Molecular docking analysis of peptide-based antiviral agents against SARS-CoV-2 main protease: an approach towards drug repurposing

Aim: Utilizing the therapeutic potentials of previously approved medications against a new target or pharmacological response is known as drug repurposing. The health and scientific communities are under continual pressure to discover new compounds with antiviral potential due to the rising reports of viral resistance and the occurrence and re-emergence of viral outbreaks. The use of antiviral peptides has emerged as an intriguing option in this search. Here, this article includes the current United States Food and Drug Administration (FDA)-approved antiviral peptides that might be enforced for the treatment of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and carried out docking study of the viral protease inhibitors. Methods: In silico techniques like molecular docking was carried out using Autodock Vina software. Results: The molecular docking studies of peptide-based antiviral agents against SARS-CoV-2 [Protein Data Bank (PDB) ID: 7P35] using docking software AutoDockTools 1.5.6. Among all the docked ligands, compound velpatasvir showed interaction with residues ILE213, GLN256, LEU141, GLN189, GLU166, HIS41, CYS145, and ASN142, and displayed the highest docking score of –8.2 kcal/mol. This medication could be a novel treatment lead or candidate for treating SARS-CoV-2. Conclusions: To conclude, a docking study of peptide based antiviral compounds for their binding mode in the catalytic domain of SARS-CoV-2 receptor is reported. On molecular docking, the compounds have showed remarkable binding affinity with the amino acids of receptor chain A. The compounds occupied the same binding cavity as the reference compound maintaining the interactions with conserved amino acid residues essential for significant inhibitory potential, especially for compound velpatasvir with binding score of –8.2 kcal/mol. The Author(s) 2023.

Liver and COVID-19 - A Review and Clinical Approach

Liver enzyme abnormalities occur frequently in patients diagnosed with Coronavirus disease 2019 (COVID-19). It has been suggested that patients with severe acute liver injury are more likely to be admitted to intensive care, require intubation or renal replacement therapy and their mortality rate is higher than patients without severe acute liver injury. This review article explores the possible aetiologies of liver dysfunction seen in patients with COVID-19 and also the effect of COVID-19 on patients with pre-existing liver disease. Finally, we suggest clinical approaches to treating a patient with liver enzyme disturbance and COVID-19 and also caring for patients who require liver transplantation in the COVID-19 era.Copyright © 2022 Bentham Science Publishers.

Drug repurposing against SARS-CoV-2: A review based on principal reports

Despite the measures taken and the molecular advances for the development of new agents for the control of SARS-CoV-2 infection, there is still insufficient development of an effective treatment. The objective of the review was to de-scribe the clinical studies and reported articles on drugs used as possible therapeutic agents for COVID-19 and the main conclusions on their reuse. A non-systematic review through PubMed, ScienceDirect, and clinical trials at ClinicalTrials. gov on original articles and case report in English and Span-ish that will report information on COVID-19 treatment and its main conclusions. Articles that were not relevant or that did not mention updated information to that reported in other articles were excluded. A total of 99 bibliographic references were included. COVID-19 appears as a multisystemic disease with variable clinical symptoms. Since no specific treatment is yet known, multiple drugs have been proposed that attack the different pathways of SARS-CoV-2. For severe disease in patients who require hospitalization and oxygen support, the use of remdesivir, dexamethasone, or tocilizumab is recommended if there are patient conditions that apply to use them. The use of ivermectin, colchicine, lopinavir/ritonavir, hydroxy-chloroquine, and chloroquine have not reported benefits that surpass adverse effects.

