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In this study in patients with HCV genotype 1 infection and prior treatment failure, those assigned to 12 weeks or 24 weeks of treatment with ledipasvir and sofosbuvir, with or without ribavirin, had high rates of sustained response (94 to 99% in all groups). Among the estimated 170 million people in the world who have chronic hepatitis C virus (HCV) infection, approximately 60% have the genotype 1 strain of the virus. 1 The treatment of patients infected with HCV genotype 1 is evolving rapidly. 2 – 6 At the end of 2013, the Food and Drug Administration (FDA) approved two new direct-acting antiviral agents for the treatment of HCV infection: the nucleotide polymerase inhibitor sofosbuvir (Gilead Sciences) and the protease inhibitor simeprevir (Janssen Therapeutics). 7 , 8 Among the regimens that have been approved by the FDA for patients with HCV genotype 1 infection who have not had a . . .

In previously untreated patients with HCV genotype 1 infection without cirrhosis, the rate of sustained virologic response was 94% with 8 weeks of ledipasvir–sofosbuvir, 93% with 8 weeks of ledipasvir–sofosbuvir plus ribavirin, and 95% with 12 weeks of ledipasvir–sofosbuvir. More than 3 million people in the United States are chronically infected with the hepatitis C virus (HCV). 1 , 2 Although the number of new infections has been declining for decades, HCV-related morbidity and mortality are projected to continue rising for another 20 years. 3 One half to three quarters of persons currently infected with HCV have not received a diagnosis and are untreated; many will have progression to decompensated cirrhosis, hepatocellular carcinoma, and other liver complications. 3 , 4 Early diagnosis and treatment are essential to improve long-term health outcomes in this population. New guidelines from the Centers for Disease Control and Prevention . . .

In this study, once-daily treatment with oral daclatasvir plus sofosbuvir was associated with high rates of sustained virologic response among patients with genotype 1, 2, or 3 HCV infection, including those in whom previous therapy with telaprevir or boceprevir had failed. Chronic infection with hepatitis C virus (HCV) affects approximately 170 million people worldwide and is a major cause of cirrhosis and hepatocellular carcinoma. 1 , 2 HCV-related morbidity and mortality are increasing; since 2007, HCV-related deaths in the United States have exceeded those from human immunodeficiency virus (HIV) infection. 3 , 4 HCV is classified into six major genotypes. 5 , 6 Genotypes 1, 2, and 3 are found worldwide, with subtype 1a predominating in the United States and subtype 1b predominating in Europe, Japan, and China. 5 , 7 , 8 Peginterferon alfa–ribavirin treatment for chronic HCV infection is associated with a sustained virologic response (undetectable HCV RNA . . .

In two studies of sofosbuvir for previously untreated HCV infection, patients with genotype 1, 4, 5, or 6 had a 90% rate of sustained virologic response in a single-group study. In a study of sofosbuvir–ribavirin versus peginterferon–ribavirin for patients with genotype 2 or 3, the response rate was 67% in each group. As many as 170 million persons are chronically infected with the hepatitis C virus (HCV) worldwide, and more than 350,000 die annually from liver disease caused by HCV. 1 , 2 Estimates of the number of persons in the United States who have chronic HCV infection range from 2.7 million to 5.2 million. 3 , 4 For previously untreated cases of HCV genotype 1 infection (representing more than 70% of all cases of chronic HCV infection in the United States), the current standard of care is 12 to 32 weeks of an oral protease inhibitor combined with 24 to 48 weeks of peginterferon alfa-2a . . .

In patients with HCV genotypes 2 and 3, sofosbuvir plus ribavirin was administered for 12 weeks in patients with genotype 2 and for 24 weeks in those with genotype 3. Rates of sustained virologic response were 93% in patients with genotype 2 and 85% in those with genotype 3. Of the six main genotypes of the hepatitis C virus (HCV), genotypes 2 and 3 account for approximately 30% of chronic infections worldwide. 1 Although these two genotypes have historically been grouped together in treatment guidelines and clinical trials, 2 , 3 accumulating evidence suggests that there are important clinical differences between them. 1 , 4 , 5 HCV genotype 3 infection is associated with a higher incidence of hepatic steatosis, more rapid progression of fibrosis, and possibly a greater risk of hepatocellular carcinoma than is HCV genotype 2 infection. 6 Moreover, patients with HCV genotype 3 infection are less responsive to peginterferon-based treatment than are patients . . .

