Terapia antiviral de acción directa para infección del virus de hepatitis C en pacientes en hemodiálisis

Introducción: La infección por el virus C de la hepatitis resulta común en pacientes en hemodiálisis y se considera endémica en estas unidades. El tratamiento utilizado lo componían el interferón pegilado y la ribavirina, combinación que presentaba niveles de toxicidad y baja respuesta. Las drogas actuales aportan mejores resultados. Objetivos: Determinar la eficacia y seguridad de la terapia antiviral de acción directa para la infección del virus de la hepatitis C en pacientes con insuficiencia renal crónica en hemodiálisis. Métodos: Estudio descriptivo prospectivo en 19 pacientes en régimen de hemodiálisis y con infección por virus C, pertenecientes al Hospital General Docente "Dr. Mario Muñoz Monroy", desde diciembre de 2020 hasta septiembre de 2021," A todos se les prescribió durante 12 semanas Sofosbuvir® 400 mg más Daclatasvir® 60 mg diarios. Se caracterizaron las variables edad, sexo, fibrosis hepática por el índice aspartato-aminotransferasa/plaquetas, reacciones adversas y respuesta viral 12 semanas después del tratamiento. Resultados: La infección predominó en el grupo de 51 a 60 años (36,84 %). La mayoría de los pacientes mostró un índice aspartato-aminotransferasa/plaquetas ≤ 0,5, lo que correspondió con ausencia de fibrosis hepática significativa (14 pacientes). Una minoría de pacientes registró reacciones adversas. No se demostró toxicidad cardiovascular ni hepática. La totalidad de los pacientes manifestaron carga viral no detectable 12 semanas después del tratamiento. Conclusiones: La combinación de Sofosbuvir® con Daclatasvir® para el tratamiento de la infección por virus de la hepatitis C en pacientes con insuficiencia renal crónica en tratamiento de hemodiálisis resultó eficaz, bien tolerada y segura.

Introduction: Hepatitis C virus infection is common in hemodialysis patients and is considered endemic in these units. The treatment used consisted of pegylated interferon and ribavirin, a combination that presented levels of toxicity and low response. Current drugs bring better results. Objectives: To determine the efficacy and safety of direct-acting antiviral therapy for hepatitis C virus infection in patients with chronic renal failure on hemodialysis. Methods: Prospective descriptive study in 19 patients on hemodialysis and with virus C infection, belonging to "Dr. Mario Muñoz Monroy" Teaching General Hospital, from December 2020 to September 2021. All were prescribed for 12 weeks with Sofosbuvir® 400 mg plus Daclatasvir® 60 mg daily. The variables age, sex, liver fibrosis were characterized by the aspartate aminotransferase/platelet index, adverse reactions and viral response 12 weeks after treatment. Results: Infection predominated in the group of 51 to 60 years (36.84%). Most patients showed an aspartate aminotransferase/platelet ratio ≤ 0.5, corresponding to the absence of significant liver fibrosis (14 patients). A minority of patients reported adverse reactions. No cardiovascular or hepatic toxicity was demonstrated. All patients had an undetectable viral load 12 weeks after treatment. Conclusions: The combination of Sofosbuvir® with Daclatasvir® for the treatment of hepatitis C virus infection in patients with chronic renal failure undergoing hemodialysis was effective, well tolerated and safe.

Efficacy and safety of sofosbuvir-based direct-acting antiviral treatment in children and adolescent patients with chronic hepatitis C / 中华传染病杂志

Objective:To explore the efficacy and safety of sofosbuvir-based direct-acting antiviral treatment in children and adolescent patients with chronic hepatitis C (CHC).Methods:A total of 52 children and adolescent patients who admitted to The Third People′s Hospital of Kunming City and The People′s Hospital of Fuyuan County aged from three to 17 years old with CHC from January 2018 to August 2022 were enrolled, and their basic information was collected. Patients were treated with sofosbuvir/velpatasvir (SOF/VEL) or ledipasvir/sofosbuvir (LDV/SOF) with or without ribavirin for 12 weeks. The biochemical and virological indexes were followed up before and after treatment and 12 weeks after withdrawal. The primary endpoint was the sustained virological response (SVR) at week 12 of follow-up after treatment, and the occurrence of adverse events (AE) during treatment. Statistical analysis was used by nonparametric test.Results:A total of 52 patients with CHC including 38 children and 14 adolescents were enrolled. Thirty-one were male and 21 were female. The age was 9(7, 12) years old. Among 52 patients, seven patients were type 1b, 11 were type 2a, three were type 2, five were type 3a, 18 were type 3b, one was type 6a, three were type 6k, four were type 6n and one was type 6v. Twelve (23.1%) patients were vertical transmission, 21(40.4%) patients had horizontal transmission among family members, two (3.8%) patients were blood fluid transmission, and 17(32.7%) were unknown transmission route. Compared with the baseline levels, Total bilirubin, alanine aminotransferase and aspartate aminotransferase were all significantly decreased after 12 weeks of treatment and 12 weeks after withdrawal, and the differences were statistically significant ( F=12.71, 30.23 and 42.52, respectively, all P<0.05). Up to September 30, 2022, 100.0%(52/52) of patients achieved SVR at the end of treatment. For patients who completed follow-up for 12 weeks after treatment, 95.8%(46/48) achieved SVR. Common AEs during treatment were fatigue (11.5%(6/52)), headache (5.8%(3/52)), dizziness (1.9%(1/52)), abdominal pain (3.8%(2/52)), diarrhea (1.9%(1/52)), rash (1.9%(1/52)) and skin pruritus (1.9%(1/52)). No patients discontinued treatment because of AE. Conclusions:Sofosbuvir-based direct-acting antiviral treatment is efficient and well-tolerated in children and adolescent patients with CHC. No patients discontinued treatment due to AE.

