Short‐duration therapy for hepatitis C: suitable for all?

Peginterferon alpha (PegIFN alpha) plus ribavirin achieves sustained virological response (SVR) in more than 50% of patients with chronic hepatitis C virus (HCV) infection. Although in the trials which led to the registration of this combination therapy, only a 48-week period of treatment had been evaluated, current international guidelines state that 48 or 24 weeks of treatment should be recommended in accordance with genotype; i.e. 48 weeks for genotypes 1 and 4, and 24 weeks for 2 and 3. However, side effects and the high cost of antiviral therapy forced investigators to evaluate further reductions in the treatment duration. Based on the new evidence that fast and persistent viral clearance is highly predictive of SVR, a week 4 negative HCV RNA by a sensitive molecular assay was recently utilized as a criterion for halving the duration of treatment to 12-16 weeks for genotypes 2 and 3, and 24 weeks for genotype 1 patients. However, some issues on this topic, are still open. In this review, existing evidence is discussed, and both the relevance and limitations of published studies are considered.     

Impact of previous hepatitis B infection on the clinical outcomes from chronic hepatitis C? A population‐level analysis

Chronic coinfection with hepatitis C virus (HCV) and hepatitis B virus (HBV) is associated with adverse liver outcomes. The clinical impact of previous HBV infection on liver disease in HCV infection is unknown. We aimed at determining any association of previous HBV infection with liver outcomes using antibodies to the hepatitis B core antigen (HBcAb) positivity as a marker of exposure. The Scottish Hepatitis C Clinical Database containing data for all patients attending HCV clinics in participating health boards was linked to the HBV diagnostic registry and mortality data from Information Services Division, Scotland. Survival analyses with competing risks were constructed for time from the first appointment to decompensated cirrhosis, hepatocellular carcinoma (HCC) and liver‐related mortality. Records of 8513 chronic HCV patients were included in the analyses (87 HBcAb positive and HBV surface antigen [HBsAg] positive, 1577 HBcAb positive and HBsAg negative, and 6849 HBcAb negative). Multivariate cause‐specific proportional hazards models showed previous HBV infection (HBcAb positive and HBsAg negative) significantly increased the risks of decompensated cirrhosis (hazard ratio [HR]: 1.29, 95% CI: 1.01‐1.65) and HCC (HR: 1.64, 95% CI: 1.09‐2.49), but not liver‐related death (HR: 1.02, 95% CI: 0.80‐1.30). This is the largest study to date showing an association between previous HBV infection and certain adverse liver outcomes in HCV infection. Our analyses add significantly to evidence which suggests that HBV infection adversely affects liver health despite apparent clearance. This has important implications for HBV vaccination policy and indications for prioritization of HCV therapy.     

Doctor‐to‐patient transmission of viral hepatitis B: is it a problem,is there a solution?

It is well-established that hepatitis B may be transmitted from surgeons to their patients. Clear strategies are needed to reduce the risk of transmission whilst not discriminating unnecessarily against surgeons who may pose no risks to their patients. This review outlines the current position and provides a blueprint for action that may reduce the risks to patients whilst minimizing the impact on practising surgeons.     

Does cirrhosis affect quality of life in hepatitis C virus‐infected patients?

Background: Hepatitis C virus (HCV) infection is a major cause of chronic liver disease and is associated with impairments in health‐related quality of life. Aims: To evaluate quality of life (QOL) in cirrhotic (compensated and decompensated) and non‐cirrhotic patients with chronic HCV infection, using preference‐based (utilities) and non‐preference‐based methods of evaluating QOL. Methods: In a tertiary care setting, 271 patients completed a self‐administered time trade‐off utility instrument, the Health Utility Index Mark 2 and Mark 3, and the Hepatitis Quality of Life Questionnaire Version 2. Mean QOL scores were compared across HCV disease stages and sociodemographical categories. We examined the association between QOL and disease stage using linear regression adjusting for age, education, marital status, log income and Charlson comorbidity scores. Mean utility scores were compared across disease stages using a propensity score method. Results: Mean utilities were lower than general population norms (0.81–0.92) and ranged from 0.62 to 0.82 in non‐cirrhotic patients (n=197), 0.56–0.84 in compensated cirrhotic patients (n=17) and 0.55–0.76 for decompensated cirrhotic patients (n=57). No significant association found was between disease stage and utility for current health status. Higher income, fewer comorbidities and living in a married or common‐law relationship were significantly associated with higher utilities and better QOL. No significant difference in utilities was found between disease stages using propensity score matching. Conclusions: Our study confirms that changes in HCV disease stage explain only small changes in QOL and suggests that factors such as underlying comorbidities, income and marital status have a greater effect on QOL than disease stage.     

Are trans‐complementation systems suitable for hepatitis C virus life cycle studies?

