Sofosbuvir Research Articles

Twelve-week of sofosbuvir/velpatasvir therapeutic regimen for chronic hepatitis C patients in northwest region of China: a real-world multicenter clinical study

Objective: To study the real-world outcome of China FDA-approved Sofosbuvir (SOF)/Velpatasvir (VEL) in Northwest China. Methods: In this multicenter, prospective, real-world cohort study, we recruited patients from 10 sites from Northwest China, who were chronically infected with HCV GTs 1-6 from 06/2018 to 09/2019. Patients received SOF (400mg)/VEL (100mg) for 12 weeks, and with ribavirin 900-1200 mg for GT3 cirrhosis and for any genotype decompensated cirrhosis. The primary endpoint was sustained virological response at 12-weeks post-treatment (SVR12) and safety. The secondary endpoint was the change of liver function after the achievement of SVR12. Results: Totally, 143 patients were enrolled in the study, four patients were lost to follow-up and one died during the follow-up, 138 patients were included in per-protocol analysis. Of the 138 patients, the mean age 53 years, 53.6% male, 94.2% Han nationality, 53.6% liver cirrhosis, 10.1% HBsAg(+), 6.5% renal dysfunction, 5.1% treatment-experienced, and 16.7% patients received ribavirin treatment. The genotype distribution was as follows: 35.5% GT1, 42.8% GT2, 15.9% GT3, and 5.8% un-typed. The SVR12 rate was 96.5% (138/143, 95%CI: 93.5%-99.6%) for intention-to-treat analysis, and in per-protocol analysis, all 138 patients obtained SVR12 (100%). Compared with baseline, the serum total bilirubin, ALT and AFP levels decreased (all P < 0.05), as well as increased ALB and platelet count (all P < 0.001) at post-treatment 12-weeks. Overall adverse events (AEs) rate is 29.0%, and the most common AEs were anemia (14.5%) and fatigue (8.0%). Severe side effects (edema and fatigue) occurred in 2 patients, one of whom needed a short-term interruption of treatment due to fatigue. Conclusion: In this real-world cohort study, 12-week SOF/VEL regimen with or without ribavirin achieved high SVR12 rates (96.5%-100% overall) with excellent safety profile among patients with HCV GT1/2/3 infection including patients with GT3 and cirrhosis, and led to improvement of liver function.

Innovative derivative/zero ratio spectrophotometric method for simultaneous determination of sofosbuvir and ledipasvir: Application to average content and uniformity of dosage units

An innovative simple, rapid and sensitive spectrophotometric method was developed for the simultaneous analysis of sofosbuvir (SOF) and ledipasvir (LED) in their combined dosage forms. Sofosbuvir with ledipasvir (SOF/LED) as a combined dosage form was tried at the pandemic COVID 19 crisis. This technique has the advantages of both zero order and first order spectrophotometry. The zero and first derivative amplitudes were measured at 274.2 nm for SOF (zero crossing point of LED in first derivative spectrum) and 314 nm for LED (zero crossing point of SOF in first derivative spectrum) over the concentration range of 2.0–50.0 μg mL−1 with coefficients of determination (R2) > 0.9999 for both drugs and mean percentage recoveries of 100.25 ± 1.61 and 99.85 ± 0.99 for SOF and LED; respectively.This original method was validated according to ICH requirements and statistically compared to published comparison methods. This method was applied to estimate the average content and the uniformity of dosage units of SOF/LED combined dosage form according to British Pharmacopeia requirements.

SPECTROPHOTOMETRIC METHODS FOR DETERMINATION OF SOFOSBUVIR AND DACLATASVIR IN PURE AND DOSAGE FORMS

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.

Predictors of residual hepatic reserve and hepatic decompensation in cirrhotic patients after ablated hepatocellular carcinoma treated by DDAs or systemic therapy

BackgroundTherapeutic 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.ResultsUnfavorable 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).ConclusionNon-invasive parameters of residual hepatic reserve are promising tools to guide therapy and avoid further complications in patients with liver cirrhosis and ablated HCC.