Efficacy and safety of the 12-week sofosbuvir-coblopasvir regimen in treatment of chronic hepatitis C / 临床肝胆病杂志

Objective To investigate the efficacy and safety of the 12-week regimen with sofosbuvir and coblopasvir hydrochloride in the treatment of chronic hepatitis C (CHC) in northwest China. Methods This study enrolled 101 patients with CHC of any genotype who received sofosbuvir (400 mg) combined with coblopasvir hydrochloride (60 mg) for 12 weeks in The First Affiliated Hospital of Air Force Medical University, The Second Affiliated Hospital of Air Force Medical University, The Second Affiliated Hospital of Xi'an Jiaotong University, and Baoji Central Hospital from July 1 to December 31, 2021, among whom 13 had liver cirrhosis and 88 did not have live cirrhosis. Other antiviral drugs such as ribavirin were not added regardless of the presence or absence of liver cirrhosis or the genotype of CHC. Related clinical data ere extracted, including HCV RNA quantification and liver biochemical parameters at baseline, at week 12 of treatment, and at 12 weeks after drug withdrawal. The primary endpoints were sustained virologic response at 12 weeks after the end of treatment (SVR12) and safety at week 12 of treatment, and the secondary endpoint was the effect of the 12-week treatment on liver biochemical parameters. The non-normally distributed continuous data were expressed as M ( P 25 - P 75 ), and the Mann-Whitney U test was used for comparison between groups. Results A total of 101 patients were included in the analysis, among whom there were 55 male patients (54.5%) and 46 female patients, and the median age was 53 years. Among these patients, 12.8% had liver cirrhosis, 1.0% had liver cancer, 3.0% were treatment-experienced patients, and 3.0% had type 2 diabetes. As for genotype distribution, 8% had CHC genotype 1, 60% had CHC genotype 2, 19% had CHC genotype 3, and 6% had CHC genotype 6, and genotype was not tested for 7% of the patients. After 12 weeks of treatment, all 101 patients had a HCV RNA level of below the lower limit of detection and an SVR12 rate of 100%, with a significant reduction in the serum level of alanine aminotransferase (ALT) from baseline to week 12 of treatment ( P < 0.05). Among these patients, 22.7% had concomitant medications such as atorvastatin calcium, aspirin, metformin, nifedipine, bicyclol, and compound glycyrrhizin. The incidence rate of adverse events was 16.8%, and fatigue (12.9%) was the most common adverse event. Conclusion The 12-week treatment with sofosbuvir and coblopasvir hydrochloride can obtain high SVR12 in CHC patients in northwest China and has good antiviral safety, with a significant improvement in abnormal serum ALT at week 12 of treatment.

Treatment of Hepatitis C with Direct-Acting Antivirals does not Induce Significant Arrhythmias

Abstract Background Chronic Hepatitis C (CHC) therapy with direct-acting antivirals (DAAs) has high efficacy and safety, but some cases of bradyarrhythmias have been described. Objective To evaluate heart rhythm disorders during DAA treatments. Methods Forty-eight patients with CHC (mean 61 years of age; 56% males; 73% HCV genotype 1) were evaluated before and during treatment with DAAs, analyzed by a resting 12-lead ECG [PR, QRS, and QT corrected (QTc) intervals measured] and a 24-h-Holter system, to evaluate the heart rate (HR) and the occurrence of arrhythmias. The Student's t-test or the Wilcoxon-Mann-Whitney test for continuous, independent variables were performed with a statistically significant p-value < 0.05. Results The electrocardiographic parameters before and during treatment were: PR interval (147.2 ± 15.6 vs 144.9 ± 15.6 ms; p = 0.21), QTc interval (427 ± 22.3 vs 421.7 ± 25.3 ms; p = 0.24), minimum HR (52.7 ± 8.4 vs 53.2 ± 8.5 bpm; p = 0.49), median HR (74.2 ± 10.4 vs 75.2 ± 9 bpm; p = 0.83), and maximum HR (117.4 ± 16.8 vs 117.9 ± 16.3 bpm; p = 0.25). These parameters proved to be similar among 11 beta-blockers or 22 ribavirin users. During treatment, the 21 cirrhotic patients presented significantly lower median HRs (72.1 ± 9.0 vs 77.9 ± 8.2 bpm; p = 0.02) and maximum HRs (108.9 ± 15.2 vs. 125.1 ± 13.2 bpm, p < 0.0001) through a 24-h-Holter monitoring than the patients without cirrhosis. No clinically relevant arrhythmias were detected. Conclusion DAAs do not significantly influence heart rate or induce significant cardiac arrhythmias in patients with CHC.

Assessment of efficacy and safety of daclatasvir, sofusbuvirand ribavirin regimen for 12 weeks as compared to daclatasvir and sofusbuvir combination regimen for 24 weeks in decompensated cirrhotic patients due to hepatitis C virus genotype 3 infection

Background: Assessment of efficacy and safety of daclatasvir+sofosbuvir+ribavirin (DCV+SOF+RBV) for 12 weeks as compare to daclatasvir and sofusbuvirfor 24 weeks in decompensated cirrhotic patients due to hepatitis C virus (HCV) genotype 3 infection. Methods: An observational, prospective, COHORTstudy over 1 year, in decompensated cirrhosis due to G3-HCV infected adult patients. Treatment was a combination of sofosbuvir 400 mg/day+daclatasvir 60 mg/day, with or without a weight-adjusted dosing of ribavirin for 12 or 24 weeks. The primary efficacyendpoint was sustained virologic response rates 12 weeks after therapy (SVR 12). The primary safety endpoint was treatment withdrawal rates secondary to severe adverse events. Results: The32 patients were screened and 2 were excluded, one patient due toassociated HBV+, one patient due to severe anemia. 30 patients were randomized. All 30 randomized patients were divided into two groups. Group 1 was given SOF+DCV+RBV for 12 weeks while group 2 patients were given SOF+DCV for 24 weeks. 81.8% of the participants in the group1 achieved SVR 12. The 90.9% of the participants in the group 2 achieved SVR12 (p=1). No other patient or treatment basal variables influenced the treatment effectiveness. No patient treatment withdrawal secondary to severe adverse events was observed. Conclusions: Both the regimen SOF+DCV with or without RBV are highly efficacious and safe. Addition of RBV can reduce the treatment duration to 12 weeks, and it will further improve compliance and more convenient for the patients.

