Long‐term RNA interference and its application to hepatitis B virus

RNA interference (RNAi) is an ancient defensive mechanism in eukaryotes to control gene expressing and defend their genomes from foreign invaders. It refers to the phenomenon that double‐stranded RNA results in the sequence‐specific silencing of target gene expression. Although it was documented in a relatively short time ago, intensive research has facilitated making its mechanism clear. Researchers have found that it was a powerful tool for analyzing the functions of genes and treating tumors, infectious diseases and genetic abnormalities that are associated with a dominant gene defect. However, delivery in vivo, low blood stability and poor intracellular uptake present significant challenges for the development of RNAi reagents in clinical use. Thus, long‐term inducible RNAi was designed. There are hundreds of millions of hepatitis B virus (HBV) carriers in the world at present, a portion of whom will lose their lives after several years due to chronic complications such as cirrhosis, hepatocellular carcinomas or both. Although a preventive vaccine is now available, the present therapeutic options for chronically infected patients are limited and of low efficiency. Admittedly, to date most RNAi experiments have been done in vitro, but it is hoped that they may be developed into a therapeutic strategy for HBV in the near future. In this article the principles and construction of long‐term RNA are discussed. Its therapeutic potentiality and attention to the potential hazards will also outlined. We conclude that this ancient defensive mechanism can be recruited as a powerful weapon in the fight against HBV.     

Exploiting the RNA interference pathway to counter hepatitis B virus replication.

Chronic infection with hepatitis B virus (HBV) is endemic to sub-Saharan Africa and parts of Asia where persistence of the virus is commonly associated with complicating cirrhosis and hepatocellular carcinoma (HCC). Licensed therapies for HBV are partially effective in selected patients and development of novel treatments remains an important global medical objective. HBV has an unusually compact genome that restricts the ability of the virus to evade potentially therapeutic nucleic acid hybridization. Thus, exploiting the RNA interference (RNAi) pathway, which enables sequence-specific target RNA degradation using small interfering RNA (siRNA), is well suited to developing novel treatment for HBV infection. Several studies, both in vitro and in vivo, have demonstrated that HBV replication can be inhibited in transfected cells by synthetic siRNA duplexes and also Pol III-derived short hairpin RNA (shRNA) sequences. The effectiveness of anti-HBV sequences varies considerably, and is likely to result from differences in activation of the RNAi pathway by individual siRNA species. Exclusion of potentially toxic off-target effects and also development of efficient methods of hepatotropic nucleic acid delivery are important prerequisites before RNAi can be used successfully for anti-HBV treatment.     

Prevalence of occult hepatitis B virus infection in hemodialysis patients from egypt with or without hepatitis C virus infection

Background

While prevalence of Hepatitis B virus (HBV) in patients with end-stage renal failure (ESRF) who are undergoing dialysis has decreased significantly during the past few decades, it still remains a distinct clinical problem. The immunosuppressive nature of renal disease often leads to chronicity of the HBV infection and an opportunity for nosocomial spread of the infection among dialysis patients. Egypt is among the countries with intermediate endemicity of HBsAg (range, 2%–7%). Large-scale geographic heterogeneity in HBV prevalence has been reported worldwide and HBV prevalence is especially heterogeneous in Egypt.

Objectives

To assess the prevalence of occult HBV infection (OBI) in hemodialysis patients with or without chronic hepatitis C (HCV) from Minia and Assuit, Upper Egypt, using HBV DNA assays.

Patient and Methods

Sera from 145 hemodialysis patients with negative HbsAg were investigated for HBV DNA using real-time polymerase chain reaction (RT-PCR). Only serum samples with repeatedly detectable HBV DNA were considered positive. Patients were divided into 2 groups: HCV RNA positive and HCV RNA negative, based on the results of a third generation enzyme linked immunosorbent assay (ELISA) anti-HCV test and HCV RNA PCR.

Results

HBV DNA was detected in 6 of the 145 patients (4.1%) and HBcAb was detected in 29/145 patients (20%). There were no statistically significant differences in the age, duration of hemodialysis, biochemical parameters, serological markers of HBV, or HBV DNA between patients with and without HCV infection.

Conclusions

Four percent of the hemodialysis patients had OBI. There was no significant difference in the prevalence of OBI between hemodialysis patients with or without HCV co-infection.     

Caesarean section to prevent transmission of hepatitis B: A meta-analysis

BACKGROUND:

Vertical transmission of hepatitis B virus (HBV) occurs in up to 10% to 20% of births.

OBJECTIVE:

To assess whether Caesarean section, compared with vaginal delivery, prevents HBV transmission.