Activation of Tenofovir Alafenamide and Sofosbuvir in the Human Lung and Its Implications in the Development of Nucleoside/Nucleotide Prodrugs for Treating SARS-CoV-2 Pulmonary Infection.

ProTide technology is a powerful tool for the design of nucleoside/nucleotide analog prodrugs. ProTide prodrug design improves cell permeability and enhances intracellular activation. The hydrolysis of the ester bond of a ProTide is a determinant of the intracellular activation efficiency and final antiviral efficacy of the prodrug. The hydrolysis is dictated by the catalytic activity and abundance of activating enzymes. The antiviral agents tenofovir alafenamide (TAF) and sofosbuvir (SBV) are typical ProTides. Both TAF and SBV have also been proposed to treat patients with COVID-19. However, the mechanisms underlying the activation of the two prodrugs in the lung remain inconclusive. In the present study, we profiled the catalytic activity of serine hydrolases in human lung S9 fractions using an activity-based protein profiling assay. We evaluated the hydrolysis of TAF and SBV using human lung and liver S9 fractions and purified enzymes. The results showed that CatA and CES1 were involved in the hydrolysis of the two prodrugs in the human lung. More specifically, CatA exhibited a nearly 4-fold higher hydrolytic activity towards TAF than SBV, whereas the CES1 activity on hydrolyzing TAF was slightly lower than that for SBV. Overall, TAF had a nearly 4-fold higher hydrolysis rate in human lung S9 than SBV. We further analyzed protein expression levels of CatA and CES1 in the human lung, liver, and primary cells of the two tissues using proteomics data extracted from the literature. The relative protein abundance of CatA to CES1 was considerably higher in the human lung and primary human airway epithelial cells than in the human liver and primary human hepatocytes. The findings demonstrated that the high susceptivity of TAF to CatA-mediated hydrolysis resulted in efficient TAF hydrolysis in the human lung, suggesting that CatA could be utilized as a target activating enzyme when designing antiviral ester prodrugs for the treatment of respiratory virus infection.

Evolutive Aspects Of Patients With Cirrhosis After Harvoni Therapy

Introduction: Cirrhosis, is a final pathway of chronic liver diseases. In recent years, Direct-Acting Antiviral Agents (DAAs) gained a leading role in the treatment of chronic hepatitis of viral etiology. Aim of the study: The proposed aims of this research are to estimate the virological response after 12 weeks after treatment completion and to evaluate the beneficial effects of the treatment on patients with decompensated cirrhosis. Patients and methods: The study was of a descriptive type, longitudinal and retrospective, conducted over a 15 months period, including patients with HCV-related cirrhosis patients. It was established the correlation between liver function, metabolic function, comorbidities and severity of cirrhosis and the level of HCV RNA before and after treatment. It was assessed also the neuroinflammatory activity from the results of Fibromas and the complication after therapy. Results: From January 2018 to April 2019, patients with liver cirrhosis were hospitalized. 48 HCV- related cirrhosis patients have fulfilled the eligibility criteria for antiviral treatment and they have constituted the study group. From all the HCV-infected patients with cirrhosis, 41.66% were women and 58.33% were men, most of them in the interval 60-70 years (37.5%) and 70-80 years (33,33%). 87.5% from the patients had compensated cirrhosis (Child-Pugh A class) and 12.5% had decompensated cirrhosis (Child-Pugh B and C class). 77.08% of the patients had severe neuroinflammatory activity – A3, 10.41% had moderate -A2 activity and 12.5% had lower neuroinflammatory activity-A1. The treatment with direct antiviral agents for the study group consisted in three treatment regimens.60% received a two-drug fixed-dose combination- sofosbuvir (SOF)/ledipasvir (LDV). 10% received SOF/LDV combination with Ribavirin. Only 1 patient with Child-Pugh C decompensated cirrhosis received SOF/LDV combination without Ribavirin. Also, a double combination received 10.48% of the patients- grazoprevir (GZR)/ elbasvir (EBR) 20.83% received quadruple combination ombitasvir (OBV)/ paritaprevir (PTV)/ritonavir(r) and dasabuvir (DSV). After 12 weeks from treatment completion, all the HCV-RNA’s level were undetectable. There were no side effects of the treatment. None of the patients didn’t stop the treatment during the period of treatment. There was a statistically significant difference between the ASAT and ALAT level before and after treatment (p&lt;0.0001). 1 patient with Child-Pugh score C, died and another patient with Child-Pugh score B had an episode of variceal bleeding. Conclusion: Treatment with direct antiviral agents as Harvoni regimen, is a safe therapy and effective for HCV-infection and advanced liver disease. Despite the efficiency of the treatment on HCV-RNA, there were patients with complications due to the cirrhotic status of the subjects. The patients with existing decompensated cirrhosis remain at an elevated risk of numerous other complications.

