AIM: To compare efficacy of telaprevir(TVR) and simeprevir(SMV) combined with pegylated interferon(PEG-IFN) and ribavirin(RBV) while treating chronic hepatitis C(CHC). METHODS: In all, 306 CHC patients were included i...AIM: To compare efficacy of telaprevir(TVR) and simeprevir(SMV) combined with pegylated interferon(PEG-IFN) and ribavirin(RBV) while treating chronic hepatitis C(CHC). METHODS: In all, 306 CHC patients were included in this study. There were 159 patients in the TVR combination therapy group and 147 patients in the SMV combination therapy group. To evaluate pretreatment factors contributing to sustained virological response at 12 wk(SVR12), univariate and multivariate analyses were performed in TVR and SMV groups. To adjust for patient background between TVR and SMV groups, propensity score matching was performed. Virological response during treatment and SVR12 were evaluated.RESULTS: Overall rates of SVR12 [undetectable serum hepatitis C virus(HCV) RNA levels] were 79.2% and 69.4% in TVR and SMV groups, respectively. Patients in the SMV group were older, had higher serum HCV RNA levels, lower hemoglobin, higher prevalence of unfavorable interleukin-28B(IL28B) genotype(rs8099917), and poorer response to previous PEG-IFN and RBV treatment. Propensity score matching was performed to adjust for backgrounds(n = 104) and demonstrated SVR12 rates of 74.0% and 73.1% in the TVR and SMV groups, respectively. In the TVR group, discontinuation rates were higher because of adverse events; however, breakthrough and nonresponse was more frequent in the in SMV group. Multivariate analysis revealed IL28 B genotype(rs8099917) as the only independent predictive factor of SVR12 in both groups.CONCLUSION: SVR12 rates were almost identical following propensity score matching.展开更多
AIM To evaluate and compare the efficacy and safety of telaprevir(TVR)-and simeprevir(SMV)-based triple therapies in elderly patients, specifically patients aged 66 years or older.METHODS The present study enrolled 11...AIM To evaluate and compare the efficacy and safety of telaprevir(TVR)-and simeprevir(SMV)-based triple therapies in elderly patients, specifically patients aged 66 years or older.METHODS The present study enrolled 112 and 76 Japanese patients with chronic hepatitis C virus genotype 1b infection who were treated with a 12-wk TVR-based or SMV-based triple therapy, respectively, followed by a dual therapy that included pegylated interferon α and ribavirin(RBV) for 12 wk. The patients were categorized into two groups according to age as follows: A younger group of patients aged ≤ 65 years old and an older group of patients aged > 65 years old. Among the patients treated with TVR-based triple therapy, 34 patients were included in the older group. The median ages were 56 years(range: 28-65 years) in the younger group and 69 years(range: 66-81 years) in the older group. Among the patients treated with SMV-based triple therapy, 39 patients were included in the older group. The median ages were 59 years(range: 36-65 years) in the younger group and 71 years(range: 66-86 years) in the older group. The clinical, biochemical and virological data were analyzed before and during treatment.RESULTS Among the patients treated with the TVR-based triple therapy, no significant difference in the sustained virological response(SVR) was found between the younger(80.8%) and older(88.2%) groups. The SVR rates for patients with the interleukin 28B(IL28B)(rs8099917) TG/GGgenotypes(73.9% and 60.0% in the younger and older groups, respectively) were significantly lower than for patients with the IL28B TT-genotype(86.3% and 92.9%, respectively). The cumulative exposure to RBV for the entire 24-wk treatment period(as a percentage of the target dose) was significantly higher in the younger group than in the older group(91.7% vs 66.7%, respectively, P < 0.01), but the cumulative exposure to TVR was not significantly different between the younger and older groups(91.6% vs 81.9%, respectively). A multivariate analysis identified the TT-genotype of IL28B(OR = 8.160; 95%CI: 1.593-41.804, P = 0.012) and the adherence of RBV(> 60%)(OR = 11.052; 95%CI: 1.160-105.273, P = 0.037) as independent factors associated with the SVR. Adverse events resulted in discontinuation of the treatment in 11.3% and 14.7% of the younger and older groups, respectively. Among the patients treated with the SMV-based triple therapy, no significant difference in the SVR rare was found between the younger(81.1%) and older(82.1%) groups. The SVR rates for patients with the IL28B TG/GG-genotypes(77.8% and 64.7% in the younger and older groups, respectively) were significantly lower than for patients with the IL28 B TT-genotype(88.2% and 100%, respectively). A multivariate analysis identified the TT-genotype of IL28B as an independent factor associated with the SVR(OR = 9.677; 95%CI:1.114-84.087, P = 0.040). Adverse events resulted in discontinuation of the treatment in 7.0% and 14.3% of patients in the younger and older groups, respectively.CONCLUSION Both TVR- and SMV-based triple therapies can be successfully used to treat patients aged 66 years or older with genotype 1b chronic hepatitis C. Genotyping of the IL28B indicates a potential to achieve SVR in these difficult-to-treat elderly patients.展开更多
Background and Aims: Treatment with a combination of the nucleotide polymerase inhibitor sofosbuvir and NS3A (non-structural protein 3A) protease inhibitor simeprevir resulted in high rates of sustained virological re...Background and Aims: Treatment with a combination of the nucleotide polymerase inhibitor sofosbuvir and NS3A (non-structural protein 3A) protease inhibitor simeprevir resulted in high rates of sustained virological response in chronic hepatitis C Genotype 4. Methods: We conducted a real life study on Egyptian patients coming to tropical medicine department clinic at El Mery main university hospital from February 2015 to February 2016 for treatment naive and treatment experienced patients with chronic HCV genotype 4, including cirrhotics and non cirrhotics. Naive (cir-rhotics and non cirrhotics) and relapsers (non cirrhotics) received nucleotide polymerase inhibitor sofosbuvir and NS3A inhibitor simeprevir once daily for 12 weeks and 24 weeks for relapser cirrhotic patients. The primary end point was a sustained virologic response at 12 weeks after end of treatment. An informed consent was obtained from each patient at the beginning of the study (Real life study: a study on Egyptian patients when the drug was available in the market). Results: 30 naive patients with HCV genotype 4 and 20 relapsers (10 non cirrhotic and 10 cirrhotic patients) were enrolled. Patient inclusion criteria: Naive patients are those who tested positive for HCV RNA by PCR