The effect of metformin on reducing symptom duration among outpatient adults with COVID-19 has not been studied. To assess metformin compared with placebo for symptom resolution during acute infection with SARS-CoV-2. The Accelerating COVID-19 Therapeutic Interventions and Vaccines platform evaluated repurposed medications for mild to moderate COVID-19. Between September 19, 2023, and May 1, 2024, participants 30 years or older with confirmed SARS-CoV-2 infection and 2 or more COVID-19 symptoms for 7 days or less were included at 90 US sites. Participants were randomized to receive metformin (titrated to 1500 mg, daily) or placebo for 14 days. The primary outcome was time to sustained recovery (3 consecutive days without COVID-19 symptoms) within 28 days of receiving the study drug. Secondary outcomes included time to clinic visit, emergency department (ED) visit, hospitalization, or death. Safety events of interest were hypoglycemia and lactic acidosis. Among 2991 participants who were randomized and received study drug, the median age was 47 (IQR, 38-58) years; 1895 (63.4%) were female, 25 (0.8%) were American Indian of Alaska Native, 77 (2.6%) were Asian, 350 (11.7%) were Black, African American, or African, 1392 (46.5%) identified as Hispanic or Latino, 8 (0.3%) were Native Hawaiian or other Pacific Islander, 2395 (80.1%) were White, and 2044 (68.3%) reported 2 or more doses of a SARS-CoV-2 vaccine. Among 1443 (48.2%) participants who received metformin and 1548 (51.8%) who received placebo, differences in time to sustained recovery were not observed (adjusted hazard ratio, 0.96; 95% credible interval [CrI], 0.89-1.03; P for efficacy = .11). The median time to sustained recovery was 9 days (95% CI, 9-10) for metformin and 10 days (95% CI, 9-10) for placebo. No deaths were reported; 103 participants reported clinic visits, ED visits, or hospitalization: 54 in the metformin group and 49 in the placebo group (hazard ratio, 1.25; 95% CrI, 0.82-1.78; P for efficacy = .13). Overall, 35 (1.2%) reported ED visits or hospitalization (1.1% in the metformin and 1.3% in the placebo group). Seven participants who received metformin and 3 who received placebo experienced a serious adverse event over 180 days. There were 4 episodes of participant-reported hypoglycemia in the placebo group and 2 in the metformin group. In this randomized clinical trial, metformin was not shown to shorten the time to symptom resolution in low-risk adults with COVID-19. The median days to symptom resolution was numerically but not significantly lower for metformin. Safety was not a limitation in the study population. ClinicalTrials.gov Identifier: NCT04885530

Abstract Background Historically, bone and joint infections have been treated with intravenous (IV) antimicrobials. IV to oral (PO) antibiotic transition implementation differs among institutions and prescribers. This practice has increased in recent years as new literature has demonstrated comparable efficacy of PO and IV treatment. Use of outpatient IV therapy often necessitates using a central line. This introduces additional risks, particularly line-related complications such as clots and central line infections. The purpose of this project was to identify opportunities for transitioning from IV to PO therapy in patients discharged on IV antibiotics for bone/joint infections at an academic medical center. Baseline Patient Characteristics Methods We performed a retrospective, cross-sectional study of adults discharged on IV antibiotics between January 2020 and December 2023. Inclusion criteria included age ≥ 18 years, patient followed by institutional outpatient parenteral antimicrobial therapy service, and receipt of at least one IV antibiotic for a bone/joint infection. Patients with axial osteomyelitis were excluded. The primary outcome was the percentage of patients with the potential to transition from IV to PO antibiotics. Secondary outcomes included incidence of adverse drug events (ADE). Results 324 patients were included. Osteomyelitis was the most common infection (48.5%) followed by joint infection (27.5%). Source control procedures were performed for 83% of patients. Cultures were positive in 75% of patients, and Staphylococcus species were the most common pathogens (45%). In total, 237 (73.1%) of patients qualified for a complete PO regimen. Half of patients (50.3%) received at least one PO antibiotic as part of their discharge therapy. Antibiotic changes occurred after discharge in 15.4% of patients, and 21% of patients experienced an antibiotic associated ADE. Conclusion Most patients discharged on IV antibiotics for bone/joint infection at this medical center could have received a complete PO regimen. While PO antibiotics are not benign, there is the potential to reduce adverse effects. These findings highlight opportunities for IV to PO transition at discharge and the potential to reduce line associated complications. Disclosures Patrick E H Jackson, MD, Gentiva Hospice: spouse employment|Kindred Hospice: spouse employment|Pfizer: Grant/Research Support

