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Respiratory failure is a lethal complication of COVID-19 that has remained resistant to drug therapy. Vasoactive intestinal peptide (VIP) is shown in nonclinical studies to upregulate surfactant production, inhibit cytokine synthesis, prevent cytopathy, and block replication of the severe acute respiratory syndrome coronavirus 2 virus in pulmonary cells. The study aims to determine whether Aviptadil (synthetic VIP) can improve survival and recovery in patients with COVID-19 respiratory failure compared with placebo and demonstrate biological effects in such patients.A multicenter, placebo-controlled trial.Ten U.S. hospitals: six tertiary-care hospitals and four community hospitals.A total of 196 patients with COVID-19 respiratory failure.Participants were randomized 2:1 to receive 3 days of IV Aviptadil or placebo.The primary end point (alive and free from respiratory failure at day 60) did not reach statistical significance (odds ratio [OR], 1.6; 95% CI, 0.86-3.11) for patients treated with Aviptadil when controlling for baseline ventilation status as prespecified in the protocol. There was, however, a statistically significant two-fold odds of improved survival (OR, 2.0; 95% CI, 1.1-3.9) at 60 days ( p = 0.035). There was significant improvement in respiratory distress ratio and reduced interleukin 6 cytokine release ( p = 0.02) by day 3.Subgroup analysis identified a statistically significant likelihood of achieving primary end point among those treated with high-flow nasal oxygen at baseline ( p = 0.039). Subjects on mechanical ventilation also experienced a 10-fold increased odds of survival with drug versus placebo ( p = 0.031).The primary end point did not reach statistical significance, indicating that there was no difference between Aviptadil versus placebo. However, Aviptadil improves the likelihood of survival from respiratory failure at day 60 in critical COVID-19 across all sites of care. Given the absence of drug-related serious adverse events and acceptable safety profile, we believe the benefit versus risk for the use of Aviptadil is favorable for patient treatment.

ImportanceThe effectiveness of ivermectin to shorten symptom duration or prevent hospitalization among outpatients in the US with mild to moderate symptomatic COVID-19 is unknown.ObjectiveTo evaluate the efficacy of ivermectin, 400 μg/kg, daily for 3 days compared with placebo for the treatment of early mild to moderate COVID-19.Design, Setting, and ParticipantsACTIV-6, an ongoing, decentralized, double-blind, randomized, placebo-controlled platform trial, was designed to evaluate repurposed therapies in outpatients with mild to moderate COVID-19. A total of 1591 participants aged 30 years and older with confirmed COVID-19, experiencing 2 or more symptoms of acute infection for 7 days or less, were enrolled from June 23, 2021, through February 4, 2022, with follow-up data through May 31, 2022, at 91 sites in the US.InterventionsParticipants were randomized to receive ivermectin, 400 μg/kg (n = 817), daily for 3 days or placebo (n = 774).Main Outcomes and MeasuresTime to sustained recovery, defined as at least 3 consecutive days without symptoms. There were 7 secondary outcomes, including a composite of hospitalization or death by day 28.ResultsAmong 1800 participants who were randomized (mean [SD] age, 48 [12] years; 932 women [58.6%]; 753 [47.3%] reported receiving at least 2 doses of a SARS-CoV-2 vaccine), 1591 completed the trial. The hazard ratio (HR) for improvement in time to recovery was 1.07 (95% credible interval [CrI], 0.96-1.17; posterior P value [HR >1] = .91). The median time to recovery was 12 days (IQR, 11-13) in the ivermectin group and 13 days (IQR, 12-14) in the placebo group. There were 10 hospitalizations or deaths in the ivermectin group and 9 in the placebo group (1.2% vs 1.2%; HR, 1.1 [95% CrI, 0.4-2.6]). The most common serious adverse events were COVID-19 pneumonia (ivermectin [n = 5]; placebo [n = 7]) and venous thromboembolism (ivermectin [n = 1]; placebo [n = 5]).Conclusions and RelevanceAmong outpatients with mild to moderate COVID-19, treatment with ivermectin, compared with placebo, did not significantly improve time to recovery. These findings do not support the use of ivermectin in patients with mild to moderate COVID-19.Trial RegistrationClinicalTrials.gov Identifier: NCT04885530

People living with HIV (PLHIV) are at a higher risk of having cerebrocardiovascular diseases (CVD) compared to HIV negative (HIVneg) individuals. The mechanisms underlying this elevated risk remains elusive. We hypothesize that HIV infection results in modified microRNA (miR) content in plasma extracellular vesicles (EVs), which modulates the functionality of vascular repairing cells, i.e., endothelial colony-forming cells (ECFCs) in humans or lineage negative bone marrow cells (lin− BMCs) in mice, and vascular wall cells. PLHIV (N = 74) have increased atherosclerosis and fewer ECFCs than HIVneg individuals (N = 23). Plasma from PLHIV was fractionated into EVs (HIVposEVs) and plasma depleted of EVs (HIV PLdepEVs). HIVposEVs, but not HIV PLdepEVs or HIVnegEVs (EVs from HIVneg individuals), increased atherosclerosis in apoE−/− mice, which was accompanied by elevated senescence and impaired functionality of arterial cells and lin− BMCs. Small RNA-seq identified EV-miRs overrepresented in HIVposEVs, including let-7b-5p. MSC (mesenchymal stromal cell)-derived tailored EVs (TEVs) loaded with the antagomir for let-7b-5p (miRZip-let-7b) counteracted, while TEVs loaded with let-7b-5p recapitulated the effects of HIVposEVs in vivo. Lin− BMCs overexpressing Hmga2 (a let-7b-5p target gene) lacking the 3′UTR and as such is resistant to miR-mediated regulation showed protection against HIVposEVs-induced changes in lin− BMCs in vitro. Our data provide a mechanism to explain, at least in part, the increased CVD risk seen in PLHIV.

