Clinical Management Of Chronic Hepatitis Research Articles

Cost-effectiveness of different monitoring strategies in a screening and treatment programme for hepatitis B in The Gambia.

Clinical management of chronic hepatitis B virus (HBV) infection is complex and access to antiviral treatment remains limited in sub-Saharan Africa. International guidelines recommend monitoring at least annually for disease progression among HBV-infected people not meeting treatment criteria at initial diagnosis. This study aimed to assess the impact and cost-effectiveness of alternative strategies for monitoring. We used a mathematical model of HBV transmission and natural history, calibrated to all available West African data, to project the population-level health impact, costs and cost-effectiveness of different monitoring strategies for HBV-infected individuals not initially eligible for antiviral treatment. We assumed that these patients were found in the year 2020 in a hypothetical community-based screening programme in The Gambia. Monitoring frequencies were varied between every 5 and every 1 year and targeted different age groups. The currently recommended annual monitoring frequency was likely to be not cost-effective in comparison with other strategies in this setting. 5-yearly monitoring in 15-45-year olds, at US$338 per disability-adjusted life year averted, had the highest probability of being the most effective cost-effective monitoring strategy. Monitoring less frequently than once a year is a cost-effective strategy in a community-based HBV screening and treatment programme in The Gambia, with the optimal strategy depending on the cost-effectiveness threshold. Efficiencies may be gained by prioritising the 15-45-year age group for more intensive monitoring.

Emerging resistance to directly-acting antiviral therapy in treatment of chronic Hepatitis C infection-A brief review of literature.

Hepatitis caused by Hepatitis C virus (HCV) is a major cause of chronic liver disease. HCV is transmitted by injection drug use, blood transfusion, hemodialysis, organ transplantation and less frequently sexual intercourse. It has been recognized as a global health problem because of the progression to cirrhosis and hepatocellular carcinoma. Globally, about 170 million people are infected with HCV. Since the discovery of this virus in 1989, the clinical management of chronic hepatitis C infection has undergone a paradigm shift from alpha interferon to direct-acting antiviral (DAA) therapy. However, resistance to many of these antiviral agents has been reported increasingly from all over the globe. This review article focuses on the emerging HCV resistance to DAAs and the relevance of in vitro DAA resistance testing in clinical practice.

Hepatitis B virus-specific T cells associate with viral control upon nucleos(t)ide-analogue therapy discontinuation.

The clinical management of chronic hepatitis B virus (HBV) patients is based exclusively on virological parameters that cannot independently determine in which patients nucleos(t)ide-analogue (NUC) therapy can be safely discontinued. NUCs efficiently suppress viral replication, but do not eliminate HBV. Thus, therapy discontinuation can be associated with virological and biochemical relapse and, consequently, therapy in the majority is life-long. Since antiviral immunity is pivotal for HBV control, we investigated potential biomarkers for the safe discontinuation of NUCs within immune profiles of chronic HBV patients by utilizing traditional immunological assays (ELISPOT, flow cytometry) in conjunction with analyses of global non-antigen-specific immune populations (NanoString and CyTOF). Two distinct cohorts of 19 and 27 chronic HBV patients, respectively, were analyzed longitudinally prior to and after discontinuation of 2 different NUC therapy strategies. Absence of hepatic flares following discontinuation of NUC treatment correlated with the presence, during NUC viral suppression, of HBV core and polymerase-specific T cells that were contained within the ex vivo PD-1+ population. This study identifies the presence of functional HBV-specific T cells as a candidate immunological biomarker for safe therapy discontinuation in chronic HBV patients. Furthermore, the persistent and functional antiviral activity of PD-1+ HBV-specific T cells highlights the potential beneficial role of the expression of T cell exhaustion markers during human chronic viral infection. This work was funded by a Singapore Translational Research Investigator Award (NMRC/STaR/013/2012), the Eradication of HBV TCR Program (NMRC/TCR/014-NUHS/2015), the Singapore Immunology Network, the Wellcome Trust (107389/Z/15/Z), and a Barts and The London Charity (723/1795) grant.

