Chronic hepatitis B and occult infection in chemotherapy patients-evaluation in oncology and hemato-oncology settings:The CHOICE study

BACKGROUND Reactivation of hepatitis B virus(HBV)infection is a well-known risk that can occur spontaneously or following immunosuppressive therapies,including cancer chemotherapy.HBV reactivation can cause significant morbidity and even mortality,which are preventable if at-risk individuals are identified through screening and started on antiviral prophylaxis.AIM To determine the prevalence of chronic HBV(CHB)and occult HBV infection(OBI)among oncology and hematology-oncology patients undergoing chemo-therapy.METHODS In this observational study,the prevalence of CHB and OBI was assessed among patients receiving chemotherapy.Serological markers of HBV infection[hepatitis B surface antigen(HBsAg)/anti-hepatitis B core antigen(HBc)]were evaluated for all patients.HBV DNA levels were assessed in those who tested negative for HBsAg but positive for total anti-HBc.RESULTS The prevalence of CHB in the study cohort was determined to be 2.3%[95%confidence interval(95%CI):1.0-4.2].Additionally,the prevalence of OBI among the study participants was found to be 0.8%(95%CI:0.2-2.3).CONCLUSION The findings of this study highlight the importance of screening for hepatitis B infection in oncology and hematology-oncology patients undergoing chemotherapy.Identifying individuals with CHB and OBI is crucial for implementing appropriate antiviral prophylaxis to prevent the reactivation of HBV infection,which can lead to increased morbidity and mortality.

Genetic diversity and occult hepatitis B infection in Africa: A comprehensive review

BACKGROUND Occult hepatitis B infection(OBI)is a globally prevalent infection,with its frequency being influenced by the prevalence of hepatitis B virus(HBV)infection in a particular geographic region,including Africa.OBI can be transmitted th-rough blood transfusions and organ transplants and has been linked to the development of hepatocellular carcinoma(HCC).The associated HBV genotype influences the infection.AIM To highlight the genetic diversity and prevalence of OBI in Africa.METHODS This systematic review followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines and involved a comprehensive search on PubMed,Google Scholar,Science Direct,and African Journals Online for published studies on the prevalence and genetic diversity of OBI in Africa.RESULTS The synthesis included 83 articles,revealing that the prevalence of OBI varied between countries and population groups,with the highest prevalence being 90.9%in patients with hepatitis C virus infection and 38%in blood donors,indicating an increased risk of HBV transmission through blood transfusions.Cases of OBI reactivation have been reported following chemotherapy.Genotype D is the predominant,followed by genotypes A and E.CONCLUSION This review highlights the prevalence of OBI in Africa,which varies across countries and population groups.The study also demonstrates that genotype D is the most prevalent.

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.

Characteristics of escape mutations from occult hepatitis B virus infected patients with hematological malignancies in South Egypt

AIM To investigate the prevalence and virological characteristics of occult hepatitis B virus(HBV) infections in patients with hematological malignancies in South Egypt.METHODS Serum samples were collected from 165 patients with hematological malignancies to monitor titers of HBV DNA, hepatitis B surface antigen(HBs Ag), and antibodies to HBV core(anti-HBc) and surface antigens. Serum samples negative for HBs Ag and positive for anti-HBc were subjected to nucleic acid extraction and HBV DNA detection by real-time polymerase chain reaction. DNA sequences spanning the S region were analyzed in cases with occult HBV infection. In vitro comparative study of constructed 1.24-fold wild type and S protein mutant HBV genotype D clones was further performed. RESULTS HBV DNA was detected in 23(42.6%) of 54 patients with hematological malignancies who were HBsA g negative, but anti-HBc positive, suggesting the presence of occult HBV infection. The complete HBV genome was retrieved from 6 occult HBV patients, and P120 T and S143 L were detected in 3 and 2 cases, respectively. Site directed mutagenesis was done to produce 1.24-fold genotype D clones with amino acid mutations T120 and L143. The in vitro analyses revealed that a lower level of extracellular HBsA g was detected by chemiluminescence enzyme immunoassay(CLEIA) with the clone containing T120 mutation, compared with the wild type or the clone with S143 L mutation despite the similar levels of extracellular and intracellular HBs Ag detected by Western blot. Southern blot experiments showed that the levels of intracellular HBV DNA were not different between these clones. CONCLUSION Occult HBV infection is common in patients with hematological malignancies and associated with P120 T and S143 L mutations. 120 T mutation impairs the detection of HBsA g by CLEIA.

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.