Complementation is a naturally occurring genetic mechanism that has been studied for a number of plus‐strand RNA viruses. Although trans‐complementation is well documented for Flaviviridae family viruses, the first such system for hepatitis C virus (HCV) was only described in 2005. Since then, the development of a number of HCV trans‐complementation models has improved our knowledge of HCV protein functions and interactions, genome replication and viral particle assembly. These models have also been used to produce defective viruses and so improvements are necessary for vaccine assays. This review provides an update on HCV trans‐complementation systems, the viral mechanisms studied therewith and the production and characterization of trans‐encapsidated particles.     

What factors determine the severity of hepatitis A‐related acute liver failure?

Summary. The reason(s) that hepatitis A virus (HAV) infection may progress infrequently to acute liver failure are poorly understood. We examined host and viral factors in 29 consecutive adult patients with HAV‐associated acute liver failure enrolled at 10 sites participating in the US ALF Study Group. Eighteen of twenty‐four acute liver failure sera were PCR positive while six had no detectable virus. HAV genotype was determined using phylogenetic analysis and the full‐length genome sequences of the HAV from a cute liver failure sera were compared to those from self‐limited acute HAV cases selected from the CDC database. We found that rates of nucleotide substitution did not vary significantly between the liver failure and non‐liver failure cases and there was no significant variation in amino acid sequences between the two groups. Four of 18 HAV isolates were sub‐genotype IB, acquired from the same study site over a 3.5‐year period. Sub‐genotype IB was found more frequently among acute liver failure cases compared to the non‐liver failure cases (chi‐square test, P < 0.01). At another centre, a mother and her son presented with HAV and liver failure within 1 month of each other. Predictors of spontaneous survival included detectable serum HAV RNA, while age, gender, HAV genotype and nucleotide substitutions were not associated with outcome. The more frequent appearance of rapid viral clearance and its association with poor outcomes in acute liver failure as well as the finding of familial cases imply a possible host genetic predisposition that contributes to a fulminant course. Recurrent cases of the rare sub‐genotype IB over several years at a single centre imply a community reservoir of infection and possible increased pathogenicity of certain infrequent viral genotypes.     

Treat chronic hepatitis C virus infection in decompensated cirrhosis – pre‐ or post‐liver transplantation? the ironic conundrum in the era of effective and well‐tolerated therapy

The management of hepatitis C virus (HCV) infection in patients with decompensated cirrhosis has evolved dramatically over the past few years mainly due to the availability of all‐oral antiviral regimens. The currently approved all‐oral direct‐acting antivirals (DAA) containing sofosbuvir, ledipasvir, daclatasvir and ribavirin, in various combinations, have shown to be safe and effective in patients with decompensated cirrhosis with sustained virological response (SVR) rates nearly comparable to those with well‐compensated liver disease. Unique issues yet remain such as the challenges with renal insufficiency, tolerability of ribavirin and risk of further hepatic decompensation with a protease inhibitor‐based regimen. While most patients who achieve SVR have demonstrated improvement in hepatic synthetic function over the short course of follow, the long‐term beneficial effects are unknown. Further, the baseline predictors of improvement in hepatic function have not been well delineated and thus have left us in a quandary as to what we might expect with successful therapy and thus we are at a loss to well educate our patients. The major concern, in potential liver transplant candidates, is of unintended ‘harm’ by achieving SVR but without improvement in hepatic function to an extent where the patients might function well. As HCV therapies are as effective in liver transplant recipients, there is a growing sentiment in some of the transplant quarters that those with decompensated liver disease and awaiting liver transplant be treated for HCV after liver transplant. This strategy would thus eliminate any concern of leaving a patient in ‘no person's’ land by treating HCV successfully pretransplant but not to the point of functional normalcy, while also would maintain the risk of HCC. Yet a contrarian view would be that not all patients have access to liver transplantation (LT), cannot bear the cost, have comorbidities or contraindications to LT. While the debate continues, it is essential that we develop robust predictors of improvement in liver function so that we can carefully select our patients for therapy in the context of liver transplantation.     

Do hepatitis B virus and hepatitis C virus co‐infections increase hepatocellular carcinoma occurrence through synergistically modulating lipogenic gene expression?

Hepatitis B virus (HBV) and hepatitis C virus (HCV) infections cause a wide range of liver diseases including hepatocellular carcinoma (HCC). Because of the similar modes of transmission, HBV HCV co-infections are found in approximately 7-20 million people globally. Compared with HBV or HCV mono-infections, co-infections are associated with more severe liver diseases and higher risk of HCC. Abnormal lipid biosynthesis and metabolism has been increasingly recognized as a cause for cancer. While HBV infection does not seem to significantly increase the risk of developing hepatic steatosis, steatosis is a prominent feature of chronic hepatitis C (CHC). In addition, steatosis in HBV or HCV mono-infections is a significant and independent risk factor for HCC. However, whether and how HBV HCV co-infections synergistically increase the risk of HCC development through modulating lipid metabolism is not well understood. Possible mechanisms by which steatosis causes HCC include: activation of sterol regulatory element-binding protein-mediated lipogenesis through the PI3K-Akt pathway, abnormal activation of peroxisome proliferator-activated receptors and endoplasmic reticulum stress. Here, we review the potential mechanisms by which HBV HCV co-infections may increase HCC risk through modulation of lipogenic gene expression. We begin with reviewing the impact of HBV and HCV on host lipogenic gene expression and carcinogenesis. We then discuss the potential mechanisms by which HBV and HCV can increase carcinogenesis through synergistically activating lipid biosynthesis and metabolism. We end by sharing our thoughts on future research directions in this emerging paradigm with an ultimate goal of developing effective therapeutics.     