The HIV-1 Rev-RRE regulatory axis plays a crucial role in viral replication by facilitating the nucleo-cytoplasmic export and expression of viral mRNAs with retained introns. In this study, we investigated the impact of variation in Rev-RRE functional activity on HIV-1 replication kinetics and reactivation from latency. Using a novel HIV-1 viral vector with an interchangeable Rev cassette, we engineered viruses with two diverse Rev functional activities and demonstrated that higher Rev-RRE activity confers greater viral replication capacity while maintaining a constant level of Nef expression. In addition, a low Rev activity virus rapidly acquired a compensatory mutation in the RRE that significantly increased Rev-RRE activity and replication. In a latency model, proviruses with differing Rev-RRE activity levels varied in the efficiency of viral reactivation, affecting both initial viral release and subsequent replication kinetics. These results demonstrate that activity differences in the Rev-RRE axis among different viral isolates have important implications for HIV replication dynamics and persistence. Importantly, our findings indicate that bolstering Rev/RRE activity could be explored as part of latency reversal strategies in HIV cure efforts.

Background We previously conducted a phase 2a randomized placebo-controlled trial of 40 subjects to assess the efficacy and safety of dupilumab use in people hospitalized with coronavirus disease 2019 (COVID-19) (NCT04920916). Based on our preclinical data suggesting that downstream pulmonary dysfunction with COVID-19 induced type 2 inflammation, we contacted patients from our phase 2a study at 1 year for assessment of post-COVID-19 conditions.Methods Subjects at 1 year after treatment underwent pulmonary function tests, high-resolution computed tomographic imaging, symptom questionnaires, neurocognitive assessments, and serum immune biomarker analysis, with subject survival also monitored. The primary outcome was the proportion of abnormal diffusion capacity for carbon monoxide (DLCO) or 6-minute walk test (6MWT) at the 1-year visit.Results Of those survivors who consented to 1-year visits (n = 16), subjects who had originally received dupilumab were less likely than those who received placebo to have an abnormal DLCO or 6MWT (Fisher exact P = .011; adjusted P = .058). As a secondary endpoint, we saw that 16% of subjects in the dupilumab group died by 1 year compared to 38% in the placebo group, though this was not statistically significant (log-rank P = .12). We did not find significant differences in neurocognitive testing, symptoms, or chest computed tomography between treatment groups but observed a larger reduction in eotaxin levels in those who received dupilumab.Conclusions In this observational study, subjects who received dupilumab during acute COVID-19 hospitalization were less likely to have a reduced DLCO or 6MWT, with a nonsignificant trend toward reduced mortality at 1 year compared to placebo. In this follow-up study, subjects who had received dupilumab during their acute COVID-19 hospitalization through a prior phase 2a randomized placebo-controlled trial were less likely to have reduced lung diffusion or abnormal 6-minute walk testing at 1 year postenrollment.