Hepatitis B virus infection reactivation in patients under immunosuppressive therapies:Pathogenesis,screening,prevention and treatment

With a 5.3%of the global population involved,hepatitis B virus(HBV)is a major public health challenge requiring an urgent response.After a possible acute phase,the natural history of HBV infection can progress in chronicity.Patients with overt or occult HBV infection can undergo HBV reactivation(HBVr)in course of immunosuppressive treatments that,apart from oncological and hematological diseases,are also used in rheumatologic,gastrointestinal,neurological and dermatological settings,as well as to treat severe acute respiratory syndrome coronavirus 2 infection.The risk of HBV reactivation is related to the immune status of the patient and the baseline HBV infection condition.The aim of the present paper is to investigate the risk of HBVr in those not oncological settings in order to suggest strategies for preventing and treating this occurrence.The main studies about HBVr for patients with occult hepatitis B infection and chronic HBV infection affected by non-oncologic diseases eligible for immunosuppressive treatment have been analyzed.The occurrence of this challenging event can be reduced screening the population eligible for immunosuppressant to assess the best strategies according to any virological status.Further prospective studies are needed to increase data on the risk of HBVr related to newer immunomodulant agents employed in non-oncological setting.

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.

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.

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).

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.

Isolated anti-HBc is an independent risk factor for tumor recurrence in intrahepatic cholangiocarcinoma after curative resection

Background:Intrahepatic cholangiocarcinoma(ICC)is a poorly understood and aggressive malignancy with increasing incidence and mortality.Hepatitis B virus(HBV)infection is recognized as one of the important risk factors of ICC.There are few reports focusing on whether isolated antibody to hepatitis B core antigen(isolated anti-HBc,IAHBc)have prognostic role in ICC,while positive hepatitis B surface antigen(HBsAg)has been reported to be associated with the prognosis of ICC.The aim of this study was to investigate the prognostic value of IAHBc in ICC patients after curative resection,in order to identify those who have the high risk of ICC recurrence in the early stage.Methods:We divided 209 ICC patients who underwent curative resection into 4 groups:groupⅠ(n=40),HBsAg(-)/antibody to hepatitis B surface antigen(anti-HBs)(-)/anti-HBc(+);groupⅡ(n=70),HBsAg(+)/anti-HBc(-);groupⅢ(n=55),HBsAg(-)/anti-HBs(+)/anti-HBc(+);and groupⅣ(n=44),HBsAg(-)/anti-HBc(-).We compared the recurrence-free survival(RFS)and overall survival(OS)among these four groups.Results:The median follow-up time was 16.93 months(range 1-34.6 months).The 1-and 2-year RFS and OS rates were 60%and 42%,and 78%and 63%respectively in all patients.Compared to the whole non-IAHBc patients(groupⅡ+groupⅢ+groupⅣ),IAHBc patients(groupⅠ)showed significantly lower RFS at 1 year(39.8%vs.64.4%,P=0.001)and 2 years(20.7%vs.46.7%,P=0.001).When compared to other three individual groups,IAHBc patients(groupⅠ)also had the lowest RFS.We did not find significant difference in OS among the four groups.Further multivariate analysis revealed that IAHBc was an independent risk factor of RFS.Conclusions:IAHBc is an independent poor prognostic factor for tumor recurrence in ICC patients after curative resection.

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.

the Study of Hepatitis B Virus Reactivation

Hepatitis B virus(HBV) reactivation after chemotherapy or immunosuppressive therapy is a cause of liver-related morbidity and mortality. Not all chronic hepatitis B patients will lead to HBV reactivation. The incidence is 0.3%-30.2% according to the reports. The mechanism of HBV reactivation is still unclear, but it is believed that the viral load is increasing due to the suppression of immune response. No uniform diagnostic criteria are available. HBV reactivation can be confirmed by an increase of serum HBV DNA level. Recently, awareness of reactivation of occult HBV has been improved, especially in HBV endemic area. Preemptive antiviral therapy was the best approach to prevent the HBV reactivation. HBV reactivation can lead to acute hepatitis, severe hepatitis and acute liver failure. Therefore, it is worthy of great attention and further study. Antiviral therapy is safe and effective to prevent HBV reactivation.

Long-term survival of occult hepatitis B associated hepatocellular carcinoma following surgery and antiviral therapy

Occult hepatitis B infection(OBI)is characterized by absent hepatitis B surface antigen(HBsAg),low or undetectable serum hepatitis B viral DNA(HBV-DNA),and detectable DNA in the liver.There is debate over whether OBI increases the risk of hepatocellular carcinoma(HCC).We present a patient with negative HBsAg and a large HCC tumor who underwent a large right hepatic lobectomy.Initially,the etiology of HCC was unknown,but through more sensitive molecular testing,it was believed to be due to OBI.In this case report,we discuss the patient’s clinical course,the effect of antiviral therapy,mechanism of carcinogenesis in OBI,and the need for more rigorous HBV DNA assay testing for the detection of OBI.