Inhaled Fluticasone Furoate for Outpatient Treatment of Covid-19.

BACKGROUND: The effectiveness of inhaled glucocorticoids in shortening the time to symptom resolution or preventing hospitalization or death among outpatients with mild-to-moderate coronavirus disease 2019 (Covid-19) is unclear. METHODS: We conducted a decentralized, double-blind, randomized, placebo-controlled platform trial in the United States to assess the use of repurposed medications in outpatients with confirmed coronavirus disease 2019 (Covid-19). Nonhospitalized adults 30 years of age or older who had at least two symptoms of acute infection that had been present for no more than 7 days before enrollment were randomly assigned to receive inhaled fluticasone furoate at a dose of 200 µg once daily for 14 days or placebo. The primary outcome was the time to sustained recovery, defined as the third of 3 consecutive days without symptoms. Key secondary outcomes included hospitalization or death by day 28 and a composite outcome of the need for an urgent-care or emergency department visit or hospitalization or death through day 28. RESULTS: Of the 1407 enrolled participants who underwent randomization, 715 were assigned to receive inhaled fluticasone furoate and 692 to receive placebo, and 656 and 621, respectively, were included in the analysis. There was no evidence that the use of fluticasone furoate resulted in a shorter time to recovery than placebo (hazard ratio, 1.01; 95% credible interval, 0.91 to 1.12; posterior probability of benefit [defined as a hazard ratio >1], 0.56). A total of 24 participants (3.7%) in the fluticasone furoate group had urgent-care or emergency department visits or were hospitalized, as compared with 13 participants (2.1%) in the placebo group (hazard ratio, 1.9; 95% credible interval, 0.8 to 3.5). Three participants in each group were hospitalized, and no deaths occurred. Adverse events were uncommon in both groups. CONCLUSIONS: Treatment with inhaled fluticasone furoate for 14 days did not result in a shorter time to recovery than placebo among outpatients with Covid-19 in the United States. (Funded by the National Center for Advancing Translational Sciences and others; ACTIV-6 ClinicalTrials.gov number, NCT04885530.).

Effect of Fluvoxamine vs Placebo on Time to Sustained Recovery in Outpatients With Mild to Moderate COVID-19: A Randomized Clinical Trial.

Importance: The effectiveness of fluvoxamine to shorten symptom duration or prevent hospitalization among outpatients with mild to moderate symptomatic COVID-19 is unclear. Objective: To evaluate the efficacy of low-dose fluvoxamine (50 mg twice daily) for 10 days compared with placebo for the treatment of mild to moderate COVID-19 in the US. Design, Setting, and Participants: The ongoing Accelerating COVID-19 Therapeutic Interventions and Vaccines (ACTIV-6) platform randomized clinical trial was designed to test repurposed medications in outpatients with mild to moderate COVID-19. A total of 1288 participants aged 30 years or older with test-confirmed SARS-CoV-2 infection and experiencing 2 or more symptoms of acute COVID-19 for 7 days or less were enrolled between August 6, 2021, and May 27, 2022, at 91 sites in the US. Interventions: Participants were randomized to receive 50 mg of fluvoxamine twice daily for 10 days or placebo. Main Outcomes and Measures: The primary outcome was time to sustained recovery (defined as the third day of 3 consecutive days without symptoms). There were 7 secondary outcomes, including a composite outcome of hospitalization, urgent care visit, emergency department visit, or death through day 28. Results: Among 1331 participants who were randomized (median age, 47 years [IQR, 38-57 years]; 57% were women; and 67% reported receiving ≥2 doses of a SARS-CoV-2 vaccine), 1288 completed the trial (674 in the fluvoxamine group and 614 in the placebo group). The median time to sustained recovery was 12 days (IQR, 11-14 days) in the fluvoxamine group and 13 days (IQR, 12-13 days) in the placebo group (hazard ratio [HR], 0.96 [95% credible interval, 0.86-1.06], posterior P = .21 for the probability of benefit [determined by an HR >1]). For the composite outcome, 26 participants (3.9%) in the fluvoxamine group were hospitalized, had an urgent care visit, had an emergency department visit, or died compared with 23 participants (3.8%) in the placebo group (HR, 1.1 [95% credible interval, 0.5-1.8], posterior P = .35 for the probability of benefit [determined by an HR <1]). One participant in the fluvoxamine group and 2 participants in the placebo group were hospitalized; no deaths occurred in either group. Adverse events were uncommon in both groups. Conclusions and Relevance: Among outpatients with mild to moderate COVID-19, treatment with 50 mg of fluvoxamine twice daily for 10 days, compared with placebo, did not improve time to sustained recovery. These findings do not support the use of fluvoxamine at this dose and duration in patients with mild to moderate COVID-19. Trial Registration: ClinicalTrials.gov Identifier: NCT04885530.

