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Ultra-performance liquid chromatographic (UPLC) method, for ledipasvir and sofosbuvir determination in bulk mixtures, and in tablets was developed and validated. The determination of the drugs, ledipasvir and sofosbuvir was carried out applying BEH C18 column (50 mm × 2.1 mm i.d, 1.6 µm particle size), with UV detector at λ max of 220 nm. The mobile phase applied for the current study, composed of two solvents, A (0.01 N w/v potassium di-hydrogen orthophosphate buffer of pH 3.5 modified with dilute orthophosphoric acid) and B (acetonitrile) in the ratio of 50:50 v/v. The isocratic mobile phase was moved at a flow rate of 0.3 ml/min. The validation study with proportionate to selectivity, linearity, robustness, precision, accuracy, stability, (LOD) limit of detection and (LOQ) limit of quantification, was performed utilizing the ICH Guidelines. Ledipasvir and Sofosbuvir displaying a linear response between 22.5-135 μg/ml for Ledipasvir 100-600 µg/ml for Sofosbuvir, with correlation coefficient (R2) 0.9997 and 0.998 for Ledipasvir and Sofosbuvir respectively. The % recovery for Ledipasvir and Sofosbuvir was 99.72 ± 0.61% and 100.21 ± 0.68 respectively. The LOD and LOQ values for Ledipasvir and Sofosbuvir were obtained to be 0.31 and 0.95 µg/ml and 1.29 and 3.91 µg/ml, respectively. The method also exhibits good robustness for different chromatographic conditions like mobile phase, temperature and flow rate. So, the approach can be successfully implemented for the quantitative analysis of ledipasvir and sofosbuvir in the (Q.C) Quality Control of in-house developed tablets, and the same can be exercised for the industrial use.

BACKGROUND & OBJECTIVES: There are reports of worsening renal functions with sofosbuvir, but there are no comparative data of different direct-acting antivirals (DAAs) on serum creatinine. In this retrospective cohort analysis, we examined the treatment effect of two commonly used regimens, sofosbuvir/ledipasvir (SOF/LDV) and glecaprevir/pibrentasvir (GLE/PIB), on serum creatinine. METHODS: We included all patients treated with SOF/LDV (n = 825) and GLE/PIB (n = 116) between December 1, 2014, and December 31, 2018. An increase of serum creatinine ≥0.3 mg/dL was considered clinically significant. The change of creatinine values from pretreatment to posttreatment between two treatment groups was tested in unadjusted and adjusted generalized linear model, and risk factors associated with creatinine change were assessed. In addition, GLE/PIB-treated patients were matched 1:2 to SOF/LDV-treated patients using propensity scores, and then serum creatinine changes were compared. RESULTS: The mean baseline creatinine was higher in the GLE/PIB group vs. SOF/LDV group (1.39 ± 1.86 vs. 0.91 ± 0.24, P = 0.007). When compared to baseline, serum creatinine at posttreatment week 4 was significantly higher in SOF/LDV group (0.97 ± 0.4 vs.0.91 ± 0.24, P

Background: Hepatitis C Virus (HCV) is one of the serious health issues affecting one-third of the world’s population. The high variations of the HCV genome are ascribed to quick replication by NS5B Polymerase and are thus the most attractive target for developing anti-HCV agents. Objective: The current study aimed to discover novel phytochemicals that harbor the potential of NS5B polymerase inhibition. Method: In this computational study, a molecular docking approach was used to screen phytochemicals with the best binding and spatial affinity with NS5B at the Palm I region. The top-ranked compounds were then subjected to in-silico pharmacokinetic and toxicological study. Results and Conclusion: The virtual screening provided seven ‘hit compounds’ including Betanin, 3,5'- dihydroxythalifaboramine, Diarctigenin, 6'-desmethylthalifaboramine, Cephalotaxine, 5alpha-O-(3'-dimethylamino-3'- phenylpropionyl) taxinine M and IsoTetrandrine with minimum binding score compared to the reference drug, Sofosbuvir (−14.7 kcal/mol). The absorption, distribution, metabolism, excretion, and toxicity (ADMET) and thorough toxicological analysis revealed a favorable and the safety profile of these compounds. The study would demonstrate the phytochemicals identified might serve as potential antiviral compounds that can potentially an alternative approach for amelioration of HCV

Background The combination of daclatasvir (DCV) and sofosbuvir (SFV) is now widely used as an ideal treatment for hepatitis C virus (HCV) infection. For this purpose, simple, sensitive, rapid, and smart spectrophotometric methods were developed and validated for the determination of these drugs in their combined dosage form. Objective Development of smart, sensitive, low-cost spectrophotometric methods for the determination of DCV and SFV in their combined dosage form. Methods Ratio subtraction (RS), amplitude modulation (AM), and mean-centering spectrophotometric methods were established and validated for the estimation of SFV in the presence of DCV without previous separation, using a unified regression equation. Results A linearity range of 2.5–25.0 µg/mL was confirmed for the direct measurement of DCV at 316 nm (because there is no interference from SFV. Linearity was confirmed over a concentration range of 10.0–80.0 µg/mL for SFV. The current methods were established according to the ICH recommendations, and specificity was examined by testing synthetic mixtures of both drugs. They were tested on their tablet dosage form, and a good recovery was obtained. Conclusion The current methods proved to be simple, specific, and economical. A statistical study of the current ratio approaches and published methods showed there was no apparent statistical variation. Highlights Both antiviral agents can be quantified in the presence of each other by the current methods, which is a significant time- and cost-saving benefit of the developed methods. This benefit is even more important in the case of the combined dosage form (Darvoni® tablets) for the pharmaceutical market.

Introduction: The sofosbuvir-velpatasvir (SOF/VEL) combination is a direct-acting antiviral therapy that is authorized and available in Mexico, making the performance of a real-world multicenter study that evaluates the sustained virologic response at 12 weeks post-treatment a relevant undertaking. Methods: A retrospective review of the case records of 241 patients seen at 20 hospitals in Mexico was conducted to assess hepatitis C treatment with the SOF/VEL combination (n = 231) and the sofosbuvir/velpatasvir/ribavirin (SOF/VEL/RBV) combination (n = 10). The primary efficacy endpoint was the percentage of patients that achieved SVR at 12 weeks after the end of treatment. Results: Overall SVR was 98.8% (95% CI 97.35–100%). Only three patients did not achieve SVR, two of whom had cirrhosis and a history of previous treatment with peg-IFN. Of the subgroups analyzed, all the patients with HIV coinfection, three patients with genotype 3, and the patients treated with the SOF/VEL/RBV combination achieved SVR. The subgroups with the lower success rates were patients that were treatment-experienced (96.8%) and patients with F1 fibrosis (95.5%). The most frequent adverse events were fatigue, headache, and insomnia. No serious adverse events were reported. Conclusion: Treatments with SOF/VEL and SOF/VEL/RBV were highly safe and effective, results coinciding with those of other international real-world studies. Resumen: Introducción: La combinación de sofosbuvir-velpatasvir (SOF/VEL) es una terapia antiviral de acción directa que está autorizada y disponible en México. Esto hace que la evaluación de la respuesta virológica sostenida (RVS) 12 semanas después del tratamiento, por medio de la realización de una revisión multicentro en el mundo real, sea una tarea relevante. Métodos: Se efectuó una revisión retrospectiva de los registros de 241 casos de pacientes atendidos en 20 hospitales en México para evaluar el tratamiento contra la hepatitis C con la combinación SOF/VEL (n = 231) y sofosbuvir/velpatasvir/ribavirin (SOF/VEL/RBV) (n = 10). El objetivo de eficacia primario fue el porcentaje de pacientes que lograron la RVS 12 semanas posterior a la finalización del tratamiento. Resultados: En general, la RVS fue de 98.8% (IC 95% 97.35 a 100%). Solo tres pacientes no lograron la RVS, de los cuales dos padecían cirrosis y una tenía historia previa de tratamiento con interferón pegilado (peg-IFN). De los subgrupos analizados, todos los casos con infección de virus de la inmunodeficiencia humana (VIH), tres con genotipo 3 y aquellos tratados con la combinación SOF/VEL/RBV, lograron RVS. Los subgrupos con tasas menores de éxito fueron los pacientes que tenían experiencia con tratamiento (96.8%) y pacientes con fibrosis F1 (95.5%). Los eventos adversos más frecuentes fueron fatiga, cefalea e insomnio. No se reportaron eventos adversos graves. Conclusión: Los tratamientos con SOF/VEL y SOF/VEL/RBV fueron altamente seguros y efectivos y los resultados coinciden con los de otros estudios internacionales realizados en el mundo real.

