Chronic hepatitis B virus infection is associated with a poorer prognosis in diffuse large B-cell lymphoma: a meta-analysis and systemic review.
ABSTRACT: Accumulating evidence from clinical trials indicates chronic hepatitis B virus (HBV) infection is associated with the incidence of diffuse large B-cell lymphoma (DLBCL) and may be associated with the prognosis of DLBCL, though this suggestion remains controversial. We performed a meta-analysis to assess whether HBV infection is associated with prognosis and response to chemotherapy in DLBCL. After a strict literature search strategy, a total of 809 HBV surface antigen (HBsAg) seropositive patients with DLBCL and 2849 HBsAg seronegative patients with DLBCL from twelve trials were included. DLBCL patients with chronic HBV infection had significantly poorer 2- and 5-year overall survival (OS) (HR 1.54, 95% CI 1.23-1.92, P<0.001 and 1.79, 1.48-2.17, P<0.001) and 2- and 5-year progression-free survival (PFS) (HR 1.44, 95% CI 1.14-1.81, P=0.002 and HR 1.34, 95% CI 1.02-1.75, P=0.03). HBsAg-seronegative patients also had a lower complete response (CR) rate (OR 0.48, 95% CI 0.34-0.68, P<0.001), higher progressive disease (PD) rate (OR 2.08, 95% CI 1.34-3.24, P=0.001), and more advanced clinical features. This meta-analysis indicates HBV infection leads to a poorer prognosis and poorer response to standard chemotherapy.
Project description:Importance:Hepatitis B virus (HBV) has been identified as a major risk factor for hepatocellular carcinoma. However, the associations between HBV infection and other cancer types are not well understood. Objective:To assess the associations between chronic HBV infection and risk of all cancer types. Design, Setting, and Participants:This population-based study involved 3 cohorts in China. The China Kadoorie Biobank (CKB) prospective cohort study, conducted between June 2004 and July 2008, used a dipstick assay for detection of serum hepatitis B surface antigen (HBsAg) among 496?732 participants to determine the association between HBV infection and risk of all cancer types. Two cohort studies were used to validate the associations by applying more precise serum HBsAg detection assays: the Qidong cohort (37?336 participants enrolled from November 2007 to April 2011) and the Changzhou nested case-control study (17?723 participants enrolled from June 2004 to September 2005). A total of 97 samples of stomach cancer tissues, 10 samples of pancreatic cancer tissues, and 9 samples of lung cancer tissues were included to assess the presence of HBV replication and expression. Statistical analysis was performed from December 2016 to October 2018. Exposures:Serum HBsAg status in the population-based stage and HBV DNA status, the expression of hepatitis B X protein, and hepatitis B core antibody (anti-HBc) in the tissue-based stage. Main Outcomes and Measures:Incidence of all cancer types during follow-up. Results:In the CKB cohort, the mean (SD) age of the 496?732 participants was 51.5 (10.7) years; 59.0% of the participants were women. After 4.4 million person-years of follow-up, participants who were HBsAg seropositive (n?=?15?355) had a higher risk of hepatocellular carcinoma (hazard ratio [HR], 15.77; 95% CI, 14.15-17.57), stomach cancer (HR, 1.41; 95% CI, 1.11-1.80), colorectal cancer (HR, 1.42; 95% CI, 1.12-1.81), oral cancer (HR, 1.58; 95% CI, 1.01-2.49), pancreatic cancer (HR, 1.65; 95% CI, 1.03-2.65), and lymphoma (HR, 2.10; 95% CI, 1.34-3.31) when compared with participants who were HBsAg seronegative (n?=?481?377). Because of the limitation of sample size, only associations of HBV infection with hepatocellular carcinoma and stomach cancer were validated in the Qidong cohort (hepatocellular carcinoma: HR, 17.51; 95% CI, 13.86-22.11; stomach cancer: HR, 2.02; 95% CI, 1.24-3.29); the Changzhou nested case-control study validated only an association between HBV infection and stomach cancer (odds ratio, 1.76; 95% CI, 1.04-2.98). Moreover, among 22 participants with stomach cancer from the Qidong cohort who were anti-HBc seropositive, 12 samples (54.5%) of cancer tissues were HBV DNA positive, while among 25 participants with stomach cancer who were anti-HBc seronegative, no HBV DNA was detected. The same negative and positive rate was observed in the validation set from Zhejiang Tumor Hospital (19 of 35 samples [54.3%] were HBV DNA positive). Moreover, among the 8 patients with stomach cancer from the Qidong cohort who were anti-HBc seropositive, anti-HBc and hepatitis B X protein were expressed in all of their stomach cancer tissue samples. The same phenomenon was observed in the patients with pancreatic cancer but not in the patients with lung cancer, which was consistent with the population-based results of the CKB cohort. Conclusions and Relevance:This study found that HBV infection was also associated with the risk of nonliver cancer, especially digestive system cancers among adults in China.