Background:Evaluating the National Institute's Health's (NIH's) response to the coronavirus disease 2019 (COVID-19) pandemic via grants and clinical trials is crucial to determining the impact they had on aiding US citizens. We determined how the NIH's funding for COVID-19 research was disbursed and used by various institutions across the United States. Methods:We queried NIH RePORTER and isolated COVID-19-related grants from January 2020 to December 2021. We analyzed grant type, geographical location, and awardee institution. Manuscripts published from these grants were quantitatively analyzed. COVID-19 clinical trials were mapped and distances from counties to clinical trial sites were calculated using ArcGis. Results:A total of 2401 COVID-19 NIH grants resulted in 14 654 manuscripts from $4.2 billion and generated more than 150 000 citations. R01s make up 32% of grants (763/2401) and 8% of funding ($329 million). UM1 grants account for the majority of funding (30.8%; $1.3 Billion). Five states received 50.6% of funding: North Carolina, Washington, New York, California, and Massachusetts. Finally, of the 1806 clinical trials across 1266 sites in the United States, the majority were in metropolitan areas in close proximity to areas of high COVID-19 disease burden. Conclusions and Relevance:Evaluating the outcome of the NIH's response to the COVID-19 pandemic is of interest to the general public. The present study finds that the NIH disbursed more than $4 billion in funding to large consortiums and clinical trials to develop diagnostics, therapeutics, and vaccines. Approximately 8% of funding was used for R01 grants. Clinical trial sites were generally located in areas of high COVID-19 burden.

ImportanceFostamatinib, a spleen tyrosine kinase inhibitor, has been reported to improve outcomes of COVID-19.ObjectiveTo evaluate the efficacy and safety of fostamatinib in adults hospitalized with COVID-19 and hypoxemia.Design, Setting, and ParticipantsThis multicenter, phase 3, placebo-controlled, double-blinded randomized clinical trial was conducted at 41 US sites and 21 international sites between November 17, 2021, and September 27, 2023; the last follow-up visit was December 31, 2023. Participants were adults aged 18 years or older hospitalized with acute SARS-CoV-2 infection and hypoxemia. Data were analyzed between January 10 and March 8, 2024.InterventionsFostamatinib, 150 mg orally twice daily for 14 days, or placebo.Main Outcomes and MeasuresThe primary outcome was oxygen-free days, an ordinal outcome classifying a participant’s status at day 28 based on mortality and duration of supplemental oxygen use. An adjusted odds ratio (AOR) greater than 1.0 was considered to indicate superiority of fostamatinib over placebo. A key secondary outcome was 28-day all-cause mortality. Safety outcomes included elevated transaminase values, neutropenia, and hypertension.ResultsOf the 400 participants randomized (median age, 67 years [IQR, 58-76 years]; 210 [52.5%] men), 199 received fostamatinib and 201 received placebo. The mean (SD) number of oxygen-free days was 13.4 (12.4) in the fostamatinib group and 14.2 (12.1) in the placebo group (unadjusted mean difference, −1.26 days [95% CI, −3.52 to 1.00 days]; AOR, 0.82 [95% credible interval (CrI), 0.58-1.17]). Mortality at 28 days occurred in 22 of 195 patients (11.3%) in the fostamatinib group and 16 of 197 (8.1%) in the placebo group (AOR, 1.44; 95% CrI, 0.72-2.90). Aspartate aminotransferase elevation occurred more commonly in the fostamatinib group (23 [11.6%]) than in the placebo group (11 [5.5%]; AOR, 2.28; 95% CrI, 1.07-4.84). Other safety outcomes were similar between groups.Conclusions and RelevanceIn this randomized clinical trial of adults hospitalized with COVID-19 and hypoxemia, fostamatinib did not increase the number of oxygen-free days compared with placebo. These results do not support the hypothesis that fostamatinib improves outcomes among adults hospitalized with hypoxemia during the Omicron era.Trial RegistrationClinicalTrials.gov Identifier: NCT04924660

Retroviruses must overcome cellular restrictions to the nucleocytoplasmic export of viral mRNAs that retain introns in order to complete their replication cycle. HIV accomplishes this using a system comprised of a trans-acting viral protein, Rev, and a cis-acting RNA secondary structure in the viral genome, the Rev-Response Element (RRE). HIV primary isolates differ with respect to the sequence and functional activity of the Rev-RRE system. Here, we describe a high throughput assay system for analyzing Rev-RRE functional activity using packageable viral vectors.

