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Treatment options are limited for patients infected by hepatitis C virus (HCV) with advanced liver disease. We assessed the safety and efficacy of ledipasvir, sofosbuvir, and ribavirin in patients with HCV genotype 1 or 4 and advanced liver disease. We did an open-label study at 34 sites in Europe, Canada, Australia, and New Zealand. Cohort A included patients with Child-Turcotte-Pugh class B (CTP-B) or CTP-C cirrhosis who had not undergone liver transplantation. Cohort B included post-transplantation patients who had either no cirrhosis; CTP-A, CTP-B, or CTP-C cirrhosis; or fibrosing cholestatic hepatitis. Patients in each group were randomly assigned (1:1) using a computer-generated randomisation sequence to receive 12 or 24 weeks of ledipasvir (90 mg) and sofosbuvir (400 mg) once daily (combination tablet), plus ribavirin (600–1200 mg daily). The primary endpoint was the proportion of patients achieving a sustained virological response 12 weeks after treatment (SVR12). All patients who received at least one dose of study drug were included in the safety analysis and all patients who received at least one dose of study drug and did not undergo liver transplantation during treatment were included in the efficacy analyses. Estimates of SVR12 and relapse rates and their two-sided 90% CI (Clopper-Pearson method) were provided. This exploratory phase 2 study was not powered for formal comparisons among treatment groups; no statistical hypothesis testing was planned or conducted. The trial is registered with EudraCT (number 2013-002802-30) and ClinicalTrials.gov (number NCT02010255). Between Jan 14, 2014, and Aug 19, 2014, 398 patients were screened. Of 333 patients who received treatment, 296 had genotype 1 HCV and 37 had genotype 4 HCV. In cohort A, among patients with genotype 1 HCV, SVR12 was achieved by 20 (87%, 90% CI 70–96) of 23 CTP-B patients with 12 weeks of treatment; 22 (96%, 81–100) of 23 CTP-B patients with 24 weeks of treatment; 17 (85%, 66–96) of 20 CTP-C patients (12 weeks treatment); and 18 (78%, 60–91) of 23 CTP-C patients (24 weeks treatment). In cohort B, among patients with genotype 1 HCV, SVR12 was achieved by 42 (93%, 84–98) of 45 patients without cirrhosis (12 weeks treatment); 44 (100%, 93–100) of 44 patients without cirrhosis (24 weeks treatment); 30 (100%, 91–100) of 30 CTP-A patients (12 weeks treatment); 27 (96%, 84–100) of 28 CTP-A patients (24 weeks treatment); 19 (95%, 78–100) of 20 CTP-B patients (12 weeks treatment); 20 (100%, 86–100) of 20 CTP-B patients (24 weeks treatment); one (50%, 3–98) of two CTP-C patients (12 weeks treatment); and four (80%, 34–99) of five CTP-C patients (24 weeks treatment). All five patients with fibrosing cholestatic hepatitis achieved SVR12 (100%, 90% CI 55–100). Among all patients with genotype 4 HCV, SVR12 was achieved by 14 (78%, 56–92) of 18 patients (12 weeks treatment) and 16 (94%, 75–100) of 17 patients (24 weeks treatment). Seven patients (2%) discontinued ledipasvir–sofosbuvir prematurely due to adverse events. 17 patients died, mainly from complications of hepatic decompensation. Ledipasvir–sofosbuvir and ribavirin provided high rates of SVR12 for patients with advanced liver disease, including those with decompensated cirrhosis before or after liver transplantation. Gilead Sciences.

Objective Entecavir (ETV) is a potent inhibitor of viral replication in chronic hepatitis B and prolonged treatment may result in regression of fibrosis. The aim of this study was to investigate the effect of ETV on disease progression. Design In a multicentre cohort study, 372 ETV-treated patients were investigated. Clinical events were defined as development of hepatocellular carcinoma (HCC), hepatic decompensation or death. Virological response (VR) was defined as HBV DNA <80 IU/ml. Results Patients were classified as having chronic hepatitis B without cirrhosis (n=274), compensated cirrhosis (n=89) and decompensated cirrhosis (n=9). The probability of VR was not influenced by severity of liver disease (p=0.62). During a median follow-up of 20 months (IQR 11–32), the probability of developing clinical events was higher for patients with cirrhosis (HR 15.41 (95% CI 3.42 to 69.54), p<0.001). VR was associated with a lower probability of disease progression (HR 0.29 (95% CI 0.08 to 1.00), p=0.05) which remained after correction for established risk factors such as age. The benefit of VR was only significant in patients with cirrhosis (HR 0.22 (95% CI 0.05 to 0.99), p=0.04) and remained after excluding decompensated patients (HR 0.15 (95% CI 0.03 to 0.81), p=0.03). A higher HBV DNA threshold of 2000 IU/ml was not associated with the probability of disease progression (HR 0.20 (95% CI 0.03 to 1.10), p=0.10). Conclusion VR to ETV is associated with a lower probability of disease progression in patients with cirrhosis, even after correction for possible baseline confounders. When using a threshold of 2000 IU/ml, the association between viral replication and disease progression was reduced, suggesting that complete viral suppression is essential for nucleoside/nucleotide analogue treatment, especially in patients with cirrhosis.

