 3 distinct CD8 T cell phenotypes: % CD28CD57CD8 T cells, % CD57 of CD28CD8 T cells, and % CD28 of all CD8 T cells., Methods: Multivariable linear regression analysis was used to estimate beta coefficients for each of 3 T-cell phenotypes. Covariates included HIV parameters (current and nadir CD4, current viral load), demographics (age, race, income, and study site), and lifestyle (tobacco and alcohol use) factors., Results: Of 225 participants, the median age was 46 years and 50% were obese (BMI >30 m/kg). Greater BMI and waist circumference were both associated with higher % CD28CD57CD8 T cells and % CD57 of all CD28CD8 T cells in multivariable analysis, including adjustment for HIV viral load (all P < 0.05). The association between greater BMI and the overall proportion of CD28 CD8 cells in fully adjusted models (0.078, 95% confidence interval: -0.053 to 0.209) was not significant., Conclusions: In this analysis, greater BMI and waist circumference are associated with greater expression of CD57 on CD28CD8 T cells and a greater proportion of CD57CD28 CD8 T cells. These findings may indicate that increasing BMI is immunologically protective in HIV-infected women. Future research is needed to understand the prognostic importance of these associations on clinical outcomes.

Background: Urine biomarkers have helped identify persons at risk for progressing to kidney disease in the setting of HIV infection. We explored factors associated with changes in 3 urine biomarkers over 10 years among women living with HIV., Methods: Prospective cohort of 294 HIV-infected women from the multicenter Women's Interagency HIV Study. Predictors included HIV viral and immunological parameters, comorbid conditions, and health-related behaviors. Outcomes were patterns of changes of urine interleukin-18 (IL-18), albumin-to-creatinine ratio (ACR), and alpha-1-microglobulin (α1m) over 10 years. We used quantile regression to examine patterns of change in each urine biomarker during follow-up and multivariable analysis of variance regression to identify predictors of biomarker changes., Results: Over 10 years, the median concentrations of IL-18 declined from 120 to 64 pg/mL, α1m rose from 0.7 to 1.5 ng/mL, and ACR remained stable (9-8 mg/g). In multivariate analyses, the strongest predictors of increases in IL-18 were higher baseline body mass index, increase in waist circumference, higher follow-up HIV viral load, lower follow-up CD4 cell count, hepatitis C virus (HCV) coinfection, and higher follow-up high density lipoprotein cholesterol. Predictors of increasing concentration of α1m were lower CD4 cell counts, higher diastolic blood pressure, HCV coinfection, and smoking. Finally, determinants of ACR increases during follow-up were higher follow-up diastolic blood pressure, HCV coinfection, higher follow-up HIV viral load, and triglyceride concentration., Conclusions: Over 10 years, HIV disease status had different associations with each urine biomarker under study. Overall, the associations with changes in each biomarker support research into their use for longitudinal monitoring of kidney health.

Objective: The efficacy of pre-exposure prophylaxis (PrEP) in HIV will diminish with poor adherence; pharmacologic measures of drug exposure have proven critical to PrEP trial interpretation. We assessed drug exposure in hair against other pharmacologic and more routinely used measures to assess pill-taking., Design: Participants were randomized to placebo, daily PrEP, or intermittent PrEP to evaluate safety and tolerability of daily versus intermittent tenofovir/emtricitabine (TFV/FTC) in 2 phase II PrEP clinical trials conducted in Africa. Different measures of drug exposure, including self-report, medication event monitoring system (MEMS)-caps openings, and TFV/FTC levels in hair and other biomatrices were compared., Methods: At weeks 8 and 16, self-reported pill-taking, MEMS-caps openings, and TFV/FTC levels in hair, plasma, and peripheral blood mononuclear cells (PBMCs) were measured. Regression models evaluated predictors of TFV/FTC concentrations in the 3 biomatrices; correlation coefficients between pharmacologic and nonpharmacologic measures were calculated. Both trials were registered on ClinicalTrials.gov (NCT00931346/NCT00971230)., Results: Hair collection was highly feasible and acceptable (100% in week 8; 96% in week 16). In multivariate analysis, strong associations were seen between pharmacologic measures and MEMS-caps openings (all P < 0.001); self-report was only weakly associated with pharmacologic measures. TFV/FTC hair concentrations were significantly correlated with levels in plasma and PBMCs (correlation coefficients, 0.41-0.86, all P < 0.001)., Conclusions: Measuring TFV/FTC exposure in small hair samples in African PrEP trials was feasible and acceptable. Hair levels correlated strongly with PBMC, plasma concentrations, and MEMS-caps openings. As in other PrEP trials, self-report was the weakest measure of exposure. Further study of hair TFV/FTC levels in PrEP trials and demonstration projects to assess adherence/exposure is warranted.