BackgroundThis is the first attempt to assess changes in liver abnormalities before and after contingency management (CM) to reduce heavy drinking beyond 30-days of follow-up.ObjectiveThe main objective was to determine whether liver fibrosis and steatosis, measured using FibroScan, change significantly between baseline, 30-days, and 90-days among older adults who drink heavily at baseline, enrolled in the CM intervention for alcohol reduction. The secondary aim of the study was to assess whether the changes in liver outcome measures differ across alcohol consumption categories.MethodsA prospective study (ClinicalTrials.govregistry:NCT03353701) of 46 older adults (63% male, 76.1% Black, mean age = 56.4) with heavy drinking at the baseline, living with or without HIV infection was evaluated. A linear mixed-effects model was used to analyze the FibroScan Transient Elastography (TE for fibrosis) and Controlled Attenuation Parameter (CAP for steatosis).ResultsThere were no significant changes in liver fibrosis and steatosis measures after 90-days of drinking abstinence among heavy drinkers with or without stratified TE or CAP values at baseline.ConclusionsCM for drinking reduction may not be effective at least short-term prospective in preventing liver fibrosis and steatosis progression for subjects without severe liver disease at baseline.

Background: In People with HIV (PWH) with virologic suppression, the CD4:CD8 ratio inversely correlates with immune senescence response. The association between CD4:CD8 ratio and cardiovascular (CV) risk in PWH remains unclear. Methods: A retrospective chart review was performed of patients who received HIV care at the University of Miami/Jackson Memorial Hospital between 2017-2019 with available CD4: CD8 ratio (n=1,137). We stratified patients according to the CD4:CD8 ratio ≥1 or Results: The prevalence of CD4:CD8 ratio Conclusion: Patients with an inverted CD4:CD8 ratio had higher total Chol/HDL levels, which has been associated with a higher risk of CV disease. Statin use in this high-risk population was lower despite having more CV risk factors and atrial fibrillation/flutter. Further studies are needed to determine the usefulness of the CD4:CD8 ratio as a marker of immune activation and predictor of CV risk in PWH.

Visual Abstract, Highlights • EVs derived from young, but not aged, MSCs rejuvenate senescent EPCs in vitro, recapitulating the effect of MSC transplantation. • Aged MSCs can be genetically modified to produce tailored EVs with increased EPC rejuvenation capacity in vitro and increased angiogenesis capacity following ischemic event in vivo. • EVs represent a promising platform to develop an acellular therapeutic approach in regenerative medicine for cardiovascular diseases., Summary Mesenchymal stromal cell (MSC) transplantation is a form of the stem-cell therapy that has shown beneficial effects for many diseases. The use of stem-cell therapy, including MSC transplantation, however, has limitations such as the tumorigenic potential of stem cells and the lack of efficacy of aged autologous cells. An ideal therapeutic approach would keep the beneficial effects of MSC transplantation while circumventing the limitations associated with the use of intact stem cells. This study provides proof-of-concept evidence that MSC-derived extracellular vesicles represent a promising platform to develop an acellular therapeutic approach that would just do that. Extracellular vesicles are membranous vesicles secreted by MSCs and contain bioactive molecules to mediate communication between different cells. Extracellular vesicles can be taken up by recipient cells, and once inside the recipient cells, the bioactive molecules are released to exert the beneficial effects on the recipient cells. This study, for the first time to our knowledge, shows that extracellular vesicles secreted by MSCs recapitulate the beneficial effects of MSCs on vascular repair and promote blood vessel regeneration after ischemic events. Furthermore, MSCs from aged donors can be engineered to produce extracellular vesicles with improved regenerative potential, comparable to MSCs from young donors, thus eliminating the need for allogenic young donors for elderly patients.

Management of cardiovascular disease risk requires many lifestyle changes involving diet, smoking, and exercise. Individuals with arterial plaque are encouraged to adopt these changes to promote longevity through a variety of interventions. This study examined behavioral changes in response to the standard of care after detection of arterial plaque, specifically among HIV-infected cocaine users. 127 individuals (HIV - COC - n = 43, HIV + COC - n = 19, HIV + COC + n = 35, HIV - COC + n = 30) were followed after a standard of care intervention and assessed 1 and 2 years later on a variety of lifestyle (diet, exercise, smoking) and physiological (blood pressure, body mass index, number of arterial plaques) outcomes. Arterial plaque was found to increase over time (b = 0.003, SE = 0.002, p = .031), and a composite measure of cardiovascular disease risk did not change (b = - 0.004, SE = 0.01, p = .548). Following provision of a standard of care cardiovascular risk reduction intervention, important health behaviors related to CVD risk were resistant to change among both those HIV-infected and uninfected and among cocaine users and non-users.El manejo del riesgo para enfermedades cardiovasculares requiere muchos cambios en el estilo de vida, como dieta, dejar de fumar, y ejercicio. Se les recomienda a las personas, con placa arterial, adoptar estos cambios a través de una variedad de intervenciones. Este estudio examinó los cambios de comportamiento, en respuesta al estándar de atención, después de la detección de la placa arterial, específicamente entre los usuarios de cocaína infectados con VIH. 127 individuos (HIV − COC − n = 43, HIV + COC − n = 19, HIV + COC + n = 35, HIV − COC + n = 30) fueron seguidos después de una intervención de atención estándar y sus resultados fisiológicos (presión arterial, índice de masa corporal, número de placas arteriales) fueron evaluados 1 y 2 años después. Encontramos que la placa arterial aumento con el tiempo (b = 0.003, SE = 0.002, p = .031), y una formula que calcula el de riesgo de enfermedad cardiovascular no cambió (b = − 0.004, SE = 0.01, p = .548). Tras la provisión de una intervención estándar de atención para la reducción del riesgo cardiovascular, los comportamientos de salud importantes relacionados con el riesgo de enfermedades cardiovasculares fueron resistentes al cambio tanto entre los infectados y no infectados por el VIH como entre los usuarios y no usuarios de cocaína.

