Reactivation of hepatitis B virus infection – an important aspect of multifaceted problem

In this editorial we comment on the article published in the recent issue of the W orld Journal of Gastroenterology.We focus specifically on the problem of occult hepatitis B virus(HBV)infection,that is a result of previous hepatitis B(PHB)and a source for reactivation of HBV.The prevalence of PHB is underestimated due to the lack of population testing programs.However,this condition not only com-plicate anticancer treatment,but may be responsible for the development of other diseases,like cancer or autoimmune disorders.Here we unveil possible mecha-nisms responsible for realization of these processes and suggest practical approa-ches for diagnosis and treatment.

Prevalence of occult hepatitis B virus infection in haemodialysis patients from central Greece

AIM:To assess the hepatitis B virus(HBV)-DNA and the prevalence of occult HBV infection in end-stage renal failure(ESRF)patients from Central Greece. METHODS:Sera from 366 ESRF patients attending five out of six dialysis units from Central Greece were investigated for HBV-DNA by real-time polymerase chain reaction.Only serum samples with repeatedly detectable HBV-DNA were considered positive.IgG antibodies to hepatitis C virus(anti-HCV)were tested by a third generation enzyme linked immunosorbent assay(ELISA),while IgG antibodies to hepatitis E virus (anti-HEV)were tested by two commercially available ELISAs.RESULTS:HBV-DNA was detected in 15/366 patient (4.1%)and HBsAg in 20/366(5.5%).The prevalenc of occult HBV infection was 0.9%(3/346 HBsAg negative patients).Occult HBV was not associate with a specific marker of HBV infection or anti-HCV o anti-HEV reactivity.There was no significant differenc in HBV-DNA titres,demographic and biochemica features,between patients with occult HBV infectio and those with HBsAg-positive chronic HBV infection. CONCLUSION:In central Greece,4%of ESRF patient had detectable HBV-DNA,though in this setting,th prevalence of occult HBV seems to be very low(0.9%).

Occult hepatitis B virus infection and surgical outcomes in non-B, non-C patients with curative resection for hepatocellular carcinoma

AIM To investigate the prevalence, clinicopathological characteristics and surgical outcomes of occult hepatitis B virus(HBV) infection(OBI) in patients with non-B, non-C(NBNC) hepatocellular carcinoma(HCC).METHODS This study retrospectively examined the cases of 78 NBNC patients with curative resection for HCC for whom DNA could be extracted from formalin-fixed paraffin-embedded tissue. OBI was determined by the HBV-DNA amplification of at least two different sets of primers by TaqM an realtime polymerase chain reaction. Possibly carcinogenetic factors such as alcohol abuse, diabetes mellitus, obesity and non-alcoholic steatohepatitis(NASH) were examined. Surgical outcomes were evaluated according to diseasefree survival(DFS), overall survival(OS) and diseasespecific survival(DSS).RESULTS OBI was found in 27/78 patients(34.6%) with NBNC HCC. The OBI patients were significantly younger than the non-OBI cases at the time of surgery(average age 63.0 vs 68.1, P = 0.0334) and the OBI cases overlapped with other etiologies significantly more frequently compared to the non-OBI cases(P = 0.0057). OBI had no impact on the DFS, OS or DSS. Only tumorrelated factors affected these surgical outcomes.CONCLUSION Our findings indicate that OBI had no impact on surgical outcomes. The surgical outcomes of NBNC HCC depend on early tumor detection; this reconfirms the importance of a periodic medical examination for individuals who have NBNC HCC risk factors.

Global prevalence of occult hepatitis C virus: A systematic review and meta-analysis

