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1.  Cohort study of non-Hodgkin lymphoma risk in association with hepatitis B virus infection in South Korea 
The lancet oncology  2010;11(9):827-834.
Background
Hepatitis B virus (HBV) infection is common throughout Asia and Africa. Evidence is inconclusive regarding whether chronic HBV infection increases risk for non-Hodgkin lymphoma (NHL).
Methods
We conducted a cohort study of 603,585 South Korean workers and their dependents enrolled during 1992–1995. Serum hepatitis B surface antigen (HBsAg) measured at baseline indicated the presence of chronic HBV infection. We ascertained hematologic malignancies using national inpatient, outpatient, and mortality databases through 2006. Cox regression was used to evaluate associations with HBsAg status, adjusting for sex, age, and enrollment year.
Results
53,045 subjects (8.8%) were HBsAg positive at baseline. Subsequently, 133 HBsAg positive and 905 HBsAg negative individuals developed NHL. HBsAg positive subjects had elevated risk of NHL overall (incidence 19.4 vs. 12.3 per 100,000 person-years; adjusted hazard ratio [HR] 1.74, 95%CI 1.45–2.09). Among NHL subtypes, risk was significantly elevated in association with HBsAg positivity for diffuse large B cell lymphoma (N=325 cases; adjusted HR 2.01, 95%CI 1.48–2.75) and non-significantly elevated for follicular NHL (N=47; 1.67, 0.71–3.95) and T-cell NHL (N=75; 1.40, 0.67–2.92); risk was also elevated for other/unknown NHL subtypes (N=591; 1.65, 1.29–2.11). Elevated risk was also observed for malignant immunoproliferation (N=14; adjusted HR 3.79, 95%CI, 1.05–13.7), a category that includes Waldenström macroglobulinemia. Risk of these malignancies was consistently elevated in HBsAg positive subjects throughout 14 years of follow-up. HBsAg positivity was not associated with Hodgkin lymphoma, multiple myeloma, or various leukemias.
Interpretation
During extended follow-up, HBsAg positive individuals manifested an elevated risk of NHL, suggesting that chronic infection promotes lymphomagenesis.
doi:10.1016/S1470-2045(10)70167-4
PMCID: PMC2933963  PMID: 20688564
2.  microRNA levels in paraffin-embedded indolent B-cell non-Hodgkin lymphoma tissues from patients chronically infected with hepatitis B or C virus 
BMC Infectious Diseases  2014;14(Suppl 5):S6.
Background
Epidemiological evidence links Hepatitis B Virus (HBV) and Hepatitis C Virus (HCV) to B-cell non-Hodgkin lymphoma (B-NHL). These B-NHLs, particularly those associated with HCV, may represent a distinct sub-group with peculiar molecular features, including peculiar expression of microRNAs (miRs).
The aim of the present study was to search for miRs whose level in indolent B-NHL tissues could be associated with HBV or HCV infection.
Methods
Fourteen formalin fixed paraffin embedded (FFPE) tissues from HBV+, HCV+ and HBV-/HCV- indolent B-NHL patients were analyzed for levels of 34 selected miRs by quantitative Real-Time PCR. Reactive lymph nodes (RLNs) from HBV-/HCV- patients were included as non-tumor control. Statistical analysis of output data included Pearson and Spearman correlation and Mann-Whitney test and were carried out by the STATA software.
Results
MiR-92a was decreased exclusively in HBV-/HCV- B-NHLs, while miR-30b was increased in HBV+ and HCV+ samples, though only the HCV+ achieved full statistical significance. Analysis of a small subset of B-NHLs belonging to the same histological subtype (Nodal Marginal Zone Lymphoma) highlighted three miRs associated with HCV infection (miR-223, miR-29a and miR-29b) and confirmed decreased level of miR-92a in HBV-/HCV- samples also when considering this restricted B-NHL group.
Conclusions
Although caution is needed due to the limited number of analyzed samples, overall the results suggest that differences at the miR expression level exist between indolent B-NHLs developed in patients with or without HBV or HCV infection. The identification of three further miRs associated with HCV by analyzing histologically homogeneous samples suggests that variations of miR levels possibly associated with HBV or HCV may be obscured by the tissue-specific variability of miR level associated with the different histological subtypes of B-NHL. Thus, the identification of further miRs will require, in addition to an increased sample size, the comparison of B-NHL tissues with the same histological classification.
doi:10.1186/1471-2334-14-S5-S6
PMCID: PMC4160900  PMID: 25236768
Lymphoma; Hepatitis B Virus; Hepatitis C Virus; microRNA; FFPE
3.  Concurrent Infection of Hepatitis B Virus Negatively Affects the Clinical Outcome and Prognosis of Patients with Non-Hodgkin’s Lymphoma after Chemotherapy 
PLoS ONE  2013;8(7):e69400.
Hepatitis B virus (HBV) is hepatotropic and lymphotropic. HBV-infected individuals have an increased risk of developing malignant lymphoma, and the HBV infection rate in lymphoma patients is significantly higher than that in the general population. However, the exact mechanism and correlation between HBV infection and lymphoma onset and progression currently remain unclear. We retrospectively analyzed clinical data from non-Hodgkin’s lymphoma (NHL) patients with different HBV infection statuses. The results showed that the HBV infection rate was significantly higher in patients with B-cell type and late stage of NHL. The chemotherapy efficacy for NHL patients with chronic active HBV infection was significantly lower than that for the patients with chronic inactive HBV infection, the patients with HBV carriers and the patients without HBV infection. In addition, the NHL chemotherapy activated HBV replication and caused significant liver dysfunction, which could further reduce the chemotherapy efficacy. Through Kaplan-Meier survival curve and log-rank analysis, we found that the HBV infection status in NHL patients was significantly correlated with the patients’ progression-free survival (PFS) and overall survival (OS). Compared with the patients without HBV infection (PFS: 95% CI 47.915 to 55.640; OS: 95% CI 81.324 to 86.858), the PFS and OS of the patients with chronic active HBV infection were significantly shorter (PFS: 95% CI 9.424 to 42.589, P < 0.001; OS: 95% CI 42.840 to 82.259, P = 0.006). The study demonstrated that the sustained HBV replication in patients with chronic active HBV infection could be a key factor that influences the prognosis of NHL patients after chemotherapy, and thus may provide information for designing rational clinical treatments for NHL patients with different HBV infection statuses and improve the treatment efficacy and prognosis.
doi:10.1371/journal.pone.0069400
PMCID: PMC3704665  PMID: 23861969
4.  Efficacy of Neonatal HBV Vaccination on Liver Cancer and Other Liver Diseases over 30-Year Follow-up of the Qidong Hepatitis B Intervention Study: A Cluster Randomized Controlled Trial 
PLoS Medicine  2014;11(12):e1001774.
In a 30-year follow-up of the Qidong Hepatitis B Intervention Study, Yawei Zhang and colleagues examine the effects of neonatal vaccination on liver diseases.
Please see later in the article for the Editors' Summary
Background
Neonatal hepatitis B vaccination has been implemented worldwide to prevent hepatitis B virus (HBV) infections. Its long-term protective efficacy on primary liver cancer (PLC) and other liver diseases has not been fully examined.