Introduction: People living with HIV (PLHIV) have a higher risk of cardiovascular diseases (CVD) compared to HIV negative (HIV - ) individuals. The molecular mechanisms underlying the increased CVD risk remain elusive. Extracellular vesicles (EVs) mediate cell-to-cell communication through cargo transfer, including microRNAs (EV-miRs). Hypothesis: HIV infection results in modification of plasma EVs cargo and these HIV positive EVs (HIV posEVs ), specifically EV-miRs, recapitulate the effects of HIV infection on CVD development. Methods: Atherosclerosis burden was assessed by carotid ultrasound in 74 PLHIV treated with antiretroviral therapy (ART) with viral loads - subjects. Circulating endothelial progenitor cell (EPC) levels were measured by colony forming unit (CFU) assay. PLHIV plasma was fractionated into plasma EVs (HIV posEVs ) and plasma-depleted of EVs (HIV plasmadepEVs ). These fractions, EVs from HIV - subjects (HIV negEVs ) and PBS were injected weekly into apoE -/- mice via tail vein for three months. Atherosclerosis burden (H&E and Oil Red O staining), bone marrow (BM) EPC senescence (β-galactosidase staining), proliferation (MTT assay) and migration (“scratch” assay) were examined. RNASeq was used to identify EV-miRs that mediated the effects of HIV posEVs . Tailored EVs (TEVs) loaded with antagomirs for top EV-miRs were generated to determine their capacity to reverse the adverse effects of HIV posEVs in mouse EPCs in vitro . Results: PLHIV had higher atherosclerosis burden and lower circulating EPC numbers. Mice treated with HIV posEVs showed increased atherosclerotic burden, higher BM EPC senescence and lower functionality. HIV posEVs also negatively affected mouse BM EPC senescence in vitro . RNAseq identified four top candidate EV-miRs upregulated in HIV posEVs : let-7b-5p, miR-16-5p, miR-423-5p, and miR-103a-2. TEVs loaded with the antagomirs for let-7b and miR103a-2 counteracted the effects of HIV posEVs on the accelerated senescence of mouse BM EPCs. Conclusion: 1) Plasma EVs from PLHIV reconstitute the effects of HIV infection on accelerated atherosclerosis via negatively affects EPC functionality; and 2) TEVs, targeting candidate EV-miRs counteracts the effects of HIV infection on EPCs.

Background Traditional risk factors associated with cardiovascular disease (CVD) include older age, smoking, poor diet, lack of exercise, obesity, high blood pressure, high cholesterol, and family history. Young-to-middle age adults (YMAA) are less often identified as being at risk of CVD, but traditional risk scores primarily target older adults and do not accurately estimate risk among YMAA. Methods This study examined biomarkers associated with CVD risk in YMAA in the context of HIV and cocaine use; risk was assessed by two methods: (1) a relative cardiovascular (CV) risk score that includes several factors and (2) carotid atherosclerotic plaque. Associations between CVD risk (CV risk score and carotid atherosclerotic plaque) and proinflammatory cytokines, markers of immune activation, HIV status, and cocaine use were examined. Participants ( N = 506) included people with and without HIV and people who use or do not use cocaine. Results Participants’ mean age was 36 (SD = 9.53); half (51%) were men. Cocaine use and C-reactive protein were associated with greater relative CV risk scores, but no associations between biomarkers and CV risk emerged. Age and CV risk scores were associated with carotid atherosclerotic plaque, but biomarkers were not. HIV was not associated with CV risk scores or carotid atherosclerotic plaque. Conclusions Among YMAA, CV risk scores may help providers identify lifestyle changes needed among those at risk for CVD before more advanced risk (e.g., atherosclerotic plaque) is identified. Implications are discussed.

Background Electronic health record (EHR)-based computable phenotype algorithms allow researchers to efficiently identify a large virtual cohort of Human Immunodeficiency Virus (HIV) patients. Built upon existing algorithms, we refined, improved, and validated an HIV phenotype algorithm using data from the OneFlorida Data Trust, a repository of linked claims data and EHRs from its clinical partners, which provide care to over 15 million patients across all 67 counties in Florida. Methods Our computable phenotype examined information from multiple EHR domains, including clinical encounters with diagnoses, prescription medications, and laboratory tests. To identify an HIV case, the algorithm requires the patient to have at least one diagnostic code for HIV and meet one of the following criteria: have 1+ positive HIV laboratory, have been prescribed with HIV medications, or have 3+ visits with HIV diagnostic codes. The computable phenotype was validated against a subset of clinical notes. Results Among the 15+ million patients from OneFlorida, we identified 61,313 patients with confirmed HIV diagnosis. Among them, 8.05% met all four inclusion criteria, 69.7% met the 3+ HIV encounters criteria in addition to having HIV diagnostic code, and 8.1% met all criteria except for having positive laboratories. Our algorithm achieved higher sensitivity (98.9%) and comparable specificity (97.6%) relative to existing algorithms (77–83% sensitivity, 86–100% specificity). The mean age of the sample was 42.7 years, 58% male, and about half were Black African American. Patients' average follow-up period (the time between the first and last encounter in the EHRs) was approximately 4.6 years. The median number of all encounters and HIV-related encounters were 79 and 21, respectively. Conclusion By leveraging EHR data from multiple clinical partners and domains, with a considerably diverse population, our algorithm allows more flexible criteria for identifying patients with incomplete laboratory test results and medication prescribing history compared with prior studies.

