Guanidine dicycloamine-based analogs: green chemistry synthesis, biological investigation, and molecular docking studies as promising antibacterial and antiglycation leads.

Dicyandiamide (DCD) reacted with amino acids 1a-f to produce biguanides 2 and 4 and guanidine pyrazolones 3, 5, 6, 7, and 8, according to the reaction. DCD exhibited the following reactions: imidodicarbonimidicdiamide 9, diazocan-2-ylguanidine 10, methyl biguanidylthion 11, N-carbamothioylimidodicarbonimidicdiamide 12, 2-guanidinebenzoimidazole 13a, 2-guanidinylbenzoxazole 13b, and 2-guanidinylbenzothiazol 13c. These reactions were triggered by 6-amino caproic acid, thioacetamide, thiourea, o-aminophenol, o-aminothiophenol, and anthranilic acid, respectively. Compound 2 had the least antimicrobial activity, while compound 13c demonstrated the most antibacterial impact against all bacterial strains. Furthermore, in terms of antiglycation efficacy (AGEs), 12, 11, and 7 were the most effective AGE cross-linking inhibitors. Eight and ten, which showed a considerable inhibition on cross-linking AGEs, come next. Compounds 4 and 6 on the other hand have shown the least suppression of AGE production. The most promising antiglycation scaffolds 8, 11, and 12 in the Human serum albumin (HAS) active site were shown to be able to adopt crucial binding interactions with important amino acids based on the results of in silico molecular docking. The most promising antiglycation compounds 8, 11, and 12 were also shown to have better hydrophilicity, acceptable lipophilicity, gastrointestinal tract absorption (GIT), and blood-brain barrier penetration qualities when their physicochemical properties were examined using the egg-boiled method.

Allopurinol versus Febuxostat: A New Approach for the Management of Hepatic Steatosis in Metabolic Dysfunction-Associated Steatotic Liver Disease.

Metabolic dysfunction-associated steatotic liver disease (MASLD) includes patients with hepatic steatosis and at least one of five cardiometabolic risk factors. Xanthine oxidase (XO) represents a treatment target for MASLD. We aimed to evaluate the effect of two xanthine oxidase inhibitors, allopurinol and febuxostat, plus lifestyle modifications compared to lifestyle modifications alone on improving steatosis. Ninety MASLD patients were assigned to one of three groups for three months. Patients with hyperuricemia were given either allopurinol 100 mg or febuxostat 40 mg daily, along with lifestyle modifications. The third control group was only given lifestyle modifications, excluding all patients with hyperuricemia due to ethical concerns. The primary outcome was to measure the change in the controlled attenuation parameter (CAP) score as an indicator of steatosis from baseline after three months. The secondary outcome was to measure the change in serum uric acid (SUA) three months from baseline. The study found that the CAP score decreased significantly in the allopurinol group (p = 0.009), but the decline in the febuxostat or lifestyle groups was non-significant (p = 0.189 and 0.054, respectively). The SUA levels were significantly reduced in both the allopurinol and febuxostat groups (p < 0.001), with no statistical difference between the two groups (p = 0.496).

Evaluation of miRNA-7, miRNA-10 and miRNA-21 as diagnostic non-invasive biomarkers of hepatocellular carcinoma.

Aim of the study: Liver cancer (hepatocellular carcinoma - HCC) remains a serious health challenge; it is the fourth leading cause of death worldwide. Egypt ranks fifteenth worldwide and the third in Africa in terms of HCC burden. The present study aimed to assess some microRNAs (miRNAs) including miRNA-7, miRNA-10, and miRNA-21, serum markers such as cluster of differentiation-14 (CD-14) and transforming growth factor b1 (TGF-b1), and other biochemical parameters as non-invasive tools for HCC diagnosis. Material and methods: The study included 100 participants divided into five groups: group I (20 normal subjects as a healthy group), group II (20 participants with chronic HCV infection but non-cirrhotic), group III (20 volunteers with chronic HCV infection and compensated cirrhosis), group IV (20 patients with chronic HCV infection and decompensated cirrhosis), and group V (20 participants with HCC). Levels of miR-7, miR-10, and miR-21 were evaluated using qRT-PCR. Serum ALT, AST, total bilirubin, total protein, albumin, PT, INR, and platelet count were determined. FIB-4 and APRI test levels were also calculated. CD-14 and TGF-ß1 serum levels were estimated using enzyme-linked immunosorbent assay (ELISA) kits. Results: The expression levels of miR-21 followed by miR-10 showed high sensitivity and specificity in predicting HCC. Serum CD-14 and TGF-b1 levels were significantly increased in all patient groups. Conclusions: From the study, it is concluded that the expression level of miR-21 has the highest sensitivity and specificity, followed by miR-10, which has high sensitivity and low specificity as non-invasive markers for HCC detection, while miR-7 exhibits high sensitivity and reasonable specificity in fibrosis detection.