Methods and Findings
The Qidong Hepatitis B Intervention Study, a population-based, cluster randomized, controlled trial between 1985 and 1990 in Qidong, China, included 39,292 newborns who were randomly assigned to the vaccination group in which 38,366 participants completed the HBV vaccination series and 34,441 newborns who were randomly assigned to the control group in which the participants received neither a vaccine nor a placebo. However, 23,368 (67.8%) participants in the control group received catch-up vaccination at age 10–14 years. By December 2013, a total of 3,895 (10.2%) in the vaccination group and 3,898 (11.3%) in the control group were lost to follow-up. Information on PLC incidence and liver disease mortality were collected through linkage of all remaining cohort members to a well-established population-based tumor registry until December 31, 2013. Two cross-sectional surveys on HBV surface antigen (HBsAg) seroprevalence were conducted in 1996–2000 and 2008–2012. The participation rates of the two surveys were 57.5% (21,770) and 50.7% (17,204) in the vaccination group and 36.3% (12,184) and 58.6% (17,395) in the control group, respectively. Using intention-to-treat analysis, we found that the incidence rate of PLC and the mortality rates of severe end-stage liver diseases and infant fulminant hepatitis were significantly lower in the vaccination group than the control group with efficacies of 84% (95% CI 23%–97%), 70% (95% CI 15%–89%), and 69% (95% CI 34%–85%), respectively. The estimated efficacy of catch-up vaccination on HBsAg seroprevalence in early adulthood was 21% (95% CI 10%–30%), substantially weaker than that of the neonatal vaccination (72%, 95% CI 68%–75%). Receiving a booster at age 10–14 years decreased HBsAg seroprevalence if participants were born to HBsAg-positive mothers (hazard ratio [HR] = 0.68, 95% CI 0.47–0.97). Limitations to consider in interpreting the study results include the small number of individuals with PLC, participants lost to follow-up, and the large proportion of participants who did not provide serum samples at follow-up.
Conclusions
Neonatal HBV vaccination was found to significantly decrease HBsAg seroprevalence in childhood through young adulthood and subsequently reduce the risk of PLC and other liver diseases in young adults in rural China. The findings underscore the importance of neonatal HBV vaccination. Our results also suggest that an adolescence booster should be considered in individuals born to HBsAg-positive mothers and who have completed the HBV neonatal vaccination series.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Hepatitis B is a life-threatening liver infection caused by the hepatitis B virus (HBV). HBV, which is transmitted through contact with the blood or other bodily fluids of an infected person, can cause both acute (short-term) and chronic (long-term) liver infections. Acute infections rarely cause any symptoms and more than 90% of adults who become infected with HBV (usually through sexual intercourse with an infected partner or through the use of contaminated needles) are virus-free within 6 months. However, in sub-Saharan Africa, East Asia, and other regions where HBV infection is common, HBV is usually transmitted from mother to child at birth or between individuals during early childhood and, unfortunately, most infants who are infected with HBV during the first year of life and many children who are infected before the age of 6 years develop a chronic HBV infection. Such infections can cause liver cancer, liver cirrhosis (scarring of the liver), and other fatal liver diseases. In addition, HBV infection around the time of birth can cause infant fulminant hepatitis, a rare but frequently fatal condition.
Why Was This Study Done?
HBV infections kill about 780,000 people worldwide annually but can be prevented by neonatal vaccination—immunization against HBV at birth. A vaccine against HBV became available in 1982 and many countries now include HBV vaccination at birth followed by additional vaccine doses during early childhood in their national vaccination programs. But, although HBV vaccination has greatly reduced the rate of chronic HBV infection, the protective efficacy of neonatal HBV vaccination against liver diseases has not been fully examined. Here, the researchers investigate how well neonatal HBV vaccination protects against primary liver cancer and other liver diseases by undertaking a 30-year follow-up of the Qidong Hepatitis B intervention Study (QHBIS). This cluster randomized controlled trial of neonatal HBV vaccination was conducted between 1983 and 1990 in Qidong County, a rural area in China with a high incidence of HBV-related primary liver cancer and other liver diseases. A cluster randomized controlled trial compares outcomes in groups of people (towns in this study) chosen at random to receive an intervention or a control treatment (here, vaccination or no vaccination; this study design was ethically acceptable during the 1980s when HBV vaccination was unavailable in rural China but would be unethical nowadays).
What Did the Researchers Do and Find?
The QHBIS assigned nearly 80,000 newborns to receive either a full course of HBV vaccinations (the vaccination group) or no vaccination (the control group); two-thirds of the control group participants received a catch-up vaccination at age 10–14 years. The researchers obtained data on how many trial participants developed primary liver cancer or died from a liver disease during the follow-up period from a population-based tumor registry. They also obtained information on HBsAg seroprevalence—the presence of HBsAg (an HBV surface protein) in the blood of the participants, an indicator of current HBV infection—from surveys undertaken in1996–2000 and 2008–2012. The researchers estimate that the protective efficacy of vaccination was 84% for primary liver cancer (vaccination reduced the incidence of liver cancer by 84%), 70% for death from liver diseases, and 69% for the incidence of infant fulminant hepatitis. Overall, the efficacy of catch-up vaccination on HBsAg seroprevalence in early adulthood was weak compared with neonatal vaccination (21% versus 72%). Notably, receiving a booster vaccination at age 10–14 years decreased HBsAg seroprevalence among participants who were born to HBsAg-positive mothers.
What Do These Findings Mean?
The small number of cases of primary liver cancer and other liver diseases observed during the 30-year follow-up, the length of follow-up, and the availability of incomplete data on seroprevalence all limit the accuracy of these findings. Nevertheless, these findings indicate that neonatal HBV vaccination greatly reduced HBsAg seroprevalence (an indicator of current HBV infection) in childhood and young adulthood and subsequently reduced the risk of liver cancer and other liver diseases in young adults. These findings therefore support the importance of neonatal HBV vaccination. In addition, they suggest that booster vaccination during adolescence might consolidate the efficacy of neonatal vaccination among individuals who were born to HBsAg-positive mothers, a suggestion that needs to be confirmed in randomized controlled trials before booster vaccines are introduced into vaccination programs.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001774.
The World Health Organization provides a fact sheet about hepatitis B (available in several languages) and information about hepatitis B vaccination
The World Hepatitis Alliance (an international not-for-profit, non-governmental organization) provides information about viral hepatitis, including some personal stories about hepatitis B from Bangladesh, Pakistan, the Philippines, and Malawi
The UK National Health Service Choices website provides information about hepatitis B
The not-for-profit British Liver Trust provides information about hepatitis B, including Hepatitis B: PATH B, an interactive educational resource designed to improve the lives of people living with chronic hepatitis B
MedlinePlus provides links to other resources about hepatitis B (in English and Spanish)
Information about the Qidong Hepatitis B intervention Study is available
Chinese Center for Disease Control and Prevention provides links about hepatitis B prevention in Chinese
doi:10.1371/journal.pmed.1001774
PMCID: PMC4280122  PMID: 25549238
5.  Long-term Outcome after Prophylactic Lamivudine Treatment on Hepatitis B Virus Reactivation in Non-Hodgkin's Lymphoma 
Yonsei Medical Journal  2007;48(1):78-89.
Hepatitis B virus (HBV) reactivation is the frequent complication after cytotoxic chemotherapy in HBsAg-positive non-Hodgkin's lymphoma (NHL) patients. Pre-chemotherapy viral load may be a risk factor and HBeAg-positive status is associated with increased viral load. The aim of this study was to investigate the long-term treatment outcome of lamivudine in preventing HBV reactivation and its associated morbidity according to HBeAg status. Twenty-four adult HBsAg-positive NHL patients were taken 100 mg of lamivudine daily before the initiation of chemotherapy. The median duration of lamivudine therapy was 11.5 months (range: 1-54 months) and the median number of chemotherapy cycles was 6 (range: 1-16 cycles). The steroid containing chemotherapy regimens were used in 18 patients (75%), and the anti-CD20 monoclonal antibody containing chemotherapy regimen was used in 6 patients (25%). Four patients received autologous peripheral blood stem cell transplantation without resultant HBV reactivation. Hepatitis related to HBV reactivation was developed in 1 patient among 14 HBeAg-positive patients and no one among 10 HBeAg-negative. One patient developed HBV reactivation after lamivudine withdrawal, and 4 patients developed the YMDD (tyrosine-methionine-aspartate-aspartate) mutation during lamivudine therapy. There were no statistical differences in HBV reactivation rate during chemotherapy according to the HBeAg status. Our results demonstrate that lamivudine should be considered preemptively before the chemotherapy for all HBsAg-positive NHL patients to prevent HBV reactivation, regardless of pre-chemotherapy HBeAg status. Finally, compared with the chronic hepatitis B patients, similar rate of HBV reactivation after lamivudine withdrawal and development of YMDD mutation was observed in NHL patients.
doi:10.3349/ymj.2007.48.1.78
PMCID: PMC2627995  PMID: 17326249
HBV reactivation; lamivudine; non-Hodgkin's lymphoma; chemotherapy; HBeAg
6.  High Seroprevalence of HBV and HCV Infection in HIV-Infected Adults in Kigali, Rwanda 
PLoS ONE  2013;8(5):e63303.