Treating Children with Hcv Close to Home through a Virtual National Multidisciplinary Network

Background and Aims Hepatitis C virus (HCV) infection is a major global health problem in adults & children. The recent efficacy of Direct Acting Anti-viral therapy (DAA) has cure rates of 99% in adults and adolescents. These drugs were licensed for children 3-12 yrs during the recent coronavirus pandemic. To ensure equitable access, safe & convenient supply during lockdown, we established a virtual national treatment pathway for children with HCV in England & evaluated its feasibility, efficacy & treatment outcomes. Method A paediatric Multidisciplinary Team Operational Delivery Network (pMDT ODN), supported by NHS England (NHSE), was established with relevant paediatric specialists to provide a single point of contact for referrals & information. Referral & treatment protocols were agreed for HCV therapy approved by MHRA & EMA. On referral the pMDT ODN agreed the most appropriate DAA therapy based on clinical presentation & patient preferences, including ability to swallow tablets. Treatment was prescribed in association with the local paediatrician & pharmacist, without the need for children & families to travel to national centres. All children were eligible for NHS funded therapy;referral centres were approved by the pMDT ODN to dispense medication;funding was reimbursed via a national NHSE agreement. Demographic & clinical data, treatment outcomes & SVR 12 were collected. Feedback on feasibility & satisfaction on the pathway was sought from referrers. Results In the first 6 months, 34 children were referred;30- England;4 - Wales;median (range) age 10 (3.9 - 14.5) yrs;15M;19F: Most were genotype type 1 (17) & 3 (12);2 (1);4(4). Co-morbidities included: obesity (2);cardiac anomaly (1);Cystic Fibrosis (1);Juvenile Arthritis (1). No child had cirrhosis. DAA therapy prescribed: Harvoni (21);Epclusa (11);Maviret (2) .27/34 could swallow tablets;3/7 received training to swallow tablets;4/7 are awaiting release of granules.11/27 have completed treatment and cleared virus;of these 7/11 to date achieved SVR 12. 30 children requiring DAA granule formulation are awaiting referral and treatment. Referrers found the virtual process easy to access, valuing opportunity to discuss their patient's therapy with the MDT & many found it educational. There were difficulties in providing the medication through the local pharmacy. However there are manufacturing delays in providing granule formulations because suppliers focused on treatments for COVID, leading to delays in referring and treating children unable to swallow tablets. Conclusion The National HCV pMDT ODN delivers high quality treatment & equity of access for children & young people, 3- 18 yrs with HCV in England, ensuring they receive care close to home with 100% cure rates.

Viral reactivation after hcv-positive renal allograft transplantation

Case Report: A 48y/o man with a history of ESRD secondary to FSGS was found to have hepatitis-C virus (HCV) reactivation after kidney transplantation (KT) with an HCV-positive allograft. The patient was HCV-negative before transplantation in July 2021. He was negative for hepatitis-B virus (HBV) core antibodies but had evidence of prior HBV vaccination and was negative for HIV 1/2. His induction therapy included thymoglobulin, and his maintenance immunosuppressive regimen included mycophenolate mofetil (MMF), tacrolimus, and prednisone. Aweek after KT, the patient tested positive for HCV genotype 1a, and he was started on sofosbuvir/velpatasvir in August 2021. Lab monitoring showed decreasing levels of HCV viral load (VL) until it was undetectable 2 months later. In January 2022, renal function remained stable, and urinalysis and hepatic function tests remained unremarkable. However, HCV viral load was positive in February 2022 and the HCV genotypewas 1a, as before. This result raised the possibility of reactivation of HCV from his allograft more than 6 months post KT. Additionally, despite negative BK polyoma VL initially, he was positive in January 2022 and discontinued his MMF. He was also positive for COVID-19 in January 2022 as well. Given his recurrence of HCV VL, he initiated sofosbuvir/velpatasvir/ voxilaprevir in April 2022 and completed therapy in July 2022, and maintained sustained viral response (SVR) as of October 2022. His BK VL was negative in May 2022. Recent guidelines on preventing HCV reactivation in allograft-positive KT recipients state that individuals should achieve SVR after 8-12 weeks of a course of direct-acting antiviral (DAA) therapy. The patient completed DAA therapy post-transplantation with a successful negative viral load 2 months later. However, he did not achieve SVR because his VL was again positive 3 months after completion of therapy. Reactivation of BKV, a DNA virus that establishes lifelong infection in renal tubular and uroepithelial cells, is common among KT recipients, but there is insufficient evidence to establish a causal association between BKV reactivation and HCV reactivation. There is no consensus on a chemotherapeutic maintenance regimen to prevent HCV reactivation. This case highlights the importance of close follow-up monitoring for HCV and BKV among KT recipients and the need to explore the relationship between BKV reactivation, HCV reactivation, and immunosuppression regimen. Copyright © 2023 Southern Society for Clinical Investigation.

