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Global Health & Medicine Aug 2022It is well-known that sustained virological response (SVR) by interferon (IFN)-based therapy against hepatitis C virus (HCV) infection reduced the incidence of...
It is well-known that sustained virological response (SVR) by interferon (IFN)-based therapy against hepatitis C virus (HCV) infection reduced the incidence of hepatocellular carcinoma (HCC). However, whether IFN-free direct-acting antivirals reduce the risk of HCC is controversial. Therefore, this study aims to compare the incidence of HCC after the achievement of SVR between sofosbuvir combined with ledipasvir (SOF/LDV) and simeprevir with pegylated interferon plus ribavirin (Sim+IFN). Japanese patients with HCV infection (genotype 1) who achieved SVR between January 2013 and December 2014 by SOF/LDV (NCT01975675, = 320) or Sim+IFN (000015933, = 289) therapy in two nationwide, multicenter, phase III studies were prospectively monitored for the development of HCC by ultrasonography for 5 years after the end of treatment (EOT). No HCC was detected before the treatment. HCC was detected in 9 and 7 patients in the SOF/LDV and the Sim+IFN group in 5 years, respectively. The cumulative incidences of HCC rates 1, 3, and 5 years after EOT were similar between the two groups (1.5%, 2.7%, and 3.2% for the SOF/LDV and 1.8%, 2.8%, and 3.0% for the Sim+IFN group, respectively). No HCC was developed 3.5 years after EOT. Interestingly, a retrospective careful review of imaging taken before therapy revealed hepatic nodules in 50% of HCC patients, suggesting HCC was pre-existed before therapy. In conclusion, we could not find any differences in the incidence of HCC after the HCV eradication between the two therapeutic regimens, suggesting no enhancement of HCC development by DAA.
PubMed: 36119787
DOI: 10.35772/ghm.2022.01026 -
Vaccines Aug 2022The pandemic of SARS-CoV-2 infections is a severe threat to human life and the world economic condition. Although vaccination has reduced the outspread, but still the...
The pandemic of SARS-CoV-2 infections is a severe threat to human life and the world economic condition. Although vaccination has reduced the outspread, but still the situation is not under control because of the instability of RNA sequence patterns of SARS-CoV-2, which requires effective drugs. Several studies have suggested that the SARS-CoV-2 infection causing hub differentially expressed genes (Hub-DEGs). However, we observed that there was not any common hub gene (Hub-DEGs) in our analyses. Therefore, it may be difficult to take a common treatment plan against SARS-CoV-2 infections globally. The goal of this study was to examine if more representative Hub-DEGs from published studies by means of hub of Hub-DEGs (hHub-DEGs) and associated potential candidate drugs. In this study, we reviewed 41 articles on transcriptomic data analysis of SARS-CoV-2 and found 370 unique hub genes or studied genes in total. Then, we selected 14 more representative Hub-DEGs (, , , , , , , , , , , , , ) as hHub-DEGs by their protein-protein interaction analysis. Their associated biological functional processes, transcriptional, and post-transcriptional regulatory factors. Then we detected hHub-DEGs guided top-ranked nine candidate drug agents (Digoxin, Avermectin, Simeprevir, Nelfinavir Mesylate, Proscillaridin, Linifanib, Withaferin, Amuvatinib, Atazanavir) by molecular docking and cross-validation for treatment of SARS-CoV-2 infections. Therefore, the findings of this study could be useful in formulating a common treatment plan against SARS-CoV-2 infections globally.
PubMed: 36016137
DOI: 10.3390/vaccines10081248 -
BioImpacts : BI 2022COVID-19 has spread out all around the world and seriously interrupted human activities. Being a newfound disease, not only many aspects of the disease are unknown, but...
COVID-19 has spread out all around the world and seriously interrupted human activities. Being a newfound disease, not only many aspects of the disease are unknown, but also there is not an effective medication to cure the disease. Besides, designing a drug is a time-consuming process and needs large investment. Hence, drug repurposing techniques, employed to discover the hidden benefits of the existing drugs, maybe a useful option for treating COVID-19. The present study exploits the drug repositioning concepts and introduces some candidate drugs which may be effective in controlling COVID-19. The suggested method consists of three main steps. First, the required data such as the amino acid sequences of targets and drug-target interactions are extracted from the public databases. Second, the similarity score between the targets (protein/enzymes) and genome of SARS-COV-2 is computed using the proposed fuzzy logic-based method. Since the classical approaches yield outcomes which may not be useful for the real-world applications, the fuzzy technique can address the issue. Third, after ranking targets based on the obtained scores, the usefulness of drugs affecting them is examined for managing COVID-19. The results indicate that antiviral medicines, designed for curing hepatitis C, may also cure COVID-19. According to the findings, ribavirin, simeprevir, danoprevir, and XTL-6865 may be helpful in controlling the disease. It can be concluded that the similarity-based drug repurposing techniques may be the most suitable option for managing emerging diseases such as COVID-19 and can be applied to a wide range of data. Also, fuzzy logic-based scoring methods can produce outcomes which are more consistent with the real-world biological applications than others.
