Combination therapy synergism prediction for virus treatment using machine learning models.

Combining different drugs synergistically is an essential aspect of developing effective treatments. Although there is a plethora of research on computational prediction for new combination therapies, there is limited to no research on combination therapies in the treatment of viral diseases. This paper proposes AI-based models for predicting novel antiviral combinations to treat virus diseases synergistically. To do this, we assembled a comprehensive dataset comprising information on viral strains, drug compounds, and their known interactions. As far as we know, this is the first dataset and learning model on combination therapy for viruses. Our proposal includes using a random forest model, an SVM model, and a deep model to train viral combination therapy. The machine learning models showed the highest performance, and the predicted values were validated by a t-test, indicating the effectiveness of the proposed methods. One of the predicted combinations of acyclovir and ribavirin has been experimentally confirmed to have a synergistic antiviral effect against herpes simplex type-1 virus, as described in the literature.

Patient profiled data for treatment decision-making: valuable as an add-on to hepatitis C clinical guidelines?

BACKGROUND AND AIMS: Systematic reviews and medical guidelines are widely used in clinical practice. However, these are often not up-to-date and focussed on the average patient. We therefore aimed to evaluate a guideline add-on, TherapySelector (TS), which is based on monthly updated data of all available high-quality studies, classified in specific patient profiles. METHODS: We evaluated the TS for the treatment of hepatitis C (HCV) in an international cohort of patients treated with direct-acting antivirals between 2015 and 2020. The primary outcome was the number of patients receiving one of the two preferred treatment options of the HCV TS, based on the highest level of evidence, cure rate, absence of ribavirin-associated adverse effects, and treatment duration. RESULTS: We enrolled 567 patients. The number of patients treated with one of the two preferred treatment options according to the HCV TS ranged between 27% (2015) and 60% (2020; p < 0.001). Most of the patients received a regimen with a longer treatment-duration (up to 34%) and/or addition of ribavirin (up to 14%). The effect on the expected cure-rate was minimal (1-6% higher) when the first preferred TherapySelector option was given compared to the actual treatment. CONCLUSIONS: Medical decision-making can be optimised by a guideline add-on; in HCV its use appears to minimise adverse effects and cost. The use of such an add-on might have a greater impact in diseases with suboptimal cure-rates, high costs or adverse effects, for which treatment options rely on specific patient characteristics.

Respiratory Syncytial Virus Infection in an Adult with Immunodeficiency.

BACKGROUND: Respiratory syncytial virus (RSV) is a single-stranded RNA virus that commonly causes symptoms of upper respiratory tract infections in humans, with a clear seasonal trend. However, in immunocompromised and elderly patients, RSV infections still result in high rates of hospitalization and even risk of death. METHODS: We report a case of RSV infection in an adult with immunodeficiency, which initially showed only mild symptoms of upper respiratory tract infection, which did not improve after receiving empirical anti-infective treatment, and the foci of infection in the lungs continued to expand, which led to the aggravation of the disease. The diagnosis of RSV infection was finally confirmed by electron bronchoscopy and pathogenetic examination of the bronchoalveolar lavage fluid. The patient was given intravenous ribavirin treatment for one week. After one week of intravenous ribavirin treatment, the patient's symptoms improved significantly. A repeat chest CT suggested that the lung lesions were smaller than before. In order to improve clinicians' awareness of this disease, we jointly conducted a literature analysis. RESULTS: The final diagnosis of RSV was made by analyzing the patient's history, symptoms, and signs and performing relevant examinations. CONCLUSIONS: For patients with poor results of empirical application of antibiotics, electronic bronchoscopy and pathogenetic examination should be carried out at an early stage to clarify the nature of the lesions and to avoid rapid deterioration of the condition leading to life-threatening conditions in the patients. More consideration should be given to the possibility of disease diagnosis to avoid misdiagnosis and underdiagnosis, and appropriate treatment should be given at an early stage.

Measures of insulin resistance and beta cell function before and after treatment of HCV infection.