Antivirais para pacientes adultos hospitalizados com infecção por SARS-CoV-2: Um estudo de Fase II/III, randomizado, multicêntrico, controlado por placebo, adaptativo, com múltiplos braços e estágios. COALITION COVID-19 BRAZIL IX - REVOLUTIOn: protocolo e plano de análise estatística / Antivirals for adult patients hospitalized with SARS-CoV-2 infection: A randomized, Phase II/III, multicenter, placebo-controlled, adaptive study, with multiple arms and stages. COALITION COVID-19 BRAZIL IX - REVOLUTIOn: protocol and statistical analysis plan

RESUMO Os medicamentos reaproveitados são importantes em contextos de recursos limitados porque as intervenções estão mais rapidamente disponíveis, já foram testadas com segurança em outras populações e são, em geral, mais baratas. Os medicamentos reaproveitados são uma solução eficaz, especialmente para doenças emergentes, como a COVID-19. O estudo REVOLUTIOn visa avaliar três medicamentos antivirais reaproveitados: atazanavir, daclatasvir e sofosbuvir, já utilizados em pacientes infectados pelo HIV ou pelo vírus da hepatite C, em um estudo randomizado, controlado por placebo, adaptativo, multibraço e em múltiplos estágios. Os medicamentos serão testados simultaneamente em um ensaio de Fase II para primeiro identificar se algum deles, isoladamente ou em combinação, reduz a carga viral. Se reduzirem, será iniciado um estudo de Fase III para investigar se tais medicamentos são capazes de aumentar o número de dias sem suporte respiratório. Os participantes devem ser adultos hospitalizados com idade ≥ 18 anos com início dos sintomas ≤ 9 dias e saturação de oxigênio ≤ 94% em ar ambiente ou necessidade de oxigênio suplementar para manter saturação de oxigênio > 94%. O tamanho total esperado da amostra varia entre 252 e 1.005 participantes, dependendo do número de estágios que serão concluídos no estudo. Assim, o protocolo é aqui descrito em detalhes, juntamente do plano de análise estatística. Em conclusão, o estudo REVOLUTIOn foi concebido para fornecer evidências se o atazanavir, o daclatasvir ou o sofosbuvir reduzem a carga viral de SARS-CoV-2 em pacientes com COVID-19 e aumentam o número de dias em que os pacientes ficam sem suporte respiratório. Neste artigo de protocolo, descrevem-se a fundamentação, o desenho e a situação do ensaio. Identificador do ClinicalTrials.gov:NCT04468087

ABSTRACT Repurposed drugs are important in resource-limited settings because the interventions are more rapidly available, have already been tested safely in other populations and are inexpensive. Repurposed drugs are an effective solution, especially for emerging diseases such as COVID-19. The REVOLUTIOn trial has the objective of evaluating three repurposed antiviral drugs, atazanavir, daclatasvir and sofosbuvir, already used for HIV- and hepatitis C virus-infected patients in a randomized, placebo-controlled, adaptive, multiarm, multistage study. The drugs will be tested simultaneously in a Phase II trial to first identify whether any of these drugs alone or in combination reduce the viral load. If they do, a Phase III trial will be initiated to investigate if these medications are capable of increasing the number of days free respiratory support. Participants must be hospitalized adults aged ≥ 18 years with initiation of symptoms ≤ 9 days and SpO2 ≤ 94% in room air or a need for supplemental oxygen to maintain an SpO2 > 94%. The expected total sample size ranges from 252 to 1,005 participants, depending on the number of stages that will be completed in the study. Hence, the protocol is described here in detail together with the statistical analysis plan. In conclusion, the REVOLUTIOn trial is designed to provide evidence on whether atazanavir, daclatasvir or sofosbuvir decrease the SARS-CoV-2 load in patients with COVID-19 and increase the number of days patients are free of respiratory support. In this protocol paper, we describe the rationale, design, and status of the trial. ClinicalTrials.gov identifier:NCT04468087

Efficacy and safety of ledipasvir/sofosbuvir versus elbasvir/grazoprevir in treatment of genotype 1b chronic hepatitis C / 中华临床感染病杂志

Objective:To compare the clinical efficacy and safety of ledipasvir/sofosbuvir (LDV/SOF) and elbasvir/grazoprevir (EBR/GZR) in treatment of patients with chronic hepatitis C (CHC).Methods:The clinical data of 143 patients with genotype 1b CHC treated in Huzhou Central Hospital from January 2020 to December 2021 were retrospectively analyzed, including 74 cases treated with LDV/SOF and 69 cases treated with EBR/GZR. The virological response after 4 and 12 weeks of treatment and 12wk after drug withdrawal was determined; and the serological and liver inflammation indexes before and after treatment in two groups were compared. SPSS 25.0 software was used for statistical analysis of the data.Results:The virological response rates of the LDV/SOF group and EBR/GZR group were 97.30% and 98.55%, 98.65% and 100.00%, 97.30% and 98.55% after 4 and 12 weeks of treatment and 12 weeks after the end of treatment, respectively (all P > 0.05). At the end of treatment, the liver inflammation indexes ALT, AST and GGT in the two groups were significantly lower than the baseline levels ( Z=-7.470 and -6.974, -9.757 and -6.832, -3.578 and -4.054, P<0.01). Adverse reactions in both groups were mild, and no serious adverse events occurred. Conclusion:Both LDV/SOF and EBR/GZR have good clinical efficacy in the treatment of genotype 1b CHC patients. And the patients are well tolerated.

