AIM To evaluate the safety and efficacy of ledipasvir/sofosbuvir on hepatitis C eradication in patients with hepatitis C virus(HCV)/human immunodeficiency virus(HIV) co-infection in an urban HIV clinic.METHODS A retro...AIM To evaluate the safety and efficacy of ledipasvir/sofosbuvir on hepatitis C eradication in patients with hepatitis C virus(HCV)/human immunodeficiency virus(HIV) co-infection in an urban HIV clinic.METHODS A retrospective cohort study of 40 subjects co-infected with HIV-1 and HCV treated with the fixed-dose combination of ledipasvir and sofosbuvir for 12 wk from 2014 to 2016.All patients included were receiving antiretroviral therapy(ART) with HIV RNA values of 100 copies/m L or fewer regardless of baseline HCV RNA level.The primary end point was a sustained virologic response of HCV at 12 wk(SVR12) after the end of therapy.RESULTS Of the 40 patients enrolled,55% were black,22.5% had been previously treated for HCV,and 25% hadcirrhosis.The patients were on a wide range of ART.Overall,39 patients(97.5%) had a SVR 12 after the end of therapy,including rates of 97.1% in patients with HCV genotype 1 a and 100% in those with HCV genotype 1 b.One patient with HCV genotype 3 a was included and achieved SVR12.Rates of SVR12 were similar regardless of previous treatment or the presence of compensated cirrhosis.Only 1 patient experienced relapse at week 12 following treatment and deep sequencing didn't reveal any resistance associated mutation in the NS5A or NS5B region.Interestingly,7(17.5%) patients who were adherent to ART experienced HIV viral breakthrough which resolved after continuing the same ART regimen.Two(5%) patients experienced HIV-1 virologic rebound due to noncompliance with HIV therapy,which resolved after resuming the same ART regimen.No severe adverse events were observed and no patient discontinued treatment because of adverse events.The most common adverse events included headache(12.5%),fatigue(10%),and diarrhea(2.5%).CONCLUSION This retrospective study demonstrated the high rates of SVR12 of ledipasvir/sofosbuvir on HCV eradication in patients co-infected with HCV and HIV,regardless of HCV baseline levels,HCV treatment history or cirrhosis condition.The oral combination of ledipasvir/sofosbuvir represents a safe and well tolerated HCV treatment option that does not require modification for many of the common HIV ART.Occasional HIV virologic rebound occurred but later resolved without the need to change ART.展开更多
AIM To evaluate sustained viral response(SVR)of 8-wk ledipasvir/sofosbuvir therapy among non-cirrhotic,genotype-1 hepatitis C virus(HCV)patients with RNA<6 million IU/m L.METHODS We performed a retrospective cohort...AIM To evaluate sustained viral response(SVR)of 8-wk ledipasvir/sofosbuvir therapy among non-cirrhotic,genotype-1 hepatitis C virus(HCV)patients with RNA<6 million IU/m L.METHODS We performed a retrospective cohort study to examine SVR rates,predictors of treatment failure and safety analysis of 8-wk ledipasvir/sofosbuvir(LDV/SOF)therapy among non-cirrhotic,genotype 1 HCV patients with viral load<6 million IU/m L.Primary outcome was an achievement of SVR at 12 wk after treatment.Secondary outcomes were identifying predictors of treatment failure and adverse events during treatment.RESULTS Total 736 patients:55%males,51%Caucasians and 65%were genotype 1a.Non-cirrhotic state of 53%was determined by clinical judgment(imaging,AST,platelet count)and 47%had documented liver fibrosis testing(biopsy,vibration-controlled transient elastography,serum biomarkers).Overall SVR12 was 96%.No difference in SVR12 was seen between patients whose non-cirrhotic state was determined by clinical judgment and patients who had fibrosis testing.Age groups,gender,ethnicity and genotype 1 subtype did not predict SVR.Non-cirrhotic state determined by clinical judgment based on simple,non-invasive tests were not associated with lower SVR[OR=1.02,95%CI:0.48-2.17,P=0.962].The AUROC for hepatitis C RNA viral load was 0.734(P<0.001,95%CI:0.66-0.82).HCV RNA 2.2 million IU/m L was identified as the cutoff value with sensitivity 73%and specificity 64%.HCV RNA<2.2 million IU/m L was associated with significantly higher SVR 98%with OR=0.22(95%CI:0.1-0.49,P<0.001)compared to SVR 92%in HCV RNA≥2.2 million IU/m L.No death or morbidities were reported.CONCLUSION Our outcomes validate safety and effectiveness of 8-wk LDV/SOF therapy in non-cirrhotic,untreated HCV genotype 1 patients with HCV RNA<6 million IU/m L.展开更多
A tablet consisting of direct-acting antiviral agents,ledipasvir（a NS5 A protein inhibitor） and sofosbuvir（a NS5 B polymerase inhibitor）,is the first fixed-dose preparation used in the antiviral therapy of hepatit...A tablet consisting of direct-acting antiviral agents,ledipasvir（a NS5 A protein inhibitor） and sofosbuvir（a NS5 B polymerase inhibitor）,is the first fixed-dose preparation used in the antiviral therapy of hepatitis C.A model-based meta-analysis of ledipasvir and GS331007,the primary metabolite of sofosbuvir,enabled the integration of pharmacokinetic（PK） information from separate clinical trials and the quantitative characterization of the population pharmacokinetics of these two drugs.A systematic publication search was conducted for the clinical studies of ledipasvir and sofosbuvir.A total of 401 arm-level aggregate concentrations of GS331007 and 188 concentrations of ledipasvir were used for PK modeling.A two-compartment disposition model was used for both ledipasvir and GS331007.Zero-order absorption was applied for ledipasvir PK modeling,and a combined zero- and first-order absorption was used for the modeling of GS331007.Absorption lag was observed in concentration-time profiles of both ledipasvir and GS331007.To aid the development of direct-acting antiviral drugs,our established PK models provided a basis for the further PK-viral kinetic studies of ledipasvir and sofosbuvir.展开更多