The association between chronic HCV infection and type 2 diabetes mellitus (T2DM) has been established; however, there is limited research on ß-cell function particularly in the pre-diabetic population. Here, we evaluated indices of ß-cell function and insulin sensitivity across the spectrum from normal glucose tolerance to T2DM in individuals with and without chronic hepatitis C (CHC), and the effects of antiviral treatments on these variables. A total of 153 non-cirrhotic, non-fibrotic CHC patients with a BMI <25 were enrolled in the study. Among them, 119 were successfully treated with either direct acting antiviral (DAA) drugs or pegylated interferon/ribavirin (IFN/RBV) anti-HCV therapy. Fasting state- and oral glucose tolerance test (OGTT)-derived indexes were used to evaluate ß-cell function and insulin sensitivity. Among all subjects, 19 (13%) had T2DM and 21% exhibited pre-diabetes including 8% isolated impaired fasting glucose (IFG) and 13% combined IFG and impaired glucose tolerance (IGT). Early and total insulin secretion adjusted for the degree of insulin resistance were decreased in pre-diabetic CHC patients compared to HCV-uninfected individuals. Viral eradication through DAA or IFN/RBV therapy demonstrated positive impacts on insulin sensitivity and ß-cell function in CHC patients who achieved sustained virologic response (SVR), regardless of fasting or OGTT state. These findings emphasize the role of HCV in the development of ß-cell dysfunction, while also suggesting that viral eradication can improve insulin secretion, reverse insulin resistance, and ameliorate glycemic control. These results have important implications for managing pre-diabetic CHC patients and could prevent diabetes-related clinical manifestations and complications.

Hepatitis C virus diversity and treatment outcomes in Benin: a prospective cohort study.

BACKGROUND: 10 million people are chronically infected with the hepatitis C virus (HCV) in sub-Saharan Africa. The assessment of viral genotypes and treatment response in this region is necessary to achieve the WHO target of worldwide elimination of viral hepatitis by 2030. We aimed to investigate the prevalence of HCV genotypes and outcomes of treatment with direct-acting antiviral agents in Benin, a country with a national HCV seroprevalence of 4%. METHODS: This prospective cohort study was conducted at two referral hospitals in Benin. Individuals were eligible for inclusion if they were seropositive for HCV and willing to consent to participation in the study; exclusion criteria were an inability to give consent or incarceration. Viraemia was confirmed by PCR. The primary outcomes were to identify HCV genotypes and measure sustained virological response rates 12 weeks after completion of treatment (SVR12) with a 12-week course of sofosbuvir-velpatasvir or sofosbuvir-ledipasvir, with or without ribavirin. We conducted phylogenetic and resistance analyses after the next-generation sequencing of samples with a cycle threshold (Ct) value of 30 or fewer cycles. The in-vitro efficacy of NS5A inhibitors was tested using a subgenomic replicon assay. FINDINGS: Between June 2, 2019, and Dec 30, 2020, 148 individuals were screened for eligibility, of whom 100 were recruited prospectively to the study. Plasma samples from 79 (79%) of the 100 participants were positive for HCV by PCR. At the time of the study, 52 (66%) of 79 patients had completed treatment, with an SVR12 rate of 94% (49 of 52). 57 (72%) of 79 samples had a Ct value of 30 or fewer cycles and were suitable for whole-genome sequencing, from which we characterised 29 (51%) samples as genotype 1 and 28 (49%) as genotype 2. Three new genotype 1 subtypes (1q, 1r, and 1s) and one new genotype 2 subtype (2xa) were identified. The most commonly detected subtype was 2d (12 [21%] of 57 samples), followed by 1s (eight [14%]), 1r (five [9%]), 1b (four [7%]), 1q (three [5%]), 2xa (three [5%]), and 2b (two [3%]). 20 samples (11 genotype 2 and nine genotype 1) were unassigned new singleton lineages. 53 (93%) of 57 sequenced samples had at least two resistance-associated substitutions within the NS5A gene. Subtype 2d was associated with a lower-than-expected SVR12 rate (eight [80%] of ten patients). For one patient, with subtype 2b, treatment was not successful. INTERPRETATION: This study revealed a high SVR rate in Benin among individuals treated for HCV with sofosbuvir-velpatasvir, including those with highly diverse viral genotypes. Further studies of treatment effectiveness in genotypes 2d and 2b are indicated. FUNDING: Medical Research Council, Wellcome, Global Challenges Research Fund, Academy of Medical Sciences, and PHARMBIOTRAC.