Effect of Higher-Dose Ivermectin for 6 Days vs Placebo on Time to Sustained Recovery in Outpatients With COVID-19: A Randomized Clinical Trial.

Importance: It is unknown whether ivermectin, with a maximum targeted dose of 600 µg/kg, shortens symptom duration or prevents hospitalization among outpatients with mild to moderate COVID-19. Objective: To evaluate the effectiveness of ivermectin at a maximum targeted dose of 600 µg/kg daily for 6 days, compared with placebo, for the treatment of early mild to moderate COVID-19. Design, Setting, and Participants: The ongoing Accelerating COVID-19 Therapeutic Interventions and Vaccines 6 (ACTIV-6) platform randomized clinical trial was designed to evaluate repurposed therapies among outpatients with mild to moderate COVID-19. A total of 1206 participants older than 30 years with confirmed COVID-19 experiencing at least 2 symptoms of acute infection for less than or equal to 7 days were enrolled at 93 sites in the US from February 16, 2022, through July 22, 2022, with follow-up data through November 10, 2022. Interventions: Participants were randomly assigned to receive ivermectin, with a maximum targeted dose of 600 µg/kg (n = 602) daily, or placebo (n = 604) for 6 days. Main Outcomes and Measures: The primary outcome was time to sustained recovery, defined as at least 3 consecutive days without symptoms. The 7 secondary outcomes included a composite of hospitalization, death, or urgent/emergent care utilization by day 28. Results: Among 1206 randomized participants who received study medication or placebo, the median (IQR) age was 48 (38-58) years, 713 (59.1%) were women, and 1008 (83.5%) reported receiving at least 2 SARS-CoV-2 vaccine doses. The median (IQR) time to sustained recovery was 11 (11-12) days in the ivermectin group and 11 (11-12) days in the placebo group. The hazard ratio (posterior probability of benefit) for improvement in time to recovery was 1.02 (95% credible interval, 0.92-1.13; P = .68). Among those receiving ivermectin, 34 (5.7%) were hospitalized, died, or had urgent or emergency care visits compared with 36 (6.0%) receiving placebo (hazard ratio, 1.0 [95% credible interval, 0.6-1.5]; P = .53). In the ivermectin group, 1 participant died and 4 were hospitalized (0.8%); 2 participants (0.3%) were hospitalized in the placebo group and there were no deaths. Adverse events were uncommon in both groups. Conclusions and Relevance: Among outpatients with mild to moderate COVID-19, treatment with ivermectin, with a maximum targeted dose of 600 µg/kg daily for 6 days, compared with placebo did not improve time to sustained recovery. These findings do not support the use of ivermectin in patients with mild to moderate COVID-19. Trial Registration: ClinicalTrials.gov Identifier: NCT04885530.

Higher-Dose Fluvoxamine and Time to Sustained Recovery in Outpatients With COVID-19: The ACTIV-6 Randomized Clinical Trial.

