Allogeneic chimeric antigen receptor-T cells with CRISPR-disrupted programmed death-1 checkpoint exhibit enhanced functional fitness.

BACKGROUND AIMS: Therapeutic disruption of immune checkpoints has significantly advanced the armamentarium of approaches for treating cancer. The prominent role of the programmed death-1 (PD-1)/programmed death ligand-1 axis for downregulating T cell function offers a tractable strategy for enhancing the disease-modifying impact of CAR-T cell therapy. METHODS: To address checkpoint interference, primary human T cells were genome edited with a next-generation CRISPR-based platform (Cas9 chRDNA) by knockout of the PDCD1 gene encoding the PD-1 receptor. Site-specific insertion of a chimeric antigen receptor specific for CD19 into the T cell receptor alpha constant locus was implemented to drive cytotoxic activity. RESULTS: These allogeneic CAR-T cells (CB-010) promoted longer survival of mice in a well-established orthotopic tumor xenograft model of a B cell malignancy compared with identically engineered CAR-T cells without a PDCD1 knockout. The persistence kinetics of CB-010 cells in hematologic tissues versus CAR-T cells without PDCD1 disruption were similar, suggesting the robust initial debulking of established tumor xenografts was due to enhanced functional fitness. By single-cell RNA-Seq analyses, CB-010 cells, when compared with identically engineered CAR-T cells without a PDCD1 knockout, exhibited fewer Treg cells, lower exhaustion phenotypes and reduced dysfunction signatures and had higher activation, glycolytic and oxidative phosphorylation signatures. Further, an enhancement of mitochondrial metabolic fitness was observed, including increased respiratory capacity, a hallmark of less differentiated T cells. CONCLUSIONS: Genomic PD-1 checkpoint disruption in the context of allogeneic CAR-T cell therapy may provide a compelling option for treating B lymphoid malignancies.

Human Immunodeficiency Virus Status, Tenofovir Exposure, and the Risk of Poor Coronavirus Disease 19 Outcomes: Real-World Analysis From 6 United States Cohorts Before Vaccine Rollout.

BACKGROUND: People with human immunodeficiency virus (HIV) (PWH) may be at increased risk for severe coronavirus disease 2019 (COVID-19) outcomes. We examined HIV status and COVID-19 severity, and whether tenofovir, used by PWH for HIV treatment and people without HIV (PWoH) for HIV prevention, was associated with protection. METHODS: Within 6 cohorts of PWH and PWoH in the United States, we compared the 90-day risk of any hospitalization, COVID-19 hospitalization, and mechanical ventilation or death by HIV status and by prior exposure to tenofovir, among those with severe acute respiratory syndrome coronavirus 2 infection between 1 March and 30 November 2020. Adjusted risk ratios (aRRs) were estimated by targeted maximum likelihood estimation, with adjustment for demographics, cohort, smoking, body mass index, Charlson comorbidity index, calendar period of first infection, and CD4 cell counts and HIV RNA levels (in PWH only). RESULTS: Among PWH (n = 1785), 15% were hospitalized for COVID-19 and 5% received mechanical ventilation or died, compared with 6% and 2%, respectively, for PWoH (n = 189 351). Outcome prevalence was lower for PWH and PWoH with prior tenofovir use. In adjusted analyses, PWH were at increased risk compared with PWoH for any hospitalization (aRR, 1.31 [95% confidence interval, 1.20-1.44]), COVID-19 hospitalizations (1.29 [1.15-1.45]), and mechanical ventilation or death (1.51 [1.19-1.92]). Prior tenofovir use was associated with reduced hospitalizations among PWH (aRR, 0.85 [95% confidence interval, .73-.99]) and PWoH (0.71 [.62-.81]). CONCLUSIONS: Before COVID-19 vaccine availability, PWH were at greater risk for severe outcomes than PWoH. Tenofovir was associated with a significant reduction in clinical events for both PWH and PWoH.