Therapeutic plasma exchange combined with ribavirin to rescue critical SFTS patients.

BACKGROUND: Severe fever with thrombocytopenia syndrome (SFTS) is a zoonotic infectious disease caused by the severe fever with thrombocytopenia syndrome virus (SFTSV). Endemic in East Asia, SFTS is characterized by an exceptionally high mortality rate. Presently, there is no established treatment for SFTS, particularly for patients in critical condition. In this study, we collected and analyzed laboratory and clinical data from 92 critically ill patients with SFTS treated at Weihai Municipal Hospital between 2019 and 2022. We hope that our study will provide some hints for the treatment of critically ill patients with SFTS. METHODS: A total of 92 critically ill patients with SFTS were included in this study. Of these patients, 45 received treatment with therapeutic plasma exchange (TPE) and ribavirin (referred to as the TPE group), while the remaining patients received only ribavirin (referred to as the non-TPE group). Clinical and laboratory parameters were analyzed retrospectively. RESULTS: The results showed significant improvements in multiple laboratory parameters following treatment with TPE and ribavirin, including white blood cell and neutrophil count, lactate dehydrogenase, creatine kinase isoenzyme-MB, prothrombin time, activated partial thromboplastin time, D-Dimer, serum sodium and copies of virus genomes. The combination of TPE with ribavirin demonstrated a significant reduction in mortality rates, with a mortality rate of 20.0% in the TPE group compared to 40.4% in the non-TPE group (P = 0.033). CONCLUSIONS: Our findings suggest that critically ill patients with SFTS who received TPE and ribavirin experienced improvements in both clinical and laboratory parameters. These results indicate that TPE combined with ribavirin may represent a promising novel therapeutic approach for managing critically ill patients with SFTS. However, comparative studies of large sample size or randomized clinical trials are warranted to confirm the effectiveness of this combination therapy in the treatment of severe SFTS cases.

Feasibility, safety, efficacy and potential scaling-up of sofosbuvir-based HCV treatment in Central and West Africa: (TAC ANRS 12311 trial).

Access to Hepatis C treatment in Sub-Saharan Africa is a clinical, public health and ethical concern. The multi-country open-label trial TAC ANRS 12311 allowed assessing the feasibility, safety, efficacy of a specific care model of HCV treatment and retreatment in patients with hepatitis C in Sub Saharan Africa. Between November 2015 and March 2017, with follow-up until mid 2019, treatment-naïve patients with HCV without decompensated cirrhosis or liver cancer were recruited to receive 12 week-treatment with either sofosbuvir + ribavirin (HCV genotype 2) or sofosbuvir + ledipasvir (genotype 1 or 4) and retreatment with sofosbuvir + velpatasvir + voxilaprevir in case of virological failure. The primary outcome was sustained virological response at 12 weeks after end of treatment (SVR12). Secondary outcomes included treatment adherence, safety and SVR12 in patients who were retreated due to non-response to first-line treatment. The model of care relied on both viral load assessment and educational sessions to increase patient awareness, adherence and health literacy. The study recruited 120 participants, 36 HIV-co-infected, and 14 cirrhotic. Only one patient discontinued treatment because of return to home country. Neither death nor severe adverse event occurred. SVR12 was reached in 107 patients (89%): (90%) in genotype 1 or 2, and 88% in GT-4. All retreated patients (n = 13) reached SVR12. HCV treatment is highly acceptable, safe and effective under this model of care. Implementation research is now needed to scale up point-of-care HCV testing and SVR assessment, along with community involvement in patient education, to achieve HCV elimination in Sub-Saharan Africa.

A comparative study of different antiviral treatment protocols in HCV related cryoglobulinemic vasculitis.