Objectives: After 14 years of no change, new blood pressure (BP) guidelines were released; yet, the impact of marijuana on BP remains unclear. Our objective was to examine the association between marijuana use and BP. Methods: We analyzed data for adults (N = 10,709; mean age 44.8 years; 50.3% men) who completed 2005-2014 National Health and Nutrition Examination Surveys. Marijuana use was defined as never (no lifetime use), past (lifetime, not in past 30 days), and current (≥ 1 in past 30 days). Frequency of use was categorized based past 30-day use. BP was categorized as elevated BP, Stage 1 hypertension (HTN-I), or Stage 2 hypertension (HTN-II) based on updated guidelines. Results: Current users had a higher prevalence of elevated BP (19.4%), HTN-I (22.7%), HTN-II (12.9%) than never users (16.1%, 21.4%, and 11.99%) respectively; p = .03). After covariate adjustment, heavy users had 1.80 higher odds of elevated BP than never users (95% CI: 1.13-2.88). There were no statistically significant differences in BP in any other marijuana use category. Conclusions: Driven by heavy use, current users had a higher prevalence of elevated BP than never users. Patients at risk for abnormal BP should use caution when engaging in heavy marijuana use.

Introduction: COVID-19 altered research in Clinical and Translational Science Award (CTSA) hubs in an unprecedented manner, leading to adjustments for COVID-19 research. Methods: CTSA members volunteered to conduct a review on the impact of CTSA network on COVID-19 pandemic with the assistance from NIH survey team in October 2020. The survey questions included the involvement of CTSAs in decision-making concerning the prioritization of COVID-19 studies. Descriptive and statistical analyses were conducted to analyze the survey data. Results: 60 of the 64 CTSAs completed the survey. Most CTSAs lacked preparedness but promptly responded to the pandemic. Early disruption of research triggered, enhanced CTSA engagement, creation of dedicated research areas and triage for prioritization of COVID-19 studies. CTSAs involvement in decision-making were 16.75 times more likely to create dedicated diagnostic laboratories (95% confidence interval [CI] = 2.17–129.39; P < 0.01). Likewise, institutions with internal funding were 3.88 times more likely to establish COVID-19 dedicated research (95% CI = 1.12–13.40; P < 0.05). CTSAs were instrumental in securing funds and facilitating establishment of laboratory/clinical spaces for COVID-19 research. Workflow was modified to support contracting and IRB review at most institutions with CTSAs. To mitigate chaos generated by competing clinical trials, central feasibility committees were often formed for orderly review/prioritization. Conclusions: The lessons learned from the COVID-19 pandemic emphasize the pivotal role of CTSAs in prioritizing studies and establishing the necessary research infrastructure, and the importance of prompt and flexible research leadership with decision-making capacity to manage future pandemics.

Inclusion of women and minorities in clinical research is critical to fully assess the safety and efficacy of innovative therapies. With inadequate representation of demography, generalizability is impaired since pharmacokinetics and pharmacodynamics differ in these patient populations. This study was designed to analyze the voluntary participation rates of different demographic groups in cell-based therapy clinical trials conducted by the Interdisciplinary Stem Cell Institute (ISCI) at the University of Miami, Miller School of Medicine. ISCI conducted eight clinical trials between 2007 and 2017. The trials enrolled patients with ischemic and non-ischemic cardiomyopathy, idiopathic pulmonary fibrosis (IPF), aging-frailty, and Type-2 Diabetes. Participants received cell-based therapy (n = 218) or placebo (n = 33). Among the 251 participants, 29.5% were Hispanic and 20% were women. The proportion of individuals participating in each trial was compared to that of the respective disease populations attending University of Miami Health System clinics to calculate the participation to prevalence ratio (PPR). Distribution of women accurately reflected the population attending the University of Miami Health System in trials for dilated cardiomyopathy (DCM) and aging-frailty but was under-represented in others. Similarly, Hispanics and whites were accurately represented in three of the five disease fields, with Hispanics under-represented in frailty and diabetes, and whites over-represented in DCM and IPF. Black patients were accurately represented in the diabetes trial but were under-represented in all others. This study provides insight into challenges of achieving representative inclusion in research. Novel community engagement strategies are necessary to improve inclusion of women and under-represented minorities in clinical research of cell-based therapy.

BackgroundThere is an ongoing critical need to improve therapeutic strategies for COVID-19 pneumonia, particularly in the most severely affected patients. Adult mesenchymal stem cell (MSC) infusions have the potential to benefit critically ill patients with acute respiratory syndrome SARS-COV-2 infection, but clinical data supporting efficacy are lacking.MethodsWe conducted a case-control study of critically ill patients with laboratory-confirmed COVID-19, severe acute respiratory distress syndrome (ARDS). To evaluate clinical responsiveness in the most critically ill patient we examined outcomes in a sub-group of those requiring extracorporeal membrane oxygenation (ECMO) support. Patients (n=9) were administered with up to 3 infusions of intravenous (IV) MSCs and compared to a local ECMO control group (n=31). The primary outcome was safety, and the secondary outcomes were all-cause mortality (or rate of hospital discharge), cytokine levels, and viral clearance.FindingsMSC infusions (12 patients) were well tolerated and no side effects occurred. Of ECMO patients receiving MSC infusions, 2 out of 9 died (22.2%; 95%CI: 2.8%, 60.0%) compared with a mortality of 15 of 31 (48.4%; 95%CI: 30.2%, 66.9%; p = 0.25) in the ECMO control group. Isolated plasma exosomes containing the SARS-COV-2 Spike protein decreased after MSC infusions between day 14 or 21 after administration (p=0.003 and p=0.005, respectively) and was associated with a decrease in COVID-19 IgG Spike protein titer at same time points (p = 0.006 and p=0.007, respectively). Control ECMO patients receiving convalescent plasma did not clear COVID-19 IgG over the same time frame.InterpretationTogether these findings suggest that MSC IV infusion is well tolerated in patients with a broad range of severity including the most severe COVID-19 ARDS requiring ECMO. These data also raise the possibility that MSCs, in addition to exerting an immunomodulatory effect, contribute to viral clearance and strongly support the conduct of randomized placebo-controlled trial.