Analysis of Severe Illness After Postvaccination COVID-19 Breakthrough Among Adults With and Without HIV in the US.

Importance: Understanding the severity of postvaccination SARS-CoV-2 (ie, COVID-19) breakthrough illness among people with HIV (PWH) can inform vaccine guidelines and risk-reduction recommendations. Objective: To estimate the rate and risk of severe breakthrough illness among vaccinated PWH and people without HIV (PWoH) who experience a breakthrough infection. Design, Setting, and Participants: In this cohort study, the Corona-Infectious-Virus Epidemiology Team (CIVET-II) collaboration included adults (aged ≥18 years) with HIV who were receiving care and were fully vaccinated by June 30, 2021, along with PWoH matched according to date fully vaccinated, age group, race, ethnicity, and sex from 4 US integrated health systems and academic centers. Those with postvaccination COVID-19 breakthrough before December 31, 2021, were eligible. Exposures: HIV infection. Main Outcomes and Measures: The main outcome was severe COVID-19 breakthrough illness, defined as hospitalization within 28 days after a breakthrough SARS-CoV-2 infection with a primary or secondary COVID-19 discharge diagnosis. Discrete time proportional hazards models estimated adjusted hazard ratios (aHRs) and 95% CIs of severe breakthrough illness within 28 days of breakthrough COVID-19 by HIV status adjusting for demographic variables, COVID-19 vaccine type, and clinical factors. The proportion of patients who received mechanical ventilation or died was compared by HIV status. Results: Among 3649 patients with breakthrough COVID-19 (1241 PWH and 2408 PWoH), most were aged 55 years or older (2182 patients [59.8%]) and male (3244 patients [88.9%]). The cumulative incidence of severe illness in the first 28 days was low and comparable between PWoH and PWH (7.3% vs 6.7%; risk difference, -0.67%; 95% CI, -2.58% to 1.23%). The risk of severe breakthrough illness was 59% higher in PWH with CD4 cell counts less than 350 cells/µL compared with PWoH (aHR, 1.59; 95% CI, 0.99 to 2.46; P = .049). In multivariable analyses among PWH, being female, older, having a cancer diagnosis, and lower CD4 cell count were associated with increased risk of severe breakthrough illness, whereas previous COVID-19 was associated with reduced risk. Among 249 hospitalized patients, 24 (9.6%) were mechanically ventilated and 20 (8.0%) died, with no difference by HIV status. Conclusions and Relevance: In this cohort study, the risk of severe COVID-19 breakthrough illness within 28 days of a breakthrough infection was low among vaccinated PWH and PWoH. PWH with moderate or severe immune suppression had a higher risk of severe breakthrough infection and should be included in groups prioritized for additional vaccine doses and risk-reduction strategies.

Tranexamic acid administration in the field does not affect admission thromboelastography after traumatic brain injury.

BACKGROUND: No Food and Drug Administration-approved medication improves outcomes following traumatic brain injury (TBI). A forthcoming clinical trial that evaluated the effects of two prehospital tranexamic acid (TXA) dosing strategies compared with placebo demonstrated no differences in thromboelastography (TEG) values. We proposed to explore the impact of TXA on markers of coagulation and fibrinolysis in patients with moderate to severe TBI. METHODS: Data were extracted from a placebo-controlled clinical trial in which patients 15 years or older with TBI (Glasgow Coma Scale, 3-12) and systolic blood pressure of ≥90 mm Hg were randomized prehospital to receive placebo bolus/placebo infusion (placebo), 1 g of TXA bolus/1 g of TXA infusion (bolus maintenance), or 2 g of TXA bolus/placebo infusion (bolus only). Thromboelastography was performed, and coagulation measures including prothrombin time, activated partial thromboplastin time, international ratio, fibrinogen, D-dimer, plasmin-antiplasmin (PAP), thrombin antithrombin, tissue plasminogen activator, and plasminogen activator inhibitor 1 were quantified at admission and 6 hours later. RESULTS: Of 966 patients receiving study drug, 700 had laboratory tests drawn at admission and 6 hours later. There were no statistically significant differences in TEG values, including LY30, between groups (p > 0.05). No differences between prothrombin time, activated partial thromboplastin time, international ratio, fibrinogen, thrombin antithrombin, tissue plasminogen activator, and plasminogen activator inhibitor 1 were demonstrated across treatment groups. Concentrations of D-dimer in TXA treatment groups were less than placebo at 6 hours (p < 0.001). Concentrations of PAP in TXA treatment groups were less than placebo on admission (p < 0.001) and 6 hours (p = 0.02). No differences in D-dimer and PAP were observed between bolus maintenance and bolus only. CONCLUSION: While D-dimer and PAP levels reflect a lower degree of fibrinolysis following prehospital administration of TXA when compared with placebo in a large prehospital trial of patients with TBI, TEG obtained on admission and 6 hours later did not demonstrate any differences in fibrinolysis between the two TXA dosing regimens and placebo. LEVEL OF EVIDENCE: Diagnostic test, level III.