Synthetic nucleoside or nucleotide analogues played a key role to the development of antiviral agents in past decades. However, low membrane permeability and insufficient cellular phosphorylation impaired the biological activity of polar nucleoside drugs because they have to penetrate the cell membrane and be phosphorylated to active metabolite stepwise by intracellular enzymes. To overcome these limitations, diverse lipophilic prodrug modifications based on nucleoside mono-, di-, and triphosphate were designed and put into practice to efficiently deliver nucleoside into the target site, and bypass the rate-limited phosphorylation step. As the most successful prodrug strategy, ProTide technology has led to the discovery of three FDA-approved antiviral agents, including sofosbuvir, tenofovir alafenadmide, and remdesivir, which has been authorized for emergency use in patients of COVID-19 in the US. In recent years, nucleoside di- and triphosphate prodrugs have also made the significant progress. This review will focus on the summary of design approach and metabolic activation path of different nucleotide prodrug strategies. The potential application of nucleotide prodrugs for the treatment of COVID-19 was also described due to the pandemic of SARS-CoV-2.

Background and study aims: Chronic hepatitis C virus (HCV) infection has always been identified as a major health threat and a potential cause of liver cirrhosis , portal hypertension , and other associated problems. The introduction of direct-acting antiviral agents (DAAs) has represented a paradigm shift in HCV management. In this study, we aim to observe the rate of sustained virologic response (SVR12) in a large scale of patients at a single center as well as record the post-treatment changes in the hematologic, hepatic, and renal biochemical profiles. Patients and methods In total, 1933 chronic HCV genotype 4 mono-infected non-HCC patients who completed the treatment with six different DAA regimens in the Faculty of Medicine, Ain Shams University Research Institute (MASRI), were retrospectively enrolled in this study. The rate of sustained virologic response after 12 weeks off-therapy (SVR12) was assessed. The baseline characteristics to predict the SVR12 were then analyzed. The post-treatment changes in many profiles were recorded and analyzed. Results The overall SVR12 rate was 96.2% (after excluding 84 cases who were lost to follow-up). It was achieved in 346/375 patients (92.3%), 466/477 patients (97.7%), 60/62 patients (96.8%), 11/11 patients (100%), 532/545 patients (97.6%), and 445/463 patients (96.1%) who received sofosbuvir/daclatasvir (SOF/DCV), sofosbuvir/daclatasvir/ribavirin (SOF/DCV/RBV), sofosbuvir/ledipasvir (SOF/LDV), sofosbuvir/ledipasvir/ribavirin (SOF/LDV/RBV), sofosbuvir/simeprevir (SOF/SMV), and ombitasvir/paritaprevir/ritonavir/ribavirin (OBV/PTV/r + RBV), respectively. In total, 73 patients (3.8%) failed to achieve SVR12. The baseline aspartate aminotransferase (AST), cirrhotic status, and treatment regimen were determined to have a significant impact on SVR12. In the overall treated population, the levels of serum AST, alanine aminotransferase , albumin , creatinine, bilirubin , and hemoglobin and platelet count improved significantly after treatment. Furthermore, sustained virologic response was strongly related to cirrhosis and its degree. Conclusion The interferon-free DAA regimens offered high SVR12 rates in Egyptian patients with chronic HCV infection. They were associated with a significant improvement in the hematologic, hepatic, and renal biochemical profiles. The baseline AST, liver cirrhosis, and treatment regimen might have an impact on achieving SVR.

Background: The combination of sofosbuvir (SOF) and daclatasvir (DCV) has shown preliminary efficacy for patients with COVID-19 in five open-label studies with small sample sizes. This larger trial aimed to assess if the addition of sofosbuvir and daclatasvir to standard care improved clinical endpoints in hospitalized patients with moderate or severe COVID-19. Methods: This was a placebo-controlled, randomized clinical trial in adults with moderate or severe COVID-19 admitted to 19 hospitals in Iran. Patients were randomized to SOF/DCV 400/60mg once-daily or placebo in addition to standard of care. Patients were included if they had positive PCR or diagnostic chest CT, O 2 saturation

The coronavirus disease 2019 (COVID-19) pandemic, due to the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), emerged in December 2019 and has rapidly spread globally. As the confirmed number of cases has reached 83 million worldwide, the potential severity and the deadly complications of the disease requires urgent development of effective drugs for prevention and treatment. No proven effective treatment for this virus currently exists. Most of the antiviral discovery efforts are focused on the repurposing of approved or clinical stage drugs. This review highlights the small-molecule repurposed antiviral agents that are currently under investigation in clinical trials for COVID-19. These include viral polymerase and protease inhibitors remdesivir, galidesivir, favipiravir, ribavirin, sofosbuvir, tenofovir/emtricitabine, baloxavir marboxil, EIDD-2801, lopinavir/ritonavir; virus-/host-directed viral entry and fusion inhibitors arbidol chloroquine/hydroxychloroquine, chlorpromazine, camostat mesylate, nafamostat mesylate, bromhexine and agents with diverse/unclear mechanism of actions as oseltamivir, triazavirin, ivermectin, nitazoxanide, niclosamide and BLD-2660. The published preclinical and clinical data to date on these drugs as well as the mechanisms of action are reviewed.

Several randomized trials have evaluated the effects of sofosbuvir-based direct-acting antivirals on the clinical outcomes in patients with COVID-19.A systematic literature search with no language restrictions was performed on electronic databases and preprint repositories to identify eligible randomized trials published up to 8 July 2021. A random-effects model was used to estimate the pooled odds ratio (OR) for outcomes of interest with the use of sofosbuvir combined with direct-acting antiviral agents relative to the nonuse of sofosbuvir-based direct-acting antiviral agents at 95% confidence intervals (CI).The meta-analysis of 11 trials (n = 2,161) revealed statistically significant reduction in the odds of mortality (pooled odds ratio = 0.59; 95% confidence interval 0.36 to 0.99) but no statistically significant difference in the odds of development of composite endpoint of severe illness (pooled odds ratio = 0.79; 95% confidence interval 0.43 to 1.44) with the administration of sofosbuvir-based direct-acting antiviral agents among patients with COVID-19, relative to non-administration of sofosbuvir-based direct-acting antiviral agents.Subgroup analysis with seven trials involving sofosbuvir-daclatasvir revealed no significant mortality benefit (pooled odds ratio = 0.77; 95% confidence interval 0.48 to 1.22).Sofosbuvir-based direct-acting antiviral agents have no protective effects against the development of severe illness in patients with COVID-19 with the current dosing regimen. Whether sofosbuvir-based direct-acting antiviral agents could offer mortality benefits would require further investigations.

Objective: Two simple, sensitive and accurate spectrophotometric methods have been developed for the determination of sofosbuvir (SOF) and daclatasvir (DAC) in pure forms and pharmaceutical formulations. Methods: The proposed methods are based on the oxidation of SOF and DAC by a known excess of cerium(IV) ammonium nitrate in sulphuric acid medium followed by determination of unreacted cerium(IV) by adding a fixed amount of indigo carmine (IC) and alizarin red S (ARS) dyes followed by measuring the absorbance at 610 and 360 nm, respectively. The experimental conditions affecting the reaction were studied and optimized. Results: The beer’s law was obeyed in the concentration ranges of 0.2-3.0, 0.2-4.0 for SOF and 0.5-4.5 and 0.5-5.0 μg/ml for DAC using IC and ARS methods, respectively with a correlation coefficient ≥ 0.9991. The calculated molar absorptivity values are 2.354 × 104, 1.933 × 104 for SOF and 1.786 × 104 and 2.015 × 104 L/mol. cm for DAC using IC and ARS methods, respectively u. The limits of detection and quantification are also reported. Intra-day and inter-day precision and accuracy of the methods have been evaluated. Conclusion: The methods were successfully applied to the assay of SOF and DAC in tablets and the results were statistically compared with those of the reference method by applying Student’s t-test and F-test. No interference was observed from the common tablet excipients. The accuracy and reliability of the methods were further ascertained by performing recovery studies using the standard addition method.