Hepatitis C virus(HCV) has infected more than 200 million people around the globe. From 2001-2011, interferon plus ribavirin remained the standard of care for patients with HCV infection. The therapy had a limited res...Hepatitis C virus(HCV) has infected more than 200 million people around the globe. From 2001-2011, interferon plus ribavirin remained the standard of care for patients with HCV infection. The therapy had a limited response with a number of side effects. Recently, results for phase III trials of ledipasvir and sofosbuvir combination therapy have been announced. In treatmentnave patients, 12 wk of therapy with ledipasvir and sofosbuvir showed a sustained virological response(SVR) rate of 99%. In treatment experienced patients, 12-24 wk of therapy with ledipasvir and sofosbuvir in the absence or presence of ribavirin showed an SVR rate of 94%-99%. In cirrhotic patients the rate of SVR was 86% and 99% for 12 and 24 wk of therapy, respectively. The ledipasvir and sofosbuvir therapy showed very good results in different subgroups of patients regardless of patient's race, alanine aminotransferase levels, sex and host genetic factors. The combination therapy was well tolerated with no emergence of resistant mutants. The most common adverse effects were nausea, headache and fatigue. With the availability of interferon free therapy with minimal adverse effects, it will be easy to decrease the future morbidity and mortality caused by HCV infection.展开更多
Chronic hepatitis C virus(HCV) infection is one of the main causes of chronic liver disease worldwide. In the last 5 years, treatment for HCV infection has experienced a marked development. In 2014, the use of ledipas...Chronic hepatitis C virus(HCV) infection is one of the main causes of chronic liver disease worldwide. In the last 5 years, treatment for HCV infection has experienced a marked development. In 2014, the use of ledipasvir/sofosbuvir with or without concomitant weight-based ribavirin was approved with a very significant increase in the sustained virological response. However, new side effects have been associated. We report the first case of an HCV infected patient treated for 12 wk with the combination of sofosbuvir/ledipasvir plus ribavirin who developed a miliary tuberculosis(TB) infection while on therapy. The patient was a 65-year-old woman, who referred malaise, asthenia, hyporexia, 7 kg weight loss, productive cough, evening fever and night sweats, right after finishing the treatment. The chest computed tomography-scan revealed a superior mediastinal widening secondary to numerous lymphadenopathies with extensive necrosis and bilateral diffuse lung miliary pattern with little subsequent bilateral pleural effusion, highly suggestive of lymph node tuberculosis with lung miliary spread. A bronchoscopy was performed and bronchial suction showed more than 50 acid-alcohol resistant bacillus per line. A Mycobacterium tuberculosis DNA was detected in blood by polymerase chain reaction, which confirmed the diagnosis of miliary tuberculosis. Some cases of TB infection have been identified with α-interferon-based therapy and with the triple therapy of pegylated interferon, ribavirin and boceprevir or telaprevir. However, significant infection has not been reported with sofosbuvir/ledipasvir plus ribavirin.We believe that the case is relevant to increase awareness of opportunistic infections and particularly TB infection. Although the international guidelines offer no recommendation regarding TB screening, we wonder whether it would be advisable to screen for opportunistic infections prior to the introduction of HCV therapy.展开更多
AIM To evaluate the efficacy and safety of a regimen containing sofosbuvir(SOF)and ledipasvir(LDV)in Japanese patients aged≥75 years with hepatitis C genotype 1.METHODS This multicenter,retrospective study consisted ...AIM To evaluate the efficacy and safety of a regimen containing sofosbuvir(SOF)and ledipasvir(LDV)in Japanese patients aged≥75 years with hepatitis C genotype 1.METHODS This multicenter,retrospective study consisted of 246 Japanese patients with HCV genotype 1 at nine centers in Miyazaki prefecture in Japan.Demographic,clinical,virological,and adverse effects(AE)-related data obtained during and after SOF/LDV therapy were collected from medical records.These patients were divided into two groups,younger(aged<75 years)and elderly(aged≥75 years).Virological data and AEs were analyzed by age group.RESULTS The sustained virological response(SVR)rates at 12 wk after treatment were 99.2%,99.4%,and 98.7%in the overall population and in patients aged<75 and≥75 years,respectively.Common AEs during therapy were headache,pruritus,constipation,and insomnia.These occurred in fewer than 10%of patients,and their incidence was not significantly different between the younger and elderly groups.Two patients discontinued treatment,one due to a skin eruption and the other due to cerebral bleeding.CONCLUSION Compared with younger patients,elderly patients had a similar virological response and tolerance to SOF/LDV therapy.展开更多
Although direct-acting antivirals(DAAs)have notably increased the sustained virological response(SVR)rates in hepatitis C virus(HCV)-infected adolescent patients,the efficacy and safety for young children under 3 year...Although direct-acting antivirals(DAAs)have notably increased the sustained virological response(SVR)rates in hepatitis C virus(HCV)-infected adolescent patients,the efficacy and safety for young children under 3 years old remain unclear.Currently,no guidelines recommend DAA therapy for this situation worldwide.Furthermore,the China National Medical Products Administration has not approved any DAA for treating children below 12 years old.Here,we described the characteristics of two children approximately 2 years old,who were infected by HCV genotype 1b and had significant clinical symptoms.Both received 12 weeks of ledipasvir/sofosbuvir(Case 1:45.00 mg/200 mg per day,weight 17 kg;Case 2:33.75 mg/150 mg per day,weight 12 kg).They achieved SVR at 12 weeks after treatment completion without obvious treatment-related adverse effects.Therefore,the safety and benefits of ledipasvir/sofosbuvir treatment in children under 3 years old seem to be confirmed.Our findings require further evaluation.展开更多
Combination therapy with peginterferon (pegIFN)-α and ribavirin (RBV) has been the standard of care (SOC) for chronic hepatitis C. Unfortunately, not all patients can achieve a sustained virologic response (SVR) with...Combination therapy with peginterferon (pegIFN)-α and ribavirin (RBV) has been the standard of care (SOC) for chronic hepatitis C. Unfortunately, not all patients can achieve a sustained virologic response (SVR) with this regimen. SVR rates are approximately 80% in patients with hepatitis C virus (HCV) genotype 2, 3, 5 and 6 and 40%-50% in patients with genotype 1 and 4. Therefore, strategies to improve SVR rates have been an important issue for clinical physicians. Several direct acting antiviral agents (DAAs) have significantly higher SVR rates when combined with pegIFN-α and RBV than pegIFN-α and RBV alone. Treatments containing DAAs have several advantages over the previous SOC, including higher specificity and efficacy, shorter treatment durations, fewer side effects, and oral administration. Based on these advantages, treatment with pegIFN-α and RBV plus telaprevir or boceprevir has become the current SOC for patients with genotype 1 HCV infection. However, many patients are either not eligible for therapy or decline treatment due to coexisting relative or absolute contraindications as well as an inability to tolerate the hematological side effects and adverse events caused by the new SOC. These factors have contributed to the advent of pegIFN-α-free regimens. The newest therapeutic regimens containing sofosbuvir and ABT-450 have shown promising results. In this review, we summarize the development of anti-HCV agents and the clinical efficacy of sofosbuvir and ABT-450-based therapies as well as the potential for future HCV studies.展开更多
