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Summary: Background: Sofosbuvir, velpatasvir and voxilaprevir (SOF/VEL/VOX) is the recommended rescue therapy for patients with chronic hepatitis C infection who fail direct‐acting antivirals (DAAs). Data are limited on the effectiveness of this treatment after the current first‐line therapies. Our aim was to analyse the effectiveness and safety of SOF/VEL/VOX among patients failing sofosbuvir/velpatasvir (SOF/VEL) or glecaprevir/pibrentasvir (GLE/PIB). Methods: Retrospective multicentre study (26 Spanish hospitals), including chronic hepatitis C patients unsuccessfully treated with SOF/VEL or GLE/PIB, and retreated with SOF/VEL/VOX ± ribavirin for 12 weeks between December 2017 and December 2022. Results: In total, 142 patients included: 100 (70.4%) had failed SOF/VEL and 42 (29.6%) GLE/PIB. Patients were mainly men (84.5%), White (93.9%), with hepatitis C virus genotype (GT) 3 (49.6%) and 47.2% had liver cirrhosis. Sustained virological response (SVR) was evaluated in 132 patients who completed SOF/VEL/VOX and were followed 12 weeks after end of treatment; 117 (88.6%) achieved SVR. There were no significant differences in SVR rates according to initial DAA treatment (SOF/VEL 87.9% vs. GLE/PIB 90.2%, p = 0.8), cirrhosis (no cirrhosis 90% vs. cirrhosis 87.1%, p = 0.6) or GT3 infection (non‐GT3 91.9% vs. GT3 85.5%, p = 0.3). However, when considering the concurrent presence of SOF/VEL treatment, cirrhosis and GT3 infection, SVR rates dropped to 82.8%. Ribavirin was added in 8 (6%) patients, all achieved SVR. Conclusion: SOF/VEL/VOX is an effective rescue therapy for failures to SOF/VEL or GLE/PIB, with an SVR of 88.6%. Factors previously linked to lower SVR rates, such as GT3 infection, cirrhosis and first‐line therapy with SOF/VEL were not associated with lower SVRs. [ABSTRACT FROM AUTHOR]

This study was conducted as a single‐site, open‐label, randomized, replicated crossover trial with 4 treatment periods. The aim was to evaluate the bioequivalence of a generic test drug containing velpatasvir and sofosbuvir compared to an established brand‐name medication in healthy White subjects under fasting conditions. Blood samples were collected at specified intervals up to 72 hours after dosing to measure the concentrations of velpatasvir and sofosbuvir using a certified high‐performance liquid chromatography with tandem mass spectrometry method. The bioequivalence of the 2 formulations was confirmed when statistical analysis showed that confidence intervals for the log‐transformed peak concentration and area under the concentration‐time curve from time 0 to the last quantifiable sample were within an acceptable range from 80% to 125%. Criteria for bioequivalence were met for both area under the concentration‐time curve from time 0 until the last quantifiable sample and peak concentration parameters. No adverse effects were reported during this trial in both groups. [ABSTRACT FROM AUTHOR]

We enrolled 21 patients with laboratory-confirmed yellow fever (YF), hospitalized at Eduardo de Menezes Hospital, Brazil, to be treated with sofosbuvir, a drug approved for hepatitis C. Given the absence of specific YF antiviral treatments, the off-label nonrandomized sofosbuvir treatment aimed to address high disease severity and the risk of fatal outcomes. Patients received a daily dose of 400 mg sofosbuvir from 4 to 10 days post–symptom onset. YF viral load (VL) comparisons were made between treated and nontreated patients who either survived or died. The genomic VL for the treated group steadily decreased after day 7 post–symptom onset, suggesting that sofosbuvir might reduce YF VL. This study underscores the urgent need for YF antiviral therapies, advocating for randomized clinical trials to further explore sofosbuvir's role in YF treatment. [ABSTRACT FROM AUTHOR]

Illicit drug and alcohol abuse have significant negative consequences for individuals who inject drugs/use drugs (PWID/UDs), including decreased immune system function and increased viral pathogenesis. PWID/UDs are at high risk of contracting or transmitting viral illnesses such as human immunodeficiency virus (HIV), hepatitis B virus (HBV), and hepatitis C virus (HCV). In South Africa, a dangerous drug-taking method known as "Bluetoothing" has emerged among nyaope users, whereby the users of this drug, after injecting, withdraw blood from their veins and then reinject it into another user. Hence, the transmission of blood-borne viruses (BBVs) is exacerbated by this "Bluetooth" practice among nyaope users. Moreover, several substances of abuse promote HIV, HBV, and HCV replication. With a specific focus on the nyaope drug, viral replication, and transmission, we address the important influence of abused addictive substances and polysubstance use in this review. [ABSTRACT FROM AUTHOR]

Hepatitis C virus core antigen (HCVcAg) testing can simplify and decrease costs of HCV infection confirmation compared to molecular testing (nucleic acid testing). We piloted HCVcAg testing for the confirmation of active infection. The study was conducted during June through December 2022 among the police and the general population of Islamabad, Pakistan age 18 years and older. Initial screening for HCV antibody was conducted using a rapid diagnostic test (RDT) for all consenting participants. Those who tested positive had venous blood samples tested for HCVcAg, platelets and aspartate aminotransferase (AST). Persons with HCVcAg values ≥3 fmol/L were defined as viremic, and they were offered treatment with direct acting antiviral (DAA) medications, sofosbuvir and daclatasvir. Aspartate aminotransferase to platelet ratio index (APRI) was calculated for each HCV infected person, and those with an APRI score <1.5 received treatment for 12 weeks, while those with APRI ≥ to 1.5 received 24 weeks of treatment. A total of 15,628 persons were screened for anti‐HCV using RDT and 643 (4.1%) tested positive. HCVcAg values of ≥3 fmol/L was found in 399/643 (62.1%), and all were offered and accepted treatment. Of those treated, 273/399 (68.4%) returned for a follow‐up SVR and HCVcAg was not detected in 261/273, a 95.6% cure rate. The pilot study demonstrated the effectiveness of reaching and treating an urban population using RDT for screening and HCVcAg for confirmation of infection and test of cure. [ABSTRACT FROM AUTHOR]

Objectives: Interleukin-28B (IL-28B) gene polymorphisms play an important role in response prediction of direct-acting antivirals (DAAs) treatment, including Sofosbuvir and Daclatasvir with or without Ribavirin. The purpose of this study was to assess the IL-28B polymorphism SNP (rs12979860) and other clinical factors as response predictors for the sustained virological response (SVR) in chronic HCV-infected patients taking DAA therapy. Methods: A cross-sectional and observational study was carried out among 104 HCV-infected patients who completed a course of Sofosbuvir and Daclatasvir along with Ribavirin. Patients were classified according to their response to therapy. Genotyping of IL-28B was determined through polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) assay, and HCV genotyping was identified by PCR method. We analyzed the response prediction of IL-28 gene polymorphism among patients receiving DAA therapy. Results: Overall, IL-28B CC, CT, and TT genotypes were found in 56 (53.8%), 22 (21.2%), and 26 (25.0%) patients, respectively. Higher early virological response (EVR) and SVR were observed in patients with the rs12979860 CC alleles (82.1% and 75%) as compared to CT/TT alleles (54.2% and 20.8%). IL-28B CC genotype (OR=0.14; 95% CI=0.04-0.44; p=0.001) and EVR (OR=0.20; 95% CI=0.05-0.71; p=0.013) remained significantly associated with SVR in the multivariate regression analysis. However, the FIB-4 score (OR=4.24; 95% CI=1.46-11.75; p=0.008) is a strong predictor of non-SVR. Conclusion: The antiviral efficacy of triple therapy (sofosbuvir, daclatasvir, and ribavirin) is influenced by the variability of the IL-28B gene, as well as the EVR and FIB-4 score. These variables also play a significant role in predicting the treatment response of patients with chronic HCV infection in Pakistan. [ABSTRACT FROM AUTHOR]