Project description:BACKGROUND:Patients with diffuse large B-cell lymphoma (DLBCL) with concurrent hepatitis B surface antigen (HBsAg)-positive hepatitis B virus (HBV) infection have distinct clinical features. Nevertheless, the prognostic value of HBsAg in DLBCL in the rituximab era remains unclear. MATERIALS AND METHODS:We conducted a retrospective cohort study to investigate the clinical relevance of HBsAg in immunocompetent patients with DLBCL treated with homogeneous rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone between 2002 and 2016. RESULTS:Among 416 analyzed patients, 98 (23.6%) were HBsAg positive. HBsAg positivity was associated with a younger age and more advanced stage at diagnosis, more frequent hepatic impairment during perichemotherapy, and a trend of higher National Comprehensive Cancer Network-International Prognostic Index (NCCN-IPI) score at diagnosis. Compared with the HBsAg-negative patients, the HBsAg-positive patients had a lower overall response rate (76.5% vs. 85.5%, p = .043), poorer 5-year overall survival (OS) rate (57.2% vs. 73.5%, p < .001), and shorter 5-year progression-free survival (PFS) rate (47.2% vs. 60.7%, p = .013). Multivariate analyses showed that HBsAg positivity was an independent unfavorable prognostic indicator for OS and PFS. A scoring system incorporating HBsAg positivity, the NCCN-IPI score, and serum albumin levels proved to be useful for stratifying prognostically relevant subgroups of patients with DLBCL. CONCLUSION:This study demonstrated that HBV infection is uniquely relevant to DLBCL. HBsAg might serve as a novel biomarker to improve clinical risk stratification of patients with DLBCL in areas with high prevalence of HBV infection. Further research investigating the etiopathogenesis of HBV infection in DLBCL is imperative. IMPLICATIONS FOR PRACTICE:A considerable disparity exists regarding the prognostic relevance of hepatitis B surface antigen (HBsAg)-positive hepatitis B virus (HBV) infection in patients with diffuse large B-cell lymphoma (DLBCL). In this large, retrospective cohort study from an area with high prevalence of HBV infection, the authors demonstrated that HBsAg was an independent unfavorable factor significantly associated with survival, highlighting its potential as a novel prognostic indicator to improve the risk stratification of patients with DLBCL in the rituximab era.
Project description:To investigate the association between preoperative HBsAg (hepatitis B surface antigen) level and risk of HCC (hepatocellular carcinoma) recurrence following curative resection, we enrolled 826 HBV-related HCC patients who underwent curative resection and received long-term follow-up at the Eastern Hepatobiliary Surgery Hospital (Shanghai, China). Multivariate analyses showed that serum HBsAg ? 2000 S/CO, seropositive hepatitis B e antigen (HBeAg), ?-glutamyl transpeptidase > 61 U/L, prothrombin time > 13 s, multinodularity, lager tumor size, and major portal vein invasion were independently associated with a increased risk of HCC recurrence. Compared with HCC patients with HBsAg level < 2000 S/CO, HCC patients with HBsAg level ? 2000 S/CO had a higher prevalence of seropositive HBeAg, antiviral therapy, and cirrhosis; were younger; and had a higher levels of alanine transaminase (ALT), aspartate aminotransferase (AST), and HBV viral load. Multivariable stratified analyses showed HCC patients with HBsAg level < 2000 S/CO tended to have a lower incidence of HCC recurrence in following subgroups of patients, including for noncirrhotic (HR, 0.561; 95% CI, 0.345-0.914), HBV DNA < 2000 IU/mL (HR, 0.604; 95% CI, 0.401-0.912), ALT ? 41 U/L (HR, 0.643; 95% CI, 0.440-0.942), AST ? 37 U/L (HR, 0.672; 95% CI, 0.459-0.983), and seronegative HBeAg (HR, 0.682; 95% CI, 0.486-0.958). When we evaluated HBeAg-negative patients with HBV DNA < 2000 IU/mL, HBsAg level still determined risk of HCC recurrence (p = 0.014), but not HBV DNA (p = 0.550) and ALT (p = 0.186). These results suggest high levels of HBsAg increase risk of HCC recurrence following curative resection. HBsAg level might serve as a new marker to complement HBV DNA level in predicting HCC recurrence, especially in HBeAg-negative patients with low viral load.