METHODS:

A systematic review and meta-analysis was conducted. Two investigators independently searched PubMed, EMBASE and other databases for relevant studies published between 1988 and 2013. A manual search of relevant topics and major conferences for abstracts was also conducted. Randomized trials, cohort and case-control studies assessing the effect of delivery mode on vertical transmission of HBV were included. Studies assessing antiviral therapy and patients with coinfection were excluded. The primary outcome was HBV transmission rates according to delivery method.

RESULTS:

Of the 430 studies identified, 10 were included. Caesarean section decreased the odds of HBV transmission by 38% compared with vaginal delivery (OR 0.62 [95% CI 0.40 to 0.98]; P=0.04) based on a random-effects model. Significant heterogeneity among studies was found (I²=63%; P=0.003), which was largely explained by variation in hepatitis B immune globulin (HBIG) administration. Meta-regression showed a significant linear association between the percentage of infants receiving HBIG per study and the log OR (P=0.005), with the least benefit observed in studies with 100% HBIG administration. Subgroup analysis of hepatitis B e-antigen-positive women who underwent Caesarean section did not show a significant reduction in vertical transmission.

DISCUSSION:

Caesarean section may protect against HBV transmission; however, convincing benefit could not be demonstrated due to significant study heterogeneity from variable HBIG administration, highlighting the importance of HBIG in HBV prevention.

CONCLUSION:

More high-quality studies are needed before any recommendations can be made.     

Serum HBV RNA and HBeAg are useful markers for the safe discontinuation of nucleotide analogue treatments in chronic hepatitis B patients

Background

Treatment for chronic hepatitis B has improved drastically with the use of nucleot(s)ide analogues (NAs). However, NA therapy typically fails to eliminate Hepatitis B virus (HBV) completely, and it is difficult to discontinue these therapies. We previously demonstrated that NA therapy induced immature viral particles, including HBV RNA in sera of chronic hepatitis B patients. In the study reported here, we analyzed the association between HBV RNA titer and the recurrence rate of hepatitis after discontinuation of NA therapy.

Methods

The study cohort comprised 36 patients who had discontinued NA therapy. Serum HBV DNA or DNA plus RNA levels were measured by real time PCR and statistical analyses were performed using clinical data and HBV markers.

Results

At 24 weeks after discontinuation of NA therapy, HBV DNA rebound was observed in 19 of the 36 patients (52.8 %), and alanine aminotransferase (ALT) rebound was observed in 12 of 36 patients (33.3 %). Multivariate statistical analysis was used to identify factors predictive of HBV DNA rebound. The HBV DNA + RNA titer following 3 months of treatment was significantly associated with HBV DNA rebound [P = 0.043, odds ratio (OR) 9.474, 95 % confidence interval (CI) 1.069–83.957)]. Absence of hepatitis B e antigen (HBeAg) at the end of treatment was significantly associated with ALT rebound (P = 0.003, OR 13.500, 95 % CI 2.473–73.705). In HBeAg-positive patients, the HBV DNA + RNA titer after 3 months of treatment was marginally associated with ALT rebound (P = 0.050, OR 8.032, 95 % CI 0.997–64.683).

Conclusions

Monitoring of serum HBV DNA + RNA levels may be a useful method for predicting re-activation of chronic hepatitis B after discontinuation of NA therapy.     

Sero-prevalence and risk factors for hepatitis B virus infection among health care workers in a tertiary hospital in Uganda

Background  

Hepatitis B virus (HBV) infection is a global public health challenge. Prevalence of current hepatitis B virus infection in the general population in Uganda is about 10%. Health care workers (HCW) have an extra risk of getting infected from their workplace and yet they are not routinely vaccinated against HBV infection. This study aimed at estimating prevalence of hepatitis B virus infection and associated risk factors among health care workers in a tertiary hospital in Uganda.     

Correlation between maternal hepatitis B surface antigen carrier status with social,medical and family factors in an endemic area: have we overlooked something?

Purpose  

Hepatitis B virus (HBV) infection is endemic in many countries, but the risk factors for HBV carriage in the obstetric population are unclear.     

Sex-differences in the association of interleukin-10 and interleukin-12 variants with the progression of hepatitis B virus infection in Caucasians

Aim

Interleukin (IL)-10 and IL-12 contribute to immune responses against hepatitis B virus (HBV) infection. Polymorphisms in the IL-10 and IL-12A genes might affect the clinical outcome of HBV infection. We evaluated the association of IL-10 rs1800896 and rs3024490, and IL-12A rs568408 and rs2243115 with the progression of HBV infection and development of severe liver disease stages in a white European population.