Background The primary analysis of the STAT study demonstrated the feasibility, efficacy, and safety of using DTG/3TC as a first-line regimen in a test-and-treat setting through 24 weeks, with therapy adjustments for baseline resistance or hepatitis B virus (HBV) co-infection. Here we present secondary analyses through Week 48 of virologic outcomes in participants by baseline viral load (VL). Methods STAT is a single-arm study of treatment-naive adults with HIV-1 infection who initiated DTG/3TC ≤ 14 days after HIV-1 diagnosis without availability of screening/baseline laboratory results. If baseline testing indicated DTG or 3TC resistance, HBV co-infection, or creatinine clearance < 30 mL/min/1.73 m2, then antiretroviral therapy (ART) was potentially adjusted and participants remained on study. Efficacy analyses included proportion of participants with HIV-1 RNA < 50 c/mL regardless of ART regimen at Week 48, among all participants (ITT-E missing = failure analysis) and among participants with available HIV-1 RNA data at Week 48 (observed analysis). Results Of 131 enrolled, DTG/3TC treatment was adjusted in 10 participants, and of those with available data (n=7), all (100%) achieved HIV-1 RNA < 50 c/mL at Week 48. At Week 48, 82% (107/131) of all participants (Figure 1) and 97% (107/110) of those with available data (Figure 2) achieved HIV-1 RNA < 50 c/mL. Of participants with baseline VL ≥ 500,000 c/mL, 89% (17/19) achieved HIV-1 RNA < 50 c/mL at Week 48; the remaining 2 withdrew from study. Of participants with baseline VL ≥ 1,000,000 c/mL, 90% (9/10) achieved HIV-1 RNA < 50 c/mL at Week 48 (Table); the remaining participant withdrew consent. Of the 17 participants with baseline VL ≥ 500,000 c/mL with available data through Week 48, 76% (13/17) achieved virologic suppression by Week 24. One participant with baseline VL ≥ 500,000 c/mL switched from DTG/3TC before the Week 48 assessment. Of the 9 participants with baseline VL ≥ 1,000,000 c/mL with available data through Week 48, most participants (8/9; 89%) were suppressed by Week 24. Figure 1. Virologic outcomes at Week 48, overall and by baseline VL and CD4+ cell count: ITT-E missing = failure analysis. Figure 2. Virologic outcomes at Week 48, overall and by baseline VL and CD4+ cell count: observed analysis. Table. Viral Load by Study Visit Among Participants with Baseline HIV-1 RNA ≥1,000,000 c/mL Conclusion These data provide evidence for the efficacy and feasibility of using DTG/3TC as a first-line regimen in a test-and-treat setting, including among participants with very high baseline VL. Disclosures Charlotte-Paige M. Rolle, MD MPH, Gilead Sciences (Grant/Research Support, Scientific Research Study Investigator, Speaker’s Bureau)Janssen Infectious Disease (Scientific Research Study Investigator, Advisor or Review Panel member)ViiV Healthcare (Grant/Research Support, Scientific Research Study Investigator, Advisor or Review Panel member, Speaker's Bureau) Tulika Singh, MD MS AAHIVS, Gilead (Grant/Research Support, Advisor or Review Panel member)ViiV (Grant/Research Support, Advisor or Review Panel member, Speaker's Bureau) Moti Ramgopal, MD FIDSA, Abbvie (Scientific Research Study Investigator, Speaker's Bureau)Gilead (Consultant, Scientific Research Study Investigator, Speaker's Bureau)Janssen (Consultant, Scientific Research Study Investigator, Research Grant or Support, Speaker's Bureau)Merck (Consultant, Scientific Research Study Investigator)ViiV (Consultant, Scientific Research Study Investigator, Speaker's Bureau) Dushyantha Jayaweera, MD, mrcog(uk), face, Gilead (Research Grant or Support)Janssen (Research Grant or Support)viiv (Research Grant or Support) Peter Leone, MD, viiv healthcare (Employee) Jessica Matthews, BS, ViiV Healthcare (Employee) Michael Cupo, Ph.D., GlaxoSmithKline (Employee) Mark Underwood, PhD, GlaxoSmithKline (Shareholder)ViiV Healthcare (Employee) Kostas Angelis, PhD, GSK (Employee, Shareholder) Brian Wynne, MD, ViiV Healthcare (Employee, Shareholder, I have shares in GSK, the part owner of ViiV) Deanna Merrill, PharmD, MBA, AAHIVP, GlaxoSmithKline (Shareholder)ViiV Healthcare (Employee) Christopher T. Nguyen, MD, ViiV Healthcare (Employee) Jean A. van Wyk, MB,ChB, GlaxoSmithKline (Shareholder)ViiV Healthcare (Employee) Andrew Zolopa, MD, GlaxoSmithKline (Shareholder)ViiV Healthcare (Employee)