Hepatitis C virus(HCV) infection is a serious problem worldwide.The use of interferon-based therapy has made HCV eradication challenging.The recent appearance of direct-acting antiviral agents(DAAs) has changed HCV th...Hepatitis C virus(HCV) infection is a serious problem worldwide.The use of interferon-based therapy has made HCV eradication challenging.The recent appearance of direct-acting antiviral agents(DAAs) has changed HCV therapy.Combining the use of DAAs with peginterferon and ribavirin has improved treatment efficacy.Furthermore,the combination of different orally administered DAAs has enabled interferon-free therapy with much higher efficacy and safety.In particular,sofosbuvir,a nucleotide-based NS5 B inhibitor,prevents HCV RNA synthesis by acting as a "chain terminator".Treatment with sofosbuvir has attained an extremely high rate of sustained virologic response.The current review summarizes the efficacy and safety of sofosbuvir therapy.展开更多
Hepatitis C virus(HCV) affects 3% of the world population. It represents the main cause of chronic liver disease and is responsible for extra-hepatic complications, such as type 2 diabetes and cardiovascular diseases....Hepatitis C virus(HCV) affects 3% of the world population. It represents the main cause of chronic liver disease and is responsible for extra-hepatic complications, such as type 2 diabetes and cardiovascular diseases. HCV includes 7 genotypes differing in the nucleotide sequence variability, the geographic distribution, the rates of viral clearance, the risk of progression to liver fibrosis and to hepatocellular carcinoma, and the response to therapy. Last years have seen remarkable advances in the field of HCV infection with the approval of direct antiviral agents(DAAs) targeting key viral proteins involved in the HCV replication. Several oral regimens combining DAAs from different families have been developed and these regimens showed increased and sustained virological response rates to above 90% reducing the treatment duration to 12 wk or less. In particular, sofosbuvir, a nucleotide analogue nonstructural(NS)5B polymerase inhibitor, and velpatasvir, a NS5 A inhibitor, have been tested in two phase 3 trials, the ASTRAL-2(against HCV genotype 2) and the ASTRAL-3(against HCV genotype 3), demonstrating to be effective, safe, and well tolerated in patients who were 18 years of age or older and had at least a 6-mo history of HCV infection with a compensated liver disease.展开更多
AIM To assess the efficacy and safety of sofosbuvir and daclatasvir regimens for kidney transplantation(KT) patients with hepatitis C virus(HCV) infection.METHODS This study enrolled a prospective cohort of consecutiv...AIM To assess the efficacy and safety of sofosbuvir and daclatasvir regimens for kidney transplantation(KT) patients with hepatitis C virus(HCV) infection.METHODS This study enrolled a prospective cohort of consecutive Chinese KT patients with HCV infection. They were given sofosbuvir combined with daclatasvir, with or without ribavirin. They were monitored regularly during and after the treatment. RESULTS Six patients were recruited in our prospective study cohort. All patients were male and naive to directacting antiviral treatment. The treatment duration was 12 wk. Most patients(4/6) were infected with HCV genotype 1b. HCV RNA was undetectable at week 4 after treatment and at the end of treatment in all patients. Sustained virological response rate at 12 wk was 100%(6/6). Two patients had to accept a half dose of sofosbuvir due to serum creatinine elevation during treatment. Kidney function in the remaining patients was stable. No serious adverse events(AEs) were observed. No patient discontinued antiviral therapy due to side effects. CONCLUSION Sofosbuvir and daclatasvir for treatment of KT recipients with HCV infection are highly efficient and safe. Patients tolerated the medications well, and no serious AEs were observed. Larger prospective cohort studies are needed to validate these results.展开更多
AIM To prospectively evaluate the efficacy of sofobuvir(SOF) in hepatitis C patients infected with hepatitis C virus(HCV) genotype 3 in Pakistan.METHODS The present study was performed with the coordination of gastroe...AIM To prospectively evaluate the efficacy of sofobuvir(SOF) in hepatitis C patients infected with hepatitis C virus(HCV) genotype 3 in Pakistan.METHODS The present study was performed with the coordination of gastroenterology and pathology departments of Shalamar Hospital Lahore from August 2014 to May 2016. The total number of patients included in this study was 1375 and all of them were infected with HCV genotype 3. On the basis of drug combinations, all the patients were separated into two groups. The first group of patients was treated for 24 wk with SOF(Sovaldi? by Gilead Sciences) plus ribavirin(RBV) [Ribazol? by Getz Pharma Pakistan(PVT) Ltd], while the patients of the second group were treated with SOF + RBV + pegylatedinterferon(peg IFN) alfa-2 a(Ropegra by Roach) for 12 wk. HCV genotyping and viral load measurement were performed on fully automated Abbott Real-Time PCR system(Abbott m24 sp automated nucleic acid extraction system and Abbott m2000 rt amplification system; abbott Molecular, Des Plaines, IL, United States). For the assessment of sustained virological response(SVR), all HCV RNA negative patients were followed for 12weeks after the treatment completion. Any patient with less than 12 IU/m L viral load after 12 wk of treatment completion was considered as a sustained virological responder(SVR-12).RESULTS A total of 1375 patients chronically infected with HCV genotype 3 were treated with two drug combinations SOF + RBV and SOF + RBV + peg IFN alfa-2 a. On the basis of these drug combinations, patients were divided into two groups(first and second). Overall SVR-12 was excellent in both groups(99.17% and 97.91%). Older patients(> 40 