In two randomized trials, the oral nucleotide polymerase inhibitor sofosbuvir combined with ribavirin for 12 or 16 weeks was effective in patients with chronic HCV genotype 2 or 3 infection for whom interferon therapy either was not an option or had failed. When studied in clinical trials, the current standard-of-care therapy for patients with hepatitis C virus (HCV) genotype 2 or 3 infection — pegylated interferon in combination with ribavirin for 24 weeks — resulted in a sustained virologic response in 70 to 85% of patients who had not received prior treatment and in 55 to 60% of those who had received treatment. 1 – 4 However, a substantial proportion of patients with HCV infection remain untreated owing to absolute or relative contraindications to interferon therapy, such as hepatic decompensation, autoimmune disease, and psychiatric illness. 5 In addition, interferon causes a range of constitutional symptoms . . .

Among patients coinfected with HIV-1 and HCV, a sustained HCV virologic response was reported in 97% of patients treated with 12 weeks of daclatasvir plus sofosbuvir. Liver disease is a leading cause of death among patients with human immunodeficiency virus type 1 (HIV-1) infection. 1 Coinfection with HIV-1 and hepatitis C virus (HCV) appears to accelerate the course of HCV-associated liver disease 2 – 5 and is widespread, particularly among injection-drug users. 6 The effect of HIV-1 coinfection on the course of HCV disease is reduced but not eliminated by antiretroviral therapy. 7 , 8 Adoption of interferon-based HCV treatments has been low among HIV–HCV coinfected patients 9 , 10 owing to a high adverse-event burden. 11 Furthermore, the rate of sustained virologic response to interferon–ribavirin is lower among patients with HIV–HCV coinfection than among . . .

Pancreatic ductal adenocarcinoma (PDA) is a lethal disease notoriously resistant to therapy 1 , 2 . This is mediated in part by a complex tumour microenvironment 3 , low vascularity 4 , and metabolic aberrations 5 , 6 . Although altered metabolism drives tumour progression, the spectrum of metabolites used as nutrients by PDA remains largely unknown. Here we identified uridine as a fuel for PDA in glucose-deprived conditions by assessing how more than 175 metabolites impacted metabolic activity in 21 pancreatic cell lines under nutrient restriction. Uridine utilization strongly correlated with the expression of uridine phosphorylase 1 (UPP1), which we demonstrate liberates uridine-derived ribose to fuel central carbon metabolism and thereby support redox balance, survival and proliferation in glucose-restricted PDA cells. In PDA, UPP1 is regulated by KRAS–MAPK signalling and is augmented by nutrient restriction. Consistently, tumours expressed high UPP1 compared with non-tumoural tissues, and UPP1 expression correlated with poor survival in cohorts of patients with PDA. Uridine is available in the tumour microenvironment, and we demonstrated that uridine-derived ribose is actively catabolized in tumours. Finally, UPP1 deletion restricted the ability of PDA cells to use uridine and blunted tumour growth in immunocompetent mouse models. Our data identify uridine utilization as an important compensatory metabolic process in nutrient-deprived PDA cells, suggesting a novel metabolic axis for PDA therapy. A metabolite screen of pancreatic cells shows that pancreatic cancer cells metabolize uridine-derived ribose via UPP1, supporting redox balance, survival and proliferation.

In this small, preliminary study of sofosbuvir, a nucleotide inhibitor of HCV polymerase, treatment with sofosbuvir and ribavirin, without peginterferon, was effective in achieving a sustained virologic response in patients with HCV genotype 1, 2, or 3 infection. Recent progress in the treatment of chronic hepatitis C virus (HCV) infection — the approval of the first-generation protease inhibitors telaprevir and boceprevir — has benefited many but not all patients with HCV infection. One quarter of patients with HCV genotype 1 infection who have not received previous therapy and 71% of those with no response to previous therapy do not have a sustained virologic response with protease-inhibitor–based regimens. 1 No direct-acting antiviral agents have yet been approved for patients with HCV genotype 2 or 3 infection. The standard of care for all patients with HCV infection continues to include 24 . . .

