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.

With a prevalence affecting over 30% of HIV infected patients, coinfection with hepatitis B (HBV) or C (HCV) virus remains one of the most frequent comorbidities in this population, with a significant impact in terms of morbidity and mortality associated with liver disease. Recent findings in the physiopathology of HIV in the liver have confirmed that it may contribute, along with hepatotoxicity of antiretrovirals and the burden of metabolic diseases, to a more rapid progression of liver fibrosis, especially when there is underlying chronic hepatitis coinfection. Both fields of research and clinical appraisal of HBV and HCV coinfection are rapidly evolving and prompt a change in the former paradigms of clinical care and management of chronic hepatic coinfection in the context of HIV. The advent of anti-HCV direct antiviral agents has indeed completely shaken up the treatment guidelines for HCV, and the tricky management of these new agents with antiretrovirals means referring patients to specialised centres. In HBV coinfection, therapeutic options have not changed recently but new challenges have emerged regarding the management of low replicating HBV-DNA in optimally treated patients and long term exposure to antivirals. Finally, the global increase in life expectancy in HIV infected patients has been accompanied in coinfected patients by a higher risk of emergence of end stage liver diseases for which access to orthotopic liver transplantation and innovative procedures such as targeted hepatocellular carcinoma therapies should be facilitated.

Until recently, the standard of care (SOC) for patients with chronic hepatitis C virus (HCV) infection has consisted of a combination of pegylated interferon-α [corrected] plus ribavirin, administered for 24- to 48-weeks depending on the HCV genotype. The sustained virologic response rate for this SOC has been only about 50% in patients infected with genotype 1 HCV, the most prevalent genotype in Europe and North America. HCV therapy has been revolutionised recently by the approval of two direct-acting antiviral agents (DAA) against the NS3/4A serine protease for use in genotype 1 HCV, the ketoamide inhibitors boceprevir and telaprevir. The novel SOC marks the beginning of an extraordinary new era in HCV therapy. We review this new SOC with an emphasis on practical issues related to protease inhibitors, e.g. prescribing guidelines, futility rules and management of adverse events. We also give a perspective on what to expect in the coming years. Newer DAA with simplified dosing regimens and/or minimal toxicity which, when used in combination, will lead to viral eradication in most if not all CHC patients who undergo treatment. The novel agents in clinical development are paving the way for future interferon-sparing regimens.

Hepatitis C virus (HCV) causes chronic infection in almost 2% of the world's population. If untreated, chronic carriers can develop severe liver disease including fibrosis, cirrhosis and hepatocellular carcinoma. Until recently, hepatitis C was treated with a combination of pegylated interferon and ribavirin, a treatment which was only partially effective and was plagued with side effects. In 2011 two inhibitors of the virally encoded NS3/4 protease have become part of standard therapy, which have improved treatment rates but can exacerbate the problematic side effects. While the addition of these first directly acting antivirals (DAAs) marks a milestone in anti-HCV therapy, new and improved combinations of drugs are desperately needed. New generations of drugs will have to address genetic variability of HCV and issues of viral resistance. Furthermore, combination therapies have to be tailored to effectively cure patient populations that have traditionally been hardest to treat, including patients with cirrhosis, those receiving liver transplants and individuals who are co-infected with HIV or hepatitis B virus. Since the discovery of HCV a plethora of experimental tools have been developed which enabled detailed analysis of various aspects of the viral life cycle and the interaction of HCV with its human host. Such studies have revealed a growing list of targets for therapeutic intervention, some of which will be discussed in this review.

Over the past few decades there has been remarkable progress in viral hepatitis. Beginning with discovery of the viral agents, we now have reliable methods to diagnose and monitor all hepatitis virus infections, as well significant advances in treatment and prevention. Nonetheless, important challenges remain. This supplement to Gut looks forward to the next generation of challenges in the field of viral hepatitis, and this introductory article highlights several key issues.

Management of Helicobacter pylori infection is evolving and in this 4th edition of the Maastricht consensus report aspects related to the clinical role of H pylori were looked at again in 2010. In the 4th Maastricht/Florence Consensus Conference 44 experts from 24 countries took active part and examined key clinical aspects in three subdivided workshops: (1) Indications and contraindications for diagnosis and treatment, focusing on dyspepsia, non-steroidal anti-inflammatory drugs or aspirin use, gastro-oesophageal reflux disease and extraintestinal manifestations of the infection. (2) Diagnostic tests and treatment of infection. (3) Prevention of gastric cancer and other complications. The results of the individual workshops were submitted to a final consensus voting to all participants. Recommendations are provided on the basis of the best current evidence and plausibility to guide doctors involved in the management of this infection associated with various clinical conditions.

The literature suggests a lack of consensus on the use of terms related to coeliac disease (CD) and gluten.