years) of second group showed lower SVR-12(93.46%) compared to first group older patients(98.79%), while in the younger patients of both groups, the SVR-12 rate was almost the same(99.54% in first group and 99.05% in second group). No such difference regarding SVR-12 rate was seen in males and females of first group patients(99.68% and 98.88%, respectively), while in second group the males were found to be better responders compared to females(98.96% and 95%). The SVR-12 rate in previously treated patients of first group was better(99.34%) than second group(93.70%), while na?ve patients of second group were marginally better responders(99.25%) than first group(97.80%). Rapid viral response at week-4 was found to be a very effective predictor for assessing the SVR rate at this stage of therapy in both groups. Headache, anemia and fatigue were common side effects in both groups either treated with SOF + RBV or SOF + RBV + peg IFN alfa-2 a, while the overall percentage of the side effects was higher in second group.CONCLUSION The remarkable SVR response rate of HCV genotype 3 infected patients to SOF provided a new way to look forward to eliminate hepatitis C from our region.展开更多
AIM To investigate the real-world efficacy and safety of sofosbuvir/ribavirin(SOF/RBV) therapy for Japanese patients with genotype 2 hepatitis C virus(GT2-HCV).METHODS A total of 182 patients with GT2-HCV infection wh...AIM To investigate the real-world efficacy and safety of sofosbuvir/ribavirin(SOF/RBV) therapy for Japanese patients with genotype 2 hepatitis C virus(GT2-HCV).METHODS A total of 182 patients with GT2-HCV infection who received SOF/RBV therapy for 12 wk at our hospital were enrolled. The patients comprised 122 men and 60 women(age range: 17-84 years; mean age ± SD: 60.1 ± 12.1 years). Relationships between virological response and clinical data were examined by logistic regression analyses. RESULTS The proportions of patients with liver cirrhosis and history of hepatocellular carcinoma(HCC) were 29.0% and 17.3%, respectively. The proportion of patients with prior interferon(IFN)-based therapy was 25.6%. SOF/RBV therapy rapidly decreased HCV RNA levels. Several patients required RBV dose reduction because of anemia or fatigue. Four patients discontinued the therapy. The rates of sustained virological response at 12 wk after the end of treatment were 87.9%(intention to treat: 160/182) and 94.1%(per protocol: 159/169). Multivariate analyses showed that history of HCC or IFN-based therapy independently reduced the efficacy of SOF/RBV therapy. CONCLUSION SOF/RBV therapy for GT2-HCV is safe, highly tolerated, and effective. History of HCC or IFN-based therapy independently reduces the efficacy of this treatment.展开更多
AIM: To determine the safety profile of new hepatitis C virus (HCV) treatments in liver transplant (LT) recipients with recurrent HCV infection.METHODS: Forty-two patients were identified with recurrent HCV infection ...AIM: To determine the safety profile of new hepatitis C virus (HCV) treatments in liver transplant (LT) recipients with recurrent HCV infection.METHODS: Forty-two patients were identified with recurrent HCV infection that underwent LT at least 12 mo prior to initiating treatment with a Sofosbuvir-based regimen during December 2013-June 2014. Cases were patients who experienced hepatic decompensation and/or serious adverse events (SAE) during or within one month of completing treatment. Controls had no evidence of hepatic decompensation and/or SAE. HIV-infected patients were excluded. Cumulative incidence of decompensation/SAE was calculated using the Kaplan Meier method. Exact logistic regression analysis was used to identify factors associated with the composite outcome.RESULTS: Median age of the 42 patients was 60 years [Interquartile Range (IQR): 56-65 years], 33% (14/42) were female, 21% (9/42) were Hispanic, and 9% (4/42) were Black. The median time from transplant to treatment initiation was 5.4 years (IQR: 2.1-8.8 years). Thirteen patients experienced one or more episodes of hepatic decompensation and/or SAE. Anemia requiring transfusion, the most common event, occurred in 62% (8/13) patients, while 54% (7/13) decompensated. The cumulative incidence of hepatic decompensation/SAE was 31% (95%CI: 16%-41%). Risk factors for decompensation/SAE included lower pre-treatment hemoglobin (OR = 0.61 per g/dL, 95%CI: 0.40-0.88, P < 0.01), estimated glomerular filtration rate (OR = 0.95 per mL/min per 1.73 m<sup>2</sup>, 95%CI: 0.90-0.99, P = 0.01), and higher baseline serum total bilirubin (OR = 2.43 per mg/dL, 95%CI: 1.17-8.65, P < 0.01). The sustained virological response rate for the cohort of 42 patients was 45%, while it was 31% for cases.CONCLUSION: Sofosbuvir/ribavirin will continue to be used in the post-transplant population, including those with HCV genotypes 2 and 3. Management of anemia remains an important clinical challenge.展开更多
AIMTo assess the effect of sofosbuvir (SOF) based regimens on glycemic and lipid control. METHODSThis is a retrospective analysis of hepatitis C virus (HCV)-infected patients treated and cured with a SOF regimen [SOF/...AIMTo assess the effect of sofosbuvir (SOF) based regimens on glycemic and lipid control. METHODSThis is a retrospective analysis of hepatitis C virus (HCV)-infected patients treated and cured with a SOF regimen [SOF/ribavirin/interferon, SOF/simeprevir, or SOF/ledipasvir (LDV) ± ribavirin] from January 2014 to March 2015. Patients with hemoglobin A1C (HbA1C) and lipid panels within six months before and six months after therapy were identified and included in our study. Due to the known hemolytic effect of ribavirin, HbA1C was obtained a minimum of three months post-treatment for the patients treated with a ribavirin regimen. Medical history, demographics, HCV genotype, pre-therapy RNA, and liver biopsies were included in our analysis. The patients who started a new medication or had an adjustment of baseline medical management for hyperlipidemia or diabetes mellitus (DM) were excluded from our analysis. RESULTSTwo hundred and thirty-four patients were reviewed, of which 60 patients met inclusion criteria. Sixty-three point three percent were male, 26.7% were Caucasian, 41.7% were African American and 91.7% were infected with hepatitis C genotype 1. Mean age was 60.6 ± 6.7 years. Thirty-nine patients had HbA1C checked before and after treatment, of which 22 had the diagnosis of DM type 2. HbA1C significantly decreased with treatment of HCV (pretreatment 6.66% ± 0.95% vs post-treatment 6.14% ± 0.65%, P vs 0.71% ± 0.83%, P = 0.070). Fifty-two patients had pre- and post-treatment lipid panels; there was a significant increase in low-density lipoprotein (LDL) and total cholesterol (TC) after treatment (LDL: 99.5 ± 28.9 mg/dL vs 128.3 ± 34.9 mg/dL, P vs 199.7 ± 40.0 mg/dL, P P = 0.684). CONCLUSIONEradication of HCV with a SOF regimen resulted in a significant drop in HbA1C and an increase in LDL and TC post therapy.展开更多
