Stephen Wong

An Update on the Management of Chronic Hepatitis C: 2015 Consensus Guidelines from the Canadian Association for the Study of the Liver

Chronic hepatitis C remains a significant medical and economic burden in Canada, affecting nearly 1% of the population. Since the last Canadian consensus conference on the management of chronic hepatitis C, major advances have occurred that warrant a review of recommended management approaches for these patients. Specifically, direct-acting antiviral agents with dramatically improved rates of virological clearance compared with standard therapy have been developed and interferon-free, all-oral antiviral regimens have been approved. In light of this new evidence, an update to the 2012 Canadian Association for the Study of the Liver consensus guidelines on the management of hepatitis C was produced. The present document reviews the epidemiology of hepatitis C in Canada, preferred diagnostic testing approaches and recommendations for the treatment of chronically infected patients with the newly approved antiviral agents, including those who have previously failed peginterferon and ribavirin-based therapy. In addition, recommendations are made regarding approaches to reducing the burden of hepatitis C in Canada.

Patient concerns regarding chronic hepatitis C infections.

Summary.  Counselling of patients with chronic hepatitis C infections is often limited to discussions regarding how the virus is transmitted and what can be done to decrease the risk of transmission to others. The purpose of the present study was to document the principal concerns of newly diagnosed and follow‐up patients with chronic hepatitis C, and thereby enhance counselling strategies and content. Seventy newly diagnosed and 115 follow‐up patients with chronic hepatitis C virus (HCV) infection were initially asked in an open‐ended manner (volunteered concerns) and then to prioritize from a prepared list of seven potential concerns (prioritized concerns), to identify those concerns that were of utmost importance to them. The most common volunteered concerns of newly diagnosed patients in decreasing order were: disease progression (27%), premature death (19%), infecting family members (13%), side‐effects of treatment (11%) and miscellaneous others. In decreasing order, prioritized concerns included: infecting family members, development of liver cancer, infecting others, development of cirrhosis, social stigma of having liver disease, need for liver transplant and loss of employment. The principal volunteered and prioritized concerns of follow‐up patients were similar to those of newly diagnosed patients. Volunteered and prioritized concerns were relatively consistent across the different genders, age groups, ethnic backgrounds, education level, marital status, employment, modes of viral acquisition and in the case of follow‐up patients, duration of follow‐up. These results indicate that health care providers who focus counselling efforts exclusively on viral transmission are unlikely to address other important concerns of newly diagnosed and follow‐up patients with chronic HCV infection.

Autoimmune Hepatitis in a North American Aboriginal/First Nations Population

North American Aboriginal populations are at increased risk for developing immune-mediated disorders, including autoimmune hepatitis. In the present study, the demographic, clinical, biochemical, serological, radiological and histological features of autoimmune hepatitis were compared in 33 First Nations (FN) and 150 predominantly Caucasian, non-FN patients referred to an urban tertiary care centre. FN patients were more often female (91% versus 71%; P=0.04), and more likely to have low serum albumin (69% versus 36%; P=0.0006) and elevated bilirubin (57% versus 35%; P=0.01) levels on presentation compared with non-FN patients. They also had lower hemoglobin, and complement levels, more cholestasis and higher serum immunoglobulin A levels than non-FN patients (P=0.05 respectively). Higher histological grades of inflammation and stages of fibrosis, and more clinical and radiological evidence of advanced liver disease were observed in FN patients, but the differences failed to reach statistical significance. The results of the present study suggest that in addition to being more common, autoimmune hepatitis may be more severe in FN populations, compared with predominantly Caucasian, non-FN populations.

