Reimagining Security: The Metaphors of Proliferation

'Proliferation' appears to have been developed as a central image in the new international security agenda in the time between Krauthammer's article and the recent NATO summit. The spur to the construction of this image was the war in the Gulf. In the first section of this paper, I trace the construction of the image of proliferation in the pronouncements and practices of the Western states following the Gulf War. This image of proliferation as a security problem is, as Krauthammer noted, a perception of the state of the world. That perception is a metaphorical one, as the image of a security problem which is created is grounded in metaphor. In the second section I discuss the nature of image and metaphor as they relate to the constitution of international security. Finally, I examine the particular metaphors of the proliferation image, in order to show how they shape the understanding of a problem, and the policy solutions which are developed in response

Determinants of HBeAg loss during follow‐up of a multiethnic pediatric cohort

Hepatitis B e antigen (HBeAg) loss is a key event in the natural history of chronic hepatitis B virus infection. The rate and determinants of HBeAg loss depend upon cohort characteristics at baseline. Few studies have examined the age‐dependent rate, and none have examined the effect of patient sex and ethnicity on the age‐dependant rate. The study of age‐dependent rates requires the identification and long‐term follow‐up of a pediatric cohort. We have studied the age‐dependent rate of HBeAg loss, and the rate of HBeAg loss measured from baseline, in a multi‐ethnic cohort of 454 pediatric patients. During observation, HBeAg loss was observed in 121/303 (39.9%) HBeAg‐positive patients. The rate of HBeAg loss was greater in the second versus the first and third decades of life. The age‐related rate of HBeAg loss was clearly affected by patient sex and ethnicity, with earlier loss observed for males and for White versus both South Asian and Chinese ethnicities. When measured from baseline, Chinese patients had a slower rate of HBeAg loss in comparison with White patients. In multivariate analysis of HBeAg loss during prolonged follow‐up, male sex, older age, and White ethnicity were associated with HBeAg loss, but antiviral treatment was not

Erratum to 'The management of chronic hepatitis B in the immunocompromised patient: recommendations from a single topic meeting' [J. Clin. Virol. 41 (4) 2008 243-254]

Patients with chronic hepatitis B virus (HBV) infection have a substantial risk of reactivation and jaundice following the use of immunosuppressant therapy. A single topic conference was convened to discuss the management of HBV patients undergoing chemotherapy for haematological malignancy, liver and renal transplantation and with HIV co-infection. In advance of the meeting a draft guideline was prepared and circulated to a participating expert panel. Presentations and consensus views were obtained on the day of conference to allow pragmatic algorithms to be established on each of these topics. Use of lamivudine prophylaxis for HBV patients undergoing chemotherapy and renal transplantation is strongly supported with good evidence. Patients with HBV cirrhosis who are candidates for transplantation should be started on nucleos(t)ide therapy prior to surgery and, in addition, hepatitis B immune globulin given from the time of transplantation onward. Co-infection with HBV and HIV offers unique challenges. If the patient is a candidate for highly active retroviral therapy then dual nucleos(t)ide analogues which are also active against HBV must be used to prevent immune reconstitution hepatitis. In all these conditions, awareness of possible HBV resistance to therapy must be kept in mind and HBV DNA levels monitored

Outcomes after successful direct acting antiviral therapy for patients with chronic hepatitis C and decompensated cirrhosis

Abstract Direct-acting antivirals have become widely used for patients with chronic hepatitis C virus infection with decompensated cirrhosis. Virological responses are excellent and early improvements in liver function, at least in a proportion of patients, have been observed but the longer term impact of viral clearance on end-stage liver disease complications is unclear. Methods Prospective study of patients with decompensated cirrhosis who received 12 weeks of all-oral direct-acting antivirals through the English Expanded Access Programme. Endpoints were deaths, liver transplantation, hepatocellular carcinoma, serious decompensation events, sepsis or hospitalisations, and MELD scores between start of therapy to 15 months post treatment start. An untreated cohort of patients was retrospectively studied over 6 months for comparison. Results Amongst 317/406 patients who achieved sustained virological response at 24 weeks post-treatment, there were 9 deaths (3%), 17 new liver cancers (5%), 39 transplantations (12%) and 52 with serious decompensations (16%), over 15 months. When compared to the first six months from treatment start and to untreated patients, there was a reduction in incidence of decompensations [30/406 (7%) in months 6-15 and 72/406 (18%) in months 0-6 for treated patients vs 73/261 (28%) in untreated patients). There was no significant difference in liver cancer incidence (10/406 (2.5%) in months 6-15 and 17/406 (4%) in months 0-6 for treated patients vs 11/261 (4%) in untreated patients). Conclusions This study suggests that antiviral therapy in patients with decompensated cirrhosis led to prolonged improvement in liver function, with no evidence of paradoxical adverse impact nor increase in liver malignancy. Lay summary This is a report of a large group of patients in England who have hepatitis C virus (HCV) infection with advanced liver disease. They have been treated with new anti-HCV drugs, which cured the infection in the majority. This study looks at their outcomes a year following treatment, in terms of deaths, cancers and other complications of advanced liver disease. We conclude that in most patients anti-HCV treatment is beneficial even in advanced liver disease