The treatment of HCV and its sequelae are used to be predominantly based on Interferon (IFN). However, this was associated with significant adverse events as a result of its immunostimulant capabilities. Since their introduction, the directly acting antiviral drugs (DAAs), have become the standard of care to treat of HCV and its complications including mixed cryoglobulinemic vasculitis (MCV). In spite of achieving sustained viral response (SVR), there appeared many reports describing unwelcome complications such as hepatocellular and hematological malignancies as well as relapses. Prolonged inflammation induced by a multitude of factors, can lead to DNA damage and affects BAFF and APRIL, which serve as markers of B-cell proliferation. We compared, head-to-head, three antiviral protocols for HCV-MCV treatment As regards the treatment response and relapse, levels of BAFF and APRIL among pegylated interferon α-based and free regimens (Sofosbuvir + Ribavirin; SOF-RIBA, Sofosbuvir + Daclatasvir; SOF-DACLA). Regarding clinical response HCV-MCV and SVR; no significant differences could be identified among the 3 different treatment protocols, and this was also independent form using IFN. We found no significant differences between IFN-based and free regimens DNA damage, markers of DNA repair, or levels of BAFF and APRIL. However, individualized drug-to-drug comparisons showed many differences. Those who were treated with IFN-based protocol showed decreased levels of DNA damage, while the other two IFN-free groups showed increased DNA damage, being the worst in SOF-DACLA group. There were increased levels of BAFF through follow-up periods in the 3 protocols being the best in SOF-DACLA group (decreased at 24 weeks). In SOF-RIBA, CGs relapsed significantly during the follow-up period. None of our patients who were treated with IFN-based protocol had significant clinico-laboratory relapse. Those who received IFN-free DAAs showed a statistically significant relapse of constitutional manifestations. Our findings suggest that IFN-based protocols are effective in treating HCV-MCV similar to IFN-free protocols. They showed lower levels of DNA damage and repair. We believe that our findings may offer an explanation for the process of lymphoproliferation, occurrence of malignancies, and relapses by shedding light on such possible mechanisms.

An Immunocompetent Mongolian Gerbil Model for Hepatitis E Virus Genotype 1 Infection.

BACKGROUND & AIMS: Hepatitis E virus (HEV), primarily genotype 1 (HEV-1), causes approximately 20.1 million infections, 44,000 deaths, and 3000 stillbirths annually. Current evidence indicates that HEV-1 is only transmitted in humans. Here, we evaluated whether Mongolian gerbils can serve as animal models for HEV-1 infection. METHODS: Mongolian gerbils were used for HEV-1 and hepatitis E virus genotype 3 infection experiments. HEV infection parameters, including detection of HEV RNA and HEV antigen, liver function assessment, and histopathology, were evaluated. RESULTS: We adapted a clinical isolate of HEV-1 for Mongolian gerbils by serial passaging in feces of aged male gerbils. The gerbil-adapted strain obtained at passage 3 induced a robust, acute HEV infection, characterized by stable fecal virus shedding, elevated liver enzymes, histopathologic changes in the liver, and seroconversion to anti-HEV. An infectious complementary DNA clone of the adapted virus was generated. HEV-1-infected pregnant gerbils showed a high rate of maternal mortality and vertical transmission. HEV RNA or antigens were detected in the liver, kidney, intestine, placenta, testis, and fetus liver. Liver and placental transcriptomic analyses indicated activation of host immunity. Tacrolimus prolonged HEV-1 infection, whereas ribavirin cleared infection. The protective efficacy of a licensed HEV vaccine was validated using this model. CONCLUSIONS: HEV-1 efficiently infected Mongolian gerbils. This HEV-1 infection model will be valuable for investigating hepatitis E immunopathogenesis and evaluating vaccines and antivirals against HEV.

Favipiravir Treatment Prolongs Survival in a Lethal BALB/c Mouse Model of Ebinur Lake Virus Infection.

Orthobunyavirus is the largest and most diverse genus in the family Peribunyaviridae. Orthobunyaviruses are widely distributed globally and pose threats to human and animal health. Ebinur Lake virus (EBIV) is a newly classified Orthobunyavirus detected in China, Russia, and Kenya. This study explored the antiviral effects of two broad-spectrum antiviral drugs, favipiravir and ribavirin, in a BALB/c mouse model. Favipiravir significantly improved the clinical symptoms of infected mice, reduced viral titer and RNA copies in serum, and extended overall survival. The median survival times of mice in the vehicle- and favipiravir-treated groups were 5 and 7 days, respectively. Favipiravir significantly reduced virus titers 10- to 100-fold in sera at all three time points compared to vehicle-treated mice. And favipiravir treatment effectively reduced the virus copies by approximately 10-fold across the three time points, relative to vehicle-treated mice. The findings expand the antiviral spectrum of favipiravir for orthobunyaviruses in vivo.