Improvements in bladder, bowel and sexual outcomes following task-specific locomotor training in human spinal cord injury.

OBJECTIVE: Locomotor training (LT) as a therapeutic intervention following spinal cord injury (SCI) is an effective rehabilitation strategy for improving motor outcomes, but its impact on non-locomotor functions is unknown. Given recent results of our labs' pre-clinical animal SCI LT studies and existing overlap of lumbosacral spinal circuitries controlling pelvic-visceral and locomotor functions, we addressed whether LT can improve bladder, bowel and sexual function in humans at chronic SCI time-points (> two years post-injury). STUDY DESIGN: Prospective cohort study; pilot trial with small sample size. METHODS: Eight SCI research participants who were undergoing 80 daily one-hour sessions of LT on a treadmill using body-weight support, or one-hour of LT and stand training on alternate days, as part of another research study conducted at the Kentucky Spinal Cord Injury Research Center, University of Louisville, were enrolled in this pilot trial. Urodynamic assessments were performed and International Data Set questionnaire forms completed for bladder, bowel and sexual functions at pre-and post-training time points. Four usual care (non-trained; regular at-home routine) research participants were also enrolled in this study and had the same assessments collected twice, at least 3 months apart. RESULTS: Filling cystometry documented significant increases in bladder capacity, voiding efficiency and detrusor contraction time as well as significant decreases in voiding pressure post-training relative to baseline. Questionnaires revealed a decrease in the frequency of nocturia and urinary incontinence for several research participants as well as a significant decrease in time required for defecation and a significant increase in sexual desire post-training. No significant differences were found for usual care research participants. CONCLUSIONS: These results suggest that an appropriate level of sensory information provided to the spinal cord, generated through task-specific stepping and/or loading, can positively benefit the neural circuitries controlling urogenital and bowel functions. TRIAL REGISTRATION: ClinicalTrials.gov NCT03036527.

Using social media for community consultation and public disclosure in exception from informed consent trials.