Project description:While the epidemiologic association between hepatitis B virus (HBV) infection and diffuse large B-cell lymphoma (DLBCL) is established, little is known more than this epidemiologic evidence. We studied a cohort of 587 patients with DLBCL for HBV infection status, clinicopathologic features, and the immunoglobulin variable region in HBV surface antigen (HBsAg)-positive patients. Eighty-one (81/587, 13.8%) patients were HBsAg-positive. Compared with HBsAg-negative DLBCL, HBsAg-positive DLBCL displayed a younger median onset age (45 vs. 55 years), more frequent involvement of spleen or retroperitoneal lymph node (40.7% vs. 16.0% and 61.7% vs. 31.0% respectively, both p < 0.001), more advanced disease (stage III/IV: 76.5% vs 59.5%, p = 0.003), and significantly worse outcome (2-year overall survival: 47% versus 70%, p < 0.001). In HBsAg-positive DLBCL patients, almost all (45/47, 96%) amino acid sequences of heavy and light chain complementarity determining region 3 exhibited a high homology to antibodies specific for HBsAg, and the majority (45/50, 90%) of IgHV and IgLV genes were mutated. We conclude that 13.8% of DLBCL cases are HBV-associated in HBV-endemic China and show unique clinical features and poor outcomes. Furthermore, our study strongly suggests that HBV-associated DLBCL might arise from HBV antigen-selected B cells.
Project description:Existing evidence remains inconclusive as to the association between chronic hepatitis B virus (HBV) infection and the risk of chronic kidney disease (CKD). We prospectively examined the association between chronic HBV infection and CKD risk, and the joint associations of HBV infection with established risk factors of several lifestyle factors and prevalent diseases on CKD risk.Participants from the China Kadoorie Biobank were enrolled during 2004-2008 and followed up until 31 December 2015. After excluding participants with previously diagnosed CKD, cancer, heart disease, and stroke at baseline, the present study included 469,459 participants. Hepatitis B surface antigen (HBsAg) was qualitatively tested at baseline. Incident CKD cases were identified mainly through the health insurance system and disease and death registries.During a median follow-up of 9.1 years (4.2 million person-years), we documented 4555 incident cases of CKD. Cox regression yielded multivariable-adjusted hazard ratios (HRs) and 95% confidence intervals (CIs). Compared with HBsAg-negative participants, the multivariable-adjusted HR (95% CI) for CKD was 1.37 (1.18, 1.60) for HBsAg-positive participants. The association was stronger in men (HR?=?1.77; 95% CI: 1.43, 2.20) than in women (HR?=?1.10; 95% CI: 0.88, 1.36). HBsAg-positive participants, with or without hepatitis or cirrhosis, whether or not under treatment, all showed increased risk of developing CKD. We observed positive additive interactions of HBsAg positivity with smoking, physical inactivity, or diabetes on CKD risk. Compared with HBsAg-negative participants who were nonsmokers, more physically active, or did not have diabetes at baseline, the greatest CKD risk for HBsAg-positive participants was for those who were smokers (HR?=?1.85; 95% CI: 1.44, 2.38), physically inactive (HR?=?1.91; 95% CI: 1.52, 2.40), or diabetic (HR?=?6.11; 95% CI: 4.47, 8.36).In countries with a high endemicity of HBV infection, kidney damage associated with chronic HBV infection should be a non-negligible concern. Our findings also highlight the importance of health advice on quitting smoking, increasing physical activity, improving glucose control, and early screening for CKD in people with chronic HBV infection.
