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BackgroundHepatitis C is an important agent of liver damage in patients with chronic kidney disease and the advent of DAAs has dramatically changed the management of HCV positive patients, including those with advanced CKD. Sofosbuvir is the backbone of many anti-HCV regimens based on DAAs but it remains unclear whether it is appropriate for HCV-infected patients with stage 4-5 CKD.Study aims and designWe performed a systematic review of the literature with a meta-analysis of clinical studies in order to evaluate the efficacy and safety of SOF-based DAA regimens in patients with stage 4-5 CKD. The primary outcome was sustained viral response (as a measure of efficacy); the secondary outcomes were the frequency of SAEs and drop-outs due to AEs (as measures of tolerability). The random-effects model of DerSimonian and Laird was adopted, with heterogeneity and stratified analyses.ResultsThirty clinical studies (n=1537 unique patients) were retrieved. The pooled SVR12 and SAEs rate was 0.99 (95% confidence intervals, 0.97; 1.0, I2=99.8%) and 0.09 (95% CI, 0.05; 0.13, I2=84.3%), respectively. The pooled SVR12 rate in studies with high HCV RNA levels at baseline was lower, 0.87 (95% CI, 0.75; 1.0, I2=73.3%) (P

Abstract A liquid chromatography–tandem mass spectrometry (LC–MS/MS) method was developed for the analysis of ribavirin in chicken. Samples was extracted with 0.1% formic acid and purified by Hypercarb cartridge prior to LC–MS/MS analysis. The eluates were evaporated to dryness, reconstituted in 1 mL 5mM ammonium acetate containing 5% acetonitrile (v/v) and 0.1% (v/v) formic acid. Chromatographic separation was performed on a Hypercarb analytical column under a gradient elution program with acetonitrile and 0.1% (v/v) formic acid in 5 mM ammonium acetate at a flow rate of 0.6 ml/min. The intraday and interday accuracy ranged from − 7.83 − 1.39%, and − 6.38 − 2.25%, with precisions between 1.34 − 3.88%% and 1.10 − 4.67%. The limits of detection (LODs) and limits of quantitation (LOQs) of ribavirin was 0.1 ng/mL and 0.5 ng/mL, respectively. The method was validated for linearity, accuracy, precision, matrix effect and stability. Application of the method confirmed 3 ribavirin positive samples out of 50 commercial chicken samples, with concentrations of ribavirin ranging from 0.9 μg/kg to 5.8 μg/kg a, respectively. Additionally, both AB Sciex 5500 and Agilent 6945B were proven to be suitable in ribavirin separation and quantification. The described method is suitable for the determination of ribavirin in chicken in analytical practice to monitor illegal addition of this kind of anti–viral drug.

Аim: diagnosis and treatment algorithms in the clinical recommendations intended for general practitioners, gastroenterologists, infectious disease specialists, hepatologists on the of chronic hepatitis C are presented.Summary. Chronic viral hepatitis C is a socially significant infection, the incidence of which in the Russian Federation remains significantly high. Over the past 10 years, great progress has been made in the treatment of hepatitis C — direct acting antiviral drugs have appeared. The spectrum of their effectiveness allows to achieve a sustained virological response in more than 90 % of cases, even in groups that were not previously considered even as candidates for therapy or were difficult to treat — patients receiving renal replacement therapy, after liver transplantation (or other organs), at the stage of decompensated liver cirrhosis, HIV co-infected, etc. Interferons are excluded from the recommendations due to their low effectiveness and a wide range of adverse events. The indications for the treatment have been expanded, namely, the fact of confirmation of viral replication. The terms of dispensary observation of patients without cirrhosis of the liver have been reduced (up to 12 weeks after the end of therapy). Also, these recommendations present approaches to active screening of hepatitis in risk groups, preventive and rehabilitation measures after the end of treatment.Conclusion. Great success has been achieved in the treatment of chronic hepatitis C. In most cases, eradication of viral HCV infection is a real task even in patients at the stage of cirrhosis of the liver, with impaired renal function, HIV co-infection, after solid organs transplantation.

Abstract Background The main differences in cases of sudden elevation of hepatic enzyme levels during immunochemotherapy are the reactivation of the hepatitis B virus or drug‐induced liver injury. Here, we report a case of acute liver injury caused by the hepatitis E virus (HEV) during chemotherapy for malignant lymphoma, wherein the patient was successfully treated for the hepatitis and resumed chemotherapy to completion. Case A 57‐year‐old woman visited her local doctor because she felt lightweight and tired. The patient underwent lower gastrointestinal endoscopy and was diagnosed with a malignant lymphoma of the small intestine (diffuse large B‐cell lymphoma). The patient had a history of oral consumption of undercooked pork liver to improve anemia and was diagnosed with acute hepatitis E. Conclusion This report highlights the successful treatment of HEV infection in a patient undergoing immunosuppressive therapy for malignant lymphomas. A novel aspect of this study is the safe and effective use of ribavirin, an antiviral medication, along with continued chemotherapy, which resulted in sustained virological response (SVR) and the completion of the planned chemotherapy regimen. This report also provides new insights into the management of HEV infections in immunosuppressed patients undergoing chemotherapy and emphasizes the importance of considering HEV as a potential cause of acute liver injury in such cases. The successful use of ribavirin along with continued chemotherapy offers a promising treatment strategy for clinicians to consider in similar scenarios.

BackgroundHuman adenovirus (HAdV) infections in children can lead to profound pulmonary injury and are frequently associated with severe complications, particularly in cases concomitant with plastic bronchitis. Managing this condition presents significant challenges and carries an exceptionally high fatality rate. Regrettably, there are currently no specific antiviral agents that have demonstrated efficacy in treating severe adenovirus pneumonia in children.Case presentationWe report a 10-month-old infant suffering from severe adenovirus pneumonia combined with plastic bronchitis (PB). He received intravenous ribavirin combined with recombinant human interferon α1b (INFα1b) aerosol inhalation and his condition eventually improved. No side effects occurred during the treatment, and the long-term prognosis was favorable.ConclusionIn this case, the combination therapy of intravenous ribavirin and INFα1b seems to have contributed to the resolution of illness and may be considered for similar cases until stronger evidence is generated.