Sofosbuvir is a new antiviral drug that has been recommended for management of hepatitis C virus(HCV)for a few years.New researches support that sofosbuvir might he useful for the management of Zika virus infection.Ba...Sofosbuvir is a new antiviral drug that has been recommended for management of hepatitis C virus(HCV)for a few years.New researches support that sofosbuvir might he useful for the management of Zika virus infection.Based on the pharmacological activity,inhibiting the HCV RNA-dependent RNA polymerase(RdRp or NS5 protein).sofosbuvir is proposed for its effectiveness against Zika virus infection.Here,the authors used a mathematical modelling theoretical approach to predict the expected dosage of sofosbuvir for inhibiting Zika virus infection.Based on the modeling study,if sofosbuvir is assigned for management of Zika virus.infection,doubled dosage of the present dosage for hepatitis C management is recommended.展开更多
文摘AIM To evaluate the safety and efficacy of ledipasvir/sofosbuvir on hepatitis C eradication in patients with hepatitis C virus(HCV)/human immunodeficiency virus(HIV) co-infection in an urban HIV clinic.METHODS A retrospective cohort study of 40 subjects co-infected with HIV-1 and HCV treated with the fixed-dose combination of ledipasvir and sofosbuvir for 12 wk from 2014 to 2016.All patients included were receiving antiretroviral therapy(ART) with HIV RNA values of 100 copies/m L or fewer regardless of baseline HCV RNA level.The primary end point was a sustained virologic response of HCV at 12 wk(SVR12) after the end of therapy.RESULTS Of the 40 patients enrolled,55% were black,22.5% had been previously treated for HCV,and 25% hadcirrhosis.The patients were on a wide range of ART.Overall,39 patients(97.5%) had a SVR 12 after the end of therapy,including rates of 97.1% in patients with HCV genotype 1 a and 100% in those with HCV genotype 1 b.One patient with HCV genotype 3 a was included and achieved SVR12.Rates of SVR12 were similar regardless of previous treatment or the presence of compensated cirrhosis.Only 1 patient experienced relapse at week 12 following treatment and deep sequencing didn't reveal any resistance associated mutation in the NS5A or NS5B region.Interestingly,7(17.5%) patients who were adherent to ART experienced HIV viral breakthrough which resolved after continuing the same ART regimen.Two(5%) patients experienced HIV-1 virologic rebound due to noncompliance with HIV therapy,which resolved after resuming the same ART regimen.No severe adverse events were observed and no patient discontinued treatment because of adverse events.The most common adverse events included headache(12.5%),fatigue(10%),and diarrhea(2.5%).CONCLUSION This retrospective study demonstrated the high rates of SVR12 of ledipasvir/sofosbuvir on HCV eradication in patients co-infected with HCV and HIV,regardless of HCV baseline levels,HCV treatment history or cirrhosis condition.The oral combination of ledipasvir/sofosbuvir represents a safe and well tolerated HCV treatment option that does not require modification for many of the common HIV ART.Occasional HIV virologic rebound occurred but later resolved without the need to change ART.
文摘AIM To evaluate sustained viral response(SVR)of 8-wk ledipasvir/sofosbuvir therapy among non-cirrhotic,genotype-1 hepatitis C virus(HCV)patients with RNA<6 million IU/m L.METHODS We performed a retrospective cohort study to examine SVR rates,predictors of treatment failure and safety analysis of 8-wk ledipasvir/sofosbuvir(LDV/SOF)therapy among non-cirrhotic,genotype 1 HCV patients with viral load<6 million IU/m L.Primary outcome was an achievement of SVR at 12 wk after treatment.Secondary outcomes were identifying predictors of treatment failure and adverse events during treatment.RESULTS Total 736 patients:55%males,51%Caucasians and 65%were genotype 1a.Non-cirrhotic state of 53%was determined by clinical judgment(imaging,AST,platelet count)and 47%had documented liver fibrosis testing(biopsy,vibration-controlled transient elastography,serum biomarkers).Overall SVR12 was 96%.No difference in SVR12 was seen between patients whose non-cirrhotic state was determined by clinical judgment and patients who had fibrosis testing.Age groups,gender,ethnicity and genotype 1 subtype did not predict SVR.Non-cirrhotic state determined by clinical judgment based on simple,non-invasive tests were not associated with lower SVR[OR=1.02,95%CI:0.48-2.17,P=0.962].The AUROC for hepatitis C RNA viral load was 0.734(P<0.001,95%CI:0.66-0.82).HCV RNA 2.2 million IU/m L was identified as the cutoff value with sensitivity 73%and specificity 64%.HCV RNA<2.2 million IU/m L was associated with significantly higher SVR 98%with OR=0.22(95%CI:0.1-0.49,P<0.001)compared to SVR 92%in HCV RNA≥2.2 million IU/m L.No death or morbidities were reported.CONCLUSION Our outcomes validate safety and effectiveness of 8-wk LDV/SOF therapy in non-cirrhotic,untreated HCV genotype 1 patients with HCV RNA<6 million IU/m L.
基金Janssen Research & DevelopmentChina，Pfizer Scholarship for Pharmacometrics during this project
文摘A tablet consisting of direct-acting antiviral agents,ledipasvir（a NS5 A protein inhibitor） and sofosbuvir（a NS5 B polymerase inhibitor）,is the first fixed-dose preparation used in the antiviral therapy of hepatitis C.A model-based meta-analysis of ledipasvir and GS331007,the primary metabolite of sofosbuvir,enabled the integration of pharmacokinetic（PK） information from separate clinical trials and the quantitative characterization of the population pharmacokinetics of these two drugs.A systematic publication search was conducted for the clinical studies of ledipasvir and sofosbuvir.A total of 401 arm-level aggregate concentrations of GS331007 and 188 concentrations of ledipasvir were used for PK modeling.A two-compartment disposition model was used for both ledipasvir and GS331007.Zero-order absorption was applied for ledipasvir PK modeling,and a combined zero- and first-order absorption was used for the modeling of GS331007.Absorption lag was observed in concentration-time profiles of both ledipasvir and GS331007.To aid the development of direct-acting antiviral drugs,our established PK models provided a basis for the further PK-viral kinetic studies of ledipasvir and sofosbuvir.