and had no experience to HCV treatment;Relapsers are those who tested positive for HCV RNA by PCR and had a previous treatment for HCV. Cirrhosis was diagnosed on ultrasound basis. Mean age was 53.57 ± 10.682 years old in naive patients and 48.30 ± 5.100 years old in relapsers. Median baseline HCV RNA was 360,069 IU/mL for naive patients and 1,245,000 IU/mL for relapsers;using Fib4 20% of naive patients were F3-F4, while 40% of relapsers were F3-F4. Degree of fibrosis was confirmed by fibrotest in relapsers. Upon treatment of patients with sofosbuvir and semiprevir once daily for 12 weeks and 24 weeks only to cirrhotic relapsers, end of treatment PCR was negative in 100% in all groups including cirrhotics and non cirrhotics. Primary end point (SVR 12) was achieved in 100% of all patients. Second end point (SVR 24) was achieved in 96.6% of naive pa-ients;SVR 24 for non-cirrhotic relapsers was achieved in 100% of patients and in 90% of cirrhotic relapsers. One patient had transient total bilirubin elevations without increased ALT (alanine aminotransferase) or AST (aspartate aminotransferase). One patient developed cutaneous rash. Conclusion: Once daily sofosbuvir and simeprevir for 12 weeks provided high rate of sustained virological response among treatment naive and treatment experienced patients with HCV genotype IV.展开更多
The effectiveness of hepatitis C treatment has improved with the development of interferon(IFN),and it has drastically improved with the development of peg-interferon-α(PEG-IFN) in combination with ribavirin(RBV) and...The effectiveness of hepatitis C treatment has improved with the development of interferon(IFN),and it has drastically improved with the development of peg-interferon-α(PEG-IFN) in combination with ribavirin(RBV) and,more recently,with the addition of a protease inhibitor.Simeprevir,which is a secondgeneration protease inhibitor,has shown clinically favorable safety and tolerability profiles.Simeprevir received its first global approval in Japan in September 2013 for the treatment of genotype 1 chronic hepatitis C in combination with PEG-IFN and RBV.One serious adverse event associated with IFN therapy is interstitialpneumonitis,which can be fatal.We experienced a patient with interstitial pneumonitis that was induced by simeprevir with PEG-IFN and RBV therapy for chronic hepatitis C in the early stages of therapy(8 wk after initiating therapy).This is the first case report of interstitial pneumonitis with simeprevir with PEG-IFN and RBV in the world.In addition,it is very interesting that the onset of interstitial pneumonitis was earlier than that in conventional PEG-IFN and RBV therapy.This finding suggests that simeprevir augments the adverse event.We present this case report in light of relevant literature on interstitial pneumonitis with conventional PEG-IFN and RBV therapy.展开更多
Objectives: To identify local resource use such as pharmaceutical treatment, medical follow-up, and patient hospitalization and estimate the budget impact of simeprevir (SMV) plus pegylated interferon (P)/ribavirin (R...Objectives: To identify local resource use such as pharmaceutical treatment, medical follow-up, and patient hospitalization and estimate the budget impact of simeprevir (SMV) plus pegylated interferon (P)/ribavirin (R) as a treatment option in the early stages of the disease in Greece. Methods: A budget impact tool was developed with a two-year time horizon, which estimated the impact on the Social Insurance Funds (SIFs) of introducing SMV + PR in the management of the early disease stages. Total direct and indirect costs were estimated for each of the following health states: non-cirrhotic chronic Hepatitis C (and within that by fibrosis stage), compensated cirrhosis, decompensated cirrhosis, and hepatocellular carcinoma. Data gaps on treatment algorithms, resource use and productivity losses were covered via an expert panel of eight leading hepatologists. Epidemiology data were taken from the published literature. Unit costs were obtained from the Ministry of Health and SIFs. The perspective was that of the SIF and the cost base year was 2015. Results: The total (direct and indirect) cost per patient per year (excluding cost of antiviral treatment) was estimated at €647, €703, €5,753, €16,313 and €37,237 for non-cirrhotic CHC, compensated cirrhosis, decompensated cirrhosis, HCC and liver transplantation, respectively. The budget impact analysis showed that adding SMV to PR in the early stages of the disease would lead to an increase in the cost of antiviral treatment by €2.03 million. Conclusions: Costs of managing CHC increase dramatically with disease severity. SMV + PR for naive patients at early disease stages has a significant but manageable budget impact, and could prevent high costs in advanced stages.展开更多
Over the last years it has started a real revolution in the treatment of chronic hepatitis C. This occurred for the availability of direct-acting antiviral agents that allow to reach sustained virologic response in ap...Over the last years it has started a real revolution in the treatment of chronic hepatitis C. This occurred for the availability of direct-acting antiviral agents that allow to reach sustained virologic response in approximately 90% of cases. In the near future further progress will be achieved with the use of pan-genotypic drugs with high efficacy but without side effects.展开更多
Due to the progressive aging of the hepatitis C virus(HCV) population which have acquired the infection during its maximum spread after the Second World War, the management of the elderly HCV-infected patient is emerg...Due to the progressive aging of the hepatitis C virus(HCV) population which have acquired the infection during its maximum spread after the Second World War, the management of the elderly HCV-infected patient is emerging as a hot topic. Unfortunately, although it is recognized that the progression of HCV-related liver disease gets faster with aging, and that even extrahepatic manifestations of HCV infection are probably worse in the elderly, till now, treatment attempts in this population have been significantly limited by the wellknown contraindications and side effects of interferon(IFN). The arrival of several new anti-HCV drugs, and the possibility to combine them in safe and effective anti-viral regimens, is relighting the hope of a cure for many elderly patients who had been cut out of IFN-based treatments. However, although these new regimens will be certainly more manageable, it should be underscored that IFN-free doesn't mean free from any contraindication or side-effect. Moreover, one issue which promises to become central is that of the possible interactions between antiviral therapy and the multiple drugs frequently assumed