Direct Relationship between Interleukin-10 Gene Polymorphism and Hepatocellular Carcinoma Complicated by Direct Acting Antiviral Treatment of Hepatitis C Virus.

Objective:This study aimed to assess the correlation between the genotyping of interleukin-10 (IL-10 polymorphism rs 1800871) and the incidence hepatocellular carcinoma (HCC) among patients with hepatitis C virus (HCV) treated with direct acting antivirals (DAAs). Method:For 200 patients with HCV infection who completed DAA treatment and followed up for 1 year, IL-10 polymorphism SNP(-819) rs 1800871 analysis was conducted via real time polymerase chain reaction. During the follow-up period, 100 patients who developed HCC were selected and compared with 100 patients who did not develop any complications. Results:The studied patients were divided into two groups according to the incidence of complications after completion of DAA treatments. During the follow-up, 100 patients with HCV infection who developed HCC were selected and compared with 100 patients with HCV infection who did not develop any complications (positive control group). For the HCC group (n = 100), the mean age was 58.1 ± 6.4 years, with 92.7% being male and 7.3% being female; 91% had cirrhosis, 10% had lymphadenitis, 75% had splenomegaly, and 17% had ascites. In the positive control group (n = 100), mean age was 46.3 ± 9.4 years, with 68% being male and 32% being female; 20% had cirrhosis, 12% had splenomegaly, and 4.2% had ascites. The results demonstrated that sofosbuvir (SOF) + daclatasvir + ribavirin regimen was the most prevalent drug treatment for patients with HCC (72%), while SOF + Simeprevir was the most safe treatment for HCV infection among patients with HCC (2%). CT genotype was the most common genotype in the HCC group (56%), among different drug regimen (67.8%). T allele was the most prevalent in HCC group (61%), while the C allele was the least prevalent (39%). Conclusion: IL-10 genotyping may help in selecting the safest and most accurate drug regimen according to the safest genotype response relationship and follow-up of genotype resistance.

Efficacy and safety of sofosbuvir plus daclatasvir with or without ribavirin in treatment of Egyptian patients infected with chronic HCV (Single Centre Study)

Abstract Background and aim As indicated by the World Health Organization (WHO), Egypt is positioned as the country with the world’s highest prevalence of Hepatitis C virus (HCV). The current study was designed to describe the efficacy and safety of Sofosbuvir plus Daclatasvir with or without Ribavirin in treatment of chronic HCV in a cohort of Egyptian patients who were referred to the viral hepatitis unit in El -Fayoum general hospital. Methods This is a prospective descriptive cross sectional study that describes the effect of 12 weeks of daily Sofosbuvir (SOF) 400 mg plus Daclatasvir (DCV) 60 mg with or without ribavirin (RBV) with dose adjustment if indicated. It included 200 patients that fulfilled the inclusion and exclusion criteria and treated in El -Fayoum general hospital, El-Fayoum, Egypt. Results In the current study, concerning viral response, SVR12 rate was achieved by 92.5% in the overall patients (185/200); by 98% (98/100) in group I, and by 87% (87/100) in group II. Concerning safety and tolerability, The main adverse effects recorded during and after 12 weeks of treatments were fatigue (46%), (66%); headache (24%), (40%); gastrointestinal upset (15%), (43%); and nausea (10%), (15%) in group 1 and group 2, respectively. Only one female patient in group II developed HCC. All patients completed treatment till the end of course. Conclusion The current study suggested that treatment of SOF plus DCV with/without RBV for chronic HCV patients in Egypt was generally safe, well tolerated, and of high efficacy, reflecting the antiviral potency and high resistance barrier of the combination regimen.

