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
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
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
AIM: To address the therapeutic efficacy of various treatment regimens in genotype 3 selecting randomized clinical trials and prospective National Cohort Studies.METHODS:(1) PEG-INF-based therapy including sofosbuvir(...AIM: To address the therapeutic efficacy of various treatment regimens in genotype 3 selecting randomized clinical trials and prospective National Cohort Studies.METHODS:(1) PEG-INF-based therapy including sofosbuvir(SOF) + RBV for 12 wk vs SOF + RBV 24 wk;(2) SOF + RBV therapy 12 wk/16 wk vs 24 wk; and(3) the role of RBV in SOF + daclatasvir(DCV) and SOF + ledipasvir(LDV) combinations. This metaanalysis provides robust information with the intention of addressing treatment strategy for hepatitis C virus genotype 3.RESULTS: A combination treatment including SOF + RBV + PEG-IFN for 12 wk notes better SVR than with only SOF + RBV for 12 wk, although its association with more frequent adverse effects may be a limiting factor. Longer duration therapy with SOF + RBV(24 wk) has achieved higher SVR rates than shorter durations(12 or 16 wk). SOF + LDV are not an ideal treatment for genotype 3. CONCLUSION: Lastly, SOF + DCV combination is probably the best oral therapy option and the addition of RBV does not appear to be needed to increase SVR rates substantially.展开更多
AIM To investigate the influence of interferon-free antivirus therapy on lipid profiles in chronic hepatitis C virus genotype 1b(HCV1b) infection.METHODS Interferon-free antiviral agents were used to treat 276 patient...AIM To investigate the influence of interferon-free antivirus therapy on lipid profiles in chronic hepatitis C virus genotype 1b(HCV1b) infection.METHODS Interferon-free antiviral agents were used to treat 276 patients with chronic HCV1 b infection, and changes in serum lipids of those who achieved sustained virologic response(SVR) were examined. The treatment regimen included 24 wk of daclatasvir plus asunaprevir(DCV + ASV) or 12 wk of sofosbuvir plus ledipasvir(SOF + LDV). SVR was achieved in 121(85.8%) of 141 patients treated with DCV + ASV and 132(97.8%) of 135 patients treated with SOF + LDV. In the two patient groups(DCV + ASV-SVR and SOF + LDV-SVR), serum total cholesterol(TC), low-density lipoprotein cholesterol(LDL-C), high-density lipoprotein cholesterol(HDL-C), and triglycerides were measured at baseline during treatment and at 4 and 12 wk after treatment. Then, longitudinal changes in lipid profiles were analyzed.RESULTS Serum levels of TC, LDL-C, and HDL-C were significantly increased throughout the observation period in both the DCV + ASV-SVR and SOF + LDV-SVR groups. During antivirus treatment, the increases in TC and LDL-C were significantly greater in the SOF + LDVSVR group than in the DCV + ASV-SVR group(P < 0.001). At 4 and 12 wk after the therapy, serum levels of TC and LDL-C were similar between the two groups and were significantly greater than those at baseline. Approximately 75%-80% of the increase in TC was derived from an increased LDL-C. In multiple regression analysis, the difference in therapy protocol(DCA + ASV or SOF + LDV) was an independent predictor that was significantly associated with the increase in TC and LDL-C at 4 wk of therapy.CONCLUSION Serum cholesterol significantly increased during SOF + LDV treatment. After treatment, HCV elimination was associated with a similar increase in cholesterol regardless of the therapy protocol.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
Nucleotide compounds like sofosbuvir,acyclovir,and tenofovir have proven to be amongst the most potent orally available antiviral treatments.These drugs exhibit high efficacy and a wide therapeutic index,with demonstr...Nucleotide compounds like sofosbuvir,acyclovir,and tenofovir have proven to be amongst the most potent orally available antiviral treatments.These drugs exhibit high efficacy and a wide therapeutic index,with demonstrated utility in a number of chronic viral infections.The approval of SovaldiTM,brand name for sofosbuvir,by the U.S.Food and Drug Administration heralded improvements in chronic hepatitis C virus (HCV) treatment.Sofosbuvir was originally discovered by Pharmasset Corporation and named PSI-7977.It was subsequently acquired and advanced through phase 3 development by Gilead Sciences,Inc.In Sofosbuvir both a unique pharmacology and a high specificity for the HCV ribonucleic acid polymerase are present in a molecule that is well tolerated and highly efficacious.Phase 2 and 3 clinical trials have consistently demonstrated durable and high rates of sustained virologic response (SVR),curing patients in excess of 80% in all genotypes and >90% in treatment-na(i)ve subjects being administered combination therapy with other agents.Harvoni~ is the combination of sofosbuvir and the NS5A inhibitor ledipasvir in a fixed-dose oral tablet,and it has demonstrated high SVR rates in patients infected with HCV genotype 1,without the need for exogenous interferon and/or ribavirin.Here,we discuss the discovery,development,pharmacologic characterization,and results from the phase 3 trials of sofosbuvir.Hepatitis C is a chronic disease,for which most patients have been undiagnosed,are unwilling to start treatment,or are ineligible for treatment because of the high toxicity and low efficacy of interferon and ribavirin-based therapy.Clinical studies with sofosbuvir have demonstrated significant improvement over the prior standard of care,thus ushering in a new paradigm of HCV treatment and an update of treatment guidelines.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AIM: To address the therapeutic efficacy of various treatment regimens in genotype 3 selecting randomized clinical trials and prospective National Cohort Studies.METHODS:(1) PEG-INF-based therapy including sofosbuvir(SOF) + RBV for 12 wk vs SOF + RBV 24 wk;(2) SOF + RBV therapy 12 wk/16 wk vs 24 wk; and(3) the role of RBV in SOF + daclatasvir(DCV) and SOF + ledipasvir(LDV) combinations. This metaanalysis provides robust information with the intention of addressing treatment strategy for hepatitis C virus genotype 3.RESULTS: A combination treatment including SOF + RBV + PEG-IFN for 12 wk notes better SVR than with only SOF + RBV for 12 wk, although its association with more frequent adverse effects may be a limiting factor. Longer duration therapy with SOF + RBV(24 wk) has achieved higher SVR rates than shorter durations(12 or 16 wk). SOF + LDV are not an ideal treatment for genotype 3. CONCLUSION: Lastly, SOF + DCV combination is probably the best oral therapy option and the addition of RBV does not appear to be needed to increase SVR rates substantially.