Comparison of SARS-Cov-2 omicron variant with the previously identified SARS-Cov-2 variants in Egypt, 2020-2022: insight into SARS-Cov-2 genome evolution and its impact on epidemiology, clinical picture, disease severity, and mortality.

BACKGROUND: The o severe acute respiratory coronavirus 2 (SARS-CoV-2) pandemic has killed millions of people and caused widespread concern around the world. Multiple genetic variants of SARS-CoV-2 have been identified as the pandemic continues. Concerns have been raised about high transmissibility and lower vaccine efficacy against omicron. There is an urgent need to better describe how omicron will impact clinical presentation and vaccine efficacy. This study aims at comparing the epidemiologic, clinical, and genomic characteristics of the omicron variant prevalent during the fifth wave with those of other VOCs between May 2020 and April 2022. METHODS: Epidemiological data were obtained from the National Electronic Diseases Surveillance System. Secondary data analysis was performed on all confirmed COVID-19 patients. Descriptive data analysis was performed for demographics and patient outcome and the incidence of COVID-19 was calculated as the proportion of SARS-CoV-2 confirmed patients out of the total population of Egypt. Incidence and characteristics of the omicron cohort from January- April 2022, were compared to those confirmed from May 2020-December 2021. We performed the whole-genome sequencing of SARS-CoV-2 on 1590 specimens using Illumina sequencing to describe the circulation of the virus lineages in Egypt. RESULTS: A total of 502,629 patients enrolled, including 60,665 (12.1%) reported in the fifth wave. The incidence rate of omicron was significantly lower than the mean of incidences in the previous subperiod (60.1 vs. 86.3/100,000 population, p < 0.001). Symptoms were reported less often in the omicron cohort than in patients with other variants, with omicron having a lower hospitalization rate and overall case fatality rate as well. The omicron cohort tended to stay fewer days at the hospital than did those with other variants. We analyzed sequences of 2433 (1590 in this study and 843 were obtained from GISAID platform) Egyptian SARS-CoV-2 full genomes. The first wave that occurred before the emergence of global variants of concern belonged to the B.1 clade. The second and third waves were associated with C.36. Waves 4 and 5 included B.1.617.2 and BA.1 clades, respectively. CONCLUSIONS: The study indicated that Omicron-infected patients had milder symptoms and were less likely to be hospitalized; however, patients hospitalized with omicron had a more severe course and higher fatality rates than those hospitalized with other variants. Our findings demonstrate the importance of combining epidemiological data and genomic analysis to generate actionable information for public health decision-making.

Epidemiological characterization of viral etiological agents of the central nervous system infections among hospitalized patients in Egypt between 2016 and 2019.

Viral infections of the central nervous system (CNS) are common worldwide and result in considerable morbidity and mortality associated with neurologic illness. Until now, there have been no epidemiologic data regarding viruses causing aseptic meningitis, encephalitis, and CNS infections in Egypt. We investigated 1735 archived cerebrospinal fluid samples collected from Egyptian patients between 2016 and 2019 and performed molecular characterization for infection for12 different viruses: herpes simplex viruses 1 and 2 (HSV-1 and HSV-2), varicella-zoster virus (VZV), Epstein-Barr virus (EBV), cytomegalovirus (CMV), human herpesviruses 6 and 7 (HHV-6 and HHV-7), human enteroviruses (HEVs), human parechovirus (HPeV), parvovirus B19 (B19V), adenovirus (AdV), and mumps virus (MuV). All included samples were negative for bacterial infection. Our results indicated a relatively high prevalence of viral infection, with HEVs being the most prevalent viruses, followed by HSV-1, EBV, and then HSV-2. The highest prevalence was among male patients, peaking during the summer. Data obtained from this study will contribute to improving the clinical management of viral infections of the CNS in Egypt.

Whole-Genome Sequence of a Human Monkeypox Virus Strain Detected in Egypt.