A case of Crimean-Congo haemorrhagic fever complicated with portal vein thrombosis and hemophagocytosis.

OBJECTIVES: Crimean-Congo haemorrhagic fever (CCHF) is a zoonotic viral infection which is an important public health problem in Turkey. CCHF causes fever and bleeding and can lead to severe health outcomes. The study aims to report a case of a male patient with severe CCHF, hemophagocytic lymphohistiocytosis (HLH) treated with steroids and portal vein thrombosis. CASE REPORT: A 37-year-old man was admitted to the emergency department with complaints of high fever, headache, myalgia and diarrhoea. The patient travelled to the endemic region of Turkey. In laboratory findings, thrombocytopenia, abnormal liver function tests and elevated coagulation parameters were observed. Real-time polymerase chain reaction assay was used for diagnosis of CCHF. Hypofibrinogenemia, hypertriglyceridemia, elevated ferritin and d-dimer levels were observed in the clinical follow-up. Prednisolone treatment was performed due to considered the diagnosis of HLH. Portal vein thrombosis was detected on abdominal computed tomography scan. He was successfully treated with ribavirin, corticosteroids, anticoagulant and supportive therapy. CONCLUSION: The clinical presentation of CCHF can range from self-limiting flu-like to severe symptoms possibly fatal. Acute portal vein embolism is a rare complication that has not been reported before to our knowledge. Corticosteroids may be a life-saving treatment for CCHF patients presenting with HLH.

The deleterious effects of sofosbuvir and ribavirin (antiviral drugs against hepatitis C virus) on different body systems in male albino rats regarding reproductive, hematological, biochemical, hepatic, and renal profiles and histopathological changes.

Sofosbuvir is one of the crucial drugs used in the treatment of chronic hepatitis C virus (HCV) in adults and children with compensated liver disease, including cirrhosis. It may be used alone or with other drugs. Ribavirin is an antiviral medication used to treat HCV infection. It is not effective when used alone and must be used in combination with other medications, such as sofosbuvir. This study pertains to a comprehensive assessment of the deleterious effects of sofosbuvir (an antiviral drug against chronic HCV) or sofosbuvir combined with ribavirin (an antiviral drug against RNA and DNA viruses) on several biological activities of the body, including hematological, hormonal, biochemical, histological, and immunohistochemical examinations during a long-standing period on male healthy rats. In addition, fertility assessments were performed, including sperm collections and semen parameter investigations. This study was conducted on 21 male rats divided into three equal groups. Group I (control group) received distilled water; group II (sofosbuvir group) received sofosbuvir (4 mg/kg); and group III (sofosbuvir + ribavirin) received sofosbuvir (4 mg/kg) plus ribavirin (30 ml/kg). All groups received the specific drug for six months. Blood and tissue samples were collected for hematological, hormonal, biochemical, histological, and immunohistochemical examinations. In addition, sperm collection and assessments of semen parameters were performed. Results revealed that sofosbuvir causes a highly significant decrease in the mean of most hematological, immunological, hormonal, and biochemical parameters, except for a few numbers of parameters such as neutrophils, monocytes, basophils, cortisol, GOT, and lipase, which exhibit a significant increase. The same occurred in the sofosbuvir + ribavirin group, but at much higher levels, as most hematological, immunological, hormonal, and biochemical parameters exhibit a highly significant decrease except for monocytes, triglyceride, and lipase, which exhibit a significant increase. When compared to the sofosbuvir group alone, the sofosbuvir + ribavirin group demonstrated a highly significant decline in the mean of most hematological, immunological, hormonal, and biochemical parameters except lymphocytes and triglycerides, which exhibit a substantial increase. For the reproductive parameters, both groups exhibit a significant decrease in the total sperm motility percentage. Finally, it can be concluded that sofosbuvir causes acute pancreatitis and combined immunodeficiency. Ribavirin is associated with hormonal deficiency, which indicates the occurrence of hypopituitarism. Moreover, sofosbuvir and ribavirin synergistically affect myelosuppression and cause iron-deficiency anemia. However, sofosbuvir, or its combination with ribavirin, is associated with a reduced risk of hepatocellular carcinoma. Besides, adding ribavirin to be combined with sofosbuvir improved the immunodeficiency caused by sofosbuvir; this confirms that using ribavirin with sofosbuvir reduces the side effects of both alone.