文摘AIM To investigate the influence of interferon-free antivirus therapy on lipid profiles in chronic hepatitis C virus genotype 1b(HCV1b) infection.METHODS Interferon-free antiviral agents were used to treat 276 patients with chronic HCV1 b infection, and changes in serum lipids of those who achieved sustained virologic response(SVR) were examined. The treatment regimen included 24 wk of daclatasvir plus asunaprevir(DCV + ASV) or 12 wk of sofosbuvir plus ledipasvir(SOF + LDV). SVR was achieved in 121(85.8%) of 141 patients treated with DCV + ASV and 132(97.8%) of 135 patients treated with SOF + LDV. In the two patient groups(DCV + ASV-SVR and SOF + LDV-SVR), serum total cholesterol(TC), low-density lipoprotein cholesterol(LDL-C), high-density lipoprotein cholesterol(HDL-C), and triglycerides were measured at baseline during treatment and at 4 and 12 wk after treatment. Then, longitudinal changes in lipid profiles were analyzed.RESULTS Serum levels of TC, LDL-C, and HDL-C were significantly increased throughout the observation period in both the DCV + ASV-SVR and SOF + LDV-SVR groups. During antivirus treatment, the increases in TC and LDL-C were significantly greater in the SOF + LDVSVR group than in the DCV + ASV-SVR group(P < 0.001). At 4 and 12 wk after the therapy, serum levels of TC and LDL-C were similar between the two groups and were significantly greater than those at baseline. Approximately 75%-80% of the increase in TC was derived from an increased LDL-C. In multiple regression analysis, the difference in therapy protocol(DCA + ASV or SOF + LDV) was an independent predictor that was significantly associated with the increase in TC and LDL-C at 4 wk of therapy.CONCLUSION Serum cholesterol significantly increased during SOF + LDV treatment. After treatment, HCV elimination was associated with a similar increase in cholesterol regardless of the therapy protocol.
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.
文摘Nucleotide compounds like sofosbuvir,acyclovir,and tenofovir have proven to be amongst the most potent orally available antiviral treatments.These drugs exhibit high efficacy and a wide therapeutic index,with demonstrated utility in a number of chronic viral infections.The approval of SovaldiTM,brand name for sofosbuvir,by the U.S.Food and Drug Administration heralded improvements in chronic hepatitis C virus (HCV) treatment.Sofosbuvir was originally discovered by Pharmasset Corporation and named PSI-7977.It was subsequently acquired and advanced through phase 3 development by Gilead Sciences,Inc.In Sofosbuvir both a unique pharmacology and a high specificity for the HCV ribonucleic acid polymerase are present in a molecule that is well tolerated and highly efficacious.Phase 2 and 3 clinical trials have consistently demonstrated durable and high rates of sustained virologic response (SVR),curing patients in excess of 80% in all genotypes and >90% in treatment-na(i)ve subjects being administered combination therapy with other agents.Harvoni~ is the combination of sofosbuvir and the NS5A inhibitor ledipasvir in a fixed-dose oral tablet,and it has demonstrated high SVR rates in patients infected with HCV genotype 1,without the need for exogenous interferon and/or ribavirin.Here,we discuss the discovery,development,pharmacologic characterization,and results from the phase 3 trials of sofosbuvir.Hepatitis C is a chronic disease,for which most patients have been undiagnosed,are unwilling to start treatment,or are ineligible for treatment because of the high toxicity and low efficacy of interferon and ribavirin-based therapy.Clinical studies with sofosbuvir have demonstrated significant improvement over the prior standard of care,thus ushering in a new paradigm of HCV treatment and an update of treatment guidelines.