Summary: Background: Hepatitis B surface antigen (HBsAg) seroclearance marks regression of hepatitis B virus (HBV) infection. However, more than one‐fifth of patients with functional cure following pegylated interferon‐based therapy may experience HBsAg seroreversion. The mechanisms causing the HBV relapse remain unclear. Aim: To investigate the level and origin of HBV transcripts in patients with functional cure and their role in predicting relapse. Methods: Liver tissue obtained from patients with functional cure, as well as uncured and treatment‐naïve HBeAg‐negative patients with chronic hepatitis B (CHB) were analysed for intrahepatic HBV markers. HBV capture and RNA sequencing were used to detect HBV integration and chimeric transcripts. Results: Covalently closed circular DNA (cccDNA) levels and the proportion of HBsAg‐positive hepatocytes in functionally cured patients were significantly lower than those in uncured and treatment‐naïve HBeAg‐negative patients. Integrated HBV DNA and chimeric transcripts declined in functionally cured patients compared to uncured patients. HBsAg‐positive hepatocytes present in 25.5% of functionally cured patients, while intrahepatic HBV RNA remained in 72.2%. The levels of intrahepatic HBV RNA, integrated HBV DNA, and chimeric transcripts were higher in functionally cured patients with intrahepatic HBsAg than in those without. The residual intrahepatic HBsAg in functionally cured patients was mainly derived from transcriptionally active integrated HBV DNA; meanwhile, trace transcriptional activity of cccDNA could also remain. Two out of four functionally cured patients with intrahepatic HBsAg and trace active cccDNA experienced HBV relapse. Conclusion: Integrated HBV DNA and cccDNA maintain transcriptional activity and maybe involved in HBsAg seroreversion in intrahepatic HBsAg‐positive patients with functional cure and linked to virological relapse. [ABSTRACT FROM AUTHOR]

Hand, foot, and mouth disease (HFMD) caused by enterovirus A71 (EV-A71) infection, currently lacks specific preventive and therapeutic interventions. Here, we demonstrated that Pien Tze Huang (PZH) could dose-dependently inhibit EV-A71 replication at the cellular level, resulting in significant reductions in EV-A71 virus protein 1 (VP1) expression and viral yields in Vero and human rhabdomyosarcoma cells. More importantly, we confirmed that PZH could protect mice from EV-A71 infection for the first time, with Ribavirin serving as a positive control. PZH treatment reduced EV-A71 VP1 protein expression, viral yields in infected muscles, and improved muscle pathology. Additionally, we conducted a preliminary mechanism study using quantitative proteomics. The results suggested that the suppression of the PI3K/AKT/mTOR and NF-κB signaling pathways may contribute to the anti-EV-A71 activity of PZH. These findings provide strong evidence supporting the potential therapeutic application of PZH for EV-A71 infection management. [ABSTRACT FROM AUTHOR]

Methicillin-resistant Staphylococcus aureus (MRSA) infection poses a severe threat to global public health due to its high mortality. Currently, polymyxins are mainly used for the treatment of Gram-negative bacterial-related infection, while exhibiting limited antibacterial activities against Staphylococcus aureus (S. aureus). However, the combination of antibiotics with antibiotic adjuvants is a feasible strategy for the hard-treated infection and toxicity reducing. We will investigate the antibacterial activity of simeprevir (SIM), which treated for genotype 1 and 4 chronic hepatitis C, combined with polymyxins against MRSA through high-throughput screening technology. In our study, the synergistic antibacterial effect of SIM and polymyxins against S. aureus in vitro was found by checkerboard assay and time-growth curve. The cytotoxicity of SIM combined with polymyxin B sulfate [PB(S)] or polymyxin E (PE) in vitro was evaluated using CCK-8, human RBC hemolysis and scratch assays. In addition, we investigated the eradication of biofilm formation of S. aureus by biofilm inhibition assay and the killing of persister cells. Moreover, we evaluated the therapeutic effect and in vivo toxicity of the combination against MRSA in murine subcutaneous abscess model. Furthermore, it was preliminarily found that SIM significantly enhanced the destruction of MRSA membrane by SYTOX Green and DISC3(5) probes. In summary, these results reveal that the therapy of SIM combined with polymyxins (especially PE) is promising for the treatment of MRSA infection. [ABSTRACT FROM AUTHOR]

Chikungunya virus (CHIKV) is an arthropod-transmitted Alphavirus endemic to countries in Africa and Asia, including Indonesia, which causes debilitating arthralgia which can last several years. The rapid spread of CHIKV to new areas makes the discovery of antiviral agents a high priority. α-mangostin is a xanthone from mangosteen (Garcinia mangostana) pericarp and has antiviral activity against Hepatitis C and Dengue viruses. We investigated the antiviral activity of α-mangostin against CHIKV in HepG2 cells in pre-, post- and combination treatments compared to the common antiviral medicine ribavirin, as well their cytotoxicity. Our results show dose-responsive reductions in viral titer in all treatment regimes, with post- and combination treatments being more effective than pre-treatment only (IC50 = 7.79, 5.99 and 6.39 μM, respectively), but with poor specificity (SI = 1.39, 1.81 and 1.70, respectively) compared to ribavirin. Neither compound showed a direct virucidal effect. These results suggest α-mangostin effectively inhibits CHIKV replication in this cell line. [ABSTRACT FROM AUTHOR]

Alphaviruses are serious zoonotic threats responsible for significant morbidity, causing arthritis or encephalitis. So far, no licensed drugs or vaccines are available to combat alphaviral infections. About 300,000 chikungunya virus (CHIKV) infections have been reported in 2023, with more than 300 deaths, including reports of a few cases in the USA as well. The discovery and development of small-molecule drugs have been revolutionized over the last decade. Here, we employed a cell-based screening approach using a series of in-house small-molecule libraries to test for their ability to inhibit CHIKV replication. DCR 137, a quinazoline derivative, was found to be the most potent inhibitor of CHIKV replication in our screening assay. Both, the cytopathic effect, and immunofluorescence of infected cells were reduced in a dose-dependent manner with DCR 137 post-treatment. Most importantly, DCR 137 was more protective than the traditional ribavirin drug and reduced CHIKV plaque-forming units by several log units. CHIKV-E2 protein levels were also reduced in a dose-dependent manner. Further, DCR 137 was probed for its antiviral activity against another alphavirus, the Ross River virus, which revealed effective inhibition of viral replication. These results led to the identification of a potential quinazoline candidate for future optimization that might act as a pan-alphavirus inhibitor. [ABSTRACT FROM AUTHOR]

