Hydrogen Bonding (Base Pairing) in Antiviral Activity.

Base pairing based on hydrogen bonding has, since its inception, been crucial in the antiviral activity of arabinosyladenine, 2'-deoxyuridines (i.e., IDU, TFT, BVDU), acyclic nucleoside analogues (i.e., acyclovir) and nucleoside reverse transcriptase inhibitors (NRTIs). Base pairing based on hydrogen bonding also plays a key role in the mechanism of action of various acyclic nucleoside phosphonates (ANPs) such as adefovir, tenofovir, cidofovir and O-DAPYs, thus explaining their activity against a wide array of DNA viruses (human hepatitis B virus (HBV), human immunodeficiency (HIV) and human herpes viruses (i.e., human cytomegalovirus)). Hydrogen bonding (base pairing) also seems to be involved in the inhibitory activity of Cf1743 (and its prodrug FV-100) against varicella-zoster virus (VZV) and in the activity of sofosbuvir against hepatitis C virus and that of remdesivir against SARS-CoV-2 (COVID-19). Hydrogen bonding (base pairing) may also explain the broad-spectrum antiviral effects of ribavirin and favipiravir. This may lead to lethal mutagenesis (error catastrophe), as has been demonstrated with molnutegravir in its activity against SARS-CoV-2.

COVID-19 outcomes in kidney transplant recipients receiving a combination of sofosbuvir-daclatasvir treatment, a single-center study

Introduction: In the coronavirus disease 2019 (COVID-19) era, kidney transplantation recipients (KTRs) are at high risk due to using immunosuppressive drugs. Considering the lack of definitive cure for COVID-19, repurposing existing pharmaceuticals is a way to find an immediate medication. Objectives: This study aimed to evaluate the COVID-19 outcomes in KTRs, receiving combination of sofosbuvir and daclatasvir (SOF-DAC) treatment. Patients and Methods: This research was an observational study of 12 adult kidney transplant recipients with COVID-19, admitted to Shariati hospital, Tehran, Iran (October to December 2020). All the patients received a once-daily combination pill of SOF-DAC at a dose of 400/60 mg for 10 days. Results: Around October to December 2020, 12 adult KTR patients were recruited;four patients (33.3%) died and eight patients survived (66.7%). Acute kidney injury (AKI) secondary to COVID-19 was seen in 11 patients of the study population (91.7%), including four dead cases. Two of the three patients who underwent dialysis due to kidney complications, died. The laboratory results showed that the mean level of each parameter white blood cells (WBC), international normalized ratio (INR), C-reactive protein (CRP), ferritin, D-dimer on the last day of hospital stay was significantly different between two groups of survived and dead patients at a 95% confidence level (P < 0.05). Conclusion: Sofosbuvir combined with DAC for treatment of KTRs with COVID-19 infection reduced the mortality rate. Further, this medication was safe. Patients tolerated it well, and no serious adverse effects were observed. Larger studies are needed to validate these results.

The Concept of Repurposing in COVID-19 Infection

The strategy of drug repurposing has been proved successful in response to the current corona-virus pandemic, with remdesivir becoming the first drug of choice, an antiviral drug approved for the treatment of COVID-19. In parallel to this, several drugs, such as antimalarial, corticosteroids, and antibi-otics, like azithromycin, are used to treat the severe condition of hospitalized COVID-19 patients, while clinical testing of additional therapeutic drugs, including vaccines, is going on. It is reasonably expected that this review article will deliver optimized and specific curative tools that will increase the attentive-ness of health systems to the probable outlook of epidemics in the future. This review focuses on the ap-plication of repurposed drugs by studying their structure, pharmacokinetic study, different mechanisms of action, and Covid-19 guidelines, which can potentially influence SARS-CoV-2. For most of the drugs, direct clinical evidence regarding their effectiveness in the treatment of COVID-19 is missing. Future clinical trial studies may conclude that one of these can be more potential to inhibit the progression of COVID-19.Copyright © 2022 Bentham Science Publishers.

A Mini Review on COVID-19 Therapeutics: Current Status and Future Di-rections

Corona viruses belong to the genus Corona virus with its high mutation rate in the Coro-naviridae. In this review article, the focus is on current status of research against SARS-CoV-2, various mobile apps launched to diagnose COVID-19 infection and status of prospective therapies available against COVID-19 virus in this early stage of COVID-19 outbreak.Copyright © 2021 Bentham Science Publishers.

