Liver-restricted Type I IFN Signature Precedes Liver Damage in Chronic Hepatitis B Patients Stopping Antiviral Therapy.

Immune-mediated liver damage is the driver of disease progression in patients with chronic hepatitis B virus (HBV) infection. Liver damage is an Ag-independent process caused by bystander activation of CD8 T cells and NK cells. How bystander lymphocyte activation is initiated in chronic hepatitis B patients remains unclear. Periods of liver damage, called hepatic flares, occur unpredictably, making early events difficult to capture. To address this obstacle, we longitudinally sampled the liver of chronic hepatitis B patients stopping antiviral therapy and analyzed immune composition and activation using flow cytometry and single-cell RNA sequencing. At 4 wk after stopping therapy, HBV replication rebounded but no liver damage was detectable. There were no changes in cell frequencies at viral rebound. Single-cell RNA sequencing revealed upregulation of IFN-stimulated genes (ISGs) and proinflammatory cytokine migration inhibitory factor (MIF) at viral rebound in patients that go on to develop hepatic flares 6-18 wk after stopping therapy. The type I IFN signature was only detectable within the liver, and neither IFN-α/ß or ISG induction could be detected in the peripheral blood. In vitro experiments confirmed the type I IFN-dependent ISG profile whereas MIF was induced primarily by IL-12. MIF exposure further amplified inflammatory cytokine production by myeloid cells. Our data show that innate immune activation is detectable in the liver before clinically significant liver damage is evident. The combination of type I IFN and enhanced cytokine production upon MIF exposure represent the earliest immunological triggers of lymphocyte bystander activation observed in hepatic flares associated with chronic HBV infection.

Altered hepatic gene expression in nonalcoholic fatty liver disease is associated with lower hepatic n-3 and n-6 polyunsaturated fatty acids.

UNLABELLED: In nonalcoholic fatty liver disease, hepatic gene expression and fatty acid (FA) composition have been reported independently, but a comprehensive gene expression profiling in relation to FA composition is lacking. The aim was to assess this relationship. In a cross-sectional study, hepatic gene expression (Illumina Microarray) was first compared among 20 patients with simple steatosis (SS), 19 with nonalcoholic steatohepatitis (NASH), and 24 healthy controls. The FA composition in hepatic total lipids was compared between SS and NASH, and associations between gene expression and FAs were examined. Gene expression differed mainly between healthy controls and patients (SS and NASH), including genes related to unsaturated FA metabolism. Twenty-two genes were differentially expressed between NASH and SS; most of them correlated with disease severity and related more to cancer progression than to lipid metabolism. Biologically active long-chain polyunsaturated FAs (PUFAs; eicosapentaenoic acid + docosahexaenoic acid, arachidonic acid) in hepatic total lipids were lower in NASH than in SS. This may be related to overexpression of FADS1, FADS2, and PNPLA3. The degree and direction of correlations between PUFAs and gene expression were different among SS and NASH, which may suggest that low PUFA content in NASH modulates gene expression in a different way compared with SS or, alternatively, that gene expression influences PUFA content differently depending on disease severity (SS versus NASH). CONCLUSION: Well-defined subjects with either healthy liver, SS, or NASH showed distinct hepatic gene expression profiles including genes involved in unsaturated FA metabolism. In patients with NASH, hepatic PUFAs were lower and associations with gene expression were different compared to SS.

Differential predictors of ART adherence among HIV-monoinfected versus HIV/HCV-coinfected individuals.