A reverse phase-high-performance liquid chromatography-diode array detector method is developed for the determination of the antiviral drug sofosbuvir in bulk and Sofos® 400 mg tablet dosage forms. Sofosbuvir is used for the treatment of chronic hepatitis C. The separation is carried out using a gradient mobile phase consisting of 0.05% H3PO4 and acetonitrile. A symmetry C18 column (4.6 × 100 mm, 2.5 µm, Waters XSELECT HSS T3) is used with a flow rate of 1.5 mL min−1 using ultraviolet detection at 260 nm with a diode array detector and an injection loop volume of 10 µL. A sharp peak is obtained at a retention time of 14 min. The method is validated appropriately according to the requirements of the United States Pharmacopeia and the International Conference on Harmonization guideline Q2 R1. System suitability, linearity, range (1.5–4.5 µg mL−1), precision, accuracy, specificity, robustness, detection and quantification limit of the method are assured. A forced degradation study of sofosbuvir is conducted under the conditions of hydrolysis, oxidation, thermal and photolysis.

John Charles Martin should be remembered as a visionary medicinal chemist who was involved in the coinvention, development, or management of many FDA-approved antiviral drugs such as ganciclovir, stavudine, didanosine, cidofovir, oseltamivir, adefovir dipivoxil, tenofovir disoproxil fumarate, tenofovir alafenamide, sofosbuvir, and remdesivir.

Viral infections are particularly common among children. They often have a mild course, are self-limiting and do not need any specific treatment. However, in some cases, the disease can be severe and lead to permanent disabilities. A variety of antiviral drugs are available for the treatments of certain infectious agents: for instance, acyclovir is used to treat herpes simplex virus encephalitis. Recommendations for flu treatment may change according to the current epidemiological surveillance data, on the basis of which antiviral sensibility can be forecast: recommended drugs for the 2020-21 flu season are oseltamivir, zanamivir, peramivir and baloxavir. Some drugs are used to treat congenital infections, such as valganciclovir and ganciclovir in congenital cytomegalovirus infection. Antiretroviral prophylaxis in newborns from HIV-1 infected mothers must be initiated as soon as possible, with one or more drugs according to therapeutic regimens based on the baby's risk category. According to the most recent guidelines, antiretroviral therapy must be started at diagnosis. Several antiretroviral drugs are available today and approved for use in children, so several combinations can be made. However, out of the 29 antiretroviral drugs approved for adults, only 38% (11/29) are approved for children under the age of two and about 60% (18/29) for children under the age of twelve. Treatment with direct antiviral agents against hepatitis C virus is approved for children over the age of three; it consists in different therapeutic regimens chosen on the basis of the viral genotype (ledipasvir/sofosbuvir for genotypes 1, 4, 5 and 6, sofosbuvir/ribavirin for genotypes 2 and 3, sofosbuvir/velpatasvir and glecaprevir/pibrentasvir for all genotypes) and it has dramatically changed the course of the illness. Many molecules have been studied in order to treat SARS-CoV-2 infection, but only remdesivir seems to play a role in shortening recovery time, although inclusion criteria are very specific and data on the use in children is limited.

Background & Aims Retreatment with glecaprevir/pibrentasvir (G/P) resulted in a rate of sustained virologic response 12 weeks after treatment completion (SVR12) of >90% in HCV genotype 1 (GT1) patients who previously failed a regimen of sofosbuvir plus an NS5A inhibitor (NS5Ai). This study investigated the prevalence and impact of baseline NS3 and NS5A resistance-associated substitutions (RASs) on the efficacy of G/P in prior GT1 sofosbuvir+NS5Ai failures and the persistence of treatment-emergent RASs. Methods Longitudinal samples from 177 patients enrolled in a phase IIIb, randomized pragmatic clinical trial were analyzed. Patients without cirrhosis were randomized to 12 or 16 weeks of G/P, and patients with compensated cirrhosis were randomized to G/P and ribavirin for 12 weeks or G/P for 16 weeks. Linkage of RAS was identified using Primer-ID next-generation sequencing at a 15% cut-off. Results Of 177 patients, 169 (95.5%) were PI-naive. All 33 GT1b-infected patients achieved SVR12. In GT1a-infected patients, baseline NS5A RASs were prevalent (74.5%, 105/141) but NS3 RASs were uncommon. Baseline NS3 RASs had no impact on G/P efficacy and patients with baseline NS5A RASs showed a numerically but not statistically significantly lower SVR12 rate compared to those without NS5A RASs (89% vs. 97%). SVR12 was achieved in 34 of 35 (97%) patients without NS5A baseline substitution, and 53 of 57 (93%), 35 of 40 (88%), 5 of 8 (63%) with single, double-linked, and triple-linked NS5A substitutions, respectively. Among 13 patients with virologic failure, 4 acquired treatment-emergent NS3 RASs and 10 acquired NS5A RASs. Conclusion Baseline NS5A RASs were highly prevalent. The presence of an increasing number of linked NS5A RASs in GT1a showed a trend in decreasing SVR12 rates, although no specific NS5A RASs or their linkage pattern were associated with lower SVR12 rates. Lay summary Direct-acting antivirals have revolutionized the treatment of chronic hepatitis C infection, but treatment failure occurs in some patients. Retreatment of patients who previously failed a regimen consisting of sofosbuvir and an NS5A inhibitor with a regimen of glecaprevir and pibrentasvir (G/P) is >90% effective. Herein, we analyzed samples from these patients and showed that retreatment efficacy with G/P is lower in patients with double- or triple-linked NS5A resistance mutations than in patients with single or no NS5A resistance mutations. Clinical trial number NCT03092375 .

Background: Hepatitis C virus infection is an important cause of many rheumatic diseases, especially cryoglobulinemic vasculitis, fibromyalgia, arthralgia and Sicca Syndrome. Direct acting antivirals are found to be highly effective for the treatment of chronic Hepatitis C virus infection. Objective: The aim of this study was to evaluate the clinical and serological course of extrahepatic rheumatic manifestations in chronic hepatitis C Egyptian patients after treatment with new direct-acting antivirals. Patients and Methods: This study was carried out on 60 Egyptian patients with chronic hepatitis C with one or more of the HCV- related rheumatic manifestations treated with sofosbuvir (400 mg daily) plus daclatasvir (60 mg daily) as a direct-acting antivirals for 3 months. All patients were subjected to clinical and serological course of extrahepatic rheumatic manifestations evaluation. Results: show that among the 60 patients, 21 patients (35.0%) met the criteria of mixed cryoglobulinemia syndrome (MC), 19 patients (31.7%) were complaining of arthralgia, 17 patients (28.3%) were complaining of fibromyalgia and 3 patients (5.0%) were complaining of Purpura without other criteria of mixed cryoglobulinemia syndrome. Complete clinical response was achieved in a significant number of patients with mixed cryoglobulinemia syndrome (MCS), the results also show significant clinical improvement in patients with fibromyalgia, arthralgia and purpura. Significant reduction but not complete normalization in auto-antibodies at short term follow-up was observed. Conclusion: It could be concluded that sustained virologic response correlates with clinical and immunological improvement in most patients with extrahepatic rheumatic manifestations among the studied group of chronic hepatitis C Egyptian populations.

Background Therapeutic interventions for hepatocellular carcinoma (HCC) particularly in patients with advanced liver disease may lead to more aggravation of clinical and biochemical parameters of liver functions. We aimed to assess the utilization of easily applied variables which evaluate residual hepatic reserve to predict liability for complications and hepatic decompensation in cirrhotic patients with ablated HCC particularly when these patients were exposed to specific medical treatment such as DAAs and systemic therapy for HCC such as sorafenib. This study included 3 groups with HCC. Group 1: patients with ablated HCC and Child-Turcotte-Pugh (CTP) class A, who received Sofosbuvir (SOF)-based treatment (n = 250), group 2: HCC patients CTP (A), managed with sorafenib after transarterial chemoembolization (TACE) (n = 250) and group 3 as a control group of non-cirrhotic patients (n = 176). Evaluation for all patients was done by routine laboratory investigations including liver and kidney functions, complete blood count, platelet indices and plasma ammonia, upper gastrointestinal (GI) endoscopy and estimation of liver volume by ultrasound and liver stiffness (LS) by Fibroscan. Results Unfavorable outcome and increased incidence of complications during DAAs were independently associated with severity of thrombocytopenia (p = 0.001) at a cut-off 78,000/μl, LS > 20 kPa (p = 0.001), liver volume < 500 ml (p = 0.002), and gamma globulin levels > 4 gm/dl (p = 0.004). In the sorafenib group, unfavorable outcome and complications were independently associated with PDW/MPV ratio > 2.74 (p = 0.001), level of ammonia > 87 μg/dl (p = 0.001), LS > 25 kPa (p = 0.001), and liver volume < 490 ml (p = 0.001). Conclusion Non-invasive parameters of residual hepatic reserve are promising tools to guide therapy and avoid further complications in patients with liver cirrhosis and ablated HCC.