Importance: The effect of higher-dose fluvoxamine in reducing symptom duration among outpatients with mild to moderate COVID-19 remains uncertain. Objective: To assess the effectiveness of fluvoxamine, 100 mg twice daily, compared with placebo, for treating mild to moderate COVID-19. Design, Setting, and Participants: The ACTIV-6 platform randomized clinical trial aims to evaluate repurposed medications for mild to moderate COVID-19. Between August 25, 2022, and January 20, 2023, a total of 1175 participants were enrolled at 103 US sites for evaluating fluvoxamine; participants were 30 years or older with confirmed SARS-CoV-2 infection and at least 2 acute COVID-19 symptoms for 7 days or less. Interventions: Participants were randomized to receive fluvoxamine, 50 mg twice daily on day 1 followed by 100 mg twice daily for 12 additional days (n = 601), or placebo (n = 607). Main Outcomes and Measures: The primary outcome was time to sustained recovery (defined as at least 3 consecutive days without symptoms). Secondary outcomes included time to death; time to hospitalization or death; a composite of hospitalization, urgent care visit, emergency department visit, or death; COVID-19 clinical progression scale score; and difference in mean time unwell. Follow-up occurred through day 28. Results: Among 1208 participants who were randomized and received the study drug, the median (IQR) age was 50 (40-60) years, 65.8% were women, 45.5% identified as Hispanic/Latino, and 76.8% reported receiving at least 2 doses of a SARS-CoV-2 vaccine. Among 589 participants who received fluvoxamine and 586 who received placebo included in the primary analysis, differences in time to sustained recovery were not observed (adjusted hazard ratio [HR], 0.99 [95% credible interval, 0.89-1.09]; P for efficacy = .40]). Additionally, unadjusted median time to sustained recovery was 10 (95% CI, 10-11) days in both the intervention and placebo groups. No deaths were reported. Thirty-five participants reported health care use events (a priori defined as death, hospitalization, or emergency department/urgent care visit): 14 in the fluvoxamine group compared with 21 in the placebo group (HR, 0.69 [95% credible interval, 0.27-1.21]; P for efficacy = .86) There were 7 serious adverse events in 6 participants (2 with fluvoxamine and 4 with placebo) but no deaths. Conclusions and Relevance: Among outpatients with mild to moderate COVID-19, treatment with fluvoxamine does not reduce duration of COVID-19 symptoms. Trial Registration: ClinicalTrials.gov Identifier: NCT04885530.

HIV Promotes Atherosclerosis via Circulating Extracellular Vesicle MicroRNAs.

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.

The Use of IV Vasoactive Intestinal Peptide (Aviptadil) in Patients With Critical COVID-19 Respiratory Failure: Results of a 60-Day Randomized Controlled Trial.

OBJECTIVES: 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. DESIGN: A multicenter, placebo-controlled trial. SETTING: Ten U.S. hospitals: six tertiary-care hospitals and four community hospitals. PATIENTS: A total of 196 patients with COVID-19 respiratory failure. INTERVENTIONS: Participants were randomized 2:1 to receive 3 days of IV Aviptadil or placebo. MEASUREMENTS AND MAIN RESULTS: 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). CONCLUSIONS: 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.

Effect of Ivermectin vs Placebo on Time to Sustained Recovery in Outpatients With Mild to Moderate COVID-19: A Randomized Clinical Trial.

Importance: The effectiveness of ivermectin to shorten symptom duration or prevent hospitalization among outpatients in the US with mild to moderate symptomatic COVID-19 is unknown. Objective: To 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 Participants: ACTIV-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 93 sites in the US. Interventions: Participants were randomized to receive ivermectin, 400 µg/kg (n = 817), daily for 3 days or placebo (n = 774). Main Outcomes and Measures: Time 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. Results: Among 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 Relevance: Among 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 Registration: ClinicalTrials.gov Identifier: NCT04885530.

Heart Health and Behavior Change in HIV-Infected Individuals.

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.

RESUMEN: 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.

Ledipasvir and Sofosbuvir for HCV in Patients Coinfected with HIV-1.

BACKGROUND: Effective treatment for hepatitis C virus (HCV) in patients coinfected with human immunodeficiency virus type 1 (HIV-1) remains an unmet medical need. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.).

MicroRNA-146a Induces Lineage-Negative Bone Marrow Cell Apoptosis and Senescence by Targeting Polo-Like Kinase 2 Expression.

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.

COVID-19 Convalescent Plasma Therapy: Long-term Implications.