Background
Data on prevalence and incidence of hepatitis B virus (HBV) and hepatitis C virus (HCV) infection in Rwanda are scarce.
Methods
HBV status was assessed at baseline and Month 12, and anti-HCV antibodies at baseline, in a prospective cohort study of HIV-infected patients in Kigali, Rwanda: 104 men and 114 women initiating antiretroviral therapy (ART) at baseline, and 200 women not yet eligible for ART.
Results
Baseline prevalence of active HBV infection (HBsAg positive), past or occult HBV infection (anti-HBc positive and HBsAg negative) and anti-HCV was 5.2%, 42.9%, and 5.7%, respectively. The active HBV incidence rate was 4.2/1,000 person years (PY). In a multivariable logistic regression model using baseline data, participants with WHO stage 3 or 4 HIV disease were 4.19 times (95% CI 1.21–14.47) more likely to have active HBV infection, and older patients were more likely to have evidence of past exposure to HBV (aRR 1.03 per year; 95%CI 1.01–1.06). Older age was also positively associated with having anti-HCV antibodies (aOR 1.09; 95%CI 1.04–1.14) while having a higher baseline HIV viral load was negatively associated with HCV (aOR 0.60; 95% CI 0.40–0.98). The median CD4 increase during the first 12 months of ART was lower for those with active HBV infection or anti-HCV at baseline. Almost all participants (88%) with active HBV infection who were on ART were receiving lamivudine monotherapy for HBV.
Conclusion
HBV and HCV are common in HIV-infected patients in Rwanda. Regular HBsAg screening is needed to ensure that HIV-HBV co-infected patients receive an HBV-active ART regimen, and the prevalence of occult HBV infection should be determined. Improved access to HBV vaccination is recommended. Active HCV prevalence and incidence should be investigated further to determine whether HCV RNA PCR testing should be introduced in Rwanda.
doi:10.1371/journal.pone.0063303
PMCID: PMC3661584  PMID: 23717409
7.  Hepatitis C virus and non-Hodgkin's lymphoma: findings from the Swiss HIV Cohort Study 
British Journal of Cancer  2006;95(11):1598-1602.
Infections with hepatitis C virus (HCV) and, possibly, hepatitis B virus (HBV) are associated with an increased risk of non-Hodgkin's lymphoma (NHL) in the general population, but little information is available on the relationship between hepatitis viruses and NHL among people with HIV (PHIV). We conducted a matched case–control study nested in the Swiss HIV Cohort Study (SHCS). Two hundred and ninety-eight NHL cases and 889 control subjects were matched by SHCS centre, gender, age group, CD4+ count at enrolment, and length of follow-up. Odds ratios (OR) and corresponding 95% confidence intervals (CI) were computed using logistic regression to evaluate the association between NHL and seropositivity for antibodies against HCV (anti-HCV) and hepatitis B core antigen (anti-HBc), and for hepatitis B surface antigen (HBsAg). Anti-HCV was not associated with increased NHL risk overall (OR=1.05; 95% CI: 0.63–1.75), or in different strata of CD4+ count, age or gender. Only among men having sex with men was an association with anti-HCV found (OR=2.37; 95% CI: 1.03–5.43). No relationships between NHL risk and anti-HBc or HBsAg emerged. Coinfection with HIV and HCV or HBV did not increase NHL risk compared to HIV alone in the SHCS.
doi:10.1038/sj.bjc.6603472
PMCID: PMC2360727  PMID: 17106439
hepatitis C virus; non-Hodgkin's lymphoma; HIV; Switzerland
8.  Correlations of hematological parameters with bone marrow findings in chronic lymphoproliferative disorders associated with hepatitis viruses 
Journal of Medicine and Life  2013;6(4):464-471.
Abstract
Background. Hepatitis B and C viruses’ infections are often associated with hematological disorders in evolution, suggesting that these viruses have a tropism for peripheral blood and/or bone marrow cells.
Aim. To analyze the hematological parameters and bone marrow findings in a group of patients diagnosed with chronic lymphoproliferative disorders (CLD) and hepatitis viruses B, C, D infections, which were included in the research grant (acronym LIMFO-VIR) between December 2007 and May 2010 in the Hematology Department of the Emergency University Hospital of Bucharest.
Methods and results. Patients were diagnosed by using immunopathology according to the WHO criteria. The analyzed group included 42 patients (both sexes), with the mean age of 60,35 years. The most frequent hematologic disease was non-Hodgkin’s lymphoma 30/42 (71,42%), followed by chronic lymphocytic leukemia (16,66%) and Hodgkin’s lymphoma (7,14%). Hepatitis viruses were distributed: 17/42 (40,47%) patients with HBV, 22/42 (52,38%) with HCV and 3/42 (7,14%) had a double/triple association of viruses. Most of the patients had an indolent type of disease - 27/42 (64,28%), whereas 15/42 (35,71%) had an aggressive one, pattern found both in the HBV and HCV infected groups. An abnormal bone marrow result was revealed in 32/42 (76,19%) patients, 19 (59,37%) of them being HCV infected. Myelodysplasia was found in 6/42(14,28%) patients, the majority being HCV infected, all having an indolent form of CLD. The antiviral therapy did not influence the hematological parameters (no significant differences were found between the groups with/without an antiviral therapy).
Discussions. Patients with hepatitis virus infections may associate neutropenia and thrombocytopenia; the mechanisms are thought to involve hypersplenism, autoimmune processes and antiviral therapy. We excluded the influence of chemotherapy, as the study was performed before the treatment. In our group, patients whether HBV or HCV infected, presented an isolated cytopenia. The abnormal bone marrow cellularity (increased or decreased) and dysplasia were found especially in the HCV group. There are studies showing no association between myelodysplasia and hepatitis viruses; others found a strong relation of these. One of the mechanisms of myelodysplasia could be a dysregulation of the immune system.
Conclusions. Bone marrow/peripheral blood features correlate with the type of viral infection and HCV is more prone to develop additional hematological changes than HBV. The degree of bone marrow involvement by CLDs influences these features. We considered mandatory to perform a bone marrow analysis at the diagnosis of CLDs to stage and to establish if other bone marrow changes were present, a crucial aspect for therapy and outcome of the disease. The association between the hepatitis viruses – myelodysplasia- autoimmunity seems to have a role in the lymphoproliferative disorders etiology.