Background Impact of interleukin 28B (IL28B) rs12979860 polymorphism on response to direct-acting antivirals agents in HCV genotype 4-infected patients is under investigation. Zinc may have an advantage in improvement of liver damage and treatment outcome. We aimed to evaluate IL28B polymorphism and zinc administration impact on patient response to treatment and amelioration of liver fibrosis. Results Three hundred patients on anti-HCV treatments were equally categorized into patients treated with dual therapy (sofosbuvir/ribavirin) for 24 weeks, triple therapy (sofosbuvir/ribavirin+pegylated interferon-alpha) for 12 weeks, dual therapy plus oral zinc and with triple therapy plus oral zinc. All patients were genotyped for IL28B. Sustained virologic response (SVR) was achieved in 100% of patients with CC genotypes while 15.5% of CT/TT carriers did not attain SVR. After treatment, patients with CC genotype showed improvement in liver-related parameters compared with CT/TT genotypes. Zinc supplementation was associated with improved SVR in CT/TT genotypes and liver parameters in both CC and CT/TT genotypes. Hepatic fibrosis was improved in higher percent of CC genotype (16.7%) compared with CT/TT genotypes (5.8%). Interestingly with zinc administration, improved fibrosis increased to 60.9% in CC genotype vs. 15.4% in CT/TT genotypes. Conclusion Absolute SVR rates in patients with IL28B CC genotype support their selection for shorter treatment duration and therefore associated with high economic value. IL28B polymorphism is associated with improvement of hepatic functions and fibrosis after antiviral treatments. Zinc is powerful supplement not only to increase SVR in non-responders but also to improve hepatic functions and fibrosis.

Despite aggressive efforts on containment measures for the coronavirus disease 2019 (COVID-19) pandemic around the world, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is continuously spreading. Therefore, there is an urgent need for an effective antiviral agent. To date, considerable research has been conducted to develop different approaches to COVID-19 therapy. In addition to early observational studies, which could be limited by study design, small sample size, non-randomized design, or different timings of treatment, an increasing number of randomized controlled trials (RCTs) investigating the clinical efficacy and safety of antiviral agents are being carried out. This study reviews the updated findings of RCTs regarding the clinical efficacy of eight antiviral agents against COVID-19, including remdesivir, lopinavir/ritonavir, favipiravir, sofosbuvir/daclatasvir, sofosbuvir/ledipasvir, baloxavir, umifenovir, darunavir/cobicistat, and their combinations. Treatment with remdesivir could accelerate clinical improvement; however, it lacked additional survival benefits. Moreover, 5-day regimen of remdesivir might show adequate effectiveness in patients with mild to moderate COVID-19. Favipiravir was only marginally effective regarding clinical improvement and virological assessment based on the results of small RCTs. The present evidence suggests that sofosbuvir/daclatasvir may improve survival and clinical outcomes in patients with COVID-19. However, the sample sizes for analysis were relatively small, and all studies were exclusively conducted in Iran. Further larger RCTs in other countries are warranted to support these findings. In contrast, the present findings of limited RCTs did not indicate the use of lopinavir/ritonavir, sofosbuvir/ledipasvir, baloxavir, umifenovir, and darunavir/cobicistat in the treatment of patients hospitalized for COVID-19.

Background. Chronic hepatitis C virus (HCV) infection is characterized by activation of natural killer (NK) cells. Here, we asked whether HCV elimination by sofosbuvir-based direct-acting antivirals (DAAs) and the addition of ribavirin (RBV) improve NK cell function in liver transplant (LTx) recipients. Methods. We analyzed NK cell degranulation and interferon (IFN)γ-response along with STAT1 and STAT4 phosphorylation in 29 HCV-infected LTx recipients and 17 HCV-infected patients during DAA treatment. Results. Compared with uninfected LTx recipients, NK cells from HCV-infected LTx recipients were polarized toward cytotoxicity with increased CD107a-degranulation (10.1% versus 14.6%; P = 0.0263) and reduced capacity to produce IFNγ (43.0% versus 26.7%; P = 0.0002). The altered phenotype of NK cells in HCV-infected LTx recipients was accompanied by increased STAT1 (44.6% versus 87.4%; P < 0.0001) and STAT1 phosphorylation (0.7% versus 8.9%; P = 0.0005) compared with pSTAT4 IFNα-induction (29.9% versus 17.6%; P = 0.0014). Successful DAA therapy did not affect CD107a-degranulation but decreased STAT1. RBV cotreatment with DAA therapy for HCV increased CD56Bright NK cell IFNγ-responses in LTx recipients (70.9% versus 89.2%; P = 0.002), and this correlated to an increase in the inducibility of pSTAT4 (MFI 157 versus 173; P = 0.0002). Conclusions. RBV cotreatment of HCV infection improved pSTAT4-dependent IFNγ-production in NK cells. This is relevant especially for immunocompromised patients such as LTx recipients or patients with end-stage liver disease.

Актуальність. Хронічний гепатит С (ХГС) залишається однією з найактуальніших проблем сучасної інфектології. Останніми роками суттєво змінилися принципи проведення противірусної терапії завдяки появі нових препаратів з прямим механізмом дії та розробці безінтерферонових режимів лікування. Для лікування хворих на ХГС, інфікованих 3-м генотипом вірусу гепатиту С, в Україні були доступними два режими з включенням інгібітору HCV NS5B полімерази. Мета: проаналізувати ефективність різних схем противірусного лікування у хворих на хронічний гепатит С, інфікованих 3-м генотипом вірусу. Матеріали та методи. В дослідження було включено 66 хворих на ХГС, інфікованих 3-м генотипом вірусу. Усім хворим проведено дослідження ступеня фіброзу печінки методом фібротесту, у динаміці досліджували вірусне навантаження, печінкові проби, показники загального аналізу крові, функціональні проби нирок. Противірусне лікування та аналіз його ефективності здійснювали згідно з уніфікованим протоколом МОЗ України. Результати. За результатами аналізу результатів лікування хворих на ХГС, інфікованих 3-м генотипом вірусу, показана висока ефективність обох схем противірусної терапії, застосованих у клінічній практиці. Швидка вірусологічна відповідь мала місце в 93,5 % хворих на ХГС, які лікувалися за схемою: пегільований інтеферон (peg-IFN) α2a + софосбувір (SOF) + рибавірин (RBV), та у 82,9 % пацієнтів, які отримали безінтерферонову терапію SOF + RBV. Безпосередня відповідь на лікування була досягнута в 90,3 та 94,3 % пацієнтів відповідно до схем терапії. Стійка вірусологічна відповідь на 24-му тижні після припинення противірусної терапії відзначена в 87,5 та 91,4 % пацієнтів відповідно. Частота формування вірусологічної відповіді на противірусне лікування у хворих на ХГС, інфікованих 3-м генотипом вірусу, не залежала від стадії фіброзу печінки як при застосуванні безінтерферонового лікування SOF + RBV, так і при лікуванні інтерферонвмісною схемою з включенням препарату з прямим механізмом дії: peg-IFN-α2a + SOF + RBV. Висновки. Противірусна терапія хворих на ХГС, інфікованих 3-м генотипом HCV, супроводжувалася формуванням стійкої вірусологічної відповіді у 87,5 % хворих після 12-тижневого курсу лікування за схемою peg-IFN-α2a + SOF + RBV та 91,4 % пацієнтів після 24-тижневого курсу терапії SOF + RBV. Ефективність лікування цих хворих не залежала від ступеня фіброзу печінки., Background. Chronic hepatitis C (CHC) remains one of the most urgent problems of modern infectology. In recent years, the principles of antiviral therapy have substantially changed due to the emergence of new drugs with a direct mechanism of action and the development of non-interferon treatment regimens. Two regimens included HCV NS5B polymerase inhibitors were available in Ukraine for treating CHC patients infected with genotype 3 virus. Objective: to analyze the effectiveness of different schemes of antiviral treatment in patients with chronic hepatitis C infected with genotype 3 virus. Materials and methods. The study included 66 patients with CHC infected with genotype 3 virus. All patients underwent study of liver fibrosis degree by the method of fibrotest; in the dynamics, we have tested viral load, liver tests, indicators of complete blood count, functional kidney tests. Antiviral treatment and analysis of its effectiveness were carried out in accordance with the Unified Protocol of the Ministry of Health of Ukraine. Results. According to the results of treating CHC patients infected with genotype 3 virus, high efficacy of both applied schemes of antiviral therapy in clinical practice is shown. A rapid virologic response occurred in 93.5 % of CHC patients treated with peginterferon (peg-IFN) α2a + sofosbuvir (SOF) + ribavirin (RBV) regimen, and in 82.9 % of patients receiving non-interferon therapy with SOF + RBV. The immediate response to treatment was achieved according to treatment regimens in 90.3 and 94.3 % of patients. Sustained virological response at week 24 after antiviral treatment was noted in 87.5 and 91.4 % of patients, respectively. The frequency of virological response to antiviral treatment in CHC patients infected with genotype 3 virus did not depend on the stage of liver fibrosis, either in the use of non-interferon treatment by SOF + RBV scheme, or in the treatment with interferon-containing scheme included the drug with peg-IFN-α2a + SOF + RBV direct mechanism of action. Conclusions. Antiviral therapy of CHC patients infected with genotype 3 virus was accompanied by the formation of sustained virological response in 87.5 % of patients after 12 weeks of treatment using peg-IFN-α2a + SOF + RBV, and in 91.4 % of patients after 24-week course of SOF + RBV therapy. The efficacy of treatment in these patients did not depend on the degree of liver fibrosis.