Patients with chronic hepatitis C virus (HCV) infection and decompensated cirrhosis are an important population for antiviral therapy yet under-represented in clinical trials. HCV direct-acting antiviral (DAA) therapies, unlike interferon-containing regimens, can be safely utilized in decompensated patients. Per guidelines from the American Association for the Study of Liver Diseases (AASLD), therapy of choice in HCV and decompensated cirrhosis is sofosbuvir, an HCV polymerase inhibitor, combined with a replication complex inhibitor (NS5A inhibitor) with or without ribavirin. Combination therapy with a HCV protease inhibitor and an NS5A inhibitor is effective in this population but is specifically not recommended in AASLD guidelines due to safety concerns. Important risk factors for further decompensation during DAA therapy are serum albumin < 3.5 g/dL, MELD (Model for End-Stage Liver Disease) score > 14, or HCV genotype 3 infection. Although sustained virologic response (SVR) is achieved less often in patients with decompensated vs compensated cirrhosis, in clinical studies response rates are > 80%. Both Child-Turcotte-Pugh Class at baseline and viral genotype can affect these response rates. Achieving SVR lowers risk of mortality, but to a lesser extent than in individuals with compensated cirrhosis. Likewise, treating patients for HCV infection along with successful treatment for hepatocellular carcinoma improves risks of both liver-related and overall mortality. In fewer than one third of cases, treating transplant-eligible, HCV-infected patients pre-transplant enables their delisting from transplant wait lists. [ABSTRACT FROM AUTHOR]

Background and aims: NS5A inhibitors are an important option for treating chronic HCV-GT4 patients. Retreatments after NS5A-based DAAs failure are limited. We aimed to determine the effectiveness and safety of SOF/VEL-containing regimens for HCV retreatment after NS5A-regimen failure. Methods: Prospective cohort study assessing the efficacy and safety of retreatment with SOF/VEL in addition to either voxilaprevir or ribavirin in patients who had failed previous NS5A-based DAA treatment. The primary outcome was SVR12. Safety and tolerability data were collected. Results: One hundred fifty patients were included. The mean age was 53 years, 64% were male, and 50% of included patients had liver cirrhosis, with a mean FIB-4 score of 3.12 (± 2.30) and Child-Turcotte-Pugh (CTP) score of 7.27 (± 0.48), and failed previous SOF/DCV + RBV, they were assigned to 24 weeks of SOF/VEL + RBV. The remaining 50% of participants had no liver cirrhosis and failed previous SOF/DCV, they were assigned to 12 weeks of treatment with SOF/VEL/VOX. Overall, SVR12 was achieved by 96% (n = 144/150) of included patients; 97.33% for SOF/VEL/VOX and 94.67% for SOF/VEL/RBV. Thirty-one patients experienced mild AEs; the most commonly reported mild AE in the SOF/VEL + RBV group was hyperbilirubinemia (n = 9) whereas in the SOF/VEL/VOX group were headache (n = 4) and vertigo (n = 4). Only one patient in SOF/VEL + RBV reported moderate treatment-related AE in the form of anemia and no reported severe AE. Conclusion: Retreatment of non-cirrhotic patients with 12 weeks SOF/VEL/VOX and treatment of cirrhotic patients with 24 weeks with SOF/VEL + RBV after the failure of first-line NS5A-based therapy was an effective and well-tolerated treatment option. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Sofosbuvir treatment regimens for chronic HCV infection have recently been linked to extra hepatic side effects. This study aimed to show how sofosbuvir affected the adult male albino rat testis. Forty adult male albino rats were used. The rats were equally split into two main groups (I and II), then each group subdivided into two subgroups (A and B). Each rat in group I (control) received 0.5 ml of distilled water every day for four weeks. Each rat in group II (sofosbuvir-treated) received 0.5 ml of distilled water containing 7.2 mg of sofosbuvir every day for four weeks. After four weeks (subgroups IA and IIA) and eight weeks (subgroups IB and IIB) of treatment, the rats were sacrificed. Histological, biochemical, and morphometric studies on the testes were conducted. The data were analyzed. Examination of testes of sovaldi treated group revealed histopathological changes. Biochemical and morphometric analysis showed reduced levels of reduced glutathione and seminiferous tubule epithelial height respectively. Following a 4-week drug withdrawal period, the testes only partially recovered. We concluded that sofosbuvir induced deteriorating changes in the adult male albino rats' testes. These changes were proved by histological and biochemical studies. These changes were incompletely reversible after cession of treatment. Researches investigating the effect of adding drugs that have antioxidant properties during sofosbuvir therapy are recommended. [ABSTRACT FROM AUTHOR]

Background: The activation of hepatic stellate cells (HSCs) has been emphasized as a leading event of the pathogenesis of liver cirrhosis, while the exact mechanism of its activation is largely unknown. Furthermore, the novel non-invasive predictors of prognosis in cirrhotic patients warrant more exploration. miR-541 has been identified as a tumor suppressor in hepatocellular carcinoma and a regulator of fibrotic disease, such as lung fibrosis and renal fibrosis. However, its role in liver cirrhosis has not been reported. Methods: Real-time PCR was used to detect miR-541 expression in the liver tissues and sera of liver cirrhosis patients and in the human LX-2. Gain- and loss-of-function assays were performed to evaluate the effects of miR-541 on the activation of LX-2. Bioinformatics analysis and a luciferase reporter assay were conducted to investigate the target gene of miR-541. Results: miR-541 was downregulated in the tissues and sera of patients with liver cirrhosis, which was exacerbated by deteriorating disease severity. Importantly, the lower expression of miR-541 was associated with more episodes of complications including ascites and hepatic encephalopathy, a shorter overall lifespan, and decompensation-free survival. Moreover, multivariate Cox's regression analysis verified lower serum miR-541 as an independent risk factor for liver-related death in cirrhotic patients (HR = 0.394; 95% CI: 0.164–0.947; P = 0.037). miR-541 was also decreased in LX-2 cells activated by TGF-β and the overexpression of miR-541 inhibited the proliferation, activation and hydroxyproline secretion of LX-2 cells. JAG2 is an important ligand of Notch signaling and was identified as a direct target gene of miR-541. The expression of JAG2 was upregulated in the liver tissues of cirrhotic patients and was inversely correlated with miR-541 levels. A rescue assay further confirmed that JAG2 was involved in the function of miR-541 when regulating LX-2 activation and Notch signaling. Conclusions: Dysregulation of miR-541/JAG2 axis might be a as a new mechanism of liver fibrosis, and miR-541 could serve as a novel non-invasive biomarker and therapeutic targets for liver cirrhosis. [ABSTRACT FROM AUTHOR]

Dengue virus (DENV) causes dengue fever and dengue hemorrhagic fever, and DENV infection kills 20,000 people annually worldwide. Therefore, the development of anti-DENV drugs is urgently needed. Sofosbuvir (SOF) is an effective drug for HCV-related diseases, and its triphosphorylated metabolite inhibits viral RNA synthesis by the RNA-dependent RNA polymerase (RdRp) of HCV. (2′R)-2′-Deoxy-2′-fluoro-2′-methyluridine (FMeU) is the dephosphorylated metabolite produced from SOF. The effects of SOF and FMeU on DENV1 replication were analyzed using two DENV1 replicon-based methods that we previously established. First, a replicon-harboring cell assay showed that DENV1 replicon replication in human hepatic Huh7 cells was decreased by SOF but not by FMeU. Second, a transient replicon assay showed that DENV1 replicon replication in Huh7 cells was decreased by SOF; however, in hamster kidney BHK-21 cells, it was not suppressed by SOF. Additionally, the replicon replication in Huh7 and BHK-21 cells was not affected by FMeU. Moreover, we assessed the effects of SOF on infectious DENV1 production. SOF suppressed infectious DENV1 production in Huh7 cells but not in monkey kidney Vero cells. To examine the substrate recognition of the HCV and DENV1 RdRps, the complex conformation of SOF-containing DENV1 RdRp or HCV RdRp was predicted using AlphaFold 2. These results indicate that SOF may be used as a treatment for DENV1 infection. [ABSTRACT FROM AUTHOR]

Background: Sofosbuvir/Velpatasvir (Epclusa, ECS) is the first pan-genotype direct-acting antiviral agent (DAA) for hepatitis C virus (HCV) infection, and Danoprevir (DNV) is the first DAA developed by a Chinese local enterprise, which is suitable for combined use with other drugs to treat genotype 1b chronic hepatitis C. However, previous reports have never compared the real-world data of ECS and DNV. Patients and methods: 178 chronic hepatitis C patients were retrospectively recruited, and 94cases were accepted with Sofosbuvir/Velpatasvir ± Ribavirin (ECS group), and others (n = 84 treated with DNV combination therapy (DNV group). The HCV genotype, virological response, adverse effects and some laboratory biochemical indexes were contrasted between above two groups in the real world study. Results: DNV group had significantly lower level of alpha-fetoprotein (AFP), lower rates of decompensated cirrhosis (P < 0.05). ECS group possessed more 6a (31.91% vs.13.10%) while DNV group was provided with more 1b (48.81% vs. 22.34%) patients. Significantly poor liver function was detected in ECS group at 4-week treatment (ALT and AST) and 12-week follow-up (AST) (all P < 0.05). The SVR12 undetectable rates of both groups were 100%, and no serious event was observed during the treatment and follow-up in both groups. Conclusion: In this retrospective real-world study, the efficacy of DNV combined therapy is similar to Sofosbuvir/Velpatasvir ± Ribavirin for chronic HCV infection, and the safety is comparable. DNV based therapy is a promising regimen for chronic hepatitis C. [ABSTRACT FROM AUTHOR]