文摘Hepatitis C virus(HCV) has infected more than 200 million people around the globe. From 2001-2011, interferon plus ribavirin remained the standard of care for patients with HCV infection. The therapy had a limited response with a number of side effects. Recently, results for phase III trials of ledipasvir and sofosbuvir combination therapy have been announced. In treatmentnave patients, 12 wk of therapy with ledipasvir and sofosbuvir showed a sustained virological response(SVR) rate of 99%. In treatment experienced patients, 12-24 wk of therapy with ledipasvir and sofosbuvir in the absence or presence of ribavirin showed an SVR rate of 94%-99%. In cirrhotic patients the rate of SVR was 86% and 99% for 12 and 24 wk of therapy, respectively. The ledipasvir and sofosbuvir therapy showed very good results in different subgroups of patients regardless of patient's race, alanine aminotransferase levels, sex and host genetic factors. The combination therapy was well tolerated with no emergence of resistant mutants. The most common adverse effects were nausea, headache and fatigue. With the availability of interferon free therapy with minimal adverse effects, it will be easy to decrease the future morbidity and mortality caused by HCV infection.
文摘Chronic hepatitis C virus(HCV) infection is one of the main causes of chronic liver disease worldwide. In the last 5 years, treatment for HCV infection has experienced a marked development. In 2014, the use of ledipasvir/sofosbuvir with or without concomitant weight-based ribavirin was approved with a very significant increase in the sustained virological response. However, new side effects have been associated. We report the first case of an HCV infected patient treated for 12 wk with the combination of sofosbuvir/ledipasvir plus ribavirin who developed a miliary tuberculosis(TB) infection while on therapy. The patient was a 65-year-old woman, who referred malaise, asthenia, hyporexia, 7 kg weight loss, productive cough, evening fever and night sweats, right after finishing the treatment. The chest computed tomography-scan revealed a superior mediastinal widening secondary to numerous lymphadenopathies with extensive necrosis and bilateral diffuse lung miliary pattern with little subsequent bilateral pleural effusion, highly suggestive of lymph node tuberculosis with lung miliary spread. A bronchoscopy was performed and bronchial suction showed more than 50 acid-alcohol resistant bacillus per line. A Mycobacterium tuberculosis DNA was detected in blood by polymerase chain reaction, which confirmed the diagnosis of miliary tuberculosis. Some cases of TB infection have been identified with α-interferon-based therapy and with the triple therapy of pegylated interferon, ribavirin and boceprevir or telaprevir. However, significant infection has not been reported with sofosbuvir/ledipasvir plus ribavirin.We believe that the case is relevant to increase awareness of opportunistic infections and particularly TB infection. Although the international guidelines offer no recommendation regarding TB screening, we wonder whether it would be advisable to screen for opportunistic infections prior to the introduction of HCV therapy.
文摘AIM To evaluate the efficacy and safety of a regimen containing sofosbuvir(SOF)and ledipasvir(LDV)in Japanese patients aged≥75 years with hepatitis C genotype 1.METHODS This multicenter,retrospective study consisted of 246 Japanese patients with HCV genotype 1 at nine centers in Miyazaki prefecture in Japan.Demographic,clinical,virological,and adverse effects(AE)-related data obtained during and after SOF/LDV therapy were collected from medical records.These patients were divided into two groups,younger(aged<75 years)and elderly(aged≥75 years).Virological data and AEs were analyzed by age group.RESULTS The sustained virological response(SVR)rates at 12 wk after treatment were 99.2%,99.4%,and 98.7%in the overall population and in patients aged<75 and≥75 years,respectively.Common AEs during therapy were headache,pruritus,constipation,and insomnia.These occurred in fewer than 10%of patients,and their incidence was not significantly different between the younger and elderly groups.Two patients discontinued treatment,one due to a skin eruption and the other due to cerebral bleeding.CONCLUSION Compared with younger patients,elderly patients had a similar virological response and tolerance to SOF/LDV therapy.
基金the Special Project of Guangdong Rural Science and Technology Commissioner of China(KTPYJ2021014)。
文摘Although direct-acting antivirals(DAAs)have notably increased the sustained virological response(SVR)rates in hepatitis C virus(HCV)-infected adolescent patients,the efficacy and safety for young children under 3 years old remain unclear.Currently,no guidelines recommend DAA therapy for this situation worldwide.Furthermore,the China National Medical Products Administration has not approved any DAA for treating children below 12 years old.Here,we described the characteristics of two children approximately 2 years old,who were infected by HCV genotype 1b and had significant clinical symptoms.Both received 12 weeks of ledipasvir/sofosbuvir(Case 1:45.00 mg/200 mg per day,weight 17 kg;Case 2:33.75 mg/150 mg per day,weight 12 kg).They achieved SVR at 12 weeks after treatment completion without obvious treatment-related adverse effects.Therefore,the safety and benefits of ledipasvir/sofosbuvir treatment in children under 3 years old seem to be confirmed.Our findings require further evaluation.
