Hepatitis B [keywords]
- Modelling the Impact of Cell-To-Cell Transmission in Hepatitis B Virus. [JOURNAL ARTICLE]
- PLoS One 2016; 11(8):e0161978.
Cell-free virus is a well-recognized and efficient mechanism for the spread of hepatitis B virus (HBV) infection in the liver. Cell-to-cell transmission (CCT) can be a more efficient means of virus propagation. Despite experimental evidence implying CCT occurs in HBV, its relative impact is uncertain. We develop a 3-D agent-based model where each hepatocyte changes its viral state according to a dynamical process driven by cell-free virus infection, CCT and intracellular replication. We determine the relative importance of CCT in the development and resolution of acute HBV infection in the presence of cytolytic (CTL) and non-CTL mechanisms. T cell clearance number is defined as the minimum number of infected cells needed to be killed by each T cell at peak infection that results in infection clearance within 12 weeks with hepatocyte turnover (HT, number of equivalent livers) ≤3. We find that CCT has very little impact on the establishment of infection as the mean cccDNA copies/cell remains between 15 to 20 at the peak of the infection regardless of CCT strength. In contrast, CCT inhibit immune-mediated clearance of acute HBV infection as higher CCT strength requires higher T cell clearance number and increases the probability of T cell exhaustion. An effective non-CTL inhibition can counter these negative effects of higher strengths of CCT by supporting rapid, efficient viral clearance and with little liver destruction. This is evident as the T cell clearance number drops by approximately 50% when non-CTL inhibition is increased from 10% to 80%. Higher CCT strength also increases the probability of the incidence of fulminant hepatitis with this phenomenon being unlikely to arise for no CCT. In conclusion, we report the possibility of CCT impacting HBV clearance and its contribution to fulminant hepatitis.
- Association of Sjögrens Syndrome in Patients with Chronic Hepatitis Virus Infection: A Population-Based Analysis. [JOURNAL ARTICLE]
- PLoS One 2016; 11(8):e0161958.
The association between Sjögren's syndrome (SS) and chronic hepatitis virus infection is inconclusive. Hepatitis B (HBV) and hepatitis C virus (HCV) infections are highly prevalent in Taiwan. We used a population-based case-control study to evaluate the associations between SS and HBV and HCV infections.We identified 9,629 SS patients without other concomitant autoimmune diseases and 38,516 sex- and age-matched controls without SS from the Taiwan National Health Insurance claims data between 2000 and 2011. We utilized multivariate logistic regression to estimate the odds ratios (ORs) and 95% confidence intervals (CIs) of the associations between SS and HBV and HCV infections. Sex- and age-specific (<55 and ≥55 years) risks of SS were evaluated.The risk of SS was higher in patients with HCV than in those without chronic viral hepatitis (OR = 2.49, 95% CI = 2.16-2.86). Conversely, HBV infection was not associated with SS (OR = 1.10, 95% CI = 0.98-1.24). Younger HCV patients were at a higher risk for SS (<55 years: OR = 3.37, 95% CI = 2.62-4.35; ≥55 years: OR = 2.20, 95% CI = 1.84-2.62). Men with HCV were at a greater risk for SS (women: OR = 2.26, 95% CI = 1.94-2.63; men: OR = 4.22, 95% CI = 2.90-6.16). Only men with chronic HBV exhibited a higher risk of SS (OR = 1.61, 95% CI = 1.21-2.14).HCV infection was associated with SS; however, HBV only associated with SS in men.
- Significant symptoms alleviation and tumor volume reduction after combined simultaneously integrated inner-escalated boost and volumetric-modulated arc radiotherapy in a patient with unresectable bulky hepatocellular carcinoma: A care-compliant case report. [JOURNAL ARTICLE]
- Medicine (Baltimore) 2016 Aug; 95(34):e4717.