Effect of sofosbuvir-based DAAs on changes in lower-density lipoprotein in HCV patients: a systematic review and meta-analysis

BackgroundPrevious 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.MethodsA 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.ResultsSix 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.ConclusionsFor 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.

Sofosbuvir plus velpatasvir combination for the treatment of chronic hepatitis C in patients with end stage renal disease on renal replacement therapy: A systematic review and meta-analysis.

Sofosbuvir (SOF) and velpatasvir (VEL) is a pan-genotypic regimen for the treatment of Hepatitis C virus (HCV) infection. The data on the efficacy and safety of this regimen is end-stage renal disease (ESRD) is scanty. This systematic review and meta-analysis was done to ascertain the efficacy and safety of SOF and VEL in patients with chronic Hepatitis C (CHC) and ESRD on renal replacement therapy (RRT). Systematic search of Pubmed, Embase, Scopus, and Google Scholar was conducted using the search term (end-stage renal disease OR renal replacement therapy OR chronic kidney failure OR severe renal impairment OR chronic kidney disease OR haemodialysis OR dialysis OR peritoneal dialysis) AND (sofosbuvir OR velpatasvir OR NS5A inhibitors OR directly acting antivirals). Pooled sustained virologic response (SVR) and adverse event rates with 95% confidence intervals were estimated. Seven studies (410 patients with CHC and ESRD on RRT) fulfilled our eligibility criteria. The overall pooled SVR rate of SOF and VEL in patients with HCV on RRT was 97.69% (95% CI: 95.71 to 98.92). There was no significant heterogeneity (I2 : 39.3%, p-value of Cochran's Q=0.13) among the studies. The pooled estimate of efficacy of SOF-VEL combination among patients with cirrhosis was 91.94% (95% CI 77.03-98.52). Pooled SVR rates in genotype 3 infection [94.6%, (95%: CI 81.3-99.4)] was comparable to that in those with documented non-genotype 3 infection [94.63%, (95% CI 87.12-98.44)]. No serious adverse event attributable to SOF and VEL was reported in the included studies. The fixed-dose combination of SOF and VEL is effective and safe in CHC patients with ESRD on RRT.

Impact of sofosbuvir/ledipasvir versus sofosbuvir/daclatasvir regimens on the male sexual function of patients with chronic hepatitis C.

Direct-acting antivirals (DAAs) are associated with remarkable efficiency and safety profiles; however, their effect on erectile function remains insufficiently studied. This study included 200 male patients with chronic hepatitis C virus (HCV) infection divided into groups A and B and 100 healthy controls. Group A received sofosbuvir (SOF) 400 mg/ledipasvir 90 mg (Harvoni), whereas group B received SOF 400 mg/ daclatasvir 60 mg for 3 months. The Arabic version of the five-item International Index of Erectile Function-5 (IIEF-5) questionnaire was used to assess erectile function before and after completion of therapy and 3 months after. Erectile dysfunction (ED) was present in 74.5% of the patients and 14% of the controls. Immediately after treatment, group B (22.5±2.6) had a significantly higher mean IIEF-5 score than did group A (17.3±3.3) (p<0.001). Three months after treatment, all groups had no significant differences in mean IIEF-5 scores (group A: 23.1±1.9, group B: 23.3±1.9, controls: 23.7±2.3); however, free testosterone (FT) levels were significantly higher compared with pre-treatment. Both treatment regimens were associated with the improvement of erectile function and sex hormonal milieu. SOF/daclatasvir was associated with earlier improvement of erectile function compared with SOF/ledipasvir.

Safety and efficacy of sofosbuvir based regimen in the treatment of hepatitis C virus infection among hemodialysis patients in Morocco

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.