by elderly patients because of comorbidities. In this review, we will revise the epidemiology pointing to HCV as an infection of the elderly, the evidences that HCV harms the health of the aged patient more than that of the young one, and the available experiences of HCV treatment in the elderly with the "old" IFN-based regimens and with the newer drugs. We will conclude that the availability of IFNfree regimens should prompt us to change our mind and consider a significantly larger number of possible candidates among elderly patients, who would take significant advantage from viral eradication. Rather than the anagraphic age, drug-drug interactions and, mainly in case of economic restrictions, an evaluation of life expectancy dependent on liver disease with respect to that dependent on comorbidities, are likely to be the key issues guiding treatment indication in the next future. The sooner we will change our mind with respect to an a priori obstacle for anti-HCV treatment in the elderly, the sooner we will begin to spare many aged HCV patients from avoidable liver-related complications.展开更多
Chronic hepatitis C infection is the leading cause of chronic liver disease, cirrhosis, hepatocellular carcinoma as well as the primary indication for liver transplantation in the United States. Despite recent advance...Chronic hepatitis C infection is the leading cause of chronic liver disease, cirrhosis, hepatocellular carcinoma as well as the primary indication for liver transplantation in the United States. Despite recent advances in drugs for the treatment of hepatitis C, predictive models estimate the incidence of cirrhosis due to hepatitis C infection will to continue to rise for the next two decades. There is currently an immense interest in the treatment of patients with fibrosis and early-stage cirrhosis as treatment can lead to decrease in the rates of decompensated cirrhosis, hepatocellular carcinoma and need for liver transplantation in these patients. The goal of this paper is to provide clinicians and health care professionals further information about the treatment of patients with hepatitis C infection and cirrhosis. Additionally, the paper focuses on the disease burden, epidemiology, diagnosis and the disease course from infection to treatment. We provide an overview of multiple studies for the treatment of chronic hepatitis C infection that have included patients with cirrhosis. We also discuss the advantages and disadvantages of treatment in cirrhotic patients and focus on the most up to date guidelines available for treatment.展开更多
AIM To gather data on the antiviral efficacy and safety of second generation direct acting antiviral(DAA) treatment with respect to sustained virological response(SVR) 12 wk after conclusion of treatment, and to deter...AIM To gather data on the antiviral efficacy and safety of second generation direct acting antiviral(DAA) treatment with respect to sustained virological response(SVR) 12 wk after conclusion of treatment, and to determine predictors of SVR12 in this setting.METHODS Two hundred and sixty patients treated with SOF combination partners PR(n = 51), R(n = 10), SMV(n = 30), DCV(n = 81), LDV(n = 73), or 3D(n = 15).144/260 were pre-treated, 89/260 had liver cirrhosis, 56/260 had portal hypertension with platelets < 100/nL, 25/260 had a MELD score ≥ 10 and 17/260 were postliver transplantation patients. 194/260 had HCV GT1, 44/260 HCV GT3.RESULTS Two hundred and forty/256(93.7%) patients achieved SVR12(m ITT); 4/260 were lost to follow-up. SVR12 rates for subgroups were: 92% for SOF/DCV, 93% for each SOF/SMV, SOF/PR, 94% for SOF/LDV, 100% for 3D, 94% for pretreated, 87% for liver cirrhosis, 82% for patients with platelets < 100/n L, 88% post-liver transplantation, 95% for GT1 a, 93% for GT1 b, 90% for GT3, 100% for GT2, 4, and 6. 12 patients suffered from relapse, 6 prematurely discontinued treatment, of which 4 died. Negative predictors of SVR12 were a platelet count < 100/nL, MELD score ≥ 10(P < 0.0001), liver cirrhosis(P = 0.005) at baseline. In Interferonfree treatment GT3 had significantly lower SVR rates than GT1(P = 0.016). Side effects were mild. CONCLUSION Excellent SVR12 rates and the favorable side-effect profile of DAA-combination therapy can be well translated into "real-world". Patients with advanced liver disease, signs of portal hypertension, especially with platelets < 100/n L and patients with GT3 are in special need for further research efforts to overcome comparatively higher rates of virological failure.展开更多
AIM: To determine risk factors associated with hepatitis C virus(HCV) treatment failure after direct acting antivirals in patients with complex treatment histories.METHODS: All HCV mono-infected patients who received ...AIM: To determine risk factors associated with hepatitis C virus(HCV) treatment failure after direct acting antivirals in patients with complex treatment histories.METHODS: All HCV mono-infected patients who received treatment at our institution were queried.Analysis was restricted to patients who previously failed treatment with boceprevir(BOC) or telaprevir(TVR) and started simeprevir(SMV) and sofosbuvir(SOF) ± ribavirin(RBV) between December 2013 and June 2014. Patients with human immunodeficiency virus(HIV)/HCV co-infection or patients who received a liver transplant in the past were excluded. Viral loads were recorded while on treatment and after treatment. Data collection continued until December,31 st 2014 when data analysis was initiated. Patients missing virologic outcomes data were not included in the analysis. Analysis of 35 patients who had virologic outcome data available resulted in eight patients who were viral load negative at the end of treatment with SMF/SOF but later relapsed. Data related to patient demographics,HCV infection,and treatment history was collected in order to identify risk factors shared among patients who failed treatment with SMF/SOF.RESULTS: Eight patients who were treated with the first generation HCV protease inhibitors BOC or TVR in combination with pegylated-interferon(PEG) and RBV who failed this triple therapy were subsequently retreated with an off-label all-oral regimen of SMV and SOF for 12 wk,with RBV in seven cases. Treatment was initiated before the Food and Drug Administration approved a 24-wk SMV/SOF regimen for patients with liver cirrhosis. All eight patients had an end of treatment response,but later relapsed. Eight(100%) patients were male. Mean age was 56(range,49-64). Eight(100%) patients had previously failed PEG/RBV dual therapy at least once in addition to prior failure with triple therapy. Total number of times treated ranged from 3-6(mean 3.8). Eight(100%) patients were male had liver cirrhosis as determined by Fibroscan or MRI. Seven(87.5%) patients had genotype 1a HCV. Seven(87.5%) patients had over 1 million IU/m L HCV RNA at the time of re-treatment.CONCLUSION: This study identifies factors associated with SMV/SOF treatment failure and provides evidence that twleve weeks of SMV/SOF/RBV is insufficient in cirrhotics with high-titer genotype 1a HCV.展开更多