Rna-Dependent Rna Polymerase (Rdrp) Inhibitor Drugs against Sars-Cov-2: A Molecular Docking Study

Objective: SARS-CoV-2 associated viral pandemic was first reported in Wuhan, China, in December 2019. Due to the rapid increase in its pathogenicity, SARS-CoV-2 was declared a global pandemic by WHO on March 11, 2020. For that reason, determining the most attractive viral protein targets became a must. One of the most important target proteins is SARS-COV-2 RNA-dependent RNA polymerase (RdRp) on which COVID-19 depends in its replication process. This study aimed to examine the possible interactions between RdRp and the most promising RdRp nucleoside inhibitors especially Purine nucleoside analogs, to detect the most important residues that commonly interact with RdRp's inhibitors and to investigate whether if there any mutations have been observed so far in these residues or not. Material(s) and Method(s): Molecular docking studies were carried out using AutoDock Vina between SARS-CoV-2 RdRp and drugs approved against different viral RdRps (Galidesivir, Remdesivir, Ribavirin, Sofosbuvir, and Favipiravir) as well as physiological nucleotides (ATP and GTP). Based on the obtained results, a detailed surface-interaction analysis was also performed using Pymol and Discovery Studio Visualizer software for the models that exhibited the most suitable location and configuration in space. Result and Discussion: All the tested molecules were able to bind to SARS-CoV-2 RdRp successfully. Also, they all commonly interact with 9 different amino acids (Arg553, Arg555, Asp618, Asp623, Ser682, Asn691, Ser759, Asp760, and Asp761), and 3 different Template-primer RNA nucleotides (U10, A11, and U20) causing inhibition of viral RdRp via non obligate RNA chain termination.Copyright © 2022 University of Ankara. All rights reserved.

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.

Repurposing of RdRp Inhibitors against SARS-CoV-2 through Molecular Docking Tools

In the present hour, the COVID-19 pandemic needs no introduction. There is continuous and keen research in progress in order to discover or develop a suitable therapeutic candidate/vaccine against the fatal, severe acute respiratory syndrome causing coronavirus (SARS-CoV-2). Drug repurposing is an approach of utilizing the therapeutic potentials of previously approved drugs against some new targets or pharmacological responses. In the presented work, we have evaluated the RNA dependent RNA polym-erase (RdRp) inhibitory potentials of FDA approved anti-viral drugs remdesivir, ribavirin, sofosbuvir and galidesivir through molecular docking. The studies were carried out using MOE 2019.0102 software against RdRp (PDB ID:7BTF, released on 8th April, 2020). All four drugs displayed good docking scores and significant binding interactions with the amino acids of the receptor. The docking protocol was validated by redocking of the ligands and the root mean square deviation (RMSD) value was found to be less than 2. The 2D and 3D binding patterns of the drugs were studied and evaluated with the help of poses. The drugs displayed excellent hydrogen bonding interactions within the cavity of the receptor and displayed comparable docking scores. These drugs may serve as new therapeutic candidates or leads against SARS-CoV-2.Copyright © 2020 Bentham Science Publishers.

Antivirals for adult patients hospitalised with SARS-CoV-2 infection: a randomised, phase II/III, multicentre, placebo-controlled, adaptive study, with multiple arms and stages. COALITION COVID-19 BRAZIL IX - REVOLUTIOn trial.