Background:The National Institutes of Health (NIH) mobilized more than $4 billion in extramural funding for the COVID-19 pandemic. Assessing the research output from this effort is crucial to understanding how the scientific community leveraged federal funding and responded to this public health crisis.Methods:NIH-funded COVID-19 grants awarded between January 2020 and December 2021 were identified from NIH Research Portfolio Online Reporting Tools Expenditures and Results using the "COVID-19 Response" filter. PubMed identifications of publications under these grants were collected and the NIH iCite tool was used to determine citation counts and focus (eg, clinical, animal). iCite and the NIH's LitCOVID database were used to identify publications directly related to COVID-19. Publication titles and Medical Subject Heading terms were used as inputs to a machine learning-based model built to identify common topics/themes within the publications.Results and Conclusions:We evaluated 2401 grants that resulted in 14 654 publications. The majority of these papers were published in peer-reviewed journals, though 483 were published to preprint servers. In total, 2764 (19%) papers were directly related to COVID-19 and generated 252 029 citations. These papers were mostly clinically focused (62%), followed by cell/molecular (32%), and animal focused (6%). Roughly 60% of preprint publications were cell/molecular-focused, compared with 26% of nonpreprint publications. The machine learning-based model identified the top 3 research topics to be clinical trials and outcomes research (8.5% of papers), coronavirus-related heart and lung damage (7.3%), and COVID-19 transmission/epidemiology (7.2%). This study provides key insights regarding how researchers leveraged federal funding to study the COVID-19 pandemic during its initial phase.

Background:We previously conducted a Phase IIa randomized placebo-controlled trial of 40 subjects to assess the efficacy and safety of dupilumab use in those hospitalized with COVID-19 (NCT04920916). Based on our pre-clinical data suggesting downstream pulmonary dysfunction with COVID-19 induced type 2 inflammation, we contacted patients from our Phase IIa study at 1 year for assessment of Post Covid-19 Conditions (PCC).Methods:Subjects at 1 year after treatment underwent pulmonary function testing (PFTs), high resolution computed tomography (HRCT) imaging, symptom questionnaires, neurocognitive assessments, and serum immune biomarker analysis, with subject survival also monitored. The primary outcome was the proportion of abnormal PFTs, defined as an abnormal diffusion capacity for carbon monoxide (DLCO) or 6-minute walk testing (6MWT) at the 1-year visit.Results:Sixteen of the 29 one-year survivors consented to the follow up visit. We found that subjects who had originally received dupilumab were less likely to have abnormal PFTs compared to those who received placebo (Fisher's exact p=0.011, adjusted p=0.058). We additionally found that 3 out of 19 subjects (16%) in the dupilumab group died by 1 year compared to 8 out of 21 subjects (38%) in the placebo group (log rank p=0.12). We did not find significant differences in neurocognitive testing, symptoms or CT chest imaging between treatment groups but observed evidence of reduced type 2 inflammation in those who received dupilumab.Conclusions:We observed evidence of reduced long-term morbidity and mortality from COVID-19 with dupilumab treatment during acute hospitalization when added to standard of care regimens.

HIV is not efficiently transmitted between hosts, and selection of viral variants occurs during the process of sexual transmission. The factors that confer selective advantage at the transmission bottleneck remain incompletely understood. We explored whether differences in the Rev-Rev Response Element (RRE) regulatory axis of HIV affect transmission fitness, since functional variation in the Rev-RRE axis in different viral isolates has been shown to affect replication kinetics and relative expression of many HIV proteins. Single genome HIV sequences were identified from nine linked subject pairs near the time of female-to-male transmission. Using a rapid flow-cytometric assay, we found that the functional Rev-RRE activity varied significantly between isolates. Moreover, it was generally lower in recipients’ viruses compared to the corresponding donor viruses. In six of nine transmission events, recipient virus Rev-RRE activity clustered at the extreme low end of the range of donor virus activity. Rev-RRE pair activity was an unpredictable product of component Rev and RRE activity variation. These data indicate selection pressure on the Rev-RRE axis during female-to-male sexual transmission. Variation in the activity of the Rev-RRE axis may permit viral adaptation to different fitness landscapes and could play an important role in HIV pathogenesis.