Monkeypox virus has recently been detected in multiple countries. Two cases of monkeypox virus were reported in Egypt as part of an ongoing international outbreak. We report the whole-genome sequence of a monkeypox virus that was retrieved from the first confirmed case in Egypt. The virus was fully sequenced on the Illumina platform, and phylogenetic analysis demonstrated that the current monkeypox strain is closely related to clade IIb, which caused recent multicountry outbreaks.

A randomized-controlled trial of SOF/VEL/VOX with or without ribavirin for retreatment of chronic hepatitis C.

BACKGROUND & AIMS: The combination of sofosbuvir, velpatasvir and voxilaprevir (SOF/VEL/VOX) is recommended for the retreatment of patients with HCV infection in whom previous direct-acting antiviral (DAA) treatment failed. However, whether ribavirin further increases the therapeutic efficacy of SOF/VEL/VOX retreatment remains unclear. We aimed to test this hypothesis in a randomized-controlled trial. METHODS: We randomly assigned 315 patients with DAA treatment failure from five Egyptian sites into two groups. Group A (n = 158) received SOF/VEL/VOX for 12 weeks, and group B (n = 157) received SOF/VEL/VOX + weight-based ribavirin for 12 weeks. Therapeutic efficacy was defined as SVR12 (sustained virologic response 12 weeks after treatment end). Safety and tolerability were evaluated by monitoring treatment-related adverse events (AEs) and laboratory abnormalities. RESULTS: Males comprised 53.9% of group A and 57.1% of group B (p = 0.58); mean ages were 51.8 and 47.3 years in group A and B, respectively. Seventeen patients in each group were lost to follow-up. SVR12 rates were 87.3% (138/158) by intention-to-treat analysis and 97.8% (138/141) by per-protocol analysis in group A; and 87.9% (138/157) and 98.5% (138/140), respectively, in group B (p = n.s. for intention-to-treat and per-protocol analyses). Both regimens were well-tolerated, with no deaths and only one serious AE (anemia) in group B, which required ribavirin discontinuation. Fifty-five patients in group A vs. 77 in group B experienced any AE (p = 0.002). CONCLUSION: This randomized-controlled trial showed equal, high efficacy of both regimens for the retreatment of previous DAA failures, although ribavirin was associated with more AEs. Therefore SOF/VEL/VOX monotherapy should be the preferred retreatment strategy. CLINCIALTRIALS. GOV NUMBER: NCT04695769. IMPACT AND IMPLICATIONS: HCV treatment guidelines recommend retreatment of direct-acting antiviral (DAA) treatment failures with the combination of sofosbuvir, velpatasvir and voxilaprevir (SOF/VEL/VOX) for 12 weeks. However, whether ribavirin exerts an additional/synergistic effect remains unclear. The present study confirmed that SOF/VEL/VOX without ribavirin is the best regimen for retreatment of DAA treatment failures, and thus will help guide clinicians caring for patients who are not cured with a first course of DAA therapy.

Prognostic and survival impact of BCL9 and RPS6KB1 copy number variation detected from circulating free DNA in hepatocellular carcinoma.

BACKGROUND: Circulating cell-free DNA (cfDNA) is a noninvasive substitute to liver biopsy for hepatocellular carcinoma (HCC) molecular profiling. This study aimed to use cfDNA to investigate copy number variation (CNV) in the BCL9 and RPS6KB1 genes and its impact on prognosis in HCC. METHODS: Real-Time Polymerase Chain Reaction was used to determine the CNV and cfDNA integrity index in 100 HCC patients. RESULTS: CNV gain in BCL9 and RPS6KB1 genes was detected in 14% and 24% of patients, respectively. Gain in CNV of BCL9 associated with risk of HCC in alcohol drinkers and hepatitis C seropositivity. In patients with RPS6KB1 gain, HCC risk increased with a high body mass index, smoking, schistosomiasis, and Barcelona clinical liver cancer stage (BCLC) A. Gain in both genes showed a high risk of HCC with elevated liver enzymes, Schistosomiasis, BCLC C, and PS > 1. The integrity of cfDNA was higher in patients with CNV gain in RPS6KB1 than those harboring CNV gain in BCL9. Lastly, BCL9 gain and BCL9 + RPS6KB1 gain led to higher mortality rates and reduced survival times. CONCLUSION: cfDNA was used to detect BCL9 and RPS6KB1 CNVs, which influence prognosis and can be used as independent predictors of HCC patient survival.