Remission of long-term hepatic and renal disease induced by HCV after direct-acting antivirals therapy / Remissão de doença hepática e renal a longo prazo induzida pelo HCV após terapia antiviral de ação direta

Abstract In addition to liver disease, the hepatitis C virus (HCV) has been associated with autoimmune phenomena, such as mixed cryoglobulin and glomerulonephritis (GN). Until recently, both chronic hepatitis and HCV extra-hepatic manifestations were treated with peg-interferon plus ribavirin, however these drugs presented low efficacy and induced severe side effects. Nowadays, the HCV chronic hepatitis has been treated with direct acting antivirals (DAA), but studies on the DAA therapy for HCV-associated glomerulonephritis are scarce. Here, we describe two cases of HCV-associated glomerulonephritis that were treated with DAAs. In these two cases, previously experienced to peg-interferon plus ribavirin, the sofosbuvir plus simeprevir therapy was effective, without significant side effects, and interrupted the evolution of at least 20 years of both hepatic and renal diseases. These cases join the seven previously described cases that were treated with this DAAs association.

Resumo Além da doença hepática, o vírus da hepatite C (HCV) tem sido associado a fenômenos autoimunes, como crioglobulinemia mista (CM) e glomerulonefrite (GN). Até recentemente, a hepatite crônica e as manifestações extra-hepáticas do HCV eram tratadas com peg-interferon com ribavirina; no entanto, essas drogas apresentavam baixa eficácia e induziam efeitos colaterais graves. Atualmente, a hepatite crônica por HCV tem sido tratada com antivirais de ação direta (AAD), mas estudos sobre a terapia com AAD para glomerulonefrite associada ao HCV são escassos. Aqui, descrevemos dois casos de glomerulonefrite associada ao HCV que foram tratados com AAD. Nestes dois casos, previamente tratados com peg-interferon e ribavirina, a terapia com sofosbuvir com simeprevir foi eficaz, sem efeitos colaterais significativos, e interrompeu a evolução de pelo menos 20 anos de doenças hepáticas e renais. Esses casos se juntam aos sete casos descritos anteriormente que foram tratados com essa associação de AAD.

Stability Indicating Hptlc Method For Sofosbuvir And Velpatasvir In Combination

The discovery of new direct-acting antiviral drugs gave rise to a leap forward in the treatment of hepatitis C viral infections. For the first time since 1998, the Food and Drug Administration (FDA) approved interferon-free oral treatment paradigms. Among the new treatment regimens, the combinations of Sofosbuvir and Velpatasvir became ideal treatment regimens for being potent, highly tolerated and used once daily. Hence an accurate, precise, selective and sensitive stability indicating method for simultaneous estimation of Sofosbuvir and Velpatasvir by High-Performance Thin Layer Chromatography has been developed and validated. Chromatographic separation was achieved on TLC plates coated with silica gel 60 F254 as stationary phase. Ethyl acetate: iso-propyl alcohol (9:1 v/v) was used as mobile phase.Densitometric scanning was carried out at 260 and 302 nm for Sofosbuvir and Velpatasvir, respectively. The method was successfully validated as per the ICH Guideline. The linear concentration range was100- 2000 ng/band (r2= 0.991) and 100-500 ng/band (r2 = 0.991) for SOF (Sofosbuvir) and VEL (Velpatasvir) respectively. The LOD were 25.16 ng/band and 9.96 ng/band for SOF and VEL, LOQ were 76.25 ng/band and 30.19 ng/band for SOF and VEL.The method could be applied to the quality control and routine analysis of Sofosbuvir and Velpatasvir in their pure forms and pharmaceutical formulations.

Tratamento da hepatite C em pacientes com doença renal crônica e pós-tranplante renal: eficácia e segurança dos esquemas de antivirais de ação direta contendo sofosbuvir / Hepatitis c treatment of renal transplant and chronic kidney disease patients: efficacy and safety of direct-acting antiviral regimens containing sofosbuvir

ABSTRACT BACKGROUND: Direct-acting antivirals have revolutionized hepatitis C treatment, also for patients with chronic kidney disease (CKD), but some controversy exists regarding the use of sofosbuvir (SOF) in patients with glomerular filtration rate (GFR) <30 mL/min. OBJECTIVE: To evaluate the efficacy and safety of these regimens for hepatitis C treatment of patients with CKD and after renal transplantation, as well as the impact of SOF on renal function in non-dialysis patients. METHODS: All patients with hepatitis C and CKD or renal transplant treated with direct-acting antivirals at a referral center in Brazil between January 2016 and August 2017 were included. Efficacy was evaluated based on viral load (HCV RNA) and a sustained virological response (SVR) consisting of undetectable RNA 12 and/or 24 weeks after the end of treatment (SVR12 and SVR24) was defined as cure. Safety was determined by adverse events and ribavirin, when combined, was administered in escalating doses to all patients with GFR <60 mL/min. The impact of SOF on renal function was determined by the measurement of baseline creatinine during and after the end of treatment and its increase was evaluated using the Acute Kidney Injury Network (AKIN) classification. RESULTS: A total of 241 patients (52.7% females) with a mean age of 60.72±10.47 years were included. The combination of SOF+daclatasvir was the predominant regimen in 75.6% of cases and anemia was present in 28% of patients who used ribavirin (P=0.04). The SVR12 and SVR24 rates were 99.3% and 97.1%, respectively. The treatment was well tolerated and there were no major clinically relevant adverse events, with the most prevalent being asthenia (57.7%), itching (41.1%), headache (40.7%), and irritability (40.2%). Among conservatively treated and renal transplant patients, oscillations of creatinine levels (AKIN I) were observed in 12.5% of cases during treatment and persisted in only 8.5% after the end of treatment. Of these, 2.0% had an initial GFR <30 mL/min and this percentage decreased to 1.1% after SOF use. Only 0.5% and 1.6% of the patients progressed to AKIN II and AKIN III elevation, respectively. CONCLUSION: The direct-acting antivirals were safe and efficacious in CKD patients treated with SOF-containing regimens, with the observation of high SVR rates, good tolerability and few severe adverse events. The combination with ribavirin increased the risk of anemia and the administration of escalating doses seems to be useful in patients with GFR <60 mL/min. In patients with GFR <30 mL/min, SOF had no significant renal impact, with serum creatinine returning to levels close to baseline after treatment.