Background:Sexual transmission of human immunodeficiency virus (HIV) is inefficient and results in selection of viral variants based on incompletely understood factors. Functional variation in the Rev-Rev response element (RRE) regulatory axis of HIV affect replication kinetics and relative expression of viral proteins. We explored whether differences in this axis among viral isolates affect transmission fitness. Methods:HIV sequences were identified from nine female-to-male transmission pairs. Using a rapid flow cytometric assay, we analyzed Rev-RRE functional activity of primary isolates. Results:Rev-RRE activity was significantly lower in recipient viruses compared with corresponding donor viruses. In most transmission events, recipient virus Rev-RRE activity clustered at the extreme low end of the range of donor virus activity. Conclusions:These data indicate selection pressure on the Rev-RRE axis during female-to-male sexual transmission. Variation in Rev-RRE activity may permit viral adaptation to different fitness landscapes and could play an important role in HIV pathogenesis.

ImportanceThe effect of higher-dose fluvoxamine in reducing symptom duration among outpatients with mild to moderate COVID-19 remains uncertain.ObjectiveTo assess the effectiveness of fluvoxamine, 100 mg twice daily, compared with placebo, for treating mild to moderate COVID-19.Design, Setting, and ParticipantsThe 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.InterventionsParticipants 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 MeasuresThe 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.ResultsAmong 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 RelevanceAmong outpatients with mild to moderate COVID-19, treatment with fluvoxamine does not reduce duration of COVID-19 symptoms.Trial RegistrationClinicalTrials.gov Identifier: NCT04885530

The relationship between diabetes and coronavirus disease 2019 (COVID-19) is bidirectional: Although individuals with diabetes and high blood glucose (hyperglycemia) are predisposed to severe COVID-19, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection can also cause hyperglycemia and exacerbate underlying metabolic syndrome. Therefore, interventions capable of breaking the network of SARS-CoV-2 infection, hyperglycemia, and hyperinflammation, all factors that drive COVID-19 pathophysiology, are urgently needed. Here, we show that genetic ablation or pharmacological inhibition of mitochondrial pyruvate carrier (MPC) attenuates severe disease after influenza or SARS-CoV-2 pneumonia. MPC inhibition using a second-generation insulin sensitizer, MSDC-0602K (MSDC), dampened pulmonary inflammation and promoted lung recovery while concurrently reducing blood glucose levels and hyperlipidemia after viral pneumonia in obese mice. Mechanistically, MPC inhibition enhanced mitochondrial fitness and destabilized hypoxia-inducible factor–1α, leading to dampened virus-induced inflammatory responses in both murine and human lung macrophages. We further showed that MSDC enhanced responses to nirmatrelvir (the antiviral component of Paxlovid) to provide high levels of protection against severe host disease development after SARS-CoV-2 infection and suppressed cellular inflammation in human COVID-19 lung autopsies, demonstrating its translational potential for treating severe COVID-19. Collectively, we uncover a metabolic pathway that simultaneously modulates pulmonary inflammation, tissue recovery, and host metabolic health, presenting a synergistic therapeutic strategy to treat severe COVID-19, particularly in patients with underlying metabolic disease.