BACKGROUND: The US Food and Drug Administration and the Department of Health and Human Services outline regulations allowing an exception from informed consent (EFIC) for research conducted in an emergency setting. Acute care clinical trials using EFIC must include community consultation and public disclosure (CC/PD) activities. We describe our experience using social media to facilitate the CC/PD process in two trauma resuscitation clinical trials. METHODS: We conducted local CC/PD activities for two multicenter trauma clinical trials, Pragmatic, Randomized Optimal Platelet and Plasma Ratios (PROPPR) and Prehospital Tranexamic Acid Use for Traumatic Brain Injury (ROC-TXA). As part of the CC/PD process, we developed research study advertisements using the social media Web site Facebook. The Facebook advertisements directed users to a regional study Web site that contained trial information. We targeted the advertisements to specific demographic users, in specific geographic areas. We analyzed the data using descriptive statistics. RESULTS: During the study periods, the PROPPR Facebook advertisement was displayed 5,001,520 times (12 displays per target population) with 374 individuals selecting the advertisement. The ROC-TXA Facebook advertisement was displayed 3,806,448 times (8 per target population) with 790 individuals selecting the advertisement. Respondents to both Facebook advertisements were mostly male (52.6%), with the highest proportion between the ages 15 years and 24 years (28.2%). Collectively, 26.9% of individuals that clicked on the Facebook advertisement spent more than 3 minutes on the study Web site (3-49 minutes). Commonly accessed Web pages were "contact us" (PROPPR, 5.5%; ROC-TXA, 7.7%), "study-specific FAQs" (PROPPR, 2.4%; ROC-TXA, 6.7%), and "opt out of research" (PROPPR, 2.5%; ROC-TXA, 3.8%). Of 51 total individuals viewing the opt out of research information (PROPPR, 19; ROC-TXA, 32), time spent on that specific page was modest (PROPPR, 62 seconds; ROC-TXA, 55 seconds), with no individuals requesting to opt out of either study participation. CONCLUSIONS: In clinical trauma trials using EFIC, social media may provide a viable option for facilitating the CC/PD process.

Damage-control resuscitation and emergency laparotomy: Findings from the PROPPR study.

BACKGROUND: The Pragmatic Randomized Optimal Platelet and Plasma Ratios (PROPPR) trial has demonstrated that damage-control resuscitation, a massive transfusion strategy targeting a balanced delivery of plasma-platelet-red blood cell in a ratio of 1:1:1, results in improved survival at 3 hours and a reduction in deaths caused by exsanguination in the first 24 hours compared with a 1:1:2 ratio. In light of these findings, we hypothesized that patients receiving 1:1:1 ratio would have improved survival after emergency laparotomy. METHODS: Severely injured patients predicted to receive a massive transfusion admitted to 12 Level I North American trauma centers were randomized to 1:1:1 versus 1:1:2 as described in the PROPPR trial. From these patients, the subset that underwent an emergency laparotomy, defined previously in the literature as laparotomy within 90 minutes of arrival, were identified. We compared rates and timing of emergency laparotomy as well as postsurgical survival at 24 hours and 30 days. RESULTS: Of the 680 enrolled patients, 613 underwent a surgical procedure, 397 underwent a laparotomy, and 346 underwent an emergency laparotomy. The percentages of patients undergoing emergency laparotomy were 51.5% (174 of 338) and 50.3% (172 of 342) for 1:1:1 and 1:1:2, respectively (p = 0.20). Median time to laparotomy was 28 minutes in both treatment groups. Among patients undergoing an emergency laparotomy, the proportions of patients surviving to 24 hours and 30 days were similar between treatment arms; 24-hour survival was 86.8% (151 of 174) for 1:1:1 and 83.1% (143 of 172) for 1:1:2 (p = 0.29), and 30-day survival was 79.3% (138 of 174) for 1:1:1 and 75.0% (129 of 172) for 1:1:2 (p = 0.30). CONCLUSION: We found no evidence that resuscitation strategy affects whether a patient requires an emergency laparotomy, time to laparotomy, or subsequent survival. LEVEL OF EVIDENCE: Therapeutic study, level IV.

A controlled resuscitation strategy is feasible and safe in hypotensive trauma patients: results of a prospective randomized pilot trial.