PubMed: 35975205
DOI: 10.34172/bi.2021.40 -
Clinical and Experimental Hepatology Mar 2022In chronic hepatitis C virus (HCV) patients in whom prior direct-acting antiviral agent (DAA) treatment had failed, outcomes after retreatment are optimal. Combination...
Successful treatment of hepatitis C genotype 4 using sofosbuvir, daclatasvir, simeprevir and ribavirin in Egyptian patients with direct-acting antiviral agent treatment failure.
INTRODUCTION
In chronic hepatitis C virus (HCV) patients in whom prior direct-acting antiviral agent (DAA) treatment had failed, outcomes after retreatment are optimal. Combination of sofosbuvir (SOF), daclatasvir (DCV), simeprevir (SIM), and ribavirin (RBV) in treatment experienced patients is recommended in current guidelines despite insufficient data. Our aim is to determine the efficacy and safety of SOF, DCV, SIM plus RBV in HCV infected patients who failed prior DAA treatment.
MATERIAL AND METHODS
One hundred and seventeen patients who failed to respond to SOF containing regimens were randomized according to previous response to therapy to non-responders and relapsers. Duration of therapy depends on fibrosis stages. SOF, DCV, SIM and weight based RBV 12 weeks for F1 and F2 (group I) and 24 weeks for F3 and F4 (group II).
RESULTS
In the non-responder group, a sustained virologic response (SVR) occurred in 100% in group I (F1 and F2) and 97% in group II (F3 and F4). Relapse was 3% in group II (F3 and F4). No patients from either group had breakthrough or non-response. In relapsers SVR was 100% in group I (F1 and F2) and 96% in group II (F3 and F4). Breakthrough, relapse and non-response were 2%, 4%, 2% respectively only in group II (F3 and F4).
CONCLUSIONS
Combining multiple DAAs with different viral targets may be effective treatment protocol in previous non-responders and relapsers with short durations of treatment.
PubMed: 35415259
DOI: 10.5114/ceh.2022.114246 -
Methods (San Diego, Calif.) Jul 2022For the last two years, the COVID-19 pandemic has continued to bring consternation on most of the world. According to recent WHO estimates, there have been more than 5.6...
For the last two years, the COVID-19 pandemic has continued to bring consternation on most of the world. According to recent WHO estimates, there have been more than 5.6 million deaths worldwide. The virus continues to evolve all over the world, thus requiring both vigilance and the necessity to find and develop a variety of therapeutic treatments, including the identification of specific antiviral drugs. Multiple studies have confirmed that SARS-CoV-2 utilizes its membrane-bound spike protein to recognize human angiotensin-converting enzyme 2 (ACE2). Thus, preventing spike-ACE2 interactions is a potentially viable strategy for COVID-19 treatment as it would block the virus from binding and entering into a host cell. This work aims to identify potential drugs using an in silico approach. Molecular docking was carried out on both approved drugs and substances previously tested in vivo. This step was followed by a more detailed analysis of selected ligands by molecular dynamics simulations to identify the best molecules that thwart the ability of the virus to interact with the ACE2 receptor. Because the SARS-CoV-2 virus evolves rapidly due to a plethora of immunocompromised hosts, the compounds were tested against five different known lineages. As a result, we could identify substances that work well on individual lineages and those showing broader efficacy. The most promising candidates among the currently used drugs were zafirlukast and simeprevir with an average binding affinity of -22 kcal/mol for spike proteins originating from various lineages. The first compound is a leukotriene receptor antagonist that is used to treat asthma, while the latter is a protease inhibitor used for hepatitis C treatment. From among the in vivo tested substances that concurrently exhibit promising free energy of binding and ADME parameters (indicating a possible oral administration) we selected the compound BDBM50136234. In conclusion, these molecules are worth exploring further by in vitro and in vivo studies against SARS-CoV-2.