Background: The long-term effect of coronavirus disease 2019 (COVID-19) acute treatments on postacute sequelae of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection (PASC) is unknown. The CONTAIN-Extend study explores the long-term impact of COVID-19 convalescent plasma (CCP) therapy on postacute sequelae of SARS-CoV-2 infection (PASC) symptoms and general health 18 months following hospitalization. Methods: The CONTAIN-Extend study examined 281 participants from the original CONTAIN COVID-19 trial (CONTAIN-RCT, NCT04364737) at 18 months post-hospitalization for acute COVID-19. Symptom surveys, global health assessments, and biospecimen collection were performed from November 2021 to October 2022. Multivariable logistic and linear regression estimated associations between the randomization arms and self-reported symptoms and Patient-Reported Outcomes Measurement Information System (PROMIS) scores and adjusted for covariables, including age, sex, race/ethnicity, disease severity, and CONTAIN enrollment quarter and sites. Results: There were no differences in symptoms or PROMIS scores between CCP and placebo (adjusted odds ratio [aOR] of general symptoms, 0.95; 95% CI, 0.54-1.67). However, females (aOR, 3.01; 95% CI, 1.73-5.34), those 45-64 years (aOR, 2.55; 95% CI, 1.14-6.23), and April-June 2020 enrollees (aOR, 2.39; 95% CI, 1.10-5.19) were more likely to report general symptoms and have poorer PROMIS physical health scores than their respective reference groups. Hispanic participants (difference, -3.05; 95% CI, -5.82 to -0.27) and Black participants (-4.48; 95% CI, -7.94 to -1.02) had poorer PROMIS physical health than White participants. Conclusions: CCP demonstrated no lasting effect on PASC symptoms or overall health in comparison to the placebo. This study underscores the significance of demographic factors, including sex, age, and timing of acute infection, in influencing symptom reporting 18 months after acute hypoxic COVID-19 hospitalization.

Safety of teropavimab and zinlirvimab with lenacapavir once every 6 months for HIV treatment: a phase 1b, randomised, proof-of-concept study.

BACKGROUND: Long-acting treatment for HIV has potential to improve adherence, provide durable viral suppression, and have long-term individual and public health benefits. We evaluated treatment with two antibodies that broadly and potently neutralise HIV (broadly neutralising antibodies; bNAbs), combined with lenacapavir, a long-acting capsid inhibitor, as a long-acting regimen. METHODS: This ongoing, randomised, blind, phase 1b proof-of-concept study conducted at 11 HIV treatment centres in the USA included adults with a plasma HIV-1 RNA concentration below 50 copies per mL who had at least 18 months on oral antiretroviral therapy (ART), CD4 counts of at least 500 cells per µL, and protocol-defined susceptibility to bNAbs teropavimab (3BNC117-LS) and zinlirvimab (10-1074-LS). Participants stopped oral ART and were randomly assigned (1:1) to one dose of 927 mg subcutaneous lenacapavir plus an oral loading dose, 30 mg/kg intravenous teropavimab, and 10 mg/kg or 30 mg/kg intravenous zinlirvimab on day 1. Investigational site personnel and participants were masked to treatment assignment throughout the randomised period. The primary endpoint was incidence of serious adverse events until week 26 in all randomly assigned participants who received one dose or more of any study drug. This study is registered with ClinicalTrials.gov, NCT04811040. FINDINGS: Between June 29 and Dec 8, 2021, 21 participants were randomly assigned, ten in each group received the complete study regimen and one withdrew before completing the regimen on day 1. 18 (86%) of 21 participants were male; participants ranged in age from 25 years to 61 years and had a median CD4 cell count of 909 (IQR 687-1270) cells per µL at study entry. No serious adverse events occurred. Two grade 3 adverse events occurred (lenacapavir injection-site erythaema and injection-site cellulitis), which had both resolved. The most common adverse events were symptoms of injection-site reactions, reported in 17 (85%) of 20 participants who received subcutaneous lenacapavir; 12 (60%) of 20 were grade 1. One (10%; 95% CI 0-45) participant had viral rebound (confirmed HIV-1 RNA concentration of ≥50 copies per mL) in the zinlirvimab 10 mg/kg group, which was resuppressed on ART, and one participant in the zinlirvimab 30 mg/kg group withdrew at week 12 with HIV RNA <50 copies per mL. INTERPRETATION: Lenacapavir with teropavimab and zinlirvimab 10 mg/kg or 30 mg/kg was generally well tolerated with no serious adverse events. HIV-1 suppression for at least 26 weeks is feasible with this regimen at either zinlirvimab dose in selected people with HIV-1. FUNDING: Gilead Sciences.