Abbreviations: CLD – chronic lymphoproliferative disorders; NHL- non-Hodgkin’s lymphoma, CLL- chronic lymphocytic leukemia, HL- Hodgkin’s lymphoma, MDS – myelodysplastic syndrome, AML – acute myeloid leukemia
PMCID: PMC4034312  PMID: 24868264
hepatitis viruses; chronic lymphoproliferative disorders; myelodysplasia; cytopenia
9.  HBV serum and renal biopsy markers are associated with the clinicopathological characteristics of HBV-associated nephropathy 
Background: Accumulated evidence has shown that hepatitis B virus infection is associated with numerous types of nephropathy but it remains to clarify the different role of HBV markers, either in serum or deposit in kidney, in the pathogenesis of HBV-associated nephropathy. In this study, we investigated the relationship between HBV markers and HBV-associated nephropathy by using multi-linear regression in Chinese patients with HBV-associated membranous nephropathy (MN). Methods: A total of 196 cases of HBV-associated MN, which were diagnosed based on renal biopsy, were collected during the period of January 2000 to December 2009 from our hospital. Serum and renal biopsy HBV markers included HBsAg, anti-HBs, HBeAg, anti-HBe, and anti-HBC. HBV-associated nephropathy was characterized by a panel of clinical manifestations and pathological parameters, which included proteinuria, hematuria, serum creatinine, hypertension, and renal damage in glomeruli, tubules, interstitium, and blood vessels. Multilinear regression was used to analyze the relationship between the HBV markers in serum and renal biopsy and the clinicopathological characteristics of HBV-associated nephropathy. Results: After analysis of the clinical and pathological data in 196 cases of HBV-associated membranous nephropathy, this study revealed that glomerular lesion was marginally associated with serum HBsAg (P = 0.0528), Anti-HBs (P = 0.0978), but significantly associated with the presence of IgA (P = 0.0242), IgG (P < 0.0001) and C3 (P = 0.0064) in renal biopsy. There was no significant association between glomerular lesion and HBV markers in kidney. The presence of crescent and renal tube impairment was not related to HBV markers. The renal fibrosis was significantly related to gender (P = 0.023), age (P = 0.0211), HBsAg (P = 0.0001) and HBcAg (P = 0.0083) and C3 (P = 0.0299) in renal biopsy. Notably, the renal blood vessel impairment was significantly related to systolic Blood Pressure (SBP) (P < 0.0001), diastolic blood pressure (DBP) (P = 0.0002), serum HBsAg (P = 0.0428), serum HBeAg (P = 0.0766), FRA (P = 0.0002), and HBsAg (P = 0.0241) and HBcAg (P = 0.0599) in renal tissues. Also, the renal interstitial infiltration was related to patient age (P = 0.015, SBP (P < 0.0001), DBP (P = 0.0001), C3 (P = 0.0028), FRA (P = 0.0165), HBsAg (P = 0.0016) and HBcAg (P = 0.0203) in kidney biopsy. These results suggest that the major pathological changes in kidneys in HBV patients are related to one or more HBV markers, such as HBsAg, HBeAg, or anti-HBs antibody. Besides, most of the pathological changes in kidneys are related to C3 and FRA in kidney tissues. The clinical markers of nephropathy, such as proteinuria, hematuria and creatine serum levels, were also evaluated for their relationship with HBV markers in serum and kidney tissues. We found proteinuria was marginally related to HBV DNA (P = 0.0537), significantly related to IgA (0.0223). Hematouria was significantly related to IgA (P = 0.0434), IgG (P < 0.0001), and C1q (P = 0.0282). The serum creatine level was related to patient gender (P = 0.0077), SBP (P < 0.0001), DBP (0.0049), IgG (P-0.0006), and C3 (P = 0.0113). These clinical manifestations were not related to HBV markers in either serum or kidney. These results indicate that some of clinical manifestations of nephropathy are related to HBV markers, but the relationship is limited.
PMCID: PMC4270632  PMID: 25550864
Hepatitis B virus; serum markers; nephropathy
10.  Management of the HBV reactivation in isolated HBcAb positive patients affected with Non Hodgkin Lymphoma 
BMC Gastroenterology  2014;14:31.
Background
Occult HBV infection (OBI) is defined by the persistence of HBV in the liver without serum HBsAg and HBVDNA. It represents a life-threatening event during immunosuppressive chemotherapies. An OBI occurs in approximately 18% of HBcAb + patients. International guidelines suggest surveillance for HBV markers in immunosuppressed patients. In Non-Hodgkin Lymphoma (NHL), the prevalence of OBI reactivation remains to be established.
Methods
In order to determine the prevalence of occult HBV reactivation in a large cohort of patients during chemotherapy for NHL, we analysed 498 NHL patients in a centre of Southern Italy. We evaluated HBV markers, NHL type, treatment type and occurrence of HBV reactivation.
Results
Forty % of patients were treated with monoclonal antibodies and 60.3% without. Ninety-six patients were HBcAb+, HBsAg-. HBV reactivation occurred in ten subjects of this subgroup. All of them were successfully treated with Lamivudine. None of the patients experienced liver-related death. The prevalence of OBI reactivation was of 10.42% in HBcAb + HBsAb- patients. This event occurred in 50% of patients treated with mild immunosuppressive therapies. Each reactivation was treated with Lamivudine.
Discussion
This report suggests that a strict surveillance is important and cost-effective in HBcAb + HBsAg- NHL patients treated with mild immunosuppressive therapies, in order to detect an occult HBV reactivation.
doi:10.1186/1471-230X-14-31
PMCID: PMC3938973  PMID: 24533834
Occult HBV infection; Non Hodgkin Lymphoma; HBV reactivation; Immunosuppression
11.  Incidence and characteristics of HBV reactivation in hematological malignant patients in south Egypt 
AIM: To investigate characteristics of hepatitis B virus (HBV) implicated in HBV reactivation in patients with hematological malignancies receiving immunosuppressive therapy.
METHODS: Serum samples were collected from 53 patients with hematological malignancies negative for hepatitis B surface antigen (HBsAg) before the start of and throughout the chemotherapy course. HBV reactivation was diagnosed when the HBsAg status changed from negative to positive after the initiation of chemotherapy and/or when HBV DNA was detected by real-time detection polymerase chain reaction (RTD-PCR). For detecting the serological markers of HBV infection, HBsAg as well as antibodies to the core antigen (anti-HBc) and to the surface antigen were measured in the sera by CEIA. Nucleic acids were extracted from sera, and HBV DNA sequences spanning the S gene were amplified by RTD-PCR. The extracted DNA was further subjected to PCR to amplify the complete genome as well as the specific genomic sequences bearing the enhancer II/core promoter/pre-core/core regions (nt 1628-2364). Amplicons were sequenced directly.
RESULTS: Thirty-five (66%) of the 53 HBsAg-negative patients were found to be negative serologically for anti-HBc, and the remaining 18 (34%) patients were positive for anti-HBc. Five of the 53 (9.4%) patients with hematologic malignancies experienced HBV reactivation. Genotype D1 was detected in all five patients. Four types of mutant strains were detected in the S gene product of HBV strains and were isolated from 3 patients with HBV reactivation: T/S120, L143, and I126. HBV DNA was detected in the pretreatment HBsAg-negative samples in one of the five patients with HBV reactivation. In this patient, sequences encompassing the HBV full genome obtained from sera before the start of chemotherapy and at the time of de novo HBV hepatitis were detected and it showed 100% homology. Furthermore, in the phylogenetic tree, the sequences were clustered together, thereby indicating that this patient developed reactivation from an occult HBV infection.
CONCLUSION: Past infection with HBV is a risk factor for HBV reactivation in Egypt. Mandatory anti-HBc screening prior to chemotherapy in patients with hematological malignancies is recommended.
doi:10.3748/wjg.v19.i37.6214
PMCID: PMC3787352  PMID: 24115819
Hepatitis B virus; Occult infection; Reactivation; Hepatitis B surface antigen
12.  Testing for hepatitis B infection in prospective chemotherapy patients: A retrospective study 
AIM: To estimate hepatitis B virus (HBV) infection testing rate in cancer patients before chemotherapy with a focus on HBV reactivation.