Background: Repurposed drugs for treatment of new onset disease may be an effective therapeutic shortcut. We aimed to evaluate the efficacy of repurposed antivirals compared to placebo in lowering SARS-CoV2 viral load of COVID-19 patients. Methods: REVOLUTIOn is a randomised, parallel, blinded, multistage, superiority and placebo controlled randomised trial conducted in 35 centres in Brazil. We include patients aged 18 years or older admitted to hospital with laboratory-confirmed SARS-CoV-2 infection, symptoms onset 9 days or less and SpO2 94% or lower at room air were eligible. All participants were randomly allocated to receive either atazanavir, daclatasvir or sofosbuvir/daclatasvir or placebo for 10 days. The primary outcome was the decay rate (slope) of the SARS-CoV-2 viral load logarithm assessed in the modified intention to-treat population. This trial was registered with ClinicalTrials.gov, number NCT04468087. Findings: Between February 09, 2021, and August 04, 2021, 255 participants were enrolled and randomly assigned to atazanavir (n = 64), daclatasvir (n = 66), sofosbuvir/daclatasvir (n = 67) or placebo (n = 58). Compared to placebo group, the change from baseline to day 10 in log viral load was not significantly different for any of the treatment groups (0.05 [95% CI, -0.03 to 0.12], -0.02 [95% CI, -0.09 to 0.06], and -0.03 [95% CI, -0.11 to 0.04] for atazanavir, daclatasvir and sofosbuvir/daclatasvir groups respectively). There was no significant difference in the occurrence of serious adverse events between treatment groups. Interpretation: No significant reduction in viral load was observed from the use of atazanavir, daclatasvir or sofosbuvir/daclatasvir compared to placebo in hospitalised COVID-19 patients who need oxygen support with symptoms onset 9 days or less. Funding: Ministério da Ciência, Tecnologia e Inovação (MCTI) - Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPQ); Cia Latino-Americana de Medicamentos (Clamed); Cia Industrial H. Carlos Schneider (Ciser); Hospital Research Foundation Incorporation, Australia, HCor São Paulo; Blanver Farmoquímica; Instituto de Tecnologia em Fármacos (Farmanguinhos) da Fundação Oswaldo Cruz (Fiocruz); Coordenação Geral de Planejamento Estratégico (Cogeplan)/Fiocruz; and Fundação de apoio a Fiocruz (Fiotec, VPGDI-054-FIO-20-2-13).

A Comprehensive Molecular and Clinical Investigation of Approved Anti-HCV Drugs Repurposing against SARS-CoV-2 Infection: A Glaring Gap between Benchside and Bedside Medicine.

The limited availability of effective treatment against SARS-CoV-2 infection is a major challenge in managing COVID-19. This scenario has augmented the need for repurposing anti-virals for COVID-19 mitigation. In this report, the anti-SARS-CoV-2 potential of anti-HCV drugs such as daclatasvir (DCV) or ledipasvir (LDP) in combination with sofosbuvir (SOF) was evaluated. The binding mode and higher affinity of these molecules with RNA-dependent-RNA-polymerase of SARS-CoV-2 were apparent by computational analysis. In vitro anti-SARS-CoV-2 activity depicted that SOF/DCV and SOF/LDP combination has IC50 of 1.8 and 2.0 µM, respectively, comparable to remdesivir, an approved drug for COVID-19. Furthermore, the clinical trial was conducted in 183 mild COVID-19 patients for 14 days to check the efficacy and safety of SOF/DCV and SOF/LDP compared to standard of care (SOC) in a parallel-group, hybrid, individually randomized, controlled clinical study. The primary outcomes of the study suggested no significant difference in negativity after 3, 7 and 14 days in both treatments. None of the patients displayed any worsening in the disease severity, and no mortality was observed in the study. Although, the post hoc exploratory analysis indicated significant normalization of the pulse rate showed in SOF/DCV and SOF/LDP treatment vs. SOC. The current study highlights the limitations of bench side models in predicting the clinical efficacy of drugs that are planned for repurposing.

Inhibition of Viral RNA-Dependent RNA Polymerases by Nucleoside Inhibitors: An Illustration of the Unity and Diversity of Mechanisms.

RNA-dependent RNA polymerase (RdRP) is essential for the replication and expression of RNA viral genomes. This class of viruses comprise a large number of highly pathogenic agents that infect essentially all species of plants and animals including humans. Infections often lead to epidemics and pandemics that have remained largely out of control due to the lack of specific and reliable preventive and therapeutic regimens. This unmet medical need has led to the exploration of new antiviral targets, of which RdRP is a major one, due to the fact of its obligatory need in virus growth. Recent studies have demonstrated the ability of several synthetic nucleoside analogs to serve as mimics of the corresponding natural nucleosides. These mimics cause stalling/termination of RdRP, or misincorporation, preventing virus replication or promoting large-scale lethal mutations. Several such analogs have received clinical approval and are being routinely used in therapy. In parallel, the molecular structural basis of their inhibitory interactions with RdRP is being elucidated, revealing both traditional and novel mechanisms including a delayed chain termination effect. This review offers a molecular commentary on these mechanisms along with their clinical implications based on analyses of recent results, which should facilitate the rational design of structure-based antiviral drugs.

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.