BACKGROUND: Optimal resuscitation of hypotensive trauma patients has not been defined. This trial was performed to assess the feasibility and safety of controlled resuscitation (CR) versus standard resuscitation (SR) in hypotensive trauma patients. METHODS: Patients were enrolled and randomized in the out-of-hospital setting. Nineteen emergency medical services (EMS) systems in the Resuscitation Outcome Consortium participated. Eligible patients had an out-of-hospital systolic blood pressure (SBP) of 90 mm Hg or lower. CR patients received 250 mL of fluid if they had no radial pulse or an SBP lower than 70 mm Hg and additional 250-mL boluses to maintain a radial pulse or an SBP of 70 mm Hg or greater. The SR group patients received 2 L initially and additional fluid as needed to maintain an SBP of 110 mm Hg or greater. The crystalloid protocol was maintained until hemorrhage control or 2 hours after hospital arrival. RESULTS: A total of 192 patients were randomized (97 CR and 95 SR). The CR and SR groups were similar at baseline. The mean (SD) crystalloid volume administered during the study period was 1.0 L (1.5) in the CR group and 2.0 L (1.4) in the SR group, a difference of 1.0 L (95% confidence interval [CI], 0.6-1.4). Intensive care unit-free days, ventilator-free days, renal injury, and renal failure did not differ between the groups. At 24 hours after admission, there were 5 deaths (5%) in the CR group and 14 (15%) in the SR group (adjusted odds ratio, 0.39; 95% CI, 0.12-1.26). Among patients with blunt trauma, 24-hour mortality was 3% (CR) and 18% (SR) with an adjusted odds ratio of 0.17 (0.03-0.92). There was no difference among patients with penetrating trauma (9% vs. 9%; adjusted odds ratio, 1.93; 95% CI, 0.19-19.17). CONCLUSION: CR is achievable in out-of-hospital and hospital settings and may offer an early survival advantage in blunt trauma. A large-scale, Phase III trial to examine its effects on survival and other clinical outcomes is warranted. LEVEL OF EVIDENCE: Therapeutic study, level I.

Effect of barcode technology with electronic medication administration record on medication accuracy rates.

PURPOSE: The effect of barcode-assisted medication administration (BCMA) with electronic medication administration record (eMAR) technology on the occurrence of medication administration errors was evaluated. METHODS: A pretest-posttest nonequivalent comparison group was used to investigate the effect of BCMA-eMAR on the medication administration accuracy rates at two community-based hospitals. Patient care units included three matched pairs in the two hospitals-two medical-surgical, two telemetry, and two rehabilitation units-plus a medical-surgical intensive care unit, an emergency department, and both an inpatient oncology unit and an outpatient oncology service at one of the hospitals. Medication administration accuracy rates were observed and recorded before (phase 1) and approximately 6 and 12 months after (phases 2 and 3, respectively) the implementation of BCMA-eMAR. RESULTS: The overall accuracy rate at hospital 1 increased significantly from phase 1 (89%) to phase 3 (90%) (p = 0.0015); if wrong-time errors are excluded, the accuracy rate improved from 92% in phase 1 to 96% in phase 3 (p = 0.000008). The overall accuracy rate did not change significantly from phase 1 to phase 3 at hospital 2; when wrong-time errors were excluded from consideration, the accuracy rate improved from 93% in phase 1 to 96% in phase 3 (p = 0.015). CONCLUSION: Implementation of BCMA-eMAR in two hospitals was associated with significant increases in total medication accuracy rates in most study units and did not introduce new types of error into the medication administration process. Accuracy rates further improved when wrong-time errors were excluded from analysis. The frequency of errors preventable by BCMA-eMAR decreased significantly in both hospitals after implementation of that technology. BCMA-eMAR and direct observation were more effective than voluntary reporting programs at intercepting and recording errors and preventing them from reaching patients.

Sequence variants affecting eosinophil numbers associate with asthma and myocardial infarction.

Eosinophils are pleiotropic multifunctional leukocytes involved in initiation and propagation of inflammatory responses and thus have important roles in the pathogenesis of inflammatory diseases. Here we describe a genome-wide association scan for sequence variants affecting eosinophil counts in blood of 9,392 Icelanders. The most significant SNPs were studied further in 12,118 Europeans and 5,212 East Asians. SNPs at 2q12 (rs1420101), 2q13 (rs12619285), 3q21 (rs4857855), 5q31 (rs4143832) and 12q24 (rs3184504) reached genome-wide significance (P = 5.3 x 10(-14), 5.4 x 10(-10), 8.6 x 10(-17), 1.2 x 10(-10) and 6.5 x 10(-19), respectively). A SNP at IL1RL1 associated with asthma (P = 5.5 x 10(-12)) in a collection of ten different populations (7,996 cases and 44,890 controls). SNPs at WDR36, IL33 and MYB that showed suggestive association with eosinophil counts were also associated with atopic asthma (P = 4.2 x 10(-6), 2.2 x 10(-5) and 2.4 x 10(-4), respectively). We also found that a nonsynonymous SNP at 12q24, in SH2B3, associated significantly (P = 8.6 x 10(-8)) with myocardial infarction in six different populations (6,650 cases and 40,621 controls).