Effectiveness and Safety of Sofosbuvir/Velpatasvir/Voxilaprevir as a Hepatitis C Virus Infection Salvage Therapy in the Real World: A Systematic Review and Meta-analysis.

INTRODUCTION: Sofosbuvir/Velpatasvir/Voxilaprevir (SOF/VEL/VOX) is the first direct-acting antiviral (DAA) therapy approved for patients who have previously failed a DAA-containing regimen including NS5A inhibitors. In clinical trials, SOF/VEL/VOX was associated with high rates of sustained virologic response at post-treatment week 12 (SVR12) and was well tolerated. However, the effectiveness and safety of SOF/VEL/VOX in the real world remained uncertain. We aimed to perform a systematic review and meta-analysis to assess the real world effectiveness and safety of SOF/VEL/VOX. METHODS: We systematically searched the PubMed, Embase, Cochrane Library, Web of Science, and ClinicalTrials.gov databases for relevant real world studies published before January 28, 2022. Patients with previous treatment failure who received SOF/VEL/VOX were included. The primary outcome was the percentage of patients achieving SVR12. Secondary outcome included adverse events (AEs) during treatment. RESULTS: Fifteen studies with a total of 1796 HCV-infected patients with previous treatment failure were included. SVR12 rates were 93% (95% CI 91-95) in the ITT populations (n = 1517, 11 cohorts) and 96% (95% CI 95-97) in the PP populations (n = 1187, 10 cohorts). SVR12 rates were significantly higher in non-GT3-infected patients (OR = 2.29, 95% CI 1.23-4.27, P = 0.009) and non-cirrhotic patients (OR = 2.22, 95% CI 1.07-4.60, P = 0.03) than in GT3-infected patients and cirrhotic patients. Furthermore, the SVR12 rates of previous treatment of SOF/VEL were significantly lower than those of other regimens in both ITT and PP populations (P ≤ 0.001). Adverse events (AEs) were reported in 30% (228/760) of patients. Serious AEs (SAEs) were reported in 3.82% (29/760) of patients. The most frequently reported AEs were headache, asthenia, nausea, fatigue, and diarrhea, which were mostly mild in severity. AE-related treatment discontinuations were reported in 0.66% (5/760) of patients. CONCLUSIONS: Consistent with clinical trials, the real world evidence indicates that SOF/VEL/VOX is a well-tolerated and highly effective salvage therapy for HCV-infected patients with previous treatment failure. However, there may still be a risk of treatment failure for patients with GT3 infection, cirrhosis, or SOF/VEL treatment failure. The protocol of this study was registered at PROSPERO, registration no. CRD 42022306828.