Objective— Lineage-negative bone marrow cells (lin− BMCs) are enriched in endothelial progenitor cells and mediate vascular repair. Aging-associated senescence and apoptosis result in reduced number and functionality of lin− BMCs, impairing their prorepair capacity. The molecular mechanisms underlying lin− BMC senescence and apoptosis are poorly understood. MicroRNAs (miRNAs) regulate many important biological processes. The identification of miRNA-mRNA networks that modulate the health and functionality of lin− BMCs is a critical step in understanding the process of vascular repair. The aim of this study was to characterize the role of the miR-146a–Polo-like kinase 2 (Plk2) network in regulating lin− BMC senescence, apoptosis, and their angiogenic capability. Approach and Results— Transcriptome analysis in lin− BMCs isolated from young and aged wild-type and ApoE −/− (apolipoprotein E) mice showed a significant age-associated increase in miR-146a expression. In silico analysis, expression study and Luciferase reporter assay established Plk2 as a direct target of miR-146a. miR-146a overexpression in young lin− BMCs inhibited Plk2 expression, resulting in increased senescence and apoptosis, via p16Ink4a/p19Arf and p53, respectively, as well as impaired angiogenic capacity in vitro and in vivo. Conversely, suppression of miR-146a in aged lin− BMCs increased Plk2 expression and rejuvenated lin− BMCs, resulting in decreased senescence and apoptosis, leading to improved angiogenesis. Conclusions— (1) miR-146a regulates lin− BMC senescence and apoptosis by suppressing Plk2 expression that, in turn, activates p16Ink4a/p19Arf and p53 and (2) modulation of miR-146a or its target Plk2 may represent a potential therapeutic intervention to improve lin− BMC–mediated angiogenesis and vascular repair.

Summary Background Effective two-drug regimens could decrease long-term drug exposure and toxicity with HIV-1 antiretroviral therapy (ART). We therefore aimed to evaluate the efficacy and safety of a two-drug regimen compared with a three-drug regimen for the treatment of HIV-1 infection in ART-naive adults. Methods We conducted two identically designed, multicentre, double-blind, randomised, non-inferiority, phase 3 trials: GEMINI-1 and GEMINI-2. Both studies were done at 192 centres in 21 countries. We included participants (≥18 years) with HIV-1 infection and a screening HIV-1 RNA of 500 000 copies per mL or less, and who were naive to ART. We randomly assigned participants (1:1) to receive a once-daily two-drug regimen of dolutegravir (50 mg) plus lamivudine (300 mg) or a once-daily three-drug regimen of dolutegravir (50 mg) plus tenofovir disoproxil fumarate (300 mg) and emtricitabine (200 mg). Both drug regimens were administered orally. We masked participants and investigators to treatment assignment: dolutegravir was administered as single-entity tablets (similar to its commercial formulation, except with a different film colour), and lamivudine tablets and tenofovir disoproxil fumarate and emtricitabine tablets were over-encapsulated to visually match each other. Primary endpoint was the proportion of participants with HIV-1 RNA of less than 50 copies per mL at week 48 in the intention-to-treat-exposed population, using the Snapshot algorithm and a non-inferiority margin of −10%. Safety analyses were done on the safety population. GEMINI-1 and GEMINI-2 are registered with ClinicalTrials.gov, numbers NCT02831673 and NCT02831764, respectively. Findings Between July 18, 2016, and March 31, 2017, 1441 participants across both studies were randomly assigned to receive either the two-drug regimen (n=719) or three-drug regimen (n=722). At week 48 in the GEMINI-1 intention-to-treat-exposed population, 320 (90%) of 356 participants receiving the two-drug regimen and 332 (93%) of 358 receiving the three-drug regimen achieved plasma HIV-1 RNA of less than 50 copies per mL (adjusted treatment difference −2·6%, 95% CI −6·7 to 1·5); in GEMINI-2, 335 (93%) of 360 in the two-drug regimen and 337 (94%) of 359 in the three-drug regimen achieved HIV-1 RNA of less than 50 copies per mL (adjusted treatment difference −0·7%, 95% CI −4·3 to 2·9), showing non-inferiority at a −10% margin in both studies (pooled analysis: 655 [91%] of 716 in the two-drug regimen vs 669 [93%] of 717 in the three-drug regimen; adjusted treatment difference −1·7%, 95% CI −4·4 to 1·1). Numerically, more drug-related adverse events occurred with the three-drug regimen than with the two-drug regimen (169 [24%] of 717 vs 126 [18%] of 716); few participants discontinued because of adverse events (16 [2%] in the three-drug regimen and 15 [2%] in the two-drug regimen). Two deaths were reported in the two-drug regimen group of GEMINI-2, but neither was considered to be related to the study medication. Interpretation The non-inferior efficacy and similar tolerability profile of dolutegravir plus lamivudine to a guideline-recommended three-drug regimen at 48 weeks in ART-naive adults supports its use as initial therapy for patients with HIV-1 infection. Funding ViiV Healthcare.

Hurricanes are devastating natural disasters which dramatically modify the physical landscape and alter the socio-physical and biochemical characteristics of the environment, thus exposing the affected communities to new environmental stressors, which persist for weeks to months after the hurricane. This paper has three aims. First, it conceptualizes potential direct and indirect health effects of hurricanes and provides an overview of factors that exacerbate the health effects of hurricanes. Second, it summarizes the literature on the health impact of hurricanes. Finally, it examines the time lag between the hurricane (landfall) and the occurrence of diseases. Two major findings emerge from this paper. Hurricanes are shown to cause and exacerbate multiple diseases, and most adverse health impacts peak within six months following hurricanes. However, chronic diseases, including cardiovascular disease and mental disorders, continue to occur for years following the hurricane impact.