Vaccine Associated Measles Complicated by Suspected Measles Inclusion Body Encephalitis in a Pediatric Leukemia Patient and Stem Cell Transplant Recipient: A Focus on Clinical Evolution and Management.

BACKGROUND: Immunocompromised individuals are at increased risk for severe disease and complications from viral infections, highlighting the importance of vaccination. However, in extremely rare situations, vaccine associated viral infections can be associated with disseminated disease and complications in immunocompromised hosts. CASE: Herein, we present a case of a 1-year-old child diagnosed with acute myeloid leukemia less than 2 weeks after receiving live viral vaccines who developed acute vaccine-strain measles virus disease, later complicated by central nervous system involvement following hematopoietic stem cell transplantation. A brain biopsy specimen was positive for vaccine-strain measles virus detected by reverse transcriptase polymerase chain reaction. MANAGEMENT AND OUTCOME: She was treated with intravenous ribavirin, inosine pranobex, intrathecal interferon-alpha and donor lymphocyte infusion following measles-mumps-rubella vaccine boost. Despite these measures, the patient suffered neurologic decline and dysautonomia, expiring after compassionate extubation. Management and ideal risk mitigation strategies are discussed within the context of existing literature for this rare complication.

[Clinical comprehensive evaluation of Houyanqing Oral Liquid in treatment of acute pharyngitis].

This study systematically combed the existing evidence of Houyanqing Oral Liquid in the treatment of acute pharyngitis from the "6+1" dimensions of safety, effectiveness, economy, innovation, suitability, accessibility, and characteristics of traditional Chinese medicine(TCM) and carried out qualitative and quantitative analysis of the data from each dimension. The multi-criteria decision analysis(MCDA) model and CSC v2.0 were used to evaluate the clinical value of this drug, so as to provide evidence for the selection of essential drugs in the department of otolaryngology and for medical and health decision-making. The dimensions are graded A, B, C, or D. The adverse reactions of Houyanqing Oral Liquid in the treatment of acute pharyngitis were mainly manifested as abdominal pain, diarrhea, rash, etc., which were relieved after drug withdrawal. In terms of safety, it was considered that Houyanqing Oral Liquid had controllable risk and high safety, which was rated as grade B. Compared with ribavirin aerosol alone, Houyanqing Oral Liquid combined with ribavirin aerosol can significantly improve the total response rate, shorten the time to abatement of fever and di-sappearance of throat pain and mucosal congestion, and alleviate mucosal congestion and cough with sputum. With medium-quality evidence, the effectiveness was rated as grade B. Compared with ribavirin aerosol alone, Houyanqing Oral Liquid combined with ribavirin aerosol had cost-effectiveness advantages in the treatment of acute pharyngitis, and its economy was rated as grade C with the evidence of general quality. For acute pharyngitis, Houyanqing Oral Liquid can shorten the disease course and obviously relieve sore throat. Moreover, it can be used for the treatment of radioactive pharyngitis and oral ulcer, and thus its innovation was rated as grade B. With convenient and simple administration and standard and complete drug information, the suitability of this drug was rated as grade B. Houyanqing Oral Liquid is derived from the folk prescription in Hunan province and has been subjected to real-world studies, and thus the TCM characteristics was rated as grade B. According to the ratings of all the dimensions, the comprehensive value of Houyanqing Oral Liquid in the clinical treatment of acute pharyngitis was determined as grade B, with sufficient evidence and clear results. It is suggested that the results should be conditionally converted into relevant policy of clinical basic drug management according to procedures.