Although adherence is an important key to the efficacy of antiretroviral therapy (ART), many people living with HIV (PLWH) fail to maintain optimal levels of ART adherence over time. PLWH with the added burden of Hepatitis C virus (HCV) coinfection possess unique challenges that potentially impact their motivation and ability to adhere to ART. The present investigation sought to (1) compare ART adherence levels among a sample of HIV/HCV-coinfected versus HIV-monoinfected patients, and (2) identify whether ART-related clinical and psychosocial correlates differ by HCV status. PLWH receiving ART (N = 215: 105 HIV/HCV-coinfected, 110 HIV-monoinfected) completed a comprehensive survey assessing ART adherence and its potential correlates. Medical chart extraction identified clinical factors, including liver enzymes. Results demonstrated that ART adherence did not differ by HCV status, with 83.7% of coinfected patients and 82.4% of monoinfected patients reporting optimal (i.e., ≥95%) adherence during a four-day recall period (p = .809). Multivariable logistic regression demonstrated that regardless of HCV status, optimal ART adherence was associated with experiencing fewer adherence-related behavioral skills barriers (AOR = 0.56; 95%CI = 0.43-0.73), lower likelihood of problematic drinking (AOR = 0.15; 95%CI = 0.04-0.67), and lower likelihood of methamphetamine use (AOR = 0.14; 95%CI = 0.03-0.69). However, among HIV/HCV-coinfected patients, optimal adherence was additionally associated with experiencing fewer ART adherence-related motivational barriers (AOR = 0.23; 95%CI = 0.08-0.62) and lower likelihood of depression (AOR = 0.06; 95%CI = 0.00-0.84). Findings suggest that although HIV/HCV-coinfected patients may face additional, distinct barriers to ART adherence, levels of adherence commensurate with those demonstrated by HIV-monoinfected patients might be achievable if these barriers are addressed.

Hepatitis C virus late relapse after sustained virologic response from interferon and ribavirin treatment as confirmed by RNA sequencing.

Hepatitis C virus (HCV) viremia is unusual (<5%) after successful treatment, defined as sustained virologic response (SVR) or undetectable HCV PCR 12 to 24 weeks after therapy. We present a case of late virologic relapse (de novo infection was excluded by RNA sequencing) after SVR followed by spontaneous viral clearance.

Health state utilities and quality of life in patients with hepatitis B.

BACKGROUND: The effect of chronic hepatitis B (CHB) infection on health-related quality of life (HRQoL) and health state utilities has not been well characterized. OBJECTIVE: To measure utility scores and HRQoL across disease states associated with CHB infection. METHODS: Patients attending four tertiary care clinics for CHB were approached between July 2007 and March 2009. Respondents completed version 2 of the Short-Form 36 Health Survey, the EQ5D, a visual analogue scale, the Health Utilities Index Mark 3, standard gamble, and demographics and risk factor surveys in English, Cantonese or Mandarin. Charts were reviewed to determine disease stage and comorbidities. RESULTS: A total of 433 patients were studied: 294 had no cirrhosis; 79 had compensated cirrhosis; seven had decompensated cirrhosis; 23 had hepatocellular carcinoma; and 30 had received a liver transplant. The mean standard gamble utilities for these disease states were 0.89, 0.87, 0.82, 0.84 and 0.86, respectively. HRQoL scores in noncirrhotic patients were similar to those of the general population. Scores of patients with compensated cirrhosis were not significantly lower; however, patients with decompensated cirrhosis and hepatocellular carcinoma had significantly lower HRQoL scores compared with noncirrhotic patients (P<0.05). Similar scores were observed among patients on and off oral antiviral treatment. Post-liver transplant patients had a higher HRQoL than patients with decompensated cirrhosis. Age, number of comorbidities and relationship status were significantly associated with HRQoL scores. CONCLUSIONS: HRQoL in CHB patients is only impaired in the later stages of liver disease. Neither CHB infection nor antiviral treatment is associated with a lower quality of life.

Tenofovir and entecavir are the most effective antiviral agents for chronic hepatitis B: a systematic review and Bayesian meta-analyses.