Clinically, elderly patients with unresectable bulky hepatocellular carcinoma (HCC) are difficult to manage, especially in those with co-infections of hepatitis B and C virus. Herein, we reported such a case treated with radiotherapy (RT) by using combined simultaneously integrated inner-escalated boost and volumetric-modulated arc radiotherapy (SIEB-VMAT). After RT, significant symptoms alleviation and durable tumor control were observed.At presentation, an 85-year-old male patient complained abdominal distention/pain, poor appetite, and swelling over bilateral lower limbs for 1 month. On physical examination, a jaundice pattern was noted. Laboratory studies showed impaired liver and renal function. Abdominal computed tomography (CT) revealed a 12.5-cm bulky tumor over the caudate lobe of the liver. Biopsy was done, and hepatocellular carcinoma (HCC) was reported histopathologically. As a result, AJCC stage IIIA (cT3aN0M0) and BCLC stage C were classified. Surgery, radiofrequency ablation (RFA), trans-catheter arterial chemoembolization (TACE), and sorafenib were not recommended because of his old age, central bulky tumor, and a bleeding tendency. Thus, RT with SIEB-VMAT technique was given alternatively. RT was delivered in 26 fractions, with dose gradience as follows: 39 Gy on the outer Plan Target Volume (PTV), 52 Gy in the middle PTV, and 57.2 Gy in the inner PTV. Unexpectedly, cyproheptadine (a newly recognized potential anti-HCC agent) was retrospectively found to be prescribed for alleviating skin itching and allergic rhinitis since the last 2 weeks of the RT course (2 mg by mouth Q12h for 24 months).After RT, significant symptoms alleviation and tumor volume reduction were observed for 32 months till multiple bone metastases. Before and after RT, a large tumor volume reduction rate of 88.7% was observed (from 608.4 c.c. to 68.7 c.c.). No severe treatment toxicity was noted during and after RT. The patient died due to aspiration pneumonia with septic shock at 4 months after bone metastases identified.SIEB-VMAT physically demonstrated double benefits of intratumor dose escalation and extra-tumor dose attenuation. Significant tumor regression and symptoms alleviation were observed in this elderly patient with unresectable bulky HCC. Further prospective randomized trials are encouraged to demarcate effective size of SIEB-VMAT with or without cyproheptadine.
- A new multiparameter integrated MELD model for prognosis of HBV-related acute-on-chronic liver failure. [JOURNAL ARTICLE]
- Medicine (Baltimore) 2016 Aug; 95(34):e4696.
Hepatitis B virus related acute-on-chronic liver failure (HBV-ACLF) is one of the most deadly diseases. Many models have been proposed to evaluate the prognosis of it. However, these models are still controversial. In this study, we aimed to incorporate some characters into model for end-stage liver disease (MELD) to establish a new reliable and feasible model for the prognosis of HBV-ACLF.A total of 530 HBV-ACLF patients who had received antiviral therapy were enrolled into a retrospective study and divided into the training cohort (300) and validation cohort (230). Logistic regression analysis was used to establish a model to predict the 3-month mortality from the patients in the training cohort, and then, the new model was evaluated in the validation cohort.Except for MELD score, 4 other independent factors, namely degree of hepatic encephalopathy (HE), alpha-fetoprotein (AFP), white blood cell (WBC) count, and age, were important for the new model called HBV-ACLF MELD (HAM) model: R = 0.174 × MELD + 1.106 × HE - (0.003 × AFP) + (0.237 × WBC) + (0.103 × Age) - 11.388. The areas under receiver-operating characteristic curve of HAM in the training and validation cohort were 0.894 and 0.868, respectively, which were significantly higher than those of other 7 models. With the best cut-off value of -1.191, HAM achieved higher sensitivity and negative predictive value.We developed a new model that has a great prognostic value of the 3-month mortality of patients with HBV-ACLF.
- Quantitative hepatitis B core antibody level is associated with inflammatory activity in treatment-naïve chronic hepatitis B patients. [JOURNAL ARTICLE]
- Medicine (Baltimore) 2016 Aug; 95(34):e4422.
Previous studies have shown that hepatitis B core antibody (anti-HBc) levels vary during different phases of disease in treatment-naïve chronic hepatitis B (CHB) patients and can be used as a predictor of both interferon-α and nucleoside analogue therapy response. However, there is no information on the association between the quantitative serum anti-HBc (qAnti-HBc) level and liver inflammation in CHB patients. Therefore, we investigated these relationships in a large cohort of treatment-naïve CHB patients. A total of 624 treatment-naïve CHB patients were included in the study. The serum qAnti-HBc level was moderately correlated with ALT and AST levels (P < 0.001) in both hepatitis B e antigen-positive (HBeAg [+]) and HBeAg-negative (HBeAg [-]) CHB patients. CHB patients with no to mild inflammation (G0-1) had significantly lower serum qAnti-HBc levels than patients with moderate to severe inflammation (G2-4) (P < 0.001). Receiver operating characteristic analysis suggested that a serum qAnti-HBc cut-off value of 4.36 log10 IU/mL provided a sensitivity of 71.68%, specificity of 73.81%, positive predictive value of 78.43%, and negative predictive value of 66.24% in HBeAg (+) CHB patients with moderate to severe inflammation (G≥2). A cut-off value of 4.62 log10 IU/mL provided a sensitivity of 54.29%, specificity of 90.00%, positive predictive value of 95.00%, and negative predictive value of 36.00% in HBeAg (-) CHB patients with moderate to severe inflammation (G≥2). Serum qAnti-HBc levels were positively associated with liver inflammation grade. Furthermore, we identified optimal serum qAnti-HBc cut-off values for the prediction of inflammation activity in both HBeAg (+) and HBeAg (-) treatment-naïve CHB patients.