BACKGROUND Hepatitis C virus (HCV)-related decompensated cirrhosis is a severe life-threatening illness. The safety of direct-acting antivirals (DAAs) has opened a gate of hope for that subgroup of patients who were previously contraindicated for interferon therapy. OBJECTIVE We aimed at the investigation of the safety and efficacy of different DAAs regimens in the treatment of HCV-related decompensated cirrhosis patients, to determine sustained virological response (SVR)12 rates and to analyze the factors associated with response. METHODS A retrospective, single-center study including HCV-related decompensated cirrhosis patients who received DAAs. Demographic, laboratory and clinical data were analyzed. The SVR12 rate was the primary outcome measure. Secondary outcomes included the predictors of response, changes in the baseline model for end-stage liver disease and child-turcotte-pugh (CTP) scores, and fibroindices (APRI and fibrosis-4 index) at 12 weeks after treatment. RESULTS In total, 145 eligible patients (141 with CTP class B and 4 with class C) were enrolled in this study. SVR12 was achieved by 88.06% (118/134) of efficacy population on different DAAs regimens, Treatment was discontinued in 11 patients because of severe side effects without any deaths. Younger age showed a significant positive association with SVR12. CONCLUSIONS DAAs can be used for the treatment of HCV-related decompensated liver disease, with acceptable SVR12 rates and safety profiles.

Hepatitis C is an urgent problem today because of the low efficiency and a significant number of side effects of conventional therapy. The problem of the treatment of hepatitis C virus (HCV) genotypes 1 and 4 is particularly acute, as they are the most resistant to traditional treatment regimens. The solution to this problem, apparently, is the use of a relatively new group of direct-acting antiviral drugs (DAAD). This article discusses the various schemes of treatment with these products, their mechanism of action and effectiveness, as well as compares two of the most effective and promising DAAD available on the global market — Harvoni (sofosbuvir/ledipasvir) and Viekira Pak (ombitasvir/paritaprevir/ritonavir + dasabuvir). Current guidelines of the European Association for the Study of the Liver (EASL), American Association for the Study of Liver Diseases (AASLD) and the Canadian Association for the Study of the Liver (CASL) on the treatment of patients with HCV genotypes 1 and 4 are also compared.

Background: Direct-acting antiviral agents therapy is considered a breakthrough in hepatology due to high rates of sustained virologic response in all patients including those with decompensated cirrhosis. However, impact of Direct-acting antiviral agents-induced sustained virologic response on hepatocellular carcinoma development remains conflicting. Aims: This study aimed at evaluating the change in circulating levels of vascular endothelial growth factor and transforming growth factor-β1, the main angiogenic factors involved in hepatocarcinogenesis process, in cirrhotic patients achieved sustained virologic response after Direct-acting antiviral agents therapy. Study Design: This was a prospective, single-center, cohort study. Place and Duration of Study: Patients were recruited from the outpatient clinic of National Liver Institute, which considered a tertiary referral center in Menoufia University, Egypt (September 2018 to February 2019). Methodology: Forty-five decompensated cirrhotic hepatitis C virus infected patients with no history of hepatocellular carcinoma participated in the study. All patients received 60mg oral daclatasvir and 400mg oral sofosbuvir once daily for 12 or 24 weeks with or without ribavirin. Serum levels of vascular endothelial growth factor and transforming growth factor-β1 were measured at baseline and 12 weeks after the end of therapy. Results: The median serum levels of vascular endothelial growth factor showed a non-statistically significant increase (from 1123 ng/L to 1269 ng/L, P = 0.126). But, transforming growth factor-β1 median serum levels exhibited a non-statistically significant reduction (from 13.22 ng/ml to 12.44 ng/ml, P = 0.163) 12 weeks after treatment. Conclusion: Our findings show direct-acting antiviral agents therapy do not affect vascular endothelial growth factor and transforming growth factor-β1 serum levels. But, a larger scale prospective cohort study on an extended follow-up period is recommended.

Background Previous studies reported worsened lipid profiles in patients infected with hepatitis C virus (HCV) during direct-acting antivirals (DAAs) treatment. This study aimed to investigate the effect of sofosbuvir (SOF)-based DAAs on changes in low-density lipoprotein (LDL) in HCV patients. Methods A systematic review of articles published before 31 May 2021 was conducted by searching MEDLINE, Cochrane Library, EMBASE, and CINAHL Plus. Eligible studies were those comparing SOF-based DAAs and non-SOF DAAs for HCV patients and providing numerical data for changes in LDL. Risk of Bias in Non-randomized Studies- of Interventions was used for assessing risk of bias, and meta-analysis was performed for changes in LDL. Results Six studies comprising 1248 patients were included, 848 patients treated with SOF-based DAAs and 400 patients with non-SOF DAAs vs. SOF-based DAAs group had significantly greater increases in LDL from baseline to week 4 than non-SOF DAAs group (P = 0.001). However, changes in LDL from baseline to the end of treatment (P = 0.060), to post-treatment week 12 (P = 0.263), and to post-treatment week 24 (P = 0.319) did not significantly differ between the two groups. Further comparison of SOF/ledipasvir with asunaprevir/daclatasvir revealed a similar trend in changes in LDL. Conclusions For HCV patients, SOF-based DAA regimens were associated with rapid and significant increases in LDL during the initial 4 weeks of treatment, and the changes did not sustain after the end of treatment. Potential mechanism might be related to the phosphoramidate side chain of SOF.