Optimization and development of orodispersible films for ledipasvir and sofosbuvir through solid dispersion using Box-Behnken design

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.

A novel fixed-dose combination treatment for chronic hepatitis C, based on NS5A inhibitor fopitasvir and NS5B inhibitor sofosbuvir.

Drug resistance caused by the extreme genetic variability of zhe hepatitis C virus has rendered effective combinations of drugs indispensable in the treatment of chronic hepatitis C (CHC). Herein, we developed a fixed-dose combination (FDC) treatment containing the NS5B inhibitor sofosbuvir (SOF) and the NS5A inhibitor fopitasvir (FOP). Then the dissolution behavior of FOP in FOP/SOF FDC was improved by co-micronizing FOP with lactose. The enhanced dissolution rate of FOP in the FDC was in good agreement with the behavior of the FOP singledrug tablet. In addition, pharmacokinetic studies showed that both FOP and SOF in the FDC exhibited similar characteristics (area under the curve, Cmax, Tmax, and T1/2) as those of tablets containing FOP or SOF alone. These results revealed that the FOP/SOF FDC represents a potential therapeutic option for the treatment of CHC.

Effective and Safe Daclatasvir Drug Exposures Predicted in Children Using Adult Formulations.

Sofosbuvir (SOF)/daclatasvir (DCV) is the direct-acting antiviral regimen of choice in many low- and middle-income countries for curative treatment of chronic hepatitis C virus (HCV) infection in adults, but data on the use of DCV in children are lacking. We performed a population pharmacokinetic (PK) analysis to predict DCV exposure in children treated with available adult formulations. DCV concentration data from HCV-infected adolescents receiving SOF/DCV [400/60 mg, once daily (OD)] who participated in a PK study in Egypt were used for model development. PK parameters were estimated using a population approach. Monte Carlo simulations were run for virtual children weighing 10 to <35 kg receiving 60 or 30 mg OD, and DCV exposures were compared with adults ranges. Seventeen HCV-infected adolescents (13 males) provided 151 DCV concentrations. Median (range) age was 14 (11-18) years and weight 50 (32-63) kg. In these adolescents receiving 60 mg DCV, median (interquartile range) DCV area under the concentration time curve 0 to 24 hours, maximum concentrations, and minimum concentrations were 11,130 (8140-14,690) ng·h/mL, 1030 (790-1220) ng/mL and 130 (110-220) ng/mL, respectively, compared with 10,343 (7661-14,095) ng·h/mL, 1132 (876-1518) ng/mL and 110 (55.7-192) ng/mL predicted in children 10 to <35 kg receiving 30 mg. The proportion of children with DCV exposures above the adult range rapidly increased for children <30 kg using 60 mg OD, similarly for children 10-14 kg using 30 mg. DCV 30 mg OD was predicted to achieve effective and safe exposures in children 14 to <35 kg, perhaps down to 10 kg. These results should be validated clinically. Low-cost available adult DCV formulations together with approved pediatric doses of SOF would expand global access to HCV treatment for children.

An intelligent method based on feed-forward artificial neural network and least square support vector machine for the simultaneous spectrophotometric estimation of anti hepatitis C virus drugs in pharmaceutical formulation and biological fluid

This study proposed simple and reliable spectrophotometry method for simultaneous analysis of hepatitis C antiviral binary mixture containing sofosbuvir (SOF) and daclatasvir (DAC). This technique is based on the use of feed-forward artificial neural network (FF-ANN) and least square support vector machine (LS-SVM). FF-NN with Levenberg–Marquardt (LM) and Cartesian genetic programming (CGP) algorithms was trained to determine the best number of hidden layers and the number of neurons. This comparison demonstrated that the LM algorithm had the minimum mean square error (MSE) for SOF (1.59 × 10−28) and DAC (4.71 × 10−28). In LS-SVM model, the optimum regularization parameter (γ) and width of the function (σ) were achieved with root mean square error (RMSE) of 0.9355 and 0.2641 for SOF and DAC, respectively. The coefficient of determination (R2) value of mixtures containing SOF and DAC was 0.996 and 0.997, respectively. The percentage recovery values were in the range of 94.03–104.58 and 94.04–106.41 for SOF and DAC, respectively. Statistical test (ANOVA) was implemented to compare high-performance liquid chromatography (HPLC) and spectrophotometry, which showed no significant difference. These results indicate that the proposed method possesses great potential ability for prediction of concentration of components in pharmaceutical formulations.