Objective To investigate the efficacy and safety of sofosbuvir/velpatasvir alone or in combination with ribavirin in Chinese patients with genotype 3B HCV/HIV infection. Methods A total of 299 patients with genotype 3B HCV/HIV infection who attended The Third People’s Hospital of Kunming from January 2017 to December 2020 were enrolled and treated with sofosbuvir/velpatasvir alone or in combination with ribavirin for 12 weeks, and they were followed up for 12 weeks after drug withdrawal. The patients were evaluated in terms of sustained virologic response at 12 weeks after treatment (SVR12) and adverse reactions. The independent-samples t test or the Mann-Whitney U test was used for comparison of continuous data between two groups, and the chi-square test was used for comparison of categorical data between two groups； the Agresti-Coull method was used to evaluate the 95% confidence interval (CI) of SVR12； univariate and multivariate non-conditional logistic regression analyses were used to investigate the influencing factors for SVR. Results The 299 patients with genotype 3B HCV/HIV infection had a mean age of 43.92±6.84 years, among whom the male patients accounted for 77.3% (231/299), the patients with liver cirrhosis accounted for 36.5% (109/299), the patients with a history of antiviral therapy accounted for 13.4% (40/299), and the patients receiving sofosbuvir/velpatasvir combined with ribavirin accounted for 27.8% (83/299) . The overall SVR was 87.0% (260/299) for all patients, and there was no significant difference in SVR12 between the patients receiving sofosbuvir/velpatasvir alone and those receiving sofosbuvir/velpatasvir combined with ribavirin (87.5% vs 85.5%，χ2 =0.203，P=0.653) . There was a significant difference in SVR12 between the patients without liver cirrhosis and those with liver cirrhosis (90.0% vs 81.7%，χ2 =4.256，P=0.039), and the patients receiving antiviral therapy for the first time had a significantly higher SVR12 than the treatment-experienced patients (93.4% vs 45.0%，χ2 =71.670，P<0.001) . The univariate and multivariate logistic regression analyses showed that platelet count (odds ratio ［OR］=0.957，95%CI：0.931— 0.984，P=0.002), liver stiffness measurement (OR=1.446，95%CI：1.147— 1.822，P= 0.002), and experience in treatment (OR=13.807，95%CI：2.970—64.174，P=0.001) were independent influencing factors for SVR in patients with genotype 3B HCV/HIV infection. There were 41 cases of serious adverse events, all of which occurred within 2 weeks after antiviral therapy, and 28 cases were resolved without drug withdrawal or active treatment, while 13 cases were not resolved after active treatment and were resolved after the antiviral drugs were stopped for 2—5 days, with no similar reactions observed when the drugs were used again after remission. Conclusion Sofosbuvir/velpatasvir alone or in combination with ribavirin has relatively good efficacy and safety in patients with genotype 3B HCV/HIV infection. [ABSTRACT FROM AUTHOR]

Background: MicroRNAs (miR) are small sequence of nucleotides that can affect multiple genes involved in the hepatitis C virus (HCV) life cycle and disease development. The purpose of the present study was to investigate the clinical significance of serum microRNA profiles in a cohort of Egyptian patients with chronic HCV infection before and after combined sofosbuvir and daclatasvir treatment, as well as to gain a better understanding of the exact interaction mechanism in HCV transcriptional activity via differentially expressed miRNAs. For 12 weeks, 50 patients were eligible for and received sofosbuvir (400 mg daily) and daclatasvir (60 mg daily) treatment. Each patient's blood was obtained twice: once before therapy began and again three months afterwards. Results: The current study found that serum levels of circulating miR-122, miR-221, miR-23a, miR-125, miR-217, miR-224, and miR-181a were high in HCV pre-treatment patients, but after 12 weeks of direct-acting antiviral (DAAs) treatment, there was a statistically significant reduction in expression levels of miR-122, miR-221, miR-23a, miR-125, miR-217, and miR-224 (p < 0.001). There is no statistical significance for miR-181a. Conclusion: The key differentially expressed microRNAs before and after the direct-acting antiviral (DAA) regimen were connected to the dynamics of chronic HCV infection, suggesting their potential as predictive biomarkers for HCV clearance after sofosbuvir and daclatasvir therapy. [ABSTRACT FROM AUTHOR]

Chronic hepatitis C (HCV) affects up to 3.25 million children and adolescents. Early treatment of HCV in children and adolescents reduces progression to advanced liver disease and cancer. Treatment for HCV has evolved to highly effective direct acting antiviral therapy in adults and now in children ≥ 3 years of age. This review focuses on the role of sofosbuvir and velpatasvir (SOF/VEL), a newer treatment of children and adolescents with chronic HCV. SOF/VEL is a pangenotypic DAA with primary clearance via the liver and biliary excretion. It has been studied in children and adolescents and is approved in the US for use in children and adolescents ≥ 3 years of age. Although the data are currently limited, SOF/VEL has demonstrated sustained viral response rates similar to comparable DAAs in the range of 95– 98%. To date, side effects have been minimal. [ABSTRACT FROM AUTHOR]

The local manufacture of advanced pharmaceutical products has been a long-standing objective of health and industry policy in many developing countries, including in Latin America. This strategy has been applied to fight epidemics such as HIV/AIDS, malaria, and the COVID-19 pandemic. However, we still know little about the politics and governance that enable such arrangements, especially when there is no consent from the originator company. This study focuses on the case of Brazil, a country that is well-known for its health-industry policy, which includes the local production of direct-acting antivirals (DAAs), a new treatment for hepatitis C. We seek to explain the factors that have contributed to Brazil’s successful production of generic versions of DAAs, and, later, to the decision by the Ministry of Health (MoH) to procure drugs from multinational pharmaceutical companies rather than from local laboratories. A lack of support for domestic production by important stakeholders, the patent holder’s attempt to block domestic production and the MoH’s adoption of more modern treatment guidelines under a different procurement logic all created an unfavourable environment for local production and procurement of DAAs. Our study draws implications for middle-income countries that wish to produce drugs domestically without voluntary license agreements. [ABSTRACT FROM AUTHOR]

This study retrospectively analyzed the medical records of 602 patients with first-time positive results for the HCV nucleic acid test between 1 May 2021 and 31 March 2023, exploring the association between DAA treatment and SARS-CoV-2 infection. The results showed that 9.8% of HCV patients were co-infected with SARS-CoV-2. Gender, age, vaccination status, and HCV genotype did not significantly affect SARS-CoV-2 infection. However, patients undergoing DAA treatment showed significantly lower rates of SARS-CoV-2 infection and mortality compared to those not undergoing DAA treatment. The analysis also compared patients undergoing different DAA treatments, with Epclusa and Maviret showing superior protection against SARS-CoV-2. Furthermore, this study explored the severity and mortality of SARS-CoV-2 infection in patients undergoing and having completed DAA treatment. It revealed that patients diagnosed with COVID-19 during DAA treatment experienced only mild symptoms, and none died, suggesting a potential protective effect of DAA treatment against severe outcomes of SARS-CoV-2 infection. The findings contribute to the understanding of the interplay between HCV, DAA treatment, and SARS-CoV-2 infection, highlighting the need for continued monitoring and healthcare measures for individuals with chronic conditions during the ongoing COVID-19 pandemic. [ABSTRACT FROM AUTHOR]

Background: The prognosis of cirrhosis is clearly stratified by liver function. Although direct-acting antiviral (DAA) has recently been used to eliminate hepatitis C virus (HCV), it is not clear whether liver function stratifies the prognosis of decompensated cirrhotic patients treated with DAA. Methods: A total of 206 HCV-associated decompensated cirrhotic patients who started DAA from February 2019 to December 2021 at 31 Japanese hospitals were prospectively registered. Results: The median age was 68, and the proportions of patients with Child–Pugh class A (CP-A), CP-B and CP-C were 10% (20/206), 76% (156/206) and 15% (30/206), respectively. Twenty-six patients died, and two patients underwent liver transplantation (LT); the 2- and 3-year LT-free survival rates were 90.0% and 83.2%, respectively. We examined factors associated with LT-free survival using 2 models including either CP class (Model 1) or MELD score (Model 2). In multivariate Cox proportional hazard analysis, CP class at 12 weeks after the end of treatment (EOT) in Model 1 and MELD score at 12 weeks after the EOT in Model 2 were significant factors, while baseline CP class or MELD score was not. Two-year LT-free survival rates were 100%, 91.6% and 60.4% for patients with CP-A, CP-B and CP-C at 12 weeks after the EOT and 95.2% and 69.6% for patients with MELD < 15 and MELD ≥ 15 at 12 weeks after the EOT, respectively. Conclusions: The prognosis of decompensated cirrhotic patients receiving DAA was stratified by liver function at 12 weeks after the EOT, not by baseline liver function. [ABSTRACT FROM AUTHOR]

