Explore the vast range of titles available.

The revolution in hepatitis C virus (HCV) treatment through the development of direct-acting antivirals (DAAs) has generated international interest in the global elimination of the disease as a public health threat. In 2017, this led WHO to establish elimination targets for 2030. We evaluated the impact of public health interventions on the global HCV epidemic and investigated whether WHO's elimination targets could be met. We developed a dynamic transmission model of the global HCV epidemic, calibrated to 190 countries, which incorporates data on demography, people who inject drugs (PWID), current coverage of treatment and prevention programmes, natural history of the disease, HCV prevalence, and HCV-attributable mortality. We estimated the worldwide impact of scaling up interventions that reduce risk of transmission, improve access to treatment, and increase screening for HCV infection by considering six scenarios: no change made to existing levels of diagnosis or treatment; sequentially adding the following interventions: blood safety and infection control, PWID harm reduction, offering of DAAs at diagnosis, and outreach screening to increase the number diagnosed; and a scenario in which DAAs are not introduced (ie, treatment is only with pegylated interferon and oral ribavirin) to investigate the effect of DAA use. We explored the effect of varying the coverage or impact of these interventions in sensitivity analyses and also assessed the impact on the global epidemic of removing certain key countries from the package of interventions. By 2030, interventions that reduce risk of transmission in the non-PWID population by 80% and increase coverage of harm reduction services to 40% of PWID could avert 14·1 million (95% credible interval 13·0–15·2) new infections. Offering DAAs at time of diagnosis in all countries could prevent 640 000 deaths (620 000–670 000) from cirrhosis and liver cancer. A comprehensive package of prevention, screening, and treatment interventions could avert 15·1 million (13·8–16·1) new infections and 1·5 million (1·4–1·6) cirrhosis and liver cancer deaths, corresponding to an 81% (78–82) reduction in incidence and a 61% (60–62) reduction in mortality compared with 2015 baseline. This reaches the WHO HCV incidence reduction target of 80% but is just short of the mortality reduction target of 65%, which could be reached by 2032. Reducing global burden depends upon success of prevention interventions, implemention of outreach screening, and progress made in key high-burden countries including China, India, and Pakistan. Further improvements in blood safety and infection control, expansion or creation of PWID harm reduction services, and extensive screening for HCV with concomitant treatment for all are necessary to reduce the burden of HCV. These findings should inform the ongoing global action to eliminate the HCV epidemic. Wellcome Trust.

In 2018, the Egyptian government initiated a massive hepatitis C screening and treatment program. The Ministry of Health set the goal of screening all adults (target population, 62.5 million) within 1 year and provided treatment paid for by the government. Nearly 50 million people participated in screening, and approximately 1 million patients were treated for HCV infection.

Chronic infection with hepatitis C virus (HCV) is a major public health problem, with nearly 170 million infected individuals worldwide. Current treatment for chronic infection is a combination of pegylated IFN-α2 and ribavirin (RBV); however, this treatment is effective in fewer than 50% of patients infected with HCV genotype 1 or 4. Recent studies identified the chemokine CXCL10 (also known as IP-10) as an important negative prognostic biomarker. Given that CXCL10 mediates chemoattraction of activated lymphocytes, it is counterintuitive that this chemokine correlates with therapeutic nonresponsiveness. Herein, we offer new insight into this paradox and provide evidence that CXCL10 in the plasma of patients chronically infected with HCV exists in an antagonist form, due to in situ amino-terminal truncation of the protein. We further demonstrated that dipeptidyl peptidase IV (DPP4; also known as CD26), possibly in combination with other proteases, mediates the generation of the antagonist form(s) of CXCL10. These data offer what we believe to be the first evidence for CXCL10 antagonism in human disease and identify a possible factor contributing to the inability of patients to clear HCV.

In chronic hepatitis C virus (HCV) infection, exhausted HCV-specific CD8 + T cells comprise memory-like and terminally exhausted subsets. However, little is known about the molecular profile and fate of these two subsets after the elimination of chronic antigen stimulation by direct-acting antiviral (DAA) therapy. Here, we report a progenitor–progeny relationship between memory-like and terminally exhausted HCV-specific CD8 + T cells via an intermediate subset. Single-cell transcriptomics implicated that memory-like cells are maintained and terminally exhausted cells are lost after DAA-mediated cure, resulting in a memory polarization of the overall HCV-specific CD8 + T cell response. However, an exhausted core signature of memory-like CD8 + T cells was still detectable, including, to a smaller extent, in HCV-specific CD8 + T cells targeting variant epitopes. These results identify a molecular signature of T cell exhaustion that is maintained as a chronic scar in HCV-specific CD8 + T cells even after the cessation of chronic antigen stimulation. Thimme and colleagues identify a molecular signature of T cell exhaustion resembling a ‘chronic scar’ that is imprinted in hepatitis C virus–specific CD8 + T cells and cannot simply be reversed by viral clearance.