Topics: Angiotensin-Converting Enzyme 2; Antiviral Agents; Drug Repositioning; Humans; Molecular Docking Simulation; Molecular Dynamics Simulation; Pandemics; SARS-CoV-2; COVID-19 Drug Treatment
PubMed: 35167916
DOI: 10.1016/j.ymeth.2022.02.004 -
Spectrochimica Acta. Part A, Molecular... May 2022Simeprevir and sofosbuvir are direct-acting antiviral drugs approved for the treatment of chronic HCV infection. Reports demonstrate the similarities between HCV and...
Simeprevir and sofosbuvir are direct-acting antiviral drugs approved for the treatment of chronic HCV infection. Reports demonstrate the similarities between HCV and SARS-CoV-2 in terms of structure and replication mechanism. Therefore, it is suggested that a combination of simeprevir and sofosbuvir may be considered for COVID-19 patients. To date, no spectrophotometric methods have been published for quantitative analysis of simeprevir and sofosbuvir in combination. In this work, two simple spectrophotometric methods allowed quantitative analysis of the studied drugs in the mixed form. The zero-order direct method allowed quantitative analysis of simeprevir at 333 nm, with sofosbuvir showing zero absorbance values. The dual wavelength method allowed quantitative analysis of sofosbuvir by measuring the difference in absorbance values at 259.40 and 276 nm, where the difference in absorbance values of simeprevir was zero. With the applied methods, the investigated drugs in the mixtures and tablets prepared in the laboratory were successfully analyzed quantitatively with acceptable results.
Topics: Antiviral Agents; COVID-19; Drug Therapy, Combination; Genotype; Hepacivirus; Hepatitis C, Chronic; Humans; SARS-CoV-2; Simeprevir; Sofosbuvir
PubMed: 35158141
DOI: 10.1016/j.saa.2022.121012 -
World Journal of Hepatology Jan 2022Hepatitis C virus (HCV) treatment has undergone major changes in recent years. Previous interferon-based therapies have been replaced by oral direct-acting antivirals...
BACKGROUND
Hepatitis C virus (HCV) treatment has undergone major changes in recent years. Previous interferon-based therapies have been replaced by oral direct-acting antivirals (DAA) regimens, with high sustained virologic response (SVR) rates, and a lower incidence of adverse events (AEs).
AIM
To evaluate the efficacy and safety of DAAs for HCV treatment in subjects from two tertiary university centers in Brazil.
METHODS
This is a multicenter retrospective cohort study of 532 patients with chronic hepatitis C (CHC), undergoing treatment with interferon-free regimens from November 2015 to November 2019. The therapeutic regimen was defined by the current Brazilian guidelines for HCV management at the time of treatment. Demographic, anthropometric, clinical, and laboratory variables were evaluated. SVRs were assessed at 12 to 24 wk after therapy by intention-to-treat (ITT), and modified ITT (m-ITT) analysis. AEs and serious adverse events (SAEs) were registered. In the statistical analysis, a value of < 0.05 was considered significant.
RESULTS
The mean age was 56.88 years, with 415 (78.5%) being HCV genotype 1, followed by genotype 3 (20.1%). Moreover, 306 (57.5%) subjects had cirrhosis, and a third of them had decompensated cirrhosis. Sofosbuvir (SOF) plus daclatasvir ± ribavirin was the most frequently used treatment (66.9%), followed by SOF plus simeprevir (21.2%). The overall ITT SVR was 92.6% (493/532), while the m-ITT SVR was 96.8% (493/509). Variables associated with treatment failure ITT evaluation were hepatic encephalopathy (OR: 4.320; 95%CI: 1.920-9.721, = 0.0004), presence of esophageal varices (OR: 2.381; 95%CI: 1.137-4.988, = 0.0215), previous portal hypertensive bleeding (OR: 2.756; 95%CI: 1.173-6.471, = 0.02), higher model for end-stage liver disease scores (OR: 1.143, 95%CI: 1.060-1.233, = 0.0005), lower serum albumin levels (OR: 0.528, 95%CI: 0.322-0.867, = 0.0115), higher serum creatinine (OR: 1.117, 95%CI: 1.056-1.312, = 0.0033), and international normalized ratio (INR) levels (OR: 5.542, 95%CI: 2.023-15.182, = 0.0009). AEs were reported in 41.1% (211/514) of patients, and SAEs in 3.7%. The female gender, higher body mass index, esophageal varices, higher INR values, and longer treatment duration were independently associated with AE occurrence.
CONCLUSION
Treatment with oral DAAs attains a high SVR rate, with fewer SAEs in a real-life cohort of subjects with CHC, from two tertiary university centers in Brazil.
PubMed: 35126848
DOI: 10.4254/wjh.v14.i1.195