Since December 2019, severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection has exploded and led to a global crisis. Currently, the global case numbers topped 200 million, and toll of dead exceeded 4 million around the world. The pathogenesis of coronavirus disease 2019 (COVID-19) is driven by two processes. During the first stage of the infection that lasts around 5-7 days, replication of SARS-CoV-2 occurs. In the second stage, the disease may progress due to an exaggerated inflammatory response leading to tissue damage. Therefore, it is anticipated that antiviral agents would be effective during the early phase of the disease, while immunomodulator agents are likely to be more beneficial in the second stage of COVID-19. This basic concept of disease development led to explore several antiviral and immunomodulator agents for the treatment of COVID-19. Currently, remdesivir is the only available Food and Drug Administration-approved antiviral agent for the treatment of COVID-19. However, some other agents have been approved by various mechanisms, including Emergency Use Authorizations, Emergency Investigational New Drug applications, compassionate use or expanded access programs. In addition, a variety of repurposed agents that were approved for other indications are being investigated for the treatment of COVID- 19 in clinical trials. A myriad of publications including randomized controlled trials (RCTs) are emerging continuously and are accessible as peer-reviewed, pre-print and press release formats. Considering the critical importance of RCTs in generating evidence and providing further guidance on COVID-19 treatment, we herein reviewed only RCTs and meta-analyses. The discussion includes antiviral agents (hydroxychloroquine, lopinavir/ritonavir, remdesivir, favipiravir and ivermectin) and, various immunomodulatory drugs (corticosteroids, tocilizumab, baricitinib, and IL-1 inhibitors). Other investigational therapies including darunavir/cobicistat, umifenovir, sofosbuvir/daclatasvir, sofobuvir/ledipasvir, ribavirin, nitazoxanide and interferon-based regimens were not evaluated due to insufficient data on the efficacy and safety of these agents.

Summary Sofosbuvir and Daclatasvir are among the direct‐acting antiviral (DAA) medications prescribed for the treatment of chronic hepatitis C (CHC) virus infection as combination therapy with other antiviral medications. DAA‐based therapy achieves high cure rates, reaching up to 97% depending on the genotype of the causative hepatitis C virus (HCV). While DAAs have been approved as an efficient and well‐tolerated therapy for CHC, emerging concerns about adverse cardiac side effects, higher risk of recurrence and occurrence of hepatocellular carcinoma (HCC) and doubts of genotoxicity have been reported. In our study, we investigated in detail physiological off‐targets of DAAs and dissected the effects of these drugs on cellular organelles using budding yeast, a unicellular eukaryotic organism. DAAs were found to disturb the architecture of the endoplasmic reticulum (ER) and the mitochondria, while showing no apparent genotoxicity or DNA damaging effect. Our study provides evidence that DAAs are not associated with genotoxicity and highlights the necessity for adjunctive antioxidant therapy to mitigate the adverse effects of DAAs on ER and mitochondria.

The introduction of a new class of drugs known as direct acting antiviral (DAA) agents represents a revolution in the treatment of hepatitis C virus (HCV) in the general population, as these regimens are associated with higher sustained virological response (SVR) rates and fewer side effects. However, for patients with advanced chronic kidney disease suffering from HVC infection, treatment options including DAA remain limited. The aim of this study is to report our experience on Sofosbuvir (SOF) based regimen in the treatment of HCV in hemodialysis patients. In this observational study, we included all patients with chronic HCV infection on hemodialysis who were treated with SOF in our Hospital between April 2016 and March 2018. All patients were treated with a combination of 400 mg of SOF three times a week after hemodialysis and of 60 mg of Daclatasvir daily for a total of 12 to 24 weeks. A total of 20 hemodialysis patients were included in this study. 12 were females and the mean age was 52.1 ± 15.5 years. 11 patients were infected with HCV genotypes 1b. All patients achieved SVR. Clinical and biological tolerance was very good for all patients and none of them had to discontinue treatment because of side effects or developed hepatobiliary and cardiac toxicity. Two patients reported fatigue and another patient reported headaches. However, these symptoms were spontaneously resolved after the end of the treatment. In Morocco, despite the absence of new DAA combination treatment regimens which are not renally eliminated, our study concludes that SOF based treatment without Ribavirin or Peginterferon was effective and safe with minimal side effects. However, larger studies are still needed in order to validate these results.

The fixed dose combination of ledipasvir (LDV) and sofosbuvir (SBV) is approved by USFDA in 2014 for the treatment of Hepatitis C virus infection and is available in the form of tablets. In the present work, the principal aim is to explore orodispersible films type dosage form to impart its characteristic advantages to these poorly soluble drugs so as to improve their bioavailability and ease of administration. Solid dispersions with low viscosity grade methyl cellulose A 15-LV (MC A 15-LV) at different ratios with LDV and SBV were prepared and evaluated to check their ability in improving the solubility of the drugs. The best drug to polymer ratio was selected to develop the films, using other excipients including plasticizer and superdisintegrant. Solvent casting method was used to develop the films. Three formulation parameters were selected as independent factors viz. thickness of the film (50-150 µm), concentration of superdisintegrant (sodium starch glycolate 6-10%) and concentration of plasticizer (polyethylene glycol 400, 10-20%). Disintegration time (DT), time for 90% dissolution (T90%) of LDV and time for 90% dissolution of SBV were taken as the response variables. The experiment was designed using Box-Behnken design. Among the polymers, MC A 15-LV produced maximum solubility at 1:2 ratio. The films obtained were found to have good tensile strength and % elongation with disintegration times in the range of 43-162 sec. The T90% values for LDV and SDV were found to be in the range of 8.4-21.2 min and 7.2-18.4 respectively. All the three formulation factors were found to have significant effect on the three responses. The optimum formulation was identified at 100 µm thickness, 10% superdisintegrant and 20% plasticizer which showed DT of 89 sec with T90% values of 8.4 min and 7.2 min for LDV and SBV respectively. The rapid disintegration and dissolution of the films signified that the set objective was achieved.

Introduction: Sofosbuvir/velpatasvir is a combination of direct-acting antivirals with pangenotypic activity for treatment of chronic hepatitis C virus infection. It was approved in 2020 for use in...

Simple, swift, selective and accurate UV and HPLC methods were developed and validated for estimation of sofosbuvir in bulk and marketed preparation. In the UV spectroscopy method mobile phase used was methanol in 70:30 ratio with a detection wavelength of 260nm and the assay value obtained was 99.36%. The method was validated as stated by ICH in Q2 R1 guidelines in which linearity was detected from 06-30µg/ml range with regression value of 0.999. In the accuracy, precision and robustness studies RSD were below 2%. In HPLC method, Cosmosil C18 (250mm×4.6ID, Particle size: 5µ) column was utilized with methanol: water (70:30) as mobile phase, 0.9ml/min of flow rate, 260nm detection wavelength for estimation of sofosbuvir. Assay value obtained using this optimized parameters was 99.77% with the time of retention of around 4.3 minutes. HPLC method was also validated as stated by ICH in Q2 R1 guidelines in which linearity was noticed to be in the span of 10-50µg/ml with 0.999 of regression coefficient. LOD and LOQ values of the optimized method were 0.5764 and 1.7468µg/ml. In the accuracy, precision, robustness studies the value of RSD was under 2%. The optimized HPLC method was also utilized for the force degradation study, in which it was found that sofosbuvir is susceptible to oxidative, acid, alkaline, photolytic and thermal degradation. From this study it can be concluded that the developed methods can be employed in the routine analysis for sofosbuvir estimation in bulk and marketed preparation and also to determine degradation of drug.

Aim: this study aimed to clarify the possible effect of direct acting antivirals (DAAs) treatment on development of hepatocellular carcinoma (HCC) in hepatitis C virus (HCV) cirrhotic patients. , Methods: this study was conducted on 400 chronic hepatitis C cirrhotic patients, divided into two groups according to treatment with DAAs, group I including (200 Patients with chronic HCV cirrhosis treated with DAAs), and group II including (200 patients with chronic HCV cirrhosis without DAAs treatment), all patients were recruited from the Gastroenterology and Hepatology department Kobry Elkobba Military Hospital, all patients were males with no previous history of HCC, human immunodeficiency virus (HIV) or hepatitis B virus (HBV) infection or history of liver transplantation. After one year of follow up all patients were divided into further two subgroups according HCC development, group III ( 11 HCV cirrhotic patients treated with DAAs (sofosbuvir and daclatasvir) and developed HCC) and group IV (22 HCV cirrhotic patients not treated and developed HCC). Results: HCC developed more in not treated group with a significant difference as 11% of not treated group developed HCC compared to 5.5% only of treated group (P=0.046). using univariate cox regression, it was shown that no treatment was an independent risk factor of getting hepatocellular carcinoma (HCC), as cases not receiving the study treatment are at higher risk for developing HCC (HR=3.4, P=0.002). conclusion: DAA treatment is not associated with a higher risk of HCC in cirrhotic patients with chronic HCV infection in the short-term. The occurrence of HCC is significantly decreased in patients treated with DAAs.