AbstractObjectivesTo quantify mortality rates for patients successfully treated for hepatitis C in the era of interferon-free, direct acting antivirals and compare these rates with those of the general population.DesignPopulation based cohort study.SettingBritish Columbia, Scotland, and England (England cohort consists of patients with cirrhosis only).Participants21 790 people who were successfully treated for hepatitis C in the era of interferon-free antivirals (2014-19). Participants were divided into three liver disease severity groups: people without cirrhosis (pre-cirrhosis), those with compensated cirrhosis, and those with end stage liver disease. Follow-up started 12 weeks after antiviral treatment completion and ended on date of death or 31 December 2019.Main outcome measuresCrude and age-sex standardised mortality rates, and standardised mortality ratio comparing the number of deaths with that of the general population, adjusting for age, sex, and year. Poisson regression was used to identify factors associated with all cause mortality rates.Results1572 (7%) participants died during follow-up. The leading causes of death were drug related mortality (n=383, 24%), liver failure (n=286, 18%), and liver cancer (n=250, 16%). Crude all cause mortality rates (deaths per 1000 person years) were 31.4 (95% confidence interval 29.3 to 33.7), 22.7 (20.7 to 25.0), and 39.6 (35.4 to 44.3) for cohorts from British Columbia, Scotland, and England, respectively. All cause mortality was considerably higher than the rate for the general population across all disease severity groups and settings; for example, all cause mortality was three times higher among people without cirrhosis in British Columbia (standardised mortality ratio 2.96, 95% confidence interval 2.71 to 3.23; P<0.001) and more than 10 times higher for patients with end stage liver disease in British Columbia (13.61, 11.94 to 15.49; P<0.001). In regression analyses, older age, recent substance misuse, alcohol misuse, and comorbidities were associated with higher mortality rates.ConclusionMortality rates among people successfully treated for hepatitis C in the era of interferon-free, direct acting antivirals are high compared with the general population. Drug and liver related causes of death were the main drivers of excess mortality. These findings highlight the need for continued support and follow-up after successful treatment for hepatitis C to maximise the impact of direct acting antivirals.

Hepatitis B and hepatitis C infections are important causes of end-stage liver disease and primary liver cancer. Successful antiviral treatment prior to the development of cirrhosis will prevent most of the morbidity and mortality associated with those infections. This can be achieved for a high proportion of patients. However, many patients present with end-stage liver disease and ongoing and clinically significant viral replication. Antiviral treatment of HBV can effect recovery of liver function and restores many patients to a state of well compensated cirrhosis. The antiviral treatment of end-stage HCV poses much greater challenges. Interferon remains an essential element of HCV antiviral treatment, but has reduced efficacy and significant toxicity at this stage of cirrhosis. Though yet to be evaluated in the setting of advanced liver disease, the development of direct acting antivirals for HCV offers hope for improved outcomes at this stage of cirrhosis.

Long praised for its accuracy, readability, and insight, theCanadian Annual Review of Politics and Public Affairsoffers a synoptic appraisal of the year's developments in Canadian politics. The first year of the new millennium saw a new conservative federal party born with the union of the Reform Party and disaffected federal Progressive Conservatives. Led by Stockwell Day, the Canadian Alliance was defeated by Jean Chrétien's liberals in the subsequent federal election. A second RCMP investigation into questionable job-creation grants in Chrétien's home riding, however, hurt the Prime Minister's reputation. The Liberals' new cigarette-packaging requirements, featuring gruesome tobacco-related images meant to discourage smoking, were challenged by tobacco companies. As well, the issue of police racism was brought to the fore when two Saskatoon police officers were suspended over allegations they abandoned a Native man on a cold winter night without a coat. Additionally, Ontario's chief coroner announced an investigation into the deaths of nine people following an outbreak of E.Coli in Walkerton. TheCanadian Annual Reviewis unique in its collection and presentation of the year in politics. The combination of the calendar and the text offers a superb, easy-access reference source for political events, both federal and provincial.

The 2009 instalment of theReviewcovers the continuation of 2008's economic and political crises from the end of Parliament's first prorogation at the beginning of the year to the start of its unprecedented second prorogation at the end.

TheCanadian Annual Review of Politics and Public Affairsis an acclaimed series that offers informed commentary on important national events and thoughtfully considers their significance in local and international contexts. This latest instalment reviews the year 2004, in which the Liberal party was elected to a minority government.

The Canadian Annual Review of Politics and Public Affairs is an acclaimed series that offers informed commentary on important national events and considers their significance in local and international contexts. This latest instalment reviews one of the most dramatic years in recent Canadian political history. While the country seemed solid both politically and economically at the beginning of 2008, by late summer trouble in the financial markets left banks and other financial institutions around the world on the brink of collapse.  As the situation unfolded, Prime Minister Harper violated the spirit of his fixed election law and called a snap election, sensing the prospect of a Conservative majority.  When the election returned another minority, Canada was plunged into a constitutional crisis that rivalled, if not surpassed, the King-Byng affair of 1926. The 2008 volume of the Canadian Annual Review of Politics and Public Affairs covers both these crises, as well as foreign, provincial, First Nations, and municipal affairs. 

TheCanadian Annual Review of Politics and Public Affairsis an acclaimed series that offers informed commentary on important national events and considers their significance in local and international contexts. This latest instalment covers a year of dramatic activity in provincial politics.

Long praised for its accuracy, readability, and insight, theCanadian Annual Review of Politics and Public Affairsoffers a synoptic appraisal of the year's developments in Canadian politics. Canada went to war in 1999, participating in a two-month NATO-led air war against Yugoslavia over its treatment of Kosovar Albanians. Attracting less public attention was an important turn in the country's constitutional arrangements - the creation of Nunavut - producing a self-governing capacity for the Inuit. The year 1999 also saw both the federal and British Columbia governments approve an historic agreement with the Nisga'a Nation. Additionally, Jean Chrétien's Liberal government pushed ahead with its plan to create a law that sets out the rules around any future referendum on Quebec's sovereignty. TheCanadian Annual Reviewis unique in its collection and presentation of the year in politics. The combination of the calendar and the text offers a superb, easy-access reference source for political events, both federal and provincial.