- Protective effect of an improved immunization practice of mother-to-infant transmission of hepatitis B virus and risk factors associated with immunoprophylaxis failure. [JOURNAL ARTICLE]
- Medicine (Baltimore) 2016 Aug; 95(34):e4390.
Although routine immunoprophylaxis has been known to reduce hepatitis B virus (HBV) transmission, immunoprophylaxis failure still occurs. The study aimed to investigate the protective efficacy of an improved immunoprophylaxis protocol to prevent mother-to-infant transmission of HBV and to explore the potential risk factors associated with immunoprophylaxis failure and low antibody response.A prospective observational cohort study was conducted from July 2012 to April 2015. A total of 863 HBsAg-positive mothers and their 871 infants (8 pairs of twins) were included in the study. Two different hepatitis B vaccine doses (20 or 10 μg) were administered to the infants based on the hepatitis B e-antigen (HBeAg) status of their mothers. Simultaneously, hepatitis B immunoglobulin (HBIG) was administered to the infants. Initial injections of HBIG and the hepatitis vaccine were given within 2 hours after birth. Rates of HBV infections among the infants were evaluated at 7 months of age. Factors associated with immunoprophylaxis failure and low responses to vaccination were analyzed by unconditional logistic regression..At 7 months of age, no immunoprophylaxis failure was observed in the 565 infants born to HBeAg-negative mothers. Among the 306 infants born to HBeAg-positive mothers, immunoprophylaxis failed in 16 infants (5.2%) of the infants and they were found to be HBsAg-positive. Further analysis showed that HBV DNA levels ≥10 IU/mL [odds ratio (OR) = 4.53, 95% confidence interval (95% CI): 1.19-17.34], delayed vaccination (OR = 4.14, 95% CI: 1.00-17.18), and inadequate initial injections (OR = 7.69, 95% CI: 1.71-34.59) were independently associated with immunoprophylaxis failure. Adequate titers of antibody to HBsAg (anti-HBs, ≥100 mIU/mL) were present in 96.5% of immunoprophylaxis-successful infants. For full-term infants, birth weights <3000 g were correlated with low immune responses to vaccination.This improved immunoprophylaxis protocol is effective in preventing perinatal transmission of HBV. Among infants with HBeAg-positive mothers, high HBV viral loads and inadequate and delayed initial injections were associated with immunoprophylaxis failure. The majority of the infants in our study produced adequate levels of protective anti-HBs titers after immunoprophylaxis. Additional efforts to further reduce perinatal transmission should be considered, especially for HBeAg-positive mothers.
- Functional Capacity, Respiratory Muscle Strength, and Oxygen Consumption Predict Mortality in Patients with Cirrhosis. [Journal Article]
- Can J Gastroenterol Hepatol 2016.:6940374.
Introduction.Liver diseases influence musculoskeletal functions and may negatively affect the exercise capacity of patients with cirrhosis.
Aim.To test the relationship between the six-minute walk test (6MWT), maximal inspiratory pressure (MIP), and exercise capacity (VO2peak) measures and the survival rate of patients with cirrhosis. Methods. This prospective cohort study consisted of 86 patients diagnosed with cirrhosis with the following aetiology: hepatitis C virus (HCV), hepatitis B virus (HBV), and/or alcoholic cirrhosis (AC). All patients were followed up for three years and submitted to the 6MWT, pressure measurements with a compound gauge, and an exercise test (VO2peak).
Results.The survival analysis showed that the individuals who covered a distance shorter than 410 m during the 6MWT had a survival rate of 55% compared with a rate of 97% for the individuals who walked more than 410 m (p = 0.0001). Individuals with MIPs below -70 cmH2O had a survival rate of 62% compared with a rate of 93% for those with MIPs above -70 cmH2O (p = 0.0001). The patients with values below 17 mL/kg had a survival rate of 55% compared with a rate of 94% for those with values above 17 mL/kg (p = 0.0001).
Conclusion.The 6MWT distance, MIP, and oxygen consumption are predictors of mortality in patients with cirrhosis.
- Functional characterization of hepatitis B virus core promoter mutants revealed transcriptional interference among co-terminal viral mRNAs. [JOURNAL ARTICLE]
- J Gen Virol 2016 Aug 23.