Hepatitis C virus (HCV) infection is a major health problem worldwide and its eradication is mandatory. Direct acting HCV polymerase inhibitors, such as Sofosbuvir (SOF), is an effective regimen. However, it has some side effects like mutagenesis, carcinogenesis, and the impairment of testicular function. It is important to evaluate the safety of SOF on the ovary, as there are no studies yet. Increasing the production of Reactive Oxygen Species (ROS), causes oxidative stress, which affects ovulation process, female reproduction, and fertility. Accumulation of SOF in the cells was demonstrated to promote ROS generation. Vitamin E (Vit E) is an antioxidant agent that has an essential role in the female reproductive system, its deficiency can cause infertility. We explored the effect of SOF treatment alone and co-treated with Vit E on ovarian ROS level and ovarian morphology experimentally using biochemical and immunohistochemical studies. Significant changes in oxidative stress markers; nitric oxide and malondialdehyde lipid peroxidation, antioxidant enzymes; catalase, super oxide dismutase, and reduced glutathione, proliferating markers; proliferation cell nuclear antigen and Ki-67 antigen and caspase 3 apoptotic marker were demonstrated. It was shown that where SOF induced oxidative stress, it also aggravated ovarian dysfunction. The essential role of Vit E as an antioxidant agent in protecting the ovarian tissue from the effect of oxidative stress markers and preserving its function was also displayed. This could be guidance to add Vit E supplements to SOF regimens to limit its injurious effect on ovarian function. [ABSTRACT FROM AUTHOR]

Objective: To compare the Sustained viral response (SVR) in patients who had taken Sofosbuvir plus Ribavirin for 24 weeks and Sofosbuvir plus Daclatasvir for 12 weeks to treat hepatitis C. Study Design: Randomized Control Trial. Setting: Medical Division of Mayo Hospital, Lahore. Period: One Year duration, 2021. Material & Methods: 130 patients of chronic Hepatitis C were divided into two categories based on whether they met the inclusion requirements. In Group A patients used sofosbuvir plus ribavirin for six months, whereas patients of Group B took sofosbuvir plus daclatasvir for 3 months. In order to determine SVR, PCR for HCV RNA Quantitative was done at week twelve after completion of the course. SPSS 23.0 was applied to enter and analyze the data. Results: All cases had an average age of 48.80 + 16.63 years, whereas it was 48.09 +16.43 years for group A and 49.51+ 16.92 years for groups B. In group A, there were 39 cases (60%) of men and 26 cases (40%) of women, while in group B, there were 34 instances (52.3% men and 31 cases (47.7% women). SVR was attained in 34 (52.34%) of group A participants and 54 (83.12%) of group B participants (p-value of 0.001). Conclusion: Sof+Dacla group had significantly high SVR than Sof+Riba group especially in non-cirrhotic and treatment-naïve individuals. [ABSTRACT FROM AUTHOR]

(1) Background: Hepatitis C virus (HCV) infection is endemic in Egypt, with the highest prevalence rate worldwide. Sofosbuvir (SOF) is a nucleos(t)ide analog that specifically inhibits HCV replication. This study aimed to explore the possible effects of the therapeutic dose of SOF on the mitochondrial biogenesis and functions of the liver, muscle, and ovarian tissues of young normal female rats. (2) Methods: This study was conducted on 20 female Wistar rats, classified into two groups, the control group and the exposed group; the latter was orally supplemented with 4 mg/kg/day of SOF for 3 months. (3) Results: The exposure to SOF impairs mitochondrial biogenesis via mitochondrial DNA copy number decline and suppressed mitochondrial biogenesis-regulated parameters at mRNA and protein levels. Also, SOF suppresses the DNA polymerase γ (POLG) expression, citrate synthase activity, and mitochondrial NADH dehydrogenase subunit-5 (ND5) content, which impairs mitochondrial functions. SOF increased lipid peroxidation and oxidative DNA damage markers and decreased tissue expression of nuclear factor erythroid 2-related factor 2 (Nfe2l2). (4) Conclusions: The present findings demonstrate the adverse effects of SOF on mitochondrial biogenesis and function in different tissues of young female rats, which mostly appeared in ovarian tissues. [ABSTRACT FROM AUTHOR]

Background: Sofosbuvir/ledipasvir (SOF/LDV), a combination of antiviral drugs, has been recently repurposed for COVID-19 management, according to Food and Drug Administration approval. Paracetamol (PAR) identified as a first-line antipyretic for COVID-19 symptoms' management. The use of these three drugs together has significantly influenced the management of COVID-19 by providing symptomatic relief via inhibiting viral activity. A validated ultra-high performance liquid chromatographic (UHPLC) method has been introduced for the quantification of these repurposed drugs in COVID-19 treatment. This novel chromatographic method allows the simultaneous detection of SOF, LDV, and PAR in bulk. Additionally, the method has been applied to determine the levels of SOF and LDV in human plasma samples with PAR used as an internal standard. Results: A new UHPLC method was developed, using a mobile phase with a combination of acetonitrile and 0.1% orthophosphoric acid in a proportion of 42:58 (v/v).Flow rate was set at 0.4 ml/min, and UV detection was adjusted at 254 nm. The concentration of SOF, LDV, and PAR were measured by their corresponding peak areas, and showed linear relationships between concentration and peak area within the ranges of (5–60) µg/ml for SOF, (2–22) µg/ml for LDV, and (1–22) µg/ml for PAR. The presented UHPLC method was used to quantify the amounts of SOF, LDV, and PAR in both bulk samples and human plasma samples being spiked with the mentioned analytes. The elution process was completed within 4 min, with retention times of 3.28 min for SOF, 2.28 min for LDV, and 1.70 min for PAR. The method showed high separation selectivity, with an injection volume of 1µl. The precision, accuracy and repeatability of the method were found to be within acceptable limits. Conclusion: The recently developed method has been successfully validated in accordance with the guidelines set by the International Council for Harmonization (ICH). This validation process ensures that the method is suitable for routine quality control analysis, making it convenient for regular use. [ABSTRACT FROM AUTHOR]

The orally available anti‐hepatitis C virus (HCV) drug simeprevir exhibits nonlinear pharmacokinetics at the clinical doses due to saturation of cytochrome P450 (CYP) 3A4 metabolism and organic anion transporting peptide (OATP) 1B mediated hepatic uptake. Additionally, simeprevir increases exposures of concomitant drugs by CYP3A4 and OATP1B inhibition. The objective of this study was to develop physiologically‐based pharmacokinetic (PBPK) models that could describe drug–drug interactions (DDIs) of simeprevir with concomitant drugs via CYP3A4 and OATP1B inhibition, and also to capture the effects on coproporphyrin‐I (CP‐I), an endogenous biomarker of OATP1B. PBPK modeling estimated unbound simeprevir inhibitory constant (Ki) of 2.89 μM against CYP3A4 in the DDI results between simeprevir and midazolam in healthy volunteers. Then, we analyzed the DDIs between simeprevir and atorvastatin, a dual substrate of CYP3A4 and OATP1B, in healthy volunteers, and unbound Ki against OATP1B was estimated to be 0.00347 μM. Finally, we analyzed the increase in the blood level of CP‐I by simeprevir to verify the Ki,OATP1B. Because CP‐I was measured in subjects with HCV with various hepatic fibrosis state, Monte Carlo simulation was performed to involve the decreases in expression levels of hepatic CYP3A4 and OATP1B and their interindividual variabilities. The PBPK modeling coupled with Monte Carlo simulation using the Ki,OATP1B value obtained from atorvastatin study reasonably recovered the observed relationship between CP‐I and simeprevir blood levels. In conclusion, the simeprevir PBPK model developed in this study can quantitatively describe the increase in exposures of concomitant drugs and an endogenous biomarker via inhibition of CYP3A4 and OATP1B. [ABSTRACT FROM AUTHOR]