BACKGROUND Occult hepatitis C infection(OCI)is characterized by the presence of hepatitis C virus(HCV)RNA in the liver,peripheral blood mononuclear cells(PBMC)and/or ultracentrifuged serum in the absence of detectable HCV-RNA in serum.OCI has been described in several categories of populations including hemodialysis patients,patients with a sustained virological response,immunocompromised individuals,patients with abnormal hepatic function,and apparently healthy subjects.AIM To highlight the global prevalence of OCI.METHODS We performed a systematic and comprehensive literature search in the following 4 electronic databases PubMed,EMBASE,Global Index Medicus,and Web of Science up to 6th May 2021 to retrieve relevant studies published in the field.Included studies were unrestricted population categories with known RNA status in serum,PBMC,liver tissue and/or ultracentrifuged serum.Data were extracted independently by each author and the Hoy et al tool was used to assess the quality of the included studies.We used the random-effect meta-analysis model to estimate the proportions of OCI and their 95%confidence intervals(95%CI).The Cochran's Q-test and the I2 test statistics were used to assess heterogeneity between studies.Funnel plot and Egger test were used to examine publication bias.R software version 4.1.0 was used for all analyses.RESULTS The electronic search resulted in 3950 articles.We obtained 102 prevalence data from 85 included studies.The pooled prevalence of seronegative OCI was estimated to be 9.61%(95%CI:6.84-12.73)with substantial heterogeneity[I^(2)=94.7%(95%CI:93.8%-95.4%),P<0.0001].Seropositive OCI prevalence was estimated to be 13.39%(95%CI:7.85-19.99)with substantial heterogeneity[I^(2)=93.0%(90.8%-94.7%)].Higher seronegative OCI prevalence was found in Southern Europe and Northern Africa,and in patients with abnormal liver function,hematological disorders,and kidney diseases.Higher seropositive OCI prevalence was found in Southern Europe,Northern America,and Northern Africa.CONCLUSION In conclusion,in the present study,it appears that the burden of OCI is high and variable across the different regions and population categories.Further studies on OCI are needed to assess the transmissibility,clinical significance,long-term outcome,and need for treatment.

Basic Study Hepatitis B virus detected in paper currencies in a densely populated city of India: A plausible source of horizontal transmission?

BACKGROUND The recent rise in the incidence of hepatitis B virus(HBV)infections in a densely populated city of eastern India(“mixing vessel”of people of varied socioeconomic and immune status)prompted this study.Applying saliva on fingers for enumerating bank notes is a common practice in the Indian subcontinent.Paper notes may be a potential source of“horizontal”transmission of this virus,especially if there are cuts/bruises on the oral mucous membrane or skin.AIM To investigate whether paper currencies could be a plausible mode of horizontal transmission of HBV infection.METHODS Polymerase chain reactions(PCR)followed by nucleotide sequencing was done for the detection of HBV.Hepatitis B virus surface antigen enzyme-linked immunosorbent assay(HBsAg ELISA)was performed on all HBV deoxyribonucleic acid-positive samples to check the detectability of the virus.Atomic force microscopy(AFM)was carried out for visual confirmation of HBV particles in ultracentrifuged/immunoprecipitated samples from currency paper washings.RESULTS HBV-specific PCRs on pellets obtained after ultracentrifugation/immunoprecipitation of the currency paper washings detected potentially intact/viable HBV(genotype D2)in 7.14%of samples(n=70).AFM gave the visual confirmation of HBV particles in ultracentrifuged/immunoprecipitated samples from currency paper washings.However,HBV isolates from the currency notes could not be detected by HBsAg ELISA.CONCLUSION It is a common practice in the Indian subcontinent to count paper currencies by applying saliva on fingertips.Paper notes may be a potential source of“horizontal”transmission of this virus,especially if there are cuts/bruises on the oral mucous membrane or skin,but it was practically not possible to demonstrate experimentally such transmission.Detection of potentially intact/viable and“occult”HBV from currency poses potential risk of silent transmission of this virus among the general population.

松毛虫质型多角体病毒的宿主域与交叉感染

自 1956年从赤松毛虫Dendrolimusspectabilis上首次发现赤松毛虫质型多角体病毒 1型 (D .spectabiliscytovirus 1,DsCPV 1)以来 ,先后从马尾松毛虫D .punctatus、油松毛虫D .tabulaeformis、赤松毛虫、德昌松毛虫D .p .tehchangensis、文山松毛虫D .p .wenshangensis和落叶松毛虫D .superans上发现了质型多角体病毒 (cytoplasmicpolyhedrosisvirus ,CPV)。病毒基因组dsRNA电泳图谱分析表明 ,这些松毛虫CPV的不同分离株均属于质型多角体病毒 1型 (cytovirus 1)。这些松毛虫CPV病毒可以感染鳞翅目 10科 3 5种昆虫 ,其中对多种昆虫具有很高的感染力和良好的杀虫效果 ,可以从中筛选替代宿主生产松毛虫CPV杀虫剂 ,用于害虫生物防治。松毛虫CPV接种某些昆虫后病毒的基因组dsRNA电泳图谱发生了改变 。