Identifying gaps in care for people with chronic hepatitis C virus (HCV) infection is important to clinicians, public health officials, and federal agencies. The objective of this study was to systematically review the literature to provide estimates of the proportion of chronic HCV-infected persons in the United States (U.S.) completing each step along a proposed HCV treatment cascade: (1) infected with chronic HCV; (2) diagnosed and aware of their infection; (3) with access to outpatient care; (4) HCV RNA confirmed; (5) liver fibrosis staged by biopsy; (6) prescribed HCV treatment; and (7) achieved sustained virologic response (SVR). We searched MEDLINE, EMBASE, and the Cochrane Database of Systematic Reviews for articles published between January 2003 and July 2013. Two reviewers independently identified articles addressing each step in the cascade. Studies were excluded if they focused on specific populations, did not present original data, involved only a single site, were conducted outside of the U.S., or only included data collected prior to 2000. 9,581 articles were identified, 117 were retrieved for full text review, and 10 were included. Overall, 3.5 million people were estimated to have chronic HCV in the U.S. Fifty percent (95% CI 43-57%) were diagnosed and aware of their infection, 43% (CI 40-47%) had access to outpatient care, 27% (CI 27-28%) had HCV RNA confirmed, 17% (CI 16-17%) underwent liver fibrosis staging, 16% (CI 15-16%) were prescribed treatment, and 9% (CI 9-10%) achieved SVR. Continued efforts are needed to improve HCV care in the U.S. The proposed HCV treatment cascade provides a framework for evaluating the delivery of HCV care over time and within subgroups, and will be useful in monitoring the impact of new screening efforts and advances in antiviral therapy.

Although direct-acting antivirals have been used extensively to treat patients with chronic hepatitis C virus (HCV) infection, their clinical effectiveness has not been well reported. We compared the incidence of death, hepatocellular carcinoma, and decompensated cirrhosis between patients treated with direct-acting antivirals and those untreated, in the French ANRS CO22 Hepather cohort. We did a prospective study in adult patients with chronic HCV infection enrolled from 32 expert hepatology centres in France. We excluded patients with chronic hepatitis B, those with a history of decompensated cirrhosis, hepatocellular carcinoma, or liver transplantation, and patients who were treated with interferon-ribavirin with or without first-generation protease inhibitors. Co-primary study outcomes were incidence of all-cause mortality, hepatocellular carcinoma, and decompensated cirrhosis. The association between direct-acting antivirals and these outcomes was quantified using time-dependent Cox proportional hazards models. This study is registered with ClinicalTrials.gov, number NCT01953458. Between Aug 6, 2012, and Dec 31, 2015, 10 166 patients were eligible for the study. 9895 (97%) patients had available follow-up information and were included in analyses. Median follow-up was 33·4 months (IQR 24·0–40·7). Treatment with direct-acting antivirals was initiated during follow-up in 7344 patients, and 2551 patients remained untreated at the final follow-up visit. During follow-up, 218 patients died (129 treated, 89 untreated), 258 reported hepatocellular carcinoma (187 treated, 71 untreated), and 106 had decompensated cirrhosis (74 treated, 32 untreated). Exposure to direct-acting antivirals was associated with increased risk for hepatocellular carcinoma (unadjusted hazard ratio [HR] 2·77, 95% CI 2·07–3·71) and decompensated cirrhosis (3·83, 2·29–6·42). After adjustment for variables (age, sex, body-mass index, geographical origin, infection route, fibrosis score, HCV treatment-naive, HCV genotype, alcohol consumption, diabetes, arterial hypertension, biological variables, and model for end-stage liver disease score in patients with cirrhosis), exposure to direct-acting antivirals was associated with a decrease in all-cause mortality (adjusted HR 0·48, 95% CI 0·33–0·70) and hepatocellular carcinoma (0·66, 0·46–0·93), and was not associated with decompensated cirrhosis (1·14, 0·57–2·27). Treatment with direct-acting antivirals is associated with reduced risk for mortality and hepatocellular carcinoma and should be considered in all patients with chronic HCV infection. INSERM-ANRS (France Recherche Nord & Sud Sida-HIV Hépatites), ANR (Agence Nationale de la Recherche), DGS (Direction Générale de la Santé), MSD, Janssen, Gilead, AbbVie, Bristol-Myers Squibb, and Roche.

Background. Achievement of a sustained virologic response (SVR) after treatment for Hepatitis C infection is associated with improved outcomes. This meta-analysis aimed to determine the impact of SVR on long-term mortality risk compared with nonresponders in a range of populations. Methods. An electronic search identified all studies assessing all-cause mortality in SVR and non-SVR patients. Eligible articles were stratified into general, cirrhotic, and populations coinfected with human immunodeficiency virus. The adjusted hazard ratio (95% confidence interval [CI] for mortality in patients achieving SVR vs non-SVR, and pooled estimates for the 5-year mortality in each group were calculated. Results. 31 studies (n = 33 360) were identified as suitable for inclusion. Median follow-up time was 5.4 years (interquartile range, 4.9–7.5) across all studies. The adjusted hazard ratio of mortality for patients achieving SVR vs non-SVR was 0.50 (95% CI, .37–.67) in the general population, 0.26 (95% CI, .18–.74) in the cirrhotic group, and 0.21 (.10–.45) in the coinfected group. The pooled 5-year mortality rates were significantly lower for patients achieving SVR compared with non-SVR in all 3 populations. Conclusions. The results suggest that there is a significant survival benefit of achieving an SVR compared with unsuccessful treatment in a range of populations infected with hepatitis C virus.