Method

A total of 636 white European patients with chronic HBV infection, 239 individuals with spontaneous HBV surface antigen seroclearance, and 254 healthy controls were enrolled. The chronic HBV infection group included patients with hepatitis B envelope antigen (HBeAg) negative chronic hepatitis B (n = 255), with HBeAg positive chronic hepatitis B (n = 99) and with HBeAg negative HBV infection (n = 228). A total of 104 chronically infected patients were diagnosed with liver cirrhosis. Serum levels of cytokines were measured in patients with HBV infection (n = 195) and in healthy controls (n = 160).

Results

In adjusted multivariate analysis, the IL-10 rs1800896 AG/GG genotypes were significantly associated with an increased probability of HBV surface antigen seroclearance (OR = 1.75, 95% CI 1.04–2.94, p = 0.034), with an increased likelihood of HBeAg negative chronic infection (OR = 1.93, 95% CI 1.05–3.54, p = 0.034) and with increased serum cytokines levels in female patients. In contrast, the IL-12A rs568408 AG/AA genotypes were independently associated with an increased risk to develop liver cirrhosis, with an OR of 1.90 (95% CI 1.07–3.39, p = 0.029) in male patients.

Conclusion

The current study shows a sex-related association of the IL-10 single-nucleotide polymorphism rs1800896 and IL-12A single-nucleotide polymorphism rs568408 with different stages of HBV infection and with HBV-related liver cirrhosis in white European patients.     

Evaluation of immune response to Hepatitis B vaccine in health care workers at a tertiary care hospital in Pakistan: an observational prospective study

Background  

Seroconversion rates reported after Hepatitis B virus (HBV) vaccination globally ranges from 85–90%. Health care workers (HCWs) are at high risk of acquiring HBV and non responders' rates after HBV vaccination were not reported previously in Pakistani HCWs. Therefore we evaluated immune response to HBV vaccine in HCWs at a tertiary care hospital in Karachi, Pakistan.     

Hepatitis B vaccinations among Koreans: Results from 2005 Korea National Cancer Screening Survey

Background  

Liver cancer is one of most commonly diagnosed cancers among Koreans. Chronic hepatitis B virus (HBV) infection is a major risk factor for liver cancer. HBV infection can be prevented by effective screening and vaccination programs. The purpose of this study is to examine the status of HBV infection and the predictors associated with HBV vaccination.     

Hepatitis B and Hepatocellular Carcinoma Screening Among Asian Americans: Survey of Safety Net Healthcare Providers

Background  

Physician patterns of screening for hepatitis B (HBV) and hepatocellular carcinoma (HCC) among Asian Americans are not well described.     

An economic analysis of premarriage prevention of hepatitis B transmission in Iran

Background  

To assess the economic aspects of HBV (hepatitis B virus) transmission prevention for premarriage individuals in a country with cultural backgrounds like Iran and intermediate endemicity of HBV infection.     

Different effect of HBV vaccine after liver transplantation between chronic HBV carriers and non-HBV patients who received HBcAb-positive grafts

Background  

Combination of nucleos(t)ide analogue and anti-HBs immunoglobulin (HBIg) is the standard protocol for prevention of HBV reactivation after liver transplantation, but because of the extremely high cost of HBIg, HBV vaccine is tried as a much cheaper and potentially safer substitute. Here we show the different effect of HBV vaccine between chronic HBV carrier and non-HBV patients who received grafts from HBc antibody-positive donors.     

Modelling the force of infection for hepatitis B and hepatitis C in injecting drug users in England and Wales

Background  

Injecting drug use is a key risk factor, for several infections of public health importance, especially hepatitis B (HBV) and hepatitis C (HCV). In England and Wales, where less than 1% of the population are likely to be injecting drug users (IDUs), approximately 38% of laboratory reports of HBV, and 95% of HCV reports are attributed to injecting drug use.     

Patients with Inflammatory Bowel Disease Have a Lower Response Rate to HBV Vaccination Compared to Controls

Background  

Hepatitis B (HBV) is a vaccine-preventable infection that may cause severe infections, particularly in patients who are being treated with immunosuppressive therapy [(i.e., inflammatory bowel disease (IBD)]. Limited data are available about IBD patients’ response rate to HBV vaccine.     

HBV/A and HBV/C genotype predominance among patients with chronic hepatitis B virus infection in Cebu City, Philippines

Context  

Chronic Hepatitis B virus (HBV) infection causes significant morbidity and mortality with widespread global distribution. Different genotypes display variations in pathogenesis, disease behavior, and treatment response. HBV/B and HBV/C are prevalent in Asia, but minimal data come from the Philippines.