A 36-year-old woman with decompensated liver cirrhosis type C was referred to our hospital to receive antiviral treatment for hepatitis C virus (HCV). She had been diagnosed with intractable epilepsy and cerebral palsy at birth and was managed by central venous nutrition and nasal gastric feeding. At age 34 years, she was diagnosed with thrombocytopenia, probably associated with HCV infection. She showed refractory ascites for several months and was therefore administered crushed sofosbuvir/velpatasvir tablets via a nasal gastric tube. Her HCV infection was successfully eradicated, her ascites disappeared, and thrombocytopenia improved with a marked decrease in platelet-associated IgG.

The aim of this study was to compare efficacy and safety of different combination regimens in re-treatment of HCV in the setting of inaccessibility of resistance testing. This real-life prospective study included 86 chronic HCV infected patients who experienced failure of treatment treated at Faculty of Medicine Ain shams Research Institute (MASRI) since 2018. 64% of the patients were males, with median age 50.2 years. They were re-treated using 1 of 3 proposed regimens of DAA combinations. One group received PAR/OMB/SOF/RBV for 12 weeks, another group received SOF/DAC/SIM/RBV for 12 weeks and a third received SOF/DAC/RBV for 24 weeks. Response to different regimens was assessed by comparing sustained virologic response (SVR) of each. Monitoring the occurrence of adverse events was performed. SVR was achieved in all but 3 patients (96.5% SVR), one in the SOF/DAC/SIM/RBV group and two in the SOF/DAC/RBV group. The group receiving RBV had more anaemia and hyperbilirubinemia. The first treatment regimen used was a significant predictor to SVR achievement. This study presents alternative treatment regimens for re-treatment of HCV patients in areas with limited resources in the case of non-availability of other regimens as velpatasvir, voxilaprevir, grazoprevir, elbasvir.

Limited experimental and clinical evidence suggests a potential role for sofosbuvir/daclatasvir in treating COVID19. We aim to evaluate the efficacy of generic sofosbuvir/daclatasvir in treating CO...

The real-world virological efficacy and safety of interferon-free direct-acting antiviral (DAA) therapy with sofosbuvir (SOF) and velpatasvir (VEL) were assessed in hepatitis C virus (HCV) genotype 1- and 2-infected patients with decompensated cirrhosis. A total of 65 patients with HCV-related decompensated cirrhosis (Child-Pugh score of 7 points or more) who were treated with the SOF/VEL regimen were enrolled. The sustained virological response (SVR) rate and safety profile were analyzed. SVR was defined as undetectable serum HCV RNA at 12 weeks after the end of treatment (SVR12). The percentages of patients with undetectable HCV RNA at 4, 8, and 12 weeks after the start of therapy were 81.2% (95% confidence interval [CI], 69.5-89.9) (52/64), 98.4% (95% CI, 91.2-100.0) (60/61), and 98.5% (95% CI, 91.7-100.0) (64/65), respectively. The overall SVR rate was 92.3% (95% CI, 83.0-97.5) (60/65). Albumin-bilirubin (ALBI) scores decreased during and after treatment (p

Background: Hepatitis C virus treatment has dramatically improved by direct-acting antiviral (DAA) therapy. The aim of this study was to assess the efficacy and safety of DAA in elderly Egyptian chronic hepatitis C (CHC) patients. Methods: The study was carried out on 327 CHC elderly patients &gt, 60 years, patients were divided into 3 age subgroups (&lt, 65, 65–75 and &gt, 75 years) on DAA therapy for 12 weeks. Ninety-one patients (27.8%) were treated with dual therapy, 234 patients (71.6%) with triple therapy and 2 patients (0.6%) with quadrable therapy. Results: All patients achieved end-of-treatment virological response (100%). ALT levels normalized during therapy. The follow-up rate of sustained virological response at 12 weeks after the end of treatment (SVR12) was 100%. One hundred and two patients had missed SVR12 data due to being lost tofollow-up. Two hundred twenty-two adverse events were reported (67.8%), including anemia in 30 patients (9.1%), leucopenia in 129 patients (39.4%) and thrombocytopenia in 63 patients (19.2%). No serious side effects led to discontinuation of therapy. No hepatic decompensation was observed, and no patients died. Conclusion: Age does not influence the success of DAA treatment and all DAA regimens are well tolerated, safe and highly efficacious, even in those aged 75 years or older.

Background Chronic hepatitis C virus (HCV) infection represents a major health-related burden in Egypt. HCV is considered as a major cardiovascular risk factor. BNP (B-type natriuretic peptide) has been determined as a credible diagnostic and prognostic cardiac biomarker. We aimed to assess plasma BNP in HCV-positive Egyptian patients prior and after HCV eradication by direct-acting antiviral agents (DAAs) therapy. Eighty-nine chronic HCV-positive patients were enrolled in our prospective research. They were provided with DAAs therapy in the form of sofosbuvir and daclatasvir without or with ribavirin for 12 weeks. History, clinical evaluation, and laboratory assessment: CBC, liver and kidney function tests, viral markers (HCVAb, HBVsAg, and HIVAb) by ELISA, HCV RNA by real-time PCR, and BNP by ELISA were assessed. FIB-4 and aspartate aminotransferase-to-platelet ratio index (APRI) scores were ranked. Results Plasma BNP displayed a non-significant (p = 0.124) increase of its serum mean values in post eradication of HCV than its baseline values. Baseline BNP exhibited a significant positive correlation with FIB4 (r = 0.411, P < 0.001) and APRI score (r = 0.418, p < 0.001) with a considerably negative correlation with platelets (r = − 0.274, p = 0.009), in addition to higher pretreatment BNP values in cirrhotic than in non-cirrhotic patients (p < 0.001), while non-significant relations were found regarding sex, BMI, and drug regimen (with or without ribavirin) (p = 0.950, 0.845, and 0.738, respectively). Additionally, plasma BNP values considerably decreased post-treatment in patients presented with higher baseline BNP values and more advanced liver disease (higher FIB4, APRI, and the presence of liver cirrhosis). Conclusion Our findings propose on the one side, the necessity of cardiac monitoring during chronic HCV infection and, on the other, the valuable impacts of HCV eradication on HCV-associated cardiac morbidities.

Tattoos have become increasingly popular worldwide making adverse effects from tattoos a growing concern. In our report, we present a 51-year-old man who developed an unusual allergic reaction to the red ink portions of his tattoos that coincided with the initiation of ledipasvir/sofosbuvir treatment for his hepatitis C. Clinical and histological features were consistent with a delayed-type hypersensitivity reaction to red ink.

Introduction: In Pakistan, for the patients of Hepatitis C virus (HCV), Direct-Acting Antiviral (DAA) therapy for 12 weeks and 24 weeks had been reported to be highly efficacious for genotype 3. We currently carried out an observational study to predict the rate of efficacy of sofosbuvir and ribavirin in hepatitis C patients to establish concrete or authentic data on this combination of DAA for long-term treatment. Materials and Method: Among 2000 subjects who attended tertiary care unit in Lahore-Pakistan from November 2018 to February 2019, 1990 satisfied the criteria set for the present investigation i.e. SVR12 after being treated with sofosbuvir and ribavirin combination. Results: It was noted that genotype 3a were more common among all the subjects under observation with 50.65 % (1008/1990) in females and 49.35% (982/1990) in males. Overall efficacy analysis was found to be 95.4% (1900/1990) in patients while the moderate response was noted in elderly subjects including both genders (61-90 years). DAA responders (male: female percentages) shown the following stats; 66.63 (42/66):36.36 (24/66) in 11-20 years, 56.6(240/424):43.39 (184/424) in 21-30 years and 44.73(272/608):55.27(336/608) in 31-40 years. Conclusion: Collectively, this combinational drug therapy was observed to be successful among the Pakistani population. However, more comprehensive follow-up studies are needed on a larger pool of population nationwide to check only this combinational therapy (sofosbuvir and ribavirin) would be beneficial or not? Or next-generation DAA regimes would be the choice for the Pakistani population.