BACKGROUND & AIMS: The relative efficacies of licensed antiviral therapies for treatment-naive chronic hepatitis B (CHB) infection in randomized controlled trials have not been determined. We evaluated the relative efficacies of the first 12 months of CHB treatments. METHODS: Drugs evaluated were lamivudine, pegylated interferon, adefovir, entecavir, telbivudine, and tenofovir, as monotherapies and combination therapies, in treatment-naive individuals. Databases were searched for randomized controlled trials of the first 12 months of therapy in hepatitis B e antigen (HBeAg)-positive and/or HBeAg-negative patients with CHB published in English before October 31, 2009. Bayesian mixed treatment comparisons were used to calculate the odds ratios, including 95% credible intervals and predicted probabilities of surrogate outcomes to determine the relative effects of each treatment. RESULTS: In HBeAg-positive patients, tenofovir was most effective in inducing undetectable levels of HBV DNA (predicted probability, 88%), normalization of alanine aminotransferase (ALT) levels (66%), HBeAg seroconversion (20%), and hepatitis B surface antigen loss (5%); it ranked third in histologic improvement of the liver (53%). Entecavir was most effective in improving liver histology (56%), second for inducing undetectable levels of HBV DNA (61%) and normalization of ALT levels (70%), and third in loss of hepatitis B surface antigen (1%). In HBeAg-negative patients, tenofovir was the most effective in inducing undetectable levels of HBV DNA (94%) and improving liver histology (65%); it ranked second for normalization of ALT levels (73%). CONCLUSIONS: In the first year of treatment for CHB, tenofovir and entecavir are the most potent oral antiviral agents for HBeAg-positive patients; tenofovir is most effective for HBeAg-negative patients.

Liver Injury Associated With Ezetimibe Monotherapy.

Statin intolerance, primarily myalgia, is not uncommon in patients treated for elevated low-density lipoprotein cholesterol. Nonstatin drugs, such as ezetimibe, can spare patients from statin exposure, while still reducing low-density lipoprotein cholesterol. Ezetimibe is generally very well tolerated, although gastrointestinal and musculoskeletal symptoms have been occasionally reported. We describe an extremely rare case of an ezetimibe-associated liver injury who required protracted treatment with prednisone and azathioprine. Ezetimibe-associated liver injury should be suspected with development of hepatic abnormalities concurrent with the timing of ezetimibe treatment and in the absence of other possible precipitating factors.

L'intolérance aux statines, se manifestant principalement par une myalgie, n'est pas rare chez les patients traités pour des taux élevés de cholestérol à lipoprotéines à basse densité (LDL). Des médicaments n'appartenant pas à la classe des statines, comme l'ézétimibe, permettent d'éviter l'exposition aux statines chez les patients, tout en réduisant le taux le cholestérol LDL. L'ézétimibe est généralement bien toléré, bien que des symptômes gastro-intestinaux et musculosquelettiques aient été signalés à l'occasion. Nous décrivons un cas extrêmement rare de lésion hépatique associée à l'ézétimibe ayant nécessité un traitement prolongé par la prednisone et l'azathioprine. Il faut soupçonner une lésion hépatique liée à l'ézétimibe lors de la survenue d'anomalies hépatiques pendant le traitement par l'ézétimibe en l'absence d'autres facteurs déclencheurs.

Endpoints of therapy in chronic hepatitis B.

Because clearance of hepatitis B virus (HBV) infection is rarely, if ever, achievable, the goals of therapy necessarily focus on prevention of bad clinical outcomes. Ideally, therapies would be shown to prevent tangible clinical endpoints like development of cirrhosis, end-stage liver disease and hepatocellular carcinoma. However, these endpoints typically take years or decades to occur and are therefore impractical targets for clinical trials which last only 1-2 years. As a result, surrogate biomarkers that are believed to correlate with long-term outcome are used to evaluate therapy. Of the clinical, biochemical, serological, virological, and histological endpoints that have been evaluated, none has been shown to be ideal on its own. Symptoms are uncommon and aminotransferase levels fluctuate spontaneously. Loss of hepatitis B e antigen (HBeAg) has been the traditional therapeutic endpoint; however, the indefinite durability off treatment and the emergence of HBeAg-negative disease have made it inadequate as the sole goal of therapy. Loss of hepatitis B surface antigen is associated with improved clinical outcomes, but it is rarely achieved with current therapies. Suppression of viral replication, as measured by serum HBV DNA levels, has become the major goal of therapy, particularly if maintained off therapy. Although useful, the significance of viral levels depends on the stage of disease, degree of liver damage, and the type of therapy. Finally, liver biopsy, often considered the gold standard, is invasive, prone to sampling error, and may take years to change significantly.At present, there is no ideal biomarker for evaluation of therapies for hepatitis B. Future research should be directed at development and validation of surrogate markers that accurately predict or reflect clinically relevant outcomes of chronic hepatitis B.