METHODS: A retrospective study was conducted from January 1, 2009 to June 30, 2010. Inclusion required that patients be naïve to cancer chemotherapy but have indications for it. Patients who did not receive chemotherapy for any reason were excluded. Important clinical information, such as the levels of HBV DNA and serological markers were collected. HBV reactivation was defined as an increase in serum HBV DNA to > 1 log higher than that of the pre-exacerbation baseline, or serum HBV DNA conversion from negative to positive. HBV DNA levels > 1000 copies/mL were defined as HBV DNA positive. The χ2 or Fisher’s exact test was used for analysis of categorized data. Multiple logistic regression analysis was used to estimate the odd ratio and 95%CI of the HBV screening rate.
RESULTS: Of 6646 patients, 5616 (84.5%) received chemotherapy. Only 17.1% of the cancer patients received pre-chemotherapy HBV testing (43.2% for hematological malignancies and 14.9% for solid tumors). Patients who had received rituximab therapy, had elevated aminotransferase levels, or had hematological malignancies were more likely to receive HBV testing. The prevalence of hepatitis B surface antigen (HBsAg) positivity was 13.4%. HBV reactivation (appearance of HBV DNA or an increase in HBV DNA levels by 1 log10) was observed in 33.1% (53/160) of the patients after chemotherapy. Among patients without prophylactic antiviral therapy, the reactivation rate was 43.9% (43/98) in the solid tumor group. Two reactivation cases occurred in patients who were HBsAg negative, but positive for hepatitis B core antibody. HBV reactivation was more likely to occur in patients with lymphoma, high levels of HBV DNA, or hepatitis B e antigen, and in men.
CONCLUSION: Less than 20% of patients received HBV testing before chemotherapy. HBV reactivation would have occurred in about 50% of infected patients with solid tumors without antiviral prophylaxis.
doi:10.3748/wjg.v19.i6.923
PMCID: PMC3574891  PMID: 23429298
Chemotherapy; Hematologic malignancy; Hepatitis B virus; Hepatitis B virus reactivation; Solid tumor
13.  Hepatitis B surface antigen seroconversion after HBV reactivation in non-Hodgkin’s lymphoma 
Reactivation of hepatitis B virus (HBV) can occur in lymphoma patients infected with HBV when they receive chemotherapy or immunotherapy. Prophylactic administration of lamivudine (LAM) reduces the morbidity and mortality associated with HBV reactivation. However, what defines HBV reactivation and the optimal duration of treatment with LAM have not yet been clearly established. HBV reactivation may occur due to the cessation of prophylactic LAM, although re-treatment with nucleoside analogs may sometimes result in hepatitis B surface antigen (HBsAg) seroconversion, which is a satisfactory endpoint for the management of HBV infection. We report a case of HBV reactivation in a 68-year-old HBsAg-positive patient who received rituximab-based immunochemotherapy for follicular lymphoma. HBV reactivation developed following cessation of prophylactic LAM therapy. The patient subsequently received treatment with entecavir (ETV), which led to a rapid and sustained suppression of HBV replication and HBsAg seroconversion. We also appraised the literature concerning HBV reactivation and the role of ETV in the management of HBV reactivation in lymphoma patients. A total of 28 cases of HBV reactivation have been reported as having been treated with ETV during or after immunosuppressive chemotherapy in lymphoma patients. We conclude that ETV is an efficacious and safe treatment for HBV reactivation following LAM cessation in lymphoma patients treated with rituximab-based immunochemotherapy.
doi:10.3748/wjg.v20.i17.5165
PMCID: PMC4009558  PMID: 24803836
Hepatitis B surface antigen; Seroconversion; Non-Hodgkin’s lymphoma; Rituximab; Entecavir
14.  Hepatitis B Virus infection in HIV-positive population in Brazil: results of a survey in the state of Mato Grosso and a comparative analysis with other regions of Brazil 
Background
End-stage liver disease is currently a major concern among HIV-positive individuals due to co-infection with hepatotropic virus. Hepatitis C has been pointed out as a remarkable factor for that. More recently, hepatitis B virus (HBV) infection has also been found to play a role on liver disease in this population. HIV-HBV co-infection prevalence remains largely unknown in vast areas of Brazil. The objective of the present study was to estimate the prevalence of HBV and HDV infection in HIV-infected subjects living in the state of Mato Grosso, in the Central region of Brazil, and compare it to other Brazilian studies. We also assess epidemiologic data regarding risk factors and vaccinal status.
Methods
HIV-positive individuals followed at the Central Laboratory of the Department of Public Health of Mato Grosso in the city of Cuiabá composed the sample. Participants answered a specific questionnaire and had a blood sample taken and tested for serologic markers.
Results
A thousand individuals were interviewed and tested for HBsAg, anti-HBc, anti-HBs and anti-HDV if positive for HBsAg. Measurements of CD4 and viral load for HIV-1 were also performed. Overall prevalence of HBV exposure (anti-HBc +ve) was 40.0%, and 3.7% for HBsAg. This prevalence data was similar or slightly lower than for other Brazilian regions, which ranged from 40% and 3% to 71% and 24%, respectively. Testing for anti-HDV in the 37 HBsAg positive patients was positive in only one subject. Factors that showed independent association with HBV exposure, after adjustment, were: male gender, older age groups, tattooing, and reporting more than ten sexual partners throughout life (p < 0.01). Eighty-one (27.5%) out of 291 HBV-unexposed individuals who reported vaccination were anti-HBs positive. Anti-HBs prevalence was higher among those who had higher levels of CD4 by multivariate analysis.
Conclusion
Our data showed HBV infection prevalence similar or slightly lower than that reported in other regions of Brazil. In addition, our data revealed a less important role for drug injection in the spread of HIV and HBV in Mato Grosso compared to other regions of the country. The high rate of non-vaccinated subjects among this HBV-unexposed, HIV-infected population is a matter of considerable health concern in this region. The relationship between CD4 levels and HBV vaccine response found in the present study reinforces the need of keeping health care workers alert to this issue.
doi:10.1186/1471-2334-6-34
PMCID: PMC1421409  PMID: 16504137
15.  Assessment of hepatitis B immunization status after antineoplastic therapy in children with cancer 
Annals of Saudi Medicine  2011;31(6):573-576.
BACKGROUND AND OBJECTIVES:
Hepatitis B is a disease that is preventable with vaccination. Antibody levels after vaccination may be affected by suppression of the immune system due to cancer therapy. Children with cancer have a high risk of hepatitis B virus (HBV) infection. We aimed to assess the pretreatment immunization status against HBV infection and the rate of continuity of immunization after therapy in children with cancer.
DESIGN AND SETTING:
Retrospective case review of patients treated from 2004 to 2008.
PATIENTS AND METHODS:
We reviewed the medical records of patients treated in the departments of pediatric hematology and oncology and collected data on immunization history and hepatitis B serology. Anti-HBs antibody titers were compared before and after treatment.
RESULTS:
This study included 159 (99 males, 60 females) children who had a serologic examination. Antineoplastic therapy had been given for acute leukemia (n=66), non-Hodgkin lymphoma (n=27), Hodgkin lymphoma (n=20), and solid tumors (n=46). Fifty-one patients had not been immunized against HBV prior to the therapy; HBV serology was negative in 49 of these patients and HBsAg was positive in 2 patients. Anti-HBs antibody positivity was present in 99 of 108 patients with an immunization history, whereas no vaccination response was present in 9 patients. The titer of anti-HBs antibody was decreased below the protection level in 33 (33%) patients with positive anti-HBs antibody, whereas the protection level was found to be maintained in 66 (67%) patients. The most significant decrease (63.6%) was observed in leukemia patients. Posttreatment HBsAg and HBV DNA positivity was detected in two of the patients with negative pretreatment serology, whereas no HBV infection developed in the group with positive anti-HBs antibody.