We conducted a phase 2a randomized, double-blind, placebo-controlled trial of dupilumab plus standard of care in patients hospitalized with COVID-19. Subjects randomized to dupilumab had a higher 60-day survival rate compared to the placebo group (89.5% vs 76.2%; P = .03). Background Based on studies implicating the type 2 cytokine interleukin 13 (IL-13) as a potential contributor to critical coronavirus disease 2019 (COVID-19), this trial was designed as an early phase 2 study to assess dupilumab, a monoclonal antibody that blocks IL-13 and interleukin 4 signaling, for treatment of inpatients with COVID-19. Methods We conducted a phase 2a randomized, double-blind, placebo-controlled trial (NCT04920916) to assess the safety and efficacy of dupilumab plus standard of care vs placebo plus standard of care in mitigating respiratory failure and death in those hospitalized with COVID-19. Results Forty eligible subjects were enrolled from June to November of 2021. There was no statistically significant difference in adverse events nor in the primary endpoint of ventilator-free survival at day 28 between study arms. However, for the secondary endpoint of mortality at day 60, there were 2 deaths in the dupilumab group compared with 5 deaths in the placebo group (60-day survival: 89.5% vs 76.2%; adjusted hazard ratio [HR], 0.05 [95% confidence interval {CI}, .004-.72]; P = .03). Among subjects who were not in the intensive care unit (ICU) at randomization, 3 subjects in the dupilumab arm were admitted to the ICU compared to 6 in the placebo arm (17.7% vs 37.5%; adjusted HR, 0.44 [95% CI, .09-2.09]; P = .30). Last, we found evidence of type 2 signaling blockade in the dupilumab group through analysis of immune biomarkers over time. Conclusions Although the primary outcome of day 28 ventilator-free survival was not reached, adverse events were not observed and survival was higher in the dupilumab group by day 60.

Background: A profound need remains to develop further therapeutics for treatment of those hospitalized with COVID-19 to prevent respiratory decline or death. Based on data implicating the type 2 cytokine interleukin (IL)-13 as a significant factor leading to critical COVID-19, this trial was designed to assess the safety and efficacy of dupilumab, a monoclonal antibody that blocks IL-13 and IL-4 signaling, in those hospitalized with COVID-19. Methods: We conducted a phase IIa randomized double-blind placebo-controlled trial to assess the safety and efficacy of dupilumab plus standard of care versus placebo plus standard of care in mitigating respiratory failure and death in those hospitalized with COVID-19. Subjects were followed prospectively for 60 days, with collection of clinical outcomes, adverse events and immunologic biomarkers at multiple time points throughout the study period. The primary endpoint was the proportion of patients alive and free of invasive mechanical ventilation at 28 days analyzed in logistic regression. Results: Forty eligible subjects were enrolled from June 23, 2021 through November 11, 2021. There was no difference in adverse events nor in proportion of patients alive and free of mechanical ventilation at day 28 between study treatment groups. However, for the secondary endpoint of mortality at day 60, subjects randomized to dupilumab had a higher survival rate: 89.5% of subjects in the dupilumab group were alive compared to 76.2% in the placebo group (adjusted HR 0.05, 95% CI: 0.0- 0.72, p=0.03). There was a trend toward reduction in ICU admission in the dupilumab group compared to the placebo group (33.3% vs 66.7%; adjusted HR 0.44, 95% CI: 0.09-2.09, p=0.30). Lastly, we saw downstream evidence of IL-4 and IL-13 signaling blockade through analysis of immune biomarkers at multiple study time points. Conclusions: Dupilumab was well tolerated and improved 60-day survival in patients hospitalized with moderate to severe COVID-19. Blockade of type 2 immunity offers promise as a novel treatment for COVID-19.