Background The risk of ischemic stroke (IS) is known to be higher in people living with HIV (PLWH) than uninfected controls. However, information about the demographics and risk factors for hemorrhagic stroke (HS) in PLWH is scant. Specifically, very little is known about the differences in the stroke risk factors between HS and IS in PLWH. The goal of this study was to determine the demographics and risk factor differences between HS and IS in PLWH. Methods We retrospectively analyzed the demographic and clinical data of PLWH in OneFlorida (1FL) Clinical Research Consortium from October 2015 to December 2018. 1FL is a large statewide clinical research network and database which contains health information of over 15 million patients, 1240 clinical practices, and 22 hospitals. We compared HS and IS based on documented ICD 9 and 10 diagnostic codes and extracted information about sociodemographic data, traditional stroke risk factors, Charlson comorbidity scores, habits, HIV factors, diagnostic modalities and medications. Statistical significance was determined using 2-sample T-test for continuous variables and adjusted Pearson chi square for categorical variables. Odds ratio (OR) and 95% confidence intervals (CI) between groups were compared. Results Overall, from 1FL sample of 13986 people living with HIV, 574 subjects had strokes during the study period. The rate of any stroke was 18.2/1000 person-years (PYRS). The rate of IS was 10.8/1000 PYRS while the rate of HS was 3.7/1000 PYRS, corresponding to 25.4% HS of all strokes in the study. Table 1 summarizes the pertinent demographic and risk factors for HS and IS in PLWH in the study. Table 1: Summary of pertinent demographic and risk factors for hemorrhagic and ischemic strokes in people living with HIV from One Florida database Conclusion In this large Floridian health database, demographics and risk factor profile differs between HS and IS in PLWH. Younger age group is associated with HS than IS. However, hypertension, hyperlipidemia and coronary artery disease are more likely to contribute to IS than HS in PLWH. Further research is needed to better understand the interplay between known and yet unidentified risk factors that may be contributing to HS and IS in PLWH. Disclosures All Authors: No reported disclosures

The increased prevalence of major adverse cardiovascular events in Persons Living with HIV (PLWH) has been well documented. However, there remains a paucity of data relating to the epidemiology of valvular heart disease (VHD) in PLWH. We performed a retrospective analysis on the prevalence and

Since the advent of HIV therapy, there has been a decrease in HIV-related mortality, but an increased risk of coronary artery disease (CAD). Previous studies suggested that patients living with HIV (PLWH) underwent less cardiac procedures including cardiac catheterization (CC), compared to the

The re-emergence of Zika virus (ZIKV) and Ebola virus (EBOV) poses serious and continued threats to the global public health. Effective therapeutics for these maladies is an unmet need. Here, we show that emetine, an anti-protozoal agent, potently inhibits ZIKV and EBOV infection with a low nanomolar half maximal inhibitory concentration (IC50) in vitro and potent activity in vivo. Two mechanisms of action for emetine are identified: the inhibition of ZIKV NS5 polymerase activity and disruption of lysosomal function. Emetine also inhibits EBOV entry. Cephaeline, a desmethyl analog of emetine, which may be better tolerated in patients than emetine, exhibits a similar efficacy against both ZIKV and EBOV infections. Hence, emetine and cephaeline offer pharmaceutical therapies against both ZIKV and EBOV infection.

Effective treatment for hepatitis C virus (HCV) in patients coinfected with human immunodeficiency virus type 1 (HIV-1) remains an unmet medical need.We conducted a multicenter, single-group, open-label study involving patients coinfected with HIV-1 and genotype 1 or 4 HCV receiving an antiretroviral regimen of tenofovir and emtricitabine with efavirenz, rilpivirine, or raltegravir. All patients received ledipasvir, an NS5A inhibitor, and sofosbuvir, a nucleotide polymerase inhibitor, as a single fixed-dose combination for 12 weeks. The primary end point was a sustained virologic response at 12 weeks after the end of therapy.Of the 335 patients enrolled, 34% were black, 55% had been previously treated for HCV, and 20% had cirrhosis. Overall, 322 patients (96%) had a sustained virologic response at 12 weeks after the end of therapy (95% confidence interval [CI], 93 to 98), including rates of 96% (95% CI, 93 to 98) in patients with HCV genotype 1a, 96% (95% CI, 89 to 99) in those with HCV genotype 1b, and 100% (95% CI, 63 to 100) in those with HCV genotype 4. Rates of sustained virologic response were similar regardless of previous treatment or the presence of cirrhosis. Of the 13 patients who did not have a sustained virologic response, 10 had a relapse after the end of treatment. No patient had confirmed HIV-1 virologic rebound. The most common adverse events were headache (25%), fatigue (21%), and diarrhea (11%). No patient discontinued treatment because of adverse events.Ledipasvir and sofosbuvir for 12 weeks provided high rates of sustained virologic response in patients coinfected with HIV-1 and HCV genotype 1 or 4. (Funded by Gilead Sciences; ION-4 ClinicalTrials.gov number, NCT02073656.).

The treatment of HIV has improved over the last decade due in part to the success of treatment with combination-therapy drug “cocktails,” better referred to as highly active antiretroviral therapy. The safety and efficacy of these regimens is often complicated by the presence of infectious hepatitis and occurrence of drug-induced liver injury. In most patients, these complications manifest as mild laboratory abnormalities and exist without clinical consequence. However, acute and chronic hepatic injury may lead to increased morbidity and mortality. It is essential to identify all potential causes of liver injury to correctly implement steps to alleviate the condition while maintaining optimal control of HIV viremia.

