Molecular epidemiology of hepatitis B virus infection in Switzerland: a retrospective cohort study.
ABSTRACT: Chronic hepatitis B virus (HBV) infection affects up to 7% of the European population. Specific HBV genotypes are associated with rapid progression to end-stage liver disease and sub-optimal interferon treatment responses. Although the geographic distribution of HBV genotypes differs between regions, it has not been studied in Switzerland, which lies at the crossroads of Europe.In a retrospective analysis of 465 HBV samples collected between 2002 and 2013, we evaluated the HBV genotype distribution and phylogenetic determinants, as well as the prevalence of serological evidence of hepatitis delta, hepatitis C and HIV infections in Switzerland. Baseline characteristics of patients were compared across their region of origin using Fisher's exact test and ANOVA, and risk factors for HBeAg positivity were assessed using logistic regression.The Swiss native population represented 15.7% of HBV-infected patients living in Switzerland. In the overall population, genotype D was most prevalent (58.3%), whereas genotype A (58.9%) was the predominant genotype among the Swiss native population. The prevalence of patients with anti-HDV antibodies was 4.4%. Patients of Swiss origin were most likely to be HBeAg-positive (38.1%). HBV genotypes of patients living in Switzerland but sharing the same original region of origin were consistent with their place of birth.The molecular epidemiology of HBV infection in Switzerland is driven by migration patterns and not by the genotype distribution of the native population. The prevalence of positive anti-HDV antibodies in our cohort was very low.
Project description:OBJECTIVES:To characterize HIV/hepatitis B virus (HBV) coinfection in the AIDS Clinical Trials Group Longitudinal Linked Randomized Trials cohort and compare long-term HBV outcomes between regimens with 1 (MONO) or 2 (DUAL) anti-HBV agents. DESIGN:A retrospective study of coinfected AIDS Clinical Trials Group Longitudinal Linked Randomized Trials subjects who received regimens containing anti-HBV agent(s). METHODS:Stored samples at baseline and weeks 16, 32, 48, 144, and 240 were tested for HBV DNA, HBV e antigen (HBeAg), HBV e antibody (HBeAb), and hepatitis D virus (HDV) antibody. Resistance and genotype were tested in samples with HBV DNA >600 IU/mL. MONO versus DUAL analyses were limited to HBV treatment-naive subjects (Naive-MONO, Naive-DUAL). RESULTS:Of 150 study subjects, median age was 40 years, 96% were male; 57% white, 26% black, 13% Hispanic. Baseline median CD4 was 224 cells per cubic millimeter, HIV RNA 4.48 log10 copies/mL, HBV DNA 6.30 log10 IU/mL; 59% HBeAg positive and 65% HBeAb negative; HBV genotypes A = 69%, G = 18%, D = 7%, <2% for A/G, B, C, F, H. Coinfection with HDV was 2%. There were 49 Naive-MONO (lamivudine) and 22 Naive-DUAL (11 lamivudine + tenofovir, 11 emtricitabine + tenofovir) with detectable HBV DNA. In the 240-week follow-up, HBV DNA suppression was not significantly higher in Naive-DUAL (P = 0.14); lower baseline HBV DNA (P < 0.01) was associated with suppression. Among 32 Naive-MONO subjects with detectable HBV DNA at baseline and results at week 48, 41% suppressed; among such 15 Naive-DUAL subjects, 53% suppressed. HBeAg and HBeAb analyses showed similar trends. CONCLUSIONS:While consistent trends toward increased HBV DNA suppression, HBeAg loss and HBeAb seroconversion were observed in Naive-DUAL compared with Naive-MONO, they were not statistically significant. Overall, HDV coinfection was low.
Project description:Various domains of hepatitis B surface antigen (HBsAg) are essential for the assembly and secretion of hepatitis D virus (HDV). This study investigated the influences of the levels and sequences of HBsAg of naturally occurring HBV variants on the assembly and secretion of HDV. Six hepatitis B virus (HBV)-producing plasmids (three genotype B and three genotype C) and six HBsAg expression plasmids that expressed various HBsAg levels were constructed from the sera of HDV-infected patients. These plasmids were cotransfected with six expression plasmids of HDV of genotype 1, 2, or 4 into the Huh-7 hepatoma cell line. Serum HBsAg and HBV DNA levels were correlated with HDV RNA levels and outcomes of chronic hepatitis D (CHD) patients. The secretion of genotype 1, 2, or 4 HDV generally correlated with HBsAg levels but not with HBV genotypes or HBV DNA levels. Swapping and residue mutagenesis experiments of HBsAg-coding sequences revealed that the residue Pro-62 in the cytosolic domain-I affects the assembly and secretion of genotype 2 and 4 HDV and not those of genotype 1. The pre-S2 N-terminal deletion HBV mutant adversely affects secretion of the three HDV genotypes. In patients, serum HDV RNA levels correlated with HBsAg levels but not with HBV DNA levels. Viremia of HDV or HBV correlated with poor outcomes. In conclusion, the assembly and secretion of HDV were influenced by the amounts and sequences of HBsAg. For an effective treatment of CHD, reduction of HBsAg production in addition to the suppression of HBV and HDV replication might be crucial.
