Sofosbuvir and ABT-450: Terminator of hepatitis C virus?

Combination therapy with peginterferon (pegIFN)-α and ribavirin (RBV) has been the standard of care (SOC) for chronic hepatitis C. Unfortunately, not all patients can achieve a sustained virologic response (SVR) with this regimen. SVR rates are approximately 80% in patients with hepatitis C virus (HCV) genotype 2, 3, 5 and 6 and 40%-50% in patients with genotype 1 and 4. Therefore, strategies to improve SVR rates have been an important issue for clinical physicians. Several direct acting antiviral agents (DAAs) have significantly higher SVR rates when combined with pegIFN-α and RBV than pegIFN-α and RBV alone. Treatments containing DAAs have several advantages over the previous SOC, including higher specificity and efficacy, shorter treatment durations, fewer side effects, and oral administration. Based on these advantages, treatment with pegIFN-α and RBV plus telaprevir or boceprevir has become the current SOC for patients with genotype 1 HCV infection. However, many patients are either not eligible for therapy or decline treatment due to coexisting relative or absolute contraindications as well as an inability to tolerate the hematological side effects and adverse events caused by the new SOC. These factors have contributed to the advent of pegIFN-α-free regimens. The newest therapeutic regimens containing sofosbuvir and ABT-450 have shown promising results. In this review, we summarize the development of anti-HCV agents and the clinical efficacy of sofosbuvir and ABT-450-based therapies as well as the potential for future HCV studies.

The role of neutrophils in the development of liver diseases

Liver disease encompasses a wide variety of liver conditions, including liver failure, liver cirrhosis and a spectrum of acute and chronic hepatitis, such as alcoholic, fatty, drug, viral and chronic hepatitis. Liver injury is a primary causative factor in liver disease; generally, these factors include direct liver damage and immune-mediated liver injury. Neutrophils （also known as neutrophilic granulocytes or polymorphonuclear leukocytes （PMNs）） are the most abundant circulating white blood cell type in humans, and PMNs are a major innate immune cell subset. Inappropriate activation and homing of neutrophils to the microvasculature contributes to the pathological manifestations of many types of liver disease. This review summarizes novel concepts of neutrophil-mediated liver iniurv that are based on current clinical and animal model studies.

Primary biliary cirrhosis-associated hepatocellular carcinoma in Chinese patients:Incidence and risk factors

AIM: To investigate the incidence, characteristics, and risk factors for hepatocellular carcinoma(HCC) in Chinese patients with primary biliary cirrhosis(PBC).METHODS: We reviewed the data of 52 PB Cassociated HCC patients treated at Beijing 302 Hospital from January 2002 to December 2013 and analyzed its incidence and characteristics between the two genders. The risk factors for PBC-associated HCC were analyzed via a case-control study comprising 20 PBC patients with HCC and 77 matched controls without HCC. The matched factors included gender, age, follow-up period and Child-Pugh scores. Conditional logistic regression was used to evaluate the odds ratios of potential risk factors for HCC development. A P < 0.05 was considered statistically significant. RESULTS: The incidence of HCC in Chinese PBC patients was 4.13%(52/1255) and was significantly higher in the males(9.52%) than in the females(3.31%). Among the 52 PBC patients with HCC, 55.76%(29/52) were diagnosed with HCC and PBC simultaneously, and 5.76%(3/52) were diagnosed with HCC before PBC. The males with PBC-associated HCCwere more likely than the females to have undergone blood transfusion(18.75% vs 8.33%, P = 0.043), consumed alcohol(31.25% vs 8.33%, P = 0.010), smoked(31.25% vs 8.33%, P = 0.010), had a family history of malignancy(25% vs 5.56%, P = 0.012), and had serious liver inflammation, as indicated by the elevated levels of alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, and γ-glutamyl transpeptidase(P < 0.05). Conditional logistic regression analysis revealed that body mass index(BMI) ≥ 25 [adjusted odds ratio(AOR) = 1.116, 95%CI: 1.002-1.244, P = 0.045] and history of alcohol intake(AOR = 10.294, 95%CI: 1.108-95.680, P = 0.040) were significantly associated with increased odds of HCC development in PBC patients. CONCLUSION: HCC is not rare in Chinese PBC patients. Risk factors for PBC-associated HCC include BMI ≥ 25 and a history of alcohol intake. In addition to regular monitoring, PBC patients may benefit from abstinence from alcohol and body weight control.