Hepatitis C-associated osteosclerosis (HCAO) is a very rare condition that can be observed in a small number of patients with Hepatitis C Virus (HCV) infection. HCAO is usually characterized by widespread bone sclerosis, associated with severe bone pain, and increased levels of bone turnover markers, especially alkaline phosphatase (ALP). In this report, we present the case of a 55-year-old woman who was affected by HCV and came to our attention for severe and diffuse bone pain. Radiological studies showed bone sclerosis, and bone mineral density (BMD) was markedly increased, as well as serum ALP levels. The patient was initially treated with intravenous pamidronate, which provided only a transient benefit on clinical symptoms. Then antiviral therapy for HCV (interferon-alfa and ribavirin) was started and it was effective in making the viral load undetectable. After a long follow-up period, we observed a persistent remission of bone pain, a reduction in BMD together with a progressive trend toward the normalization of bone turnover markers. In conclusion, HCAO, although rare, should be considered among the potential causes of increased bone mass in patients with HCV infection, and treatment for the underlying infection may be effective in controlling the manifestations of this disease. [ABSTRACT FROM AUTHOR]

Combining antiviral drugs with different mechanisms of action can help prevent the development of resistance by attacking the infectious agent through multiple pathways. Additionally, by using faster and more economical screening methods, effective synergistic drug candidates can be rapidly identified, facilitating faster paths to clinical testing. In this work, a rapid method was standardized to identify possible synergisms from drug combinations. We analyzed the possible reduction in the antiviral effective concentration of drugs already approved by the FDA, such as ivermectin (IVM), ribavirin (RIBA), and acyclovir (ACV) against Zika virus (ZIKV), Chikungunya virus (CHIKV), and herpes virus type 2 (HHV-2). Essential oils (EOs) were also included in the study since they have been reported for more than a couple of decades to have broad-spectrum antiviral activity. We also continued studying the antiviral properties of one of our patented molecules with broad-spectrum antiviral activity, the ferruginol analog 18-(phthalimid-2-yl)ferruginol (phthFGL), which presented an IC99 of 25.6 μM for the three types of virus. In general, the combination of IVM, phthFGL, and oregano EO showed the greatest synergism potential against CHIKV, ZIKV, and HHV-2. For instance, this combination achieved reductions in the IC99 value of each component up to ~8-, ~27-, and ~12-fold for CHIKV, respectively. The ternary combination of RIBA, phthFGL, and oregano EO was slightly more efficient than the binary combination RIBA/phthFGL but much less efficient than IVM, phthFGL, and oregano EO, which indicates that IVM could contribute more to the differentiation of cell targets (for example via the inhibition of the host heterodimeric importin IMP α/β1 complex) than ribavirin. Statistical analysis showed significant differences among the combination groups tested, especially in the HHV-2 and CHIKV models, with p = 0.0098. Additionally, phthFGL showed a good pharmacokinetic profile that should encourage future optimization studies. [ABSTRACT FROM AUTHOR]

(1) Background. Hepatitis C infection often leads to extrahepatic manifestations, including cryoglobulinemic vasculitis. This systematic review aimed to assess the efficacy and safety of rituximab in treating hepatitis C-associated cryoglobulinemic vasculitis. (2) Methods. Following PRISMA guidelines, databases were searched for relevant studies. Eligibility criteria included studies on hepatitis C-associated cryoglobulinemic vasculitis treated with rituximab. (3) Results. Nine studies met the eligibility criteria and were included in this analysis. Rituximab was commonly administered at 375 mg/m2 weekly for one month. The results consistently demonstrated the efficacy of rituximab, whether as a standalone treatment or as part of a therapeutic regimen. The combination of rituximab with Peg-IFN-α and ribavirin significantly increased the complete response rate compared to Peg-IFN-α and ribavirin alone (54.5% vs. 33.3%, p < 0.05). The 3-year sustained response rate was notably higher in the rituximab combination group (83.3% vs. 40%). In another trial, rituximab achieved remission in 83.3% of patients at 6 months, compared to only 8.3% in the control group. The efficacy of rituximab was supported by long-term experience, with clinical benefits in patients with severe cryoglobulinemic vasculitis, including those resistant to standard therapies. Mild adverse events were generally reported, with rare severe reactions in some studies. (4) Conclusions: In conclusion, rituximab appeared to be effective and safe in managing hepatitis C-associated cryoglobulinemic vasculitis, either alone or with antiviral therapy. [ABSTRACT FROM AUTHOR]

Ribavirin is an important antiviral with demonstrated activity against coronaviruses such as severe acute respiratory syndrome coronavirus and coronavirus disease 2019 virus. However, abuse of ribavirin will cause great environmental damage and threaten human health owing to its reproductive toxicity and teratogenicity. Therefore, an innovative detection method is demanded for simple and sensitive detection of ribavirin. This work reports an imprinted colloidal crystal array (ICCA) for ribavirin sensing. The building blocks of the ICCA are ribavirin imprinted spheres, which possess superior binding efficiency toward ribavirin. Benefiting from the highly ordered structure, the ICCA exhibits optical properties which change upon binding ribavirin. The changes in reflectance wavelength enable a fast and label‐free detection of ribavirin between 21 and 245 μmol L−1. Moreover, the sensor shows excellent selectivity for ribavirin detection in river water. Overall, all the results reported in this work demonstrate that the ICCA should be a promising detection tool for antivirals. © 2023 Society of Industrial Chemistry. [ABSTRACT FROM AUTHOR]