A novel noninvasive index for the prediction of moderate to severe fibrosis in chronic hepatitis B patients

BackgroundsThe evaluation of liver fibrosis stages is essential for the clinical management of chronic hepatitis B (CHB). AimsTo develop and validate a novel noninvasive index for moderate to severe fibrosis (≥S2) in CHB patients. MethodsA total of 401 CHB patients who underwent liver biopsy were divided into the training (n = 300) and validation (n = 101) cohort. Histological severity was scored using a modified Scheuer system. Clinical and laboratory assessments were collected. ResultsIn the training cohort, PACG, a novel index combining the quantitative hepatitis B core antibody (qAnti-HBc), platelet count (PLT), and albumin globulin ratio (A/G), presented better diagnostic performance (AUROC = 0.814) than that of APRI (0.735, p = 0.007) and FIB-4 (0.749, p = 0.014). In the validation cohort, the AUROC of the PACG, APRI, FIB-4 and Fibroscan were 0.834, 0.806, 0.791 and 0.810, respectively. More importantly, a higher and lower cutoff of PACG for predicting ≥S2 fibrosis or not had a >90% sensitivity and specificity, with a diagnostic accuracy of 85.9%. ConclusionPACG is a promising noninvasive alternative to liver biopsy in CHB patients for the evaluation of moderate to severe fibrosis.

Rapid fluorescent lateral-flow immunoassay for hepatitis B virus genotyping.

Hepatitis B virus (HBV) genotyping plays an important role in the clinical management of chronic hepatitis B (CHB) patients. However, the current nucleic acid based techniques are expensive, time-consuming, and inconvenient. Here, we developed a novel DNA-independent HBV genotyping tool based on a one-step fluorescent lateral flow immunoassay (LFIA). Epitope-targeting immunization and screening techniques were used to develop HBV genotype specific monoclonal antibodies (mAbs). These mAbs were used to develop a multitest LFIA with a matched scanning luminoscope for HBV genotyping (named the GT-LFIA). The performance of this novel assay was carefully evaluated in well-characterized clinical cohorts. The GT-LFIA, which can specifically differentiate HBV genotypes A, B, C, and D in a pretreatment-free single test, was successfully developed using four genotype specific mAbs. The detection limits of the GT-LFIA for HBV genotypes A, B, C, and D were 2.5-10.0 IU HBV surface antigen/mL, respectively. Among the sera from 456 CHB patients, 439 (96.3%; 95% confidence interval (CI), 94.1-97.8%) were genotype-differentiable by the GT-LFIA and 437 (99.5%; 95% CI, 98.4-99.9%) were consistent with viral genome sequencing. In the 21 patients receiving nucleos(t)ide analogue therapy, for end-of-treatment specimens that were HBV DNA undetectable and were not applicable for DNA-dependent genotyping, the GT-LFIA presented genotyping results that were consistent with those obtained in pretreatment specimens by viral genome sequencing and the GT-LFIA. In conclusion, the novel GT-LFIA is a convenient, fast, and reliable tool for differential HBV genotyping, especially in patients with low or undetectable HBV DNA levels.

DI-013 Boceprevir vs. telaprevir: results in the clinical management after 24 and 48 weeks