Unexpected long‐lasting anti‐HEV IgM positivity: Is HEV antigen a better serological marker for hepatitis E infection diagnosis?

Hepatitis E virus (HEV) is the leading cause of acute hepatitis worldwide. The minimum criterion for diagnosis of acute infection is detection of anti‐HEV antibodies, although there are scant data on IgM duration. Our aim was to assess the persistence of HEV markers after acute self‐limited hepatitis E. HEV serological tests (IgM by Mikrogen and Wantai and HEV‐Ag) and HEV RNA were carried out in two cohorts: (a) patients with prior acute hepatitis E (ALT >10 x ULN plus positive IgM ± HEV RNA) currently self‐limited and (b) 50 blood donors with positive HEV RNA. Among 25 cases of prior acute hepatitis E, after a median follow‐up of 34 months, all presented undetectable HEV RNA. However, anti‐HEV IgM remained detectable in 14 (56%) by Mikrogen, 6 (24%) by Wantai and none for HEV‐Ag. Anti‐HEV IgM tested positive in 80%‐100% within the second year and 17%‐42% over 3 years later, by Wantai and Mikrogen, respectively. Among HEV RNA‐positive donors, 12 (25%) tested positive for either IgM by Mikrogen or Wantai, 9 (18%) for both and 18 (36%) for HEV‐Ag. HEV‐Ag positivity was more likely as HEV RNA was higher (14% if <2.2 log IU/mL; 64% if RNA ≥ 3.7). Overall, HEV‐Ag performed best, with a positive predictive value of 100% and diagnostic accuracy of 57%. Anti‐HEV IgM exhibited unexpectedly long persistence after a self‐limited acute hepatitis E. HEV‐Ag had the best performance and could be especially useful in settings where HEV RNA is not available.     

Mother‐to‐child transmission of hepatitis B: What more needs to be done to eliminate it around the world?

Mother‐to‐child transmission (MTCT) of hepatitis B virus (HBV) is a key component of the hepatitis B burden worldwide. Despite its efficacy to prevent HBV transmission, infant vaccination is not enough to control HBV MTCT. Additional efforts are urgently needed to evaluate and scale‐up preventive strategies especially in endemic countries, which are most affected. This review highlights the efficacy and barriers of the currently validated measures for the prevention of HBV MTCT and proposes alternatives adapted to resource‐limited settings to eventually achieve HBV elimination worldwide.     

Chronic hepatitis B and non‐alcoholic fatty liver disease: Conspirators or competitors?

Despite the widespread use of vaccines and antiviral drugs, approximately 350‐400 million patients with chronic hepatitis B (CHB) remain worldwide, who carry high risk of cirrhosis and liver carcinoma. Moreover, owing to improvements in global living standards and lifestyle changes, non‐alcoholic fatty liver disease (NAFLD) has become the most common chronic liver disease. Coexistence of NAFLD and CHB is commonly observed, especially in Asian CHB populations; however, little is known regarding the relationship between these two diseases as comorbidities. In this review, we summarize recent advances in clinical and basic researches related to the underlying mutual interactions, as well as potential animal models to facilitate further investigation.     

How do people in prison feel about opt‐out hepatitis C virus testing?

The prison population is central to the campaign to eliminate hepatitis C virus as a public health threat. In the UK, this has led to the introduction of a national ‘opt‐out’ policy, requiring people in prison to be tested for HCV unless they decline, with a target to test 75% of those admitted. However, in a representative prison estate in the East Midlands of England (20,000 prison entrants per annum) testing rates were only 13.4%. This qualitative study explains why the rates of test uptake are so far short of target. This qualitative study examines the experiences of 45 people in prison about hepatitis C virus testing in an English category C (low security) prison. The data collection method was semi‐structured interviews. The data were coded and analysed according to the research questions, and interpretation of the data was aided by the use of a thematic network approach. The themes Fear, Insufficient Knowledge, Stigma, Privacy, Choice and Prison Life emerged as the principal barriers to test uptake. Test Uptake Facilitators that promoted testing were identified by participants and benefits presented of prison health care being a Health Farm. In order to increase hepatitis C virus test uptake, significant changes and flexibility in the timing, location, and staff deployed to test are required. Providing information to people in prison about hepatitis C virus transmission and treatment may reduce fears and enable the test uptake target to be met and sustained.