Effects on viral suppression and the early-immune expression of ribavirin against spring viremia of carp virus in vitro.

Spring viremia of carp virus (SVCV) is a globally distributed virus that causes severe clinical symptoms and high mortality in fish belonging to the families Cyprinidae and Siluridae. To protect the host against viral infection, understanding the relatedness between viral susceptibility and antiviral mechanisms must be crucial. Thus, we evaluated the viral suppression efficacy of ribavirin by measuring the transcription levels of viral and immune genes in vitro. The results showed that following ribavirin treatment after SVCV infection (MOI 0.1), ribavirin inhibited SVCV replication in epithelioma papulosum cyprini (EPC) cells and completely inhibited viral gene (G and N) expression at concentrations above 10 µg/mL at 48 h post-infection. Ribavirin does not directly damage SVCV particles but inhibits early viral replication. In the absence of SVCV infection, the immunological dynamics triggered by ribavirin resulted in upregulated pattern recognition receptors and proinflammatory cytokine-related genes (i.e., PI3K, MYD88, IRAK1, RIG-І, MAVS, Mx1, TNF-α, and NF-κB). Furthermore, EPC cells treated with ribavirin following SVCV infection showed upregulation of PI3K, MYD88, IRAK1, RIG-І, TNF-α, and NF-κB genes within 24 h post-SVCV infection, suggesting that ribavirin positively inhibits the SVCV infection in vitro.

Diabetic patients with chronic hepatitis C virus response compared to non diabetics when treated with directly acting antiviral therapy.

BACKGROUND AND STUDY AIMS: Hepatitis C virus (HCV) impairs glucose homoestasis, thus influences its clinical picture and prognosis. This study aimed at evaluating Diabetes mellitus (DM) on Egyptian patients with chronic hepatitis C (CHC), and its impact on their virologic response when treated with directly acting antiviral (DAA) medications. PATIENTS AND METHODS: Adult patients with CHC were divided into 2 groups; Diabetic patients, and Non diabetic patients serving as control group. All patients were subjected to thorough clinical evaluation, basic biochemical laboratory tests including fasting blood glucose/glycosylated haemoglobin (HbA1C), and virologic assay. They were treated with various combined DAAs, and were monitored during, at and after end of treatment. RESULTS: Diabetic patients constituted 9.85 % of CHC, and had generally worse laboratory tests (significantly higher transaminases, platelet count, Fib4 and hepatic steatosis) than non diabetic patients, and a less sustained virologic response (SVR) (significantly in Sofosbuvir (SOF) + pegylated interferon (PegIFN) + ribavirin (RBV), SOF + RBV, SOF + daclatasvir (DAC)). Although DM did not play a significant influence on SVR, yet Fib4 and SOF + RBV + PEG-IFN were significant factors affecting SVR among diabetics, while female gender and viraemia were significant factors affecting SVR among non diabetics. Hepatic fibrosis and SOF/RBV significantly influenced SVR in both groups. CONCLUSIONS: Diabetic patients with CHC have worse liver biochemical profile, yet DM per se did not influence the virologic response to DAAs, however, some factors played roles in affecting SVR among them.

Favipiravir for treating COVID-19.

