Prevention of Hepatitis B reactivation in the setting of immunosuppression.

Advances in the treatment of malignant and inflammatory diseases have developed over time, with increasing use of chemotherapeutic and immunosuppressive agents of a range of drug classes with varying mechanism and potency in their effects on the immune system. These advances have been met with the challenge of increased risk of hepatitis B virus (HBV) reactivation in susceptible individuals. The magnitude of risk of HBV reactivation is associated with the individual's HBV serological status and the potency and duration of immunosuppression. Individuals with chronic hepatitis B (CHB) and previously infected but serologically cleared HBV infection are both susceptible to HBV reactivation. HBV reactivation in the setting of immunosuppression is a potentially life threatening condition leading to liver failure and death in extreme cases. It is important to recognize that HBV reactivation in the setting of immunosuppression is potentially preventable. Therefore, identification of patients at risk of HBV reactivation and institution of prophylactic antiviral therapy prior to initiation of immunosuppression is essential.

Hepatitis B reactivation in the setting of chemotherapy and immunosuppression - prevention is better than cure.

Due to the inherent relationship between the immune system and the hepatitis B virus (HBV) in exposed and infected individuals, immunomodulation associated with the treatment of solid tumours, haematological malignancies and inflammatory disorders has been linked to HBV reactivation (HBVr). Reactivation of HBV infection in the setting of chemotherapy and immunosuppression may lead to fulminant liver failure and death, but there is a cumulative body of evidence that these are potentially preventable adverse outcomes. As chronic hepatitis B is largely asymptomatic but also endemic worldwide, clinicians caring for patients requiring chemotherapy or immunosuppression need to be vigilant of the potential for HBVr in susceptible individuals. Serological screening and prophylactic and pre-emptive antiviral treatment with a nucleos(t)ide analogue should be considered in appropriate settings. Hepatitis B prevalence is examined in this review article, as are the risks of HBVr in patients receiving chemo- and immunosuppressive therapy. Recommendations regarding screening, monitoring and the role of antiviral prophylaxis are outlined with reference to current international associations' guidelines and the best available evidence to date.

Longer duration of transient elastography predicts unreliable liver stiffness measurements.

BACKGROUND: Transient elastography (TE) is a noninvasive, validated method to assess liver fibrosis by obtaining liver stiffness measurements (LSM). However, TE can be limited by unreliable measurement (UM). The relationship between the time taken to perform TE (duration) and UM has not been studied. OBJECTIVES: To determine whether the duration of TE correlates with UM. MATERIALS AND METHODS: We prospectively studied the frequency and predictors of UM over a 5-year period. UM was defined as follows: less than 10 successful measurements, success rate less than 60%, or interquartile range more than 30% of the median LSM value (IQR/LSM>30%). RESULTS: Among the 2834 patients with LSM analysed, UM occurred in 19.0%. Duration [odds ratio (OR) 4.2, 95% confidence interval (CI) 2.8-6.4; P<0.0001] was the strongest predictor of UM, followed by BMI more than 28 kg/m (OR 2.1, 95% CI 1.5-3.0; P<0.0001), age more than 52 (OR 1.6, 95% CI 1.1-2.3; P=0.007) and non-HBV aetiology (OR 1.6, 95% CI 1.1-2.3; P=0.02). An optimal cut-off of 3 min 47 s was calculated for predicting UM (sensitivity 70%, specificity 65%, OR 4.2, 95% CI 2.7-6.6, P<0.0001). Examinations that took longer than 8 min 10 s had a 90% chance of UM. CONCLUSION: In experienced hands, duration is a strong predictor of UM in patients undergoing TE. Examinations longer than 4 min are more likely to be unreliable. Examinations longer than 8 min are unlikely to yield a valid result and should be considered a futility endpoint. Older age and increased BMI and nonhepatitis B aetiology are independent, albeit weaker, predictors of UM.

Entecavir versus lamivudine for hepatitis B prophylaxis in patients with haematological disease.