Non-alcoholic fatty liver disease in HIV infection associated with altered hepatic fatty acid composition.

Hepatic fatty acid (FA) composition, especially a reduction in n-3 polyunsaturated FA (PUFA) may contribute to the pathogenesis of non-alcoholic fatty liver disease (NAFLD), which is common in HIV-infection.. In a cross-sectional study we compared hepatic FA composition between 20 HIV-infected men with NAFLD (HIV/NAFLD), 21 HIV-negative men with NAFLD (NAFLD), and 7 healthy controls. Within HIV/NAFLD we compared simple steatosis (HIV/SS) to steatohepatitis (HIV/NASH). FA composition in liver and erythrocytes, oxidative stress, diet, and exercise were assessed. Major findings (P<0.05) were: 1) higher hepatic n-6/n-3 ratio in HIV/NAFLD [median (range)] [8.08 (1.08-21.52)] compared to controls [5.83 (3.58-6.93)] and NAFLD [5.97 (1.46-10.40)], with higher n-6 PUFA in HIV/NAFLD compared to NAFLD; 2) lower n-3 PUFA in erythrocytes (mol%), a marker for dietary intake, in HIV/NAFLD [5.26 (1.04-11.75)] compared to controls [8.92 (4.79-12.67)]; 3) the ratios of long-chain PUFA products to essential FA precursors of the n-6 and n-3 series were lower in HIV/NAFLD and NAFLD compared to controls. In contrast, the ratio of oleic/stearic acid was higher in HIV/NAFLD compared to the other groups. These ratios are indirect markers of enzymatic FA desaturation and elongation. Hepatic PUFA, especially biologically active long-chain PUFA, were also lower in HIV/NASH compared to HIV/SS. Oxidative stress was not different among the groups. We conclude that HIV/NAFLD is associated with altered hepatic FA composition. Changes may be due to impaired FA metabolism or suboptimal n-3 PUFA intake. The potential role of n-3 PUFA (e.g. fish oil) to treat or prevent HIV/NAFLD warrants further investigation.

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 B virus genotypes, precore and core promoter variants among predominantly Asian patients with chronic HBV infection in a Canadian center.

BACKGROUND AND AIMS: The epidemiology of hepatitis B virus (HBV) infection in North America may be changing as a result of immigration from endemic countries. The purpose of this study was to determine the prevalence of HBV genotypes, precore (PC) and core promoter (CP) variants, and the proportion of patients meeting treatment criteria for HBV. METHODS: A cross-sectional study of consecutive HBV patients attending a Canadian tertiary liver center was conducted. HBV DNA was quantified by polymerase chain reaction assay. HBV genotypes and variants were determined using a line probe assay. RESULTS: Two hundred and seventy-two patients were enrolled; 200 were not receiving treatment at enrollment, of whom 116 were men and 84 women with a mean age 42+/-14 years. Among this group, 177 (88%) patients were Asian and 19 (10%) were Caucasian and 69 (35%) patients were hepatitis B e antigen (HBeAg) positive. Genotypes B and C were found in 42% and 50% untreated patients, respectively; while CP and PC were detected in 52% and 43% patients, respectively. Approximately 20% patients not receiving treatment (29% HBeAg positive, 14% HBeAg negative) met AASLD guidelines for antiviral therapy. If lower cutoff values for alanine aminotransferase and HBV DNA levels were used, 49% patients would qualify for treatment. CONCLUSIONS: The vast majority of patients at a Canadian tertiary referral center were Asian. Virological and clinical characteristics of these patients reflect their country of origin. Our findings highlight the need to monitor the changing patterns of HBV infection in countries with large immigrant populations.