The year 2014 marked the beginning of the end of the interferon era and the triumph of the all-oral interferon-free regimens for treatment of hepatitis C virus(HCV) infection. These innovative therapies are safe and y...The year 2014 marked the beginning of the end of the interferon era and the triumph of the all-oral interferon-free regimens for treatment of hepatitis C virus(HCV) infection. These innovative therapies are safe and yield a cure rate of over 90%. The scientifichepatology community is euphoric about the possibility of elimination and even eradication of HCV infection. However,the current high cost of the new all-oral regimens allows access to treatment only for a restricted number of HCV-infected patients. In addition,many other conditions such as modality of access and delivery of care,inadequate knowledge of HCV epidemiology and political commitments to be undertaken,hamper the fulfillment of the dream to eliminate the virus. Since,such conditions are not impossible to overcome,a global urgent effort must be made to allow a widespread access to the new treatments which will permit in the next years to avoid million of HCV-related deaths.展开更多
Hepatitis C is an infection caused by the hepatitis C virus that attacks the liver and leads to inflammation. The current standard-of-care regimens include a protease inhibitor—telaprevir or boceprevir—in combinatio...Hepatitis C is an infection caused by the hepatitis C virus that attacks the liver and leads to inflammation. The current standard-of-care regimens include a protease inhibitor—telaprevir or boceprevir—in combination with pegylated interferon and ribavirin. Hepatitis?C treatment options on the horizon hold promise for better viral clearance with less toxicity than current regimens. There are new data about new drugs, both direct-acting antivirals while minimizing intolerable side effects or adverse events. Developed new data from 4 phase 3 trials with the hepatitis C drug sofosbuvir and ribavirin show that a 12-week regimen is effective in treating HCV genotypes 1 through 6. In the Annual Scientific Meeting and Postgraduate Course of the American College of Gastroenterology, different research was presented that was drawn from 4 phase 3 studies: NEUTRINO, FISSION, POSITRON and FUSION which enrolled different types of patients, who received Sofosbuvir with Peginterferon Alfa 2a and Ribavirin for 12 or 24 weeks in treatment;for all studies, the primary end point was sustained virologic response at 12 and 24 weeks posttreatment. In all studies, sofosbuvir was well tolerated, with a low incidence of adverse events. In conjunction with the suggested brief duration of this regimen, this indicates that drug combinations should improve treatment adherence compared with IFN-based treatment. In conclusion, 2 novel direct-acting antiviral agents—sofosbuvir and simeprevir—target various components of the HCV genome. Advantages of these drugs include a high barrier to viral resistance, a shorter duration of treatment, once-daily dosing, absence of food restrictions, few clinically significant drug interactions, and similar efficacy in all genotypes.展开更多
The first interferon-free regimens have been approved for the treatment of patients with chronic hepatitis C virus(HCV). In the liver transplant(LT) setting, these regimens are expected to have an important effect, be...The first interferon-free regimens have been approved for the treatment of patients with chronic hepatitis C virus(HCV). In the liver transplant(LT) setting, these regimens are expected to have an important effect, because graft loss due to HCV recurrence is a serious problem after LT. The response to the hitherto conventional treatment with pegylated interferon and ribavirin is poor. The significantly better responserates achieved with boceprevir-based and telaprevirbased triple therapy have led to better graft and patient survival rates, but severe drug interactions with immunosuppressants limit the feasibility of this therapy for LT patients. With the approval of sofosbuvir in January 2014, of simeprevir in May 2014, and of daclatasvir in August 2014, three antiviral agents are now available and promise to be applicable without relevant adverse effects or negative interactions with immunosuppressants. Thus, 2014 marks the beginning of a new era of treatment options for HCV recurrence after LT. Although safety and efficacy studies of several interferon-free regimens for patients with HCV recurrence after LT have achieved good preliminary results, reports of clinical experiences with LT patients are scarce. The lack of randomized studies, the small number of enrolled and carefully selected patients, and the heterogeneity of these studies make the results questionable. Real-life experiences are eagerly awaited so that clinicians can estimate the usefulness and the pitfalls of these new regimens. Additionally, the high costs of these agents may limit their accessibility for many patients. The aim of this review is to summarize the current experience with and the expectations of the new direct-acting antiviral agents for LT patients.展开更多
The first generation direct antiviral agents(DAAs) highlighted substantial prognosis improvement among liver transplant(LT) candidates and recipients with recurrent hepatitis C virus(HCV) infection. During2014, second...The first generation direct antiviral agents(DAAs) highlighted substantial prognosis improvement among liver transplant(LT) candidates and recipients with recurrent hepatitis C virus(HCV) infection. During2014, second generation DAAs are associated with high sustained virological response rates(> 95%), shortened duration courses and relatively few toxicities. In keeping with the currently available data, patients with decompensated cirrhosis awaiting LT is preferable to be treated with interferon-free, new generation DAAs, with or without ribavirin combinations. Although data about the safety of new DAAs combinations in this patient population are limited, sofosbuvir and daclatasvir pharmacokinetics do not appear to change significantly in moderate or severe liver impairment, while other new DAAs(simeprevir, asunaprevir) seem to be contraindicated in patients with severe liver impairment(Child-Pugh class C). On the other hand, sofosbuvir should not be given in patients with glomerular filtration rate ≤ 30 m L/min, but ongoing trials will clarify better this issue. With the objective that newer antiviral combinations will yield safer and more efficient manipulation of HCV recurrence posttransplant, the European Association for the Study of the Liver has recently updated its recommendations towards this direction. Nevertheless the new antivirals' high cost may be the biggest challenge to their implementation worldwide.展开更多