During HIV infection, intron-containing viral mRNAs are exported from the cell nucleus to the cytoplasm to complete the replication cycle. Cellular restrictions on the export of incompletely spliced transcripts are overcome by a viral protein, Rev, and an RNA structure found in all unspliced and incompletely spliced viral mRNAs, the Rev Response Element (RRE). Primary HIV isolates display substantial variation in the sequence and functional activity of Rev proteins. We analyzed Rev from two primary isolates with disparate activity that resulted in differences in in vitro fitness of replication-competent viral constructs. The results showed that amino acid differences within the oligomerization domain, but not the arginine-rich motif or the nuclear export signal, determined the level of Rev activity. Two specific amino acid substitutions were sufficient to alter the low-activity Rev to a high-activity phenotype. Other mutations in Rev sequences had unpredictable effects on activity that differed between the two Rev backbones. The sensitivity of Rev function level to small sequence changes likely permits modulation of Rev-RRE activity during HIV infection, which may play a role in pathogenesis. The functional consequences of Rev mutations differed between primary isolates, highlighting the challenge of generalizing studies of Rev conducted using laboratory HIV strains.

BACKGROUND:Functional impairment of interferon, a natural antiviral component of the immune system, is associated with the pathogenesis and severity of COVID-19. We aimed to compare the efficacy of interferon beta-1a in combination with remdesivir compared with remdesivir alone in hospitalised patients with COVID-19. METHODS:We did a double-blind, randomised, placebo-controlled trial at 63 hospitals across five countries (Japan, Mexico, Singapore, South Korea, and the USA). Eligible patients were hospitalised adults (aged ≥18 years) with SARS-CoV-2 infection, as confirmed by a positive RT-PCR test, and who met one of the following criteria suggestive of lower respiratory tract infection: the presence of radiographic infiltrates on imaging, a peripheral oxygen saturation on room air of 94% or less, or requiring supplemental oxygen. Patients were excluded if they had either an alanine aminotransferase or an aspartate aminotransferase concentration more than five times the upper limit of normal; had impaired renal function; were allergic to the study product; were pregnant or breast feeding; were already on mechanical ventilation; or were anticipating discharge from the hospital or transfer to another hospital within 72 h of enrolment. Patients were randomly assigned (1:1) to receive intravenous remdesivir as a 200 mg loading dose on day 1 followed by a 100 mg maintenance dose administered daily for up to 9 days and up to four doses of either 44 μg interferon beta-1a (interferon beta-1a group plus remdesivir group) or placebo (placebo plus remdesivir group) administered subcutaneously every other day. Randomisation was stratified by study site and disease severity at enrolment. Patients, investigators, and site staff were masked to interferon beta-1a and placebo treatment; remdesivir treatment was given to all patients without masking. The primary outcome was time to recovery, defined as the first day that a patient attained a category 1, 2, or 3 score on the eight-category ordinal scale within 28 days, assessed in the modified intention-to-treat population, defined as all randomised patients who were classified according to actual clinical severity. Safety was assessed in the as-treated population, defined as all patients who received at least one dose of the assigned treatment. This trial is registered with ClinicalTrials.gov, NCT04492475. FINDINGS:Between Aug 5, 2020, and Nov 11, 2020, 969 patients were enrolled and randomly assigned to the interferon beta-1a plus remdesivir group (n=487) or to the placebo plus remdesivir group (n=482). The mean duration of symptoms before enrolment was 8·7 days (SD 4·4) in the interferon beta-1a plus remdesivir group and 8·5 days (SD 4·3) days in the placebo plus remdesivir group. Patients in both groups had a time to recovery of 5 days (95% CI not estimable) (rate ratio of interferon beta-1a plus remdesivir group vs placebo plus remdesivir 0·99 [95% CI 0·87-1·13]; p=0·88). The Kaplan-Meier estimate of mortality at 28 days was 5% (95% CI 3-7%) in the interferon beta-1a plus remdesivir group and 3% (2-6%) in the placebo plus remdesivir group (hazard ratio 1·33 [95% CI 0·69-2·55]; p=0·39). Patients who did not require high-flow oxygen at baseline were more likely to have at least one related adverse event in the interferon beta-1a plus remdesivir group (33 [7%] of 442 patients) than in the placebo plus remdesivir group (15 [3%] of 435). In patients who required high-flow oxygen at baseline, 24 (69%) of 35 had an adverse event and 21 (60%) had a serious adverse event in the interferon beta-1a plus remdesivir group compared with 13 (39%) of 33 who had an adverse event and eight (24%) who had a serious adverse event in the placebo plus remdesivir group. INTERPRETATION:Interferon beta-1a plus remdesivir was not superior to remdesivir alone in hospitalised patients with COVID-19 pneumonia. Patients who required high-flow oxygen at baseline had worse outcomes after treatment with interferon beta-1a compared with those given placebo. FUNDING:The National Institute of Allergy and Infectious Diseases (USA).