Reported safety of HCV direct-acting antivirals with opioids: 2017 to 2021

Background and aims: As a result of disengagement in addiction care during the COVID-19 pandemic, there has been a record increase in mortality associated with opioid overdoses (primarily fentanyl), particularly in North America. In the USA there were over 100, 000 overdose deaths in 2021, while over 2000 were recorded in the province of British Columbia. As we attempt to develop novel ways to increase HCV treatment following ≥30% declines during the pandemic, we evaluated publicly available adverse events (AEs) reports for opioids and DAAs to assess whether safety concerns from potential drug interactions arewarranted, particularly amongst those using fentanyl. Method: Data were downloaded from the US Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS) Public Dashboard. AEswith the DAAs glecaprevir/pibrentasvir (G/P), sofosbuvir/ velpatasvir (SOF/VEL), ledipasvir/sofosbuvir (LDV/SOF), sofosbuvir/ velpatasvir/voxilaprevir (SOF/VEL/VOX), andelbasvir/grazoprevir (EBR/ GZR) listed as the suspect product were analyzed with an initial received date from July 28, 2017-December 31, 2021, as were opioidassociated AEs for all 2017–2021. Subsequently, AEs were counted based on listed concomitant use of opioids (fentanyl, oxycodone, hydrocodone), or overdose outcomes irrespective of concomitant opioid use. Data are descriptivewithout any statistical analyses. Results: In the reporting period, 40 total AEs were recorded with concomitant DAA and fentanyl use, 14 resulting in death (G/p = 3, SOF/VEL = 11;Table 1);626 total AEs were recorded with concomitant DAA and oxycodone or hydrocodone use, 28 resulting in death. Separately, overdose events were reported 196 times, 32 resulting in death. The number of overdoses declined each year from 2018 (N = 56) to 2021 (N = 29). Fentanyl AEs showed no trend year to year. Table 1: FAERs AEs and deaths with opioids and with concomitant HCV DAAs. (Table Presented) *N represents the sum of fentanyl, oxycodone, and hydrocodone overdose AEs and deaths, whereas n’s for DAA overdose AEs and deaths are irrespective of concomitant opioids. Conclusion: With the limitations of FAERS data (under or duplicate reporting, inability to establish causation or incidence), these data showthat among ~58, 000 fentanyl, ~189, 000 oxycodone, and ~100, 000 hydrocodone AEs reported to FAERS since 2017, a small proportion (0.19%) have been reported in association with concomitant DAA therapy, with no association between recorded events and a specific DAA regimen. This should reassure HCV treaters on a lack of safety signal for concomitant opioid and DAA use.

Treating children with HCV close to home through a virtual national multidisciplinary network

Background and aims: Hepatitis C virus (HCV) infection is a major global health problem in adults & children. The recent efficacy of Direct Acting Anti-viral therapy (DAA) has cure rates of 99% in adults and adolescents. These drugs were licensed for children 3–12 yrs during the recent coronavirus pandemic. To ensure equitable access, safe & convenient supply during lockdown, we established a virtual national treatment pathway for children with HCV in England & evaluated its feasibility, efficacy & treatment outcomes. Method: A paediatric Multidisciplinary Team Operational Delivery Network (pMDT ODN), supported by NHS England (NHSE), was established with relevant paediatric specialists to provide a single point of contact for referrals & information. Referral & treatment protocolswere agreed for HCV therapy approved byMHRA& EMA. On referral the pMDT ODN agreed the most appropriate DAA therapy based on clinical presentation & patient preferences, including ability to swallow tablets. Treatment was prescribed in association with the local paediatrician & pharmacist, without the need for children & families to travel to national centres. All children were eligible for NHS funded therapy;referral centres were approved by the pMDT ODN to dispense medication;funding was reimbursed via a national NHSE agreement. Demographic & clinical data, treatment outcomes & SVR 12 were collected. Feedback on feasibility & satisfaction on the pathway was sought from referrers. Results: In the first 6 months, 34 childrenwere referred;30- England;4-Wales;median (range) age 10 (3.9–14.5) yrs;15M;19F: Most were genotype type 1 (17) & 3 (12);2 (1);4 (4). Co-morbidities included: obesity (2);cardiac anomaly (1);Cystic Fibrosis (1);Juvenile Arthritis (1). No child had cirrhosis. DAA therapy prescribed: Harvoni (21);Epclusa (11);Maviret (2). 27/34 could swallow tablets;3/7 received training to swallowtablets;4/7 are awaiting release of granules.11/27 have completed treatment and cleared virus;of these 7/11 to date achieved SVR 12. 30 children requiring DAA granule formulation are awaiting referral and treatment. Referrers found the virtual process easy to access, valuing opportunity to discuss their patient’s therapy with the MDT & many found it educational. There were difficulties in providing the medication through the local pharmacy. However there are manufacturing delays in providing granule formulations because suppliers focused on treatments for COVID, leading to delays in referring and treating children unable to swallow tablets. Conclusion: The National HCV pMDT ODN delivers high quality treatment & equity of access for children & young people, 3–18 yrs with HCV in England, ensuring they receive care close to home with 100% cure rates.