Risk factors for liver-related mortality in chronic hepatitis C patients:A deceased case-living control study

AIM:To investigate the risk factors for liver-related mortality in chronic hepatitis C(CHC)patients.METHODS:All deceased CHC inpatient data were collected from the Beijing 302 Hospital clinical database,which includes more than 8250 CHC inpatients during the period from 2002 to 2012.The controls were matched to cases by age(±2 years),sex and date of hospital admission(within the same year).Potential risk factors were included for the evaluation,and odds ratios(OR)and 95%CI were estimated using univariate(unadjusted)and multivariate(adjusted OR,AOR)conditional logistic regression.All statistical tests were two-sided.P values<0.05 were considered statistically significant.RESULTS:Based on examinations of 144 CHC-related deceased cases and 576 controls,we found that antiviral therapy with interferon-αwas associated with a 47%decrease in the risk of hepatic mortality(AOR=0.53,95%CI:0.28-0.99,P=0.048).Additionally,the initial diagnostic stage of the disease(AOR=2.89,95%CI:1.83-4.56 and P<0.001 for liver cirrhosis/AOR=8.82,95%CI:3.99-19.53 and P<0.001for HCC compared with CHC),diabetes(AOR=2.35,95%CI:1.40-3.95,P=0.001),hypertension(AOR=1.76,95%CI:1.09-2.82,P=0.020),alcohol consumption(AOR=1.73,95%CI:1.03-2.81,P=0.037)and HBsAg positivity(AOR=22.28,95%CI:5.58-89.07,P<0.001)were associated with a significant increase in the risk of liver-related mortality in CHC patients.CONCLUSION:This study indicates that interferon-αtreatment,the stage at the initial diagnosis of the disease and comorbidities are all independent risk factors for liver-related mortality in CHC patients.

Overview of the special issue on HBV immunity

Hepatitis B virus （HBV） has a unique rela- tionship with humans. It is not only very suc- cessful in spreading amongst our species （a third of the human population has been in contact with the virus and approximately 200-300 million people are actively infected）, but it has adapted to and co-evolved with us. This long-term relationship is demonstrated by the recent detection of hepadnavirus gen- omes in Mesozoic birds2 and by the estima- tion that HBV was already present in early humans at least 40, 000 years ago.3

The efficacy of miRNA122, a novel therapeutic target, for predicting the progression of hepatocellular carcinoma （HCC）

Hepatocellular carcinoma （HCC） is the fifth most prevalent malignancy worldwide, and it accounts for 85-90% ot all primary liver cancers. Owing to the limited therapeutic options available, the 5-year survival rate remains relatively low for patients with HCC. The development of HCC is a multistage process1 that involves changes in the expression of multiple oncogenes, tumor suppressor genes and microRNAs that are involved in the cell cycle, as well as in cell growth, apoptosis, migration and tumor metastasis.2,3 Finding an accurate biomarker that can predict HCC progression is import- ant for clinicians to be able to determine the optimal therapeutic strategy.

Improved survival ratios correlate with myeloid dendritic cell restoration in acute-on-chronic liver failure patients receiving methylprednisolone therapy