Hepatitis C virus (HCV) is a leading cause of cirrhosis and hepatocellular carcinoma (HCC) in the US and Japan.Therefore,eradication of HCV may reduce the occurrence of HCC in HCV-infected individuals.In 2011,the use ...Hepatitis C virus (HCV) is a leading cause of cirrhosis and hepatocellular carcinoma (HCC) in the US and Japan.Therefore,eradication of HCV may reduce the occurrence of HCC in HCV-infected individuals.In 2011,the use of firstgeneration HCV NS3/4A protease inhibitors such as telaprevir and boceprevir was initiated for clinical treatment of HCV.Administration of telaprevir and boceprevir plus peginterferon and ribavirin increased rates of sustained virological response (SVR) in HCV genotype 1-infected patients.However,this treatment regimen also led to severe adverse events.Second-generation direct-acting antiviral agents (DAAs) for HCV,such as simeprevir plus peg-interferon and ribavirin also resulted in higher SVR rates,with similar adverse events to other peg-interferon and ribavirin treatments.Higher SVR rates in HCV genotype 1-and 2-infected patients were achieved with 12-16 weeks of sofosbuvir plus other class DAAs with/without ribavirin and 12 weeks of sofosbuvir plus ribavirin,respectively,For "difficult-to-treat"HCV-infected patients,more therapeutic options are needed.Further studies examining the efficacy and adverse effects of such therapies will be required for the development of additional treatments.展开更多
文摘AIM: To compare efficacy of telaprevir(TVR) and simeprevir(SMV) combined with pegylated interferon(PEG-IFN) and ribavirin(RBV) while treating chronic hepatitis C(CHC). METHODS: In all, 306 CHC patients were included in this study. There were 159 patients in the TVR combination therapy group and 147 patients in the SMV combination therapy group. To evaluate pretreatment factors contributing to sustained virological response at 12 wk(SVR12), univariate and multivariate analyses were performed in TVR and SMV groups. To adjust for patient background between TVR and SMV groups, propensity score matching was performed. Virological response during treatment and SVR12 were evaluated.RESULTS: Overall rates of SVR12 [undetectable serum hepatitis C virus(HCV) RNA levels] were 79.2% and 69.4% in TVR and SMV groups, respectively. Patients in the SMV group were older, had higher serum HCV RNA levels, lower hemoglobin, higher prevalence of unfavorable interleukin-28B(IL28B) genotype(rs8099917), and poorer response to previous PEG-IFN and RBV treatment. Propensity score matching was performed to adjust for backgrounds(n = 104) and demonstrated SVR12 rates of 74.0% and 73.1% in the TVR and SMV groups, respectively. In the TVR group, discontinuation rates were higher because of adverse events; however, breakthrough and nonresponse was more frequent in the in SMV group. Multivariate analysis revealed IL28 B genotype(rs8099917) as the only independent predictive factor of SVR12 in both groups.CONCLUSION: SVR12 rates were almost identical following propensity score matching.
基金Supported by Grants-in-Aid for Scientific Research(C)(to Yamagiwa S)from Japan Society for the Promotion of Science(JSPS),No.15K08991
文摘AIM To evaluate and compare the efficacy and safety of telaprevir(TVR)-and simeprevir(SMV)-based triple therapies in elderly patients, specifically patients aged 66 years or older.METHODS The present study enrolled 112 and 76 Japanese patients with chronic hepatitis C virus genotype 1b infection who were treated with a 12-wk TVR-based or SMV-based triple therapy, respectively, followed by a dual therapy that included pegylated interferon α and ribavirin(RBV) for 12 wk. The patients were categorized into two groups according to age as follows: A younger group of patients aged ≤ 65 years old and an older group of patients aged > 65 years old. Among the patients treated with TVR-based triple therapy, 34 patients were included in the older group. The median ages were 56 years(range: 28-65 years) in the younger group and 69 years(range: 66-81 years) in the older group. Among the patients treated with SMV-based triple therapy, 39 patients were included in the older group. The median ages were 59 years(range: 36-65 years) in the younger group and 71 years(range: 66-86 years) in the older group. The clinical, biochemical and virological data were analyzed before and during treatment.RESULTS Among the patients treated with the TVR-based triple therapy, no significant difference in the sustained virological response(SVR) was found between the younger(80.8%) and older(88.2%) groups. The SVR rates for patients with the interleukin 28B(IL28B)(rs8099917) TG/GGgenotypes(73.9% and 60.0% in the younger and older groups, respectively) were significantly lower than for patients with the IL28B TT-genotype(86.3% and 92.9%, respectively). The cumulative exposure to RBV for the entire 24-wk treatment period(as a percentage of the target dose) was significantly higher in the younger group than in the older group(91.7% vs 66.7%, respectively, P < 0.01), but the cumulative exposure to TVR was not significantly different between the younger and older groups(91.6% vs 81.9%, respectively). A multivariate analysis identified the TT-genotype of IL28B(OR = 8.160; 95%CI: 1.593-41.804, P = 0.012) and the adherence of RBV(> 60%)(OR = 11.052; 95%CI: 1.160-105.273, P = 0.037) as independent factors associated with the SVR. Adverse events resulted in discontinuation of the treatment in 11.3% and 14.7% of the younger and older groups, respectively. Among the patients treated with the SMV-based triple therapy, no significant difference in the SVR rare was found between the younger(81.1%) and older(82.1%) groups. The SVR rates for patients with the IL28B TG/GG-genotypes(77.8% and 64.7% in the younger and older groups, respectively) were significantly lower than for patients with the IL28 B TT-genotype(88.2% and 100%, respectively). A multivariate analysis identified the TT-genotype of IL28B as an independent factor associated with the SVR(OR = 9.677; 95%CI:1.114-84.087, P = 0.040). Adverse events resulted in discontinuation of the treatment in 7.0% and 14.3% of patients in the younger and older groups, respectively.CONCLUSION Both TVR- and SMV-based triple therapies can be successfully used to treat patients aged 66 years or older with genotype 1b chronic hepatitis C. Genotyping of the IL28B indicates a potential to achieve SVR in these difficult-to-treat elderly patients.