A model to eradicate HCV in undocumented migrants and low-income refugees in Italy

Background and aims: To validate an innovative eradication model for HCV infection in undocumented migrants and low-income refugees living Southern Italy. Method: a prospective, multicenter, collaborative study was started in June 2018 with The studywas stopped in February 2020 due to the outbreak of SARS-CoV-2 infection in Italy and was resumed in February 2021. At the six 1st level centers participating to the study volunteer associations that deal with the first needs of disadvantaged people performed the enrolment and the screening for anti-HCV, HBsAg and anti-HIV;epidemiological data were collected in an electronic database. Anti-HCV-positive subjects were sent to two 3rd level centers for the clinical, virological and therapeutic evaluation. For the HCV-RNA-positive subjects HCV genotyping and a clinical, biochemical and ultrasound staging was performed. The HCV RNApositive subjects have been treated with sofosbuvir-velpatasvir for 12 weeks and followed for 12 months from the end of therapy. Results: Of the 3, 991 migrants observed in the study period, 3, 897 (97.6%) accepted to be screened. They were young (median age 26 years), predominantly male (85.9%) and came from North Africa (3.8%), from Sub-Saharan Africa (68.4%), from Eastern Europe (8.1%), from Indo-Pakistan (17%) and from other countries (2.7%). Of the 3, 897 enrolled subjects, 185 (4.7%) resulted anti-HCV positive. The Figure shows the HCV-cure cascade. All the 185 anti-HCV-positive subjects were linked to care at 3rdID and tested for HCV RNA and 53 (28.6%) resulted HCV-RNA positive. Of these, 46 (86.8%) started DAA regimen with sofosbuvir plus velpatasvir (15 with GT 1b, 10 with 1a, 16 with 3, 3 with 4 and 2 with 2). Forty-two completed the follow-up and 4 was still pending. Of these 42 subjects, 41 (97.6%) showed a SVR12 and SVR 24, and one dropped-out in follow-up after the stop of DAA treatment. No subject had adverse event. (Figure Presented) Conclusion: This model seems to be effective to eradicate HCV infection among a difficult-to-manage population, such as undocumented migrants and low-income refugees

LESSONS FROM HEPATITIS C TREATMENT DURING THE COVID-19 PANDEMIC: DECREASED RESOURCE UTILIZATION LEADS TO SIMILAR EFFICACY IN BRITISH COLUMBIA, CANADA

Background: Early studies show that the COVID-19 pandemic has led to reduced prescription of direct-acting anti-viral (DAA) treatment for hepatitis C (HCV) infection. We sought to characterize HCV patients started on DAAs during the pandemic in British Columbia, Canada. Methods: A retrospective chart review of multiple sites was conducted using the British Columbia HCV Network. Patients initiated on DAA for HCV treatment from 09/17/2018- 09/17/2021 were included. Those treated for 18 months prior to 03/17/2020 were included as the pre-pandemic group (pre-PG) and those treated after 03/17/2020 comprised the pandemic group (PG). Results: A total of 393 patients were included, with 221 pre-PG patients and 172 PG patients, representing a 23% decline in HCV treatment during the pandemic. PG patients were significantly younger with mean age 55 years (vs 56 years pre- PG, p<0.01) and a higher proportion were on opioid agonist therapy (OAT) at 28% (vs 12% pre-PG, p<0.01). Rates of alcohol and active substance use were similar between both groups. Both groups had similar HCV genotypes, viral load, and FIB-4 scores. Pre-treatment transient elastography (TE) within 3 months of initiating treatment was completed in significantly fewer PG patients at 37% compared with 70% pre-PG (p<0.01). Of PG and pre-PG patients who completed TE, cirrhosis was found in 15 (9%) and 32 (14%) respectively, with mean liver stiffness measure of 8.69 kPa and 10.21 kPa, respectively. Beyond less utilization of TE, the pandemic also led to reduced total appointments at mean 3.1 visits per PG patient compared to 4.2 visits per pre-PG patient (<0.01). Considering the different types of appointments, PG patients had fewer office appointments at mean 1.6 per PG patient (vs 3.1 per pre-PG patient, p <0.01) but more telehealth appointments at mean 2.5 per PG patient (vs 2.1 per pre-PG patient, p <0.01). Treatment regimen was similar in both groups with predominant use of glecaprevir/pibrentasvir and sofosbuvir/velpatasvir. Treatment completion rate was 95% in PG patients compared to 89% pre-PG (p=0.03). Fewer PG patients completed lab work for sustained virologic response (SVR) at 61% (vs 88% pre-PG) however, SVR rate was similar between both groups (96% pre-PG and 99% PG, p=NS). Active drug use or OAT was not associated with treatment completion or SVR in either group. Conclusion: The COVID-19 pandemic has led to a decrease in HCV treatment rates. However, treatment completion and SVR rates remained high among those treated, suggesting minimal-pre-treatment investigations and use of telemedicine can optimize scarce resources with similar efficacy. (Figure Presented)