Background: Respiratory viruses, particularly adenoviruses (ADV), influenza A virus (e.g., H1N1), and coronaviruses (e.g., HCoV-229E and SARS-CoV-2) pose a global public health problem. Therefore, developing natural wide-spectrum antiviral compounds for disrupting the viral life cycle with antioxidant activity provides an efficient treatment approach. Herein, biosurfactant (Sur) and C50 carotenoid pigment (Pig) of haloalkaliphilic archaeon Natrialba sp. M6 which exhibited potent efficacy against hepatitis and anti-herpes simplex viruses, were investigated against pulmonary viruses. Methods: The cytotoxicity of the extracted Sur and Pig was examined on susceptible cell lines for ADV, HIN1, HCoV-229E, and SARS-CoV-2. Their potential against the cytopathic activity of these viruses was detected with investigating the action modes (including, virucidal, anti-adsorption, and anti-replication), unveiling the main mechanisms, and using molecular docking analysis. Radical scavenging activity was determined and HPLC analysis for potent extract (Sur) was performed. Results: All current investigations stated higher anti-pulmonary viruses of Sur than Pig via mainly virucidal and/or anti-replicative modes. Moreover, Sur had stronger ADV's capsid protein binding, ADV's DNA polymerase inhibition, suppressing hemagglutinin and neuraminidase of H1N1, and inhibiting chymotrypsin-like (3CL) protease of SARS-CoV-2, supporting with in-silico analysis, as well as radical scavenging activity than Pig. HPLC analysis of Sur confirmed the predominate presence of surfactin in it. Conclusion: This study declared the promising efficacy of Sur as an efficient pharmacological treatment option for these pulmonary viruses and considered as guide for further in vivo research. [ABSTRACT FROM AUTHOR]

In its 'Road map for neglected tropical diseases 2021–2030', the World Health Organization outlined its targets for control and elimination of neglected tropical diseases (NTDs) and research needed to achieve them. For many NTDs, this includes research for new treatment options for case management and/or preventive chemotherapy. Our review of small-molecule anti-infective drugs recently approved by a stringent regulatory authority (SRA) or in at least Phase 2 clinical development for regulatory approval showed that this pipeline cannot deliver all new treatments needed. WHO guidelines and country policies show that drugs may be recommended for control and elimination for NTDs for which they are not SRA approved (i.e. for 'off-label' use) if efficacy and safety data for the relevant NTD are considered sufficient by WHO and country authorities. Here, we are providing an overview of clinical research in the past 10 years evaluating the anti-infective efficacy of oral small-molecule drugs for NTD(s) for which they are neither SRA approved, nor included in current WHO strategies nor, considering the research sponsors, likely to be registered with a SRA for that NTD, if found to be effective and safe. No such research has been done for yaws, guinea worm, Trypanosoma brucei gambiense human African trypanosomiasis (HAT), rabies, trachoma, visceral leishmaniasis, mycetoma, T. b. rhodesiense HAT, echinococcosis, taeniasis/cysticercosis or scabies. Oral drugs evaluated include sparfloxacin and acedapsone for leprosy; rifampicin, rifapentin and moxifloxacin for onchocerciasis; imatinib and levamisole for loiasis; itraconazole, fluconazole, ketoconazole, posaconazole, ravuconazole and disulfiram for Chagas disease, doxycycline and rifampicin for lymphatic filariasis; arterolane, piperaquine, artesunate, artemether, lumefantrine and mefloquine for schistosomiasis; ivermectin, tribendimidine, pyrantel, oxantel and nitazoxanide for soil-transmitted helminths including strongyloidiasis; chloroquine, ivermectin, balapiravir, ribavirin, celgosivir, UV-4B, ivermectin and doxycycline for dengue; streptomycin, amoxicillin, clavulanate for Buruli ulcer; fluconazole and isavuconazonium for mycoses; clarithromycin and dapsone for cutaneous leishmaniasis; and tribendimidine, albendazole, mebendazole and nitazoxanide for foodborne trematodiasis. Additional paths to identification of new treatment options are needed. One promising path is exploitation of the worldwide experience with 'off-label' treatment of diseases with insufficient treatment options as pursued by the 'CURE ID' initiative. [ABSTRACT FROM AUTHOR]

Objective: We sought to evaluate the variability of HIV-1 and its effect on immuno-virological response among adolescents living with perinatally acquired HIV (APHI). Methods: A cohort study was conducted from 2018–2020 among 311 APHI receiving antiretroviral therapy (ART) in Cameroon. Sequencing of protease and reverse transcriptase regions was performed for participants experiencing virological failure, VF, (Plasma viral load, PVL ≥ 1000 RNA copies/ml). HIV-1 subtypes were inferred by phylogeny; immuno-virological responses were monitored at 3-time points (T1-T3). Cox regression modeling was used to estimate adjusted hazard ratios (aHRs) of progression to: CD4 < 250, and PVL > 5log10, adjusted for acquired drug resistance, gender, ART line, adherence, and duration on treatment; p < 0.05 was considered statistically significant. Results: Of the 141 participants in VF enrolled, the male-female ratio was 1:1; mean age was 15 (±3) years; and median [IQR] duration on ART was 51 [46–60] months. In all phases, 17 viral clades were found with a predominant CRF02_AG (58.2%, 59.4%, and 58.3%). From T1-T3 respectively, there was an increasing CD4 count (213 [154–313], 366 [309–469], and 438 [364–569] cells/mm3) and decline log10 PVL (5.23, 4.43, and 4.43), similar across subtypes. Among participants with CRF02_AG infection, duration of treatment was significantly associated with both rates of progression to CD4 < 250, and PVL > 5log10, aHR = 0.02 (0.001–0.52), and aHR = 0.05 (0.01–0.47) respectively. Moreover, four potential new HIV-1 recombinants were identified (CRF02_AG/02D, CRF02_AG/02A1F2, D/CRF02_AG, and AF2/CRF02_AG), indicating a wide viral diversity. Conclusion: Among APHI in settings like Cameroon, there is a wide genetic diversity of HIV-1, driven by CRF02_AG and with potential novel clades due to ongoing recombination events. Duration of treatment significantly reduces the risk of disease progression. [ABSTRACT FROM AUTHOR]