Project description:<h4>Objectives</h4>Chronic hepatitis B virus (HBV) infection is associated with a higher risk of liver diseases. Substantial uncertainty remains, however, about the associations of HBV infection with mortality from extrahepatic causes, especially from subtypes of cardiovascular diseases. We prospectively examined the association of chronic HBV infection with total and cause-specific mortality.<h4>Design</h4>Population-based prospective cohort study.<h4>Setting</h4>China Kadoorie Biobank in which participants from 10 geographically diverse areas across China were enrolled between 2004 and 2008.<h4>Participants</h4>475?801 participants 30-79 years of age without reporting major chronic diseases at baseline were enrolled. Hepatitis B surface antigen (HBsAg) was tested using an on-site rapid test strip at baseline.<h4>Primary and secondary outcome measures</h4>Total and cause-specific mortality.<h4>Results</h4>A total of 35?822 deaths were recorded during ~10 years of follow-up. In multivariable-adjusted analyses, compared with HBsAg-negative participants, HBsAg-positive participants had an increased risk of total mortality (HR=2.01, 95% CI: 1.91 to 2.12), which was higher in men (HR=2.16, 95%?CI: 2.01 to 2.31) than in women (HR=1.74, 95%?CI: 1.60 to 1.90). Presence of HBsAg was associated with increased mortality from liver cancer (1339 deaths, HR=13.95, 95%?CI: 12.46 to 15.62), infections (410 deaths, HR=10.30, 95%?CI: 8.21 to 12.94), digestive diseases (688 deaths, HR=6.83, 95%?CI: 5.49 to 8.50), intracerebral haemorrhage (4077 deaths, HR=1.38, 95%?CI: 1.14 to 1.68) and ischaemic heart diseases (4624 deaths, HR=1.31, 95%?CI: 1.09 to 1.58). The positive association between HBsAg status and risk of death was stronger in participants younger than 50 years, smokers, physically active or non-hypertensive participants.<h4>Conclusions</h4>Among Chinese adults, chronic HBV infection was associated with increased mortality from a range of hepatic and extrahepatic diseases.
Project description:BACKGROUND:Previous studies examining the relationship between hepatitis B virus (HBV) infection and non-Hodgkin lymphoma (NHL) show inconsistent results in different endemic areas. Furthermore, studies evaluating the association between stratified HBV status and NHL with a well-matched case-control design are rare. METHODS:We conducted a 1:2 case-control study enrolling 3502 NHL cases and 7004 controls, and performed an updated meta-analysis evaluating the association between HBV and NHL subtypes. RESULTS:The HBsAg-negative/anti-HBc-positive/anti-HBs-positive population, implying naturally acquired immunity after infection, had increased B-NHL risk (Adjusted odds ratio (AOR) (95% confidence interval (95% CI)): 2.25 (1.96-2.57)). The HBsAg-positive/HBeAg-positive population, indicating current HBV infection, had high risk of B-NHL (AOR (95% CI): 6.23 (3.95-9.82)). Specifically, for diffuse large B-cell lymphoma (DLBCL), there was no significant difference in HBsAg status between the germinal centre B (GCB) and non-GCB subtypes. Additionally, our meta-analysis showed in a random effects model, HBV-infected individuals had a pooled OR of 2.09 (95% CI 1.76-2.50; P < 0.01) for NHL. CONCLUSIONS:Chronic HBV infection was positively associated with B-NHL in China. However, acquired immunity by natural infection also increased B-NHL risk. Thus, we further speculated that regardless of whether HBsAg was cleared, the infected population had higher risk of B-NHL. Our study might expand our knowledge on tumorogenesis of NHL and thus provides clues for novel treatment strategies.
Project description:OBJECTIVES:To estimate hepatitis B virus (HBV) seroprevalence from natural infection or vaccination in 10-25-year-olds in Mexico, using the 2012 National Health and Nutrition Survey (ENSANUT). METHODS:Randomly selected serum samples (1,581) from adolescents and young adults, representative of 38,924,584 Mexicans, were analyzed to detect hepatitis B surface antigen (HBsAg), hepatitis B surface antibody (anti-HBs) and hepatitis B core antibody (anti-HBc). Weighted HBV seroprevalence in the Mexican population and association with sociodemographic variables were calculated. RESULTS:Overall weighted seroprevalence from natural infection (positive for anti-HBs and anti-HBc) was 0.23% (95% confidence interval [95% CI] 0.10-0.52). No HBsAg was detected, indicating no acute or chronic infection. Vaccine-derived immunity (positive ≥ 10.0 mIU/ml for anti-HBs and negative to anti-HBc) was 44.7% (95% CI: 40.2-49.4) overall; lower in persons aged 20-25 years (40.83%) than in persons aged 10-19 years (47.7%). Among the population analyzed, 54.2% (95% CI: 49.6-58.8) were seronegative to HBV (negative for all three markers) and no sociodemographic risk factors were identified. CONCLUSIONS:HBV seroprevalence from natural infection was low. Vaccination-induced immunity was higher among Mexican adolescents than young adults, possibly due to vaccination policies since 1999.