A real-world study of sofosbuvir-based drug treatment for hepatitis C virus genotype 6 infection in Hainan region of China

Objective: To explore the real-world effectiveness and safety of sofosbuvir-based regimen for patients with chronic hepatitis C virus (HCV) genotype 6 infection in Hainan Island. Methods: Fifty-three cases with chronic hepatitis C virus (HCV) genotype 6 infection who were initially treated with a sofosbuvir (SOF)-based regimen [sofosbuvir/velpatasvir (SOF/VEL) for 12 weeks or sofosbuvir combined with ribavirin (SOF+RBV) for 24 weeks], followed by 24 weeks of follow-up after discontinuation of the drug from January 2018 to March 2020 were selected. The primary outcome measures were incidence of sustained virological response at 12 weeks (SVR12) after the drug withdrawal. The secondary outcome measures were adverse drug events with sustained virological response at the end of treatment and 24 weeks after the end of treatment. The occurrence of adverse events was observed during the treatment. An intragroup comparison was performed by t-test. Intention-to-treat and modified intention-to-treat analysis was used for sustained virological respons. Results: The subtype distribution of chronic hepatitis C virus (HCV) genotype 6 in 53 cases of chronic hepatitis C infection were as follows: 22 cases of type 6a, 5 cases of type 6w, 5 cases of type 6xa, 3 cases of type 6v, 2 cases of type 6e, 2 cases of type 6r, 1 case of type 6xh, and 13 cases of special virus strains with undetermined genotype. The overall sustained virological response rate at 12 weeks after the drug withdrawal was 100%. Furthermore, HCV RNA was undetectable during the treatment period (4 weeks), at the end of treatment and after the treatment (24 weeks). There were seven cases of adverse events, mainly including fatigue, anorexia, and mild anemia; however, no serious adverse events were reported. Conclusion: Sofosbuvir-based regimen combined with ribavirin or velpatasvir cannot only achieve high response rate to HCV subtype 6a, but also obtain a good sustained virological response to the rare prevalent sub-genotypes and special virus strains of HCV genotype 6, with mild adverse reactions and acceptable safety profile.

Patient acceptability and efficacy of simeprevir and sofosbuvir in hepatitis C after allogeneic stem cell transplantation

The treatment goal of chronic hepatitis C virus (HCV) infection is sustained virological response (SVR) and the combination of simeprevir (SMV) and sofosbuvir (SOF) has been well tolerated in various studies. The study aimed to assess the patient acceptability and response to SMV-SOF in allogenic stem cell transplant. To assess the physical and mental health related quality of life (HRQoL) before during and after treatment using EQ-5D-5L instrument. To assess the sustained virologic response (SVR). Sixty patients were included in our study with HCV genotype1 using a combination of SMV-SOF for a fixed period of 12 weeks. The EQ-5D-5L questionnaire and visual analog scale (VAS) were given to calculate coefficient's utility. Utility EQ index was calculated and statistical analysis were performed. The mean age of the cohort was 55 years with 61% males. The SVR for intent to treat was 78% and relapse rate of 14%. The per protocol SVR was 84% and relapse was 13%. The VAS score was positive indicating a better quality of life. Post treatment EQ index was statistically better in group that received SMV and SOF. Addition of SMV and SOF was more tolerable and effective in allogeneic stem cell transplant patients. There was only minimal interaction with the immunosuppressive drugs. The EQ index values are also higher in the duel regimen.