Prescrire's ratings of new drugs in 2021: A brief review

Three new drugs, all based on messenger RNA or small interfering RNA technology, represented a major therapeutic advance in 2021. But the bigger picture is that most of the new authorisations that advanced patient care were adaptations of existing drugs. And that more than half of this year's new authorisations were not advances, and in fact about one-tenth represented a step backwards compared to existing options.

Real-world effectiveness of sofosbuvir/velpatasvir for the treatment of hepatitis C virus in prison settings

Plain language summary Achievement of elimination of HCV as a major public health threat requires focus on vulnerable populations such as people in prison. The prison population is at high risk of HCV infection but their treatment is complicated by social issues such as mental health disorders and drug use. Simple and effective treatment regimens are required to increase access to treatment and improve cure rates. This real-world analysis across Europe and Canada analyzed data from 20 prison populations. HCV-infected individuals were treated with sofosbuvir/velpatasvir, a once daily treatment which requires minimal monitoring. This regimen achieved high cure rates in the prison population despite the existence of complicating social issues. Background: People in prison are at high risk of hepatitis C virus (HCV) infection and often have a history of injection drug use and mental health disorders. Simple test-and-treat regimens which require minimal monitoring are critical. Methods: This integrated real-world analysis evaluated the effectiveness of once daily sofosbuvir/velpatasvir (SOF/VEL) in 20 prison cohorts across Europe and Canada. The primary outcome was sustained virological response (SVR) in the effectiveness population (EP), defined as patients with a valid SVR status. Secondary outcomes were reasons for not achieving SVR, adherence and time between HCV RNA diagnosis and SOF/VEL treatment. Results: Overall, 526 people in prison were included with 98.9% SVR achieved in the EP (n = 442). Cure rates were not compromised by drug use or existence of mental health disorders. Conclusion: SOF/VEL for 12 weeks is highly successful in prison settings and enables the implementation of a simple treatment algorithm in line with guideline recommendations and test-and-treat strategies.

Clinical effectiveness and safety of sofosbuvir-velpatasvir as add-on treatment for COVID-19 patients: Study protocol and preliminary data for the randomized controlled trial