RESUMO CONTEXTO: Os antivirais de ação direta revolucionaram o tratamento da hepatite C, inclusive para os pacientes com doença renal crônica (DRC), porém ainda há divergências no emprego do sofosbuvir (SOF) quando taxa de filtração glomerular (TFG) <30 mL/min. OBJETIVO: Avaliar a eficácia e segurança desses esquemas no tratamento da hepatite C em pacientes com DRC e pós-transplante renal, além de avaliar o impacto do SOF sobre a função renal dos não-dialíticos. MÉTODOS: Todos os pacientes com hepatite C e DRC ou transplante renal que realizaram tratamento com antivirais de ação direta em centro referenciado do Brasil no período de janeiro/2016 a agosto/2017 foram incluídos. A eficácia foi avaliada por meio da carga viral (HCV-RNA), considerando-se cura uma resposta virológica sustentada (RVS) com resultado indetectável após 12 e/ou 24 semanas do término do tratamento (RVS12 e RVS24). A segurança foi determinada pelos eventos adversos e a ribavirina, quando associada, foi introduzida de forma escalonada em todos os pacientes com TFG <60 mL/min. Para determinação do impacto do SOF sobre a função renal, foram observadas as dosagens de creatinina basal, durante e após término do tratamento com seu incremento avaliado por meio da classificação de AKIN (acute kidney injury network). RESULTADOS: Foram incluídos 241 pacientes, sendo 52,7% do sexo feminino, com média de idade de 60,72±10,47 anos. A associação de SOF+daclatasvir predominou em 75,6% dos casos e anemia esteve presente em 28% dos pacientes que utilizaram ribavirina (P=0,040). As taxas de RVS12 e RVS24 foram de 99,3% e 97,1%. O tratamento foi bem tolerado, com eventos adversos pouco relevantes, sendo os mais prevalentes: astenia (57,7%), prurido (41,1%), cefaleia (40,7%) e irritabilidade (40,2%). Entre os pacientes em tratamento conservador e transplantados renais, os valores de creatinina sofreram oscilações AKIN I em 12,5% dos casos, durante o tratamento, persistindo em apenas 8,5% da amostra após o término, dos quais 2,0% apresentavam TFG <30 mL/min inicialmente, com queda para 1,1% após uso do SOF. Apenas 0,5% e 1,6% evoluíram com elevação AKIN II e AKIN III. CONCLUSÃO: Os antivirais de ação direta foram seguros e eficazes em pacientes com DRC tratados com esquemas contendo SOF, apresentando altas taxas de RVS, boa tolerabilidade e poucos eventos adversos graves. A associação com ribavirina aumentou o risco de anemia, portanto sua introdução de forma escalonada parece ser útil nos pacientes com TFG <60 mL/min. Em pacientes com TFG <30 mL/min o SOF não apresentou impacto renal significativo, com creatinina sérica retornando a valores próximos ao basal após o tratamento.

Combined ns5a & ns5b nucleotide inhibitor therapy for patients with chronic hepatitis c with stage 5 chronic kidney disease on hemodialysis / Terapia inibidora de nucleotídeo NS5A& NS5B combinada para pacientes com hepatite C crônica com doença renal crônica em estágio 5, em hemodiálise

ABSTRACT BACKGROUND: Hepatitis C virus (HCV) infection is the most common hepatotropic viral infection affecting the patients on maintenance hemodialysis. Treatment of chronic HCV infection in stage 4 and 5 CKD includes a combination of elbasvir/grazoprevir and glecaprevir/pibrentasvir, which are not available in many countries. OBJECTIVE: Hence, we have conducted this study to look for the safety and efficacy of sofosbuvir combination therapy in this difficult to treat population. METHODS: We conducted a single-center, prospective, open-label study in which Stage 5 CKD patients on maintenance hemodialysis with HCV infection. Total of 18 patients was included. sofosbuvir with daclatasvir or ledipasvir was used according to genotype for 12 weeks. HCV RNA, genotype, transient elastography (TE) was considered for every patient. HCV RNA was quantified at 4th week, 12th week and 12 weeks post-treatment to look for sustained virologic response (SVR 12). RESULTS: Infection due to genotype 1 was seen in 12 (66.7%) patients followed by genotype 3 in 4 (22.3%) with each patient of genotype 2 and 5. The median value of HCV RNA was 2,35,000 IU/mL. On TE, all had liver stiffness of <9.4 KPa. All patients had HCV RNA of <15 IU/mL at 4th and 12th week of treatment and 12 weeks post-treatment. No significant change in hemoglobin, eGFR and liver stiffness was observed. CONCLUSION: Full dose sofosbuvir i.e. 400 mg, in combination with NS5A inhibitors daclatasvir or ledipasvir is found to be safe and effective in patients with end stage renal disease, who are on maintenance hemodialysis.