Efficacy and safety of sofosbuvir in the treatment of SARS-CoV-2: an open label phase II trial

Objective: Despite the worldwide spread of the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), an effective specific antiviral treatment for coronavirus disease of 2019 (COVID-19) is yet to be identified.We did this study to investigate the safety and efficacy of sofosbuvir as antiviral therapy among hospitalized adult patients with SARS-CoV-2. Methods: Patients were randomized into intervention arm receiving sofosbuvir or comparison arm receiving usual antiviral agents in addition to standard of care. The primary end point of the study was clinical recovery as defined by normal body temperature and normal oxygen saturation. The main secondary outcome was all-cause mortality during the admission in hospital or within 14 days after discharge if applicable. Reports of severe adverse events were observed in the intervention arm. Results: Fifty-seven patients enrolled into either the clinical trial arm (n=27) or the comparison arm (n=30). Primary outcome was achieved by 24 (88.9%) and 10 (33.3%) in the intervention and comparison arms, respec-tively. Median hospital length of stay was significantly shorter in the intervention arm (10 days [IQR: 5-12] vs. 11.5 days [IQR: 8.5-17.75], P = 0.016). All-cause mortality was two and thirteen in intervention and comparison groups, respectively. No serious adverse events were reported by the patients receiving sofosbuvir during the study. Conclusion: Among patients hospitalized with SARS-CoV-2, those who received sofosbuvir had more clinical recovery rate and had a shorter hospital length of stay than those who received usual antiviral agents in the study and these differences were statistically significant. © 2023 Tehran University of Medical Sciences.

Determination of the Efficacy of Daclatasvir Plus Sofosbuvir in Patients with Acute Respiratory Coronavirus Syndrome (SARS-COV-2): A Randomized Clinical Trial

Background: To tackle the 2019 coronavirus infection (COVID-19) disease pandemic, effective antiviral therapy is critical. We assessed the efficacy of sofosbuvir and daclatasvir for treating patients with COVID-19. Methods: This was a randomized controlled trial in adults with moderate-to-severe COVID-19 disease admitted to Razi Teaching Hospital in Ahvaz, Khuzestan Province, Iran. Patients were randomly assigned to the sofosbuvir and daclatasvir group (n=35, intervention group) and control group (n=35, standard care). The primary endpoint of this study was the length of hospital stay, clinical improvement, mechanical ventilation, mortality, and side effect. Results: We found that the combination of Daclatasvir and Sofosbuvir (DCV+SOF) did not make a statistically significant difference in terms of mortality. There was no significant difference in the duration of hospitalization between the two groups. The two groups did not differ significantly in terms of the frequency of side effects. There were 2 cases of intubation and death in both groups. Conclusion: The medications used in this study, i.e, the combination of daclatasvir and sofosbuvir, failed to show a significant effect in patients, and despite promising laboratory studies, there were no improvements observed in vital signs and the indicators studied, including clinical signs. Hospitalization days, ventilator requirements and mortality did not make a significant difference. To confirm the results of this study, conducting researches with a larger sample size are needed. © 2022 Seventh Sense Research Group®

Prevalence of hepatitis C virus estimates of undiagnosed individuals in different Italian regions: a mathematical modelling approach by route of transmission and fibrosis progression with results up to January 2021

This study provides an update on hepatitis C virus (HCV) estimates across Italy up to January 2021. A mathematical probabilistic modelling approach, including a Markov chain for liver disease progression, was used to estimate current HCV viraemic burden. Prevalence was defined by geographic area using an estimated annual historical HCV incidence by age, treatment, and migration rate from the Italian National database (ISTAT). Viraemic infection was estimated for the main HCV transmission routes by stages F0-F3 (patients without liver cirrhosis, i.e., potentially asymptomatic liver disease) and F4 (patients with liver cirrhosis, i.e., potentially symptomatic liver disease). By January 2021, we estimated that there were 398,610 individuals in Italy with active HCV infection (prevalence of 0.66%;95% CI: 0.66-0.67), of which 287,730 (0.48%;95% CI: 0.46-0.59%) were stage F0-F3. Prevalence values for all individuals with active HCV infection were: North 0.54% (95% CI: 0.53-0.54%), Central 0.88% (95% CI: 0.87-0.89%), South 0.72% (95% CI: 0.71-0.73%), and the Isles 0.67% (95% CI: 0.66-0.68%). The population at risk for previous/current drug injection accounted for 48.6% of all individuals with active HCV infection. A modelling approach such as this to estimate and update the prevalence of active HCV infection could be a useful methodology for the evaluation of healthcare policies related to HCV elimination plans.