Objectives: COVID-19 is a worldwide health problem. Although the most infected patients experience a mild-to-moderate disease, some patients (especially older people) develop pulmonary distress with fatal lung failure and multi-organ damage. There is currently no known effective treatment for this disease. Sofosbuvir, an FDA-approved drug for the treatment of hepatitis C virus, is also able to inhibit other members of positive strand RNA viruses with conserved polymerase and may be helpful for the treatment of SARS-CoV-2. The goal of the current trial is to determine the usefulness of 'standard of care (SOC) plus hydroxychloroquine and lopinavir/ritonavir' vs. 'SOC plus a combination of lopinavir/ritonavir hydroxychloroquine and sofosbuvir/velpatasvir' in patients hospitalized with COVID-19. The Design of Clinical Trial: In this randomized controlled trial, patients over 18 years who have been diagnosed with COVID-19 by the positive SARS-CoV-2 reverse transcriptase-polymerase chain reaction (RT-PCR) test or compatible chest computed tomography (CT) scan were candidates for the study. Eighty patients from Kermanshah province, West of Iran were allocated to treatment with SOC plus hydroxychloroquine and lopinavir/ritonavir (dual therapy) or SOC plus a combination of hydroxychloroquine and lopinavir/ritonavir and sofosbuvir/velpatasvir (triple therapy) for 10 days. Allocation was conducted using simple randomization. The primary outcomes were reducing mortality up to 28 days after hospitalization. Adverse events were handled and reported in accordance with the Good Clinical Practice guidelines. Participants: Patients who were hospitalized with COVID-19 (with positive SARS-CoV-2 RT-PCR test and/or compatible chest CT scan) were screened for eligibility at Farabi Hospital, Kermanshah University of Medical Sciences (KUMS), Kermanshah, Iran. Intervention and Comparator: Both arms received active treatment and none was given placebo. The intervention arm received hydroxychloroquine 400 mg single dose and lopinavir-ritonavir (400 and 100 mg) twice daily plus sofosbuvir-velpatasvir (400 and 100 mg) once daily orally, plus SOC for 10 days. The comparator arm received hydroxychloroquine 400 mg single dose and lopinavir-ritonavir (400 and 100 mg) twice daily orally, plus SOC for 10 days. SOC includes oxygen therapy, non-invasive and invasive ventilation, antibiotic agents, vasopressor support, renal-replacement therapy, and corticosteroids. Primary Outcomes: The main outcomes are reducing mortality until 28 days after hospitalization. Other outcomes can be found in full protocol file. Randomization: For the purpose of allocation sequence generation, using an Excel file (random-numbers table) and simple random allocation, 80 included patients entered to the study, 40 patients in each group (1:1 ratio). In order to maintain the allocation sequence concealment, the details of treatment for each patient were contained in a sealed envelope, labeled by the numbers from 1 to 80. In fact, our study was a randomized open label clinical trial in which all the physicians and nurses plus all patients were aware of the type of treatment. Blinding: Our study was a randomized open label clinical trial in which all the physicians and nurses plus all patients were aware of the type of treatment. Numbers to be Randomized (Sample Size): Eighty included patients entered to the study, 40 patients in each group using simple random allocation. Trial Status: The finalized protocol version 1.5 was used in the trial study and the recruitment/intervention process started on April 11, 2020, finished on May 11, and the related follow-up finished on June 8, 2020. Registry of Clinical Trial: This clinical trial has been registered on March 30, 2020 under IRCT number 46790, in the Iranian Registry of Clinical Trials (https://www.irct.ir/trial/46790) and by KUMS under Grant No. 990097. Full Protocol: The full protocol and other details are attached as a Supplementary File (full protocol), accessible from the journal website. Preliminary Data: The sofosbuvir/ve patasvir regimen does not improve survival, clinical improvement, and duration of hospitalization in hospitalized COVID-19 patients.

High Rates of Hidden HCV Infections among Hospitalized Patients Aged 55-85.

BACKGROUND AND AIMS: The WHO has solicited all countries to eliminate HCV by 2030. The Italian government started routine screening for HCV infection in January 2021, initially targeting subjects born between 1969 and 1989. With the aim of achieving micro-elimination, we designed a hospital-wide project focusing on inpatients born from 1935 to 1985 and conducted it in our institution. METHOD: All inpatients aged 35 to 85, admitted from 10 February 2020 to 9 February 2021 for many different diseases and conditions underwent HCV antibody (HCVAb) testing by third-generation ELISA. When positive, reflex HCV RNA testing and genotyping were performed. Clinical history, fibrosis diagnosis, laboratory data and concomitant medications were available for all. RESULTS: The HCV screening rate of inpatients was 100%. In total, 11,748 participants were enrolled, of whom 53.50% were male. The HCVAb positivity rate was 3.03%. The HCVAb rate increased with age and was higher for patients born between 1935 and 1944 (4.81%). The rate of HCV RNA positivity was 0.97%. The vast majority (80.70%) of HCV RNA-positive participants were 55 or older; in about 40% of cases, HCV RNA-positive patients were unaware of their infection. Although 16 patients died after HCV chronic infection diagnosis (two due COVID-19) or HCV treatment prescription (one due to COVID-19), 74.56% of patient HCV diagnoses were linked to HCV treatment, despite their co-morbidities. All patients older than 65 who died had an active HCV infection. CONCLUSION: The present study revealed a rate of active HCV infections among inpatients lower than what has been reported in the past in the general population; this appears to be a result of the widespread use of pangenotypic direct-acting antiviral agents (DAAs). The overall rate of active infection was lower than the rate observed in the 1935-1954 cohort. The high rate of inpatients unaware of HCV infections and the high number of deaths among subjects with an active HCV infection born from 1935 to 1954, suggest that, at least in southern Italy, targeted screening of this birth cohort may be required to reduce the number of undiagnosed cases and hidden infections.