Zika virus (ZIKV) infection during pregnancy can result in severe birth defects, such as microcephaly, as well as a range of other related health complications. Heparin, a clinical-grade anticoagulant, is shown to protect neural progenitor cells from death following ZIKV infection. Although heparin can be safely used during pregnancy, it retains off-target anticoagulant effects if directly employed against ZIKV infection. In this study, we investigated the effects of chemically modified heparin derivatives with reduced anticoagulant activities. These derivatives were used as experimental probes to explore the structure–activity relationships. Precursor fractions of porcine heparin, obtained during the manufacture of conventional pharmaceutical heparin with decreased anticoagulant activities, were also explored. Interestingly, these modified heparin derivatives and precursor fractions not only prevented cell death but also inhibited the ZIKV replication of infected neural progenitor cells grown as neurospheres. These effects were observed regardless of the specific sulfation position or overall charge. Furthermore, the combination of heparin with Sofosbuvir, an antiviral licensed for the treatment of hepatitis C (HCV) that also belongs to the same Flaviviridae family as ZIKV, showed a synergistic effect. This suggested that a combination therapy approach involving heparin precursors and Sofosbuvir could be a potential strategy for the prevention or treatment of ZIKV infections. [ABSTRACT FROM AUTHOR]

Introduction: Direct-acting antiviral (DAA) regimens were approved in 2013 with a response rate exceeding 95% and minimal side effects. The response rate of sofosbuvir and ledipasvir exceeds 95% with minimal side effects. Aim: To identify the effects of this regimen in the eradication of viruses from the patients. Material and methods: A prospective observational, open-label study took place between July 2018 and September 2020. The study included 37 patients, about two-thirds of them were male 23 (62.16%), while females comprised 14 (37.84%). All patients received a combination of sofosbuvir 400 mg and ledipasvir 90 mg in a single oral daily dose according to their weight. Results: The most common HCV genotype was HCV-4, followed by HCV-1 and HCV-2. And by comparing parameters at baseline, end of the treatment, and 12 weeks after completing the treatment, the laboratory data revealed dramatic drops of all liver function tests, the mean of alanine aminotransferase (ALT) (31.1 ±1.42 IU/l vs. 95.5 ±23.16, p < 0.05), aspartate aminotransferase (AST) (29.86 ±1.75 IU/l vs. 89.19 ±24.83, p < 0.05), total serum bilirubin (TSB) (0.57 ±0.07 mg/dl vs. 1.73 ±0.38 mg/dl, p < 0.05), mean HCV PCR (1605168 ±368223.72), after finishing the treatment course, and 12 weeks after that it was non-detectable (p < 0.05). Conclusions: Treatment with dose-adjusted oral DAAs (SOF/LED) for 12 weeks was well tolerated in Iraqi children and adolescents infected with chronic HCV infections, with a high success rate and trivial adverse effects. [ABSTRACT FROM AUTHOR]

Sofosbuvir (SOF), a nucleos(t)ide polymerase inhibitor, has been used during the past decade for mass treatment of viral hepatitis C in endemic countries like Egypt, increasing the exposure of women at childbearing age to SOF. This study investigated the long-lasting consequences of the pre-conceptional exposure of young female rats to SOF on the ovarian tissues of F1 offspring and explored the possible molecular mechanisms of these intergenerational effects at various levels. The study was conducted on young female rats that were divided into control group and SOF-exposed group at a dose of 4 mg/kg/day for three months. After that, pregnancy was induced in both groups by mating with healthy male rats. After delivery, the female neonates were followed for 4 months, and the ovarian tissues were collected to assess the studied parameters. Pre-conceptional exposure to SOF affected the ovarian functions of F1 offspring through modulation of estrogen receptors, ovarian Kiss1 and its receptor, increased lipid peroxidation marker, DNA oxidation marker, and redox-sensitive nuclear factor kappa B, and decreased nuclear erythroid-2-related factor 2, mitochondrial function, and biogenesis. SOF affected the ovarian function of the F1 offspring by inducing oxidative stress and inflammation, leading to the modulation of mitochondrial functions and biogenesis. [ABSTRACT FROM AUTHOR]

Hepatitis C virus (HCV) infection is more prevalent in people living with HIV‐AIDS (PLHA) and portends a poorer prognosis. Pharmacokinetic studies suggest the absence of significant interaction between velpatasvir and dolutegravir which has been recently recommended as part of preferred first‐line antiretroviral therapy (ART) regimens by WHO. However, clinical data on the use of velpatasvir‐based regimen in PLHA taking dolutegavir is lacking. Hence, we aimed to assess the efficacy and safety of sofosbuvir and velpatasvir (SOF + VEL) in HCV and HIV coinfected patients on dolutegravir‐based ART. Forty‐five consecutive PLHA with HCV coinfection on dolutegravir‐based ART were prospectively enrolled. All patients were treated SOF + VEL for 12 weeks. Complete haemogram, liver and renal function tests were assessed at baseline, 4 weeks and at end of treatment. Sustained virological response (SVR) was assessed at 12 weeks after end of treatment. The majority were males (95.5%) with a mean age of 32.8 ± 12.3 years. Cirrhosis was present in 6 (13.3%) patients. All patients completed 12 weeks of therapy with SOF + VEL, but SVR could not be assessed in two patients. Forty‐two (97.7%) of the remaining 43 patients attained SVR‐12. SVR‐12 rate was 97.7% and 93.3% by per protocol and intention to treat analysis, respectively. No grade III/IV adverse events were reported, and there was no worsening of blood counts, liver or renal function test parameters. The pan‐genotypic regimen of SOF + VEL is safe and effective in PLHA with HCV coinfection who are on dolutegravir‐based ART. [ABSTRACT FROM AUTHOR]

The major goal of this research work was to augment bioavailability of the fixed-dose combination drugs, ledipasvir (LDV) and sofosbuvir (SBV) by developing orodispersible tablets and films and to estimate it by in vivo pharmacokinetic studies in rats. The pre-optimized amorphous solid dispersions of the LDV-SBV combination with HPMC E15 were made into orodispersible films (ODFs) and the pre-optimized inclusion complexes with dimethyl-ß-cyclodextrin were made into orodispersible tablets (ODTs). The ODFs and ODTs were studied for the in vitro physical characterization studies and dissolution. Best of both the products were evaluated for in vivo pharmacokinetic studies in comparison with the marketed formulation of film coated tablets, Ledifos. The dissolution rate constants for the LDV from the optimized ODFs, ODTs and the marketed tablets were found to be 0.269, 0.13 and 0.073 min.-1 respectively. The dissolution rate constants for the SBV from the optimized ODFs, ODTs and the marketed tablets were found to be 0.302, 0.168 and 0.094 min.-1 respectively. Area under the curve (AUC) values for the LDV from the films, tablets and the marketed tablets were found to be 4231.4, 4050.3 and 3662.5 h*ng/mL respectively. AUC values for the SBV from the films, tablets and the marketed tablets were found to be 2173.2, 2084.6 and 1452.4 h*ng/mL respectively. Conclusion: The obtained results indicated that the optimized ODFs and the ODTs exhibited improved in vitro dissolution and in vivo bioavailability for the fixed-dose combination of LDV and SBV over the reference product. [ABSTRACT FROM AUTHOR]

The aim of the study is to evaluate the effectiveness of the pediatric sofosbuvir weight-based dosing strategy in providing an equitable drug exposure compared to the marketed dose. The physiologically based pharmacokinetic (PBPK) modeling and simulation is a valuable tool in assessing drug dosing and toxicity in populations with physiological, pathological, and genetic pharmacokinetic (PK) variability. The PBPK model of the sofosbuvir compound was developed using Simcyp® V20. The model was developed and verified using the published sofosbuvir's physicochemical properties and clinical data from multiple studies on healthy adult volunteers, hepatitis C virus (HCV)-infected adults, and HCV-infected pediatrics. The AUC and Cmax fold ratio of (predicted/observed) fell within the acceptable range of 0.5–2 in all tested adults' data, confirming the successful development of the sofosbuvir Simcyp® compound model. Using this model, a weight-based dosing regimen of 6 mg/kg in pediatric patients was simulated and compared to the 150 mg and 200 mg approved dose for 3–6 and 6–12 y/o pediatric patients, respectively. No dose adjustment was recommended in patients ages 6–12 y/o. However, compared to the approved 150 mg for 3–6 y/o, the weight base dose provided an equitable drug exposure to adults. Further clinical studies are warranted to verify this finding. [ABSTRACT FROM AUTHOR]