Outcomes from a randomized controlled trial of a multi-component alcohol use preventive intervention for urban youth: project northland Chicago.

AIMS: The goal of this group-randomized trial was to test the effectiveness of an adapted alcohol use preventive intervention for urban, low-income and multi-ethnic settings. DESIGN AND SETTING: Sixty-one public schools in Chicago were recruited to participate, were grouped into neighborhood study units and assigned randomly to intervention or 'delayed program' control condition. PARTICIPANTS: The study sample (n = 5812 students) was primarily African American, Hispanic and low-income. INTERVENTION: Students, beginning in sixth grade (age 12 years), received 3 years of intervention strategies (curricula, family interventions, youth-led community service projects, community organizing). MEASUREMENTS: Students participated in yearly classroom-based surveys to measure their alcohol use and related risk and protective factors. Additional evaluation components included a parent survey, a community leader survey and alcohol purchase attempts. FINDINGS: Overall, the intervention, compared with a control condition receiving 'prevention as usual', was not effective in reducing alcohol use, drug use or any hypothesized mediating variables (i.e. related risk and protective factors). There was a non-significant trend (P = 0.066) that suggested the ability to purchase alcohol by young-appearing buyers was reduced in the intervention communities compared to the control communities, but this could be due to chance. Secondary outcome analyses to assess the effects of each intervention component indicated that the home-based programs were associated with reduced alcohol, marijuana and tobacco use combined (P = 0.01), with alcohol use alone approaching statistical significance (P = 0.06). CONCLUSIONS: Study results indicate the importance of conducting evaluations of previously validated programs in contexts that differ from the original study sample. Also, the findings highlight the need for further research with urban, low-income adolescents from different ethnic backgrounds to identify effective methods to prevent and reduce alcohol use.

PPARdelta activation normalizes cardiac substrate metabolism and reduces right ventricular hypertrophy in congestive heart failure.

Previously, it was shown that selective deletion of peroxisome proliferator activated receptor delta (PPARdelta) in the heart resulted in a cardiac lipotoxicity, hypertrophy, and heart failure. The aim of the present study was to determine the effects of chronic and selective pharmacological activation of PPARdelta in a model of congestive heart failure. PPARdelta-specific agonist treatment (GW610742X at 30 and 100 mg/kg/day for 6-9 weeks) was initiated immediately postmyocardial infarction (MI) in Sprague-Dawley rats. Magnetic resonance imaging/spectroscopy was used to assess cardiac function and energetics. A 1-(13)C glucose clamp was performed to assess relative cardiac carbohydrate versus fat oxidation. Additionally, cardiac hemodynamics and reverse-transcription polymerase chain reaction gene expression analysis was performed. MI rats had significantly reduced left ventricle (LV) ejection fractions and whole heart phosphocreatine/adenosine triphosphate ratio compared with Sham animals (reduction of 43% and 14%, respectively). However, GW610742X treatment had no effect on either parameter. In contrast, the decrease in relative fat oxidation rate observed in both LV and right ventricle (RV) following MI (decrease of 58% and 54%, respectively) was normalized in a dose-dependent manner following treatment with GW610742X. These metabolic changes were associated with an increase in lipid transport/metabolism target gene expression (eg, CD36, CPT1, UCP3). Although there was no difference between groups in LV weight or infarct size measured upon necropsy, there was a dramatic reduction in RV hypertrophy and lung congestion (decrease of 22-48%, P<0.01) with treatment which was associated with a >7-fold decrease (P<0.05) in aterial natriuretic peptide gene expression in RV. Diuretic effects were not observed with GW610742X. In conclusion, chronic treatment with a selective PPARdelta agonist normalizes cardiac substrate metabolism and reduces RV hypertrophy and pulmonary congestion consistent with improvement in congestive heart failure.