Background No Purpose To evaluate the prescription pattern and efficacy of telaprevir (TLP) and boceprevir (BOC) in the clinical management of chronic hepatitis C (HCV) infection in a region. Material and methods Multicentre observational cohort study of HCV patients treated with protease-inhibitor triple therapy from September 20012 to April 2014. The information extracted from electronic health records was: age, gender, comorbidity and previous experience of HCV treatment. The virological response (VR) was assessed in patients who reached 24 and 48 weeks treatment; quick virological response rate (QVR) and discontinued treatment rates were also assessed. Results 124 patients were included (TLP = 82; BOC = 42), 65% were male (63.4% treated with TVR and 69% with BOC p = 0.533). There was no difference between the selection of treatment according to comorbidity, with the exception of HIV co-infected patients (total: 8.9%; TVR: 13.6% vs. BOC: 0%; p = 0.012) or with mental illness (21.2%; 27.3% vs. 10.5%; p = 0.044). The distribution of patients according to previous experience was: treatment-naive patients (total: 41.1%; TLP: 36.6% vs. BOC: 50%; p = 0.151), null responders (18.5%; 14.6% vs. 26.2%; p = 0.117), partial responders (12.9%; 11% vs. BOC = 16.7%; p = 0.371), relapsers (26.6%; 36.6% vs. 7.1%; p = 0.0001). At week 24, 83 patients achieved VR: 62.7%; (TLP = 66.7% BOC = 55.2%; p = 0.346). QVR rates were 53.1%; (62.2% vs.50.7%; p = 0.023). According the previous treatment experience, VR were: relapsers 81.8%, treatment-naive patients 63.8%, partial responders: 58.3% and null responders: 37.5% (p = 0.048). At week 48, 61 patients achieved VR or 57.4% (TLP: 62.2% vs. BOC: 50%; p = 0.348). Discontinuation rate was 13.6% (TLP: 20% vs. BOC: 3.8%, p = 0.062). Conclusion TLP was the preferred treatment in HIV co-infected patients, mentally ill patients or relapsers. The statistical trend shows higher efficacy and discontinued treatment rate with TLP, but the differences are statistically irrelevant. Both drugs showed worse results in clinical management than reported in clinical trials. References and/or acknowledgements No conflict of interest.

Clinical management of chronic hepatitis B infection: results from a registry at a German tertiary referral center.

We studied a cohort of adult patients with chronic hepatitis B (CHB) infection, followed at a tertiary referral liver center in Germany over 12.5 years to analyze the clinical features and impact of management on disease progression and survival of CHB patients in general and of those with CHB and HCC in particular. We retrospectively evaluated the medical records of 242 adult (age ≥ 18 years) patients. CHB was defined as positive hepatitis B surface antigen (HBsAg) and/or HBV-DNA levels >10 IU/mL for at least 6 months. Patient demographics, HBV markers, antiviral treatment, laboratory parameters, liver imaging and histology were recorded for each visit. HCC patients were divided into two groups and separately analyzed (group 1: n = 24, HCC at first visit and group 2: n = 11, HCC during surveillance). The mean age was 44 years in CHB patients without HCC (63% male) and about 59 years in patients with HCC (77% male). Antiviral therapy was given to 59% of patients without HCC compared to only 25% in group 1 and 18% in group 2 with comparable median HBV DNA levels of approximately 36,000 IU/mL. There was no statistically significant difference concerning the HCC stages (Milan, UCSF, BCLC) at first diagnosis. Five-year survival was 19% in group 1 vs. 64% in group 2 (p = 0.019), with LTx performed in 12 vs. 45%, respectively. Surveillance of CHB patients did not result in early stage detection of HCC but in a higher likelihood to receive potentially curative treatments.

Prediction models of long-term Cirrhosis and hepatocellular carcinoma risk in chronic hepatitis B patients: Risk scores integrating host and virus profiles

Integrating host and HBV characteristics, this study aimed to develop models for predicting long-term cirrhosis and hepatocellular carcinoma (HCC) risk in chronic hepatitis B virus (HBV) patients. This analysis included hepatitis B surface antigen (HBsAg)-seropositive and anti-HCV-seronegative participants from the Risk Evaluation of Viral Load Elevation and Associated Liver Disease/Cancer in HBV (R.E.V.E.A.L.-HBV) cohort. Newly developed cirrhosis and HCC were ascertained through regular follow-up ultrasonography, computerized linkage with national health databases, and medical chart reviews. Two-thirds of the participants were allocated for risk model derivation and another one-third for model validation. The risk prediction model included age, gender, HBV e antigen (HBeAg) serostatus, serum levels of HBV DNA, and alanine aminotransferase (ALT), quantitative serum HBsAg levels, and HBV genotypes. Additionally, the family history was included in the prediction model for HCC. Cox's proportional hazards regression coefficients for cirrhosis and HCC predictors were converted into risk scores. The areas under receiver operating curve (AUROCs) were used to evaluate the performance of risk models. Elder age, male, HBeAg, genotype C, and increasing levels of ALT, HBV DNA, and HBsAg were all significantly associated with an increased risk of cirrhosis and HCC. The risk scores estimated from the derivation set could accurately categorize participants with low, medium, and high cirrhosis and HCC risk in the validation set (P<0.001). The AUROCs for predicting 3-year, 5-year, and 10-year cirrhosis risk ranged 0.83-0.86 and 0.79-0.82 for the derivation and validation sets, respectively. The AUROC for predicting 5-year, 10-year, 15-year risk of HCC ranged 0.86-0.89 and 0.84-0.87 in the derivation and validation sets, respectively. The risk prediction models of cirrhosis and HCC by integrating host and HBV profiles have excellent prediction accuracy and discriminatory ability. They may be used for clinical management of chronic hepatitis B patients.