A fixed-dose combination of sofosbuvir/velpatasvir (SOF/VEL) plus weight-based ribavirin (RBV) for 12 weeks is recommended for the treatment of patients with hepatitis C virus (HCV)-associated decompensated cirrhosis. However, large global studies, while confirming the effectiveness of SOF/VEL in a broad range of patients, often exclude these patients. This Phase 2, single-arm, open-label study in adult patients with HCV-associated decompensated cirrhosis in France and the USA aimed to provide further data on the safety and efficacy of SOF/VEL plus RBV for 12 weeks in this population. Patients were treated with a fixed-dose combination of SOF 400 mg/VEL 100 mg plus weight-based RBV once daily for 12 weeks. The inclusion criteria were chronic HCV infection (≥6 months), quantifiable HCV RNA at screening, Child–Turcotte–Pugh class B or C cirrhosis, and liver imaging within 6 months of Day 1 to exclude hepatocellular carcinoma. Among 32 patients who initiated treatment, 78.1% achieved sustained virologic response 12 weeks after the end of treatment (SVR12). Failure to achieve SVR12 was due to non-virologic reasons (investigator discretion, n = 1; death, n = 6). All 25 patients in the per-protocol population achieved SVR12 and all but one achieved sustained virologic response 24 weeks after the end of treatment. Adverse events (AEs) were as expected for a patient population with advanced liver disease. All Grade 3–4 and serious AEs and deaths were deemed unrelated to treatment. In patients with HCV-associated decompensated cirrhosis, SOF/VEL plus RBV achieved high SVR12 rates and was generally well tolerated. [ABSTRACT FROM AUTHOR]

The hepatitis E virus (HEV) is increasingly acknowledged as the primary cause of acute hepatitis. While most HEV infections are self-limiting, cases of chronic infection and fulminant hepatitis necessitate the administration of anti-HEV medications. However, there is a lack of specific antiviral drugs designed for HEV, and the currently available drug (ribavirin) has been associated with significant adverse effects. The development of innovative antiviral drugs involves targeting distinct steps within the viral life cycle: the early step (attachment and internalization), middle step (translation and RNA replication), and late step (virus particle formation and virion release). We recently established three HEV reporter systems, each covering one or two of these steps. Using these reporter systems, we identified various potential drug candidates that target different steps of the HEV life cycle. Through rigorous in vitro testing using our robust cell culture system with the genotype 3 HEV strain (JE03-1760F/P10), we confirmed the efficacy of these drugs, when used alone or in combination with existing anti-HEV drugs. This underscores their significance in the quest for an effective anti-HEV treatment. In the present review, we discuss the development of the three reporter systems, their applications in drug screening, and their potential to advance our understanding of the incompletely elucidated HEV life cycle. [ABSTRACT FROM AUTHOR]

About 40% of the Guillain-Barré syndrome (GBS) cases are associated with prodromal infections; occasionally, it has been associated to chronic hepatitis C or its reactivation. A 38-year-old man came to our attention after transaminase elevation occurred during recovery from GBS. All the possible causes of acute hepatitis were excluded except for the positivity of HCVRNA, and a diagnosis of new onset hepatitis C was made. Recalling patient history, we observed that (i) anti-HCV antibodies were negative and liver enzymes were normal 7 weeks before GBS onset; (ii) in the early stages of ICU admission, liver enzymes started to rise, but the elevation remained mild under steroid treatment; (iii) serum aminotransferase peak occurred 11 weeks after GBS onset; and (iv) HCV RNA was already significantly high when anti-HCV antibodies became positive, consistent with an acute hepatitis. Furthermore, anti-HCV seroconversion was likely delayed or blurred by steroids and immunoglobulin infusions. The interval of time between GBS onset and transaminase elevation compared with the patient clinical history allows us to establish a cause-effect relationship between the two diseases. All patients with GBS should be tested for hepatitis C, or its reactivation if already present, and followed up for an early diagnosis and treatment. [ABSTRACT FROM AUTHOR]

Ribavirin use for respiratory syncytial virus (RSV) infection in patients with haematologic malignancies (HM) and haematopoietic stem cell transplant (HSCT) recipients remains controversial. To summarize the current evidence of ribavirin treatment in association with mortality and progression to lower respiratory tract infection (LRTI) among patients with HM/HSCT with RSV infection. MEDLINE, Embase, and the Institute for Scientific Information Web of Science. Randomized controlled trials and observational studies investigating the effects of ribavirin, compared with treatment without ribavirin, for RSV infection. Patients with HM/HSCT. Ribavirin versus no ribavirin. The risk of bias in non-randomized studies of exposure (ROBIN-E). The random-effects model was used to calculate the pooled OR (pOR) with 95% CI for the pooled effect estimates of ribavirin benefits. Grading of recommendation assessment, development, and evaluation was used to evaluate the certainty of evidence. One randomized controlled trial and 14 observational studies were included, representing 1125 patients with HM/HSCT. Ribavirin use was not associated with lower all-cause or RSV-associated mortality with pORs [95% CI] of 0.81 [0.40, 1.66], I2 = 55% (low certainty of evidence) and 0.48 [0.11, 2.15], I2 = 64% (very low certainty of evidence), respectively. In subgroup analyses, ribavirin use was associated with lower mortality in patients with HM/HSCT with LRTI with pOR [95% CI] of 0.19 [0.07, 0.51], I2 = 0% (moderate certainty of evidence). In subgroup analyses among studies providing adjusted OR, ribavirin use was associated with lower all-cause mortality with pOR of 0.41 [0.23, 0.74], I2 = 0% (moderate certainty of evidence). In addition, aerosolized ribavirin was associated with lower progression to LRTI with pOR [95% CI] of 0.27 [0.09, 0.80], I2 = 71% (low certainty of evidence). Ribavirin may be a reasonable option to treat RSV in patients with HM/HSCT in the absence of other effective antiviral agents. [ABSTRACT FROM AUTHOR]