文摘Background and Aims: Treatment with a combination of the nucleotide polymerase inhibitor sofosbuvir and NS3A (non-structural protein 3A) protease inhibitor simeprevir resulted in high rates of sustained virological response in chronic hepatitis C Genotype 4. Methods: We conducted a real life study on Egyptian patients coming to tropical medicine department clinic at El Mery main university hospital from February 2015 to February 2016 for treatment naive and treatment experienced patients with chronic HCV genotype 4, including cirrhotics and non cirrhotics. Naive (cir-rhotics and non cirrhotics) and relapsers (non cirrhotics) received nucleotide polymerase inhibitor sofosbuvir and NS3A inhibitor simeprevir once daily for 12 weeks and 24 weeks for relapser cirrhotic patients. The primary end point was a sustained virologic response at 12 weeks after end of treatment. An informed consent was obtained from each patient at the beginning of the study (Real life study: a study on Egyptian patients when the drug was available in the market). Results: 30 naive patients with HCV genotype 4 and 20 relapsers (10 non cirrhotic and 10 cirrhotic patients) were enrolled. Patient inclusion criteria: Naive patients are those who tested positive for HCV RNA by PCR and had no experience to HCV treatment;Relapsers are those who tested positive for HCV RNA by PCR and had a previous treatment for HCV. Cirrhosis was diagnosed on ultrasound basis. Mean age was 53.57 ± 10.682 years old in naive patients and 48.30 ± 5.100 years old in relapsers. Median baseline HCV RNA was 360,069 IU/mL for naive patients and 1,245,000 IU/mL for relapsers;using Fib4 20% of naive patients were F3-F4, while 40% of relapsers were F3-F4. Degree of fibrosis was confirmed by fibrotest in relapsers. Upon treatment of patients with sofosbuvir and semiprevir once daily for 12 weeks and 24 weeks only to cirrhotic relapsers, end of treatment PCR was negative in 100% in all groups including cirrhotics and non cirrhotics. Primary end point (SVR 12) was achieved in 100% of all patients. Second end point (SVR 24) was achieved in 96.6% of naive pa-ients;SVR 24 for non-cirrhotic relapsers was achieved in 100% of patients and in 90% of cirrhotic relapsers. One patient had transient total bilirubin elevations without increased ALT (alanine aminotransferase) or AST (aspartate aminotransferase). One patient developed cutaneous rash. Conclusion: Once daily sofosbuvir and simeprevir for 12 weeks provided high rate of sustained virological response among treatment naive and treatment experienced patients with HCV genotype IV.
文摘The effectiveness of hepatitis C treatment has improved with the development of interferon(IFN),and it has drastically improved with the development of peg-interferon-α(PEG-IFN) in combination with ribavirin(RBV) and,more recently,with the addition of a protease inhibitor.Simeprevir,which is a secondgeneration protease inhibitor,has shown clinically favorable safety and tolerability profiles.Simeprevir received its first global approval in Japan in September 2013 for the treatment of genotype 1 chronic hepatitis C in combination with PEG-IFN and RBV.One serious adverse event associated with IFN therapy is interstitialpneumonitis,which can be fatal.We experienced a patient with interstitial pneumonitis that was induced by simeprevir with PEG-IFN and RBV therapy for chronic hepatitis C in the early stages of therapy(8 wk after initiating therapy).This is the first case report of interstitial pneumonitis with simeprevir with PEG-IFN and RBV in the world.In addition,it is very interesting that the onset of interstitial pneumonitis was earlier than that in conventional PEG-IFN and RBV therapy.This finding suggests that simeprevir augments the adverse event.We present this case report in light of relevant literature on interstitial pneumonitis with conventional PEG-IFN and RBV therapy.
文摘Objectives: To identify local resource use such as pharmaceutical treatment, medical follow-up, and patient hospitalization and estimate the budget impact of simeprevir (SMV) plus pegylated interferon (P)/ribavirin (R) as a treatment option in the early stages of the disease in Greece. Methods: A budget impact tool was developed with a two-year time horizon, which estimated the impact on the Social Insurance Funds (SIFs) of introducing SMV + PR in the management of the early disease stages. Total direct and indirect costs were estimated for each of the following health states: non-cirrhotic chronic Hepatitis C (and within that by fibrosis stage), compensated cirrhosis, decompensated cirrhosis, and hepatocellular carcinoma. Data gaps on treatment algorithms, resource use and productivity losses were covered via an expert panel of eight leading hepatologists. Epidemiology data were taken from the published literature. Unit costs were obtained from the Ministry of Health and SIFs. The perspective was that of the SIF and the cost base year was 2015. Results: The total (direct and indirect) cost per patient per year (excluding cost of antiviral treatment) was estimated at €647, €703, €5,753, €16,313 and €37,237 for non-cirrhotic CHC, compensated cirrhosis, decompensated cirrhosis, HCC and liver transplantation, respectively. The budget impact analysis showed that adding SMV to PR in the early stages of the disease would lead to an increase in the cost of antiviral treatment by €2.03 million. Conclusions: Costs of managing CHC increase dramatically with disease severity. SMV + PR for naive patients at early disease stages has a significant but manageable budget impact, and could prevent high costs in advanced stages.
文摘Over the last years it has started a real revolution in the treatment of chronic hepatitis C. This occurred for the availability of direct-acting antiviral agents that allow to reach sustained virologic response in approximately 90% of cases. In the near future further progress will be achieved with the use of pan-genotypic drugs with high efficacy but without side effects.