CONCLUSIONS:
This study demonstrated the importance of routine childhood vaccination in reducing the risk of HBV infection in patients with cancer.
doi:10.4103/0256-4947.87091
PMCID: PMC3221126  PMID: 22048500
16.  Occult hepatitis B virus infection among Egyptian blood donors 
World Journal of Hepatology  2013;5(2):64-73.
AIM: To identify blood donors with occult hepatitis B virus (HBV) infection (OBI) to promote safe blood donation.
METHODS: Descriptive cross sectional study was conducted on 3167 blood donors negative for hepatitis B surface antigen (HBsAg), hepatitis C antibody (HCV Ab) and human immunodeficiency virus Ab. They were subjected to the detection of alanine aminotransferase (ALT) and aspartate transaminase (AST) and screening for anti-HBV core antibodies (total) by two different techniques; [Monoliza antibodies to hepatitis B core (Anti-HBc) Plus-Bio-Rad] and (ARC-HBc total-ABBOT). Positive samples were subjected to quantitative detection of antibodies to hepatitis B surface (anti-HBs) (ETI-AB-AUK-3, Dia Sorin-Italy). Serum anti-HBs titers > 10 IU/L was considered positive. Quantitative HBV DNA by real time polymerase chain reaction (PCR) (QIAGEN-Germany) with 3.8 IU/mL detection limit was estimated for blood units with negative serum anti-HBs and also for 32 whose anti-HBs serum titers were > 1000 IU/L. Also, 265 recipients were included, 34 of whom were followed up for 3-6 mo. Recipients were investigated for ALT and AST, HBV serological markers: HBsAg (ETI-MAK-4, Dia Sorin-Italy), anti-HBc, quantitative detection of anti-HBs and HBV-DNA.
RESULTS: 525/3167 (16.6%) of blood units were positive for total anti-HBc, 64% of those were anti-HBs positive. Confirmation by ARCHITECT anti-HBc assay were carried out for 498/525 anti-HBc positive samples, where 451 (90.6%) confirmed positive. Reactivity for anti-HBc was considered confirmed only if two positive results were obtained for each sample, giving an overall prevalence of 451/3167 (14.2%) for total anti-HBc. HBV DNA was quantified by real time PCR in 52/303 (17.2%) of anti-HBc positive blood donors (viral load range: 5 to 3.5 x 105 IU/mL) with a median of 200 IU/mL (mean: 1.8 x 104 ± 5.1 x 104 IU/mL). Anti-HBc was the only marker in 68.6% of donors. Univariate and multivariate logistic analysis for identifying risk factors associated with anti-HBc and HBV-DNA positivity among blood donors showed that age above thirty and marriage were the most significant risk factors for prediction of anti-HBc positivity with AOR 1.8 (1.4-2.4) and 1.4 (1.0-1.9) respectively. Other risk factors as gender, history of blood transfusion, diabetes mellitus, frequent injections, tattooing, previous surgery, hospitalization, Bilharziasis or positive family history of HBV or HCV infections were not found to be associated with positive anti-HBc antibodies. Among anti-HBc positive blood donors, age below thirty was the most significant risk factor for prediction of HBV-DNA positivity with AOR 3.8 (1.8-7.9). According to HBV-DNA concentration, positive samples were divided in two groups; group one with HBV-DNA ≥ 200 IU/mL (n = 27) and group two with HBV-DNA < 200 IU/mL (n = 26). No significant difference was detected between both groups as regards mean age, gender, liver enzymes or HBV markers. Serological profiles of all followed up blood recipients showed that, all were negative for the studied HBV markers. Also, HBV DNA was not detected among studied recipients, none developed post-transfusion hepatitis (PTH) and the clinical outcome was good.
CONCLUSION: OBI is prevalent among blood donors. Nucleic acid amplification/HBV anti core screening should be considered for high risk recipients to eliminate risk of unsafe blood donation.
doi:10.4254/wjh.v5.i2.64
PMCID: PMC3642725  PMID: 23646231
Hepatitis B virus; Total anti-HBc; Occult hepatitis B virus infection; Hepatitis B surface antigen; Hepatitis B virus-DNA
17.  Characterization of Treatment-Naive HIV/HBV Co-Infected Patients Attending ART Clinic of a Tertiary Healthcare Centre in Eastern India 
PLoS ONE  2013;8(8):e73613.
Objective
The study was designed to assess the hepatitis B virus (HBV) and hepatitis C virus (HCV) co-infection scenario among the human immunodeficiency virus (HIV) infected patients attending a tertiary healthcare unit in eastern India. Additionally, clinical and virological characterization of these viruses, prior to antiretroviral therapy (ART) initiation was also done for better understanding of the disease profile.
Methods
Pool of ART-naive HIV/HBV co-infected and HIV mono-infected patients, participating in two different studies, were included in this study. HBV DNA was detected by nested-PCR amplification followed by HBV genotype determination and HBV reverse transcriptase (RT) region amplification and direct sequencing for detecting drug resistance.
Results
The prevalence of HBsAg (11.3%) was higher compared to anti-HCV (1.9%) among the HIV infected ART-naive patients. Moreover, majority of the HBeAg positive HIV/HBV co-infected patients (87.7%) had HBV DNA ≥20,000 IU/ml with median HBV DNA significantly higher than that of HBeAg negative subjects (5.7 log10 IU/ml vs. 4.2 log10 IU/ml; p<0.0001). Multivariate analysis also showed that HBeAg-positive status was independently associated with higher HBV DNA level (p = <0.001). Notably, 60.9% of the HBeAg negative co-infected subjects had HBV DNA ≥2,000 IU/ml of which 37.0% had HBV DNA ≥20,000 IU/ml. Genotype HBV/D (68.2%) was the predominant genotype followed by HBV/A (24.3%) and HBV/C (7.5%). Anti-HBV drug resistant mutations were detected in two (3.8%) of the ART-naive patients.
Conclusion
The prevalence of HIV/HBV co-infection was relatively higher in our study subjects. HBeAg testing might provide clue for early treatment initiation. Furthermore, HBeAg negative patients are also associated with high HBV DNA levels and therefore require appropriate medical attention. Pre-treatment screening for anti-HBV drug resistant mutations is not necessary before ART initiation.
doi:10.1371/journal.pone.0073613
PMCID: PMC3758335  PMID: 24023688
18.  Prevalence, Risk Factors, and Impact of Isolated Antibody to Hepatitis B Core Antigen and Occult Hepatitis B Virus Infection in HIV-1–Infected Pregnant Women 
Among hepatitis B (HB) surface antigen–negative/human immunodeficiency virus–infected pregnant women in Thailand, 14% had isolated antibody to HB core antigen (anti-HBc); of whom 24% had occult HB virus (HBV) infection with low HBV DNA levels. None transmitted HBV to their infants.
Background. Prevalence and risk factors for isolated antibody to hepatitis B core antigen (anti-HBc) and occult hepatitis B virus (HBV) infection are not well known in human immunodeficiency virus type 1 (HIV-1)–infected pregnant women. It is unclear if women with occult infections are at risk of transmitting HBV to their infants.
Methods. HIV-1–infected and HBV surface antigen (HBsAg)–negative pregnant women were tested for antibody to HBsAg (anti-HBs) and anti-HBc using enzyme immunoassay. Women with isolated anti-HBc were assessed for occult HBV infection, defined as HBV DNA levels >15 IU/mL, using the Abbott RealTime HBV DNA assay. Infants born to women with isolated anti-HBc and detectable HBV DNA were tested at 4 months of age for HBV DNA. Logistic regression analysis was used to identify factors associated with isolated anti-HBc and occult HBV infection.