Project description:BACKGROUND:Patients coinfected with HBV and hepatitis D virus (HDV) have a greater risk of HCC and cirrhosis. The current study was undertaken to assess HDV genotype distribution and determine clinical characteristics of hepatitis delta virus (HDV) among HBsAg positive individuals in Shanghai. METHOD:This retrospective study involved 225 serum samples from HBsAg positive hospitalized patients from October 2010 to April 2013. HDV-specific RT-nested PCR was used to amplify HDV RNA. HDV genotypes were characterized by Next-generation sequencing (NGS), followed by phylogenetic analyses. HDV/HBV co-infected patients and HBV mono-infected patients were compared clinically and virologically. RESULTS:Out of the 225 HBsAg-positive serum samples with elevated transaminases, HDV-RNA was identified in 11 (4.9%) patients. The HBV loads in the HDV positive group were significantly lower than the HDV negative HBV-infected patients. The aminotransferase enzymes were significantly higher in HDV/HBV co-infected compared to HDV negative patients (P?<?0.05). Phylogenetic analyses indicated that HDV-2 genotype being the predominant genotype, other HDV genotypes were not observed. HDV/HBV patients were significantly associated with a rather unfavourable clinical outcome. CONCLUSION:In summary, the prevalence of HDV infection in patients with elevated transaminases is not low and the predominance of HDV genotype 2 infection in Shanghai. This finding helps us to better understand the correlation of HDV/HBV co-infection. Moreover, Next-generation sequencing (NGS) technologies provide a rapid, precise method for generating HDV genomes to define infecting genotypes.
Project description:Hepatitis B virus (HBV) and hepatitis D virus (HDV) infections are major public health problems in sub-Saharan Africa. Whereas it is known that HBV infection is endemic in Nigeria, there is only little data about HDV prevalence available. Here, we assessed the HDV seroprevalence and determined the HDV and HBV genotypes distribution among HBsAg positive individuals in Southwestern Nigeria.This cross-sectional study involved 188 serum samples from HBsAg positive outpatients recruited at four tertiary hospitals in Southwestern Nigeria. Anti-HDV antibodies were detected by ELISA while HDV-RNA was detected by RT-PCR. Sequencing followed by phylogenetic analyses and HBV genotype-specific PCR were used to characterize HDV and HBV genotypes, respectively.Out of 188 HBsAg positive serum samples, 17 (9 %) showed detectable HDV-RNA. Anti-HDV antibodies test was possible from 103 samples and were observed in 4.9 % (5/103) patients. There was no significant difference in HDV prevalence between four main cities across the country. 64.7 % of HDV-RNA positive samples were from males and 35.3 % from females (P < 0.05). No significant associations were observed with regard to HDV seroprevalence and available demographic factors. Phylogenetic analyses demonstrated a predominance of HDV genotype 1 and HBV genotype E among the HDV-RNA/HBsAg positive patients.In conclusion, our study showed a high prevalence of HDV infection in HBsAg carriers and the predominance of HDV genotype 1 infection in Nigerian HBV endemic region. The findings contribute to a better understanding of the relevance of HDV/HBV co-infection and circulating genotypes.
Project description:Hepatitis D caused by the hepatitis delta virus (HDV) is a serious health problem in many regions of the world. A total of 546 HBV-infected patients were enrolled from 2013 to 2015 and classified clinically into the subgroups of chronic hepatitis B (CHB, n?=?191), liver cirrhosis (LC, n?=?147) and hepatocellular carcinoma (HCC, n?=?208). The patients were screened for HDV-RNA by nested PCR assays. HDV genotypes were assessed by direct sequencing, followed by phylogenetic analysis. HDV-RNA was identified in 13% (71/546) of HBV-infected patients. The highest HDV prevalence was found in the LC group (19.7%), followed by the HCC (12%) and CHB (8.9%) groups (P?=?0.017). HDV/HBV coinfections were significantly associated with a rather unfavourable clinical outcome, in particular with LC development compared to HBV monoinfection. Phylogenetic analyses indicated that the genotype HDV1 was, with a prevalence of 91%, by far the most common genotype in Vietnam, followed by HDV2 with 9%. Other HDV genotypes were not observed. In accordance with previous data obtained a decade ago, our results confirm a continuing high prevalence of HDV infection in hepatitis B patients in northern Vietnam with the HDV1 genotype still being the predominant genotype. HDV nucleic acid testing to minimize the associated risk should be considered.