Persistent pro‐inflammatory cytokines following the initiation of pegylated IFN therapy in hepatitis C infection is associated with treatment‐induced depression

Summary.  Pegylated interferon (IFN), the basis for chronic hepatitis C virus (HCV) treatment, causes depression in 30–40% of patients. The potential for cytokine mRNA patterns from baseline into early treatment to associate with the onset of treatment‐induced depression (TID) was examined. Depression was measured by the Beck Depression Inventory at baseline and weeks 2, 4, 8 and 12 of treatment (n = 38). At baseline and weeks 2 and 4, peripheral blood mononuclear cell (PMBC, n = 28), isolated ex vivo, were examined for tumour neurosis factor (TNF)‐alpha, interleukin (IL)‐1beta and IL‐10 mRNA expression. In patients that developed treatment‐induced depression, pro‐inflammatory TNF‐alpha mRNA levels from baseline into week 4 of therapy remained constant (1.1‐fold increase); whereas IL‐1beta transcripts decreased 3.5 fold. However, corresponding TNF‐alpha (3‐fold, P < 0.05) and IL‐1beta (7.5‐fold) transcript expression diminished to a greater extent in the absence of TID. Changes in TNF‐alpha mRNA values correlated to the average change in BDI scores over the 12 weeks (r = 0.56, P < 0.05). Concomitantly, anti‐inflammatory IL‐10 transcript levels decreased in (TID), relative to increased expression in the absence of TID (P < 0.05). The potential influence of IL‐10 was observed upon calculation of individual pro‐ verses anti‐inflammatory mRNA ratios. Stable in the presence of depression, TNF‐alpha/IL‐10 and IL‐1beta/IL‐10 mRNA ratios declined significantly over time in its absence (P < 0.05). This study suggests that in chronic HCV infection, upon pegylated IFN administration persistent pro‐inflammatory cytokine MRNA expression associates with TID. In contrast, therapeutic activation of mechanisms that decrease pro‐inflammatory immunity may protect against depression during therapy.

Treatment outcomes in a centralized specialty clinic for hepatitis C virus are comparable with those from clinical trials

BACKGROUND Outcomes from industry-sponsored registration trials are often considered to be more favourable than those achieved in clinical practice because patients involved in the former are highly selected and supported, but it is not known if this impression is valid. OBJECTIVE To determine the outcome of hepatitis C virus (HCV)-infected patients who received therapies for chronic HCV in a single urban centre and compare the results with those derived from contemporary, industry-sponsored trials. DESIGN Retrospective chart review of HCV-infected patients referred to the Viral Hepatitis Investigative Unit in Winnipeg, Manitoba, between 1998 and 2003. METHODS The Viral Hepatitis Investigative Unit database was used to identify all referred patients with positive anti-HCV antibodies. Charts were reviewed for the following data: patient demographics; viral genotype; indications and contraindications to treatment; treatment type; and outcome of antiviral therapy. RESULTS For 1800 anti-HCV positive patients identified, 1078 charts were available for review. Of these patients, the mean age was 47 years (range 11 years to 90 years) and 53% were men. Genotype 1 was the most common (65%). A total of 331 patients (31%) had received antiviral therapy. The sustained viral responses were similar to those described in industry-sponsored registration trials. Specifically, the sustained viral responses for interferon-alpha monotherapy (n=81) was 22.2%, interferon-alpha plus ribavirin (n=180) 44.4%, pegylated interferon monotherapy (n=38) 44.7% and pegylated interferon plus ribavirin (n=24) 54.2%. CONCLUSION HCV treatment outcomes from a single urban centre were similar to those described in industry-sponsored registration trials despite the high selection and support provided to patients enrolled in the latter studies.

Treatment of chronic hepatitis C in a Canadian Aboriginal population: results from the PRAIRIE study.