The treatment of patients infected with the hepatitis C virus (HCV) has been revolutionised by the development of direct-acting antiviral agents (DAAs) that target specific HCV proteins involved in viral replication. The first DAAs were associated with clinical problems such as adverse drug reactions and pharmacokinetic drug–drug interactions (DDIs). Current FDA/EMA-approved treatments are combinations of DAAs that simultaneously target the HCV N5A-protein, the HCV N5B-polymerase and the HCV NS3/4A-protease. Adverse events and DDIs are less likely with these DAA combinations but several DDIs of potential clinical significance remain. Much of the available information on the interaction of DAAs with CYP drug-metabolising enzymes and influx and efflux transporters is contained in regulatory summaries and is focused on DDIs of likely clinical importance. Important DDIs perpetrated by current DAAs include increases in the pharmacokinetic exposure to statins and dabigatran. Some mechanistic information can be deduced. Although the free concentrations of DAAs in serum are very low, a number of these DDIs are likely mediated by the inhibition of systemic influx transporters, especially OATP1B1/1B3. Other DDIs may arise by DAA-mediated inhibition of intestinal efflux transporters, which increases the systemic concentrations of some coadministered drugs. Conversely, DAAs are victims of DDIs mediated by cyclosporin, ketoconazole, omeprazole and HIV antiretroviral drug combinations, especially when boosted by ritonavir and, to a lesser extent, cobicistat. In addition, concurrent administration of inducers, such as rifampicin, carbamazepine and efavirenz, decreases exposure to some DAAs. Drug-drug interactions that increase the accumulation of HCV N3/4A-protease inhibitors like grazoprevir may exacerbate hepatic injury in HCV patients. Plain Language Summary: Direct-acting antiviral (DAA) drugs have revolutionised the treatment of patients with hepatitis C. Compared to the earlier agents, currently-approved DAA combinations have fewer adverse effects and are less likely to be associated with pharmacokinetic drug-drug interactions (DDIs). However, adverse events and DDIs still occur when DAAs are coadministered with certain drugs. In most cases DAAs likely perpetrate DDIs by inhibiting drug transporters. However, access to more detailed information on HCV DAAs as substrates and inhibitors of drug-metabolising enzymes and transporters, and the incidence of DDIs in target populations, would enhance the understanding of the significance of the likelihood of DDIs with DAAs. [ABSTRACT FROM AUTHOR]

Background Alpha kinase 1 (ALPK1) agonist has recently been reported to demonstrate anti–hepatitis B virus (HBV) efficacy via activating NF-κB signaling, which is crucial for maximizing interferon (IFN) responses. Here, we investigated the impact of ALPK1 on HBV replication and explored ALPK1 variants for predicting the response to pegylated IFN-α (PegIFN-α) treatment. Methods The potential anti-HBV effect of ALPK1 was evaluated in HBV-integrated and HBV-infected hepatoma cells. The potentially functional genetic variants of ALPK1 were screened out, and their correlations with PegIFN-α treatment response were assessed in 945 hepatitis B e antigen (HBeAg)–positive patients with chronic hepatitis B (CHB). Results We revealed that ALPK1 inhibited HBV replication in hepatocytes via activating the JAK-STAT pathway. ALPK1 overexpression improved the anti-HBV effect of IFN-α in cell models. A missense variant, rs35389530 (P660L), of ALPK1 was strongly associated with combined response (CR; namely, HBeAg seroconversion and HBV DNA level <3.3log10 IU/mL) to PegIFN-α treatment in patients with CHB (P = 2.12 × 10−6). Moreover, a polygenic score integrating ALPK1 _rs35389530 and 2 additional genetic variants was further significantly associated with CR (P trend = 9.28 × 10−7), hepatitis B surface antigen (HBsAg) level (P trend =.0002), and HBsAg loss (P trend =.025). Conclusions The anti-HBV effects of ALPK1 through activating JAK-STAT pathway provides a new perspective for CHB therapy. ALPK1 _rs35389530 and polygenic score are potential biomarkers to predict PegIFN-α treatment response and may be used for optimizing CHB treatment. [ABSTRACT FROM AUTHOR]

The impact of direct-acting antivirals (DAA) therapy on lipid and glucose metabolism and kidney function in patients with hepatitis C virus (HCV) infection, along with its side effects on blood cells, remains controversial. Therefore, we conducted a study that enrolled 280 patients with HCV infection who achieved sustained virologic response after treatment with DAA therapy without ribavirin to evaluate the metabolic changes, renal function, and anemia risk based on real-world data. This study was an observational prospective study with a follow-up period of 12 weeks after the initiation of DAA therapy. Data on biochemical tests, renal function, blood counts, viral load, and host genomics were recorded before treatment and after 12 weeks of treatment with DAAs. DAA therapy reduced fibrosis-4 scores and improved liver function, with significant reductions in aspartate transaminase, alanine aminotransferase, and total bilirubin levels. However, DAA therapy slightly increased uric acid, cholesterol, and low-density lipoprotein cholesterol levels. It significantly reduced fasting blood glucose levels and hemoglobin A1C index (HbA1C) in the study group, while hemoglobin (Hb) and hematocrit (HCT) concentrations decreased significantly (4.78 ± 21.79 g/L and 0.09% ± 0.11%, respectively). The estimated glomerular filtration rate (eGFR) decreased by 12.89 ± 39.04 mL/min/1.73m2. Most variations were not related to the genotype, except for Hb, HCT, and HbA1C. Anemia incidence increased from 23.58% before treatment to 30.72% after treatment. Patients with HCV-1 genotype had a higher rate of anemia than did patients with genotype 6 (36.23% vs. 24.62%). Multivariate analysis showed that the risk of anemia was related to female sex, cirrhosis status, fibrosis-4 score, pretreatment eGFR, and pretreatment Hb level. The results of our study can provide helpful information to clinicians for the prognosis and treatment of HCV infection. [ABSTRACT FROM AUTHOR]

Crystallization selectivity is an important principle in polymorph control. Ribavirin Form I, Form II, DMSO solvate, and amorphous ribavirin are prepared, and the short-range order similarities between these solid forms and ribavirin aqueous solution and DMSO solution are compared via mid-frequency Raman difference spectra (MFRDS). The crystallization process from amorphous ribavirin to Form I and from solution to amorphous phase is explained. Reasons for the difficulty in preparing the DMSO solvate are proposed. The rationale provided for the crystallization selectivity provides a foundation for the synthesis of metastable phases with a robust and convenient method. [ABSTRACT FROM AUTHOR]