Project description:<h4>Background</h4>Hepatitis B virus (HBV) is a major global health challenge with approximately 250-350 million chronically infected individuals. An improved understanding of the demographic features and outcomes of chronic HBV infection and hepatitis D virus (HDV) infection in low-endemic areas may improve prevention, early identification and management both at individual and community levels. Here, we retrospectively analyzed the demographic and clinical characteristics, treatment rates and outcomes of adult patients with chronic HBV infection with or without HDV coinfection examined at Lausanne University Hospital, Switzerland over a 10-year period.<h4>Methods</h4>We analyzed the medical records of all adult patients with chronic HBV and HDV infection examined in our center between 2007 and 2016. Liver-related outcome was defined as the occurrence of cirrhosis, hepatocellular carcinoma, liver transplantation or liver-related death. Analyses were performed using logistic regression and results were reported as odds ratio (OR) and 95% confidence interval (CI).<h4>Results</h4>Of 672 consecutive patients, 421 (62.6%) were male, median age was 36 years (interquartile range, 28-46 years), and 233 (34.7%) were of African origin. The prevalence of HDV coinfection was 7.1% and the proportion of anti-HDV-positive patients with detectable HDV RNA was 70.0%. In multivariate analysis, HDV coinfection was the strongest predictor for liver-related outcome (OR 6.06, 95% CI 2.93-12.54, p<0.001), followed by HBeAg positivity (OR 2.47, 95% CI 1.30-4.69, p = 0.006), age (OR per 10-year increase 2.03, 95% CI 1.63-2.52, p<0.001) and sex (OR for female 0.39, 95% CI 0.22-0.71, p = 0.002). The predictive accuracy of the multivariate model was high (receiver operator characteristic area under the curve 0.81).<h4>Conclusion</h4>This retrospective study underscores the importance of migration in the epidemiology of chronic hepatitis B in low-endemic areas. HDV coinfection, HBeAg positivity and age predicted liver-related outcomes while female sex had a protective effect.
Project description:BACKGROUND:Characteristics of hepatitis B (HBV) and delta (HDV) coinfection in various geographical regions, including Israel, remain unclear. Here we studied HDV seroprevalence in Israel, assessed HDV/HBV viral loads, circulating genotypes and hepatitis delta antigen (HDAg) conservation. METHODS:Serological anti HDV IgG results from 8969 HBsAg positive individuals tested in 2010-2015 were retrospectively analyzed to determine HDV seroprevalence. In a cohort of HBV/HDV coinfected (n=58) and HBV monoinfected (n=27) patients, quantitative real-time PCR (qRT-PCR) and sequencing were performed to determine viral loads, genotypes and hepatitis delta antigen (HDAg) protein sequence. RESULTS:6.5% (587/8969) of the HBsAg positive patients were positive for anti HDV antibodies. HDV viral load was >2 log copies/ml higher than HBV viral load in most of the coinfected patients with detectable HDV RNA (86%, 50/58). HDV genotype 1 was identified in all patients, most of whom did not express HBV. While 66.6% (4/6) of the HBV/HDV co-expressing patients carried HBV-D2 only 18.5% (5/27) of the HBV monoinfections had HBV-D2 (p=0.03). Higher genetic variability in the HDAg protein sequence was associated with higher HDV viral load. CONCLUSIONS:The overall significant prevalence of HDV (6.5%) mandates HDV RNA testing for all coinfected patients. Patients positive for HDV RNA (characterized by low HBV DNA blood levels) carried HDV genotype 1. Taken together, the significant HDV seroprevalence and the lack of effective anti-HDV therapy, necessitates strict clinical surveillance especially in patients with higher HDV viral loads and increased viral evolution.