Spontaneous Mutations in the HBV Genome and their Clinical Implications

Chronic hepatitis B infection remains a significant cause of morbidity and mortality worldwide despite the availability of an effective vaccine. The clinical management of chronic hepatitis B infection is complex often requiring the use of nucleotide analogs as well as immune modulators. The natural history and response to therapy are affected by the presence of naturally occurring mutations in the HBV genome particularly those in the basal core promoter and precore sites. Understanding the role of these mutations in outcome of infection and response to therapy can enable physicians to customize management in order to achieve optimal clinical outcomes.

The COBAS® TaqMan® hepatitis C virus assays: automated systems for accurate and sensitive viral load quantification

In recent years, the real time-based TaqMan® technology has allowed the development of highly sensitive hepatitis viral load tests with broad dynamic ranges. The increasing applications of these tests in clinical diagnostics have shown the utility of viral load as a predictive marker of treatment response and proven its key role in invidualized antiviral therapies. Future refinement in viral load assays, including higher sensitivity, genotype inclusivity, standardization and automation, will further foster the concept of personalized healthcare in the clinical management of chronic hepatitis C.

Current understanding of insulin resistance in hepatitis C

Important breakthroughs have been made in recent years into understanding the close interaction between hepatitis C virus (HCV) infection and glucose homeostasis. Both cross-sectional and longitudinal studies have demonstrated that infection with HCV is associated with an increased risk of developing insulin resistance and Type 2 diabetes. A direct effect of HCV on hepatocyte insulin signaling has been shown in experimental models. Some preliminary observations seem to suggest that indirect mechanisms involving extrahepatic organs might also play a role. The interaction between HCV and glucose metabolism has significant clinical consequences. Insulin resistance and Type 2 diabetes not only accelerate the histological and clinical progression of chronic hepatitis C, but also reduce the virological response to IFN-α-based therapy. Thus, understanding the mechanisms underlying HCV-associated glucose metabolism derangements is of paramount interest in order to improve the clinical management of chronic hepatitis C. This article will focus on the studies that consistently argue in favor of an interrelation between HCV and insulin resistance and will highlight the latest discoveries in this field.

Impact of menopause on the clinical management of chronic hepatitis C in women

Impact of menopause on the clinical management of chronic hepatitis C in women

Noninvasive Fibrosis Markers for the Prediction of Significant Fibrosis in Patients With Chronic Hepatitis C Virus Infection in Tunisia

Summary: Optimized clinical management of chronic hepatitis C requires precise definition of the stage of liver fibrosis. Liver biopsy is viewed as the criterion standard for staging fibrosis in chronic hepatitis, but simple, noninvasive tests for the detection of significant fibrosis would be beneficial. Aim: To evaluate and compare the diagnostic accuracies of the simple fibrosis tests such as aspartate aminotransferase-to-alanine aminotransferase ratio (AAR), platelet count, and aspartate aminotransferase-to-platelet ratio index (APRI) for the prediction of significant fibrosis in patients with chronic hepatitis C. Methods: We studied 38 patients with chronic hepatitis C who underwent a liver biopsy. To evaluate diagnostic accuracies of the simple fibrosis tests, sensitivity, specificity, and the area under the receiver operating characteristic curve were calculated. Results: The AAR increased and platelet count decreased as liver fibrosis worsened, but there was no significant correlation with the fibrosis score. The receiver operating characteristic curves of AAR, platelet count, and APRI were 0.68, 0.38, and 0.91, respectively. The APRI identified patients with significant fibrosis with a positive predictive value of 86.6%. Conclusions: Our study confirms that the APRI can predict significant fibrosis in chronic hepatitis C patients with a high degree of accuracy.