INTRODUCTION: Data are scarce regarding the virologic impact and safety of immune checkpoint inhibitors (ICI) in patients with chronic hepatitis C virus (HCV) infection. We examined the virologic impact of ICI in HCV-infected patients with solid tumors and their safety. METHODS: HCV-infected patients with solid tumor treated with ICI at our institution between April 26, 2016, and January 5, 2022, were enrolled in a prospective observational study. The primary outcomes were ICI-induced changes in HCV viremia (HCV inhibition and HCV reactivation) and safety of ICI. RESULTS: We enrolled 52 consecutive patients with solid tumors treated with ICI. Most were men (41; 79%), White (31; 59%), without cirrhosis (34; 65%), and with HCV genotype 1 (40; 77%). Four patients (7.7%) experienced HCV inhibition while receiving ICI including 1 patient who developed undetectable viremia for 6 months in the absence of direct-acting antivirals (DAA). Two patients (4%) developed HCV reactivation, both while receiving immunosuppressive therapy for ICI-related toxic effects. Adverse events occurred in 36 patients (69%), and 39 of the 47 adverse events (83%) were grade 1-2. Grade 3-4 adverse events occurred in 8 patients (15%), and in all cases, they were related to ICI, not to HCV. No HCV-associated liver failure or death occurred. DISCUSSION: Inhibition of HCV replication with virologic cure can develop in patients receiving ICI without DAA. HCV reactivation occurs primarily in patients receiving immunosuppressants for ICI-related toxic effects. ICI are safe in HCV-infected patients with solid tumors. Chronic HCV infection should not be considered a contraindication for ICI therapy. [ABSTRACT FROM AUTHOR]

Objective: Crimean-Congo Hemorrhagic Fever (CCHF) is a zoonotic viral disease mainly transmitted by tick contact and progresses with fever and bleeding. This study aimed to examine the epidemiological, clinical, and laboratory characteristics of the patients who were followed up with the diagnosis of Crimean-Congo Hemorrhagic Fever in the last 11 years in our hospital's Infectious Diseases and Clinical Microbiology clinic. Methods: Patients older than 18 years of age who were followed up with the diagnosis of Crimean-Congo Hemorrhagic Fever between January 2011 and December 2022 were included in the study. Patients' age, gender, occupation, etc. sociodemographic characteristics, complaints on admission, tick contact histories, laboratory parameters, length of hospital stay, and 3-month survival were retrospectively analyzed from the data in the patient files. The diagnosis of the disease was based on the detection of virus-specific IgM by ELISA (enzyme-linked immunosorbent assay) or detection of viral RNA by RT-PCR (Reverse Transcriptase-Polymerase Chain Reaction). Results: Of the 106 patients, 73 (68.9%) were male, and 33 (33.1%) were female. The mean age was 49.43±14.16 years. 105 (99.1%) of the patients lived in rural areas. There were 76 (71.7%) patients with a history of tick contact, and 58 (76.3%) of them stated that they removed the tick by their means. The month with the highest number of applications was June (n=55, 51.8%). The year 2022 (n=38, 35.9%) had the highest number of patients detected. The time between the onset of symptoms and admission to the hospital was 3.14±7.66 (min 1-max 13) days. While the most common complaints of body pain (n=101, 95.3%), fatigue (n=101, 95.3%), and fever (n=81, 76.4%) were described at the first admission, the most common findings in physical examination were high fever (n= 79, 74.5%), hematuria (n=9, 8.5%), hypotension, and tachycardia (n=8, 7.5%). While 42 (39.6) patients were referred to a 3rd level center, 64 (60.4%) were discharged with good recovery. One patient died in the 3rd level center to which he was referred. Conclusion: In this study, it was determined that livestock workers/farmers and men were more likely to get the disease, the history of tick contact was significantly described in disease transmission, and the cases occurred more frequently, especially in June. Especially in the spring and summer when the incidence increases, tick contact history should be questioned in patients presenting with suspicious clinical findings, and the preliminary diagnosis of CCHF should not be ignored. [ABSTRACT FROM AUTHOR]

Sofosbuvir (S), daclatasvir (D), ledipasvir, or velpatasvir (V) containing first-line hepatitis C virus (HCV) treatment regimens fail to cure viremia in 5–10%. We report our experience of HCV retreatment using these first-line drugs, in a setting where second-line anti-HCV drugs are not available. Adults, who had relapsed after first complete course of a sofosbuvir-containing first-line, pegylated interferon free, anti-HCV treatment regimen with or without ribavirin (Riba) were included. Retreatment regimen, tailored to the failed anti-HCV regimen, was based on principle of using first-line drugs for 24 weeks with ribavirin and swapping between pangenotypic and genotype-specific regimens. Retreatment outcome was categorized as successful (achieved undetectable HCV RNA at the end of treatment [ETR] and sustained viral response at week 12 [SVR12]), non-responder (failed to achieve ETR), or relapse (achieved ETR but not achieved SVR12). Twelve patients (9 male; 7 cirrhosis; all genotype 3) who had relapsed to prior anti-HCV treatment (4 SD12, 4 SD24, 1 SDRiba12, 1 SDRiba24, 2 SV12) were included. Following retreatment (2 SDRiba24, 10 SVRiba24), all achieved ETR but only 9 (75%) achieved SVR12. Two among three, in whom retreatment failed, achieved SVR12 following another course of sofosbuvir/velpatasvir/ribavirin for 24 weeks. Overall, 11/12 (92%) patients achieved SVR12 following retreatment with the first-line anti-HCV drugs. HCV retreatment could be a treatment option if second-line anti-HCV drugs are not available. Successful retreatment could be achieved, in a large proportion, with the use of first-line drugs for 24 weeks with ribavirin and swapping of pangenotypic/genotype-specific regimens (NCT03483987). [ABSTRACT FROM AUTHOR]