Asymptomatic Hepadnaviral Persistence and Its Consequences in the Woodchuck Model of Occult Hepatitis B Virus Infection

Woodchuck hepatitis virus (WHV) is molecularly and pathogenically closely related to hepatitis B virus (HBV).Both viruses display tropism towards hepatocytes and cells of the immune system and cause similar liver pathology,where acute hepatitis can progress to chronic hepatitis and to hepatocellular carcinoma (HCC).Two forms of occult hepadnaviral persistence were identified in the woodchuck-WHV model:secondary occult infection (SOI) and primary occult infection (POI).SOI occurs after resolution of a serologically apparent infection with hepatitis or after subclinical serologically evident virus exposure.POI is caused by small amounts of virus and progresses without serological infection markers,but the virus genome and its replication are detectable in the immune system and with time in the liver.SOI can be accompanied by minimal hepatitis,while the hallmark of POI is normal liver morphology.Nonetheless,HCC develops in about 20% of animals with SOI or POI within 3 to 5 years.The virus persists throughout the lifespan in both SOI and POI at serum levels rarely greater than 100 copies/mL,causes hepatitis and HCC when concentrated and administered to virus-na(i)ve woodchucks.SOI is accompanied by virusspecific T and B cell immune responses,while only virusspecific T cells are detected in POI.SOI coincides with protection against reinfection,while POI does not and hepatitis develops after challenge with liver pathogenic doses >1000 virions.Both SOI and POI are associated with virus DNA integration into the liver and the immune system genomes.Overall,SOI and POI are two distinct forms of silent hepadnaviral persistence that share common characteristics.Here,we review findings from the woodchuck model and discuss the relevant observations made in human occult HBV infection (OBI).

Previous hepatitis B viral infection–an underestimated cause of pancreatic cancer

BACKGROUND The etiology of pancreatic cancer remains unclear. This limits the possibility of prevention and effective treatment. Hepatitis B virus(HBV) is responsible for the development of different types of cancer, but its role in pancreatic cancer is still being discussed.AIM To assess the prevalence of previous HBV infection and to identify viral biomarkers in patients with pancreatic ductal adenocarcinoma(PDAC) to support the role of the virus in etiology of this cancer.METHODS The data of 130 hepatitis B surface antigen-negative subjects were available for the final analysis,including 60 patients with PDAC confirmed by cytology or histology and 70 sex-and age-matched controls. All the participants were tested for HBV biomarkers in blood [antibody to hepatitis B core antigen(anti-HBc), antibody to hepatitis B surface antigen(anti-HBs) and HBV DNA], and for those with PDAC, biomarkers in resected pancreatic tissues were tested(HBV DNA, HBV pregenomic RNA and covalently closed circular DNA). We performed immunohistochemistry staining of pancreatic tissues for hepatitis B virus X antigen and Ki-67 protein. Non-parametric statistics were used for the analysis.RESULTS Anti-HBc was detected in 18/60(30%) patients with PDAC and in 9/70(13%) participants in the control group(P = 0.029). Accordingly, the odds of PDAC in anti-HBc-positive subjects were higher compared to those with no previous HBV infection(odds ratio: 2.905, 95% confidence interval: 1.191-7.084, standard error 0.455). HBV DNA was detected in 8 cases of PDAC and in 6 of them in the pancreatic tumor tissue samples only(all patients were anti-HBc positive). Blood HBV DNA was negative in all subjects of the control group with positive results of the serum anti-HBc test. Among 9 patients with PDAC, 5 revealed signs of replicative competence of the virus(covalently closed circular DNA with or without pregenomic RNA) in the pancreatic tumor tissue samples. Hepatitis B virus X antigen expression and active cell proliferation was revealed by immunohistochemistry in 4 patients with PDAC in the pancreatic tumor tissue samples.CONCLUSION We found significantly higher risks of PDAC in anti-HBc-positive patients. Detection of viral replication and hepatitis B virus X protein expression in the tumor tissue prove involvement of HBV infection in pancreatic cancer development.