Effect of Montelukast vs Placebo on Time to Sustained Recovery in Outpatients with COVID-19: The ACTIV-6 Randomized Clinical Trial.

Importance: The effect of montelukast in reducing symptom duration among outpatients with mild to moderate coronavirus disease 2019 (COVID-19) is uncertain. Objective: To assess the effectiveness of montelukast compared with placebo in treating outpatients with mild to moderate COVID-19. Design Setting and Participants: The ACTIV-6 platform randomized clinical trial aims to evaluate the effectiveness of repurposed medications in treating mild to moderate COVID-19. Between January 27, 2023, and June 23, 2023, 1250 participants ≥30 years of age with confirmed SARS-CoV-2 infection and ≥2 acute COVID-19 symptoms for ≤7 days, were included across 104 US sites to evaluate the use of montelukast. Interventions: Participants were randomized to receive montelukast 10 mg once daily or matched placebo for 14 days. Main Outcomes and Measures: The primary outcome was time to sustained recovery (defined as at least 3 consecutive days without symptoms). Secondary outcomes included time to death; time to hospitalization or death; a composite of hospitalization, urgent care visit, emergency department visit, or death; COVID clinical progression scale; and difference in mean time unwell. Results: Among participants who were randomized and received study drug, the median age was 53 years (IQR 42-62), 60.2% were female, 64.6% identified as Hispanic/Latino, and 56.3% reported ≥2 doses of a SARS-CoV-2 vaccine. Among 628 participants who received montelukast and 622 who received placebo, differences in time to sustained recovery were not observed (adjusted hazard ratio [HR] 1.02; 95% credible interval [CrI] 0.92-1.12; P(efficacy) = 0.63]). Unadjusted median time to sustained recovery was 10 days (95% confidence interval 10-11) in both groups. No deaths were reported and 2 hospitalizations were reported in each group; 36 participants reported healthcare utilization events (a priori defined as death, hospitalization, emergency department/urgent care visit); 18 in the montelukast group compared with 18 in the placebo group (HR 1.01; 95% CrI 0.45-1.84; P(efficacy)=0.48). Five participants experienced serious adverse events (3 with montelukast and 2 with placebo). Conclusions and Relevance: Among outpatients with mild to moderate COVID-19, treatment with montelukast does not reduce duration of COVID-19 symptoms. Trial Registration: ClinicalTrials.gov ( NCT04885530 ).

Hepatitis C Cascade of Care in the Direct-Acting Antivirals Era: A Meta-Analysis.

INTRODUCTION: The hepatitis C virus (HCV) epidemic remains a public health problem worldwide. A systematic review and meta-analysis were conducted to provide evidence of outcomes attained across the HCV care cascade in the era of direct-acting antivirals. METHODS: Studies from North America, Europe, and Australia (January 2014 through March 2021) reporting on HCV care cascade outcomes (screening to cure) were included. When calculating the proportions of individuals completing each step, the numerator for Steps 1-8 was the number of individuals completing each step; the denominator was the number of individuals completing the previous step for Steps 1-3 and Step 3 for Steps 4-8. In 2022, random effects meta-analyses were conducted to estimate pooled proportions with 95% CIs. RESULTS: Sixty-five studies comprising 7,402,185 individuals were identified. Among individuals with positive HCV ribonucleic acid test results, 62% (95% CI=55%, 70%) attended their first care appointment, 41% (95% CI=37%, 45%) initiated treatment, 38% (95% CI=29%, 48%) completed treatment, and 29% (95% CI=25%, 33%) achieved cure. HCV screening rates were 43% (95% CI=22%, 66%) in prisons or jails and 20% (95% CI=11%, 31%) in emergency departments. Linkage to care rates were 62% (95% CI=46%, 75%) for homeless individuals and 26% (95% CI=22%, 31%) for individuals diagnosed in emergency departments. Cure rates were 51% (95% CI=30%, 73%) in individuals with substance use disorder and 17% (95% CI=17%, 17%) in homeless individuals. Cure rates were lowest in the U.S. DISCUSSION: Despite the availability of effective all-oral direct-acting antiviral therapies, persistent gaps remain across the HCV care cascade, especially among traditionally marginalized populations. Public health interventions targeting identified priority areas (e.g., emergency departments) may improve screening and healthcare retention of vulnerable populations with HCV infection (e.g., substance use disorder populations).