文摘Due to the progressive aging of the hepatitis C virus(HCV) population which have acquired the infection during its maximum spread after the Second World War, the management of the elderly HCV-infected patient is emerging as a hot topic. Unfortunately, although it is recognized that the progression of HCV-related liver disease gets faster with aging, and that even extrahepatic manifestations of HCV infection are probably worse in the elderly, till now, treatment attempts in this population have been significantly limited by the wellknown contraindications and side effects of interferon(IFN). The arrival of several new anti-HCV drugs, and the possibility to combine them in safe and effective anti-viral regimens, is relighting the hope of a cure for many elderly patients who had been cut out of IFN-based treatments. However, although these new regimens will be certainly more manageable, it should be underscored that IFN-free doesn't mean free from any contraindication or side-effect. Moreover, one issue which promises to become central is that of the possible interactions between antiviral therapy and the multiple drugs frequently assumed by elderly patients because of comorbidities. In this review, we will revise the epidemiology pointing to HCV as an infection of the elderly, the evidences that HCV harms the health of the aged patient more than that of the young one, and the available experiences of HCV treatment in the elderly with the "old" IFN-based regimens and with the newer drugs. We will conclude that the availability of IFNfree regimens should prompt us to change our mind and consider a significantly larger number of possible candidates among elderly patients, who would take significant advantage from viral eradication. Rather than the anagraphic age, drug-drug interactions and, mainly in case of economic restrictions, an evaluation of life expectancy dependent on liver disease with respect to that dependent on comorbidities, are likely to be the key issues guiding treatment indication in the next future. The sooner we will change our mind with respect to an a priori obstacle for anti-HCV treatment in the elderly, the sooner we will begin to spare many aged HCV patients from avoidable liver-related complications.
文摘Chronic hepatitis C infection is the leading cause of chronic liver disease, cirrhosis, hepatocellular carcinoma as well as the primary indication for liver transplantation in the United States. Despite recent advances in drugs for the treatment of hepatitis C, predictive models estimate the incidence of cirrhosis due to hepatitis C infection will to continue to rise for the next two decades. There is currently an immense interest in the treatment of patients with fibrosis and early-stage cirrhosis as treatment can lead to decrease in the rates of decompensated cirrhosis, hepatocellular carcinoma and need for liver transplantation in these patients. The goal of this paper is to provide clinicians and health care professionals further information about the treatment of patients with hepatitis C infection and cirrhosis. Additionally, the paper focuses on the disease burden, epidemiology, diagnosis and the disease course from infection to treatment. We provide an overview of multiple studies for the treatment of chronic hepatitis C infection that have included patients with cirrhosis. We also discuss the advantages and disadvantages of treatment in cirrhotic patients and focus on the most up to date guidelines available for treatment.
文摘AIM To gather data on the antiviral efficacy and safety of second generation direct acting antiviral(DAA) treatment with respect to sustained virological response(SVR) 12 wk after conclusion of treatment, and to determine predictors of SVR12 in this setting.METHODS Two hundred and sixty patients treated with SOF combination partners PR(n = 51), R(n = 10), SMV(n = 30), DCV(n = 81), LDV(n = 73), or 3D(n = 15).144/260 were pre-treated, 89/260 had liver cirrhosis, 56/260 had portal hypertension with platelets < 100/nL, 25/260 had a MELD score ≥ 10 and 17/260 were postliver transplantation patients. 194/260 had HCV GT1, 44/260 HCV GT3.RESULTS Two hundred and forty/256(93.7%) patients achieved SVR12(m ITT); 4/260 were lost to follow-up. SVR12 rates for subgroups were: 92% for SOF/DCV, 93% for each SOF/SMV, SOF/PR, 94% for SOF/LDV, 100% for 3D, 94% for pretreated, 87% for liver cirrhosis, 82% for patients with platelets < 100/n L, 88% post-liver transplantation, 95% for GT1 a, 93% for GT1 b, 90% for GT3, 100% for GT2, 4, and 6. 12 patients suffered from relapse, 6 prematurely discontinued treatment, of which 4 died. Negative predictors of SVR12 were a platelet count < 100/nL, MELD score ≥ 10(P < 0.0001), liver cirrhosis(P = 0.005) at baseline. In Interferonfree treatment GT3 had significantly lower SVR rates than GT1(P = 0.016). Side effects were mild. CONCLUSION Excellent SVR12 rates and the favorable side-effect profile of DAA-combination therapy can be well translated into "real-world". Patients with advanced liver disease, signs of portal hypertension, especially with platelets < 100/n L and patients with GT3 are in special need for further research efforts to overcome comparatively higher rates of virological failure.
基金Supported by The Grants No.R01 DK090317 and No.R01 DA031095(in part)
文摘AIM: To determine risk factors associated with hepatitis C virus(HCV) treatment failure after direct acting antivirals in patients with complex treatment histories.METHODS: All HCV mono-infected patients who received treatment at our institution were queried.Analysis was restricted to patients who previously failed treatment with boceprevir(BOC) or telaprevir(TVR) and started simeprevir(SMV) and sofosbuvir(SOF) ± ribavirin(RBV) between December 2013 and June 2014. Patients with human immunodeficiency virus(HIV)/HCV co-infection or patients who received a liver transplant in the past were excluded. Viral loads were recorded while on treatment and after treatment. Data collection continued until December,31 st 2014 when data analysis was initiated. Patients missing virologic outcomes data were not included in the analysis. Analysis of 35 patients who had virologic outcome data available resulted in eight patients who were viral load negative at the end of treatment with SMF/SOF but later relapsed. Data related to patient demographics,HCV infection,and treatment history was collected in order to identify risk factors shared among patients who failed treatment with SMF/SOF.RESULTS: Eight patients who were treated with the first generation HCV protease inhibitors BOC or TVR in combination with pegylated-interferon(PEG) and RBV who failed this triple therapy were subsequently retreated with an off-label all-oral regimen of SMV and SOF for 12 wk,with RBV in seven cases. Treatment was initiated before the Food and Drug Administration approved a 24-wk SMV/SOF regimen for patients with liver cirrhosis. All eight patients had an end of treatment response,but later relapsed. Eight(100%) patients were male. Mean age was 56(range,49-64). Eight(100%) patients had previously failed PEG/RBV dual therapy at least once in addition to prior failure with triple therapy. Total number of times treated ranged from 3-6(mean 3.8). Eight(100%) patients were male had liver cirrhosis as determined by Fibroscan or MRI. Seven(87.5%) patients had genotype 1a HCV. Seven(87.5%) patients had over 1 million IU/m L HCV RNA at the time of re-treatment.CONCLUSION: This study identifies factors associated with SMV/SOF treatment failure and provides evidence that twleve weeks of SMV/SOF/RBV is insufficient in cirrhotics with high-titer genotype 1a HCV.