Results. Among 1812 HIV-infected pregnant women, 1682 were HBsAg negative. Fourteen percent (95% confidence interval [CI], 12%–15%) of HBsAg-negative women had an isolated anti-HBc that was independently associated with low CD4 count, age >35 years, birth in northern Thailand, and positive anti–hepatitis C virus serology. Occult HBV infection was identified in 24% (95% CI, 18%–30%) of women with isolated anti-HBc, representing 2.6% (95% CI, 1.9%–3.5%) of HIV-1–infected pregnant women, and was inversely associated with HIV RNA levels. None of the women with isolated anti-HBc and occult HBV infection transmitted HBV to their infants.
Conclusions. HIV-1–infected pregnant women with isolated anti-HBc and occult HBV infection have very low HBV DNA levels and are thus at very low risk to transmit HBV to their infants.
doi:10.1093/cid/cit166
PMCID: PMC3707427  PMID: 23487379
HIV-1–infected pregnant women; isolated anti-HBc; occult HBV infection; perinatal transmission
19.  The prophylactic use of lamivudine can maintain dose-intensity of adriamycin in hepatitis-B surface antigen (HBs Ag)-positive patients with Non-Hodgkin's lymphoma who receive cytotoxic chemotherapy. 
Journal of Korean Medical Science  2003;18(6):849-854.
We investigated the effectiveness of lamivudine to prevent hepatitis flare up due to reactivation of hepatitis-B virus (HBV) in hepatitis-B surface antigen (HBsAg)-positive patients with Non-Hodgkin's lymphoma (NHL) during cytotoxic chemotherapy. HBsAg-positive patients with NHL were identified from the lymphoma database of the Asan Medical Center from January 1995 to August 2002, and their medical records were reviewed. We found that 31 patients were received cytotoxic chemotherapy among 41 NHL patients with HBsAg-positive during same period. We divided them into 2 groups of HBsAg patients with NHL as follows: Group A who received cytotoxic chemotherapy with lamivudine 100 mg daily; Group B without any prophylactic antiviral therapy. There were no significant differences between Group A and B in several clinical variables. Seventeen patients (85%) in group B and one patient (9%) in Group A had hepatitis due to reactivation of HBV (p<0.001), with one hepatic failure related death in Group B and none in group A. The mean dose intensity of adriamycin actually delivered was 13.3 mg/m2/week (80% Relative Dose intensity (RDI)) in Group A and 9.1 mg/m2/week (55% RDI) in Groups B (p<0.001). Our data suggest that the frequency of chemotherapy-related HBV reactivation may be significantly decreased by lamivudine prophylaxis with maintenance of the dosage of adriamycin.
PMCID: PMC3055150  PMID: 14676442
20.  Current State of and Needs for Hepatitis B Screening: Results of a Large Screening Study in a Low-Prevalent, Metropolitan Region 
PLoS ONE  2014;9(3):e92266.
Background
In low hepatitis B virus (HBV)-prevalent countries, most HBV-infected persons are unaware of their status. We aimed to evaluate whether (i) previous HBV-testing, (ii) physicians decision to screen, and (iii) CDC's recommendations identified infected individuals and which risk-factor groups needing testing.
Methods
During a mass, multi-center HBV-screening study from September 2010-August 2011, 3929 participants were screened for hepatitis B surface antigen (HBsAg), anti-HBs and anti-Hepatitis B core antibodies (anti-HBcAb). Questions on HBV risk-factors and testing practices were asked to participants, while participants' eligibility for HBV-testing was asked to study medical professionals.
Results
85 (2.2%) participants were HBsAg-positive, while 659 (16.8%) had either resolved HBV infection or isolated anti-HBcAb. When comparing practices, HBV-testing was more likely to occur in HBV-infected participants if Centers for Disease Control and Prevention (CDC) recommendations were used (Sensitivity = 100%, 95%CI: 95.8–100) than physicians' discretion (Sensitivity = 87.1%, 95%CI: 78.0–93.4) or previous HBV-test (Sensitivity = 36.5%, 95%CI: 26.3–47.6) (p<0.0001). Nevertheless, many non-infected individuals would still have been screened using CDC-recommendations (Specificity = 31.1%, 95%CI: 29.6–32.6). Using multivariable logistic regression, HBsAg-positive status was significantly associated with the following: males, originating from high HBV-endemic region, contact with HBV-infected individual, without national healthcare, and intravenous-drug user (IDU). Of these risk-factors, physician's discretion for testing HBV was not significantly associated with participants' geographical origin or IDU.
Conclusions
Missed opportunities of HBV-screening are largely due to underestimating country of origin as a risk-factor. Applying CDC-recommendations could improve HBV-screening, but with the disadvantage of many tests. Further development of HBV-testing strategies is necessary, especially before severe disease occurs.
doi:10.1371/journal.pone.0092266
PMCID: PMC3963888  PMID: 24663387
21.  Immunological mechanisms of hepatitis B virus persistence in newborns 
Chronic hepatitis B virus (HBV) infection affects millions of people worldwide and about a half million people die every year. India represents the second largest pool of chronic HBV infection worldwide with an estimated 40 million infected people. The prevalence of chronic HBV infection in pregnant women is shown to be 0.82 per cent with the risk of mother-to-child vertical transmission. Hepatitis B e antigen (HBeAg) positivity indicates replicative form of HBV which may play a role in immunotolerance in utero by crossing the placenta. In case of HBeAg positivity and high viral load of mother, HBV immunoglobulin is preferably given along with HBV vaccination. Antiviral therapy is recommended for use in the third trimester of pregnancy to reduce the perinatal transmission of HBV, however, use of antiviral therapy should be individualized during pregnancy. Chronic HBV infection in neonates is linked with strong presence of Tregs (T regulatory cells) and defective CD8 T cells pool to produce interferon (IFN)-γ. T cell receptor (TCRζ) chain defects were also associated with decreased CD8 T cell dysfunction. Decreased TCRζ expression could be due to persistent intrauterine exposure of the viral antigens early in embryonic development leading to immune tolerance to HBV antigens in the newborns positive for hepatitis B surface antigen (HBsAg+ve). Therefore, due to HBV infection, T cell tolerance to HBV-antigen may probably leave the newborn as a chronic carrier. However, HBV vaccination may have benefits in restoring acquired immunity and better production of HBV specific antibodies.
PMCID: PMC3928700  PMID: 24434322
Chronic infection; HbeAg; HbsAg; hepatitis B virus (HBV); perinatal; pregnancy
22.  Role of hepatitis B virus genotype D & its mutants in occult hepatitis B infection 
Background & objectives:
Non-detection of hepatitis B virus (HBV) envelope protein (hepatitis B surface antigen, HBsAg) in a chronically HBV infected individual has been described as occult infection. One possible reason for this phenotype is alteration in large (L-HBsAg) to small (S-HBsAg) envelope protein ratio associated with reduced or non secretion of HBsAg. This results in quantitative levels of serum HBsAg below the detection limit of enzyme immunoassays. Genotype D of HBV has a characteristic 33 nucleotide (nt) deletion upstream of the pre-S2/S promoter. This deletion may reduce HBsAg secretion in occult infection patients infected with genotype D HBV. Additional deletions in the pre-S2/S promoter may further aggravate reduced HBsAg secretion in patients infected with genotype D HBV. Thus, the aim of the present study was to determine the role of genotype D specific 33nt deletion and additional pre-S2/S promoter deletions in causing reduced or no secretion of HBsAg, in occult infection. Since these deletions overlap virus polymerase, their effect on virus replication was also investigated.