Efficacy and safety of ombitasvir/paritaprevir/ritonavir-based therapy in HCV patients with chronic kidney disease.

BACKGROUND AND STUDY AIMS: Hepatitis C virus (HCV) prevalence inchronic kidney disease (CKD) patients is significantly higher than in the general population. This study evaluated the efficacy and safety of combined ombitasvir/paritaprevir/ritonavir-based therapy in HCV patients with renal impairment. PATIENTS AND METHODS: Our study included 829 patients with normal kidney functions (group 1) and 829 patients with CKD (group 2),which were subdivided into patients not requiring dialysis (group 2a) and those on hemodialysis (group2b). Patients received regimens of ombitasvir/paritaprevir/ritonavir with or without ribavirin or sofosbuvir/ombitasvir/paritaprevir/ritonavir with or without ribavirin for 12 weeks. Clinical and laboratory assessment was done before treatment, and patients were followed up for12 weeks after treatment. RESULTS: The sustained virological response (SVR) at week 12 was significantly higher in group 1 than in the other three groups/subgroups, being 94.2% vs 90.2%, 90%, and 90.7%, respectively. The regimen with the highest SVR was ombitasvir/paritaprevir/ritonavir with ribavirin. The most common adverse event was anemia, which was more common in group 2. CONCLUSION: Ombitasvir/paritaprevir/ritonavir-based therapy in chronic HCV patients with CKD is highly effective, with minimal side effects despite ribavirin-induced anemia.

Evaluation of GALAD Score in Diagnosis and Follow-up of Hepatocellular Carcinoma after Local Ablative Therapy.

Background and Aims: Strategies for detection of early hepatocellular carcinoma (HCC) are still limited. The GALAD score is a serum biomarker-based model designed to predict the probability of having HCC. We aimed to assess the ability of GALAD score to diagnose early HCC and its validity to follow patients after local ablation therapy. Methods: This multicenter prospective study included 108 patients in two groups, 58 HCC patients (67 focal lesions) with local ablative therapy (study group), and a control group of 50 patients with liver cirrhosis. The GALAD scores of the study and control groups, and of the HCC patients before and after ablative therapy were compared. Results: Most patients were men (74.1% in study group and 76% in controls) with hepatitis C virus infection (98.30% in the study group, and 94% in controls). GALAD scores were significantly higher in HCC patients than in those with benign cirrhosis (2.65 vs. -0.37, p=0.001). Ablative therapy was successful in 94.4% of focal lesions <2 cm, and in 86.10% of 2-5 cm lesions. The GALAD score was also significantly lower at 1 month after ablation in patients with well-ablated tumors (2.19 vs. 0.98, p=0.001). The best cutoff values of GALAD score for diagnosis of early HCC, and for prediction of well ablation of HCC were 0.74 and ≤3.31 (areas under the curve of 0.92 and 0.75, sensitivities of 84.48% and 76.19%, specificities of 89.13% and 83.33%, positive predictive values of 90.74% and 94.1%, and negative predictive values of 82% and 35.7% respectively). Conclusion: The GALAD score was effective for the diagnosis of early HCC and for follow-up after ablative therapy.

Evaluation of factors affecting patients' refusal of HCV treatment in a cohort of Egyptian patients.

BACKGROUND: Treatment refusal, defined as active refusal of a patient to receive treatment despite physician recommendations, has not been extensively evaluated before in hepatitis C virus in the era of direct acting antivirals. OBJECTIVE: To investigate the reasons for refusal to receive hepatitis C virus treatment in Egypt. METHODS: an observational study conducted between July 2018 and November 2019 in Egypt. Enrollment was done to all patients who refused to get hepatitis C virus treatment during the national screening and treatment campaign. Reasons for their refusal were identified using a questionnaire as an instrument for data collection. RESULTS: Out of the 220 280 Egyptian hepatitis C virus patients who did not show up to start treatment and were contacted to get therapy, only 84 patients (0.038%) refused to receive treatment. The main reason for their refusal was having concerns about treatment (82.14%) and their main concern was the fear of adverse events (85.5%). Other causes of refusal were non-satisfactory experience at treatment centers (13.09%) and patients preferred to receive complementary and alternative medicines (4.7%). Most patients (65.4%) trusted the efficacy of directly acting antivirals for hepatitis C. None of the study participants was found to suffer from any psychiatric morbidity and the average score of the GHQ-12 was 10.7155. CONCLUSION: Proper health education and awareness regarding hepatitis C virus treatment safety and efficacy is needed to increase treatment acceptance rates.