文摘The year 2014 marked the beginning of the end of the interferon era and the triumph of the all-oral interferon-free regimens for treatment of hepatitis C virus(HCV) infection. These innovative therapies are safe and yield a cure rate of over 90%. The scientifichepatology community is euphoric about the possibility of elimination and even eradication of HCV infection. However,the current high cost of the new all-oral regimens allows access to treatment only for a restricted number of HCV-infected patients. In addition,many other conditions such as modality of access and delivery of care,inadequate knowledge of HCV epidemiology and political commitments to be undertaken,hamper the fulfillment of the dream to eliminate the virus. Since,such conditions are not impossible to overcome,a global urgent effort must be made to allow a widespread access to the new treatments which will permit in the next years to avoid million of HCV-related deaths.
文摘Hepatitis C is an infection caused by the hepatitis C virus that attacks the liver and leads to inflammation. The current standard-of-care regimens include a protease inhibitor—telaprevir or boceprevir—in combination with pegylated interferon and ribavirin. Hepatitis?C treatment options on the horizon hold promise for better viral clearance with less toxicity than current regimens. There are new data about new drugs, both direct-acting antivirals while minimizing intolerable side effects or adverse events. Developed new data from 4 phase 3 trials with the hepatitis C drug sofosbuvir and ribavirin show that a 12-week regimen is effective in treating HCV genotypes 1 through 6. In the Annual Scientific Meeting and Postgraduate Course of the American College of Gastroenterology, different research was presented that was drawn from 4 phase 3 studies: NEUTRINO, FISSION, POSITRON and FUSION which enrolled different types of patients, who received Sofosbuvir with Peginterferon Alfa 2a and Ribavirin for 12 or 24 weeks in treatment;for all studies, the primary end point was sustained virologic response at 12 and 24 weeks posttreatment. In all studies, sofosbuvir was well tolerated, with a low incidence of adverse events. In conjunction with the suggested brief duration of this regimen, this indicates that drug combinations should improve treatment adherence compared with IFN-based treatment. In conclusion, 2 novel direct-acting antiviral agents—sofosbuvir and simeprevir—target various components of the HCV genome. Advantages of these drugs include a high barrier to viral resistance, a shorter duration of treatment, once-daily dosing, absence of food restrictions, few clinically significant drug interactions, and similar efficacy in all genotypes.
文摘The first interferon-free regimens have been approved for the treatment of patients with chronic hepatitis C virus(HCV). In the liver transplant(LT) setting, these regimens are expected to have an important effect, because graft loss due to HCV recurrence is a serious problem after LT. The response to the hitherto conventional treatment with pegylated interferon and ribavirin is poor. The significantly better responserates achieved with boceprevir-based and telaprevirbased triple therapy have led to better graft and patient survival rates, but severe drug interactions with immunosuppressants limit the feasibility of this therapy for LT patients. With the approval of sofosbuvir in January 2014, of simeprevir in May 2014, and of daclatasvir in August 2014, three antiviral agents are now available and promise to be applicable without relevant adverse effects or negative interactions with immunosuppressants. Thus, 2014 marks the beginning of a new era of treatment options for HCV recurrence after LT. Although safety and efficacy studies of several interferon-free regimens for patients with HCV recurrence after LT have achieved good preliminary results, reports of clinical experiences with LT patients are scarce. The lack of randomized studies, the small number of enrolled and carefully selected patients, and the heterogeneity of these studies make the results questionable. Real-life experiences are eagerly awaited so that clinicians can estimate the usefulness and the pitfalls of these new regimens. Additionally, the high costs of these agents may limit their accessibility for many patients. The aim of this review is to summarize the current experience with and the expectations of the new direct-acting antiviral agents for LT patients.
文摘The first generation direct antiviral agents(DAAs) highlighted substantial prognosis improvement among liver transplant(LT) candidates and recipients with recurrent hepatitis C virus(HCV) infection. During2014, second generation DAAs are associated with high sustained virological response rates(> 95%), shortened duration courses and relatively few toxicities. In keeping with the currently available data, patients with decompensated cirrhosis awaiting LT is preferable to be treated with interferon-free, new generation DAAs, with or without ribavirin combinations. Although data about the safety of new DAAs combinations in this patient population are limited, sofosbuvir and daclatasvir pharmacokinetics do not appear to change significantly in moderate or severe liver impairment, while other new DAAs(simeprevir, asunaprevir) seem to be contraindicated in patients with severe liver impairment(Child-Pugh class C). On the other hand, sofosbuvir should not be given in patients with glomerular filtration rate ≤ 30 m L/min, but ongoing trials will clarify better this issue. With the objective that newer antiviral combinations will yield safer and more efficient manipulation of HCV recurrence posttransplant, the European Association for the Study of the Liver has recently updated its recommendations towards this direction. Nevertheless the new antivirals' high cost may be the biggest challenge to their implementation worldwide.
文摘Hepatitis C virus (HCV) is a leading cause of cirrhosis and hepatocellular carcinoma (HCC) in the US and Japan.Therefore,eradication of HCV may reduce the occurrence of HCC in HCV-infected individuals.In 2011,the use of firstgeneration HCV NS3/4A protease inhibitors such as telaprevir and boceprevir was initiated for clinical treatment of HCV.Administration of telaprevir and boceprevir plus peginterferon and ribavirin increased rates of sustained virological response (SVR) in HCV genotype 1-infected patients.However,this treatment regimen also led to severe adverse events.Second-generation direct-acting antiviral agents (DAAs) for HCV,such as simeprevir plus peg-interferon and ribavirin also resulted in higher SVR rates,with similar adverse events to other peg-interferon and ribavirin treatments.Higher SVR rates in HCV genotype 1-and 2-infected patients were achieved with 12-16 weeks of sofosbuvir plus other class DAAs with/without ribavirin and 12 weeks of sofosbuvir plus ribavirin,respectively,For "difficult-to-treat"HCV-infected patients,more therapeutic options are needed.Further studies examining the efficacy and adverse effects of such therapies will be required for the development of additional treatments.