Hepatitis B virus (HBV) genotype determination by the COBAS® AmpliPrep/COBAS® TaqMan® HBV Test, v2.0 in serum and plasma matrices

BackgroundViral load quantification is established in the clinical management of chronic Hepatitis B virus (HBV) infection for assessing efficacies and resistance developments in anti-viral drug treatment. ObjectivesThe fully automated COBAS® AmpliPrep/COBAS® TaqMan® HBV Test, v2.0 was evaluated for the linear measuring range and the inclusivity of HBV genotype determination in EDTA plasma and serum samples. Study designTwo kit lots of the test were used to determine the linear measuring range as well as linearity and limit of detection applying different concentration levels of specimens representing HBV genotypes A to H along with a pre-core mutant and the WHO Standard. ResultsThe COBAS® AmpliPrep/COBAS® TaqMan® HBV Test, v2.0 displayed a linear measuring range of seven log10 steps from 20IU/mL (lower limit of quantification) to 2.3E+08IU/mL (upper limit of quantification) yielding similar results for EDTA plasma and serum. Inclusivity was shown by reliable quantification of HBV genotypes A to H at different concentration levels. The ≥95% hit rate LOD was 15IU/mL for genotypes C, D, F, G, the pre-core mutant and the WHO Standard and 20IU/mL for genotypes A, B, E and H matching the test's lower limit of quantification. 95% PROBIT analysis yielded concentrations of 8.9IU/mL for the WHO Standard and of 6.0–16.4IU/mL for the genotypes. ConclusionsThe COBAS® AmpliPrep/COBAS® TaqMan® HBV Test, v2.0 provides genotype inclusivity for accurate viral load monitoring in serum and EDTA plasma samples and supports clinical routine in the management of HBV infection.

Hepatitis C virus and type 2 diabetes.

This review focuses on the relationship between hepatitis C virus (HCV) infection and glucose metabolism derangements. Cross-sectional and longitudinal studies have shown that the chronic HCV infection is associated with an increased risk of developing insulin resistance (IR) and type 2 diabetes (T2D). The direct effect of HCV on the insulin signaling has been analyzed in experimental models. Although currently available data should be considered as preliminary, HCV seems to affect glucose metabolism via mechanisms that involve cellular pathways that have been implicated in the host innate immune response. IR and T2D not only accelerate the histological and clinical progression of chronic hepatitis C, but also reduce the early and sustained virological response to interferon-alpha-based therapy. Thus, a detailed knowledge of the mechanisms underlying the HCV-associated glucose metabolism derangements is warranted, in order to improve the clinical management of chronic hepatitis C patients.

Natural history and clinical management of chronic hepatitis B virus infection in children

Hepatitis B virus (HBV) infection may cause acute, fulminant, or chronic hepatitis, leading to liver cirrhosis or hepatocellular carcinoma. Despite the availability of effective vaccine, HBV infection during infancy or early childhood is common in areas of high endemicity. In these regions, mother-to-infant transmission accounts for approximately 50% of chronic infections. Although the natural history of HBV infection in adults is well characterized, little information is available in the literature regarding the natural history of HBV infection in children. Similar to infection in adults, chronic HBV infection in children can be divided into distinct phases: immune tolerant, immune clearance, and inactive carrier state. However, acute exacerbation, with reactivation of HBV replication and re-elevation of alanine aminotransferase levels after hepatitis B e antigen seroconversion, is relatively rare in children, in comparison to adults. Although several potent antiviral agents are now available for the treatment of chronic hepatitis B, experience with these agents in the pediatric setting is limited. To date, conventional interferon alpha and lamivudine are the only two antiviral agents approved to treat chronic hepatitis B in children. The rapid emergence of resistant HBV associated with long-term lamivudine therapy, as well as poor tolerability associated with conventional interferon alpha, are factors that should be considered before initiating antiviral therapy. This article reviews current knowledge regarding the natural history and treatment of chronic hepatitis B in children. Factors that affect the natural history of HBV infection in children are also reviewed.