Acute-on-chronic liver failure （ACLF） is a severe life-threatening complication. Liver transplantation is the only available therapeutic option; however, several limitations have restricted its use in patients. The use of corticosteroids as an optional therapy for ACLF has received a great deal of interest. The rationale behind its use is the possible role of the immune system in initiating and perpetuating hepatic damage. In order to assess the relationship between myeloid dendritic cells （mDCs） and the efficacy of methylprednisolone （MP） treatment for hepatitis B virus （H BV）-associated ACLF patients, we recruited 30 HBV-associated ACLF patients who had received MP treatment at lO-day intervals; 26 patients received conservative medical （CM） management as a control. The functionality of DC subsets was lower in these ACLF patients compared with healthy subjects. In addition, compared with survivors, dead/transplanted patients had lower functional mDC in both groups. Furthermore, a decreased numbers of mDC at baseline was associated with high mortality of ACLF patients. Importantly, MP treatment resulted in a significant decrease in 28-day mortality, and all MP patients exhibited an initial rapid decrease in circulating mDC numbers within 10 days of MP treatment. Subsequently, MP survivors displayed a continuous increase in mDC numbers accompanied by a decrease in total bilirubin levels by more than 30%. However, MP dead/ transplanted patients lacked these sequential responses compared with survivors. This evidence suggests strongly that the higher mDC numbers at baseline and the recovery of mDC number at the end of treatment may represent a prognostic marker for favorable response to corticosteroid treatment in ACLF patients.

Guideline of Prevention and Treatment for Chronic Hepatitis B (2nd Version)

This guideline is established to standardize the prevention,diagnosis and antiviral therapy of chronic hepatitis B(CHB).For other treatment regimens and methods involving CHB,please refer to relevant guidelines and consensuses.The Chinese Society of Hepatology,Chinese Medical Association(CMA)and the Society of Infectious Diseases,CMA organized relevant native experts to establish this Guideline of Prevention and Treatment for Chronic Hepatitis B(1st version)in 2005,and made the first revision in 2010.In the past 5 years,great progress has been made in the native and foreign fundamental and clinical research with respect to CHB,necessitating additional revision of this guideline.

Reversal of B-cell hyperactivation and functional impairment is associated with HBsAg seroconversion in chronic hepatitis B patients

B cells play an important role in the clearance of hepatitis B virus （HBV） and protection against reinfection. However, the functional characteristics of these cells that are associated with the outcome of chronic HBV infection remain unknown. We comprehensively investigated the frequency, phenotype, and function of peripheral B-cell subsets from CHB patients in different phases： immune tolerance （IT）, immune activation （IA）, immune clearance （IC）, responders with HBsAg seroconversion （resolved patients, RP）, and healthy controls （HC）. IA patients displayed lower percentages of peripheral blood memory B cells compared with the other groups. Overall polyclonal activation of B cells, indicated by higher levels of activation markers and secretion of IgG and IgM, was observed in IA patients. This B-cell hyperactivation could be induced by increased IFN-a and soluble CD40 ligands in IA patients. Notably, the expression of the co-stimulator molecule CD80 and serum HBsAb and the frequency of HBsAg-specific B cells were significantly decreased in IT, IA, and IC patients compared with HC subjects. More importantly, the B-cell hyperactivation, co-stimulatory molecule downregulation and HBsAg-specific B-cell impairment were reversed in RP patients. The reversal of B-cell hyperactivation and functional impairment is associated with HBsAg seroconversion in chronic hepatitis B patients.

Complement 5a receptor-mediated neutrophil dysfunction is associated with a poor outcome in sepsis

Complement 5a （C5a） has been implicated in the pathogenesis of sepsis by inducing the functional impairment of neutrophils; however, the utility of C5a receptors （C5aRs; C5aR and C5L2） as biomarkers for the management of sepsis is uncertain. This study investigated the dynamic expression of C5aR and C5L2 on neutrophits and their effects on neutrophil function. We found that sepsis patients displayed low expression levels of C5aR and C5L2 on neutrophils compared to healthy and systemic inflammatory response syndrome （SIRS） subjects, and this expression pattern was correlated with disease severity. Additionally, the expression levels of C5aR and C5L2 were associated with the survival of sepsis patients. In vitro, the addition of C5a significantly reduced C5aR and C5L2 expression levels and IL-8 production in neutrophils from sepsis patients. Those findings suggest that the reduced expression of C5aRs was associated with the functional impairment of neutrophils and a poor prognosis for sepsis patients. Overall, these findings may help establish C5aRs expression levels as early markers to predict the severity of sepsis.