Compared with other countries, patients with chronic hepatitis C infection in Japan tend to be older, have more advanced liver disease, and are more likely to have been previously treated for hepatitis C. We aimed to assess the efficacy and safety of an all-oral, fixed-dose combination of the hepatitis C virus NS5A inhibitor ledipasvir and the NS5B nucleotide polymerase inhibitor sofosbuvir with and without ribavirin for 12 weeks in treatment-naive and previously treated Japanese patients with chronic genotype 1 hepatitis C virus infection. In this randomised, open-label study, we enrolled patients from 19 clinical Japanese centres. Patients were randomly assigned (1:1) to receive either ledipasvir (90 mg) and sofosbuvir (400 mg) or ledipasvir, sofosbuvir, and ribavirin (dosed according to the Japanese Copegus product label—ie, patients ≤60 kg received 600 mg daily, patients >60 kg to ≤80 kg received 800 mg daily, and patients >80 kg received 1000 mg daily) orally once daily for 12 weeks. After completion or early discontinuation of treatment, patients were followed up off-treatment for 24 weeks. Eligible patients were at least 20 years of age with chronic genotype 1 hepatitis C virus infection with serum hepatitis C virus RNA concentrations of at least 5 log10 IU/mL, creatinine clearance of at least 1·0 mL/s, and a platelet count of at least 50 × 109 per L. An interactive web response system was used to manage patient randomisation and treatment assignment. Randomisation was stratified by the presence or absence of cirrhosis for treatment-naive patients and stratified by presence or absence of cirrhosis and by previous treatment category (relapser or breakthrough, non-responder, or interferon-intolerant) for previously treated patients. Within each strata, patients were sequentially assigned to either treatment with ledipasvir-sofosbuvir or ledipasvir-sofosbuvir plus ribavirin in a 1:1 ratio with block size of 4. The primary endpoint was sustained virological response 12 weeks after completion of treatment (SVR12) assessed in all patients who were randomly assigned and received at least one dose of study drug; safety outcomes were assessed in all patients who received at least one dose of study drug. This trial is registered with ClinicalTrials.gov, number NCT01975675. Between Oct 15, 2013 and Dec 13, 2013, 341 patients were randomly assigned to treatment groups and received at least one dose of study treatment. SVR12 was achieved in all 171 (100%) patients (83 of 83 treatment naive and 88 of 88 treatment experienced) receiving ledipasvir-sofosbuvir (95% CI 98–100) and 167 (98%) of 170 patients (80 of 83 treatment naive and 87 of 87 treatment experienced) receiving ledipasvir-sofosbuvir plus ribavirin (95% CI 95–100). Of the 76 patients with baseline NS5A resistant variants, 75 (99%) achieved SVR12. Two (1·2%) of 170 patients in the ledipasvir-sofosbuvir plus ribavirin group discontinued treatment because of adverse events. The most common adverse events were nasopharyngitis (50 [29·2%] of 171), headache (12 [7·0%] of 171), and malaise (nine [5·3%] of 171) in patients receiving ledipasvir-sofosbuvir; and nasopharyngitis (40 [23·5%] of 170), anaemia (23 [13·5%] of 170), and headache in those receiving ledipasvir-sofosbuvir and ribavirin (15 [8·8%] of 170). Although existing regimens for the treatment of hepatitis C virus are effective for many patients, medical needs remain unmet, particularly in Japan where the population with hepatitis C virus genotype 1 is generally older and treatment-experienced, with advanced liver disease. The efficacy, tolerability, and absence of drug–drug interactions of ledipasvir-sofosbuvir suggest that it could be an important option for treatment of genotype 1 hepatitis C virus in Japanese patients. Gilead Sciences.