Anxiety, depression and coping strategies among chronic medical patients with coronavirus disease-2019: a multicenter follow-up cohort study.

BACKGROUND: Studies have shown that COVID-19 patients experience high levels of anxiety, depression, and stress during the pandemic. Patients adopt different coping strategies to reduce their psychological distress. AIM: To compare the immediate and long-term psychological impact of COVID-19 disease on patients with and without chronic medical illnesses (CMI) and identify coping styles of both groups during the peak of COVID-19 disease in Egypt. METHODS: This is a cohort follow-up study, that included an online survey consisting of General Health Questionnaire-12, Taylor Manifest Anxiety Scale, Beck Depression Inventory and Brief-COPE scale. The Post-Traumatic Stress Disorder (PTSD) Checklist was completed after 6 months. Questionnaires were distributed to adult patients with a confirmed diagnosis of SARS-CoV-2 virus infection during their quarantine in Egypt. RESULTS: There was no significant difference between the two groups regarding anxiety and depression during the acute infection. Patients without CMI relied significantly on the use of informational support to cope with COVID-19 disease. Patients with CMI continued to show significant depressive symptoms after 6 months without significant PTSD symptoms. CONCLUSIONS: COVID-19 has similar immediate psychological impact on patients with and without CMI. However, patients with CMI continue to show depression on long-term follow-up.

Medical Masks Versus N95 Respirators for Preventing COVID-19 Among Health Care Workers : A Randomized Trial.

BACKGROUND: It is uncertain if medical masks offer similar protection against COVID-19 compared with N95 respirators. OBJECTIVE: To determine whether medical masks are noninferior to N95 respirators to prevent COVID-19 in health care workers providing routine care. DESIGN: Multicenter, randomized, noninferiority trial. (ClinicalTrials.gov: NCT04296643). SETTING: 29 health care facilities in Canada, Israel, Pakistan, and Egypt from 4 May 2020 to 29 March 2022. PARTICIPANTS: 1009 health care workers who provided direct care to patients with suspected or confirmed COVID-19. INTERVENTION: Use of medical masks versus fit-tested N95 respirators for 10 weeks, plus universal masking, which was the policy implemented at each site. MEASUREMENTS: The primary outcome was confirmed COVID-19 on reverse transcriptase polymerase chain reaction (RT-PCR) test. RESULTS: In the intention-to-treat analysis, RT-PCR-confirmed COVID-19 occurred in 52 of 497 (10.46%) participants in the medical mask group versus 47 of 507 (9.27%) in the N95 respirator group (hazard ratio [HR], 1.14 [95% CI, 0.77 to 1.69]). An unplanned subgroup analysis by country found that in the medical mask group versus the N95 respirator group RT-PCR-confirmed COVID-19 occurred in 8 of 131 (6.11%) versus 3 of 135 (2.22%) in Canada (HR, 2.83 [CI, 0.75 to 10.72]), 6 of 17 (35.29%) versus 4 of 17 (23.53%) in Israel (HR, 1.54 [CI, 0.43 to 5.49]), 3 of 92 (3.26%) versus 2 of 94 (2.13%) in Pakistan (HR, 1.50 [CI, 0.25 to 8.98]), and 35 of 257 (13.62%) versus 38 of 261 (14.56%) in Egypt (HR, 0.95 [CI, 0.60 to 1.50]). There were 47 (10.8%) adverse events related to the intervention reported in the medical mask group and 59 (13.6%) in the N95 respirator group. LIMITATION: Potential acquisition of SARS-CoV-2 through household and community exposure, heterogeneity between countries, uncertainty in the estimates of effect, differences in self-reported adherence, differences in baseline antibodies, and between-country differences in circulating variants and vaccination. CONCLUSION: Among health care workers who provided routine care to patients with COVID-19, the overall estimates rule out a doubling in hazard of RT-PCR-confirmed COVID-19 for medical masks when compared with HRs of RT-PCR-confirmed COVID-19 for N95 respirators. The subgroup results varied by country, and the overall estimates may not be applicable to individual countries because of treatment effect heterogeneity. PRIMARY FUNDING SOURCE: Canadian Institutes of Health Research, World Health Organization, and Juravinski Research Institute.