Human beings are in dire need of developing an efficient treatment against fierce viruses like hepatitis C virus (HCV) and Coronavirus (COVID-19). These viruses have already caused the death of over two million people all over the world. Therefore, over the last years, many direct-acting antiviral drugs (DAADs) were developed targeting nonstructural proteins of these two viruses. Among these DAADs, several drugs were found more effective and safer than the others as sofosbuvir, ledipasvir, grazoprevir, glecaprevir, voxilaprevir, velpatasvir, elbasvir, pibrentasvir and remdesivir. The last one is indicated for COVID-19, while the rest are indicated for HCV treatment. Due to the valuable impact of these DAADs, larger number of analytical methods were required to meet the needs of the clinical studies. Therefore, this review will highlight the current approaches, published in the period between 2017 to present, dealing with the determination of these drugs in two different matrices: pharmaceuticals and biological fluids with the challenges of analyzing these drugs either alone, with other drugs, in presence of interferences (pharmaceutical excipients or endogenous plasma components) or in presence of matrix impurities, degradation products and metabolites. These approaches include spectroscopic, chromatographic, capillary electrophoretic, voltametric and nuclear magnetic resonance methods that have been reported during this period. Moreover, the analytical instrumentation and methods used in determination of these DAADs will be illustrated in tabulated forms.

Worldwide more than 180 million people get infected by chronic Hepatitis C Virus (HCV) and around 700,000 people pass away every year due to HCV related problems. Sofosbuvir and Ribavirin are prescribed as combined medication for the management of HCV infection globally. Therefore, optimization of a pharmaceutical dosage form containing Sofosbuvir and Ribavirin can open a new hope in the treatment of HCV infection. This study was conducted by using the Design of Experiments (DoE) approach. It is a systematic process aiming to determine the correlation between formulation factors affecting the approach and the output of the approach. During the development of formulations, two factors were considered, which are Croscarmellose Sodium (CCS) and Povidone K30 (PK30) at different concentrations ranging from 0.19% to 2.31% of the total tablet weight in 9 different formulations. Their effect on disintegration time (DT) was evaluated through statistical method and it was found between 3±0.003 and 6.5±0.015 minutes. The use of these two different disintegrants exhibited a significant effect on DT. The contour plot showed predicted ranges of concentrations of CCS and PK30 for desired DT. Fourier Transform Infrared Spectroscopy (FTIR) data, Thermogravimetric Analysis (TGA) and X-ray Diffractometry (XRD) spectrums confirmed that there was no interaction between Sofosbuvir and Ribavirin or with any other excipients used in this experiment. Dhaka Univ. J. Pharm. Sci. 20(1): 121-133, 2021 (June)

Purpose This systematic review and meta-analysis aimed to evaluate the effect of sofosbuvir/daclatasvir (SOF/DCV) on mortality, the need for intensive care unit (ICU) admission or invasive mechanical ventilation (IMV) and clinical recovery in patients with COVID-19. Methods We performed a systematic literature search through the PubMed, Scopus and Embase from the inception of databases until 6 April 2021. The intervention group was SOF/DCV, and the control group was standard of care. The primary outcome was mortality, defined as clinically validated death. The secondary outcomes were (1) the need for ICU admission or IMV and (2) clinical recovery. The pooled effect estimates were reported as risk ratios (RRs). Results There were four studies with a total of 231 patients in this meta-analysis. Three studies were randomised controlled trial, and one study was non-randomised. SOF/DCV was associated with lower mortality (RR: 0.31 (0.12, 0.78); p=0.013; I2: 0%) and reduced need for ICU admission or IMV (RR: 0.35 (0.18, 0.69); p=0.002; I2: 0%). Clinical recovery was achieved more frequently in the SOF/DCV (RR: 1.20 (1.04, 1.37); p=0.011; I2: 21.1%). There was a moderate certainty of evidence for mortality and need for ICU/IMV outcome, and a low certainty of evidence for clinical recovery. The absolute risk reductions were 140 fewer per 1000 for mortality and 186 fewer per 1000 for the need for ICU/IMV. The increase in clinical recovery was 146 more per 1000. Conclusion SOF/DCV may reduce mortality rate and need for ICU/IMV in patients with COVID-19 while increasing the chance for clinical recovery. Protocol registration PROSPERO: CRD42021247510.

In this study, rapid resonance Rayleigh scattering (RRS), spectrophotometric, and spectrofluorimetric methods were performed for facile quantitation of daclatasvir dihydrochloride without interference from sofosbuvir (a co-formulated anti-hepatitis C virus drug). The proposed approaches were based on forming a binary complex between daclatasvir dihydrochloride and merbromin reagent at pH 4.1. The binary complex was measured spectrophotometrically at λmax = 544 nm. The spectrofluorimetric approach relied on the quenching effect of daclatasvir dihydrochloride on the fluorescence strength of merbromin at λEmission = 545 nm. The RRS approach depended on augmentation in the merbromin RRS spectrum at 363 nm upon addition of daclatasvir dihydrochloride. The presented methodologies were linear over the concentration ranges 2.5-15.0, 0.2-1.6 and 0.15-3.0 μg ml-1 with detection limits of 0.45, 0.046, and 0.036 μg ml-1 for the spectrophotometric approach, the spectrofluorometric approach, and RRS approach, respectively. Current approaches were validated in compliance with International Council for Harmonisation guidelines and utilized practically to estimate daclatasvir dihydrochloride either in binary mixtures with sofosbuvir or in its commercial tablet dosage form with good results. Moreover, the test for content uniformity was applied successfully on commercial tablets using the current spectroscopic approaches.

Background and study aims Occult hepatitis C viral infection (OCI) may have serious complications, such as relapse, ongoing histological impairment, hepatic decompensation , hepatocellular carcinoma, and the possible risk of transmission. This study was conducted to assess the occurrence and prevalence of secondary OCI in patients with chronic hepatitis C viral infection (HCV) who received a complete course of directly acting antivirals (DAAs). Patients and methods Antiviral therapy consisted of sofosbuvir + daclatasvir ± ribavirin for 12 weeks to 90 treatment-naive, compensated, chronic HCV patients. Plasma and peripheral blood mononuclear cells (PBMCs) were tested for HCV RNA viral load by quantitative, reverse transcription, real-time PCR at 8, 12 (Group I, n = 45), and 24 (Group II, n = 45) weeks after treatment initiation. Results By week 8, only 2 and 7 patients were positive for HCV RNA in plasma and PBMCs, respectively. No HCV RNA was detected by weeks 12 or 24 in the PBMCs of Groups I and II, respectively. Older age was significantly associated with HCV RNA positivity in plasma and PBMCs (n = 8) at week 8 compared with HCV RNA negativity (n = 82). No other significant differences were observed for any other variables. Conclusion The development of secondary OCI among easy-to-treat patients following a full course of DAA treatment doesn't exist, hence, we do not recommend testing the HCV RNA in the PBMCs after complete course of treatment in this patient category. The detection of HCV RNA in PBMCs is recommended as a confirmatory test of cure following a shortened DAA treatment regimen.

Objectives The aim of this study was to evaluate the efficacy and safety of sofosbuvir/ledipasvir ± ribavirin in Malagasy patients with hepatitis C virus genotypes 1 and 2, in real conditions. Patients and methods This was a retrospective monocentric clinical study, carried out over a period of 3 years from March 1, 2017 to February 28, 2020, in a hospital hepato-gastroenterology department. Results In total, 26 patients (M/F: 11/15) with hepatitis C virus genotype 1 (n = 13) or genotype 2 (n = 13), were treated with sofosbuvir/ledipasvir without (n = 21) or with (n = 5) ribavirin for 12 weeks. The mean age was 61.38 ± 7.09 years. Seventeen patients (65.4%) had cirrhosis. The overall sustained virological response was 96.2% (95% CI = 80.4–99.9%). There was no significant difference between the sustained virological responses of genotypes 1 and 2 (92.3% vs 100%; p = 0.31) or those of cirrhotic or non-cirrhotic patients (94.1% vs 100%; p = 0.46). A relapse was observed in one patient (5.9%) — cirrhotic and genotype 1b — under sofosbuvir/ledipasvir with ribavirin. Seven patients (26.9%) experienced mild adverse reactions, including asthenia (57.1%) and insomnia (42.9%). Conclusion Treatment with sofosbuvir/ledipasvir ± ribavirin for infection with hepatitis C virus genotype 1 has been shown to be safe and effective, even in the presence of cirrhosis. The sofosbuvir/ledipasvir combination is a good option for genotype 2 non-cirrhotic patients.