Covalent CES2 Inhibitors Protect against Reduced Formation of Intestinal Organoids by the Anticancer Drug Irinotecan.

BACKGROUND: Irinotecan is widely used to treat various types of solid and metastatic cancer. It is an ester prodrug and its hydrolytic metabolite (SN-38) exerts potent anticancer activity. Irinotecan is hydrolyzed primarily by carboxylesterase-2 (CES2), a hydrolase abundantly present in the intestine such as the duodenum. We have identified several potent and covalent CES2 inhibi¬tors such as remdesivir and sofosbuvir. Remdesivir is the first small molecule drug approved for COVID-19, whereas sofosbuvir is a paradigm-shift medicine for hepatitis C viral infection. Irinotecan is generally well-tolerated but associated with severe/life-threatening diarrhea due to intestinal accu¬¬mula¬tion of SN-38. OBJECTIVE: This study was to test the hypothesis that remdesivir and sofosbuvir protect against irinotecan-induced epithelial injury associated with gastrointestinal toxicity. METHODS: To test this hypothesis, formation of organoids derived from mouse duodenal crypts, a robust cellular model for intestinal regeneration, was induced in the presence or absence of irinotecan +/- pretreatment with a CES2 drug inhibitor. RESULTS: Irinotecan profoundly inhibited the formation of intestinal organoids and the magnitude of the inhibition was greater with female crypts than their male counterparts. Consistently, crypts from female mice had significantly higher hydrolytic activity toward irinotecan. Critically, remdesivir and sofosbuvir both reduced irinotecan hydrolysis and reversed irinotecan-reduced formation of organoids. Human duodenal samples robustly hydrolyzed irinotecan, stable CES2 transfection induced cytotoxicity and the cytotoxicity was reduced by CES2 drug inhibitor. CONCLUSION: These findings establish a therapeutic rationale to reduce irinotecan-gastrointestinal injury and serve as a cellular foundation to develop oral formulations of irinotecan with high safety.

Safety and efficacy of four drug regimens versus standard-of-care for the treatment of symptomatic outpatients with COVID-19: A randomised, open-label, multi-arm, phase 2 clinical trial.

BACKGROUND: This exploratory study investigated four repurposed anti-infective drug regimens in outpatients with COVID-19. METHODS: This phase 2, single centre, randomised, open-label, clinical trial was conducted in South Africa between 3rd September 2020 and 23rd August 2021. Symptomatic outpatients aged 18-65 years, with RT-PCR confirmed SARS-CoV-2 infection were computer randomised (1:1:1:1:1) to standard-of-care (SOC) with paracetamol, or SOC plus artesunate-amodiaquine (ASAQ), pyronaridine-artesunate (PA), favipiravir plus nitazoxanide (FPV + NTZ), or sofosbuvir-daclatasvir (SOF-DCV). The primary endpoint was the incidence of viral clearance, i.e., the proportion of patients with a negative SARS-CoV-2 RT-PCR on day 7, compared to SOC using a log-binomial model in the modified intention-to-treat (mITT) population. FINDINGS: The mITT population included 186 patients: mean age (SD) 34.9 (10.3) years, body weight 78.2 (17.1) kg. Day 7 SARS-CoV-2 clearance rates (n/N; risk ratio [95% CI]) were: SOC 34.2% (13/38), ASAQ 38.5% (15/39; 0.80 [0.44, 1.47]), PA 30.3% (10/33; 0.69 [0.37, 1.29]), FPV + NTZ 27.0% (10/37; 0.60 [0.31, 1.18]) and SOF-DCV 23.5% (8/34; 0.47 [0.22, 1.00]). Three lower respiratory tract infections occurred (PA 6.1% [2/33]; SOF-DCV 2.9% [1/34]); two required hospitalisation (PA, SOF-DCV). There were no deaths. Adverse events occurred in 55.3% (105/190) of patients, including one serious adverse event (pancytopenia; FPV + NTZ). INTERPRETATION: There was no statistical difference in viral clearance for any regimen compared to SOC. All treatments were well tolerated. FUNDING: Medicines for Malaria Venture, with funding from the UK Foreign, Commonwealth and Development Office, within the Covid-19 Therapeutics Accelerator in partnership with Wellcome, the Bill and Melinda Gates Foundation, and Mastercard.

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.