Seroprevalence of HBV/HCV coinfection among patients with HCV screened during the national campaign for HCV eradication in Egypt.

BACKGROUND AND STUDY AIMS: Little is known about the true prevalence of hepatitis B virus (HBV) coinfection in patients with hepatitis C virus (HCV). This multicenter nationwide study aimed to assess the seroprevalence of HBV among Egyptian patients with HCV and its possible risk factors. PATIENTS AND METHODS: This is a cross-sectional, multicenter, nationwide study. Data were extracted from the National Network of Viral Hepatitis Treatment Centers database. Baseline data of patients proved to be viremic during the national campaign for HCV eradication (October 2018-April 2019) were retrieved. Data included demographics, laboratory tests (HBsAg, CBC, liver biochemical profile, creatinine, AFP, HbA1c, and viral load), FIB-4 score calculation, and abdominal ultrasound results. RESULTS: Results of 297,965 patients showed that HBsAg was positive in 2,347 (0.8%) patients. Patients with HBV/HCV were 57% females and had a mean age of 51 ± 13 years. Patients with positive HBsAg showed significantly more tobacco consumption, intravenous drug abuse, hypertension, and diabetes. No significant difference was noted in HCV viremia between patients with HCV and those with HBV/HCV. Only 14% of patients with HBV/HCV had cirrhosis compared with the 9% of those with HCV; two of them had HCC. CONCLUSION: Although Egypt has a heavy HCV burden, the overall prevalence of HBV is low among patients with HCV infection. Comorbid conditions seem to favor coinfection.

Colchicine and aspirin in community patients with COVID-19 (ACT): an open-label, factorial, randomised, controlled trial.

BACKGROUND: The large number of patients worldwide infected with the SARS-CoV-2 virus has overwhelmed health-care systems globally. The Anti-Coronavirus Therapies (ACT) outpatient trial aimed to evaluate anti-inflammatory therapy with colchicine and antithrombotic therapy with aspirin for prevention of disease progression in community patients with COVID-19. METHODS: The ACT outpatient, open-label, 2 × 2 factorial, randomised, controlled trial, was done at 48 clinical sites in 11 countries. Patients in the community aged 30 years and older with symptomatic, laboratory confirmed COVID-19 who were within 7 days of diagnosis and at high risk of disease progression were randomly assigned (1:1) to receive colchicine 0·6 mg twice daily for 3 days and then 0·6 mg once daily for 25 days versus usual care, and in a second (1:1) randomisation to receive aspirin 100 mg once daily for 28 days versus usual care. Investigators and patients were not masked to treatment allocation. The primary outcome was assessed at 45 days in the intention-to-treat population; for the colchicine randomisation it was hospitalisation or death, and for the aspirin randomisation it was major thrombosis, hospitalisation, or death. The ACT outpatient trial is registered at ClinicalTrials.gov, NCT04324463 and is ongoing. FINDINGS: Between Aug 27, 2020, and Feb 10, 2022, 3917 patients were randomly assigned to colchicine or control and to aspirin or control; after excluding 36 patients due to administrative reasons 3881 individuals were included in the analysis (n=1939 colchicine vs n=1942 control; n=1945 aspirin vs 1936 control). Follow-up was more than 99% complete. Overall event rates were 5 (0·1%) of 3881 for major thrombosis, 123 (3·2%) of 3881 for hospitalisation, and 23 (0·6%) of 3881 for death; 66 (3·4%) of 1939 patients allocated to colchicine and 65 (3·3%) of 1942 patients allocated to control experienced hospitalisation or death (hazard ratio [HR] 1·02, 95% CI 0·72-1·43, p=0·93); and 59 (3·0%) of 1945 of patients allocated to aspirin and 73 (3·8%) of 1936 patients allocated to control experienced major thrombosis, hospitalisation, or death (HR 0·80, 95% CI 0·57-1·13, p=0·21). Results for the primary outcome were consistent in all prespecified subgroups, including according to baseline vaccination status, timing of randomisation in relation to onset of symptoms (post-hoc analysis), and timing of enrolment according to the phase of the pandemic (post-hoc analysis). There were more serious adverse events with colchicine than with control (34 patients [1·8%] of 1939 vs 27 [1·4%] of 1942) but none in either group that led to discontinuation of study interventions. There was no increase in serious adverse events with aspirin versus control (31 [1·6%] vs 31 [1·6%]) and none that led to discontinuation of study interventions. INTERPRETATION: The results provide no support for the use of colchicine or aspirin to prevent disease progression or death in outpatients with COVID-19. FUNDING: Canadian Institutes for Health Research, Bayer, Population Health Research Institute, Hamilton Health Sciences Research Institute, and Thistledown Foundation. TRANSLATIONS: For the Portuguese, Russian and Spanish translations of the abstract see Supplementary Materials section.