In this trial, the safety and efficacy of a recombinant chimpanzee adenovirus 3 vector priming vaccination and a recombinant modified vaccinia Ankara boost was assessed in adults who were at risk for HCV infection because of injection drug use. The vaccine did not cause serious adverse events and did elicit HCV-specific T-cell responses, but it did not prevent chronic HCV infection.

Key Points Hepatitis B virus (HBV) and hepatitis C virus (HCV) are major aetiological agents of chronic liver disease and hepatocellular carcinoma (HCC). HCC is the fifth most prevalent tumour type and the third leading cause of cancer-related deaths worldwide, which is why it is so important to find early diagnostic markers and therapeutic targets, particularly when these markers and targets are common to both chronic infections. Alterations in multiple signalling pathways and patterns of host gene expression have been documented following HBV and HCV infections, but their relative importance to the pathogenesis of HCC has not been clearly defined. This has limited the ability to design appropriate therapeutic intervention strategies, and to determine the best time during chronic infection for their application. The pathogenesis of HBV and HCV infections is generally immune mediated, although these viruses have evolved multiple mechanisms to escape immune elimination and to continue replicating in an infected host for many years. Chronic infection with either virus can result in inflammation and oxidative stress. A prolonged fibrotic response, resulting in cirrhosis, is also common in both infections, which is accompanied by the appearance of localized hypoxia, rearrangement of tissue architecture (epithelial–mesenchymal transition) and angiogenesis. Altered host gene expression in chronic liver disease may be mediated by epigenetic changes, by inhibition of DNA repair and/or by differential expression of microRNAs. These alterations include constitutive upregulated expression of factors involved in 'stemness', suggesting that both viruses may contribute to HCC by promoting stemness. Early biomarkers and tumour-specific treatments for HCC are mostly lacking, although several signalling cascades that are activated in the liver before tumour appearance suggest that oncogene addiction may be important to the pathogenesis of HCC. Understanding common mechanisms of HBV and HCV pathogenesis will help to focus efforts on therapeutic targets that may be most useful in the development of new treatment approaches. Hepatocellular carcinoma (HCC) is mainly associated with chronic hepatitis B virus (HBV) and/or hepatitis C virus (HCV) infections. This Review outlines pathogenic mechanisms that seem to be common to both HBV and HCV, in the hope that this might suggest innovative approaches for the prevention and treatment of HCC. Hepatocellular carcinoma (HCC) is a highly lethal cancer, with increasing worldwide incidence, that is mainly associated with chronic hepatitis B virus (HBV) and/or hepatitis C virus (HCV) infections. There are few effective treatments partly because the cell- and molecular-based mechanisms that contribute to the pathogenesis of this tumour type are poorly understood. This Review outlines pathogenic mechanisms that seem to be common to both viruses and which suggest innovative approaches to the prevention and treatment of HCC.

Key Points Over 184 million people worldwide have chronic HCV infection, most HCV cases remain undetected; HCV prevalence increases with increasing age until the peak prevalence at 55–64 years HCV genotype 1 is the predominant type in most countries; genotype 3 is common in South Asia and genotype 4 has the highest frequency in Central Africa to the Middle East The annual incidence of HCV infection has reached its peak in most countries (except Russia); however, in the USA, there has been a nationwide increase in cases of acute HCV infection In patients with chronic HCV infection, progressive hepatic fibrosis leading to cirrhosis (in 15–35% after 25–30 years) is responsible for most of the HCV-related morbidity and mortality, including hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma HCV infection duration, gender and ageing are major risk factors for severe fibrosis, cirrhosis and HCC; other factors include HCV genotype 3 infection, host genetic polymorphisms, hepatic steatosis, diabetes and obesity Virologic cure of HCV results in reduction of hepatic and extrahepatic complications; however, residual elevated risk remains in several subgroups of cured patients Chronic HCV infection is a global health problem. In this Review, the authors describe the global burden of hepatitis C and HCV-related disease, including hepatocellular carcinoma, cirrhosis and extrahepatic manifestations. How the new direct-acting antiviral agents might influence disease burden is also discussed. Chronic HCV infection is a global health problem that affects >184 million people worldwide. HCV is associated with several hepatic and extrahepatic disorders, including several malignancies. The burden of HCV-related disorders is influenced by the number of new and existing cases, number of existing cases and the natural history of the infection. The natural history of HCV is affected by several demographic, virological, clinical and lifestyle factors. Major variations exist in the burden of HCV among different populations and geographical regions, as well as over time. With the advent of new and efficacious antiviral treatments, it is important to learn the determinants of HCV burden to design appropriate strategies for detection, prognostication and treatment. Furthermore, with the expected growth of patients cured of HCV, it is essential to learn about the possible change in natural history and burden of disease in these patients. In this Review, we will discuss the global epidemiology and burden of HCV and its complications, as well as the natural history and clinical course of chronic and cured HCV infection.