Project description:Objective:To determine the clinical features and survival difference of HBV related and Non-HBV related diffuse large B-cell lymphoma (DLBCL) and to evaluate the occurrence of HBV reactivation in DLBCL patients and related risk factors for HBV reactivation after R-CHOP therapy. Methods:A total of 246 patients diagnosed with CD20+ DLBCL were enrolled from June 2010 to June 2015. The medical records and survival data were analysed. Multivariate logistic regression analysis was used to identify predictors of HBV reactivation. Survival curves were performed by the Kaplan-Meier method. Results:Among patients enrolled, 80 patients were HBsAg sero-positive and 166 patients were HBsAg sero-negative. Findings showed that HBsAg sero-negative patients were significantly older than that of patients with HBsAg sero-positive (P?<? 0.001). Proportion of B symptom positive patients in HBsAg sero-positive were higher (p?=?0.002). Higher LDH level (P?=?0.019) and late Ann Arbor stage (P?=?0.010) were more often observed in patients with HBsAg sero-positive. The rate of complete response, partial response, stable disease and progress disease in HBsAg sero-negative group were 63.9, 16.9, 1.1 and 18.1%, respective, which is significantly higher than that in HBsAg sero-positive group (36.2, 18.8, 1.2 and 43.8%). Kaplan-Meier analysis showed that DLBCL patients with HBsAg sero-negative had better prognosis. In total, 17 patients showed HBV reactivation among 166 patients (10.2%) with HBsAg sero-negative after R-CHOP treatment, while a significant higher HBV reactivation 18.75% (9/48) in HBsAb negative group were observed, with 8.25% (8/97) patients in HBsAb level 10-100?U/mL group, and 0% patients in HBsAb level higher than 100?U/mL group. Multivariable analysis showed that serum HBsAb and serum HBcAb were independent risk factors for HBV reactivation in DLBCL patients. Conclusion:Our data revealed that characteristics and prognosis were significantly different between HBV related DLBCL than non-HBV related DLBCL patients. DLBCL patients with resolved hepatitis B are at a higher risk of developing HBV reactivation after R-CHOP chemotherapy compared with HBsAg-negative/HBcAb negative patients.
Project description:Men who have sex with men (MSM) are at increased risk of exposure to hepatitis B virus (HBV) compared with the general population. This study aims to assess the epidemiological and virological characteristics of HBV infection in a sample of MSM in Brazil, where data are scarce.A cross-sectional study was conducted among MSM in the City of Goiânia, Central Brazil, from March to November 2014, using Respondent-Driven Sampling (RDS). After signing the consent form, participants were interviewed and a blood sample collected. All samples were tested for HBV serological markers and HBV DNA. HBV nucleotide sequence analysis was also performed.A total of 522 MSM were recruited in the study. The prevalence of HBV infection (current or past [presence of anti-HBc marker]) was 15.4% (95% CI: 8.7-25.8) and the rate of HBsAg carriers was 0.6% (95% CI: 0.2-1.6). About 40% (95% CI: 32.3-48.8) of the participants had serological evidence of previous HBV vaccination (reactive for isolated anti-HBs). In addition, 44.3% (95% CI: 36.1-52.9) were seronegative for all HBV markers. Age over 25 years old, receptive anal intercourse, previous sex with women, and history of sexually transmitted infections (STIs) were factors associated with HBV infection. HBV DNA was detected only in HBsAg-positive individuals. HBV isolates were classified into genotype A (subgenotypes A1 and A2), and some mutations were identified throughout the genome. Therefore, occult HBV infection was not observed in the study population.Public health strategies should be improved for the MSM population in order to prevent HBV and other STIs, as well as to provide appropriate management of patients with active infections.