Chronic hepatitis B

PREAMBLE These guidelines have been written to assist physicians and other health care providers in the recognition, diagnosis, and management of patients chronically infected with the hepatitis B virus (HBV). They are intended to suggest preferable approaches to the clinical management of chronic hepatitis B. The recommendations are flexible and are not intended as the only acceptable approach to management and treatment. As the appropriate course of treatment will vary in light of the relevant facts and circumstances surrounding each individual patient with chronic hepatitis B, guidelines are not intended to define the applicable standard of medical care and may be updated periodically as new information becomes available. These guidelines were developed under the auspices of, and approved by, the Practice Guidelines Committee of the American Association for the Study of Liver Diseases. They should be taken as guidelines and not “standards of care.” Data used to support the recommendations made were obtained by a literature search of peer-reviewed articles concerning the natural history, diagnosis, and treatment of chronic hepatitis B. In addition, the proceedings of a recent National Institutes of Health workshop on the “Management of Hepatitis B” were considered in the development of these guidelines. 1 The strength of each recommendation is categorized based on the quality of evidence in the literature according to the rating system indicated in Table 1. 2

European Multicenter Evaluation of High-Density DNA Probe Arrays for Detection of Hepatitis B Virus Resistance Mutations and Identification of Genotypes

Polymorphisms along the hepatitis B virus (HBV) genome have an impact on disease outcome, sensitivity to antiviral treatment, escape from vaccination, and laboratory diagnosis. We have designed a diagnostic tool based on duplex amplification of the whole HBV genome and a high-density DNA chip designed to detect 245 mutations, 20 deletions, and 2 insertions at 151 positions and to determine the genotype of the virus in serum. Assay performances were evaluated with 170 samples, characterized by determination of viral load and sequencing of the Pol, S, and precore genes and the basal core promoter. One hundred fifty-three samples (90%) could be amplified and analyzed by the chip. Only two samples with more than 10(3) genome copies/ml could not be analyzed. Genotype had no impact on analytical sensitivity. Reproducibility studies showed no difference between repeats for codon and genotype determination. Genotype determination by sequencing and the chip were concordant in 148 of 151 samples. Twelve thousand one hundred sixty-one codons were analyzed by both techniques. Only 89.4% could be determined by sequencing, and among the remaining 11,335 codons, 92.8% were identical by sequencing and the chip. Failures to identify an amino acid by the chip were mainly due to reduced hybridization efficiency attributed to unexpected polymorphisms. Optimization of the chip-based reagent for the analysis of the HBV genome is ongoing. This first evaluation showed that DNA chip technology can provide important information in relation to the clinical management of chronic hepatitis B.

Management of chronic hepatitis B virus infection: Current perspectives for the nurse practitioner

To address the clinical management of chronic hepatitis B virus (HBV) infection. Studies from the National Library of Medicine that examine the natural history, prevention, and antiviral therapy of chronic HBV infection, with emphasis on recent studies. Chronic infection with HBV is a frequent cause of cirrhosis, liver cancer, and liver-related mortality worldwide. Strategies to prevent infection, screen for liver cancer in HBV carriers, and treat chronic hepatitis B are all important in managing this disorder. Much can be done to prevent and treat infection. Both classes of drugs to treat hepatitis B, nucleoside analogues and interferons, have advantages and disadvantages. Selection of therapy should be based on biochemical, histological, and virological parameters as well as consideration of several practical issues.

Treatment of chronic hepatitis B: current challenges and future directions.

The clinical management of chronic hepatitis B infection has entered a new era with the introduction and widespread use of oral nucleoside analogues such as lamivudine and nucleotides such as adefovir dipivoxil. From this, new challenges have now emerged in terms of preventing antiviral drug resistance, promoting viral clearance and improving long-term survival. For example, the natural history of nucleoside or nucleotide analogue-associated hepatitis B virus resistant mutants has yet to be determined. Furthermore, the increasing prevalence of HBeAg negative disease with its reduced response to current therapies represents an ongoing challenge to attempts to improve standard of care. There is increasing recognition of the pivotal role that viral load and genotype, and their complex interactions with the host immune response, play in determining the outcome of these treatment interventions. The purpose of this paper is to highlight several key factors that should be considered in the context of future clinical research and management of chronic hepatitis B.