RESUMO CONTEXTO: A infecção pelo vírus da hepatite C (HCV) é a infecção viral hepática mais comum que afeta pacientes em hemodiálise de manutenção. O tratamento da infecção crônica por HCV no estágio 4 e 5 da doença renal crônica inclui uma combinação de elbasvir/grazoprevir e glecaprevir/pibrentasvir, que não estão disponíveis em muitos países. OBJETIVO: Portanto, realizamos este estudo para procurar a segurança e eficácia da terapia combinada de sofosbuvir nesta população de difícil tratamento. MÉTODOS: Realizamos um estudo de centro único, prospectivo e aberto, no qual pacientes com doença renal crônica em estágio 5 em hemodiálise de manutenção com infecção por HCV. Um total de 18 pacientes foi incluído. Sofosbuvir com daclatasvir ou ledipasvir foi usado de acordo com o genótipo por 12 semanas. O HCV RNA, genótipo, elastografia transitória foi considerado para cada paciente. O HCV RNA foi quantificado na 4ª semana, 12ª semana e 12 semanas após o tratamento para procurar uma resposta virológica sustentada. RESULTADOS: A infecção por genótipo 1 foi observada em 12 (66,7%) pacientes, seguido pelo genótipo 3 em 4 (22,3%), em um paciente do genótipo 2 e em outro, 5. O valor mediano do HCV RNA foi de 2.35.000 IU/mL. Na elastografia transitória, todos tinham rigidez hepática de <9.4 KPa. Todos os pacientes tinham RNA HCV <15 IU/mL na 4ª e 12ª semana de tratamento e 12 semanas após o tratamento. Não foi observada nenhuma alteração significativa na hemoglobina, eGFR e rigidez hepática. CONCLUSÃO: A dose completa sofosbuvir ou seja, 400 mg, em combinação com inibidores NS5A daclatasvir ou ledipasvir foi considerada segura e eficaz em pacientes com doença renal em estágio final, que estão em manutenção hemodiálise.

Treatment of chronic hepatitis C in patients with chronic kidney disease with Sofosbuvir-basead regimes

ABSTRACT Background: To analyze the effectiveness and the safety of Sofosbuvir-based regimens to treat patients with chronic hepatitis C virus (HCV) infection and chronic kidney disease (CKD). Methods: A retrospective, observational study in patients with chronic HCV infection and CKD treated with Sofosbuvir-based regimens was performed. Liver fibrosis, comorbidities, HCV genotype and sustained virological resposnse (SVR) at 12th week post-treatment were evaluated. Kidney function was accessed by serum creatinine and glomerular filtration rate (GFR). The assumed level of significance was 5 %. Results: Thirty-five patients were treated. The mean age was 52.1 ± 10.9 years, 19 (54.3 %) were women, 32 (91.4 %) were already kidney transplanted and 3 (8.6 %) were on hemodialysis. The SVR by intention to treat was 88.6 %. The mean GFR was 65.8 ± 28.6 and 63.7 ± 28.3 ml/min pre- and post-treatment respectively (p > 0.05). Treatment was interrupted in 1 (2.85 %) patient due to anemia and in 2 (5.7 %) due to loss of kidney function. Conclusion: Sofosbuvir-based regimens are effective to treat HCV in patients with CKD. In patients with mild CKD this type of therapy seems to be safe.

Bioequivalence and safety of sofosbuvir tablets in the healthy Chinese subjects / 临床肝胆病杂志

ObjectiveTo investigate the pharmacokinetic characteristics of sofosbuvir tablets, and to evaluate the bioequivalence and safety of two preparations. MethodsHealthy volunteers were recruited through the platform of clinical trial recruitment in The Affiliated Hospital of Changchun University of Chinese Medicine. Screening physical examination was performed for fasting group on September 18, 2018 and for postprandial group on September 28, 2018, and the volunteers were enrolled after their physical examination results met the inclusion criteria. The fasting group and the postprandial group, with 40 volunteers in each group, were given oral administration of the test preparation sofosbuvir tablets or the reference preparation sofosbuvir tablets (SOVALDI, 400 mg). This was a randomized, open-label, two-sequence, four-cycle, single-dose, and completely repeated cross-over bioequivalence test in the fasting or postprandial state in the healthy population; in the fasting group, 20 volunteers each received oral administration of the test preparation and the reference preparation, and in the postprandial group, 20 volunteers each received oral administration of the test preparation and the reference preparation. Liquid chromatography-tandem mass spectrometry was used to measure the content of sofosbuvir and its major metabolite GS-331007 in human EDTA-K2 plasma; the plasma concentration of sofosbuvir was measured at 15 time points from 0 hour to 8 hours after administration, and that of GS-331007 was measured at 16 time points from 0 hour to 72 hours after administration. WinNonlin software was used to calculate pharmacokinetic parameters and evaluate bioequivalence. ResultsAfter the administration of the test preparation and the reference preparation in the fasting state, when the pharmacokinetic parameters of sofosbuvir was used to evaluate the bioequivalence of the test preparation and the reference preparation, the ratios of the geometric means of Cmax, AUC0-t, and AUC0-inf were 90.55%, 97.26%, and 94.62%, respectively; when the pharmacokinetic parameters of GS-331007 was used to evaluate the bioequivalence of the test preparation and the reference preparation, the ratios of the geometric means of Cmax, AUC0-t, and AUC0-inf were 98.91%, 98.98%, and 99.46%, respectively. All of the above values were within the range of 80.00%-125.00%. An analysis of variance was performed after the pharmacokinetic parameters of sofosbuvir Cmax, AUC0-t, and AUC0-inf were transformed by natural logarithm, and the results showed that sequence, cycle, and preparation had no marked influence on Cmax, AUC0-t, and AUC0-inf (all P＞0.05). ConclusionThe test preparation of sofosbuvir tablets is bioequivalent to the reference preparation in the fasting and postprandial states.