Colchicine and the combination of rivaroxaban and aspirin in patients hospitalised with COVID-19 (ACT): an open-label, factorial, randomised, controlled trial.

BACKGROUND: COVID-19 disease is accompanied by a dysregulated immune response and hypercoagulability. The Anti-Coronavirus Therapies (ACT) inpatient trial aimed to evaluate anti-inflammatory therapy with colchicine and antithrombotic therapy with the combination of rivaroxaban and aspirin for prevention of disease progression in patients hospitalised with COVID-19. METHODS: The ACT inpatient, open-label, 2 × 2 factorial, randomised, controlled trial was done at 62 clinical centres in 11 countries. Patients aged at least 18 years with symptomatic, laboratory confirmed COVID-19 who were within 72 h of hospitalisation or worsening clinically if already hospitalised were randomly assigned (1:1) to receive colchicine 1·2 mg followed by 0·6 mg 2 h later and then 0·6 mg twice daily for 28 days versus usual care; and in a second (1:1) randomisation, to the combination of rivaroxaban 2·5 mg twice daily plus aspirin 100 mg once daily for 28 days versus usual care. Investigators and patients were not masked to treatment allocation. The primary outcome, assessed at 45 days in the intention-to-treat population, for the colchicine randomisation was the composite of the need for high-flow oxygen, mechanical ventilation, or death; and for the rivaroxaban plus aspirin randomisation was the composite of major thrombosis (myocardial infarction, stroke, acute limb ischaemia, or pulmonary embolism), the need for high-flow oxygen, mechanical ventilation, or death. The trial is registered at www. CLINICALTRIALS: gov, NCT04324463 and is ongoing. FINDINGS: Between Oct 2, 2020, and Feb 10, 2022, at 62 sites in 11 countries, 2749 patients were randomly assigned to colchicine or control and the combination of rivaroxaban and aspirin or to the control. 2611 patients were included in the analysis of colchicine (n=1304) versus control (n=1307); 2119 patients were included in the analysis of rivaroxaban and aspirin (n=1063) versus control (n=1056). Follow-up was more than 98% complete. Overall, 368 (28·2%) of 1304 patients allocated to colchicine and 356 (27·2%) of 1307 allocated to control had a primary outcome (hazard ratio [HR] 1·04, 95% CI 0·90-1·21, p=0·58); and 281 (26·4%) of 1063 patients allocated to the combination of rivaroxaban and aspirin and 300 (28·4%) of 1056 allocated to control had a primary outcome (HR 0·92, 95% CI 0·78-1·09, p=0·32). Results were consistent in subgroups defined by vaccination status, disease severity at baseline, and timing of randomisation in relation to onset of symptoms. There was no increase in the number of patients who had at least one serious adverse event for colchicine versus control groups (87 [6·7%] of 1304 vs 90 [6·9%] of 1307) or with rivaroxaban and aspirin versus control groups (85 [8·0%] vs 91 [8·6%]). Among patients assigned to colchicine, 8 (0·61%) had adverse events that led to discontinuation of study drug, mostly gastrointestinal in nature. 17 (1·6%) patients assigned to the combination of rivaroxaban and aspirin had bleeding compared with seven (0·66%) of those allocated to control (p=0·042); the number of serious bleeding events was two (0·19%) versus six (0·57%), respectively (p=0·18). No patients assigned to rivaroxaban and aspirin had serious adverse events that led to discontinuation of study drug. INTERPRETATION: Among patients hospitalised with COVID-19, neither colchicine nor the combination of rivaroxaban and aspirin prevent disease progression or death. FUNDING: Canadian Institutes for Health Research, Bayer, Population Health Research Institute, Hamilton Health Sciences Research Institute, Thistledown Foundation. TRANSLATIONS: For the Portuguese, Russian and Spanish translations of the abstract see Supplementary Materials section.