BACKGROUND: The coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) continues to challenge the health workforce and societies worldwide. Favipiravir was suggested by some experts to be effective and safe to use in COVID-19. Although this drug has been evaluated in randomized controlled trials (RCTs), it is still unclear if it has a definite role in the treatment of COVID-19. OBJECTIVES: To assess the effects of favipiravir compared to no treatment, supportive treatment, or other experimental antiviral treatment in people with acute COVID-19. SEARCH METHODS: We searched the Cochrane COVID-19 Study Register, MEDLINE, Embase, the World Health Organization (WHO) COVID-19 Global literature on coronavirus disease, and three other databases, up to 18 July 2023. SELECTION CRITERIA: We searched for RCTs evaluating the efficacy of favipiravir in treating people with COVID-19. DATA COLLECTION AND ANALYSIS: We used standard Cochrane methodological procedures for data collection and analysis. We used the GRADE approach to assess the certainty of evidence for each outcome. MAIN RESULTS: We included 25 trials that randomized 5750 adults (most under 60 years of age). The trials were conducted in Bahrain, Brazil, China, India, Iran, Kuwait, Malaysia, Mexico, Russia, Saudi Arabia, Thailand, the UK, and the USA. Most participants were hospitalized with mild to moderate disease (89%). Twenty-two of the 25 trials investigated the role of favipiravir compared to placebo or standard of care, whilst lopinavir/ritonavir was the comparator in two trials, and umifenovir in one trial. Most trials (24 of 25) initiated favipiravir at 1600 mg or 1800 mg twice daily for the first day, followed by 600 mg to 800 mg twice a day. The duration of treatment varied from five to 14 days. We do not know whether favipiravir reduces all-cause mortality at 28 to 30 days, or in-hospital (risk ratio (RR) 0.84, 95% confidence interval (CI) 0.49 to 1.46; 11 trials, 3459 participants; very low-certainty evidence). We do not know if favipiravir reduces the progression to invasive mechanical ventilation (RR 0.86, 95% CI 0.68 to 1.09; 8 trials, 1383 participants; very low-certainty evidence). Favipiravir may make little to no difference in the need for admission to hospital (if ambulatory) (RR 1.04, 95% CI 0.44 to 2.46; 4 trials, 670 participants; low-certainty evidence). We do not know if favipiravir reduces the time to clinical improvement (defined as time to a 2-point reduction in patients' admission status on the WHO's ordinal scale) (hazard ratio (HR) 1.13, 95% CI 0.69 to 1.83; 4 trials, 721 participants; very low-certainty evidence). Favipiravir may make little to no difference to the progression to oxygen therapy (RR 1.20, 95% CI 0.83 to 1.75; 2 trials, 543 participants; low-certainty evidence). Favipiravir may lead to an overall increased incidence of adverse events (RR 1.27, 95% CI 1.05 to 1.54; 18 trials, 4699 participants; low-certainty evidence), but may result in little to no difference inserious adverse eventsattributable to the drug (RR 1.04, 95% CI 0.76 to 1.42; 12 trials, 3317 participants; low-certainty evidence). AUTHORS' CONCLUSIONS: The low- to very low-certainty evidence means that we do not know whether favipiravir is efficacious in people with COVID-19 illness, irrespective of severity or admission status. Treatment with favipiravir may result in an overall increase in the incidence of adverse events but may not result in serious adverse events.

Treatment of the most difficult-to-cure hepatitis C virus-infected population with sofosbuvir / velpatasvir.

INTRODUCTION: Pangenotypic therapies for infections with hepatitis C virus (HCV), although universal and highly effective, entail a risk of treatment failure. OBJECTIVES: Our study aimed to identify the population of HCV­infected patients most difficult to cure with the sofosbuvir / velpatasvir (SOF/VEL) regimen. PATIENTS AND METHODS: The effectiveness of the SOF/VEL regimen with a possible addition of ribavirin (RBV) was evaluated in populations known to be less responsive to treatment, and then in a population characterized by the combination of all factors impairing effectiveness, comprising patients treated with this regimen in the EpiTer­2 multicenter retrospective study. RESULTS: A total of 2267 patients were treated with SOF/VEL±RBV. Of those, 2078 (96.4%) achieved sustained virologic response. The cure rate was 93.5% among 646 patients infected with genotype (GT) 3, 92.3% among 635 patients with cirrhosis, 95.5% in a population of 1233 men, and 94.1% among 421 patients with body mass index (BMI) above 30. An analysis in a group of 43 men with cirrhosis and obesity infected with GT3 showed the effectiveness of pangenotypic therapy at only 79.1%, falling to 66.7% in individuals with previous treatment failure. CONCLUSIONS: In a large population of SOF/VEL­treated HCV­infected patients, we showed relatively low effectiveness of the regimen in treatment­experienced men with cirrhosis and obesity, infected with GT3. Triple therapy should be considered when initiating the treatment of HCV infections in this group, which, however, needs to be confirmed in further studies. Previous studies were conducted in less demanding populations, because they did not take into account sex and BMI, which significantly affect the treatment effectiveness.