Hepatitis B virus (HBV) has a 3.2-kb circular DNA genome. It employs four promoters in conjunction with a single polyadenylation signal to generate 3.5-, 2.4-, 2.1-, and 0.7-kb co-terminal RNAs. The 3.5-kb RNA is subdivided into the precore RNA for e antigen expression and pregenomic RNA for genome replication. When introduced to a genotype A clone, several core promoter mutations markedly enhanced HBV genome replication but suppressed e antigen expression through up regulation of pregenomic RNA at the expense of precore RNA. In the present study, we found such mutations also diminished envelope proteins and hepatitis B surface antigen, products of the 2.1-kb and 2.4-kb subgenomic RNAs. Indeed, Northern blot analysis revealed overall increase in 3.5-kb RNA, but reduction in all subgenomic RNAs. To validate transcriptional interference, we subcloned 1.1x, 0.7x, and 0.6x HBV genome, respectively, to a vector with or without a CMV promoter at the 5' end, so as to produce the pregenomic RNA, 2.4-kb RNA, and 2.1-kb RNA in large excess or not at all. Parallel transfection of the three pairs of constructs into a human hepatoma cell line confirmed ability of pregenomic RNA to suppress all subgenomic transcripts, and established ability of the 2.4-kb and 2.1-kb RNAs to suppress the 0.7-kb RNA. Consistent with our findings, pregenomic RNA of the related duck hepatitis B virus has been reported to interfere with transcription of the subgenomic RNAs. Transcriptional interference might explain why HBV produces so little 0.7-kb RNA and HBx protein despite a strong X promoter.
- Association between mannose-binding lectin variants, haplotypes and risk of hepatocellular carcinoma: A case-control study. [Journal Article]
- Sci Rep 2016.:32147.
The innate immunity gene mannose-binding lectin2 (MBL2) has played an important role in hepatitis B virus (HBV) infection, and the relationship between MBL2 variants and hepatocellular carcinoma (HCC) risk has not yet been identified. In total, 315 HCC cases and 315 healthy controls were enrolled and blood samples were acquired. High resolution melt analysis (HRM) was employed to genotype 6 polymorphisms in MBL2 gene. Increased HCC risk in carriers of LL genotype of -550 polymorphism with an adjusted OR (AOR) of 1.61 (95%CI = 1.00-2.57) was observed but no significant association detected in HL genotype. Both YX and XX genotype demonstrated a significantly elevated HCC risk in the analysis of -221 polymorphism. The B variants in codon 54 was also significantly associated with elevated HCC risk. HYB was identified as the protective factor of HCC while LXB was significantly associated with increase HCC risk. ELISA technique revealed that the MBL2 protein was significantly reduced in HCC cases. Moreover, both IL-1β and IL-6 were inversely associated with plasma MBL2 level.The mutations in MBL2 could lead to compromised innate immunity, and possibly lead to elevated HCC risk, and a novel haplotype HXB has been identified with a rate of 12.5%.
- Development of a multisystem surveillance database for transfusion-transmitted infections among blood donors in the United States. [JOURNAL ARTICLE]
- Transfusion 2016 Aug 25.
The frequency of positive test results for transfusion-transmitted infections (TTIs) among blood donors is an important index of safety; thus, appropriate monitoring is critical, particularly when there are changes in policies affecting donor suitability.Testing algorithms from three large blood systems were reviewed and consensus definitions for a surveillance-positive result for hepatitis B virus (HBV), hepatitis C virus (HCV), human immunodeficiency virus (HIV), and human T-cell lymphotropic virus (HTLV) established. In addition, information on each donation, including donor demographics and location, was collected. Combined data were analyzed to characterize the epidemiology of TTIs by person, place, and time.Data from 14.8 million donations were collected for 2011 to 2012, representing more than 50% of the US blood supply. Surveillance-positive rates per 10,000 donations were as follows: HBV, 0.76; HCV, 2.0; HIV, 0.28; and HTLV 0.34. Rates did not vary between the 2 years, although there was variation within a year. With the exception of HTLV, rates were higher among males, and all rates were higher among first-time donations. Window-period donations (those positive only in nucleic acid tests) were infrequent (HBV, 13; HCV, 60; HIV, 14) during the 2-year period. Frequencies of surveillance-positive results varied by donor age and residence location.We demonstrated that standardized data from multiple major US blood systems can be combined and analyzed for change. However, TTI frequencies are low, impacting their sensitivity to change. Furthermore, observed fluctuations in TTI frequencies may be secondary to changes in blood donor demographics rather than necessarily reflecting the immediate impact of policy modification.