BACKGROUND: Hepatitis B reactivation in patients receiving immunosuppressive therapy or chemotherapy may be associated with acute hepatitis, liver failure and/or death. AIM: To audit the efficacy of entecavir as compared to lamivudine for the prophylaxis of HBV reactivation in patients with haematological disease receiving immunosuppression or chemotherapy. METHODS: Patients treated for haematological disease with pretreatment serological evidence of chronic hepatitis B (CHB) (HBV surface antigen, HBsAg positive) or resolved HBV infection (HBsAg negative but HBV core antibody positive) are included in this study. Patients received lamivudine 100 mg or entecavir 0.5 mg daily. Hepatitis B serology, HBV DNA and ALT were audited at baseline, 6 months, year 1, 2 and 3. HBV reactivation was defined as a 1 log increase in HBV DNA from baseline or reversion to sAg positivity. The occurrence of jaundice, symptomatic hepatitis, liver failure or death were audited. RESULTS: Of the 40 patients included in the study, 65% (4 CHB and 22 resolved HBV) received entecavir and 35% (11 CHB and 3 resolved HBV) received lamivudine. One patient with resolved HBV experienced HBV seroreversion related to premature cessation of entecavir. Eight patients with CHB (two from entecavir group and six from lamivudine group) had detectable HBVDNA levels at baseline; one case of HBV reactivation related to probable lamivudine resistance was identified. No HBV related deaths occurred. CONCLUSION: Lamivudine and entecavir are both efficacious in the prophylaxis of hepatitis B reactivation. Entecavir should be used in preference to lamivudine in patients CHB with detectable baseline HBV DNA levels.

A 24-week dietary and physical activity lifestyle intervention reduces hepatic insulin resistance in the obese with chronic hepatitis C.

BACKGROUND/AIMS: Obesity- and virus-mediated insulin resistance (IR) are associated with adverse hepatic and metabolic outcomes in chronic hepatitis C (CHC). This study evaluates the tolerability and effects of a dietary and physical activity (PA) intervention in obese patients with insulin-resistant CHC. METHODS: Obese patients (body mass index, BMI ≥30 kg/m(2) ) with CHC were recruited prospectively. Non-diabetic patients with IR (homeostasis model assessment of IR, HOMA-IR >2.0) proceeded to a 24-week lifestyle intervention comprising pedometer monitored increase in PA (≥10 000 steps/day) and an individualised dietary plan. RESULTS: Ten non-cirrhotic and six cirrhotic patients [age 52 ± 8.5 years, BMI 35.9 (31.46-38.21)kg/m(2) ] were recruited, of whom all 16 (100%) completed the 24-week protocol. Increase in PA from 6853 (2440-9533) to 10 697 (7959-13566) steps/day (P = 0.001) and reduction in caloric intake from 2263 (1805.4-2697.0) to 1281 (1099.5-1856.3) kcal/day (equivalent to reduction of median 33% (25.3-49.8%), P < 0.001) were achieved. These behaviour changes led to a BMI reduction to 31.21 (28.72-36.10) (P < 0.001) and the HOMA-IR fell from 3.62 (2.75-4.87) to 2.08 (1.82-3.59) (P = 0.002). The hepatic insulin sensitivity index (ISI) improved significantly, but the skeletal muscle ISI did not. At week 24, 8/16 (50%) patients were no longer insulin-resistant (P = 0.008). CONCLUSIONS: This 24-week intervention reduced BMI and reversed IR in significant proportion of patients. Such adjunctive therapy may improve hepatic and metabolic status in obese insulin-resistant CHC.

Combining semiquantitative measures of fibrosis and qualitative features of parenchymal remodelling to identify fibrosis regression in hepatitis C: a multiple biopsy study.

AIMS: A fall in hepatic fibrosis stage may be observed in patients with chronic hepatitis C (CHC); however, parenchymal architectural changes may also signify hepatic remodelling associated with fibrosis regression. The aim of this study was to utilize semiquantitative and qualitative methods to report the prevalence and factors associated with fibrosis regression in CHC. METHODS AND RESULTS: Paired liver biopsies were scored for fibrosis (Ishak), and for the presence of eight qualitative features of parenchymal remodelling, to derive a qualitative regression score (QR score). Combined fibrosis regression was defined as ≥2-stage fall in Ishak stage (Reg-I) or <2-stage fall in Ishak stage with a rise in QR score (Reg-Qual). Among 159 patients (biopsy interval 5.4 ± 3.1 years), Reg-I was observed in 12 (7.5%) and Reg-Qual in 26 (16.4%) patients. The combined diagnostic criteria increased the diagnosis rate for fibrosis regression (38 patients, 23.9%) compared with use of Reg-I alone (P < 0.001). Combined fibrosis regression was observed in nine patients (50%) who achieved sustained virological response (SVR), and in 29 of 141 (21%) patients despite persistent viraemia. SVR was the only clinical factor associated independently with combined fibrosis regression (odds ratio 3.05). CONCLUSIONS: The combination of semiquantitative measures and qualitative features aids the identification of fibrosis regression in CHC.