Introduction: Efficacy and safety of the attachment inhibitor fostemsavir + optimized background therapy (OBT) were evaluated through 48 and 96 weeks in the phase 3 BRIGHTE trial in heavily treatment-experienced (HTE) adults failing their current antiretroviral regimen. Here, we report 240-week efficacy and safety of fostemsavir + OBT in adults with multidrug-resistant human immunodeficiency virus (HIV)-1 in BRIGHTE. Methods: Heavily treatment-experienced adults failing their current regimen entered the randomized cohort (RC; 1–2 fully active antiretrovirals available) or non-randomized cohort (NRC; no fully active antiretrovirals available) and received open-label fostemsavir + OBT (starting Day 8 in RC and Day 1 in NRC). Endpoints included proportion with virologic response (HIV-1 RNA < 40 copies/mL, Snapshot), immunologic efficacy, and safety. Results: At Week 240, 45% and 22% of the RC and NRC, respectively, had virologic response (Snapshot); 7% of the RC and 5% of the NRC had missing data due to coronavirus disease 2019 (COVID-19)-impacted visits. In the observed analysis, 82% of the RC and 66% of the NRC had virologic response. At Week 240, mean change from baseline in CD4+ T-cell count was 296 cells/mm3 (RC) and 240 cells/mm3 (NRC); mean CD4+/CD8+ ratio increased between Weeks 96 and 240 (RC 0.44 to 0.60; NRC 0.23 to 0.32). Between Weeks 96 and 240, four participants discontinued for adverse events, one additional participant experienced a drug-related serious adverse event, and six deaths occurred (median last available CD4+ T-cell count, 3 cells/mm3). COVID-19-related events occurred in 25 out of 371 participants; all resolved without incident. Conclusion: Through ~5 years, fostemsavir + OBT demonstrated durable virologic and immunologic responses with no new safety concerns between Weeks 96 and 240, supporting this regimen as a key therapeutic option for HTE people with multidrug-resistant HIV-1. Trial registration: ClinicalTrials.gov, NCT02362503. [ABSTRACT FROM AUTHOR]

Introduction: Sofosbuvir is one of the direct acting antiviral drugs (DAAs) acting on specific Hepatitis C virus (HCV) target proteins which are important for virus replication and assembly. Sofosbuvir can be used alone or combined with ribavirin which is a purine nucleoside analogue with antiviral activity against a wide range of RNA viruses. Ribavirin has a little antiviral activity against HCV when used alone. Aim of Study: The present study aims at investigating the histopathological effect of sofosbuvir as compared to sofosbuvir used in combination with ribavirin on submandibular salivary glands of adult male albino rats. Materials and Methods: 21 male albino rats were classified into 3 groups. Control group consisting of 5 rats, group A consisting of 8 rats which received sofosbuvir at a dose of 40 mg/kg/day for 5 weeks and group B consisting of 8 rats which received sofosbuvir at a dose of 40 mg/kg/day and ribavirin at a dose of 30mg/kg/day for 5 weeks. At the end of the experiment, submandibular glands were dissected and examined histologically and by immuno-fluorescent microscope. Results: The submandibular salivary gland in rats treated with sofosbuvir (group A) showed degenerative effects, while those in group B showed more degenerative effects. Immunofluorescent expression of immunoglobulin M (IgM) was more pronounced in group B as compared to group A. Conclusion: Treatment with sofosbuvir had a degenerative effect on submandibular gland which got worsen when used in combination with ribavirin. In addition, the immunoglobulin M expression was clear-cut in the group received both drugs. [ABSTRACT FROM AUTHOR]

Background: Hepatitis C virus (HCV) is the primary contributor to chronic hepatic diseases. A rapid change in the situation took place with the advent of oral direct-acting antivirals (DAAs). However, a comprehensive review of the adverse event (AE) profile of the DAAs is lacking. This cross-sectional study aimed to analyze the reported Adverse Drug Reactions (ADRs) with DAA treatment using data from VigiBase, the WHO Individual Case Safety Report (ICSR) database. Methods: All ICSRs reported to VigiBase with sofosbuvir (SOF), daclatasvir (DCV), sofosbuvir /ledipasvir (SOF/LDV) and ombitasvir/paritaprevir/ritonavir (OBV/PTV/r) in Egypt were extracted. Descriptive analysis was performed to summarize patients' and reactions' characteristics. Information components (ICs) and proportional reporting ratios (PRRs) for all reported ADRs were calculated to identify signals of disproportionate reporting. Logistic regression analysis was performed to identify the DAAs association with serious events of concern while adjusting for age, gender, pre-existing cirrhosis, and ribavirin use. Results: Out of 2925 reports, 1131 (38.6%) were serious. The most commonly reported reactions; anaemia (21.3%), HCV relapse (14.5%) and headache (14%). For the disproportionality signals; HCV relapse was reported with SOF/DCV (IC 3.65, 95% CrI 3.47–3.79) and SOF/RBV (IC 3.69, 95% CrI 3.37–3.92), while anaemia (IC 2.85, 95% CrI 2.26–3.27) and renal impairment (IC 2.12, 95% CrI 0.7–3.03) were reported with OBV/PTV/r. Conclusion: The highest severity index and seriousness were reported with SOF/RBV regimen. A significant association was found for OBV/PTV/r with renal impairment and anaemia although being the superior regimen in terms of efficacy. The study findings call for further population-based studies for clinical validation. [ABSTRACT FROM AUTHOR]

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Acute pneumonia (AP), triggered primarily by pathogens like bacteria and viruses, is a leading cause of human mortality. Ribavirin, a broad-spectrum antiviral agent, plays a pivotal role in the treatment of AP. However, its therapeutic use is hindered by the need for high dosages and the associated cardiac and hepatic toxicities. In this study, we synthesized polyethylene glycol-modified cationic liposomes to encapsulate ribavirin (RBV-PCL) and formulated it into a spray, aiming to enhance the effectiveness of RBV through respiratory administration. Lipopolysaccharide (LPS), a compound known to induce AP models in animals, was utilized in our research. Successfully, we established an acute pneumonia model in mice using aerosol inhalation. Through animal experiments, we investigated the therapeutic effects of RBV-PCL on mice with AP. In vivo studies revealed promising results. RBV-PCL effectively prolonged the survival of mice with AP, significantly reduced the levels of inflammatory markers such as interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α), and inhibited the infiltration of neutrophils in the lungs and spleens of mice. These findings suggest that RBV-PCL can effectively suppress the inflammatory response in mice with AP, thus holding significant potential as a novel therapeutic approach for the treatment of acute pneumonia.

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.