Project description:Current interferon alfa (IFN) treatment of chronic hepatitis B has limited efficacy. The role of hepatitis B virus (HBV) genotypes for response to IFN was investigated.HBV genotype was determined by direct sequencing of the HBV X gene in 165 consecutive patients with chronic replicative hepatitis B treated with standard IFN. HBV genotype A or D was found in 144 cases.Sustained response (six months after treatment) to standard IFN therapy was higher in HBV genotype A compared with HBV genotype D infected patients (49% v 26%; p<0.005). Sustained response to IFN was 46% versus 24% (p<0.03) in hepatitis B e antigen (HBeAg) positive hepatitis (n = 99) and 59% versus 29% (p<0.05) in HBeAg negative hepatitis (n = 45) for HBV genotype A compared with HBV genotype D. HBeAg status had no negative impact on IFN response. Multivariate logistic regression identified HBV genotype A and high pretreatment alanine aminotransferase levels (>2 x upper limit of normal) as independent positive predictive parameters of IFN response.The present study indicates that HBV genotypes A and D are important and independent predictors of IFN responsiveness in chronic hepatitis B. HBV genotype adapted treatment regimens may further improve treatment efficacy in chronic hepatitis B.
Project description:Hepatitis delta virus (HDV) coinfection will additionally aggravate the hepatitis B virus (HBV) burden in the coming decades, with an increase in HBV-related liver diseases. Between 2018 and 2019, a total of 205 HBV patients clinically characterized as chronic hepatitis B (CHB; <i>n</i> = 115), liver cirrhosis (LC; <i>n</i> = 21), and hepatocellular carcinoma (HCC; <i>n</i> = 69) were recruited. HBV surface antigen (HBsAg), antibodies against surface antigens (anti-HBs), and core antigens (anti-HBc) were determined by ELISA. The presence of hepatitis B viral DNA and hepatitis delta RNA was determined. Distinct HBV and HDV genotypes were phylogenetically reconstructed and vaccine escape mutations in the "a" determinant region of HBV were elucidated. All HBV patients were HbsAg positive, with 99% (<i>n</i> = 204) and 7% (<i>n</i> = 15) of them being positive for anti-HBc and anti-HBs, respectively. Anti-HBs positivity was higher among HCC (15%; <i>n</i> = 9) compared to CHB patients. The HBV-B genotype was predominant (65%; <i>n</i> = 134), followed by HBV-C (31%; <i>n</i> = 64), HBV-D, and HBV-G (3%; <i>n</i> = 7). HCC was observed frequently among young individuals with HBV-C genotypes. A low frequency (2%; <i>n</i> = 4) of vaccine escape mutations was observed. HBV-HDV coinfection was observed in 16% (<i>n</i> = 33) of patients with the predominant occurrence of the HDV-1 genotype. A significant association of genotypes with alanine aminotransferase (ALT) and aspartate aminotransferase (AST) enzyme levels was observed in HBV monoinfections. The prevalence of the HDV-1 genotype is high in Vietnam. No correlation was observed between HDV-HBV coinfections and disease progression when compared to HBV monoinfections.
Project description:<h4>Background aims</h4>The clinical relevance of single nucleotide polymorphisms (SNPs) near the IL28B gene is controversial in patients with hepatitis B virus (HBV) infection. This study aimed to investigate the role of viral and host factors, including IL28B genotypes, in the natural course of chronic hepatitis B (CHB).<h4>Methods</h4>The study enrolled consecutive 115 treatment-naive CHB patients. HBV viral loads, genotypes, precore and basal core promotor mutations, serum hepatitis B surface antigen (HBsAg) and interferon-gamma inducible protein 10 (IP-10) levels as well as four SNPs of IL28B were determined. Serial alanine transaminase (ALT) levels in the previous one year before enrollment at an interval of three months were recorded. Factors associated with active hepatitis, defined as persistent ALT >2× upper limit of normal (ULN) or a peak ALT level >5× ULN, were evaluated.<h4>Results</h4>The prevalence of rs8105790 TT, rs12979860 CC, rs8099917 TT, and rs10853728 CC genotypes were 88.3%, 87.4%, 88.4% and 70.9%, respectively. In HBeAg-positive patients (n?=?48), HBV viral load correlated with active hepatitis, while in HBeAg-negative patients (n?=?67), rs10853728 CC genotype (p?=?0.032) and a trend of higher IP-10 levels (p?=?0.092) were associated with active hepatitis. In multivariate analysis, high viral load (HBV DNA >10(8) IU/mL, p?=?0.042, odds ratio?=?3.946) was significantly associated with HBeAg-positive hepatitis, whereas rs10853728 CC genotype (p?=?0.019, odds ratio?=?3.927) was the only independent factor associated with active hepatitis in HBeAg-negative population.<h4>Conclusions</h4>HBV viral load and IL28B rs10853728 CC genotype correlated with hepatitis activity in HBeAg-positive and HBeAg-negative CHB, respectively. Both viral and host factors play roles in disease activity during different phases of CHB.