Hepatic cell-type specific gene expression better predicts HCV treatment outcome than IL28B genotype.

BACKGROUND & AIMS: Cell-type specific expression patterns of hepatic interferon-stimulated genes (ISGs) and single nucleotide polymorphisms (SNPs) near the IL28B gene are associated with response to interferon-based therapy in patients with chronic hepatitis C virus (HCV) infection. It is not known how the IL28B genotype influences the ISG expression pattern and which is a better predictor of treatment response. METHODS: Patients at the Toronto Western Hospital Liver Centre with known outcome to interferon-based treatment for HCV infection were evaluated. Analysis included hepatic gene expression profile using complementary DNA microarrays, genotype at the IL28B SNP rs12979860, and immunostaining for human myxovirus A protein 1 (MxA) in hepatocytes and macrophages. RESULTS: The level of ISG immunostaining in hepatic macrophages correlated inversely with that of hepatocytes and was strongly associated with treatment outcome. Gene expression profiles and the IL28B genotype were associated with treatment response, but only absence of MxA staining in macrophages accurately predicted nonresponse to treatment. The positive predictive value (PPV) of the IL28B genotype was 94% and the negative predictive value (NPV) was 51% (n = 209). For messenger RNA expression, the PPV was 94% and the NPV was 54% (n = 65). For detection of MxA in macrophages, the PPV was 60% and the NPV was 98% (n = 110). Of 53 patients with undetectable macrophage MxA staining, only one had a sustained virologic response. IL28B genotype was strongly associated with cell-type specific staining for MxA. There was a stepwise increase in macrophage staining and decrease in hepatocyte staining from the TT (lack of response) to CC SNP (associated with response) in IL28B. By logistic regression, after controlling for the presence of macrophage MxA staining, the IL28B genotype was no longer associated with treatment response. CONCLUSIONS: The cell-type-specific expression pattern of ISGs varies among patients with different IL28B genotypes and is a strong predictor of response to interferon-based treatment.

Poor Perception of Body Weight Category amongst the Overweight and Obese with Chronic Hepatitis C: A Target for Intervention.

Obesity in chronic hepatitis C (CHC) is associated with adverse hepatic and metabolic outcomes. This prospective study evaluates the agreement between self-perceived body weight (BW) status and measured body mass index (BMI) category and factors associated with its underestimation in CHC. Body size perception was measured with the Contour Drawing Rating Scale. Two hundred and seventy-three patients with CHC (overweight 45%, obese 18%) participated in this study. Although both overweight and obese demonstrated good body size perception, agreement between perceived BW and measured BMI categories was poor (κ = 0.315, 95% CI 0.231-0.399); 33% of overweight/obese respondents considered themselves normal or underweight. Male gender (OR 2.84) and overweight (OR 2.42) or obese BMI (OR 14.19) were associated with underestimation of BW category. Targeted interventions are needed to improve body weight perception, thereby enhancing the uptake of health advice on management of excess body weight in CHC.

Influence of hepatitis C virus on neurocognitive function in patients free from other risk factors: validation from therapeutic outcomes.

BACKGROUND AND AIMS: Mild neurocognitive dysfunction and altered cerebral proton magnetic resonance spectroscopy ((1) H-MRS) have been demonstrated in patients with chronic hepatitis C (CHC). This longitudinal study aimed to quantify these abnormalities in a cohort of patients free from correlated risk factors and determine whether treatment-induced viral clearance abolished these abnormalities. METHODS: Treatment-naïve, non-cirrhotic patients with CHC, rigorously screened and excluded for other causes of impaired neurocognition, underwent neurocognitive testing, (1) H-MRS and evaluation for quality of life (QOL), mood and fatigue, before and 6 months after the completion of antiviral therapy. A comparison group of healthy controls was similarly assessed at baseline and 1 year later. RESULTS: Post-treatment results in 40 patients with CHC [31 sustained virological responders, hepatitis C virus (HCV)-R and 9 non-responders, HCV-NR] were compared with their pretreatment results, and with the baseline and follow-up assessments of 39 healthy controls. Before receiving treatment, patients had impaired learning efficiency, poorer QOL and higher fatigue scores compared with the controls. Viral clearance was associated with a significant albeit small improvement in the QOL score that did not reach control levels. Cerebral (1) H-MRS demonstrated a lower N-acetyl aspartate/creatine (CRE) ratio in the globus pallidus (GP) of patients with hepatitis C, which was unchanged with viral clearance. The GP choline/CRE ratio increased in HCV-R following treatment, without a correlation with cognitive measures. CONCLUSIONS: The hepatitis C virus has a measurable effect on CNS integrity in patients screened for other medical and/or psychiatric comorbidities. Viral clearance has not been demonstrated to abolish these abnormalities.