Efficacy and safety of sofosbuvir based antiviral therapy for chronic hepatitis C infection in patients with advanced chronic kidney disease

Background: Screening studies for hepatitis C have proved that it is more prevalent in patients with renal diseases. Chronic hepatitis C infection in patients with kidney disease not only accelerates renal deterioration but also adversely effects morbidity and mortality. Availability of direct acting antiviral drugs has revolutionized treatment of hepatitis C even in difficult patients. In advanced kidney diseases, selection of treatment is difficult. Aim of this study was to evaluate the efficacy and safety of Sofosbuvir based DAAs in patients with advanced CKD.Methods: In this Quasi experimental study, CHC patients with or without cirrhosis having advance CKD (eGFR <30 ml/min per 1.73 m2) and/or on dialysis were enrolled. End points of the study were documentation of SVR 12 or discontinuation of therapy. Different regimens of oral DAAs with or without Ribavirin were used.Results: 86 patients with a median age of 53 years were enrolled. 37 patients were on maintenance dialysis and 49 were not on dialysis with eGFR <30 ml/min per 1.73 m2. Virological response was 92.68% at the end of treatment and SVR was achieved by 90.2% twelve weeks after therapy. Insomnia 14%, headache 11% and anemia 7% were main dverse effects. Mean eGFR and creatinine before and after treatment remained the same. Only 2 patients relapsed, both were on dialysis thrice weekly.Conclusions: All Sofosbuvir based regimens used for the treatment of CHC in patients with end stage renal disease are effective and well tolerated. Close follow up is advised to monitor side effects.

An Innovative Method Development And Forced Degradation Studies For Simultaneous Estimation Of Sofosbuvir And Ledipasvir By Rp Hplc

Objective: To develop an innovative, rapid, simple, cost-effective, stability indicating reverse phase-high performance liquid chromatography (RP-HPLC) method for simultaneous estimation of ledipasvir (LP) and sofosbuvir (SB) in combination pill dosage form. Methods: The method was developed using C8 column, 250 mm x 4.6 mm, 5 mm using mobile section comprising of 0.1% (v/v) orthophosphoric acid buffer at pH 2.2 and acetonitrile in the ratio of 45:55 that was pumped through the column at a flow rate of 0.8 ml/min. Temperature was maintained at 30 °C, the effluents were monitored at 260 nm with the help of usage of PDA detector. Results: The retention time of LP and SB were found to be 2.246 min and 3.502 min. The approach was found to be linear with the variety of 9-36 µg/ml and 40-240 μg/ml for LP and SB respectively, the assay of estimated compounds were found to be 99.65% and 99.73% w/v for LP and SB respectively. Conclusion: The pressured samples changed into analyzed and this proposed a technique turned into determined to be particular and stability indicating as no interfering peaks of decay compound and excipients were observed. Hence, the approach was easy and economical that may be efficiently applied for simultaneous estimation of both LP and SB in bulk and combination tablet system.

Recurrent hepatitis C treatment with direct acting antivirals - a real life study at a Brazilian liver transplant center

Recurrent hepatitis C (HCV) after liver transplantation (LT) is an important cause of morbidity and mortality. Antiviral treatment is recommended to avoid unfavorable outcomes. Direct-acting antivirals (DAA) have transformed HCV treatment, with higher efficacy and fewer side-effects than interferon-based therapies traditionally used. To evaluate DAA treatment outcomes at a Brazilian transplant unit, data of patients who finished HCV treatment at the Liver Transplant Unit of the University of Campinas were analyzed. Treatment consisted of sofosbuvir, daclatasvir, and ribavirin, for 12 or 24 weeks, according to the national guidelines. Fifty-five patients completed antiviral treatment and 54 had HCV-viral load results available. The majority of patients were male (78%), 58 years old on average, 65% had hepatocellular carcinoma (HCC) before LT, and 67% were interferon treatment-experienced. Most patients had HCV genotype 1 (65%), 35% had genotype 3, and started treatment on an average of 38 months after LT (range: 2-228). Fifty-eight percent were treated for 12 weeks and 42% for 24 weeks, using a mean dose of ribavirin of 10.1 mg/kg (4.2-16.1). There were no treatment interruptions due to serious side effects. The sustained virological response rate was 98%. Only one patient relapsed, a genotype 3 cirrhotic treated for 12 weeks. The average follow-up after starting antivirals was 20 months. There were no recurrences of HCC, but there was one rejection episode and one cirrhosis decompensation episode, both 12 weeks after treatment. DAA treatment is safe and effective in the post-LT setting and was not associated to HCC recurrence in the cohort studied.

Upcoming direct acting antivirals for hepatitis C patients with a prior treatment failure

Despite the high efficacy of direct acting antivirals (DAAs) not all patients successfully clear hepatitis C virus infection, in fact, approximately 1–3% fail to reach a sustained virological response 12 weeks after end of treatment. DAA failures are characterized by advanced liver disease, specific genotypes/subtypes and resistance associated substitutions to the DAA class they have been treated with. Current European Association for the Study of the Liver guidelines recommend three therapeutic options for such patients. The first is a 12 week course of sofosbuvir (SOF), velpatasvir (VEL) and voxilaprevir (VOX), which has shown to be effective in 90–99% of patients and was granted A1 level recommendation. The second option, reserved for patients who have predictors of failure consists in 12 weeks regimen with glecaprevir (GLE) and pibrentasvir (PIB), effective in 90–97%. Finally, although not supported by published data, for especially difficult to treat patients there should theoretically be a benefit in prolonged combinations of SOF+GLE/PIB or SOF/VEL/VOX±ribavirin. This review presents the latest evidence from both clinical trials and real-life on such therapeutic strategies.