Background: To complete its replication cycle, HIV-1 requires the nucleocytoplasmic export of intron-containing viral mRNAs. This process is ordinarily restricted by the cell, but HIV overcomes the block by means of a viral protein, Rev, and an RNA secondary structure found in all unspliced and incompletely spliced viral mRNAs called the Rev Response Element (RRE). In vivo activity of the Rev-RRE axis requires Rev binding to the RRE, oligomerization of Rev to form a competent ribonucleoprotein complex, and recruitment of cellular factors including Crm1 and RanGTP in order to export the targeted transcript. Sequence variability is observed among primary isolates in both Rev and the RRE, and the activity of both can be modulated through relatively small sequence changes. Primary isolates show differences in Rev-RRE activity and a few studies have found a correlation between lower Rev-RRE activity and slower progression of clinical disease. Lower Rev-RRE activity has also been associated with the evasion of cytotoxic T lymphocyte mediated killing. Conclusions: The HIV-1 Rev-RRE regulatory axis is an understudied mechanism by which viral adaptation to diverse immune milieus may take place. There is evidence that this adaptation plays a role in HIV pathogenesis, particularly in immune evasion and latency, but further studies with larger sample sizes are warranted.

BACKGROUND:Severe coronavirus disease 2019 (Covid-19) is associated with dysregulated inflammation. The effects of combination treatment with baricitinib, a Janus kinase inhibitor, plus remdesivir are not known. METHODS:We conducted a double-blind, randomized, placebo-controlled trial evaluating baricitinib plus remdesivir in hospitalized adults with Covid-19. All the patients received remdesivir (≤10 days) and either baricitinib (≤14 days) or placebo (control). The primary outcome was the time to recovery. The key secondary outcome was clinical status at day 15. RESULTS:A total of 1033 patients underwent randomization (with 515 assigned to combination treatment and 518 to control). Patients receiving baricitinib had a median time to recovery of 7 days (95% confidence interval [CI], 6 to 8), as compared with 8 days (95% CI, 7 to 9) with control (rate ratio for recovery, 1.16; 95% CI, 1.01 to 1.32; P = 0.03), and a 30% higher odds of improvement in clinical status at day 15 (odds ratio, 1.3; 95% CI, 1.0 to 1.6). Patients receiving high-flow oxygen or noninvasive ventilation at enrollment had a time to recovery of 10 days with combination treatment and 18 days with control (rate ratio for recovery, 1.51; 95% CI, 1.10 to 2.08). The 28-day mortality was 5.1% in the combination group and 7.8% in the control group (hazard ratio for death, 0.65; 95% CI, 0.39 to 1.09). Serious adverse events were less frequent in the combination group than in the control group (16.0% vs. 21.0%; difference, -5.0 percentage points; 95% CI, -9.8 to -0.3; P = 0.03), as were new infections (5.9% vs. 11.2%; difference, -5.3 percentage points; 95% CI, -8.7 to -1.9; P = 0.003). CONCLUSIONS:Baricitinib plus remdesivir was superior to remdesivir alone in reducing recovery time and accelerating improvement in clinical status among patients with Covid-19, notably among those receiving high-flow oxygen or noninvasive ventilation. The combination was associated with fewer serious adverse events. (Funded by the National Institute of Allergy and Infectious Diseases; ClinicalTrials.gov number, NCT04401579.).