Methods:
We examined the in vitro expression of HBsAg, ratio of cure and ‘e’ antigen (HBcAg/HBeAg), their secretion and virus replication, using overlength 1.3 mer/1.86 mer genotype A replicons, and genotype D replicons with and without additional pre-S2/S promoter deletions from cases of occult infection.
Results:
Genotype D replicon showed a decrease in HBsAg secretion compared to the wild-type genotype A. Genotype D replicons carrying additional pre-S2/S promoter deletions, showed further reduction in HBsAg secretion, demonstrated presence of intracellular HBcAg/HBeAg, virus replication intermediates and ‘e’ antigen secretion.
Interpretation & conclusions:
The characteristic 33 nt deletion of genotype D HBV reduces HBsAg secretion. Additional pre-S2/S promoter deletions may further diminish HBsAg secretion, leading to occult infection. Pre-S2/S promoter deletions do not affect HBV replication.
PMCID: PMC3818595  PMID: 24135177
Genotypes; HBV; occult; pre-S2/S; promoter mutants; surface antigen (HBsAg)
23.  Hepatitis B virus infection among first-time blood donors in Italy: prevalence and correlates between serological patterns and occult infection 
Blood Transfusion  2013;11(2):281-288.
Background
A prospective, 1-year study was performed among Italian first-time, volunteer blood donors, who account for 12% of all donations, in order to assess the frequency and serological patterns of hepatitis B virus infection and the presence of occult infection.
Materials and methods
Consecutive donors (n=31,190) from 21 blood transfusion centres, from age classes not subjected to universal HBV vaccination, were tested for HBsAg and anti-HBc by commercial immunoassays. Other HBV serological markers were searched for and qualitative and quantitative assessments of HBV-DNA were made in HBsAg and/or anti-HBc-positive individuals.
Results
Of the 31,190 donors studied, 100 (0.32%) were positive for both HBsAg and anti-HBc, 2 for HBsAg (0.01%) alone, and 2,593 (8.3%) for anti-HBc. Of these last, 86.7% were also positive for anti-HBs (with or without anti-HBe), 2.9% were positive for anti-HBe without anti-HBs and 10.4% had no other HBV markers (anti-HBc alone). A general north-south increasing gradient of HBV prevalence was observed. Circulating HBV-DNA was found in 96.8% of HBsAg-positive subjects as compared to 0.55% (12/2,186) of anti-HBc-positive/HBsAg-negative subjects, with higher frequencies among anti-HBs-negative than among anti-HBs-positive ones (1.68% vs 0.37%; p <0.01) and among the 57 cases positive for both anti-HBc and anti-HBe (7%). HBV-DNA levels were significantly higher in HBsAg-positive subjects than in HBsAg-negative ones (median: 456 IU/mL vs 38 IU/mL).
Conclusions
The prevalence of HBV infection among Italian first-time blood donors is much lower than in the past. The presence of occult infections in this group was confirmed (frequency: 1 in 2,599), supporting the hypothesis of long-term persistence of HBV infection after clearance of HBsAg. HBsAg and nucleic acid amplification testing for blood screening and vaccination against HBV are crucial in order to further reduce the risk of transfusion-transmitted HBV towards zero.
doi:10.2450/2012.0160-12
PMCID: PMC3626481  PMID: 23399361
HBV; anti-HBc; blood screening; occult infection; HBV-DNA
24.  Coexistence of Hepatitis B Virus Quasispecies Enhances Viral Replication and the Ability To Induce Host Antibody and Cellular Immune Responses 
Journal of Virology  2014;88(15):8656-8666.
ABSTRACT
Hepatitis B virus (HBV) quasispecies contain a large number of variants that serve as a reservoir for viral selection under antiviral treatment and the immune response, leading to the acute exacerbation and subsequent development of liver failure. However, there is no clear experimental evidence for a significant role of HBV quasispecies in viral pathogenesis. In the present study, HBV sequences were amplified from a patient with severe liver disease and used for construction of HBV replication-competent plasmids. Western blotting, enzyme-linked immunosorbent assay (ELISA), and immunofluorescence staining were performed to analyze the expression, secretion, and subcellular localization of viral proteins in vitro. Viral replication intermediates were detected by Southern blotting. HBV gene expression and replication and the induction of specific immune responses in an HBV hydrodynamic injection (HI) mouse model were investigated. The results demonstrated that two naturally occurring HBV variants, SH and SH-DPS, were identified. The variant SH-DPS expressed only a nonexportable hepatitis B virus surface antigen (HBsAg) with abnormal intracellular accumulation. The coexistence of the HBV variants at a ratio of 1 to 4 (SH to SH-DPS) increased HBV replication. Significantly stronger intrahepatic cytotoxic T lymphocyte (CTL) responses and antibody responses specific to HBsAg were induced in mice by the HBV variants when coapplied by HI. These findings uncovered an unexpected aspect of HBV quasispecies: the coexistence of different variants can significantly modulate specific host immune responses, representing a novel mechanism for the immunopathogenesis of HBV infection.
IMPORTANCE Hepatitis B virus (HBV) is an important human pathogen. HBV quasispecies with genetically heterogenous variants are thought to play a role in the progression of HBV-associated liver diseases. So far, direct evidence is available in only a few cases to confirm the proposed role of HBV variants in the pathogenesis. We report here that the coexistence of two naturally occurring HBV variants at a ratio of 1 to 4 increased HBV replication and induced significantly stronger intrahepatic cytotoxic T lymphocyte responses and antibody responses specific to HBV surface antigen (HBsAg) in mice. Our discovery uncovered an unexpected aspect of HBV quasispecies: the coexistence of different variants can significantly modulate specific host immune responses and may enhance immune-mediated liver damage under some circumstances, representing a novel mechanism for the immunopathogenesis of HBV infection.
doi:10.1128/JVI.01123-14
PMCID: PMC4135971  PMID: 24850745
25.  Low Rates of Hepatitis B Virus Screening at the Onset of Chemotherapy 
Journal of Oncology Practice  2012;8(4):e32-e39.
Future research directed toward identifying best screening methods and HBV risk tools will be necessary to reduce the risk of reactivation of HBV infection after chemotherapy.
Purpose:
Patients with hepatitis B virus (HBV) infection are at risk for reactivation after chemotherapy. Effective prophylaxis is available but depends on detection of prior infection. Previous studies have shown low screening rates, but no large-scale US studies have been conducted. We sought to determine predictors of screening and positive HBV test results in patients receiving chemotherapy.
Methods:
We conducted a retrospective cohort study of patients with newly diagnosed cancer who received chemotherapy between January 2004 and September 2007 at a comprehensive cancer center. We determined rates and predictors of screening for HBV infection with HB surface antigen (HBsAg) and antibody to hepatitis B core antigen (anti-HBc) tests as well as the prevalence and predictors of positive results. We explored rates of acutely elevated liver function tests and liver decompensation after chemotherapy.
Results:
Of 10,729 new patients who received chemotherapy, 1,787 (16.7%) underwent HBsAg or anti-HBc screening. Less than 20% of patients with HBV risk factors were screened, even though their odds of HBV infection were increased four-fold compared with those without risk factors. The prevalence of chronic HBV infection was 1.5%. whereas 7.4% had positive anti-HBc only. The strongest predictors of HBV screening were having a history of HBV infection, hematologic malignancy, and rituximab treatment (P < .001). Asian ethnicity was not a significant predictor of screening, despite being a strong and highly significant predictor of positive test results (P < .001).
Conclusion:
HBV screening among patients with cancer is low, especially among those known to be at high risk for HBV infection. Future research directed toward identifying best screening methods and HBV risk tools will be necessary to reduce the risk of reactivation of HBV infection after chemotherapy.
doi:10.1200/JOP.2011.000450
PMCID: PMC3396827  PMID: 23180996

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