Occult Hepatitis C Virus Infection:A Review

Occult hepatitis C virus(HCV)infection(OCI),first described in 2004,is defined as the presence of HCV RNA in hepatocytes or peripheral blood mononuclear cells without detectable HCV RNA in the serum.Here,we aimed to review the epidemiology,diagnostic methods,clinical implications and potential man-agement recommendations currently described in the litera-ture,as well as the future directions for investigation of this entity.PubMed and Cochrane databases were searched with combination of the following keywords:"occult","hepatitis C virus",and"occult HCV infection".There are data to support OCI as a potential culprit in cryptogenic liver disease.There are also consistent data demonstrating the existence of OCI in specific populations,such as dialysis,human immunodefi-ciency virus-infected and hepatitis B virus-infected patients,and also in the general population.While the gold standard for diagnosis is liver biopsy,examination of peripheral blood mononuclear cells may be a reliable,safer alternative method of diagnosis.Occult HCV infection is likely associated with liver fibrosis and progression of liver disease.Additional studies are required to determine the infectivity of OCI patients,as well as clarify the natural course and specific clinical implications of OCI.Lastly,studies are needed to determine whether treat-ment of OCI leads to decreased morbidity and/or mortality.

Booster Vaccination in Infancy Reduces the Incidence of Occult HBV Infection in Maternal HBsAg-positive Children

Background and Aims: Occult HBV infection (OBI) in chil-dren has proven to be associated with their immune re-sponse to hepatitis B vaccine (HepB). This study aimed to investigate the effect of a booster HepB on OBI, which is rarely investigated. Methods: This study enrolled 236 ma-ternal HBsAg-positive children who were followed up annu-ally until 8 years of age and were hepatitis B surface antigen (HBsAg) negative. Of those 100 received a booster HepB be-tween 1 and 3 years of age (booster group), and 136 were never boosted (non-booster group). Serial follow-up data of children and baseline data of their mothers were collected and between-group differences were analyzed. Results: The incidence of OBI varied dynamically during follow-up, with 37.14% (78/210), 19.09% (42/220), 20.85% (44/211), 31.61% (61/193), 8.65% (18/208) and 12.71% (30/236) at 7 months, 1, 2, 3, 4, and 8 years of age. At 8 years of age, the negative conversion rate of HBV DNA in the booster group was significantly higher than that in non-booster group [57.89% (11/19) vs. 30.51% (18/59), p=0.032]. For chil-dren without OBI at 7 months old, the incidence of OBI in booster group was significantly lower than that in non-boost-er group [25.64% (10/39) vs. 67.74% (63/93), p<0.001]. Conclusions: The incidence of OBI in maternal HBsAg-positive children was high, serum HBV DNA in children with OBI was intermittently positive at low levels, and a booster HepB in infancy reduced the incidence of OBI in children with HBsAg-positive mothers.

Extremely high titer of hepatitis B surface antigen antibodies in a primary hepatocellular carcinoma patient:A case report

BACKGROUND Hepatocellular carcinoma(HCC)may be caused by hepatitis B virus(HBV)infection.Post-infection recovery-associated changes of HBV indicators include decreased hepatitis B surface antigen(HBsAg)level and increased anti-HBsAg antibody titer.Testing to detect HBV DNA is conducted rarely but could detect latent HBV infection persisting after acute infection and prompt administration of treatments to clear HBV and prevent subsequent HBV-induced HCC deve-lopment.Here,we present an HCC case with an extremely high anti-HBsAg antibody titer and latent HBV infection.CASE SUMMARY A 57-year-old male patient with abdominal pain who was diagnosed with primary HCC presented with an extremely high level(over 2000 ng/mL)of serum alpha-fetoprotein.Abdominal B-ultrasonography and computed tomography scan results indicated focal liver lesion and mild splenomegaly.Assessments of serological markers revealed a high titer of antibodies against hepatitis B core antigen(anti-HBcAg antibodies),an extremely high titer(1000 mIU/mL)of hepatitis B surface antibodies(anti-HBsAg antibodies,anti-HBs)and absence of detectible HBsAg.Medical records indicated that the patient had reported no history of HBV vaccination,infection or hepatitis.Therefore,to rule out latent HBV infection in this patient,a serum sample was collected then tested to detect HBV DNA,yielding a positive result.Based on the aforementioned information,the final diagnosis was HCC associated with hepatitis B in a compensated stage of liver dysfunction and the patient was hospitalized for surgical treatment.CONCLUSION A rare HCC case with high serum anti-HBsAg antibody titer and detectable HBV DNA resulted from untreated latent HBV infection.