This study describes the prevalence of abuse and mental health issues among a cohort of HIV-infected Haitian women living in the United States. We present data on 96 women, ages 19–73 years ( M = 47.6, SD = 11.1), who were screened for mental health concerns between 2009 and 2012. Results demonstrated that 12.5% of the women reported a history of abuse. However, posttraumatic stress disorder (PTSD) secondary to HIV was reported by approximately 34% of women. Depression and anxiety were also highly reported, with rates of 49% and 43%, respectively. Women who reported a history of abuse were more likely to report anxiety, PTSD, and PTSD related to HIV symptoms than those without. Our findings suggest that Haitian HIV-infected women may underreport abuse and experience significant depression and anxiety. These preliminary results could be used to develop future studies and to design and implement culturally sensitive interventions for this underserved population.

Background Prior studies have reported improved adherence, persistency, virologic outcomes and lower risk of hospitalizations with single tablet (STR) vs. multi-tablet regimens (MTR) in HIV treatment. However, most studies were conducted using prescription and medical claims data limited to EFV-based therapies. In this study, we utilized EMR, prescription, and pharmacy dispensing data to assess STR and MTR adherence and persistency as observed in a network of clinical practices. Methods Data were collected for HIV-infected patients in care at six US-based HIV treatment centers. Patients eligible for the study initiated their first ARV between January 2015 and December 2016. First ARV regimen was assigned based on absence of prior ARV prescriptions and a 30-day pre-treatment period with no ARV dispensed or for rapid starts, a high baseline viral load (≥10,000 copies/mL). Adherence was assessed using proportion of days covered (PDC). Follow-up was ≥365 days with duration capped at 365 days for persistency comparisons. Results A total of 1,499 patients met the criteria for the study; 66% (982/1,499) received STR and 34% (517/1,499) MTR. Top STRs were EVG/c/TDF/FTC (265/982, 27%), EVG/c/TAF/FTC (250/982, 26%), and DTG/ABC/3TC (171/982, 17%). Top MTRs were DTG + TDF/FTC (69/517, 13%), DRV + RTV + TDF/FTC (60/517, 12%), and DRV/c + TDF/FTC (40/517, 8%). Average persistency for STRs was significantly longer at 252 days vs. 233 days for MTRs (P = 0.002). Average PDC adherence rates were significantly higher for STRs at 91% vs. 83% for MTRs (P < 0.001). Within the STR group, older age was significantly associated with greater adherence (average age: 45 in 80%+ adherent group vs. 42 in

Highly active antiretroviral therapy (ART) has improved survival of HIV patients, accompanied by an increase in prevalence of cardiovascular disease and its complications, including pulmonary hypertension (PH). While this could be attributed to a heightened inflammatory state current data on PH and

Background HIV and HCV infections are both characterized by increased oxidative stress. Information on the magnitude of this increase and its consequences in HIV/HCV co-infection and viral replication is limited. We investigated the relationship between oxidative stress and HIV-progression in HIV/HCV co-infected and HIV mono-infected adults. Methods 106 HIV/HCV co-infected and 115 HIV mono-infected participants provided demographic information and blood to determine 8-oxo-dG and percent oxidized glutathione. Results HIV/HCV co-infected subjects had higher percent oxidized glutathione, higher HIV viral load, lower mtDNA copies and higher liver fibrosis than mono-infected subjects. In a small sample of HIV/HCV co-infected participants with liver biopsy, 8-oxo-dG was significantly lower in participants with low fibrosis scores than those with high fibrosis scores, and the grade of inflammation was strongly associated with oxidized glutathione. Conclusions HIV/HCV co-infection seems to diminish the capacity of the antioxidant system to control oxidative stress, and increases HIV replication.

OBJECTIVES The aim of the study was to compare the effects on lipids, body composition and renal function of once-daily ritonavir-boosted saquinavir (SQV/r) or atazanavir (ATV/r) in combination with tenofovir/emtricitabine (TDF/FTC) over 48 weeks. METHODS An investigator-initiated, randomized, open-label, multinational trial comparing SQV/r 2000/100 mg and ATV/r 300/100 mg once daily, both in combination with TDF/FTC, in 123 treatment-naive HIV-1-infected adults was carried out. The primary endpoint was to demonstrate noninferiority of SQV/r compared with ATV/r with respect to the change in fasting cholesterol after 24 weeks. Secondary outcome measures were changes in metabolic abnormalities, body composition, renal function, and virological and immunological efficacy over 48 weeks. Patients who had used at least one dose of trial drug were included in the analysis. RESULTS Data for 118 patients were analysed (57 patients on SQV/r and 61 on ATV/r). At week 24, changes in lipids were modest, without increases in triglycerides, including a significant rise in high-density lipoprotein (HDL) cholesterol and a nonsignificant decrease in the total:HDL cholesterol ratio in both arms with no significant difference between arms. Lipid changes at week 48 were similar to the changes observed up to week 24, with no significant change in the homeostasis model assessment (HOMA) index. Adipose tissue increased regardless of the regimen, particularly in the peripheral compartment and to a lesser extent in the central abdominal compartment, with an increase in adipose tissue reaching statistical significance in the ATV/r arm. A slight decline in the estimated glomerular filtration rate (eGFR) was observed in both arms during the first 24 weeks, with no progression thereafter. The immunological and virological responses were similar over the 48 weeks. CONCLUSIONS Combined with TDF/FTC, both SQV/r 2000/100 mg and ATV/r 300/100 mg had comparable modest effects on lipids, had little effect on glucose metabolism, conserved adipose tissue, and similarly reduced eGFR. The virological efficacy was similar.