BACKGROUND The Aboriginal population of Canada is at increased risk of exposure to the hepatitis C virus (HCV). Previous data indicate that spontaneous clearance of HCV occurs more often in Aboriginals than Caucasians. Whether this enhanced response extends to antiviral therapy for chronic HCV remains to be determined. OBJECTIVES To document and compare the biochemical and virological responses to antiviral therapy in HCV-infected Canadian Aboriginals and Caucasians. METHODS A total of 101 treatment-naive adult patients (46 Aboriginal, 55 Caucasian) with chronic HCV genotype 1 infections were prospectively treated with pegylated-interferon and ribavirin and followed as per national guidelines. RESULTS Aboriginals had higher HCV-RNA loads at baseline (6.42log(10) versus 5.98log(10); P<0.03). Although normalization of serum aminotransferase levels, decreases in viral loads, and rapid, early and end-of-treatment virological responses were similar in the two cohorts, sustained virological responses were significantly lower in Aboriginals (35% versus 55%; P=0.047). Premature discontinuation of treatment and⁄or loss of patients to follow-up was common (Aboriginals 37%, Caucasians 27%). Treatment-related side effects were similar in the two cohorts. CONCLUSION Despite higher rates of spontaneous HCV clearance, the response to antiviral therapy was similar, if not lower, in Aboriginals compared with Caucasians with chronic HCV genotype 1 infections. Compliance with treatment is an issue that needs to be addressed in the management of these patients.

Baseline Comorbidities Enhance the Risk of Treatment-Induced Depression in HCV-Infected Men A Pilot Study

Background. Hepatitis C virus (HCV) infection is associated with clinical depression,a condition that is aggravated on interferon-based therapy. In HCV infection, men often appear more resilient to depression than women. However, men are subject to depression in diseases that tend to be comorbid in HCV-infected. Aim. This study examined whether HCV-infected men with baseline comorbidities were more or less susceptible to depression prior to and on treatment. Methods. Patients with chronic HCV infection preparing to begin treatment participated (n = 37). The presence of baseline comorbidities was determined by pretreatment medication regimes. Depression was measured by the Beck Depression Inventory prior to and following 2, 4, 8, and 12 weeks of interferon therapy. Results. At baseline, cohorts with (n = 16) and without (n = 21) comorbidities had equivocal demographics and infection characteristics. Comorbidities did not associate with baseline depression. However, on treatment, men with baseline comorbidities demonstrated an elevated risk for the onset of de novo depression (odds ratio = 19.25; confidence interval = 1.41, 582.14; p = .008). This was not observed for women. Baseline comorbidities did not alter the need for treatment discontinuations or the ability to achieve a sustained viral response. Conclusion. The results of this study suggest that baseline comorbidities render men more susceptible to interferon treatment–induced depression.

Concomitant nonalcoholic fatty liver disease does not alter the activity, severity or course of primary biliary cholangitis

The impact of nonalcoholic fatty liver disease (NAFLD) on the natural history of primary biliary cholangitis (PBC) has yet to be described. The aim of this study was to document the activity, severity and progression of PBC in patients with concomitant NAFLD and compare the findings to those with PBC alone.

HCV protein-induced cytokine predicts treatment outcomes in chronic hepatitis C virus infection

Immune‐mediated processes are thought to influence the efficacy of treatment in chronic hepatitis C virus (HCV) infection. This study evaluated the association of baseline immune responses with the achievement of a sustained viral response (SVR) upon pegylated interferon and ribavirin treatment.

Liver Enzymes as Surrogate Markers of Hepatitis C Histopathology – Avoiding the Liver Biopsy Needle?

A retrospective cohort study of 79 patients with chronic hepatitis C was performed to assess the predictive nature of various variables (age, sex, route of transmission, extent of steatosis, alcohol consumption and serum aminotransferase values), with the underlying hepatic histopathology. The newly modified Knodell histological activity index by Desmet et al (1), which separately scores the inflammation from the fibrosis on the liver biopsy, was used. Using stepwise multivariate logistic regression, it was discovered that serum aspartate aminotransferase (AST) values had a predictive relationship with overall histological activity (r=0.62), portal inflammation (r=0.58), piecemeal necrosis (r=0.61) and extent of hepatic fibrosis (r=0.64). Serum AST values correctly predicted the inflammatory grade in 63 of 79 (80%) patients, and the fibrosis stage in 50 of 79 (63%) patients - higher than the predictive values of ALT. Serum alanine aminotransferase (ALT) values did not correlate with the degree of histological inflammation (r=0.39) but did correlate mildly with the extent of hepatic fibrosis (r=0.51). There were no significant correlations of the other variables with histological inflammation or fibrosis.