Purpose: We aimed to compare the effects of P-glycoprotein (ABCB1) on the intestinal uptake of tenofovir disoproxil fumarate (TDF), tenofovir alafenamide fumarate (TAF), and metabolites, tenofovir isoproxil monoester (TEM) and tenofovir (TFV), and to study the molecular mechanism of drug-drug interaction (DDI) between sofosbuvir (SOF) and TDF/TAF. Methods: Bidirectional transport experiments in Caco-2 cells and accumulation studies in precision-cut intestinal slices prepared from the ileal segment of rodent (rPCIS) and human (hPCIS) intestines were performed. Results: TDF and TAF were extensively metabolised but TAF exhibited greater stability. ABCB1 significantly reduced the intestinal transepithelial transfer and uptake of the TFV(TDF) and TFV(TAF)-equivalents. However, TDF and TAF were absorbed more efficiently than TFV and TEM. SOF did not inhibit intestinal efflux of TDF and TAF or affect intestinal accumulation of TFV(TDF) and TFV(TAF)-equivalents but did significantly increase the proportion of absorbed TDF. Conclusions: TDF and TAF likely produce comparable concentrations of TFV-equivalents in the portal vein and the extent of permeation is reduced by the activity of ABCB1. DDI on ABCB1 can thus potentially affect TDF and TAF absorption. SOF does not inhibit ABCB1-mediated transport of TDF and TAF but does stabilise TDF, albeit without affecting the quantity of TFV(TDF)-equivalents crossing the intestinal barrier. Our data thus suggest that reported increases in the TFV plasma concentrations in patients treated with SOF and TDF result either from a DDI between SOF and TDF that does not involve ABCB1 or from a DDI involving another drug used in combination therapy. [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]

Background and Aims: The aim of this non‐commercial, open‐label, real‐life, non‐randomized clinical trial was to analyse the efficacy and safety of a pangenotypic regimen sofosbuvir/velpatasvir (SOF/VEL) in patients aged 6–18 years with chronic hepatitis C virus (HCV) infection. Methods: Fifty patients qualified for the 12‐week treatment were divided into two weight groups: 15 children weighting between 17 and <30 kg received a fixed dose of 200/50 mg of SOF/VEL (tablet) once daily, and 35 patients weighting ≥30 kg were treated with 400/100 mg SOF/VEL. The primary endpoint of the study was efficacy defined as sustained viral response (undetectable HCV RNA using an real‐time polymerase chain reaction method) at 12 weeks posttreatment (SVR12). Results: Median age of the participants was 10 (IQR 8–12) years, 47 were infected vertically, and 3 patients were previously ineffectively treated with pegylated interferon and ribavirin. Thirty‐seven participants were infected with HCV genotype 1, 10 with HCV genotype 3 and the remaining 3 with genotype 4. There was no case of cirrhosis. SVR12 was 100%. Thirty‐three reported adverse events (AEs) were considered related to the administration of SOF/VEL, all of them were mild or moderate. Children presenting with AEs were older compared to these without AEs: 12 (9.5–13) versus 9 (IQR 8–11) years (p = 0.008). Conclusions: Results of the PANDAA‐PED study indicated a 100% effectiveness of a 12‐week therapy with SOF/VEL in children aged 6–18 years with chronic HCV infection and its good safety profile, in particular in younger patients. [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: COVID-19 has emerged as the most serious outbreak in recent years. Certain medications such as sofosbuvir (SOF), ledipasvir (LDV) and paracetamol (PAR) were proposed as a safer and recommended substance to control symptoms of COVID-19. Results: Using built-in spectrophotometer software, zero order and derivative spectra of the studied components, two extremely clear, quick, and sensitive spectrophotometric techniques for simultaneous determinations of SOF, LDV, as well as PAR have been developed. LDV was calculated using a zero order absorption spectrum at wavelength maxima of 333 nm. SOF and PAR were evaluated simultaneously using a first derivative spectrophotometer at 247.2 nm and 260.8 nm, respectively. The calibration graphs for SOF, LDV, and PAR are linear over ranges of concentrations of 8–60 µg/mL, 4–22 µg/mL, and 2–14 µg/mL, consequently. The suggested methodologyspecificity was investigated using laboratory manufactured (different ratios) mixtures, which were then effectively used to the analysis of Mpiviropack plus® and Panadol® pills. Valid limitations included accuracy, precision, and specificity. The methodologies were validated in accordance with some ICH standards. Conclusions: The methods proposed were simple, accurate, precise, and neither require any complex equipment nor specific software. [ABSTRACT FROM AUTHOR]

The major challenges encountered by medical researchers in developing new drugs are time consumption, increased cost, establishing a safety profile for the drugs, poor solubility, and inadequate experimental data. In its theoretical aspects, chemical graph theory plays a vital role in drug design and development by analyzing the structural parameters of molecules. Topological indices aim at the mathematical representation of a molecular structure, which is used to analyze the effectiveness of drugs and enhance the drug development process. In this study, we consider certain recently used drugs such as dexamethasone, molnupiravir, nirmatrelvir, ivermectin, ribavirin, baricitinib, favipiravir, duvelisib, L‐ascorbic acid, sofosbuvir, remdesivir, and pioglitazone for omicron, delta and other variants of coronaviruses. For these drug molecules, we propose a generalized form of reverse degree parameters and compute their associated topological indices with limiting behaviors. We undertake QSPR study on the potential of generalized reverse‐degree indices using linear and cubic regression models. [ABSTRACT FROM AUTHOR]

The introduction of direct‐acting antiviral (DAA) treatment of hepatitis C virus (HCV) infected patients has greatly increased treatment success rates. However, viral response kinetics to DAA treatment may depend on pre‐existing resistance‐associated substitutions (RASs) in HCV. The aim of this study was to describe how pre‐existing RASs affect DAA treatment‐induced reduction in HCV RNA titers in HCV genotypes 1‐ and 3‐infected individuals. Patients with HCV genotype 1 infection (N = 31) treated with either sofosbuvir/ledipasvir/ribavirin or paritaprevir/ombitasvir/ritonavir/dasabuvir/ribavirin and HCV genotype 3‐infected patients (N = 16) treated with either sofosbuvir/daclatasvir/ribavirin or sofosbuvir/ribavirin were analyzed. HCV RNA levels were determined at baseline and frequently during treatment, and RAS profiles were obtained by deep sequencing at baseline. In total, 33/47 (70.2%) of the patients had baseline RASs. However, treatment‐specific RASs were detected at baseline only in 12.9% and 18.8% of HCV genotypes 1‐ and 3‐infected patients, respectively. In genotype 1‐infected individuals, reduction in HCV RNA titer during the first week of treatment was not affected by evidence of either treatment‐specific RASs or cirrhosis or treatment regimen. In genotype 3‐infected individuals receiving sofosbuvir/daclatasvir/ribavirin, the presence of daclatasvir‐specific NS5A RASs at baseline correlated with a reduced decline of HCV RNA in the first treatment week. For both genotypes 1‐ and 3‐infected individuals, cirrhosis but not treatment‐specific RAS were associated with the time of clearance of HCV RNA. It is, however, important to note that this study involves DAA regimens that were used only during the original introduction of interferon‐free DAA‐based treatments. [ABSTRACT FROM AUTHOR]

Background and Aim: Hepatic fibrosis is a common pathogenic outcome of almost all chronic liver diseases and a growing public health problem globally. However, the key genes or proteins driving liver fibrosis and cirrhosis are not well understood. We aimed to identify novel hepatic fibrosis genes of human primary hepatic stellate cells (HSCs). Methods: Human primary HSCs were isolated from surgically resected advanced fibrosis liver tissues (n = 6) and surgical resection of normal liver tissue around hemangioma (n = 5). Differences in the expression levels of mRNA and proteins from HSCs in advanced fibrosis group and the control group were analyzed using RNA sequencing and mass spectrometry as transcriptomic and proteomic approaches. The obtained biomarkers were further validated through real‐time quantitative polymerase chain reaction (RT‐qPCR), immunofluorescence, and Western blot. Results: A total of 2156 transcripts and 711 proteins were found to be differently expressed between the advanced fibrosis group and the control group patients. The Venn diagram shows that a total of 96 upregulated molecules are overlapped in both the transcriptomic and proteomic datasets. Gene Ontology enrichment analysis and Kyoto Encyclopedia of Genes and Genomes analysis indicated that those overlapped genes were mainly involved in wound healing, cell adhesion regulation, and actin binding, which reflects the major biological conversions in liver cirrhosis process. Pyruvate kinase M2 and EH domain‐containing 2 were identified as potential new markers for advanced liver cirrhosis, which have been validated in primary human HSCs and in vitro cellular hepatic fibrosis model Lieming Xu‐2 (LX‐2) cells. Conclusions: Our results revealed the major transcriptomic and proteomic changes during liver cirrhosis process and identified new biomarkers and potential therapeutic targets for advanced liver fibrosis. [ABSTRACT FROM AUTHOR]