Microelimination of hepatitis C in patients with chronic hemolytic anemias: a single-center experience

BackgroundPatients with chronic hemolytic anemias (CHA) are at a high risk for transfusion-transmitted infections. Various studies in Egypt have shown a prevalence of hepatitis C virus (HCV) infection in 24–37% of those patients. Elimination of hepatitis C virus (HCV) in patients with CHA would prevent early progression of liver disease. In this study, we aimed to assess the efficacy, safety, and tolerability of sofosbuvir (SOF) and daclatasvir (DAC) in the special population of HCV-infected patients with CHA. In this prospective study, 21 consenting hepatitis C patients were recruited and treated using ribavirin-free SOF/DAC regimen for either 12 or 24 weeks according to categorization of patients into easy or hard-to-treat in accordance with the national protocols. Sustained virological response was assessed by RT-PCR for HCV-RNA at 12 weeks post-treatment (SVR12). Any treatment-related adverse events were noted.ResultsAll patients were adherent to treatment with no discontinuation of therapy. SVR12 was achieved in 19 out of 21 patients (90.5%). There was a significant improvement in levels of ALT (p<0.009) after completion of therapy. On the other hand, the hemoglobin, total bilirubin, and ferritin levels showed a non-significant difference (p<0.501, p<0.542, and p<0.339, respectively). Moderate adverse events were observed in 2 out of 21 patients (9.5%), including sickling crisis and hepatic decompensation.ConclusionThe results of this study substantiate the favorable efficacy, safety, and tolerability of ribavirin-free direct-acting antivirals (DAAs) in the special population of HCV-infected patients with CHA. Micro-elimination of HCV in special patient populations allows for pragmatic delivery of care to patients with co-morbid conditions who are in most need for treatment and allows for achievement of global elimination of HCV worldwide.

Cost-effective green chromatographic method for the simultaneous determination of four commonly used direct-acting antiviral drugs in plasma and various pharmaceutical formulations

This article presents the simultaneous determination of multiple recently approved direct-acting antiviral (DAA) regimens using a sensitive, robust method. Reversed-phase high-performance liquid chromatographic method (RP-HPLC) has been developed to represent a green alternative of other reported methods for the simultaneous determination of the most common four DAAs used for chronic hepatitis C treatment, including sofosbuvir (SF), ledipasvir (LD), daclatasvir (DC), velpatasvir (VP) and tenofovir (TO) as internal standard (IS) in bulk, pharmaceutical dosage form and plasma samples. This method was performed with an environment-friendly mobile phase with the least amount of energy consumption and waste generation. Chromatographic conditions have been optimized in order to obtain well-resolved symmetrical peaks within a reasonable elution time. Separation was achieved using Waters XBridge BEH C18 Column (4.6 × 150 mm) using isocratic elution mode at a flow rate 0.8 mL.min−1 with the mobile phase 0.1% (v/v) triethylamine acidified water with ortho-phosphoric acid (OPA) pH 2.53 and acetonitrile in the ratio (70:30 v/v). Sample extraction was done using diethyl ether for the analyte and IS extraction from the plasma samples. The suggested method was validated within the concentration range (0.4–20 μg.mL−1) for all the studied drugs according to the ICH guidelines. Calibration plots showed a linear relationship for SF, LD, DC and VP with correlation coefficients ≥ 0.9995 and acceptable recoveries. The method has been applied for the analysis of the studied drugs in plasma samples and pharmaceutical dosage forms without any matrix interference and with % RSD less than 2%, indicating the method to be precise. The suggested method was also assessed using the analytical Eco-scale tool and Green Analytical Procedure Index (GAPI) by comparing the method with other reported methods in terms of sample preparation, consuming hazardous reagents, instrument energy consumption and waste generation. Eco-scale and GAPI results proved the greenness of our proposed method. Moreover, the proposed method has the advantage of analyzing several pharmacologically related drugs in the same run simultaneously, which allows the analysis of alternative therapeutic formulations under the same running conditions. Thus, much effort and time is saved for developing a specific method for every pharmaceutical mixture. This promotes the proposed method to be used for both quality control analysis and any bioavailability study for the simultaneous determination of any of the four antiviral drugs in the pharmaceutical formulation or plasma samples without any harmful effect on the environment or human health.