Organelle dysfunction in hepatitis C virus-associated steatosis: anything to learn from nonalcoholic steatohepatitis?

Nonalcoholic fatty liver disease (NAFLD) spans a pathological spectrum from nonalcoholic steatosis to steatohepatitis. The pathophysiology of this disorder is complex, but includes insulin resistance and disrupted lipid and carbohydrate homeostasis, which at a subcellular level results in oxidative stress, free fatty acid-mediated lipotoxicity, defects in mitochondrial function, endoplasmic reticulum stress and cytokine-mediated toxicity. In chronic hepatitis C (CHC), systemic metabolic derangements similar to NAFLD may be operative, but in addition, virus-specific factors contribute to steatosis. The mechanisms for steatosis in CHC appear to share common pathways with those observed in NAFLD. This article outlines our current understanding of the subcellular mechanisms of steatosis in NAFLD and CHC, including their similarities and differences.

Superior response to pegylated interferon and ribavirin in Asians with chronic hepatitis C.

PURPOSE: Reported sustained virological response (SVR) rates in Asians with chronic hepatitis C (CHC) exceed those of other ethnic groups, but differences in body weight across races potentially confound this observed superior response. Our aim was to determine whether Asian race independently predicts SVR within a multicultural clinic setting. METHODS: Patients with genotype 1, 2 and 3 CHC prescribed peginterferon and weight-based ribavirin were included in this retrospective study. Logistic regression was performed to identify factors associated with SVR. RESULTS: Three-hundred ninety-two patients (BMI 26.9 ± 5.0 kg/m(2), genotype 1 66%, viral load 5.9 ± 0.66 log(10) IU/ml, advanced fibrosis 53%) were included in this study. Caucasians comprised 81%, South Asians 9% and Asians (Non-South) 10%. SVR was achieved by 54% overall, but was highest amongst Asians (Non-South) (79%) compared with South Asians (56%, P = 0.04) and Caucasians (50%, P < 0.001) despite a predominance of genotype 3 infection amongst the South Asians. Asians (Non-South) had the highest SVR rate even amongst those infected with genotype 1 (75%) and those with advanced fibrosis (77%). Independent of viral genotype, Asian (Non-South) race was a strong predictor of SVR (OR 5.10 vs. Caucasians, 95% CI 1.72-17.71, OR 7.84 vs. South Asians, 95% CI 1.62-37.84), as were treatment naïve status (OR 3.85, 95% CI 1.76-8.89), non-diabetic status (OR 3.70, 95% CI 1.30-11.11), non-obesity (OR 2.13, 95% CI 1.06-4.35), peginterferon α2a (2.08 vs. α2b, 95% CI 1.16-3.85), steatosis <10% (OR 2.0, 95% CI 1.05-3.85) and ribavirin exposure (mg/kg/day) (OR 1.13, 95% CI 1.01-1.28). CONCLUSION: Asian (Non-South) race is a strong independent predictor of SVR.

Hepatitis C and diabetes: one treatment for two diseases?

Abstract Epidemiological data clearly indicate a link between chronic hepatitis C (CHC) and disturbed glucose homeostasis. The prevalences of both type 2 diabetes mellitus (T2DM) and insulin resistance (IR) are higher among those chronically infected with hepatitis C when compared with the general population and those with other causes of chronic liver disease. Both IR and diabetes are associated with adverse outcomes across all stages of CHC including the liver transplant population. The adverse effects that directly influence patient outcome are reduced responsiveness to antiviral therapy, more rapid progression of fibrosis to cirrhosis and a higher incidence of hepatocellular carcinoma. Although both viral and host factors are known to contribute to IR (and therefore the risk of T2DM), there is a paucity of evidence to support interventions targeting IR with pharmacotherapy or lifestyle intervention. The purpose of this review is to examine the impact of abnormalities of glucose homeostasis in CHC, and in so doing, to raise a number of questions. How do we identify those at risk of diabetes in CHC? Can we reduce the incidence of hepatoma and reduce transplant-related morbidity and mortality by preventing or treating diabetes? Can we improve the response to antiviral therapy by pretreating IR and T2DM in treatment candidates? Ultimately, can we cure two diseases, diabetes and CHC, with one treatment?