With no approved antiviral therapies, the continuous emergence and re-emergence of tick-borne encephalitis virus (TBEV) and yellow fever virus (YFV) is a rising concern. We performed head-to-head comparisons of the antiviral activity of available nucleos(t)ide analogs (nucs) using relevant human cell lines. Eight existing nucs inhibited TBEV and/or YFV with differential activity between cell lines and viruses. Remdesivir, uprifosbuvir and sofosbuvir were the most potent drugs against TBEV and YFV in liver cells, but they had reduced activity in neural cells, whereas galidesivir retained uniform activity across cell lines and viruses. Ribavirin, valopicitabine, molnupiravir and GS-6620 exhibited only moderate antiviral activity. We found antiviral activity for drugs previously reported as inactive, demonstrating the importance of using human cell lines and comparative experimental assays when screening the activity of nucs. The relatively high antiviral activity of remdesivir, sofosbuvir and uprifosbuvir against TBEV and YFV merits further investigation in clinical studies. • Screening of 14 compounds for anti-TBEV or anti-YFV activity in liver Huh7.5 cells. • Eight drugs were found active in Huh7.5 and in neural (Daoy and SH-SY5Y) cells. • Cytotoxicity and antiviral activity varied between cell lines. • Remdesivir, uprifosbuvir and sofosbuvir were the most effective drugs. • These drugs could be rapidly repurposed if they show clinical value. [ABSTRACT FROM AUTHOR]

Objective: To measure the outcomes of direct acting Antiviral therapy in terms of frequency of Hepatocellular carcinoma after its use of in HCV patients infected with 3a genotype and to analyze the efficacy of double and triple regimen in HCV patients of Child Pugh's class A and B respectively. Study Design: Quasi- experimental study. Place and Duration of Study: Mayo Hospital, Lahore Pakistan, from May to Dec 2019. Methodology: After applying inclusion and exclusion criteria 262 patients of 3a genotype were awarded as Child Pugh's Class A and B and were treated with double and triple regimen for 12 and 24 weeks respectively. They were followed up with Ultrasound Abdomen every month and PCR Quantitative was done for evaluating Sustained Virological Response after 3 months of completing treatment. Results: Out of 262 patients, 141(53.8%) were male and 121(46.2%) were female. 243(92.7%) patients achieved Sustained Virological Response. 9(3.4%) developed Hepatocellular carcinoma of which 8 were on triple regimen and 1 on double regimen. Conclusion: direct Acting Antivirals are effective in achieving Sustained Virological Response but pose a greater risk for Hepatocellular carcinoma. So, they should be used with caution and serial monitoring. [ABSTRACT FROM AUTHOR]

(1) Background: Little is known about the long-term impact of sustained virological response (SVR) on fibrosis progression and patient survival in liver transplantation (LT) recipients treated with direct-acting antivirals (DAAs). We investigated liver fibrosis evolution and patient survival in hepatitis C virus (HCV)-infected patients receiving DAAs after LT. (2) Methods: All consecutive HCV-infected patients treated with DAAs after LT between May 2014 and January 2019 were considered. The clinical and virological features were registered at the baseline and during the follow-up. The liver fibrosis was assessed by liver biopsy and/or transient elastography (TE) at the baseline and at least 1 year after the end of treatment (EoT). (3) Results: A total of 136 patients were included. The SVR12 was 78% after the first treatment and 96% after retreatment. After the SVR12, biochemical tests improved at the EoT and remained stable throughout the 3-year follow-up. Liver fibrosis improved after the SVR12 (p < 0.001); nearly half of the patients with advanced liver fibrosis experienced an improvement of an F ≤ 2. The factors associated with lower survival in SVR12 patients were the baseline platelet count (p = 0.04) and creatinine level (p = 0.04). (4) Conclusions: The long-term follow-up data demonstrated that SVR12 was associated with an improvement in hepatic function, liver fibrosis, and post-LT survival, regardless of the baseline liver fibrosis. The presence of portal hypertension before the DAAs has an impact on patient survival, even after SVR12. [ABSTRACT FROM AUTHOR]

Background: Acupuncture points are known for their unique bioelectric properties. Medication testing at acupuncture points has not previously been used to determine the daily doses of sofosbuvir in patients with chronic hepatitis C virus infection. Results: This pilot study included 61 patients with a confirmed diagnosis of chronic hepatitis C virus infection. Medicament testing of acupuncture points of the liver meridian ("Xing-jian") and Voll's circulation meridian ("Cells and lobules of the liver") was performed to determine the daily doses of sofosbuvir. A correlation analysis was carried out between the tested doses of the drug and the viral load in the blood of patients to confirm the results of testing the daily doses of sofosbuvir. Patients with chronic hepatitis C virus infection showed a significant positive correlation between tested daily doses of sofosbuvir and viral load in their blood. The mean values of the tested doses of sofosbuvir did not vary at different acupuncture points and significantly differed depending on viral load. Conclusions: This study showed that acupuncture points can serve as a diagnostic tool in the process of medicament testing and allow the determination of daily doses of sofosbuvir in patients with chronic hepatitis C virus infection. To further assess the clinical applications and physiological basis of medicament testing methods, additional clinical and instrumental studies are needed with a large sample of patients. [ABSTRACT FROM AUTHOR]

The present work was developed to create three rapid, simple, eco-friendly, cheap spectrophotometric methods for concurrent assay of Sofosbuvir (SOF) and Simeprevir (SMV) in their pure, laboratory prepared mixture and pharmaceutical dosage form with high degree of accuracy and precision. Three methods were developed including iso-absorptive point, ratio subtraction and dual wavelength. The linear range of the proposed methods was 3.0–50.0 and 2.0–50.0 µg mL−1 for SMV and SOF, respectively. The proposed methods were validated according to ICH guidelines in terms of linearity, accuracy, precision, limit of detection and limit of quantitation. The proposed approach is highly simple and the procedure is environmentally green making it suitable for the drug analysis in routine works. [ABSTRACT FROM AUTHOR]

Introduction: According to current guidelines of Infectious Diseases Society of America (IDSA), hepatitis C of all genotypes in dialysis population is recommended to treat with Glecaprevir 300mg/ Pibrentasvir 120mg given for 8 to 16 weeks. Due to commercial unavailability of these drugs in Pakistan, we have compared two alternative regimes, Sofosbuvir+Daclatsvir and Sofosbuvir alone in HCV confirmed subjects on hemodialysis. Objective: To compare the efficacy of Sofosbuvir + Daclatasvir and Sofosbuvir alone in treating HCV patient on hemodialysis. It is a Randomized controlled trial spanned on Six months at Department of Nephrology, PIMS Islamabad. Subjects and Methods: In the present randomized controlled trial, a total of one hundred and eight (n=108) patients of either gender on hemodialysis and diagnosed as HCV positive were enrolled. All the patients were between age ranges 18 to 65 years and had an HCV RNA level of ≥100,000 IU/mL. All the enrolled patients were treatment naïve patients. All the enrolled patients were randomly divided into two groups by lottery method. Patients in Group A were given the combination of Sofosbuvir and Daclatasvir while patients in group B were treated with Sofosbuvir alone in dialysis department. The outcomes of the study were determined in terms of viral load detected at 3 months and sustained virological response (SVR) at six months. Results: There were 50.0% (n=27/54) males and 50.0% (n=27/54) females in group A and there were 53.7% (n=29/54) males and 46.3% (n=25/54) females in group B. Mean age of group A patients was 42.8 years ± 12.1 SD and mean age of group B patients was 47.2 years ± 10.7 SD. Mean duration of dialysis in group A patients was 28.3 months ± 25.7 SD and mean duration of dialysis in group B patients was 24.3 years ± 17.3 SD. In group A, 7.4% (n=4/54) had no baseline comorbidity, 5.6% (n=3/54) had hypertension, 55.6% (n=30/54) had diabetes, 1.9% (n=1/54) had IHD and 29.6% (n=16/54) had multiple comorbidities at baseline. The percentages in group B were 14.8% (n=8/54), 1.9% (n=1/54), 53.7% (n=19/54), 1.9% (n=1/54) and 27.8% (n=15/54), respectively. Three months after start of treatment, viral load was not detected in 98.1% (n=53/54) of patients in group A and 96.3% (n=52/54) of patients in group B (P=0.558). At six month after the start of treatment, SVR was achieved in 98.1% (n=53/54) of patients in group A and 96.3% (n=52/54) of patients in group B (P=0.558). Conclusions: Efficacy of treatment was found better at 3 and 6 months of treatment in patients who were treated with combination of Sofosbuvir and Daclatasvir (group A) when compared those treated with Sofosbuvir alone. The difference, however, was not statistically significant. [ABSTRACT FROM AUTHOR]