Is positivity for hepatitis C virus antibody predictive of lower risk of death in COVID-19 patients with cirrhosis?

Liver injury has been reported in coronavirus disease 2019 (COVID-19) cases but the impact of pre-existing liver damage and related etiology have not been completely elucidated. Our research interests include the potential reciprocal influence of COVID-19 and pre-existing liver damage related to hepatitis C virus (HCV) infection, in particular. To this end, we have evaluated three cohorts of patients admitted at three Italian hospitals during the coronavirus pandemic; these included 332 patients with COVID-19 and 1527 patients with HCV who were from established real-world antiviral treatment study cohorts (sofosbuvir/velpatasvir), with either liver disease (various severities; n = 1319) or cirrhosis (n = 208). Among the COVID-19 patients, 10 had cirrhosis (3%), including 7 of metabolic origin and 3 of viral origin. Mortality among the COVID-19 patients was 27.1%, with 70% of those with cirrhosis of metabolic etiology having died. Cirrhosis, older age, low white blood cell count and lymphocyte count being identified as risk predictors of death [odds ratio (OR) = 13.7, 95% confidence interval (CI): 2.59-83.01, P = 0.006; OR = 1.05, 95%CI: 1.03-1.08, P = 0.0001; OR = 1.09, 95%CI: 1.36-1.16, P = 0.001; OR = 0.61, 95%CI: 0.39-0.93, P = 0.023, respectively]. In the two cohorts of HCV patients, COVID-19 diagnosis was made in 0.07% of those with liver disease and 1% of those with cirrhosis. Thus, the prevalence of HCV antibodies among COVID-19-infected patients was comparable to that currently reported for the general population in Italy. Amongst the COVID-19 patients, pre-existing metabolic cirrhosis appears to be associated with higher mortality, while HCV antibodies may be suggestive of "protection" against COVID-19.

Prediction of the SARS-CoV-2 (2019-nCoV) 3C-like protease (3CL pro) structure: virtual screening reveals velpatasvir, ledipasvir, and other drug repurposing candidates.

We prepared the three-dimensional model of the SARS-CoV-2 (aka 2019-nCoV) 3C-like protease (3CL pro) using the crystal structure of the highly similar (96% identity) ortholog from the SARS-CoV. All residues involved in the catalysis, substrate binding and dimerisation are 100% conserved. Comparison of the polyprotein PP1AB sequences showed 86% identity. The 3C-like cleavage sites on the coronaviral polyproteins are highly conserved. Based on the near-identical substrate specificities and high sequence identities, we are of the opinion that some of the previous progress of specific inhibitors development for the SARS-CoV enzyme can be conferred on its SARS-CoV-2 counterpart.  With the 3CL pro molecular model, we performed virtual screening for purchasable drugs and proposed 16 candidates for consideration. Among these, the antivirals ledipasvir or velpatasvir are particularly attractive as therapeutics to combat the new coronavirus with minimal side effects, commonly fatigue and headache.  The drugs Epclusa (velpatasvir/sofosbuvir) and Harvoni (ledipasvir/sofosbuvir) could be very effective owing to their dual inhibitory actions on two viral enzymes.