Sofosbuvir-based regimens combined with ribavirin for recipients with genotype 1 hepatitis C after liver transplantation: a Meta-analysis / 器官移植

Objective To evaluate whether sofosbuvir (SOF)-based direct-acting antiviral agents (DAAs) combined with ribavirin (RBV) (combined RBV) can yield benefits to the recipients infected with hepatitis C virus (HCV) genotype 1 (GT1) after liver transplantation through systematic evaluation and Meta-analysis. Methods Multiple databases at home and abroad were systematically searched, the literature screening was conducted according to relevant standards, the quality of literatures was evaluated and data extraction was performed. The literature was divided into two groups according to the recipients with HCV-GT1 hepatitis after liver transplantation who received the treatment combined RBV or SOF-based DAAs alone without RBV (not combined RBV). Meta-analysis of the data was carried out using Rev Man 5.3 and R3.4.3 software. The incidence of sustained virological response 12 weeks (SVR12) after therapy was evaluated. Results A total of 2 195 articles were retrieved, and 6 articles published in English were eventually included according to the inclusion criteria. The Meta-analysis results demonstrated that the incidence of SVR12 did not significantly differ between the combined RBV and not combined RBV groups (P=0.28). However, the incidence of anemia in the combined RBV group was significantly higher than that in the other group (P < 0.01). Both combined RBV and not combined RBV therapies were efficacious in treating HCV-GT1a and HCV-GT1b subtypes after liver transplantation with similar clinical efficacy (P=0.33). The incidence of SVR in HCV-GT1 recipients did not significantly differ after receiving 12- and 24-weeks therapy after liver transplantation (P=0.95). Conclusions When SOF-based DAAs regimen is adopted to treat HCV-GT1 in recipients after liver transplantation, combination with RBV not only fails to improve the virus clearance rate and bring clinical benefits, but also increases the risk of anemia in the recipients.

Clinical effect and safety of sofosbuvir-based regimens in treatment of hepatitis C virus-associated glomerulonephritis / 临床肝胆病杂志

ObjectiveTo investigate the clinical effect and safety of sofosbuvir-based regimens in the treatment of hepatitis C virus (HCV)-associated glomerulonephritis (HCV-GN). MethodsA retrospective analysis was performed for the clinical data of 5 patients with HCV-GN who were given sofosbuvir-based antiviral therapy in The Second Affiliated Hospital of Xi’an Jiaotong University from April 2015 to October 2018, and their clinical outcome and safety were analyzed. The patients were evaluated in terms of sustained virologic response at 12 weeks after treatment ended (SVR12), changes in liver/renal function and urinary protein during and after treatment, and safety. ResultsFive patients were enrolled, with an age of 27-81 years. There were 4 male patients, among whom 2 had liver cirrhosis. Of all patients, 4 had genotype 1b and 1 had genotype 2a. Renal biopsy was performed for 2 patients, who were diagnosed with membranoproliferative glomerulonephritis and mesangial proliferative glomerulonephritis, respectively. Of all patients, 2 received sofosbuvir+ribavirin, 2 received ledipasvir/sofosbuvir, and 1 received sofosbuvir/velpatasvir for 12 or 24 weeks. All 5 patients achieved SVR12. There were significant reductions in alanine aminotransferase and 24-hour urinary protein excretion from baseline to the end of treatment and 12 weeks of follow-up, with a slight increase in serum albumin. Blood urea nitrogen and serum creatinine were improved or showed no change. Only 1 patient experienced adverse gastrointestinal events associated with ribavirin. ConclusionSofosbuvir-based regimens have good clinical effect and tolerability in patients with HCV-GN. Long-term follow-up should be performed to evaluate the long-term prognosis of renal disease after HCV clearance.

A phase II, single-arm, open-label, multicenter clinical study to evaluate the efficacy and safety of sofosbuvir combined with ribavirin in patients with genotype 2 chronic hepatitis C virus infection / 中华肝脏病杂志

Objective@#To evaluate the efficacy and safety of sofosbuvir (Nanjing Zhengda Tianqing Pharmaceutical Co., Ltd.) combined with ribavirin in patients with genotype 2 chronic hepatitis C virus infection.@*Methods@#Treatment-naïve or treatment experienced genotype 2 chronic hepatitis C patients from sixteen research centers of China were screened. All subjects received once-daily dose of sofosbuvir (400 mg) combined with ribavirin (body weight < 75 kg, 1 000 mg/day, 400 mg in the morning and 600 mg in the evening; body weight > 75 kg, 1 200 mg/d, 600 mg in the morning and 600 mg in the evening) for 12 weeks. Patients were followed-up for a period of 12 weeks after discontinuation of treatment. Continuous variables were expressed as mean ± standard deviation. The proportion of subjects with virologic response at different follow-up time points and 95% confidence intervals were estimated by maximum likelihood ratio and Clopper-Pearson interval.@*Results@#132 cases with genotype 2 chronic hepatitis C virus infection from sixteen research centers of China were included, 12 cases of whom were associated with cirrhosis, and the remaining 120 cases were not associated with cirrhosis. One hundred and thirty-one cases completed the study, and one patient lost to follow-up at week 4 after the end of treatment. The sustained virological response rate was 96.2% (95% confidence interval: 92.37% - 99.16%) after 12 weeks of drug withdrawal. Virological relapse occurred in four cases. Of the 132 subjects enrolled in the study, 119 (90.2%) reported 617 adverse events during treatment, of which 359 (76.5%) were TEAE related to sofosbuvir and/or ribavirin. There were nine TEAEs of grade 3 and above, and six cases (4.5%) of them had six severe adverse events. Only one serious adverse event was associated with sofosbuvir and ribavirin (unstable angina pectoris). There were no adverse events leading to drug discontinuation or death.@*Conclusion@#Sofosbuvir combined with ribavirin has a high SVR rate in the treatment of genotype 2 chronic hepatitis C virus infection, and most of the adverse events occurred were mild with acceptable safety profile.