基金Supported by Grants from the National Key Basic Research Program of China, No. 2009CB522507, No. 2012CB519005Beijing Nova Program of China, No. Z12110702512071
文摘Combination therapy with peginterferon (pegIFN)-α and ribavirin (RBV) has been the standard of care (SOC) for chronic hepatitis C. Unfortunately, not all patients can achieve a sustained virologic response (SVR) with this regimen. SVR rates are approximately 80% in patients with hepatitis C virus (HCV) genotype 2, 3, 5 and 6 and 40%-50% in patients with genotype 1 and 4. Therefore, strategies to improve SVR rates have been an important issue for clinical physicians. Several direct acting antiviral agents (DAAs) have significantly higher SVR rates when combined with pegIFN-α and RBV than pegIFN-α and RBV alone. Treatments containing DAAs have several advantages over the previous SOC, including higher specificity and efficacy, shorter treatment durations, fewer side effects, and oral administration. Based on these advantages, treatment with pegIFN-α and RBV plus telaprevir or boceprevir has become the current SOC for patients with genotype 1 HCV infection. However, many patients are either not eligible for therapy or decline treatment due to coexisting relative or absolute contraindications as well as an inability to tolerate the hematological side effects and adverse events caused by the new SOC. These factors have contributed to the advent of pegIFN-α-free regimens. The newest therapeutic regimens containing sofosbuvir and ABT-450 have shown promising results. In this review, we summarize the development of anti-HCV agents and the clinical efficacy of sofosbuvir and ABT-450-based therapies as well as the potential for future HCV studies.
文摘Hepatitis C virus(HCV) infection is a serious problem worldwide.The use of interferon-based therapy has made HCV eradication challenging.The recent appearance of direct-acting antiviral agents(DAAs) has changed HCV therapy.Combining the use of DAAs with peginterferon and ribavirin has improved treatment efficacy.Furthermore,the combination of different orally administered DAAs has enabled interferon-free therapy with much higher efficacy and safety.In particular,sofosbuvir,a nucleotide-based NS5 B inhibitor,prevents HCV RNA synthesis by acting as a "chain terminator".Treatment with sofosbuvir has attained an extremely high rate of sustained virologic response.The current review summarizes the efficacy and safety of sofosbuvir therapy.
文摘Hepatitis C virus(HCV) affects 3% of the world population. It represents the main cause of chronic liver disease and is responsible for extra-hepatic complications, such as type 2 diabetes and cardiovascular diseases. HCV includes 7 genotypes differing in the nucleotide sequence variability, the geographic distribution, the rates of viral clearance, the risk of progression to liver fibrosis and to hepatocellular carcinoma, and the response to therapy. Last years have seen remarkable advances in the field of HCV infection with the approval of direct antiviral agents(DAAs) targeting key viral proteins involved in the HCV replication. Several oral regimens combining DAAs from different families have been developed and these regimens showed increased and sustained virological response rates to above 90% reducing the treatment duration to 12 wk or less. In particular, sofosbuvir, a nucleotide analogue nonstructural(NS)5B polymerase inhibitor, and velpatasvir, a NS5 A inhibitor, have been tested in two phase 3 trials, the ASTRAL-2(against HCV genotype 2) and the ASTRAL-3(against HCV genotype 3), demonstrating to be effective, safe, and well tolerated in patients who were 18 years of age or older and had at least a 6-mo history of HCV infection with a compensated liver disease.
基金Supported by the Project of Science and Technology Development Plan of Jinan City,No.201506004Youth Fund of the Second Hospital of Shandong University,No.Y2014010014
文摘AIM To assess the efficacy and safety of sofosbuvir and daclatasvir regimens for kidney transplantation(KT) patients with hepatitis C virus(HCV) infection.METHODS This study enrolled a prospective cohort of consecutive Chinese KT patients with HCV infection. They were given sofosbuvir combined with daclatasvir, with or without ribavirin. They were monitored regularly during and after the treatment. RESULTS Six patients were recruited in our prospective study cohort. All patients were male and naive to directacting antiviral treatment. The treatment duration was 12 wk. Most patients(4/6) were infected with HCV genotype 1b. HCV RNA was undetectable at week 4 after treatment and at the end of treatment in all patients. Sustained virological response rate at 12 wk was 100%(6/6). Two patients had to accept a half dose of sofosbuvir due to serum creatinine elevation during treatment. Kidney function in the remaining patients was stable. No serious adverse events(AEs) were observed. No patient discontinued antiviral therapy due to side effects. CONCLUSION Sofosbuvir and daclatasvir for treatment of KT recipients with HCV infection are highly efficient and safe. Patients tolerated the medications well, and no serious AEs were observed. Larger prospective cohort studies are needed to validate these results.
文摘AIM To prospectively evaluate the efficacy of sofobuvir(SOF) in hepatitis C patients infected with hepatitis C virus(HCV) genotype 3 in Pakistan.METHODS The present study was performed with the coordination of gastroenterology and pathology departments of Shalamar Hospital Lahore from August 2014 to May 2016. The total number of patients included in this study was 1375 and all of them were infected with HCV genotype 3. On the basis of drug combinations, all the patients were separated into two groups. The first group of patients was treated for 24 wk with SOF(Sovaldi? by Gilead Sciences) plus ribavirin(RBV) [Ribazol? by Getz Pharma Pakistan(PVT) Ltd], while the patients of the second group were treated with SOF + RBV + pegylatedinterferon(peg IFN) alfa-2 a(Ropegra by Roach) for 12 wk. HCV genotyping and viral load measurement were performed on fully automated Abbott Real-Time PCR system(Abbott m24 sp automated nucleic acid extraction system and Abbott m2000 rt amplification system; abbott Molecular, Des Plaines, IL, United States). For the assessment of sustained virological response(SVR), all HCV RNA negative patients were followed for 12weeks after the treatment completion. Any patient with less than 12 IU/m L viral load after 12 wk of treatment completion was considered as a sustained virological responder(SVR-12).RESULTS A total of 1375 patients chronically infected with HCV genotype 3 were treated with two drug combinations SOF + RBV and SOF + RBV + peg IFN alfa-2 a. On the basis of these drug combinations, patients were divided into two groups(first and second). Overall SVR-12 was excellent in both groups(99.17% and 97.91%). Older patients(> 40 years) of second group showed lower SVR-12(93.46%) compared to first group older patients(98.79%), while in the younger patients of both groups, the SVR-12 rate was almost the same(99.54% in first group and 99.05% in second group). No such difference regarding SVR-12 rate was seen in males and females of first group patients(99.68% and 98.88%, respectively), while in second group the males were found to be better responders compared to females(98.96% and 95%). The SVR-12 rate in previously treated patients of first group was better(99.34%) than second group(93.70%), while na?ve patients of second group were marginally better responders(99.25%) than first group(97.80%). Rapid viral response at week-4 was found to be a very effective predictor for assessing the SVR rate at this stage of therapy in both groups. Headache, anemia and fatigue were common side effects in both groups either treated with SOF + RBV or SOF + RBV + peg IFN alfa-2 a, while the overall percentage of the side effects was higher in second group.CONCLUSION The remarkable SVR response rate of HCV genotype 3 infected patients to SOF provided a new way to look forward to eliminate hepatitis C from our region.