High Sustained Virologic Response Rates of Glecaprevir/Pibrentasvir in Patients With Dosing Interruption or Suboptimal Adherence

INTRODUCTION: Pangenotypic, all-oral direct-acting antivirals, such as glecaprevir/pibrentasvir (G/P), are recommended for treatment of hepatitis C virus (HCV) infection. Concerns exist about the impact on efficacy in patients with suboptimal adherence, particularly with shorter treatment durations. These post hoc analyses evaluated adherence (based on pill count) in patients prescribed 8- or 12-week G/P, the impact of nonadherence on sustained virologic response at post-treatment week 12 (SVR12), factors associated with nonadherence, and efficacy in patients interrupting G/P treatment. METHODS: Data were pooled from 10 phase 3 clinical trials of treatment-naive patients with HCV genotype 1-6 without cirrhosis/with compensated cirrhosis (treatment adherence analysis) and 13 phase 3 clinical trials of all patients with HCV (interruption analysis). RESULTS: Among 2,149 patients included, overall mean adherence was 99.4%. Over the treatment duration, adherence decreased (weeks 0-4: 100%; weeks 5-8: 98.3%; and weeks 9-12: 97.1%) and the percentage of patients with ≥80% or ≥90% adherence declined. SVR12 rate in the intention-to-treat (ITT) population was 97.7% (modified ITT SVR12 99.3%) and remained high in nonadherent patients in the modified ITT population (<90%: 94.4%-100%; <80%: 83.3%-100%). Psychiatric disorders were associated with <80% adherence, and shorter treatment duration was associated with ≥80% adherence. Among 2,902 patients in the interruption analysis, 33 (1.1%) had a G/P treatment interruption of ≥1 day, with an SVR12 rate of 93.9% (31/33). No virologic failures occurred. DISCUSSION: These findings support the impact of treatment duration on adherence rates and further reinforce the concept of "treatment forgiveness" with direct-acting antivirals.SCOPUS: ar.jinfo:eu-repo/semantics/publishe

Effect of scavenger receptor BI antagonist ITX5061 in patients with hepatitis C virus infection undergoing liver transplantation

Hepatitis C virus (HCV) entry inhibitors have been hypothesized to prevent infection of the liver after transplantation. ITX5061 is a Scavenger Receptor B-I (SR-BI) antagonist that blocks HCV entry and infection in vitro. We assessed the safety and efficacy of ITX5061 to limit HCV infection of the graft. The study included 23 HCV infected patients undergoing liver transplantation. The first 13 "control" patients did not receive drug. The subsequent 10 patients received ITX5061 150 mg immediately pre- and post-transplant, and daily for 1 week thereafter. ITX5061 pharmacokinetics and plasma HCV RNA were quantified. Viral genetic diversity was measured by ultradeep pyrosequencing. ITX5061 was well tolerated with measurable plasma concentrations during therapy. Whilst the median HCV RNA reduction was greater in ITX treated patients at all time points in the first week after transplantation there was no difference in the overall change in the area over the HCV RNA curve in the 7-day treatment period. However, in genotype 1 infected patients treatment was associated with a sustained reduction in HCV RNA levels compared to the control group (area over the HCV RNA curve analysis, p=0.004). Ultradeep pyrosequencing revealed a complex and evolving pattern of HCV variants infecting the graft during the first week. ITX5061 significantly limited viral evolution where the median divergence between day 0 and day 7 was 3.5% in the control group compared to 0.1% in the treated group.CONCLUSIONS: ITX5061 reduces plasma HCV RNA post transplant notably in genotype 1 infected patients and slows viral evolution. Following liver transplantation the likely contribution of extrahepatic reservoirs of HCV necessitates combining entry inhibitors such as ITX5061 with inhibitors of replication in future studies. Clinicaltrials.gov NCT01292824. This article is protected by copyright. All rights reserved.</p

Mortality rates among patients successfully treated for hepatitis C in the era of interferon-free antivirals: population based cohort study

OBJECTIVES: To 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. DESIGN: Population based cohort study. SETTING: British Columbia, Scotland, and England (England cohort consists of patients with cirrhosis only). PARTICIPANTS: 21 790 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 MEASURES: Crude 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. RESULTS: 1572 (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&lt;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&lt;0.001). In regression analyses, older age, recent substance misuse, alcohol misuse, and comorbidities were associated with higher mortality rates. CONCLUSION: Mortality 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