Folic acid supplementation for 3 wk reduces pulse pressure and large artery stiffness independent of MTHFR genotype.

BACKGROUND: Folic acid reduces plasma homocysteine and may be an important therapy for preventing cardiovascular disease. A key mechanism may be the reduction of arterial stiffness. OBJECTIVE: The effect of folic acid supplementation on blood pressure and large artery stiffness was examined in relation to methylenetetrahydrofolate reductase (MTHFR) genotype. DESIGN: Forty-one asymptomatic men with normal or high-normal ambulatory blood pressure (systolic: >130 to <145 mm Hg; diastolic: >80 to <90 mm Hg) participated. The study had a randomized, placebo-controlled, double-blind, crossover design that incorporated 3-wk treatments with 5 mg folic acid/d or matching placebo; each treatment was separated by a 4-wk washout phase. RESULTS: Folic acid reduced brachial pulse pressure by 4.7 +/- 1.6 mm Hg (P < 0.05) without changing mean arterial pressure. Systemic arterial compliance increased by 0.15 +/- 0.03 mL/mm Hg (P < 0.05) after folic acid treatment but did not change after placebo treatment. These responses did not significantly correlate with either homocysteine or folate plasma concentrations. MTHFR genotype CC homozygotes (without the 677C-->T polymorphism) with normal blood pressure had a larger reduction in homocysteine concentrations in response to folic acid than did T allele carriers. Blood pressure and arterial stiffness responses were independent of MTHFR genotype. CONCLUSION: Folic acid is a safe and effective supplement that targets large artery stiffness and may prevent isolated systolic hypertension.

Association between highly active antiretroviral therapy and hypertension in a large cohort of men followed from 1984 to 2003.

OBJECTIVE: UO1-AI-35041: To examine the impact of HIV infection and highly active antiretroviral therapy on systolic and diastolic hypertension. DESIGN: Cohort study with semi-annual assessment of the outcome. METHODS: We studied 5578 participants of the Multicenter AIDS Cohort Study with blood pressure measurements obtained between 1984 and 2003. The primary outcomes were systolic hypertension (SH; systolic blood pressure > 140 mmHg) and diastolic hypertension (DH; diastolic blood pressure > 90 mmHg). Statistical analyses were performed using multiple logistic regression with robust variance estimation. RESULTS: Of the 84 813 person-visits available for analysis, 7.3 and 8.0% showed SH and DH, respectively. Controlling for age, race, body mass index, and smoking, HIV positive men not taking antiretroviral therapy were significantly less likely than HIV negative men to have SH [odds ratio (OR), 0.79; 95% confidence interval (CI), 0.70-0.89], as were men taking mono/combination therapy (OR, 0.69; 95% CI, 0.59-0.80). The prevalence of SH among men taking highly active antiretroviral therapy (HAART) for less than 2 years was similar to that among HIV negative men (OR, 1.06; 95% CI, 0.87-1.30), but was significantly higher thereafter; for 2 to 5 years of HAART (OR, 1.51; 95% CI, 1.25-1.82) and for more than 5 years of HAART (OR, 1.70; 95% CI, 1.34-2.16). In contrast, DH was not significantly higher among men with prolonged HAART use compared to that among HIV negative controls. CONCLUSIONS: Prolonged HAART use was significantly associated with a higher prevalence of SH. This finding suggests that individuals taking HAART may be at increased risk of developing hypertension-related conditions and underscores the importance of blood pressure monitoring among these individuals.