About 5% of chronic hepatitis C (CHC) patients experienced treatment failure with direct-acting antiviral (DAA) treatment. The global data on the practice and treatment outcomes of Sofosbuvir/Velpatasvir/Voxilaprevir (SOF/VEL/VOX) in DAA-experienced CHC patients remains sparse. We performed a systematic review and meta-analysis to evaluate the efficacy and safety of SOF/VEL/VOX as a salvage treatment in DAA-experienced CHC patients. We searched five electronic databases from inception to 31 January 2023. The study outcomes were SVR12 and treatment-related adverse effects, with subgroup analysis performed based on genotype, cirrhosis, HCC, prior SOF/VEL exposure, and region. We identified and analyzed data from 24 studies (2877 DAA-experienced CHC patients); 17.2% had prior SOF/VEL exposure, 25% received ribavirin with SOF/VEL/VOX, and 42% had pre-treatment resistance-associated substitution (RAS) testing performed. Eastern Mediterranean had a higher pooled SVR12 than the America and Europe regions (p < 0.05). Predictors of SOF/VEL/VOX failure were genotype 3, active HCC, baseline cirrhosis, and prior SOF/VEL. Baseline RAS mutation and ribavirin supplementation were not associated with higher SVR12. Treatment discontinuation because of drug-related adverse events was uncommon (10 studies, 0.2%). In summary, SOF/VEL/VOX is efficacious and safe for retreatment in DAA-experienced CHC patients, even with RAS mutation. Our findings support SOF/VEL/VOX as a first-line rescue treatment for DAA-experienced CHC patients. [ABSTRACT FROM AUTHOR]

Background: Hepatitis C virus (HCV) infection is a global public health problem and Egypt has the highest HCV prevalence worldwide. Hence, global efforts target to eliminate HCV by 2030. Sofosbuvir is a nucleotide analogue inhibitor of HCV polymerase essential for viral replication. Animal studies prove that Sofosbuvir metabolites cross the placenta and are excreted in the milk of nursing animals. We aimed to investigate the possible effects of preconception maternal exposure to Sofosbuvir on mitochondrial biogenesis in prenatal fetal liver, skeletal muscle, and placental tissues. Methods: The study was conducted on 20 female albino rats divided into a control group receiving a placebo and an exposed group receiving 4 mg/kg orally/day for 3 months of Sofosbuvir. At the end of the treatment period, pregnancy was induced in both groups by mating with healthy male rats overnight. At gestational day 17, all pregnant female rats were sacrificed. Each fetus was dissected to obtain the fetal liver, skeletal muscle, and placental tissues. Results: The results of our study indicated that the exposure of young female rats to Sofosbuvir affects pregnancy outcomes. Fetal liver and muscle showed lower mitochondrial DNA-copy number (mtDNA-CN) by about 24% and 29% respectively, peroxisome proliferator-activated receptor-gamma coactivator-1 alpha and its downstream targets; nuclear respiratory factor-1 and mitochondrial transcription factor A. While the placental tissues showed different patterns, particularly elevated in mtDNA-CN by about 43%. Conclusions: The study provides preliminary evidence of the detrimental effects of Sofosbuvir on the pregnancy outcomes of the exposed females and may impair the placental and fetal organs' development. These effects may be mediated through modulating mitochondrial homeostasis and functions. [ABSTRACT FROM AUTHOR]

Background and Aims: Chronic hepatitis C [CHC] is a risk factor for porphyria cutanea tarda [PCT]. To assess whether ledipasvir/sofosbuvir is effective for treating both PCT and CHC, we treated patients with CHC + PCT solely with ledipasvir/sofosbuvir and followed them for at least 1 year to assess cure of CHC and remission of PCT. Methods: Between September 2017 and May 2020, 15 of 23 screened PCT + CHC patients were eligible and enrolled. All were treated with ledipasvir/sofosbuvir at recommended doses and durations, according to their stage of liver disease. We measured plasma and urinary porphyrins at baseline and monthly for the first 12 months and at 16, 20, and 24 mos. We measured serum HCV RNA at baseline, 8–12, and 20–24 mos. Cure of HCV was defined as no detectable serum HCV RNA ≥ 12 weeks after the end of treatment (EOT). Remission of PCT was defined clinically as no new blisters or bullae and biochemically as urinary uro- plus hepta-carboxyl porphyrins ≤ 100 mcg/g creatinine. Results: All 15 patients, 13 of whom were men, were infected with HCV genotype 1. 2/15 withdrew or were lost to follow-up. Of the remaining 13, 12 achieved cure of CHC; 1 had complete virological response, followed by relapse of HCV after ledipasvir/sofosbuvir but was subsequently cured by treatment with sofosbuvir/velpatasvir. Of the 12 cured of CHC, all achieved sustained clinical remission of PCT. Conclusions: Ledipasvir/sofosbuvir [and likely other direct-acting antivirals] is an effective treatment for HCV in the presence of PCT and leads to clinical remission of PCT without additional phlebotomy or low-dose hydroxychloroquine treatment. Trial Registration: ClinicalTrials.gov NCT03118674. [ABSTRACT FROM AUTHOR]

Sofosbuvir has demonstrated several advantages over the traditional anti-hepatitis C (HCV) therapies; however, it has been found susceptible to hydrolysis and has a risk of hepatic carcinoma. The development of drug nanoparticles allows reduced side effects and increased stability. Silver nanoparticles have long been explored for their intrinsic antiviral characteristics. Therefore, the silver nanoparticles of sofosbuvir were synthesized and capped with various polymers including polyvinylpyrrolidone, polyethylene glycol, and dextran. The stable charachterized surface plasmon resonance band of AgNPs was achieved via optimizing various parameterters for instance volume and concentraion of reducing agent, ratio of ligand and metal, rate of mixing, and pH of medium. The AgNPs and drug-loaded nanoparticles were characterized by UV spectroscopy, atomic force microscopy (AFM), dynamic light scattering (DLS), and zeta potential techniques. The 20–70 nm sized, round, negativly charged dextran-capped and dextran-reduced, nanoparticle were found to be the most stable and monodispersed in aqeous medium for 6 weeks at room temperature and 4 °C. Furthermore, both formulations were evaluated for drug release 90% of the drug was released from the formulations after 23 h while 99% was found to be released after 6 days. Dextran capped sofosbuvir–AgNP was found non-toxic to Huh-7 cell line as compared to the drug. Combined these results indicate that when sofosbuvir is encapsulated in the NP formulations, the formulations show intact potent anti-HCV activity in a less cytotoxic way. [ABSTRACT FROM AUTHOR]

To evaluate the safety and tolerability of the fixed‐dose, single‐tablet regimen sofosbuvir/velpatasvir (SOF/VEL) for the treatment of hepatitis C virus (HCV) infection in three Phase 3 studies in patients with and without compensated cirrhosis. Data from three registrational trials (ASTRAL‐1, NCT02201940; ASTRAL‐2, NCT02220998; ASTRAL‐3, NCT02201953) were pooled by treatment regimen. Researchers assessed treatment‐emergent adverse events (TEAEs) and laboratory abnormalities in patients randomized to SOF/VEL or placebo for 12 weeks in ASTRAL‐1 and SOF/VEL for 12 weeks in ASTRAL‐2 and ASTRAL‐3. Overall, 1035 patients were treated with SOF/VEL, and 116 patients received placebo. Rates of any TEAE were generally similar between patients receiving SOF/VEL (79.4%) and those receiving placebo (76.7%). The majority of TEAEs were mild to moderate, with 23 (2.2%) treatment‐emergent serious AEs in patients treated with SOF/VEL. Of these treatment‐emergent serious AEs, none led to premature study discontinuation, nor were they considered related to treatment. Presence of compensated cirrhosis, greater age and mild renal impairment did not impact incidence or severity of TEAEs with SOF/VEL treatment. The most common TEAEs (incidence ≥10%) were headache, fatigue, nausea and nasopharyngitis in patients receiving SOF/VEL; similar rates were observed in placebo‐treated patients. Three deaths (<1%) were reported in patients treated with SOF/VEL, all posttreatment and none assessed as related to study treatment. Similar to that of placebo, SOF/VEL treatment of HCV infection had a safety/tolerability profile that was not affected by baseline factors, such as the presence of compensated cirrhosis, mild renal impairment or advanced age. [ABSTRACT FROM AUTHOR]