Sustained Virologic Suppression With Dolutegravir/Lamivudine in a Test-and-Treat Setting Through 48 Weeks.

Background: We assessed the efficacy and safety of dolutegravir/lamivudine (DTG/3TC) in a US test-and-treat setting at a secondary 48-week time point of the multicenter, single-arm, phase IIIb STAT study. Methods: Participants were eligible adults newly diagnosed with human immunodeficiency virus (HIV)-1 and had started once-daily DTG/3TC within 14 days of diagnosis, before laboratory results were available. Antiretroviral therapy (ART) was modified if baseline testing indicated DTG or 3TC resistance, hepatitis B virus (HBV) coinfection, or creatinine clearance <30 mL/min per 1.73 m2, and these participants remained in the study. A proportion with HIV-1 ribonucleic acid (RNA) <50 copies/mL at Week 48 was calculated among all participants (intention-to-treat-exposed [ITT-E] missing = failure analysis) and those with available data (observed analysis). Results: At Week 48, 82% of all participants regardless of ART (107 of 131; ITT-E missing = failure) and 97% with available data (107 of 110; observed analysis) achieved HIV-1 RNA <50 copies/mL. High proportions of virologic response were seen overall, including in participants with high viral load (≥500 000 copies/mL; 89%) or low CD4+ cell count (<200 cells/mm3; 78%) at baseline. Ten participants had treatment modification (baseline HBV coinfection, n = 5; participant/proxy decision, n = 2; baseline M184V resistance mutation, adverse event [AE; rash], and pregnancy, n = 1 each) before Week 48. Two participants met confirmed virologic failure criteria. No treatment-emergent resistance was observed. Ten participants reported drug-related AEs (all grade 1-2); no serious drug-related AEs occurred. Conclusions: Results demonstrated high proportions of participants with sustained virologic suppression, no treatment-emergent resistance, and good safety over 48 weeks, supporting first-line use of DTG/3TC in a test-and-treat setting.

Opioids exacerbate inflammation in people with well-controlled HIV.

Introduction: People with HIV (PWH) are known to have underlying inflammation and immune activation despite virologic control. Substance use including opioid dependence is common in this population and is associated with increased morbidity and reduced lifespan. The primary objective of the present study termed opioid immunity study (OPIS), was to investigate the impact of chronic opioids in PWH. Methods: The study recruited people with and without HIV who had opioid use disorder (OUD). Study participants (n=221) were categorized into four groups: HIV+OP+, n=34; HIV-OP+, n=66; HIV+OP-, n=55 and HIV-OP-, n=62 as controls. PWH were virally suppressed on ART and those with OUD were followed in a syringe exchange program with confirmation of OP use by urine drug screening. A composite cytokine score was developed for 20 plasma cytokines that are linked to inflammation. Cellular markers of immune activation (IA), exhaustion, and senescence were determined in CD4 and CD8 T cells. Regression models were constructed to examine the relationships of HIV status and opioid use, controlling for other confounding factors. Results: HIV+OP+ participants exhibited highest inflammatory cytokines and cellular IA, followed by HIV-OP+ for inflammation and HIV+OP- for IA. Inflammation was found to be driven more by opioid use than HIV positivity while IA was driven more by HIV than opioid use. In people with OUD, expression of CD38 on CD28-CD57+ senescent-like T cells was elevated and correlated positively with inflammation. Discussion: Given the association of inflammation with a multitude of adverse health outcomes, our findings merit further investigations to understand the mechanistic pathways involved.