文摘AIM To investigate the real-world efficacy and safety of sofosbuvir/ribavirin(SOF/RBV) therapy for Japanese patients with genotype 2 hepatitis C virus(GT2-HCV).METHODS A total of 182 patients with GT2-HCV infection who received SOF/RBV therapy for 12 wk at our hospital were enrolled. The patients comprised 122 men and 60 women(age range: 17-84 years; mean age ± SD: 60.1 ± 12.1 years). Relationships between virological response and clinical data were examined by logistic regression analyses. RESULTS The proportions of patients with liver cirrhosis and history of hepatocellular carcinoma(HCC) were 29.0% and 17.3%, respectively. The proportion of patients with prior interferon(IFN)-based therapy was 25.6%. SOF/RBV therapy rapidly decreased HCV RNA levels. Several patients required RBV dose reduction because of anemia or fatigue. Four patients discontinued the therapy. The rates of sustained virological response at 12 wk after the end of treatment were 87.9%(intention to treat: 160/182) and 94.1%(per protocol: 159/169). Multivariate analyses showed that history of HCC or IFN-based therapy independently reduced the efficacy of SOF/RBV therapy. CONCLUSION SOF/RBV therapy for GT2-HCV is safe, highly tolerated, and effective. History of HCC or IFN-based therapy independently reduces the efficacy of this treatment.
基金Supported by National Institutes of Health,No.DA031095 and No.DK090317
文摘AIM: To determine the safety profile of new hepatitis C virus (HCV) treatments in liver transplant (LT) recipients with recurrent HCV infection.METHODS: Forty-two patients were identified with recurrent HCV infection that underwent LT at least 12 mo prior to initiating treatment with a Sofosbuvir-based regimen during December 2013-June 2014. Cases were patients who experienced hepatic decompensation and/or serious adverse events (SAE) during or within one month of completing treatment. Controls had no evidence of hepatic decompensation and/or SAE. HIV-infected patients were excluded. Cumulative incidence of decompensation/SAE was calculated using the Kaplan Meier method. Exact logistic regression analysis was used to identify factors associated with the composite outcome.RESULTS: Median age of the 42 patients was 60 years [Interquartile Range (IQR): 56-65 years], 33% (14/42) were female, 21% (9/42) were Hispanic, and 9% (4/42) were Black. The median time from transplant to treatment initiation was 5.4 years (IQR: 2.1-8.8 years). Thirteen patients experienced one or more episodes of hepatic decompensation and/or SAE. Anemia requiring transfusion, the most common event, occurred in 62% (8/13) patients, while 54% (7/13) decompensated. The cumulative incidence of hepatic decompensation/SAE was 31% (95%CI: 16%-41%). Risk factors for decompensation/SAE included lower pre-treatment hemoglobin (OR = 0.61 per g/dL, 95%CI: 0.40-0.88, P < 0.01), estimated glomerular filtration rate (OR = 0.95 per mL/min per 1.73 m<sup>2</sup>, 95%CI: 0.90-0.99, P = 0.01), and higher baseline serum total bilirubin (OR = 2.43 per mg/dL, 95%CI: 1.17-8.65, P < 0.01). The sustained virological response rate for the cohort of 42 patients was 45%, while it was 31% for cases.CONCLUSION: Sofosbuvir/ribavirin will continue to be used in the post-transplant population, including those with HCV genotypes 2 and 3. Management of anemia remains an important clinical challenge.
文摘AIMTo assess the effect of sofosbuvir (SOF) based regimens on glycemic and lipid control. METHODSThis is a retrospective analysis of hepatitis C virus (HCV)-infected patients treated and cured with a SOF regimen [SOF/ribavirin/interferon, SOF/simeprevir, or SOF/ledipasvir (LDV) ± ribavirin] from January 2014 to March 2015. Patients with hemoglobin A1C (HbA1C) and lipid panels within six months before and six months after therapy were identified and included in our study. Due to the known hemolytic effect of ribavirin, HbA1C was obtained a minimum of three months post-treatment for the patients treated with a ribavirin regimen. Medical history, demographics, HCV genotype, pre-therapy RNA, and liver biopsies were included in our analysis. The patients who started a new medication or had an adjustment of baseline medical management for hyperlipidemia or diabetes mellitus (DM) were excluded from our analysis. RESULTSTwo hundred and thirty-four patients were reviewed, of which 60 patients met inclusion criteria. Sixty-three point three percent were male, 26.7% were Caucasian, 41.7% were African American and 91.7% were infected with hepatitis C genotype 1. Mean age was 60.6 ± 6.7 years. Thirty-nine patients had HbA1C checked before and after treatment, of which 22 had the diagnosis of DM type 2. HbA1C significantly decreased with treatment of HCV (pretreatment 6.66% ± 0.95% vs post-treatment 6.14% ± 0.65%, P vs 0.71% ± 0.83%, P = 0.070). Fifty-two patients had pre- and post-treatment lipid panels; there was a significant increase in low-density lipoprotein (LDL) and total cholesterol (TC) after treatment (LDL: 99.5 ± 28.9 mg/dL vs 128.3 ± 34.9 mg/dL, P vs 199.7 ± 40.0 mg/dL, P P = 0.684). CONCLUSIONEradication of HCV with a SOF regimen resulted in a significant drop in HbA1C and an increase in LDL and TC post therapy.
文摘Sofosbuvir is a new antiviral drug that has been recommended for management of hepatitis C virus(HCV)for a few years.New researches support that sofosbuvir might he useful for the management of Zika virus infection.Based on the pharmacological activity,inhibiting the HCV RNA-dependent RNA polymerase(RdRp or NS5 protein).sofosbuvir is proposed for its effectiveness against Zika virus infection.Here,the authors used a mathematical modelling theoretical approach to predict the expected dosage of sofosbuvir for inhibiting Zika virus infection.Based on the modeling study,if sofosbuvir is assigned for management of Zika virus.infection,doubled dosage of the present dosage for hepatitis C management is recommended.