Hospitalisation and surgery are considered to be markers of more severe disease in Crohn's disease. These are costly events and limiting these costs has emerged as one rationale for the cost of expensive biologic therapies. The authors sought to review the most recent international literature to estimate current hospitalisation and surgery rates for Crohn's disease and place them in the historical context of where they have been, whether they have changed over time, and to compare these rates across different jurisdictions. It is in this context that the authors could set the stage for interpreting some of the early data and studies that will be forthcoming on rates of hospitalisation and surgery in an era of more aggressive biologic therapy. The most recent data from Canada, the United Kingdom and Hungary all suggest that surgical rates were falling prior to the advent of biologic therapy, and continue to fall during this treatment era. The impact of biologic therapy on surgical rates will have to be analysed in the context of evolving reductions in developed regions before biologic therapy was even introduced. Whether more aggressive medical therapy will decrease the requirement for surgery over long periods of time remains to be proven.

This review illustrates promising regenerative medicine technologies that are being developed for the treatment of gastrointestinal diseases. The main strategies under validation to bioengineer or regenerate liver, pancreas, or parts of the digestive tract are twofold: engineering of progenitor cells and seeding of cells on supporting scaffold material. In the first case, stem cells are initially expanded under standard tissue culture conditions. Thereafter, these cells may either be delivered directly to the tissue or organ of interest, or they may be loaded onto a synthetic or natural three-dimensional scaffold that is capable of enhancing cell viability and function. The new construct harbouring the cells usually undergoes a maturation phase within a bioreactor. Within the bioreactor, cells are conditioned to adopt a phenotype similar to that displayed in the native organ. The specific nature of the scaffold within the bioreactor is critical for the development of this high-function phenotype. Efforts to bioengineer or regenerate gastrointestinal tract, liver and pancreas have yielded promising results and have demonstrated the immense potential of regenerative medicine. However, a myriad of technical hurdles must be overcome before transplantable, engineered organs become a reality.

Throughout the human gastrointestinal tract a variety of reactive nitrogen oxides are continuously formed as a result of a complex interplay between the host, commensal bacteria and dietary factors. These compounds include nitric oxide, nitrite, nitrate, peroxynitrite, S-nitrosothiols, nitrated fatty acids and N-nitrosamines, all of which are bioactive with the potential to affect physiological and pathological processes locally in the gut as well as systemically after absorption. Historically, the literature has been dominated by studies on the formation of potentially carcinogenic nitrosamines, but the focus was shifted in the 1980s with the seminal discovery of the L-arginine-nitric oxide pathway and its profound impact on normal physiological functions. More recently, a nitrate-nitrite-nitric oxide pathway has been discovered, with implications for local host defence and gut mucosal integrity and, intriguingly, also for systemic regulation of cardiovascular and metabolic function. This review discusses recent advances in the understanding of the formation, biochemistry, physiology and pathophysiology of reactive nitrogen oxides in the gastrointestinal tract. In addition, opportunities for nitric oxide-based pharmacological or dietary interventions are highlighted.

The treatment of inflammatory bowel disease is becoming more complicated with new medications and new treatment paradigms. Although data are accumulating that the earlier use of immunomodulators and anti-tumor necrosis factor agents are more effective than the standard "step-up" pyramidal treatment algorithm, patients may not be comfortable with this more intensive therapeutic approach. The process of shared decision making engages patients in treatment decisions to optimize the chance that a chosen therapy matches their personal preferences for care. Decision aids are standard shared decision making tools, which are used to present evidence-based data in a patient-friendly manner to help patients with preference-sensitive decisions. Not all care decisions are preference-sensitive, and not all patients are interested in being part of a shared medical decision. The responsibility of the provider is to identify how much of a role patients want, and then determine which decisions need their input to provide the best patient-centered care. The overall goal is to involve patients in decisions so that they are educated about their options, confident in the plan, adherent to chosen therapy and ultimately have a better quality of life.

Knowledge of the immunological events necessary to control hepatitis B virus (HBV) infection has accelerated in recent years, but their translation towards therapeutic strategies able to achieve a durable HBV suppression has been challenging. The scenario of how HBV deals with the host immunity is presented and used to discuss how the immune response can be harnessed to potentially achieve infection control.

Reactive oxygen species (ROS) possess important cell signalling properties. This contradicts traditional thought which associated ROS activity with cell death. Emerging evidence clearly demonstrates that ROS signalling acts as a key regulator in tumour cell survival and in the cellular processes required for tumour cells to successfully metastasise and proliferate. The discovery of the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (Nox) family of enzymes in the last decade has unravelled much of the mystery surrounding how ROS are generated. Tumour cells are now known to express Nox enzymes which produce ROS required for cellular signalling. Activation of Nox enzymes occurs via interaction with proinflammatory cytokines and growth factors, all of which are released following surgical trauma. As our understanding of the signalling capabilities of ROS grows, the oncological implications of ROS activity are gradually being revealed. Nox-derived ROS are known to play a central role in each step of the metastatic cascade including invasion, adhesion, angiogenesis and proliferation. This article describes how surgery creates a ROS-rich environment, which facilitates redox signalling, and also examines the role played by Nox enzymes in this process. The authors then explore current knowledge of the oncological implications of surgery-induced redox signalling, and discuss current and future therapeutic strategies targeted at ROS and Nox enzymes in cancer patients.