Predicting COVID-19 cases using SARS-CoV-2 RNA in air, surface swab and wastewater samples.

Genomic footprints of pathogens shed by infected individuals can be traced in environmental samples, which can serve as a noninvasive method of infectious disease surveillance. The research evaluates the efficacy of environmental monitoring of SARS-CoV-2 RNA in air, surface swabs and wastewater to predict COVID-19 cases. Using a prospective experimental design, air, surface swabs, and wastewater samples were collected from a college dormitory housing roughly 500 students from March to May 2021 at the University of Miami, Coral Gables, FL. Students were randomly screened for COVID-19 during the study period. SARS-CoV-2 concentration in environmental samples was quantified using Volcano 2nd Generation-qPCR. Descriptive analyses were conducted to examine the associations between time-lagged SARS-CoV-2 in environmental samples and COVID-19 cases. SARS-CoV-2 was detected in air, surface swab and wastewater samples on 52 (63.4 %), 40 (50.0 %) and 57 (68.6 %) days, respectively. On 19 (24 %) of 78 days SARS-CoV-2 was detected in all three sample types. COVID-19 cases were reported on 11 days during the study period and SARS-CoV-2 was also detected two days before the case diagnosis on all 11 (100 %), 9 (81.8 %) and 8 (72.7 %) days in air, surface swab and wastewater samples, respectively. SARS-CoV-2 detection in environmental samples was an indicator of the presence of local COVID-19 cases and a 3-day lead indicator for a potential outbreak at the dormitory building scale. Proactive environmental surveillance of SARS-CoV-2 or other pathogens in multiple environmental media has potential to guide targeted measures to contain and/or mitigate infectious disease outbreaks within communities.

Efficacy and safety of rilpivirine in treatment-naive, HIV-1-infected patients with hepatitis B virus/hepatitis C virus coinfection enrolled in the Phase III randomized, double-blind ECHO and THRIVE trials.

OBJECTIVES: The efficacy and hepatic safety of the non-nucleoside reverse transcriptase inhibitors rilpivirine (TMC278) and efavirenz were compared in treatment-naive, HIV-infected adults with concurrent hepatitis B virus (HBV) and/or hepatitis C virus (HCV) infection in the pooled week 48 analysis of the Phase III, double-blind, randomized ECHO (NCT00540449) and THRIVE (NCT00543725) trials. METHODS: Patients received 25 mg of rilpivirine once daily or 600 mg of efavirenz once daily, plus two nucleoside/nucleotide reverse transcriptase inhibitors. At screening, patients had alanine aminotransferase/aspartate aminotransferase levels ≤5× the upper limit of normal. HBV and HCV status was determined at baseline by HBV surface antigen, HCV antibody and HCV RNA testing. RESULTS: HBV/HCV coinfection status was known for 670 patients in the rilpivirine group and 665 in the efavirenz group. At baseline, 49 rilpivirine and 63 efavirenz patients [112/1335 (8.4%)] were coinfected with either HBV [55/1357 (4.1%)] or HCV [57/1333 (4.3%)]. The safety analysis included all available data, including beyond week 48. Eight patients seroconverted during the study (rilpivirine: five; efavirenz: three). A higher proportion of patients achieved viral load <50 copies/mL (intent to treat, time to loss of virological response) in the subgroup without HBV/HCV coinfection (rilpivirine: 85.0%; efavirenz: 82.6%) than in the coinfected subgroup (rilpivirine: 73.5%; efavirenz: 79.4%) (rilpivirine, P = 0.04 and efavirenz, P = 0.49, Fisher's exact test). The incidence of hepatic adverse events (AEs) was low in both groups in the overall population (rilpivirine: 5.5% versus efavirenz: 6.6%) and was higher in HBV/HCV-coinfected patients than in those not coinfected (26.7% versus 4.1%, respectively). CONCLUSIONS: Hepatic AEs were more common and response rates lower in HBV/HCV-coinfected patients treated with rilpivirine or efavirenz than in those who were not coinfected.